Abstract: A method for encapsulating a biological substance is biocompatible microcapsules is disclosed, said method comprising:a) maintaining a coating-forming liquid film sheet comprising a solution of a soluble organic polymer in an organic solvent,b) causing droplets comprising biological substance is an aqueous medium to pass through said sheet to form microcapsules comprising cores of said droplets coated by said liquid film, andc) permitting said microcapsules to pass through said sheet so that a portion of said polymer precipitates in the presence of water in said droplets while evaporating a portion of said solvent to form a continuous permeable polymer coating of sufficient structural that said microcapsules are self-supporting.

Abstract: Improved Implant assemblies and methodologies provide immuno-protection for implanted allografts, xenografts, and isografts. The assemblies and methodologies establish an improved boundary between the host and the implanted cells. The boundary structure is laminated, combining elements having different characteristics beneficial to the survival of the implanted cells. Filaments of adhesive material lay in between the elements. The filaments of adhesive material have been melted in place by the application of heat and solidified in place by cooling to secure the elements together into a composite laminated structure.

Abstract: Methods and pharmaceutical compositions for reducing the biological fluid level of a lipid soluble waste in a subject are provided. The methods involve selecting a subject diagnosed as having a hyperlipidemia-associated condition and subcutaneously introducing into the subject a biodegradable implant containing a pro-inflammatory lipid that promotes formation of an angiogenic tissue capsule containing a plurality of foam cells. The pro-inflammatory lipid is delivered in an amount sufficient to attain a detectable reduction in the biological fluid level of the lipid soluble waste.

Abstract: A medical device and a method for its manufacture. The function of the medical device requires exposure of the device to the tissue of a patient. The device has a tissue-exposed portion constructed to release an agent that inhibits adverse reaction to the presence of the device defined by a polymeric surface-layer overlying in a supported manner a polymer defining a reservoir. The reservoir incorporates the agent in a manner that permits substantially free outward release of the agent from the reservoir and the overlying layer defines metering outward passages constructed to control the outward migration of the agent to enable prolonged release of the agent from the surface of the medical device to prevent the adverse reaction due to the presence of the device.

Abstract: An implantable multiple-agent biologic delivery system includes a pod proportioned for subcutaneous implantation beneath the dermis of the skin, the pod including a porous surface and having at least one internal chamber which is in fluid communication with the porous surface. The system includes a dome proportioned for selectable detachable securement to the chamber of the pod. The dome includes interior chambers, each in fluid communication with the interior of the pod. Bio-acting agents, such as hormones, enzymes, biologic response modifiers, free radical scavengers, and other genetically altered cell cultures may be provided, within the chambers of the dome, prior to implantation. Such agents within the dome will, through the use of time release micropumps, enter the interior chambers of the pod for transmission, through the porous surfaces into a growth factor stimulated capillary matrix and then to the bloodstream of the user.

Abstract: Disclosed are controlled rate-release devices for releasing a pharmaceutically active agent into the oral cavity by the dissolving action of the saliva, and a method of preparing such devices.

Abstract: A device for the controlled delivery of an insoluble or partially aqueous insoluble beneficial agent to an aqueous containing environment. The device comprises a shaped wall that surrounds and defines an internal reservoir. The wall is formed at least in part of a sintered polymer microporous membrane permeable to a beneficial agent-containing hydrophobic medium when the wall is present in the aqueous containing environment. The reservoir contains a mixture of a hydrophilic swellable composition and a beneficial agent-containing hydrophobic medium.

Abstract: A transplant comprising a core of a viable, physiologically active cells coated with a non-fibrogenic alkaline earth metal alginate free from fibrogenic amounts of fucose, sulfate, phloroglucinol and protein moieties, having a mannuronate to guluronate molar ratio of from 1.2 to 6. The coating protects the core from host immunological destruction after transplantation. The coating is sufficiently permeable to permit the diffusion of nutrients and cell products through the coating.A process for coating the transplant core comprising coating the core with alginate substantially free from fibrogenic compounds and reacting the alginate coating with alkaline earth metal cations comprising calcium ions or magnesium ions or mixture thereof to form an alkaline earth metal alginate coating.

