WO2020197968A1 - Devices and methods for the incorporation of a microneedle array analyte-selective sensor - Google Patents
Devices and methods for the incorporation of a microneedle array analyte-selective sensor Download PDFInfo
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- WO2020197968A1 WO2020197968A1 PCT/US2020/023771 US2020023771W WO2020197968A1 WO 2020197968 A1 WO2020197968 A1 WO 2020197968A1 US 2020023771 W US2020023771 W US 2020023771W WO 2020197968 A1 WO2020197968 A1 WO 2020197968A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- A61M5/168—Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body
- A61M5/172—Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic
- A61M5/1723—Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic using feedback of body parameters, e.g. blood-sugar, pressure
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- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/14507—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood
- A61B5/1451—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid
- A61B5/14514—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid using means for aiding extraction of interstitial fluid, e.g. microneedles or suction
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- A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
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- A61B5/14546—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring analytes not otherwise provided for, e.g. ions, cytochromes
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- A61B5/4836—Diagnosis combined with treatment in closed-loop systems or methods
- A61B5/4839—Diagnosis combined with treatment in closed-loop systems or methods combined with drug delivery
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- A61B5/6801—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
- A61B5/683—Means for maintaining contact with the body
- A61B5/6832—Means for maintaining contact with the body using adhesives
- A61B5/6833—Adhesive patches
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- A61B5/6847—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
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- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- A61M5/142—Pressure infusion, e.g. using pumps
- A61M5/14244—Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body
- A61M5/14248—Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body of the skin patch type
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- G—PHYSICS
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- G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
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- G16H20/10—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance relating to drugs or medications, e.g. for ensuring correct administration to patients
- G16H20/17—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance relating to drugs or medications, e.g. for ensuring correct administration to patients delivered via infusion or injection
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- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- A61M5/168—Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body
- A61M5/172—Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic
- A61M5/1723—Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic using feedback of body parameters, e.g. blood-sugar, pressure
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- A61M2230/00—Measuring parameters of the user
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- A61M2230/201—Glucose concentration
Definitions
- insulin pumps also known as continuous subcutaneous insulin infusion (CSII) systems.
- CSII continuous subcutaneous insulin infusion
- Insulin pumps were developed in the 1980’s and commercialized in the 1990’s to provide a more physiological method of insulin delivery than the infrequent injection of insulin by syringe.
- the importance of improved methods of insulin delivery was further recognized in the aftermath of the publication of the Diabetes Control and Complication Trial (DCTT) in 1992 which showed that intensive insulin therapy dramatically reduced the incidence and severity of long-term complications of diabetes.
- DCTT Diabetes Control and Complication Trial
- insulin pumps have been configured to automatically suspend insulin infusion in the event of actual or impending
- hypoglycemia as determined by algorithms designed to use inputs from continuous glucose monitoring systems to minimize the occurrence, severity or duration of hypoglycemia.
- Insulin pumps have also been configured to modulate insulin delivery continuously to maintain glucose levels at a euglycemic setpoint or within a euglycemic window (or zone) as determined by algorithms designed to use inputs from continuous glucose monitoring systems to achieve improved glycemic control.
- Such systems are variously described as artificial pancreas devices, automated insulin delivery systems, automated glucose control systems and closed loop systems, among other descriptions, In these scenarios, both the analyte sensing and therapeutic delivery modalities comprise two distinct and extricable devices, which are worn on the body.
- CSII Continuous subcutaneous insulin infusion
- CSII devices There are two general classes of CSII devices - one with a tube for delivering insulin and the other without a tube (or tubeless) with a small cannula protruding from the device and directly inserted into the tissue.
- the tubed devices consist of a programmable electromechanical pump device with an LED display and a touchpad for command entry.
- Tubed pumps are typically 6-8 cm long, 4-6 cm wide and 2-4 cm thick and contain a reservoir with insulin which is delivered to the body through a 24-48” plastic tube that terminates in an infusion set with a cannula or needle that is inserted into the subcutaneous adipose tissue.
- the tubeless devices (sometimes referred to as patch pumps) consist of an
- Patch pumps are typically 3-5 cm long, 2-4 cm wide and 2-3 cm thick and also contain a reservoir with insulin which is delivered to the body through a short 2-3 cm cannula that protrudes from the bottom of the patch pump and is also inserted into the subcutaneous adipose tissue.
