Tissue interface device

A tissue interface device (10) suitable for positioning on or about one or more artificial openings in a biological membrane of an organism and for coupling to a monitor and control unit and a vacuum source. The tissue interface device (10) comprises a housing (100), a sensor channel (130), and a sensor (150). The housing (100) defines an orifice (120), the orifice (120) having an open inlet port (122) on the bottom end (102) of the housing (100) and a distal end (124) that is in fluid communication with the sensor channel (130). The orifice (120) is in fluid communication with fluid that flows from the artificial opening formed in the biological membranes. The sensor channel (130) is for coupling to, and fluid communication therewith, the vacuum source. The sensor (150) is positioned in the sensor channel (130) in a flow path of the fluid for sensing a characteristic of the fluid as it flows out from the artificial opening. The sensor generates a sensor signal representative thereof.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to tissue interface devices, and more particularly to a tissue interface device wherein fluid is extracted from a biological tissue and placed into contact with a sensor for sensing a characteristic of the fluid flowing from an artificial opening in a biological membrane.

2. Background Art

Monitoring systems that sample and measure characteristics of fluids from a biological tissue, such as on a human, are well known. Many of these systems involve implanting sensors and related devices into the organism (such as under the skin) in order to obtain fluid samples and make measurements of those samples. Implanted sensors, in addition to the pain caused to the organism during the implantation of the sensor, degrade rapidly when introduced into the organism. Even for short term implants, it has been shown that within the first several hours after implantation a rapid deposition of fibroblasts, macrophage plaques, fibrogen growth and other natural physiological encapsulation processes surround the implant and thereby impair, restrict, and modify, in a dynamic fashion, the free flow of the analytes of interest into the active sensor region of the implanted device.

Alternatively, fluids may be drawn from the biological membrane of the organism through the use of needle or cannula that penetrate deep into the membrane (such as penetrating deep into the dermis or subcutaneous tissue of a human). The extracted fluid is drawn toward a remote sensor or sensor array for measurement of the desired characteristic. This solution requires a large volume of fluid be drawn before the fluid reaches the sensor. Further, this solution can have detrimental effects on the measurement of a desired current analyte concentration level because of the lag time imposed by the large inherent time delay required for the fluid to reach the sensor from the point of fluid withdrawal. Because of the lag time, approximation techniques must be applied to provide a more time-accurate indication of the current concentration of the desired analyte in the fluid.

SUMMARY OF THE INVENTION

Briefly, according to one aspect, the present invention is directed to a tissue interface device for extracting biological fluid from a biological tissue and for sensing a characteristic of the fluid. The tissue interface device is suitable for positioning on or about the surface of the biological membrane of the biological tissue and is adapted to be removably coupled to a remote monitor and control unit and a vacuum source. The tissue interface device comprises a housing that defines an orifice having an open inlet port on a bottom end of the housing to receive fluid and an opposing distal end. In use, the orifice of the housing is in fluid communication with fluid produced from one or more artificial openings formed in the biological membrane.

The housing also has a sensor channel and a sensor. The sensor channel is in fluid communication with the distal end of the orifice. The sensor is positioned in the sensor channel and in a flow path of the fluid for continuously sensing a characteristic of the fluid as it is produced from the artificial opening, and generates a sensor signal representative thereof.

The present invention involves positioning the sensor ex vivo, proximate the surface of the organism, and coupling the sensor to the organism via the fluid conducting tapered orifice of the housing. Consequently, oxygen (if necessary) to support the sensor reaction is readily available, allowing for a simpler basic array design, higher signal-to-noise ration, faster response, better linear tracking of the physiological changes in an analyte of interest, and longer life of the sensor. By keeping all of the foreign material of the tissue interface device outside of the body, the auto-immune derived encapsulation and rejection responses naturally occurring with any implanted device never begin.

