Highly miniaturized closed-loop biosensing and drug delivery

Abstract

Systems and methods for closed-loop biosensing systems are described herein. Various embodiments are directed to biosensing chip configurations to collect and transmit biomarker signal data. Systems and methods for closed-loop drug delivery systems are described herein. Several embodiments are directed to integrated circuits of drug delivery chips to deliver drugs. In many embodiments, closed-loop biosensing systems and / or drug delivery systems can be configured for real time monitoring and / or treatment of patients.

Description

HIGHLY MINIATURIZED CLOSED-LOOP BIOSENSING AND DRUG DELIVERYCROSS-REFERENCES TO RELATED APPLICATIONS

[0001] The current application claims priority to Provisional Application No.63 / 780,086, filed March 28, 2025, the disclosure of which is incorporated herein by reference.FIELD OF THE INVENTION

[0002] This disclosure generally refers to systems and methods for closed-loop biosensing and / or drug delivery systems.BACKGROUND

[0003] Disease management involves single-point measurements of a patient. Disease management typically involves discrete interval drug dosing based on singlepoint measurements. Administration of single-point measurements can require continual monitoring of the patient by clinicians. Many patients receive disease management in medical treatment facilities such that discrete drug dosing can be administered.SUMMARY OF THE INVENTION

[0004] Systems and methods in accordance with some embodiments of the invention are directed to closed-loop biosensing and / or drug delivery systems.

[0005] In some embodiments, the techniques described herein relate to a closed-loop biosensing chip comprising: an array of aptamer electrodes, wherein the array of aptamer electrodes comprises a plurality of aptamer electrodes, wherein each aptamer electrode is configured to detect a signal current; a multi-channel sensing system configured to process the signal current detected by each aptamer electrode, comprising: a duty-cycling timer configured to activate each aptamer electrode in the array of aptamer electrodes; and an analog to digital converter (ADC) configured to transform the signal current into a quantized signal current; and an antenna configured to output a maximum sensed current from the quantized signal current based upon output of a relaxation oscillator configured as a duty-cycling timer, wherein the array of aptamer electrodes, the multi-channel sensing system, and the antenna are in communication.

[0006] In some embodiments, the techniques described herein relate to a closed-loop biosensing chip, wherein the array of aptamer electrodes, the multi-channel sensing system, and the antenna are in communication on an integrated circuit.

[0007] In some embodiments, the techniques described herein relate to a closed-loop biosensing chip, wherein the integrated chip is implantable.

[0008] In some embodiments, the techniques described herein relate to a closed-loop biosensing chip, wherein the duty-cycling timer can activate each aptamer electrode in series such that one aptamer electrode is activated simultaneously.

[0009] In some embodiments, the techniques described herein relate to a closed-loop biosensing chip, wherein each aptamer electrode is sensitive to one biomarker signal current.

[0010] In some embodiments, the techniques described herein relate to a closed-loop biosensing chip, further comprising: a waveform generator comprising at least two counters, wherein the at least two counters use a pulse modulated staircase ramp to quantize the signal current.

[0011] In some embodiments, the techniques described herein relate to a closed-loop biosensing chip comprising: a drug delivery chip comprising: a sub-resonance antenna, wherein the sub-resonance antenna is configured to receive a signal current: a matching network; a passive envelope detector, wherein the matching network matches an impedance of the passive envelope detector; a relaxation oscillator, wherein the relaxation oscillator transforms the signal current to a correlated current, wherein the correlated current signal is transformed into a wake-up trigger when the correlated current signal exceeds a threshold; and an LED driver, wherein the LED driver is activated by the wake-up trigger; wherein the drug delivery chip is an integrated circuit; and a drug delivery plug comprising: an LED signal light, wherein the LED signal light is activated by the LED driver; a drug reservoir; and wherein the drug delivery plug is incorporated on the integrated circuit.

[0012] In some embodiments, the techniques described herein relate to a closed-loop biosensing chip, wherein the closed integrated circuit is configured to be implanted.

[0013] In some embodiments, the techniques described herein relate to a closed-loop biosensing chip, wherein the drug delivery reservoir is configured to release a stored drug in response to the LED signal light.