- Current infusion systems configured for the delivery of a solution-phase therapeutic agent (i.e. insulin) are often paired with needle- and cannula-based sensor systems configured for continuous quantification of an analyte (i.e. glucose).
- both systems operate in unison and are configured to operate in similar physiological compartments, such as the subcutaneous adipose layer of tissue, both systems are not amenable for co-location within a single body-worn device. This is due in part to the challenges associated with the insertion of two cannulae physically attached to a single integrated device. However, the primary challenge arises due to the lack of isolation while operating both systems in close proximity.
- undesired chemical interactions are likely to occur in scenarios of concurrent operation of an analyte sensor device and a therapeutic delivery device co- located in a given physiological compartment; among these undesired effects are cross-talk, interference, contamination, and localized dilution, which directly affect the sensor’s ability to quantify the desired analyte with a specified degree of selectivity, sensitivity, stability, and response time.
- FIG. 11 is an illustration (not to scale) of a patient’s skin 40 including epidermis 41, dermis 42 and the subcutaneous tissue 43, with an infusion system 45 configured to operate within the subcutaneous tissue 45.
- Graphs 1200, 1210, 1220 and 1230 of FIGS. 12A-12D below from Jockel et al shows the preferential pattern of asymmetric horizontal diffusion for different volumes of insulin injected into tissue. Jockel et al. have shown that this preferential diffusion of insulin in the horizontal direction limits the vertical extent of the insulin depot, even for large volumes of insulin, to approximately 4 mm.
- Algorithms for artificial pancreas devices rely heavily on accepted principles from control theory and chemical engineering and can be divided into several categories.
- algorithms for artificial pancreas devices are unihormonal or bihormonal.
- Uni hormonal systems use insulin infusion alone to avoid hyperglycemia and maximize time in euglycemia.
- hypoglycemia can be prevented or treated by suspending insulin based on actual readings of a continuous glucose monitoring systems or on predicted glucose values derived from continuous glucose monitoring data.
- biohormonal systems hyperglycemia is avoided or treated with insulin infusion as in unihormonal systems but hypoglycemia is prevented or treated by infusing glucagon which stimulates the liver to produce endogenous glucose.
- Prior art embodiments of the analyte sensing modality include cannula-assisted, subcutaneously-implanted wire- based sensors configured to quantify an analyte using electrochemical transduction techniques.
- Prior art embodiments of the therapeutic delivery modality include cannula-based patch pumps and infusion sets configured to deliver a therapy to the subcutaneous adipose tissue.
- FIG. 1 A is a prior art needle-/cannula-based analyte- selective sensor 110 with a user interface device 115 and mobile phone 105 configured for the quantification of glucose in the subcutaneous adipose tissue.
- FIG. IB is a prior art needle-/cannula-based analyte-selective sensor 130 with a user interface device 125 configured for the quantification of glucose in the subcutaneous adipose tissue.
- FIG. 1C is a prior art needle-/cannula-based analyte- selective sensor 150 with a user interface device 145 configured for the quantification of glucose in the subcutaneous adipose tissue. More recent prior art has instructed of the co- location of both sensing and delivery modalities within a single body -worn device, albeit featuring sufficient lateral or spatial isolation between sensing and delivery contingents to minimize interactions between the two even when operating in the same physiological compartment.
- One aspect of the present invention is a device for the manual delivery of a therapeutic intervention in response to a physiological state of a user.
- the device comprises a sensor, an infusion system, a singular body-worn component and a control algorithm.
- the sensor is configured to penetrate the stratum corneum to access the viable epidermis or dermis and measure the presence of an analyte or plurality of analytes in a selective fashion.
- the infusion system is configured to deliver, in a controlled fashion, a solution-phase therapeutic agent or collection of therapeutic agents to a separate physiological compartment distinct from the viable epidermis and dermis.
- the singular body-worn component integrates the sensor and the infusion system.
- the device is configured to deliver a specified dosage of said therapeutic agent via the infusion system based on the output of said control algorithm.
- the device comprises a sensor, an infusion system, and a singular body-worn component.
- the sensor is configured to penetrate the stratum corneum to access the viable epidermis or dermis and measure the presence of an analyte or plurality of analytes in a selective fashion.
- the infusion system is configured to deliver, in a controlled fashion, a solution-phase therapeutic agent or collection of therapeutic agents to a separate physiological compartment distinct from the viable epidermis and dermis.
- the singular body-worn component integrates the sensor and the infusion system.
- the device is configured to deliver a specified dosage of said therapeutic agent via the infusion system based on an action of a user.