Further, by avoiding actual penetration of the body to insert a sensor, needle, or cannula, a significant disadvantage of the prior art devices and methods is obviated by the tissue interface device of the present invention. Also, risks of infection that are present in the prior art systems are dramatically reduced in connection with the present invention because neither sensor implantation is involved nor a membrane breaching connection to a needle or cannula.

Still further, the tissue interface device of the present invention provides for high interstitial fluid flux rates without causing increased erythema that may prolong skin healing. Additionally, by minimizing the dead volume between the artificial opening in the membrane and the sensor, and hence minimizing the lag time, a further significant disadvantage of the prior art systems and method is obviated by the device of the present invention.

The present invention is useful in a system that performs a single (one time) measurement of an analyte in a biological fluid of an organism from a tissue interface device placed in contact with the biological membrane, as well as in a system that continually monitors an analyte from an organism from such a tissue interface device. Thus, it is contemplated that an analyte in a biological fluid of an organism may be repeatedly assayed at regular and frequent intervals.

The above and other objects and advantages of the present invention will become more readily apparent when reference is made to the following description taken in conjunction with the accompanying drawings.

DETAILED DESCRIPTION OF THE INVENTION

The present invention may be understood more readily by reference to the following figures and their previous and following description, in which like numbers indicate like parts throughout the figures. It is to be understood that this invention is not limited to the specific devices described, as specific device components as such may, of course, vary. It is also understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

As used in this specification and the appended claims, the singular forms “a,”“an” and “the” may mean one or more than one. For example, “a” sensor may mean one sensor or more than one sensor.

Ranges may be expressed herein as from “about” or “approximately” one particular value and/or to “about” or “approximately” another particular value. When such a range is expressed, another embodiment comprises from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment.

As used herein, the term “biological membrane” means the structure separating one area of an organism from another area of the organism, such as a capillary wall, or the outer layer of an organism which separates the organism from its external environment, such as skin, buccal mucosa or other mucous membrane.

As used herein, the term “suction” or “pressure” relates to the relative pressure as compared to the internal pressure of the organism to which the system is interfaced. “Vacuum” is used synonymously with the term “suction.”

As used herein, the term “biological fluid” means blood serum, whole blood, interstitial fluid, lymph fluid, spinal fluid, plasma cerebrospinal fluid, urine, prostatic fluid, bile, pancreatic secretions, or any combination of these fluids. Other fluids that may be harvested from the surface of various tissues include, but are not limited to, fluids selected from the group consisting of mucus, saliva, breast milk, tears, gastric secretions and perspiration.

As used herein, “artificial opening” means any physical breach of the biological membrane of a suitable size for delivering or extraction fluid therethrough, including micropores.

As used herein, “poration,” “microporation,” or any such similar term means the artificial formation of a small hole, opening or pore to a desired depth in or through a biological membrane, such as skin or mucous membrane, or the outer layer of an organism to lessen the barrier properties of this biological membrane to the passage of biological fluids, such as analytes from within the biological membrane or the passage of permeants or drugs from without the biological membrane into the body for selected purposes, or for certain medical or surgical procedures. The size of the hole or “micropore” so formed is approximately 1000 micrometers in diameter.

As used herein, “monitor and control unit” means a device or devices suitable for being coupled to the tissue interface device of the present invention. The monitor and control unit includes means of receiving a sensor signal from the tissue interface device indicative of a characteristic of fluid flowing from an artificial opening in the biological membrane and deriving a measurement of a characteristic of the fluid. The monitor and control unit may also supply and/or control a vacuum source for coupling to the tissue interface device. The monitor and control unit may comprise a unified system (such as a single unit) or may be separate systems (such as a monitor and a control unit) interconnected as known in the art. The monitor and control unit may be designed for one time, i.e., discrete use, or may be designed to be placed in contact with the tissue for longer periods of time, e.g., hours, days or weeks, for periodic, continual or continuous analyte monitoring. An example of a monitor and control unit is disclosed in commonly assigned International Application No. PCT/US99/16378, entitled “System and Method for Continuous Analyte Monitoring,” filed Jul. 20, 1999, which is incorporated herein by reference.

