DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0048] As used herein, the term “analyte” means an atom, ion, molecule, macromolecule, organelle, or cell, or, optionally, a mixture thereof, that is detected and measured. The term “analyte” also means a substance in a medium including, but not limited to molecules such as proteins, glycoproteins, antibodies, antigens, hemoglobin, enzymes, target molecules that bind to or react with specific enzymes or other proteins, metal salts, ions (e.g., hydrogen ions, hydroxy ions, sulfates, sulfonates, phosphates, nitrates, nitrites, or electrolytes such as sodium potassium, lithium, or calcium ions), fatty acids, neurotransmitters, hormones, growth factors, cytokines, monokines, lymphokines, lipocalins, nutrients, sugars, receptors, nucleic acids, fragments of DNA or RNA, and pharmaceutical agents or derivatives or metabolites thereof. The term “analyte” also means structured elements such as macromolecular structures, organelles and cells, including, but not limited to cells of ectodermal, mesodermal, and endodermal origin such as cells, blood cells, neural cells immune cells, and gastrointestinal cells, and also microorganisms, such as fungi, viruses, bacteria and protozoa, or characteristic compounds produced by the same. For example, in pH measurement, the analyte can be hydrogen ions and/or hydroxy ions. Some analytes indicate a possible disease condition by either a higher or lower than normal level.

[0049] As used herein, “medium” and “biological sample” can refer to any material that can contain an analyte to be measured. A medium or biological sample can be any body fluid, including blood or any of its components (plasma, serum, etc.), menses, mucous, sweat, tears, urine, feces, saliva, sputum, semen, uro-genital secretions, gastric washes, pericardial or peritoneal fluids or washes, a throat swab, pleural washes, ear wax, hair, skin cells, nails, mucous membranes, amniotic fluid, vaginal secretions or any other secretions from the body, spinal fluid, human breath, gas samples containing body odors, flatulence or other gases, any biological tissue or matter, or an extractive or suspension of any of these.

[0050] As used herein, “biosensor,” following the definitions given in the CancerWeb Online Medical Dictionary at www.graylab.ac.uk/cgi-bin/omd?biosensor, refers to any sensor that collects data about a biological or physiological process. Biosensors can include any probe, such as those including biological material, which measures the presence or concentration of analytes such as biological molecules, biological structures, microorganisms, etc., by translating a biochemical interaction with the probe into a physical signal. More specifically, the term can refer to the coupling of a biological material (for example, enzyme, receptor, antibody, whole cell, organelle) with a microelectronic system or device to enable rapid low level detection of various substances in body fluids, water, and air.

[0051] As used herein, a “biosensor signal” refers to a quantitative or qualitative measurement reading provided by a biosensor, which, without limitation, can be in the form of any of the following:

[0052] electronic data, either a digital or analog signal (such as electrical current or a voltage generated directly by the biosensor or indirectly by another device in response to a biosensor reading) that can in turn result in a display on an output device or in data being transmitted to a computer;

[0053] a visual cue such as a color change or altered position of an indicator needle or other visible indication of qualitative or quantitative information on devices such as liquid crystal panels, LED arrays, “electronic paper,” or a visible computer display of text or a static or animated image;

[0054] a sound such as a beep, a synthesized voice or a prerecorded message;

[0055] a temperature change induced by the biosensor; or

[0056] any other suitable means of generating a signal to convey information about a measurement made by the biosensor.

[0057] As used herein, “medium” can refer to any material that can contain an analyte to be measured. A medium can be any body fluid, including blood or any of its components (plasma, serum, etc.), menses, mucous, sweat, tears, urine, feces, saliva, sputum, semen, uro-genital secretions, gastric washes, pericardial or peritoneal fluids or washes, a throat swab, pleural washes, ear wax, hair, skin cells, nails, mucous membranes, amniotic fluid, vaginal secretions or any other secretions from the body, spinal fluid, human breath, gas samples containing body odors, flatulence or other gases, any biological tissue or matter, or an extractive or suspension of any of these.

[0058] As used herein, a “mobile biosensor” is one that can move freely with the subject while a time-dependent biosensor signal (i.e., a time series) is being generated without causing significant disruption or loss of the biosensor signal. A mobile biosensor generally includes a sensing element that is attached to or associated with the person of the subject, such as a sensor in an article of clothing, an absorbent article, or one attached to the skin or implanted in the subject. A mobile biosensor can include signal transmission means such as wireless transmission to receive and process the biosensor signal either continuously or periodically, and/or can include storage means such that a time series of the biosensor signal is stored for later retrieval and processing. Small batteries or other power sources may also be part of the biosensor, when a power source is needed. Biosensors may be small and portable but outside the scope of “mobile” as used herein. For example, a simple pH test strip in a diaper that gives a one-time indication of pH in urine is portable, but not mobile as used herein because it does not provide a time series of pH values.

[0059] As used herein, “treatment means” can be any means for delivering a medication, nutritional substance, medical therapy, or other physical or medical care to the subject. Surgery is within the scope of the term. It can also include manual activity, such as turning over a patient in a bed in response to biosensor-detected indicators suggestive of bedsore development or changing a wound cover. It can include administration of a physical treatment such as application of light (e.g., ultraviolet light, simulated sunlight, infrared light, and the like), radiation (e.g., microwave therapy, nuclear radiation, and the like), application of an electrical pulse, movement of the subject, change of a disposable or durable article such as a bed pad or linens, and the like. Oxygen gas or other non-pharmaceutical agents may also be administered.

[0060] One aspect of the present invention is depicted in the flow chart of FIG. 1 . One or more biosensors 20 associated with a subject 22 generates a biosensor signal 40 which is received by a personal data control means 24 . The personal data control means 24 can include a computer or microprocessor, software for acquisition and interpretation of biosensor data, data acquisition means, a display system such as a monitor, and user input means to allow the user 23 (either the subject 22 or a representative of the subject 22 ) to provide a privacy signal 42 to specify how the data or results from the data can be shared with others and/or to provide a means for annotating biosensor results. In one embodiment, the personal data control means 24 can include a programmable portable data acquisition and display device such as a personal digital assistant (PDA) equipped to receive a wireless signal from a biosensor and then provide a display to the user 22 showing a preliminary assessment of the meaning of the signal, whereafter the user 23 can then choose to transmit the data for review by a doctor or other expert and can specify whether the information will be available to other parties such as an employer or insurance agency (though in one embodiment, the outside source can be informed of the user's refusal to forward health-related data from the biosensor). In another embodiment, the data acquisition and display device can be an I-STAT portable clinical analyzer from i-STAT Corporation (East Windsor, N.J.) or a modification thereof. Two or more electronic devices cooperatively associated, such as a data display device and a user input device can be used. A wide variety of electronic dataloggers can be used as a component of the personal data control means 24 for receiving and storing a biosensor signal 40 over a period of time and then optionally computing and displaying results from the accumulated biosensor signal 40 , or transferring the data to another device for optional computation and display of an interpretation of the data for review by the user 23 or other party. Exemplary dataloggers include the cable and wireless dataloggers of Ellab A/S of Denmark (with offices in San Jose, Calif.), and other suitable dataloggers. Smart cards can also be used, as described more fully below.