- Yet another aspect of the present invention is a method for the manual
- the method includes measuring the presence of an analyte or plurality of analytes in a selective fashion in the viable epidermis or dermis by means of a sensor.
- the method also includes inputting the measurement of an analyte or plurality of analytes into a control algorithm.
- the method also includes causing an infusion system to deliver a specified dosage of a solution-phase therapeutic agent or collection of therapeutic agents to a physiological compartment beneath the dermis based on the output of said control algorithm.
- FIG. 1 A is a prior art needle-/cannula-based analyte-selective sensors
- FIG. IB is a prior art needle-/cannula-based analyte-selective sensors
- FIG. 1C is a prior art needle-/cannula-based analyte-selective sensors
- FIG. 2 is a prior art embodiment of an analyte-selective sensor device (left) and an infusion system (right), both devices featuring extensive spatial separation circumvent undesired interactions.
- FIG. 3 is a prior art needle-/cannula-based analyte-selective sensor (left) configured for the quantification of glucose in the subcutaneous adipose tissue and a microneedle array -based analyte-selective sensor (right) configured for the quantification of glucose in the dermis.
- FIG. 4 is a pictorial representation (not to scale) of an infusion system
- an analyte-selective sensor configured to operate within the dermis (right), with both located in close spatial proximity.
- FIG. 5 A is an illustration of an integration of a microneedle array -based
- analyte-selective sensor into an infusion set.
- FIG. 5B is a proposed integration of a microneedle array -based analyte- selective sensor into a patch pump.
- FIG. 6A is a proposed integration of a microneedle array-based analyte- selective sensor into a patch pump.
- FIG. 6B is a proposed integration of a microneedle array -based analyte- selective sensor into a patch pump.
- FIG. 6C is an isolated view of circle 6C of FIG. 6B.
- FIG. 7 is a block / process flow diagram illustrating the major method steps of the OPEN LOOP embodiment of the invention.
- FIG. 8 is a block / process flow diagram illustrating the major method steps of the CLOSED LOOP embodiment of the invention.
- FIG. 9 is a block / process flow diagram illustrating the inputs, outputs, and major constituents of the invention under the OPEN LOOP embodiment.
- FIG. 10 is a block / process flow diagram illustrating the inputs, outputs, and major constituents of the invention under the CLOSED LOOP embodiment.
- FIG. 11 is an illustration (not to scale) of an infusion system configured to operate within the subcutaneous tissue.
- FIG. 12A is an illustration of a graph related to insulin depot formation in subcutaneous adipose tissue.
- FIG. 12B is an illustration of a graph related to insulin depot formation in subcutaneous adipose tissue.
- FIG. 12C is an illustration of a graph related to insulin depot formation in subcutaneous adipose tissue.
- FIG. 12D is an illustration of a graph related to insulin depot formation in subcutaneous adipose tissue.
- FIG. 13 is a top perspective view of an insulin patch pump with a fully
- FIG. 14 is a bottom perspective view of an insulin patch pump with a fully integrated microarray sensor.
- FIG. 15 is a side elevation view of an insulin patch pump with a fully
- FIG. 16 is a bottom perspective view of an insulin patch pump with a
- microarray sensor connected via a connector.
- FIG. 17 is an isolated view of a microarray sensor connected to a connector.
- FIG. 18 is a bottom perspective view of an insulin patch pump with a recess for a microarray sensor that has been applied to a patient’s skin.
- physiological fluid such as interstitial fluid, dermal interstitial fluid blood, serum, and plasma.
- These devices consist of an array of at least two protrusions on a substrate, each protrusion attached to the said substrate at the proximal end and extending between 200 and 2000 micrometers to a distal end.
- At least one said protrusion is configured to feature at least one electrode comprising a metallic, semiconductor, or polymeric material, which may be further coated with one or more polymeric membranes.
- a recognition element is located on the said electrode or within the said membrane to impart a selective sensing capability towards an endogenous or exogenous chemical species occupying the said physiological fluid.
- the said chemical species can include at least one of a biomarker, chemical, biochemical, metabolite, electrolyte, ion, hormone, neurotransmitter, vitamin, mineral, drug, therapeutic, toxin, enzyme, protein, nucleic acid, DNA, and RNA.
- Modes of sensing can include electrical, chemical, electrochemical (voltammetric, amperometric, potentiometric), optical, fluorometric, colormetric, absorbance, emission, conductance, impedance, resistance, capacitance.
