KR20220013542A - Apparatus and Method for Incorporation of Microneedle Array Analyte-Selective Sensors - Google Patents

Abstract

Disclosed herein are an apparatus 1300 and a method 700 for passively delivering a therapeutic intervention in response to a physiological condition of a user. Device 1300 includes a sensor 20 , an infusion system, and a single body-worn component 1305 . The sensor 20 is configured to penetrate the stratum corneum, access the viable epidermis or dermis, and measure the presence of an analyte. The infusion system is configured to deliver a solution-phase therapeutic agent based on a user action or control algorithm.

Description

Apparatus and Method for Incorporation of Microneedle Array Analyte-Selective Sensors

The technology described herein relates to therapeutic delivery mechanisms, analyte-selective sensors, and methods of constructing the same.

Continuous delivery of therapeutics remains an important technology in modern medical devices. The most important example of such a medical device is an insulin pump, also known as a continuous subcutaneous insulin infusion (CSII) system. Insulin pumps were developed in the 1980s and commercialized in the 1990s, providing 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 raised 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. was recognized More recently, insulin pumps automatically administer insulin infusions upon actual or impending occurrence of hypoglycemia as determined by an algorithm designed to use input from a continuous glucose monitoring system to minimize the occurrence, severity, or duration of hypoglycemia. designed to be reserved. The insulin pump also continuously maintains glucose levels at an euglycemic setpoint or within an euglycemic window (or region) determined by an algorithm designed to use input from a continuous glucose monitoring system to achieve improved glycemic control. constructed to modulate insulin delivery. The system is variously described as an artificial pancreas device, an automatic insulin delivery system, an automatic glucose control system, and a closed loop system, among other detailed descriptions. In this scenario, both analyte sensing and therapeutic delivery modalities involve two separate and detachable devices worn on the body. However, a major hurdle for many patients in using this technique is two separate body mounted devices, as shown in FIG. 2 , with two devices 205 and 210 positioned on a user 215 . -body) is the use of the device. Co-deployment of both analyte sensing and therapeutic delivery components in a single wearable device, in response to the goal for an integrated sensing-therapeutic system and the need for miniaturized body-worn devices, is an enabling development is the area As discussed above, the co-position of sensing and therapeutic contingents has its own problems (delivery of therapeutic agents in close proximity to analyte sensing modalities is often a key technical problem such as cross-talk of the analyte being detected). talk), causing interference, contamination and local dilution). For this reason, sensing and transmitting components have often been attributed to physically separate locations in the body.

Continuous subcutaneous insulin infusion (CSII) systems are widely used in patients with type 1 diabetes. An increasing number of patients with type 2 diabetes are also using the CSII system. There are two general classes of CSII devices: one with a tube for delivery of insulin, the other with a small cannula that protrudes from the device and is inserted directly into the tissue and is tubeless (or tubeless). The tubular device consists of an LED display and a touchpad for command entry with a programmable electromechanical pump device. Tubular pumps are typically 6-8 cm long, 4-6 cm wide, and 2-4 cm thick, delivered to the body via a 24-48" plastic tube that ends with an infusion set with a needle or cannula inserted into the subcutaneous adipose tissue. Tubeless devices (sometimes referred to as patch pumps) do not have an LED display or touchpad for commands, but instead consist of a dedicated medical device or a smartphone running a regulated mobile medical application. It consists of an electromechanical pump unit with radio function for a separate control unit The patch pump is typically 3-5 cm long, 2-4 cm wide and 2-3 cm thick, and protrudes from the bottom of the patch pump and also Contains a reservoir with insulin delivered to the body via a short 2-3 cm cannula inserted into subcutaneous adipose tissue Current infusion systems configured for delivery of solution-phase therapeutic agents (i.e. insulin) are often paired with a needle- and cannula-based sensor system configured for continuous quantification of analytes (i.e. glucose), although the system operates in concert and is configured to operate in similar physiological compartments, such as the subcutaneous fat layer of tissue; Neither system is well tolerated for co-deployment within a single wearable device.Partly this is due to the problems associated with the insertion of two cannulas physically attached to a single integrated device.However, the main problem is that the two This occurs due to the lack of isolation during operation of both systems in close proximity, i.e., unwanted chemical interactions would occur in the scenario of simultaneous operation of an analyte sensor device and a therapeutic delivery device co-located in a given physiological compartment. Most likely; unwanted effects of these are crosstalk, interference, contamination and local dilution, which directly affect the ability of the sensor to quantify the desired analyte with a certain degree of selectivity, sensitivity, stability and response time.