[0061] The personal data control means 24 combines the biosensor signal 40 and a privacy input 42 in generating a response signal 44 that is sent to a data allocation and processing module 26 , which may be physically remote from the personal data control means 24 or may be adjacent to or integrated with the personal data control means 24 . The data allocation and processing module 26 can include a central server or other computer database means where data from the biosensor 20 may be allocated (selectively distributed) for use by outside parties and for optional storage in health records 28 . In one embodiment, the data allocation and processing module 26 is on a server of a private network remote from the subject 22 and the personal data control means 24 .

[0062] The data allocation and processing module 26 handles the allocation of health-related data pertaining to the subject 22 in response to the response signal 44 . One or more output signals 46 are generated and directed to one or more outside sources, including a signal directly sent to doctors 32 or other health professionals 46 a , which can be shared in whole or part with nurses or other caregivers 30 ; personal health data 46 b that can be entered into personal health records 28 , either in electronic form (e.g., a searchable, archived record with restricted access) or as a printed record entered into a file, or both; and other information 46 c suitable for use by an insurer 34 or other agency, an employer, or the like. Portions of the data in the output signal 46 may be interpreted and combined with other information to result in instructions being given to a pharmacist 36 , nurse or caregiver 30 , insurer 34 , other providers of health care services 38 , and other parties, preferably in compliance with best medical practices. These parties can in turn provide services or treatments 50 , 52 , 54 , 56 for the benefit of the subject 22 in response to the instructions received. The data allocation and processing module 26 can include storage means (e.g., a tape backup, hard disk, floppy disk, and other means) to store the response signal 44 or information derived therefrom, including the storage (archiving) of medical records including data derived from the response signal 44 .

[0063] Access to biosensor-derived information in the health records 28 may be partly restricted or coupled with annotations from the user 23 or other party, in response to the privacy input 42 . The same applies to all other uses of biosensor-derived information.

[0064] The response signal 44 can be transmitted to the data allocation and processing module 26 by a radiofrequency signal, infrared (IR) signal, electronic signal over a cable or wire (e.g., an Internet connection, a phone line, and so forth), optical signal over a fiber optic cable or other means, and the like.

[0065] After data allocation and processing 26 , portions of the data (or all the data) can be sent to a doctor 32 , who can share it with nurses or other caregivers 30 to guide the actions taken to care for the subject 22 . Portions of the data may be shared with insurers 34 or other agencies or institutions (e.g., the Center for Disease Control, or the National Institutes of Health), as determined during data allocation and processing 26 . Recommendations regarding medication, for example, may be made by doctors 36 and payment authorization therefor may be provided by an insurer 34 , resulting in an order sent to a pharmacist 36 or other providers 38 to prepare materials required for care of the subject (e.g., drugs or other medical aids). A new treatment or change in treatment may be administered to the subject 22 , and the biosensor can again be used to track the efficacy of the treatment. The treatment may include not only changes in therapy, diet, medication, and the like, but also may include a recommendation for one or more additional biosensors or for a new biosensor to monitor additional analytes or biological processes.

[0066] A doctor may be authorized to review current biosensor data and past medical records and biosensor data. Depending on options selected by the user 23 , the doctor may then adjust medications or other services provided to the subject 22 based on information from the biosensor. Some information may be directly shared with a nurse or other caregiver, and the insurer, who may need to be apprised of medical needs and recent sensor readings in order to authorize coverage for some services. Decision made by doctors in light of the biosensor data may be used to direct a change in prescription drugs or other care services provided to the subject 22 . Authorization from insurers may be obtained, either manually or via an automatic electronically generated request. The ability of a doctor to reliably alter medication based on remote biosensor data may require that the identity of the user 23 be authenticated through methods such as biometrics or multi-factor authentication, and may require the user 23 to waive some levels of privacy protection to ensure that transmitted data is complete and accurate.

[0067] FIG. 2 shows additional details associated with the personal data control means 24 . A biosensor 20 interacts with a subject 22 to yield an analyte measurement 60 conveyed via a biosensor signal 40 . The biosensor signal 40 can be read by an electronic display device for measurement display and interpretation 62 . A portable device or computer may receive the signal and generate a reading that can be interpreted by the user 23 . For example, the display may show that the analyte level is abnormal or potentially indicative of a pathological condition, or it may show that a possible malfunction has occurred. Alternatively, a datalogger, smart card, or other device may record and store the biosensor signal, which later can be reduced or manipulated for display to the user 23 , either by circuitry and display features integral with the datalogger or smart card, or with the assistance of one or more additional devices.

[0068] The user 23 is then provided with an opportunity to send the data to a data allocation and processing module 26 . If approval is not given, measurement can continue 70 to provide further opportunities for measurement.

[0069] When approval is given, the user 23 can be prompted to provide a privacy input 42 to add comments and limitations 66 regarding the use of the data, or circumstances relating to the data, or other information that can assist in properly interpreting the data and protecting the privacy of the subject 22 . Data from the biosensor signal 40 and the privacy input 46 are combined in a response signal 44 that is transmitted to a data allocation and processing module 26 .

