MXPA01001996A - Optical-based sensing devices - Google Patents

Abstract

An optical-based sensor (10) for detecting the presence or amount of an analyte using both indicator and reference channels. The sensor has a sensor body (12) with a source of radiation embedded therein (18). Radiation emitted by the source interacts with indicator membrane (3) indicator molecules (16) proximate the surface of the body. At least one optical characteristic of these indicator molecules varies with analyte concentration. For example, the level of fluorescence of fluorescent indicator molecules or the amount of light absorbed by light-absorbing indicator molecules can vary as a function of analyte concentration. In addition, radiation emitted by the source also interacts with reference membrane indicator molecules proximate the surface of the body. Radiation (e.g., light) emitted or reflected by these indicator molecules enters and is internally reflected in the sensor body. Photosensitive elements within the sensor body generate both indicator channel and reference channel signals toprovide an accurate indication of the concentration of the analyte. Preferred embodiments are totally self-contained and are sized and shaped for use in vivo in a human being. Such embodiments preferably include a power source, e.g. an inductor, which powers the source of radiation using external means, as well as a transmitter, e.g. an inductor, to transmit to external pickup means the signal representing the level of analyte.

Description

OPTICAL BASE DETECTION DEVICES The present invention is a continuation in part of the patent application of E.U.A. No. 09 / 304,831, issued May 5, 1999 and the patent application of E.U.A. No.09 / 140,747, issued August 26, 1998, the descriptions of which are incorporated herein by reference as hereby referred to in their entirety.

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION The invention relates to electro-optical detection devices for detecting the presence or concentration of an analyte in a liquid or gaseous medium. More particularly, the invention relates to (but is not necessarily limited in all cases a) optical base detection devices that are characterized by fully integrating with a soft, oblong shape rounded, oval, or elliptical (e.g. of bean or pharmaceutical capsule) and an extraordinarily compact size that allows the device to be implanted in humans for in-situ detection of several analytes.

TECHNICAL BACKGROUND The patent of E.U.A. No. 5,517,313, the disclosure of which is incorporated herein by reference, discloses a fluorescence based detection device comprising indicator molecules and a photosensitive element, for example, a photodetector. Generally speaking, in the context of the field of the present invention, the indicator molecules are molecules whose optical characteristics are affected by the local presence of an analyte. In the device according to the patent of E.U.A. No. 5,517,313, a light source, for example, a light emitting diode ("LED"), is located at least partially within a layer of material containing the fluorescent indicator molecules or, alternatively, at least partially within a waveguide layer so that the radiation (light) emitted by the source will shock and cause the indicator molecules to fluoresce. A high-pass filter allows the fluorescent light emitted by the indicator molecules to reach the photosensitive element (photodetector) while filtering the diffuse light from the light source. The fluorescence of the indicator molecules used in the device described in the U.S.A. No. 5,517,313, is modulated, that is, attenuated or improved, by the local presence of an analyte. For example, the orange-red fluorescence of the perchlorate complex of tris (4,7-diphenyl-1,10-phenanthroline) ruthenium (ll) is extinguished by the local presence of oxygen. Therefore, this complex can be usefully used as the indicator molecule in an oxygen detector. Indicator molecules whose fluorescence properties are affected by various analytes are also known. In addition, indicator molecules that absorb light, with the level of absorption affected by the presence or concentration of an analyte, are also known. See, for example, the patent of E.U.A. No. 5,512,246, the disclosure of which is incorporated herein by reference, which discloses compositions whose spectral responses are attenuated by the local presence of polyhydroxyl compounds such as sugars. However, it is believed that said light absorbing indicator molecules have not previously been used in a sensor constructed as taught in U.S. Patent No. 5,517,313, or in a sensor constructed as shown herein. In the sensor described in the patent of E.U.A. No. 5,517,313, the material containing the indicator molecules is permeable to the analyte. In this way, the analyte can propagate in the material from the surrounding test medium, thus affecting the fluorescence of the indicator molecules. The light source, the matrix material containing the indicator molecule, the high pass filter, and the photodetector are configured so that the fluorescent light emitted by the indicator molecules impacts the photodetector so that an electrical signal is generated that is indicative of the concentration of the analyte in the surrounding medium.

The detection device described in the patent of E.U.A. No. 5,517,313 represents a remarkable improvement over the devices constituting the prior art in connection with the U.S. Patent No. 5,517,313. However, the need for sensors that allow the detection of several analytes in an extremely important environment, the human body, has remained. In addition, additional improvements have been made in the field, whose improvements have resulted in smaller and more efficient devices.

BRIEF DESCRIPTION OF THE INVENTION In general, a sensor according to an aspect of the invention is fully incorporated, with a radiation source (for example LED) and a photosensitive element (for example a photodetector) both completely embedded inside a detector body that transmits light that It works like a waveguide. The indicator molecules are located on the outer surface of the detector body, for example, coated directly thereon or immobilized within a layer of polymer matrix. When the radiation source emits radiation, a substantial portion of the radiation is reflected within the detector body due to internal reflection from the interface of the detector body and the surrounding medium (polymer matrix or medium in which the analyte is present). When the radiation impacts the interface of the detector body and the surrounding medium, it interacts with the indicator molecules immobilized on the surface of the detector body. The radiation emitted by the indicator molecules (ie, fluorescent light in the case of fluorescent indicator molecules) or emitted by the source and not absorbed by the indicator molecules (for example, in the case of indicator molecules that absorb light) is reflects through the detector body due to internal reflection. The internally reflected radiation strikes the photosensitive element so that a signal is generated which is indicative of the presence and / or concentration of the analyte. A sensor in accordance with this aspect of the invention is constructed with the components that allow the radiation source to be energized either by external means, for example, an electromagnetic wave, ultrasound, or infrared light, or by entirely internal means, by example, when using radioluminescence or components such as microbatteries, microgenerators, piezoelectric, etc. The sensor also has components to transmit a signal indicating the level of internally reflected light or other radiation, at which level of internally reflected radiation the analyte concentration can be determined. Said components can be an inductor that is separated from an energy receiving inductor, or the same inductor can be used both to receive electromagnetic energy that generates energy and to transmit electromagnetic signal waves carrying information.

According to another aspect of the invention, a sensor is constructed to facilitate its use subcutaneously in a living human being. For that purpose, in accordance with this aspect of the invention, a sensor is approximately the size and shape of a cold bean or pharmaceutical capsule. In addition, the sensor is preferably provided with a sensor / tissue interface layer that prevents, or scar tissue formation or that overcomes the formation of scar tissue by promoting inward growth of the analyte carrying vascularity. It has been found that the shape of a sensor in accordance with this aspect of the invention provides beneficial optical properties, and therefore said sensor can be constructed for applications other than those of the human body, ie without an interfacial layer and / or with electrical connections that extend inside and outside the sensor. A sensor according to another aspect of the invention is constructed with indicator molecules that absorb light (absorbing other radiation) that absorb the radiation generated by the source. The level of absorption varies as a function of the analyte concentration. By measuring the amount of radiation reflected internally, the concentration of the analyte can be determined. A sensor according to another aspect of the invention takes advantage of the relationship between the density of a medium and its refractive index to measure the concentration of the analyte. As the analyte concentration varies, the density of the medium to which the sensor is exposed changes, and therefore the refractive index of the surrounding medium also changes. As the refractive index of the surrounding medium changes, the amount of light that is reflected internally (or, vice versa, passing through the sensor / medium interface) also changes, and this change in illumination can be measured by means of a photosensitive element within the sensor and can be correlated with the concentration of the locally surrounding analyte. In accordance with a further aspect of the invention, a sensor is provided which includes: (a) at least one analyte detection channel that works as described above; and (b) at least one additional channel that serves as an optical reference channel. The optical reference channel preferably: (a) measures one or more optical characteristics of the indicator molecule (ie, the indicator molecule of the analyte detection indicator channel) that are not affected or are generally unaffected by the presence or concentration of the analyte. analyte; and / or (b) measures the optical characteristic of a second control indicator molecule that is not affected or generally unaffected by the presence or concentration of the analyte. In the field of the present invention, reporter molecules that are unaffected or that are not generally affected by the presence or concentration of the analyte are extensively mentioned herein as control indicator molecules. The optical reference channel can be used, for example, to compensate or correct: changes or deviations in the operation of the component intrinsic to the constitution of the sensor; environmental conditions external to the sensor; or combinations thereof. For example, the optical reference channel may be used to compensate for or correct internal variables induced by, among other things: wear of the radiation source of the sensor, changes affecting the performance or sensitivity of the light-sensitive element; deterioration of the indicator molecules; changes in the transmissivity of the radiation of the detector body, of the indicator matrix layer, etc .; changes in other detector components; etc. In other examples, the optical reference channel can also be used to compensate for or correct environmental factors (eg, factors external to the sensor) that can affect the optical characteristics or apparent optical characteristics of the indicator molecule without taking into account the presence or concentration of the analyte. In this regard, exemplary external factors may include, among other things: the temperature level; the pH level; the present ambient light; the reflectivity or turbidity of the medium to which the sensor is applied; etc. These and other aspects, features and advantages will be apparent based on the following description along with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS These and other aspects of the invention will be apparent from the following detailed description of the invention and the following figures, which are given by way of example and not in a limiting manner, in which: Figure 1 is a sectional view, Schematic of a fluorescence based sensor according to the invention; Fig. 2 is a schematic diagram of the fluorescence based sensor shown in Fig. 1 illustrating the waveguide properties of the sensor; Figure 3 is a detailed view of the circular portion of Figure 1 demonstrating internal reflection within the detector body and a preferred construction of the sensor / tissue interface layer; Figure 4 is a schematic diagram, similar to Figure 2, illustrating the reflection within the detector body by means of the radiation generated by an internal radiation source and by fluorescent light emitted by the external indicator molecules; Figure 5 is a schematic diagram showing the use of a sensor according to the invention in a human being; Figure 6 is a schematic sectional view of a radioluminescent light source; Figures 7a and 7b are schematic illustrations demonstrating the operation of a sensor based on indicator molecules that absorb light in accordance with another aspect of the invention; Figure 8 is a formula for one embodiment of the matrix layer, wherein the polymerized macromolecule of the matrix layer contains a pendant amino group on about one of four monomers; Figure 9 illustrates an interleaved and doped segment of the matrix layer according to the present invention; Figure 10 shows an absorbance-modulated indicator molecule, sensitive to glucose, 2,3-dihydroxyboron-4-hydroxy-azobenzene ("boronate red") according to the present invention; Figure 11 shows a further embodiment of an glucose-sensitive absorbance-modulated indicator molecule according to the present invention; Figure 12 shows a standard Mannich reaction for attaching the reporter molecule and the EEA doped monomer; Figures 13a and 13b are schematic illustrations demonstrating the principle of operation of a sensor based on the refractive index in accordance with another aspect of the invention. Figure 14a is a top plan view of a sensor according to another embodiment of the invention incorporating a reference channel and a normal indicator channel; Figure 14b is a side view of the sensor shown in Figure 14a; Figure 14c is a partial side view of the modified sensor similar to that shown in Figure 14a including a reference channel and an indicator channel; Figure 14d is a perspective view of another embodiment of the invention, incorporating a reference channel and an indicator channel similar to that shown in Figure 14c; Figure 14e is a cross-sectional view taken in the direction of the arrows A-A shown in Figure 14d, the device is shown inside an external object; Figure 14f is a cross-sectional view taken in the direction of the arrows B-B shown in Figure 14d, the device is shown inside an external object; Figure 15a is a top plan view of a sensor according to another embodiment of the invention incorporating a reference channel and an indicator channel; Figure 15b is a side view of the sensor shown in Figure 15a. Figure 15c is a side view of the modified sensor similar to that shown in Figure 15a including a reference channel and an indicator channel; Figure 16a is a top plan view of a sensor according to another embodiment of the invention incorporating a reference channel and an indicator channel; Figure 16b is a side view of the sensor shown in Figure 16a; Figure 17a is a side view of the sensor in accordance with another embodiment of the invention incorporating a reference channel and an indicator channel in a sensor construction having an inner capsule and an outer sleeve; Figure 17b is a top plan view of the sensor shown in Figure 17a; Figure 17c is a side view of a sensor according to another embodiment of the invention incorporating a reference channel and an indicator channel in a sensor construction having an inner capsule and an outer sleeve; Figure 17d is a top plan view of the sensor shown in Figure 17c; Figure 17e is a side view of a sensor according to another embodiment of the invention incorporating a reference channel and an indicator channel in a sensor construction having an inner capsule and an outer sleeve; Figure 17f is a top plan view of the sensor shown in Figure 17e; Figure 18a is a side view of a sensor according to an embodiment of the invention having an inner capsule and an outer sleeve without a reference channel; Figure 18b is a top plan view of the sensor shown in Figure 18a; Figures 19a-19j show side views of a variety of possible sleeve constructions demonstrating various bag arrangements and sleeve structures; Figures 20a-20b show a top view and a side view, respectively, of another embodiment of the invention including a removable film containing detection membrane (s); and Figure 21 is a graph (provided for illustrative purposes only, which was reprinted for the benefit of Figure 10 of U.S. Patent No. 5,137,833, which is incorporated herein by reference) of light absorption (e.g. optical density) on the axis? against the excitation wavelengths (for example, emitted from a radiation source) on the α axis, which demonstrates an isosbestic point (ie a wavelength) at which the absorption does not vary based on the concentration of the analyte . Fig. 22 (A) is a top plan view of a sensor according to another embodiment of the invention having a protection sleeve (with the protection sleeve partially removed).

Figure 22 (B) is a cross-sectional side view of the sensor shown in Figure 22 (A). Figure 22 (C) is an enlarged view of a portion of the illustration shown in Figure 22 (B). Fig. 22 (D) is a cross-sectional side view of a sensor in accordance with another embodiment of the invention. Figure 23 (A) is a cross-sectional side view of a sensor in accordance with another embodiment of the invention having an LED radiation source that emits radiation in two directions. Figure 23 (B) is an amplified view of a portion of the illustration shown in Figure 23 (A). Figure 23 (C) is a cross-sectional side view taken along the arrows 23 (C) -23 (C) in Figure 23 (A). Fig. 23 (D) is a schematic side view showing a common LED integrated circuit mounted within a reflecting cup. Figure 24 (A) is an explanatory graph showing illumination from two sides of an LED, in accordance with an illustrative example of the embodiment shown in Figure 23 (A). Figure 24 (B) is an explanatory graph showing the illumination from an existing LED mounted on a flat surface. Figure 25 (A) is a cross-sectional side view of another embodiment of the sensor having radiation emitted from the upper and lower sides of a radiation source (the sensor membrane omitted).

Figure 25 (B) is a cross-sectional side view of the embodiment shown in Figure 25 (A) with the sensor membrane positioned on the sensor. Figure 26 is a cross-sectional side view of another embodiment of the sensor having an optically transparent circuit substrate. Figure 27 (A) is a cross-sectional side view, taken along line 27-27 in Figure 27 (B), of another embodiment of the sensor having an internal heating element to inhibit condensation in the sensor. Figure 27 (B) is a top view of the sensor shown in Figure 27 (A). Figure 27 (C) is an exploded perspective view showing the sensor components in Figure 27 (A). Figures 28 (A) and 28 (B) illustrate the actual test data of an increase in partial pressure of a gas in an exemplary construction of the embodiment of Figures 27 (A) -27 (C).

