Abstract:
A biomedical monitor is disclosed. The biomedical monitor has an array of moveable microneedles coated with a first chemical sensing media. The biomedical monitor also has an actuator configured to move at least one microneedle in the array of microneedles from a retracted position to an engaged position whereby the at least one microneedle enters a subject&#39;s skin. The biomedical monitor further has an optical system configured to illuminate the at least one microneedle during or after entering the subject&#39;s skin and monitor the first chemical sensing media from the at least one microneedle, whereby at least one biomedical characteristic is determined based on at least one spectral property of the monitored first chemical sensing media. A method of monitoring at least one biomedical characteristic is also disclosed.

Description:
RELATED APPLICATIONS  
       [0001]     This patent application claims priority to U.S. provisional patent application 60/803,289 entitled “Compact Minimally Invasive BioMedical Monitor,” which was filed May 26, 2006. The 60/803,289 patent application is hereby incorporated by reference in its entirety. 
     
    
     FIELD  
       [0002]     The claimed invention relates to biomedical monitors, and more specifically to compact minimally invasive biomedical monitors.  
       BACKGROUND  
       [0003]     Existing methods to measure blood glucose suffer from a number of disadvantages. The well-known fingerstick monitor requires the use of a fine lancet that pierces the skin and is able to draw blood for subsequent measurement. Unfortunately, as a result of the discomfort and inconvenience of the process, compliance tends to be low, especially for younger (active) and older patients. Repeated piercing can also lead to sensitivity and/or hardening of the subject&#39;s skin since fingertips are one of the body&#39;s most sensitive regions. Furthermore, fingerstick-based monitors only provide a sampled measurement of the subject&#39;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. It would be desirable to have a more continuous monitoring process that is fully automated, requiring little or no periodic calibration that is less invasive to the patient.  
         [0004]     Microneedle technology provides a useful minimally-invasive method to sample blood. 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, microneedle systems described in the prior art are still somewhat invasive since they extract blood from the patient for the measurement. Implanted in vivo sensors provide another means to sample blood chemistry that do not require blood extraction. Unfortunately, long term use of in vivo sensors or microneedles inserted into subjects 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&#39;s presence. At best, bio-fouling requires frequent calibration to compensate for these changes; more often than not these changes are irreversible and require device replacement.  
         [0005]     It would be desirable to achieve a less invasive approach to biomedical monitoring that does not extract blood from the patient, provides longer useful life than in vivo devices, and requires little or no calibration.  
       SUMMARY  
       [0006]     A biomedical monitor is disclosed. The biomedical monitor has an array of moveable microneedles coated with a first chemical sensing media. The biomedical monitor also has an actuator configured to move at least one microneedle in the array of microneedles from a retracted position to an engaged position whereby the at least one microneedle enters a subject&#39;s skin. The biomedical monitor further has an optical system configured to illuminate the at least one microneedle during or after entering the subject&#39;s skin and monitor the first chemical sensing media from the at least one microneedle, whereby at least one biomedical characteristic is determined based on at least one spectral property of the monitored first chemical sensing media.  
         [0007]     A replaceable array of moveable microneedles is also disclosed. The replaceable array of microneedles has a plurality of microneedles coated with at least one chemical sensing media. The replaceable array of microneedles also has a substrate defining wells to house the microneedles. The replaceable array of microneedles further has at least one restoring spring element coupled between each microneedle and the substrate such that each microneedle is held at least partially in an associated well.  
         [0008]     A method of monitoring at least one biomedical characteristic is disclosed. A first microneedle coated with a first chemical sensing media is engaged into a subject&#39;s skin. The first chemical sensing media is illuminated. One or more spectral characteristics of light reflected from the first chemical sensing media are monitored. At least one biomedical characteristic is determined based on the one or more spectral characteristics of light reflected from the first chemical sensing media.  
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0009]      FIG. 1A  illustrates one embodiment of a single microneedle device.  
         [0010]      FIG. 1B  is a magnified view of one embodiment of a single microneedle device.  
         [0011]      FIG. 2A  illustrates one embodiment of a microneedle array having multiple microneedles such as the one illustrated in  FIG. 1 .  
         [0012]      FIG. 2B  illustrates the reverse side of the embodied microneedle array of  FIG. 2 .  
         [0013]      FIG. 3A  schematically illustrates an embodiment of a biomedical monitor prior to testing.  
         [0014]      FIG. 3B  schematically illustrates an embodiment of a biomedical monitor during testing.  