[0014] In some embodiments, the techniques described herein relate to a closed-loop biosensing chip, wherein the relaxation oscillator is configured to generate a clock signalfor a 1 -bit ADC, wherein the 1 -bit ADC is configured to quantize the signal current, and wherein the quantized current is correlated with a programmed codebook.

[0015] In some embodiments, the techniques described herein relate to a closed-loop biosensing chip comprising: a closed-loop biosensing chip comprising: an array of aptamer electrodes, wherein the array of aptamer electrodes comprises a plurality of aptamer electrodes, wherein each aptamer electrode is configured to detect a signal current; a multi-channel sensing system configured to process the signal current, comprising: a duty-cycling timer configured to activate each aptamer electrode in the array of aptamer electrodes; and an analog to digital converter (ADC) configured to transform the signal current into a quantized signal current; and an antenna configured to output a maximum sensed current from the quantized signal current based upon output of a relaxation oscillator configured as a duty-cycling timer, wherein the array of aptamer electrodes, the multi-channel sensing system, and the antenna are in communication; a transmitter comprising a microprocessor and a Bluetooth low energy; wherein the transmitter is configured to receive the quantized signal current from the closed-loop biosensing chip; and a processor, wherein the transmitter is configured to transmit the quantized signal current from the closed-loop biosensing chip to the processor; wherein the closed-loop drug delivery chip comprises: a drug delivery chip comprising: a subresonance antenna, wherein the sub-resonance antenna is configured to receive an input signal current; a matching network; a passive envelop detector, wherein the matching network matches an impedance of the passive envelop detector; a relaxation oscillator, wherein the relaxation oscillator transforms the input signal current into a correlated signal, wherein the correlated signal is a wake-up trigger when the correlated signalexceed a threshold; and an LED driver, wherein the LED driver is activated by the wakeup trigger; wherein the drug delivery chip is an integrated circuit; and a drug delivery plug comprising: an LED signal light, wherein the LED signal light is activated by the LED driver; a drug reservoir; and wherein the drug delivery plug is incorporated on the integrated circuit.

[0016] In some embodiments, the techniques described herein relate to a closed-loop biosensing chip, wherein the array of aptamer electrodes, the multi-channel sensing system, and the antenna are in communication on an integrated circuit.

[0017] In some embodiments, the techniques described herein relate to a closed-loop biosensing chip, wherein the integrated chip is implantable.

[0018] In some embodiments, the techniques described herein relate to a closed-loop biosensing chip, wherein the duty-cycling timer can activate each aptamer electrode in series such that one aptamer electrode is activated simultaneously.

[0019] In some embodiments, the techniques described herein relate to a closed-loop biosensing chip, wherein each aptamer electrode is sensitive to one biomarker signal current.

[0020] In some embodiments, the techniques described herein relate to a closed-loop biosensing chip, wherein the relaxation oscillator further comprises: an analog-to-digital converter; a waveform generator comprising at least two counters, wherein the at least two counters use a pulse modulated staircase ramp to quantize the signal current; and a digital-to-analog converter, wherein the digital-to-analog converter outputs the quantized signal current to the antenna.

[0021] In some embodiments, the techniques described herein relate to a closed-loop biosensing chip, wherein the processor is configured to analyze the quantized signal current.

[0022] In some embodiments, the techniques described herein relate to a closed-loop biosensing chip, wherein the processor is configured to transmit drug delivery commands to the transmitter, wherein a closed-loop drug delivery chip is configured to receive the transmitted drug delivery commands as an input signal current.

[0023] In some embodiments, the techniques described herein relate to a closed-loop biosensing chip, wherein the transmitter is configured to transmit the quantized signal current from the closed-loop biosensing chip to the sub-resonance antenna of the drug delivery chip.

[0024] In some embodiments, the techniques described herein relate to a closed-loop biosensing chip, wherein the transmitter comprises a first antenna and a second antenna, wherein the first antenna is configured to receive quantized signal current from the closed-loop biosensing chip, wherein the second antenna is configured to transmit a signal to the sub-resonance antenna of the drug delivery chip.

