Abstract: There are numerous medical situations involving deficiencies of living bone or periodontal tissue and where increase of living bone or periodontal tissue mass is desired. Methods are described wherein a configured, shell-like device that is capable of being penetrated by living cells and tissues, is implanted into the body of a mammal in such a way as to establish a space, the space being at least partly, bounded by the device. The configuration of the device is such that the configuration of the established space is essentially the same as the configuration of living bone or periodontal tissue that is desired for treatment of the tissue deficiency. At least one protein from the Transforming Growth Factor-Beta Superfamily of proteins is placed within the established space for the purpose of stimulating the growth of living bone or periodontal tissue within the established space. A kit for the generation of living bone or periodontal tissue, comprised of the components mentioned above, is also disclosed.

Abstract: A bone regeneration material uses polyphosphoric acid and/or a polyphosphate together with a biocompatible material, a filler for cosmetic surgery, or a bone morphogenetic protein, to expedite new bone formation and shorten healing time or restoration in the treatment of bone fractures or damage.

Abstract: Crosslinked compositions formed from a water-insoluble copolymer are disclosed. These compositions are copolymers having a bioresorbable region, a hydrophilic region and at least two crosslinkable functional groups per polymer chain. These compositions are able to form hydrogels in aqueous environments when crosslinked. These hydrogels are good sealants for implantable prostheses when in contact with an aqueous environment. In addition, such hydrogels can be used as delivery vehicles for therapeutic agents.

Abstract: An artificial pancreas is described herein which comprises one or more viable and physiologically active pancreatic islet cells capable of producing insulin, encapsulated within a semipermeable spheroidal membrane comprising agar gel. Further disclosed are a method for producing agar microbeads, a tissue implantation method and a reseeding method for the artificial pancreas.

Abstract: The invention is directed to a device for delivering an active agent formulation for a predetermined administration period. An impermeable reservoir is divided into a water-swellable agent chamber and an active agent formulation chamber. Fluid from the environment is imbibed through a semipermeable plug into the water-swellable agent chamber and the active agent formulation is released through a back-diffusion regulating outlet. Delivery periods of up to 2 years are achieved.

Abstract: The invention is directed to a biodegradable implant precursor having a two-part structure made of an outer sac and a liquid content. The implant precursor is composed of a biodegradable, water-coagulable thermoplastic polymer and a water-miscible organic solvent. When administered to an implant site in an animal, the implant precursor will solidify in situ to a solid, microporous matrix by dissipation of the organic solvent to surrounding tissue fluids and coagulation of the polymer. The invention also includes methods of making the implant precursor, an apparatus for forming the precursor, and a kit containing the apparatus. Also provided are methods of using the implant precursor for treating a tissue defect in an animal, for example, for enhancing cell growth and tissue regeneration, wound and organ repair, nerve regeneration, soft and hard tissue regeneration, and the like, for delivery of biologically-active substances to tissue or organs, and other like therapies.

Abstract: A medical device and method for transportation and release of a therapeutic agent into a mammalian body are disclosed. The medical device is coated with alternating layers of a negatively charged therapeutic agent and a cationic polyelectrolyte, following a controlled adsorption technique. The method is simple,' with minimal perturbation to the therapeutic agent and uses clinically acceptable biopolymers such as human serum albumin. The amount of the therapeutic agent that can be delivered by this technique is optimized by the number of the layers of the therapeutic agent adsorbed on the surface of medical device. There is a washing step between alternate layers of the therapeutic agent and cationic polyelectrolyte carrier, so that the amount of the therapeutic agent on the insertable medical device represents the portion that is stably entrapped and adsorbed on to the medical device.

Abstract: The invention provides a method for delivering biologically active molecules to the eye by implanting biocompatible capsules containing a cellular source of the biologically active molecule. Also provided is a method of treating ophthalmic diseases using biocompatible capsules.