[0070] For example, a smart card such as the Data Concern TM Smart Card marketed by Lifestream Technologies (Post Falls, Id.) can be used to store cholesterol information provided by a biosensor signal 40 from a Lifestream Technologies® Personal Cholesterol Monitor taken over a period of time. The Data Concern™ Smart Card can then be used to provide data for display on another device than can also provide input means for the user 23 to enter a privacy input 42 . A smart card can be used with non-volatile memory, including FRAM (ferroelectric RAM). The Data Concern TM Smart Card utilizes a microprocessor and Microsoft® Smart Card for Windows operating system. Optionally, the Data Concern™ Smart Card can be combined with the Privalink™ software package to add emergency medical information directly to a Personal Health Card™, including drug and food allergies, prescriptions, insurance company, primary care physician and hospital preference, as well as other critical information. Physicians and pharmacists can be authorized to access test results and personal health records over the World Wide Web. It is within the scope of the present invention to adapt such smart card systems to issues other than cholesterol monitoring, including hormone monitoring during hormone replacement therapy (HRT); clotting time (prothrombin time) monitoring during anti-coagulant therapy; thyroid hormone monitoring during therapy; and blood pressure monitoring during anti-hypertensive therapy. Another system of potential value is disclosed in WO 00/52457, “Card-Based Biosensor Device,” issued to W. Y. Wong et al. of Helix Biopharma Corp., Canada.

[0071] Measurement display and interpretation 62 typically results in an intermediate output signal that is displayed for reading or interpretation by the user 23 or other caregiver. The intermediate output signal can include qualitative or quantitative results displayed on a screen or other display device in the form of text, a bar graph, a numerical value, a pie chart, an icon, a color, and so forth, or can be a sound such as a synthetic voice, a beeping of variable frequency or intensity, a vibration of a physical device, and the like. Detailed display of information with interpretative guidance on a computer screen or the like with live hypertext for additional information represents one embodiment for the intermediate output signal. A display responsive to measurement by a biosensor 20 can also employ electrochromic inks, wherein a displayed color is related to an applied voltage. Information on electrochromic inks is available at composite.about.com/library/PR/2001/blufl1.htm, unisci.com/stories/20012/0515016.htm, and I. Schwendeman, et al., “Combined Visible and Infrared Electrochromism Using Dual Polymer Devices,” Adv. Mater., Vol. 13, 2001, pp. 634-637, and B. C. Thompson et al., “In Situ Colorimetric Analysis of Electrochromic Polymers and Devices,” Chemistry of Materials, Vol. 12, No. 6, June 2000, pp. 1563-1571. Display of information can also occur with LCD screens or other LDC displays, or with “electric paper” such as that described in U.S. Pat. No. 6,284,352, “Ferrofluidic Electric Paper,” issued Sep. 4, 2001 to Biegelsen et al., incorporated herein by reference. Colorimetric film can also be used, in this application as well as in direct response to an analyte or signal generated by a sensing element, including the use of calorimetric film described in U.S. Pat. No. 6,001,556, incorporated herein by reference.

[0072] In general, the personal data control means 24 permits the user 23 or other party to control what information (e.g., a subset of the data derived from the biosensor signal 40 ) is transmitted to other parties, and/or to whom it is transmitted, and/or what additional information (such as user comments or explanatory notes) is sent with the data. The response signal 44 from the personal data control means 24 , as well as the output signal 46 from the data allocation and processing module 26 , can be encrypted. Encryption of data for security can be by any suitable means, including methods based on chaos theory such as fractal-based encryption (see, for example, “Fractal-based Encryption,” Photonic Tech Briefs, Vol. 25, No. 7, July 2001, pp. 14a-16a), including the methods provided by Catnaz, Inc. of Columbus, Ohio.

[0073] The output signal 46 can also include unique identification information such as a user ID and password or PIN from the user 23 or from each person modifying the data or adding comments. The serial number of one or more devices associated with the personal data control means 24 or other hardware-related identifying information can also be sent, as well as identifying information pertaining to the biosensor 20 (e.g., a product code conveyed via an RFID or smart tag system) or other data signals (not shown) such as a personal identification code for the subject, signals from temperature sensors and other sensors, and the like. Unique registered ID labels for each biosensor 20 or for other devices associated with the biosensor 20 can be included in the signal sent to the data allocation and processing center 26 to track specific sensors and ensure that proper equipment is used or that equipment signals are not falsified.

[0074] The personal data control means 24 optionally can provide additional feedback to the user 23 about how transmitted data have been used. The user 23 can select, for example, to permit a hospital or doctor to continuously observe the biosensor signal 40 , or can choose to transmit data derived from the biosensor signal 40 periodically or at arbitrary intervals selected by the user 23 . The user 23 may wish to not transmit some data, especially when there was a problem such as temporarily disconnecting the biosensor 20 from the user 23 . Or the user 23 may choose not to transmit data for other reasons. For the best health care, the data should be readily available to primary care providers. The method of integrating a biosensor 20 to a health care system may also include the step of providing electronic confirmation to the user 23 that a transmission of data has occurred, and separately indicating when and by whom the data has been reviewed. Thus, after biosensor data have been transmitted to a doctor, for example, the user 23 can know how long before a doctor saw and considered the data (or considered a computer-generated analysis of the data). Further, the patient may be electronically provided with the doctor's comments on the biosensor data and with his or her planned course of action in response. The patient may then have the option to challenge the planned course of action or call for a second opinion before accepting adjustments in treatment.

[0075] FIG. 3 shows one system for sharing of information from a remote biosensor 20 with a central network in a way that protects the security of the data. The response signal 44 from the personal data control means 24 provides data to a remote network 70 , which can include a lone data transmission device that can be part of the personal data control means 24 . The remote network 70 provides the data in the form of a signal to a client router 72 , with an intermediate encryption step 82 occurring to encrypt the data. The encryption step 82 can also include decryption of a signal received from another source via the client router 72 . The client router 72 directs a signal including the encrypted data over the Internet 74 to a server router 76 , which provides the signal to a private network 78 with an intermediate decryption step 84 . The decryption step 84 can also include encryption for a signal sent from the private network 78 to another source such as the remote network 70 . The private network 78 can form part or all of the data allocation and processing module 26 (not shown). In this process, a secure tunnel can be provided between the client router 72 and server router 76 , as explained at www.linuxdoc.org/HOWTONPN-HOWTO-2.html#ss2.1. To establish the secure tunnel, any suitable method can be used, including Point-to-Point Tunneling Protocol (PPTP).

[0076] Secure transmission of data to authorized recipients can be achieved using Microsoft's Platform for Privacy Preferences, or P3P (see, for example, “The Battle Over Web Privacy” by G. R. Simpson, Wall Street Journal, Mar. 21, 2001, pp. B1, B4). User settings determine the level of privacy, and can be adapted more specifically for the needs of the present invention.

