Transdermal sensing of analytes in interstitial fluid and associated data transmission systems
Provided are transdermal microneedle-based devices for sensing the presence and concentration of analytes such as electrolytes, biomarkers, drugs, and proteins in interstitial fluid. Also provided are methods and systems to transmit the data obtained by wired or wireless connection to a receiver and to relay the data to the user or a clinician.
This application is a continuation of U.S. application Ser. No. 16/442,229 filed 14 Jun. 2019, pending, which is a continuation of U.S. application Ser. No. 14/827,186 filed 14 Aug. 2015, now U.S. Pat. No. 10,321,858 B2, and claims priority under 35 U.S.C. § 119(e) from U.S. provisional application Ser. No. 62/070,182 filed 18 Aug. 2014, expired. Each of the prior applications is incorporated by reference in its entirety into the present application.
BACKGROUND OF THE INVENTIONThe present invention relates to biomedical testing of body fluids, to sensing device processing and fabrication, and more particularly to a method of fabricating a transdermal or interstitial fluid analyzer that integrates microneedles with micro-sensors with multiple integration layers and structures. The analyzer 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.
Frequent testing for biological materials such as K+, Na+, or Cl− ions, glucose, creatinine, cholesterol, as well as 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.
This testing process results in high costs related to performing the blood or fluid extraction in a clinical setting, delays of hours to days related to the testing frequently being done by specialized personnel or laboratories, and inconvenience to the patient related to travel 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.
The use of microneedles 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 microneedles provide access to the interstitial fluid among subcutaneous cells and permit the delivery of drugs or access to the interstitial fluid for analysis. Microneedles 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 microneedles can access the transdermal region, when manufactured to the correct dimensions, they are not deep enough to reach the blood capillaries or nerve endings. Their application is therefore practically painless and does not produce bleeding.
Research in the use of microneedles has focused mostly on methods for delivering drugs into the subcutaneous region. Separately, sensors using specially formulated biochemical films to obtain electrical readings and transistors fabricated in semiconductors such as silicon, modified to be sensitive and specific for ions such as K+ have also been occasionally 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 necessary to achieve large volumes and low cost. As a result, to the best knowledge of the inventors, practical devices that allow routine testing of transdermal fluid at low cost by non-specialized personnel are not available in the marketplace.
The following patents and publications relate to the field of the invention.
The invention provides processes and methods that enable and make practical the integration of microneedles with biochemical micro-sensors and other associated or useful elements such as reference electrodes, pH sensors, and temperature sensors. The invention further allows for their miniaturization to achieve low cost and high precision manufacturing methods required for a dependable and accurate medical grade device. It achieves these objectives 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 in materials with biochemical sensor devices and membranes that have been proposed for biochemical testing. As described below, in particular implementations the invention provides a specialized applicator or carrier that allows the use of the device by non-specialized medical personnel or patients themselves. Built-in data analysis and communication capabilities allow the results to 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 interstitial fluid sensor architecture 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 the prior art, and no equivalent capability devices have been offered or are in the process of being offered in the marketplace.
The advantages of the invention can be more readily be ascertained from the following description of the invention when read in conjunction with the accompanying drawings.
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 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 description is therefore not to be taken in a limiting sense, but only as a means to illustrate and explain the scope of the 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.
Methods of forming transdermal and interstitial fluid sensing and data transmission systems (i.e., the integration of microneedles, micro-sensors, reference electrodes, applicators, wireless communication and data processing capabilities) and associated structures are described. Those methods comprise forming a microneedle unit that can pierce the stratum corneum of the skin; forming a micro-sensor unit for the ion or molecule species of interest (e.g., 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; and 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. The methods of the invention provide a device that is safe and easy to use by non-specialized personnel. The invention also provides 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.
An embodiment of the invention, as illustrated in
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The controlling circuitry 205 and reference electrode 207 can then be formed on substrate 222. When the structure containing the sensors 208, control circuitry 205, and electrode 207 is integrated with the structure containing the microneedles 106 and microneedle substrate 102, a spacer 210 enables the formation of a microfluidics cavity 214 as shown in
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Claims
1. An apparatus for testing interstitial fluid in a subject comprising a disposable integrated micro-sensing unit and an applicator,
- wherein the micro-sensing unit comprises a plurality of hollow transdermal microneedles, a microfluidics chamber, a vent, and one or more sensors in the microfluidics chamber capable of detecting the presence or concentration of one or more analytes;
- and wherein the applicator comprises a switch capable of initiating the testing event, circuitry for processing data from the sensors, and circuitry for wirelessly transmitting data that result from the testing to a receiver.