A major obstacle to the successful co-deployment of glucose sensing and insulin infusion is the detrimental effect of preservatives in current insulin formulations on the enzymatic properties of standard commercial glucose sensors. Insulin diffuses much more easily horizontally than vertically along the path of least resistance in the subcutaneous adipose tissue layer. These recent discoveries are aimed at obtaining a single body-mounted device that can measure glucose in the dermis (<1 mm below the surface of the skin) and simultaneously inject insulin into the subcutaneous adipose tissue (~10-40 mm below the surface of the skin). Supports the invention described in this application. 11 is an illustration (not shown to scale) of an injection system 45 configured to operate within subcutaneous tissue 45 with a patient's skin 40 including epidermis 41 , dermis 42 , and subcutaneous tissue 43 . is not). Graph 1200 , graph 1210 , graph 1220 , and graph 1230 of FIGS. 12A-12D from Jockel et al. show preferential patterns of asymmetric horizontal diffusion for different volumes of insulin injected into tissue. Jockel et al. showed that this preferential diffusion of insulin in the horizontal direction limits the vertical extent of insulin storage to about 4 mm, even for large volumes of insulin. Therefore, to achieve a physical separation of 10 mm or more between the microneedle array in the dermis for measuring glucose and the distal tip of the cannula injecting insulin into the adipose tissue, it is possible to prevent contamination of the glucose sensor and maintain the insulin delivery system. sufficient to allow physical integration of the glucose monitor.

Algorithms for artificial pancreatic devices rely heavily on control theory and accepted theories in chemical engineering, and can be divided into several categories. In the first category, algorithms for artificial pancreatic devices are unihormonal or bihormonal. The monohormonal system uses insulin infusion alone to avoid hyperglycemia and maximize time at normoglycemia. In monohormonal systems, hypoglycemia can be prevented or treated by withholding insulin based on actual readings of the continuous glucose monitoring system or predicted glucose values derived from continuous glucose monitoring data. In bihormonal systems, hyperglycemia is avoided or treated by insulin infusion as in monohormonal systems, but hypoglycemia is prevented or treated by injecting glucagon, which stimulates the liver to produce endogenous glucose. In a second category, optimization of insulin delivery and glycemic control is achieved through different algorithmic approaches such as Model Predictive Control (MPC), Proportional Integral Derivative (PID), or Fuzzy Logic (FL). can be achieved by Finally, artificial pancreas can also be categorized by degree of automation. Hybrid closed-loop systems require user initiation of a meal boluse based on a quantitative or qualitative estimate of meal size. In contrast, a fully closed-loop system automates insulin delivery at mealtime and requires no user intervention on the meal bolus.

Prior art solutions have been of great interest in operating both sensing and delivery systems as removable, wearable devices that operate in the same physiological compartment, although they are spatially separated to a sufficient extent to avoid interaction between the two systems. . Interactions can take many forms (crosstalk, interference, contamination, and dilution). Prior art implementations of analyte sensing schemes include cannula-assisted, subcutaneously-implanted wire-based sensors configured to quantify analytes using electrochemical transformation techniques. Prior art embodiments of therapeutic delivery modalities include cannula-based patch pumps and infusion sets configured to deliver therapy to subcutaneous adipose tissue. 1A is a prior art needle-/cannula-based analyte-selective sensor 110 having a mobile phone 105 and a user interface device 115 configured for quantification of glucose in subcutaneous adipose tissue. 1B is a prior art needle-/cannula-based analyte-selective sensor 130 having a user interface device 125 configured for quantification of glucose in subcutaneous adipose tissue. 1C is a prior art needle-/cannula-based analyte-selective sensor 150 having a user interface device 145 configured for quantification of glucose in subcutaneous adipose tissue. Although more recent prior art features sufficient lateral or spatial isolation between the sensing and transmissive agents to minimize the interaction between the two, even when operating in the same physiological compartment, The co-placement of both sensing and delivery modalities within a single wearable device was taught.

Although the motivation for the integration of both devices may seem obvious, a number of physiological and technical problems have prevented successful resolution of these problems. The biggest obstacle to the co-location of insulin infusion and glucose sensing appears to be the preservatives used for stabilization of insulin formulations that impair the enzymes used in typical glucose sensors.

The invention described herein achieves the object of disposing these components in separate physiological compartments, while at the same time allowing their integration into a single body mounted device.

One aspect of the invention is a device for passively delivering a therapeutic intervention in response to a physiological condition of a user. The device includes a sensor, an injection system, a single wearable component, and a control algorithm. The sensor is configured to penetrate the stratum corneum to access the viable epidermis or dermis and to measure the presence of an analyte or a plurality of analytes in a selective manner. The infusion system is configured to deliver the solution-phase therapeutic agent or collection of therapeutic agents in a controlled manner to separate physiological compartments separate from the living epidermis and dermis. A single wearable component integrates the sensor and injection system. The device is configured to deliver a specified dose of the therapeutic agent through an infusion system based on an output of the control algorithm.

Another aspect of the invention is a device for passively delivering a therapeutic intervention in response to a physiological condition of a user. The device includes a sensor, an injection system, and a single wearable component. The sensor is configured to penetrate the stratum corneum to access the living epidermis or dermis and to measure the presence of an analyte or a plurality of analytes in a selective manner. The infusion system is configured to deliver the solution-phase therapeutic agent or collection of therapeutic agents in a controlled manner to separate physiological compartments separate from the living epidermis and dermis. A single wearable component integrates the sensor and injection system. The device is configured to deliver a specified dose of the therapeutic agent through the infusion system based on the user's action.

