CN114144113A

CN114144113A - Mechanical coupling of analyte-selective sensor and infusion system

Info

Publication number: CN114144113A
Application number: CN202080050777.2A
Authority: CN
Inventors: J·温德米勒; J·唐尼; T·A·佩瑟
Original assignee: Biolinq Inc
Current assignee: Biolinq Inc
Priority date: 2019-06-17
Filing date: 2020-06-12
Publication date: 2022-03-04
Also published as: JP2022537341A; EP3982832A4; IL288979A; CA3143465A1; WO2020257069A1; KR20220024506A; EP3982832A1

Abstract

Disclosed herein are devices (2000) and methods (1300) of coupling an analyte-selective sensor (20) and an infusion system (800) as a single-piece, wearable device (2000). After coupling, information and/or power is exchanged between the two modes (analyte selective sensor (20) and infusion system (800)) via wireless electromagnetic transmission or electrical connectors. The analyte-selective sensor (20) is configured to penetrate the stratum corneum to approximate viable epidermis or dermis and measure the presence of an assay. The infusion system (800) is configured to penetrate the stratum corneum and deliver a solution phase therapeutic agent.

Description

Mechanical coupling of analyte-selective sensor and infusion system

Technical Field

The present invention relates generally to therapy delivery mechanisms, analyte-selective sensors, and methods of configuring the same.

Background

Continuous delivery of therapeutic agents remains an important technology in modern medical devices. The most important example of such a medical device is the insulin pump, also known as the Continuous Subcutaneous Insulin Infusion (CSII) system, which is widely used by individuals suffering from insulin-dependent diabetes. Insulin pumps were developed in the 1980 s and commercialized in the 1990 s to provide a more physiological method of insulin delivery than subcutaneous injections of insulin infrequently via syringes and hypodermic needles. The importance of improved insulin delivery methods was further recognized after the diabetes control and complications trial (DCTT) was published in 1992, which indicated that intensive insulin treatment significantly reduced the incidence and severity of long-term complications of diabetes. More recently, insulin pumps have been configured to automatically suspend insulin infusion in the event of actual or impending hypoglycemia as determined by continuous glucose monitoring systems. The insulin pump is also configured to continuously regulate insulin delivery in response to glucose levels measured by the continuous glucose monitoring system. In these cases, both the analyte sensing and therapy delivery modes include two distinct and separable devices, both worn on the body. However, in keeping with the goals of integrated sensing-therapy systems and the need for miniaturized body-worn devices, the integration of both analyte sensing and therapy delivery components into a single wearable device is an active area of development. However, one major obstacle in the use of these techniques by many patients is the use of two separate body devices, as shown in fig. 2, with two

devices

205 and 210 located on the user 215. In keeping with the goals of integrated sensing-therapy systems and the need for miniaturized body-worn devices, co-locating both analyte sensing and therapy delivery components into a single wearable device is an active area of development. In view of the above, the integration of a sensing and therapy assembly (continent) faces a unique set of challenges, namely the development of a robust method for mechanical coupling and electrical interface between these two separable components configured to operate as a single body-worn device. In view of the challenges associated with integration of two elements that may be coupled into a single body worn device using different methods, the sensing and delivery components are typically embodied by different and non-couplable components. In such embodiments, the user is downgraded to applying and wearing the different components at spatially different locations on the body.

The prior art solutions are primarily directed to operating the sensing and delivery systems as distinct body-worn entities that are spatially separated by a sufficient distance to avoid the challenges associated with inserting two cannulas that are physically connected to a single integrated device. Furthermore, implementing the analyte sensing and therapy delivery modes as physically distinct devices so that these assemblies can be worn in different areas solves the challenge of unwanted interaction between the two systems. This interaction can take many forms-crosstalk, interference, contamination, and dilution-which can affect the performance, accuracy, and reliability of the sensing procedure. Prior art embodiments of analyte sensing modes include cannula-assisted, subcutaneously implanted wire-based sensors configured to quantify analytes using electrochemical conversion techniques; a continuous glucose monitoring system is an example. Prior art embodiments of therapy delivery modes include cannula-based patch pumps and infusion devices configured to deliver therapeutic agents to subcutaneous adipose tissue (subcutaneous tissue) by applying pressure on a reservoir containing therapy in a solution phase; an insulin infusion system is an example. Fig. 1A is a prior art needle/cannula based analyte selective sensor 110 having a user interface device 115 and a mobile phone 105 configured for quantifying glucose in subcutaneous adipose tissue. Fig. 1B is a prior art needle/cannula based analyte selective sensor 130 having a user interface device 125 configured for quantifying glucose in subcutaneous adipose tissue. Fig. 1C is a prior art needle/cannula based analyte selective sensor 150 having a user interface device 145 configured for quantifying glucose in subcutaneous adipose tissue. Recent prior art has indicated co-location of sensing and delivery modes within a single, individual-worn device, although both modes in such prior art are indivisible. In this manner, if the supply of therapeutic agent in the therapy delivery assembly is exhausted, the entire system, including the analyte sensing mode, must be removed and replaced despite the fact that the analyte sensing mode may still result in a remaining time life of many days. In another embodiment, the analyte selective sensor may be replaced with the same frequency as the infusion system by reducing the number of components of the sensor to a minimum while utilizing circuitry and power sources resident in the infusion system.

Current needle and cannula based infusion systems configured for delivery of solution phase therapeutics (i.e., insulin) are typically paired with needle and cannula based sensor systems configured for continuous quantification of analytes (i.e., glucose). While such systems operate in unison and are configured to operate as distinct components (sensing and delivery), the two systems have not been implemented as a single body-worn device. While this is due in part to the challenges associated with inserting two ferrules physically connected to a single integrated device, the primary challenge is due to the mechanical coupling of the two systems while supporting the method of information transfer between the two systems. That is, the coupling of the analyte sensing and therapy delivery assemblies requires a method for retaining the components in a single body worn device while facilitating the one-way or two-way transfer of information and/or power between the components (or transfer through an intervening information processing device). In all embodiments, information and power are considered to constitute electromagnetic quantities. Furthermore, current advances in analyte-selective sensors (e.g., continuous glucose monitors) have enabled the commercialization of devices with a seven to fourteen day wear life. However, current therapy delivery mechanisms, such as insulin infusion systems, can only accommodate a three day supply of therapeutic agent on board, meaning that the therapy delivery assembly will need to be replaced prematurely before the functional life of the analyte-selective sensor is over. As suggested in the prior art, if the two systems were integrated into a single body worn assembly, this would require both systems to be removed from the skin and replaced at the same time to replenish the internal supply of therapeutic agent within the therapy delivery assembly, resulting in a compromise in the useful life produced by the analyte selective sensor. There is a need to address the problem of disproportionate usage times for current glucose sensors and insulin infusion systems.