[0025] Additional embodiments and features are set forth in part in the description that follows, and in part will become apparent to those skilled in the art upon examination of the specification or may be learned by the practice of the disclosure. A further understanding of the nature and advantages of the present disclosure may be realized by reference to the remaining portions of the specification and the drawings, which forms a part of this disclosure.BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The description will be more fully understood with reference to the following figures, which are presented as embodiments of the invention and should not be construed as a complete recitation of the scope of the invention, wherein:

[0027] Fig. 1 illustrates a closed-loop biosensing system in accordance with an embodiment of the invention.

[0028] Fig. 2 illustrates a closed-loop drug delivery system in accordance with an embodiment of the invention.

[0029] Figs. 3A and 3B illustrate examples of an implanted closed-loop biosensing and drug delivery system in accordance with an embodiment of the invention .

[0030] Fig. 4 illustrates an example of a closed-loop biosensing and drug delivery system with two-step communication in accordance with an embodiment of the invention.

[0031] Fig. 5 schematically illustrates an example process of a closed-loop biosensing and drug delivery system with two-step communication in accordance with an embodiment of the invention.DETAILED DESCRIPTION OF THE INVENTION

[0032] Various embodiments of the invention are directed to closed loop biosensing and drug delivery systems. In many embodiments, a multi-channel sensing system is configured to acquire data from biosensors. The multi-channel sensing system can be configured to transmit the collected data to allow real-time monitoring and analysis. In various embodiments, sensing can occur periodically. The periodic sensing can be configured to optimize power consumption to increase the lifespan of the multi-channelsensing system. In some embodiments, the multi-channel sensing system can include a relaxation oscillator. The relaxation oscillator can serve as a duty-cycling timer, where the relaxation oscillator is clocking a counter that generates signals. The mechanism may activate the chip periodically, for example, every 10 minutes for a few seconds, then power it down after biomarker detection and data transmission.

[0033] Fig. 1 provides an example of a multi-channel sensing system in accordance with an embodiment of the invention. In many embodiments, the multi-channel sensing system, which can also be referred to as a sensing plug, is configured to be activated for a period of time and then deactivated after biomarker detection and / or data transmission. In some embodiments, the multi-channel sensing system can include an array of aptamer electrodes 101 sensitive to a specific biomarker. A duty-cycling timer 102 can be configured to enable and disable one or more aptamer electrodes to scan for different combinations of targeted biomarkers such as, but not limited to, MMP-9 and IgE. In many embodiments, when the multi-channel sensing system is activated, another relaxation oscillator 103 can generate the clock signal for all system blocks, including (but not limited to) a waveform generator for voltammetry and an analog-to-digital converter (ADC). The waveform generator may include at least two counters 104a, 104b: one loaded with zero and another loaded with offset bits. The outputs of these counters can be alternately fed to a digital-to-analog converted (DAC) 105. In some embodiments, the DAC can generate the signal. This configuration, in accordance with certain embodiments, can be used when the waveform is a pulse modulated on top of a staircase ramp. In many embodiments, for each level of the staircase, the current can be quantized at the end of the high- and low-level pulses. These currents can flow through a trans-impedance amplifier. In certainembodiments, the currents can be converted into voltages and then quantized by a successive approximation register (SAR) ADC 106. In various embodiments, the quantized current values at the end of the high- and low-level pulses can be stored in registers. To obtained a sensed current at each voltage step, the quantized current values stored in the registers can be subtracted from each other in the digital domain. In many embodiments, after each quantization, the differential current can be compared with the value from the previous step and the higher value can be stored in a maximum search register. At the end of the scan, the value stored in the maximum value stored can represent the maximum sensed current among all the steps. In certain embodiments, the maximum sensed current can be serialized, pulse-shaped, and / or transmitted to as an output. The multi-channel signal sensing system can comprise an ultra-wide-band transmitter to transmit the maximum sensed current. For example, the ultra-wide-band transmitter can operate at 5 GHz to minimize the current drain from the battery. In some embodiments, identifying the maximum sent current can be repeated for all of the biomarkers of interest. In some embodiments of the invention, a sensing chip includes all the components including wireless transmission, instrumentation amplifiers, ADCs, serializers, clock and data recovery and power management circuits.