Yet another aspect of the present invention is a method for passively delivering a therapeutic intervention in response to a physiological condition of a user using a single wearable component. The method comprises measuring the presence of an analyte or a plurality of analytes in a live epidermis or dermis by a sensor in a selective manner. The method also includes inputting measurements of the analyte or plurality of analytes to the control algorithm. The method also includes causing the infusion system to deliver a specified dose of the solution-phase therapeutic agent or collection of therapeutic agents to the physiological compartment under the dermis based on the output of the control algorithm.

1A is a prior art needle-/cannula-based analyte-selective sensor configured for quantification of glucose in subcutaneous adipose tissue.
1B is a prior art needle-/cannula-based analyte-selective sensor configured for quantification of glucose in subcutaneous adipose tissue.
1C is a prior art needle-/cannula-based analyte-selective sensor configured for quantification of glucose in subcutaneous adipose tissue.
2 is a prior art implementation of an analyte-selective sensor device (left) and an injection system (right), both of which feature extensive spatial separation avoiding unwanted interactions.
3 shows a prior art needle-/cannula-based analyte-selective sensor configured for quantification of glucose in subcutaneous adipose tissue (left) and a microneedle array-based analyte-selective sensor configured for quantification of glucose in the dermis. (right).
Figure 4 is a pictorial representation (not scaled) of an injection system configured to act in subcutaneous tissue (left) and an analyte-selective sensor configured to act in the dermis (right), both placed in very close proximity.
5A is an illustration of integration of a microneedle array-based analyte-selective sensor into an infusion set.
5B is the proposed integration of a microneedle array-based analyte-selective sensor into a patch pump.
6A is the proposed integration of a microneedle array-based analyte-selective sensor into a patch pump.
6B is the proposed integration of a microneedle array-based analyte-selective sensor into a patch pump.
FIG. 6C is an exploded view of the circle 6C of FIG. 6B .
7 is a block/process flow diagram illustrating the main method steps of an OPEN LOOP implementation of the present invention.
8 is a block/process flow diagram illustrating the main method steps of a CLOSED LOOP implementation of the present invention.
9 is a block/process flow diagram illustrating the input, output and key components of the present invention under an open loop implementation.
Figure 10 is a block/process flow diagram illustrating the input, output and key components of the present invention under a closed loop implementation.
11 is an illustration (not to scale) of an infusion system configured to operate within subcutaneous tissue.
12A is an illustration of a graph related to insulin depot formation in subcutaneous adipose tissue.
12B is an illustration of a graph related to insulin storage formation in subcutaneous adipose tissue.
12C is an illustration of a graph related to insulin storage formation in subcutaneous adipose tissue.
12D is an illustration of a graph related to insulin storage formation in subcutaneous adipose tissue.
13 is a top perspective view of an insulin patch pump with fully integrated microarray sensors.
14 is a bottom perspective view of an insulin patch pump with fully integrated microarray sensors.
15 is a side view of an insulin patch pump with fully integrated microarray sensors.
16 is a bottom perspective view of an insulin patch pump with microarray sensors connected via connectors.
17 is an exploded view of a microarray sensor connected to a connector.
18 is a bottom perspective view of an insulin patch pump with grooves for microarray sensors applied to a patient's skin.

Microneedle-based analyte-selective sensors have increased development activity in recent years and are promising for minimally-invasive quantification of a number of related analytes in physiological fluids such as interstitial fluid, dermal interstitial fluid blood, serum and plasma. indicates ability. Such a device consists of an array of at least two protrusions on a substrate, each protrusion attached to the substrate at its proximal end and extending 200 to 2000 micrometers to its distal end. At least one of said protrusions is configured to feature at least one electrode comprising a metallic, semiconducting or polymeric material, which may be further coated with one or more polymeric films. In certain embodiments, a recognition element is disposed on the electrode or within the membrane to confer selective sensing capability for endogenous or exogenous chemical species occupying the physiological fluid. The chemical species comprises at least one of biomarkers, chemicals, biochemicals, metabolites, electrolytes, ions, hormones, neurotransmitters, vitamins, minerals, drugs, therapeutics, toxins, enzymes, proteins, nucleic acids, DNA, and RNA. may include The sensing method may include electrical, chemical, electrochemical (voltage current, current measurement, potential difference), optical, fluorescence analysis, chromaticity analysis, absorbance, radiation, conductivity measurement, impedance, resistance, and capacitance. Typical modes of application include user-supplied forces, packaging in which stored potential energy is transferred to kinetic energy upon actuation actuation performed by the user, and sensing within the living epidermis or dermis where microneedle components of the array penetrate the stratum corneum. In an applicator capable of accelerating the microneedle-based analyte-selective sensor, facilitating intradermal analysis of an appropriate analyte from a living physiological medium (interstitial fluid, blood) occupying the layers of the living epidermis and dermis by achieving including by Sensing is achieved in a continuous, semi-continuous, periodic or single-shot manner. The sensor device, in some implementations, contains a wireless radio configured to relay data, measurements or readings to connected wireless-enabled devices such as smartphones, smartwatches and therapeutic delivery systems. In another embodiment, the device contains at least one electrical contact configured to relay data, measurements or readings to a mechanically-coupled therapeutic delivery system.

