DIAGNOSTIC TEST SYSTEM AND METHOD FOR OPERATING A DIAGNOSTIC TEST SYSTEM

专利摘要:
these are subsets and improved control methods for use in a diagnostic test system adapted to receive a test cartridge. such subsets include: a brushless dc motor, a door open / close mechanism and cartridge loading mechanism, a syringe and valve drive mechanism, a sonication sonotrode, a thermal control device and optical detection / excitation. such systems may additionally include a communications unit configured to communicate wirelessly with a user's mobile device in order to receive a user input related to the system's functionality in relation to a test cartridge received in it and to retransmit a diagnostic result related to the test cartridge for the mobile device.
公开号:BR112018001352B1
申请号:R112018001352-8
申请日:2016-07-22
公开日:2020-10-06
发明作者:Doug Dority；Tien PHAN；David FROMM；Rick Casler；Dustin Dickens；Stuart Morita；Matthew Piccini
申请人:Cepheid；
IPC主号:

专利说明:

CROSS REFERENCES FOR RELATED ORDERS
[0001] This application claims the priority benefit of U.S. Provisional Patent Application No. 62 / 196,845 entitled "Molecular Diagnostic Assay System," filed on July 24, 2015; the entire contents of which are incorporated herein by reference.
[0002] This application is generally related to U.S. Patent Application No. [Representative Certificate No. 85430-1017353-011410US] entitled "Thermal Control Device and Methods of Use" filed concurrently with it; U.S. Patent Application [Representative Certificate No. 85430-0971600-01061 OUS] entitled "Encoderless Motor with Improved Granularity and Methods of Use" filed concurrently with it; U.S. Patent Application No. 13 / 843,739 entitled “Honeycomb tube,” filed March 15, 2013; U.S. Patent Application No. 13 / 828,741 entitled “Remote Monitoring of Medical Devices,” filed March 14, 2013; U.S. Patent No. 8,048,386 entitled “Fluid Processing and Control,” filed February 25, 2002; and U.S. Patent No. 6,374,684 entitled “Fluid Control and Processing System,” filed August 25, 2000; each of which is incorporated herein by reference in its entirety for all purposes. BACKGROUND OF THE INVENTION
[0003] Technological advances have made the world today an increasingly connected environment. While air travel allows an average person to travel around the globe from one continent to another within a day, it can also allow the rapid spread of contagious pathogens and expose the global population to deadly diseases with potentially devastating consequences. In the recent past, outbreaks of Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and Ebola Hemorrhagic Fever serve as examples of how a public health event that originated in an area on a continent can quickly evolve into a significant global concern. The highly mobile nature of today's world requires reliable diagnostic tools to provide real-time results and to facilitate early detection and immediate response to any potential epidemics.
[0004] [0001] On the other hand, very remote and underdeveloped areas remain in this world where health care is not readily available to local residents. Inadequate accessibility to healthcare facilities such as hospitals and clinics, or health product / service retailers (eg pharmacies), seriously impedes any effort to obtain adequate diagnosis and treatment of patients, especially those suffering from an infectious disease, making it difficult to properly assess the risk of an epidemic or effectively contain a rapidly spreading epidemic. Thus, there is an urgent need for new and improved diagnostic tools that are highly mobile, capable of performing complex molecular tests to generate fast, reliable, and accurate results, regardless of location, whether in a health care facility, clinic neighborhood, retail service provider, or in a resource-limited setting where electricity, communication (for example, the Internet), traditional health care services and / or health care professionals may not be routinely available.
[0005] The present inventors have developed a highly sophisticated, yet completely portable and surprisingly easy to use molecular diagnostic assay system that meets the needs mentioned above. Enhanced over existing molecular diagnostic test systems (for example, the Cepheid GeneXpert® system), the new molecular diagnostic test system described here includes a medical diagnostic device, which is optionally battery powered, typically small in size. size and light in weight, thus allowing complete portable use wherever patients may be, away from hospitals, laboratories, or even pharmacies. The diagnostic device is capable of performing fully automated molecular diagnostic tests (optionally to detect multiple pathogens at the same time), quickly obtaining accurate results (typically within 1 or 2 hours and as fast as 15 to 20 minutes). It is easy to operate, using one or more pre-made test cartridges you can quickly obtain test results indicating whether a patient is carrying a particular pathogen (s), or afflicted with a particular disease state.
[0006] This newly designed molecular diagnostic test system also includes components that provide cloud-based connectivity to transport the diagnostic results from the portable test device to a remote reporting system, which can be a centralized data collection or center processing, or mobile devices such as portable devices used by a doctor or patient to receive a diagnostic report. With such cloud-based connectivity, data sharing can take place virtually instantly, not only allowing doctors to start treating patients without any delay, but also enabling the monitoring and reporting of any potential epidemics on a large scale.
[0007] These important characteristics circumvent current limitations that tend to prevent or prevent early diagnosis and effective treatment of patients in poor, remote areas where health care facilities are few and the capacity to test diagnostics is scarce. This newly designed molecular diagnostic test system is the first true point of care diagnostic tool possessing the power of rapid mobilization and complete operation in virtually any environment. It truly takes diagnostic testing for people, no matter where they are. The combination of its mobility, its fast and accurate diagnostic functionality, its technical sophistication despite its ease of operation, and its cloud-based connectivity make this new molecular diagnostic test system the most modern and up-to-date solution for emerging markets and the revolutionary trendsetter who defines the future of medical diagnostic testing. BRIEF SUMMARY OF THE INVENTION
[0008] In one aspect, the invention provides an improved diagnostic test system. Such systems may include improvements related to several subassemblies including: a door drive assembly, a syringe drive and a valve drive, a sonotrode, a thermal and optical sensing assembly, and a system control / communication system. It is appreciated that any of these subassemblies can be included in such a diagnostic test system separately or in combination with any other subassembly to provide improved performance aspects as described herein.
[0009] In some embodiments, the invention includes a diagnostic test system adapted to receive a test cartridge (also occasionally referred to as a "sample cartridge" or "test cartridge"). Such systems can include any or combination of the various features and subassemblies described herein.
[00010] In some embodiments, the diagnostic test system includes a brushless DC motor (BLDC) operatively coupled with, for example, any of a door opening / closing mechanism and cartridge loading system, a syringe drive, and / or a valve drive.
[00011] In some embodiments, the diagnostic test system includes a door opening / closing mechanism operatively coupled with a cartridge loading mechanism and driven by a reversible transmission mechanism.
[00012] In some embodiments, the diagnostic test system includes a syringe drive operatively coupled with a n-phase BLDC motor and controlled based at least in part on the monitored current absorption of the BLDC motor.
[00013] In some embodiments, the diagnostic test system includes a valve drive mechanism operatively coupled with a n-phase BLDC motor based at least in part on a voltage signal provided by BLDC n voltage sensors without using any encoder hardware or position sensors.
[00014] In some embodiments, the diagnostic test system includes a sonotrode that can be coupled with a test cartridge for the lysis of biological material inside the test cartridge and operatively coupled with a controller configured to control sonication based on at least partly at a frequency that provides a higher output amplitude as a resonant frequency.
[00015] In some embodiments, the diagnostic test system includes a thermal control device having a first thermoelectric cooler thermally engageable with a reaction vessel (also occasionally referred to as a “reaction tube”) of the test cartridge and at least another thermal manipulation device thermally coupled with the first thermoelectric cooler and controlled in order to increase the efficiency of the first thermoelectric cooler to facilitate the rapid thermal cyclization of the reaction vessel between a first and second temperatures with the first thermoelectric cooler.
[00016] In some embodiments, the diagnostic test system includes an optical excitation / detection block mountable in relation to the reaction vessel in order to emit excitation energy in a fluid sample within the reaction vessel at a substantially orthogonal angle from which the excitation is detected through one or more edges (smaller face) and / or a main face of the reaction vessel.
[00017] In some embodiments, the diagnostic test system includes a communications unit configured to communicate wirelessly with a user's mobile device in order to receive user input related to the system's functionality with respect to a test cartridge received therein and relay a diagnostic result related to the test cartridge to the mobile device.
[00018] Some embodiments of the invention refer to a door opening system for a diagnostic test system. The system may include a diagnostic test system chassis. A brushless DC motor (BLDC) can be attached to the chassis of the diagnostic test system. A reversible transmission can be operated by the BLDC engine. A door can be movable relative to the chassis of the diagnostic test system from a closed position to an open position (and from an open position to a closed position). The BLDC motor can be configured to operate the reversible transmission based on the current measurements of the BLDC motor, the current measurements being associated with reverse drive events against the reversible transmission.
[00019] Some embodiments of the invention relate to a method for operating a door opening / closing system for a diagnostic test system. In the method, a command can be received to open a cartridge receiving port on the diagnostic test system. A brushless DC motor (BLDC) coupled to a reversible transmission can be operated to open the door from a closed position (and vice versa), the reversible transmission being operationally coupled to the door and a cartridge loading mechanism. A first reverse drive event occurring against the reversible transmission can be detected, based on current monitoring. Based on the detection of the first reverse actuation event, the operation of the BLDC motor to place the door in an open position can be stopped, and an aspect of the cartridge loading mechanism can be placed in position to accept a test cartridge.
[00020] Some embodiments of the invention relate to a system for operating a syringe for a diagnostic test system. The system may include a chassis for a diagnostic test system. A brushless DC motor (BLDC) can be attached to the chassis of the diagnostic test system. A reversible lead screw can be operable by the BLDC engine. A plunger rod can be operable by the lead screw to engage a plunger tip in a syringe passage on the test cartridge. The BLDC motor can be configured to operate the lead screw based on the BLDC motor's monitored current absorption, the current being associated with pressure changes within the removable test cartridge.
[00021] Some embodiments of the invention relate to a method for operating a syringe for a diagnostic test system. A command to power a brushless DC motor (BLDC) can be received. The BLDC motor can be operable to turn a reversible lead screw. A plunger rod can be attached to and moved by the lead screw. Power to the BLDC engine can be applied to move the plunger rod to engage a plunger tip within a syringe passage of a test cartridge. At least one current associated with the operation of the BLDC engine can be monitored to determine the quality of the removable test cartridge. A change in the current of the BLDC motor can be detected. The operation of the BLDC motor can be changed within the removable test cartridge based on the detection of the change in current.
[00022] Some embodiments of the invention refer to a sonotrode assembly having an ultrasonic sonotrode and a sonotrode housing that engages with the disposable test cartridge through a mobile mechanism that moves the ultrasonic sonotrode between a disengaged or retracted position to facilitate the loading and ejecting the test cartridge from the diagnostic device module and an engaged or advanced position to pressurely engage the sonotrode against a test cartridge sonication chamber to facilitate lysis of biological cells within the chamber as part of an assay diagnostic, which may include but is not limited to a polymerase chain reaction analysis. In some embodiments, the movable mechanism includes a spring or tilt mechanism and a cam which engages a wedge surface of the sonotrode housing to effect movement of the sonotrode between the lowered and raised positions. In some embodiments, the movement of the sonotrode assembly is carried out by a common actuator for other moving components, such as a loading / ejection arm and a cartridge module door to provide efficient coordinated movement of components within the device module. diagnostic.
[00023] Some embodiments of the invention refer to a sonotrode having an ultrasonic sonotrode and at least one controlled piezoelectric actuator (s) under closed loop feedback. In some modalities, the sonotrode comprises a control circuit that uses sinusoidal control and phase matching for the control of resonant frequency. These features guarantee in-phase vibration between the piezoelectric actuator (s) in order to provide a consistent, robust release of ultrasonic energy with an ultrasonic sonotrode having reduced size and power requirements than would be feasible.
[00024] Some embodiments of the invention relate to a method for operating a valve actuation mechanism. A command can be received to power a brushless DC motor (BLDC) coupled to the chassis to move a valve drive to a particular position. The valve drive can be configured to rotate positions of a valve body from a removable test cartridge. A transmission can be coupled between the BLDC engine and the valve drive. The BLDC motor does not include any positional sensors or encoding hardware, but it can include a plurality of Hall effect sensors. The BLDC motor can be powered to rotate a BLDC motor shaft a particular number of turns to move the valve drive to the particular position based on a sinusoidal signal generated by the Hall effect sensors.
[00025] Some modalities refer to a system for operating a valve actuation mechanism. The system may include a valve drive mechanism chassis. A brushless DC motor (BLDC) can be attached to the chassis. The BLDC motor does not include any positional hardware or encoder, but it can include a plurality of Hall effect sensors. A transmission can be coupled to the BLDC engine. A valve drive can be coupled to the transmission. The valve drive can be configured to rotate positions of a valve body from a removable test cartridge. The valve drive output position can be determined based on the analysis of a sinusoidal signal generated by the Hall effect sensors.
[00026] Some embodiments of the invention refer to a diagnostic device which may include a Thermo-Optical Sub-Assembly ("TOS") comprising a thermal control device component and an optical excitation / detection component. In some embodiments, the thermal control device includes a thermoelectric cooling component (“TEC”) that performs the thermal cycling of a reaction vessel. The optical excitation component / detection component performs optical excitation and detection for a target analysis with improved control, speed and efficiency. In some embodiments, TOS includes mounting components to interface the thermal control device with the optical component and defines a cavity to receive a reaction vessel having a fluid sample prepared to perform an assay for a target test. In some embodiments, the assembly components provide the thermal control device and optical component in proximity to the reaction vessel in order to perform the thermal cycling for amplification, excitation and optical detection of the target test simultaneously or in rapid succession. In some embodiments, the reaction vessel comprises a microarray or a plurality of separate reaction wells and / or a pre-amplification chamber within the reaction vessel. In some embodiments, TOS includes one or more mechanisms that move the thermal control device so as to pressurably engage at least one surface of the reaction vessel when positioned within the diagnostic device in order to improve thermal cycling efficiency. In some embodiments, TOS is integrated with one or more printed circuit boards (PCBs), processors and controllers in order to coordinate thermal cycling and optical excitation / detection according to a particular test. In some embodiments, TOS includes a sensor to detect proximity to a reaction vessel or associated sample test cartridge to facilitate the positioning of the thermal control device and / or optical component in relation to the reaction vessel or its operation.
[00027] Some embodiments of the invention refer to a thermal control device that can include a first TEC having an active face and a reference face; a second TEC having an active face and a reference face; and a thermal capacitor or thermal interleaver disposed between the first and second TECs such that the reference face of the first TEC is thermally coupled with the active face of the second TEC through the thermal capacitor. In some embodiments, a thermal interleaver is positioned between the first and second TEC devices. In some embodiments, the thermal interleaver acts as a thermal capacitor. In some embodiments, the thermal control device includes a controller operatively coupled to each of the first and second TECs, the controller configured to operate the second TEC concurrent with the first TEC in order to increase speed and efficiency in the operation of the first TEC as a temperature of the active face of the first TEC changes from an initial temperature to a desired target temperature.
[00028] Some embodiments of the invention refer to an optical component which can include an optical excitation block and an optical detection block positioned in an optical assembly that is configured to receive a reaction vessel. In some embodiments, the reaction vessel comprises two larger planar walls that are spaced apart separately from each other by the smaller planar walls, in which at least two of the smaller planar walls are displaced from each other by about 90 degrees. In some embodiments, the optical excitation block is positioned to transmit excitation energy in the reaction vessel through one of the smaller walls, and the optical detection block is positioned for detection along a larger planar surface of the reaction vessel. In some embodiments, excitation and detection occurs through smaller walls that are opposite the reaction vessel. In some embodiments, the optical excitation and optical detection components are orthogonal to each other. The optical components are fitted with a relatively low numerical orifice (for example low angular divergence) when compared to conventional systems. Such a configuration provides a greater detection volume with lower numerical angles, thereby providing improved optical sensitivity and facilitating optical alignment.
[00029] In another aspect, TOS includes a sensor to detect proximity and / or location as well as the identity of a test cartridge or reaction vessel in relation to TOS. In some embodiments, the sensor is a near-field communication sensor adapted to detect when a test cartridge has been loaded into the diagnostic device (also occasionally referred to as a “diagnostic module”) of the diagnostic test system, to identify the test , and connect the cartridge to a sample identifier. In some embodiments, TOS includes a controller to coordinate the operation of the thermal control device and the optical module in response to the sensor.
[00030] Some embodiments of the invention relate to a method of controlling a diagnostic test system with a mobile device. On a mobile device, user input can be received to control the functionality of a diagnostic device. In response to receiving user input, with the mobile device, control information can be sent to the diagnostic test device. On the mobile device, data (for example, medical data) can be received from the diagnostic test device. The data can be relayed to a server without storing or decrypting the data.
[00031] Some embodiments of the invention relate to a diagnostic test device having a communications subsystem. The system can include a diagnostic component. A processor communicatively can be coupled with the communications subsystem and the diagnostic component. The processor can be configured to cause the diagnostic test device to receive wirelessly, using the communications subsystem, a device command from a mobile device. The processor can also be configured to send wirelessly, using the communications subsystem, a command response from the device to the mobile device. The processor can also be configured to conduct a test using the diagnostic component. The processor can also be configured to send wirelessly, using the communications subsystem, encrypted diagnostic information (for example, medical information), indicative of a test result, to a remote server. BRIEF DESCRIPTION OF THE DRAWINGS
[00032] FIG. IA is a perspective view of a diagnostic test system, according to some embodiments of the invention.
[00033] FIG. 1B is an exploded view of a diagnostic test system, according to some embodiments of the invention.
[00034] FIGS. 2A-2C are perspective views of a brushless DC motor (BLDC), according to some embodiments of the invention.
[00035] FIG. 2D is a graph of a sinusoidal variable voltage output pattern of a BLDC motor, with additional distinguishing marks to illustrate a process for encoding the mechanical angular position of the motor rotor according to some embodiments of the invention.
[00036] FIG. 2E is a circuit diagram for controlling a BLDC motor, according to some embodiments of the invention.
[00037] FIGS. 3A-3C are model diagrams for determining torque output of a BLDC motor, according to some modalities of the invention.
[00038] FIG. 4A is a perspective view of a door opening mechanism, in accordance with some embodiments of the invention.
[00039] FIGS. 4B-4E are cross-sectional views of a diagnostic test system in use, according to some embodiments of the invention.
[00040] FIG. 5A is a cross-sectional view of a diagnostic test system in use, according to some embodiments of the invention.
[00041] FIGS. 5B and 5C are flow diagrams of a method for operating aspects of a diagnostic test system, according to some embodiments of the invention.
[00042] FIGS. 6A and 6B are perspective views of a valve actuation mechanism, according to some embodiments of the invention.
[00043] FIG. 6C is a graph reporting an output signal for valve actuation position, according to some modalities of the invention.
[00044] FIGS. 7A-B illustrate an ultrasonic sonotrode assembly for use in a diagnostic test system according to some embodiments of the invention.
[00045] FIGS. 8A-D illustrate ultrasonic sonotrode assembly component views according to some embodiments of the invention.
[00046] FIGS. 9A-B illustrate cross-sectional views of a diagnostic test system during and after loading a test cartridge according to some embodiments of the invention.
[00047] FIG. 10A illustrates a cross-sectional view of a test cartridge and FIG. 10B illustrates a sectional view of a test cartridge loaded into a diagnostic test system with an ultrasonic sonotrode assembly in accordance with some embodiments of the invention.
[00048] FIGS. 11Al-2 to 11B1-2 illustrate side and cross-sectional views of a sonotrode assembly in an uncoupled position and a coupled position, respectively, according to some embodiments of the invention.
[00049] FIG. 12A illustrate an exemplary ultrasonic sonotrode and FIG. 12B illustrates a control diagram for the operation of an ultrasonic sonotrode according to some embodiments of the invention.
[00050] FIG. 13 illustrates a transfer function for controlling a sonotrode assembly according to some embodiments of the invention.
[00051] FIG. 14 illustrates a schematic of controlling a sonotrode assembly according to some embodiments of the invention.
[00052] FIGS. 15-17 illustrate control diagrams for a sonotrode assembly according to some embodiments of the invention.
[00053] FIG. 18 illustrates an exemplary TOS subassembly prior to insertion into the test module according to some embodiments of the invention.
[00054] FIGS. 19A-19B illustrate front and rear views of an exemplary TOS subassembly according to some embodiments of the invention.
[00055] FIGS. 20A-20B illustrate exploded views of an exemplary TOS according to some embodiments of the invention.
[00056] FIGS. 21A-B illustrate optical components and associated PCBs of an exemplary TOS according to some embodiments of the invention.
[00057] FIGS. 22A-B illustrate exemplary thermal control device components and PCBs associated with a rigid flexible connection in a TOS example according to some embodiments of the invention.
[00058] FIGS. 23A-B illustrate an exemplary thermal control device component configured to interface with an optical assembly of an example of TOS according to some embodiments of the invention.
[00059] FIGS. 24A-B illustrate an exemplary mobile thermal control device component coupled to an optical assembly in an open configuration and a fixed configuration, respectively, according to some embodiments of the invention.
[00060] FIG. 25 illustrates a component of an exemplary mobile thermal control device coupled to an optical assembly and a sliding base according to some embodiments of the invention.
[00061] FIGS. 26A-B illustrate an exemplary mobile control device component movably coupled with a sliding base actuated by a module door frame according to some embodiments of the invention.
[00062] FIG. 27 illustrates an exemplary block control diagram of TOS components according to some embodiments of the invention.
[00063] FIG. 28 illustrates an exemplary schematic of TOS optical and thermal control components according to some embodiments of the invention.
[00064] FIG. 29 illustrates an exemplary TOS for use in a diagnostic test system in accordance with some embodiments of the invention.
[00065] FIGS. 30A-B illustrate two exemplary optical component configurations for use with a reaction vessel in a diagnostic device according to some embodiments of the invention and FIG. 30C illustrates a detailed schematic of an exemplary optical component configuration according to some embodiments of the invention.
[00066] FIG. 31 illustrates exemplary detailed views of excitation block 310 and detection block 320 according to some embodiments of the invention.
[00067] FIGS. 32 illustrate fluorescence detection with the excitation components and detection of an exemplary optical component according to some embodiments of the invention.
[00068] FIG. 33A illustrates a schematic of a thermal control device according to some embodiments of the invention.
[00069] FIGS. 33B-C illustrate models of an exemplary thermal control device according to some embodiments of the invention.
[00070] FIG. 34 shows a thermal cycle under closed loop control according to some embodiments of the invention.
[00071] FIG. 35 shows ten successive thermal cycles in a complete range of PCR thermocycling according to some embodiments of the invention.
[00072] FIG. 36A shows thermal cycling performance for five cycles at the beginning of the thermal cycling and after two days of continuous thermal cycling.
[00073] FIG. 36B shows a control diagram of target values used in control loops according to some modalities of the invention
[00074] FIG. 37 shows a diagram of target values used in control loops according to some modalities of the invention.
[00075] FIG. 38 is an exemplary illustration of the architecture of a diagnostic test system according to some embodiments of the invention.
[00076] FIG. 39 provides a logical view of software executed by the diagnostic device, according to some embodiments of the invention.
[00077] FIG. 40 is a block diagram of the diagnostic test system (Epsilon Instrument Core Architecture), according to some modalities of the invention.
[00078] FIGS. 41-1 through 41-4 show a diagram illustrating various states of the Hierarchical System Machine (HSM) component, according to some embodiments of the invention.
[00079] FIG. 42 is a diagram illustrating internal instrument core components and interfaces, in accordance with some embodiments of the invention.
[00080] FIG. 43 is a block diagram illustrating software components executed on a mobile device, in accordance with some embodiments of the invention.