Disclosure of Invention

The present invention teaches methods for coupling separable analyte sensing and therapy delivery modes that are assembled by a user to form a single body worn device configured in either an open-loop or closed-loop embodiment. The coupling operation is performed in a simple manner by the user in sequence before application to the user's skin or after application of a pattern (sensing or delivery). After coupling, information and/or power is exchanged between the two modes through wireless electromagnetic transmission or electrical connectors. Alternatively, information may be transferred between the two modes through electromagnetic interaction with an intermediate electronic device. In one embodiment, the intermediary electronic device retains the analyte sensing and therapy delivery modes and, in another embodiment, constitutes a separate and physically distinct information processing device, such as a smartphone, smartwatch, tablet, computer, or other body-worn device. Embodiments of the overall system may include an open loop system whereby the wearer adjusts the dosage of the therapeutic intervention based on the level of the one or more analytes, and a closed loop system whereby the control algorithm autonomously adjusts the dosage of the one or more therapeutic interventions. The invention disclosed herein allows for replacement of a therapy delivery assembly, such as an insulin infusion system, while the analyte sensing assembly remains undisturbed and continues the sensing operation. In this manner, the user can achieve the full functional life of the analyte sensor, let alone the therapy delivery assembly. The present invention describes a convenient method for mechanically coupling and decoupling a therapeutic delivery assembly from an analyte-selective sensor, while facilitating an electromagnetic interface therebetween for information or power transfer purposes.

One aspect of the invention is a method for coupling an analyte-selective sensor and an infusion system into a single body-worn device. The method includes first positioning an analyte-selective sensor on the skin of a wearer. The analyte-selective sensor is configured to penetrate the stratum corneum to approximate the viable epidermis or dermis and measure the presence of one or more analytes in a selective manner. Selective mode is generally understood to refer to the ability of an analyte selective sensor to measure at least one analyte of interest while mitigating the deleterious signal contributions produced by co-circulating endogenous (i.e., metabolites, ions, proteins) and exogenous (i.e., pharmaceutical agents, therapeutic agents) electroactive compounds that occupy the biological environment. The method further includes, second, positioning the infusion system on the skin of the wearer. The infusion system is configured to penetrate the stratum corneum and deliver a solution-phase therapeutic agent or a collection of therapeutic agents in a controlled manner to the physiological compartment beneath the dermis. It is generally understood that a controlled manner refers to the ability of an infusion system to deliver a particular dose, concentration, or amount of a therapeutic agent; this may include bolus delivery, where the therapeutic agent is administered over a short time, or basal delivery, where the therapeutic agent is administered over an extended duration. The positioning requires mechanical retention between the infusion system and the analyte-selective sensor to form a single body-worn device. The method also includes finally transferring electromagnetic energy between the analyte-selective sensor and the infusion system to effect interaction between the analyte-selective sensor and the infusion system.

Other aspects of the invention are a method for coupling an analyte-selective sensor and an infusion system into a single body-worn device. The method includes first positioning the infusion system on the skin of the wearer. The infusion system is configured to penetrate the stratum corneum and deliver a solution-phase therapeutic agent or a collection of therapeutic agents in a controlled manner to the physiological compartment beneath the dermis. The method further includes, second, positioning an analyte-selective sensor on the skin of the wearer. The analyte-selective sensor is configured to penetrate the stratum corneum to approximate the viable epidermis or dermis and measure the presence of one or more analytes in a selective manner. The positioning requires mechanical retention between the analyte-selective sensor and the infusion system to form a single body-worn device. The method also includes finally transferring electromagnetic energy between the analyte-selective sensor and the infusion system to effect interaction between the analyte-selective sensor and the infusion system.

Yet another aspect of the invention is a method of coupling an analyte-selective sensor configured to penetrate the stratum corneum to enter the viable epidermis or dermis and measure the presence of an analyte or analytes in a selective manner and an infusion system configured to penetrate the stratum corneum and deliver a solution-phase therapeutic agent or a collection of therapeutic agents in a controlled manner to a physiological compartment beneath the dermis. The method includes first engaging a mechanical retention mechanism between the analyte-selective sensor and the infusion system to form a unitary device. The method further includes secondarily positioning the single device on the skin of the wearer. The method also includes finally transferring electromagnetic energy between the analyte-selective sensor and the infusion system to effect interaction between the analyte-selective sensor and the infusion system.

Yet another aspect of the invention is a method of coupling an analyte-selective sensor configured to penetrate the stratum corneum to enter the viable epidermis or dermis and measure the presence of an analyte or analytes in a selective manner and an infusion system configured to penetrate the stratum corneum and deliver a solution-phase therapeutic agent or a collection of therapeutic agents in a controlled manner to a physiological compartment beneath the dermis. The method includes first engaging a mechanical retention mechanism between the intermediate device and both the analyte-selective sensor and the infusion system to form a single apparatus. The method further includes secondarily positioning the single device on the skin of the wearer. The method also includes finally transferring electromagnetic energy between the analyte-selective sensor and the infusion system to effect interaction between the analyte-selective sensor and the infusion system. It is generally understood that the intermediate device or apparatus is configured with two geometric features in which the analyte-selective sensor and the infusion system may be held or otherwise mechanically coupled so as to hold the two apparatuses in a fixed position relative to each other. In one embodiment, the intermediary device is purely a mechanical device that couples the analyte-selective sensor and the infusion system into a single integrated device; the intermediary device has no embedded electronic system. In another embodiment, the intermediary device contains an embedded electronic system capable of transferring electromagnetic energy (i.e., power, data) between the analyte-selective sensor and the infusion system.

Drawings

Fig. 1A is a prior art needle/cannula based analyte selective sensor.

FIG. 1B is a prior art needle/cannula based analyte selective sensor.

Fig. 1C is a prior art needle/cannula based analyte selective sensor.

Fig. 2 is a prior art embodiment of a sensor device (left) and an infusion system (right).