[0034] In many embodiments, voltametric senhe antsors are integrated into the multichannel sensing system. The integrated circuits (IC) can interface with the voltammetry electrodes to sense, amplify, digitize, and / or transmit the multi-channel electrochemical signals. In some embodiments, communication from the IC to an external output can be a two-step relay: 1) implant IC to the external receiver on a wearable glass, and 2) communication from wearable glass to an external processor for cloud storage andanalysis. In various embodiments, this enables the implant IC to exhibit reduced power consumption due to the short-distance communication to the relay glass. The burden of long-distance communication is shifted to the external wearable glass which can be easily recharged. The improved reliability of communication can extend the lifetime of the implanted sensing IC. In some embodiments, the external processor is a smart phone, tablet, or computer.

[0035] Various embodiments are directed to a closed-loop drug delivery chip. In many embodiments, the closed-loop drug delivery chip can be configured to deliver drugs to a patient. The closed-loop drug delivery chip can be configured to release doses of one or more drugs to a patient in real time. In certain embodiments, the closed-loop drug delivery chip can be configured to release drugs to a patient in response to one or more biomarker signals received from the patient. The closed-loop drug delivery chip can be configured to deliver drugs to a patient on a schedule. In some embodiments, the close-loop drug delivery chip includes a drug delivery plug. The drug delivery plug can be configured to deliver the drugs to the patient. The closed-loop drug delivery chip can be configured to activate and / or deactivate drug delivery by the drug delivery plug.

[0036] To enable on-demand drug release, an ultra-low-power wake-up receiver can continuously monitor for signal transmission. In many embodiments, the signal transmission is wirelessly transmitted. The signal transmission can include biomarker signal data from the patient. In certain embodiments, the signal transmission is from a multi-channel signal sensing system. The wake-up receiver can be configured to detect a sequence of data that matches a programmed 32-bit codebook. The signal transmitted by the drug delivery chip can be modulated at a rate of 10 bits per second. For example,the signal transmitted can be on-off key-modulated (OOK). In many embodiments, given the low frequency of drug delivery and the short distance between the drug delivery chip and the drug delivery plug, the wake-up receiver’s power consumption can be maintained at a few nanowatts. One skilled in the art will recognize that various embodiments of the invention may utilize different types of encoding and / or modulation as appropriate to any particular application.

[0037] Fig. 2 provides an example of a drug delivery chip and a drug delivery plug in accordance with various embodiments of the invention. In many embodiments, a subresonance antenna 201 embedded within the drug delivery plug can receive signals transmitted from a relay glass. In some embodiments, the antenna is 3 mm. Biomarker data signals can be transmitted as an output from a multi-channel signal sensing system to a relay glass in connection with the drug delivery chip. A matching network 202 may match the impedance of the passive envelop detector 203 with that of the sub-resonance antenna. For example, the passive envelope detector 203 is a passive Dickson envelope detector. A passive Dickson envelope detector can be configured to convert the energy of the received low-bandwidth signal into baseband data. In some embodiments, the received signal may be OOK-modulated.

[0038] The drug delivery chip can further include a relaxation oscillator 204 comprising one or more clocks 205. In many embodiments, the relaxation oscillator 204 can operate at 10x the data rate (e.g., 100 Hz) and can generate the clock 205 for a 1 -bit ADC. The clock 205 may drive a compactor that samples the envelope signal at a rate higher than the data rate. In some embodiments, the compactor can compensate for phase incoherence. The quantized, oversampled baseband data can be correlated witha programmed codebook to detect a wake-up event. In several embodiments, a wake-up event can be triggered when the correlated output exceeds a predefined threshold for a specific biomarker. In some embodiments, after a brief delay, the signal and correlator memory elements can be reset after a detected wake-up event. In certain embodiments, the drug delivery chip includes a monostable multivibrator 206 configured to extend the narrow wake-up signal into a pulse that can be, for example, 20-seconds. The extended wake-up signal can ensure LED activation time sufficient for drug release. The LED driver 207 can be configured to activate an LED 208 light. In many embodiments, the LED driver 207 may include a feedback loop that maintains the LED voltage when active and drawing current. For example, the LED voltage may be approximately 700 mV. In certain embodiments, the LED 208 light signal initiates the drug release within the drug delivery plug. The NIR light 209 emitted from the LED 208 can penetrate the nano-drug reservoir shell 210 to release the stored drug. In various embodiments an integrated circuit (IC) can be developed to incorporate the drug delivery chip and the drug delivery plug. For example, data can be transferred using RF wireless communication at 2.4 GHz for wakeup operation.