DETAILED DESCRIPTION OF THE INVENTION Initial Modes of the Optical Base Sensor An optical base sensor ("sensor") 10 according to one aspect of the invention, which operates based on the fluorescence of the fluorescent indicator molecules, is shown in Figure 1. The sensor 10 has as its main components a detector body 12; a matrix layer 14 coated on the exterior surface of the detector body 12, with fluorescent indicator molecules 16 distributed through the layer; a radiation source 18, for example an LED, that emits radiation, including radiation on a scale of wavelengths that interact with the indicator molecules (referred to herein simply as "radiation at a wavelength that interacts with the indicator molecules "), that is, in the case of a fluorescence based sensor, a wavelength which causes the indicator molecules 16 to fluoresce; and a photosensitive element 20, for example, a photodetector, which, in the case of a fluorescence-based sensor, is sensitive to the fluorescent light emitted by the indicator molecules 16 so as to generate a signal in response to it. be indicative of the fluorescence level of the indicator molecules. In the simplest embodiments, the indicator molecules 16 can simply be coated on the surface of the detector body. In preferred embodiments, however, the reporter molecules are contained within the matrix layer 14, which comprises a biocompatible polymer matrix that is prepared according to methods known in the art and coated on the surface of the detector body as explained then. Biocompatible matrix materials, which must be permeable to the analyte, include methacrylates and hydrogels that can be usefully selectively made permeable, particularly to the analyte, that is, perform a molecular weight cutoff function. The sensor 12 is usefully formed from a suitable optically transmissible polymer material having a refractive index sufficiently different from that of the medium in which the sensor will be used so that the polymer will act as a guide optical wave. Preferred materials are acrylic polymers such as polymethylmethacrylate, polyhydroxypropylmethacrylate and the like, and polycarbonates such as those sold under the tradename Lexan®. The material allows the radiation employed by the device, radiation generated by the radiation source 18 (for example, light at an appropriate wavelength in modes in which the radiation source is an LED) and, in the case of a Fluorescence-based mode, fluorescent light emitted by the indicator molecules, travel through it. As shown in Figure 2, the radiation, (for example, light) is emitted by the radiation source 18 and (at least some) is reflected internally on the surface of the detector body 12, for example, as in location 22. , thus "bouncing" from one side to the other through the interior of the detector body 12. It has been found that the light reflected from the interface of the detector body and the surrounding medium is able to interact with the indicator molecules coated in the detector body. surface (whether they are coated directly thereon or contained within a matrix) for example, by stimulating fluorescence in the fluorescent indicator molecules coated on the surface. In addition, the light that falls on the interface at angles, measured in relation to a normal to the interface, too small to reflect, passes through the interface and also stimulates fluorescence in fluorescent indicator molecules. 10. Other modes of interaction between light (or other radiation) and the interface and the indicator molecules have also been found to be useful depending on the construction of and the application for the sensor. The other modes include ephemeral excitation and surface plasmo resonance type excitation. As shown in Figures 3 and 4, at least some of the light emitted by the fluorescent indicator molecules 16 enters the detector body 12 either directly or after being reflected by the outermost surface (relative to the detector body). 12) of the matrix layer 14, as illustrated in region 30. Said fluorescent light 28 is subsequently reflected internally through detector body 12, very similar to how radiation is reflected by radiation source 18, and likewise the radiation emitted by the radiation source, some light will strike the interface between the detector body and the surrounding medium at too small angles to reflect and pass back out of the detector body. The internal reflection of radiation emitted by the source 18 and, for fluorescence-based sensors, the fluorescent light emitted by the fluorescent indicator molecules 16, schematically illustrated in FIG. 4, strikes against the photosensitive element 20, which perceives the level of said internal illumination As further illustrated in Figure 1, the sensor 10 may also include reflection coatings 32 formed at the ends of the detector body 12, between the outer surface of the detector body and the matrix layer 14, to maximize or improve the internal reflection of the radiation and / or light emitted by fluorescent indicator molecules. Reflective coatings may be formed, for example, of paint or metallized material (provided that the metallized material does not impede the transmission of telemetry signals to and from the sensor as described below). As also illustrated in Figure 1, an optical filter is provided 34 preferably on the light sensitive surface of the photosensitive element (photodetector) 20. This filter, as known from the prior art, substantially prevents or reduces the amount of radiation generated by the source 18 striking the photosensitive surface of the photosensitive element. At the same time, the filter allows the fluorescent light emitted by the fluorescent indicator molecules to pass through it to strike the photosensitive region of the detector. This significantly reduces "noise" in the photodetector signal that is attributed to the incident radiation from the source 18. The application for which the sensor 10 was developed in particular in accordance with an aspect of the invention, although it is not the only means of suitable application, is the measurement of various biological analytes in the human body, for example, glucose, oxygen, toxins, pharmaceuticals or other medicines, hormones and other metabolic analytes. The specific composition of the matrix layer 14 and the indicator molecules 16 may vary depending on the particular analyte for which the sensor is used to detect and / or where the sensor is used to detect the analyte (i.e. in the blood or in the blood). subcutaneous tissues). However, the two constant requirements are that the matrix layer 14 facilitates the exposure of the indicator molecules to the analyte and that the optical characteristics of the indicator molecules (e.g., the fluorescence level of fluorescent indicator molecules) are a function of the concentration of the specific analyte to which the indicator molecules are exposed. To facilitate in-situ use in the human body, the sensor 10 is formed in a smooth, oblong or rounded shape. Conveniently, it has the approximate size and shape of a bean or a pharmaceutical gelatin capsule, i.e. it is in the order of about 500 microns to about 1.27 cm in length L and in the order of about 300 microns to about 0.76. cm in diameter D, with generally smooth surfaces, rounded therethrough. This configuration allows the sensor 10 to be implanted in the human body ie in the dermis or in the underlying tissues (including organs or veins) without the sensor interfering with essential bodily functions or causing excessive pain or discomfort. Furthermore, it will be appreciated that any implant placed inside the human body (or any animal), even an implant that is comprised of "biocompatible" materials, will cause, to a certain degree, a "response to foreign bodies" within the organism in which it is inserted. the implant simply, by virtue of the fact that the implant presents a stimulus. In the case of a sensor 10 that is implanted within the human body, the "response to foreign bodies" most often is a fibrotic encapsulation, ie the formation of scar tissue. Glucose, a primary analyte whose sensors according to the invention are expected to be used to detect, may have their diffusion or transport rate blocked by said fibrotic encapsulation. Even molecular oxygen (O2), which is very small, can also have its diffusion or transport speed blocked by said fibrotic encapsulation. This is simply because the cells that form the fibrotic encapsulation (scar tissue) may be very dense in nature or may have metabolic characteristics different from those of normal tissue. To overcome this potential obstacle or to delay the exposure of the indicator molecules to the biological analytes, two main approaches are contemplated. According to one approach, which is perhaps the simplest approach, a sensor / tissue interface layer, which lies on the surface of the detector body 12 and / or the indicator molecules themselves when the indicator molecules are immobilized directly on the surface of the detector body, or lies on the surface of the matrix layer 14 when the indicator molecules are contained therein, is prepared from a material that causes small or acceptable levels of fibrotic encapsulation to form. Two examples of such materials described in the literature having these characteristics are Preclude ™, Periocardial Membrane, available from WL Gore and polyisobutylene covalently combined with hydrophilic as described in Kennedy, "Tailoring Polymers for Biological Uses," Chemtech, February 1994, pp. 24-31. Alternatively, a sensor / tissue interface layer that is composed of many layers of specialized biocompatible materials can be provided on the sensor. As shown in Figure 3, for example, the sensor / fabric interface layer 36 may include three sublayers 36a, 36b, and 36c. The sublayer 36a, a layer that promotes tissue ingrowth, is preferably made of a biocompatible material that allows the penetration of capillaries 37 therein, even though the fibrotic cells 39 (scar tissue) accumulate therein. . Gore-Tex® Vascular Graft material (ePTFE), Dacron® (PET) Vascular Graft materials that have been used for many years, MEDPOR Biomaterial produced from high density polyethylene (available from POREX Surgical Inc.) are examples of materials whose Basic composition, pore size, and pore architecture promote internal tissue growth and vascular interior growth in the inner tissue growth layer. The sublayer 36b, on the other hand, is preferably a biocompatible layer with a pore size (less than 5 micrometers) that is significantly smaller than the pore size of the growth sublayer in the fabric 36a to prevent inward growth. of the tissue. A currently preferred material from which sublayer 36b is made is Preclude Periocardial Membrane (formerly called GORE-TEX Surgical Membrane), available from W.L. Gore, Inc., which consists of expanded polyether-fluoroethylene (ePTFE). The third sublayer 36c acts as a molecular sieve, that is, it provides a molecular weight cutting function, excluding molecules such as immunoglobulins, proteins, and glycoproteins while allowing the analyte or analytes of interest to pass through to the indicator molecules (already either coated directly on the detector body 12 or immobilized within the matrix layer 14). Many of the well-known cellulose membranes, for example, of the type used in kidney dialysis filter cartridges, can be used for the molecular weight cut layer 36c. Although the sensor / fabric interface layer 36 is described and shown in Figure 3 as including a third molecular weight cut-off layer 36c, it will be appreciated that it is possible to select a polymer from which a matrix layer can be made. , for example a methacrylate or a hydrophilic acrylic hydrate, in such a way as to perform the function of cutting molecular weight without the need for a separate sublayer 36c. However, it is recommended that the two sublayers 36a and 36b that are used with the outer layer 36a promote the inward growth of the fabric and the layer 36b preventing the inner growth of the fabric, since the inner layer 36b functions as a barrier additional (or "prefilter") between the outer layer 36a and the molecular weight shear layer (whether provided separately or by the matrix layer 14 itself). This reduces the likelihood that the molecular weight cut-off layer will be obstructed or entangled by macromolecules such as immunoglobulins, extracellular matrix proteins, lipids, and the like, and thereby maximizing the speed and efficiency at which the analyte or analytes of interest come into contact with the indicator molecules. (For a sensor to be useful for an in vivo test, the delay time of the analyte exposure, ie the amount of time it takes the concentration of the analyte to which the indicator molecules are exposed directly to enter a stable state, should be relatively short that is, two to five minutes). Many combinations and permutations of biocompatible materials from which the sensor / tissue interface layer is constructed will be apparent to those skilled in the medical implant art. Finally, in relation to the sensor / tissue interface layer, in addition to avoiding adverse reactions, it is believed that the interface layer improves the reflection of light (whether it is of fluorescent indicator molecules or of the radiation source 18) from the surface that is further away from the matrix layer 14 and in the detector body 12. An additional aspect of a sensor according to the invention is that it can be fully incorporated. In other words, in specific embodiments, the sensor can be constructed in such a way that the electrical connections in and out of the detector body are not extended to supply power to the sensor (for example, to start the source 18) or to transmit signals from the sensor. the sensor. Preferably, a sensor in accordance with this aspect of the invention can include a power source 40 (Figure 1) that is embedded or encapsulated entirely within the detector body 2 and a transmitter 42 (Figure 1) that is also fully embedded or encapsulated. within the detector body 12. (However, it has been found that the shape of the sensor 10, inside and outside of itself, provides superior optical properties, as well as the sensor modalities that have connections that transmit signals and / or energy that extend in and / or outside the detector body are also within the scope of the invention. In a preferred embodiment, the power source 40 is an inductor, as is the transmitter 42. In this way, when the sensor is implanted in the body, for example between the skin 50 and the subcutaneous tissues 52 as shown in figure 5, the sensor can be energized, i.e. the radiation source can cause radiation to be emitted that interacts with the indicator molecules 16, by exposing the sensor to an electromagnetic radiation field 54 created, for example, by an inductor spiral 56 which is stored in an appropriately configured instrument (not shown) placed near the sensor. In the same way, the transmitter 42, as an inductor, generates an electromagnetic field 58 which is an indicator of the level of light that hits the photosensitive element and improves the presence or concentration of the analyte. Field 58 constitutes a signal that can be detected by an external receiver 60. The signal can be, for example, a 50 megahertz carrier, a modulated amplitude signal; a frequency modulated signal; a digital signal; or any other type of electromagnetic wave signal that can be known to those skilled in the art. Alternatively, it is possible to use an individual coil and an individual inductor for all telemetry. In said embodiment, the spiral 56 generates the electromagnetic wave 54 at a frequency to induce a current in the inductor 40, which energizes the radiation source 18; the amount of internally reflected light captured by the photosensitive element 20 is transmitted by the same inductor 40 as a modulated electromagnetic wave that induces a current in the spiral 56. This modulated wave is generated by the modulation of the current flowing through the inductor 40 by the photosensitive element 20 as a detected light function and is detected by measuring the resultant induced current in the spiral 56. Alternatively, the system can be configured to switch (in rapid sequence) between a power generating mode and a transmitting mode. signal. These and other telemetry schemes will be familiar to those skilled in the art, as such techniques are commonly used, for example, in connection with "smart cards" having an implanted integrated circuit that can pass through a sensor to gain access to a construction, sometimes referred to as radio frequency identification.

Other introduced energy sources contemplated to activate the radiation source 18 include microbatteries; piezoelectric (which generate a voltage when exposed to mechanical energy such as ultrasound, microgenerators, acoustically activated generators (for example, ultrasound), and photovoltaic cells, which can be energized by passing light (infrared) through the skin 50. Alternatively, instead of an LED, a radiant luminescent light source can be used, as illustrated in Figure 6, said radio-luminescent light source includes an optically transmissive, sealed container 80 (eg, cylindrical, spherical, or cubic) with a radioisotope sample 82, for example tritium, contained therein The radioisotope emits beta particles which impinge on the intermediate luminophore molecules 84 coated on the inner surface of the container 80, thereby causing the intermediate luminophore molecules to emit light. Although the beta particles are too weak to pass through the walls of the vessel, the light emits through the intermediate luminophore molecules does not pass through, thus illuminating the sensor with light, similar to an LED, which interacts with the indicator molecules. Said radioluminescent generation of light, and similar generation of light, is known in the art. See, for example, the patent of E.U.A.

No. 4,677,008, the disclosure of which is incorporated herein by reference, and Chuang and Arnold, "Radioluminescent Light Source for Optical Oxygen Sensors, "69 Analytical Chemistry No. 10, 1899-1903, May 15, 1997, the disclosure of which is also incorporated herein by reference. As another alternative to an LED, the sensor may employ an electroluminescent lamp such as the one shown. in U.S. Patent No. 5,281, 825. With regard to the other components shown in Figure 1, a temperature sensor 64 and an optional signal amplifier 66 are also provided in a useful manner. the locally surrounding temperature of the environmental tissues and the environment of the indicator molecule and provides this information to the control logic circuit (not shown) The control logic circuit correlates the level of fluorescence, for example, with the concentration level of the analyte thus correcting the output signal for variations affected by temperature.Amplifier 66 is a relatively simple amplifier circuit that amplifies the signal g The photodetector 20. In order to make a sensor according to the invention, several components and sensor circuitry are assembled in a precut, 0.508 cm by the ceramic substrate 70 of 1.016 cm (for example alumina). The thickness of the substrate is 0.0508 cm. All circuit elements are standard surface mount components available, for example, from Digi-Key, Garrett, and others. The components are attached to the substrate using a standard silver conductive epoxy such as Ablebond-84, available from Ablebond.

Next, a high-pass filter should be installed on the photosensitive element when applying a two-part high-pass filter epoxy, commonly available from CVI Laser and others. The thickness of the filter is controlled by precision depending on whether a Rainin Micropippettor is used. The high pass filter epoxy is cured in an oven at 125 ° C for 2 hours, as indicated by the manufacturer's instructions. Likewise, if desired, a low pass filter can be coated on the radiation source (LED) by the same method using a commercially available low pass epoxy formulation. Customary formulations of optical filters can be prepared by adding a dye of the desired absorption spectrum in an Epotek epoxy. The proper concentration of the dopant can be determined by monitoring the wavelength against transmission in a UV-Vis scanner from the spectrometer until the desired spectrum properties are obtained. Said epoxies formulated in a customary manner can be cured in the same way. Glass, polymer or prefabricated coated filters can also be used and simply adhered to the light-sensitive element or devices using an optical coupling adhesive, as is typical. The circuit board with optical filters (if installed and cured) is subsequently encapsulated using, for example, a two-part Lilly No. 4 gelatin capsule as a mold. Other gelatin capsules also work well. The long "half" of an empty capsule is placed vertically in a grid. Many drops of optically clear encapsulation of appropriate detector body material, as described above, are added to fill the capsule to about one-third of its volume. The substrate with the previously assembled circuit is inserted into the capsule and the optical encapsulation, which is introduced by wicking effect around and in small spaces of the circuit board assembly to help exclude air and thus prevent the subsequent formation of bubbles in the finished sensor device. The additional optical encapsulation is added using a micropipette until the level reaches the top of the capsule while it is in an upright position. The partial assembly is later degassed by placing the capsule (supported by the grid) under a glass bell vacuum and allowing it to be vacuum until no bubbles are seen escaping from the capsule. The assembly is removed from the vacuum and "filled completely" with additional optical encapsulation allowing the surface tension to fill the gelatin capsule above the middle of its flange and to create a rounded hemispherical dome shape that will be assimilated to the extreme opposite. Subsequently, the capsule is placed under ultraviolet light and cured for several hours, the healing time depending on the intensity of the available UV source. Heat cure and catalytic cure can be used alternatively, depending on the encapsulation material. A sufficiently strong cure is obtained by subsequently incubating the UV cure assembly at 60 ° C for 12 hours, or otherwise by the manufacturer's instructions.