[00081] FIG. 44 is a block diagram illustrating software components performed by a remote diagnostic reporting service, in accordance with some embodiments of the invention.
[00082] FIG. 45 is a data flow diagram illustrating high level data flow in a diagnostic test system, according to some embodiments of the invention.
[00083] FIG. 46 is a data flow diagram illustrating an embodiment of a more detailed data flow than FIG. 45, in which components of the mobile device are depicted separately.
[00084] FIG. 47 is a data flow diagram illustrating the process for a local configuration of a diagnostic test system, according to some embodiments of the invention.
[00085] FIG. 48 is a data flow diagram illustrating the process for providing operational updates to a mobile device in a diagnostic test system, in accordance with some embodiments of the invention.
[00086] FIG. 49 is a data flow diagram illustrating the process for providing operational updates for a diagnostic device in a diagnostic test system, in accordance with some embodiments of the invention.
[00087] FIG. 50 is a data flow diagram of such a process in a diagnostic test system, according to some embodiments of the invention.
[00088] FIG. 51 is a data flow diagram illustrating the process for providing diagnostic device commands in a diagnostic test system, in accordance with some embodiments of the invention.
[00089] FIG. 52 is a data flow diagram illustrating the process for providing medical diagnostic recording device in a network of a diagnostic test system, according to some embodiments of the invention.
[00090] FIG. 53 is an illustration of a computerized system, according to some embodiments of the invention, which can be incorporated, at least in part, into the devices and components of the diagnostic test system described herein.
[00091] FIG. 54 is a flow diagram of a method of controlling a diagnostic test system with a mobile device, according to some embodiments of the invention. DETAILED DESCRIPTION OF THE INVENTION I. System Overview
[00092] FIG. 1A shows a perspective view of a system 10 for testing a biological sample, according to embodiments of the invention. The system's compact form factor 10 provides a portable sample testing device that can communicate wirelessly or directly (wired) with a local computer or cloud-based network. As such, system 10 can be advantageously used for point-of-care applications including mobile diagnostic centers in emerging countries and in medical office laboratories.
[00093] System 10 is usable with a disposable test cartridge, which is configured to accept a biological sample and adapted to perform a particular test. The system and cartridges are highly flexible and can be used to detect a variety of tests, including nucleic acid and protein. Exemplary non-limiting tests that can be detected using the system and test cartridges include, bacteria, viruses, and disease specific markers for a variety of pathogenic disease states including Health Associated Infections (MRSA, C. Difficile, resistant enterococci Vancomycin (VRE), Norovirus), Critical Infectious Diseases (MTB / R1F, Flu, RSV, EV), Sexual Health (CT / NG, GBS), Oncology (for example, breast and bladder cancer) and Genetics (FII / FV). In some embodiments, system 10 can identify the type of cartridge via almost integrated field communication capabilities (for example RFID, laser scanning), and thus apply the appropriate test routine to the cartridge. In some embodiments, cartridge identification uses Bluetooth technology, RFID characters, bar codes, QR labels, and the like.
[00094] Once a test cartridge is physically inserted into and initialized by system 10, the system will perform specimen processing functions, which may in some embodiments include sample preparation, nucleic acid amplification, and a detection process of analysis. The results of the detection process can be transmitted wirelessly or directly over the wire to a local computer or cloud-based network. Advantageously, the local computer can be a wireless communication device, such as a tablet or cell phone, having a software application specifically designed to control the system and communicate with a network.
[00095] System 10 can be powered by an external power source, but can portray an uninterrupted power supply (for example batteries) in the event of a power interruption or use in the field. The uninterrupted power supply (UPS) allows for use in the field of the system, and in some embodiments it can supply power to the system for at least one day, preferably up to two days. In some modes, UPS allows up to four hours of continuous operation. As shown in this external view, the system 10 can include an external cover 12 and a port 14 for accepting a test cartridge (not shown). Different styles of outer cover 12 can be configured as needed by a particular user. Typically, the outer cover 12 is formed of a substantially rigid material in order to protect and support the components within, for example, a hardened polymer or metal construction. Although not shown here, in some embodiments the outer cover 12 can be heavily reinforced (armored) for use in the field, or as shown here made decorative for use in a doctor's office.
[00096] FIG. IB shows an exploded view of system 10 (without the outer cover) and with the main subsystems visibly represented. An overview of the subsystems is provided below. Additional details for each subsystem are described in the following sections.
[00097] Several subsystems are disclosed that make use of brushless DC motors (BLDC). Generally, each motor can have a stator assembly that is mounted on a printed circuit board (PCB) substrate, and can include a reversible transmission mechanism, such as a lead screw. In some modalities, such BLDC motors make use of analog sensors (for example, Hall sensors) to determine angular positioning and current monitoring based on force as a triggering tool. Such BLDC motors can include a rotor with multiple magnets arranged on it and mounted on a stator on a substrate with at least as many sensors as the motor phases. The three sensors are positioned so that the rotor displacement can be controlled based on the linear measurement portions of the sensors, thereby providing improved resolution and granularity without requiring the use of any position-based sensors or encoding hardware. Thus, the BLDC motors described here do not require the use of encoder hardware and their associated drive trains do not require the use of position sensors. For example, the system may include a syringe drive mechanism 16 that includes a brushless BLDC motor having an output shaft that is attached to a reversible lead screw. The lead screw drives a plunger rod that can interface with a plunger tip on a removable test cartridge. Such a syringe drive mechanism 16 can share a PCB 30 with a door drive mechanism 18. The door drive mechanism also includes a BLDC motor having an output shaft that is attached to a reversible lead screw. The motors of the syringe drive mechanism 16 and door drive mechanism 18 are shown directly mounted to the opposite sides of a PCB board, however, this is not critical and both motors can be mounted on the same side. In some embodiments, each engine can be mounted on its own. It is advantageous to use such BLDC motors since the improved resolution and granularity allows for improved precision and efficiency, and also allows for additional miniaturization of driven mechanisms for such motors. It is assessed, however, that the use of such BLDC motors is not required and that any of the mechanisms described here would also be driven by motors of the conventional type if desired, but additional sensors and / or circuitry may be required for some modalities.
[00098] As mentioned above, the BLDC motor is unique in that it includes a plurality of Hall effect sensors, but does not include any traditional encoder hardware. In some embodiments, the syringe drive mechanism and door drive mechanism, and associated subsystems, do not include position sensors. In some embodiments, the angular position of the BLDC rotor and output shaft can be derived solely from the sine wave input of the analog sensors and the circuitry on the PCB. Thus, traditional position sensors (for example encoders, optical sensors, etc.) are not required for use in conjunction with BLDC motors as used in the present invention. In order for the BLDC motor to provide smooth torque production, motor control techniques such as sine wave switching can be implemented. In addition, implementation of pulse width modulation can be used to centralize drive voltages to achieve high operating speed.
[00099] In addition, because the lead screws of the mechanisms are reversible, with end-of-stroke detection, based on force, they can be used to determine the starting and stopping points for the mechanisms to be activated. Force-based limit switch detection can be derived by monitoring the current of the BLDC motors, for example, the current of a bridge circuit, which will deviate (increase or decrease) from a norm when a force-based event occurs. Consequently, this deviation can be used as a trigger event to start, stop, reverse, slow down, and / or accelerate a BLDC motor. For example, in the case of the syringe drive mechanism 16, the feel of the current can be correlated with the pressure, and thus be used to release a compatible or intentionally variable pressure to the piston rod by adjusting the RPM of the associated BLDC motor. . This alleviates the need for an inline pressure sensor to monitor the pressure in the cartridge.
[000100] The valve drive mechanism 20 can make similar use of the same type of BLDC engine. In some embodiments, the valve drive mechanism 20 may include a helical drive gear train, which ultimately exits to a turntable valve drive to rotate the valve from a removable test cartridge. In some embodiments, the helical drive mechanism is not reversible as in the aforementioned syringe drive and door drive mechanism. However, the same type of position determination by the Hall effect and deflagration based on force (current monitoring) can be used for the valve actuation mechanism. For example, if turning the valve drive unexpectedly requires substantially less or more current, then such an event could be indicative of an interference or failure of a test cartridge. Here, force-based deflagration can be used to experience a poor function of cartridge integrity.
[000101] The sonotrode mechanism 22 is partially integrated with the valve drive mechanism 20. The sonotrode mechanism 22 can apply a programmable sonication power for a programmable duration for the cartridge, for example, in order to smooth a target sample inside the cartridge. In some embodiments, the sonotrode mechanism 22 may use a resonant piezoelectric actuator to apply vibration at a frequency of about 30 kHz or greater, about 40 kHz or greater, such as about 50 kHz (for example 50.5 kHz ). The sonotrode mechanism 22 includes a control circuit that uses the current phase measured in relation to the voltage excitation to determine the resonant frequency. The frequency can be adjusted by the control circuit to maintain a preset phase relationship. In some embodiments, the amplitude of the voltage excitation can be continuously adjusted to maintain the required power level. Based on these functions, the control circuit can maximize the sonotrode's power output.
[000102] System 10 also includes a cartridge drive and loading door system 24 that is powered by door drive mechanism 18. The lead screw of door drive mechanism 18 produces power for the drive and loading door system of cartridge 24 for both opening and closing door 14 as well as engaging and admitting a test cartridge 32.
[000103] A rear chassis portion 26 and a front chassis portion 28 provide structural support for system 10, as well as mounting provisions for the other subsystems. Chassis portions are generally stretched to provide a lower overall footprint for system 10, and to allow portability of system 10. In some embodiments, the system can have a footprint of: 9.1 ”x 3.0” x 4, 2 ”, and an approximate weight of 2.2 pounds (998 g). The elongated circuit board or PCB 30 generally adapts to the footprint of the chassis portions. PCB 30 includes most or all of the processors, subprocessors, memory, and control circuits required to control system 10. However, the aforementioned BLDC motors can be integrated with their own printed circuit boards that have control circuits. controls that connect separately to PCB 30. PCB 30 also includes aspects of the communication circuit (eg near-field communication circuits, USB, wireless) as well as a power supply circuit.
[000104] System 10 is compatible with several types of test cartridges 32, which are generally configured to receive and retain a sample of material, such as a body fluid (for example, blood, urine, saliva) or solid (for example , soil, spores, chemical residue) that is soluble in liquid. The test cartridge 32 can be a wall structure having one or more fluid channels and connection holes. The test cartridge 32 can be relatively small, such that it can be easily held in one hand, portable and / or disposable. Examples of such cartridges (usable with system 10) are disclosed in U.S. Pat. No. 6,660,228, Pub. Int. No. WO 2014052671 Al, Pat. No. 6,374,684, which are each incorporated herein by reference for all purposes.
[000105] Test cartridge 32 may include a reaction vessel 33 that extends out of the rear, which connects via interface with a thermal cycling and detection module 34. Module 34 includes one or more devices configured for release energy to, and also remove energy from, an aspect of test cartridge 32. Such an apparatus may include a dual thermoelectric cooler. Module 34 also includes one or more aspects of detection, as discussed in more detail below. II. Brushless DC Motor Architecture (BLDC)
[000106] FIG. 2A is a plan view diagram illustrating elements of a brushless DC motor (BLDC) 100, for use with some embodiments of the invention. Further details of the BLDC engine can be found in Commonly Provisional US Provisional Application No. 62/195449, filed on July 22, 2015, and entitled “Simple Centroid Implementation of Commutation and Encoding for DC Motor,” which is hereby incorporated by reference for all purposes.
[000107] In one aspect, the BLDC motor includes a rotor and stator configured to produce a smoothly variable Hall effect voltage without any need for filtration or noise reduction. In some embodiments, this feature is provided by the use of permanent magnets within the rotor that extends a distance beyond the magnetic stator core. In some embodiments, the BLDC motor includes as many Hall effect sensors as motor phases, which are positioned such that the motor can be controlled based on substantially only the linear portion of the measured voltage patterns received from the sensors. In some embodiments, this includes spacing the sensors radially around the stator such that the linear portions of the measured voltage waveforms intersect. For example, a three-phase BLDC can include three Hall effect sensors spaced 40 degrees radially from each other, thus allowing the system to control a sensor position within a 40 degree increment.
[000108] In some embodiments, the motor comprises an internal stator assembly 101 having nine pole teeth extending radially from the center, each pole tooth ending in a pole contact 103, and each pole tooth having a spiral which provides an electromagnetic coil 102. The motor further comprises an outer rotor 104 having an outer cylindrical skirt 105 and twelve permanent magnets 106 arranged with alternating polarity around the inner periphery of skirt 105. Permanent magnets are formed to provide a cylindrical inner surface for the rotor with immediate proximity to the external curved surfaces of the pole contacts. The BLDC motor in this example is a three-phase, twelve-pole motor. The controls provided, but not shown in FIG. 2A, changes the current in the coils 102 that provide electromagnetic interaction with the permanent magnets 106 to drive the rotor, as is well known in the art.
[000109] It must be mentioned that the number of pole teeth and poles, and in fact the disclosure of an internal stator and an external rotor are exemplary, and not limiting in the invention, which is operable with motors of a variety of different designs.
[000110] FIG. 2B is a side elevation view, partly in section, of the engine of FIG. 2A, in section to show a pole tooth and the coil of the nine, ending at the pole contact 103 in immediate proximity to one of the twelve permanent magnets 106 disposed around the inner periphery of the cylindrical skirt 105 of the external rotor 104. The teeth of pole and pole contacts of stator assembly 101 are a part of the core, and define a distal end of the core at line 204. The stator assembly 101 is supported in this implementation on a substrate 201, which in some embodiments is a plate printed circuit board (PCB), this PCB can comprise controls and tracks to control the switching of the electric current to the coils 102, which provide electromagnetic fields interacting with the permanent magnet fields 106 to drive the rotor. The PCB as a substrate can also comprise a set of control circuits for coding and switching. The rotor 104 physically engages with the stator 101 by driving the shaft 107, which engages a bearing assembly on the stator to precisely guide the rotor in rotation. The drive shaft 107 in this implementation passes through a special opening in the PCB 107, and can be coupled to the mechanical drive devices.
[000111] Three linear Hall effect sensors 202a, 202b, and 202c are illustrated in FIG. 2B, supported by substrate 201, and strategically positioned according to some embodiments of the invention to produce a variable voltage pattern that can be used in a process to encode the angular position of the rotor and provide switching for motor 100. In FIG. 2B the overall height of the skirt 105 of the rotor 104 is represented by dimension D. The dimension dl represents the extension of the distal end of the rotor magnets below the distal end of the core in line 204. In conventional motors there is no reason or motivation to extend this edge below the end of the core, particularly since this can increase the height of the motor and require increased clearance between the rotor and the substrate. In fact, the skilled technician would limit the D dimension so that there is none of such an extension, since the additional dimension would only add unnecessary cost and volume to a conventional engine. In addition, on conventional motors at the distal end of the rotor, at or above the distal end of the core, the switching current in the coils 102 creates a considerable field effect, and a signal detected by a Hall effect sensor placed for feeling permanent magnets in this position would not produce a mildly variable Hall effect voltage. Instead, the effect on a conventional engine is substantially corrupted noise. The conventional method for this dilemma is to introduce noise filtration, or more commonly to use an encoder.
[000112] Extending the rotor magnets below the distal end of the iron core prevents the corrupted effect of changing the stator coil fields on the signal detected by Hall effect sensors. The particular length dl will depend on several factors specific to the particular engine arrangement, and in some embodiments it will be 1 mm or more (eg 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, or greater), although in in some modalities the extension will be less than 1 mm. In some modalities, the distance is a function of the size of the permanent magnets and / or the strength of the magnetic field. In some modalities, as detailed here, 1 mm in length is sufficient to produce a sinusoidal signal of variable voltage without noise or saturation. Placing the Hall effect sensors in a cl2 separation to produce a Hall effect voltage produces a smoothly variable voltage, devoid of noise. In some embodiments, Hall effect sensors produce a mildly variable DC voltage in the range of about 2 volts to about 5 volts devoid of noise or saturation. The d2 dimension can vary depending on the choice of sensor, design of a rotor, strength of the permanent magnets in the rotor, and other factors that are well known to those of skill in the art. A workable separation is easily discovered for any particular circumstance, to avoid sensor saturation and to produce a smoothly variable DC voltage substantially noise free.
[000113] Fig. 2C is a plan diagram of a substrate portion 201 taken in the direction of arrow 3 of Fig. 2B, showing the placement of Hall effect sensors 202a, 202b, and 202c in relation to the distal edge of the rotor 104, which can be seen in FIG. 2B extends below the distal edge of the nucleus by the dimension dl. In FIG. 2C the rotation path of rotor 104 including the twelve permanent magnets 106 is shown on the dotted line 302. The rotor rotates in each direction 303 depending on the details of the switching.
[000114] As illustrated in this exemplary non-limiting modality, each of the Hall effect sensors 202a, 202b, and 202c is positioned radially behind the distal edge of the rotor magnets, exactly facing the inside of the central track of the magnets rotating. The Hall effect sensor 202b is located at the arc of forty degrees from the Hall effect sensor 202a along the rotation path of the rotor magnets. Similarly, the Hall effect sensor 202c is located an additional forty degrees around the rotor track from the Hall effect sensor 202b.
[000115] Fig. 2D illustrates three voltage patterns 401, 501 and 601 produced by passing permanent magnets 106 from rotor 104 over Hall effect sensors 202a, 202b, and 202c in a three-phase BLDC motor. A sinusoidal variable voltage pattern 401 produced by passing permanent magnets 106 of rotor 104 over Hall effect sensor 202a. The 0 degree starting point is arbitrarily adjusted to be at a point of maximum stress. Three complete sine waveforms are produced in a complete 360 degree revolution of the rotor. The voltage pattern 501 produced by the passage of permanent magnets 106 of the rotor 104 over the Hall effect sensor 202b. In addition, a substantially noise-free sinusoidal variable voltage pattern 501 produced by passing permanent magnets 106 of rotor 104 over Hall effect sensor 202b. Since the Hall effect sensor 202b is positioned at an arc length of 40 degrees from the position of the Hall effect sensor 202a, the sinusoidal pattern 501 is shifted 120 degrees from that of the sinusoidal pattern 401. Furthermore, a substantially noise-free sinusoidal variable voltage pattern 601 produced by passing permanent magnets 106 of rotor 104 over the Hall effect sensor 202c. Since the Hall effect sensor 202c is positioned at an arc length of 40 degrees from the position of the Hall effect sensor 202b, the sinusoidal pattern 601 is shifted 120 degrees from that of the sinusoidal pattern 501. The patterns are repeated every 360 degrees of the rotor.
[000116] The three voltage patterns 401, 501 and 601 each have substantially the same max and min peaks, since the Hall effect sensors are identical, and are feeling the same peripheral magnetic fields at the same distances. In addition, patterns 401, 501 and 601 intersect at multiple points, points 402, 502, and 602 being examples. Notably, the standard segments between the points of intersection are substantially straight lines, and can be observed to provide an endless, continuous sequence of connected straight line segments. In addition, the zero crossing points for each straight line segment, and the max and min peaks for each pattern can be felt and recorded.
[000117] Fig. 2D further illustrates two straight line segments between the crossing points 402, 502, and 602. As a non-limiting example, the segment between the crossing points 402 and 502 is shown divided into 20 segments in length the same, which can conveniently be done by sensing the tension at the crossing points 402 and 502, and simple division. Because the physical rotation of the rotor, in this example, from one standard intersection to another is twenty degrees of motor rotation, each change in voltage by the calculated amount then represents 20/20, that is, 1.00 degree of rotation of the rotor. This is a relatively crass example to merely illustrate the method. In some embodiments of the invention, the circuitry on the PCB 201 senses the crossing points and divides by an 11-bit analog to digital converter (ADC) between the intersections. This provides 2048 count. In this implementation the mechanical rotational translation of rotor 205 for each count is about 0.0098 degrees. System resolution can be increased (or decreased) using an ADC with a higher (or lower) bit resolution. For example, using an 8-bit ADC would resolve each count to about 0.078 degrees, a 16-bit ADC would resolve each count to 0.00031 degrees, and using a 20-bit ADC would resolve each count to about 0.00002 degrees. Alternatively, increasing or decreasing the number of poles correspondingly will increase or decrease the resolution of the system.
[000118] In some embodiments, the invention provides a high degree of accuracy and precision for the mechanisms driven by engine 100. In the non-limiting example described above using an 11-bit ADC, the position of the engine can be controlled to 0.0098 degrees mechanical. Coupled with gear reduction, extremely fine control of translation and rotation of mechanisms can be achieved. In some embodiments, the motor 100 is coupled with a translational drive to a syringe pump unit to admit and expel fluid in the diagnostic processes.
[000119] FIG. 2E is a diagram representing the circuitry in some modalities of the invention to control the motor 100 using the output of the Hall effect sensors and the only method of analyzing only the linear portions of phase-separated curves produced by the sensors, the linear portions divided into equal divided segments as described above. The output of Hall effect sensors 202a, 202b, and 202c is provided for a set of proportional-integral-derived motion control (PID) circuits for switching purposes, and the waveforms produced by the interaction of the rotor magnets with Hall effect sensors are provided for multiplexer circuitry as shown in FIG. 2E. As described above in the exemplary non-limiting modalities, an ADC is used to produce the division of the straight portions of the phase-separated waveforms and the motor 100, which can be driven, for example, by a DRV8313 motor drive circuit from Texas Instruments . The skilled person will understand that the circuitry is not necessarily unique, and will further understand that there will be other circuitry arrangements that could be used while still falling within the scope of the present invention. In some embodiments, the set of circuits and coded instructions for sensing Hall effect sensors and providing coding for the motor can be implemented in a programmable system on a chip (PSoC) on the PCB. The circuit set can also include a torque estimation circuit, which can be provided to estimate torque values generated by the motor based on current and voltage measurements taken on the PSoC, thus avoiding the need for additional force sensors throughout the main system. III. Engine Torque Estimation
[000120] In some modalities, aspects of the BLDC 100 motor and control circuits can be used to detect torque without the need for external sensors. This can be done in different modes, for example by estimating the torque based on the principle that the electrical energy produced in the BLDC motor is equal to the mechanical energy extracted from the motor in addition to the electrical energy dissipated by the motor (ie loss of copper) , as illustrated by the model shown in FIG. 3A. This principal is quantified by the following equation:
* ■ internal 1 external 1 DOG
[000121] Where dissipated energy is calculated from:

[000122] Referring to the energy balance equation above, it logically follows that:

[000123] The substitution of the power variables results in the following balanced equation:

[000124] Consequently, solving for the motor torque Tm, the following equation results:

[000125] It follows that here there are two possible calculated solutions for the motor torque, which are the most positive and negative torque solutions generated by the previous equation, using bridge current hi, as shown below:

[000126] Since the torque is calculable from the motor constant and other variables, the motor torque can also be calculated using the motor constant Kt, as represented in the motor models as shown in FIGS. 3B and 3C.
, where VEME = KTWM
[000127] Thus, the calculated solution or rm2 that is closest to the calculation for (using ^ e) is assumed to be the correct solution. The following table defines the variables above.


