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McFarlane Toys delivers again with MLB 15, the newest Sports Picks lineup featuring the brightest stars from Major League Baseball. It's a strong cross-section of big-league talent, providing power, defense, starting and relief pitching and more. Take the rubber bands off your glove and crease your hat a bit -- it's time to play ball!
DERREK LEE: Chicago's first baseman has spent much of his career under the radar, despite winning a World Series with the Marlins in 2004. Lee didn't make national headlines until his Triple Crown chase in 2005. He won the batting title, finished second in the home run chase and trailed down to seventh in RBIs, but Lee's stellar 2005 season landed him his first All-Star selection and Silver Slugger award. While he brings thunder to the plate, the North Side's biggest star also rocks in the field, where his first baseman's mitt turned gold for the second time in 2005.
JOHAN SANTANA: Minnesota brought Johan Santana out of the bullpen for the first four years of his career, but his entry into the starting rotation in 2004 was a revelation. Santana went 20-2 with a 2.69 ERA and 265 strikeouts. While Boston's Curt Schilling won 21 games to deny Santana the "Triple Crown of Pitching," he couldn't keep the Twins ace from landing the Cy Young award as the American League's best pitcher. Minnesota rewarded Santana with a long-term contract, and he proved 2004 was no fluke with a 16-7 mark for an underachieving Minnesota squad in 2005. The future looks bright for the Venezuelan hurler -- I wonder if Florida regrets trading him for Jared Camp...
CHAD CORDERO: The Washington Nationals surpassed expectations in their debut season and defied the odds by winning a slew of one-run games -- Frank Robinson's bullpen turned in night after night of brilliant relief, headlined by closer Chad Cordero's breakout season. Cordero led the National League with 47 saves and earned a trip to his first All-Star Game. His hat brim also led the league in total flatness. Democrats and Republicans can agree on one thing in D.C. -- the ninth inning is safe down at old RFK.
MIGUEL CABRERA: While Florida traded away a lot of their established talent this off-season, there was one star deemed absolutely untouchable. Miguel Cabrera already owns two All-Star selections and a World Series championship and he won't turn 23 until this April. Back-to-back 33-homer seasons have established Cabrera as baseball's best young star, with talent to spare and a future that looks downright scary.
CARLOS DELGADO: How does a player with 30 or more home runs in nine straight seasons get overlooked? After 12 seasons in Toronto, the powerhouse signed a long-term deal to man first base for the Marlins, but the team's subsequent break-up saw Delgado shipped to New York. If media attention has eluded him thus far, Delgado will see plenty of it this season as the new-look Mets look to be serious contenders in the National League East.
ANDRUW JONES 2: 50-homer seasons went out of style recently, with no one cracking that plateau since Jim Thome and Alex Rodriguez in 2002 -- until Atlanta's Andruw Jones crushed 51 home runs to lead both leagues in 2005. With an injury to Chipper Jones and the Braves' roster stocked with rookies, it was Jones who provided the leather and the lumber to capture a record-setting 14th consecutive division title. Jones' unbelievable 2005 saw him make his 4th All-Star Team, while winning his ninth straight Gold Glove and finishing second in National League MVP voting.
RICHIE SEXSON (Surprise Figure): If the lights are bright at SafeCo Field, it's because Richie Sexson is providing the power. The 6'8 slugger celebrated his first season in Seattle with 39 homers and 121 RBIs -- both good enough for sixth place in the American League. Sexson is a "surprise figure" in MLB 15, meaning he isn't listed on the packaging and will be randomly inserted into cases on a limited basis.
Look for MLB 15 at your favorite stores in early June!


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Hi everyone- I have scheduled our first meeting for Friday, October 22nd from 7-9pm at the UConn Health Center in Farmington. YAY!
For Driving Directions, click here:
It's in the main building at the top of the hill. The Charlotte Johnson Hollfelder Center for Women's Health is on the right just past the information desk. VERY easy to find! Post here or email me with any questions, ok? I really look forward to getting together in person with you! [:D]
Jennifer 33
Kyle born 8-13-03 @ 38 weeks (PE and Class I HELLP)
Connecticut Coordinator

subset: commoncrawl


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Here at Your Lowcountry, we see a lot of requests for contest entries and, normally, we pass them onto readers without comment.
But this particular contest struck a chord because it rewards young entrepreneurs and helps them build skills.
The Build-A-Bear Workshop is looking for Huggable Heroes, defined as young social entrepreneurs who are changing the world."
The Heroes program wants to make this 10th year special.
The program is looking for young people ages 8-18 who are making their world a better place.
Ten of these heroes will receive $12,200, which includes an educational scholarship, a donation to a charity of their choice and mentoring scholarship to support their charitable entrepreneurships.
The company also is joining forces with the prestigious Jefferson Awards for Public Service, one of the nation's top community service recognition programs founded 40 years ago by Jacqueline Kennedy Onassis.
According to a press release from Build-A-Bear, the Jefferson Awards' Globechangers training and mentoring systems will help equip this newest generation of philanthropists with the tools it needs to build a lifetime of public service.
Each hero will be paired with a mentor through the Jefferson Awards system for a year to develop valuable skills for writing business plans, networking and fundraising.
Now, if you are a young entrepreneur, and we have written about an amazing number in our area in the past two years, this is an great opportunity.
Winners will benefit from some hands-on training by qualified people. There is no better way for a young person to learn than joining forces with those who have already done what they want to do.
I had a recent exchange of emails about this same topic with former state Rep. Jimmy Bailey, who now runs YESCarolina, the South Carolina organization dedicated to teaching youths the principles of entrepreneurship and free enterprise.
Both of us agree that learning these skills at an early age is fundamental to America's future. Not everyone is going to be able to go to college, especially with the increasing cost of higher education, but learning basic business skills can help anyone have a better life as an adult.
Bailey said he thinks that the education system as a whole doesn't understand this yet, but students do. Given the tools, young people can have great experiences that will show them business basics, whether they are going to be an employee all of their life, or want to build a business of their own.
That's why entering this contest seems like a great idea for some of you who are already experimenting with businesses.
Nominations will be accepted through the website buildabear.com/huggableheroes or by mail until Feb. 28.
And if you or someone you know happens to be one of the finalists, let us know and we will feature you in Your Lowcountry.
Reach Stephanie Harvin at 937-5557 or firstname.lastname@example.com.
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Majoring in Exercise Science involves the study of human movement and how to help people live healthier lives through exercise, rehabilitation and nutrition. You'll learn kinesiology concepts in human movement, exercise and management. How can athletes avoid injury? What role does strength conditioning play? How can diet affect the body? You'll gain knowledge and skills that are important for any career in fitness or wellness as you take 70 credit hours towards a Bachelor of Science degree. (The B.S. degree carries a larger course load for the major than the B.A. degree, with additional coursework in biology, mathematics and human anatomy.)
You'll also have real opportunities to learn beyond the classroom via Concordia Health Alliance for Majors in Physical Education & Kinesiology (CHAMP) Club activities; participation in conferences, workshops, seminars and clinics locally and nationally; and internship opportunities with a variety of organizations and sports teams. Because we design our exercise science program to be responsive to the exact needs of the marketplace, it will be a relevant major if you're considering graduate study in areas such as exercise physiology or a career as a personal trainer, sports coach, chiropractor, community wellness director, occupational therapist, athletic trainer or physical therapist.
Athletic TrainerChiropractorCollege CoachCommunity Wellness DirectorHigh School CoachMiddle School CoachOccupational TherapistPersonal TrainerPhysical TherapistPhysician's Assistant
Some careers may require additional education.
Responsiveto the needs of today's students.Relevantto the skills employers seek.Realpreparation for thoughtful living and service.
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The following graphic compares the cost of living between Kumamoto, Japan and the Akashi, Japan and assumes earnings of $50,000 in the base city.
If you are earning 50,000 Japanese Yen in Kumamoto, Japan you would need to earn 46,820 Japanese Yen in the Akashi, Japan to maintain the same standard of living.
Currency in Japanese Yen


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Devices and methods for determining analyte levels are described. The devices and methods allow for the implantation of analyte-monitoring devices, such as glucose monitoring devices that result in the delivery of a dependable flow of blood to deliver sample to the implanted device. The devices include unique architectural arrangement in the sensor region that allows accurate data to be obtained over long periods of time.
1. An implantable device for measuring an analyte, the device comprising:
a sensor body comprising a sensor configured to measure an analyte; and
a composite bilayer membrane comprising an angiogenic material configured to promote angiogenesis and a bioprotective membrane disposed on at least a portion of the sensor, wherein the bioprotective membrane comprises polycarbonate urethane and polyvinylpyrrolidone, and wherein the angiogenic material is adjacent to the bioprotective membrane.
2. The device of
3. The device of
4. The device of
This application is a continuation of Ser. No. 11/546,157, filed Oct. 10, 2006, which is a continuation of Ser. No. 11/039,269, filed Jan. 19, 2005, now U.S. Pat. No. 7,136,689, which is a continuation of Ser. No. 09/916,858, filed Jul. 27, 2001, now U.S. Pat. No. 6,862,465, which is a continuation-in-part of Ser. No. 09/447,227, filed Nov. 22, 1999, which is a divisional of Ser. No. 08/811,473, filed Mar. 4, 1997, now U.S. Pat. No. 6,001,067.