A therapeutic delivery system is configured to inject a therapy, drug, medicament, pharmaceutical, or active ingredient into a physiological compartment of a user. Such devices most typically contain a reservoir for the therapy, a dispensing mechanism or actuator to control the amount or dosage of the therapy, a power source (ie, a battery), and an electrical control containing a built-in control algorithm programmed in firmware. contains the device. In some preferred embodiments, such systems feature a wireless radio configured to relay data, measurements or readings to connected wireless-enabled devices such as smartphones, smartwatches and persistent analyte monitors. Embodiments of the therapeutic delivery system include a skin-worn integrated patch pump that incorporates both a pump and a cannula for subcutaneous delivery of therapy. In another embodiment, the therapeutic delivery system contains a non-skin worn pump and a skin-adorned infusion set. A continuous subcutaneous insulin infusion (CSII) and automatic insulin delivery (AID) system comprising an insulin pump, a control algorithm, and a data interface method with a continuous glucose monitor, responds to blood glucose fluctuations and time-in- Due to the potential for closed-loop operation aimed at automating the delivery of insulin to maximize the user's time in normoglycemia, also known as range), it has been at the forefront of development activities in this area.

A control algorithm designed to coordinate delivery of therapy through a therapeutic delivery system based on data input provided by a persistent analyte sensor provides automatic delivery of a therapeutic intervention whose dosage is controlled to correspond to a pathophysiological condition. make it possible While basal rate delivery involves a fixed time rate of therapeutic delivery, the ability to measure at least one analyte provides an effective feedback method, making it suitable for fully autonomous closed-loop therapy. Specifically, the analyte sensor may comprise a continuous glucose monitor and the therapeutic delivery system may constitute a continuous subcutaneous insulin infusion (CSII) system. The continuous glucose monitor is configured to measure glucose under the skin, the CSII system comprising a pump paired with an infusion set or otherwise integrated into a skin-adhesive patch (also known as a tubeless pump) and prescribed dosage is configured to deliver insulin. A control algorithm present within the CSII, persistent glucose monitor, or radio-paired device responds to a pathophysiological condition based on readings from the continuous glucose monitor, preferably in the normoglycemic range (70 - 180 mg/dL). Calculate the dosage of therapy needed to achieve tight glycemic control in The control algorithm is designed to monitor a controlled process variable (ie, glucose level with a continuous glucose monitor) and compare it to a baseline or setpoint (ie, glucose level within the normoglycemic range). The difference between the actual value and the desired value of the process variable, referred to as the error signal or SP-PV error, is applied as feedback to generate a control action that brings the controlled process variable to a value equal to the set point. In other words, the main purpose of the control algorithm is to minimize the error signal. The system is capable of either closed-loop control (i.e., the control action from the controller relies 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 the process independent of the output value). In various implementations, no feedback or negative feedback may be used. Negative feedback has the advantage that unstable processes can be stabilized, reduce sensitivity to parameter changes, and improve set-point performance. In a preferred embodiment, the control algorithm resides in a memory or processor embedded within the CSII system. Typically, the control algorithm (resident in the processor or memory) is either entered manually by the user (eg from a finger-stick blood sample) or streamed from a persistent glucose monitor (usually wirelessly, but The processor may have a direct electrical connection co-located in a single device) and receives glucose data as input.

An exemplary closed loop controller architecture is a proportional-integral-derivative (PID) controller. Like other exemplary systems, the PID controller makes extensive use of transfer functions, also known as system functions or network functions, which are mathematical models of the relationship between the input and output values of the system (i.e., time- or process- set of dependent equations). Another implementation of the control algorithm may consist of at least one of proportional-integral-derivative, model predictive control, fuzzy logic and safety supervision design (Ann. NY Acad. Sci. 2014 Apr:1311:102-23). ).