[000128] The above principles can be relied on to estimate torque values based on readily available current and voltage measurements, which are obtainable using a low cost Programmable Chip System integrated circuit, such as the PSoC® line of available circuits Cyprus Semiconduzoror Corp. Additional variables such as friction can be considered, as well as toothed effects that arise from the harmonic disturbance torques using a Kalman filter for example. As a person of ordinary skill in the art would understand, the advantage of using a low cost and simple integrated circuit for torque estimation provides a huge advantage over previous devices that have sensors (pressure sensors, encoders, etc.) to provide device feedback, thereby reducing the number of parts required and the cost of the system as a whole. This advantage is enormously realized when torque sensing is used to trigger commands, as represented in the Door Open and Cartridge Loading, Syringe Drive, and Valve Drive subsystems described below. IV. Door Opening and Cartridge Loading Subsystems
[000129] In another aspect, the invention provides a door opening / closing and cartridge loading subsystem that is driven by a retractable mechanism in order to facilitate the manual loading and unloading of a test cartridge from the diagnostic test system . In some embodiments, the door open / close mechanism and cartridge loading system are integrated to provide coordinated movement such that manual loading of the cartridge into an open compartment of the system initiates the closing of the compartment door, typically on detection mechanism recoil as the user manually pushes the cartridge into the system. It is evaluated that such mechanisms can be activated by a BLDC motor, as described here, and use Motor Torque estimation, or use several conventional motors and methods as would be known to a person skilled in the art. Examples of such configurations are detailed below.
[000130] FIG. 4A shows a perspective view of a door opening and cartridge loading subsystem. The system includes a brushless DC motor (BLDC) 100, as described above, mounted on a 30 'PCB. The BLDC 100 motor includes an output shaft (not shown) to which a lead screw 109 is attached. Lead screw 109 is a reversible aspect of a transmission which operates to open and close door 14 as well as feeding a cartridge loading mechanism.
[000131] The lead screw 109 is threadedly engaged with a bridge nut 108, consequently, when the lead screw 109 rotates, the bridge 108 moves up or down (as the device is oriented in FIG. 4A) depending on the direction the lead screw 109 rotates. A first trestle portion 110 and a second trestle portion 112 are attached to the bridge 108. Both trestle portions are elongated to include an easel 114 and a meat path 116, which forms an "L" type track.
[000132] A pair of pinion gears 118 are interlocked with the stands 114. The up and down movement of the stands 114 is caused by the movement of the bridge 108 and the lead screw 109, which causes the pinions 118 to rotate accordingly . Pinion gears 118 are connected together by a shared shaft 120 which is supported by a subframe 122, which is attached to a main portion of the system 10, such as the rear frame portion 26. Each pinion gear 118 includes a finger 124 to stop the rotation of pinion gear 118 at certain interfaces.
[000133] Each pinion gear 118 is integrated with a larger door gear 126. Consequently, pinion gears 118 and door gears 126 rotate at the same RPM. The door gears 126 interface with the door trestles 128 of door 14. Consequently, when the door gears 126 rotate, the door trestles 128 and door 14 move up or down according to the direction the gears are. door 126 are rotated.
[000134] FIGS. 4B-4E graphically represent a method of loading a test cartridge. In FIG. 4B, a command is sent to the BLDC 100 engine to open port 14 to place the system in position to accept insertion of cartridge 32. When the command is received, system 100 operates the BLDC 100 engine to turn the lead screw 109. This action causes the bridge 108 and the fixed easel portions 110/112 to move upwards, and consequently initiate the rotation of the pinion gears 118 and door gears 126. This movement will cause the door 14 to move upwards as door gears 126 rotate against door frames 128.
[000135] After the door 14 is completely opened, the pinion gears 118 disengage from the stands 114 of the first and second portions of stands 110/112, which continue to move upwards. The upward movement of the first and second easel portions 110/112 also causes the cartridge loading arms 130 to be actuated by the pins 132 which are driven to move along the cam paths 116 of the first and second easel portions. 110/112. The cartridge loading arms 130 are forced by this movement to rotate around the axes 134, which places the primary arm portions 136 in an upward position.
[000136] The first and second easel portions 110/112 will move upwards, until a force-based event occurs that retracts the drives of the lead screw 109. Such an event can be, for example, the bridge 108 meeting a tongue or the first and second easel portions 110/112 pulling against cartridge loading arms 130. The kickback event can be detected in a BLDC motor bridge circuit as a change in current. Based on the recoil event, the BLDC motor is commanded to stop the rotation and rest in the position shown. Advantageously, this step is carried out without the aid of any position sensors.
[000137] In FIG. 4C, test cartridge 32 is inserted into system 10 until a portion of test cartridge 32 is brought into contact with the first arm portions 136. Light movement against the first arm portions 136 results in another indentation event in the lead screw 109 which is detectable in the BLDC motor bridge circuit as a change in current. This event serves as a command for the BLDC engine to reverse the direction of the previous door opening step in order to capture the cartridge and close the door.
[000138] As shown in FIG. 4D, the upward movement of the first and second easel portions 110/112 causes the pins 132 to be guided around the length of the meat paths, which in turn causes the cartridge loading arms 130 to rotate in one hourly direction. This causes the second arm portions 138 of the cartridge loading arms 130 to push the cartridge inwardly in an internal position. In addition, the first and second trestle portions 110/112 are raised until the fingers 124 of the pinion gears 118 are rotated by the notches 140 of the first and second trestle portions 110/112, which initiates the movement of the pinion gears 118 against the easel 114, as well as the door gears 120 against the easel 128. In this way, the door 14 is made to move downwards in the direction of a closed position.
[000139] As shown in FIG. 4E, the door 14 is moved downward by continuous movement of the lead screw 109 to completely close the door. The BLDC motor is powered to do so until a force-based event occurs that drives backward against the lead screw 109. Such an event can be, for example, bridge 108 meeting a tongue or the first and second 110/112 easel portions pushing against cartridge loading arms 130. The kickback event can be detected in the BLDC motor bridge circuit as a change in current. Based on the detection of the recoil event, the BLDC motor is controlled so that the tongue turns and rests in the position shown. Advantageously, this step is carried out without the aid of any position sensors. V. Syringe Drive Subsystem
[000140] As described above, the embodiments of the invention can include aspects of the syringe drive mechanism 16. As shown in FIG. 5A, the syringe drive mechanism 16 includes a BLDC 200 motor as described above. The BLDC 200 engine includes an output shaft that is connected to a 209 reversible lead screw.
[000141] A laterally extending arm 206 includes a nut that is threaded to the lead screw 209. The laterally extending arm 206 is also attached to a plunger rod 208. The laterally extending arm 206 and the piston 208 can be driven up and down by controlling the BLDC 200 motor to turn the lead screw 209 in an appropriate direction.
[000142] After the test cartridge 32 is secured and the door 14 is closed, the syringe drive mechanism 16 can be used to interface with the test cartridge 32. The test cartridge includes a syringe passage 210 to retain a plunger tip 212. The downward movement of the plunger rod 208 in the syringe passage 210, which causes the tip of the plunger rod 208 to engage the plunger tip 212. In this way, the combined plunger tip 212 and the rod plunger 208, together with the syringe passage, act as a syringe to pressurize / depressurize the test cartridge 32. The programmed pumping of the test cartridge 32 causes the fluid to flow in and out of several chambers of the test cartridge 32 to affect a trial.
[000143] After engaging with the plunger tip 212, the plunger rod 208 can be actuated by the BLDC 200 motor to any desired position within the syringe passage 210, including the representation of various syringe pumping algorithms. The BLDC 200 motor currents can be continuously monitored to release a compatible pressure to the plunger rod, thereby alleviating the need for an inline pressure sensor to monitor the cartridge pressure.
[000144] Consequently, because the lead screw 209 can be retracted, a pressure decrease within the test cartridge 32 can cause a stationary piston rod 208 to be pushed down. The pressure drop can be detected by monitoring the measured current of the BLDC 200 motor, detecting a relative change, and then changing the output of the BLDC 200 motor accordingly. Similarly, a decrease in pressure within the test cartridge 32 can cause a stationary plunger rod 210 to be pushed upwards. The pressure increase can be detected by monitoring the measured current of the BLDC 200 motor, detecting a relative change, and then changing the output of the BLDC 200 motor accordingly. This can advantageously be accomplished without the aid of any pressure sensors.
[000145] In another example, the current associated with a movable piston rod 208 can be monitored for changes that indicate an increase or decrease in the pressure rate. Consequently, after detecting a relative change, the BLDC 200 motor output can be changed to increase or decrease the pressure rate that is applied by the movable piston rod 208. Advantageously, this can be accomplished without the help of any pressure sensors .
[000146] An example of a method 220, using the aforementioned BLDC current monitoring principles, to determine proper loading of a test cartridge and to test the integrity of this cartridge is shown in FIG. 5B. It is assumed that the test cartridge 32 has already been physically loaded as shown in FIG. 5 A.
[000147] In operation 222, a command is sent to start the loading procedure. As a result, an over limit force is set in operation 224. The over limit force is the maximum force that the BLDC 200 engine can exert on the piston rod 208 for the purposes of this operation, which is associated with the piston rod 208 which compresses the plunger tip 212 against the bottom of the syringe passage 210. In operation 226, the BLDC 200 motor is operated to move the plunger rod 208 into the syringe passage 210, which causes the tip of the plunger rod 208 engage the plunger tip 212. In operation 228 the torque of the BLDC 200 motor is continuously monitored, using the torque estimation circuit of FIG. 2E and the methodology of FIGS. 3A-3C, to determine whether the plunger rod 208 has moved to the bottom of the syringe passage 210. If the over-force limit is not exceeded then it is determined that the loading procedure failed in operation 230. Occasionally, the plunger tip 212 can be lost due to a manufacturing error or physically defective. In each case, the plunger rod 208 will reach the end of its possible course with the passage of syringe 210 without properly reaching the bottom against a plunger tip 212, and consequently, the over limit force will not be exceeded.
[000148] If the over-limit force is exceeded then it is determined that the plunger rod 208 pushed the plunger tip 212 to the bottom of the syringe passage 210, and method 220 moves to operation 232, where a sub-limit force is adjusted. The limit sub-force is the maximum force that the BLDC 200 motor can exert on the plunger rod 210 for the purpose of this operation, which is related to the decompression of the plunger tip 212. In operation 234 the BLDC 200 motor is operated to move the plunger rod 210 upward into syringe passage 210. In operation 236 the torque of the BLDC 200 motor is continuously monitored to determine whether the sub-limit has been exceeded. As a result of operation 228, plunger tip 212 will be highly compressed. The sub-limit is the amount of force required to decompress the plunger tip and thus zero the position of the plunger tip 212 for later operation. Once the sub-limit is exceeded, the BLDC 200 engine will cease operation and the method will move to operation 238, where it is determined whether the syringe has drawn a vacuum. In this operation, the test cartridge valve system 32 is operated to seal the syringe passage 210 to the atmosphere, which was not the case in the preceding steps. After this is complete, the BLDC 200 motor is operated to pull the plunger rod 208 upwards against the vacuum inside the syringe passage 210. If the plunger rod 208 does not move freely and force is detected, then in operation 240 it is determined that a vacuum has been established and thus the integrity of the test cartridge 32 is not understood. If the piston rod 208 moves freely without detection of force, then in operation 242 it is determined that no vacuum has been established and thus the integrity of the test cartridge 32 is compromised.
[000149] Another example of a method 248, using the aforementioned principles of BLDC current monitoring, to determine the initialization of the test cartridge syringe (ie, plunger rod 208, syringe pass 210, and tip of plunger 212) is shown in FIG. 5C. It is assumed that the test cartridge 32 has already been physically loaded as shown in FIG. 5A, and the cartridge has been properly loaded as shown in FIG. 5B.
[000150] In operation 250, a command is sent to start the loading procedure. As a result, an over-limit force is set in operation 252. The over-limit force is the maximum force that the BLDC 200 motor can exert on the piston rod 208 for the purpose of this operation, which is associated with the placement of the plunger 212 in an appropriate upward position (relative to the orientation of the device as shown in FIG 5 A) at the top of syringe passage 210.
[000151] In operation 254, the BLDC 200 motor is operated to move the plunger rod 208 upward into the syringe passage 210, which causes the plunger tip 212 to reach the top in a position within the syringe passage 210 In operation 256 the torque of the BLDC 200 motor is continuously monitored, using the torque estimation circuit of FIG. 2E and the methodology of FIGS. 3A-3C.
[000152] Once the over limit force is exceeded then it is determined that the plunger tip 212 has reached the top, and method 248 moves to operation 258, where a lower limit force is adjusted. The lowest limit force is the maximum force that the BLDC 200 motor can exert on the plunger rod 210 for the purpose of this operation, which is related to the placement of the plunger tip 212 against the bottom of the syringe passage 210, but without excessive compression of the plunger tip 212. In operation 260 the BLDC 200 motor is operated to move the plunger rod 210 down into the syringe passage 210. In operation 262, the torque of the BLDC 200 motor is continuously monitored to determine whether the lowest limit force set in operation 258 has been exceeded. Once the lower limit is exceeded, the BLDC 200 engine will cease operation, and it is assumed that the plunger tip 212 has been placed at the bottom of the syringe passage 210. Thereafter, method 248 will move to the operation 238, where it is determined whether the syringe has moved a predetermined amount of distance (for example 60 mm). This is accomplished by using the BLDC 200 engine Hall effect sensors to count the revolutions of the lead screw 209 and reporting that the count for a linear path amount of syringe rod 208. In some cases the highest limit forces and lower will be triggered by obstructions or excessive friction within the syringe passage 210. Consequently, the travel check step is performed to ensure that the syringe rod 208 has moved freely without obstruction. If the syringe rod 208 has moved at least the predetermined amount of travel, then it is determined that initialization is successful in operation 266. However, if the syringe rod 208 has not been moved at least the predetermined amount of travel, then it is determined that initialization is not successful in operation 268. [0002] VI. Valve Drive Subsystem
[000153] As described above, the embodiments of the invention can include aspects of the valve drive mechanism 20. As shown in FIGS. 6A and 6B, the valve drive mechanism 20 includes a BLDC motor 300 as described above.
[000154] The BLDC 300 motor is mounted on a chassis 304 having a plurality of reinforcement ribs 306 that contribute to the rigidity of the chassis 304. The chassis 304 includes an elongated first portion 307 that serves as a mount for a motor stator 308 BLDC 300. An elongated shaft 310 extends from the BLDC 300 motor and holds a first worm thread 312. The first worm thread 312 cooperates with and rotates a first helical gear 314, which rotates on an axis 316 shared with a second thread without end 318.
[000155] The second auger 318 cooperates with and rotates a second helical gear 320. The second helical gear 320 is integrated with a turntable valve actuation 322, which is configured to cooperate with a rotary valve mechanism of the cartridge test 32. Valve drive 322 is mounted on an elongated secondary portion 324 of frame 304. The elongated secondary portion 324 includes a passage 325 for cooperation with the sonotrode mechanism 22.
[000156] In use, the BLDC 300 motor is powered to rotate and in this way the valve drive 322 rotates through the auger drive described above. Valve drive 322 is substantially downward, which allows for greater accuracy when positioning valve valve 322. The syringe drive mechanism 16 does not include any position sensors, because the angular position of stator 308 can be derived solely from sinusoidal wave input of the Hall effect sensors, and through this position of the valve drive by knowing the gear ratio of the final drive.
[000157] Worm drives are not reversible as in the aforementioned syringe drive and door drive mechanisms. However, the same type of positional bypass and deflagration as the Hall effect based on force can be used for the valve actuation mechanism. Here, deflagration based on force can be indicative of a poor function of cartridge integrity. For example, if turning the valve drive unexpectedly requires substantially less or more power, then such an event could be indicative of an interference or failure of a test cartridge. Although each of the syringe drive, door drive mechanisms and valve drive mechanisms are described as using the improved BLDC motor described here, it is assessed that any or all of the drives and mechanisms could also use a conventional type BLDC motor, a servo motor or other suitable motor, as would be understood by a person skilled in the art, however some features may require additional sensors or circuitry.
[000158] In addition, the BLDC motor is configured to start and centralize the position of the valve actuation output by performing a centralization protocol based on the sinusoidal signal generated by the Hall effect sensors. This can compensate for gear gap and gear wear over time. This is illustrated by the Hall voltage signal for the valve actuation position graph shown in FIG. 6C. As shown, a given position of valve drive 322 can vary according to the clearance and wear between gears. VII. Sonotrode subassembly
[000159] In some embodiments, an ultrasonic sonotrode subassembly is provided for use in a diagnostic assay system as described herein. In some embodiments, the ultrasonic sonotrode assembly includes an ultrasonic sonotrode, a sonotrode housing, a spring, a chassis and set of control circuits configured for the operation of the sonotrode. The sonotrode housing is adapted to support and protect the ultrasonic sonotrode and includes a section for retaining a helical spring to facilitate movement between a disengaged and engaged sonotrode position and a wedge for interfacing with a system cam mechanism to actuate sonotrode movement between disengaged (lowered) and engaged (raised) positions. Although a coil spring is described herein, it is appreciated that several other types of springs or tilt mechanisms can be used. In the disengaged position, the tip of the ultrasonic sonotrode is straight or below a base surface on which the test cartridge rests to facilitate loading and removing the test cartridge from the system. In the engaged position, the tip of the ultrasonic sonotrode extends above the base surface to engage a convex portion of a sonication chamber in the test cartridge to facilitate sonication of biological material in a fluid sample contained within the sonication chamber during the preparation and / or processing of the sample analysis. In some embodiments, the movement of the sonotrode is effected by an actuating mechanism common to one or more other mobile components of the system, such as a system door. The sonotrode assembly also includes a circuitry, such as a printed circuit board, with interfaces adapted for electrical connection with the corresponding circuitry within the system to facilitate the operation of the ultrasonic sonotrode by the system.
[000160] In some embodiments, the diagnostic test system is placed horizontally during the performance of a test (as shown in FIGS. 9A-B) such that the sonotrode moves between the disengaged position (lowered below the cartridge) and the engaged position (raised towards the cartridge) in order to engage and contact the cartridge's sonication chamber. It is estimated that in some modalities, the design would be different such that in the disengaged and engaged positions the sonotrode would be in several other orientations and / or locations in relation to the cartridge depending on the design of the cartridge and the diagnostic test system. VIL A. Design and Assembly of the Sonotrode Subassembly
[000161] FIG. 7A illustrates an ultrasonic sonotrode 700 subassembly configured for use in a diagnostic test system according to some embodiments of the invention. FIG. 7B represents an exploded view of the sonotrode assembly of FIG. 7A. In this embodiment, the sonotrode subassembly includes an ultrasonic sonotrode 710, sonotrode housing 720, helical spring 730, control circuit assemblies 740, and chassis 750. The sonotrode subassembly can be tested as an autonomous subassembly before insertion into the system and it can also be removed or replaced as needed.
[000162] FIGS. 8A-E illustrate the components of the sonotrode assembly during various stages of assembly. As shown in FIG. 8A, the ultrasonic sonotrode 710 fits into the sonotrode housing 720 (shown in section to show the sonotrode residing within). The housing can be designed such that the fitting of the sonotrode to the housing rests or times the sonotrode within a predetermined orientation and position in relation to the housing. For example, the ultrasonic sonotrode may be of a design that includes features that are not perfectly symmetrical axis around a longitudinal axis of the sonotrode such that features or corresponding surfaces on an internal portion of the housing hitch to hold the sonotrode in position within the housing and start rotating the sonotrode in it. The non-axisymmetric feature may include, but is not limited to, a flat portion on one or both sides of the sonotrode or a protrusion or flap that visibly extends from the sonotrode or a contact through which the sonotrode is electrically connected.
[000163] In some embodiments, the sonotrode 720 is incorporated into the subassembly and controlled with the set of control circuits to provide an adequate output for the lysis of biological materials as necessary for a particular test.
[000164] As can be seen in FIG. 8A, the outer surface of the sonotrode housing 720 includes a retaining spring portion 722 to retain a helical spring 730 to effect movement of the housing 720 between the disengaged and engaged positions. The retaining portion includes an upper retaining surface 722a and a lower retaining surface 722b that engages the spring when in an uncompressed state. The housing 720 may also include one or more details of initial retention 723 to secure and / or guide the conductor cables electrically connected to the sonotrode 710 during the movement of the sonotrode between the disengaged / engaged positions. The sonotrode housing 720 includes a wedge portion 721 for interfacing with a system cam.
[000165] As shown in FIG. 8C, the partially assembled sonotrode assembly can be fitted to a sonotrode chassis 750. The chassis includes a location feature 751 that engages a corresponding feature of housing 720 in order to secure the position and orientation of the housing when snapped into place. The chassis also includes one or more features to protect the entire sonotrode assembly 700 within the diagnostic test system, for example, the chassis may include a base portion with one or more holes through which the chassis can be mounted to the module . In some embodiments, the chassis is formed from a polymeric material by injection molding, although it is estimated that it can be formed from various other materials (for example polymer, ceramic, metal) by various other manufacturing processes (for example, pressing, machining, etc.). After placing the sonotrode assembly inside the chassis, a 740 circuit pack component is attached to the chassis. The chassis may include one or more mounting features 752a through which the circuitry component (for example PCB) can be secured by one or more fasteners or screws 752b. The circuitry component can be electrically connected to the sonotrode before or after its coupling to the chassis. The completed sonotrode 700 assembly can then be tested and supplied to a user separately or within a diagnostic test system. VIL B. Sonotrode Positioning Interface
[000166] In some respects, the ultrasonic sonotrode is mounted on a mobile mechanism by which the ultrasonic sonotrode is positioned in relation to a sonication chamber of a test cartridge disposed within a diagnostic test system. In some embodiments, the test cartridge includes a sonication chamber positioned at the bottom of the cartridge (as shown in FIG. 10A) with a dome facing downwards (the outer surface of the dome being convex with respect to the test cartridge), as shown in the example of FIG. 10A, which corresponds to a rounded tip 711A of the convex outlet portion 711 of the ultrasonic sonotrode. Although the tip is round in this embodiment, it is assessed that the tip of the dome portion can be formed in a variety of shapes, including, but not limited to, flat, pointed, concave, convex, rounded, or convex, as desired. The dome-shaped portion of the sonication chamber and the rounded sonotrode tip focus on the ultrasonic energy transmitted from the sonotrode in order to efficiently reach the desired ultrasonic levels required to lyse cellular material (e.g. reinforced cell, spores, etc.) and release DNA in the fluid sample with ultrasonic sonotrode power and minimum size requirements. It is preferred that the rounded tip 711a of the convex outlet portion 711 of the ultrasonic sonotrode is pressed against the dome 1211 of the sonication chamber 1210 with sufficient strength to ensure that contact is maintained between the tip of the sonotrode and the convex surface of the sonication chamber. sonication during the release of ultrasonic energy. In some embodiments, the movable mechanism is configured to move the ultrasonic sonotrode upwards (in the engaging direction) to pressably engage the sonication chamber domes and the ultrasonic sonotrode together with at least 0.5 lb-F (0, 23 kgF). In some embodiments, the force applied to ensure that the rounded tip of the sonotrode and the dome portion of the sonication chamber is between about 1 lb-F to about 2 lb-F (0.45 to 0.9 kgF). In some embodiments, the applied force is about 1.4 lb-F (0.64 kgF). Although an interfacing cam and wedge are described herein, it is assessed that several other mechanisms can be used with or without an oblique member to facilitate the movement of the sonotrode between the disengaged and engaged positions. For example, in some embodiments, such mechanisms may include a lead screw, cable and the like.
[000167] In some embodiments, the mobile mechanism by which the ultrasonic sonotrode is positioned to press against the sonication chamber is integrated within an interconnecting network of actuators that effect movement of various other components of the diagnostic test system, such as opening and closing a system door, loading and ejecting the system test cartridge, moving a valve assembly and a syringe assembly inside the system. It is assessed that the mobile mechanism can be integrated with actuators of one or more other components or the mobile mechanism can be totally independent from other mechanisms and actuators.