- Typical modes of application include by means of a user-supplied force, a packaging wherein stored potential energy is transferred to kinetic energy upon an actuation action instigated by a user, and an applicator capable of accelerating the said microneedle-based analyte- selective sensors, causing the microneedle constituents of the array to penetrate the stratum comeum and achieve sensing within the viable epidermis or dermis to facilitate the intradermal analysis of pertinent analytes from the viable physiological medium (interstitial fluid, blood) occupying the layers of the viable epidermis and dermis. Sensing is achieved on a continuous, quasi-continuous, periodic, or single- shot fashion.
- the sensor device contains, in some embodiments, a wireless radio configured to relay data, measurements, or readings to connected wirelessly-enabled devices such as smartphones, smartwatches, and therapeutic delivery systems.
- the said device contains at least one electrical contact configured to relay data, measurements, or readings to a mechanically-coupled therapeutic delivery system.
- Therapeutic delivery systems are configured to infuse a therapy, drug,
- a user most commonly contain a reservoir for said therapy, a dispensing mechanism or actuator to control the quantity or dosage of said therapy, a power source (i.e. battery), and an electrical controller containing an embedded control algorithm programmed into firmware.
- these systems feature a wireless radio configured to relay data, measurements, or readings to connected wirelessly-enabled devices such as smartphones, smartwatches, and continuous analyte monitors.
- Embodiments of therapeutic delivery systems include skin-worn integrated patch pumps integrating both the pump and cannula for subcutaneous delivery of the therapy.
- said therapeutic delivery systems contain a non-skin worn pump and a skin-adorned infusion set.
- Continuous subcutaneous insulin infusion (CSII) and automated insulin delivery (AID) systems comprised of an insulin pump, control algorithm, and method of data interface with a continuous glucose monitor, have been at the forefront of development activities in this domain owing to the potential for closed-loop operation aimed at automating the delivery of insulin to counteract glycemic excursions and maximize the user’s time in euglycemia, otherwise known as time-in-range.
- CSII continuous subcutaneous insulin infusion
- AID automated insulin delivery
- Control algorithms which are designed to modulate the delivery of a therapy via a therapeutic delivery system based on a data input provided by a continuous analyte sensor, enable the automated delivery of a therapeutic intervention, the dosage of which is controlled to counteract pathophysiological states. While basal rate delivery entails a fixed temporal rate of therapeutic delivery, the ability to measure at least one analyte provides for an effective method of feedback, hence lending itself to fully autonomous closed-loop therapy.
- analyte sensors may comprise continuous glucose monitors and therapeutic delivery systems may constitute continuous subcutaneous insulin infusion (CSII) systems.
- CSII continuous subcutaneous insulin infusion
- Continuous glucose monitors are configured to measure glucose beneath the skin and CSII systems comprise a pump paired with an infusion set or are otherwise integrated into a skin- adhered patch (also known as a tubeless pump) and configured to deliver a prescribed dose of insulin.
- a control algorithm residing within the CSII, continuous glucose monitor, or wirelessly-paired device calculates the dosage of therapy required to counteract a pathophysiological state based on the readings from said continuous glucose monitor and achieve tight glycemic control, preferably within the euglycemic range (70 - 180 mg/dL).
- Said control algorithm is designed to monitor the controlled process variable (i.e. glucose level by means of the continuous glucose monitor), and compares it with the reference or set point (i.e.
- the difference between the actual and desired value of the process variable, called the error signal, or SP-PV error, is applied as feedback to generate a control action to bring the controlled process variable to the same value as the set point.
- the primary objective of the control algorithm is the minimization of the error signal.
- the system can operate under closed-loop control (i.e. the control action from the controller is dependent on feedback from the process in the form of the value of the process variable) or open-loop control (i.e. the control action from the controller is independent of the process output). In various embodiments, no feedback or negative feedback may be employed. Negative feedback has the advantage that unstable processes can be stabilized, reduced sensitivity to parameter variations, and improved set point performance.
- the control algorithm resides in a memory or processor embedded within the CSII system.
- the control algorithm receives as an input glucose data manually entered by the user (such as from a finger-stick blood sample), or streamed from a continuous glucose monitor (usually wirelessly, but the processor could have a direct electrical connection co-located in a single device).
- An exemplary closed-loop controller architecture is the proportional-integral- derivative (PID) controller.