[0039] Various embodiments are directed to a closed-loop cloud-based system configured to apply treatment based on the measurement of various biomarkers. In some embodiments, the closed-loop cloud-based system is configured to be an implant in communication with an external processor. In many embodiments, the implant can be configured to deliver drugs in real time in response to detected biomarker signals. For example, the implant can include a multi-channel signal sensing system, a drug delivery chip, and / or a drug delivery plug. The multi-channel signal sensing system can beconfigured to be external to the body such as a patch. In numerous embodiments, the multi-channel signal sensing system can detect biomarker signals and transmit detected biomarker signals to the drug delivery chip. The detected biomarker signals can trigger a wake-up event within the drug delivery chip to activate drug release within the drug delivery plug. In various embodiments, a software-controlled external transmitter can be configured to independently and / or automatically controlled by the external processor, for example, a cell phone. The external transmitter can be configured to receive signals of detected biomarkers from the multi-channel signal sensing system. The external transmitter can be configured to transmit the detected biomarker signals to the external processor to store and analyze the detected biomarker signals. In certain embodiments, the external transmitter can be configured to transmit the detected biomarker signals to the drug delivery chip to trigger a wake-up event. The external processor can be directed by a user, for example, to A user, for example, can direct the external transmitter to transmit the detected biomarker signal to the drug delivery chip to trigger a wake-up event.

[0040] Figs. 3A and 3B provide an example of a closed-loop cloud-based system for delivery of vagus nerve stimulation based on real time measurement of ECG. Fig. 3A schematically illustrates a wireless implant 301 in connection with the vagus nerve 302. A sensing patch 303 and wireless implant 301 are in communication with the handheld device 304. The handheld device can comprise the external transmitter and the external processor.

[0041] Fig. 3B provides a block diagram of the closed-loop cloud-based system. The sensing patch 303 can be in communication with the external transmitter 304a. The external transmitter 304a can be in communication with the external processor 304b. Theexternal processor 304b can be configured to direct the external transmitter 304a to signal the wireless implant 301 to stimulate the vagus nerve.

[0042] In some embodiments, the closed-loop system can include two-step communication for the closed-loop biochemical sensing and drug delivery. In many embodiments, the overall system can integrate an implanted multi-channel sensing system, a voltage activated infrared drug delivery plug, a cloud-based decision-making algorithm, and a transceiverfro (TRX) chip that responds to physician-approved commands. The communication architecture of various embodiments can incorporate a wearable relay glass. The wearable relay glass can enable secure transmission of data and commands. For example, the wearable relay glass can incorporate two or more dipole antennas. The dipole antennas can operate at 2.4 GHz and 5.8 GHz for drug release and electrochemical sensing communication from the implanted multi-channel sensing system. In many embodiments, the at least two dipole antennas 1 ) receive ultra-wideband (UWB) uplink from the multi-channel sensing system at, for example, 5.8 GHz and 2) transmit the downlink data to the implanted drug delivery plug at, for example, 2.4 GHz. In many embodiments, after amplification and envelope detection of the uplink signal from the multi-channel sensing system, the sensing data can be recovered and stored in a microprocessor unit (MPU). In some embodiments, the MPU can communicate wirelessly, for example, with a Bluetooth Low Energy (BLE) module via UART protocol. In some embodiments, a smartphone application can retrieve the sensing data using BLE. In many embodiments, for the downlink, a user, such as a physician, can send drug delivery commands from the smartphone to the wearable relay glass. For example, the downlink can be sent using BLE. In some embodiments, the wearable relay glassreceives the drug delivery data and transmits the drug release wake-up command signal to the drug delivery chip using, for example, 2.4 GHz 00K modulation.