Fig. 3 is a prior art needle/cannula based analyte selective sensor and microneedle array based analyte selective sensor (right).

Fig. 4 is a diagrammatic view of an infusion system and an analyte selective sensor.

Fig. 5A is an integration of a sensor into an infusion device.

Fig. 5B is an integration of the sensor into a patch pump.

Fig. 6A is an integration of a sensor into a patch pump.

Fig. 6B is an integration of the sensor into a patch pump.

FIG. 6C is an isolated view of circle 6C of FIG. 6B.

Fig. 7A is a top perspective view of a sensor having six electrical pads.

Fig. 7B is a plan view of a sensor with six electrical pads.

Fig. 7C is a side view of the sensor.

Fig. 7D is a bottom view of the sensor.

Fig. 7E is a bottom perspective view of the sensor.

Fig. 8A is a top view of a therapy delivery system having a lumen designed to hold and electromagnetically couple to an analyte selective sensor (not shown) as found in fig. 7A-7E.

Fig. 8B is a side view of the therapy delivery system.

Fig. 8C is a bottom plan view of the therapy delivery system.

Fig. 8D is a bottom plan view of the therapy delivery system.

Fig. 9A is a side perspective view of a therapy delivery system.

Fig. 9B is a front view of the therapy delivery system.

Fig. 9C is a side perspective view of the therapy delivery system.

Fig. 9D is a rear view of the therapy delivery system.

FIG. 10 is an illustration of an analyte selective sensor applied to the skin of a wearer.

Fig. 10A is an illustration of a therapy delivery system applied to the rear of an analyte selective sensor.

Fig. 10B is a diagram of mechanically and electromagnetically coupled analyte-selective sensors and therapy delivery systems on the skin of a wearer.

Fig. 11 is a side perspective view of mechanically and electromagnetically coupled analyte-selective sensors and therapy delivery systems.

Fig. 12 is a flow chart of a method for coupling an analyte selective sensor and an infusion system into a single body-worn device.

Fig. 13 is a flow chart of a method for coupling an infusion system and an analyte selective sensor into a single, wearable device.

Fig. 14 is a flow chart of a method for coupling an analyte selective sensor and an infusion system into a single body-worn device prior to dermal application.

Fig. 15 is a flow chart of a method for facilitating coupling of an analyte-selective sensor and an infusion system by an intermediary device prior to dermal application.

Fig. 16 is a flow chart of a method of an open loop embodiment.

Fig. 17 is a flow chart of a method of the closed loop embodiment.

Fig. 18 is a block/process flow diagram illustrating the inputs, outputs and major components under an open-loop embodiment.

Fig. 19 is a block/process flow diagram illustrating the inputs, outputs and major components under a closed-loop embodiment.

Fig. 20 is a cross-sectional view of an intermediate device for coupling an infusion system and an analyte selective sensor into a single, wearable apparatus.

Fig. 21 is a cross-sectional view of an intermediate device integrated with an infusion system and an analyte-selective sensor into a single, wearable apparatus.

Fig. 22 is a cross-sectional view of an alternative embodiment of an intermediary device for coupling an infusion system and an analyte selective sensor in a single, wearable apparatus.

Detailed Description

The technology disclosed herein juxtaposes an analyte sensor system and a therapy delivery system to operate in different physiological compartments while maintaining minimal spatial separation between the two. This is achieved by dispensing an analyte sensor into the viable epidermis or dermis of the wearer, whereby the system is configured to quantify one or more analytes residing therein. Instead, the therapy delivery system is distributed in the subcutaneous region. The lateral separation of both the sensing and delivery modes, confining the sensing routine to the viable epidermis or dermis and the delivery routine to the subcutaneous adipose tissue, enables isolation of the two routines, thereby mitigating the possible occurrence of cross-talk, interference, contamination and local dilution of the analyte being detected, should be co-located in a given physiological compartment. In a preferred embodiment of the invention, the system operates in an open loop paradigm whereby treatment is initiated by the user and guided by measurements from the sensors. Alternatively, the system includes a control algorithm to autonomously deliver a therapeutic intervention in response to a sensor reading or readings. This paradigm is expected to have profound effects on diabetes management, especially in those undergoing intensive insulin therapy.

The present invention discloses a simplified method for mechanical coupling and concomitant decoupling of an analyte-selective sensor and a therapy delivery mode, while facilitating an electromagnetic interface therebetween for information and/or power transfer purposes. In this manner, the therapy delivery assembly (i.e., the insulin infusion system) may be removed and replaced while the analyte selective sensor assembly continues to operate unreliably.

Body-worn analyte-selective sensors, such as continuous glucose monitors, are sensitive electrochemical systems configured to sense one or more analytes in a selective manner with a high degree of accuracy. Also, a body-worn therapeutic delivery mechanism (e.g., an insulin infusion system) is configured to deliver a therapeutic intervention in a controlled manner in response to a circulating level of an analyte or analytes. In the present invention, the analyte sensor and the infusion system are configured to mechanically and electromagnetically couple to each other to create a single body-worn device comprised of these two separable modes.

The mechanical coupling constitutes a mechanical retention mechanism and takes the form of an interference fit, a clearance fit, or a transition fit, etc., to locate the sensing and delivery modes at invariant positions relative to each other. The user engages the coupler to maintain both modes and, similarly, disengages the coupler to disengage both modes. In an alternative embodiment, a third "intermediate" element is employed to position and hold the analyte sensor and the therapy delivery assembly in a fixed and unchanging position. In these embodiments, the user is still able to mechanically couple and decouple the analyte sensing and therapy delivery modes according to their needs.

In a first embodiment, a user first applies an analyte-selective sensor to the skin, allowing the sensing element to penetrate the stratum corneum to approximate the viable epidermis or dermis for analyte sensing operations. In one particular embodiment, the sensor device consists of an analyte-selective sensor mounted on a circuit board having a lock and key feature to allow correct spatial orientation when mated with a therapy delivery mechanism such as a patch pump or other insulin infusion system. The top of the sensor device may also have electrical contact pads or connectors for mounting to the bottom of the infusion system, providing a path for electrical transmission of electromagnetic quantities to enable power or signal transmission. Sensor devices mounted at the bottom of the therapy delivery system in this manner utilize embedded electrical subsystems in the therapy delivery system, resulting in extremely low cost sensor elements for goods.

