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Polymerizable biodegradable polymers including carbonate or dioxanone linkages

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USRE39713E1
USRE39713E1 US10351930 US35193003A USRE39713E US RE39713 E1 USRE39713 E1 US RE39713E1 US 10351930 US10351930 US 10351930 US 35193003 A US35193003 A US 35193003A US RE39713 E USRE39713 E US RE39713E
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macromer
groups
carbonate
biodegradable
peg
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Amarpreet S. Sawhney
Peter K. Jarrett
Arthur J. Coury
Ronald S. Rudowsky
Michelle D. Lyman
Luis Z. Avila
David J. Enscore
Stephen D. Goodrich
William C. Nason
Fei Yao
Douglas Weaver
Shikha P. Barman
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Genzyme Corp
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Genzyme Corp
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    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08GMACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/64Polyesters containing both carboxylic ester groups and carbonate groups
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L24/00Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001Use of materials characterised by their function or physical properties
    • A61L24/0042Materials resorbable by the body
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L24/00Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/046Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L26/00Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0019Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04Macromolecular materials
    • A61L31/06Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148Materials at least partially resorbable by the body
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1635Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Abstract

Water-soluble macromers including at least one hydrolysable linkage formed from carbonate or dioxanone groups, at least one water-soluble polymeric block, and at least one polymerizable group, and methods of preparation and use thereof are described. The macromers are preferably polymerized using free radical initiators under the influence of long wavelength ultraviolet light or visible light excitation. Biodegradation occurs at the linkages within the extension oligomers and results in fragments which are non-toxic and easily removed from the body. The macromers can be used to encapsulate cells, deliver prophylactic, therapeutic or diagnostic agents in a controlled manner, plug leaks in tissue, prevent adhesion formation after surgical procedures, temporarily protect or separate tissue surfaces, and adhere or seal tissues together.

Description

This application is a divisional of application Ser. No. 08/944,739, filed Oct. 6, 1997, now U.S. Pat. No. 6,083,524 which is a continuation-in-part of application Ser. No. 08/710,689 filed Sep. 23, 1996, now U.S. Pat. No. 5,900,245.

FIELD OF THE INVENTION

The present invention relates to improved photopolymerizable biodegradable hydrogels for use as tissue adhesives, coatings, sealants and in controlled drug delivery devices. The improved materials incorporate carbonate and/or dioxanone linkages. These biodegradable linkages allow improved control of various properties of the macromers, particular increasing viscosity while preserving biodegradability.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 5,410,016 to Hubbell et al. discloses biocompatible, biodegradable macromers which can be polymerized to form hydrogels. The macromers are block copolymers that include a biodegradable block, a water-soluble block with sufficient hydrophilic character to make the macromer water-soluble, and one or more polymerizable groups. The polymerizable groups are separated from each other by at least one degradable group, Hubbell specifically discloses using polyhydroxy acids, such as polylactide, polyglycolide and polycaprolactone as the biodegradable polymeric blocks. One of the disclosed uses for the macromers is to plug or seal leaks in tissue.

Other hydrogels have been described, for example, in U.S. Pat. No. 4,938,763 to Dunn et al., U.S. Pat. Nos. 5,100,992 and 4,826,945 to Cohn et al., U.S. Pat. Nos. 4,741,872 and 5,160,745 to De Luca et al., U.S. Pat. No. 5,527,864 to Suggs et al., and U.S. Pat. No. 4,511,478 to Nowinski et al. Methods of using such polymers are described in U.S. Pat. No. 5,573,934 to Hubbell et al. and PCT WO 96/29370 by Focal.

While numerous references disclose using homopolymers and copolymers including carbonate linkages to form solid medical devices, such as sutures, suture coatings and drug delivery devices (see, for example, U.S. Pat. No. 3,301,824 to Hostettler et al., U.S. Pat. No. 4,243,775 to Rosensaft et al., U.S. Pat. No. 4,429,080 to Casey et al., U.S. Pat. No. 4,716,20 to Casey et al., U.S. Pat. No. 4,857,602 to Casey et al., U.S. Pat. No. 4,882,168 to Casey, EP 0 390 860 B1 by Boyle et al., U.S. Pat. No. 5,066,772 to Tang et al., U.S. Pat. No. 5,366,756 to Chesterfield et al., U.S. Pat. No. 5,403,347 to Roby et al. and U.S. Pat. No. 5,522,841 to Roby et al.), none of these publications discloses incorporating polymerizable groups on the polymers so that the polymers can be further polymerized. Accordingly, none of these polymers can be used in the same manner as the macromers in U.S. Pat. No. 5,410,016 to Hubbell et al.

Sealing or plugging holes in lung tissue is inherently more difficult than sealing other types of tissue because the tissue is constantly expanded and contracted during normal respiration. It would be advantageous to provide macromers which can be rapidly polymerized in vivo to form hydrogels which are more elastic than conventional hydrogels, for example, for use in sealing lung tissue.