[0077] The system of WO 01/39021 can also be used. This describes an interactive system for transferring and submitting information, having: an external user interface; an external content administrator in communication with an external submission data store and external user interface, wherein the external content administrator includes executable instructions for collecting technical information from an external user; an internal content administrator in communication with an internal submission data store and the external content administrator, wherein the internal content administrator includes executable instructions for processing technical information from the external user; and a security module, wherein the security module includes executable instructions for limiting access between the external user interface and the internal submission data store through the external content administrator.

[0078] The remote network 70 can include or be part of the family information management system and related database structures proposed in WO 00/77667 by S. E. Young et al., published Dec. 21, 2000, which claims priority from U.S. patent application Ser. No. 60/139,111, filed Jun. 14, 1999, incorporated herein by reference.

[0079] Biosensors 20 tied to care networks may be used for numerous purposes, including:

[0080] detecting the onset of infection or the status of an infection for a recovering patient;

[0081] monitoring the health of fetus or mother during pregnancy (pregnancy management), detecting such things as premature delivery by monitoring uterine contractions, antiphospholipid antibodies, fetal fibronectin proteins, and so forth;

[0082] monitoring reproductive status (e.g., onset of ovulation or other factors associated with fertility);

[0083] other hormone detection (e.g., growth factors, thyroid, menopause-related ones, etc.)

[0084] detecting the onset of menstruation;

[0085] monitoring analytes associated with renal disease, including analytes in the blood or urine measured before, during, or after dialysis, and analytes measured in any body fluids at home or for patients not receiving dialysis,

[0086] monitoring risk factors for osteoporosis, or the onset or status of the disease, or hormone levels or other agents correlated with the development or treatment of osteoporosis and other bone pathologies, through means such as monitoring bone-specific alkaline phosphatase or calcitonin;

[0087] monitoring factors related to heart disease, including analytes such as myoglobin, troponins, homocysteine, creatine kinase, thrombus precursor protein, fatty acid binding protein, CRP, and the like;

[0088] monitoring factors related to rheumatoid arthritis, including MMP-3, fibrin degradation products, anti-type II collagen, and collagen cross-linked N-telopeptides;

[0089] detecting factors related to stroke, including D-dimer in the blood or other body fluids;

[0090] monitoring the effectiveness or presence of a pharmaceutical agent such as an antibiotic;

[0091] detecting an enzyme or other factor associated with heart disease to alert a patient and/or care givers of a potential cardiovascular problem;

[0092] identifying rheumatoid arthritis by detecting type I collagen crosslinked N-telopeptides in urine;

[0093] monitoring cyanosis or circulatory disorders in newborns, diabetics, and so forth;

[0094] monitoring the onset of a sleep apnea episode, coupled with treatments to enhance sleep when needed; such a concept could include the system disclosed in WO 99/34864, published Jul. 15, 1999 by N. Hadas, the U.S. parent of which is incorporated herein by reference;

[0095] optically monitoring nail beds as a tool for assessing blood condition (for some tests, nails can be more transparent than skin to changes such as bluing);

[0096] tracking body position in a bed and applied pressure against the skin of the patient in order to prevent or care for bedsores (decubitus ulcers) and other ulcers or wounds (one means for tracking applied pressure includes the printed arrays of pressure detecting films marketed by Tekscan, Inc. of South Boston, Mass., which can serve as a sensor indicating pressure applied by the body to various points under the body; videocameras, load cells, and other tools can also be employed for tracking position and load; and position detectors can monitor the level and position of the bed over time to ensure that patient position is regularly adjusted); biosensors indicative of wound health and protein-degrading enzymes can also be employed in cooperative association with pressure and position sensors for this purpose;

[0097] tracking indicators of health by monitoring of body odors or analytes in the gas phase near the body, using electronic nose technology or other sensors;

[0098] tracking stress with cortisol measurement in saliva or seratonin measurement, including establishing moving baselines to distinguish between acute stress and chronic stress, and optionally relating the time history of measured stress-related analytes to factors that may have induced the stress;

[0099] using archived time histories of one or more analytes as a record for identification of sudden changes in the treatment of a subject that may be traceable to changes in personnel, medication, and the like, wherein the time history may serve as a tool in detecting malpractice or other problems, or in verifying (or refuting) claims made by the user regarding health status of the subject;

[0100] detecting allergies using as analytes any of IgE (immunoglobulin E), eosinophilic cationic protein, cytokines such as IL-4 or IL-5 in mucous or in the blood or other body fluids, including the use of facial tissue equipped with biosensors for such analytes or with biosensors for bacteria or virus infection;

[0101] detecting bacterial infections using analytes such as cytokines (e.g., IL-6), C-reactive protein, calcitonin or pro-calcitonin, CD11b, ESBL enzymes (particularly for drug-resistant bacteria), and lipocalins;

[0102] detecting risk factors for cervical cancer by monitoring nuclear matrix protein (NMP) 179 or human papilloma virus from a pap smear;

[0103] monitoring levels of taurine in the body or in a local region, including monitoring taurine levels in a non-human mammal such as a domestic cat;

[0104] urinary tract infection testing;

[0105] yeast infection, bacterial infection, or other forms of vaginitis, including pH imbalance;

[0106] UV exposure detection;

[0107] nutritional monitoring or detection of nutrient levels, also including hydration monitoring, cholesterol testing, energy assessment, and anemia assessment;

[0108] monitoring of pesticides, preservatives, and other harmful compounds in a food product (e.g., milk produced from cattle in a dairy operation, or in food to be consumed by humans), including, for example, a biosensor based a cotton cytokinin receptor, as disclosed by V. V. Uzbekov et al., “Chemical Modification of Components of the Cotton Cytokinin Hormone-Receptor Complex for Creation of Pesticide Biosensors,” Chem. Nat. Compd. Vol. 36, No. 6, 2001, pp. 611-615;

[0109] measurement or monitoring of stress indicators;

[0110] allergy testing or detection of allergens;

[0111] detection or screening for ear infection;

[0112] cardiovascular/respiratory health (including pre-heart attack detection, post heart attack detection/monitoring, overall heart health, oxygenation monitoring, pulse, heart dysrythmia alert, respirations, stroke detection, pneumonia detector, respiratory differential, sleep apnea detection);

[0113] detection of influenza with devices such as the FLU OIA™ biosensor of Thermo BioStar (Boulder, Colo.), or detection of other diseases with Thermo BioStar biosensor materials, or with other methods such as lateral flow analysis, diffraction-based methods, electrochemical detection;

[0114] musculoskeletal testing (muscle performance, osteoporosis, body fat);

[0115] monitoring health factors in neonates, such as bilirubin levels for jaundice detection; and

[0116] monitoring blood sugar levels for diabetics; and so forth, as set forth in more detail below.

