Apparatus and methods for transdermal and cell interstitial body fluid examination, sensing of analytes, biomarkers and drug concentrations and associated data transmission systems

[0001] A Provisional patent related to the invention was submitted:

[0002] ‘Apparatus’ and methods for transdermal and interstitial body fluid examination, sensing and associated data transmission systems”

[0003] U.S. Provisional Patent Application 62/070,182

[0004] Not Applicable

[0005] Not Applicable

[0006] Not Applicable

[0007] 1. Field of the Invention

[0008] The present invention relates to the field of Biomedical testing of body fluids, sensing device processing and fabrication, and more particularly to a method of fabricating a transdermal or interstitial fluid analyzer that integrates micro-needles with micro-sensors along with multiple integration layers and structures and uses a specially fabricated applicator, patch or carrier to communicate with a smart device, analyze the sensed data and communicate the results to both patient and medical personnel.

[0009] 2. Description of Related Art

[0010] Frequent testing for relevant biological materials such as K+, Na+, Cl− ions, glucose, creatinine, cholesterol etc. and therapeutic agents such as drugs used in the treatment of cardiovascular, renal, neurological, oncological and other medical conditions is often required for the effective treatment and monitoring of patients. The standard of care involves blood extraction in a clinical setting with subsequent serum analysis for the concentrations of one or more electrolytes or other biological or therapeutic molecules of interest.

[0011] This testing process results in high costs related to the blood or fluid extraction being performed in a clinical setting, delays of hours to days related to the testing being frequently done by specialized personnel or laboratories, and inconvenience to the patient related to travelling to the medical facility and the significant time required. As a result, testing is often performed at suboptimal frequency and risks a delayed response to a medically significant event.

[0012] The use of micro-needles that can perforate the Stratum Corneum (the outer layer of the epidermis) and reach the transdermal fluid under the skin is part of the existing state of the art. When made hollow, the micro-needles provide access to the interstitial fluid among subcutaneous cells and permit the delivery of drugs or accessing the interstitial fluid for analysis. Micro-needles have been made from a large variety of materials from metals to ceramics to polymers to silicon with varying degrees of performance and process control. While these micro-needles can access the transdermal region, when manufactured to the correct dimensions, they are not deep enough to reach the blood capillaries or nerve endings and their application is therefore practically painless and does not produce bleeding. Research in the use of micro-needles has focused mostly on methods for delivering drugs into the subcutaneous region. Separately, sensors using especially formulated biochemical films to obtain electrical readings and transistors fabricated in semiconductors such as silicon and modified to make them sensitive and specific to ions such as K+ have also been sporadically described. Key difficulties with existing approaches are the lack of sufficient process control to achieve medical grade devices and complex integration methods that are not best suited for the high volume manufacturing that is necessary to achieve large volumes and low cost. As a result, practical devices that allow routine testing of transdermal fluid at low cost by non-specialized personnel are not available in the marketplace to the best knowledge of the inventors.

[0013]

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[0014] This invention provides processes and methods that enable and make practical the integration of micro-needles with biochemical micro-sensors and other associated or useful elements like reference electrodes, pH, and temperature sensors. The invention further allows for their miniaturization to achieve low cost and the enabling of high precision manufacturing methods required for a dependable and accurate medical grade device. It achieves this by implementing innovative process and integration architectures that leverage, adapt and take advantage of the state of the art in semiconductor wafer and thin film processing and materials with biochemical sensor devices and membranes that have been proposed for biochemical testing. It further describes a specialized applicator or carrier that allows its use by non-specialized medical personnel or by patients themselves along with built-in data analysis and communication capabilities so that the results can be communicated in real time to the patient and/or to medical staff (doctor, nurse etc.) without any specialized or skilled action by the user. The overall system described by the invention achieves a low cost, medical grade, easy to use transdermal and cell interstitial sensor architecture that is suitable for use in both clinical and non-clinical environments by non-specialized personnel as well as by the patient him(her)self. To the best understanding of the inventors, this capability to simultaneously achieve low cost, ease of use, medical grade accuracy and suitability for high volume manufacturing has not been accomplished by integration architectures described in prior art and no equivalent capability devices have been offered or are in the process of being offered in the marketplace