         [0015]      FIG. 4  illustrates an exploded view of one embodiment of a biomedical monitor.  
         [0016]      FIG. 5 . illustrates a side view of another embodiment of a biomedical monitor.  
         [0017]      FIG. 6  illustrates an exploded view of another embodiment of a biomedical monitor. 
     
    
       [0018]     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, and that the various elements in the drawings have not necessarily been drawn to scale in order to better show the features.  
       DETAILED DESCRIPTION  
       [0019]      FIG. 1A  illustrates one embodiment of a top view of a single microneedle device  20 . A substrate  22  has been micromachined to produce a microneedle element  24 , supported on microneedle base  26 , and at least one restoring spring element  28 . Microneedle element  24  should have dimensions such that it is of sufficient length to penetrate the subject&#39;s stratum corneum and reach the underlying interstitial fluid or capillary network, e.g. 20-2000 microns, however, in other embodiments, smaller or larger microneedles may be used. Restoring spring element  28  could be patterned directly out of substrate material  22  or out of a layer having desirable mechanical properties that has been deposited onto substrate  22 . Alternatively, restoring spring  28  may also be patterned out of one or more materials in a multi-material substrate where additional materials have been deposited or bonded to the substrate  22 . For example, an oxidized substrate may be etched to form a microneedle  24  out of silicon and a restoring spring  28  out of either the silicon dioxide layer or a combination of the silicon dioxide layer and the silicon layer. Although not illustrated in this embodiment, other embodiments may include positional sensors on the restoring springs  28  for use in determining the deflection of the microneedle  24 . Restoring spring element  28  can be patterned in a number of geometries such as spiral spring (as shown), cantilever structures or other geometries as long as they provide the freedom of movement that allows microneedle element  24  to protrude far enough out of the plane defined by substrate  22  in order to penetrate a subject&#39;s skin to a desired depth. A number of substrate  22  and/or microneedle  24  materials maybe used, e.g. silicon, silicon dioxide, silicon nitride, all commonly used in microfabrication or, in general, dielectrics, plastics, metals, glass, or quartz. The microneedle  24  and the microneedle base  26  are preferably transparent, but may be translucent in some embodiments. Several fabrication techniques for the microneedle device  20  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. Although hollow microneedles are typically used for drug delivery and diagnostics applications,  24  may be solid, although in some cases, hollow ones may be utilized. Although the embodied microneedle  24  is illustrated as being solid with a smoothly varying cross-section, other embodiments of microneedles may have a constant cross-section. Still other embodiments of microneedles may take on a variety of cross-sectional shapes, including, but not limited to square, circular, triangular, and grooved. Other embodiments of microneedles may be hollow or even corrugated.  
         [0020]      FIG. 1B  is a magnified view of an actual embodiment of a microneedle device  20  which is this case was formed from quartz.  
         [0021]      FIG. 2A  illustrates one embodiment of an array configuration  30  for the single microneedle device  20  and its supporting elements. The surface in view represents the needle-up side of the device which would normally come in contact with a subject being monitored. Other embodiments may include a film over the microneedles in the microneedle array to prevent the microneedles and the sensing media on the microneedles from interacting with a subject prior to engagement of a particular microneedle. In the example shown, the array of microneedles  30  is patterned radially, although other geometrical arrangements are possible.  
         [0022]      FIG. 2B  illustrates the needle-down side of the embodiment of  FIG. 2A , exposing microneedle bases  26  and restoring spring elements  28 . Additional elements may be patterned on the needle-down side of microneedle array configuration  30  such as positional encoder slots  32 . Slots  32  are aligned relative to microneedle elements  20 , but may be placed at integral number ratios relative to the microneedles, e.g. 1:1, 1:2, 1:3, etc. In this nomenclature, a 1:1 ratio refers to an array having an equal number of microneedles and slots, whereas a 1:3 ratio refers to an array having three times as many microneedles as slots. An optional cylindrical alignment slot  34  may be defined on  30  that is concentric to the circle defined by the array of microneedle devices and their associated positional encoder slots  32 .  