[0043] Fig. 4 provides an example of a two-step communication system in accordance with various embodiments configured using glasses. In some embodiments the multichannel signal sensing and drug delivery chip and plug are implanted into a patient. The implants can be in communication with an external receiver on the glasses 401. In various embodiments, the glasses can be in communication with an external processor such as a smartphone 402 for cloud storage and analysis. The glasses 401 can include two dipole antennas, a first antenna 403a for receiving the signal uplinks and a second antenna 403b for transmitting a downlink to the drug delivery chip. The glasses 401 can also incorporate a TRX chip 404 to respond to commands from the handheld processor. In various embodiments, the TRX chip 404 includes an MPU 405a and a BLE 405b for wireless communication between the implanted chips and / or smartphone 402. In many embodiments, the glasses 401 are configured for secure transmission of data and / or commands between the implanted chips, the external processor, and the cloud. The TRX chip 404 can be in communication with both dipole antennas 403a, 403b. Biomarker signal data can be collected by the first antenna 403a, processed within the TRX chip 404, and wirelessly transmitted to the smartphone 402. In some embodiments, the TRX chip 404 comprises an amplifier 406a and an envelope detector 406b to process the collected biomarker data. Drug delivery commands, such as wake-up triggering events can be wirelessly transmitted from the smartphone 402 to the TRX chip 404, the TRX chip 404 can then wirelessly transmit the drug delivery commands to the second antenna 403b, which can wirelessly transmit to the implanted drug delivery chip.

[0044] In many embodiments of the invention, a closed-loop algorithm, based on the sensed data, changes the parameters for drug release, such as the frequency and volume of the drug released. Fig. 5 provides a process diagram for two-step communication of a closed-loop biosensing and drug delivery system. The closed-loop biosensing system detects (501) biomarker signals. Sensing can occur periodically, for example every 10 minutes. The closed-loop biosensing system transmits (502) the detected biomarker signals to a TRX chip. The TRX chip can transmit (503) the biomarker signals to an external processor. The external processor can analyze (504) the biomarker signals. In some embodiments, the external processor can determine (504a) drug delivery commands based on the biomarker signal analysis. In various embodiments, the external processor can output (504b) the biomarker signals and receive (504c) drug delivery commands from a user. The external processor can transmit (505) the drug delivery commands to the TRX chip. The TRX chip can transmit (506) the drug delivery commands to the closed-loop drug delivery system. The closed-loop drug delivery system can deliver (507) drugs to the patient based on the drug delivery commands.

[0045] It will be understood that the components of the embodiments, as generally described herein and illustrated in the appended figures, may be arranged and designed in a variety of different configurations. Thus, the following more detailed description of various embodiments, as represented in the figures, is not intended to limit the scope of the present disclosure but is merely representative of various embodiments. While various aspects of the embodiments are presented in drawings, the drawings are not necessarily drawn to scale unless specifically indicated.

[0046] The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive.

[0047] Reference throughout this specification to features, advantages, or similar language does not imply that all of the features and advantages that may be realized with the present invention should be or are in any single embodiment of the invention. Rather, language referring to the features and advantages is understood to mean that a specific feature, advantage, or characteristic described in connection with an embodiment is included in at least one embodiment of the present invention. Thus, discussions of the features and advantages and similar language throughout this specification may, but do not necessarily, refer to the same embodiment.

[0048] Furthermore, the described features, advantages, and characteristics of the invention may be combined in any suitable manner in one or more embodiments. One skilled in the relevant art will recognize, in light of the description herein, that the invention can be practiced without one or more of the specific features or advantages of a particular embodiment. In other instances, additional features and advantages may be recognized in certain embodiments that may not be present in all embodiments of the invention.