Subsequently, the user applies the therapy delivery mechanism to the skin, the action of which causes the cannula or needle to penetrate through the three upper layers of the skin (stratum corneum, epidermis, and dermis) to enter the subcutaneous adipose tissue, mechanically coupling the therapy delivery mechanism with the analyte-selective sensor, thereby forming a single, invariable, body-worn response therapy system.

In a second embodiment, the user first applies the therapy delivery mechanism to the skin, allowing the delivery elements to penetrate the outer layer of the skin to access the subcutaneous adipose tissue for the therapy delivery operation. Subsequently, the user applies the analyte-selective sensor to the skin, the action of which causes the microneedles or microneedle arrays to penetrate the stratum corneum into the viable epidermis or dermis, mechanically coupling the analyte-selective sensor with the therapy delivery mechanism, thereby forming a single, non-variable, body-worn, responsive therapy system.

In a third embodiment, the user mechanically couples the analyte-selective sensor and the therapy delivery mechanism through a third element, an intermediary, prior to application to the body. The intermediate piece holds the analyte sensor and the delivery device in a fixed position relative to each other to form a single, body-worn response therapy system. It should be noted that the analyte-selective sensor and the treatment system each preferably have a skin-facing adhesive to adhere the devices in a fixed position on the surface of the wearer's body. The unitary body worn device also preferably includes a skin patch, a dermal patch, an adhesive patch, an infusion device, a patch pump, a response therapy system, or an automated therapy delivery system.

The electromagnetic coupling constitutes a means of communicating or transferring at least one of information and electrical power between the analyte-selective sensor and the therapy delivery mechanism. The communication or transfer is unidirectional (analyte-selective sensor to therapy delivery mechanism or therapy delivery mechanism to analyte-selective sensor) or bidirectional in nature (analyte-selective sensor to and from therapy delivery mechanism). Information or power transfer is either achieved wirelessly by electromagnetic waves propagating in free space or facilitated by an electrical connector having at least two electrically conductive pads. In one instance, the act of mechanically coupling both the analyte-selective sensor and the therapy delivery mechanism facilitates the exchange of at least one of electromagnetic information and energy between the two modes. The use of wireless transmission is by BLUETOOTH, Wi-Fi, NFC, RFID, cellular radio, ZigBee, Thread, ANT, proprietary radio technology, proprietary microwave technology, proprietary millimeter wave technology, inductive coupling, capacitive coupling, resonant coupling or light waves.

In another embodiment, both the analyte-selective sensor and the therapy delivery mechanism must be paired by action of the user. It should be noted that the therapy delivery mode is typically larger in spatial extent than the analyte sensing assembly, and therefore is better suited to accommodate batteries with larger charge storage capacity and more complex microelectronic systems (i.e., computing power, wireless functionality). Thus, a preferred embodiment includes a housing for the energy source, microprocessor, and wireless data transmission functions within the therapy delivery mechanism, and optionally, an analog front end responsible for operating the analyte-selective sensor.

Another embodiment places the analog front end within the analyte-selective sensor, while the remaining electronic components (energy source, microprocessor, and wireless data transceiver) are housed within the therapy delivery mechanism.

Another embodiment places the analog front end and microprocessor within the analyte-selective sensor, while the remaining electronic components (energy source and wireless data transceiver) are housed within the therapy delivery mechanism.

Another embodiment places the analog front end, microprocessor, and energy source within the analyte-selective sensor, while the wireless data transceiver is mounted within the therapy delivery mechanism.

Yet another embodiment places all of the electronic components (energy source, microprocessor, wireless data transceiver, and analog front end) within the analyte-selective sensor so that it can operate as a detachable device without a therapy delivery mechanism.

Yet another embodiment of the disclosed invention includes an analyte-selective sensor positioned on skin and configured for more than three days of analyte monitoring (e.g., 7, 10, or 14 days, as in current continuous glucose monitors), while the therapy delivery mechanism is configured to be replaced every three days (e.g., in the case of insulin infusion systems), such that removal of the therapy delivery mechanism does not require removal or otherwise interference with the analyte-selective sensor. The analyte-selective sensor is preferably an electrochemical, optoelectronic or all-electronic device based on a microneedle array configured to measure endogenous or exogenous biochemical, metabolite, drug, pharmacological, biological or pharmacological agent in the dermal interstitium, indicative of a specific physiological or metabolic state in a physiological bodily fluid of the user. In particular, the microneedle array comprises a plurality of microneedles, having a vertical extent of between 200 and 2000 μm, configured to selectively quantify the level of at least one analyte located within the viable epidermis or dermis. The analyte-selective sensor is preferably an electrochemical sensor, a chemical sensor, an electrical sensor, a potentiometric sensor, an amperometric sensor, an impedance sensor, a conductometric sensor or a biosensor. The infusion system or therapy delivery mechanism is preferably a fluid delivery device configured to infuse a solution phase therapeutic agent into the dermal interstitium, subcutaneous fat layer, circulatory system (vein, artery, or capillary), or muscle tissue via a microneedle, macroneedle (macroneedle), hypodermic needle, cannula, catheter, or oral delivery route. Delivering a solution-phase therapeutic agent in a controlled manner in response to the metabolic state provided by the analyte-selective sensor. The therapeutic agent (also referred to as "therapy") is preferably a solution phase drug, pharmacological, biological, or pharmaceutical agent.

Yet another embodiment is a coupling system that integrates sensors and infusion systems (including embedded therapies) with a responsive therapy system. This embodiment is a body-worn device that incorporates both sensors and an infusion system to initiate delivery of therapy, occupying physically distinct compartments. Alternatively, the body worn device combines the sensor, infusion system and therapy in a single housing.

A mechanical coupling mechanism is a mechanism designed to hold a sensor within the housing of an infusion system and vice versa. Alternatively, the body-worn device features a third element (intermediate piece) configured to hold both the sensor and the infusion system therein. The coupling mechanism may take the form of an interference fit, a clearance fit or a transition fit.

The electromagnetic energy transfer mechanism is an electromagnetic mechanism designed to transfer information and/or power from the sensor to the infusion system in one direction or between the sensor and the infusion system in two directions. Alternatively, an intermediary such as a third device may enable interaction between the sensor and the infusion system. The transmission mechanism may take the form of wireless electromagnetic transmission or electromagnetic communication facilitated by the connector device.

