Patent Application
20110224515
This technology generally relates to replaceable test cartridges for biomedical monitors, and more specifically to replaceable test cartridges having an array of minimally invasive microneedles.
Existing methods for measuring blood glucose and other blood and/or interstitial fluid-based parameters suffer from a number of disadvantages. For example, the well-known fingerstick monitor requires the use of a fine lancet which invasively pierces the skin to draw blood for subsequent analysis. Unfortunately, as a result of the discomfort and inconvenience of the process, compliance tends to be low, especially for younger and older patients. Repeated lancet piercing can also lead to sensitivity and/or hardening of the subject's skin since fingertips are one of the body's most sensitive regions. Furthermore, fingerstick-based monitors only provide a sampled measurement of the subject's blood chemistry even though glucose levels fluctuate rapidly after meals. This creates problems especially for diabetics who need to monitor their glucose levels over 5 times a day, exacerbating usage issues for the patient. With growing numbers of patients requiring regular blood/fluid based biomedical testing, patients and physicians have been searching for a more continuous monitoring process that is less painful or even painless, less invasive, more convenient, automatable, and which requires little or no periodic calibration.
As described in The Pursuit of Non-Invasive Glucose: “Hunting the Deceitful Turkey” by John L. Smith, a large number of attempts to bring a non-invasive glucose monitor to market have been made, and so far none has been successful. Generally, the many methods that have been pursued exhibit poor accuracy because of glucose interferents and other uncontrolled variables.
Microneedle technology provides a useful minimally-invasive method to sample body fluids. Due to their small size, microneedles can pierce skin and sample minute quantities of blood or interstitial fluid with minimal impact and/or pain to the subject. In spite of their advantages for reducing patient discomfort, many microneedle systems described in the prior art are still somewhat invasive since they extract and transport blood or interstitial fluid from the patient for the measurement. Furthermore, the small quantity of fluid sampled by microneedles can lead to great variability in concentration measurements.
Implanted in vivo sensors have also been developed to sample blood chemistry. Such implanted sensors have the advantage of not requiring blood extraction. Unfortunately, however, long term use of implanted sensors is hampered by a process known as “bio-fouling”. Bio-fouling refers to changes in device characteristics caused by its interaction with the in vivo environment as a result of the device's long term presence in the subject. At best, bio-fouling requires frequent calibration to compensate for these changes; more often than not these changes are irreversible and require device replacement. Implanted in vivo sensors also require an accommodation period, typically hours, after implantation before useful monitoring can begin. In addition, implanted sensors are inserted subcutaneously into a very complex environment comprising a large number of anatomical structures including hair follicles, sebaceous tissue, sweat glands, nerve fibers, and more. The implanted sensors are blind to their precise local environments. Accuracy achieved using continuous glucose monitoring with implanted sensors is not adequate for therapeutic use.
A replaceable microneedle array for a biomedical monitor is disclosed. The microneedle array includes a plurality of moveable microneedles coated with at least one chemical sensing material coupled with a porous material. The microneedle array also includes a substrate defining wells to house the microneedles. The microneedle array further includes at least one restoring spring element coupled between each microneedle and the substrate such that each of the plurality of microneedles is held at least partially in an associated well.
This technology provides a number of advantages. A biomedical monitor may be configured to receive the convenient replaceable microneedle array. Such biomedical monitors may be removably attached to a subject and are able to make multiple sequential blood chemistry measurements. The biomedical monitor provides a highly useful device configuration and convenient fabrication process for dense arrays of individually actuated microneedles having integral chemical sensors. The compact wearable device can sample body chemistry without extracting a significant amount of blood or interstitial fluid either during or after the microneedle is inserted in the subject. Consequently, the degree of invasiveness and risk of contamination is reduced, while improving the hygiene of the process. Due to their high multiplicity, microneedles with integral chemical sensing material may be inserted in the subject in sequence over an extended period of time, each chemical sensing element being required to make measurements for only a short time period. The use of each microneedle for a limited time will eliminate the effect of bio-fouling. Sequential actuation of a multiple microneedles provides the ability for long term monitoring. Control of the serial actuation process can be programmed for a specific monitoring schedule, making the process practically continuous, if desired, and convenient for a subject. Due to their dense spacing and integrated actuation capability, many measurements may be made for extended time periods using a compact device worn by the subject as a small patch or chip. The biomedical monitor may be configured to sense chemicals which are naturally produced and/or found in a subject's body as well as chemicals which a subject has been exposed to, for example harmful toxins or biological components.