The present invention relates generally to devices and methods for determining analyte levels, and, more particularly, to implantable devices and methods for monitoring glucose levels in a biological fluid.
The continuous measurement of substances in biological fluids is of interest in the control and study of metabolic disorders. Electrode systems have been developed for this purpose whereby an enzyme-catalyzed reaction is monitored (e.g., by the changing concentrations of reactants or products) by an electrochemical sensor. In such electrode systems, the electrochemical sensor comprises an electrode with potentiometric or amperometric function in close contact with a thin layer containing an enzyme in dissolved or insoluble form. Generally, a semipermeable membrane separates the thin layer of the electrode containing the enzyme from the sample of biological fluid that includes the substance to be measured.
Electrode systems that include enzymes have been used to convert amperometrically inactive substances into reaction products that are amperometrically active. For example, in the analysis of blood for glucose content, glucose (which is relatively inactive amperometrically) may be catalytically converted by the enzyme glucose oxidase in the presence of oxygen and water to gluconic acid and hydrogen peroxide. Tracking the concentration of glucose is thereby possible since for every glucose molecule reacted a proportional change in either oxygen or hydrogen peroxide sensor current will occur [U.S. Pat. Nos. 4,757,022 and 4,994,167 to Shults et al., both of which are hereby incorporated by reference]. Hydrogen peroxide is anodically active and produces a current that is proportional to the concentration of hydrogen peroxide. [Updike et al., Diabetes Care, 11:801-807 (1988)].
Despite recent advances in the field of implantable glucose monitoring devices, presently used devices are unable to provide data safely and reliably for long periods of time (e.g., months or years) [See, e.g., Moatti-Sirat et al., Diabetologia 35:224-30 (1992)]. For example, Armour et al., Diabetes 39:1519-26 (1990), describes a miniaturized sensor that is placed intravascularly, thereby allowing the tip of the sensor to be in continuous contact with the blood. Unfortunately, probes that are placed directly into the vasculature put the recipient at risk for thrombophlebosis, thromboembolism, and thrombophlebitis.
Currently available glucose monitoring devices that may be implanted in tissue (e.g., subcutaneously) are also associated with several shortcomings. For example, there is no dependable flow of blood to deliver sample to the tip of the probe of the implanted device. Similarly, in order to be effective, the probe must consume some oxygen and glucose, but not enough to perturb the available glucose which it is intended to measure; subcutaneously implanted probes often reside in a relatively low oxygen environment in which oxygen or glucose depletion zones around the probe tip may result in erroneously low measured glucose levels. In addition, implantable devices that utilize electrode sensors require membranes of the appropriate composition to protect the sensor from harsh in vivo environmental conditions. Current membrane technology has allowed the development of a single structural membrane that performs the same functions that previously required multiple membranes. However, these single membranes have been observed to delaminate and thus prevent accurate long-term glucose monitoring. Finally, the probe may be subject to "motion artifact" because the device is not adequately secured to the tissue, thus contributing to unreliable results. Partly because of these limitations, it has previously been difficult to obtain accurate information regarding the changes in the amounts of analytes (e.g., whether blood glucose levels are increasing or decreasing); this information is often extremely important, for example, in ascertaining whether immediate corrective action is needed in the treatment of diabetic patients.
There is a need for a device that accurately and continuously determines the presence and the amounts of a particular analyte, such as glucose, in biological fluids. The device should be easy to use, be capable of accurate measurement of the analyte over long periods of time, and should not readily be susceptible to motion artifact.
The present invention relates generally to devices and methods for determining analyte levels, and, more particularly, to implantable devices and methods for monitoring glucose levels in a biological fluid.
In one aspect of the present invention, an implantable device for measuring an analyte in a biological fluid is provided, which includes the following: a housing including an electronic circuit; and a sensor operably connected to the electronic circuit of the housing, the sensor including i) a member for determining the amount of glucose in a biological sample ii) a bioprotective membrane, the bioprotective membrane positioned more distal to the housing than the glucose determining member and substantially impermeable to macrophages, and iii) an angiogenic layer, the angiogenic layer positioned more distal to the housing than the bioprotective membrane.
The present invention further encompasses a method of monitoring glucose levels, the method including the steps of providing a host, and an implantable device as described above and implanting the device in the host under conditions such that the device measures glucose for a period exceeding 360 days.
In one embodiment of this aspect, the invention encompasses a method of measuring glucose in a biological fluid that includes the steps of providing a host, and an implantable device as provided above, wherein the glucose determining member of the implantable device is capable of continuous glucose sensing, and implanting the device in the host.
In order to facilitate an understanding of the present invention, a number of terms are defined below.
The term "accurately" means, for example, 95% of measured values within 25% of the actual value as determined by analysis of blood plasma, preferably within 15% of the actual value, and most preferably within 5% of the actual value. Alternatively, "accurately" means that 85% of the measured values fall into the A and B regions of a Clarke error grid, or preferably 90%, or most preferably 95% of the measured values fall into these regions. It is understood that like any analytical device, calibration, calibration validation and recalibration are required for the most accurate operation of the device.
The term "analyte" refers to a substance or chemical constituent in a biological fluid (e.g., blood or urine) that can be analyzed. A preferred analyte for measurement by the devices and methods of the present invention is glucose.
The terms "sensor interface," "sensor means," "sensor" and the like refer to the region of a monitoring device responsible for the detection of a particular analyte. For example, in some embodiments of a glucose monitoring device, the sensor interface refers to that region wherein a biological sample (e.g., blood or interstitial fluid) or a portion thereof contacts (directly or after passage through one or more membranes or layers) an enzyme (e.g., glucose oxidase); the reaction of the biological sample (or portion thereof) results in the formation of reaction products that allow a determination of the glucose level in the biological sample. In preferred embodiments of the present invention, the sensor means comprises an angiogenic layer, a bioprotective layer, an enzyme layer, and an electrolyte phase (i.e., a free-flowing liquid phase comprising an electrolyte-containing fluid [described further below]). In some preferred embodiments, the sensor interface protrudes beyond the plane of the housing.
The term "tissue interface" refers to that region of a monitoring device that is in contact with tissue.
The terms "operably connected," "operably linked," and the like refer to one or more components being linked to another component(s) in a manner that allows transmission of, e.g., signals between the components. For example, one or more electrodes may be used to detect the amount of analyte in a sample and convert that information into a signal; the signal may then be transmitted to electronic circuit means (i.e., the electrode is "operably linked" to the electronic circuit means), which may convert the signal into a numerical value in the form of known standard values.
The term "electronic circuit means" or "electronic circuit" refers to the electronic circuitry components of a biological fluid measuring device required to process information obtained by a sensor means regarding a particular analyte in a biological fluid, thereby providing data regarding the amount of that analyte in the fluid. U.S. Pat. No. 4,757,022 to Shults et al., previously incorporated by reference, describes suitable electronic circuit means (see, e.g., FIG. 7); of course, the present invention is not limited to use with the electronic circuit means described therein. A variety of circuits are contemplated, including but not limited to those circuits described in U.S. Pat. Nos. 5,497,772 and 4,787,398, hereby incorporated by reference.
The terms "angiogenic layer," "angiogenic membrane," and the like refer to a region, membrane, etc. of a biological fluid measuring device that promotes and maintains the development of blood vessels microcirculation around the sensor region of the device. As described in detail below, the angiogenic layer of the devices of the present invention may be constructed of membrane materials alone or in combination such as polytetrafluoroethylene, hydrophilic polyvinylidene fluoride, mixed cellulose esters, polyvinylchloride, and other polymers including, but not limited to, polypropylene, polysulfone, and polymethylmethacrylate.
The phrase "positioned more distal" refers to the spatial relationship between various elements in comparison to a particular point of reference. For example, some embodiments of a biological fluid measuring device comprise both a bioprotective membrane and an angiogenic layer/membrane. If the housing of the biological fluid measuring device is deemed to be the point of reference and the angiogenic layer is positioned more distal to the housing than the bioprotective layer, then the bioprotective layer is closer to the housing than the angiogenic layer.
The terms "bioprotective membrane," "bioprotective layer," and the like refer to a semipermeable membrane comprised of protective biomaterials of a few microns thickness or more that are permeable to oxygen and glucose and are placed over the tip of the sensor to keep the white blood cells (e.g., tissue macrophages) from gaining proximity to and then damaging the enzyme membrane. In some embodiments, the bioprotective membrane has pores (typically from approximately 0.1 to approximately 1.0 micron). In preferred embodiments, a bioprotective membrane comprises polytetrafluoroethylene and contains pores of approximately 0.4 microns in diameter. Pore size is defined as the pore size provided by the manufacturer or supplier.
The phrase "substantially impermeable to macrophages" means that few, if any, macrophages are able to cross a barrier (e.g., the bioprotective membrane). In preferred embodiments, fewer than 1% of the macrophages that come in contact with the bioprotective membrane are able to cross.