- PID controller makes extensive use of the transfer function, also known as the system function or network function, which is composed of a mathematical model (i.e. set of time- or process-dependent equations) of the relation between the input and output of the system.
- Another embodiment of the control algorithm can comprise of at least one of a proportional-integral-derivative, model predictive control, fuzzy logic, and safety supervision design (Ann. NY Acad. Sci. 2014 Apr: 1311 : 102-23).
- the current invention teaches of devices and methods for sensing an analyte, or plurality of analytes, and delivering a concomitant therapeutic intervention, or plurality of therapeutic interventions, in distinct physiological compartments, using a single body-worn device, to avoid issues associated with cross-talk, interference, contamination, and/or dilution that arise when performing both actions in a spatial vicinity.
- the single body-worn device is configured to be easily applied to the skin of a wearer and engages in a sensing routine in the viable epidermis or dermis of said wearer. Delivery or infusion of a therapeutic intervention is directed at the deeper and anatomically separate and distinct subcutaneous adipose tissue layer.
- Embodiments can either include an open-loop system, whereby the wearer adjusts dosing of said therapeutic intervention based on levels of said analyte, or plurality of analytes, and a close-loop system, whereby a control algorithm autonomously adjusts dosing of the therapeutic intervention or plurality of therapeutic interventions.
- a solution-phase therapeutic agent i.e. insulin
- needle- and cannula-based sensor systems configured for continuous quantification of an analyte (i.e. glucose).
- analyte i.e. glucose
- both systems are not amenable for co-location within a single body- worn device.
- undesired chemical interactions are likely to occur in scenarios of concurrent operation of an analyte sensor device and a therapeutic delivery device co-habilitating a given physiological compartment; among these undesired effects are cross-talk, interference, contamination, and localized dilution, which directly affect the sensor’s ability to quantify the desired analyte with a specified degree of selectivity, sensitivity, stability, and response time.
- insulin liquid formulations which are often employed in insulin pumps, include m-Cresol and methyl p- hydroxybenzoate as preservative agents. 1 Although both compounds are effective in preserving the activity of insulin over extended duration of storage and in the wake of significant temperature fluctuations, these substances are electroactive and interfere with the concurrent electrochemical detection of glucose.
- the analyte sensing and therapeutic delivery modalities are both configured to operate in the subcutaneous adipose tissue otherwise known as the subcutis, sub-dermis, or hypodermis. If co-location of both systems into a singular body-worn device is desired, a key challenge arises - sufficient spatial separation of the analyte-sensing and therapeutic delivery modalities such that both can operate in an isolated manner (i.e. either system remaining unaffected by the routines executed at the other contingent).
- Body-worn analyte sensors (such as continuous glucose monitors) are sensitive electrochemical systems that are configured to sense an analyte, or plurality of analytes, in a selective fashion with a high-degree of accuracy.
- the senor can be configured to exclude other endogenous analytes from interfering with the detection process, however, the perturbation of equilibrium conditions (such as those arising from infusion) in the vicinity of said sensor can instigate errant readings that are not reflective of the level of the analyte in situ, not to mention that a multitude of exogenous therapeutic agents can directly interfere with the quantification of said analyte.
- the current invention addresses the challenge of co-location of both the analyte sensing and therapeutic delivery modalities in the same on-body device in the same physiological compartment by facilitating the separation of the analyte sensing and therapeutic delivery routines in distinct physiological compartments (skin strata) that are transversely rather than laterally separated.
- the innovation represents an alternative approach facilitating the delivery of a therapeutic treatment without causing a subsequent and undesired response in an analyte-selective sensor operating in close proximity to the therapeutic solution; this is achieved by locating both the sensing and delivery contingents in unalike physiological compartments even in scenarios where both modalities are located in the same lateral spatial vicinity, such as within a singular body -worn device.
- An exemplary embodiment of the analyte sensor in this invention constitutes a microneedle or microneedle array configured to sense at least one analyte in the viable epidermal or dermal layer of the skin and a cannula-based infusion set or patch pump configured to deliver at least one of a therapeutic intervention such as a solution-phase drug, pharmacologic, biological, or medicament into subcutaneous adipose tissue layer.
- Transverse separation between the two contingents in various embodiments can be in the range of 2mm to 50mm, and most preferably from 5mm to 25mm. Both physiological compartments are expected to be sufficiently isolated so as to mitigate likely occurrences of cross-talk, interference, contamination, and localized dilution of the analyte undergoing detection.