The term “continuously” or “continually” means acting on an ongoing basis at a frequency or event rate that may vary depending on a particular application. For example, the output of the sensor may be read on a periodic basis, such as every minute, several minutes, hour, several hours, etc. Moreover, at each reading event, the sensor output is optionally sampled multiple times, so as to obtain a plurality of readings relatively close in time, whereby an average or other adjustment of those multiple readings is made for determining a final reading that is displayed or logged.

As used herein, “analyte” means any chemical or biological material or compound suitable for passage through a biological membrane by the technology taught in this present invention, or by technology previously known in the art, of which an individual might want to know the concentration or activity inside the body. Glucose is a specific example of an analyte because it is a sugar suitable for passage through the skin, and individuals, for example those having diabetes, might want to know their blood glucose levels. Other examples of analytes include, but are not limited to, such compounds as sodium, potassium, bilirubin, urea, ammonia, calcium, lead, iron, lithium, salicylates, and the like.

FIG. 1illustrates one embodiment of system comprising a tissue interface device10and a monitor and control unit20having a vacuum source30. The tissue interface device10is provided for use in an analyte monitoring system, which may operate on a continuous, continual and/or discrete basis. The tissue interface device10is operatively coupled, via an electrical umbilical cord40and a vacuum line50, to the monitor and control unit20and the vacuum source30. The electrical umbilical cord40provides electrical and optionally optical communication between the monitor and control unit20and the tissue interface device10. Alternatively, the electrical umbilical cord40can be replaced by a wireless link in which case the monitor and control unit20and the tissue interface device10would each have a suitable transceiver to communicate over the wireless link. The vacuum line50provides mechanical communication between the vacuum source30and the tissue interface device10. Generally, the function of the tissue interface device10is to attach to the surface of the biological membrane (BM) of the organism, collect fluid from the organism, and obtain a measurement of a characteristic of the fluid. The tissue interface device10ultimately produces an electrical signal that is indicative of a presence of concentration of an analyte. The tissue interface device10is composed of inexpensive materials and components and is designed to be disposable.

Referring toFIGS. 2–6, a first embodiment of the tissue interface device10according to the present invention is shown. In this embodiment, the tissue interface device10comprises a housing100that defines an orifice120. The orifice120has an open inlet port122on a bottom end102of the housing to receive fluid from one or more artificial openings (O) in a biological membrane. The orifice120terminates at a distal end124. The inlet port122has a first diameter D and the distal end124has a second diameter d. The orifice120may be tapered so that the second diameter d is less than the first diameter D. The orifice120may be shaped such that it closely conforms to the biological membrane when vacuum is applied to the biological membrane.

The housing100of the present invention also has a sensor channel130and a sensor150. The sensor channel130is in fluid communication with the distal end124of the orifice and has an outlet port132for discharging fluid. The outlet port132is suitable for connection to the vacuum source30. The sensor150is positioned in the sensor channel130and in a flow path of the fluid for sensing a characteristic of the fluid as it is produced from the artificial opening in the biological membrane. In one example, the sensor150is positioned proximate the distal end124of the orifice120to minimize the effective dead volume of the device between the distal end124of the orifice120and the sensor150. The sensor150generates an electrical sensor signal representing the characteristic of the biological fluid.

The tissue interface device10may also comprise an electrical connector160and an electrical lead line162. The electrical lead line162is in operative communication with the sensor150and couples the electrical sensor signal to the electrical connector160. The electrical connector160is complementarily shaped so that it can be removably connected to an electrical umbilical cord40of the monitor and control unit20.