It will be appreciated that for purposes of clarity and where deemed appropriate, reference numerals have been repeated in the figures to indicate corresponding features. Illustrations are not necessarily drawn to scale. While spatial imaging methods and a replaceable microneedle cartridge for biomedical monitoring are described herein by way of example for several embodiments and illustrative drawings, those skilled in the art will recognize that the system and method are not limited to the embodiments or drawings described. It should be understood, that the drawings and detailed description thereto are not intended to limit embodiments to the particular form disclosed. Rather, the intention is to cover all modifications, equivalents and alternatives falling within the spirit and scope of the appended claims. Any headings used herein are for organizational purposes only and are not meant to limit the scope of the description or the claims. As used herein, the word “may” is used in a permissive sense (i.e., meaning having the potential to), rather than the mandatory sense (i.e., meaning must). Similarly, the words “include”, “including”, and “includes” mean including, but not limited to.
A number of substrate 24 and/or microneedle 26 materials maybe used, e.g. silicon, silicon dioxide, silicon nitride, all commonly used in microfabrication or, in general, dielectrics, plastics, metals, glass, quartz, or sapphire. The microneedle 26 and a base 30 of the microneedle 26 are preferably transparent, but may be translucent in some embodiments. Another option would be to have the bulk material of the microneedle be transparent, while its surface be scattering or translucent. Several fabrication techniques for the one or more microneedles 26 are disclosed in the literature, such as photolithography, reactive ion etching, isotropic etching (e.g. for glass), plastic molding, water jet milling, and others may be used. The one or more microneedles 26 may be solid or hollow. The microneedle 26 cross-sections may be variable or constant, and can take on a variety of cross-sectional shapes, including, but not limited to square, circular, triangular, and grooved. Other embodiments of microneedles 26 may even be corrugated.
The one or more microneedles 26 can be coated with a chemical sensing material (not shown) that either changes its color or fluoresces or changes its fluorescence characteristics when in contact with one or more specific chemical species. The chemical sensing material may be optically transparent, reflective, opaque, or scattering. Different chemical sensing materials are discussed later with regard to
The microneedle array 22 may be configured to be placed in proximity or contact with a test subject's skin 32. In
The biomedical monitor 20 also has at least one actuator 36 configured to move the one or more microneedles 26 from the inactive position illustrated in
The actuator 36 schematically illustrated in the embodiment of
The biomedical monitor 20 also has an optical system 44 for capturing images of the one or more microneedles 26. The optical system 44 may include one or more light sources 46, an image sensor 48, and optics 50 for focusing an image of the microneedle 26 onto the image sensor 48. In this embodiment, the use of an off-axis light source 46 allows diffuse light reflected from the sensing material coating the microneedles 26 to be captured by the image sensor 48 which is located directly above the sensing material. Other embodiments may have different light source and/or image sensor locations. The symmetrical illumination made possible by the multiple light sources 46 in this embodiment also results in a reduction of shadowing in the microneedle images captured by the image sensor 48. Other embodiments may use different numbers and/or locations of light sources, however.
The optical system 44 may also optionally include obstructions 52 which function to restrict certain angles of illumination and reduce specular reflections from the top surface of the microneedles.
After the microneedle 26 penetrates the subject, the sensing material (not shown) coated on the microneedle 26 undergoes a change in color or exhibits fluorescence which is sampled using the one or more light beams 54 emanating from the one or more light sources 46. As non-limiting examples, light source 46 could be an incandescent source with collimation optics, a light emitting diode, or a laser diode. The spectral requirements for optics 50 will depend on the wavelength required to monitor absorption of the colorant reagent or excite fluorescence in the sensing material coated on the microneedle 26. Signal beam 56 emanating from the sensing material coated on the microneedle 26 includes information regarding the color change of the sensing material, and is focused by optics 50 to form an image of the sensing material on the imaging sensor 48. The imaging sensor 48 may be made selective to the optical absorption or fluorescence wavelengths of the sensing material coated on the microneedles 26. Those skilled in the art will recognize that the exemplary optical path illustrated in
The image sensor 48 is coupled to the computing device 42. The image sensor 48 provides image-based output 58 to the processor. Suitable non-limiting examples for an image sensor 48 include a charged coupled device (CCD) image sensor and a complementary metal oxide semiconductor (CMOS) image sensor. Image processing techniques, as will be described later, are employed to intelligently assess the image and modify it to eliminate spatial regions that are determined to be non-representative of good data. Image processing and data manipulation may be performed by computing device 42 to determine a concentration of one or more chemicals being monitored. The determined concentration may be an actual concentration or a number representative of or proportional to the concentration of the chemical being monitored.