[0117] The biosensor 20 may provide measurements in real time, measurements at periodic intervals (e.g., snapshots in time), time-averaged results, and the like. The biosensor 20 can be worn on the body or against the body. By way of example, it may be placed inside or on an absorbent article such as a bed pad, a diaper, a sanitary napkin, facial tissue, ostomy bag, tampon, disposable garment, incontinence product, and so forth. It can also be an electrode, optical device, or other instrument, preferably miniaturized, that can respond to health indicators from the subject's body. The biosensor 20 may detect one or more analytes directly. Any suitable biosensor technology can be used, including dielectrophoresis, free-flow electrophoresis, ATP bioluminescence, DEFT, impedance, LAL, ELISA and other immunoassay methods, pH measurement, optical diffraction-based techniques, agglutination techniques, chromogenic agars, molecular imprinting for the real-time analysis, and the like.

[0118] Analysis of the detected signal to assess the health of the subject can be based on comparison to fixed parameters or parameters that are adjusted over time. One useful example of the latter approach is disclosed in U.S. Pat. No. 5,555,191, incorporated herein by reference, which describes an automated statistical tracker that can detect malfunctions in equipment. Messages are received from the sensor over a significant period of time to form message subgroups consisting of selected numbers of messages, and the messages in each of the subgroups are compared to predefined units for that subgroup to determine whether the number of messages in that subgroup that are statistically unusual. Thereafter, an alert signal is generated whenever a statistically significant number of unusual signals are detected. Threshold limits for the measurements are automatically calculated and regularly updated, rather than using fixed limits. The data can be fit to normal or Poisson distributions, for example, from which upper and/or lower limits of acceptable messages per time period can be calculated.

[0119] In addition to the biosensor signal 40 , any number of additional signals (not shown) may be received by the sent to a data allocation and processing module 26 . Such signals can be transmitted by any means such as UWB signals, AM or FM radiofrequency signals, direct wiring, the Internet, a modem, and the like. The additional signals can include readings from other sensors providing measurements of factors such as room temperature, light levels, the location of the subject via a signal from a Global Positioning System (GPS) device or other positioning means, information regarding medications received, operational status of therapeutic devices, the presence of others in the room, whether or not the individual is in bed (e.g., using a load sensor in the bed), and the like. In one embodiment, the presence of specified objects or persons near the subject can be detected by detection means and transmitted with or in addition to the biosensor signal to the data allocation and processing module 26 or to another module (not shown) for continuous monitoring of the well-being of the patient.

[0120] For example, objects comprising “smart tags” for radiofrequency identification (RFID), such as the smart tags under development at the Auto-ID Center at Massachusetts Institute of Technology (Cambridge, Mass.) can convey a unique electronic product code via a miniature antenna in response to a radio signal from an RFID reader, which can read the code of the object. The object code can be used to determine the nature of the object. In one embodiment, an RFID scanner associated with the subject reads a plurality of objects in the room and transmits the object codes to a processor or other computer-device that can determine if appropriate or inappropriate objects are present. The product code can be sent via the Intranet or other means to a server containing information relating product codes and object descriptions, which can return the information to the processor (not shown) or other device or party for evaluation or recoding of relevant information. Inappropriate objects that could be detected could include a pack of cigarettes, a food product to which the individual is allergic, weaponry or other contraband, a person forbidden to have contact with the individual, or electronic devices unsuitable for a patient with a pacemaker. Appropriate objects could include a humidifier, a wheelchair, a caregiver, an oxygen tank, devices to assist walking, and so forth. An RFID reader can also read a unique ID code from a smart tag or other device associated with the individual or the biosensor or both and the code or codes can be sent to the data allocation and processing module 26 .

[0121] FIG. 4 depicts one embodiment of a computer network 90 supporting the healthcare network of the present invention. Communication between the computer 94 of the user 23 with the computer network 90 can be provided via a Web-based interface beginning. Upon entering a predetermined URL for the Web page, the URL request is sent via the firewall to a Cisco router 102 , which employs either a primary domain name server (DNS) 104 or a secondary DNS 106 to determine the IP address to be used for the requested URL. A signal is then sent to an Internet application server 108 , which generates a signal to create a Web page display. The signal is routed back to the computer 94 of the user 23 such that a Web page is displayed on a monitor 92 . The displayed Web page requires the user to log in using a user ID and password (or other authentication means such as biometrics). When the user ID and password are entered, that information is routed again through the firewall 96 to a second Cisco router 110 that directs the information to an ID/password authentication server 112 (e.g., an SQL server). If a valid user ID and password have been entered, a welcome page for the computer network 90 is then displayed (e.g., a signal is sent to the Internet application server 108 which then sends a signal back to the computer 94 of the user 23 to display the computer network welcome page). The welcome page displayed after logging in is unique to the subject 23 and can provide access to additional pages that contain information unique to the user 23 and/or subject 22 , including default settings for access to data and distribution of data, biosensor 20 information such as model type and serial number, insurer information, special directions for emergency response, and so forth. This information can be stored on the Internet application server 108 or a data allocation server 114 , and/or the computer 94 of the user 23 .

[0122] In this embodiment, once the user 23 has been authenticated, access is granted to the data allocation server 114 .

[0123] The biosensor 20 measuring health-related information from the subject 22 provides a biosensor signal 40 which is received by the computer 94 of the user 23 , who can be the subject 22 or a representative of the subject 22 . The computer 94 displays an intermediate output signal 37 summarizing the biosensor data over a period of time (variable or predetermined) and optionally indicating problems or a potential diagnosis. The user 23 can enter a privacy input 42 through the keyboard 35 that can be sent with the biosensor signal 40 or information derived therefrom to a firewall 96 . The privacy input 42 can be prompted, meaning that the computer 94 of the user 23 issues a request for a privacy input 42 before data are transmitted to the firewall 96 . The prompting for a privacy input 42 may occur periodically, such as one a day, or before any data can be transmitted in response to a manual or automatic request to transmit data. Alternatively, a privacy input may be sent within a predetermined time period after data (e.g., 1 hour or 1 day) have been sent to the computer network 90 , such that the user 23 can modify access to the data after data have been received but preferably before others have had access to the data.