- FIG. 5A is an illustration of an integration of a microneedle array-based
- FIGS. 5B, 6A and 6B illustrate the integration of a microneedle array-based analyte-selective sensor 20 into a patch pump 525.
- FIG. 6C illustrates the microneedle array -based analyte- selective sensor 20 and microneedles 25.
- the technology disclosed herein juxtaposes the analyte sensor system and therapeutic delivery system to operate in different physiological compartments yet maintain minimum spatial separation between the two. This is achieved by dispensing the analyte sensor in the viable epidermis or dermis of a wearer, whereby the system is configured to quantify an analyte, or plurality of analytes, residing therein.
- the therapeutic delivery system is dispensed in the subcutaneous region.
- Transverse separation of both the sensing and delivery modalities, confining the sensing routine to the viable epidermis or dermis and delivery routine to the subcutaneous adipose tissue, enables the isolation of both routines, thus mitigating likely occurrences of cross-talk, interference, contamination, and localized dilution of the analyte undergoing detection should both be co-located in a given physiological compartment.
- the system can function under an open-loop paradigm whereby therapy is instigated by a user and guided by measurements from said sensor.
- the system can feature a control algorithm to autonomously deliver a therapeutic intervention in response to a sensor reading or plurality of readings. It is expected that this paradigm will have profound implications for diabetes management and, in particular, those who are undergoing intensive insulin therapy.
- An open loop embodiment of the present invention comprises a system
- the system is preferably a body- worn device capable of incorporating both the sensor and the infusion sub-system to deliver a therapeutic agent in a physically-distinct compartment from the region in which the analyte is detected.
- the sensor is preferably a plurality of microneedles, possessing vertical extent between 200 and 2000 mm, configured to selectively quantify the levels of at least one analyte located within the viable epidermis or dermis.
- FIG. 3 illustrates the microneedle arrary sensor 325 in relation to a dime 301 and needle 305.
- the sensor is designed to measure the analyte in one distinct layer of the skin, for example, the viable epidermis or dermis.
- the infusion sub-system is designed to deliver the therapeutic agent to a different and physically distinct layer of the skin, for example the subcutaneous adipose tissue.
- the infusion sub-system is preferably a fluid delivery apparatus configured to provide infusion of a solution- phase therapeutic agent into the subcutaneous adipose layer, circulatory system (venous, arterial, or capillary), or musculature via intravenous line, hypodermic needle, infusion cannula or oral delivery route.
- the therapeutic agent is preferably a solution-phase drug, pharmacologic, biological, or medicament.
- the sensor may be incorporated onto the bottom of an insulin infusion cannula set adhered to the skin with medical adhesive and attached to the insulin pump by a hollow plastic tube.
- the sensor may be incorporated onto the bottom of an insulin patch pump adhered to the skin with medical adhesive.
- a closed loop embodiment of the present invention comprises a system
- the system is preferably a body- worn device, with a control algorithm, capable of incorporating both the sensor and the infusion sub-system to deliver a therapeutic agent in a physically-distinct compartment from the region in which the analyte is detected.
- the sensor is preferably a plurality of microneedles, possessing vertical extent between 200 and 2000 pm, configured to selectively quantify the levels of at least one analyte located within the viable epidermis or dermis.
- the sensor is designed to measure the analyte in one distinct layer of the skin, for example, the viable epidermis or dermis.
- the infusion sub-system is designed to deliver the therapeutic agent to a different and physically distinct layer of the skin, for example the subcutaneous adipose tissue.
- the infusion sub-system is preferably a fluid delivery apparatus configured to provide infusion of a solution-phase therapeutic agent into the subcutaneous adipose layer, circulatory system (venous, arterial, or capillary), or musculature via intravenous line, hypodermic needle, infusion cannula or oral delivery route.
- the therapeutic agent is preferably a solution-phase drug, pharmacologic, biological, or medicament.
- the sensor may be incorporated onto the bottom of an insulin infusion cannula set adhered to the skin with medical adhesive and attached to the insulin pump by a hollow plastic tube.
- the senor may be incorporated onto the bottom of an insulin patch pump adhered to the skin with medical adhesive.
- Therapy is defined as the dose profile of the therapeutic agent in response to the measurement of the analyte, which may be controlled by an algorithm.
- the control algorithm is preferably a software or firmware routine employing one or more mathematical transformations to control dosing of a therapeutic agent, either by means of controlling the quantity delivered, duration of delivery, and/or frequency of delivery, based on input from a user or from measurements recorded by a microneedle array analyte-selective sensor.