The phrase "material for securing said device to biological tissue" refers to materials suitable for attaching the devices of the present invention to, the fibrous tissue of a foreign body capsule. Suitable materials include, but are not limited to, poly(ethylene terephthalate). In preferred embodiments, the top of the housing is covered with the materials in the form of surgical grade fabrics; more preferred embodiments also contain material in the sensor interface region (see
The phrase "member for determining the amount of glucose in a biological sample" refers broadly to any mechanism (e.g., enzymatic or non-enzymatic) by which glucose can be quantitated. For example, some embodiments of the present invention utilize a membrane that contains glucose oxidase that catalyzes the conversion of glucose to gluconate: Glucose+O2=Gluconate+H2O2. Because for each glucose molecule converted to gluconate, there is a proportional change in the co-reactant O2 and the product H2O2, one can monitor the current change in either the co-reactant or the product to determine glucose concentration.
The phrase "apparatus for transmitting data to a location external to said device" refers broadly to any mechanism by which data collected by a biological fluid measuring device implanted within a subject may be transferred to a location external to the subject. In preferred embodiments of the present invention, radiotelemetry is used to provide data regarding blood glucose levels, trends, and the like.
The terms "radiotelemetry," "radiotelemetric device," and the like refer to the transmission by radio waves of the data recorded by the implanted device to an ex vivo recording station (e.g., a computer), where the data is recorded and, if desired, further processed (see, e.g., U.S. Pat. Nos. 5,321,414 and 4,823,808, hereby incorporated by reference; PCT Pat. Publication WO 94/22367).
The term "host" refers to both humans and animals.
The phrase "continuous glucose sensing" refers to the period in which monitoring of plasma glucose concentration is continuously carried out. More specifically, at the beginning of the period in which continuous glucose sensing is effected, the background sensor output noise diminishes and the sensor output stabilizes (e.g., over several days) to a long-term level reflecting adequate microcirculatory delivery of glucose and oxygen to the tip of the sensor (see
The term "filtrate layer" refers to any permeable membrane that is able to limit molecules from passing through the membrane based on their properties including molecular weight. More particularly, the resistance layer, interference layer and bioprotective membrane are examples of layers that can function as filtrate layers, depending on the materials from which they are prepared. These layers can control delivery of analyte to a sensing means. Furthermore, these layers can reduce a number of undesirable molecular species that may otherwise be exposed to the sensor for detection and provide a controlled sample volume to the analyte sensing means.
The present invention relates generally to devices and methods for determining analyte levels, and, more particularly, to implantable devices and methods for monitoring glucose levels in a biological fluid. In a preferred embodiment, the device and methods of the present invention are used to determine the level of glucose in a host, a particularly important measurement for individuals having diabetes.
Although the description that follows is primarily directed at glucose monitoring devices and methods for their use, the devices and methods of the present invention are not limited to glucose measurement. Rather, the devices and methods may be applied to detect and quantitate other analytes present in biological fluids (including, but not limited to, amino acids and lactate), especially those analytes that are substrates for oxidase enzymes [see, e.g., U.S. Pat. No. 4,703,756 to Gough et al., hereby incorporated by reference]. Moreover, the devices and methods of the present invention may be utilized to present components of biological fluids to measurement methods which are not enzyme-based, including, but not limited to, those based on surface plasmon resonance, surface acoustic waves, optical absorbance in the long wave infrared region, and optical rotation of polarized light.
For example, surface plasmon resonance sensors that analyze a region within less than one wavelength of analysis light near the flat surface of the sensor have been described (See U.S. Pat. No. 5,492,840). These sensors have been used, for example, in the study of immunochemistry and other surface bound chemical reactions (Jonsson et al., Annales de Biologies Clinique 51(10:19, 1993). This type of sensor may be incorporated into the implantable device of the present invention for the detection of a number of different analytes including glucose. One skilled in the art would recognize that the surface plasmon resonance sensor is an optical sensor and that the implantable device of the present invention may further include a source of coherent radiation (e.g. a laser operating in the visible or near infrared).
In one application, referred to here as a consumptive approach, an enzyme that consumes the analyte producing a detectable product is immobilized on the sensor in the filtrate layer. When the enzyme consumes the analyte, the reaction products diffuse away from the enzyme at a rate dependent on the permeability of the layers distal to the enzyme layer. As a result, reaction products will accumulate at a higher concentration near the sensor, within one wavelength of analysis light, where they may be detected and measured. One example of such a system that detects the presence of glucose would immobilize a glucose oxidase enzyme layer on the sensor surface.
The layers of the present invention play an important role in the effective operation and function of this type of sensor. In particular, the angiogenic layer assures a constant supply of analyte from the tissues of the subject, the bioprotective membrane protects the underlying layers from cellular attack, the resistance layer controls the rate of delivery of analyte and the filtrate layer performs many functions including; providing a low molecular weight filtrate, reducing the number of undesirable molecular species available to the sensor for detection and providing a controlled volume of sample for detection by the sensor. As mentioned above, the bioprotective membrane, resistance layer and interference layer can function as filtrate layers. For example, it is well within the contemplation of the present invention that the bioprotective membrane can be made of a material that is able to exclude certain molecules from passing through the membrane based on their size.
One skilled in the art would recognize that the reaction kinetics associated with each type of enzyme that may be selected for use with this sensor is unique. However, in general, if an excess of enzyme is provided, the enzyme turnover rate is proportional to the flux of analyte to the enzyme and independent of the enzyme concentration. Therefore, the actual analyte concentration may be calculated utilizing the diffusion rate of the detectable analyte across the bioprotective resistance layers.
In another application, referred to here as a non-consumptive approach, an analyte-binding compound is provided on the surface plasmon resonance sensor surface within one wavelength of analysis light. This compound reversibly binds, but does not consume, the analyte. In this application, the analyte moves reversibly onto and off of attachment sites on the binding compound. This reaction provides a steady state condition for bound and unbound analyte that may be quantitated and analyte concentration mathematically calculated. One skilled in the art would recognize that the reaction kinetics associated with binding and release of the analyte is unique for each type of binding compound selected. Examples of such a system that detects the presence of glucose provide a binding compound comprised of conconavalin A or a wide range of borate containing compounds (See U.S. Pat. No. 6,011,985).
Since this is a chemical equilibrium-based approach, a filtrate layer is not necessarily required to maintain an analyte concentration near the sensor. However, such a membrane would still be desired to reduce the number of undesirable molecular species available to the analyte-binding layer. Preferably, the bioprotective layer is thin to allow rapid sensor equilibration to changes in analyte levels. As described above, one skilled in the art would recognize that the function of the filtrate layer could be incorporated into the bioprotective membrane by selection of the appropriate molecular exclusion, such as exclusion by molecular weight, if desired.
A variety of materials may be utilized to construct a combination angiogenic/bioprotective membrane, many of which are described below under the angiogenic layer and bioprotective membrane headings. Preferably, this combination membrane is ePTFE embedded in a layer of PVP containing urethane hydrogel. However, any material that performs a similar function as the PVP containing polyurethane hydrogel could be substituted.
In either application, consumptive or non-consumptive, one skilled in the art would recognize that the response time of the sensor is subject to Fick's law of diffusion. More specifically, sensors with thick membrane layers or that have low analyte diffusivity will respond slower to change in analyte concentration than sensors with thin membranes or that have high analyte diffusivity. Consequently, reasonable optimization experimentation with the membrane and layers would be required to meet various use requirements.
One skilled in the art would further recognize that the consumptive or non-consumptive approaches of the previous example could be applied to additional sensor modalities as follows:
1. Another sensor that may be incorporated into the device of the present invention that has been previously described is a surface acoustic wave sensor (See U.S. Pat. No. 5,932,953). This sensor, also referred to as a bulk-acoustic wave piezoelectric resonator, typically includes a planar surface of piezoelectric material with two respective metal layers bonded on opposite sides that form the electrodes of the resonator. The two surfaces of the resonator are free to undergo vibrational movement when the resonator is driven by a signal within the resonance band of the resonator. One of these surfaces is adapted to provide reversible binding sites for the analyte being detected. The binding of the analyte on the surface of the resonator alters the resonant characteristics of the resonator and changes in the resonant characteristics may be detected and interpreted to provide quantitative information regarding the analyte concentration.
2. Another sensor that may be incorporated into the device of the present invention is an optical absorbance sensor (See U.S. Pat. No. 6,049,727). This sensor utilizes short to medium wavelength infrared light that is passed through a sample with the unabsorbed infrared light being monitored by an optical detector.
Previously developed methods for analysis of analytes such as glucose in tissues and blood have been relatively unsuccessful for two reasons, interference from other chemicals present in the complex biological sample and signal variation due to poor control of sample volume. These problems may be solved by providing a low molecular weight filtrate of biological fluid in a controlled volume of sample to the sensor. In one system of the present invention, biological analyte is provided to the sensor through the angiogenic layer. This analyte is then filtered through the bioprotective membrane to produce a desirable filtrate. Alternatively, a third filtrate layer, such as an interference layer, may be utilized having specific filtration properties to produce the desired filtrate. The three-dimensional structure of the bioprotective membrane and/or other filtrate layers is utilized to define and stabilize the sample volume. One skilled in the art would recognize that any material that provides a low molecular weight filtrate to the sensor in a controlled volume might be utilized. Preferably, this material is polyurethane.