Abstract: A delivery system for providing growth promoters to food animals is provided and a method of promoting growth in food animals using such delivery systems is described.

Abstract: A delivery system for providing growth promoters to food animals is provided and a method of promoting growth in food animals using such delivery systems is described.

Abstract: ACTH polymeric controlled release systems are described wherein the ACTH retains good biological activity and is released over an extended period of time following administration by injection. In the preferred embodiment, the ACTH polymeric microspheres are made using very cold temperatures to freeze the polymer-ACTH mixtures into polymeric microspheres with very high retention of biological activity and material. Sustained release of biologically active ACTH is achieved when the microspheres are tested in vitro, extending over a period of greater than one day to several months. Altered release can be achieved by inclusion of degradation modifiers, pore forming agents, and stabilizers of the ACTH.

Abstract: Provided by the invention are methods and compositions for increasing the growth rate and feed efficiency of turkeys by administration of an effective amount of 5-alpha-dihydrotestosterone or biocompatible derivatives such as alkanoic acid ester derivatives, as an implant.

Abstract: A delivery system for providing growth promoters to food animals is provided and a method of promoting growth in food animals using such delivery systems is described.

Abstract: An implantable multiple-agent biologic delivery system includes a pod proportioned for subcutaneous implantation beneath the dermis of the skin, the pod including a porous surface and having at least one internal chamber which is in fluid communication with the porous surface. The system includes a dome proportioned for selectable detachable securement to the chamber of the pod. The dome includes interior chambers, each in fluid communication with the interior of the pod. Bio-acting agents, such as hormones, enzymes, biologic response modifiers, free radical scavengers, and genetically altered cell cultures, may be provided, within the chambers of the dome, prior to implantation. Such agents within the dome will, through the use of time release micropumps, enter the interior of the pod for transmission through the porous surfaces into a vascular growth factor stimulated capillary matrix and then to the bloodstream of the user.

Abstract: An implantable bioartificial pancreas device having an islet chamber containing glucose responsive and insulin-secreting islets of Langerhans or similar hormone secreting cells, the islet chamber having baffle means inside thereof to assist in even distribution of the islets in the chamber, one or more vascularizing chambers open to surrounding tissue, a semi-permeable membrane between the islet and vascularizing chambers that allows passage of small molecules including insulin, oxygen and glucose and does not allow passage of agents of the immune system such as white cells and antibodies, the vascularizing chambers containing a growth factor soaked fibrous or foam matrix having a porosity of about 40 to 95%, the matrix providing small capillary growth and preventing the blood from clotting in the lower chamber.

Abstract: A system for controlled release, site-specific delivery of therapeutic agents, particularly myocardial agents such as antiarrhythmic agents, comprises a biocompatible polymeric matrix with an incorporated therapeutic agent for direct placement at the epicardium. Advantageously, the dosage form can be fabricated in such a manner as to tailor the release characteristics as required by the nature of the physical condition desired to be treated. In a specific illustrative embodiment, lidocaine, an antiarrhythmic depressant, is incorporated in polyurethane by a unique method which permits drug-loading of the polymeric matrix from about 5% up to 40% by weight, with about 25% to 30% in a preferred embodiment. A novel FeCl.sub.3 catalyst causes the polyurethane to polymerize despite the presence of drug in the polymeric matrix mixture.

Abstract: The present invention relates to a sustained-release injection, which comprises a suspension of a powder comprising an active ingredient and a pharmaceutically acceptable biodegradable carrier (e.g. proteins, polysaccharides and synthetic high molecular compounds, preferably collagen, atelocollagen, gelatin, and a mixture thereof) in a viscous solvent for injection (e.g. vegetable oils, polyethylene glycol, propylene glycol, silicone oil, and medium-chain fatty acid triglycerides). The sustained-release injection can release the active ingredient at an effective level for a long period of time when injected.

Abstract: Biocompatible microcapsules useful for transplanting foreign material into an animal body, and the method of their production, are described, wherein the microcapsules contain an outermost layer of water soluble non-ionic polymers such as PEO to create resistance to cell adhesion on the surface of the microcapsules.