         [0023]     A possible embodiment of array configuration  30  used as a diagnostic device or monitor is schematically illustrated in  FIGS. 3A and 3B .  FIG. 3A  shows a cross-section of microneedle element  24  in its inactivated state positioned within array configuration  30 . Microneedle  24  is preferably transparent, but may be translucent. Microneedle element  24  can be coated with chemical sensing material  48  that either changes its color or fluoresces when in contact with a specific chemical specie. For example, sensing material  48  for blood glucose monitoring may use a large number of known glucose sensitive chemicals, e.g. glucose oxidase, glucose dehydrogenase, hexokinase-glucokinase, rhenium bipyridine, boronic acid containing fluorophores, NBD-fluorophores, or any other materials that exhibit the desired chemical and optical response. 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 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, alcohol, estrogen-progesterone, cortisol, and other physiological chemicals of interest.  
         [0024]      FIG. 3A  also illustrates an embodiment of an optical system  36  having an electronic light source or light emitter  38 , imaging lens  40 , reflector  42 , and transparent depressor element  44 , all of them mounted on transparent actuator substrate  46 . Although it is preferred that depressor  44  and actuator substrate  46  are transparent, in some embodiments one or both elements may optionally be translucent.  FIG. 3B  shows the activated or engaged state of the monitor, achieved when the optical system is pushed against the microneedle array  30 . This movement causes the transparent depressor  44  to exert a force on  24  so as to bend restoring spring assembly  28  and achieve penetration of microneedle element  24  into the subject. After the microneedle  24  penetrates the subject, sensing material  48  undergoes a change in color or exhibits fluorescence which is sampled using light beam  50  emanating from light emitter  38 . Light emitter  38  could be an incandescent source with collimation optics, a light emitting diode, or a laser diode, for example. The spectral requirements for imaging lens  40  will depend on the wavelength required to monitor absorption of the reagent or excite fluorescence in sensing material  48 . Imaging lens  40  focuses light beam  50  to optically sample sensing material  48  as it changes color. Signal beam  52  emanating from sensing material  48  contains information regarding the color change of sensing material  48 , is captured by imaging lens  40 , and directed toward a light detector  47  via beam splitter (not shown). The light detector  47  may be made selective to the optical absorption or fluorescence wavelengths of sensing material  48 . Output from light detector  54  is processed by processor  56  to produce digital data signal  58  representative of the concentration of chemical being monitored. After the measurement is made and data  58  is captured, the optical sensor assembly is withdrawn away from the subject, returning the entire assembly to the configuration shown in  FIG. 3A .  
         [0025]     Although  FIGS. 3A and 3B  depict a useful system configuration for the diagnostic device, it should be apparent to those skilled in the art that other system configurations are possible. For example, reflector  42  and/or beam splitter may be omitted or varied if beams  50  and  52  follow trajectories perpendicular to  30 . Some embodiments may utilize an off-axis light source so that diffuse light reflected from sensing material  48  may be captured by an image sensor which is located directly above the sensing material  48 . In another example, the optical measurement shown in  FIG. 3B  may be made after optical sensor assembly  36 , restoring spring assembly  28 , and microneedle  24  are withdrawn from the subject. In this case, sufficient time must elapse such that sensing material  48  integral to microneedle  24  undergoes enough of a color change to result in an accurate measurement.  
         [0026]     The needle structures shown in  FIGS. 1-3  can be very fine, on the order of a few to fifty microns in diameter at the tip. The fine geometries of  24  along with the relatively shallow penetration required to make the measurement significantly reduce the pain and discomfort to the subject. Another very significant issue for subjects requiring periodic glucose or other types of monitoring is compliance. Unfortunately many tests in the market such as the fingerprick test require the subject to take time away from their activities and make a measurement. Even other minimally-invasive prior art that use microneedles may require the subject to make the measurement. The embodiments described herein, and their equivalents, are uniquely advantaged in that they can be automated to perform periodic measurements without user intervention. As a result of its planar geometry, diagnostic systems can be made wearable having convenient, unobtrusive form factors and flat profiles.  