The present invention provides an analyte in separate physiological compartments, using a single wearable device, to avoid the problems associated with crosstalk, interference, contamination and/or dilution that occur when both operations are performed in an adjacent space. or devices and methods for sensing a plurality of analytes and delivering a concomitant therapeutic intervention or a plurality of therapeutic interventions. The single wearable device is configured to be easily applied to the skin of a wearer and engages in a sensing routine in the living epidermis or dermis of the wearer. Delivery or infusion of a therapeutic intervention is directed to a deeper, anatomically separate and distinct subcutaneous adipose tissue layer. An embodiment provides an open loop system in which a wearer adjusts the dosage of the therapeutic intervention based on the level of the analyte or plurality of analytes, and a control algorithm automatically administers the dosage of the therapeutic intervention or plurality of therapeutic interventions. It may include a closed-loop system that adjusts to

Current needle- and cannula-based infusion systems configured for delivery of solution-phase therapeutic agents (ie, insulin) are often paired with needle- and cannula-based sensor systems configured for continuous quantification of analytes (ie, glucose). make up Although the systems work harmoniously and are configured to operate in the same physiological compartment, such as the subcutaneous fat layer of tissue, neither system is well tolerated for co-deployment within a single wearable device. Although in part this is due to problems associated with the insertion of two cannulas physically attached to a single integrated device, the main problem arises from the lack of isolation while both systems operate in close proximity. That is, undesired chemical interactions are more likely to occur in the scenario of simultaneous operation of an analyte sensor device and a therapeutic delivery device coexisting in a given physiological compartment; Among these unwanted effects are crosstalk, interference, contamination and local dilution, which directly affect the ability of the sensor to quantify the desired analyte with a certain degree of selectivity, sensitivity, stability and response time. For example, liquid insulin formulations often used in insulin pumps contain m -cresol and methyl p -hydroxybenzoate as preservatives. ¹ Although both compounds are effective in preserving the activity of insulin over extended storage periods and as a result of significant temperature fluctuations, these substances are electroactive and prevent simultaneous electrochemical detection of glucose. Therefore, in order to measure glucose accurately, the delivery of insulin must be spatially isolated from the sensor; This spatial isolation makes the integration of both sensing and therapeutic modalities into a single wearable device impractical. In addition, the co-deployment of both analyte sensing and therapeutic delivery agents in a single wearable device presents a notable challenge for application due to the difficulties associated with implantation of two cannulas simultaneously or in succession. Taken together, there is a strong incentive to integrate both analyte sensors and therapeutic delivery modalities in a single wearable device for wearer convenience and simplicity. This is driven especially by the current challenge of automatic insulin delivery, which has great promise for more effective management of insulin-dependent diabetes mellitus. Today, due to current design implementations, both analyte sensing and therapeutic delivery modalities are configured to operate in subcutaneous adipose tissue, otherwise known as the subcutis, sub-dermis or hypodermis. If co-deployment of both systems on a single wearable device is desired, a key challenge is (i.e., sufficient spatial separation of analyte-sensing and therapeutic delivery modalities so that they can both operate in an isolated manner (i.e., if the system remains unaffected by routines executed in )). Also, to a lesser extent, the co-deployment of both analyte sensing and therapeutic delivery systems in a single wearable device with a robust form-factor, particularly the macro-scale features and packaging of both systems, , because of its unique requirements for control electronics and hardware, it faces certain integration challenges.

A wearable analyte sensor (eg, a persistent glucose monitor) is a sensitive electrochemical system configured to sense an analyte or a plurality of analytes in a selective manner with high accuracy. In many cases, the sensor can be configured to exclude other endogenous analytes that interfere with the detection process, however, fluctuations in equilibrium conditions in the vicinity of the sensor (eg, rising from infusion) cause multiple exogenous therapeutic agents to quantify the analyte. It can lead to erroneous readings that do not reflect the level of the analyte in situ, not to mention that it can directly interfere with The present invention facilitates the separation of analyte sensing and therapeutic delivery routines in separate physiological compartments (skin layers) that are separated laterally rather than laterally, thereby providing analyte sensing and analyte sensing to the same body-mounted device in the same physiological compartment and Addresses the issue of co-location of both modalities of therapeutic delivery. The innovation represents an alternative approach that facilitates delivery of a therapeutic treatment without causing subsequent and unwanted responses in analyte-selective sensors operated in close proximity to the therapeutic solution; This is achieved by placing both sensing and delivery agents in dissimilar physiological compartments, even in scenarios where both approaches are deployed in the same adjacent lateral space, such as within a single wearable device. Exemplary embodiments of analyte sensors in the present invention include microneedles or microneedle arrays configured to sense at least one analyte in a living epidermal or dermal layer of skin, and therapeutic interventions such as solution-phase drugs, pharmacological, A cannula-based infusion set or patch pump configured to deliver at least one of a biological, or a medicament, to the subcutaneous adipose tissue layer. In various embodiments the lateral separation between the two agents (analyte sensor integrated in a patch pump or cannula-based infusion set) is in the range of 2 mm to 50 mm, most preferably in the range of 5 mm to 25 mm. can be Both physiological compartments are expected to be sufficiently isolated to mitigate the potential for cross-talk, interference, contamination, and local dilution of the analyte being detected.

5A is an illustration of integration of a microneedle array-based analyte-selective sensor 20 into an infusion set 500 .