Abstract: A method and device for treating a mammalian organism to obtain a desired local or systemic physiological or pharmacological effect is provided. The method includes administering a sustained release drug delivery system to a mammalian organism in need of such treatment at an area wherein release of an effective agent is desired and allowing the effective agent to pass through the device in a controlled manner. The device includes an inner core or reservoir comprising the effective agent; a first coating layer, which is essentially impermeable to the passage of the effective agent; and a second coating layer, which is permeable to the passage of the effective agent. The first coating layer covers at least a portion of the inner core; however, at least a small portion of the inner core is not coated with the first coating layer. The second coating layer essentially completely covers the first coating layer and the uncoated portion of the inner core.

Abstract: Methods are described for assisting the restoration of periodontal tissue in a periodontal pocket and for retarding migration of epithelial cells along the root surface of a tooth. The methods involve placement of an in-situ forming biodegradable barrier adjacent the surface of a tooth. The barrier is microporous and includes pores of defined size. The barrier can include a biologically active agent.

Abstract: Methods and compositions are provided for the treatment and repair of defects or lesions in the cartilage of humans and other animals. The defect or lesion in the cartilage may be first treated with an enzyme to remove proteoglycans from the defect area. To induce cartilage formation, the defect is filled or otherwise dressed with a biodegradable matrix having pores sufficiently large to allow repair cells to populate the matrix. The matrix filling the defect contains a proliferation agent at a concentration sufficient to stimulate proliferation of repair cells and a transforming factor in an appropriate delivery system to release the transforming factor at a concentration sufficient to transform repair cells in the matrix and defect area into cartilage-producing chondrocytes. The matrix may also contain a chemotactic agent to attract repair cells. The entire treatment may be carried out in a single arthroscopic or open surgical procedure.

Abstract: The present invention provides compositions for use in bone tissue regeneration containing a barrier material and a graft material. The barrier material can be calcium sulfate, while the graft material can be any suitable material, including a composite graft material containing demineralized, freeze-dried, allogenic bone (DFDBA) and calcium sulfate. Alternatively, the barrier material can be any suitable material, while the graft material can be a composition of DFDBA and calcium sulfate. Methods of using the compositions for bone tissue regeneration are also provided, as well as kits containing calcium sulfate, a rehydrant and optionally DFDBA.

Abstract: The present invention relates to polymeric microspheres as injectable, drug-delivery systems for use to deliver bioactive agents to sites within the central nervous system, and for the stimulation of nerve fiber growth by implanting such microspheres within the central nervous system of a patient.

Abstract: Disclosed are (1) osteogenic devices comprising a matrix containing substantially pure natural-sourced mammalian osteogenic protein; (2) DNA and amino acid sequences for novel polypeptide chains useful as subunits of dimeric osteogenic proteins; (3) vectors carrying sequences encoding these novel polypeptide chains and host cells transfected with these vectors; (4) methods of producing these polypeptide chains using recombinant DNA technology; (5) antibodies specific for these novel polypeptide chains; (6) osteogenic devices comprising these recombinantly produced proteins in association with an appropriate carrier matrix; and (7) methods of using the osteogenic devices to mimic the natural course of endochondral bone formation in mammals.

Abstract: Cell-penetrable medical material made of denatured collagen which is prepared by heating, in the presence of water is disclosed, the collagen having cross-linking structure. Artificial skin prepared by using this medical material as a wound-contacting layer (2) is also disclosed.

Abstract: Improved Implant assemblies and methodologies provide immuno-protection for implanted allografts, xenografts, and isografts. The assemblies and methodologies establish an improved chamber for holding the implanted cells. The chambers include first and second wall elements and an intermediate sealing element. The first and second wall elements overlie an open area in the sealing member to form a chamber for holding cells for implantation. A sealed region is created between the wall elements and the sealing element body to close the chamber. In one arrangement, the sealed region is created by means of a sonic weld made while the implanted cells are present in the chamber. In another arrangement, the sealed region is created by means of applying an external force to compress the peripheral edges of the wall elements and the sealing element together while the implanted cells are present in the chamber.