[000168] FIGS. 9A-9B illustrate cross-sectional views of a diagnostic test system during and after loading a test cartridge into the system by demonstrating a mechanism that positions the ultrasonic sonotrode in coordination with closing a system door and loading the test cartridge. test. FIG. 9A represents a partially inserted test cartridge 32 in which a facing portion distal from a base of the test cartridge begins to engage an ejection tooth of an ejection / loading meat 1120. In this position of the cam 1120, the external surface of the meat engages an upper surface 721 of the wedge portion 721 of the sonotrode housing, as can be seen in more detail in the side view and cross section of FIG. 11A-1 and 11A-2.
[000169] As test cartridge 32 is more fully inserted, the test cartridge presses against the ejection tooth and the ejection / loading meat 1120 rotates clockwise so that then a cam loading tooth engages a surface by underneath the test cartridge by pulling the cartridge inwards to a fully charged position. As the ejection / loading cam 120 rotates the outer surface 1121 of the cam slides along the tip of the wedge 721a of the wedge portion 721 of sliding the sonotrode housing, which presses the sonotrode housing away from the cartridge to the disengaged position, which partially compresses the coil spring 730. As the test cartridge is fully inserted, the wedge tip 721a is received within an inwardly curved portion 1121a of the rounded portion of the cam 1120 which allows the sonotrode housing 720 to move upward a short distance allows the spiral to at least partially not compress such that the rounded tip 711a of the ultrasonic sonotrode protrudes above the surface over which the test cartridge was loaded and with pressure engages the dome-shaped portion of the sonication chamber . This position can be seen in greater detail in the side view and cross section of FIG. 11B-1 and FIG. 11B-2, respectively. As can be seen in FIGS. 9A and 9B, the rotation of the meat 120 is actuated by a closing movement of the first easel portion 110 of the door easel mechanism, which in this embodiment is the downward movement (in the direction of the arrow). Through a network of interrelated gears, this movement of closing the door also simultaneously acts in closing the door 100 of the system 1000 from an open position in FIG. 9A to facilitate the insertion and loading of the test cartridge 32 to a closed position, as shown in FIG. 9B, after loading the cartridge. The movement of the door frame mechanism can be carried out by one or more motors, such as any of those described herein.
[000170] FIG. 10A illustrates a cross-sectional view of a test cartridge for use in a diagnostic test system according to some embodiments of the invention. The dome-shaped portion 1211 of the sonication chamber 1210, described above, is positioned on the bottom surface of the test cartridge. The sonication chamber 1210 is in fluid communication with a network of channels in the test cartridge, through which fluid is transported by the movement of a valve and syringe to effect pressure changes during the test procedure. After the sample is prepared and / or processed, the prepared fluid sample is transported in a reaction vessel chamber 33, while an excitation medium and an optical detection medium are used to optically sense the presence or absence of an analyte. target (for example a nucleic acid) of interest (for example, a bacterium, virus, pathogen, toxin, or other target test). It is estimated that such a reaction vessel could include several different chambers, conduits, microwell arrangements for use in detecting the target test. An exemplary use of such a reaction vessel to analyze a fluid sample is described in US Patent No. 6,818,185, entitled “Cartridge for Conducting a Chemical Reaction,” filed on May 30, 2000, the total contents of which are incorporated herein by reference for all purposes. VII C. Sonotrode control
[000171] In some embodiments, the operation of the ultrasonic sonotrode is performed by using a sonotrode control circuit configured to control the current amplitude and phase estimation in a way to optimize excitation and provide a robust robust release of ultrasonic power , which is proportional to the current at the fixed voltage, as necessary for a particular test. In some embodiments, the system provides fully digital control of the sonication power release. In some embodiments, the system provides operation of the ultrasonic sonotrode without a conventional transformer and full-wave rectifying analog circuitry, thus allowing the use of decreased power, reduced sonotrode mounting size and an overall reduction in the size of the system. In some modalities, power release and control is performed in a way that real control power (which is the total power) in the ultrasonic sonotrode (as opposed to reactive power). The control circuit is configured to apply a programmable sonication power for a programmable duration to the assay cartridge to lyse target cells as needed for a particular assay.
[000172] In some embodiments, (for example with reference to FIG. 12A), an ultrasonic sonotrode includes a mass 713 (typically a solid metal core) adjacent to one or more piezoelectric actuators 714 that vibrate when connected to a power supply 716 through electrical contacts 715. The solid mass includes a tapered portion 712 'leading to an elongated portion 712 that focuses on the ultrasonic wave and ends at a convex outlet portion 711 that further focuses the ultrasonic waves to the outlet at the tip 711a of the portion 711 convex output. Typically, multiple piezoelectric actuators can be used to provide greater ultrasonic output with lower relative requirements (when compared to an actuator adapted to release higher ultrasonic energies).
[000173] In some embodiments, the sonotrode assembly can use an immediately available sonotrode with a sonotrode control circuit that operates the sonotrode with a closed loop or feedback control that provides consistent, robust ultrasonic energy at desired levels with power requirements lower relative value than would otherwise be possible with the sonotrode. For example, such a sonotrode immediately available having multiple piezoelectric actuators when operated to release ultrasonic energy levels suitable for cell lysis in a diagnostic assay may not operate in a compatible manner by merely applying a current level adjustment due to the actuators operating out of phase. Piezoelectric actuators expand outward when current is applied and if this outward expansion occurs even at slightly different times (out of phase), then the result is a low frequency connection in vibration that prevents the sonotrode from releasing adequate levels of ultrasonic energy. For this reason, such sonotrodes can operate properly only at lower ultrasonic levels or may not be dependent on providing compatible energy release for the duration required in a particular diagnostic test.
[000174] In some embodiments, the system applies an improved control scheme that allows the compatible release of ultrasonic energy levels suitable for cell lysis in a diagnostic assay for a specific duration using such a sonotrode as described above. In some embodiments, the sonotrode assembly is configured to use resonant piezoelectric actuators to apply vibration at a frequency of around 50.5 kHz. In some embodiments, the sonotrode assembly is configured to apply a vibration frequency in the range of about 20 kHz to about 50 kHz. For example, the frequency of vibration can be about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or about 50 kHz. In some embodiments, the frequency of vibration is greater than 50 kHz. In some modalities, the system uses a closed loop control system to provide excitation of the piezoelectric that is kept in phase with each other for the duration required for the sonication of biological material.
[000175] In some modalities, the system applies current and / or voltage to the piezoelectric actuators by raising the applied power to the desired levels to minimize out-of-phase excitation. An example of this scheme is shown in FIG. 10B. In some modalities, power release and control are performed in order to control the real power (which is the total power) in the ultrasonic sonotrode (as opposed to reactive power). Maintaining substantially a specific phase relationship between voltage and current, it allows the reactive power to be substantially eliminated. Reactive power is when the piezo actuators are not in the locked phase and the sonotrode merely vibrates. By raising the power, as opposed to just turning on the power, the elevation allows the system to maintain the phase relationship between current and voltage and prevents vibration to allow the sonotrode to release the desired levels of required ultrasonic energy.
[000176] FIG. 12B illustrates a simulated sonotrode power transfer function demonstrating the phase relationship between the excitation current and the voltage at the energy resonance.
[000177] In some embodiments, the sonotrode's control circuit uses closed control loops to operate the sonotrode. In an internal control loop, the frequency is adjusted to maintain the present phase relationship. In an external loop, the amplitude of the voltage excitation is continuously adjusted to maintain the required energy level. An example of these internal and external control loops is illustrated in FIG. 14.
[000178] FIG. 13 illustrates a schematic for controlling the assembly of the sonotrode according to some modalities of the invention. The sonication interface is configured in power (Watts) and duration (seconds) as necessary for a particular test. Typical power levels of 5 to 10 Watts are applied between 15 and 30 seconds to sufficiently lyse typical spore cells and release ~ 50% of spore-bound DNA into the solution into sample chamber 1210, as shown in FIG. 10B. It is assessed however, that the required sonication power, duration and efficiency vary per test and can be higher or lower than the levels described depending on the needs of the test, design and the type of cells or material that are sonicated. In some modalities, the PSoC DAC generates a sine wave from 0 to 4 V. The DAC output goes through a TI audio amplifier. The TI amplifier multiplies the signal by 20 db. The amplified signal in TI goes through an elevator transformer before being released to the sonotrode. The power is estimated by the voltage (DAC voltage amplified through TI and the transformer) and the current read by the sensor (P = v * I cos (d))) (real power). Thus, the power released to the sonotrode is controlled via DAC voltage control. A control loop conducts the input voltage to keep the power at the desired level. See for example FIG. 15.
[000179] In some embodiments, the sonotrode's control circuit is configured so that a frequency that gives the highest real power amplitude of a frequency sweep is established as the resonant frequency. The phase between the input voltage and the output voltage is measured at the resonant frequency. During sonication, a control loop locks the phase measured between the input and output voltages by adjusting the input frequency. The current amplitude is a product of the sensor factor and the amplified PSoC that amplifies the signal before reading. An exemplary relationship between power vs. input voltage can be seen in FIG. 16. An exemplary relationship between the current amplitude of the sonotrode and the phase versus frequency can be seen in FIG. 17.
[000180] In some modalities, the sonotrode control circuit uses a sinusoidal control that controls the amplitude input for the sonotrode driver. The circuit can use phase pairing to control the resonant frequency to ensure that the voltage and current maintain a specified phase relationship, which can be used for example to eliminate reactive power. In some modalities, the circuit uses frequency scanning with a resolution of 1 Hz, however, it is estimated that this configuration can provide an effectively unlimited frequency resolution. Such a configuration allows for consistent and robust release of ultrasonic energy levels with an ultrasonic sonotrode having reduced power and size requirements than would otherwise be possible with such a device. VIII. Thermo-Optical Subassembly
[000181] In some embodiments, the invention provides a Thermo-Optical Subassembly (TOS) for use in a diagnostic test system. In some embodiments, TOS includes a thermal control device component and an optical excitation / detection component. TOS can interface with other components of the diagnostic test system, including the ultrasonic sonotrode, port, syringe and valve. In some embodiments, TOS includes a thermal control device instrument and an optical component instrument having an excitation means and an optical detection means. The TOS unit is constructed to define a cavity in which a reaction vessel can be inserted to perform nucleic acid amplification and / or detection of a target test using the thermal control and optical interrogation component of the target test using the optical component instrument. TOS is used in a system with one or more circuit boards (for example motherboard) that controls the operation and coordination between the various components of the test system. In some modalities, a Cell Nucleus hitches a ride on the motherboard. In some embodiments, each hardware subassembly carries its own dedicated PSoC processor and associated electronics. In some embodiments, the diagnostic test system includes a means of communication (for example wireless, NFC, USB) that allows modifying and / or updating the control software or control parameters used by the system. The TOS may also include one or more sensors (for example, NFC reader) to determine a location or presence of a test cartridge or a position of the valve component in order to coordinate the operation of multiple system components. In some embodiments, the TOS comprises a cartridge position sensor (for example NFC reader) located physically in the TOS to allow it to be physically in close proximity to the test cartridge when inserted into the diagnostic test system. In some modalities, TOS can be connected in series to other electronic subsystems via USB and / or wireless interfaces such as NFC or bluetooth. [0003] VIII. A. TOS Project
[000182] It is evaluated that the device of the thermal control instrument and the optical detection device can be defined in various configurations, as desired. In the modalities described here, the thermal control and optical detection device is configured for use with a reaction vessel having two opposing larger faces and two edges (smaller faces). The thermal control device can be configured to heat one side of one main face of the reaction vessel, or to heat two sides of both major faces. In the embodiments described here, the thermal control device is configured to be positioned adjacent to a main face of the reaction vessel on one or both sides. Likewise, the optical detection device can be configured according to various configurations, such as optical detection of a main face of the reaction vessel or one or more edges (smaller face (s)) of the reaction vessel. Typically, the optical detection configuration corresponds to a configuration of the thermal control device, for example, the optical detection device is positioned to detect optics through a part of the reaction vessel not covered by the thermal control device. In some embodiments, where heating on one side is used, the opposite unheated main face can be covered with a transparent insulating material in order to control thermal transfer while still allowing optical detection through the insulating material. In some embodiments, the system uses a thermal control device configured to heat one side and an optical detection device configured to excite / detect a main face and / or one or more edges (smaller face) of the reaction vessel. In other embodiments, the system uses a thermal control device configured to heat two sides with an optical detection device configured for the excitation / optical detection of one or more edges of the reaction vessel. Exemplary configurations are provided below.
[000183] FIG. 18 shows an exemplary diagnostic test system 1000 for detecting a target test in a fluid sample prepared within a disposable test cartridge (not shown) when inserted into the system. The diagnostic test system 1000 includes multiple components and subassemblies, as described herein, one of which is the TOS 1100 subassembly. As shown in FIG. 18, the TOS 1100 subassembly can be located at the front of the system. The TOS can be inserted into the pinions or housing of the system 1000 with door 14 open and secured with one or more screws (not shown) so that the faceplate 1110 faces the receptacle of the system that receives the test cartridge. Front plate 1110 defines a cavity 1111 opening or slot through which a reaction vessel from a planar test cartridge can be inserted. In some embodiments, TOS can be tested as an autonomous subassembly before insertion into the diagnostic test system. In some embodiments, TOS can be removed or replaced as needed.
[000184] In some embodiments, the diagnostic test system uses a disposable test cartridge. An exemplary test cartridge suitable for use with the system as described herein is described in US Patent No. 6,818,185, entitled “Cartridge for Conducting a Chemical Reaction,” deposited on May 30, 2000, the entire contents of which are incorporated herein by reference for all purposes.
[000185] In some embodiments, the TOS 1111 slot and the cavity are dimensioned to accommodate the reaction vessel (typically within +/- 0.020 ”(5 mm)) and the optical assembly and associated components are adapted to establish the optical components in relation to the reaction vessel to facilitate optical excitation and detection for the target test. In some embodiments, the TOS is spatially configured to establish a thermal control device, such as a dual TEC device, in relation to the reaction vessel to control and facilitate the thermal cycling of the fluid sample within the reaction cartridge of the test cartridge . In some embodiments, TOS moves the thermal control device, for example, picking up the dual TEC before inserting the reaction vessel and then engaging and securing the dual TEC against the reaction vessel when the reaction vessel is in place.
[000186] FIGS. 19A-B illustrate the front and rear views of an exemplary TOS 1100 subassembly according to some embodiments of the invention. In FIG. 19A, an exemplary reaction vessel 33 is shown inserted in the opening of the cavity 1111 of the front plate 1110 and the thermal control / heat sink assembly 820 can be observed, as well as a cooling fan 822 (see Fig. 20B). In FIG. 19B, a rigid flex PCB configuration and thermal contact mechanism 840 allowing lateral movement of the thermal control device before the fixing fitting of the reaction vessel 33 can be observed. The PCBs 830 and 831 through which the thermal control device 800 and the optical component 900 are fed and controlled can be coupled via a rigid flex connection 832 that allows lateral movement. The thermal contact mechanism 840 includes a sliding component that translates movement between an open configuration (see FIG. 24B) and a fixed configuration (see FIG. 24A) in which a TEC 810 face of the thermal control device is engaged against the side of a reaction vessel 33. In some embodiments, the thermal contact mechanism 840 includes a movable and / or adjustable support 842 that can slide up and down along a vertically extending assembly 844 to ensure proper alignment with the optical component 900 and the reaction vessel, and is movable laterally towards the thermal control device to ensure adequate thermal contact with the reaction vessel 33 to facilitate efficient thermal cycling. In some embodiments, the thermal contact mechanism 840 includes a support or bottom guide 846 to facilitate the insertion of the reaction vessel into the thermal contact mechanism 840. In some embodiments, this movement is effected by the axial movement of the actuation bridge of the port 110 as shown in FIGS. 26A-B.
[000187] FIGS. 20A-B illustrate exploded views of an example of TOS according to some embodiments of the invention. As can be seen, the TOS assembly includes an optical assembly 930 having windows through which the excitation component 910 and the optical sensing component 920 can operate when assembled. The optical assembly is attached to the front plate 1110 by means of a support 1113 and at least partially surrounds the flange 1112 around the opening of the reaction vessel 1111. The thermal control device 800 is coupled to the optical assembly 930 by two pins 834 which extend through the thermal contact mechanism 840 and two holes through the optical assembly 930. The assembly can also include a sensor to detect a proximity location, or cartridge identity within the system. In some embodiments, the sensor is an 1190 near field communication (NFC) sensor, although it is estimated that several other sensors can be used. It is assessed that, in some modalities, NFC can be adapted to detect several different things, including, but not limited to: the location / presence of a cartridge, the type of cartridge, the particular assay, the microfluidic procedures that are unique to a particular test, the presence of a mobile device (eg PDA) and several other batch-specific parameters. In some embodiments, NFC allows for a workflow associated with a particular system / cartridge, thereby removing the need for a separate database in the cloud that the diagnostic test system would otherwise have to access. This feature is particularly useful in a resource-limited setting where the internet may not be readily available.
[000188] FIGS. 21A-B illustrate optical components and associated PCBs of an exemplary TOS according to some embodiments of the invention. The optical components include an excitation component 910, an optical detection component 920 and associated PCB components 830, 831 and electrical circuit set 833. In some embodiments, the PCBs are connected via a rigid flex connection 832 that allows lateral movement of the thermal control device against the reaction vessel. FIGS. 22A-B illustrate the thermal control device and PCB components associated with a rigid flex connection in an exemplary TOS. FIGS. 23A-B illustrate a thermal control device 800 before being attached to the optical assembly 930 of an exemplary TOS. In some embodiments, optical assembly 930 includes an alignment feature 931 to ensure proper alignment between optical component 900 and a portion of the reaction chamber of the reaction vessel 33. The alignment feature can include one or more features that match the corresponding characteristics of the reaction vessel, for example, a hole that receives a distally extended pin from the reaction tube, a protuberance or rib that engages a corresponding recess of the reaction vessel, a pair of magnets, or any suitable characteristics to facilitate the alignment between the reaction vessel and the optical component 900.
[000189] FIGS. 24A-24B and 25 illustrate a mobile thermal control device component coupled to an optical assembly and a sliding base according to some embodiments of the invention. In some embodiments, the thermal control mechanism 840 engages under pressure against the reaction vessel of a test cartridge. In some embodiments, the force applied to engage the thermal control device against the reaction vessel is at least 1 pound-F (0.45 kgf). In some embodiments the amount of force used is between 1 and 3 lb-F (0.45 to 1.4 kgf), typically about 1.3 F-pounds (0.6 kgf) of tightness, to ensure that the face of the TEC remains parallel to and in sufficient contact with a main face of the reaction vessel 33. FIGS. 26A-B illustrates the operation of the door frame 110 by making lateral movement of the thermal control device between the fixed and open positions (see FIGS. 24A-B, respectively).
[000190] FIG. 28 illustrates a schematic of the assembly of the optical module and thermal module 810 of TOS according to some embodiments of the invention. The optical module includes a detection block chip or detection component 920 and an excitation block chip or excitation component 910 arranged on a PCB charger. FIG. 28 illustrates an exemplary TOS for use in a diagnostic assay system as disclosed herein. [0004] VIII. B. Optical component
[000191] FIG. 30A illustrates an exemplary optical component configuration for use with a diagnostic assay system as disclosed herein and FIG. 30B illustrates a detailed schematic of an exemplary optical component configuration according to some embodiments of the invention. In some embodiments, the optical means of excitation and detection operate through a smaller face (edge) of a reaction vessel from a test cartridge while the thermal control device engages against one or more larger opposite faces of the reaction vessel. In some embodiments, the thermal control device component thermally engages a main face of the reaction vessel on one side. In some embodiments, the thermal control device component thermally engages a main face of the reaction vessel on both sides. This latter configuration can be particularly useful for heating and cooling larger volumes of fluid sample. Such configurations can use ceramic plate heaters for passive heating and cooling means (for example ambient air blown through ceramic heaters) to obtain the thermocycling of the fluid in the reaction vessel or can include any of the TEC configurations described here.
[000192] According to some modalities of the invention, a miniaturized LED excitation chip that can excite the fluid sample through a smaller edge of the reaction vessel, while a miniaturized detection chip collects fluorescence through a main face reaction vessel 33, as in the configuration shown in FIG. 30B. In addition, the TEC dual design provides controlled heating and cooling across the opposite face, which provides improved temperature control when compared to passive cooling as used in some thermal cycling devices. In some reaction vessels, such as the configuration in FIG. 30A, the edge portholes are narrow (about 1.0mm x 4.5mm) and the small size makes the traditional lens effect difficult. Collect fluorescence from a main face of the reaction vessel, as in FIG. 30B, provides a larger detection window that allows more signal to be collected while still allowing excitation and detection to be orthogonal to each other. In some embodiments, the optical detection chip is sized to be equal to the size of the reaction vessel. FIG. 30C illustrates a detailed view of each of an exemplary excitation block and detection block according to some embodiments of the invention. As shown, excitation block 910 includes LED light sources 911 that direct light through filters and lenses 912 and then stem lenses 913 in order to emit the desired wavelengths of light to the desired locations of the reaction vessel 33 The optical detection block 920 includes photodiode detectors 921 that detect the light emitted from the reaction vessel 33, the light emitted through the stem lens 923, and filters and lens 922 before being received by the photodiode detectors 921 to ensure the detection of particular wavelengths that may indicate a reaction that corresponds to the presence of the target test within the reaction vessel 33.
[000193] In some embodiments, the optical component 900 includes an optical excitation component 910 and an optical detection component 920 positioned in an optical assembly adapted to receive a planar reaction vessel 33. The optical excitation component 910 is positioned to emit excitation energy across an edge (minor face) of a planar surface of the reaction vessel 33 and the optical sensing component 920 is positioned along a larger planar surface of the reaction vessel. In one aspect, the optical excitation and optical detection components are orthogonal to each other. In some embodiments, the optical components are configured to use lenses with a high numerical orifice. In some modalities, the optical components are configured to operate in low numerical holes without requiring the use of lenses. In such modalities, the light path can travel from the source, through a filter and to the detection component without requiring the use of lenses to focus the light produced by the excitation. Such modalities can be configured such that the excitation and detection light paths are spatially arranged in relation to each other to improve the detection of the light produced by the excitation in low numerical holes without requiring the use of lenses. Such use of spatial discrimination in the detection of excited light allows the detection of light without lenses, which enables a reduced size system.
[000194] In fluorescent detection systems, the excitation light typically exceeds the amount of the fluorescent light signal emitted. In order to efficiently detect the emitted signal it is important to collect as much emitted light as possible. Thus, most conventional systems use a high numerical orifice in their optical detection systems. A high numeric orifice allows for the collection of more light, which in turn provides higher resolution, while a low numeric orifice typically results in the collection of less light resulting in a lower resolution. The most conventional fluorescent optical detection systems use a configuration involving a lens and a bandpass filter in the light path between the light source and the detector. The filter is typically placed between the lens and the detector such that the lens provides collimated light passing through the filter. In the absence of a lens (and collimated light) the filter becomes much less efficient since light from high-incidence angles that collide with the bandpass filter merely passes through without being filtered. The lens eliminates this problem as the same collima (reduces high incident angle beams) resulting in more efficient filtering of excitation wavelengths.
[000195] In some embodiments of the present invention, the optical system does not include a lens. In the absence of a lens, a low numeric orifice configuration is used with the light path consisting only of the light source, a bandpass filter and the detector. Using a low numerical orifice with this configuration reduces the high incident light angles (without using a lens) thereby improving the filtration efficiency which in turn results in a strong light signal emitted with most of the filtered excitation wavelengths .