It will be appreciated from the above that, in operation, the tissue interface device10is positioned on a site overlying one or more artificial openings in the biological membrane. The openings in the membrane may be made by a variety of means, such as those disclosed in commonly assigned U.S. Pat. No. 5,885,211. When positioned, the orifice120of the housing100is positioned in fluid communication with fluid produced from the artificial opening formed in the biological membrane. Fluid enters the tissue interface device10through the inlet port122and/or orifice120. Under application of vacuum (V) at the outlet port132, the surface of the biological membrane is drawn therein the orifice120and fluid is drawn from the artificial opening into the orifice120and the sensor channel130and across the sensor150. The sensor150reacts with the fluid to generate the electrical sensor signal indicative of a characteristic of the biological fluid. The fluid continues through the sensor channel130and the outlet port132whereupon it exits the housing100of the tissue interface device10.

Referring now to the particular embodiment shown inFIGS. 4–6, the housing100of the tissue interface device10comprises a body103, a well-forming adhesive layer110, and a sensor member115. The body103has a passage104extending therein that forms a first portion of the sensor channel130. The proximal end of the passage104forms the outlet port132of the housing100. The body103also has a body surface105that has a groove106therein. The body surface105also defines the distal end124of the orifice120. The distal end of the passage104is connected to the proximal end of the groove106.

The body103provides structural support to the tissue interface device10and in combination with the well-forming adhesive layer110, serves as the interface between the fluid source and the sensor150. Any suitable material may be used for the body103of the housing100. Example suitable materials include acrylic, polyester, plastic, ceramic, polycarbonate and polyvinylchloride.

The well-forming adhesive layer110has a top surface, an opposing bottom surface and defines an opening112or channel cut through the well-forming adhesive layer110. At least a portion of the bottom surface of the well-forming adhesive layer110is connected to a portion of the body surface105so that it overlies the groove106. The well-forming adhesive layer110is positioned relative to the body surface105so that a portion of the opening112of the well-forming adhesive110overlies a portion of the body surface106to form a well114. The well114is connected to a distal end of the groove106of the body surface105(by, for example, a portion of the opening112of the well-forming adhesive layer110overlying the distal end of the groove106) and is in fluid communication with the distal end of the orifice120.

The well-forming adhesive layer110forms the well114to limit the volume of fluid exposed to the sensor150. Suitable materials for the well-forming adhesive layer110are compatible with the fluid of interest, provide adhesive support to the sensor member115, and are thick enough to provide a well114from a opening112or channel cut into the well-forming adhesive layer110. For example, the well-forming adhesive layer110may be formed from a layer of pressure sensitive adhesive. In another example, if the fluid of interest is blood or interstitial fluid, the well-forming adhesive layer110may be constructed from adhesive-like materials that are not water-soluble.

The sensor member115is provided to completely form the sensor channel130and to place the sensor150in the flow path of the fluid exiting the distal end124of the orifice120. The sensor member115has a lower surface upon which is mounted the sensor150. A portion of the lower surface of the sensor member115is connected to the top surface of the well-forming adhesive layer110so that at least a portion of the sensor150overlies the well114. As one skilled in the art will appreciate, by the layered application of the well-forming adhesive layer110and the sensor member115, the groove106and the well114are effectively enclosed to form a second portion of the sensor channel130that is in fluid communication with the distal end124of the orifice120. It will be further appreciated that the second portion of the sensor channel130is operatively connected to the first portion of the sensor channel130to form the sensor channel130of the housing100. The sensor member115may be of any thickness effective to provide support and bind the sensor150.

Moreover, to provide support for the sensor member115and to protect the sensor150from damage, the housing100may further comprise an adhesive bonding layer170and a support member180. The adhesive bonding layer170binds the support member180to the upper surface of the sensor member115. The material of construction and dimension of the adhesive bonding layer170is not critical to the present invention, thereby allowing any effective adhesive to be used. The support member180, like the body103, provides structural support to the sensor member115and the sensor150. To minimize expense, the support member180may be constructed of the same material or compatible material as the body103.