5B , 6A and 6B illustrate integration of a microneedle array-based analyte-selective sensor 20 into a patch pump 525 . 6C illustrates a microneedle array-based analyte-selective sensor 20 and microneedle 25 .

The technology disclosed herein juxtaposes an analyte sensor system and a therapeutic delivery system, operating in different physiological compartments while maintaining minimal spatial separation between the two. This is accomplished by providing an analyte sensor in the living epidermis or dermis of the wearer, whereby the system is configured to quantify the analyte or plurality of analytes present therein. Conversely, the therapeutic delivery system is provided in the subcutaneous region. The lateral separation of both sensing and delivery modalities, confining the sensing routine to the living epidermis or dermis and the delivery routine to subcutaneous adipose tissue, enables the isolation of both routines, which must both be co-located in a given physiological compartment. Thus, the possibility of occurrence of crosstalk, interference, contamination, and local dilution of the detected analyte is mitigated. In a preferred embodiment of the present invention, the system can function under an open loop paradigm in which therapy is administered by the user and guided by measurements from said sensors. Alternatively, the system may feature a control algorithm for automatically delivering a therapeutic intervention in response to a sensor reading or plurality of readings. This paradigm is expected to have profound implications for diabetes management and especially for those undergoing intensive insulin therapy.

An open loop embodiment of the present invention includes a system that integrates a sensor and an infusion sub-system, and requires user action to effect delivery of a therapeutic intervention. The system is preferably a wearable device capable of incorporating both an injection sub-system for delivery of the sensor and therapeutic agent in a compartment physically-separate from the region where the analyte is to be detected. The sensor is preferably a plurality of microneedles, having a vertical dimension of 200 to 2000 μm, configured to selectively quantify the level of at least one analyte disposed within the living epidermis or dermis. 3 illustrates a microneedle array sensor 325 compared to a dime 301 and a needle 305 . The sensor is designed to measure an analyte in one distinct layer of skin, for example the living epidermis or dermis. The infusion sub-system is designed to deliver therapeutic agents to different and physically distinct layers of the skin, eg, subcutaneous adipose tissue. The infusion sub-system is preferably a fluid configured to provide infusion of a solution-phase therapeutic agent into the subcutaneous fat layer, the circulatory system (venous, arterial or capillary), or muscle tissue via an intravenous line, hypodermic needle, infusion cannula, or oral delivery route. It is a transmission device. The therapeutic agent is preferably a solution-phase drug, pharmacological, biological, or pharmaceutical. The sensor may be incorporated into the underside of a set of insulin infusion cannulaes that are adhered to the skin with a medical adhesive and attached to an insulin pump by a hollow plastic tube. Alternatively, the sensor may be incorporated into the underside of an insulin patch pump that is adhered to the skin with a medical adhesive.

A closed loop embodiment of the present invention includes a system that integrates a sensor and an infusion sub-system, and uses a control algorithm to effect delivery of a therapeutic intervention. The system is preferably a wearable device having a control algorithm that can incorporate both a sensor and an injection sub-system for delivering the therapeutic to a compartment physically-separate from the area where the analyte is detected. The sensor is preferably a plurality of microneedles, having a vertical dimension of 200 to 2000 μm, configured to selectively quantify the level of at least one analyte disposed within the living epidermis or dermis. The sensor is designed to measure an analyte in one distinct layer of skin, for example the living epidermis or dermis. The infusion sub-system is designed to deliver therapeutic agents to different and physically distinct layers of the skin, eg, subcutaneous adipose tissue. The infusion sub-system is preferably a fluid configured to provide infusion of a solution-phase therapeutic agent into the subcutaneous fat layer, the circulatory system (venous, arterial or capillary), or muscle tissue via an intravenous line, hypodermic needle, infusion cannula, or oral delivery route. It is a transmission device. The therapeutic agent is preferably a solution-phase drug, pharmacological, biological, or pharmaceutical. The sensor may be incorporated into the underside of a set of insulin infusion cannulaes that are adhered to the skin with a medical adhesive and attached to an insulin pump by a hollow plastic tube. Alternatively, the sensor may be incorporated into the underside of an insulin patch pump that is adhered to the skin with a medical adhesive. A regimen is defined as a dosage profile of a therapeutic agent in response to a measure of the analyte that can be controlled by an algorithm. The control algorithm, preferably based on input from the user or from measurements recorded by the microneedle array analyte-selective sensor, by controlling the amount delivered, the duration of delivery, and/or the frequency of delivery, A software or firmware routine that uses one or more mathematical transformations to control the dosage of a therapeutic agent. Mathematical transformations can use additional inputs provided by the user or automatically incorporated from elsewhere.