The computing device 42 may include a central processing unit (CPU), controller or processor, a memory, and an interface system which are coupled together by a bus or other link, although other numbers and types of each of the components and other configurations and locations for the components can be used. The processor in the computing device 42 may execute a program of stored instructions for one or more aspects of the methods and systems as described herein, including for biomedical monitoring, although the processor could execute other types of programmed instructions. The memory may store these programmed instructions for one or more aspects of the methods and systems as described herein, including methods for biomedical monitoring, although some or all of the programmed instructions could be stored and/or executed elsewhere. A variety of different types of memory storage devices, such as a random access memory (RAM) or a read only memory (ROM) in the system or a floppy disk, hard disk, CD ROM, DVD ROM, or other non-transitory computer readable medium which is read from and/or written to by a magnetic, optical, or other reading and/or writing system that is coupled to the processor, may be used for the memory. The interface system may include one or more of a computer keyboard, a computer mouse, and a computer display screen (such as a CRT or LCD screen), although other types and numbers of interface devices may be used.
Although some embodiments of computing devices 42 for use in the biomedical monitor 20 have been discussed herein for exemplary purposes, many variations of the specific hardware and software used to implement the computing device 42 are possible, as will be appreciated by those skilled in the relevant art(s). Furthermore, the computing device 42 of the biomedical monitor 20 may be conveniently implemented using one or more general purpose computer systems, microprocessors, digital signal processors, micro-controllers, application specific integrated circuits (ASICs), programmable logic devices (PLDs), field programmable logic devices (FPLDs), field programmable gate arrays (FPGAs) and the like, programmed according to the teachings as described and illustrated herein, as will be appreciated by those skilled in the computer, software and networking arts.
In addition, two or more computing systems or devices may be substituted for the computing device 42. Accordingly, principles and advantages of distributed processing, such as redundancy, replication, and the like, also can be implemented, as desired, to increase the robustness and performance of the biomedical monitor 20. The computing device 42 may also be implemented on a computer system or systems that extend across any network environment using any suitable interface mechanisms and communications technologies including, for example telecommunications in any suitable form (e.g., voice, modem, and the like), Public Switched Telephone Network (PSTNs), Packet Data Networks (PDNs), the Internet, intranets, a combination thereof, and the like.
The computing device 42 can further be configured to store data (remotely and/or locally) corresponding to the biomedical characteristic being measured, together with subject information, date, and time, all of which may comprise an electronic medical record. The electronic medical record can be generated automatically and can be recalled and displayed on the biomedical monitor 20. The electronic medical record can also be transmitted automatically or on command using wireless or other techniques well known in the information technology arts.
A particularly preferred colorant for glucose testing includes potassium iodide and amylose. Potassium iodide is oxidized to produce polyiodide ion that in the presence of amylose forms a complex that is a very strong optical absorber having a blue-violet color. Amylose is a polysaccharide and a component of vegetable starches. Vegetable starch may in fact be used directly in the chemical sensing material 60, the starch also providing function as a binder and film-forming agent. Other strongly colored tri-iodide ion-host systems include tri-iodide plus polyvinyl acetate, polyvinyl alcohol, polyvinyl pyrrolidone, nylon, cellulose, chitosan or combinations of these host materials. Other poly-atom iodide ions exist and can also form strongly colored complexes in the above host systems.
It should be apparent to those skilled in the chemical arts that these examples of chemical sensing materials are merely illustrative of broader families of chemicals. It will be apparent to those skilled in the chemical arts that the example materials may be modified while still performing the same or similar function of providing or facilitating a spectral response in the presence of a target chemical or chemical compound. All such modifications and equivalents to the listed chemical sensing media as well as alternates for other target media besides glucose are intended to be included in this disclosure. In some cases, the reagent or fluorophore may need to be incorporated into a polymeric matrix in order to achieve coatability, adhesion, or chemical stability. Other reagents or fluorophores may be used to monitor cholesterol, HDL cholesterol, LDL cholesterol, alcohol, estrogen-progesterone, cortisol, and other physiological chemicals of interest.