[0124] The privacy input 42 and biosensor signal 40 or data derived therefrom are securely routed from the computer 94 of the user 23 through the firewall 96 and to the data allocation server 114 , where software and hardware function as the data allocation and processing module 26 . Data from the biosensor signal 40 , as determined by the privacy input 42 , can then be made available to outside parties. Information may be entered into secure medical records on a medical database server 116 . A doctor 32 may receive a signal 138 from the data allocation and processing module 26 indicating that biosensor signal data are available for review, whereupon the doctor 32 may access medical information 136 from the medical database server 116 .

[0125] The data allocation server 114 and other aspects of the computer network 90 can also be accessed by other medical staff 122 via a proxy server 102 . The other staff 122 can include an administrator who maintains the data allocation server 114 and makes any needed corrections.

[0126] Other third parties 128 can access portions of the biosensor data or other medical information about the subject 22 using a Web-based system or other means via the firewall 96 , allowing data to be received on third-party computers 130 and displayed on third-party monitors 132 for decision making, approval of claims, or other purposes, with access responsive to the privacy input 42 of the user 23 .

[0127] The privacy input 42 can also include an electronic signature from the user 42 , along with data of entry, subject ID, and other information.

[0128] As shown in FIG. 5 , biosensor signal 40 can be combined with a subject ID code 182 and a biosensor ID code 188 to form a composite signal 184 which is directed to a processor 200 in control of the user (not shown) and cooperatively associated with personal data control means 24 . The processor 200 may also received data from other sensors and other data sources 190 , such as annotations or instructions entered by a physician or caregiver, medical history of the patient, insurance status, and so forth. Based on the rules established by the user or the decisions made by the user in directing the personal data control means, the data from the composite signal 184 and other sources 190 , 192 can be filtered such that only a subset is available to the data allocation and processing module 26 , or such that different components of the information have different levels of access by third parties responsive to the privacy input of the user governing the personal data control means 24 .

a. Biosensor Details

[0129] The biosensors used in the present invention can be suitable for use outside of a hospital, such as for home use or use in a managed care facility. While many biosensors require that a skilled medical professional take the reading and/or interpret the results, it is within the scope of the present invention to employ biosensors for which quantitative or qualitative data can be obtained or read by the user and/or family member or caregiver with or without specialized medical training. While interpretation and diagnosis of the data may typically require a skilled medical professional, biosensors can be used that enable the user to understand the nature of a health factor, such as a blood glucose level, and take or request appropriate action in response to the biosensor signal.

[0130] Biosensors for any disease or ailment can be considered, including cancer. For example, markers in urine can be detected for bladder cancer (e.g., BLCA-4, a nuclear matrix protein found in the nuclei of bladder cancer cells, a described in Diagnostics Intelligence, v 10, no 5, p.12). Vascular endothelial growth factor and NMP 22 can also be useful analytes. For melanoma, circulating S-100B can be a useful analyte. For prostrate cancer, human glandular kallikrein, prostrate-specific antigen, and E-cadherin can all serve as useful analytes (in the case of E-cadherin, lower levels may be associated with cancer). U.S. Pat. No. 6,200,765, issued Mar. 13, 2001 and incorporated herein by reference, discloses a noninvasive method of detecting prostrate cancer using a body fluid sample, which can be urine. Thus, incontinence products or other absorbent articles could be equipped with biosensors for prostrate cancer, bladder cancer, or other cancers. Feminine care products could also be equipped with biosensors for detecting cervical cancer. One useful marker for cervical cancer is a marker known as NMP-179, (NMP=nuclear matrix protein), which has been linked to cervical cancer by Matritech. Breast epithelial antigen can also be a marker for breast cancer, and has been proposed as an analyte for detection with flexural plate-wave (FPW) sensors. WO 01/20333 discloses a system for cancer detection by detecting midkine in urine or blood. In vitro detection of diseases such as cancer is disclosed in WO 01/20027.

[0131] Various types of sensors employing electrical, optical, acoustical, chemical, electrochemical or immunological technologies can serve as biosensors. The can be miniaturized to function as microsensors. The biosensors of the present invention can be disposable (single-use or multi-use devices), or can be durable sensors for repeated use or continuous use over a prolonged period of time. Those based on bioaffinity, biocatalysis, or other operating principles can be used.

[0132] Many biosensors include a sensing layer associated with a transducer. The sensing layer interacts with a medium including one or more targeted analytes. The sensing layer can include a material that can bind to the analyte and can be, for example, an enzyme, an antibody, a receptor, a microorganism, a nucleic acid, and the like. Upon binding of the analyte with the sensing layer, a physicochemical signal induces a change in the transducer. The change in the transducer permits a measurement that can be optical (e.g., a viewable diffraction pattern), potentiometric, gravimetric, amperoteric, conductimetric, dielectrimetric, calorimetric, acoustic, and the like.

[0133] Many biosensors for particular analytes use ELISA (enzyme-linked immunosorbent assays), wherein specific enzyme-labeled antibodies are employed to detect an analyte. Any suitable ELISA method can be employed herein. Solid-substrate assay techniques are typically combined with colorimetric or fluorescent signals to indicate the presence of the analyte, though gravimetric measurement can also be employed. One such example is given by Amy Wang and Richard White at the Berkeley Sensor and Actuator Center, University of Berkeley, described at buffy.eecs.berkeley.edu/IRO/Summary/97abstracts/wanga.1.html , which discloses the use of flexural plate-wave (FPW) sensor wherein the amount of protein bound to the solid substrate (the flexing plate of the FPW device, a micromachined, acoustic sensor along which ultrasonic flexural waves propagate) is measured by a change in acoustic wave velocity caused by the added mass of the bound proteins. Any other measurement technology can be used. Basic principles of immunological sensors are given in P. Tijssen, Practice and Theory of Enzyme Immunoassay, Elsevier, Oxford, 1985, and D. Diamond, Principles of Chemical and Biological Sensors, Wiley and Sons, New York, 1998. Other principles of biosensors employing antibodies are disclosed in WO 01/27621; WO 01/27626; WO 01/27627; WO 01/20329′ WO 00/08466; and WO 99/64620.