In another embodiment, which is a closed-loop embodiment, the elements are as follows: the microneedle array analyte selective sensor is a plurality of microneedles, having a vertical extent between 200 and 2000 μm, configured to selectively quantify the level of at least one analyte located within the dermal stroma. A therapy delivery mechanism, infusion system, is a fluid delivery device configured to infuse a solution phase therapeutic agent into the dermal interstitium, subcutaneous fat layer, circulatory system (vein, artery, or capillary), or muscle tissue, preferably via a microneedle, large needle (macroneedle), hypodermic needle, cannula, catheter, or oral delivery route. The therapeutic agent, therapy is a solution phase drug, pharmacology, biology, or pharmaceutical agent. A coupled system that combines a sensor and infusion system (including embedded therapy) with a responsive therapy system is a body-worn device that can combine both the sensor and infusion system to facilitate delivery of therapy occupying physically distinct anatomical or physiological compartments. Alternatively, the body worn device combines the sensor, infusion system and therapy in a single housing. The control algorithm is a software routine that employs one or more mathematical transformations to control the dosage of the therapeutic agent by controlling the amount delivered, the duration of delivery, and/or the frequency of delivery based on input from the user or measurements recorded from the microneedle array analyte selective sensor. The administration may include bolus delivery, where the therapy is delivered immediately, or basal delivery, where the therapy is delivered over an extended period of time. The mathematical transform may take additional input, be provided by the user or be autonomously integrated from elsewhere. A mechanical coupling mechanism is a mechanism designed to hold a sensor within the housing of an infusion system and vice versa. Alternatively, the body-worn device may include a third element (intermediate piece) configured to hold both the sensor and the infusion system therein. The coupling mechanism preferably takes the form of an interference fit, a clearance fit or a transition fit. The information transfer mechanism is an electromagnetic mechanism designed to transfer information and/or power from the sensor to the infusion system in one direction or between the sensor and the infusion system in two directions. Alternatively, an intermediary, such as a third device, mitigates or judges interaction between the sensor and the infusion system. The transmission mechanism preferably takes the form of wireless electromagnetic transmission or electromagnetic communication facilitated by the connector arrangement.

Another embodiment is an analyte selective sensor first method embodiment. In a first step, the user applies the sensor to the skin. The analyte-selective sensor is configured to penetrate the stratum corneum to approximate the viable epidermis or dermis and measure the presence of one or more analytes in a selective manner. In one sub-embodiment, the sensor is configured with a geometry that exactly matches a similar geometry of the bottom of the infusion system, such that the infusion system is properly mounted to the sensor and makes appropriate electrical connections as needed to properly operate the combined system.

In the next step, the user applies the infusion system to the skin while engaging the infusion system with the sensor through the mechanical coupling, thereby forming a single body-worn device. The therapy delivery transducer is configured to penetrate the stratum corneum and deliver a solution-phase therapeutic agent or a collection of therapeutic agents in a controlled manner to a physiological compartment below the stratum corneum, which positioning requires mechanical retention between the therapy delivery mechanism and the analyte-selective sensor to form a single body-worn device.

In the next step, the transfer of relevant information and/or power between the sensor and the infusion system takes place. The electromagnetic signals that transmit power and/or carry information related to the sensor and/or the infusion system are relayed between the two assemblies in a unidirectional manner (sensor to infusion system/infusion system to sensor) or a bidirectional manner (sensor to access the infusion system) or through middleware (sensor to middleware to infusion system/infusion system to middleware to sensor/sensor to access the infusion system).

Another embodiment is a first method embodiment of a therapy delivery mechanism. In a first step, the user applies the infusion system to the skin. The therapeutic delivery mechanism is configured to penetrate the stratum corneum and deliver a solution-phase therapeutic agent or a collection of therapeutic agents in a controlled manner to a physiological compartment below the stratum corneum.

Next, the user applies the sensor to the skin while engaging the sensor with the infusion system through a mechanical coupling, thereby forming a single body-worn device. The analyte-selective sensor is configured to penetrate the stratum corneum to approximate the viable epidermis or dermis and measure the presence of one or more analytes in a selective manner, the positioning requiring mechanical retention between the analyte-selective sensor and the therapy delivery mechanism to form a single body-worn device. The dermis preferably comprises dermal interstitium, dermal interstitial fluid, papillary dermis, reticular dermis, or dermal capillary bed. The analyte or analytes preferably include at least one of glucose, lactate, ketone bodies, uric acid, ascorbic acid, alcohol, glutathione, hydrogen peroxide, metabolites, electrolytes, ions, drugs, pharmacology, biology, or pharmaceuticals.

Next, a transfer of relevant information is performed between the sensor and the infusion system. The electromagnetic signals that transmit power and/or carry information related to the sensor and/or the infusion system are relayed between the two assemblies in a unidirectional manner (sensor to infusion system/infusion system to sensor) or a bidirectional manner (sensor to access the infusion system) or through middleware (sensor to middleware to infusion system/infusion system to middleware to sensor/sensor to access the infusion system).

Another embodiment is a coupling of an analyte selective sensor and a therapy delivery mechanism method. First, the sensor is engaged with the infusion system through a mechanical coupling. This is the mechanical coupling of the analyte-selective sensor and the therapy delivery mechanism to form a single device ready for application to the skin. Optionally, a third element is used to hold both the analyte-selective sensor and the therapy delivery mechanism prior to application to the skin.

Next, the user applies the coupled sensor and infusion system to the skin as a single device. Both the analyte-selective sensor and the therapy delivery mechanism, which comprise a single mechanical coupling device, are applied to the skin simultaneously. The analyte-selective sensor is configured to penetrate the stratum corneum to approximate the viable epidermis or dermis and measure the presence of one or more analytes in a selective manner. The therapeutic delivery mechanism is configured to penetrate the stratum corneum and deliver a solution-phase therapeutic agent or a collection of therapeutic agents in a controlled manner to a physiological compartment below the stratum corneum.

Next, a transfer of relevant information is performed between the sensor and the infusion system. Transmitting electrical power and/or electromagnetic signals carrying information related to a sensor and/or an infusion system in a unidirectional manner (sensor → infusion system/infusion system → sensor) or in a bidirectional manner (sensor ← → infusion system) or through a middleware (sensor → middleware → infusion system/sensor ← → middleware)

Either ← → infusion system) relays between the two assemblies.