Abstract: The subject invention is directed to the prevention of elastic fiber injury by administering HA or any other polysaccharide or carbohydrate moiety that binds to and coats elastic fibers, thereby preventing enzymes, oxidants, or other injurious agents from contacting and damaging these fibers. The method may be used to prevent elastic fiber damage which occurs to the skin and blood vessels as a consequence of aging, to the uterus during pregnancy, and in diseases such as pulmonary emphysema, aortic aneurysm, and joint disease. The treatment is intended for humans and a variety of other mammals. The polysaccharide or carbohydrate moiety may be administered orally, cutaneously, subcutaneously, intravenously, intratracheally, or by any other route deemed efficacious. It may be administered alone or in combination with another polysaccharide or carbohydrate moiety, with or without a carrier such as saline solution, DMSO, alcohol or water.

Abstract: The present invention provides an osmotic device containing controlled release alprazolam in the core optionally in combination with an anti-psychotic agent, in a rapid release external coat. A wide range of anti-psychotic agents can be used in this device. Particular embodiments of the invention provide osmotic devices having predetermined release profiles. One preferred embodiment of the osmotic device includes an external coat that has been spray coated rather compression coated onto the device. The device with spray coated external core is smaller and easier to swallow than the similar device having a compression coated external coat. The device is useful for the treatment of depression, anxiety or psychosis related disorders.

Abstract: This invention provides rate controlling membranes for controlled drug delivery devices that are stable over time and exhibit more predictable and consistent membrane functionality. According to another aspect, the membranes have enhanced permeability. According to the invention, the rate controlling membrane of a controlled drug delivery device is subjected to a pre-treatment annealing process wherein it is subjected to an elevated temperature for a predetermined time period and subsequently cooled to ambient conditions before incorporation into a controlled drug delivery device.

Abstract: Bioartificial implants and methods for their manufacture and use are described, particularly bioartificial pancreases. In particular, the implants may be thin sheets which enclose cells, may be completely biocompatible over extended periods of time and may not induce fibrosis. The high-density-cell-containing thin sheets are preferably completely retrievable, and have dimensions allowing maintenance of optimal tissue viability through rapid diffusion of nutrients and oxygen and also allowing rapid changes in the secretion rate of insulin and/or other bioactive agents in response to changing physiology. Implantations of living cells, tissue, drugs, medicines and/or enzymes, contained in the bioartificial implants may be made to treat and/or prevent disease.

Abstract: Implantable devices that include a source of a therapeutic substance and a capture agent are disclosed.

Abstract: The present patent describes a three-dimensional interconnected open cell porous foams that have a gradient in composition and/or microstructure through one or more directions. These foams can be made from a blend of absorbable and biocompatible polymers that are formed into foams having a compositional gradient transitioning from predominately one polymeric material to predominately a second polymeric material. These gradient foams are particularly well suited to tissue engineering applications and can be designed to mimic tissue transition or interface zones.

Abstract: This invention provides rate controlling membranes for controlled drug delivery devices that are stable over time and exhibit more predictable and consistent membrane functionality. According to another aspect, the membranes have enhanced permeability. According to the invention, the rate controlling membrane of a controlled drug delivery device is subjected to a pre-treatment annealing process wherein it is subjected to an elevated temperature for a predetermined time period and subsequently cooled to ambient conditions before incorporation into a controlled drug delivery device.

Abstract: The present invention provides systems and methods for administering a therapeutic agent to a patient in need an initial loading dose of the therapeutic agent administered in conjunction with a long-term maintenance dose of the therapeutic agent. The present invention discloses subcutaneous-implantable dosage forms capable of administering the long-term maintenance dose of the therapeutic agent in a steady state or zero order manner. Systems and methods for administering an initial loading dose of a therapeutic agent administered in conjunction with an extended release dosage form of the therapeutic agent, and optionally in conjunction with a receptor loading dose of the therapeutic agent, are useful in the treatment of various diseases and disorders.