The gelatin mold is subsequently removed from the detector body by immersing the encapsulated assembly in water for several hours to dissolve the gelatin. Many changes in water and wash over time help to remove gelatin from the surface. Subsequently, the capsule is air dried (or dried with the oven at 60 ° C) in preparation for the coating. Once the detector body is completely dried, it is coated with the indicator molecules. The reporter molecules can be immobilized directly on the surface of the detector body using techniques known in the art, or they can be contained within a matrix layer solution that is coated in the central body. (A matrix layer solution containing fluorescent indicator molecules can be prepared in accordance with methods known in the art, a matrix layer solution containing light-absorbing indicator molecules can be prepared as described below). One convenient method of coating the sensor with a matrix layer is to attach a small wire (eg, 32 gauge) to one end of the encapsulated circuit to produce a suspension rod. This can be done using the same UV-curing optical encapsulation material. Approximately 1 to 2 microliters of optical encapsulation are placed on the end of the wire. The encapsulated circuit is placed on the front of the UV lamp with the UV lamp off. The wire with optical encapsulation at the tip is touched towards the end of the capsule and the lamp is turned on. The small amount of "adhesive" optical encapsulation will be cured immediately, thereby joining the tip of the wire to the capsule. The capsule can now be conveniently immersed in the matrix layer solutions (and separate indicator molecule solutions, as appropriate) and hung by the wire to cure. The wire can be removed simply by pulling it after the sensor is fully assembled. Once the indicator molecules are securely attached to the surface of the detector body, either directly on the same or on a matrix layer, the sensor / tissue interface layer is constructed by inserting the detector body into a tubular sleeve pre-formed material and sealing each end using heat or epoxy or, if desired, the desired sensor / tissue interface layer material is in sheet form, by rolling the detector body longitudinally into the material and sealing the seam Longitudinal and end seams using heat or epoxy. Although the mode of a sensor 10 according to the invention shown and described in its entirety has an individual radiation source 18 (LED) and photosensitive elements 20 (photodetector), thus enabling the detection of an individual analyte, other configurations and components. For example, two or more different types of indicator molecules can be provided to sense the presence or concentration of two or more analytes, receptively, with two or more photosensitive elements provided in the ceramic substrate 70, each with its own respective transmitter. Each photosensitive element must have its own filter 34 designed to allow the light of the respective indicator molecules to pass therethrough. Similarly, a "two channel" modality can be developed to measure the analyte concentration by two different detection schemes. In one embodiment, for example, some of the indicator molecules may be fluorescent indicator molecules and the rest of the indicator molecules may be indicator molecules that absorb radiation (as described below). Two separate phosphorsensitive elements can be provided, each with its appropriate filter, one to measure the fluorescent light emitted by the fluorescent indicator molecules and another to measure the radiation generated by the source and reflected through the sensor, with some absorption by the molecules indicating radiation absorption. Additionally, other types of photosensitive elements can be used, for example, photoresistors, phototransistors, photodiodes, photodariingtons, photovoltaic cells, negative positive isolation photodiodes, large area photodiodes, avalanche photodiodes, charge coupling devices, etc. In addition, although a sensor according to the invention has been described above mainly working on the basis of the fluorescence of the indicator molecules, the invention is not limited. According to another aspect of the invention, a construction of the sensor according to the invention can operate based on the light absorption characteristics of the light-absorbing indicator molecules. A sensor in accordance with this aspect of the invention can use a sensor that is constructed in a manner similar to that shown in the US patent. No. 5,517,313, which was mentioned above; more preferably, it uses a capsule or a pharmaceutical gelatin bean constructed as described above. As illustrated in Figures 7a and 7b when a sensor 110 according to this aspect of the invention is not exposed to any analyte, the light-absorbing indicator molecules 116 (which are preferably immobilized in a matrix layer 114) absorb a certain amount of radiation (light) 119 generated by the radiation source, falling within a particular scale of wavelengths and passing outside the detector body, and the unabsorbed radiation 121 is reflected back into the detector body. When the sensor 110 is exposed to the analyte so that the light absorbing indicator molecules 116 are exposed to analyte 117 molecules, the light absorbing properties of the indicator molecules are affected. For example, as shown in Figure 7b, the light absorption capacity of the indicator molecules 116 may be decreased so that the intensity of light 121 reflected back in the detector body 12 increases. The level of light within the detector body is measured by a photosensitive element (not shown), as described above. It will be appreciated that the sensor based on indicator molecules that absorb light should be calibrated by determining the illumination intensity levels of various known concentrations of various analytes of interest.

In addition, since the radiation (light) that was measured is the radiation that is emitted by the source itself, it will be further appreciated that if the radiation source has a very broad emission profile and the indicator molecule that absorbs light has a Very narrow scale of absorption wavelengths, a high-pass, low-pass, or band-pass filter is provided on the photosensitive element to allow only this wavelength scale of radiation to be detected by the photosensitive element. Indicator molecules whose light absorbing properties are affected by various analytes are known in the art. (However, as noted above, it is believed that said light-absorbing indicator molecules have not been used in conjunction with the construction of the sensor or in the manner shown herein or in U.S. Patent No. 5,517,313). For example, the patent of E.U.A. No. 5,512,246 describes indicator molecules that absorb light whose ability to absorb light varies as a function of local glucose concentration. In particular, as the local concentration of glucose increases, the ability of the indicator molecules to absorb light at a wavelength of 515 nanometers decreases. Therefore, if said indicator molecules are used together with a cold capsule or bean-shaped sensor constructed as described herein, the level of internal illumination by light at that wavelength will decrease. The local glucose concentration level can then be determined from the illumination level of that wavelength.

Indicator molecules that absorb light that are sensitive to other analytes are well known in the art, for example, as exemplified by phenolphthalein, which changes color in response to the change in pH. As in the case of the sensor based on fluorescent indicator molecules, a sensor that uses indicator molecules that absorb light can have indicator molecules placed directly on the surface of the detector body. However, it is preferred that the indicator molecules are immobilized within a matrix layer 114, as shown in Figures 7a and 7b. The matrix layer 114 can be manufactured by low density polymerization of various organic monomers, including hydroxyethyl methacrylate (HEMA), HEMA is widely available from sources such as PolySciences in Warrington, Pennsylvania and Sigma in St. Louis, Missouri, and can be polymerized by heating or exposing the monomers to ultraviolet light, as is more fully known and understood in the art. In a preferred embodiment, the light absorbing indicator molecules 116 are immobilized within the matrix layer 114 by reacting the HEMA with a doped monomer, for example, aminoethyl methacrylate (EEA). During the polymerization, the AEMA introduces a pendant amino group in the matrix layer 114. The monomers other than the EEA can also be used during the manufacture of the matrix layer 114, including the aminopropyl methacrylate (APMA) and other commercially available monomers having groups. different pendants and carbon chain lengths variable between the amino group and the rest of the monomer. In addition, monomers containing primary amine groups (e.g., EEA), monomers containing secondary amine groups can also be used to form matrix layer 114. Alternatively, pendant entanglements other than amine groups can also be used for covalently attaching the indicator molecules 116 to the polymer material of the matrix layer 114. Examples of alternative pendant entanglement groups include sulfhydryl (-SH), carboxyl (COOH), aldehyde (COH), hydroxyl (OH), cyano (CN) ), ether and epoxyl groups. Although a scale of doped ratios can be used to immobilize the indicator molecules 116, an impurity ratio of about 1: 4 to about 1: 20 AEMA to HEMA is preferred. The matrix layer 114 is provided to have a pendant amino group stoichiometrically for every three HEMA residues in the fully polymerized macromolecule of the matrix layer 114. This is illustrated by the formula in Figure 8. The polymer material of the layer of matrix 114 can be interlaced by standard interlacing methods known in the art, including in a preferred embodiment a method that utilizes a bifunctional poly (ethylene glycol) (n) dimethacrylate as an entanglement group. The interlaced group can be added by normal practice during the initial formulation of the monomer. This and other interlacing groups are commercially available from PolySciences (Warrington, Pa). Although variable (n) may vary from one to more than one thousand, in a preferred embodiment of the invention, n = 1000. The variable (n) may vary depending on the density, porosity and desired hydrophilic properties of the matrix layer 114. Figure 9 illustrates a segment of the matrix layer 114 in accordance with the preferred embodiment of the present invention, which includes a suspended amino impurity monomer (EEA), a HEMA base structure, and a bifunctional interlaced group. The matrix layer 114 offers many advantages to the present invention, including the allowed access of the analyte (eg, glucose) to the light-absorbing indicator molecules.; immobilizing the indicator molecules 116 to prevent them from leaching; maintain the stability of the optical system of the invention; minimize the amount of non-specific binding to the porous matrix of molecules other than the desired analyte; restrict access of molecules larger than the desired analyte; and allowing the porous matrix material to support one or more additional biocompatible interface layers. The matrix layer 114 is also optically compatible with the detector body 12 and is capable of transmitting wavelengths of the excitation, emission, absorbance, or refractive index of the indicator molecules 116.

Various methods for immobilizing the reporter molecules 116 within the matrix layer 114 are described in the literature and may vary from mechanical subjection to covalent immobilization. See, for example, A.P. Turner, Biosensors, pp. 85-99, Oxford Science Publications, 1987. In a preferred embodiment, the reporter molecule 116 is an indicator molecule modulated by glucose-sensitive absorbance which can be covalently immobilized within the matrix layer 114. During the polymerization, the reporter molecule 116 is covalently bound to the base structure of the polymer through a pendant primary amine group, and together they form a matrix layer 114. This form of immobilization is adapted to several methods using different types of indicator molecules and different pendant groups in the polymer base structure. Examples of indicator molecules modulated by glucose-sensitive absorbance include 2,3'-dihydroxyboron-4-hydroxy-azobenzene (also known as "boronate red"), as described in Figure 10. Glucose can interact with molecules indicators 116, as described in the US patent No. 5,512,246. Other preferred indicator molecules prepared in a similar manner for use in the present invention are described in Figure 11. In a preferred method for immobilizing indicator molecules 116 shown in Figure 10 and 11 in matrix layer 114, the position of hydrogen ortho of the phenol group (represented by an "*" in the indicator molecules presented in Figures 10 and 11) is the aminoalkylated, using the Mannich reaction, which is known in organic chemistry as a reaction wherein certain ketone hydrogens, esters, phenols and organic compounds can be condensed in the presence of formaldehyde and an amine. The reagents for carrying out the Mannich reaction are commercially available from various chemical supply companies, including Pierce Chemicals. A standard Mannich reaction for the binding of the indicator molecule 116 to the EEA is shown in Figure 12. By copolymerizing EEA and HEMA in the polymer base structure of the matrix layer 114, the indicator molecule 116 can be attached to the polymer material of the matrix layer 114 and remain accessible to the analyte, for example, glucose. The reporter molecule 116 can be attached to the polymer material of the matrix layer 114 in various forms, including the first coupling of the reporter molecule 116 to the EEA prior to the copolymerization with HEMA. Alternatively, no non-covalent mechanical attachment of the reporter molecule 116 can be used by first immobilizing the reporter molecule 116 to the pendant polylysine amine groups. The pre-immobilized polylysine / indicator molecule precursor can then be mixed with HEMA prior to polymerization. After the polymerization of the methacrylate, the polylysine / indicator molecule complex is trapped within the methacrylate matrix while at the same time the reporter molecule 116 remains covalently immobilized to the polylysine.

The sensor 110 is otherwise constructed as described above. A sensor according to a third aspect of the invention takes advantage of the construction in cold capsule or bean form described above (although by no means limited to said construction) to facilitate the ability to detect the presence or concentration of an analyte based on changes in the refractive index of the medium to which the sensor is disposed (or the refractive index of a matrix that encapsulates the sensor, if one is used). In general, the light traveling through the first medium having a refractive index will not pass through the interface between the first medium and a second medium having a refractive index n2 if the angle of incidence of the light impinges. about the interface (measured in relation to a normal interface) is less than a critical angle? c; on the other hand, the light that falls on the interface at an angle of incidence greater than the critical angle will be reflected internally within the first medium. The critical angle? C = sin "1 (n2 / n1) .Thus, for the limiting case of n -?» N2 such that (n2 / n?) Reaches 0 and the critical angle reaches 0o, the light it will be completely internally reflected internally within the first medium, otherwise, for the limiting condition of ni = n2 in such a way that the critical angle = 90 °, there will be no internal reflection within the first medium and all the light will pass to through the interface in the second medium This principle is illustrated schematically in Figures 13a and 13b in the context of a sensor constructed as shown herein In Figure 13a, the refractive index or the detector body 12 is substantially Therefore, all the internal light generated by the source 18, whose light, due to the waveguide properties of the detector body, will have possible angles of incidence of 0 to 90 °. , which affect the interface with the ang different from perpendicular, it will be reflected internally within the detector body and will be detected by photosensitive elements 20. In contrast, as shown in Figure 13b, where the refractive index n2 is equal to the refractive index of the detector body 12, the critical angle will be 90 ° (ie, tangent to the interface between the detector body and the surrounding medium), and therefore all the light generated by the source 18 will pass outside the detector body 12 and none (or almost none ) will be detected by the photosensitive elements 20. It is possible to capitalize a relationship between the critical angle and the relative refractive indices to determine the concentration of an analyte to which the sensor will be exposed since, in general, the refractive index of a medium increases with the density of the medium. For example, if the detector body is encapsulated in a membrane (not shown) that is selectively permeable (by means of size exclusion, charge exclusion, or permeable selectivity) to the analyte of interest, the membrane density will increase to as the analyte propagates in it. This allows more light to pass out of the detector body and cause less light to strike the photosensitive elements. In other words, with the increase in analyte concentration, the level of internal reflection will decrease, and this decrease can be measured and correlated with the concentration of local analyte. It should be noted that some biological materials such as proteins, hormones, etc., do not dissolve in water and therefore do not penetrate the membrane. However, glucose, salts, and other small molecular weight compounds, are the primary metabolic analytes that will propagate into the membrane and therefore are the analytes that a refractive-based sensor can use most effectively to measure them. In the most basic mode of a refractive-based sensor, a surrounding membrane will not need to be used. Said basic modality can be used where only material variable in concentration is the analyte of interest. For example, as the wine or champagne ages, the sugar content decreases, as does the density and hence the refractive index of the fluid. Therefore, a sensor in accordance with this aspect of the invention can be placed in a champagne bottle or wine barrel while it is processed and used to measure the sugar content as wine or champagne is aged. Other potential applications are to determine the level of the liquid inside a container or determine the amount of moisture in the fuel oil. Finally, although specific embodiments of various aspects of the invention have been described above, it will be appreciated that those skilled in the art make numerous modifications and variations of these modalities. Said modifications and variations must be within the scope of the following claims.