As one skilled in the art will appreciate, the sensor channel130may be in any position and in any dimension/shape to allow sufficient flow of fluid across the sensor150disposed therein. As noted above, the outlet port132of the sensor channel130is suitable for connection to a vacuum source sufficient to draw the surface of the biological membrane therein the orifice120and to draw fluid through the well114. The vacuum is sufficient to produce fluid from the biological membrane at a site where small holes/porations (microporations) have been made in the tissue. The well114serves to expose the sensor150to the fluid that is monitored. Therefore, the well114is of a dimension that the sensor150does not obstruct the flow of fluid.

The housing100of the tissue interface device10may also have a thermo-well190that extends therein the housing100. The base192of the thermo-well190is proximate the distal end124of the orifice120and is in operative receipt of a thermistor194. The thermistor194generates an electrical temperature sensor signal indicative of the temperature of the fluid proximate the distal end124of the orifice120. The thermistor194is connected to the electrical connector160via a lead196for the communication of the temperature sensor signal to the monitor and control unit20.

A portion of the bottom end102of the housing100may include adhesive to facilitate attachment of the device to the biological membrane. The adhesive also is useful to form a pneumatic seal on the biological membrane to allow modulation of the of the pressure levels in those areas proximal the artificial openings.

To further reduce imposed erythema and the dead volume within the orifice, the orifice120may be tapered. In this embodiment, the tapered orifice120has a shaped orifice surface126that extends from the inlet port122to the distal end124of the orifice120. Portions of the shaped orifice surface126may be straight or may be curved in cross-section. For example, the orifice120may have a truncated cone shape or a bell curve shape in cross-section. As one skilled in the art will appreciate, other cross-sectional shapes are contemplated in which the slope of the orifice surface generally slopes inwardly from the inlet port122to the distal end124of the orifice120so that the second diameter d of the orifice120is less than the first diameter D of the orifice120. Hence, in this exemplified embodiment, the relative volume of the tapered orifice120near the distal end124of the orifice120is less than the relative volume of the orifice120proximate the inlet port122.

It is contemplated that at least a portion of the orifice surface126may be curved in cross-section. For example, a portion of the orifice surface126proximate the bottom end102of the housing100may be curved so that the translation from the bottom end102of the housing100to the inlet port122portion of the orifice120is radiused, i.e., cambered, to form a smoothly contoured inner edge128. The smoothly contoured inner edge128and the generally inward slope of the orifice surface126minimize erythema onto the biological membrane during operation as the surface of the biological membrane is drawn into contact and is supported by portions of the orifice120. The outer edge103of the bottom end102of the housing100may also be radiused to further aid in reducing erythema onto the biological surface during operation of the device10.

In an embodiment where the orifice120is tapered, the first diameter D of the inlet port122preferably is about 1.0 to about 20.0 mm in diameter and, more preferably, is about 4.0 to about 10.0 mm in diameter. Similarly, the second diameter d of the distal end124of the orifice120is about 0.33 to about 10.0 mm in diameter and, more preferably, is about 0.75 to about 3.5 mm in diameter. The diameter of distal end124of the orifice120is sufficiently large to achieve desired target fluid flow rates. The height H of the orifice120from the open inlet port122to the distal end124is about 0.25 to about 7.0 mm and, more preferably, is about 0.5 to about 5.0 mm. Still more preferably, the height H of the orifice120is about 1.0 to about 3.0 mm.

The shape and dimensions of the orifice120minimize dead volume and thus minimize time lag. Referring toFIGS. 2 and 3, when the surface of the biological membrane is drawn into the orifice120of the housing110during the application of a vacuum or a partial vacuum V, the surface of the biological membrane is drawn upwards into the orifice120towards the distal end124of the orifice120and fills a portion of the orifice120. Thus, the effective dead volume that must be filled with fluid produced from the opening is reduced by the design of the present invention. The general tapered shape and dimensions of the tapered orifice120embodiment allow for a stretching of the surface of the biological membrane which may increase the effective pore size of the artificial openings in the biological membrane. By increasing the effective pore size, continuous and or discrete fluid flow rates may be more readily maximized and/or maintained at a constant level for extended periods of time. For example, the application of the vacuum to a skin surface results in a stretching of the skin that may increase the effective pore size of the capillary wall and intervening interstitial spaces which may provide additional access to sources of interstitial fluid.