The input of the present invention is a coupling, which is a mechanism designed to hold the sensor within the infusion system housing, and vice versa. Alternatively, the body-worn device may include a third element configured to retain both the sensor and the infusion system therein. The coupling mechanism preferably takes the form of an interference fit, a clearance fit or a transition fit. The output of the present invention is a transmission, which is an electromagnetic signal carrying electrical power and/or information related to the sensor and/or the infusion system that is relayed between the two assemblies in a unidirectional manner (sensor to infusion system/infusion system to sensor) or a bidirectional manner (sensor to in and out of the infusion system) or through middleware (sensor to middleware to infusion system/sensor to in and out of the infusion system).

The sensor is preferably a plurality of microneedles having a vertical extent of between 200 and 2000 μm configured to selectively quantify the level of at least one analyte located within the viable epidermis or dermis. Fig. 3 illustrates a micro-needle array sensor 325 associated with a coin 301 and a needle 305.

Fig. 4 is a diagram 40 of a therapy delivery device 25 configured to operate within subcutaneous tissue 43 and an analyte-selective sensor 20 configured to operate within dermis 42 and through epidermis 41. It should be noted that the two are located in close spatial proximity.

Fig. 5A is a diagram of a microneedle array-based analyte selective sensor 20 integrated into an infusion set 500. Fig. 5B, 6A and 6B illustrate the integration of a microneedle array-based analyte selective sensor 20 into a patch pump 525. Fig. 6C illustrates a microneedle array-based analyte selective sensor 20 and microneedles 25.

Fig. 7A, 7B, 7C, 7D and 7E illustrate a microneedle-based analyte selective sensor 20 having an array of microneedles and excitation and measurement circuitry not shown. The microneedle analyte selective sensor 20 preferably includes a housing member 125, a back plate, inner pads, a circuit board cover, outer pads and adhesive pads, a front panel, microneedles 150, and a printed circuit board containing electronic components necessary to convert the biochemical signals into digital data that is wirelessly transmitted to an external device via an embedded wireless transceiver. The electrochemical simulation front-end preferably comprises: texas instruments LMP91000 sensor AFE system, configurable AFE potentiostat for low power chemical sensing applications; texas instruments LMP91200 configurable AFE for low power chemical sensing applications; or an on-chip Analog Devices ADuCM 35016 bit precision low power meter with Cortex-M3 and connection functions. The wireless transceiver is preferably a BLUEGIGA BLE-113A BLUETOOTH Intelligent Module, or a Texas instruments CC2540 SimpleLink BLUETOOTH Intelligent Wireless MCU with USB. The microneedles 150 penetrate the stratum corneum to approximate the viable epidermis or dermis. The microneedle-based analyte-selective sensor 20 also has a plurality of electrical pads 127 for transmitting power and/or information between the therapy delivery system and the microneedle-based analyte-selective sensor 20. The microneedle-based analyte selective sensor 20 preferably has between two and ten pads 127, and most preferably has six pads 127.

Fig. 8A-8C illustrate a therapy delivery system 800 having a body 801 with an inner surface 805 with a port 802, a button 810, a lumen 820 with a plurality of electrical pads 827 for coupling with a microneedle-based analyte-selective sensor 20. Fig. 8D illustrates a therapy delivery system 800 coupled with a microneedle-based analyte-selective sensor 20 and a cannula 803 attached to a port 802. Fig. 9A and 9B illustrate a therapy delivery system 800 having a needle 804. Fig. 9C and 9D illustrate a therapy delivery system 800 having a cannula 803 attached to a port 802.

Fig. 10, 10A, and 10B are illustrations of application processes of an analyte-selective sensor and a therapy delivery system, illustrating mechanical and electromagnetic coupling operations therebetween. Referring to fig. 10, the application of an analyte-selective sensor to the skin of a wearer 215 is shown, where the analyte-selective sensor 20 has six conductive pads 127 for delivering electromagnetic energy (power and/or information). In fig. 10A, the application of therapy delivery system 800 to the rear of an analyte selective sensor is shown. In fig. 10B, the mechanically and electromagnetically coupled analyte-selective sensor 20 and therapy delivery system 800 on the skin of the wearer 215 are shown.

Fig. 11 is a diagram of mechanically and electromagnetically coupled analyte-selective sensor 20 and therapy delivery system 800, showing a microneedle array of analyte-selective sensor 20 and cannula 803 of therapy delivery system 20.

Fig. 12 illustrates a method 1200 for coupling an analyte-selective sensor and an infusion system as a single, wearable device. At block 1201, an analyte-selective sensor is positioned on the skin of a wearer. The analyte-selective sensor is configured to penetrate the stratum corneum to approximate the viable epidermis or dermis and measure the presence of one or more analytes in a selective manner. At block 1202, an infusion system is positioned on the skin of a wearer. The infusion system is configured to penetrate the stratum corneum and deliver a solution-phase therapeutic agent or a collection of therapeutic agents in a controlled manner to the physiological compartment beneath the dermis. At block 1203, the analyte-selective sensor is coupled to an infusion system to form a single body-worn device. The coupling results in mechanical retention between the analyte-selective sensor and the infusion system. At block 1204, electromagnetic energy is transferred between the analyte-selective sensor and the infusion system. The communication enables interaction between the analyte-selective sensor and the infusion system.

Fig. 13 illustrates a method 1300 for coupling an infusion system and an analyte-selective sensor as a single, wearable device. At block 1301, an infusion system is positioned on the skin of a wearer. The infusion system is configured to penetrate the stratum corneum and deliver a solution-phase therapeutic agent or a collection of therapeutic agents in a controlled manner to the physiological compartment beneath the dermis. At block 1302, an analyte-selective sensor is positioned on the skin of a wearer. The analyte-selective sensor is configured to penetrate the stratum corneum to approximate the viable epidermis or dermis and measure the presence of one or more analytes in a selective manner. At block 1303, the analyte-selective sensor is coupled to an infusion system to form a single body-worn device. The coupling results in mechanical retention between the analyte-selective sensor and the infusion system. At block 1304, electromagnetic energy is transferred between the analyte-selective sensor and the infusion system. The communication enables interaction between the analyte-selective sensor and the infusion system.