ADDITIONAL MODALITIES OF THE INVENTION In other embodiments of the invention, a sensor is provided which includes: (a) at least one indicator channel for detecting analytes that operates as described above; and (b) at least one additional channel that serves as an optical reference channel. The optical reference channel preferably: (a) measures one or more optical characteristics of the indicator molecule (i.e., the indicator molecule of the indicator channel for analyte detection) that is unaffected or generally affected by the presence or concentration of the analyte; and / or (b) measures one or more optical characteristics of a second control indicator molecule that is unaffected or generally affected by the presence or concentration of the analyte. The optical reference channel can operate, for example, generally as the indicator channel. In the present application, reporter molecules that are unaffected or generally affected by the presence or concentration of an analyte are broadly referred to herein as control indicator molecules. The optical reference channel can be used, for example, to compensate or correct: (1) changes or deviations in the operations of the component intrinsic to the manufacture of the sensor; and / or (2) environmental conditions external to the sensor. For example, the optical reference channel can be used to compensate for or correct internal variables induced by, among other things: wear of the radiation source of the sensor; changes that affect the performance or sensitivity of a photosensitive element thereof; deterioration or alteration of the indicator molecules; changes in the radiation transmission of the detector body, or of the indicator matrix layer, etc., changes in other sensor components; etc. In other examples, the optical reference channel may also be used to compensate for or correct environmental factors (eg, factors external to the sensor) that may affect the optical characteristics or apparent optical characteristics of the indicator molecules in relation to the presence or concentration of the analyte. In this regard, exemplary external factors may include, among other things: the temperature level; the pH level; the present ambient light; the reflectivity or turbidity of the medium to which the sensor is applied; etc. In the following description, similar reference numbers refer to the parts similar to the previously described embodiments, and all the alternatives and variations described herein above with respect to said similar parts may also be employed in any of the following embodiments where be appropriate Since a variety of methods can be used to obtain separate indicator channels and reference channel readings, a number of exemplary methods are discussed in the following paragraphs. These and other methods may be employed in any of the embodiments described herein below and will be apparent based on this disclosure. First, an indicator membrane (e.g., such as membrane 14 'described below) can include reporter molecules that are sensitive to a particular analyte, such as fluorescent indicator molecules that are sensitive to oxygen, and that are contained within of the material that is permeable to the analyte while a reference membrane (eg, such as membrane 14"described below) can include the same reporter molecules within a material that is not permeable to the analyte. for example, the indicator membrane may have an oxygen permeable matrix that contains the indicator molecules such that oxygen freely passes through and contacts the indicator molecules (in one example, silicon rubber may be used for the indicator membrane, which is very permeable to oxygen.) As a result, variations in values obtained in the reference channel should not be attributed to substantially to the presence or concentration of the analyte (e.g., oxygen), unlike how it was described above, for example (1) intrinsic variables to the sensor itself or (2) external environmental factors. Materials that are not substantially permeable to an analyte (ie for the reference channel) may include, for example: a) materials that substantially prevent the penetration of elements (see as an example, US Patent No. 3,612,866, which described below, where the reference channel is coated with varnish); and b) permeable selective membranes, wherein the control indicator molecules are located within a matrix that is selectively permeable so as to allow certain elements to pass while blocking other elements such as the particular analyte (as an example, the matrix may allow them to pass through). negatively charged molecules while blocking positively charged molecules). Second, the reporter membrane may include reporter molecules that are sensitive to particular analytes, such as, for example, fluorescent reporter molecules that are sensitive to glucose, and that are contained within a material that is permeable to the analyte while the membrane Reference may also include a material that is permeable to the analyte, but does not include the same indicator molecules, but, however, the control indicator molecules are, in essence, substantially imperceptible to the analyte. For example, when the analyte is glucose and said glucose is in a liquid (such as, for example, body fluids such as blood, serum, tissue interstitial fluid, etc., or other fluids), placing the control indicator molecules within of a material that is not permeable to said glucose will have an additional effect of blocking other factors such as changes in pH, etc., so that the first example described above is not desirable. Also, in the second basic method, the analyte is allowed to penetrate, however, the selected control indicator molecules in the reference channel are chosen to be substantially imperceptible to the analyte. As a result, the variations measured by the reference channel should not be substantially attributable to changes in the presence or concentration of that analyte. Some illustrative, non-limiting examples of control indicator molecules that are substantially imperceptible to an analyte can be made in the following manner. First, reference is made to the patent application of E.U.A. Serial No. 09 / 265,979, issued March 11, 1999, entitled "Detection of Analyzes by Fluorescent Lanthanide Metal Chelate Complexes Containing Substituted Ligands," which is also owned by the attorney-in-fact hereof, the entire disclosure of which is incorporated herein by reference (and which is a continuation in part of the application serial No. 09 / 037,960, issued March 11, 1998, the full description of which is also incorporated herein by reference), which describes a recognition element, for example boronic acid, HO-B-OH, which is used to facilitate the binding in glucose. It is contemplated that, as in some examples, control indicator molecules that are substantially "bound" to glucose, for example, can be made by omitting or altering said recognition element. In particular, the '960 application describes reporter molecules with a fluorescent lanthanide metal chelate complex having the formula: M (-Ch (-Rx))? wherein: M represents a lanthanide metal ion; Ch represents a chelator comprising a ligand, preferably an organic ligand which may comprise one or more of a β-diketone or a nitrogen analogue thereof, a dihydroxyl, a carboxyl which coordinates a heterocycle, an enol, a microbicyclic cryptan say, a box type ligand), a phenylphosphonic acid, or a polyamino-polycarboxylic acid. The organic Ch ligand may also comprise one or more of a nitrogen, sulfur, and intercalated carboxyl heterocycle. The organic ligand of Ch may also comprise one or more of an alkane or alkene group, preferably containing from 1 to 10 carbon atoms, as well as aromatic, carbocyclic or heterocyclic portions, including benzyl, naphthyl, anthryl, phenanthryl, or tetracyl groups . In addition, one or more chelators that complex with M can be the same or a mixture of different chelators ("mixed ligand or ternary chelates" so-called). R represents a specific analyte recognition element, one or more of which is linked to one or more ligands of a chelate complex, but does not need to be attached to each ligand of the chelate complex. In a preferred embodiment, R can be a boronate group or a boronate group-containing compound for detecting glucose or other cis-diol compounds. X represents the number of recognition elements R attached to each or more of the chelators. X can be an integer from 0 to 8 and in certain preferred embodiments of the invention, X = 0 to 4 or X = 0 to 2. Additionally the number of recognition elements R attached to each or more chelators can be the same or different , either for one or more chelators, X >; 0. Y represents the number of chelators that have complexed with M, and can be an integer from 1 to 4. In certain preferred embodiments of the invention Y = 1, Y = 3 or Y = 4. Also, in these illustrative cases, to make control indicator molecules that are substantially bound to the analyte, the recognition element R may be omitted or altered as previously described by those skilled in the art. Third, another method for obtaining a separate indicator channel and reference channel reading involves using an indicator molecule having an isosbestic point at a particular frequency wavelength (e.g., at 440 nm in the non-limiting example that is showed in the illustrative purposes in figure 21). An "isosbestic point" implies a point (i.e., substantially a particular wavelength) where the absorption, for example, is the same with respect to the presence or concentration of an analyte. That is, where a radiation source emits radiation, for example, light according to the frequency scale, the absorbance of light at certain frequencies will vary based on the presence or concentration of the analyte, but the absorbance of light at the isosbestic point will remain substantially constant with respect to said presence of the analyte or concentration. Also, in this third example, the indicator and reference channels will include indicator molecules that have a specific isosbestic point (for example, the same indicator molecules can be used in each channel). The indicator channel may include a filter (e.g., see filter 34 mentioned above) on a photosensitive element (e.g., a photodetector) 20-1 mentioned below, allowing light outside the isosbestic point to be detected by the photosensitive element (for example, around 500 nm in Figure 21). On the other hand, the reference channel will include a filter (e.g., 34 which is presented below) on a photosensitive element (e.g., a photodetector) 20-2 mentioned below, allowing light substantially at wavelength Isosbéstic penetrate and be detected by the photosensitive element 20-2. As a result, any variation detected in the reference channel should be largely related to the presence or concentration of the analyte and can be used as a reference as described hereinabove. Other indicator molecules having said isosbestic point can be used based on the particular application. Some examples are presented here, see among other known sources: (a) M. Uttamial, ef al., A Fiber-Optic Carbon Dioxide Sensor for Fermentation Monitorinq, BIOTECHNOLOGY, Vol. 19, pp. 597-601 (June 1995) (which discloses hydroxypyrenetrisulfonic acid (HPTS) (and also seminaftorhodafluor (SNARF)) for the detection of CO2) whose full disclosure is incorporated herein by reference; (b) A. Mills, ef al., Flourescence Plástic Thin-film Sensor for Carbon Dioxide, ANALYST, Vol. 118, p. 839-843 O'ulio, 1993) (Department of Chemistry, Swansea University, Singleton Park, Swansea UK) (HPTS indicators for CO2 detection are described) whose full description is incorporated herein by reference; (c) US patent. No. 5,137,833 (which shows a glucose indicator with an isosbestic point at about 440 nm, see, for example, patent figure 10 '833 reproduced herein in Figure 21) the entire disclosure of which is incorporated herein by reference. When the indicator molecules having a water point are used, since the number of radiation sources (e.g. LED) may vary depending on the circumstances, then it is preferable to use a plurality of radiation sources (e.g., LED) in certain cases. For example, sometimes a source of radiation (for example, an LED) may not provide sufficient illumination at wavelengths around the isosbestic point so that it is desired to include an additional LED to provide sufficient illumination at said wavelengths. The reference channels and indicator channels of the present invention may use materials as described herein and as is known in the art depending on the particular application. Many examples are known in the art for using reference or control during the detection of analytes. For example, the patent of E.U.A. No. 3,612,866, the entire disclosure of which is incorporated herein by reference, discloses the fluorescent oxygen detector having a reference channel containing the same chemical compound of the indicator as the measuring channel, except that the reference channel is coated with varnish instead of being impermeable to oxygen. The patents of E.U.A. Nos. 4,861, 727 and 5,190,729, the total descriptions of which are incorporated herein by reference, describe oxygen sensors that employ two chemical indicators based on different lanthanides that mimic two different wavelengths, a terbium-based indicator that is It is followed by oxygen and a europium-based indicator that is not greatly affected by oxygen. The patent of E.U.A. No. 5,094,959, the entire disclosure of which is incorporated herein by reference, discloses an oxygen detector in which the individual reporter molecule is irradiated at a certain wavelength and the fluorescence emitted by the molecule is measured on two emission spectra that have two different sensitivities to oxygen. Specifically, the emission spectrum that is less sensitive to oxygen is used as a reference to the ratio of the two emission intensities. The patents of E.U.A. Nos. 5,462,880 and 5,728,422, the disclosures of which are hereby incorporated by reference in their entirety, describe a radiometric fluorescence oxygen detection method employing a reference molecule that is not substantially affected by oxygen and has a similar photodecomposition rate to the indicator molecule. Additionally, Muller, B., ef al., ANALYST, vol. 121, pp. 339-343 (March 1996), the entire description of which is incorporated herein by reference, describes a fluorescence sensor for dissolved CO2, in which a blue LED light source is directed through a fiber optic coupler to a channel indicator and a separate reference photodetector that detects changes in the LED light intensity.

Also in the patent of E.U.A. No. 4,580, .059, the entire disclosure of which is incorporated herein by reference, discloses a fluorescent light based sensor containing a reference light which measures the cell 33 to measure changes in the intensity of the excitation of the source of light, for example, column 10, lines 1, et seq. In addition, the patent of E.U.A. No. 4,617,277, the entire disclosure of which is incorporated herein by reference, discloses an absorbance-based sensor for carbon monoxide, in which a reference element 12 reflects light from a source 14 to a reference photocell to determine when an element of measurement 10 needs a replacement due to the irreversible heat change. Although a number of embodiments described herein are described in relation to the use of fluorescent reporter molecules, it should be understood based on this disclosure that these disclosed embodiments may be modified to use any type of reporter molecules or combinations thereof depending on the circumstances particular. For example, membranes 14 'and 14"(described below) both may include light-absorbing indicator molecules, such as those described hereinbefore.As another example, in some circumstances, it may also be possible to use molecules fluorescent indicators in one of the indicators or membranes of reference 14 'or 14"while using indicator molecules that absorb light in the other indicator or reference membrane 14' or 14", in most cases, however, the membranes Indicators and reference 14 'and 14"will use both similar reporter molecules, such as those described herein. In addition to the above, a variety of control methods can be employed. For example, in other embodiments, the control channel may use materials or substances that are not completely related to the indicator molecules in the indicator channel. In this regard, for example, the reference membrane substance may have desirable characteristics relative to one or more, from some examples, reflectivity, temperature, pH, and / or various factors. Notably, in certain embodiments, the reference membrane may have "chemistry" that does not correspond, but may, for example, be used to monitor the reflection (this can be used, for example, to evaluate whether an LED goes dark or if, for example , the surface of the membrane was affected in some way). It is contemplated that one or more reference channels may be incorporated in any of the modalities described in this application. A variety of preferred embodiments of sensors incorporating reference indicators are discussed herein below. Although some of the alternatives and variations in the following embodiments are described below, similar reference numbers refer to the parts similar to the embodiments described previously, and all alternatives and variations described hereinbefore in relation to said parts. Similar can also be used in any of the following modalities where appropriate.

Figures 14 (A) -14 (B) illustrate a first embodiment of a sensor 10 incorporating an optical reference channel. As shown, the sensor 10 preferably includes: a detector body 12; an indicator membrane 14 'having fluorescent indicator molecules distributed across the membrane; a reference membrane 14"having fluorescent control indicator molecules distributed across the membrane, a radiation source 18, such as for example an individual LED similar to that described hereinabove, a channel-sensitive light element 20-1 indicator, made, for example, similar to the photosensitive element 20 described hereinbefore, a photosensitive element of similar reference channel 20-2; a circuit substrate 70 (schematically shown with exemplary circuit elements 70i mounted thereon); an energy source 40, such as, for example, a spiral of induction energy as shown; and a transmitter 42 such as for example a transmitter coil as shown. In any of the embodiments described herein, the membranes 14 'and 14"may be made, for example, with materials similar to any of the embodiments of the matrix layer 14 discussed above or may comprise any of the appropriate materials within which indicator molecules can be contained or in which indicator molecules can be coated.Membranes 14 'and 14"(and / or sensor group) can also include, if desired, a similar sensor / tissue interface layer. to any of the modalities of layer 36, as discussed above. This illustrated embodiment may also include additional elements, such as those shown for example: a filter 34 (for example, to exclude a wavelength or a spectrum of wavelengths of light by an LED, for example blue, and allow the passage of a wavelength or a spectrum of wavelengths of light emitted by the fluorescent material, such as red); a reflector 130 (for example, to inhibit "crosstalk" of light radiated from the indicator channel and the reference channel); a notch 35 surrounding the opening to each of the photosensitive elements; and / or a temperature sensor 64 (for example, as described above). In operation, the sensor 12 can operate similar to that described above with reference to the modes shown in Figures 1-13. However, two separate detection readings are obtained to cover: a) an indicator reading (through the channel including an indicator membrane 14 'and the photosensitive element 20-1); and b) a reference reading (through the channel including the reference membrane 14"and the photosensitive element 20-2) .Then, the reference reading can be used, for example to provide more accurate sensor readings. The example of the device shown in FIGS. 14 (A) -14 (B) is as follows: First, the energy source 40 causes the radiation emitter 18, for example an LED, to emit radiation. of the sensor and reaches both the indicator membrane 14 'and the reference membrane 14"(as generally shown with arrows). Then, the molecules within their respective membranes increase their activity, for example by florescence, and light is radiated from them (as also shown with arrows) and it is received by the respective photosensitive elements 20-1 and 20-2 . This operation is essentially as described with reference to the modalities described hereinabove and is not repeated for this reason. In order to eliminate or reduce "crosstalk" between the light emitted by the membranes 14 'and 14", a reflector 130 may also be included. The reflector is preferably impervious to the reaction which could affect the photosensitive elements for example, painted black In this way, for example, a single source of radiation, for example, an LED, can be used for both "channels." Although the device can be manufactured in a variety of ways by those skilled in the art based on As an example, an exemplary method for making the device shown in Figures 14 (A) -14 (B) can be as follows: Initially, a ceramic alumina substrate, which can be easily manufactured by a large number of distributors, can be provided for the circuit substrate 70. In addition, inductors may be provided, for example, as the power source 40 and the transmitter 42. The inductors and separate components can be electrically connected to the substrate. to, using for example welding paste or conductive epoxy commonly obtainable. further, other electronic components may be added thereto, using for example a conductive epoxy, such as a preferred example ABLEDOND 84 from Ablestick Electronic Materials. Components can be wired to complete circuit connections. Silicon photo diodes, such as for example part No. 150-20-002 of Advanced Photonics, are preferably provided, preferably as photosensitive elements 20-1 and 20-2, and are preferably mounted with cantilever chip using spherical connections and conductive epoxy. In addition, the edges of the apertures of the photosensitive element in the substrate are preferably masked with a black, non-transparent and non-conductive material, such as for example E320 from Epoxy Technology, Inc. An optical filter material is preferably placed, such as example, LP-595 of CVI Laser Corp., in the photo diode apertures (e.g., apertures cut within the substrate 70) for light from the radiation source and / or attenuate ambient light. The radiation source used can be, for example, LED that emits light in the blue or ultra-violet bands. Then, this circuit structure is preferably molded as an optically transparent oxidant. The encapsulant can serve as a waveguide and can also provide environmental protection for the circuit system. Then, the indicator and the reference reflective membranes can be connected into cavities in the capsule (for example, inside the depressions at the periphery of the capsule). This connection can be made by molding, for example, cavities in the capsule and again by placing the sensor membranes thereon or by placing the indicator membranes in the mold before encapsulation, so that cavities are formed around the membranes during the encapsulation. As indicated, this is only a preferred method of construction and can be constructed in a variety of ways. In addition, while the embodiments used herein have only two channels (eg, an indicator channel and a reference channel), other embodiments could contain multiple reference and / or multiple reference channels. It is contemplated that the structure illustrated in Figures 14 (A) -14 (B) can be modified in a variety of ways. For example, as shown in Fig. 14 (C), the device can be modified, so that the circuit board 70 is fixed with a flexible circuit (e.g., a cable) as shown, for example through wires or electrical contacts 71. This allows, for example, that the circuit system extends from the body of the capsule or the like (only a portion thereof is shown in Figure 14 (C), such as for example: a) transmit power to the sensor from an external power source; b) transmit sensor signals with an external sector; and / or c) for other purposes, as another example, as shown in Figure 14 (C), it is not necessary to completely encapsulate the circuitry within the sensor. In this respect, the sensor 10 may include, for example, as shown, an outer cover 3 'of an encapsulating waveguide portion 12' formed in, for example, the polished region, with cross stripes, between the elements photosensitive and the indicator and reference membranes. Although less preferred, the interior of the sensor 10 could include a cavity for the circuit system having a gas such as for example air or even a liquid or other medium through which light can be propagated, for example photons of lengths of desired wave. Preferably, the waveguide material having a refractive index that matches or is close to the refractive index of the indicator material and the reference membranes is provided in order to ensure propagation of the light of the membranes for the element photosensitive. In an exemplary and non-limiting construction, the waveguide portion 12 'of a PMMA material (ie, polymethyl methacrylate) can be made, the circuit board 70 can be made with a ceramic material, the reference coating 14" may contain Ru (ruthenium) in an expoxy, the indicator liner 14"may contain Ru in silicone, the reflector 130 may be made with a black epoxy material, the radiation source 18 may be an LED, and the outer shell may be made 3 'with a glass material. Figure 14 (D) is a perspective view of a sensor 10 similar to that shown in Figure 14 (C), with similar numbers indicating similar parts. Figures 14 (E) and 14 (F) show cross-sections across the width and along the modality shown in Figure 14 (D) with the device inserted in a medium B (e.g., liquid, gas, etc.) . As shown in Figure 14 (F), flexible circuit or cable 70 'can be made to extend from an outer surface of medium B to a remote power source, receiver or other device (not shown) as discussed previously. As shown in Figures 14 (E) and 14 (F), the detector body 123 may include an encapsulating waveguide material as described above, or an encapsulating waveguide material may be in a region 12 '. as shown in Figure 14 (C) or, although less preferred, another substance can be used as described above. Figures 15 (A) -15 (B) show a further embodiment of the invention which is similar to that shown in Figures 14 (A) - 14 (B), in which the radiation source 18 is provided as two sources of separate radiation, for example LED, 18-1 and 18-2 which are supported on a 18 m frame. As shown, the LED 18-1 is directed towards the indicator window 14 ', while the LED 18-2 is directed towards the reference window 14. "As shown, a reflector 130 is preferably included once more, that case between the LEDs Since multiple radiation sources are used, for example LED, in this mode, the radiation sources, for example LED 18-1 and 18-2, can be the same, for example emitting the same light, or they may be different depending on the circumstances In embodiments in which a plurality of radiation sources, for example LED, are used, certain considerations are preferably raised: When the radiation source is used, for example LED, aging or other factors in However, when plural sources of radiation are used (for example, for each channel), the differences in the radiation sources can create some discrepancies between the two channels. Therefore, in such cases, it is desirable: a) to take measures to provide similar radiation sources (eg, LED) for each channel; and / or b) calibrate the radiation sources (eg, LED) to each other. For example, when the LEDs are formed of silicon platelets that are cut into LED chips (typically rectangular flat platelets having diameters of approximately 7.62-20.32 cm which are cut into a set of tiny LED chips), they are preferably selected the LEDs of the adjacent LEDs within the rectangular tile or preferably within a small distance from one another in the set) for example within about 1.27 cm, or more preferably within about 0.635 cm, or more preferably within about 0.317 cm, or more preferably within about 0.159 cm) to be cut from the platelet. In this way, the qualities of the selected LED integrated circuits should more likely be analogous to each other. In addition, if plural integrated circuits are used which have mismatches between them, calibrations preferably of standardization between the LED integrated circuits are conducted, and known test conditions to determine any discrepancies. It should be understood, as described herein, in some cases, the provision of a plurality of radiation sources (eg, LED) may have certain advantages, as some examples: a) a plurality of sources may facilitate illumination in desired locations; and / or b) one or the other state of a plurality of sources can be alternated, in some cases, to reduce crosstalk between the channels, as discussed below. The device shown in Figures 15 (A) -15 (B) can be used, for example, in the same manner as the device shown in Figures 14 (A) -14 (B). Learn to further reduce the "crosstalk" between the light emitted from the membranes 14 'and 14", instead of or in addition to a reflector 130, you can also name 2 radiation sources, for example LED 18-1 and 18-2 , so as to alternate the emissions between the respective LEDs, for example, LED 18-1 can be activated for a fraction of a second, LED 18-2 can be activated for a fraction of a second, etc. ., with one LED remaining disconnected for a short interval while the other is connected, thus, crosstalk can be substantially reduced.In another alternative, the device can be adapted to provide a time delay between the readings for the indicator channel and the reference channel (for example, the indicator membrane may have a delay of one second peak, while the reference membrane may have a delay of one nanosecond, or vice versa, so that separate channel readings can be made, to temporary differences in radiation emissions). Although Figure 15 (B) shows the LEDs with each of the central axes at angles? and approximately 25 degrees from the generally horizontal upper surface of substrate 70, these angles can be flexed as desired and can vary, only as some examples, between about 0 and 90 degrees depending on the circumstances. In preferred modalities, for example, the angles? they are about 60 degrees or less, or alternatively about 25 degrees or less. It is contemplated that the structure illustrated in Figures 15 (A) -15 (B) may be modified in a variety of ways, similarly to the embodiment shown in Figures 14 (A) -14 (B). For example, Figure 15 (C) illustrates that modifications may also be made as shown in Figure 14 (C), such as: (a) by including a flexible circuit (e.g., a cable) as shown, such as through conductors and electrical contacts 71; (b) providing the sensor either of a fully encapsulated interior, or of a largely encapsulated interior or a portion of encapsulating waveguides 12 'formed therein; (c) etc. In an exemplary and non-limiting construction, a waveguide portion 12 'of a PMMA encapsulating material can be made, a circuit terrain 70 can be made with a ceramic FR4 circuit board, a radiation source can include two LEDs, a mount 18m can be a mount Cu LED (copper) and an outer cover 3 'can be made with glass material. In a preferred embodiment, as shown, a low index layer 12 'is also provided on the filters 34 above photosensitive elements 20-1 and 20-2. Once, the device can be constructed in a manner based on this arrangement and the former is only one of many exemplary constructions.