[000196] In some modalities, the optical module includes UV, blue, green, yellow and red LEDs, relevant optical filters, optical connection elements and protective glass. In some embodiments, the optical device is completely encapsulated in epoxy, which provides shock protection and protects against the incursion of dust and moisture. In some embodiments, the optical excitation and detection chips are small in size, such as less than 10 mm in each dimension, typically about 5 mm (length) x 4 mm (width) x 3 mm (height).
[000197] FIG. 31 illustrates detailed views of excitation block 910 and detection block 920 with an indication of the relative area of the adjacent reaction vessel through which light is emitted from the excitation block and collected by the detection block.
[000198] FIG. 32 illustrates the detection of fluorescence with the excitation and detection components of the optical component according to some embodiments of the invention. As can be seen, the configuration in FIG. 32 adapts to the arrangement pattern for the excitation and detection blocks with respect to the use of the low numerical orifice, according to some modalities. VIII. C. Thermal control device [0005] VIII. C. 1. Overview
[000199] FIG. 27 illustrates a control block diagram of a thermal control device 800 on a TOS board according to some embodiments of the invention. In some embodiments, the thermal control device includes dual thermoelectric coolers (TEC) with a thermal capacitor arranged between them. In some modalities, the thermal control device uses closed loop control using two thermistors to control the operation of each TEC in order to optimize the heating and cooling of the active surface engaged with the reaction vessel or vessel. This configuration provides lower noise, improved temperature stability, high gain and high bandwidth, when compared to conventional temperature control device controls. In some embodiments, a thermal control device is used to heat / cool a sample of fluid through a main face of a reaction vessel. In some embodiments, a fluid sample is heated / cooled across the main faces of a reaction vessel, using a thermal control device with each main face of the reaction vessel.
[000200] In any of the described modalities that include first and second thermoelectric coolers, the second thermoelectric cooler can be replaced with a thermal manipulation device. Such a thermal manipulation device includes any one of a heater (e.g., a thermoset heater), a chiller, or any suitable means for adjusting a temperature. In some embodiments, the thermal manipulation device is included in a microenvironment common to the first thermoelectric cooler such that the operation of the thermal manipulation device changes the temperature of the microenvironment in relation to an ambient temperature. In this respect, the device changes the surroundings of the environment to allow the first thermoelectric cooler to cycle between a first temperature (for example an amplification temperature between 60 and 70 ° C) and a second higher temperature (for example a denaturation temperature of 95 ° C), cycling between these temperatures as quickly as possible. If both the first and second temperatures are above the true ambient temperature, it is more efficient for a second thermal source (for example a thermoelectric cooler or heater) within a microenvironment to raise the temperature within the microenvironment above room temperature. Alternatively, if the ambient temperature exceeds the second, higher temperature, the thermal manipulation device would cool the microenvironment to an ideal temperature to allow rapid cycling between the first and second temperatures more effectively.
[000201] In some embodiments, the thermal control device includes a first thermoelectric cooler having an active face and a reference face, a thermal handling device, and a controller operatively coupled to each of the first thermoelectric cooler and the device of thermal manipulation. The controller can be configured to operate the first thermoelectric cooler in coordination with the thermal manipulation device in order to increase the efficiency of the first thermoelectric cooler as a temperature of the active face of the first thermoelectric cooler changes from an initial temperature to a desired target temperature. Thermal handling devices may include a thermoset heating element or a second thermoelectric cooler or any suitable means for adjusting the temperature.
[000202] In some embodiments, the thermal control device also includes one or more temperature sensors coupled with the controller and arranged along or near the first thermoelectric cooler, the thermal manipulation device and / or a microenvironment common to the first cooler thermoelectric and thermal manipulation device. The thermal manipulation device can be thermally coupled with the first thermoelectric cooler through a microenvironment defined within a diagnostic test system in which the thermal manipulation device is arranged such that a temperature of the microenvironment can be controlled and adjusted to a temperature environment outside the system.
[000203] In some embodiments, the thermal control device includes a controller coupled with each of the thermoelectric cooler and the thermal manipulation device that is configured to control the temperature in order to control a temperature inside a reaction vessel chamber in thermal communication with the thermal control device. In some embodiments, the controller is configured to operate the first thermoelectric cooler based on thermal modeling of a reaction chamber temperature in situ within the reaction vessel. Thermal modeling can be performed in real time and can use Kalman filtration depending on the model's accuracy.
[000204] In some embodiments, the thermal control device is disposed within a device diagnostic test system and positioned to be in thermal communication with a test cartridge reaction vessel disposed within the system. The controller can be configured to perform thermal cycling in a polymerase chain reaction process within a reaction vessel chamber.
[000205] In some embodiments, the thermal control device includes a first thermoelectric cooler having an active face and a reference face, a thermal handling device, a thermal interleaver disposed between the first thermoelectric cooler and the thermal handling device such that the reference face of the first thermoelectric cooler is thermally coupled with the thermal manipulation device through the thermal interleaver (which can be a thermal capacitor as disclosed here), and a first temperature sensor adapted to sense the temperature of the active face of the first cooler thermoelectric. The device may further include a controller operatively coupled to each of the first thermoelectric cooler and the thermal manipulation device. The controller can be configured to operate the thermal manipulation device in coordination with the first thermoelectric cooler to increase the speed and efficiency of the first thermoelectric cooler as an active face temperature of the first thermoelectric cooler is changed from an initial temperature to a desired target temperature . In some embodiments, the controller is configured with a closed control loop having a predicted temperature feedback input based on a thermal model that includes an input from the first temperature sensor.
[000206] Various aspects of such a thermal control device are described in detail in the competently filed US Non-Interim Order No. [Representative Certificate #: 85430-1017353- 011410US] entitled, “Thermal Control Device and Methods of Use,” deposited in, the entire contents of which are incorporated herein by reference for all purposes. It is appreciated that a thermal control device used in a TOS system according to some embodiments of the invention can include any combination of elements as described therein. VIII. C. 2. TEC project
[000207] In some embodiments, the thermal control device includes a first TEC having an active face and a reference face; a second TEC having an active face and a reference face; and a thermal interleaver disposed between the first and second TECs such that the reference face of the first TEC is thermally coupled with the active face of the second TEC through the thermal interleaver. In some embodiments, the thermal interleaver acts as a thermal capacitor. In some embodiments, the thermal control device includes a controller operatively coupled to each of the first and second TECs, the controller configured to operate the second TEC concurrent with the first TEC in order to increase speed and efficiency in the operation of the first TEC as a temperature of the active face of the first TEC changes from an initial temperature to a desired target temperature. In some embodiments, the first and second thermoelectric coolers are thermally coupled through a thermal capacitor with sufficient thermal conductivity and mass to transfer and store thermal energy in order to reduce the time when switching between heating and cooling, thus providing more thermal cycling faster and more efficient. In some embodiments, the device uses a thermocouple within the first thermoelectric cooling device and another thermocouple within the thermal capacitor layer and operates using the first and second closed control loops based on the temperature of the first and second thermocouples, respectively. In order to use the thermal energy stored in the thermal capacitor layer, the second control loop can be configured to advance or delay the first control loop. Using one or more of these aspects described herein, the modalities of the present invention provide a faster, more robust thermal control device to perform rapid thermal cycling, preferably in about two hours or less, even in problematic high temperature environments described above.
[000208] In some embodiments, the thermal control device includes a thermal capacitor formed from a thermally conductive material of sufficient mass to store sufficient thermal energy to facilitate the increased speed in switching between thermal cycles and efficiency in heating and cooling a TEC. In some embodiments, the thermal capacitor includes a material having a higher thermal mass than that of the active and reference faces of the first and second TECs, which can be formed from a ceramic material. In some embodiments, the thermal capacitor is formed of a copper layer with a thickness of about 10 mm or less, (for example, about 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 mm, or less). This configuration allows a thermal control device of relatively thin construction, planar so as to be suitable for use with a reaction vessel in a small size nucleic acid analysis device.
[000209] In some modalities, the thermal control device includes a first temperature sensor adapted to sense the temperature of the active face of the first TEC; and a second temperature sensor adapted to sense a temperature from the thermal capacitor. In some embodiments, the first and second temperature sensors are coupled with the controller such that the operation of the first and second TECs is based, at least in part, on an input from the first and second temperature sensors to the controller, respectively. In some embodiments, the second temperature sensor is embedded or at least in thermal contact with the thermally conductive material of the thermal capacitor. It is estimated that in any of the modalities described here the temperature sensor can be arranged in several other locations as long as the sensor is in thermal contact with the respective layer sufficiently to sense the temperature of the layer.
[000210] In some embodiments, the thermal control device includes a controller configured with a primary control loop in which the input of the first temperature sensor is provided, and a secondary control loop in which the input of the second temperature sensor is provided. The controller can be configured such that a bandwidth response from the primary control loop is faster in time (or slower) than a bandwidth response from the secondary control loop. Typically, both the primary and the secondary control loop are closed-loop. In some embodiments, the controller is configured to cycle between a heating cycle in which the active face of the first TEC is heated to a high target temperature and a cooling cycle in which the active face of the first TEC is cooled to a reduced target temperature . The controller can be configured such that the secondary control loop switches the second TEC between heating and cooling modes before the primary control loop is switched between heating and cooling in order to thermally charge the thermal capacitor. In some embodiments, the secondary control loop maintains a temperature of the thermal capacitor within about 40 ° C of the temperature of the active face of the first TEC. In some embodiments, the secondary control loop maintains a temperature of the thermal capacitor within about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 degrees C of the temperature of the active face of the first TEC. The controller can be configured such that the efficiency of the first TEC is maintained by operating the second TEC such that heating and cooling with the active face of the first TEC occurs at an elevation rate of about 10 ° C per second. Exemplary non-limiting elevation rates that can be obtained with the present invention include 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 ° C per second. In some embodiments, the high target temperature is about 90 ° C or higher and the reduced target temperature is about 40 ° C or less. In some embodiments, the elevated temperature is about 95 ° C and the reduced target temperature is in the range of about 60 ° C to about 75 ° C, including all temperatures between the ends of the range.
[000211] In some embodiments, the thermal control device also includes a heat sink coupled with the reference face of the second TEC to prevent thermal avalanche during cycling. The thermal control device can be constructed in a generally planar configuration and sized to correspond to a planar reaction chamber portion of a test cartridge reaction vessel. In some embodiments, the planar dimension has a length of about 45 mm or less and a width of about 20 mm or less, or a length of about 40 mm by about 12.5 mm, such as about 11 mm for 13 mm, so as to be suitable for use with a reaction vessel in a miniature PCR analysis device. The generally planar configuration can be configured and scaled to have a thickness of an active face from the first TEC to an opposite side of the heat sink of about 20 mm or less. Advantageously, in some embodiments, the thermal control device can be adapted to engage with a reaction vessel for the thermal cycling of the reaction vessel on a single side of it to allow the optical detection of a target test on the opposite side of the vessel reaction during thermal cycling.
[000212] In some embodiments, methods of controlling the temperature are provided here. Such methods include steps of: operating a first TEC having an active face and a reference face to heat and / or cool the active face from an initial temperature to a target temperature; and operating a second TEC having an active face and a reference face in order to increase the efficiency of the first TEC as the temperature of the active face of the first TEC changes from the initial temperature to the desired target temperature, the active face of the second TEC being thermally coupled to the reference face of the first TEC through a thermal capacitor. Such methods may also include steps of: operating the first TEC comprises operating a primary control loop having a temperature input from a temperature sensor on the active face of the first TEC, and operating the second TEC comprises operating a secondary control loop having a temperature input of a temperature sensor inside the thermal capacitor. In some embodiments, the method also includes: cycling between a heating mode in which the active face of the first thermoelectric device heats up to a high target temperature and a cooling mode in which the active face is cooled to a reduced target temperature; and to store thermal energy from thermal fluctuations between heating and cooling modes in the thermal capacitor, the thermal capacitor comprising a layer having increased thermal conductivity when compared to the active and reference faces of the first and second thermoelectric cooling devices, respectively.
[000213] In some embodiments, methods of controlling the temperature in thermal cycling include: cycling between a heating mode and a cooling mode of the second thermoelectric device concurrent with the cycling between the heating and cooling modes of the first thermoelectric device maintaining this the efficiency of the first thermoelectric device during cycling. In some embodiments, the controller is configured such that a bandwidth response from the primary control loop is faster than a bandwidth response from the secondary control loop. The controller can also be configured such that the cycling is timed by the controller to switch the second thermoelectric device between modes before changing the first thermoelectric device between modes in order to thermally charge the thermal capacitor. In some embodiments, the elevated target temperature is about 95 ° C or higher and the reduced target temperature is about 50 ° C or less.
[000214] In some embodiments, methods of controlling the temperature also include: maintaining a temperature of the thermal capacitor within about 40 ° C of the temperature of the active face of the first TEC by controlling the operation of the second TEC during the cycling of the first TEC in order to maintain an efficiency of the first TEC during cycling. In some embodiments, the efficiency of the first TEC is maintained by operating the second TEC such that heating and / or cooling with the active face of the first TEC occurs at an elevation rate of around 10 ° C per second or less. Such methods may also include: operating a heat sink coupled to the reference face of the second TEC during cycling with the first and second TECs in order to prevent the thermal avalanche.
[000215] In some embodiments, thermal cycling methods in a polymerase chain reaction process are provided here. Such methods may include the steps of: engaging a thermal control device with a reaction vessel having a fluid sample in it to perform a polymerase chain reaction to amplify a target polynucleotide such that the active face of the first TEC thermally engages the vessel reaction; and thermal cycling the thermal control device according to a particular protocol to amplify the target polynucleotide contained in the fluid sample. In some embodiments, engaging the thermal control device with the reaction vessel comprises engaging the active face of the first TEC against one side of the reaction vessel such that an opposite side remains uncovered by the thermal device to allow optical detection of the opposite side. In some embodiments, each of the heating mode and cooling mode uses one or more operating parameters, where the one or more operating parameters are asymmetrical between the heating and cooling modes. For example, each of the heating mode and cooling mode has a bandwidth and loop gain, where the bandwidth and loop gains of the heating mode and cooling mode are different.
[000216] In some embodiments, methods of controlling the temperature with a thermal control device are provided. Such methods include the steps of: providing a thermal control device with a first and second TEC with a thermal capacitor between them, where each of the first and second TECs has an active face and a reference face; warm the active face; cool the active face; heat the reference face; and cool the reference face. In some modalities, each of heating the active face and cooling the active face is controlled by one or more operating parameters. In some embodiments, the magnitude of one or more operating parameters is different during the heating of the active face when compared to the cooling of the active face.
[000217] In some embodiments, methods include testing the reliability between multiple thermal control devices by using an alternative accessory. Such methods include the steps of: alternating the thermal cycling between the thermal control device and a second or more thermal control devices, to effect the thermal cycling of a second or more reaction vessels by operating an accessory that alternates device positions thermal control and the second or more thermal control devices in an active location where the thermal cycling of the respective reaction vessel is carried out. In some embodiments, the accessory is a rotary axis with the thermal control device and the two or more thermal control devices distributed circumferentially around the outside of the axis such that the operation of the accessory comprises rotating the axis. VIII. C. 2. a. Example TEC Project Settings
[000218] FIG. 33A shows an exemplary thermal control device that includes a first TEC 811 (primary TEC) and a second thermal manipulation device such as secondary TEC 812 or thermal resistive element) thermally coupled through a thermal capacitor 813, also referred to as a thermal interleaver. The TECs are configured such that an active face 811a of the first TEC 811 is thermally coupled with a reaction vessel 33 to facilitate the control of thermal cycling in it. The device can optionally include a coupling accessory 819 to mount the device to the tube. In some embodiments, the device can be attached to an accessory that positions the device adjacent to the tube. The opposite reference face 811b of the first TEC is thermally coupled with an active face 812a of the second TEC 812 through the thermal capacitor layer. This configuration can also be described as the reference face 811b being in direct thermal contact with one side of the thermal capacitor layer 813 and the active face 812a being in direct thermal contact with the opposite side of the thermal capacitor layer 813. In some embodiments , the reference face 812b of the second TEC is thermally coupled with a heat sink 817 and / or a cooling fan 818, as shown in the embodiment of FIG. 33B. In this embodiment, the thermal control device 800 is configured such that it is thermally coupled along one side of a planar portion of the reaction vessel 33 in order to allow optical excitation from another direction (for example one side of the tube ) with an optical excitation means 910, such as a laser, and optical detection from another direction (for example an opposite side of the tube) with an optical detection means 920.
[000219] A thermocouple 816 is included in the first TEC 811 on or near the active face 81 la to allow precise control of the reaction vessel temperature. The temperature output of this thermocouple is used in a primary control loop 814 that controls heating and cooling with the active face 11a. A second thermocouple 816 'is included within or near the thermal capacitor layer and an associated temperature output is used in a second control loop 814' that controls heating and cooling with the active face 812a of the second TEC. In one aspect, the first control loop is faster than the second control loop (for example the second control loop is behind the first), which is responsible for the thermal energy transferred and stored within the thermal capacitor layer. By using these two control loops, the differential temperature between the active face 811a and the reference face 811b of the first TEC 811 can be controlled in order to optimize and improve the efficiency of the first TEC, which allows for faster and faster heating and cooling consistent with the first TEC, while the thermal capacitor allows faster switching between heating and cooling, as described here and demonstrated in the experimental results presented below.
[000220] Instead of connecting a standard heatsink to the ceramic plate opposite the reaction vessel, another TEC (secondary) is used to maintain a temperature within about 40 ° C of the active face of the primary TEC. In some modalities, two PID control loops (Derivative Integral Proportional gain) are used to maintain this operation. In some embodiments, non-PID control loops are used to maintain the temperature of the active face of the primary TEC. Typically, a fast PID control loop drives the primary TEC to a predetermined temperature setpoint, monitored by a thermistor mounted under the ceramic plate in contact with the reaction vessel. This loop operates at maximum speed to ensure that the control temperature can be reached quickly and accurately. In some embodiments, a second, slower PID control loop maintains the temperature for the bottom face of the primary TEC to maximize thermal efficiency (experimentally determined to be within ~ 40 ° C of the active face temperature). As discussed above, non-PID control loops can also be used to maintain the TEC temperature to maximize thermal efficiency. In some modalities, it is advantageous to moderate the interaction between the two control loops to eliminate one loop to control the other. It is also advantageous to cushion and store thermal energy from the first and / or second TEC by using the thermal capacitor layer to facilitate the quick change between heating and cooling.
[000221] Two exemplary non-limiting ways to achieve a quick and efficient exchange between heating and cooling as used in some embodiments of the invention are detailed here. First, the bandwidth response for the secondary control loop is intentionally limited to be much lower than the fast primary loop, a so-called "lazy loop". Second, a thermal capacitor is sandwiched between two TECs. Although it is desirable for the entire thermal control device to be relatively thin to allow use of the device in a portion of the reaction chamber of a reaction vessel, it is assessed that the thermal capacitor layer can be thicker as long as it provides mass and sufficient conductivity to function as a thermal capacitor for the TECs on each side. In some embodiments, the thermal capacitor layer is a thin copper plate about 1 mm thick or less. Copper is advantageous because of its extremely high thermal conductivity, although the thickness of 1 mm is experimentally determined to sufficiently cushion the two TECs while providing sufficient mass for the thin layer to store thermal energy to act as a thermal capacitor. Although copper is particularly useful due to its thermal conductivity and high mass, it is assessed that several other metals or materials having similar thermal conductivity and high mass properties can be used, preferably materials that are thermally conductive (even if less than each TEC ) and with a mass the same or higher than each TEC to allow the layer to operate as a thermal capacitor in the storage of thermal energy. In another aspect, the thermal capacitor layer can contain a second thermistor that is used to monitor the “rear” temperature (eg reference face) used by the secondary PID control loop. Both control loops can be digitally implemented within a single PSoC chip (Programmable System on Chip) that sends control signals to two bipolar Peltier current stocks. It will be assessed by the skilled person that in some embodiments, non-PSOC chips can be used to control, for example, programmable field gate arrays (FPGAs) and the like are suitable for use with the present invention. In some embodiments, the dual TEC module includes a heat sink to prevent thermal avalanche, which can be attached to the rear of the secondary TEC using, for example, thermally conductive epoxy silver. Alternative bonding methods and materials suitable for use with the invention are well known to those of skill in the art.
[000222] FIG. 33B shows a schematic of dual TEC design. The temperature of the PCR reaction vessel (measured by a thermistor, (16) (ellipse) is controlled by the primary TEC and controlled by a loop in the PSoC firmware. The optimal thermal efficiency of the primary TEC is maintained by a second thermistor (816 ') (ellipse) in thermal contact with a copper layer, which feeds into a secondary PsoC loop, controlling a second TEC. VIII. C. 2. b. Dual Dual TEC Manufacturing
[000223] FIG. 33C shows a dual TEC heating / cooling example module with a thermal control device 800 thermally engaged against a main face of the reaction vessel, an optical excitation block adjacent to a smaller face (e.g. edge) of the reaction vessel, and an optical detection block 920 against an opposite main face of the reaction vessel 33. In some embodiments, both the Primary and Secondary TEC (Laird, OptoTEC HOT20.65.F2A.1312, data sheet below) measure 13 (w) x 13 (I) x 2.2 (t) mm, and have a maximum thermal efficiency = 60%. In some embodiments, the planar area affected by the TEC module is combined with the GX reaction vessel. In some embodiments, it is configured to accommodate reaction vessels ranging from 25 pl to 100 pl.
[000224] FIG. 33B shows an exemplary dual TEC module for heating and cooling single side of a reaction vessel in a chemical analysis system. It is estimated that this design could be modified to provide dual TEC on both sides for double sided heating in some modalities. As can be seen, the heatsink includes a mini fan to flow heat and maintain TEC efficiency. The temperature of the primary TEC cycles (top) in the reaction vessel, monitored by a thermistor mounted on the underside of the ceramic in contact with the tube. The "rear" TEC maintains the temperature of an interstitial copper layer (using a thermistor) to ensure optimal thermal efficiency of the primary TEC. A heatsink with integrated mini fan keeps the entire module in thermal equilibrium.
[000225] In some embodiments, a small thermistor with +/- 0.1 ° C temperature tolerance is attached to the underside of the top face of the primary TEC using epoxy silver. This thermistor probes the temperature applied to the reaction vessel and is an input to the primary control loop in the PSoC, which controls the drive current for the primary TEC. The bottom surface of the primary TEC is connected to a 1 mm thick copper plate with epoxy silver. The copper plate has a slot containing a second thermistor TR136-170, wrapped with epoxy silver to monitor the “rear temperature,” the signal input to the secondary control loop on the PSoC. The secondary TEC, controlled by the secondary control loop, is then sandwiched between the copper plate and an aluminum heat sink. The heatsink is machined to an overall pressure = 6.5 mm, keeping the entire package <13 mm thick, and a planar size = 40.0 (length) x 12.5 (width) mm, required by the constraints of space within a small instrument. A 12 x 12 mm Sunon Mighty Mini Fan (data sheet below) is glued inside a machined insert on the heatsink where the TECs interact with the heatsink. Note that the mini fan does not need to directly cool the heat sink; a quiet, durable, inexpensive, low voltage (3.3 V max) brushless motor is sufficient to maintain the heatsink performance by removing surface hot air from the aluminum / air interface using shear flow, as opposed to direct air cooling (as in some conventional analysis devices).