7 is a block/process flow diagram illustrating the main method steps of an open loop implementation of the present invention. A method 700 for performing an open loop embodiment begins at block 701 with a microneedle array analyte-selective sensor that records measurements of the analyte or plurality of analytes in the living epidermis or dermis. The circulating level of the analyte within the living epidermis or dermis is quantified by a sensor. Next, at block 702, the measurement or measurements from the microneedle array analyte-selective sensor are displayed to the user. The user receives a reading of the circulating level of the analyte or plurality of analytes on a display or interface. Alternatively, the user is notified that the circulating level of the analyte or plurality of analytes extends beyond a pre-defined range of criteria or values. Next, at block 703, the user adjusts the dosage of the therapeutic agent or the plurality of therapeutic agents as needed. The user manipulates the amount, duration or frequency of infusion of therapy based on measurements of the analyte or plurality of analytes provided by the sensor. Next, at block 704, the therapeutic agent or plurality of therapeutic agents is administered to the subcutaneous fat layer, the circulatory system (venous, arterial or capillary), muscle tissue, or oral delivery route by a therapeutic delivery mechanism. The regimen is delivered to the user via the infusion sub-system and is based on the user's dosage determination taking into account or measurements from the sensor.

8 is a block/process flow diagram illustrating the main method steps of a closed loop implementation of the present invention. A method 800 for performing a closed loop embodiment begins at block 801 with a microneedle array analyte-selective sensor that records measurements of the analyte or plurality of analytes in the living epidermis or dermis. The circulating level of the analyte within the living epidermis or dermis is quantified by a sensor. Next, at block 802 , the measurement or measurements from the microneedle array analyte-selective sensor are input to a control algorithm; Optionally, the measurement or measurements are displayed to the user. The present and optionally past stored measurements are used as input or inputs to the algorithm. Alternatively, the user also receives a reading of the circulation level of the analyte or plurality of analytes on a display or interface. Alternatively, the user is notified that the circulating level of the analyte or plurality of analytes extends beyond a pre-defined range of criteria or values. Next, at block 803, the control algorithm adjusts the dosage of the therapeutic agent or the plurality of therapeutic agents, if necessary based on the programmed mathematical transformation. The algorithm automatically manipulates the amount, duration or frequency of infusion of therapy based on measurements of the analyte or plurality of analytes provided by the sensor. Next, in block 804, the therapeutic agent or plurality of therapeutic agents is administered to the subcutaneous fat layer, the circulatory system (venous, arterial or capillary), muscle tissue, or oral delivery route by a therapeutic delivery mechanism. The regimen is delivered to the user via the infusion sub-system and is based on a dosage determination taking into account the output of the algorithm.

An input of the circulating level of an analyte or a plurality of analytes in the living epidermis or dermis may be an endogenous or exogenous biochemical agent, metabolite, drug, pharmacological agent in the living epidermis or dermis, indicative of a particular physiological or metabolic state. , biological, or pharmaceutical.

The output is the administration of a therapeutic agent or multiple therapeutic agents to the circulatory system (venous, arterial or capillary), muscle tissue, or oral route of delivery. Measurements provided by the sensor are used to effect release of therapy by the infusion sub-system. In an open loop embodiment, delivery of therapy is controlled by the user. In a closed loop embodiment, an algorithm is used to control the dosage, duration and frequency of therapy.

9 is a block/process flow diagram 900 illustrating the input, output and key components of the present invention under an open loop implementation. At block 901 , the analyte or circulating level of analytes is in the dermis. At block 902 , the sensor measures analytes. In block 903, the user adjusts the dosage of the therapeutic agent or the plurality of therapeutic agents as needed. User 903 manipulates 904 the amount, duration, or frequency of infusion of therapy based on measurements of the analyte or plurality of analytes provided by the sensor. In block 905, the therapeutic agent or the plurality of therapeutic agents is administered to the subcutaneous fat layer, the circulatory system (venous, arterial or capillary), muscle tissue, or oral delivery route by a therapeutic delivery mechanism. The regimen is delivered to the user via the infusion sub-system and is based on the user's dosage determination taking into account or measurements from the sensor.

Figure 10 is a block/process flow diagram 1000 illustrating the input, output and key components of the present invention under a closed loop implementation. At block 1001 , the analyte or circulating level of analytes is in the dermis. At block 1002 , the sensor measures analytes. The control algorithm 1003 adjusts the dosage of the therapeutic agent or the plurality of therapeutic agents as needed based on the programmed mathematical transformation. The algorithm automatically manipulates the amount, duration, or infusion frequency of therapy based on measurements of the analyte or plurality of analytes provided by the sensor ( 1004 ). Next, in block 1005, the therapeutic agent or plurality of therapeutic agents is administered to the subcutaneous fat layer, the circulatory system (venous, arterial or capillary), muscle tissue, or oral delivery route by a therapeutic delivery mechanism. The regimen is delivered to the user via the infusion sub-system and is based on a dosage determination taking into account the output of the algorithm.

13-15 illustrate an insulin patch pump 1300 having a body 1305 with microarray sensors 20 fully integrated into a lower surface 1310 .

16-17 illustrate an alternative embodiment in which there is an insulin patch pump 1300 having microarray sensors 20 connected via a connector 1350 on a lower surface 1310 of the patch pump 1300 .