The sensor may be enhanced by partial metallization of the distal side of the filtrate producing material that would serve to isolate by reflection the optical signal to the space within the filtrate region directly adjacent to the sensor. This metal film may be a durable metal including, but not restricted to, gold or platinum and may be vacuum deposited onto the filtrate producing material.
One skilled in the art would recognize that the optical absorbance sensor requires a source of short to medium wavelength infrared light. Consequently, the implantable device of the present invention would further include a source of infrared radiation and an optical detector.
3. Another sensor that may be incorporated into the device of the present invention that has been previously described is a polarized light optical rotation sensor (See U.S. Pat. No. 5,209,231). This sensor may be used to detect an analyte that rotates polarized light such as glucose. In particular, glucose concentrations in biological fluids in the range of 0.05 to 1.00% w/v may be detected and quantitated. Normal non-diabetic subjects generally have biological glucose concentrations ranging from 0.07 to 0.12% w/v.
In this type of sensor, the optical detector receives polarized light passed through a biological sample and then further through a polarizing filter. The optical activity of an analyte in the sample rotates the polarized light in proportion to its concentration. Unfortunately, accurate measurements of glucose in complex biological samples has proven difficult because of the optical activity of interfering substances and poor control of sample volume. These problems may be solved by providing a low molecular weight filtrate of biological fluid in a controlled volume to the sensor. The present invention meets this criterion by providing a continuous supply of biological glucose to the sensor through the angiogenic layer that is filtered through a bioprotective membrane and/or a filtrate layer as described previously for the optical absorbance sensor. One skilled in the art would recognize that any material that provides a low molecular weight filtrate to the sensor in a controlled geometry might be utilized. Preferably, this material is polyurethane. In addition, one skilled in the art would recognize that the polarized light optical rotation sensor requires a source of polarized light. Consequently, the implantable device of the present invention would further include a source of polarized radiation.
4. Another sensor that may be incorporated into the device of the present invention that has been previously described is a fluorescence sensor (See U.S. Pat. No. 5,341,805). The invention of Colvin provides a method for incorporating an ultraviolet light source and fluorescent sensing molecules in an implantable device. However, Colvin does not describe how the sensor would survive harsh in vivo environmental conditions, how the device would be functionally integrated into body tissues or how a continuous supply of glucose would be maintained for detection by the sensor. These problems may be solved by providing a low molecular weight filtrate of biological fluid in a controlled volume to the sensor.
In this example, a continuous supply of biological glucose passes to the sensor through the angiogenic layer that prevents isolation of the sensor by the body tissue. The glucose is then filtered through the bioprotective membrane to produce a desirable filtrate having fewer interfering molecules and to protect the sensor from in vivo environmental conditions. Alternatively, a filtrate layer may be utilized having specific filtration properties to produce the desired filtrate. The three-dimensional structure of the bioprotective membrane and/or filtrate layer also provides stabilized sample volume for detection by the sensor.
One skilled in the art would recognize that a fluorescence sensor requires a source of light. Consequently, the implantable device of the present invention would further comprise a source of radiation, as well as fluorescent sensing molecules to detect the presence of analyte.
I. Nature of the Foreign Body Capsule
Devices and probes that are implanted into subcutaneous tissue will almost always elicit a foreign body capsule (FBC) as part of the body's response to the introduction of a foreign material. Therefore, implantation of a glucose sensor results in an acute inflammatory reaction followed by building of fibrotic tissue. Ultimately, a mature FBC including primarily a vascular fibrous tissue forms around the device (Shanker and Greisler, Inflammation and Biomaterials in Greco RS, ed. Implantation Biology: The Host Response and Biomedical Devices, pp 68-80, CRC Press (1994)).
Although fluid is frequently found within the capsular space between the sensor and the capsule, levels of analytes (e.g., glucose and oxygen) within the fluid often do not mimic levels in the body's vasculature, making accurate measurement difficult.
In general, the formation of a FBC has precluded the collection of reliable, continuous information, reportedly because of poor vascularization, the composition of a FBC has prevented stabilization of the implanted device, contributing to motion artifact that renders unreliable results. Thus, conventionally, it has been the practice of those skilled in the art to attempt to minimize FBC formation by, for example, using a short-lived needle geometry or sensor coatings to minimize the foreign body reaction ("Biosensors in the Body" David M. Fraser, ed.; 1997 pp 117-170. Wiley & Sons Ltd., West Sussex, England),
In contrast to the prior art, the teachings of the present invention recognize that FBC formation is the dominant event surrounding long term implantation of any sensor and must be orchestrated to support rather than hinder or block sensor performance. For example, sensors often do not perform well until the FBC has matured sufficiently to provide ingrowth of well-attached tissue bearing a rich supply of capillaries directly to the surface of the sensor. With reference to
II. The Implantable Glucose Monitoring Device of the Present Invention
The present invention contemplates the use of a unique micro-geometry at the sensor interface of an implantable device. Moreover, the present invention contemplates the use of materials covering all or a portion of the device to assist in the stabilization of the device following implantation. However, it should be pointed out that the present invention does not require a device comprising particular electronic components (e.g., electrodes, circuitry, etc). Indeed, the teachings of the present invention can be used with virtually any monitoring device suitable for implantation (or subject to modification allowing implantation); suitable devices include, but are not limited, to those described in U.S. Pat. No. 6,001,067 to Shults et al.; U.S. Pat. No. 4,703,756 to Gough et al., and U.S. Pat. No. 4,431,004 to Bessman et al.; the contents of each being hereby incorporated by reference, and Bindra et al., Anal. Chem. 63:1692-96 (1991).
In the discussion that follows, an example of an implantable device that includes the features of the present invention is first described. Thereafter, the specific characteristics of, for example, the sensor interface contemplated by the present invention will be described in detail.
Generally speaking, the implantable devices contemplated for use with the present invention are cylindrical or oval shaped; of course, devices with other shapes may also be used with the present invention. The sample device includes a housing composed of radiotransparent ceramic.
As indicated in detail in
In a preferred embodiment, the device is cylindrical, as shown in
Maintaining the blood supply near an implanted foreign body like an implanted analyte-monitoring sensor requires stable fixation of FBC tissue on the surface of the foreign body. This can be achieved, for example, by using capsular attachment (anchoring) materials (e.g., those materials that includes the sensor interface and tissue anchoring layers) developed to repair or reinforce tissues, including, but not limited to, polyester (DACRON�; DuPont; poly(ethylene terephthalate)) velour, expanded polytetrafluoroethylene (TEFLON/�; Gore), polytetrafluoroethylene felts, polypropylene cloth, and related porous implant materials. In a preferred embodiment, porous silicone materials are used for anchoring the device. In another embodiment, non-woven polyester fibers are used for anchoring the device. Tissue tends to aggressively grow into the materials disclosed above and form a strong mechanical bond (i.e., tissue anchoring); this fixation of the implant in its capsule is essential to prevent motion artifact or disturbance of the newly developed capillary blood supply.
In a preferred embodiment, the anchoring material is attached directly to the body of the device. In the case of non-woven polyester fibers, they may be sutured into place by rolling the material onto the circumferential periphery of the device and further encircling the membrane with PTFE sutures and tying the sutures to hold the membrane in place. In another preferred embodiment, porous silicone is attached to the surface of the cylindrical device using medical grade silicone adhesive. In either case, the material may be further held in place by an o-ring (
As shown in
The housing of the devices of the present invention preferably contain a biocompatible ceramic material. A preferred embodiment of the device contains a radiofrequency transmitter and antenna within the body of the ceramic device. Ceramic materials are radiotransparent and, therefore, are preferred over metals that are radioopaque. Ceramic materials are preferred over plastic materials (which may also be radiotransparent) because they are more effective than plastics at preventing water penetration. In one embodiment of the invention, the ceramic head and body are connected at an approximately 0.9 cm long taper joint sealed with epoxy. In other embodiments, the head and body may be attached by sealing with metals to produce a completely hermetic package.
In one preferred embodiment of the inventive device, each of the membrane layers is affixed to the ceramic head 10 in
The present invention contemplates the construction of the membrane layers of the sensor interface region using standard film coating techniques. This type of membrane fabrication facilitates control of membrane properties and membrane testing.
III. The Sensor Interface Region
As mentioned above and disclosed in
Measurement of analyte in a filtrate of biological fluid samples has been shown to be preferred over direct measurement of analyte in biological fluid in order to minimize effects of interfering substances and improve control of sample volume. It is well known in the art that electrode surfaces exposed to a wide range of biological molecules will suffer poisoning of catalytic activity and failure. However, utilizing the layers and membranes of the present invention, the active electrochemical surfaces of the sensor electrodes are preserved, allowing activity to be retained for extended periods of time in vivo. By limiting exposure of the platinum sensor surface to certain molecular species (e.g., molecules having a molecular weight below 34 Daltons, the molecular weight of hydrogen peroxide), in vivo sensor operating life in excess of one year in canine subjects has been observed.