- the mathematical transformation can employ additional inputs, either provided by a user or integrated autonomously from elsewhere.
- FIG. 7 is a block / process flow diagram illustrating the major method steps of the OPEN LOOP embodiment of the invention.
- the method 700 for performing the open loop embodiment begins at block 701 with a microneedle array analyte-selective sensor recording a measurement of an analyte or plurality of analytes in the viable epidermis or dermis. Circulating levels of an analyte within the viable epidermis or dermis is quantified by means of the sensor.
- a measurement or measurements from the microneedle array analyte- selective sensor is displayed to a user.
- the user receives a reading of the circulating level of an analyte or plurality of analytes on a display or interface. Alternatively, user receives notification that the circulating level of an analyte or plurality of analytes extends beyond a pre-defmed criteria or range of values.
- the user adjusts dosing, if necessary, of a therapeutic agent or plurality of therapeutic agents. The user manipulates a quantity, duration, or frequency of infusion of the therapy based on measurement of analyte or plurality of analytes tendered by the sensor.
- the therapeutic agent or plurality of therapeutic agents is administered into the subcutaneous adipose layer, circulatory system (venous, arterial, or capillary), musculature or oral delivery route by means of the therapeutic delivery mechanism.
- the therapy is delivered to the user via the infusion sub-system and is based on the user’s determination of dosage given measurement or measurements from the sensor.
- FIG. 8 is a block / process flow diagram illustrating the major method steps of the CLOSED LOOP embodiment of the invention.
- the method 800 for performing the closed loop embodiment begins at block 801 with a microneedle array analyte- selective sensor recording a measurement of an analyte or plurality of analytes in the viable epidermis or dermis. Circulating levels of an analyte within the viable epidermis or dermis is quantified by means of the sensor.
- a measurement or measurements from the microneedle array analyte-selective sensor is input into a control algorithm; optionally, the measurement or measurements are displayed to the user.
- the control algorithm adjusts dosing, if necessary, of a therapeutic agent or plurality of therapeutic agents based on a programmed mathematical transformation.
- the algorithm autonomously manipulates a quantity, duration, or frequency of infusion of the therapy based on measurement of analyte or plurality of analytes tendered by the sensor.
- the therapeutic agent or plurality of therapeutic agents is administered into the subcutaneous adipose layer, circulatory system (venous, arterial, or capillary), musculature or oral delivery route by means of the therapeutic delivery mechanism.
- the therapy is delivered to the user via the infusion sub-system and is based on the determination of dosage given output of the algorithm.
- the input of circulating levels of an analyte or plurality of analytes within the viable epidermis or dermis is an endogenous or exogenous biochemical agent, metabolite, drug, pharmacologic, biological, or medicament in the viable epidermis or dermis, indicative of a particular physiological or metabolic state.
- the output is an administration of a therapeutic agent or plurality of
- therapeutic agents into the circulatory system (venous, arterial, or capillary), musculature or oral delivery route.
- a measurement tendered by the sensor is employed to instigate the release of the therapy by means of the infusion sub-system.
- the delivery of the therapy is controlled by a user.
- the algorithm is employed to control the dose, duration, and frequency of the therapy.
- FIG. 9 is a block / process flow diagram 900 illustrating the inputs, outputs, and major constituents of the invention under the OPEN LOOP embodiment.
- circulating levels of an analyte or an analytes are within the dermis.
- a sensor measures the analytes.
- the user adjusts dosing, if necessary, of a therapeutic agent or plurality of therapeutic agents.
- the user 903 manipulates a quantity, duration, or frequency of infusion of the therapy 904 based on measurement of analyte or plurality of analytes tendered by the sensor.
- the therapeutic agent or plurality of therapeutic agents is administered into the subcutaneous adipose layer, circulatory system (venous, arterial, or capillary) musculature or oral delivery route by means of the therapeutic delivery mechanism.
- the therapy is delivered to the user via the infusion sub-system and is based on the user’s determination of dosage given measurement or measurements from the sensor.
- FIG. 10 is a block / process flow diagram 1000 illustrating the inputs, outputs, and major constituents of the invention under the CLOSED LOOP embodiment.
- circulating levels of an analyte or an analytes are within the dermis.
- a sensor measures the analytes.
- the control algorithm 1003 adjusts dosing, if necessary, of a therapeutic agent or plurality of therapeutic agents based on a programmed mathematical transformation.