18 illustrates an insulin patch pump 1300 having a groove 1335 in the lower surface 1310 of the patch pump 1300 for positioning over a microarray sensor (not shown) already applied to a patient's skin.

Claims (20)

A device for passively delivering a therapeutic intervention in response to a physiological condition of a user, comprising: penetrating the stratum corneum to access a viable epidermis or dermis and in a selective manner the presence of an analyte or a plurality of analytes a sensor configured to measure an infusion component configured to deliver a predetermined amount of a solution-phase therapeutic agent or a plurality of therapeutic agents to a physiological compartment separate from the living epidermis and dermis; and a single body-worn component for integrating the sensor and the injection component, wherein the single wearable component constitutes an injection configuration based on a user action informed by measurements from the sensor. configured to deliver a specified dose of said therapeutic agent via a component. The device of claim 1 , wherein the therapeutic intervention comprises at least one of a solution-phase drug, pharmacological, biological, or medicament. The device of claim 1 , wherein the physiological condition comprises at least one of an acute metabolic condition, a chronic metabolic condition, disease, injury, disease, disorder, or infection. According to claim 1, wherein the sensor is an electrochemical sensor, a chemical sensor, an electrical sensor, a potential difference sensor, a current measuring sensor, a voltammetric sensor, a galvanometric sensor, an impedance sensor (impedimetric sensor), a conductivity measuring sensor, or a biosensor. The method of claim 1, wherein the analyte or a plurality of analytes are glucose, lactate, ketone body, uric acid, ascorbic acid, alcohol, glutathione, hydrogen peroxide, metabolite, electrolyte, ion, drug, pharmacological, biological, or pharmaceutical A device comprising at least one. The device of claim 1 , wherein the infusion component comprises a fluid delivery device configured to provide infusion via a macroneedle, hypodermic needle, cannula, catheter, or oral delivery route. The device of claim 1 , wherein the single wearable component comprises a skin patch, a dermal patch, an adhesive patch, an infusion set, a patch pump, or an automated therapeutic delivery system. The device of claim 1 , wherein the specified dosage comprises an amount of therapeutic agent, concentration of therapeutic agent, volume of therapeutic agent, duration of delivery of therapeutic agent, or frequency of delivery of therapeutic agent. A device for automatically delivering a therapeutic intervention in response to a physiological condition of a user, comprising: penetrating the stratum corneum to access the living epidermis or dermis, and selectively measuring the presence of an analyte or a plurality of analytes; configured sensor; an infusion component configured to deliver an amount of a solution-phase therapeutic agent or a plurality of therapeutic agents to a physiological compartment separate from the living epidermis and dermis; a single wearable component for integrating the sensor and the injection component; and control algorithms; wherein the single wearable component is configured to deliver a specified dose of the therapeutic agent through an infusion system based on an output of the control algorithm. 10. The apparatus of claim 9, wherein the control algorithm comprises a software or firmware routine that uses at least one mathematical transformation. The device of claim 10 , wherein the input of the mathematical transformation is a measurement of the analyte or a plurality of analytes. The device of claim 9 , wherein the output of the control algorithm is the specified dose of the therapeutic agent. A method for passively delivering a therapeutic intervention in response to a physiological condition of a user, using a single wearable component, comprising: measuring presence; presenting an analyte or measurement of a plurality of analytes to a user; and causing the infusion component to deliver a specified dose of a solution-phase therapeutic agent or collection of therapeutic agents to a physiological compartment under the dermis based on an action of the user or an output of the control algorithm. 14. The method of claim 13, wherein the physiological condition comprises at least one of an acute metabolic condition, a chronic metabolic condition, disease, injury, disease, disorder, and infection. 14. The method of claim 13, wherein the analyte or a plurality of analytes are glucose, lactate, ketone body, uric acid, ascorbic acid, alcohol, glutathione, hydrogen peroxide, metabolite, electrolyte, ion, drug, pharmacological, biological, or pharmaceutical A method comprising at least one. The method of claim 13 , wherein the sensor is an electrochemical sensor, a chemical sensor, an electrical sensor, a potentiometric sensor, an amperometric sensor, a voltammetric sensor, a galvanometer amperometric sensor, an impedance sensor, a conductivity measurement sensor, or a biosensor. 14. The method of claim 13, wherein the control algorithm comprises a software or firmware routine that uses at least one mathematical transformation. 14. The method of claim 13, wherein the physiological compartment below the dermis comprises subcutaneous adipose tissue (subdermal, subcutis, hypodermis), or muscle tissue. The method of claim 13 , wherein the specified dosage comprises an amount of the therapeutic agent, a concentration of the therapeutic agent, a volume of the therapeutic agent, the duration of delivery of the therapeutic agent, or the frequency of delivery of the therapeutic agent. 14. The method of claim 13, wherein the output of the control algorithm is a signal, stimulus or drive indicative of a dose of the therapeutic agent.

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