During the wetting of the chemical sensing material 60 with body fluid, the mass flow into the chemical sensing material will tend to mitigate potential diffusion of components of the chemical sensing material into the subject. After filling, however, slow diffusion from the chemical sensing material 60 to the subject may occur. Therefore, in some embodiments, such as the microneedle 26 illustrated in
Although the tissues within the dermis are diffusely reflective and can function to reflect light incident on the microneedle back to the image sensor, the amount of the light reaching the image sensor may be enhanced by utilizing a roughened microneedle 64 as illustrated in
The amount of light reaching the image sensor may alternatively be enhanced with the inclusion of micro-particulate diffuse reflection/scattering particles with the chemical sensing material. For example, the microneedle 68 shown in
The chemical sensing material 60 may include the specific analyte selective agent or agents, typically enzymes, the oxidizable colorant system or fluorescent material, and film-forming binders. Binding materials of use may include natural or synthetic polymers such as latex, starch, polyvinyl alcohol, polyvinylpyrrolidone, ethyl cellulose, methylvinylether/maleic anhydride copolymer, and acrylic, vinyl acetate, styrene and butadiene homo- and copolymers and the like. It is preferred that the film 72 is well-adhered to the microneedle at interface 74, and that it exhibits good cohesion. It is also preferred that the film 72 exhibits an openly porous microstructure. The openly porous structure will facilitate a rapid filling with body fluid by capillary forces when microneedle 68 is inserted into the subject. The openly porous structure can be achieved using the micro-particulate diffuse particles disclosed above together with appropriate amounts of binder. Increasing the amount of binder tends to result in more mechanical strength at the expense of fluid retention speed, while reducing the amount of binder tends to increase fluid retention speed at the expense of mechanical strength.
In alternate embodiments, porous metal oxide or mixed metal oxide films (comprising the chemical sensing material) may be prepared by the sol-gel method, well known in the art. Alternatively, polymeric materials can form porous film coatings by use of the well-known mixed-solvent techniques for producing porous polymer films. In a related approach, immiscible mixtures of polymers can form films having segregated polymer phases that can form porous films by dissolving away one of the polymer phases. Cellulose systems are particularly useful for forming porous polymer films. For example, ethyl cellulose and hydroxypropylcellulose or hydroxypropyl methylcellulose constitute preferred mixed phase systems. Preferred mixed solvent systems for ethyl cellulose include water and propanol, water and ethanol, acetone and propanol, and the like. Cellulose acetate or cellulose acetate-butyrate used with a mixed acetone/water solvent or pore formers such as magnesium perchlorate, polyethylene glycol also are preferred porous film-forming systems. Microfibrous films having a paper-like microstructure are also useful porous films. Once-filled with body fluid, for example interstitial fluid found in the dermis, the coated microneedle can optionally be retracted and imaging of the imbibed coated microneedle undergoing reaction can be continued as described above. To achieve the desired rapid filling, it is preferred that the porous film 72 which includes chemical sensing material 60 have a means to vent the air that will be initially contained within it. This can be accomplished at the upper portions of the film 72 that are positioned in a dry zone above the location of the skin penetration.
Optionally, a semi-permeable membrane overlay 62, as discussed above, may be included on the microneedle 68 as illustrated in
In the microneedle 76 embodiment illustrated in
Optionally, a semi-permeable membrane overlay 62, as discussed above, may be included on the microneedle 76 as illustrated in
In the embodiments of
Optionally, a semi-permeable membrane overlay 62, as discussed above, may be included on the microneedle 86 as illustrated in
Combinations of one or more configurations as shown in
Although the analyte-selective species and the indicator materials may be sufficiently immobilized by physical sequestering, it is sometimes desirable to use chemical techniques. It is known in the art that enzymes and dyes may be immobilized at surfaces of both inorganic and polymeric materials. For example, benzoate, carboxylate, sulfonate, salicylate and phosphonate compounds are useful in binding dyes to inorganic oxides as taught in Electrochemistry of Nanomaterials by G. Hodes p. 148 and in U.S. Patent Application Publication No. 2008/0128286 to Wu et al. paragraph 34, both of which are hereby incorporated by reference in their entirety. “Comparison of techniques for enzyme immobilization on silicon supports” by Aravind Subramanian et al. published in Enzyme Microb. Technology, 1999, 24, 26-34, also incorporated herein by reference, teaches techniques for anchoring enzymes such as glucose oxidase to silicon/silicon dioxide surfaces. N. Gupta et al in Journal of Scientific and Industrial Research, Vol 65, 2006, p. 535, further incorporated herein by reference, teaches the use of a number of immobilizing matrices for the enzyme glucose oxidase. These include tetrathiofulvalene with tetracyanoquinodimethane, polypyrrole, poly(ethylene-vinyl alcohol), polyphenol, polyurethane, and polyethylene-g-acrylic acid Immobilization of enzymes in hydrogel matrices of sol-gel oxide films, e.g. SiO2 gel is also well known. For polymeric porous media, surface functionalization with reactive groups, epoxy or amino groups, for example, is a well-known technique for immobilization of enzymes.