[0024] In the following detailed description, reference is made to the accompanying drawings that show, by way of illustration and examples, some specific embodiments in which the invention may be practiced. These embodiments are described in sufficient detail to enable those skilled in the art to practice the invention. Although the various embodiments of the invention are different, they are in no way mutually exclusive. For example, a particular feature, structure, or characteristic described herein, in connection with one embodiment, may be implemented within other embodiments without departing from the spirit and scope of the invention. In addition, it is to be understood that the location or arrangement of individual elements within each disclosed embodiment may be modified without departing from the spirit and scope of the invention. The following detailed description is, therefore, not to be taken in a limiting sense, but only as a mean to illustrate, and explain the scope of the present invention which is defined only by the appended claims, appropriately interpreted, along with the full range of equivalents to which the claims are entitled. In the drawings, like numerals refer to the same or similar functionality throughout the several views.

[0025] Methods of forming transdermal and cell interstitial body fluid sensing and data transmission systems (i.e. the integration of micro-needles, micro-sensors, reference electrodes, applicators, wireless communication and data processing capabilities) and associated structures are described. Those methods comprise forming a micro-needle unit that can pierce the Stratum Corneum portion of the skin, forming a micro-sensor unit for the ion or molecule species of interest (i.e. electrolytes, biomolecules and drugs whether therapeutic or otherwise) along with its associated control circuitry, forming a reference electrode, integrating all of them as a self-contained consumable unit in a way that can be greatly miniaturized to reduce cost, forming an applicator, patch, holder, or carrier that holds the consumable during the test, powers the sensors, acquires the data and transmits it to a smart device in a way that makes the device safe and easy to use by non-specialized personnel and an application for the smart device specifically developed to direct the sensing event, analyze the results and send them in real time to the patient and or appropriate medical personnel.

[0026] In an embodiment of the present invention, as illustrated in FIG. 1, an integrated system capable of transdermal and cell interstitial fluid examination, sensing of analytes, biomarkers and drug concentrations is described. An integrated disposable sensing unit 200 is fabricated by forming micro-needles, micro-sensors, a reference electrode, their supporting electronic circuitry and integrating them into a unit that is suitable for low cost manufacturing and easy to handle by non-specialized personnel. An applicator 300 such a pen-like or a patch-like or carrier with a different form factor but same function and that is reusable is specially designed to handle the integrated disposable unit. This applicator 300 carries a battery unit to provide power, includes electronic circuits to power the sensors and read the resulting sensing data, and has additional electronic circuits for processing and preparing that data for transmission along with electronic circuits to transmit wirelessly or by wired connection that data to a smart device. A smart device 400 such as a smart phone, smart watch, smart bracelet or general computing device capable of sending data to and receiving data from the applicator and a software application that directs the sensing event, analyzes the sensing results, communicates it to a central or cloud based data repository system and communicates it to both the patient and authorized clinician or clinic. A computing device 500 with an especially designed software application whether local, at a dedicated server farm or in the cloud to accept the data store it and provide secure access to only authorized personnel by following protocols generally accepted to handle sensitive medical information.