- the algorithm autonomously
- the therapeutic agent or plurality of therapeutic agents is administered into the subcutaneous adipose layer, circulatory system (venous, arterial, or capillary), musculature or oral delivery route by means of the therapeutic delivery mechanism.
- the therapy is delivered to the user via the infusion sub-system and is based on the determination of dosage given output of the algorithm
- FIGS. 13-15 illustrate an insulin patch pump 1300 having a body 1305 with a fully integrated microarray sensor 20 in a bottom surface 1310.
- FIGS. 16-17 illustrate an alternative embodiment with an insulin patch pump 1300 with a microarray sensor 20 connected via a connector 1350 on a bottom surface 1310 of the patch pump 1300.
- FIG. 18 illustrates an insulin patch pump 1300 with a recess 1335 in a bottom surface 1310 of the patch pumpml300 for positioning over a microarray sensor (not shown) that has already been applied to a patient’s skin
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Priority Applications (7)
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KR1020217033487A KR20220013542A (en) | 2019-03-25 | 2020-03-20 | Apparatus and Method for Incorporation of Microneedle Array Analyte-Selective Sensors |
AU2020244743A AU2020244743A1 (en) | 2019-03-25 | 2020-03-20 | Devices and methods for the incorporation of a microneedle array analyte-selective sensor |
JP2021558506A JP2022527794A (en) | 2019-03-25 | 2020-03-20 | Devices and Methods for Incorporating Microneedle Array Analyte Selection Sensors |
EP20777285.6A EP3946513A4 (en) | 2019-03-25 | 2020-03-20 | Devices and methods for the incorporation of a microneedle array analyte-selective sensor |
CN202080030685.8A CN113727747A (en) | 2019-03-25 | 2020-03-20 | Apparatus and method for incorporating a microneedle array analyte selective sensor into an infusion set, patch pump, or automated therapy delivery system |
CA3131168A CA3131168A1 (en) | 2019-03-25 | 2020-03-20 | Devices and methods for the incorporation of a microneedle array analyte-selective sensor |
IL286594A IL286594A (en) | 2019-03-25 | 2021-09-22 | Devices and methods for the incorporation of a microneedle array analyteselective sensor |
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US201962823628P | 2019-03-25 | 2019-03-25 | |
US62/823,628 | 2019-03-25 | ||
US16/824,700 US20200254240A1 (en) | 2016-05-15 | 2020-03-20 | Devices and Methods For The Incorporation Of A Microneedle Array Analyte-Selective Sensor Into An Infusion Set, Patch Pump, Or Automated Therapeutic Delivery System |
US16/824,700 | 2020-03-20 |
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KR (1) | KR20220013542A (en) |
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WO2011091061A1 (en) * | 2010-01-19 | 2011-07-28 | Medtronic Minimed, Inc. | Insertion device for a combined sensor and infusion sets |
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EP2732837A2 (en) | 2007-08-29 | 2014-05-21 | Medtronic MiniMed, Inc. | Combined sensor and infusion set using separated sites |
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2020
- 2020-03-20 AU AU2020244743A patent/AU2020244743A1/en not_active Abandoned
- 2020-03-20 WO PCT/US2020/023771 patent/WO2020197968A1/en unknown
- 2020-03-20 KR KR1020217033487A patent/KR20220013542A/en unknown
- 2020-03-20 JP JP2021558506A patent/JP2022527794A/en active Pending
- 2020-03-20 CA CA3131168A patent/CA3131168A1/en active Pending
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2021
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EP0789540A1 (en) | 1994-11-04 | 1997-08-20 | Elan Medical Technologies Limited | Analyte-controlled liquid delivery device and analyte monitor |
US20120065482A1 (en) * | 2005-04-08 | 2012-03-15 | Mark Ries Robinson | Determination of blood pump system performance and sample dilution using a property of fluid being transported |
EP2732837A2 (en) | 2007-08-29 | 2014-05-21 | Medtronic MiniMed, Inc. | Combined sensor and infusion set using separated sites |
WO2011091061A1 (en) * | 2010-01-19 | 2011-07-28 | Medtronic Minimed, Inc. | Insertion device for a combined sensor and infusion sets |
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JP2022527794A (en) | 2022-06-06 |
KR20220013542A (en) | 2022-02-04 |
IL286594A (en) | 2021-12-01 |
AU2020244743A1 (en) | 2021-10-14 |
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