Abstract: Delivery devices capable of delivering one or more active substances by diffusion through plural micropores in the membrane or by osmotic pumping through one or more preformed passageways in the membrane are provided. The device has an about centrally located expandable core completely surrounded by an active substance-containing layer, which is completely surrounded by the membrane. The device is capable of delivering insoluble, slightly soluble, sparingly soluble and very soluble active substances to an environment of use. The preferred delivery rate is zero order. The device can deliver an active substance for a period of about 12-24 hours.

Abstract: Boronic acid containing polymers are used to form bioinert gels and multilayer surface structures. These polymers form crosslinked hydrogels, which are highly swollen in water. The crosslinking can either be chemical or physical. Water soluble polymers containing boronic acid groups, such as phenylboronic acid (PBA), can be physically crosslinked by mixing the polymers in water with other polymers containing hydroxyls or carboxylic acids. Alternatively, surfaces can be treated by stepwise incubation with a solution of the boronic acid containing polymer, followed by incubation with a solution of a diol or carboxylic acid containing polymer. Many successive layers can be generated, increasing the thickness of the formed structure at each step. The bioinert gel or surface coating can be used for passivating the surfaces of medical implants (especially those based on transplanted tissue), or for passivating the surfaces of tissues in situ.

Abstract: Premature Rupture of the Membranes (PROM) is a serious complication of pregnancy. PROM is treated by creation of a seal or barrier at the site of the rupture or in or near the cervix, thereby controlling the loss of amniotic fluid and preventing bacterial access. Instruments and techniques for application of sealing and barrier-forming materials at appropriate sites are described, as well as appropriate selection of materials and formation techniques. The instruments and techniques facilitate application of any fluent material to physiology associated with pregnancy and rendering the fluent material non fluent so as to form a barrier of seal.

Abstract: Methods and pharmaceutical compositions for using desmethylselegiline. In particular, the present invention provides novel compositions and methods for using desmethylselegiline for selegiline-responsive diseases and conditions. Diseases and conditions responsive to selegiline include those produced by neuronal degeneration or neuronal trauma and those due to immune system dysfunction. Desmethylselegiline is the R-(−) enantiomer of N-methyl-N-(prop-2-ynyl)-2-aminophenylpropane. Claimed compositions include both the R-(−) isomer and mixtures of the R-(−) and S(+) isomers. Pharmaceutically acceptable acid addition salts may also be used. Effective dosages are a daily dose of at least about 0.015 mg/kg of body weight.

Abstract: The present patent describes a three-dimensional inter-connected open cell porous foams that have a gradient in composition and/or microstructure through one or more directions. These foams can be made from a blend of absorbable and biocompatible polymers that are formed into foams having a compositional gradient transitioning from predominately one polymeric material to predominately a second polymeric material. These gradient foams are particularly well suited to tissue engineering applications and can be designed to mimic tissue transition or interface zones.

Abstract: Controlled release devices are disclosed which are biocompatible and can be implanted into the eye. The devices have a core comprising a drug and a polymeric outer layer which is substantially impermeable to the entrance of an environmental fluid and substantially impermeable to the release of the drug during a delivery period, and drug release is effected through an orifice in the outer layer. These devices have an orifice area of less than 10% of the total surface area of the device and can be used to deliver a variety of drugs with varying degrees of solubility and or molecular weight. Methods are also provided for using these drug delivery devices.

Abstract: A method for making, storing and using a surgical graft from human amniotic membrane; the resulting graft; and the storage solution. The amniotic membrane is obtained from human placenta, from which the chorion has been separated. Sheets of the amniotic membrane are cut to size and mounted on filter paper. The cells of the amniotic membrane are killed, preferably while being frozen and thawed in the storage solution. The storage solution comprises a culture medium and a hyperosmotic agent, wherein the hydration of the amniotic membrane is maintained. The membrane can be impregnated with therapeutic agents, prior to storage, for use in post surgical healing or other therapies.