[0027] In an embodiment of the present invention, as illustrated in FIG. 2, a method of forming an integrated disposable sensing unit 200 is described by forming micro-needles, micro-sensors for one or multiple analytes or bio-chemical species of interest, a reference electrode and integrating them into a unit that is suitable for low cost manufacturing and easy to handle by non-specialized personnel. Referring to FIG. 2a, an array of micro-needles 106 are fabricated on a silicon block 102 by using photolithographic techniques, preferential crystal plane wet etch methods, isotropic and anisotropic dry etch techniques or a combination of all of them as it is well known to those skilled in the art. In this embodiment, the length of the micro-needles is between 25 micrometers and several millimeters as appropriate to the specific sensing function pursued. In the case of transdermal sensing lengths between 25 micrometers and 500 micrometers can be considered to ensure perforation of the Stratum Corneum and perform the testing without any significant pain or bleeding. Dimensions between 25 micrometers and several millimeters can be considered when probing for cell interstitial fluids in diseased body tissues. The micro-needles and supporting silicon block are formed with hollow perforations 104 which are formed commonly but not exclusively by Deep Reactive Ion Etching (DRIE) or alternative techniques as it is well known to those skilled in the art. FIG. 2b illustrates the formation of micro-sensors 108 designed to measure presence or concentration of the ion or biomolecule of interest, a reference electrode 107, electronic circuitry 105 designed to power and control them with all of the being formed on the surface opposite from that used to form the micro-needles by using photolithography and commonly used thin and thick film processing techniques. These micro-sensors 108 can be formed in a manner that is optimized for the specific ion species, biomarker or drug and could be based on Ion Sensitive Field Effect Transistors, especially modified thin films whose conductivity is modulated by the concentration of the chemical species to be tested or optimized to use voltammetry or amperommetry techniques as it is known to those skilled in the art. The micro-sensors 108 could be all similar so as to measure the concentration of a single species of analyte, biomarker/drug or may be formed to contain multiple sensor types so that multiple types of analytes, biomarkers and drugs can be measured simultaneously. The reference electrode 107 can be formed by adapting processing techniques commonly used in semiconductor technology and the use of different kinds of materials but preferably as a Ag/AgCl reference electrode as it is commonly used by those skilled in the art. The sensors 108 may be formed to include measurements of pH, temperature, ions such as K+, Na+, Cl− and others, important biomolecules such as creatinine, glucose, lactic acid, lactates, cholesterol, nitrates etc., therapeutic drugs such as those used to treat cardiovascular, renal, neurological and oncological conditions and any other of biological interest. The same FIG. 2b illustrates the formation of specially designed electronic circuits 105 and metallic contacts 109 on the same surface than the micro-sensors 108 whose function is to power the micro-sensors, read the sensing results, and prepare the data for transmission to the electronic circuits in the applicator through the metallic contacts 109 and which are formed by standard processing techniques used to fabricate semiconductor devices. Referring to FIGS. 2c and 2d, a specially formed casing 112 is used to assemble the micro-needle/micro-sensor(s) integrated block in a way that it creates a microfluidics chamber 114 and which allows the transdermal fluid to reach the sensor units. Making the dimensions of the hollow portion of the micro-needle 104 and the fluid chamber 114 small and their surfaces hydrophilic, along with the presence of a vent 120, will allow the transdermal fluid to travel by capillary action and reach the micro-sensors. Preferred embodiments for the hollow portion of the micro-needles are below 150 micrometers although larger dimensions are possible. Preferred embodiments for the height of the microfluidics chamber are in the 10-500 micrometers although dimension of 1 millimeter and larger can be made work. The casing 112 may comprise materials such as metals, ceramics, polymers and plastics or others that provide similar structural function. Perforations 116 in the casing 112 are used to incorporate electrical conductors and provide electrical access to the sensors 108 and sensing circuitry 105, to provide power, read the results and may be formed in sufficient quantity to tend the needs of the multiple sensors formed. A perforation formed in the casing 120 and identified as a vent allows air to be vented out of the chamber as the transdermal fluid fills the sensing chamber 114 by capillary action and can be formed anywhere that is convenient in the walls micro-fluidics chamber. Conductive pads 118 are formed on the casing to complete forming the consumable unit (FIG. 2d). In a preferred embodiment of this invention the integrated disposable unit 200 and described in more detail in FIG. 2d is between 0.5 millimeters and 10 millimeters wide with the dimension being dictated primarily by number of distinct sensor devices incorporated into the unit. In a preferred embodiment of this invention the integrated disposable unit 200 has a thickness between 500 micrometers and 5 millimeters.

[0028] In another embodiment of the invention and referring to the same FIGS. 2a-2d, the substrate 102 and micro-needles 106 are formed in a material different that silicon such as metal, ceramic, polymer, carbon or plastic and the micro-sensors 108, controlling circuitry 105 and reference electrode 107 are fabricated separately either in silicon or in another suitable material such as a different semiconductor, carbon, metal or nanoparticle structure and are placed appropriately over the substrate 102 while allowing a similar method of integration of the consumable portion of the device.