Abstract: The present invention provides pharmaceutical or veterinary implants which, when subdermally administered releases a peptide or protein in a substantially continuous manner. The implant includes the peptide or protein and an excipient encased within a polymeric coating which is permeable, swellable and, at normal physiological pH, is non-rupturing, non-dissolving and does not degrade over the useful life the implant. The coating forms a release rate limiting barrier. All of the components used to make the implant are of a biocompatible nature. The implant is particularly useful for the sustained release of proteins or peptides for regulating the hormonally controlled reproductive cycle in sheep.

Abstract: Compositions and methods which are effective to inhibit conception and to treat benign gynecological disorders for extended periods of time are described, wherein an effective amount of a gonadotropin hormone releasing hormone composition and an effective amount of an estrogenic composition are provided over a first period of time, in addition to a progestogen and optionally an androgenic composition. According to one protocol, the progestogen is provided for a second, shorter period of time; the progestogen is provided at a higher level for at least 5 to about 20 days, and then at a lower level for the remainder, if any, of the second period of time. In an alternative protocol, the progestogen is provided at a lower level substantially throughout the period of administration of gonadotropin hormone releasing hormone composition and estrogenic composition. An effective amount of the androgenic hormone is optionally provided over the first period of time.

Abstract: Provided is a method for enhancing and accelerating the repair of chronic cellular and molecular damage to skin. Also provided is a method for thinning stratum corneum of mammalian, preferably human, skin thickened by extrinsic free radicals and restoring elastic tissue damaged by extrinsic free radicals. Both methods comprise the topical administration to mammalian, preferably human, skin of a composition comprising selenoamino acids in a pharmaceutically acceptable transdermal carrier.

Abstract: The method of tissue-specific delivery of therapeutic agents via a bio-oncotic pump which includes the steps of furnishing an implantable element which is biodegradable in situ within human tissue. Such an element defines a series of respective concentric shells having different therapeutic agents disposed upon each of the shells such that the outermost shell and associated agents will be delivered earliest, while the innermost shell and its agents will be delivered last. The material of the biodegradable element is selected from the group of materials including processed sheep dermal collagen, Hench's bioglass, fibrinogen, polyimino-carbonate, and polylactic acid. A vaso-inductive agent is integrated into the surface of the element. Selected groups of therapeutic agents are incorporated into the element, which is followed by the subcutaneous implantation and securing of said element into the human tissue at the site of interest.

Abstract: An implantable structure for incorporation into the tissues of a body is provided which retains therein fluid substances or biological substances which produce, or cause to be produced, biochemicals deliverable to the body. The implantable structure is configured to provide insertion and removal of substances therefrom as needed. The implantable structure generally comprises a porous outer member configured to encourage ingrowth of vascularized tissue therethrough, and an inner member of selectively permeable material providing interior space for inserting substances therein and which is structured to prevent ingrowth of tissue therethrough. The inner member is capable of providing immunoisolation to the substances therein as required.

Abstract: The invention is directed to a composition composed of a thermoplastic or thermosetting polymer which is capable of forming a biodegradable and/or bioerodible microporous, solid or gelatinous polymer matrix. The matrix is useful as an implant in animals for enhancing regeneration of cells and tissue, such as bone and nerve cells, or for delivery of biologically-active substances to tissue or organs. The composition is administered to an implant site as a liquid. The invention also includes a method of preventing and treating disorders and diseases, such as bone or nerve growth disorders, or of altering body functions such as birth control, using the compositions and implants of the invention.

Abstract: Hard tissue replacement materials and methods for making same are disclosed. In one embodiment, the present composition comprises a synthetically derived, substantially homogenous composite containing collagen component and calcium phosphate-containing component precipitated from a liquid medium in which the collagen component is contained.

Abstract: Implant assemblies and methodologies provide immuno-protection for implanted allografts, xenografts, and isografts. The assemblies and methodologies establish a boundary between the host and the implanted cells. The boundary has a pore size, an ultimate strength, and a metabolic transit value that assures the survival of the cells during the critical ischemic period and afterward. The boundary allows the fabrication and clinical use of implant assemblies and methodologies that can carry enough cells to be of therapeutic value to the host, yet occupy a relatively small, compact area within the host.