The sensor150of the present invention may be one of any number of known types of sensors, including, but not limited to, an electrochemical biosensor, reactive enzyme based, reflectance, calorimetric, absorbance, fluoresence intensity, or fluorescence lifetime based. Biosensors, such as, for example, an analyte biosensor, may be utilized to detect any number of characteristics contained in the withdrawn fluid, including, but not limited to, detecting: glucose, vitamins (for example, A, C, B6, E, B12, etc.), CO2, lactic acid, or other analyte. One or more sensors150may be positioned therein the sensor channel130.

For example, and as shown inFIG. 5, the sensor may comprise a plurality of electrodes200. Electrode210is a working electrode, electrode220is a working electrode, electrode230is a reference electrode and electrode240is a counter-electrode. At least one of the working electrodes210and220may be coated by a reactant. The electrodes200are disposed on the sensor member115using screen-printing, pad printing, sputter coating, photolithography or other suitable techniques, using known inks and dialectrics.

Each working electrode210and220may be made from a variety of materials such as carbon and metals such as gold or silver. For example, each working electrode210and220may be made from catalytic metals such as platinum, palladium, chromium, ruthenium, rubidium, or mixtures thereof.

In the exemplified electrode sensor150discussed above, in order to detect and/or measure the level of an analyte or desired characteristic present in a fluid, at least one working electrode and at least one reference electrode are necessary. However, more than one working electrode and one or more counter-electrodes may also be present. For example, the working electrode210may not contain the reactant and will therefore produce an electrical signal that is indicative of the fluid without an analyte. This allows reduction or elimination of the signal due to various interferent compounds by subtracting the electrical signal of the working electrode210from the electrical signal of the working electrode220. Alternatively, one working electrode may be used if the levels of interference are not significant.

The reference electrode230establishes a potential relative to the fluid. The reference electrode230may, for example, contain silver/silver-chloride. The counter-electrode240, which is optional, serves to ground the current generated by the working electrodes210and220. For simplicity, the counter-electrode240may contain the same materials as the working electrodes210and220. The exemplified sensor150may contain more than one working electrode, more than one reference electrode and more than one counter-electrode, as is well known in the art.

The active surface of the electrodes200may be any shape and dimension to effectively operate. Particularly, the surface area of any of the electrodes200can be varied as long as there is sufficient sensitivity to measuring the current. For example, the electrodes200in the exemplified sensor150have active surface areas between 0.1 mm2and 10 mm2. Preferably, the electrodes400have a surface area of about 1 mm2.

As noted above, the sensor150is connected to the electrical lead line162that terminates in the electrical connector160for coupling to the remote monitor and control unit20. In the exemplified sensor150, the electrical lead lines162that couple the electrodes200to the connector160may be traces of graphite or silver/silver-chloride. However, other conductive material such-as-gold or tin are suitable to connect the electrodes200to the connector160. These traces could be applied via any method that provides a sufficient resolution such as ink-jet printing or pad printing. In addition, the printed traces could be replaced with traditional connection techniques.

Further reductions in dead volume and time delay may be achieved through the incorporation of a flexible skin interface which can adapt to variations in skin distension between patients. Variations in dead volume and hence time lag occur due to variation in the distension of an organism's biological membrane. In addition, the distension may vary over time on the same organism. Referring toFIG. 7, an alternate embodiment of the tissue interface device10is shown. This embodiment includes a notch300and a flexible insert320. The notch300is formed in the bottom end102of the housing100and opens out to the portion of the orifice120proximate the distal end124of the orifice120. The flexible insert320has a chamber322extending therethrough, a base surface324and is shaped to be complementarily received within the notch300. When the flexible insert320is received therein the notch300, the base surface324of the flexible insert320is coplanar to a portion of the bottom end102of the housing100and the chamber322and the portion of the orifice120embodied in the housing100form the orifice120of the tissue interface device10. As illustrated inFIG. 7, the chamber322may be shaped so that the orifice120is tapered.