The microneedles in the microneedle array do not need to be limited to having a single sensing region. For example,
Optionally, a semi-permeable membrane overlay, as discussed above, may be included on the microneedles as illustrated in
As discussed above, it is also possible in other embodiments to position the capillary layer so that it is disposed outside of the region of chemical sensing material 90. Capillary flow can be quite significant causing the displacement of interstitial fluid to the region of chemical sensing material 90 within seconds of placing at least a portion of the microneedle 98 beneath the skin surface. Diffusion of the reagent species within the region of chemical sensing material 90 and into the capillary layer 100 is opposed to this flow and thereby contamination of the patient by the backflow of the reagent species is precluded. One or more scattering centers 124 are illustrated within the region of chemical sensing material 90. Such scattering centers 124 redirect the path of an optical ray 126 from its normal straight line path into a different direction. Multiple scattering events can cause the path of the optical ray 126 to come back upon its original direction. Thus, through the use of such scattering centers 126, the light from a light source (not shown) can be brought back up through the microneedle and made available for image detection.
The scattering centers 124 may take a variety of material forms, for example, but not limited to titanium dioxide and silicon dioxide. Additionally, porous silicon or titanium dioxide are materials that exhibit capillary action and so could act as either the capillary layer 100 or the scattering centers 124. Other materials such as polymers, organic compounds, and inorganic compounds are also candidate materials, as discussed earlier in the detailed description. One guideline for material suitability for scattering centers is that they scatter light in the wavelength of interest and do not interfere with the chemical reactions described below that result in detection of the analyte. Although
Reagent centers 128 include those specific molecules or materials that respond with a change in some optical property to the presence of the analyte. For glucose detection, there are many chemistries known that exhibit change in some optical property due to the presence of the glucose molecule, some of which were described previously in this disclosure. Following is a more detailed description of sensing material chemistries and optical properties that can be used in microneedle arrays. One such optical property change is a color change in which a dye molecule or other species undergoes a shift in its absorption or reflectance spectrum as a result of reaction with an analyte (for example, glucose) or a product of a reaction of the analyte with some other molecule or species that reacts specifically with the analyte. Thus generally the chemistries are divided into analyte sensing components that produce a reaction product and analyte indicator components that react with the reaction product to produce an optical change. One example of an analyte sensing component is the enzyme glucose oxidase. Dyes, nano-sized metal particles (e.g. gold), and a variety of inorganic and organic materials have demonstrated the ability for reflective or transmissive color change in the presence of a specific analyte or analyte reaction product.
Another optical property to be considered is luminescence. Those skilled in the art will appreciate that luminescence includes both fluorescent and phosphorescent light emission mechanisms. Reagent centers 128 can indicate the presence of the analyte by the production of a luminescent compound, or by producing a change in a luminescent compound property, such as emission wavelength, emission lifetime, emission polarity, and others. The specificity of the reagent centers 128 is largely determined by the chemical binding properties of the analyte to the reagent center 128 molecule or molecules. Examples of fluorescent-based reagent centers 128 include, but are not limited to synthetic boronic acid derivatives and as has been already mentioned, the enzyme glucose oxidase. Glucose oxidase (GOx) has been widely employed in glucose sensing. GOx catalyzes the conversion of D-glucose and oxygen to D-glucono-1,5 lactone and hydrogen peroxide. The detection of oxygen consumption, hydrogen peroxide production, or local pH change has been widely utilized in the development of GOx-based glucose sensors as they correlate with the levels of glucose present in a given sample. The simplest strategy employed for the development of a fluorescent glucose sensing system based on GOx takes advantage of the intrinsic fluorescence of the biomolecule. GOx exhibits an intense fluorescence signal with excitation at wavelengths of 224 nm and 278 nm, and emission at 334 nm.
The use of two or more types of reagent centers 128 enables a multi-analyte microneedle 98 to overcome the limitations of certain detection chemistries described above. Imperfect specificity of reagent center detection chemistry may result in the production of false positive measurements of a particular analyte. For example, certain boronic acid derivatives useful in fluorescent change detection schemes have significant sensitivity to fructose. A combination of reagent centers 128 with differing sensitivity and specificity to specific analytes could provide a superior measurement of the analyte using a matrix algebra approach to the analysis data.