As shown in Figure 15 (B), the indicator membrane 14 'and the reference membrane 14"can be formed within a cavity or the like on the surface of the body 12. Alternatively, the membranes 14' and 14"on the surface of the body 12 and not within a cavity or the like. The use of a cavity or the like, however, may come to protect the membranes 14 'and 14"in use and / or prevent them from buckling outwardly from the face of the body (for example, the elimination of the buckles may facilitate the handling , such as if the sensor is inserted into a patient through a trocar tube or the like.) As described above, the sensor 10 may also include a sensor / tissue interface layer 36 on it or partially on it (and / or on membranes 14 'and 14"), made for example with biocompatible materials, for example such as any materials described herein. Figures 16 (A) -16 (B) show an additional mode of dimension that is similar to that shown in Figures 15 (A) -15 (B), in which the radiation source 18 is provided as two sources of radiation separate, for example LED 18-1 and 18-2 which are supported on frames 18m1 and 18m2 on opposite sides of circuit board 70, respectively. As shown, the LED 18-1 is directed towards the indicator window 14 ', while the LRD 18-2 is directed towards the reference membrane 14. In this way, for example, a circuit terrain 70 can operate previously as a reflector to reduce or eliminate crosstalk.As with the modalities shown in Figures 15 (A) -15 (C), the angle? can be selected as desired and is preferably between about 0 and 90 degrees - and is in some preferred embodiments less than about 45 degrees A device shown in Figures 16 (A) -16 (B) may be used, for example, in the same manner as the device shown in Figures 15 (A) -15 (B). In addition, the mode shown in FIGS. 16 (A) -16 (B) can also be modified in each of the same ways as described above with respect to the embodiment shown in FIGS. 15 (A) -15 (B) As shown, the upper and lower surfaces of the substrate 70 also include pre preferably hidden areas 35 as shown. The radiation sources 18-1 and 18.2 are preferably located within these hidden regions 35. In the embodiment shown in FIGS. 16 (A) -16 (B), the photosensitive elements 20-1 and 20-2 are mounted on the same side of the circuit board 70 as the respective membranes 14 'and 14", while in the preceding examples, the boards 70 had cut regions through which radiation, for example light, passed to the photosensitive elements. shown in Figures 16 (A) -16 (B) a filter material 34 is preferably provided above its photosensitive elements rather than within such cuts It should be understood that the various examples herein may be modified depending on the Circumstances by those skilled in the art on the basis of this disclosure As an example, the photosensitive elements of the above embodiments could be mounted above the boards 70 in a manner similar to that shown in FIG. Figure 16 (B) (for example, on one side of the board). Figures 17 (A) -17 (F) illustrate additional modalities of multiple channel sensors that are made with: (a) an inner capsule containing the photosensitive elements, etc; and (b) an outer sleeve having sensing membranes. With reference to Figure 17 (A), a sensor 10 having electronic components within a capsule 3 'is shown. The capsule is preferably made of glass, but can be made of any suitable material as described below. The capsule can also be made of biocompatible materials if desired. As another example, a soda and lime glass capsule material such as that of the Electronic Animal Identification Capsules of Detron-Fearing Company of St. Paul may also be used., MN. Preferably, the capsule is hermetically sealed. As shown, a sleeve S is preferably located around the outer surface of the glass capsule. The sleeve S preferably contains an indicator membrane 14 'and a reference membrane 14"(for example, fluorescent membranes for detecting, for example glucose, etc.) The electronic circuit system can be as used in any of the described modalities Hereinafter, of a preferred construction, the electronic circuitry includes: components to facilitate the induction of power to the device; an excitation light source for the fluorochrome; means for detecting light; and means for signal transduction through radio frequency (RF) or inductive or passive telemetry to an external vector. As with the preferred embodiments described hereinabove, in an exemplary construction the entire sensor 10 is configured to be implanted subcutaneously under the skin of a patient. The components for facilitating the induction of energy to the device preferably include an inductor winding 40 which will generate the voltage and current necessary to supply the energy of the circuit from an external magnetic field generator. The inductor winding 40 can be mounted, for example, on a ceramic circuit 70 ground or at the end of the circuit board (as shown). Alternatively, inductor windings can be used in multiple locations in various orientations, so that they are better coupled with the external magnetic field generator. The radiation sources, for example LED, 18-1 and 18-2 are preferably mounted on the substrate 70 appropriately to stimulate the indicator membranes 14 'and 14"(e.g., areas of fluorochrome) with light photons (as shown). with the arrows A1) As described hereinabove, the photons of light preferably stimulate the membranes 14 'and 14"in order to emit fluorescence (as shown by the arrows A2), which is detected by the photosensitive elements 20- 1 and 20-2, respectively. In addition, other components may include an IC amplifier 70A and various passive components 70B to provide amplification and modulation circuits to transduce the intensity of the photosensitive elements on the telemetry windings. A preferred method of constructing the device is, for example only, as follows. First, an electronic circuit is placed inside the glass tube 3 'which initially opens at the left end E. Preferably, the glass is borosilicate glass, such as in a N51A type 1 borosilicate glass made by Kimble Glass. (A wide variety of glasses and other materials may be used in other modalities). After the electronic circuit is placed inside the glass tube 3", it is brought inside partially with waveguide material 12 'encapsulating at the level indicated by the dashed lines at 12 L. As described hereinabove, a Encapsulating waveguide material can help, for example, optically coupling light A-1 to membrane surfaces 14 'and 14"and optically coupling fluorescent signals A-2 back to photosensitive elements 20-1 and 20 -2. Any suitable optically suitable waveguide materials described hereinabove or known in the art can be used. As mentioned above, the encapsulating wave material could also be applied through the entire interior of the glass tube 3", or in less preferred embodiments, the glass tube could be filled entirely with air or other substance such as waveguides. In some preferred embodiments, the waveguide material may include one or more of the following materials: silicone; GE RTV 615; PMMA; an optical adhesive, such as NORLAND 63. The capsule is then sealed 3"preferably at the end E to enclose the capsule. Preferably, the capsule is a glass capsule that is flame-sealed at the E-end to provide a smooth rounded end and provide a watertight seal. Preferably, before sealing the capsule, the electronic device is treated to remove moisture. For example, the device can be baked (eg, at about 75 ° C or more for about 12 hours) and can be placed in a nitrogen atmosphere to expel any residual moisture from the device and its components. Then, you can supply the power and test the assembled device, if desired, to evaluate its operating capacity before proceeding to the next assembly step-for example, the step of applying the detector membranes. In an exemplary construction, especially for in vivo use, the length / shown in Fig. 17 (A) may be about 10-15 mm in length and more preferably about 12.5 mm in length, while the width h may be about 2-3 mm wide and more preferably about 2.5 mm wide. In other preferred embodiments, the sensor may be substantially smaller - see, for example, the preferred size ranges described hereinabove (eg, from about 500 microns to about 1.27 cm in length, etc.). It should be evident, however, that the invention can be manufactured in any size and shape depending on the circumstances. An advantage of this embodiment is that the sensing membranes 14 'and 14"can be constructed in a separate piece that is placed, for example, slid, over the sensor capsule 3" following the assembly procedure described above. In this way, the manufacturing steps of the membranes of the electronics and encapsulation manufacturing steps can advantageously be separated. In a preferred embodiment, the sleeve S can be made from a plastic material, (for example, it can preferably be made from polyethylene and most preferably from a medical grade polyethylene) (for example, UHMWPE) ultra high molecular weight polyethylene)). The sleeve can be made of any suitable material depending on the circumstances and the particular use of the sensor. For example, when the in vivo sensor is used, the sleeve may be constructed of biocompatible materials - some additional preferred, non-limiting examples of biocompatible materials include polypropylene, PMMA, polyolefins, polysulfones, ceramics, hydrogels, silicone rubbers and glass. The sleeve S is preferably an injection molded plastic sleeve, dimensioned in such a way that the internal diameter of the sleeve can be precisely adjusted on the capsule. When assembled on the capsule, the sleeve S preferably has sufficient elasticity to allow a tight mechanical fit, so that it will not easily detach from the capsule 3. The sleeve S is preferably formed of holes, cells or cavities H to accommodate the indicator membranes 14 'and 14"(for example, to mechanically trap the membranes). For example, molded H cells can be easily inserted into the sleeve. Figures 19 (A) -19 (I) demonstrate a variety of exposures of the holes, etc., H over several sleeves S that can be used in various modalities. Notably, the sleeve S can be configured in such a way that when it is mounted on the capsule 3", the holes, etc., can be sufficiently aligned with the respective photosensitive elements 20-1 and 20-2 The device shown in the figures 17 (A) -17 (B) preferably has a sleeve constructed as shown in Figure 19 (E) -for example, the holes H having an oval shape disposed substantially on the surface of the photosensitive elements.Alternatively, although less preferred as discussed above, the indicator membranes could be formed on the peripheral surface of the sleeve (for example, in order to protrude outwardly therefrom) without such cells for the sleeve.) Another advantage of using an outer sleeve S is that the materials (for example, those discussed above) that can be used for the same, may have surfaces of medical class so that the subcutaneous tissue is attached to them, which can advantageously helping to prevent movement and migration of the device within a patent, in vivo, when the sensor is of the implanted type within a person (or within another animal). further, the natural dividing lines and the roughness of the edges of such molded sleeve can also help to prevent such movement and migration. The prevention of movement or migration after implantation can be very important in some modalities - for example, so that windings of inducing energy and telemetry can be maintained in the optimal alignment between the implanted device of an external reader. In other alternative constructions, the sleeve S could also be extruded in the form of a tube (for example, to a cylinder as shown in Figure 19 (1), discussed below) and could be applied to the capsule with compression fit . In addition, the sleeve S could also be formed as a tube that shrinks by heat on the capsule 3. "The membrane cells H could also be formed thereon by molding, cutting, laser-machining or laser-drilling. some designs, thousands of small holes H can be manufactured with laser machines in the side wall of the sleeve S. Another advantage of using the membrane sleeve S is the ability to protect the indicator and reference membranes during manufacture, handling, storage and, very importantly, during injection through a trocar into the subcutaneous tissue, as has to be done in some preferred modalities.Mechanical forces and movement, while implanting the sensor through a metal trocar, can damage the outside of the device, if the surface is not adequately protected.