In operation, this embodiment of the tissue interface device10is positioned on a site overlying one or more artificial openings in the biological membrane. When positioned, the orifice120of the housing100is positioned in fluid communication with fluid produced from the artificial opening formed in the biological membrane. Fluid enters the tissue interface device10through the inlet port122. Under application of vacuum at the outlet port132, the surface of the biological membrane is drawn therein the orifice120and into contact with the surface of the flexible insert320(i.e., into contact with the shaped orifice surface126of the orifice120) which resiliently molds itself to closely conform to the surface condition of the biological membrane. Because the space between the surface of the biological membrane and the shaped orifice surface126is reduced, effective dead volume and hence the time delay is reduced.

Also, due to the resilient nature of the flexible insert320, a resistive force is produced which acts on the surface of the biological membrane to reduce the erythema imposed by the tissue interface device10. Suitable materials for the flexible insert320are flexible enough to allow the biological membrane to distend against it to an acceptable degree of compression. Example suitable materials include silicone rubber, urethane, and pliable polymers.

Further in operation, the fluid is drawn from the artificial opening within the biological membrane into the orifice120and hence into the sensor channel130and across the sensor150. The sensor150reacts with the fluid to generate the electrical sensor signal indicative of a characteristic of the biological fluid. The fluid continues through the sensor channel130and the outlet port132whereupon it exits the housing100of the tissue interface device10. Thus, this embodiment of the tissue interface device10incorporates all of the advantages of the first embodiment described immediately above while beneficially further reducing dead volume, time lag, and imposed erythema.

Referring now toFIGS. 8 and 9, a variation of the tissue interface device10is shown in which an opening410in a flexible membrane400opens into the inlet port122of the housing100. The opening410extends therethrough the membrane400and has a diameter less than the diameter of the inlet port122of the orifice120. A portion of the surface of the flexible membrane400is affixed, for example, by use of a pressure sensitive adhesive, to the bottom end102of the housing100. The flexible membrane400is positioned so that the opening410of the flexible membrane400is positioned approximately opposed to the inlet port122of the housing100.

In operation, this embodiment of the tissue interface device10is positioned on a site overlying one or more artificial openings in the biological membrane. To form a pneumatic seal on the biological membrane to allow modulation of the pressure levels in those areas proximal the artificial openings and to facilitate attachment of the device10to the biological membrane, at least a circumferential portion of the flexible membrane400and/or the bottom end102of the housing100may include adhesive. When positioned, the opening410of the flexible membrane400and the orifice120of the housing100are positioned in fluid communication with fluid produced from the artificial opening formed in the biological membrane. Fluid enters the tissue interface device10through the opening in the flexible membrane400and is drawn into the interior of the orifice120. Under application of vacuum at the outlet port132, the surface of the biological membrane is drawn into contact with the flexible membrane400and the flexible membrane400and the biological membrane are drawn into the interior of the orifice120. The flexible membrane400is placed into contact with the shaped orifice surface126of the orifice120and resiliently molds itself to closely conform to the surface condition of the biological membrane and the shaped orifice surface126. The orifice120may be tapered as previously described.

Because the space between the surface of the biological membrane and the flexible membrane400is reduced, effective dead volume and hence the time delay is reduced. The fluid expressed from the artificial opening is drawn through the tissue interface device10as described in the embodiments above. Thus, similar to the embodiment described immediately above, this embodiment of the tissue interface device incorporates all of the advantages of the first embodiment while beneficially further reducing dead volume, time lag, and imposed erythema.