Distribution of the multiple regions of chemical sensing materials on a microneedle may be performed in a number of ways.
A number of substrate 24 and/or microneedle 26 materials maybe used, e.g. silicon, silicon dioxide, silicon nitride, all commonly used in microfabrication or, in general, dielectrics, plastics, metals, glass, quartz, or sapphire. The microneedle 26 and a base of the microneedle 26 are preferably transparent, but may be translucent in some embodiments. Another option would be to have the bulk material of the microneedle be transparent, while its surface be scattering or translucent. Several fabrication techniques for the one or more microneedles 26 are disclosed in the literature, such as photolithography, reactive ion etching, isotropic etching (e.g. for glass), plastic molding, water jet milling, and others may be used. The one or more microneedles 26 may be solid or hollow. The microneedle 26 cross-sections may be variable or constant, and can take on a variety of cross-sectional shapes, including, but not limited to square, circular, triangular, and grooved. Other embodiments of microneedles 26 may even be corrugated.
The one or more microneedles 26 can be coated with one or more regions of a chemical sensing material 156 that either changes its color or fluoresces or changes its fluorescence characteristics when in contact with one or more specific chemical species as discussed above. The chemical sensing material 156 may be optically transparent, reflective, opaque, or scattering.
In some embodiments, the microneedle array 154 may be sealed on at least a test-subject-facing side by a protective film 34. Other embodiments can also include a protective film 35 on the opposite side of the array 154 in order to seal the one or more microneedles 26 from interaction with the external environment and/or test subject, and in general to help maintain a sterile, dry environment for the one or more coated microneedles 26, prior to use. Some embodiments may also include a desiccant layer (not shown) on one or more of the protective films 34, 35 to provide a dry environment for the one or more coated microneedles 26. If a protective film 35 is used on the base side of the microneedle array 154, then the protective film is preferably transparent or translucent. Non-limiting examples for a protective films 34, 35 include polyvinylidene fluoride, polyvinyl chloride, polyvinylidene chloride, polypropylene, polyethylene terepthalate, polyethylene napthenate, ethylene-vinyl acetate copolymer, and low density polyethylene. The microneedle array 154 may be a removable and replaceable subassembly which the biomedical monitor 20 is configured to receive.
The one or more microneedles 26 can be coated with one or more regions of a chemical sensing material 156 that either changes its color or fluoresces or changes its fluorescence characteristics when in contact with one or more specific chemical species as discussed above. The chemical sensing material 156 may be optically transparent, reflective, opaque, or scattering.
In some embodiments, the microneedle array 155 may also be sealed on at least a test-subject-facing side by a protective film 34. The microneedle array 155 may be a removable and replaceable subassembly which the biomedical monitor 20 is configured to receive.
Alternatively,
The distributions shown in
When measuring intensity changes before and after exposure of the analyte to the chemical sensing material, it is important to account for the background signal of the initial condition. As an alternative to subtracting the background signal, a ratio of the initial intensity to the intensity after exposure to the analyte may be used. The logarithm of this ratio yields a quantity that is directly proportional to the analyte concentration. For example, in a glucose concentration measurement, if Cg is the glucose concentration, ∈g(Cg,λ) is the molar extinction coefficient of the colorant as a function of Cg and the wavelength of light, and Iout is the measured output intensity, then:
log10{Iout(Cg=0,λ)/Iout(Cg,λ)}=∈g(Cg,λ)(α)(Cg)(teff)
where α is the yield of colorant per molecule of glucose, and teff is the effective optical thickness of the sensing material coating.
Thus, the log of the ratio of measured intensities before and after glucose exposure is a quantity directly proportional to glucose concentration. The log of the ratio of measured intensities is also generally a preferred computational method for analytes other than glucose, when using a change in the absorption of a colorant based on exposure to an analyte.
Though it is possible to determine analyte concentration by measuring changes in intensity within the sampled area before and after insertion of the coated microneedle, preferably as described above, it is further preferred that the change in color ratios (ratio of R/B, R/G, and G/B) be measured as well. By using ratios of response in different wavelengths, results are intrinsically normalized.
In step 182, one or more digital images of the first microneedle are captured, wherein at least one of the one or more digital images is captured after the first coated microneedle has been actuated to penetrate a subject's skin. The digital image capture may occur while the microneedle is still penetrating the subject's skin and/or after the microneedle has been extracted from the subject's skin. Optionally, at least another of the one or more digital images is captured before the first coated microneedle has been actuated to penetrate the subject's skin. Such a pre-penetration image can be used as a baseline image for later comparison.