Abstract: Described is a device for the controlled release and delivery to mammalian tissue of a pharmacologically active agent comprising:(i) an impermeable backing member;(ii) a control membrane lamina consisting essentially of a first polymeric composition of matter which consists essentially of at least one C.sub.2 -C.sub.4 lower olefin-C.sub.1 -C.sub.8 alkyl acrylate and/or methacrylate copolymer having 2-90% by weight of alkyl acrylate and/or methacrylate monomeric units, taken alone, or taken further together with in intimate admixture, a second polymeric composition consisting essentially of a C.sub.2 -C.sub.4 polyalkylene corresponding to the C.sub.2 -C.sub.

Abstract: An apparatus is provided for continuous and regular liberation of active constituents into domestic water supplies. The apparatus comprises a receptacle having a body portion which is impermeable to water and to the active constituent. The receptacle is provided with an aperture closed by a membrane which is permeable to water and to the active constituent. An operculum surrounds the membrane to secure the membrane to the receptacle. The active constituent is provided into the receptacle and is released through the membrane in a controlled manner over an extended period of time. Preferably, the membrane has a mean pore diameter greater than 0.05 microns.

Abstract: A delivery for providing growth promoters to food animals is provided and a method of promoting growth in food animals using such delivery systems is described.

Abstract: Improved means for constraining a rumen drug delivery device in a rolled configuration, said means comprising a laminate, which may be perforated, comprising a water-permeable material having a low friction surface in the presence of water, said material being bonded by means of a water-dispersible pressure sensitive adhesive to a repulpable tape, said tape having said water-dispersible pressure sensitive adhesive on both its surfaces; a laminate comprising a flexible, water-permeable polymeric material bonded between the low friction surface material and the repulpable tape; and devices constrained by said means.

Abstract: A composite living skin equivalent is described comprising an epidermal layer of cultured keratinocyte cells, a layer of non-porous collagen, and a dermal layer of cultured fibroblast cells in a porous cross-linked collagen sponge matrix. Preferably the non-porous collagen is Type 1, Type 3 or mixtures of Types 1 and 3 bovine collagen, which has been pepsin treated. A process for preparing the skin equivalent is described, as well as a test kit for in vitro testing of the skin equivalent. The skin equivalent has use for skin grafting as well as in vitro testing of the effects of various substances on skin.

Abstract: A method of inhibiting cell proliferation in mammals which comprises the local delivery of an inhibitory amount of dipyridamole. Inhibiting cell proliferation is useful for the treatment of proliferaive diseases such as vascular restonesis, scleroderma, psoriasis, and rheumatoid arthritis. This method includes the local delivery of dipyridamole to the proliferative site by various techniques including local delivery catheters, site specific carriers, implants, direct injection, or direct application.

Abstract: Methods and compositions are provided for the treatment and repair of defects in the cartilage or bone of humans and other animals as in full-thickness defects in joints. The defect in bone is filled with a matrix having pores large enough to allow cells to populate the matrix and to form blood vessels. The matrix filling the bone defect contains an angiogenic factor and also contains an osteogenic factor in an appropriate delivery system. To induce cartilage formation, a defect in cartilage is filled with a matrix having pores sufficiently large to allow cartilage repair cells to populate the matrix. The matrix filling the defect in cartilage contains a proliferation agent and also contains a transforming factor in an appropriate delivery system. The matrix may also contain a chemotactic agent to attract cartilage repair cells.

Abstract: A dextrin derivative, in which a proportion of the hydroxyl groups in the dextrin have been replaced by strongly acidic groups, is useful in treatment of poisoning or drug overdose, particularly by compounds having basic groups. Dextrin sulphate is a preferred derivative for use in the treatment of paraquat poisoning.

Abstract: Solid dosage forms of bioactive materials for parenteral administration such as porcine or bovine somatotropin pellets intended for subcutaneous implantation to improve food production of farm animals are coated with polyvinyl alcohol to extend the release characteristics of the material. The polyvinyl alcohol preferably has a molecular weight of from about 20,000 to 100,000, a degree of hydrolysis of at least about 98%, and is applied from an aqueous solution by spray coating to form a continuous uniform covering of from about 3 to 25 ug PVA/mm.sup.2 surface area of pellet.