As noted for the embodiment described above, a resistive force is produced by the resilient nature of the flexible membrane400which acts on the surface of the biological membrane to reduce the erythema imposed by the tissue interface device10. Suitable materials for the flexible membrane400are flexible enough to allow the biological membrane to distend against it to an acceptable degree of compression, provide an degree of elongation which allows the flexible membrane400to stretch under the applied suction force, and are thick enough to provide to conform to the surface of the biological membrane. Suitable materials preferably have an elongation rating from about 125% to 350%, and more preferably, from about 175% to 225%; and a thickness from about 0.2 mm to about 2.5 mm, and more preferably, from about 0.5 mm to 1.5 mm. Example suitable materials include a polymer film, a polyester film, a polyethylene film and a polyolefinic film.

FIGS. 10–11shown another embodiment of a tissue interface device10which has a flexible membrane500for beneficially reducing dead volume, time lag, and imposed erythema. This embodiment includes a housing510, a flexible membrane conduit520, and the flexible membrane500. The housing510has a orifice530that extends therein from an open inlet port532on the bottom end512of the housing510and terminates in a distal end534. The housing510also includes a sensor channel540and a vacuum channel550that may be suitably coupled to the vacuum source30. The vacuum channel550is in fluid communication with the distal end534of the orifice530.

The flexible membrane500has a top surface, a bottom surface, and an opening502that extends therethrough the membrane500. The opening502of the flexible membrane500is less than the diameter of the inlet port532of the orifice530. At least a portion of the top surface of the flexible membrane530is connected to the bottom end512of the housing510, such as, for example, by a circumferentially extending ring of adhesive. Suitable materials for the flexible membrane500are flexible enough to allow the flexible membrane500to provide an degree of elongation which allows the flexible membrane500to stretch under the applied suction force and are gas permeable. An example suitable material is a flexible hydrophobic gas permeable polymer film, such as Hydrolon, produced by Pall Specialty Materials, Port Washington, N.Y.

The flexible conduit520is connected to, and in fluid communication therewith, an inlet end of the sensor channel540and the opening502in the flexible membrane500. Thus, the top surface of the flexible membrane500, the exterior of the flexible conduit520, and the orifice530form an enclosed void that is in communication with the vacuum channel550so that at least a portion of the top surface of the flexible membrane500is in fluid communication with the vacuum source30.

In operation, this embodiment of the tissue interface device10is positioned on a site overlying one or more artificial openings in the biological membrane. At least a circumferential portion of the bottom surface of the flexible membrane500may include adhesive to form a pneumatic seal on the biological membrane to allow modulation of the pressure levels in those areas proximal the artificial openings and to facilitate attachment of the device10to the biological membrane. When positioned, at least a portion of the bottom surface of the flexible membrane500is positioned in temporarily sealed contact with the biological membrane around the artificial opening so that the opening502of the flexible membrane500is in fluid communication with the artificial opening. Fluid enters the tissue interface device10through the opening502in the flexible membrane and is drawn into the flexible conduit520upon application of vacuum to the outlet port of the sensor channel540. Under application of vacuum to the vacuum channel550, the top surface of the flexible membrane500is drawn into the interior of the orifice530and the bottom surface of the flexible membrane is pulled fractionally away from the surface of the biological membrane which creates a gap506. Fluid flows into the gap506, and through the applied suction and/or capillary action, the fluid passes through the opening502of the flexible membrane500into the flexible conduit520and therethrough the sensor channel540to pass the sensor150. Because the volume between the surface of the biological membrane and the sensor150is reduced, effective dead volume and hence the time delay is reduced. Thus, this embodiment of the tissue interface device10incorporates all of the advantages of the first embodiment while beneficially further reducing dead volume, time lag, and for beneficially providing a degassed sample of fluid to the sensor150.

It should be understood that the preceding is merely a detailed description of various embodiments of this invention and that numerous changes to the disclosed embodiments can be made in accordance with the disclosure herein without departing from the spirit or scope of the invention. The preceding description, therefore, is not intended to limit the scope of the invention. Rather, the scope of the invention is to be determined only by the appended claims and their equivalents.