Although a variety of S-sleeves of exemplary membranes, various other materials, sizes, locations, geometric designs, fabrication methods, etc. have been described. of membrane could be employed by those skilled in the art in view of the aforementioned. Again, the arrangement of the parts within the sensor can also be varied by those skilled in the art. For example, Figures 17 (C) -17 (D) show a second embodiment similar to the embodiment shown in Figures 17 (A) -17 (B) with the indicator membrane 14 'and the reference membrane 14"thereof. side of the circuit board 70 and with a single source of radiation, for example LED, 18 - similar to the embodiments shown in figures 14 (A) -14 (C) All the applicable variations described above with respect to figures 14 (A) -14 (C) to Figures 17 (A) -17 (B) could be applied to the modality shown in Figures 17 (C) -17 (B) As another example, Figures 17 (E) -17 (F) show another embodiment similar to the embodiment shown in FIGS. 17 (A) -17 (C) with the indicator membrane 14 'and the reference membrane 14"on the same side of the circuit board 70, but with two radiation sources, for example LED, 18-1 to 18-2 similar to the embodiments shown in Figures 15 (A) -15 (C), but with the LED spaced further apart in the illustrated example. All the applicable variations described above with respect to Figures 15 (A) -15 (C) and Figures 17 (A) -17 (C) could be applied to the embodiment shown in Figure 17 (C) -17 (D ). Although the embodiments described hereinabove included an indicator channel and a reference channel, as indicated above, the various embodiments described hereinabove may be modified, by including a plurality of indicator membranes (e.g., measuring equal or different properties). ) and / or a plurality of reference membranes (e.g., by measuring identical or different optical properties). Furthermore, it is indicated that principles related to the production of a sensor 10 having a two-part construction as shown in FIGS. 17 (A) -17 (F), could also be sent within a basic sensor as described hereinabove that does not use such a reference channel- for example, Figures 18 (A) -18 (B) illustrate a modality with a single photosensitive element 20 and a single source 18 that can be used to obtain a sensory reading as is described above with reference to Figures 1-13 without a reading of the reference channel. Although Figure 18 (A) -18 (B) was described without reference indication, it is indicated that a device having a single source and / or a single photosensitive element could still be used to provide separate indicator and reference readings in some modalities, such as for example: a) a single LED can alternate emissions at different frequencies to alternate the readings of the indicator and reference channel; b) in cases where the indicator membrane and the reference membrane have different frequency characteristics of the radiation emission, they could be adapted to a filter on the photosensitive element to alternate the passage of such different frequencies to the photosensitive elements; c) in cases where the indicator membrane and the reference membrane have different time characteristics of the radiation emission, they could be adapted to the device to provide a time-delayed reading for the indicator channel and the reference channel (e.g. , the indicator channel could have a delay and a picosecond while the reference channel has a delay of one to a second or vice versa); d) etc. As described above, Figures 19 (A) -19 (I) show some examples of alternative designs of sleeve S and cell H. It is indicated that the devices shown in Figures 17 (C) -17 (F) preferably include a sleeve S as illustrated in figure 19 (E), configured in such a way that the cells H can be easily aligned on the respective photosensitive elements. In addition, the design of the sleeve could be as shown in Figure 19 (1) in which the sleeve S is formed with a tube that is open at both ends and that can be slid over the capsule. In addition, an embodiment of sleeves S (e.g., each containing a respective membrane) could also be employed, as shown in Figure 19 (A) where two sleeves S can be fitted over opposite ends of the capsule . In embodiments such as those shown in Figs. 19 (D), 19 (G) and 19 (H), where bags are provided around the perimeter of the sleeve S, the sleeve can be applied over the capsule without having to orient the sleeve and the capsule in certain embodiments with the photosensitive elements on one side of a board in the circuit 70 (for example, when two channels are used, the cells towards their left side of the sleeve may contain reference membranes, while the cells on the side right may contain indicator membranes). Again, these are merely exemplary designs and those skilled in the art could make a variety of other sleeve and / or cell designs. Figure 19 (J) still shows another embodiment of the invention wherein the sleeve S is made with an outer annular flange F. The annular flange F is preferably formed so as to extend naturally (e.g., un-turned state) ) laterally outward from the sensor side as shown. Preferably, the flange F is made of absorbable or biodegradable material. The modality shown in Figure 90 (J) can be used, for example, in applications where vibration is to be avoided. For example, even when the connective tissue is expected to hold the sensor in place over time, this modality can facilitate maintenance of proper positioning even before the ingrowth of the connective tissue. That is, the annular flange can help prevent movement of the sensor within a medium in which it is applied or inserted (such as within a patient). In a highly preferred embodiment, the flange is flexible and capable of being clouded (e.g., to a position shown in dashed lines of Figure 19 (J) after insertion in the direction of arrow A to trocar tube TT) of Such a way that the sensor can be inserted to a patient. Then, after inserting the sensor 10 to a patient through the trocar tube and then removing the trocar tube TT, the flange F will revert to its original shape (or substantially recover that shape) and facilitate the maintenance of the sensor in its own position inserted. As indicated, the flange F is probably made of an absorbable or biodegradable material, such that after a certain time the flange F is degraded - for example, so that it can be: a) easily removed; b) keeping in place by other means (for example, such as inward capillary growth as described hereinabove); and / or c) for other reasons. In alternative embodiments, a flange embodiment F may be provided. In other alternative embodiments, the flange F may extend only partially around the circumference of the sensor (as it is completely opposed annularly around). The sleeve F shown in Figure 19 (J) preferably includes the respective indicator and control indicator molecules (e.g., within the membranes of cells H) as described hereinabove. However, it is contemplated that an annular F-flange could be provided around a sensor in any of the embodiments set forth herein, even if such a sleeve S is not included. With respect to this, one or more flanges F could be fixed ( for example, preferably biodegradable) to the outside of any of the sensors described herein for similar functions and purposes.

Although the annular flange F is shown to be generally planar (e.g., with a generally rectangular cross-section) the flange F could also have other shapes in cross-section - for example, a band of structure material (preferably biodegradable) could be wrapped around it. of the sensor. Although the flange F is preferably capable of bending inwardly and outwardly as shown, in certain embodiments the flange or the band could also be made without such capabilities. It is contemplated that the construction of the particular sensor (and especially the particular locations of the indicator membrane 14 'and the reference membrane 14"on the sensor) can be selected partly on the particular environment within which the sensor is used. , the indicator molecules (ie, in the indicator membrane) and the control indicator molecules (ie, in the reference membrane) should be exposed to substantially the same environment (i.e., the environment containing the analyte which Therefore, the membrane locations on the sensor will depend in part on the methods of use, as some examples: a) if a sensor with its vertical longitudinal axis is placed in a solution in which an attribute that can vary is being tested based on the depth within the solution (for example, inside a bottle of wine, etc.) It may be desirable to use, for example, one of the sensor instructions shown in Figures 16-17 in which the photosensitive elements are in similar axial positions, but on opposite sides of the sensor, so that the membranes 14 'and 14"may be arranged at similar vertical elevations; whereas b) a sensor was made to be used, for example, subcutaneously with its axis generally parallel to the skin of the patient, it may be desirable to use, for example, one of the sensors shown in FIGS. 14 (A) or 15 (A ). Among other factors, it should be understood that the sizes and locations of the membranes 14 'and 14"(and the H cells containing such membranes) will also depend in part on the mission field of the radiation sources, eg LEDs, selected. Figures 20 (A) -20 (B) show another embodiment which is similar to the embodiment shown in Figures 17 (C) -17 (D) except that the sleeve S is replaced by a removable film F. As shown , the film F includes the indicator membrane 14 'and the reference membrane 154"thereon. As with the sleeve S, the membranes 14 'and 14"are preferably formed inside cells, but, although less preferred, the windows could also be formed on the film surface.The film F can be made of some types of materials that the sleeve S as described above The film F is preferably removably fixable on the capsule by means of the tack or adhesiveness of the material of the film itself or by means of an adhesive which does not appreciably affect the transmission of the radiation (for example , an adhesive could be applied as used for POST-IT ™ notes manufactured by 3M Corporation, between the F film and the 3"capsule). The film F is preferably sized, as shown, to be large enough to support the indicator membrane 14 'and the reference membrane 14"at their appropriate locations on the capsule 3". As shown, for removing the film F, for example, the corner C could be pulled and the film F could be removed in a manner similar to the removal of a BAND-AID ™ adhesive bandage from a person's skin. One could also modify the other various embodiments shown hereinabove, so that a film F is included as a myth S. In addition, although a rectangular film member F is shown, the film can be constructed in other configurations and shapes depending on the existing circumstances. further, plural films F could be used, such as for example including separate films for the reference and indicator membranes. Thus, the embodiment shown in Figs. 20 (A) -20 (B) and the various alternatives thereof can have a variety of benefits similar to that obtainable with embodiments using a removable S-sleeve as described hereinbefore. . Figures 22 (A) -22 (C) show another embodiment of the invention in which a protective sleeve S 'is formed around the body 12. In this embodiment, the sleeve S' is constructed to provide protection against external light. Two problems associated with the sensors, such as with fluorescent glucose sensors, involve light different from that emitted by the radiation source 18. A light source is from environmental sources such as sunlight and artificial lighting. Light of sufficient intensity can potentially saturate the sensor, rendering it unusable for detecting fluorescent light. In addition, most artificial light sources have a significant CA component (variable in time); Although filtering techniques can be employed to attenuate this source of noise, it can significantly degrade the signal obtained. Another source of parasitic light is the fluorescent emission of materials outside the sensor, the latter problem being particularly difficult in the sense that in general the resulting signal can not be filtered electronically from the fluorescence of the indicator. The mode shown in Figures 22 (A) -22 (C) can be used to substantially eliminate those effects of outside light interference. In a preferred construction, the sleeve S 'is formed of a layer of substantially optically opaque, substantially non-reflective material, containing a plurality of small holes H extending therethrough of outer surface to the membranes 14' and 14 '. In an exemplary embodiment, the sleeve S 'may be made by a black Teflon tube which is shrunk by heat, for example, on the body 12. However, the sleeve S' may be formed of any suitable material. Holes H are preferably formed at an angle that is transverse, and preferably substantially orthogonal, to the respective light preparation directions RL of the radiation source to the membranes 14 'and 14"(for example, see angles? i and? 2). The diameter of each orifice H is preferably sufficiently small to substantially prevent light from passing directly from the radiation source 18 leaving the sensor and this preferably varies sufficiently large to allow analyte diffusion, or penetration into the membranes. 'and 14.' The number of holes H is preferably selected to allow relatively unrestricted diffusion of the analyte to the membranes, so although a pruning of ambient light AL, see FIG. 22 (C), can enter the sensor through of the holes H, the penetration of the ambient light through it must be greatly attenuated.Figure 22 (D) shows another alternative embodiment, in which a 3"inner glass capsule is used inside a capsule 3 '" of outer glass (other modalities could use an outer glass sleeve) with an indicator membrane 14 'and a reference membrane 14"between the two capsules and with machine holes h laser through the anterior capsule to allow analyte migration (eg, glucose) to the indicator membrane 14 '. It should be apparent from this disclosure that other internal components were included (e.g., similar to those shown in Figures 16 (A) -16 (B)) and, thus, no such components are described or shown in more detail with reference. to figure 22 (D). Figures 23 (A) -23 (C) show yet another embodiment of the invention in which a single LED 18 is used to excite both the indicator molecules in the indicator membrane 14 'and the control indicator molecules in the membrane of reference 14 '.

Typically, LEDs (e.g., LED integrated circuits) are made by growing crystalline layers of 18-S semiconductor material (e.g., epitaxy) on an 18-S substrate material. The LED integrated circuits can be made very small-for example, the entire thickness of the semiconductor layers can be less than about 10 μm, or even less than about 5 μm, or even thinner. Typically the substrate on which the semiconductor layers are formed is substantially thicker-for example, greater than about 50 μm, or even greater than about 100 μm, or even thicker. LEDs are traditionally used to emit light from the upper side 18-A of the LED opposite the surface on which the LED integrated circuit is mounted (eg, a reflective cup surface). As shown schematically in Figure 23 (D), an LED integrated circuit 18 is typically placed within an 18-RC reflecting cup that guarantees the transmission of light in the upward direction UD. In Figure 23 (D), one or two small wires 18-W are typically connected to the upper surface 18-A of the integrated circuit 18 (for example, through gold contacts). In addition, the substrate 18-S is typically substantially transparent in such a way that the light transmitted by the semiconductor material is internally reflected inside the substrate and reflected out of the 18-RC reflector, preventing transmission through the bottom of the LED 18-B. Indeed, it has generally been considered in the art that LED integrated circuits are only for the emission of light in an outward direction from the upper surface 18-A of the LED integrated circuit. The present inventors have found, however, that an integrated LED circuit 18 can be made to emit light efficiently from both the upper side 18-A and the lower side 18-B of the integrated LED circuit. In a preferred embodiment, as shown in Figs. 23 (A) -23 (C), the integrated LED circuit 18 is formed on a substantially transparent substrate (appropriately transparent substrate materials may include, for example, sapphire, carbide of silicon and other suitable material) which is mounted transversely to the upper surface of the circuit board 70 (for example on an 18-m frame as shown) (preferably, the upper and lower surfaces 18-A and 18-B of LED they are generally arranged to maximize the illumination of the indicator and reference channel and / or to maximize the internal illumination of the detector body). Preferably, a mask 34 is also included to inhibit crosstalk between the indicator channel and the reference channel. In this way, a single LED can be effectively used to illuminate both a display membrane 14 'and a reference membrane 14. "Figure 24 (D) is an illustrative example of a lighting field of a known LED when it is conventionally mounted. On a non-transparent flat surface, the angles of 0 degrees and 180 degrees are parallel to the upper surface of the flat LED integrated circuit while the 90 degree angle is perpendicular to it. side of the LED integrated circuit - that is, on the upper side 18-A In contrast, Figure 24 (A) illustrates an example of illumination that can be achieved through both the upper and lower sides, 18-A and 18- b, of an integrated circuit of LED 18. In Figure 24 (A), the right side of the figure of 0 degrees at 90 degrees represents the light transmitted through the lower part 18-B of the LED, while the side left of the figure of 0 degrees at -90 degrees represents the light transmitted through the upper side 18-A of the LED. Thus, as shown in this example, a large amount of light can actually be emitted from the lower side 18-B of the LED. In this illustrative case, a larger amount of light is actually emitted from the underside 18-B of the LED, which may be due, for example, to the presence of wires, electrical contacts (for example, one or more gold contacts are typically applied on the part top of an integrated LED circuit 18), or other materials on top of the upper side of the LED integrated circuit. The measurements shown in Figure 24 (A) were obtained using a gonometric analyzer and LED-1100 ™ model made by Labsphere, of North Sutton, N.H. The LED used in Figure 24 (A) was an LED # NSHU550E ™ by Nichia Chemical Industries, LTD, Tokyo, Japan. The LED used in Figure 24 (B) was a C470-9 ™ LED from Cree Research, Inc., of Durham, N.C.

In these embodiments in which light is radiated both what is typically considered to be the upper side 18-A and the lower side 18-B of the integrated LED circuit to excite both the indicator and the control indicator molecules with a single LED, preferably a sufficient amount of light is transmitted both above and below the LED to sufficiently illuminate both channels. Preferably, the amount of light transmitted from one side is about 6 times or less, the amount of light transmitted from the other side, or more preferably about 4 times or less, or more preferably about 2 times or less, and in more preferred embodiments about same. However, the amount of light radiated up and down the LED can vary significantly depending on the circumstances. Figure 25 (A) -25 (A) shows a sensor 10 according to another embodiment having: a) a detector body with a peripheral cavity 12C machined around a circumference of the sensor body containing an indicator membrane 14; b) a substrate 70 with a hole or window 70H below a radiation source (e.g., an LED) 18; and c) an optical reflector D with a generally triangular cross-section extending around the circumference of the sensor body. This embodiment is otherwise as shown in Figures 14 (A) -14 (B). The electrical components and others (not shown) are like those described hereinabove and, thus, need not be described in more detail with respect to Figures 26 (A) -25 (B).

In the embodiment shown in FIGS. 25 (A) -25 (B), the radiation source 18 emits radiation through its upper and lower sides 18-A and 18-B, as in the embodiments described above. The radiation L, as shown by the arrows, is reflected inside the detector body, as in the modalities described above. As shown, the radiation emitted through the window or orifice 70H is reflected within the detector body in such a way that radiation from the upper and lower sides of the radiation source is used for detection. As shown, the detector body 12 preferably includes a radiation reflector D located such that the radiation emitted generally vertically (ie above the top side or below the bottom side) of the radiation source is reflected laterally for better distribution and internal reflection and / or to ensure that the radiation is directed to outer regions of the indicator membrane. Although the modality shown in Figures 25 (A) -25 (B) includes both the indicator and control channels, it should be understood by those skilled in the art based on this disclosure that the control channel can be eliminated in other modalities and / or that any modifications described herein with respect to other embodiments may also be applied, to the embodiment shown in Figures 25 (A) -25 (C) where appropriate. Figure 26 shows another embodiment of a sensor 10 having a substantially optically transparent circuit substrate 70. The essentially optically transparent circuit substrate 70 allows the radiation to pass through the substrate 70. This facilitates the penetration of both the radiation and, in the non-limiting example a fluorescent indicator, the emission radiation through the entire detector body. 12, making it possible for more radiation to be received by the photosensitive members. As a result, the detection area in the light can be increased (for example, by picking up signals on the upper and lower sides of the photosensitive elements) to substantially intensify the detection of signals. Preferably, the radiation source 18 is mounted on the substrate 70 in such a manner that the radiation is also emitted from the underside of the radiation source. The embodiment shown in Figure 26 can thus be generally similar to that shown in Figures 23 (A) -23 (C) with respect to the radiation that is emitted from the upper and lower sides of the radiation source 18. Alternatively, the radiation could only be transmitted from one of the upper or lower sides. The radiation source preferably includes an LED that is optically coupled to the optical substrate 70 (such as for example with an optical epoxy) to guide the excitation light to the substrate. The optically transparent substrate 70 can be made, for example, of sapphire, quartz, silicon carbide, GaN or other inorganic substrate materials that can mimic metallization. Alternatively, organic polymeric materials may be used to make the substrate. Any substantially translucent material that can support the manufacture of printed or etched electronic circuits can be used for this application. Other suitable materials apparent to those skilled in the art may also be used, based on this disclosure. In an exemplary but not limiting construction, the substrate 70 is made of quartz. Several vendors offer quartz substrates because such substrates are advantageous in other unrelated applications in the telecommunications industry, such as in high frequency applications. For example, MIC Technologies ™ (Aeroflex Company, 797 Turnpike St. MA 01845) offers the manufacture of quartz substrates as an option of circuit substrates. The substantially optically transparent substrate can then be used, with methods well known in the art, to join parts using a common hybrid method of circuit collection (e.g. conductive epoxy, solder, wire adhesion, non-conductive epoxy, etc.) . Once all the parts have been joined, the entire circuit can be immersed, for example, in a monomer solution and a polymer reaction can then be initiated using for example heat or regression, so that a circuit can be formed which is boxed, enclosed and sealed within a waveguide polymer (e.g., PMMA) (i.e. as described hereinabove). As indicated above, the embodiment shown in FIG. 16 preferably includes photosensitive elements that can detect directed radiation at its upper and lower sides. Typically, the photosensitive elements can detect only radiation directed to their upper sides. In a preferred construction, the photosensitive elements include photoresistors.