Abstract: An in vivo method is described for treating a subject for periodontal disease by placing a mixture of a glyceride composition and a therapeutic agent in the periodontal pocket of subject such that the therapeutic agent is released in a sustained manner. The glyceride composition is selected such that the mixture of the glyceride composition and the therapeutic agent is capable of forming a gel in the environment of the periodontal pocket. Also described is a sustained release delivery system comprising the mixture of the glyceride composition and therapeutic agent.

Abstract: The subject invention provides a method of encapsulating viable tissue or cells within a double walled bead, the double-walled bean produced as a result of the method, as well as a method of pretreating the tissue or cells with an immunosuppressant such as UV-B irradiation prior to their encapsulation.

Abstract: Contraceptive devices which are effective for extended periods of time are described, in the form of means for releasing an effective amount of a gonadotropin hormone releasing hormone composition and means for releasing an effective amount of an estrogenic hormone over a first period of time, and means for releasing an effective amount of a progestogen for a second period of time, the second period of time being substantially shorter than and running simultaneously with a portion of the first period of time. The gonadotropin hormone releasing hormone composition is selected from gonadotropin hormone releasing hormone, gonadotropin hormone releasing hormone analogues, gonadotropin hormone releasing hormone agonists, gonadotropin hormone releasing hormone antagonists and mixtures thereof. Contraceptive methods employing the devices are also described.

Abstract: Methods and compositions are provided for the treatment and repair of defects or lesions in the cartilage of humans and other animals. The defect or lesion in the cartilage may be first treated with an enzyme to remove proteoglycans from the defect area. To induce cartilage formation, the defect is filled or otherwise dressed with a biodegradable matrix having pores sufficiently large to allow repair cells to populate the matrix. The matrix filling the defect contains a proliferation agent at a concentration sufficient to stimulate proliferation of repair cells and a transforming factor in an appropriate delivery system to release the transforming factor at a concentration sufficient to transform repair cells in the matrix and defect area into cartilage-producing chondrocytes. The matrix may also contain a chemotactic agent to attract repair cells. The entire treatment may be carried out in a single arthroscopic or open surgical procedure.

Abstract: There is provided an implantable multiple-agent delivery system which includes a pod proportioned for subcutaneous implantation beneath the dermis of the skin, the pod including a porous surface having at least one internal chamber there within which is in fluid communication with the porous surface. The system further includes a dome proportioned for complemental, selectable detachable securement upon the pod. The dome includes a plurality of interior chambers, each in fluid communication with the internal chambers of the pod. Bio-acting agents, such as hormones, biologic response modifiers, free radical scavengers, and other therapeutic agents may be provided, within the chambers of the dome, prior to implantation. Such agents with the chambers of the dome will, through the use of time release microelectronics, enter at least one of the interior chambers of the pod for transmission, through the porous surfaces thereof, into a growth factor stimulated capillary matrix and then to the bloodstream of the user.

Abstract: A time release bolus comprises a tubular member and an end cap secured to each other. The tubular member contains an inner bag which is adapted to receive and contain a nutrient or medicament substance. A capsule is provided in the tubular member, and upon fracture thereof, applies pressure to the inner bag. The end cap includes a plug which fits into an open end of the tubular member and a top portion. A passage is provided which leads from the tubular member to the exterior, such that nutrient or medicament can flow from the inside of the tubular member to the outside of the time release bolus. The bolus further includes in the end cap a mesh in the flow path of the substance, the mesh further restricting and controlling the amount of substance which may pass from the bolus to the exterior.

Abstract: Methods and devices are disclosed for the delivery of an active factor from an implanted co-culture of an active factor-secreting cell obtained from a first source and an augmentary substance-secreting cell obtained from a second source different from the first source, to a target region in a subject. The co-culture is maintained within a biocompatible, semipermeable membrane in which the augmentary substance secreted by the augmentary substance-producing cells stimulates the active factor-producing cells to secrete active factor. The semipermeable membrane permits the diffusion of the active factor therethrough while excluding detrimental agents present in the extenral environment from gaining access to the co-culture.