[0049] Reference throughout this specification to “one embodiment,” “an embodiment,” or similar language means that a particular feature, structure, or characteristic described in connection with the indicated embodiment is included in at least one embodiment. Thus, the phrases “in one embodiment,” “in an embodiment,” and similar language throughout this specification may but do not necessarily, all refer to the same embodiment.DOCTRINE OF EQUIVALENTS

[0050] This description of the invention has been presented for the purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise form described, and many modifications and variations are possible in light of the teaching above. The embodiments were chosen and described in order to best explain the principles of the invention and its practical applications. This description will enable others skilled in the art to best utilize and practice the invention in various embodiments and with various modifications as are suited to a particular use. The scope of the invention is defined by the following claims.

[0051] As used herein, the singular terms “a,” “an,” and “the,” may include plural referents unless the context clearly dictates otherwise. Reference to an object in the singular is not intended to mean “one and only one” unless explicitly so stated, but rather “one or more.”

[0052] As used herein, the terms “approximately” and “about” are used to describe and account for small variations. When used in conjunction with an event or circumstance, the terms can refer to instances in which the event or circumstance occurs precisely as well as instances in which the event or circumstance occurs to a close approximation. When used in conjunction with a numerical value, the terms can refer to a range of variation of less than or equal to ± 10% of that numerical value, such as less than or equal to ±5%, less than or equal to ±4%, less than or equal to ±3%, less than or equal to ±2%, less than or equal to ±1 %, less than or equal to ±0.5%, less than or equal to ±0.1 %, or less than or equal to ±0.05%.

[0053] Additionally, amounts, ratios, and other numerical values may sometimes be presented herein in a range format. It is to be understood that such range format is used for convenience and brevity and should be understood flexibly to include numerical values explicitly specified as limits of a range, but also to include all individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly specified. Where ranges are described, the range should be understood to include the endpoints of the ranges, and the endpoints of such ranges are also contemplated to stand on their own as inventive, individual data points and to form the endpoints of other ranges. For example, a ratio in the range of about 1 to about 200 should be understood to include the explicitly recited limits of about 1 and about 200, but also to include individual ratios such as about 2, about 3, and about 4, sub-ranges such as about 1 to about 10, about 10 to about 50, about 20 to about 100, about 100 to about 200, and so forth, and related ranges such as greater than about 1 or less than about 200.

Claims

WHAT IS CLAIMED IS:

1. A closed-loop biosensing chip comprising:an array of aptamer electrodes, wherein the array of aptamer electrodes comprises a plurality of aptamer electrodes, wherein each aptamer electrode is configured to detect a signal current;a multi-channel sensing system configured to process the signal current detected by each aptameraptamer electrode, comprising:a duty-cycling timer configured to activate each aptamer electrode in the array of aptamer electrodes; andan analog to digital converter (ADC) configured to transform the signal current into a quantized signal current; andan antenna configured to output a maximum sensed current from the quantized signal current based upon output of a relaxation oscillator configured as a duty-cycling timer, wherein the array of aptamer electrodes, the multichannel sensing system, and the antenna are in communication.

2. The closed-loop biosensing chip of claim 1 , wherein the array of aptamer electrodes, the multi-channel sensing system, and the antenna are in communication on an integrated circuit.

3. The closed-loop biosensing chip of claim 2, wherein the integrated chip isimplantable.

4. The closed-loop biosensing chip of claim 1 , wherein the duty-cycling timer can activate each aptamer electrode in series such that one aptamer electrode is activated simultaneously.

5. The closed-loop biosensing chip of claim 1 , wherein each aptamer electrode is sensitive to one biomarker signal current.

6. The closed-loop biosensing chip of claim 1 , further comprising:aveform generator comprising at least two counters, wherein the at least two counters use a pulse modulated staircase ramp to quantize the signal current7. A closed-loop drug delivery chip comprising:a drug delivery chip comprising:a sub-resonance antenna, wherein the sub-resonance antenna is configured to receive a signal current;a matching network;a passive envelope detector, wherein the matching network matches an impedance of the passive envelope detector;a relaxation oscillator, wherein the relaxation oscillator transforms the signal current to a correlated current, wherein the correlatedcurrent signal is transformed into a wake-up trigger when the correlated current signal exceeds a threshold; andan LED driver, wherein the LED driver is activated by the wake-up trigger; wherein the drug delivery chip is an integrated circuit; anda drug delivery plug comprising:an LED signal light, wherein the LED signal light is activated by the LED driver;a drug reservoir; andwherein the drug delivery plug is incorporated on the integrated circuit.