A. Angiogenic Layer
For implantable glucose monitoring devices, a sensor/tissue interface must be created which provides the sensor with oxygen and glucose concentrations comparable to that normally available to tissue comprised of living cells. Absent such an interface, the sensor is associated with unstable and chaotic performance indicating that inadequate oxygen and/or glucose are reaching the sensor. The development of interfaces in other contexts has been reported. For example, investigators have developed techniques that stimulate and maintain blood vessels inside a FBC to provide for the demanding oxygen needs of pancreatic islets within an implanted membrane. [See, e.g., Brauker et al., J. Biomed. Mater. Res. (1995) 29:1517-1524]. These techniques depend, in part, on the use of a vascularizing layer on the exterior of the implanted membrane. However, previously described implantable analyte-monitoring devices have not been able to successfully maintain sufficient blood flow to the sensor interface.
As described above, the outermost layer of the electrode-membrane region includes an angiogenic material. The angiogenic layer of the devices of the present invention may be constructed of membrane materials such as hydrophilic polyvinylidene fluoride (e.g., Durapore�; Millipore Bedford, Mass.), mixed cellulose esters (e.g., MF; Millipore Bedford, Mass.), polyvinyl chloride (e.g., PVC; Millipore Bedford, Mass.), and other polymers including, but not limited to, polypropylene, polysulphone, and polymethylmethacrylate. Preferably, the thickness of the angiogenic layer is about 10 μm to about 20 μm. The angiogenic layer comprises pores sizes of about 0.5 μm to about 20 μm, and more preferably about 1.0 μm to about 10 μm, sizes that allow most substances to pass through, including, e.g., macrophages. The preferred material is expanded PTFE of a thickness of about 15 μm and pore sizes of about 5 μm to about 10 μm.
To further promote stable foreign body capsule structure without interfering with angiogenesis, an additional outermost layer of material comprised of a thin low-density non-woven polyester (e.g., manufactured by Reemay) can be laminated over the preferred PTFE described above. In preferred embodiments, the thickness of this layer is about 120 μm. This additional thin layer of material does not interfere with angiogenesis and enhances the manufacturability of the angiogenic layer. [See U.S. Pat. No. 5,741,330 to Brauker et al., hereby incorporated by reference; also U.S. Pat. No. 5,782,912, U.S. Pat. No. 5,800,529, U.S. Pat. No. 5,882,354 U.S. Pat. No. 5,964,804 assigned to Baxter].
B. Bioprotective Membrane
The inflammatory response that initiates and sustains a FBC is associated with both advantages and disadvantages. Some inflammatory response is needed to create a new capillary bed in close proximity to the surface of the sensor in order to i) continuously deliver adequate oxygen and glucose and ii) create sufficient tissue ingrowth to anchor the implant and prevent motion artifact. On the other hand, inflammation is associated with invasion of tissue macrophages that have the ability to biodegrade many artificial biomaterials (some of which were, until recently, considered nonbiodegradable). When activated by a foreign body, tissue macrophages degranulate, releasing from their cytoplasmic myeloperoxidase system hypochlorite (bleach), H2O2 and other oxidant species. Both hypochlorite and H2O2 are known to break down a variety of polymers, including polyurethane, by a phenomenon referred to as environmental stress cracking. [Phillips et al., J. Biomat. Appl., 3:202-227 (1988); Stokes, J. Biomat. Appl. 3:228-259 (1988)]. Indeed, environmental stress cracking has been shown to limit the lifetime and performance of an enzyme-active polyurethane membrane stretched over the tip of a glucose sensor. [Updike et al., Am. Soc. Artificial Internal Organs, 40:157-163 (1994)].
Because both hypochlorite and H2O2 are short-lived chemical species in vivo, biodegradation will not occur if macrophages are kept a sufficient distance from the enzyme active membrane. The present invention contemplates the use of a bioprotective membrane that allows transport of glucose and oxygen but prevents the entry of inflammatory cells such as macrophages and foreign body giant cells. The bioprotective membrane is placed proximal to the angiogenic membrane. It may be simply placed adjacent to the angiogenic layer without adhering, or it may be attached with an adhesive material to the angiogenic layer, or it may be cast in place upon the angiogenic layer as described in Example 1. The devices of the present invention are not limited by the nature of the bioprotective layer. However, the bioprotective layer should be biostable for long periods of time (e.g., several years); the present invention contemplates the use of polymers including, but not limited to, polyurethane, polypropylene, polysulphone, polytetrafluoroethylene (PTFE), and poly(ethylene terephthalate) (PET).
The bioprotective membrane and the angiogenic layer may be combined into a single bilayer membrane as more fully described in Example 1. The active angiogenic function of the combined membrane is based on the presentation of the ePTFE side of the membrane to the reactive cells of the foreign body capsule and further to the response of the tissue to the microstructure of the ePTFE. This bioprotective/angiogenic membrane is unique in that the membrane does not delaminate as has been observed with other commercially available membranes (see
C. Sensing Membrane
The present invention contemplates membranes impregnated with enzyme. It is not intended that the present invention be limited by the nature of the enzyme membrane. The sensing membrane of a preferred embodiment is depicted in
Resistance Layer
There is a molar excess of glucose relative to the amount of oxygen in samples of blood. Indeed, for every free oxygen molecule in extracellular fluid, there are typically more than 100 glucose molecules present [Updike et al., Diabetes Care 5:207-21 (1982)]. However, an immobilized enzyme-based sensor using oxygen (O2) as cofactor must be supplied with oxygen in non-rate-limiting excess in order to respond linearly to changes in glucose concentration while not responding to changes in oxygen tension. More specifically, when a glucose-monitoring reaction is oxygen-limited, linearity is not achieved above minimal concentrations of glucose. Without a semipermeable membrane over the enzyme layer, linear response to glucose levels can be obtained only up to about 40 mg/dL; however, in a clinical setting, linear response to glucose levels are desirable up to at least about 500 mg/dL.
The resistance layer includes a semipermeable membrane that controls the flux of oxygen and glucose to the underlying enzyme layer (i.e., limits the flux of glucose), rendering the necessary supply of oxygen in non-rate-limiting excess. As a result, the upper limit of linearity of glucose measurement is extended to a much higher value than that which could be achieved without the resistance layer. The devices of the present invention contemplate resistance layers comprising polymer membranes with oxygen-to-glucose permeability ratios of approximately 200:1; as a result, one-dimensional reactant diffusion is adequate to provide excess oxygen at all reasonable glucose and oxygen concentrations found in the subcutaneous matrix [Rhodes et al., Anal. Chem., 66:1520-1529 (1994)].
In preferred embodiments, the resistance layer has a thickness of less than about 45 μm, more preferably in the range of about 15 to about 40 μm, and most preferably in the range of about 20 to about 35 μm.
The resistance layer is desirably constructed of a mixture of hydrophobic and hydrophilic polyurethanes.
Enzyme Layer
In addition to glucose oxidase, the present invention contemplates the use of a membrane layer impregnated with other oxidases, e.g., galactose oxidase, uricase. For an enzyme-based electrochemical glucose sensor to perform well, the sensor's response must, neither be limited by enzyme activity nor cofactor concentration. Because enzymes, including the very robust glucose oxidase, are subject to deactivation as a function of ambient conditions, this behavior needs to be accounted for in constructing sensors for long-term use.
Excess glucose oxidase loading is required for long sensor life. When excess glucose oxidase is used, up to 1.5 years of performance may be possible from the glucose-monitoring devices contemplated by the present invention.
In one preferred embodiment, the enzyme layer includes a polyurethane latex.
Interference Layer
The interference layer includes a thin, hydrophobic membrane that is non-swellable and restricts diffusion of low molecular weight species. The interference layer is permeable to relatively low molecular weight substances, such as hydrogen peroxide, but restricts the passage of higher molecular weight substances, including glucose and ascorbic acid. The interference layer serves to allow analytes and other substances that are to be measured by the electrodes to pass through, while preventing passage of other substances.
Preferred materials from which the interference layer can be made include polyurethanes. In one desired embodiment, the interference layer includes an aliphatic polyetherurethane.
The interference layer has a preferred thickness of less than about 5 μm, more preferably in the range of about 0.1 to about 5 μm and most preferably in the range of about 0.5 to about 3 μm. Thicker membranes also may be useful, but thinner membranes are preferred because they have a lower impact on the rate of diffusion of hydrogen peroxide from the enzyme membrane to the electrodes.
Electrolyte Layer
To ensure electrochemical reaction, the electrolyte layer comprises a semipermeable coating that maintains hydrophilicity at the electrode region of the sensor interface. The electrolyte layer enhances the stability of the interference layer of the present invention by protecting and supporting the membrane that makes up the interference layer. Furthermore, the electrolyte layer assists in stabilizing operation of the device by overcoming electrode start-up problems and drifting problems caused by inadequate electrolyte. The buffered electrolyte solution contained in the electrolyte layer also protects against pH-mediated damage that may result from the formation of a large pH gradient between the hydrophobic interference layer and the electrode (or electrodes) due to the electrochemical activity of the electrode.