A photoresistor is usually manufactured by a simple chemical deposition procedure that puts a photosensitive chemical substance into a circuit. When the photons make contact with the surface of deposited material, a change in the resistance occurs and the circuit thus varies its resistance as a function of the intensity of the incident light. Typically, photoresist is deposited on opaque substrates such as ceramics. This causes the resulting photoresistor device to be sensitive only in one direction because light can not penetrate the opaque substrate from the underside (i.e., the side adjacent to the substrate). In common applications of photoresistors, this "unidirectional" construction is suitable in preferred embodiments of the present invention, however, both the excitation and emission light is scattered throughout the device. Two notable objects in preferred embodiments of the invention are to maximize the amount of light from the excitation source that is incident on the indicator membranes and to maximize the amount of fluorescent signal light that is captured by the photosensitive elements. Contrary to these objectives, opaque circuit substrates (such as those made of ceramic, polyimides, fiberglass, etc.) can prevent a substantial amount of light from propagating through the entire device and, thus, reduce the general sensitivity of the sensor. On the other hand, the modality illustrated in Figure 26 can greatly promote these two objectives.

By depositing the sensing material on a substantially key substrate, the substrate can function as a capture waveguide with larger area and can thus bring, for example, additional fluorescent signal light to the photosensitive element. In addition, by mounting the radiation source, e.g., LED, on a substantially clear substrate, substantially all of the radiation, e.g., light, radiated from the excitation source, can propagate more evenly throughout the device and is directed , thus, more uniformly and with higher energy efficiency, to the indicator membrane. The embodiment illustrated in FIG. 26 is not, of course, limited to photoresistors, but other photosensitive elements, such as, for example, photodiodes, transistors, darlingtons, etc., may be used where appropriate. When radiation is received on both sides of the photosensitive elements, high-pass filters 34A and 34B are preferably provided above and below photosensitive elements 20-1 and 20-2 in order to separate, for example, radiation excitation radiation. of fluorescent emission. A high-pass filter can be installed on both sides of the photosensitive elements, for example applying a filter epoxy, such as the CVI Laser obtainable, and others described above with respect to the legality shown in Figure 1. Instead and in addition of using filters 34A and 34B, the photosensitive elements can be made of materials that can be adapted, for example, adjusted, to be sensitive to particular wavelengths. The photosensitive elements could thus be adjusted to substantially detect for example fluorescent emission radiation rather than excitation radiation from the radiation source. In this regard, the photoresistive detectors may be chemically adjusted to be substantially responsive to a specific wavelength, thus reducing or eliminating the need for a separate filter element. The appropriate materials are easily obtainable commercially. Known devices are produced and sold for example by Silonex Inc. ™, (2150 Ward Ave, Montreal, Quebec, Canada, H4M 1T7) in which the peak wavelength sensitivity is adjusted and optimized based on varying ratios of dopants and ratios. mixed within a base of cadmium sulfide (and others). Although it was discussed with reference to the modality of figure 26, the "adjustable" photosensitive elements described herein may also advantageously be incorporated into any of the embodiments described herein in other embodiments of the invention. The embodiment shown in Figure 26 preferably operates as the embodiments described hereinabove. To avoid unnecessary repetition, the elements of the sensor shown in Figure 26, for example, electronic components etc, are not shown and / or described in connection with this embodiment. It is contemplated that the embodiment shown in Figure 26 may be modified by those skilled in the art in the same manner as any of the other embodiments described herein where appropriate. Figures 27 (A) -27 (C) show another embodiment of a sensor 1000 with an internal heater. In the illustrated example, the sensor 1000 is not necessarily required to include a circuit substrate embedded entirely within a waveguide, capsule or the like. It is contemplated, however, that a heater of this embodiment may be employed in any of the embodiments described herein, or in any other appropriate sensor housing. In the illustrated example, the sensor 1000 has a construction similar to the integrated circuit with a generally rectangular configuration with connectors 1110 extending therefrom. The connectors can be used to provide power, signals, etc. to the sensor and / or it. The embodiment illustrated in Figures 27 (A) -27 (C) incorporates several unique design features that have particular advantages, for example in the detection and measurement of analytes in humidified gases. In a preferred, but not limiting example, the illustrated device is used as an oxygen detector. Some exemplary applications include, but are not limited to, the measurement of breath-by-breath oxygen during respiration of humans or animals - for example, in which the sensor is exposed to cold / dry air during inhalation and to warm breathing / wet during exhalation. The illustrated model can be precisely measured, for example the oxygen content during all phases of variation of water vapor temperature (humidity). Although the example illustrated for the measurement of oxygen is preferably used, other examples can be used to measure other analytes - for example, sensitive membranes could be used for the measurement of carbon dioxide, another gas or various gases. In summary, in the illustrated example, the sensor 1000 includes a cover 1200 having an upper wall 1210 with an opening 1220 and four dependent side walls 1230. The lower part of the cover is configured to fit over the top of a substrate 700 to form a box-like envelope. As shown, the substrate 700 has photosensitive elements 20-1 and 20-2, a radiation source 18 and other electronic components (not shown) and a heating element 1400 mounted thereon. In the illustrated embodiment, the heating element 1400 extends over the photosensitive elements 20-1 and 20-1. The heating element has cut openings 1410 to allow the radiation from the source 18 to pass to the membranes 14-1 and 14-2 which are preferably located above the heating element. As shown, the membranes are preferably exposed through an orifice 1220 in the cover 1200. The entire R region between the heating element, the sensor membranes and the substrate preferably contains a waveguide material as in the embodiments described above. at the moment.

The heating element 1400 can be made of any suitable material (for example, heat conducting materials, such as for example copper alloys, other heat conductive metals or the like.) The heating element 1400 can be made of any material that thongs Suitable thermal properties In order to heat the heating element 1400, the substrate 700 preferably includes a plurality of heat generators 710 (eg, heater resistors or semiconductor resistors) thereon which transfer heat to the heating element. illustrated, but not limiting mode, four heater resistors 710b are used.The heat generators 710 are preferably located adjacent (eg, making contact or sufficiently close) to the sides of the heating element 1400 to transfer heat thereto. heating element 1400 serves for example for the following two pro tanks: 1) maintain the signal and reference membrane 14-1 and 14-2 substantially in the same thermal equilibrium, and / or 2) heat the membranes 14-1 and 14-2 to a temperature that is above the point of dew of humidified gases to be measured. In the example of human respiratory monitoring this temperature value may for example be slightly above about 37 ° C. In an exemplary construction, the invention employs a thermal set point of about 40 ° C through the use of heat resistors 710 and a feedback thermistor 711. In an exemplary construction, the heat resistors 710 include four surface mount resistors. of 390 ohm 1/2 W that are in parallel. In alternative embodiments, other numbers of heating generators 710 and / or other types of heating generators 710 (such as sifted resistors, thick film resistors, heating tape, etc.) may be employed. In addition, alternative modes may use other forms of temperature control. Notable methods of temperature control use one or more thermistors, thermocouples, RTD and / or other solid-state temperature measuring devices for temperature control. Preferred embodiments, however, use a thermistor 711 in view of the lower costs. One notable advantage of heating membrane surfaces is the prevention of moisture condensation on the sensor surface. When a condensation layer is formed, the condensation layer can cause diffusion and optical aberrations on the surface of the sensor, which substantially reduces the accuracy of the measurement when, for example, a measurement based on fluorescence amplitude modes is used. The condensation layer can also reduce the gaseous response time of the sensor because the mass diffusion properties on the sensor surface can be altered. It should be noted that by measuring the time or phase delay properties of the fluorochrome, the accuracy of the sensor can be improved because the measurement is not substantially affected by the amplitude variation. However, the degradation of the response time is not mitigated because it is based on the diffusion on the surface of the sensor. This embodiment can also provide other notable advantages that are particularly beneficial for use for example in the preferred, but non-limiting, modalities, such as an oxygen detector, as well as in other applications. In particular, a significant advantage of this embodiment (and in other embodiments also described herein) is the ability of the sensor to respond extremely rapidly to a gradual change of critical respiratory gases such as oxygen and CO2. With this modality, response speeds of 100 milliseconds or greater (some up to 30-40 milliseconds) can be achieved, making it possible an almost real time determination of the respiratory gas content (here: the response time is defined as the time required for the sensor performance to change from 10% to 90% of the steady state level with the application of a gradual change of The partial pressure of the gas in question The ability of this modality to observe and measure for example substantially waveforms and oxygen levels of inhaled and exhaled gases has significant medical utility.You can use a respiratory gas sensor with this rapid characteristic of answer, and connection with flow or volume measuring devices to determine the absorption and release of respiratory gases, making it possible to measure critical medical parameters, such as metabolic rate (caloric consumption), indirect cardiac output based on the principle of Fick (first described in theory by Adolph Fick in 1870), lung function and shock attack. Many of these medical diagnostic determinations require the measurement of partial pressure breathing gases at the exact end of an exhalation (known as final periodic p02 levels or final periodic pCO2). Since the amount of time between the end of a normal exhalation and the inhalation of the next breath is extremely short, a faster response sensor may be important to determine final periodic levels that have not already been affected by fresh air inhalation. the next next breath. In addition to having a sensor with response time high enough to change the gas concentration, the sensor must have the ability to compensate equally rapidly changes in temperature and humidity levels in inspired and expired gases. In the preferred embodiments, this has been achieved by the use of a reference channel, as illustrated. The present invention is also advantageous because it makes it possible to perform medical diagnostic procedures in a non-invasive manner and without the need for expensive analytical instruments that are otherwise commonly used to be similar determinations with the common technique. Figures 28 (A) and 28 (B) illustrate the actual test data of a gradual change of the partial pressure of a gas in an exemplary construction of the embodiment of Figures 27 (A) -27 (C). In particular, Figures 28 (A) and 28 (B) represent actual response time determinations employing a construction of this embodiment for use in the non-limiting example oxygen detector. Figure 18A is a measurement of the response time of the sensor to a gradual change from ambient air (approximately 21% oxygen) to 100% oxygen that was supplied from a cylinder of certified compressed gas (reference is made to the response time of a sensor of a lower to higher analyte concentration as "recovery time"). Figure 28 (B) is a measurement of the response time of the same sensor to a gradual change of 100% nitrogen supplied from a cylinder to ambient air. The recovery and response times were, in these illustrative but not limiting examples, of approximately 41.2 and 32.1 mii-seconds (as shown), respectively, as determined with a Tektronix two-channel oscilloscope model TDS ™. Preferably, the recovery and response times are below about 100 milliseconds and more preferably below about 80 milliseconds and even more preferably below about 60 milliseconds. Preferred embodiments have a range of about 40 to 80 milliseconds. In operation, the sensor 1000 operates as the two-channel modes described hereinabove. In this embodiment, however, the heat generators 710 impart heat to the heating element 1400 which at the same time acts as an extender to distribute the heat within the sensor and within the membranes 14-1 and 14-2. The cover 1200 is preferably formed of an insulating material, for example, of an elastomer such as plastic or the like. In this way, the cover 1200 can help to conserve heat and maintain a temperature of the membranes. As a result, the heater does not need so intensely or consume so much energy to operate. In the illustrated embodiment, the membranes 14-1 and 14-2 are also preferably recessed below a lower surface of the hole 1220, when assembled as shown in Figure 27 (A), so that the membranes are less likely to be subject to external factors or to be damaged. The cover 1200 may be made, for example, by injection molding or by other suitable means. Cover 1200 is optional and can be removed in some cases. However, the cover is preferred because it can advantageously provide insulating properties for the heating element 1400, making it possible to use a smaller heating element and improved uniformity of heat distribution to the sensing and reference membranes, especially under of rapid thermal changes and / or high flux velocities in the medium in which the analyte is contained. The cover is thus preferably installed on the sensor to assist in the performance of the heating element 1400 and / or to the direct gases on the surfaces of the membranes.

As indicated, the sensor 1000 preferably uses two photosensitive elements 20-1 and 20-2. Preferably, the photosensitive element 20-1 detects fluorescence of oxygen signals from an indicator channel membrane 14-1 and the photosensitive element 20-2 detects a signal from the reference channel membrane 14-2. Preferably, the reference channel membrane 14-2 is not substantially sensitive to oxygen, but is sensitive to temperature substantially to the same degree as the signal channel membrane 14-1. This is a remarkable feature in cases where the device is used to detect oscillatory (inhale / exhale) respiration of a human or other animal, because temperature and water vapor change. With this embodiment, the temperature equilibrium of the indicator and reference channels can be maintained through the heating element 1400. In the illustrated example, each of the membranes 14-1 and 14-2 is preferably made with a substrate of borosilicate glass of substantially equal thickness. Preferably, the membranes 14-1 and 14-2 have similar thermal properties. A preferred matrix for the detection of gaseous or dissolved oxygen or other gases is an inorganic polymer support matrix called sol-gels or ormosiles, to which the indicator molecule is immobilized or trapped. These materials and methods are well known (See for example: McDonagh et al., "Tailoring of Sol-Gel Films for Optical Sensing of Oxygen in Ga or Aqueous Phase", Analytical Chemistry, Vol 70, No. 1, January 1 1998, pp. 45-50; Lev. O. "Organically Modified Sol-Ge! Sensors, Analytical Chemistry, Vol 67, No. 1, January 1, 1995; MacCraith et al.," Development of a LED-based Fiber Optic Oxygen Sensor Using a Sol-Gel Derived Coating ", SPIE, Vol. 2293, pp. 110-120 ('94); Shahriari et al.," Ormosil Thin Films for Chemical Sensing Platforms ", SPIE, Vol. 3105, pp. 50-51 ('97); krihak et al., "Fiber Optic Oxygen Sensors Based on the Sol-Gel Coating Technique", SPIE, Vol. 2836, pp. 105-115 ('96), whose entire exposures they are incorporated herein by reference.) These types of membranes can be applied to the appropriate substrate by a number of procedures that are well known in the art, such as immersion, spreading, application Roller, silk screening, bearing printing, vapor deposition, ink jet printing, etc. These types of membrane can also be advantageously incorporated into any other embodiment of the invention described herein where appropriate. Preferably, each membrane is thus formed with a glass substrate (borosilicate glass) that is coated with a thin film sol-gel matrix coating that uses the same base chemistry in each membrane. Preferably, the reference membrane 14-2 is further processed to block oxygen diffusion. In examples of this mode for the detection of O2, a preferred indicator molecule includes, as an example, a perchlorate molecule of tris (4,7-diphenyl-1, 10-phenanthroline) ruthenium (II), as mentioned in column I, line 17 of the US patent No. 5,517,313, the description of which is incorporated herein in its entirety. It is contemplated that the membranes may include a variety of other materials as set forth hereinbefore in other embodiments of the invention. The radiation source preferably includes an LED (eg, blue) that is mounted so that its light output is guided by a wave to the indicator and reference channel membranes 14-1 and 14-2 through guide material of wave within the R region. In an exemplary embodiment, the waveguide material is Epoxy Technologies 301 ™ which has good optical characteristics although other suitable materials may be used. Preferably, the fluorescent emissions of the membranes are waveguided in a manner similar to the photosensitive elements 20-1 and 20-2 that are mounted on the substrate 700. Preferably, an optical filter 34 is provided for each photosensitive element. In exemplary embodiments, as described above, each optical filter 34 may include a filter epoxy, such as a filter resin available from CVI Laser, with, for example, a 600 nm cut that surrounds the photosensitive elements. Other suitable filters can be employed as discussed hereinabove. The optical filters 34 preferably separate the fluorescent emission from the membrane from the excitation energy of the radiation source 18 (e.g., a blue LED). As it should be understood based on the foregoing, more preferably, the complete optical path (e.g., between the waveguide material in the R region and the membranes 14-1 and 14-2, etc.) is a refractive index matched so that maximum light capture occurs with minimal internal reflection. While FIGS. 27 (A) and 27 (B) show the excitation source located centrally between the photosensitive elements 20-1 and 20-2 and the indicator and the reference membranes 14-1 and 14-2, the source of excitation 18 may otherwise be localized, while providing adequate excitation to the indicator and reference membranes 14-1 and 14-2. As with other embodiments described herein, it is contemplated that the embodiment shown in Figures 27 (A) -27 (B) may be modified in a variety of ways. For example, a heating element can be provided in the modes where a control channel is not used. Furthermore, as noted, an internal heater can be applied within a variety of sensor constructions to reduce condensation on a periphery of a sensor, especially in sensing membranes or the like. In addition, other embodiments may include other known heating methods. For example, heating coils, wires or the like may be distributed within the sensor, preferably at least partially adjacent the position of the indicator membranes. As indicated above, although the specific embodiments of the invention have been described, numerous modifications and variations of these modalities can be made by those skilled in the art. For example, aspects of various modalities described herein may be applied in advance or interchanged with other modalities described above as will be apparent to those skilled in the art based on this description.; for example, various embodiments may be adapted to have one or more of the indicator molecules described hereinabove (or otherwise known) and may be adapted to use any of the control reference methods described herein (or that are known differently). As another example, it should be understood that various modifications of electronic devices, etc. can be made by those skilled in the art based on this description, such as, for example, several components can be incorporated into an IC integrated circuit or other modifications can be employed. or known techniques as one or more aspects of this invention are maintained. Further, where the sensors are energized by and / or communicate with an external device, the external device may be made in a variety of ways depending on the circumstances, for example, the external device may include: a case mounted on the wrist ( for example, similar to a watch) that can be used in conjunction with a sensor implanted next to a patient's wrist; a case mounted on the belt or trousers (for example, similar to a common "beeper" locator) that can be used together with an implanted sensor next to the patient's hip or waist; a cover that has internal electronic components (for example, similar to an electric cover) in which an individual can lie down with an implanted device near the cover, for example, to obtain easy reading while the patient sleeps; any structure that the sensor can locate near or approach and / or any structure that can approach the sensor; or a variety of other structures and designs. In addition, as described hereinabove, sensors of various modalities can be used in a variety of applications and environments, for example, in any environment that has to detect one or more analytes. For example, various embodiments may be employed within various means, including, gases (e.g., air and / or any other gas), liquids, solids, combinations thereof. In addition, various embodiments described herein can be easily employed in various applications and in various industries, such as, for example: in the medical industry (for example, where the sensors can be inserted internally into a patient or animal); in the food industry (for example, such as where the sensors can be inserted into liquids (for example: beverages, such as alcoholic beverages, for example, wine, beer, etc., and non-alcoholic beverages, and other liquids); creams, solids, etc.); the consumer products industry (for example, where said detection capabilities are appropriate); and in other industries as described hereinbefore and as will be apparent based on this description.