8. The closed-loop drug delivery chip of claim 7, wherein the closed integrated circuit is configured to be implanted.

9. The closed-loop drug delivery chip of claim 7, wherein the drug delivery reservoir is configured to release a stored drug in response to the LED signal light.

10. The closed-loop drug delivery chip of claim 7, wherein the relaxation oscillator is configured to generate a clock signal for a 1 -bit ADC, wherein the 1 -bit ADC is configured to quantize the signal current, and wherein the quantized current is correlated with a programmed codebook.

11. A closed-loop biosensing and drug delivery system comprising:a closed-loop biosensing chip comprising:an array of aptamer electrodes, wherein the array of aptamer electrodes comprises a plurality of aptamer electrodes, wherein each aptamer electrode is configured to detect a signal current;a multi-channel sensing system configured to process the signal current, comprising:a duty-cycling timer configured to activate each aptamer electrode in the array of aptamer electrodes; and an analog to digital converter (ADC) configured to transform the signal current into a quantized signal current; and an antenna configured to output a maximum sensed current from the quantized signal current based upon output of a relaxation oscillator configured as a duty-cycling timer, wherein the array of aptamer electrodes, the multi-channel sensing system, and the antenna are in communication;a transmitter comprising a microprocessor and a Bluetooth low energy; wherein the transmitter is configured to receive the quantized signal current from the closed-loop biosensing chip; anda processor, wherein the transmitter is configured to transmit the quantized signal current from the closed-loop biosensing chip to the processor; wherein the closed-loop drug delivery chip comprises:a drug delivery chip comprising:a sub-resonance antenna, wherein the sub-resonance antenna is configured to receive an input signal current;a matching network;a passive envelop detector, wherein the matching network matches an impedance of the passive envelop detector; a relaxation oscillator, wherein the relaxation oscillator transforms the input signal current into a correlated signal, wherein the correlated signal is a wake-up trigger when the correlated signal exceed a threshold; andan LED driver, wherein the LED driver is activated by the wake-up trigger;wherein the drug delivery chip is an integrated circuit; and a drug delivery plug comprising:an LED signal light, wherein the LED signal light is activated by the LED driver;a drug reservoir; andwherein the drug delivery plug is incorporated on the integrated circuit.

12. The system of claim 11 , wherein the array of aptamer electrodes, the multichannel sensing system, and the antenna are in communication on an integrated circuit.

13. The system of claim 12, wherein the integrated chip is implantable.

14. The system of claim 11 , wherein the duty-cycling timer can activate each aptamer electrode in series such that one aptamer electrode is activated simultaneously.

15. The system of claim 11 , wherein each aptamer electrode is sensitive to one biomarker signal current.

16. The system of claim 11 , wherein the relaxation oscillator further comprises: an analog-to-digital converter;a waveform generator comprising at least two counters, wherein the at least two counters use a pulse modulated staircase ramp to quantize the signal current; anda digital-to-analog converter, wherein the digital-to-analog converter outputs the quantized signal current to the antenna.

17. The system of claim 11 , wherein the processor is configured to analyze the quantized signal current.

18. The system of claim 11 , wherein the processor is configured to transmit drug delivery commands to the transmitter, wherein a closed-loop drug delivery chip is configured to receive the transmitted drug delivery commands as an input signal current.

19. The system of claim 11 , wherein the transmitter is configured to transmit the quantized signal current from the closed-loop biosensing chip to the subresonance antenna of the drug delivery chip.

20. The system of claim 11 , wherein the transmitter comprises a first antenna and a second antenna, wherein the first antenna is configured to receive quantized signal current from the closed-loop biosensing chip, wherein the second antenna is configured to transmit a signal to the sub-resonance antenna of the drug delivery chip.

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