[000226] The testing of prototype units can be used to determine whether the heating / cooling speed, thermal stability, robustness with increased ambient temperature, and overall system reliability are sufficient to meet the engineering requirement specifications. The thermal performance was shown to be acceptable such that the design goals are achieved for an exemplary reduced size system: smaller, robust, and inexpensive size (fewer parts needed than with two-sided heating / cooling). In addition, single-sided heating / cooling enables more efficient optical detection through the side of the reaction vessel.
[000227] FIG. 33C shows a CAD drawing of the dual TEC heating / cooling module, as well as the Excitation and LED Detection blocks, and the reaction vessel within an exemplary system. The reaction vessel is thermal cycling on one side (first main face of the reaction vessel) and the fluorescence detected through the opposite side (second main face of the reaction vessel). LED lighting remains through the edge (smaller face) of the reaction vessel. VIII. C. 2. c. Initial Heating / Cooling Performance
[000228] The heating and cooling performance of the exemplary TEC assembly was measured using an adapted accessory that securely holds the TEC assembly against a surface of a reaction vessel. Care was taken to thermally insulate the TEC assembly from the accessory by making it from thermally insulating Delrin. To mimic a thermal load from a PCR, the reaction vessel was filled with a fluid sample that was in secure contact with a fluorescent detection block on the surface of the tube opposite the TEC assembly. It should be mentioned that the temperature at the top TEC surface that contacts the pipe in this geometry was independently measured to be equal to or higher than the temperature measured at the primary TEC thermistor. Therefore, it is reasonable to use the temperature read from the primary TEC thermistor to initially characterize the thermal performance of the dual TEC heating / cooling system. Any divergence between the temperature of the thermistor and that of the reaction vessel can be characterized and adjusted using feedback loops between the primary TEC thermistor and the temperature of the fluid sample in the reaction vessel. In some embodiments, a fixture accessory is used to attach the thermal control device to a reaction vessel for thermal characterization. In one example, a reaction vessel can be filled with a fluid sample and secured to make thermal contact between the heating / cooling module and a face of the reaction vessel. The other side of the tube can be secured against a fluorescent detection block. An LED excitation block illuminates the solution through the edge of the tube. In some modalities, both excitation and detection are done through smaller tube faces.
[000230] In some embodiments, a PSoC control card uses PID control to maintain a temperature setpoint of the primary TEC thermistor and to provide dual polarity drive current for TEC devices (positive voltage when heating, negative voltage when cooling), and to power the mini fan. This PID loop has been tuned to maximize the performance of the primary TEC. A script was written to cite the tube's setpoint between high and low temperature extremes characteristic of PCR thermocycling. Specifically, the low temperature setpoint = 50 ° C, with a residence time of 12 seconds, starting once the measured temperature is within +/- 0.1 ° C for a 1 second. Similarly, the high temperature setpoint = 95 ° C for 12 seconds, starting once the temperature is maintained +/- 0.1 ° C from the set point for 1 second. The route cycled between 50 ° C and 95 ° C ad infinitum. The secondary control loop was also maintained within the same PSoC chip, reading the temperature of the secondary thermistor in thermal contact with the copper damper / thermal capacitor layer (see Fig. 33A) and acting on the secondary TEC. A different set of PID tuning parameters has been found to properly maintain the system's thermal performance by controlling the temperature of this copper layer, called the “rear” temperature. This control loop had a significantly lower bandwidth than the primary TEC control loop, as expected. The PSoC and associated program also allows multiple rear temperature setpoints, which are useful in the performance of the maximization elevation rate while keeping the primary TEC operating under optimally efficient thermal conditions. FIG. 34 shows an exemplary thermal cycle of a reaction vessel temperature, the traces measured for a thermal cycle of 50 ° C 95 ° C 50 ° C (primary trace) under closed loop control. Closed-loop heating and cooling rates are ~ 7 ° C / second. The control primary is the desired temperature setpoint of the thermal cycle (the square function of the time between 0 seconds and 20 seconds) and the primary trace is the measured temperature of the tube. As can be seen, the actual thermal cycle delays the desired thermal cycle indicated by the primary control function. It was determined that the thermal efficiency of the primary TEC was higher with a temperature differential between the tube and the rear of no higher than 30 ° C, so the rear temperature was controlled to be 65 ° C when heating up to maximum temperature (tube 95 ° C) and 45 ° C when cooling the tube to 50 ° C (rear stroke). Once the primary TEC rose to the highest temperature, the rear temperature would be slow and controlled to a lower temperature in anticipation of the next thermal cycle shown starting at about 37 seconds elapsed). This scheme is analogous to that used by the rear TEC to properly load a “hot spring” acting on the primary TEC, and is applicable for use with PCR systems, because the thermal profile to be applied for a particular PCR assay is known to priori by a trial designer. Note that the closed loop lift rate for stable and repeatable heating and cooling is ~ 6.5 seconds for the 45 ° C range, as shown for ten successive thermal cycles, as shown in FIG. 35, corresponding to a true closed loop elevation rate of ~ 7 ° C / second for both heating and cooling. Performance is maintained for all multiple cycles over the complete PCR thermocycling range.VIII. C. 2. d. Initial and Short-Term Reliability Experiments
[000234] A typical PCR assay has about 40 thermal cycles from the annealing temperature (~ 65 ° C) to the DNA denaturation temperature (~ 95 ° C) and back to the annealing temperature. To assess reliability, an exemplary thermal control module was cycled between 50 ° C (approximately the minimum temperatures used for PCR experiments) and 95 ° C, with a 10 second waiting time at each temperature to allow thermal equilibrium of the system.
[000235] FIG. 36A shows a comparison of the first and final 5 cycles of a 5,000 cycle test. Note that the time axis of the dash on the right is from a small data sampling range; 5,000 cycles took approximately 2 days. This module has since been cycled more than 10,000 times with maintained performance. As can be seen, thermal cycling performance for cycles 1 to 5 (left) remains constant after 5,000 cycles (cycles 4,995 to 5,000 on the right) and there is no change in thermal performance between the initial and final cycles. This is encouraging for two reasons. First, the closed loop parameters for rapid heating / cooling are quite stable with repeated thermal cycling. Even small thermal instability leads to trends in the temperature curves measured for both primary and rear TECs, quickly escalating to the thermal avalanche (which would induce a fault current due to excessive current in the firmware). Properly adjusted systems do not demonstrate this behavior, demonstrating the robustness of the system. Second, the thermal efficiency of the module is stable above 5,000 cycles. In fact, this unit was subsequently healed> 10,000 times without catastrophic or gradual erosion of performance. FIG. 36B shows thermal cycling performance for five cycles at the beginning of the thermal cycling and after two days of continuous thermal cycling. VIII. D. Thermal Modeling Method to Control Thermal Cycling
[000236] In another aspect, the thermal control device can be configured to control the temperature based on thermal modeling. This aspect can be used in a thermal control device configured to heat heating on one side or on two sides. In some embodiments, such devices include a first thermoelectric cooler and another thermal manipulation device, each being coupled to a controller that controls the first thermoelectric cooler in coordination with the thermal manipulation device to improve control, speed and efficiency of heating and cooling. / or cooling with the first thermoelectric cooler. It is assessed, however, that this aspect of thermal modeling can be incorporated into the controls of any of the configurations described here.
[000237] An example of such a method is illustrated in the model state diagram shown in FIG. 37. This figure illustrates a seven-state model for use with a single-sided version of the thermal control device. This model applies electrical theories to model the real-world thermal system of temperature that include the temperatures of the thermoelectric faces of the chiller, the reaction vessel or vessel, and the fluid sample within the reaction vessel. The diagram shows the seven states of the model and the three measured states used in the Kalman algorithm to arrive at an ideal estimate of the contents of the reaction vessel assuming that it is water.
[000238] In the circuit model of FIG. 37, capacitors represent the thermal capacitance of the material, the resistors represent the thermal conductivity of the material, the voltage in each capacitor and source represents temperature, and the current source represents the thermal energy input from the thermoelectric cooler (TEC) on the front, adjacent to the pipe face. In this mode, the inputs for the model are the temperature of the rear TEC which can be predicted from the model T1-T7, the heat input of the thermoelectric cooler on the front side (Watts), and the temperature of the “Block” that resides adjacent to the opposite vessel or pipe face. This completes the model portion of the algorithm. As previously mentioned, Kalman algorithms typically use a model in conjunction with measured signal / sensor signals that are also part of the model outputs. Here, the measured thermistor signals converted to temperature are used for the front side thermoelectric cooler, and also for the rear thermoelectric cooler. For the measured rear temperature, it is not an output of the model, but it is assumed that they are the same. One reason for this hypothesis is that Rl is negligible in terms of the overall thermal conductance. VIII. C. 2. e. Alternative TEC Projects
[000239] The variability in the construction of the module can cause slight differences in the performance of the device. For example, current modules are manually assembled, with machined heat sinks and interstitial layers of copper, and all components are joined together manually using conductive epoxy. Variation in epoxy thickness or the creation of small angles between components within the module's sandwich construction causes different thermal performance. Most significantly, thermistors are also attached to the ceramic using thermal epoxy. Small intervals between the thermistor and the ceramic lead to errors between the control and measured temperatures. Finally, it takes a long time to weld the small wires to make electrical contacts for the two TECs, two thermistors, and the fan power cables.
[000240] In some embodiments, the thermal device includes a heating and cooling surface (e.g. TEC device as described here) on each main face (opposite sides) of the reaction vessel. In such modalities, optical detection can be carried out along the smallest face (for example edges). In some embodiments, optical detection is performed along a first minor face and optical excitation is performed along a second minor face that is orthogonal to the first minor face. Such modalities can be particularly useful where heating and cooling of large volumes is required (100 to 500 μl of fluid sample).
[000241] In some embodiments, the thermal control device modules use an adapted Peltier device that contains an integrated surface mounted thermistor mounted on the underside of the ceramic plate in contact with the reaction vessel. A tiny packet thermistor 0201 (0.60 (length) x 0.30 (width) x 0.23 (thickness) mm) can be used to minimize convection within the Peltier device leading to temperature variation by limiting the thickness part. Also, because the thermal contact and the position of the surface-mounted thermistors can be precisely controlled, these parts will have very consistent differences, characterized between the measured and the actual ceramic temperature.
[000242] In some embodiments, the thermal control device may include adapted Peltiers designed to be fully integrated into a heating / cooling module using semiconductor mass production techniques (pick and place machines and reflux welding) . The interstitial copper substrate can be replaced with a Bergquist thermal interface PC board (1 mm thick copper substrate), which precisely controlled the copper thickness and panel dimensions. Bergquist substrates also provided connection cables for the rear thermistor and all electrical connections inside and outside the module. The rear Peltier will become a device similar to the one currently used. Finally, the entire TEC assembly can be encapsulated in silicone to make it water resistant. In some embodiments, an aluminum mounting bracket can also double as a heatsink. IX. Diagnostic Platform
[000243] FIG. 38 is a simplified block diagram illustrating an architectural overview of a diagnostic test system, according to some embodiments of the invention. As with all the FIGS shown here, various embodiments may differ from the examples shown. For example, some embodiments may combine, separate, add to, and / or omit components shown in FIG. 38. In addition, the functionality of each component can be provided by one or more devices (for example, computing devices) arranged in one or more geographic locations.
[000244] Although the figures may refer to an “Epsilon Instrument,” “Epsilon Hand Platform,” and specific remote services, several modalities that fall within the scope of the invention are not so limited. The techniques described here are more generally described, and can be used by any variety of medical, mobile or other computing devices, and remote servers. In addition, the specific software and functionality components described here can be replaced with software that works in a similar manner for various types. One of ordinary skill in the art will recognize some variations to the modalities illustrated and described below.
[000245] As illustrated in FIG. 38, the diagnostic test system can generally include three types of components: a diagnostic device (the “Epsilon Instrument Hardware,” also referred to here and in the figures as an “instrument” or “diagnostic device module” or “device diagnostics ”), a mobile device (the“ Epsilon Hand Platform ”), and remote services (referring to the illustrated“ Remote Xpert System ”and“ Remote Xpert + System ”). Detailed descriptions of these components are provided below. The diagnostic device and the mobile device can be placed in a point of care, such as a health clinic, hospital, or other facility, while remote services can be located in one or more remote locations. Depending on the desired functionality, and as indicated above, the modalities can use multiple diagnostic devices, mobile devices, and / or remote services.
[000246] The diagnostic devices illustrated in FIG. 38 comprise the Epsilon Instrument Hardware illustrated and the various software components illustrated therein, including the Epsilon Instrument Core Software, Epsilon XpertReporter Software, Epsilon Instrument Interface Software, and distributive testing !. These components can communicate with each other using various interfaces and application programming interfaces (APIs) as illustrated. As mentioned earlier, the diagnostic device can comprise a diagnostic test system having a combination of test and computational components configured to conduct diagnostic tests and deliver the resulting data to remote services via the mobile device. In some embodiments, the diagnostic device can additionally process and / or store test data from one or more test results. The components can be implemented, at least in part, using a combination of software and hardware, which can be incorporated into a computerized system (such as those described in relation to FIG. 53).
[000247] In some embodiments, the diagnostic device can allow the patient samples (specimen) to be processed without interference and provide both summary and detailed results of the test data to remote services. The interface software (shown as the “Epsilon Instrument Interface Software”) may allow the diagnostic device to communicate with the mobile device software (shown as the “Epsilon Handheld Software”) running on the mobile device. Communication can be done wirelessly using any of a variety of wireless technologies, such as near field communication (NFC), Bluetooth®, Wi-Fi, and the like.
[000248] By establishing this communication with the mobile device, the interface software can thus allow a user of the mobile device to control various characteristics of the diagnostic device. For example, using a graphical user interface (GUI) provided on a mobile device screen, the user may be able to control the device settings of the diagnostic device; start, pause, or cancel tests conducted by the diagnostic device; specify the remote services to which the diagnostic device sends data; specify the type, content, and / or format of the data; and the like. According to some modalities, the mobile device can additionally allow a user to access medical data and / or other data stored on the diagnostic device. In some modalities, however, the data accessed may not be stored on the mobile device, thereby helping to ensure that data security is not compromised if the mobile device is lost or stolen. This feature is advantageous, helping the system to satisfy and comply with the various laws, regulations and other privacy standards.
[000249] The level of control provided to a user by the interface software via the mobile device, may be dependent on an authorization level provided by the user and / or mobile device. A user with a higher level of authorization can, for example, access the characteristics of the diagnostic device to which a user with a lower level of authorization does not have access. The interface software can provide the authorization and / or authentication of the user and / or the mobile device before and / or during communication by requirement, for example, login information or similar unique data to help ensure the security of the system.
[000250] The diagnostic device can communicate with a plurality of mobile devices, and can do this at the same time (or substantially at the same time). As such, it can allow multiple users to control the diagnostic device. To do so, the interface software can provide authorization and / or authentication for each of the plurality of mobile devices. In some embodiments, where a diagnostic device is in active communication with a plurality of mobile devices, one of the mobile devices can be designed as the primary mobile device through which all data is sent to remote services. In other words, in some embodiments, although a diagnostic device can be controlled by a plurality of mobile devices, the diagnostic device can also be connected to a single primary mobile device through which the diagnostic device directs data to remote services.
[000251] The mobile device can comprise a mobile electronic device, such as a smartphone, tablet computer, laptop and the like. The mobile device software can run with an application on the mobile device, and can also be an agnostic of the mobile device's operating system (OS). As such, anyone from a wide variety of mobile devices may be able to function as the mobile device described in the modalities contained herein, since the mobile device software is installed on the mobile device and appropriate authentication is provided. As illustrated in FIG. 38, the mobile device can also be connected with a printing device, such as a standard thermal printer.
[000252] In some embodiments, the mobile device software may allow authorization and / or authentication of the mobile device with a plurality of diagnostic devices, such that a user can control a plurality of diagnostic devices at once with a mobile device single. In addition to providing control of the diagnostic device via the mobile device software, the mobile device can also allow the diagnostic device to communicate with remote services (for example, providing data to remote services) through a connection that allows data to communicate from the diagnostic device to the mobile device (for example, via NFC, Bluetooth, Wi-Fi, etc.) to be relayed to remote services using the mobile device's connectivity to a network wide area (WAN), which can use a cell phone (for example, third generation (3G), long-term evolution (ETE), etc.), satellite, and / or other wireless technologies.
[000253] More generally, the techniques described here can provide a diagnostic test system in which one or more diagnostic tests can be controlled with a mobile device using a local area network (FAN) based functionality on a database basis. pairs. This same protocol can be used for WAN communication for remote services discreetly on the mobile device. Thus, for this latter feature, the mobile device can become an autonomous router. Although the modalities described here describe the use of a mobile or “portable” device, other modalities may use computer systems that may not be considered mobile or portable, such as a personal computer. The characteristics of the mobile device and other computing devices described herein are described in greater detail below with reference to FIG. 53.
[000254] According to some modalities, the connection feature can provide connectivity between the diagnostic device and the remote services without any persistent data being stored on the mobile device. In other words, the mobile device may not know anything about the data being transferred. In some embodiments, for example, the mobile device can receive sensitive encrypted data, such as patient data, from the diagnostic device that is simply passed through the remote reporting system without being stored or deciphered by the mobile device. In such modalities, data security will therefore not be compromised if the mobile device is lost or stolen, thereby adding another layer of privacy protection to the system that can help the system comply with laws, regulations and other privacy standards. from the government. In addition, the functionality of the diagnostic test system can be restored in a relatively simple way by replacing the lost or stolen mobile device. With such functionality, the techniques described here can be used not only in a laboratory, but also in the field (for example, an Ebola clinic in a remote region in Africa) where a mobile device may be more susceptible to loss or theft.
[000255] Again referring to FIG. 38, remote services can be performed in the “cloud” by one or more servers, which can be located in one or more remote locations of the mobile device and / or diagnostic device. Remote services can obtain data from one or more diagnostic devices, synthesize the data, and store the data in a database. Remote services can obtain data not only from one or more diagnostic devices in a single location (for example, communicating via a particular mobile device), but also obtain information more widely from diagnostic devices at various facilities in various geographic locations being able to provide large-scale epidemiological data and to determine other valuable health and disease information among one or more populations.
[000256] In addition or alternatively, remote services can aggregate and process data and provide a viewing entity (such as a government agency) with a secure portal (accessible, for example, via the Internet) through which processed data can be evaluated in various ways (for example, lists, graphs, geographic maps, and the like). The way in which processed data is viewed is in accordance with the viewing entity's authorization level. Again, data sent to and processed by remote services may be encrypted (or otherwise securely transferred) and / or manipulated in a manner that is in accordance with applicable laws, regulations, standards, and / or other government requirements.
[000257] It will be understood that the components illustrated in FIG. 38 can communicate with each other using the wireless technologies mentioned above directly or as part of one or more broader data communication networks, such as the LAN and / or WAN described in the above modalities. The data communication network (s) may comprise any combination of a variety of data communication systems, for example, cable, satellite, wireless / cellular, or Internet systems, or others, using various technologies and / or protocols, such as radio frequency (RF), optics, satellite, coaxial cable, Ethernet, cellular, twisted pair, other wired and wireless technologies, and the like. The data communication network (s) may comprise packet and / or circuit type exchanges, and may include one or more open, closed, public, and / or private networks, including the Internet, depending on functionality, cost, security, and other desired factors. The remaining description and figures illustrate the various aspects of the diagnostic test system modality illustrated in FIG. 38. Although the particular hardware and software components are described with respect to the disclosed modality, the one of ordinary skill in the art will recognize that, in some modalities, some of such components may be replaced, replaced, omitted, and / or otherwise altered when compared to the other modalities. For example, Programmable Chip Systems (PSoC) can be replaced with multiple components to provide substantially the same functionality. One of ordinary skill in the art will be familiar with the various mixed and / or analog signal microcontrollers that are suitable for use with the invention. Representational State Transfer (REST) interfaces can be relocated and / or used in conjunction with other software structures and / or protocols where appropriate, such as Create, Read, Update and Delete (CRUD); Domain Application Protocol (DAP); Hypermedia as the State of Application Engine (HATEOAS); Open Data Protocols (OData); RESTful API Modeling Language (RAML); RESTful Service Description Language (RSDL); and the like. IX. B. Epsilon Instrument Core Software
[000258] As illustrated in FIG. 38, in some modalities Epsilon Instrument Core Software (also referred to as diagnostic test system software) may include a variety of software modules. Suitable modules that can be included in Instrument Core Software can include a Cellcore system operating module, a hardware state machine (HSM) module, an iCORE software module, a valve software module, a syringe / port, and / or a sonotrode ultrasonic software module. In some modalities, the Cellcore system operating module is a version of Linux and ancillary services being operated on the Cellcore processor. In some modalities, the HSM module can include all the specific software of the diagnostic device being operated on the Cellcore processor and outside a Java Virtual Machine (JVM). In some modalities, the iCore Software module includes all software being operated on the iCore PsoC. In some modalities, the Valve Software module includes all software being operated on the Valve PsoC. In some modalities, the Syringe / Port module includes all software operating the Syringe / Port PsoC. In some modalities, the sonotrode software module includes all software that operates on the sonotrode's PSoC.
[000259] In some modalities the Epsilon Instrument interface software may include an Epsilon Instrument REST interface module and an Epsilon Assay Runner Software module.
[000260] In some modalities, Epsilon Xpert Reporter Software operates as a Remote Xpert Software client and operates on the Epsilon Instrument Hardware Cellcore processor on the same JVM as the Epsilon Instrument Software interface.
[000261] Epsilon Instrument Hardware can be the physical subsystem that performs tests. In some embodiments, this subsystem can only include the instrument's hardware, with the software being operated on the instrument as a separate subsystem. IX. C. Mobile device
[000262] As illustrated in FIG. 38, in some embodiments the mobile device may include a variety of software modules. For example, the modes of the illustrated Epsilon Handheld Software may comprise an Android application, run by the mobile device, specifically designed to support the system illustrated in FIG. 38 when deployed in the field context. In some embodiments, an application for another operating system can be used. In some embodiments, the software may include all the features necessary to support performance tests on patients in the field using the diagnostic device, and / or the features to facilitate the Cepheid Service Department (or a service department from another supplier) ) support these instruments remotely.