It should also be understood that those skilled in the art can make a variety of applications, modifications and variations within the scope of the following claims.

Claims (76)

NOVELTY OF THE INVENTION CLAIMS

1. - An optical basis sensor for determining the presence or concentration of an analyte in a medium, said sensor comprising: an enclosed detector body having an outer space surrounding said detector body; a source of radiation in said detector body that emits radiation within said detector body; an indicator element having an optical characteristic that is affected by the presence or concentration of an analyte, said indicator element being positioned on said detector body to receive radiation propagating from said radiation source and transmitting radiation to said detector body; a photosensitive element located in said detector body and placed to receive radiation within the detector body and which emits a signal sensitive to the radiation received from said indicator element; and said sensor body being configured in such a way that part of the radiation received by said photosensitive element is reflected internally inside said detector body before striking said photosensitive element.

2. The sensor according to claim 1, further characterized in that the sensor is integrated with a power source contained within said detector body and a transmitter contained within said detector body.

3. - The sensor according to claim 2, further characterized in that at least one of said power source and said transmitter is energized by an external means.

4. The sensor according to claim 2, further characterized in that at least one of said power source and said transmitter includes an inductor.

5. The sensor according to claim 4, further characterized in that said transmitter includes an inductor that generates electromagnetic radiation that is detectable by a signal capture device that is located externally to said detector body and said power source includes an inductor and said radiation source is caused to emit radiation by exposing the sensor to a field of electromagnetic radiation that is generated externally to said detector body.

6. The sensor according to claim 1, further characterized in that the circuit system is completely contained within said sensor without connectors or wires that extend through said peripheral surface of said sensor.

7. The sensor according to claim 1, further characterized in that said radiation source and said photosensitive element are mounted on a circuit substrate that is contained entirely within said detector body.

8. - The sensor according to claim 1, further characterized in that said indicator element includes indicator molecules distributed proximally to the surface of the detector body.

9. The sensor according to claim 8, further characterized in that said indicator molecules are contained within an indicator membrane that is permeable to the analyte to be detected.

10. The sensor according to claim 8, further characterized in that said indicator molecules include fluorescent indicator molecules.

11. The sensor according to claim 10, further characterized in that said indicator molecules have a fluorescence characteristic that is a function of the concentration of the analyte to which said indicator molecules are exposed, said indicator membrane allowing radiation from said source of radiation to interact with said indicator molecules.

12. The sensor according to claim 11, further characterized in that said photosensitive element detects the fluorescent light emitted by said indicator molecules and is configured to provide a response signal indicating a characteristic of such fluorescent light detected and therefore the presence or the concentration of the analyte.

13. - The sensor according to claim 8, further characterized in that the optical characteristics of said indicator molecules vary depending on the concentration of oxygen.

14. The sensor according to claim 8, further characterized in that said indicator molecules include light absorbing indicator molecules.

15. The sensor according to claim 14, further characterized in that said photosensitive element is arranged so as to detect the radiation emitted by said source of radiation and is not absorbed by said indicator molecules, and is configured to provide a response signal indicator of the amount of such radiation absorbed no. detected and therefore the presence or concentration of said analyte.

16. The sensor according to claim 14, further including a filter that allows the radiation emitted by said source and at a wavelength absorbed by said light-absorbing indicator molecules to strike said photosensitive element, and substantially prevents the radiation emitted by said source, and not by a wavelength absorbed by said light absorbing indicator molecules, impinges on said photosensitive element.

17. The sensor according to claim 8, further characterized in that the optical characteristics of said indicator molecules vary depending on the concentration of glucose.

18. - The sensor according to claim 8, further characterized in that said indicator molecules include indicator molecules having an isosbestic point substantially at a particular wavelength and because a reference channel detects light substantially at the isosbestic wavelength.

19. The sensor according to claim 8, further characterized in that said indicator molecules interact with the radiation emitted by said source of radiation by means of evanescent excitation.

20. The sensor according to claim 8, further characterized in that said indicator molecules interact with the radiation emitted by said radiation source by means of excitation of the plasmo resonance type on the surface.

21. The sensor according to claim 8, further characterized in that said indicator molecules interact with the radiation emitted by said radiation source by means of direct illumination.

22. The sensor according to claim 1, further characterized in that said sensor has an oblong rounded shape with which said sensor can be arranged inside the body of an animal.

23. The sensor according to claim 22, further characterized in that said sensor has a total length of about 500 microns to about 12.7 mm and a diameter of about 300 microns to about 7.62 mm.

24. The sensor according to claim 1, further comprising a sensor / tissue interface layer around at least a portion of said detector body.

25. The sensor according to claim 24, further characterized in that said sensor / tissue interface layer retards the formation of fibrotic encapsulation or scar tissue.

26.- The sensor according to claim 24, further characterized in that said sensor / tissue interface layer includes a sublayer that promotes the inward growth of the tissue therein.

27. The sensor according to claim 26, further characterized in that said tissue inward growth comprises vascularization.

28. The sensor according to claim 24, further characterized in that said sensor / tissue interface layer includes a molecular sieve sublayer that performs a molecular weight cutting function.

29. The sensor according to claim 24, further characterized in that said indicator element includes indicator molecules and said sensor / tissue interface layer is selectively permeable so as to allow said analyte to make contact with said indicator molecules., while preventing the cells or macrocells from making contact with said indicator molecules.

30. The sensor according to claim 24, further characterized in that said sensor / tissue interface layer is biocompatible.

31. The sensor according to claim 8, further characterized in that said detector body includes an optically transmitting encapsulating material that encapsulates at least one region between said photosensitive element and said indicator molecules.

32. The sensor according to claim 8, further characterized in that said detector body includes an optically transmitting encapsulating material that encapsulates at least one region between said radiation source and said indicator molecules and said photosensitive element.

33.- The sensor according to claim 8, further characterized in that said detector body includes a capsule shell.

34. The sensor according to claim 8, further characterized in that said indicator molecules are arranged within a layer of matrix applied on the surface of said detector body, said matrix layer being permeable to the analyte and allowing said matrix layer to be the radiation emitted by the radiation source enters the same.

35. - The sensor according to claim 10, which further includes a filter that allows the fluorescent light emitted by said indicator molecules and passing to said detector body to strike said photosensitive element, substantially avoiding said filter that the radiation emitted by said source affects on said photosensitive element.

36.- The sensor according to claim 1, further including a reflection intensification layer disposed on a portion of the surface of said detector body to intensify reflection within said radiation detector body emitted by said source and / or fluorescent light emitted by said indicator molecules and passing to said detector body.

37. The sensor according to claim 1, further characterized in that said source of radiation includes a light emitting diode.

38.- The sensor according to claim 1, further characterized in that said radiation source includes a radioluminescent light source.

39.- The sensor according to claim 8, further characterized in that said indicator molecules include different first and second indicator molecules disposed on the surface of said detector body.

40.- The sensor according to claim 39, further characterized in that said first and second indicator molecules are sensitive in each case to changes in the concentration of the same analyte in said medium.

41. The sensor according to claim 40, further characterized in that said first and second indicator molecules have the same optical characteristic that is affected by the presence or concentration of the analyte.

42. The sensor according to claim 40, further characterized in that said first and second indicator molecules have different optical characteristics that are affected by the presence or concentration of the analyte.

43.- The sensor according to claim 39, further characterized in that said first indicator molecules are sensitive to changes in the concentration of a first analyte in said medium and said second indicator molecules are sensitive to changes in the concentration of one second. analyte in said medium.

44. The sensor according to claim 43, further characterized in that said first and second indicator molecules have the same optical characteristic that is affected by the presence or concentration of the analytes.

The sensor according to claim 43, further characterized in that said first and second indicator molecules have different optical characteristics that are affected by the presence or concentration of the analytes.

46. - The sensor according to claim 8, further characterized in that said indicator molecules include first and second indicator molecules arranged on the surface of said detector body, said first indicator molecules having an optical characteristic that is sensitive to changes in the concentration of a analyte to which said first indicator molecules are exposed and said second indicator molecules having an optical characteristic that is sensitive to changes in the concentration of an analyte to which said second indicator molecules are exposed; said source of radiation includes a source that emits radiation that interacts with said first indicator molecules according to the optical characteristic sensitive to the analyte thereof; said photosensitive element includes the first and second photosensitive elements embedded within said detector body, said first photosensitive element providing a response signal indicating the level of interaction of said first indicator molecules with radiation interacting therewith and consequently indicating the presence or the concentration of the analyte to which said first indicator molecules are exposed, and said second photosensitive element providing a response signal indicating the level of interaction of said second indicator molecules with radiation interacting therewith and consequently indicating the presence or the concentration of the analyte to which said second indicator molecules are exposed

47. - The sensor according to claim 1, further characterized in that said indicator element includes a portion of said detector body on the surface thereof having a refractive index such that the optical characteristic that is affected by the presence or concentration of the analyte involves the amount of radiation that passes from said detector body that varies as a function of the ratio of said refractive index with a refractive index of the medium containing the analyte and therefore as a function of the concentration of said analyte in said medium, reflecting at least part of the radiation that passes from said detector body internally inside said detector body before passing from said detector body.

48. The sensor according to claim 1, further including a reference photosensitive element located in said detector body and positioned to receive radiation that is substantially unaffected by the presence or concentration of the analyte to provide a reading of the reference channel.

49.- The sensor according to claim 48, further characterized in that said indicator element includes indicator molecules disposed within an indicator membrane proximate the periphery of said detector body, said indicator membrane containing indicator molecules that are affected by the presence or concentration of an analyte and placed to receive radiation from said radiation source, and a reference membrane disposed proximate the periphery of said detector body and placed to receive radiation from said radiation source, the reference membrane being substantially unaffected by the presence and concentration of the analyte.

50.- The sensor according to claim 49, further characterized in that said indicator membrane is permeable to the analyte to be detected.

51.- The sensor according to claim 49, further characterized in that said reference membrane is substantially non-permeable to said analyte.

52. The sensor according to claim 49, further characterized in that said perm-selectable reference membrane.

53. The sensor according to claim 49, further characterized in that said reference membrane is permeable to said analyte, but includes control indicator molecules that are substantially not sensitive to said analyte.

54.- The sensor according to claim 49, further characterized in that said reference membrane contains control indicator molecules.

55.- The sensor according to claim 48, further characterized in that it has at least two LEDs as the source of radiation.

56. - The sensor according to claim 48, further characterized in that said source of radiation is a single LED.

57.- The sensor according to claim 49, further characterized in that said radiation source includes an LED that is mounted in such a way that an upper side of the LED is oriented generally towards one of said indicator and reference membranes, and one side lower of the LED is generally oriented towards the other of said indicator and reference membranes, said LED emitting light through both said upper side and said lower side of said LED to sufficiently illuminate both said indicator and reference membranes.

58.- The sensor according to claim 57, further characterized in that said radiation source and said photosensitive element are mounted on a substantially transparent substrate.

59. The sensor according to claim 1, further characterized in that said radiation source includes an LED that is mounted in such a way that said light is emitted from both its upper and lower sides. The sensor according to claim 59, further including an optical reflector having a generally triangular cross-section extending around a circumference of the detector body and positioned to deflect the light emitted from said LED.

61. - The sensor according to claim 59, further characterized in that said LED is mounted on a circuit board having a hole or a window through which the radiation emitted from the underside of the LED passes. 62.- The sensor according to claim 1, further characterized in that said photosensitive element and said source of radiation are mounted on a substantially optically transparent substrate. 63.- The sensor according to claim 62, further characterized in that said photosensitive element detects the radiation incident on its upper and lower sides, the radiation incident on said lower side passing through said essentially optically transparent substrate. 64.- The sensor according to claim 48, further characterized in that said photosensitive element, said reference photosensitive element and said radiation source are mounted on a substantially optically transparent substrate. The sensor according to claim 64, further characterized in that said photosensitive element detects the radiation incident on its upper and lower sides, the radiation incident on said lower side passing through said essentially optically transparent substrate.

66. - The sensor according to claim 1, further including a heater located inside said detector body, said heater being configured to limit the condensation on a periphery of said sensor. 67.- The sensor according to claim 66, further characterized in that said sensor is adapted to provide a sensor response time of less than about 100 milliseconds. 68.- The sensor according to claim 67, further characterized in that said sensor response time is less than about 60 milliseconds. 69.- The sensor according to claim 67, further characterized in that said analyte is oxygen. The sensor according to claim 1, further characterized in that said sensor is adapted to provide a sensor response time of less than about 100 milliseconds. 71.- The sensor according to claim 49, further characterized in that at least one of said membranes is made with a sol-gel or an inorganic polymer support matrix of ormosil. 72.- The sensor according to claim 49, further characterized in that said detector body includes a peripheral sleeve that contains at least one of said indicator membrane and said reference membrane. 73.- The sensor according to claim 8, further characterized in that said detector body includes a peripheral sleeve containing said indicator molecules. The sensor according to claim 73, further characterized in that said sleeve is removable in such a way that said indicator and reference membranes can be removed and replaced. The sensor according to claim 73, further characterized in that said sleeve is made of elastomeric material. 76.- An optical basis sensor for determining the presence or concentration of an analyte in a medium, said medium having a first index of refraction that varies depending on the concentration of said analyte in said medium, said sensor comprising: a body an optically transmitting detector that functions as an optical waveguide, said detector body having a second refractive index and a surface; a radiation source that emits radiation, said radiation source being embedded within said detector body in such a way that the radiation emitted by said source propagates inside said detector body; and a photosensitive element that is sensitive to the radiation emitted by said radiation source, said photosensitive element being embedded within said detector body.; further characterized in that a quantity of radiation emitted by said source passes from said detector body, the amount of radiation passing from said detector body varying according to the ratio of said first and second indices and consequently as a function of the concentration of said analyte in said medium, internally reflecting at least part of the radiation that passes from said detector body, inside said detector body before passing from said detector body; and because the radiation that does not pass from said detector body is detected by said photosensitive element, internally reflecting at least part of the radiation that is not detected by said photosensitive element, inside said detector body before striking said photosensitive element. SUMMARY OF THE INVENTION An optical basis sensor for detecting the presence or quantity of an analyte using both indicator and reference channels; the sensor has a detector body with a radiation source embedded therein; the radiation emitted by the source interacts with the indicator molecules of the indicator membranes, close to the surface of the body; at least one optical characteristic of these indicator molecules varies with the analyte concentration; for example, the fluorescence level of the fluorescent indicator molecules or the amount of light absorbed by the light-absorbing indicator molecules can vary as a function of the analyte concentration; In addition, the radiation emitted by the source interacts with the indicator molecules of the reference membrane near the surface of the body; the radiation (e.g., light) emitted or reflected by these indicator molecules enters and is reflected internally in the detector body; the photosensitive elements within the sensor body generate both the signals from the indicator channel and the reference channel to provide an accurate indication of the concentration of the analyte; the preferred embodiments are totally independent and are sized and shaped for use in vivo in a human being; such embodiments preferably include a source of energy, for example, an inductor that supplies the source of radiation with energy using external means, as well as a transmitter, for example, an inductor, for transmitting to external capture means the signal representing the level of analyte. PM * GC / yro * mmf * jtr * ald * aom * jrg * igp * pbg * eos * yac P01 / 226F