Preferably, the coating includes a flexible, water-swellable, substantially solid gel-like film having a "dry film" thickness of about 2.5 μm to about 12.5 μm, preferably about 6.0 μm. "Dry film" thickness refers to the thickness of a cured film cast from a coating formulation onto the surface of the membrane by standard coating techniques. The coating formulation includes a premix of film-forming polymers and a crosslinking agent and is curable upon the application of moderate heat.
Suitable coatings are formed of a curable copolymer of a urethane polymer and a hydrophilic film-forming polymer. Particularly preferred coatings are formed of a polyurethane polymer having anionic carboxylate functional groups and non-ionic hydrophilic polyether segments, which is crosslinked in the present of polyvinylpyrrolidone and cured at a moderate temperature of about 50� C.
Particularly suitable for this purpose are aqueous dispersions of fully reacted colloidal polyurethane polymers having cross-linkable carboxyl functionality (e.g., BAYBOND�; Mobay Corporation, Pittsburgh, Pa.). These polymers are supplied in dispersion grades having a polycarbonate-polyurethane backbone containing carboxylate groups identified as XW-121 and XW-123; and a polyester-polyurethane backbone containing carboxylate groups, identified as XW-110-2. Particularly preferred is BAYBOND� 123, an aqueous anionic dispersion of an aliphate polycarbonate urethane polymer, sold as a 35 weight percent solution in water and co-solvent N-methyl-2-pyrrolidone.
Polyvinylpyrrolidone is also particularly preferred as a hydrophilic water-soluble polymer and is available commercially in a range of viscosity grades and average molecular weights ranging from about 18,000 to about 500,000, under the PVP K� homopolymer series by BASF Wyandotte (Parsippany, N.J.) and by GAF Corporation (New York, N.Y.). Particularly preferred is the homopolymer having an average molecular weight of about 360,000, identified as PVP-K90 (BASF Wyandotte). Also suitable are hydrophilic, film-forming copolymers of N-vinylpyrrolidone, such as a copolymer of N-vinylpyrrolidone and vinyl acetate, a copolymer of N-vinylpyrrolidone, ethylmethacrylate and methacrylic acid monomers, and the like.
The polyurethane polymer is crosslinked in the presence of the polyvinylpyrrolidone by preparing a premix of the polymers and adding a cross-linking agent just prior to the production of the membrane. Suitable cross-linking agents can be carbodiimides, epoxides and melamine/formaldehyde resins. Carbodiimide is preferred, and a preferred carbodiimide crosslinker is UCARLNK� XL-25 (Union Carbide, Chicago, Ill.).
The flexibility and hardness of the coating can be varied as desired by varying the dry weight solids of the components in the coating formulation. The term "dry weight solids" refers to the dry weight percent based on the total coating composition after the time the crosslinker is included. A preferred useful coating formulation can contain about 6 to about 20 dry weight percent, preferably about 8 dry weight percent, of polyvinylpyrrolidone; about 3 to about 10 dry weight percent, preferably about 5 dry weight percent of cross-linking agent; and about 70 to about 91 weight percent, preferably about 87 weight percent of a polyurethane polymer, preferably a polycarbonate-polyurethane polymer. The reaction product of such a coating formulation is referred to herein as a water-swellable cross-linked matrix of polyurethane and PVP.
D. The Electrolyte Phase
The electrolyte phase is a free-fluid phase including a solution containing at least one compound, usually a soluble chloride salt that conducts electric current. The electrolyte phase flows over the electrodes (see
Generally speaking, the electrolyte phase should have the same or less osmotic pressure than the sample being analyzed. In preferred embodiments of the present invention, the electrolyte phase includes saline.
E. The Electrode
The electrode assembly of this invention may also be used in the manner commonly employed in the making of amperometric measurements. The interstitial fluids containing the analyte to be measured is in contact with a reference electrode, e.g., silver/silver-chloride, and the anode and cathode of this invention, which are preferably formed of platinum. In the preferred embodiment, the electrodes are connected to a circuit board in the body of the sensor, the current is read and the information is radiotransmitted to a receiver. The invention is not limited to this preferred embodiment. Indeed the membranes of the present invention could be used with any form of implantable sensor and adapted to the particular features of the sensor by one skilled in the art.
The ability of the present device electrode assembly to accurately measure the concentration of substances such as glucose over a broad range of concentrations enables the rapid and accurate determination of the concentration of those substances. That information can be employed in the study and control of metabolic disorders including diabetes.
IV. Sensor Implantation and Radiotelemetric Output
Long-term sensor performance is best achieved, and transcutaneous bacterial infection is eliminated, with implanted devices capable of radiotelemetric output. The present invention contemplates the use of radiotelemetry to provide data regarding blood glucose levels, trends, and the like. The term "radiotelemetry" refers to the transmission by radio waves of the data recorded by the implanted device to an ex vivo recording station (e.g., a computer), where the data is recorded and, if desired, further processed.
Although totally implanted glucose sensors of three month lifetime, with radiotelemetric output, have been tested in animal models at intravenous sites [see, e.g. Armour et al., Diabetes, 39:1519-1526 (1990)], subcutaneous implantation is the preferred mode of implantation [see, e.g., Gilligan et al., Diabetes Care 17:882-887 (1994)]. The subcutaneous site has the advantage of lowering the risk for thrombophlebitis with hematogenous spread of infection and also lowers the risk of venous thrombosis with pulmonary embolism. In addition, subcutaneous placement is technically easier and more cost-effective than intravenous placement, as it may be performed under local anesthesia by a non-surgeon health care provider in an outpatient setting.
Preferably, the radiotelemetry devices contemplated for use in conjunction with the present invention possess features including small package size, adequate battery life, acceptable noise-free transmission range, freedom from electrical interference, and easy data collection and processing. Radiotelemetry provides several advantages, one of the most important of which is the ability of an implanted device to measure analyte levels in a sealed-off, sterile environment.
The present invention is not limited by the nature of the radiotelemetry equipment or methods for its use. Indeed, commercially available equipment can be modified for use with the devices of the present invention (e.g., devices manufactured by Data Sciences). Similarly, custom-designed radiotelemetry devices like those reported in the literature can be used in conjunction with the implantable analyte-measuring devices of the present invention [see, e.g., McKean and Gough, IEEE Trans. Biomed. Eng. 35:526-532 (1988); Shichiri et al., Diabetes Care 9:298-301 (1986); and Shults et al., IEEE Trans. Biomed. Eng. 41:937-942 (1994)]. In a preferred embodiment, transmitters are programmed with an external magnet to transmit at 0.5 or 5-minute intervals, depending on the need of the subject; presently, battery lifetimes at transmission intervals of 5 minutes are approximately up to 1.5 years.
V. Experimental
The following examples serve to illustrate certain preferred embodiments and aspects of the present invention and are not to be construed as limiting the scope thereof.
In the preceding description and the experimental disclosure which follows, the following abbreviations apply: Eq and Eqs (equivalents); mEq (milliequivalents); M (molar); mM (millimolar) μM (micromolar); N (Normal); mol (moles); mmol (millimoles); μmol (micromoles); nmol (nanomoles); g (grams); mg (milligrams); μg (micrograms); Kg (kilograms); L (liters); mL (milliliters); dL (deciliters); μL (microliters); cm (centimeters); mm (millimeters); μm (micrometers); nm (nanometers); h and hr (hours); min. (minutes); s and sec. (seconds); � C. (degrees Centigrade); Astor Wax (Titusville, Pa.); BASF Wyandotte Corporation (Parsippany, N.J.); Data Sciences, Inc. (St. Paul, Minn.); DuPont (DuPont Co., Wilmington, Del.); Exxon Chemical (Houston, Tex.); GAF Corporation (New York, N.Y.); Markwell Medical (Racine, Wis.); Meadox Medical, Inc. (Oakland, N.J.); Mobay (Mobay Corporation, Pittsburgh, Pa.); Sandoz (East Hanover, N.J.); and Union Carbide (Union Carbide Corporation; Chicago, Ill.).
The angiogenic layer may be an ePTFE filtration membrane (Zefluor™, 3.0 μm P5PI001, Pall Gelman, Ann Arbor, Mich.) and the bioprotective membrane (C30P) may then be coated on the angiogenic layer. For example, the C30P coating solution was prepared by placing approximately 706 gm of dimethylacetamide (DMAC) into a 3 L stainless steel bowl to which a polycarbonateurethane solution (1325 g, Chronoflex AR 25% solids in DMAC and 5100 cp) and polyvinylpyrrolidone (125 g, Plasdone K-90D) were added. The bowl was then fitted to a planetary mixer with a paddle type blade and the contents were stirred for 1 hour at room temperature. This solution was then coated on the ePTFE filtration membrane by knife-edge drawn at a gap of 0.006″ and dried at 60� C. for 24 hours.