Abstract: The invention is directed toward a malleable bone putty and a flowable gel composition for application to a bone defect site to promote new bone growth at the site which comprises a new bone growth inducing compound of demineralized lyophilized allograft bone powder. The bone powder has a particle size ranging from about 100 to about 850 microns and is mixed in a high molecular weight hydrogel carrier, the hydrogel component of the carrier ranging from about 0.3 to 3.0% of the composition and having a molecular weight of about at least 10,000 Daltons. The composition contains about 25% to about 40% bone powder and can be additionally provided with BMP's and a sodium phosphate buffer.

Abstract: A sleeved organized tissue is formed of a biocompatible structure surrounding organized tissue in at least one dimension and along a length of the tissue In certain preferred embodiments the tissue is attached to the sleeve, subjecting the organized tissue to internal tension within the sleeve.

Abstract: An immunoisolatory vehicle for the implantation into an individual of cells which produce a needed product or provide a needed metabolic function. The vehicle is comprised of a core region containing isolated cells and materials sufficient to maintain the cells, and a permselective, biocompatible, peripheral region free of the isolated cells, which immunoisolates the core yet provides for the delivery of the secreted product or metabolic function to the individual.

Abstract: The present intention relates to an implant for the controlled release of at least one pharmaceutically active principle comprising a core containing at least one active principle and a sheath surrounding said core, wherein said sheath is composed of at least one polymeric film applied around said core. It also relates to a process for the preparation of such an implant, characterised by the production of a core containing at least one active principle, preparation of at least one polymeric film, application of the polymeric film(s) around said core by juxtaposition and/or superposition thereof, and sterilisation of the implant thus obtained.

Abstract: Crosslinked compositions formed from water-insoluble copolymers are disclosed. These compositions are copolymers having a bioresorbable region, a hydrophilic region and at least two cross-linkable functional groups per polymer chain. Crosslinking of these polymers can be effected in solution in organic solvents or in solvent-free systems. If crosslinking occurs in a humid environment, a hydrogel will form. If crosslinking occurs in a non-humid environment, a xerogel will form which will form a hydrogel when exposed to a humid environment and the resulting crosslinked materials form hydrogels when exposed to humid environments. These hydrogels are useful as components in medical devices such as implantable prostheses. In addition, such hydrogels are useful as delivery vehicles for therapeutic agents and as scaffolding for tissue engineering applications.

Abstract: The invention is directed to medical devices having a drug-releasing coating and methods for making such coated devices. The coating permits timed or prolonged pharmacological activity on the surface of medical devices through a reservoir concept. Specifically, the coating comprises at least two layers: an outer layer containing at least one drug-ionic surfactant complex overlying a reservoir layer containing a polymer and the drug which is substantially free of an ionic surfactant. Upon exposure to body tissue of a medical device covered with such coating, the ionically bound drug in the outer layer is released into body fluid or tissue. Following release of such bound drug, the ionic surfactant binding sites in the outer layer are left vacant.

Abstract: A cell culture medium and hydrogel matrix for long term storage and proliferation of cells is provided. The cell culture medium and hydrogel matrix include an effective amount of polar amino acids, the polar amino acids selected from the group consisting of arginine, lysine, histidine, glutamic acid, and aspartic acid. The cell culture medium comprises about 5 to about 150 mM of polar amino acids. The hydrogel matrix comprises about 3 to about 150 mM of polar amino acids. Arginine and glutamic acid are preferably supplemented in the cell culture medium. Arginine, lysine, and glutamic acid are preferably supplemented in the hydrogel matrix. A method of maintaining viability and functioning of a transplant is also provided. The method of maintaining viability of a transplant includes encapsulating the cells in a hydrogel matrix and injecting the encapsulated cells into the host organism.

Abstract: A method of inducing resistance to tumor growth comprising placing tumor cells in culture in vitro supplemented with a pro-apoptotic agent for a period of time, transferring the tumor cells into a diffusion chamber, thereby producing a cell-containing chamber, inserting the chamber into a mammal for a therapeutically effective time, thereby inducing resistance to tumor growth. The pro-apoptotic agents include nucleic acid molecules, proteins or peptides, non-proteins or non-polynucleotide compounds, and a physical conditions.