In step 184, pixel information is spatially extracted from the captured one or more images to define one or more pixel sample areas corresponding to the one or more regions of a chemical sensing material. The one or more regions of chemical sensing material coated on the microneedle may be in known patterns/locations. Not every portion of the captured digital images needs to be evaluated or used. For example, in some embodiments, only pixels corresponding to known locations of the regions of chemical sensing material will be extracted and defined as the one or more pixel sample areas to be used for further analysis. In some embodiments, a pre-penetration image can be subtracted from a post-penetration image to subtract a background from consideration and to help more accurately define the one or more pixel sample areas. Preferably, the image used for background subtraction is captured at the moment that the coated microneedle is filled with fluid post penetration, but before any reaction with the analyte takes place.
In step 186, one or more spectral characteristics are determined for each of the one or more pixel sample areas. Each of the one or more pixel sample areas may correspond to a different region of chemical sensing material. Each region of chemical sensing material may be configured to react to different analytes or the same analyte, depending on the embodiment. In some embodiments, determining the one or more spectral characteristics for each of the one or more pixel sample areas can occur by determining a red pixel histogram, a green pixel histogram, and a blue pixel histogram for each of the one or more pixel sample areas. Such histograms may be compiled, for example, for reflected light exposures and fluorescence exposures and the histograms may be determined for each of the one or more captured digital images. The determined one or more spectral characteristics will be the basis for determining the at least one biomedical characteristic in a later step. In embodiments using histograms, the spectral characteristic determined from the histogram may include, but is not limited to an average, a window-average, a maximum, or a minimum. For example, in the case of glucose measurements, by being able to consider maxima for the spatially determined pixel sample area, the measurement can effectively filter out glucose measurements in areas where perhaps local cells have already started to consume the localized glucose, thereby avoiding data points which would tend to contribute to a less accurate glucose concentration measurement. In some embodiments, the determined one or more spectral characteristic is a ratio of measured intensities in different images. For example, an initial intensity may be determined from the pixel sample area of a digital image captured prior to insertion/penetration of the microneedle, or preferably, immediately after penetration. Then, a post-actuation intensity may be determined from the pixel sample area of a digital image captured after penetration of the microneedle and after such time as analyte-induced spectral changes have occurred. In some embodiments, the determined spectral characteristic may be the ratio of these two intensities.
In step 188, the at least one biomedical characteristic is determined for each of the one or more pixel sample areas based on the determined one or more spectral characteristics for each of the one or more pixel sample areas. In some embodiments, the at least one biomedical characteristic may be a concentration of an analyte. In such embodiments, the concentration may be determined by taking the log of the ratio of measured intensities described above. The log ratio of measured intensities may be proportional to a concentration of the target analyte in a predictable fashion as described previously. In some embodiments, rather than determining the at least one biomedical characteristic to be a concentration of an analyte, the at least one biomedical characteristic could be a true/false indicator for the presence of an analyte or a true/false indicator for the crossing of a threshold analyte level. Such non-limiting examples of biomedical characteristics may be determined, for example, in relation to glucose, cholesterol, HDL cholesterol, LDL cholesterol, alcohol, estrogen-progesterone, cortisol, a physiological chemical, and an exposed chemical.
Optionally, as discussed previously, an insertion depth may be determined for the microneedle based on the determined one or more spectral characteristics, or on the change in reflectivity induced by filling the porous layer with fluid, for each of the one or more pixel sample areas. Optionally, the at least one biomedical characteristic for each of the one or more pixel sample areas may be determined as a function of microneedle insertion depth. Furthermore, biomedical characteristics corresponding to insertion depths which are not of interest may be ignored to improve measurement accuracy.
Optionally, a calibration microneedle coated with one or more calibration regions of the chemical sensing material may be illuminated. One or more digital calibration images of the calibration microneedle may be captured, wherein at least one of the one or more digital calibration images is captured after the calibration microneedle has been actuated to contact a reference analyte. The digital calibration microneedle may be blunt in some embodiments. Pixel information may be spatially extracted from the captured one or more calibration images to define one or more calibration pixel sample areas corresponding to the one or more calibration regions of the chemical sensing material. One or more spectral calibration characteristics may be determined for each of the one or more calibration pixel sample areas. The determination of the at least one biomedical characteristic may be corrected for each of the one or more pixel sample areas based on the determined one or more spectral characteristics for each of the one or more pixel sample areas and the determined one or more spectral calibration characteristics.