[0029] In another embodiment of the invention, and as described in FIG. 3a-3b, the substrate 102 with the micro-needles 106 (FIG. 2a) are formed in a separate block than the micro-sensors 208, control circuitry 205 and reference electrode 207 which are formed on a substrate 222 as is described in FIG. 3a. The micro-needles 106 and the micro-needle substrate 102 can be formed in a variety of materials including, but not limited to silicon, metals, ceramics, polymers, carbon or plastics. The substrate 222 can be formed in a variety of materials including, but not limited to silicon, metals, ceramics, polymers, carbon or plastics. The micro-sensors themselves 208 can be formed in silicon or in another material suitable for the fabrication of micro-sensors such as a different type of semiconductor, or a properly formulated carbon or polymer based paste and could be based on Ion Sensitive Field Effect Transistors, especially modified thin films whose conductivity is modulated by the concentration of the chemical species to be tested or optimized to use voltammetry or amperommetry techniques as it is known to those skilled in the art. The controlling circuitry 205 and reference electrode 207 can then be formed on substrate 222. In this embodiment (FIG. 3b), the electrical connections 216, electrical contacting pads 218 and the vent 220 are also formed in the substrate 222. During operation, and when the transdermal needles 106 pierce the stratum corneum, the interstitial fluid moves up the hollow portion of the needle 104 by capillary action reaching the cavity 214 and the micro-sensors 208 and generates an electrical sensing signal that can be read through the electrical pads 218.

[0030] In another embodiment of the invention and as illustrated in FIG. 4a-4c, the micro-fluidics chamber 230 is formed in the micro-needle block 102 by chemical etching, abrasion, stamping, laser processing or other suitable method. In the case where the micro-needle block 102 is made out of silicon, the micro-fluidics chamber 130 can be formed by anisotropic dry etching or by wet chemical etching of the silicon which preferentially etches or stops along certain crystalline planes or by other wet or dry etching methods as it is well known to those skilled in the art. An example is the case where Silicon <100> wafers are used and a KOH based etchant is used to preferentially stop etching when it reaches a <111> plane forming the desired cavity. However, multiple other options based in the same concept are possible as it is well known to those skilled in the art. Additionally, the venting perforation 220 is shown in block 222 for convenience but could also be easily formed laterally from the micro-fluidics chamber in the micro-needle block 102 and be equally effective.

[0031] In another embodiment of the invention and as it is illustrated in FIG. 5, a reusable applicator 300 is designed and formed to facilitate the handling of the sensing operation in a way that is easy to use by non-specialized personnel. The applicator can be formed by using metals, ceramics, plastics, polymers or a combination of them. As a method of illustration, the applicator 300 includes a grab and hold mechanism 302 that securely picks and holds the integrated sensing unit 200, a method of providing electrical connectivity 304, an electronic circuit unit 306 that provides power to the sensors by a battery or other means, has the capability to processes the results, and transmits them wirelessly or by a wired connection to a smart device 400. The applicator 300 also contains a mechanical grab and hold actuator 310 which in one embodiment of the invention could be similar to the operation of a mechanical pencil, and an electrical switch 308 that initiates the sensing sequence under user control. The description of the mechanisms, actuators and switches illustrated in FIG. 5 are provided as examples and should not be interpreted as limiting the method of executing the inventions as many related options are available to those skilled in the art. The applicator 300 itself illustrated in FIG. 5 is a pen like device but many other options in the form of a patch or carrier device with alternative geometries are possible and this example should not be construed as limiting the application of the invention. The patch-like device 320 in FIG. 5 illustrates such an embodiment example of the reusable applicator with its grab and hold mechanism 302, an adhesive 322 to secure it to the skin and the electronics module 306 to confer it a substantially similar capability and function than that described for the pen-like applicator.

[0032] In another embodiment of the invention as illustrated in FIG. 6 a smart device 400 such as, but not limited to a smartphone, smart-watch, tablet or computer has been equipped with a specialized application or software program that directs the sensing sequence, communicates by wire or wirelessly with the applicator 300, instructs the sensing to be done, collects and analyzes the results and communicates them by wire or wirelessly to devices 500 under the control of the patient and/or appropriate medical personnel as illustrated in FIG. 7. An example of the architecture of the integrated operation is described in FIG. 1 and an example of the operational flow is described in FIG. 8. It should be clear to those skilled in the art that the architecture of the integrated operation described in FIG. 1 and the operational flow described in FIG. 8, are examples and that variants in the sequence of events or modification in the flow that accomplish the same result are part of the claimed invention.