Abstract: Novel burst-free, sustained release biocompatible and biodegrable microcapsules which can be programmed to release their active core for variable durations ranging from 1-100 days in an aqueous physiological environment. The microcapsules are comprised of a core of polypeptide or other biologically active agent encapsulated in a matrix of poly(lactide/glycolide) copolymer, which may contain a pharmaceutically-acceptable adjuvant, as a blend of upcapped free carboxyl end group and end-capped forms ranging in ratios from 100/0 to 1/99.

Abstract: The invention is directed to a filamentous porous film that can act as a support for cellular attachment, growth and organization. The film is formed from filaments which define a matrix structure with pores.

Abstract: The present invention is directed to materials that assist respiration of living cells contained in cell-containing systems. The materials form air-filled conduits or channels through which gases, such as oxygen and carbon dioxide, can readily exchange by diffusional means between regions of different gas partial pressures. When the present invention is placed within an aqueous environment, such as cell-culture media or host tissue, the invention provides aid to cellular respiration in cell-containing systems.

Abstract: The present invention provides a method for treating a demyelinating disease in a subject which includes administering to the subject a therapeutically effective amount of a high affinity neuromodulatory Na,K-ATPase so as to treat the demyelinating disease.

Abstract: Methods are provided for inhibiting stenosis or restenosis following vascular trauma in a mammalian host, comprising administering to the host a therapeutically effective dosage of a cytostatic agent and/or cytoskeletal inhibitor so as to biologically stent the traumatized vessel. Also provided is a method to inhibit or reduce vascular remodeling following vascular trauma, comprising administering an effective amount of a cytoskeletal inhibitor. Further provided are pharmaceutical compositions and kits comprising the therapeutic agents of the invention.

Abstract: An implant device is provided which incorporates a retinoid for improving the biocompatibility of the device in tissue. The device may be bioerodible for the purpose of systemically or locally releasing a therapeutic agent in tissue or it may be a permanent implant which includes a surface treated with a retinoid for increasing the biocompatibility thereof.

Abstract: Endotoxins, in a preparation of ice granules, from Bacillus thuringiensis and/or Bacillus sphaericus are used to combat mosquito larva.

Abstract: The present invention is directed to bioactive composition that induce the repair of damaged or diseased connective tissues upon contact of the damaged or diseased tissues with the composition in vivo. More particularly the present invention is directed to the use of a composition comprising an effective amount of endothelin to enhance the repair of damaged or diseased bone and cartilage tissues.

Abstract: A device is prepared having cells or tissue attached to a non-degradable filamentous matrix surrounded by a semi-permeable membrane. The matrix is preferably formed of a plurality of monofilaments twisted into a yarn or woven into a mesh, and can be in the form of a cylinder. When implanting the device, the semi-permeable membrane is preferably immunolsolatory, and the cells or tissue may produce a biologically active molecule to provide therapy. To enhance cell or tissue adhesion, the matrix is coated with extracellular matrix molecules or treated to provide a surface charge. The device can be made by inserting the matrix into a capsule formed of the semi-permeable membrane, distributing the cells or tissue on the matrix through an opening of the capsule, and sealing the opening of the capsule.

Abstract: The invention relates to a pharmaceutical implant for controllably releasing a drug in a subject and methods for manufacturing and administering the implant. The implant is made of associated microparticles of a drug dispersed in a biodegradable polymer. The microparticles are sufficiently associated so that the implant maintains a predetermined shape but are not fused together so as to form a single monolithic structure. The drug can be controllably released in a subject by administration of the pharmaceutical implant without the need of a suspending fluid.