2. The apparatus of claim 1 wherein the micro-sensing unit further comprises a reference electrode, a pH sensor, a temperature sensor, electronic circuitry to control the testing, a casing, and electrical contacts.
3. The apparatus of claim 2 further comprising a substrate, wherein the substrate and microneedles are formed in a first material; the analyte sensors, reference electrode, pH and temperature sensors, and electronic control circuitry are formed in one or more additional material(s) and placed over the substrate; and the first and additional materials may be the same or different.
4. The apparatus of claim 3 wherein the microfluidics chamber is a cavity formed by a spacer between the substrate and the additional material(s), a cavity formed by the casing, or a cavity in a block of material comprising the microneedles.
5. The apparatus of claim 2 wherein the microneedles, microfluidics chamber, analyte sensors, reference electrode, pH and temperature sensors, and electronic control circuitry are formed in a monolithic block of silicon.
6. The apparatus of claim 1 wherein the sensor(s) are conductivimetric, voltammetric, or amperometric.
7. The apparatus of claim 1 wherein the interior width of the hollow portion of the microneedles is less than 1 mm, the interior length, width, and height of the microfludics chamber are each from 10 μm to 2 mm, the length and width of the micro-sensing unit are each from 0.5 mm to 10 mm, and the thickness of the micro-sensing unit is from 0.5 mm to 5 mm.
8. The apparatus of claim 1 wherein the applicator comprises a battery and electronic circuitry to power the micro-sensing unit.
9. A method for detecting the presence or concentration of one or more analytes in the interstitial fluid of a subject, comprising
- providing to a user a testing apparatus comprising a disposable integrated micro-sensing unit and an applicator, wherein the micro-sensing unit comprises a plurality of hollow transdermal microneedles, a microfluidics chamber, a vent, and one or more sensors in the microfluidics chamber capable of detecting the presence or concentration of the one or more analytes; and wherein the applicator comprises a switch capable of initiating the testing event, circuitry for processing data from the sensors, and circuitry for wirelessly transmitting data that result from the testing to a receiver;
- providing a receiver running a software application configured to receive and optionally to further transmit the data, wherein the receiver is a computer, smart phone, smart watch, tablet computing device, or wearable computing device;
- applying the micro-sensing unit to the skin of the subject such that the microneedles contact interstitial fluid in the subject;
- actuating the switch and thereby initiating a testing event, wherein the execution of the testing event and transmission of the data proceed under full automatic control without further intervention by the user;
- collecting data from the sensor(s), processing the data, and transmitting the processed data to the receiver; and
- analyzing the data in the software application.
10. The method of claim 9 further comprising communicating the results of the testing to the user in real time.
11. The method of claim 9 wherein the user is the subject.
12. The method of claim 9 wherein the user initiates the testing event by actuating the switch on the applicator.
13. The method of claim 9 wherein the software application is further configured to actuate the switch on the applicator, and wherein the user instructs the software to initiate the testing event.
14. The method of claim 9 wherein the software application controls or directs the testing event.
15. The method of claim 9 wherein the receiver further transmits the data to a server.
16. The method of claim 9 wherein the micro-sensing unit further comprises a reference electrode, a pH sensor, a temperature sensor, electronic circuitry to control the testing, a casing, and electrical contacts.
17. The method of claim 16 wherein the micro-sensing unit further comprises a substrate, and wherein the substrate and microneedles are formed in a first material; the analyte sensors, reference electrode, pH and temperature sensors, and electronic control circuitry are formed in one or more additional material(s) and placed over the substrate; and the first and additional materials may be the same or different.
18. The method of claim 17 wherein the microfluidics chamber is a cavity formed by a spacer between the substrate and the additional material(s), a cavity formed by the casing, or a cavity in a block of material comprising the microneedles.
19. The method of claim 16 wherein the microneedles, microfluidics chamber, analyte sensors, reference electrode, pH and temperature sensors, and electronic control circuitry are formed in a monolithic block of silicon.
20. The method of claim 9 wherein the sensor(s) are conductivimetric, voltammetric, or amperometric.
Type: Application
Filed: Feb 20, 2022
Publication Date: Dec 8, 2022
Inventors: Jose Antonio Maiz-Aguinaga (Vancouver, WA), Lennart Olsson (Los Altos Hills, CA)
Application Number: 17/676,194