Fig. 14 illustrates a flow chart of a method 1400 for analyte-selective sensor and infusion system coupling prior to dermal application. At block 1401, a mechanical retention mechanism is engaged between an analyte-selective sensor and an infusion system to form a unitary body-worn device. At block 1402, a single body worn device is positioned on the skin of a wearer. At block 1403, electromagnetic energy is transferred between the analyte-selective sensor and the infusion system.

Fig. 15 illustrates a flow diagram of a method 1500 for analyte-selective sensor and infusion system coupling prior to dermal application, facilitated by an intermediary device. At block 1501, a mechanical retention mechanism is engaged between the intermediary device and both the analyte-selective sensor and the infusion system to form a single body-worn device. At block 1502, a single body worn device is positioned on the skin of a wearer. At block 1503, electromagnetic energy is transferred between the analyte-selective sensor and the infusion system.

Fig. 16 is a flow chart of a method 1600 of an open loop embodiment of the present invention. A method 1600 for performing an open-loop embodiment begins at block 1601 where a microneedle array analyte-selective sensor records measurements of one or more analytes in the dermal stroma. Circulating levels of viable epidermal or intradermal analytes are quantified by the sensor. Next, at block 1602, one or more measurements from the microneedle array analyte selective sensor are displayed to a user. The user receives a reading of the circulating level of the one or more analytes on a display or interface. Alternatively, the user receives notification that the circulating level of the one or more analytes is outside of a predetermined standard or range of values. Next, at block 1603, the user adjusts the dosage of the one or more therapeutic agents, if necessary. The user manipulates the infusion amount, duration, or frequency of the therapy based on the measurement of the one or more analytes provided by the sensor. Next, at block 1604, one or more therapeutic agents are administered into the dermal interstitium, the subcutaneous fat layer, the circulatory system (veins, arteries, or capillaries), or the muscle tissue by the therapy delivery mechanism. Therapy is delivered to the user via the infusion subsystem and is determined based on the user dose given one or more measurements from the sensor.

Fig. 17 is a flow chart of a method 1700 of a closed loop embodiment of the present invention. A method 1700 for performing a closed-loop embodiment begins at block 1701 where a microneedle array analyte selective sensor records measurements of one or more analytes in the dermal stroma. Circulating levels of viable epidermal or intradermal analytes are quantified by the sensor. Next, at block 1702, one or more measurements from the microneedle array analyte selective sensor are input into a control algorithm; optionally, the one or more measurements are displayed to a user. The current and optionally past stored measurements are used as one or more inputs to the algorithm. Alternatively, the user also receives a reading of the circulating level of the one or more analytes on a display or interface. Alternatively, the user receives notification that the circulating level of the one or more analytes is outside of a predetermined standard or range of values. Next, at block 1703, the control algorithm adjusts the dosage of one or more therapeutic agents based on the programmed mathematical transformation, if necessary. The algorithm autonomously manipulates the infusion volume, duration, or frequency of the therapy based on the measurement of the one or more analytes provided by the sensor. Next, at block 1704, one or more therapeutic agents are administered into the dermal interstitium, the subcutaneous fat layer, the circulatory system (veins, arteries, or capillaries), or the muscle tissue via the therapy delivery mechanism. The therapy is delivered to the user via an infusion subsystem and is determined based on the dose output by a given algorithm.

The input of circulating levels of one or more analytes within the viable epidermis or dermis is an endogenous or exogenous biochemical, metabolite, drug, pharmacological, biological, or pharmaceutical agent in the viable epidermis or dermis indicative of a particular physiological or metabolic state.

The output is administration of one or more therapeutic agents into the circulatory system (venous, arterial, or capillary), muscle tissue, or oral delivery route. The measurements provided by the sensors are used to initiate the release of therapy by the infusion subsystem. In an open loop embodiment, the delivery of therapy is controlled by the user. In a closed loop embodiment, an algorithm is employed to control the dose, duration and frequency of treatment.

Fig. 18 is a block/process flow diagram 1800 illustrating inputs, outputs, and principal components under an open-loop embodiment. At block 1801, the circulating level of the one or more analytes is within the dermis. At block 1802, a sensor measures an analyte. User 1803 adjusts the dosage of one or more therapeutic agents if needed. The user 1803 manipulates the amount, duration, or frequency of infusion of the therapy 1804 based on the measurement of the one or more analytes provided by the sensor. At block 1805, one or more therapeutic agents are administered into the dermal interstitium, the subcutaneous fat layer, the circulatory system (veins, arteries, or capillaries), or the muscle tissue by the therapy delivery mechanism. The therapy is preferably delivered to the user via an infusion subsystem and is determined based on the user dose given one or more measurements from the sensor.

Fig. 19 is a block/process flow diagram 1900 illustrating inputs, outputs, and principal components under a closed-loop embodiment. At block 1901, the circulating level of the one or more analytes is within the dermis. At block 1902, a sensor measures an analyte. If desired, the control algorithm 1903 adjusts the dosage of one or more therapeutic agents based on the programmed mathematical transformation. The algorithm autonomously manipulates the infusion volume, duration, or frequency of the therapy 1904 based on the measurement of the one or more analytes provided by the sensor. Next, at block 1905, one or more therapeutic agents are administered by the therapeutic delivery mechanism into the subcutaneous fat layer, the circulatory system (venous, arterial, or capillary), muscle tissue, or oral delivery route. The therapy is delivered to the user via an infusion subsystem and is determined based on the dose output by a given algorithm.

Fig. 20 and 21 show an alternative embodiment having an intermediate apparatus 2010 integrated with an infusion system 800 'and an analyte-selective sensor 20' into a single, single-piece wearable device 2000. The intermediary device 2010 includes a compartment 2025 for detachable integration with the infusion system 800', a compartment 2020 for detachable integration with the analyte selective sensor 20', a CPU 2040, a memory 2045, a transceiver 2050, an interface 2055, and a communication/connection line 2030. In this embodiment, the user mechanically couples the analyte-selective sensor 20' and the infusion system (therapy delivery mechanism) 800', preferably prior to application to the wearer's body, through an intermediary device 2010. Intermediate device 2010 maintains analyte sensor 20 'and infusion system 800' in a fixed position relative to one another to form a unitary, body-worn, responsive therapy system 2000. Unitary-worn device 2000 preferably further comprises a skin patch, a dermal patch, an adhesive patch, an infusion set, a patch pump, a response therapy system, or an automated therapy delivery system. In an alternative embodiment, the connecting wires 2030 are not present and communication between the infusion system 800 'and the analyte selective sensor 20' is wireless. In the most preferred embodiment, the intermediary apparatus 2010 preferably has a length ranging from 2 centimeters (cm) to 13cm, a width ranging from 1cm to 8cm, and a height ranging from 1cm to 8 cm. The analyte-selective sensor 20' preferably has a diameter ranging from 1cm to 5cm and a thickness ranging from 0.1cm to 3 cm. The infusion system preferably has a length ranging from 2 centimeters (cm) to 12cm, a width ranging from 1cm to 7cm, and a height ranging from 1cm to 7 cm.