         [0027]      FIG. 4  illustrates an exploded view of one embodiment of an automatic blood monitor that incorporates microneedle array configuration  30  and optical sensor assembly  36 . In this embodiment, optical sensor assembly  36  rotates concentrically relative to microneedle array configuration  30 , revolving transparent depressors  44  over each microneedle base  26 . Optical sensor assembly  36  is made to rotate around its axis using a motorized drive or other motion mechanism which may be meshed to a gearing mechanism  62  or any other rotary transport system. During this process, a spring or other biasing mechanism may be used to apply a force pushing the optical system  36  towards the microneedle array  30 . Two, preferably three or more mechanical wedge spacers  60  are used to maintain a gap distance separating the microneedle array  30  and the optical system  36 . Mechanical wedge spacers  60  are defined on the surface of the optical system assembly  36  such that when the transparent depressors  44  are located over microneedle bases  26 , mechanical wedge spacers  60  all fall into positional encoder slots  32 , pushing microneedle array  30  and optical system assembly  36  into close proximity. This action consequently forces the associated microneedle  24  toward the subject as shown in  FIG. 3B . Mechanical wedge spacers  60  may have a, wedge-like geometry to activate the motion precisely, although other geometries may be used. Positional encoder slots  32  may also be shaped in a wedge-like geometry matching wedge spacers  60  and with a controlled slope, allowing mechanical wedge spacers  60  to rise out of mechanical encoder slots  32  as the optical system assembly  36  rotates. A radial alignment peg  64  concentric to the microneedle array  30  and optical system assembly  36  may be added to restrict lateral motion of the microneedle array  30  relative to the optical system assembly  36  during activation.  
         [0028]     The number of mechanical encoder slots  32  relative to the number of microneedles maybe varied if needed. A 1:2 ratio in the number of microneedle:slot would result in only half of the needles being activated during a full rotation of the optical system assembly  36 . This approach may be used for patients that require less number of measurements per interval of time. The same result may be achieved if the ratio is 1:1 and the rotational speed of the optical system assembly  36  is controlled.  
         [0029]     As mentioned previously, the invention provides a highly compact, programmable chemical monitoring system.  FIG. 5  shows a side view of an embodiment of a biomedical monitor having a complete system configured for operation, including a biasing compression spring element  66  that provides a constant force on the optical system assembly  36  and microneedle array  30 . The force applied by biasing spring  66  onto the optical system assembly  36  and microneedle array  30  needs to be sufficient to actuate the device (see  FIG. 3B ) and achieve insertion of the microneedles  24  into the subject. As a result of microfabrication methods and the efficient form factor of this design, full device dimensions could be highly compact, e.g. in the millimeter to centimeter range, although other dimensions may be used by those skilled in the art in order to meet various design goals. Microneedle array  30 , due to its low cost, could be disposed of after the set of measurements is performed in accordance with the number of microneedles actuated. Although microneedle array  30  may be designed to monitor only one chemical such as glucose, different sensing materials  48  may be coated onto different microneedles, thereby providing the capability for more than one chemical to be monitored. In still other embodiments, more than one type of chemical sensing media may be coated onto a single microneedle, provided the multiple sensing media do not have conflicting spectral responses. In this manner, more than one chemical test could be performed at the same time with the same microneedle.  
         [0030]      FIG. 6  illustrates an exploded view of another embodiment of a biomedical monitor that includes an electrically-controlled biasing device  68 . In this example, electrically controlled biasing device  68  is activated causing moveable plunger  70  to apply pressure onto optical system assembly  36  and microneedle array  30 . Given the additional degrees of control associated with electrically controlled biasing device  68 , mechanical wedge spacers  60  and positional encoder slots  32  may not be required. In this configuration, the rate of revolution of optical system assembly  36  defines when activation can occur such that at least one transparent depressor  44  is aligned with a corresponding microneedle base  26 . An optional cylindrical slot  72  may be used in optical system assembly  36  to restrict lateral motion of optical system assembly  36  relative to electronically controlled biasing device  68  and plunger  70 .  
         [0031]     The embodiments of biomedical monitors disclosed herein, and their equivalents have a variety of advantages which have been discussed throughout the specification. The embodied biomedical monitors may be 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 sensors. The compact wearable device can sample body chemistry without extracting 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 media 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 may significantly reduce or 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 more continuous 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&#39;s body as well as chemicals which a subject has been exposed to, for example harmful toxins or biological components.  
         [0032]     Having thus described several embodiments of the claimed 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 the scope of the claimed invention. As just one example, it should be apparent that the biomedical monitor could be fabricated with individually addressable actuators for each microneedle, and individually readable image sensors for each microneedle such that neither the microneedle array nor the optical system would have to rotate. In such an embodiment, microsolenoids may be used for the individually addressable actuators. As one other non-limiting example, although rotational embodiments have been described herein, other embodiments may be translational in nature, such that the actuation motion is linear. Furthermore, the recited order of the processing elements or sequences, or the use of numbers, letters, or other designations therefore, is not intended to limit the claimed processes to any order except as may be specified in the claims. Accordingly, the claimed invention is limited only by the following claims and equivalents thereto.