[0134] Biosensors can include multiple sensing elements or other technologies to detect multiple analytes. For example, one can employ the multiple analyte technology of U.S. Pat. No. 6,294,392, “Spatially-Encoded Analyte Detection,” issued Sep. 25, 2001 to Kuhr et al. provides a flow-through microfluidic (e.g., capillary) biosensor for detecting different target analytes (e.g. nucleic acids) in a sample after binding to their cognate “binding partners” (e.g. nucleic acids, antibodies, lectins, etc.). In general, binding partner “probes”, specific to various analytes are immobilized in different sections of a capillary channel, e.g. using photolabile biotin/avidin technology. The sample is then flushed through the capillary, so that the target analytes are bound to the binding partners (capture agents) immobilized on the capillary wall and the rest of the sample is eluted from the capillary. Finally, the complexed (bound) analyte is released along the entire length of the channel and flushed past a detector. In a preferred embodiment, the desorbed, target-analytes are detected at a copper electrode poised downstream using sinusoidal voltammetry (Singhal and Kuhr, Analytical Chemistry, Vol. 69, 1997, pp. 3552-3557; Singhal et al., Analytical Chemistry, Vol. 69, 1997, pp. 1662-1668). The time from the elution of the target analyte(s) to detection is used to determine the identity of each analyte. Multiple analytes, of the same species of molecule (e.g., all nucleic acids), or of different species (e.g. proteins and nucleic acids), can be diagnosed by using a single biosensor in this manner. The sensor is said to be highly specific due to the use of specific binding partners, and extremely sensitive due to electrochemical detection.

[0135] Numerous techniques exist for immobilizing an enzyme or other bioactive material on a substrate. Recent developments include siloxane-based biocatalytic films and paints, in which enzymes are immobilized by sol-gel entrapment of covalent attachment into a polydimethylsiloxane matrix, as described by Y. D. Kim et al., “Siloxane-Based Biocatalytic Films and Paints for Use as Reactive Coatings,” Biotechnology and Bioengineering, Vol. 72, No. 4, 2001, pp. 475-482. Methods for using polytetrafluorethylene (PTFE) substrates have also been developed to enable PTFE use as a polyfunctional support, as described in M. Keusgen et al., “Immobilization of Enzymes on PTFE Surfaces,” Biotechnology and Bioengineering, Vol. 72, No. 5, 2001, pp. 530-540. Elemental sodium and then ozone or peroxide oxidation is used to open up covalent attachment points for enzyme binding. Enzymes can also be immobilized in silica gels, as described by M. Schuleit and P. Luisi, “Enzyme Immobilization in Silica-Hardened Organogels,” Biotechnology and Bioengineering, Vol. 72, No. 2, 2001, pp. 249-253.

[0136] Another useful substrate and biosensor is that of Dieter Klemm and Lars Einfeldt, “Structure Design of Polysaccharides: Novel Concepts, Selective Synthesis, High Value Applications,” Macromolecular Symposia, Vol. 163, pp. 35-47, 2001. This discloses polymer matrices useful in biosensors that could be developed by immobilization of enzymes like glucose oxidase and aromatic redox-chromogenic structures at 6-deoxy-6-(4-aminophenyl)-aminocellulose. Also disclosed are p-toluenesulfonic acid esters of cellulose (tosylcelluloses) as intermediates, reacting with 1,4, phenylenediamine (PDA) to form “PDA cellulose.” PDA cellulose esters can then be formed into films onto which enzymes can be immobilized by glutardialdehyde reaction, diazo coupling, an ascorbic acid reaction, or other suitable means, as cited by Klemm and Einfeldt. No enzyme activity is lost within several days, according to the authors. The authors suggest biosensors using fiber optics to convey an optical signal. Redox-chromogenic properties were demonstrated by oxidative coupling reactions of phenols onto the PDA groups in the presence of H2O2 and peroxidase.

[0137] Another class of bioanalytical sensor has been developed that instead of using an enzyme to detect its substrate, senses the enzyme directly. This work is described by Michael R. Neuman in the publication, “Biomedical Sensors for Cost-Reducing Detection of Bacterial Vaginosis,” cect.egr.duke.edu/sensors.html, reporting work supported by NSF grant #9520526 and the Whitaker Foundation. Any suitable immunosensor and method of making the same can be used, including those of N. Trummer, N. Adányi, M. Varadi, I. Szendro in “Modification of the Surface of Integrated Optical Wave-Guide Sensors for Immunosensor Applications,” Fresenius Journal of Analytical Chemistry, Vol. 371, No. 1, August 2001, pp. 21-24, who disclose methods for attaching amino and epoxy groups to the surface of integrated optical wave-guide sensors for immunosensors. The SiO ₂ —TiO ₂ surfaces were modified by use of the trifunctional silane reagents.

[0138] Lateral flow or immunochromatographic technology in any suitable form can be used in the biosensors as well. For example, Quidel (San Diego, Calif.) offers a variety of lateral flow devices that can be used in the present invention, including the QuickVue H.pylori gII test, which is a lateral-flow immuno-chromatographic assay intended for rapid detection of IgG antibodies specific to Helicobacter pylori in human serum, plasma or whole blood.

[0139] Biosensors can also function based on other scientific principles suitable for detection of analytes, including surface plasmon resonance (SPR), phase fluorescence, chemiluminescence, protein nucleic acid (PNA) analysis, baculovirus expression vector systems (BEVS), phage display, and the like. Examples of sensors incorporating such principles can be found in many sources, including the products of HTS Biosystems, such as their Proteomatrix™ Solution for proteomics. Basic information is provided at http://www.htsbiosystems.com/technology/spr.html. For example, HTS Biosystems' FLEX CHIP™ Kinetic Analysis System is based on grating-coupled SPR technology wherein measurements are made of optical properties of a thin film in close to a noble metal surface (e.g., gold or silver). Changes in molecular composition (e.g., when a target binds to a surface-bound capture probe) cause changes in the surface optical properties that are proportional to the amount of binding that occurs. The manufacturers state that this technology can be considered, in a way, to allow monitoring of surface-binding events in real time without the use of reporter labels. Grating-coupled SPR-based disposable biosensor chip can be made employing the technology currently used in producing digital video disc (DVD) media. An optical grating on a plastic base is produced. Amperometric immunosensors can also be used, such as those being developed at the Paul Scherrer Institute of Villigen, Switzerland, as described at Imn.webψch/molnano/immuno.htm. Biorecognition, the binding of antibodies to an antigen, for example, results in an electrical signal at an electrode. Antibodies are labeled with microperoxidase for generation of an electrochemical signal via electrocatalytic reduction of hydrogen peroxide. One application includes detection of antibiotics in milk, as described at Imn.webψch/molnano/penisens.htm and in Swiss Pat. Appl. No. 1764/99 (1999), by A. Grubelnik, C. Padeste and L. Tiefenauer.