Alternatively, the C30P solution prepared above can be coated onto a PET release liner using a knife over roll coating machine. This material is then dried at 305� F. for approximately 2 minutes. Next, the Zefluor™ is immersed in 50:50 (w/v) mixture of tetrahydrofuran/DMAC and then placed upon the coated polyurethane polyvinylpyrrolidone material. Light pressure atop the assembly intimately embeds the ePTFE into the C30P layer. The membrane is then dried at 60� C. for 24 hours.
The sensing membrane includes a resistance layer, an enzyme layer, an interference layer and an electrolyte layer. The resistance layer was prepared by placing approximately 281 gm of DMAC into a 3 L stainless steel bowl to which a solution of polyetherurethaneurea (344 gm of Chronothane H, 29,750 cp at 25% solids in DMAC) was added. To this mixture was added another polyetherurethaneurea (312 gm, Chronothane 1020, 6275 cp at 25% solids in DMAC). The bowl was fitted to a planetary mixer with a paddle type blade and the contents were stirred for 30 minutes at room temperature. The resistance layer coating solution produced is coated onto a PET release liner (Douglas Hansen Co., Inc. Minneapolis, Minn.) using a knife over roll set at a 0.012″ gap. This film is then dried at 305� F.
The enzyme layer was prepared by placing 304 gm polyurethane latex (Bayhydrol 140AQ, Bayer, Pittsburgh, Pa.) into a 3 L stainless steel bowl to which 51 gm of pyrogen free water and 5.85 gm of glucose oxidase (Sigma type VII from Aspergillus niger) is added. The bowl was then fitted to a planetary mixer with a whisk type blade and the mixture was stirred for 15 minutes. Approximately 24 hr prior to coating, a solution of glutaraldehyde (15.4 ml of a 2.5% solution in pyrogen free water) and 14 ml of pyrogen free water was added to the mixture. The solution was mixed by inverting a capped glass bottle by hand for about 3 minutes at room temperature. This mixture was then coated over the resistance layer with a #10 Mayer rod and dried above room temperature preferably at about 50� C.
The interference layer was prepared by placing 187 gm of tetrahydrofuran into a 500 ml glass bottle to which an 18.7 gm aliphatic polyetherurethane (Tecoflex SG-85A, Thermedics Inc., Woburn, Mass.) was added. The bottle was placed onto a roller at approximately 3 rpm within an oven set at 37� C. The mixture was allowed to roll for 24 hr. This mixture was coated over the dried enzyme layer using a flexible knife and dried above room temperature, preferably at about 50� C.
The electrolyte layer was prepared by placing 388 gm of polyurethane latex (Bayhydrol 123, Bayer, Pittsburgh, Pa. in a 3 L stainless steel bowl to which 125 gm of pyrogen free water and 12.5 gm polyvinylpyrrolidone (Plasdone K-90D) was added. The bowl was then fitted to a planetary mixer with a paddle type blade and stirred for 1 hr at room temperature. Within 30 minutes of coating, approximately 13.1 ml of carbodiimide (UCARLNK) was added and the solution was mixed by inverting a capped polyethylene jar by hand for about 3 min at room temperature. This mixture was coated over the dried interference layer with a #10 Mayer rod and dried above room temperature preferably at about 50� C.
In order to affix this multi-region membrane to a sensor head, it is first placed into phosphate buffer (pH 7.4) for about 2 minutes. It is then stretched over the nonconductive body of sensor head and affixed into place with an o-ring.
In vivo sensor function was determined by correlating the sensor output to blood glucose values derived from an external blood glucose meter. We have found that non-diabetic dogs do not experience rapid blood glucose changes, even after ingestion of a high sugar meal. Thus, a 10% dextrose solution was infused into the sensor-implanted dog. A second catheter is placed in the opposite leg for the purpose of blood collection. The implanted sensor was programmed to transmit at 30-second intervals using a pulsed electromagnet. A dextrose solution was infused at a rate of 9.3 ml/minute for the first 25 minutes, 3.5 ml/minute for the next 20 minutes, 1.5 ml/minute for the next 20 minutes, and then the infusion pump was powered off. Blood glucose values were measured in duplicate every five minutes on a blood glucose meter (LXN Inc., San Diego, Calif.) for the duration of the study. A computer collected the sensor output. The data was then compiled and graphed in a spreadsheet, time aligned, and time shifted until an optimal R-squared value was achieved. The R-squared value reflects how well the sensor tracks with the blood glucose values.
To test the importance of the composite membrane of the invention described in Example 1, implantable glucose sensors including the composite and sensing membranes of the present invention were implanted into dogs in the subcutaneous tissues and monitored for glucose response on a weekly basis. Control devices including only a bioprotective C30P layer ("Control") were compared with devices including both a bioprotective and an angiogenic layer ("Test"), which corresponded to the composite bioprotective/angiogenic membrane of the device of the present invention described in Example 1.
Four devices from each condition were implanted subcutaneously in the ventral abdomen of normal dogs. On a weekly basis, the dogs were infused with glucose as described above in order to increase their blood glucose levels from about 120 mg/dl to about 300 mg/dl. Blood glucose values were determined with a LXN blood glucose meter at 5-minute intervals. Sensor values were transmitted at 0.5-minute intervals. Regression analysis was done between blood glucose values and the nearest sensor value within one minute. Devices with an R-squared value greater than 0.5 were considered functional.
The description and experimental materials presented above are intended to be illustrative of the present invention while not limiting the scope thereof. It will be apparent to those skilled in the art that variations and modifications can be made without departing from the spirit and scope of the present invention.
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Novice Member
Joined: 2/20/12
Originally posted by Distopia
true how the classes are spread really has a huge impact.. with Rift it wasn't too bad because every class could take on multiple roles.. i just really dislike when I game pigeon holes you into a single role and you have no way to either spec out or have a dual role type build.
I angered the clerk in a clothing shop today. She asked me what size I was and I said actual, because I am not to scale. I like vending machines 'cause snacks are better when they fall. If I buy a candy bar at a store, oftentimes, I will drop it... so that it achieves its maximum flavor potential. --Mitch Hedberg
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Advanced Member
Joined: 8/28/06
No, I would like to see more games with an alternative to the holy trinity. I don't think GW2 combat model offered the best alternative. Most of the issues in GW2 were because 99% of mmos use the trinity and gamers had trouble with the learning curve and gamers are adverse to change. I like GW2 for many of its features. I would say the combat being what I liked the least.
Apprentice Member
Joined: 6/13/10
While GW2 combat isn't perfect I find it much better than holy trinity. I think I could never play holy trinity mmo anymore.
Joined: 11/22/05
"what a boring life, HATING everything" -Gorilla Biscuits
Originally posted by Aerowyn
Agreed, there's nothing that has me dropping a game faster than having limited options with classes.
For every minute you are angry , you lose 60 seconds of happiness."-Emerson
It is a sign of a defeated man, to attack at ones character in the face of logic and reason- Me
Originally posted by Homitu
It's been pointed out before, but none of the commenters seem to get it,( and it's funny because they criticize game developers for not being able to think outside of the box), the holy trinity originally was not tank/heal/dps. It was Tank, Heal, crowd control (which is another form of damage mitigation).
When the term was invented the DPS was assumed... you needed DPS + the holy trinity (or rather, the holy trinity, plus 3 more fillers). You also wanted some other things like buffers, and snarers - but the trinity was the start of the group, and you filled in the remainder with the best that you could.
You can make it the four horsemen, or whatever, by just making more necessary combat mechanics and giving them to more classes.
Certain content in EQ required someone to snare monsters - so it adventure in that area, you needed a snarer, plus the "holy trinity". Or you could do outdoor areas where monsters were single pulled, and an enchanter was not required, so you could just tank and heal your way to experience. In the same area, you could also "quad kite" four monsters at once with snare effects, and more than one player could group up to do this.
The problem was that they didn't balance the content... the majority of the content, the dungeon content, which had the best expereince (until later expansions) and the best loot was indoor content, which required enchanters (crowd control) and someone to stand next to the mobs and smack them.
Had EQ not done this design - had the best experience and loot been in outdoor regions that was dominated by Druids, Mages and Necromancers - the "holy trinity" may never have come into popular use.
So one way to fix it, is to balance your content so that it requires a diverse combination of groups to beat.
Make a dungeon where unstunnable monsters come in pairs, so you need two tanks and crowd control doesn't work. Make outdoor areas where the monsters regenerate hit points so quickly that you need 3 DPS on them to kill them - and then put the best Tank and Healer loot on those mobs so that the tanks and healers will ask the DPS to help them, rather than the inverse.
As to what a couple other people say about "roleplaying not being about playing roles". That's actually character playing. Combat based RPG's have always had roles, and they're fun. Emotes and gestures are nifty and all, but the cool mechanic of these games is playing a combat role, and doing it well.
Originally posted by mikuniman
No offense, but this makes no sense. If WoW was your first MMORPG, no one would have liked it because they didn't have any experience with the combat mechanics. Their entire player base would have been 1 million people from EQ and DAOC (who wouldn't have liked those games).