Abstract: An osmotic delivery system has a membrane plug retention mechanism which can also be used to control the delivery rate of a beneficial agent from the osmotic delivery system. The osmotic delivery device includes an implant capsule containing a beneficial agent and an osmotic agent. Holes are formed along a side wall of the implant capsule at an open end of the capsule. When the membrane plug is inserted into the open end of the capsule the membrane material swells into the holes in the capsule side wall creating a large frictional force which prevents expulsion of the membrane plug. A beneficial agent delivery rate of the osmotic delivery system is controllable by varying the size and number of the holes to change the amount of exposed surface area of the membrane plug. An increase in the surface area of the membrane plug exposed to the exterior environment causes a corresponding increase in the liquid permeation rate of the membrane and thus, increases the beneficial agent delivery rate.

Abstract: Compositions and methods of the topical treatment of equine laminitis are disclosed. In particular, combinations of a fast acting nitric oxide (NO) donor, a sustained acting NO donor and an NSAID mixed in a lipid-based carrier are described. The application of such combinations to the affected areas, e.g., the hoofs and surrounding tissues, of an equine afflicted with laminitis provides relief from the debilitating effects of this painful, often life-threatening condition.

Abstract: A method of inhibiting the proliferation and causing the differentiation of undifferentiated cells comprising contacting the undifferentiated cells with an effective amount of an antisense oligonucleotide having a sequence which is complementary to a region of the IGF-1 receptor RNA. The sequence of the antisense oligonucleotide is selected from an oligodeoxynucleotide sequence complementary to codons −29 to −24 of the signal sequence of the IGF-1 receptor and an oligoribodeoxynucleotide sequence complementary to codons 1 to 309 of the sequence of the IGF-1 receptor. The oligoribodeoxynucleotide sequence may be provided by an expression vector.

Abstract: An osmotic delivery system has a membrane plug retention mechanism which can also be used to control the delivery rate of a beneficial agent from the osmotic delivery system. The osmotic delivery device includes an implant capsule containing a beneficial agent and an osmotic agent. Holes are formed along a side wall of the implant capsule at an open end of the capsule. When the membrane plug is inserted into the open end of the capsule the membrane material swells into the holes in the capsule side wall creating a large frictional force which prevents expulsion of the membrane plug. A beneficial agent delivery rate of the osmotic delivery system is controllable by varying the size and number of the holes to change the amount of exposed surface area of the membrane plug. An increase in the surface area of the membrane plug exposed to the exterior environment causes a corresponding increase in the liquid permeation rate of the membrane and thus, increases the beneficial agent delivery rate.

Abstract: A pharmaceutical dosage form comprises, in a portion thereof, substantially single enantiomer (R)-verapamil and, in another, separate, portion thereof, substantially single enantiomer (S)-verapamil, wherein, in use, the different enantiomers are released at different rates from the dosage form.

Abstract: The invention is directed to a device for delivering an active agent formulation for a predetermined administration period. An impermeable reservoir is divided into a water-swellable agent chamber and an active agent formulation chamber. Fluid from the environment is imbibed through a semipermeable plug into the water-swellable agent chamber and the active agent formulation is released through a back-diffusion regulating outlet. Delivery periods of up to 2 years are achieved.

Abstract: The present invention provides a method of stimulating vascularization at a site in a mammal, said method comprising contacting said site with a matrix comprising gelatin and a nitric oxide inhibitor. The gelatin is preferably denatured collagen. The nitric oxide inhibitor may be a sulfonated moiety. The inhibitor may be an L-arginine analog, such as aminoguanidine, N-monoethyl L-arginine, N-nitro-L-arginine and D-arginine. The matrix may further comprise a nitric oxide scavenger, such as dextran, heparin, cysteine and cystine.

Abstract: A method for preventing or treating pathological changes which occur in association with cataract formation in the mammalian eye by protecting lens cells against the cataractogenic effects of transforming growth factor-&bgr; (TGF&bgr;). Estrogen or an estrogenic substance can be administered to the mammal or directly to or near the eye of the mammal. The means of administration can be by a pharmaceutical composition comprising estrogen, a membranous ocular patch impregnated with estrogen or a lens or lens implant coated or impregnated with estrogen.

Abstract: The invention relates to a membrane system for controlled tissue regeneration of the periodontium, comprising a resorbable polymer membrane and anti-adhesion molecules.