Optionally, in some embodiments, an electronic medical record may be updated to include the determined at least one biomedical characteristic.
The methods disclosed herein, and their embodiments, may optionally be configured to check one or more microneedles of a microneedle array for evidence of prior use. For example, optionally, one or more screening digital images may be captured of the first microneedle (as well as any other or all microneedles of the microneedle array) prior to penetration of the subject's skin with the first microneedle. A used microneedle or microneedle array may have a pre-existing color change which can be detected and analyzed using the methods discloses above. For example, it may be determined whether or not the first microneedle has been previously used from a comparison of one or more spectral characteristics for each of one or more spatially extracted pixel sample areas, corresponding to the one or more regions of the chemical sensing material in the captured at least one screening digital image, with an expected standard. If it is determined that the first microneedle has been previously used, then the first microneedle may be prevented from penetrating the subject's skin. Additionally, the subject may be alerted if the at least one microneedle has previously been used.
The one or more microneedles 196 can be coated with one or more regions of a chemical sensing material 156 that either changes its color or fluoresces or changes its fluorescence characteristics when in contact with one or more specific chemical species as discussed above. The chemical sensing material 156 may be optically transparent, reflective, opaque, or scattering.
In some embodiments, the microneedle array 190 may be sealed on at least a test-subject-facing side by a protective film 34. Other embodiments can also include a protective film 35 on the opposite side of the array 190 in order to seal the one or more microneedles 196 from interaction with the external environment and/or test subject, and in general to help maintain a sterile, dry environment for the one or more coated microneedles 196, prior to use. Some embodiments may also include a desiccant layer (not shown) on one or more of the protective films 34, 35 to provide a dry environment for the one or more coated microneedles 196. If a protective film 35 is used on the base side of the microneedle array 154, then the protective film is preferably transparent or translucent. Non-limiting examples for a protective films 34, 35 include polyvinylidene fluoride, polyvinyl chloride, polyvinylidene chloride, polypropylene, polyethylene terepthalate, polyethylene napthenate, ethylene-vinyl acetate copolymer, and low density polyethylene. The microneedle array 190 may be a removable and replaceable subassembly which the biomedical monitor 20 is configured to receive.
The embodiments of biomedical monitors disclosed herein, and their equivalents have a variety of advantages which have been discussed throughout the specification. The biomedical monitors may be removably attached to a subject and are able to make multiple sequential blood chemistry measurements. The biomedical monitor provides a highly useful device configuration and convenient fabrication process for dense arrays of individually actuated microneedles having integral chemical sensors. The compact wearable device can sample body chemistry without extracting a significant amount of blood or interstitial fluid either during or after the microneedle is inserted in the subject. Consequently, the degree of invasiveness and risk of contamination is reduced, while improving the hygiene of the process. Due to their high multiplicity, microneedles with integral chemical sensing material may be inserted in the subject in sequence over an extended period of time, each chemical sensing element being required to make measurements for only a short time period. The use of each microneedle for a limited time will eliminate the effect of bio-fouling. Sequential actuation of a multiple microneedles provides the ability for long term monitoring. Control of the serial actuation process can be programmed for a specific monitoring schedule, making the process practically continuous, if desired, and convenient for a subject. Due to their dense spacing and integrated actuation capability, many measurements may be made for extended time periods using a compact device worn by the subject as a small patch or chip. The biomedical monitor may be configured to sense chemicals which are naturally produced and/or found in a subject's body as well as chemicals which a subject has been exposed to, for example harmful toxins or biological components. The biomedical monitor may also be configured to receive a convenient replaceable microneedle array.
Having thus described the basic concept of the invention, it will be rather apparent to those skilled in the art that the foregoing detailed disclosure is intended to be presented by way of example only, and is not limiting. Various alterations, improvements, and modifications will occur and are intended to those skilled in the art, though not expressly stated herein. These alterations, improvements, and modifications are intended to be suggested hereby, and are within the spirit and scope of the invention. Additionally, the recited order of processing elements or sequences, or the use of numbers, letters, or other designations therefor, is not intended to limit the claimed processes to any order except as may be specified in the claims. Accordingly, the invention is limited only by the following claims and equivalents thereto.
This application claims priority to U.S. Provisional Patent Application No. 61/276,116 filed Sep. 8, 2009 and entitled, “COMPACT MINIMALLY INVASIVE BIOMEDICAL MONITOR USING IMAGE PROCESSING”. U.S. Provisional Patent Application No. 61/276,116 is also hereby incorporated by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 61276116 | Sep 2009 | US |