[000263] In some modalities, the mobile device may comprise a standard Android portable target platform, selected to support the field context. IX. D. Xpert + Remote System
[000264] In some embodiments, the Xpert + Remote System illustrated in FIG. 38 can comprise a collection of web applications exposed as services to be used by the Xpert Remote System and Epsilon Handheld Software. REST and / or similar services (as previously described) can be used for internal communication within Remote Xpert +. In some embodiments, a limited number of Xpert + Remote System services can be exposed to external systems, such as Remote Xpert and Epsilon Handheld Software. According to some modalities, a primary role of Remote Xpert + may be to allow the central management of users, institutions, commands and kits. IX. E. Xpert Remote System
[000265] In some embodiments, the Xpert Remote System illustrated in FIG. 38 can comprise a collection of web applications used by institutions to manage their instruments and clinical data. Such institutions may include, for example, national or international agencies (for example, the World Health Organization), emergency response organizations, universities, hospitals and the like. In some embodiments, the Remote Xpert software may also include analysis software to analyze the input and / or output data. IX. F. Distributive Essay
[000266] In some embodiments, the components of a distributive assay embodiment of the diagnostic device illustrated in FIG. 38 can include a test header (summary information used to manage the test), a test definition (which can be, for example, a received file), and / or adaptation test UI (which defines the specific test UI as such as the specific preparation of the sample submission instructions. Such adaptation may be limited to the areas identified by the UI project, such as the sample preparation steps and / or specific assay help screens). In some modalities, the distributive test can optionally include the specific test software, which can allow the incorporation of new algorithms as necessary for future tests. This may require the software that runs the tests to support this type of extension. Additionally, in some embodiments, the distributive test may include localized portable test sources, as needed. This can include several sources used to implement the UI for a specific test. Examples include localized strings for supported languages, new graphic fonts such as icons if any, and / or any required help files (for example, Portable Document Format (PDF) of the packaging insert or training videos). It may also be mentioned that, in some modalities, localized sources may need to be separated into a “test language pack” or kit due to size restrictions (for example, localized training videos) and regional variations. IX. G. External Interfaces - Diagnostic device
[000267] In some embodiments, the diagnostic device illustrated in FIG. 38 can include one or more external interfaces. For example, the Epsilon Handheld App GUI can be a user interface on the mobile device that also acts as the diagnostic device's user interface. The Remote Xpert GUI can be a web-based user interface provided by Remote Xpert. Remote Xpert + GUI can be a web-based user interface provided by Remote Xpert +. In some modalities, this GUI may be accessible only by the entity that provides and / or maintains Remote Xpert +. In an additional or alternative way, the external interfaces can include SMS messages, which can be used to report the results to an institutional clearing house, and can be provided by the loader through the operating system of the mobile device. The diagnostic device can include a data transmission interface (the GX Streaming Data interface illustrated in FIG. 38) that allows a personal computer (PC) or other computing device to provide a view of the data, which can assist in development and debugging . As such, this interface may not be used when deployed in the field, in some modalities. IX. H. Internal Interfaces - Diagnostic device
[000268] In some embodiments, the diagnostic device illustrated in FIG. 38 can include one or more internal interfaces. For example, the Epsilon Instrument Hardware / Software interface can comprise an interface between the instrument hardware and the Epsilon Instrument Core Software. The GXIP + interface can comprise an interface provided by Epsilon Instrument Core Software and used by some software both in the context of clinical monitoring and in use in the field context. The Assay Runner Interface can be provided by the Epsilon Instrument Software interface and used by the Epsilon Assay Runner Software or similar testing software. The Instrument Persistence API can comprise an interface provided by the Epsilon Instrument Software interface and used by the Epsilon Xpert Reporter Software. IX. I. Mobile Interfaces Device
[000269] In some embodiments, the mobile device may include a variety of interfaces. For example, the Epsilon Instrument Services interface can comprise the primary interface provided by the Epsilon Instrument Software interface. For use in the field context, this can be the interface used by Epsilon Handheld Software to perform tests, obtain updates on instrument status, and other normal operations.
[000270] The Thermal Print Interface can comprise an interface provided by the optional thermal printer, which can be a standard model with a Wi-Fi network connection. This can allow Epsilon Handheld Software to print test results to the printer automatically or on the printer. a user's request after a test result is available. In some embodiments, printers that use other technologies (for example, ink, inkjet, etc.) can be used. The Android API Platform can comprise interfaces provided by the Android Operating System used to access services from the mobile device hardware and the network. As previously indicated, alternative modalities may include equivalent or similar components for alternative operating systems.
[000271] The coordination interface, which is illustrated in the embodiment of FIG. 38, provides coordination between mobile devices when multiple mobile devices are simultaneously active in a particular location, which can occur in busy sites when more than one user is working or when there is a standby mobile device that is active. The coordination interface can be implemented to cross-connect all modules to the functional control layer of the user interface on the mobile device. Purposes and functions allow multiple instruments to be controlled and monitored via the mobile device as stand-alone units, and provide workflow coordination between devices so that the operator can use the correct instruments to operate a given diagnosis. User-to-user instruments controlled by Wi-Fi can have specific control guaranteed by device and maintain the chain of custody and critical patient identification parameters. The resulting functionality allows a ratio of X: Y from mobile devices to diagnostic devices, where X is any number of mobile devices, and Y is any number of diagnostic devices. In some modalities, X and Y can be the same number. IX. J. Remote Service Interfaces
[000272] As shown in FIG. 38, remote services may include several interfaces, in some modalities. For example, the Epsilon Xpert Reporter Interface can comprise a collection of REST services that exposes the following capabilities: sending clinical data and / or synchronizing instruments. The Remote Xpert + Services Interface can comprise the REST services collection that exposes the following capabilities: kit management, user management, institution and site management, remote service commands, and / or instrument synchronization. IX. K. Clinical Laboratory Enhanced Amendments Waived Applications (CLIA)
[000273] In some embodiments, the core software interface of the diagnostic device of FIG. 38 can be used in a Clinical Laboratory Enhanced Amendments Waived Applications (CLIA). At this point, the diagnostic device can provide information to proprietary software running on a personal computer via an Ethernet connection. The alternative modalities may use other computer hardware and software and / or physical or wireless connections. Additional details regarding the GXIP + interface are provided below. IX. L. DIAGNOSTIC DEVICE - SOFTWARE COMPONENTS
[000274] FIG. 39 provides a logical view of the software executed by the diagnostic device, according to a modality. As illustrated, the software may include low-level drivers, including the Universal Serial Bus (USB) driver stack, SM I / F Bus, and Wi-Fi, Bluetooth, and USB dongle drivers. The application layer includes the operating system, as well as other applications. These applications can include a JVM having XpertReporter and Epsilon Rest interface components, a JVM having an Epsilon Assay Runner component, a port application having a DX Port component, and / or an Epsilon Instrument Core application having Gxlp +, Gx Transmission, USB PSoC, HSM Layer, and Battery I / F and power management components.
[000275] FIG. 40 is a block diagram of the Epsilon Instrument Core Architecture, according to some modalities. The block diagram illustrates the interaction of several Epsilon Instrument Core Architecture subcomponents including the NFC Interface, Gxlp + Interface, HSM. PSoC I / F, Gx transmission interface, Xpert Reporter / Epsilon REST interface, Epsilon Assay Runner, Port Dx, and USB NB, as described here.
[000276] In some modalities, the Gxlp + interface can be the primary component supporting the Gxlp protocol and can implement the required Dx service logic. The service logic can be adapted from legacy code 683xx as a basis for the “Northbound” instrument interface to ensure compliance with how tests and commands are performed. In some modalities, the Gxlp + Interface may also contain the adaptive layer connecting the Gxlp “Northbound” Legacy and “Southbound” Epsilon PSoC command interfaces. For the HBDC context, this can be the equivalent Dx interface used by the Epsilon Instrument Software interface to operate and monitor the assays.
[000277] In some modalities, the Port interface can be the component supporting the Gxlp ‘Discovery’ protocol. Once discovery is complete, this component can act as a router for remote Gxlp with base components and the Gxlp + interface. In some modalities, the Porta interface can be the discovery interface in Epsilon Instrument.
[000278] In some embodiments, the Gx transmission interface may be the primary component supporting the transmission of Epsilon Core state vectors to a remote client. During development, this interface can be used to support the Engendering Visualization Tool (VT) to monitor and tune the performance of PSoC, sonication and fluorimetric equivalence monitoring with respect to the Legacy system. In some embodiments, the Gx transmission interface allows the transmission of status change data to the mobile device.
[000279] FIG. 41 is a diagram illustrating various states of the HSM component, according to some modalities. As used in this disclosure, HSM can comprise the primary component that manages the state of the core instrument as well as substrates compatible with legacy DX. Additionally, the HSM can interact with the Gxlp component to allow or disable Gxlp commands depending on the current instrument's core state. As illustrated in FIG. 104, high-level states may include, in some modalities, POST - Power On Self Test, RECOVERY, IDLE, WAITING_FOR_CART, LOADING.CART, CARTRIDGE-LOADED, RUNNING-ASSAY, ABORTING, and CARTRIDGE-PRELOAD . It will be understood by one of ordinary skill in the art that the names of these states are provided as non-limiting examples, and the names and functionality of such states may vary, depending on the desired functionality.
[000280] FIG. 42 is a diagram illustrating components and internal interfaces of the instrument's core, according to some modalities. USB PSoC, for example, is an internal interface that can be a primary component supporting the “Southbound” interface to PSoC Components (Sonotrode, Port, Syringe, Valve and ICORE). The component can use USB 2.0 to create a ‘back data panel’ between the Cell Core and each PSoC. In some embodiments, during boot, PSoCs can be specified as loadable boot parameters, allowing new firmware to be programmed on each PSoC. In some embodiments, during normal operations, PSoCs can be specified as a command parameter and a State Change parameter. At this point, State Exchange can yield high speed PSoC data virtualization on Cell Core, allow monitoring and / or analysis of high speed PSoC data on Cell Core, and / or support the Gx Transmission component on Cell Core.
[000281] In some modalities, the instrument's external PSoC interfaces include Comms_Task, which can be a primary PSoC component supporting the “Southbound” interface between PSoC and Cell Core. This can also be a major Pn component of PSoC to create a “back data panel” between Cell Core and each PSoC. Additionally or alternatively, Comms_Task can be common to all PSoCs and can create and manage the Command Parameter Interface and USB State Change.
[000282] In some modalities, the Analytics Task comprises another external PSoC interface, which can be a primary PSoC component supporting the execution of PSoCs commands. In some modalities, the Analytics Task may include the common execution for the common commands shared by all PSoCs.
[000283] External Instrument PSoC Interfaces may also include ISRs, according to some embodiments of the invention. ISRs can allow common execution over time in PSoCs, and / or specific priority processes to support the bottom trajectory. IX. M. MOBILE DEVICE - SOFTWARE COMPONENTS
[000284] FIG. 43 is a block diagram illustrating the software components executed on a mobile device according to some embodiments of the invention. Here, the User Interface can follow common Android design patterns (or other OS). Activities can be the components that control the flow through the user interface and whose views are visible at any time. Visualizations can be the set of components that present information to the user. In some embodiments, most of the service logics can be contained in the Service Components shown in FIG. 43.
[000285] In some modalities, the User Interface can present the specific workflow required to perform the diagnostics based on cartridge in a stand-alone module and guarantees the accuracy and granularity of the patient data correlated with a specific diagnosis result. This includes the automated chain of custody of the sample, recording through a cartridge and in the instrument database.
[000286] According to some modalities, the Data Layer can include a Data Manager that provides all the persistence of the databases in the application. In some ways, the Mobile Database can be SQLite and can be encrypted using SQLCipher. The mobile database can include authorized users, credentials, and / or registration information. Because the mobile device can act as a standalone mobile router for transporting data for diagnostics, the data in the database can provide credentials and authentication to initiate and terminate transport connections. Additional information regarding the establishment of these connections is provided below. In some embodiments, the Data Layer can also provide two APIs to the rest of the system: a Data API for normal database objects, and a Registry API for registry key events. These APIs allow the mobile diagnostic device to connect to the remote database and transparently move diagnostics and other descriptive data through the diagnostic device's mobile device to the contextually correct Internet instance of RemoteXpert.
[000287] As illustrated in FIG. 43, modalities may include a Site Manager, which manages the state of the site and can maintain a list of known users, known diagnostic devices, known mobile devices, known tests, and / or known printers. When the mobile device is connected to the internet, the Site Manager can coordinate with Remote Xpert + to manage the remote service command for each site. The site manager can also interact with peer mobile devices as needed to manage the state of the site, and / or control user authentication.
[000288] Some modalities may also include Cloud Communications, which can provide access to Remote Xpert + Services, and / or a Configuration Manager, which manages the current configuration of the mobile device. In other words, the Cloud Communications component can establish and manage a two-way communication link with one or more remote services (for example, Remote Xpert + as illustrated in FIG. 38). Communications can be established through one or more APIs that can analyze, interpret, and transmit data (for example, in a proprietary format) in a standard readable format.
[000289] As further illustrated in FIG. 43, modalities can include an Instrument Manager, which manages the current list of instruments (medical diagnostic devices), and monitors the status of all instruments on the site. The Instrument Manager can also provide the ability to perform operations on the diagnostic device (s). Such operations may include, for example, running a test using a test, installing a test, installing a software update, performing diagnostics, and / or synchronizing the time reference. The Instrument Manager can also select an instrument when requesting a test and / or controlling errors reported by an instrument. According to some modalities, Instrument Communications can encapsulate the communication with the API REST of the medical diagnostic device.
[000290] Some modalities may also include a Test Manager who can manage the list of active tests, manage the workflow of performing a test, report test results after completion, and / or “archive” the test when no longer active. In some modalities, SMS communications can encapsulate the results report via SMS to an institutional clearinghouse. In some embodiments, printer communications can encapsulate the ability to print reports on a local thermal printer.
[000291] Generally speaking, the functionality of the mobile device may be dependent on the available software development kits (SDKs) and APIs for various platforms. For example, for Android SDK and APIs, application functionality is limited by the public Android SDK APIs. Still, the Android SDK and APIs can be used to provide access to NFC, Camera, GPS, SMS Messaging, and / or the network.
[000292] Some modalities can use SQLite and SQLCipher, which are the standard databases on Android. For example, SQLCipher is indicated by the Open Web Application Security Project (OWASP) as the preferred way to protect data on the phone. However, alternative modalities may use other platforms, such as iOS, Windows Mobile, and the like. In addition or alternatively, other data structures and / or query languages can be used, such as SQL, HTSQL, jOOQ and the like.
[000293] Some modalities may provide a third-party remote support application that allows remote viewing and, if available, the remote control of the mobile device provided by a third-party application. In some embodiments, mobile device software versions may use a related SDK to provide remote control of the application.
[000294] Among other things, the invention provides consolidation of control of the diagnostic device (s), management of the device (s), and LAN and WAN connectivity functions (LAN to WAN routing, as previously provided) described) on the mobile device, which are not used by controls and communications from the traditional medical diagnostic industry. The segmentation of the local control of the devices (the LAN layer) and the communication with each of the diagnostic instruments can be done at a point-to-point level (for example, via Wi-Fi) and manages the data flow for each instrument - both for the functional UI control interface and then the data path interface forwards RemoteXpert in the cloud.
[000295] The use of NFC on the mobile device, the NFC Adapter shown in FIG. 43, can be used to control the chain of custody for patient samples. The medical data provided for the claim may enable the ability to track these functions, which can be stored in a central cloud repository. The NFC can retain a cartridge containing a patient sample simultaneously with an NFC signal separate from the diagnostic device to ensure pairing for custody and reporting accuracy requirements.
[000296] FIG. 43 further illustrates the instrument communication component, which can establish a point-to-point Wi-Fi connection between the mobile device and the diagnostic device. The instrument communication component can allow multiple mobile devices to communicate with each other. In some modalities, the Portable Coordinator can provide coordination between multiple mobile devices via Wi-Fi. IX. N. REMOTE DIAGNOSTICS REPORT SERVICE - SOFTWARE COMPONENTS
[000297] FIG. 44 is a block diagram illustrating the software components performed by a remote diagnostic reporting service for medical diagnostics and epidemiology, in accordance with some embodiments of the invention. The remote diagnostics that report the service comprise, among other things, a web server, application server, database server, and file storage.
[000298] According to some modalities, the logical components of the remote diagnostics that report the service illustrated in FIG. 44 can be described as follows. Remote Xpert + Services can comprise REST web services to be used by the mobile device and Remote Xpert. The GUI application can comprise a web application to be used by an entity that provides service and support to the diagnostic test system. Private Services can comprise REST web services to be used by the GUI application. Core Service Logical Services may comprise REST web services containing all service logic. The Registration and Verification Service can comprise REST web services containing all registration and verification capabilities. Finally, the File Transfer Service can comprise a REST web service to summarize the file storage solution.
[000299] Among other benefits, the diagnostic reporting services illustrated in FIG. 44 allow automated remote diagnostics reporting reporting from a Class 2 or Class 3 medical diagnostic device into a remote database and presentation layer. Additionally, layered authentication allows for real-time remote control for debugging and diagnostics on a Class 2 or Class 3 remote medical diagnostic device over a WAN connection. This can be a service consolidation of discrete functions, including real-time diagnostics and data at time intervals specifically for application in a PCR-based diagnostic environment. IX. O. CONFIGURATION OF A DIAGNOSTIC TEST SYSTEM - WORKFLOW
[000300] An exemplary workflow for configuring a molecular diagnostic assay system such as the system shown in FIG. 38 can include the following stages. It will be understood that, while specific wireless technologies (for example, GSM, CDMA, Wi-Fi, etc.) are mentioned in the exemplary modalities provided below, additional or alternative technologies can be used, depending on the desired functionality.
[000301] First, mobile devices can be commissioned to work on the diagnostic test system. Here, mobile devices use an internet connection (for example, a cellular connection, Wi-Fi, etc.). For cellular connections (for example, GSM, CDMA, etc.), mobile devices may need to be provisioned by a charger. In addition, mobile devices can be configured through Remote Xpert-i-, which may require the download of an initial set of users, determining an authorized set of tests, and being assigned to a site.
[000302] Second, the Wi-Fi Network can be configured. At this point, a mobile device can be selected to become the Wi-Fi access point (for example, the bridge between the LAN and WAN networks), and other mobile devices can connect with the Wi-Fi access point. In some embodiments, all diagnostic devices can use a single mobile device acting as a Wi-Fi access point to access the Remote Xpert directly. Additionally or alternatively, one or more additional mobile devices can connect via Wi-Fi to the mobile device acting as the access point. If the mobile device acting as the access point fails, runs out of power, or is lost, a second mobile device can be used instead. Third, the diagnostic devices can be configured. In some ways, this process may involve sharing Wi-Fi information (for example, SSID and passphrase) and / or other information with the mobile device. The mobile device can also obtain identification information from the diagnostic device, such as MAC address, serial number, etc. Such information sharing can be conducted using point-to-point NFC. Additional diagnostic devices can be added in the manner above. If physical order is important, the UI of the mobile device can allow a user to specify where the new instrument should be placed. IX. P. DIAGNOSTIC TEST SYSTEM DATA FLOWS
[000304] FIGS. 45 to 46 are data flow diagrams illustrating different aspects of a diagnostic test system, according to some embodiments of the invention. As with other figures provided herein, FIGS. 45 to 46 are provided as non-limiting examples. The alternative modalities can include a feature in addition to that shown in the figure, and / or the feature shown in the figure can be omitted, combined, separated, and / or performed simultaneously. The means for carrying out the functionality of the blocks can include one or more hardware and / or software components, such as those shown in FIGS. 38 and 53. One of ordinary skill in the art will recognize some variations. IX. Q. High Level Data Flow Diagnostic Test System
[000305] FIG. 45 is a data flow diagram illustrating the high level data flow in a diagnostic assay system, such as that illustrated in FIG. 38. Here, the components of the diagnostic test system - remote services, mobile device, and diagnostic device - are represented as circles, and the data flow is represented as arrows.
[000306] The data flow can start with the mobile device by sending a request for the location configuration to the remote services (1). The request can be made when the mobile device is in a new location where the diagnostic device is located. As indicated in FIG. 45, the request may only need to be made once per location.
[000307] The remote services then respond to the location configuration (2), and the remote services and mobile device change the configuration description (3). As previously indicated, this involves downloading data from remote services to the mobile device, an initial set of users, determining an authorized set of tests, and more. Remote services can also provide operational updates (4) to the mobile device.
[000308] The mobile device can then engage in a configuration process with the diagnostic device. In this process, the mobile device provides the registration of the diagnostic device (5), an operational update (6) to the diagnostic device.
[000309] Once configured, the diagnostic device can receive operating instructions from the mobile device. The mobile device can then provide device commands (7) to the diagnostic device, which can be based on user input. As previously indicated, such commands can include, for example, running a test using a test, installing a test, installing a software update, performing diagnostics, and / or synchronizing the time reference. The diagnostic device can provide command responses (8), such as validations, status updates, and the like.
[000310] Where device commands (7) resulting in the execution of medical diagnostics, the diagnostic device can then provide encrypted medical diagnostic results (9) to remote services. As previously indicated, the mobile device can provide an access point through which the diagnostic device can send the results of encrypted medical diagnostics (9). However, the mobile device may not decode or store the data. As such, according to some modalities, the mobile device simply acts as a conduit through which the results of encrypted medical diagnostics (9) can be reported to remote services. In some modalities, the results of encrypted medical diagnostics (10) can be sent to the mobile device and stored. (As previously discussed, in some modalities, the data may not be stored on the mobile device. In such modalities, the mobile device may send the data to another device - for example, a LAN storage device, a computer, etc. - for storage.) Depending on the desired functionality, the results of encrypted medical diagnostics (10) sent to the mobile device can be the same or different from those sent to remote services. IX. A. Mobile Device Detailed Flow Data
[000311] FIG. 46 is a data flow diagram illustrating a more detailed data flow in which the components of the mobile device - WAN interface component, medical diagnostic logic, and LAN interface component - are represented separately.
[000312] Similar to the flow of FIG. 45, the flow shown in FIG. 46 can begin with a configuration process between the mobile device and the remote services. Here, the medical diagnostic logic sends a request for the local configuration (1,1) to the WAN interface component, which then sends a request for local configuration (1,2) to the remote services. The remote services respond by providing the local configuration (2.1) to the WAN interface component, which provides the local configuration (2.2) to the medical diagnostic logic. The configuration description is then exchanged between the remote services and the WAN interface component (3.1), the WAN interface component and medical diagnostic logic (3.2), medical diagnostic logic and the LAN interface component (3, 3), and LAN interface component and medical diagnostic device (3,4). Operational updates are then passed from remote services to the WAN interface component (4.1) and from the WAN interface component to medical diagnostic logic (4.2).
[000313] The diagnostic device configuration can include the medical diagnostic record device (5.1), (5.2), using medical diagnostic logic, LAN interface component, and the device. These components also pass the operational updates (6.1), (6.2) of the medical diagnostic logic to the diagnostic device.
[000314] Command devices (7.1), (7.2) can then be sent from medical diagnostic logic to the diagnostic device, and command responses (8.1), (8.2) can be sent again from the diagnostic device to the medical diagnostic logic.
[000315] The encrypted device results (9.1), (9.2) can be sent from the diagnostic device to the LAN interface component and then straight to the WAN interface component without going through the medical diagnostic logic. The results of encrypted diagnostics (9.3) can then be sent to remote services. As previously discussed, the results of encrypted diagnostics (10.1), (10.2) can be separately sent to a medical diagnostic logic, which can then send them to an encrypted diagnostic results store (10.3) . Depending on the desired functionality, this storage can be separated from the mobile device. The results of encrypted diagnostics (11.1), (11.2) can also be sent from the medical diagnosis logic of the remote services, via the WAN interface component.
[000316] In some modalities, remote services may request a diagnosis. As illustrated, remote services request a diagnosis (12.1), (12.2), (12.3), (12.4) which is relayed to the diagnostic device. This can induce a diagnostic response (13.1), (13.2), (13.3), (13.4) that is relayed to remote services. IX. S. WORKFLOWS OF THE DIAGNOSTIC TEST SYSTEM
[000317] FIGS. 47 to 52 are flow maps illustrating the functions of different aspects of a diagnostic test system, such as that illustrated in FIG. 38, according to some embodiments of the invention. As with other figures provided herein, FIGS. 47 to 52 are provided as non-limiting examples. Alternative embodiments may include functionality in addition to that shown in the figure, and / or the functionality shown in the figure may be omitted, combined, separated, and / or performed simultaneously. The means for realizing the functionality of the blocks can include one or more hardware and / or software components, such as those shown in FIGs. 38 AND 53. The one with skill in the technique will recognize some variations. IX. T. Network Workflow Location Configuration
[000318] FIG. 47 is a data flow diagram illustrating the process for a local configuration of a diagnostic test system, according to a modality. The means for making one or more blocks illustrated in FIG. 47 may include remote services as described herein.