Fig. 22 illustrates an embodiment having an intermediary 2010 as a housing for holding an infusion system in a recess 2025 and an analyte selective sensor in a recess 2020 to form a single body worn device. In this embodiment, the intermediate device is preferably formed of plastic and contains no electronic components. The

recesses

2025 and 2020 may be shaped to hold various shapes of sensors and infusion systems.

Claims

1. A method for coupling an analyte-selective sensor and an infusion system as a single-body-worn device, the method comprising: positioning the analyte-selective sensor on the skin of a wearer, the analyte-selective sensor configured to penetrate the stratum corneum into the viable epidermis or dermis and measure the presence of an analyte or analytes in a selective manner; positioning the infusion system on the skin of a wearer, the infusion system configured to penetrate the stratum corneum and deliver a solution-phase therapeutic agent or a collection of therapeutic agents to a physiological compartment beneath the dermis, the positioning requiring mechanical retention between the infusion system and the analyte-selective sensor to form a single body-worn device; and transferring electromagnetic energy between the analyte-selective sensor and the infusion system to effect interaction between the analyte-selective sensor and the infusion system.

2. The method of claim 1, wherein the analyte-selective sensor includes a geometric feature configured to mechanically couple with a corresponding structure on a bottom portion of the infusion system during the positioning of the infusion system on a wearer's skin, thereby allowing the infusion system to be placed in a proper spatial orientation on a top surface of the analyte-selective sensor that has been applied to the wearer's skin.

3. The method of claim 1, wherein the analyte-selective sensor is first positioned on the wearer's skin.

4. The method of claim 1, wherein the analyte-selective sensor is an electrochemical sensor, a chemical sensor, an electrical sensor, a potentiometric sensor, a amperometric sensor, an impedance sensor, a conductometric sensor, or a biosensor.

5. The method of claim 1, wherein the infusion system comprises a fluid delivery device configured to provide infusion via a microneedle, microneedle array, large needle, hypodermic needle, cannula, catheter, or oral delivery route.

6. The method of claim 1, wherein the single body worn device comprises a skin patch, a dermal patch, an adhesive patch, an infusion device, a patch pump, a responsive therapy system, or an automated therapy delivery system.

7. The method of claim 1, wherein the analyte or analytes comprise at least one of glucose, lactate, ketone bodies, uric acid, ascorbic acid, alcohol, glutathione, hydrogen peroxide, metabolites, electrolytes, ions, drugs, pharmacology, biology, or pharmaceutical agents.

8. The method of claim 1, wherein the transmission of electromagnetic energy is to convey at least one of information and energy.

9. The method of claim 1, wherein the transmission of electromagnetic energy is through an electrical connector characterized by a conductive element or through wireless transmission.

10. A method for coupling an analyte-selective sensor configured to penetrate the stratum corneum to enter the viable epidermis or dermis and measure the presence of an analyte or analytes in a selective manner and an infusion system configured to penetrate the stratum corneum and deliver a solution-phase therapeutic agent or a collection of therapeutic agents in a controlled manner to a physiological compartment beneath the dermis, the method comprising: engaging a mechanical retention mechanism between the analyte-selective sensor and the infusion system to form a unitary device; placing the single device on the skin of a wearer; and transferring electromagnetic energy between the analyte-selective sensor and the infusion system to effect interaction between the analyte-selective sensor and the infusion system.

11. The method of claim 10, wherein the analyte-selective sensor is an electrochemical sensor, a chemical sensor, an electrical sensor, a potentiometric sensor, a amperometric sensor, an impedance sensor, a conductometric sensor, or a biosensor.

12. The method of claim 10, wherein the analyte or analytes comprise at least one of glucose, lactate, ketone bodies, uric acid, ascorbic acid, alcohol, glutathione, hydrogen peroxide, metabolites, electrolytes, ions, drugs, pharmacology, biology, or pharmaceutical agents.

13. The method of claim 10, wherein the infusion system comprises a fluid delivery device configured to provide infusion via a microneedle, microneedle array, large needle, hypodermic needle, cannula, catheter, or oral delivery route.

14. The method of claim 10, wherein the single device comprises a skin patch, a dermal patch, an adhesive patch, an infusion device, a patch pump, a responsive therapy system, or an automated therapy delivery system.

15. The method of claim 10, wherein the transmission of electromagnetic energy is to convey at least one of information and energy.

16. The method of claim 10, wherein the transmission of electromagnetic energy is through an electrical connector characterized by a conductive element or through wireless transmission.

17. A method for coupling an analyte-selective sensor configured to penetrate the stratum corneum to enter the viable epidermis or dermis and measure the presence of an analyte or analytes in a selective manner and an infusion system configured to penetrate the stratum corneum and deliver a solution-phase therapeutic agent or a collection of therapeutic agents in a controlled manner to a physiological compartment beneath the dermis, the method comprising: engaging a mechanical retention mechanism between an intermediate device and both the analyte-selective sensor and the infusion system to form a single apparatus; placing the single device on the skin of a wearer; and transferring electromagnetic energy between the analyte-selective sensor and the infusion system to effect interaction between the analyte-selective sensor and the infusion system.

18. The method of claim 17, wherein the analyte-selective sensor is a microneedle or microneedle array.

19. The method of claim 17, wherein the analyte or analytes comprise at least one of glucose, lactate, ketone bodies, uric acid, ascorbic acid, alcohol, glutathione, hydrogen peroxide, metabolites, electrolytes, ions, drugs, pharmacology, biology, or pharmaceutical agents.

20. The method of claim 17, wherein the infusion system comprises a fluid delivery device configured to provide infusion via a microneedle, microneedle array, large needle, hypodermic needle, cannula, catheter, or oral delivery route.