Abstract:
Embodiments of the invention enable sensing the presence and concentration of molecules such as electrolytes, biomarkers, chemically defined drugs and proteins in transdermal and cell interstitial body fluids. Today, these tests are generally performed by blood extraction in a clinic environment and a later analysis resulting in inconvenience to the patient, high cost, the need for specialized personnel and a delay in the results. The present invention enables performing those tests at a low cost, by non-specialized personnel or the patient him(her)self, in a home or clinic environment and provides near real time results that get communicated to the patient and authorized clinician. The invention achieves that by describing an innovative product architecture that integrating micro-needles with micro-sensors in a low cost disposable unit, a specially designed applicator for ease of use and automated wireless transmission and data analytics.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    A Provisional patent related to the invention was submitted: 
     
    
     TITLE OF PROVISIONAL PATENT 
       [0002]    ‘Apparatus’ and methods for transdermal and interstitial body fluid examination, sensing and associated data transmission systems” 
       APPLICATION NUMBER 
       [0003]    U.S. Provisional Patent Application 62/070,182 
       FILING OR 371(C) DATE filed on Aug. 18, 2014  
     STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT 
       [0004]    Not Applicable 
       THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT 
       [0005]    Not Applicable 
       INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A COMPACT DISK OR AS TEXT FILE VIA THE OFFICE ELECTRONIC FILING SYSTEM (EFS-WEB) 
       [0006]    Not Applicable 
       BACKGROUND OF THE INVENTION 
       [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. 
       CROSS-REFERENCE TO RELATED APPLICATIONS 
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       BRIEF SUMMARY OF THE INVENTION 
       [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 
     
    
     
       BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS 
         [0015]    While the specification concludes with claims particularly pointing out and distinctly claiming that which is regarded as the present invention, the advantages can be more readily be ascertained from the following description of the invention when read in conjunction with the accompanying drawings in which: 
           [0016]      FIG. 1  represents the overall transdermal sensing system consisting of the integrated micro-needle/sensor element  200 , an specially designed applicator  300  with a wired or wireless connection system to a smart device, an application for the smart device  400  to direct the sensing event and analyze results, a wired or wireless connection to a data server or the cloud and a software application in the server or cloud  500  for data analysis, storage and distribution while preserving the medically required protocols for privacy and data integrity. 
           [0017]      FIG. 2   a - 2   d  in  FIG. 2  represent cross-sections of structures used to form the integrated micro sensor unit. It integrates the operation of the micro-needles with the micro-sensors and a reference electrode in a monolithic block of silicon with a surrounding packaging structure that provides for the formation of a microfluidics chamber and electrical connections and may be formed when carrying out an embodiment of the method of the present invention. 
           [0018]      FIG. 3   a - 3   b  in  FIG. 3  represent cross-sections of structures that integrate the operation of the micro-needles with the micro-sensors and reference electrode as fabricated in separate blocks of silicon, a spacer enabling the formation of a microfluidics cavity and the surrounding packaging structure which may be formed when carrying out another embodiment of the method of the present invention. 
           [0019]      FIG. 4   a - 4   c  in  FIG. 4  represent cross sections of structures that integrate the operation of the micro-needles with the sensors and reference electrode as fabricated in separate blocks of silicon but where the etching in one of the silicon forming blocks provides for the microfluidics chamber and that may be formed when carrying out yet another embodiment of the method of the present invention. 
           [0020]      FIG. 5  represent an applicator and handling pen-like device  300 , or alternatively patch-like device  320 . designed to facilitate securely picking and electrically contacting the micro-needle/sensor assembly and containing the power source and electronics circuit to direct and execute the sensing event and to communicate wirelessly or by wired connection the sensing results to a smart device such as a smart phone or smart watch. 
           [0021]      FIG. 6  represents a smart device such as a computer, a smart phone or smartwatch  400  with a specially designed application to request and direct the sensing event by communicating wirelessly or by wired connection with the applicator device, to analyze the results, to communicate the results to a computer server or application in the cloud for storage and safekeeping and to communicate the results to the patient or appropriate clinician. 
           [0022]      FIG. 7  represents a server computer or server in the cloud  500  with a database and a software application that receives the sensing data, performs further analysis, provides secure safekeeping of the results and communicates the results to those with the right to know by using secure protocols appropriate to handle medical data. 
           [0023]      FIG. 8  represents a flow chart of the sensing event as directed by the server computer and the application in the smart device and executed by the applicator and the integrated micro-needle/sensor devices. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [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. 2   a , 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. 2   b  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. 2   b  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. 2   c  and  2   d , 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. 2   d ). In a preferred embodiment of this invention the integrated disposable unit  200  and described in more detail in  FIG. 2   d  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. 2   a - 2   d , 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. 3   a - 3   b , the substrate  102  with the micro-needles  106  ( FIG. 2   a ) 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. 3   a . 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. 3   b ), 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. 4   a - 4   c , 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 &lt;100&gt; wafers are used and a KOH based etchant is used to preferentially stop etching when it reaches a &lt;111&gt; 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.