[0140] Many forms of electrodes can be incorporated in the biosensors of value in the present invention. The electrodes can be created with photolithography, printing technologies such as ink-jet or screen printing, mechanical assembly, any technique suitable in the production of semiconductor chips, and the like. An example of screen-printed sensor is found in the work of A. J. Killard, et al. of Dublin City University, “A Screen-printed Immunosensor Based on Polyaniline,” described at www.mcmaster.ca/inabis98/newtech/killard0115/ and www.mcmaster.ca/inabis98/newtech/killard0115/two.html. Chips in biosensors can also include optical devices. For example, Motorola has developed a silicon chip integrated with a photon chip in which light-emitting gallium arsenide is bonded with strontium titanate to silicon (see Bill Scanlon, “Motorola Solves 30-Year Optical-Silicon Chip Puzzle,” Interactive Week, Sep. 10, 2001, p.18). Similar technology is being applied to bond light-emitting indium phosphide to silicon. Both approaches can be adapted for biosensors in which a chip generates and measures an optical signal that interacts with a medium to detect an analyte. Chips can also include light emitting diodes, diode lasers, or other light-emitting devices for biological sensing, as described, for example, in S. Dorato and A. Ongstad, “Mid-Infrared Semiconductor Laser Materials Engineering,” AFRL Technology Horizons, Vol. 2, No. 3, September 2001, pp. 14-15. Semiconductor lasers can generate beams in the near-IR spectral region (700-1000 nanometers). Bluegreen light can also be generated by semiconductor lasers, such as those based on III-V gallium nitrogen and II-VI zinc-sulfur compounds, which emit radiation in the range of 490 to 55 nanometers. Long wavelength diodes can also be used, with infrared radiation in the range of 2000 to 12,000 nanometers. Mid-IR devices, including tunable mid-IR semiconductor lasers, can also be used, as well as quantum-well lasers (e.g., a “W-laser”) and antimonide lasers.

[0141] Numerous biosensor chips can be used in the present invention, including those providing miniaturized, microfluidic assay chemistries. Exemplary devices are described in the article “Biochips” in Nature Biotechnology, Vol. 16, 1998, pp. 981-983, which also describes several examples of protein biochips, particularly the Affymetrix GeneChips. The p53 GeneChip, designed to detect single nucleotide polymorphisms of the p53 tumor-suppressor gene; the HIV GeneChip, is designed to detect mutations in the HIV-1 protease and also the virus's reverse transcriptase genes; and the P450 GeneChip focuses on mutations of key liver enzymes that metabolize drugs. Affymetrix has additional GeneChips in development, including biochips for detecting the breast cancer gene, BRCA1, as well as identifying bacterial pathogens. Other examples of biochips used to detect gene mutations include the HyGnostics modules made by Hyseq. Examples of biochips designed for gene expression profile analysis include Affymetrix's standardized GeneChips for a variety of human, murine, and yeast genes, as well as several custom designs for particular strategic collaborators; and Hyseq's HyX Gene Discovery Modules for genes from tissues of the cardiovascular and central nervous systems, or from tissues exposed to infectious diseases.

[0142] A wide variety of biosensor chips are provided by Biacore International AB (Uppsala, Sweden). Products are described at www.biacore.com/products/chips_all.shtml. In an example disclosed in the document at www.biacore.com/company/pdf/poster_ahm_use.pdf, a Biacore 3000 sensor was used to track the interaction of two enantiomers of a drug with human albumin. From this one can infer that real-time monitoring can be done of the interaction of a pharmaceutical agent with blood to assess the effectiveness of the drug. For example, a drug can be administered to the patient and a biosensor can then track the state of the drug in the blood to better guide application of the drug to the patient.

[0143] Another example is Caliper's LabChip, which uses microfluidics technology to manipulate minute volumes of liquids on chips. Applications include chip-based PCR as well as high-throughput screening assays based on the binding of drug leads with suitable drug targets.

[0144] In addition to suitable DNA and RNA-based chips, protein chips are being developed with increasing frequency. For example, a recent report describes the development of a quantitative immunoassay for prostate-specific membrane antigen (PSMA) based on a protein chip and surface-enhanced laser desorption/ionization mass spectrometry technology. Some protein biochips employ surface plasmon resonance (SPR). V. Regnault, et al. in British Journal of Haematology, Vol. 109, 2000, pp. 187-194 disclose the use of SPR to detect the interaction between autoantibodies and 2-glycoprotein I (a2GPI) immobilized on protein sensor chips, an interaction correlated with lupus. SPR enabled the interaction to be detected at a very low density of protein immobilization on the chip.

[0145] Microcantilevers and quartz crystals can serve as sensing elements for the detection of particular analytes, as described by C. Henry, “Biosensors Detect Antigens, Viruses,” Chemical and Engineering News, Vol. 79, No. 37, Sep. 10, 2001, p. 13. For example, G. Wu et al. in “Bioassay of Prostate-Specific Antigen (PSA) Using Microcantilevers,” Nature Biotechnology, Vol. 19, No. 9, September 2001, pp. 856-60, describe a sensitive microdevice employing microcantilevers that detects the presence of prostrate-specific antigen, a marker for early detection of prostrate cancer and for monitoring its progression. PSA antibodies are attached to a gold-coated silicon nitride microcantilever. Fluid passing over the device brings PSA, which binds to the antibodies, causing a change in the deflection of the microcantilever that can be measured by a laser. Levels of 0.2 ng/ml were detectable, even in a background of unrelated human serum proteins. The threshold for cancer detection of 4 ng/ml. Arrays of microcantilevers are possible, and could be employed to detect a plurality of analytes.

[0146] Quartz crystal microbalances (QCMs) have been used to detect viruses that bind to antibodies on the surface of the quartz, as described by M. A. Cooper, “Direct and Sensitive Detection of a Human Virus by Rupture Event Scanning,” Nature Biotechnology, Vol. 19, No. 9, September 2001, pp. 833-37. As the quartz crystal is oscillated an increasing frequencies in the presence of an alternating electrical field, a critical frequency is reached where the virus-antibody bond is ruptured. The quartz crystal, acting like an acoustic device, converts the acoustic emission from the bond rupture to an electrical signal. Proteins that are less strongly attached to the crystal are shaken off early during oscillation, allowing the device to distinguish between specific and non-specific adsorption.

[0147] A particularly sensitive class of microsensors includes acoustic sensors, such as those using surface acoustic wave (SAW), bulk acoustic wave (BAW), and acoustic plate modes (APM). Selectivity is typically achieved by coating a thin polymeric or metallic film on the sensing