[000319] The process can start when a mobile device requests the location configuration. As previously explained, the data flows of the examples for such a request are illustrated in FIGS. 45 and 46. If local configuration is available, it is provided by remote services. If not, the remote services return an error. IX. U. Operational Updates Network Workflow - Mobile
[000320] FIG. 48 is a data flow diagram illustrating the process for providing operational updates to a mobile device in a diagnostic test system, in accordance with some embodiments of the invention. The means for making one or more blocks illustrated in FIG. 48 may include remote services and / or mobile devices as described herein.
[000321] The process can start when a locally configured mobile device connects to remote services. The remote services then obtain a description of the operational description of the mobile device. If the description matches the configuration of the required mobile device, the process can then end. Otherwise, remote services send an operational configuration update to the mobile device. IX. V. Operational Updates Network Workflow - Diagnostic Device
[000322] FIG. 49 is a data flow diagram illustrating the process for providing operational updates to a diagnostic device in a diagnostic test system, according to some modalities. The means for making one or more blocks illustrated in FIG. 49 may include the mobile device and / or diagnostic device as described herein.
[000323] The process can start when the mobile device obtains a description of the diagnostic device configuration from the diagnostic device. If the configuration of the diagnostic device is correct, the process can end. Otherwise, the mobile device can send an operational configuration update to the diagnostic device. IX. W. Remote Diagnostics Network Workflow
[000324] As discussed above in relation to FIG. 46, remote services can request diagnostic information remotely. FIG. 50 is a data flow diagram of such a process in a diagnostic test system, according to one embodiment. The means for making one or more blocks illustrated in FIG. 50 may include the remote services, mobile device, and / or diagnostic device as described herein.
[000325] The process can start when the remote services request diagnostic information. The mobile device receives the request for diagnostic information. If the diagnostic request is for the mobile device, the mobile device will perform the diagnosis on the requested mobile device and send the diagnostic information from the mobile device to the remote services. Otherwise, the diagnosis request is sent by the mobile device to the specified diagnostic device (which can be one of several on the site and / or linked communicatively with the mobile device). The diagnostic device then performs the requested diagnostics, and sends the diagnostic information to the mobile device. Finally, the mobile device sends diagnostic information from the diagnostic device to remote services. IX. X. Medical Diagnostic Device Command Network Workflow
[000326] FIG. 51 is a data flow diagram illustrating the process for providing diagnostic device commands in a diagnostic test system, in accordance with some embodiments of the invention. The means for making one or more blocks illustrated in FIG. 51 may include the mobile device and / or diagnostic device as described herein.
[000327] The process can start with the mobile device by sending a command to a diagnostic device. The diagnostic device then processes the received command. Finally, the diagnostic device sends the response to the mobile device. [0006] IX. Y. Diagnostic Device Registration Network Workflow
[000328] FIG. 52 is a data flow diagram illustrating the process for providing the registration of the diagnostic device on a network of a diagnostic test system, according to some embodiments of the invention. The means for making one or more blocks illustrated in FIG. 52 may include the mobile device and / or the diagnostic device as described herein.
[000329] The process can start when the mobile device inquires the diagnostic device regarding the physical network identifier of the device, such as a MAC address. The mobile device then provides information to the network to the diagnostic device as previously described here. Such information may include an SSID, username, and the like. In some modalities, as previously described, the communication between the mobile device and the diagnostic device at this point can be via NFC and / or other wireless technologies. The diagnostic device then connects to the network, and the mobile device assigns a local identifier to the diagnostic device. IX. Z. COMPUTERIZED SYSTEM
[000330] FIG. 53 is an exemplary illustration of a computerized system 5300, which can be incorporated, at least in part, into the devices and components of the diagnostic test system shown in FIG. 38, including the diagnostic device (Instrument Epsilon), mobile device (Epsilon Hand Platform), and / or remote services (Remote Xpert System and Remote Xpert + System). FIG. 53 provides a schematic illustration of a computerized system 5300 that can perform the methods provided by various embodiments of the invention. It should be mentioned that FIG. 53 it is only intended to provide a generalized illustration of various components, any or all of which can be used as appropriate.
[000331] The computerized system 5300 is shown to comprise hardware elements that can be electrically coupled via a 5306 bus (or may be in communication in another way, as appropriate). The hardware elements may include a processing unit, such as a 5310 processor (s), which may include, without limitation, one or more general-purpose processors, one or more special-purpose processors (such as processing chips). digital signal, graphics acceleration processors, and / or the like), and / or other processing means; one or more 5315 input devices, which may include, without limitation, a mouse, keyboard, camera, microphone, touch screen, medical test hardware and / or diagnostic components, and / or the like; and one or more 5320 device outputs, which may include, without limitation, a screen device, a printer, and / or the like.
[000332] The 5300 computer system may also include (and / or be in communication with) one or more 5325 non-transitory storage devices, which may include, without limitation, accessible local and / or network storage, and / or may include , without limitation, a disk drive, a drive arrangement, an optical storage device, a solid state storage device, such as a random access memory (“RAM”), and / or a read-only memory ( “ROM”), which can be programmable, flashable, and / or others. Such storage devices can be configured to implement any appropriate data storage, including without limitation, various file systems, database structures, and / or the like.
[000333] In some embodiments, the 5300 computer system may include a 5330 communications subsystem, which may include without limitation a modem, a network card (wireless or wired), an infrared communication device, a wireless communication device wire, and / or a chipset (such as an NFC transmitter, a Bluetooth device, an 802.11 device, a Wi-Fi device, a WiMax device, a cellular communication receiver, etc.), and / or similar. The 5330 communications subsystem can include one or more inbound and / or outbound communication interfaces to allow data to be exchanged with a network, other computer systems (for example, using point-to-point communication, as described here) , and / or any other electrical device described herein. In some embodiments, the computerized system 5300 will comprise a working memory 5335, which may include a RAM or ROM device, as described above.
[000334] The 5300 computer system may comprise software elements, shown to be correctly located within the 5335 working memory, including a 5340 operating system, device drivers, executable libraries, and / or other code, such as one or more programs 5345 applications, which can comprise computer programs provided by various modalities (for example, mobile device software, interface software, etc.), and / or can be designed to implement software methods and / or architecture, as here described. Just by way of example, the methods and / or architecture provided in other figures attached to them, can be implemented as code and / or instructions executable by a computer (and / or a processing unit inside a computer); in one aspect, then, such codes and / or instructions can be used to configure and / or adapt a general purpose computer (or other device) to perform one or more operations according to the methods described.
[000335] A set of these instructions and / or code can be stored on a non-transitory computer-readable storage medium, such as the 5325 storage device (s) described above. In some embodiments, the storage medium may be incorporated into a computerized system, such as a 5300 computerized system. In some embodiments, the storage medium may be separated from a computerized system (for example, a removable medium, such as a disk optical), and / or provided in an installation package, such that the storage medium can be used to program, configure, and / or adapt a general purpose computer with the instructions / code stored therein. These instructions may take the form of executable code, which is executable by the 5300 computer system and / or may take the form of the source and / or installable code, which, when compiling and / or installing on the 5300 computer system (for example, using any one of a variety of commonly available compilers, installation programs, compression / decompression utilities, etc.), then takes the form of executable code.
[000336] It will be evident to those skilled in the art that substantial variations can be made according to specific requirements. For example, custom hardware can be used, and / or particular elements can be implemented in hardware, software (including portable software, such as applets, etc.), or both. The connection to other computing devices such as network input / output devices can be used.
[000337] Some embodiments can use a computerized system (such as the computerized system 5300) to carry out the methods according to some modalities of the invention. In some embodiments, some of all procedures for such methods are performed by the 5300 computer system in response to the 5310 processor (s) executing one or more sequences of one or more instructions (which can be incorporated into the 5340 and / or other code, such as an application program 5345) contained in working memory 5335. Such instructions can be read in working memory 5335 from another computer-readable medium, such as one or more of the device (s) ( s) storage 5325. Just by way of example, the execution of the instruction sequences contained in the working memory 5335 can cause the processor (s) 5310 to perform one or more procedures of the methods described herein. Additionally or alternatively, the portions of the methods described here can be performed using specialized hardware.
[000338] The terms "machine-readable storage medium" and "computer-readable storage medium," as used herein, refer to any storage medium that participates in providing the data that makes a machine operate in a specific way. In some modalities implemented using the 5300 computerized system, several computer-readable means may be involved in providing instructions / code to the 5310 processor (s) for execution and / or can be used to store and / or load such instructions / code. In some embodiments, a computer-readable storage medium is a physical and / or tangible storage medium. Such a medium may take the form of a non-volatile medium or a volatile medium. Non-limiting examples of non-volatile media may include optical and / or magnetic disks, such as the 5325 storage device (s). Non-limiting examples of volatile media may include, without limitation, dynamic memory , such as working memory 5335.
[000339] Common non-limiting forms of physical and / or tangible computer-readable media may include, for example, a floppy disk, floppy disk, hard disk, magnetic tape, or any other magnetic medium, a CD-ROM, any other optical medium, a RAM, a PROM, EPROM, a FLASH-EPROM, any other chip or memory cartridge, or any other medium from which a computer can read instructions and / or code.
[000340] Various forms of computer-readable media can be involved in loading one or more sequences of one or more instructions to the 5310 processor (s) for execution. Just by way of example, instructions can initially be carried out on a magnetic disk and / or an optical disk on a remote computer. A remote computer can load the instructions into its dynamic memory and send the instructions as signals about a transmission medium to be received and / or executed by the 5300 computer system.
[000341] The 5330 communications subsystems (and / or components thereof) will generally receive signals, and the 5306 bus can then load the signals (and / or the data, instructions, etc. loaded by the signals) into the 5335 working memory, from which the processor (s) 110 retrieve and execute the instructions. Instructions received by the 5335 working memory can optionally be stored on a 5325 non-transitory storage device before or after execution by the 5310 processor (s). IX. AA. PROCESS FLOW OF THE MANAGEMENT OF A DIAGNOSTIC TEST SYSTEM
[000342] FIG. 54 is a 5400 flow diagram of a method of administering a diagnostic test system with a mobile device, according to some embodiments of the invention. As with the other figures provided here, FIG. 54 is provided as a non-limiting example. Some modalities may include functionality in addition to that shown in the figure, and / or the functionality shown in one or more of the blocks in the figure can be omitted, combined, separated, and / or performed simultaneously (or in close temporal proximity). The means for carrying out the functionality of the blocks can include a mobile device as described herein, which can implement one or more hardware and / or software components, such as those shown in FIG. 53. One of ordinary skill in the art will recognize some variations that are suitable for use with the invention as disclosed herein.
[000343] In block 5410, the mobile device receives user input to control the functionality of a diagnostic device. As previously described, the mobile device can run a software application that provides a GUI with which a user can control various functions of the diagnostic device, such as settings for the diagnostic device management device; start, pause, or cancel medical tests conducted by the diagnostic device; specify the remote services to which the diagnostic device sends data; specify the type, content, and / or format of the data; and the like. In block 5420, in response to receiving user input, the mobile device sends control information to the diagnostic device. If the mobile device is communicatively connected with a plurality of diagnostic devices, the mobile device may first need to select or identify the diagnostic device from a plurality of diagnostic devices.
[000344] In the block, the mobile device receives data from the diagnostic device. The data received may correspond to the type, content, and / or format of the data specified in block 5410 (if such characteristics have been specified). However, as indicated, the mobile device can act simply as a device passthrough through which the diagnostic device can communicate with a remote server (for example, one or more remote services as shown in FIG. 101). In other words, the mobile device can act as a transparent bridge, connecting a LAN (which can be connected point-to-point, as described here) to a WAN. But, as specified in block 5440, the received data can be relayed to the server without storing or decrypting the data, thereby helping to ensure that the patient's sensitive data is not compromised by the mobile device.
[000345] The methods, systems, and devices disclosed above are examples. Various configurations can omit, replace, or add various procedures or components as appropriate. For example, in alternative configurations, the methods can be performed in a different order than described, and / or several stages can be added, omitted and / or combined. In addition, the features described with respect to some configurations can be combined into several other configurations. The different aspects and elements of the configurations can be combined in a similar way. In addition, the technology involves and comments on some of the elements as described are provided as non-limiting examples and thus do not limit the scope of the disclosure or claims.
[000346] Specific details are given in the description to provide a complete understanding of exemplary configurations (including implementations). However, configurations can be practiced without these specific details. For example, well-known circuits, processes, algorithms, structures, and techniques can be shown without unnecessary details in order to avoid obscuring the settings. This description provides exemplary configurations that do not limit the scope, applicability, or configurations of the claims. Instead, the preceding description of the settings will provide those skilled in the art with a description that allows you to implement the described techniques. Several changes can be made to the function and arrangement of the elements without breaking the spirit or scope of the disclosure.
[000347] In addition, configurations can be described as a process that is represented as a flow diagram or block diagram. While each can describe operations as a sequential process, some of the operations can be performed in parallel or concurrently. In addition, examples of the methods can be implemented with hardware, software, firmware, middleware, microcode, hardware description languages, or any combination of these. When implemented in software, firmware, middleware, or microcode, program code or code segments to perform the necessary tasks can be stored in a non-transitory, computer-readable medium such as a storage medium. Processors can perform the tasks described.
[000348] The terms "e" and "or" as used herein, can include a variety of meanings that are also expected to depend at least in part on the context in which such terms are used. Typically, "or" if used to associate a list, such as A, B, or C, is intended to mean A, B, and C, used here in an inclusive sense, as well as A, B, or C, used here exclusive. In addition, the term "one or more" as used herein can be used to describe any aspect, structure, or feature in the singular or can be used to describe some combinations of aspects, structures or features. However, it must be mentioned that this is merely an example and the main subject claimed is not limited to this example. In addition, the term “at least one of” if used to associate a list, such as A, B, or C, can be interpreted to mean any combination of A, B, and / or C, such as A, AB, AA , AAB, AABBCCC, etc.
[000349] Having described several exemplary configurations, several modifications, alternative constructions, and the like can be used without breaking the spirit of the invention. For example, the above elements can be components of a larger system, where other rules can take precedence over or otherwise modify the application of the invention. In addition, several steps can be performed before, during, or after the above elements are considered. Consequently, the above description does not compromise the scope of the claims. All patents, patent applications, and other publications cited in this application are incorporated by reference in their entirety for all purposes.

权利要求:
Claims (25)
[0001]
1. Diagnostic testing system adapted to receive a test cartridge, the system characterized by the fact that it comprises a door opening / closing system and a cartridge loading system comprising: a brushless DC motor (BLDC) coupled with operative mode to that; a door opening / closing mechanism cooperatively coupled with a cartridge loading mechanism and driven by a reversible transmission mechanism, a system chassis for diagnostic testing; a movable door in relation to the system chassis for diagnostic testing between a closed position and an open position, where the door is operable between the open and closed position by the BLDC motor via the reversible transmission, where the end displacement position top of the reversible transmission corresponds to the open position of the door and the displacement position of the base end corresponds to the closed position of the door; a cartridge loading mechanism configured to engage and admit a sample cartridge within the system for diagnosis, wherein the cartridge loading mechanism is operatively coupled with the BLDC engine via the reversible transmission; where the BLDC motor is configured to: operate the reversible transmission based on a current measurement of the BLDC motor, and current measurements are associated with reverse drive events against the reversible transmission at the top and bottom offset positions base; detecting a first reverse drive event against reversible transmission; and based on the detection of the first reverse actuation event, terminate the operation of the BLDC motor to place the door in an open position, and place the cartridge loading mechanism in position to engage and admit the sample cartridge into the system for diagnosis .
[0002]
2. System, according to claim 1, characterized by the fact that the reversible transmission comprises a lead screw driven by the BLDC engine, in which the lead screw is reversible.
[0003]
3. System according to claim 2, characterized by the fact that a bridge is threaded to the lead screw.
[0004]
4. System according to claim 3, characterized by the fact that a first and a second elongated easel portion are connected to the bridge, in which the first and second elongated easel portions are both movable between the positions of top and bottom end displacement.
[0005]
5. System according to claim 4, characterized in that the first and second elongated easel portions include first and second easels respectively.
[0006]
6. System according to claim 5, characterized by the fact that the first and the second elongated easel portions additionally include, respectively, the first and second meat paths, optionally the first and second meat paths are mobilely attached to meat followers of first and second cartridge loading arms.
[0007]
7. System according to claim 5, characterized by the fact that it additionally comprises first and second differential pinions engaged respectively with the first and second easel portions, still optionally comprising: first and second door gears driven respectively by the first and second pinions, where the door includes first and second door frames engaged with the first and second gears respectively.
[0008]
8. System according to claim 1, characterized by the fact that the BLDC motor does not include any encoding hardware and the reversible transmission does not include any position sensors.
[0009]
9. System according to claim 1, characterized by the fact that the reversible transmission is coupled to a cartridge loading mechanism, and in which the force applied to the cartridge loading mechanism by a cartridge inserted in the door reverses the transmission reversible, and said force is detected as a torque applied to the reversible transmission.
[0010]
10. System, according to claim 1, characterized by the fact that it additionally comprises: a system for operating a syringe drive for a system for diagnostic testing; a brushless DC motor (BLDC) coupled to the system chassis for diagnostic testing; a reversible lead screw operable by the BLDC engine; a plunger rod operable by the lead screw to engage a removable test cartridge, in which the BLDC motor is configured to operate the lead screw based on monitoring current absorption from the BLDC motor, the current being associated with changes in pressure inside the removable test cartridge.
[0011]
11. System, according to claim 10, characterized by the fact that any of the: the lead screw is not associated with any position sensor; the BLDC engine does not include any encoder hardware; wherein the plunger rod is coupled to the lead screw by a side arm, optionally the plunger rod is operable to engage with a plunger tip of a removable test cartridge; and the BLDC motor is configured to change the operation to change the pressure inside the removable test cartridge based on detecting the change in current.
[0012]
12. System according to claim 1, characterized by the fact that it additionally comprises a valve actuation mechanism comprising: a valve actuation mechanism chassis; a brushless DC motor (BLDC) coupled to the chassis, where the BLDC motor comprises a plurality of hall effect sensors and does not include any encoder hardware; a transmission coupled to the BLDC engine; and a valve drive coupled to the transmission, the valve drive being configured to rotate positions of a valve body of a removable test cartridge, where the position of the valve drive outlet is determined based on analysis of a sinusoidal signal generated by the hall effect sensors.
[0013]
13. System according to claim 12, characterized by the fact that either: the transmission comprises a first series of helical gears directly attached to an output shaft of the BLDC motor, and a second series of helical gears coupled between the first series of helical gears and the valve drive output; the BLDC engine located on the bottom side of the valve drive chassis and the valve drive outlet is located on the top side of the valve drive chassis; valve drive comprising a turntable; BLDC motor configured to monitor cartridge integrity based on current measurements from a BLDC motor bridge circuit, current absorption measurements are associated with events that indicate loss of removable test cartridge integrity; and the BLDC motor configured to initiate and centralize the position of the valve actuation output, performing a centralization protocol based on the sinusoidal signal generated by the hall effect sensors.
[0014]
14. Method for operating a diagnostic test system that has a door opening / closing system and cartridge loading system, characterized by the fact that it comprises: receiving a command to open a cartridge receiving door from the system for testing diagnosis to accept a sample cartridge; operate a brushless DC motor (BLDC) coupled to a reversible transmission to open the door from a closed position, the reversible transmission being operationally coupled to the door and a cartridge loading mechanism configured to engage and admit the sample cartridge within the system for diagnosis; detecting a first reverse triggering event that occurs against reversible transmission; based on the detection of the first reverse actuation event, terminate the operation of the BLDC motor that places or keeps the door in an open position, and place the cartridge loading mechanism in position to engage and admit the sample cartridge into the system to diagnosis.
[0015]
15. Method, according to claim 14, characterized by the fact that the BLDC motor does not include any encoding hardware and the reversible transmission does not include any position sensors.
[0016]
16. Method, according to claim 15, characterized by the fact that the first reverse actuation event is detected by monitoring the current input of the BLDC motor.
[0017]
17. Method according to claim 14, characterized by the fact that any one of: the first reverse drive event comprises an aspect of the reversible transmission that reaches a travel limit; the reversible transmission comprises a lead screw; and further comprises detecting a second reverse actuation event that occurs against the reversible transmission while the door is in the open position.
[0018]
18. Method according to claim 17, characterized in that the second reverse actuation event is caused by a cartridge body which is pushed against the cartridge loading mechanism.
[0019]
19. Method according to claim 18, characterized in that it additionally comprises, based on the detection of the second reverse actuation event, operating the BLDC motor to place the door back in the closed position.
[0020]
20. Method, according to claim 19, characterized by the fact that it additionally comprises any of: detecting a third reverse activation event that occurs against reversible transmission; and based on the detection of the third reverse actuation event, terminate the operation of the BLDC motor to place the door in a closed position.
[0021]
21. Method, according to claim 14, the method characterized by the fact that it additionally comprises: receiving a command to power a brushless DC motor (BLDC) from a syringe driver, the BLDC motor operable to turn a lead screw reversible, with a piston rod attached to and movable by the lead screw; applying power to the BLDC engine to move the plunger rod to engage a plunger tip within a syringe passage of a removable test cartridge; monitor the movement of the plunger rod inside the syringe passage by monitoring at least one current associated with the operation of the BLDC engine; detect a change in the current of the BLDC motor; and changing the operation of the BLDC motor to effect change in the movement of the piston rod inside the removable test cartridge based on the detection of the change in the current of the BLDC motor.
[0022]
22. Method, according to claim 21, characterized by the fact that the monitoring of at least one current of the BLDC motor occurs when the piston rod is moving.
[0023]
23. Method, according to claim 22, characterized by the fact that any of: altering the operation of the BLDC engine comprises raising the piston rod to decrease the pressure inside the removable test cartridge; changing the operation of the BLDC engine comprises lowering the plunger rod to increase the pressure inside the removable test cartridge; changing the operation of the BLDC engine comprises slowing the piston rod to decrease the rate of pressure change within the removable test cartridge; and changing the operation of the BLDC engine comprises accelerating the plunger rod to increase the rate of pressure change within the removable test cartridge.
[0024]
24. Method according to claim 14, characterized in that it additionally comprises operating a valve drive mechanism by: receiving a command to power a brushless DC motor (BLDC) coupled to the chassis to move a drive valve to a particular position, the valve drive being configured to rotate positions of a valve body of a removable test cartridge, where a coupled transmission between the BLDC motor and the valve drive and where the BLDC motor comprises a plurality of hall effect sensors that do not include any encoder hardware; and feeding the BLDC motor in response to rotating a BLDC motor shaft a particular number of times to move the valve drive to the particular position based on a sinusoidal signal generated by the hall effect sensors.
[0025]
25. Method according to claim 24, characterized by the fact that either: the transmission comprises a first series of helical gears directly attached to an output shaft of the BLDC motor, and a second series of helical gears coupled between the first series of helical gears and the valve drive output; the valve drive comprises a turntable; the BLDC motor is configured to monitor cartridge integrity based on current measurements from a BLDC motor bridge circuit, and current absorption measurements are associated with events that indicate loss of integrity of the removable test cartridge; and the BLDC motor is configured for the start and center position of the valve drive output by performing a centralization protocol based on the sinusoidal signal generated by the hall effect sensors.

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CA2992831A1|2017-02-02|

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US20200188922A1|2020-06-18|

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