People didn't like GW2 because its combat was a mess, and your actions didn't have any impact on the world. GW2's combat is sort of like Jazz. Some people really love it, but in the end mpst, people like more structured music (and all jazz fans are convinced that Jazz is the best music there is).
Novice Member
Joined: 7/10/09
the holy trinity promotes teamwork, something I feel is lacking in a big way on a large scale that MMO's need to really capture that MMO feel.
WAR, despite its flaws had a great large scale teamwork feel. If that game had 3 factions I would still be playing it today.
WoW Vanilla..... you were what you were, and thats all people expected you to be. You teamed up with people to actually get somewhere in raiding. Now you are everything, and unless you want raiding epics.. which are useless anywhere but raiding, and raiding is small scale anyway... everything in wow is small scale now....... *sigh*
I am done playing MMO's without a holy trinity. I want real consequences to my class choices, i want real consequences to my spec choices. I want real guilds again that rely on every member.
Novice Member
Joined: 8/27/12
The lack of the holy trinity is the main reason I logged off last night and do not plan on coming back...I enjoy playing a healer and really making that class click in whatever mmo I play...GW2 was fun for a while, but I miss my defined role.
Novice Member
Joined: 3/02/12
Originally posted by Isturi
Wildstar will most definitely be using the Holy Trinity.
Novice Member
Joined: 2/20/12
Originally posted by steamtank
to me non holy trinity promotes "more" teamwork depending how the combat is setup.. when you have set roles and everyone knows there role it turns into auto pilot mode and you basically just follow your role and it really doesn't change ever. With a bit more chaos thrown into the mix and everyone needing to play mutliple roles in a single encounter it not only encourages more teamwork it actually requires people to really know how to play in various roles to complete objectives. Just preference i suppose but after playing both i prefer the non set roles as it adds more variety to the encounters imho, especially when running the same dungeon multiple times.
I angered the clerk in a clothing shop today. She asked me what size I was and I said actual, because I am not to scale. I like vending machines 'cause snacks are better when they fall. If I buy a candy bar at a store, oftentimes, I will drop it... so that it achieves its maximum flavor potential. --Mitch Hedberg
Hard Core Member
Joined: 12/17/10
My problem with gw 2 is that it is not a good implementation of the no holy trinity idea. I think City of X did it way better and people were still able to have clear roles which is the main reason it fails in gw 2.
Originally posted by kitarad
They must have changed from CoH, because CoH definitely copied the EQ, Tank, Heal, CC, DPS methodology.
Novice Member
Joined: 4/10/07
I hated the lack of the trinity.
Been playing MMOs for years now and while I thought it sounded great on paper, I knew it was doomed to fail.
It basically failed on all the expectations I had:
There's a couple of other minor things that made me dislike it a lot but yea those are the main ones.
So yeah, I hope no game tries that garbage again because I don't think it works at all in an MMO setting. It's like playing an FPS game where they've decided to give everyone the same gun, it's boring as hell.
Novice Member
Joined: 7/08/12
I find an all-hybrid system reduces the pride/feeling of accomplishment that I get from being really good at a particular role. I like defining myself and striving to be the best at that particular nitch, but while I do prefer having individual roles in a group setting, the classes themselves should be able to fill multiple roles based on gear,spec,etc. If a player's class can be specced for dps or healing then the developer needs to make sure that both/all roles are totally viable for that class and its up to the player to choose which he wants to pursue at any given time. This way the roles are there for you to swap between, but you need to put in the effort to gear for and learn how to play that role. Maybe "skill trees" could also be versatile enough to allow a hybrid spec for soloing.
In short, having defined group roles is good but each class needs the flexability to define itself as one of those roles depending on the players choice. Some classes may have two options while others may have three or more if you include hybrid specs.
What will eventually win the day is neither of the two poll options. It will be something wonderful and grand that you never imagined until Toyota entered the MMO business.
P.S. I'm from the future.
Advanced Member
Joined: 8/28/06
Originally posted by grimfall
It doesn't really matter then it matters now, when you have 10+ years of trinity mmos under a larger mmo player base and gamers generally brainwashed that that's the only system that could possible work because it's been done for so long and in so many mmos.
And as I mentioned GW2 did not do an alternative to holy trinity any justice. If I was to ask generally how many gamers that play mmos have experienced other alternatives to the holy trinity my guess the percentage would be low. That's all I was getting at.
As a musician myself I get your jazz reference as GW2 combat model being all over the place. I would add that the people that "got it" had no issues with the way it worked. Whether they liked over another is a matter of opinion. Yeah, I would agree that when someone is brand loyal they do think it's the best in the world.
Apprentice Member
Joined: 6/13/10
After GW2....I want a game that has world class realm vs realm warfare.....as my #1 desire.There are two games that offer that possibility...ELDER SCROLLS ONLINE...and THE REPOPULATION that I'm watching..
As for the trinity(not trio) of the three classes..or not.I'm for the freedom to specialize..or not.I'm for not being limited to a mainly cleric class or mainly mage class etc.That would be my preference.
Novice Member
Joined: 6/23/06
I prefer the old EQ system of Tank, Healer, Crowd control + DPS. The GW2 system doesn't feel anymore fun or challenging to me, chaotic yes, but not more fun.
GW2 reminds me a lot of the early days of EQ when we were still trying to figure out how to play our classes, manage agro and mana consumption and didn't have the optimal group makeup. It would take every ounce of concentration and quick thinking, kiting, ranger healing, fearing the mobs while everyone bandaged and eventually running back to finish off the mob before it could heal up again if you died. It was very intense and sometimes fun, but also very limiting because it was impossible to take on the more challenging content that was designed to challenge specialty classes.
I am glad GW2 went with the model they did so the anti-role community has more choices now, but I'll gladly stick to more structured combat.
Novice Member
Joined: 4/05/12
I prefer the defined roles myself. I was really looking forward to the idea of "No waiting for certain types of characters" to do a dungeon and the extreme homonogization of classes. However when I actually played with it... I was sorely disappointed.
I would like to see all classes have the option to perform all three roles. If you want to tank, well there's a way for your class to do it. Want to heal or DPS? Well you can do both as well. Design the classes to be able to do all three, but make the encounters require dedication for each role. Could easily be done IMHO by just swapping out skills. 5 random people all queue up for a dungeon, decide then who fills what role. Problem solved. If no one wants to fill a certain role, you have no one to blame but your group because everyone is capable of performing each role.
Apprentice Member
Joined: 2/08/06
I don't mind it but it seems GW2 just didn't make their game right at all. It is way faster puting a group together, and that is a massive bonus.
Novice Member
Joined: 10/23/08
To be as honest as i can: Holy Trinity was never good, never is and never will be, in my opinion. This is the thing i hated the most in MMORPG (next to the "gear treadmill").
However, is GW2's class system a good implementation of "non-trinity"? Well, while it have its flaws, it surely do its job. So, yes it can always be better, in GW2's case, but i will support every person who think that combat in MMORPG can be more diverse than standard "Tank\Healer\DPS" mechanic (which is a nice thing on paper, but it brings more bad stuff than good, in my opinion).
Bottom line: wanting "holy trio" back would be like wanting more of the same and i think its time for something different.
Main MMO at the moment: Guild Wars 2


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Relocating to Montreal? 6 Things to Do for Easter
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On Town Meeting day, Moretown residents will vote on an article that could raise the ceiling on the limit the town can spend without holding a townwide vote; select board members voted in favor of increasing the expenditure level requirement from $5,000 to $10,000 at their January 3 meeting.
As it stands, the town cannot spend over $5,000 without first getting
the authorization of the voters via a townwide Australian ballot vote
unless they tap into the Capital Reserve Fund.
Select board member David Van Deusen said that raising the ceiling on the expenditure level requirement would increase Town Meeting participation by allowing more discussion from the floor.
"I don't think it gives anybody an advantage in town, and I don't think it gives anybody a disadvantage; I think it's a healthy thing and we should have that discussion," he said.
Select board chair John Hoogenboom said, "At one point we agreed it would be a good idea."
Select board assistant Cheryl Brown asked what would happen if the voters amended the article and lowered the expenditure level limit. "If you have an emergency under $5,000, you have to wait for a vote and that takes at least 30 days," she said.
Van Deusen said he didn't think lowering the limit would be an issue with the way the town's finances are currently set up.
"We have the cushion of the reserve fund."
Brown said that the town cannot use reserve funds for everything--legal fees included.
Select board member Stephanie Venema abstained. "I'm abstaining because I don't see the advantage of it," she said.
Van Deusen said he knew the Town Meeting moderator was in favor of the idea and that it "isn't something to be afraid of."
"People are going to be at Town Meeting, engaged on this issue; the more choices you give people on the floor the more engaged your community is going to be," he continued.
Van Deusen announced that he will not seek re-election to the select board in March. In a circulated newsletter he said that for the duration of his term, top priorities include "property tax relief for wounded military veterans, exploring the possibility of establishing a wind farm in Moretown, and expanding the democratic powers of the people as gathered at Town Meeting by increasing the monetary limit placed on floor votes (versus Australian ballot).