It is therefore an object of the present invention to provide biodegradable, biocompatible macromers that can be rapidly polymerized in vivo to form hydrogels which are more elastic than conventional hydrogels.

It is a further object of the present invention to provide a macromer solution which can be administered during surgery or outpatient procedures and polymerized as a tissue adhesive, cell encapsulating medium, tissue sealant, wound dressing or drug delivery device.

It is a still further object of the present invention to provide a macromer solution which can be polymerized in vivo on a surface to be coated in a very short time frame to form conformal coating layers.

SUMMARY OF THE INVENTION

Biocompatible, biodegradable, polymerizable and at least substantially water-soluble macromers and methods of preparation and use thereof are disclosed. The macromers are block copolymers that include at least one water-soluble block, at least one biodegradable block, and at least one polymerizable group. At least one of the biodegradable blocks comprises a linkage based on a carbonate or dioxanone group, and the macromers can contain other degradable linkages or groups in addition to carbonate or dioxanone.

The carbonate and dioxanone linkages impart more elasticity to the polymer and degrade at a different rate than hydroxy acid linkages. Carbonate linkages can also increase macromer viscosity, at a given concentration, without requiring increased molecular weight of the nondegradable components of the macromer. The macromers can also include poly(hydroxy acid) linkages which degrade by hydrolysis into relatively non-toxic hydroxy acid residues, or other biodegradable blocks such as polycaprolactones, polyorthoesters, polyanhydrides, and polypeptides. The degradation time of the polymers can be controlled, for example, by selecting the types and proportion of the biodegradable blocks.

The polymerizable groups can be polymerized by either free radical (homolytic) processes or by heterolytic processes (such as cationic polymerization). Preferably, the groups are polymerized photochemically. The macromer can be polymerized in the presence of prophylactic, therapeutic or diagnostic agents, for delivery of the incorporated agents in a controlled manner as the resulting polymer degrades. The macromers are useful for delivering hydrophobic, hydrophilic and/or labile materials. They can be particularly useful for delivery of hydrophobic materials.

The macromers can be polymerized in an interfacial manner to form ultrathin coatings which are intimately adhered to the coated surface, or in a bulk manner to form relatively thick coatings which may or may not be intimately adhered to the coated surface. Alternatively, the two methods can be combined to provide a relatively thick coating which is intimately adhered to the surface. Each of these methods is advantageous for certain applications.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of the elastic strength (seal pressure, mm Hg) over time (hr) of five different sealant materials: 10% 35K T, 20% 35K T, 10% 20K TL, 10% 20 K TL, and 20% 35K TL K is defined as 100 Daltons (weight average molecular weight, T is trimethylene carbonate (TMC), L is lactide, and TL is a copolymer of TMC and lactide.

FIGS. 2A and 2B are graphs of the degradation (% mass loss) over time (days) for 20K T (FIG. 2A) and 35K T (FIG. 2B) for subcutaneous polymeric implants in rats.

DETAILED DESCRIPTION OF THE INVENTION

Polymers

Water-soluble, biocompatible, biodegradable macromers and methods of preparation and use thereof, are disclosed. The macromers include at least one water-soluble block, at least one biodegradable block, and at least one polymerizable group. At least one biodegradable block contains a carbonate or dioxanone group. To obtain a biodegradable material after polymerization, each polymerizable group must be separated from any other polymerizable group on the macromer by at least one biodegradable linkage or group.

At least a portion of the macromers will contain more than one reactive group and thereby be effective as crosslinkers, so that the macromers can be crosslinked to form a gel. The minimal proportion required will vary with the nature of the macromer and its concentration in solution, and the proportion of crosslinker in the macromer solution can be as high as 100% of the macromer solution.

For example, the macromers include at least 1.02 polymerizable groups on average, and, more preferably, the macromers each include two or more polymerizable groups on average.

Since in the preferred homolytic (free radical) polymerization reactions each polymerizable group will polymerize into a chain, crosslinked hydrogels can be produced using only slightly more than one reactive group per macromer (i.e., about 1.02 polymerizable groups on average). However, higher percentages are preferable, and excellent gels can be obtained in polymer mixtures in which most or all of the molecules have two or more reactive double bonds. Poloxamines, an example of a water-soluble block, have four arms and thus may readily be modified to include four polymerizable groups.

As used herein, a “biocompatible” material is one which stimulates only a mild, often transient, implantation response, as opposed to a severe or escalating response.

As used herein, a “biodegradable” material is one which decomposes under normal in vivo physiological conditions into components which can be metabolized or excreted.

As used herein, a “block” is a region of a copolymer differing in subunit composition from neighboring regions. Blocks will generally contain multiple subunits, up to about one thousand subunits or less for non-degradable materials, and without an upper limit for degradable materials. In the lower limit, the size of a block depends on its function; the minimum size is that which is sufficient to allow the function to be performed. In the case of a block conferring water-solubility on the macromer, this will by typically 400 daltons or more, preferably 600 daltons or more, more preferably at least 1000 daltons, and most preferably in the range of 2000 to 40,000 daltons. For degradable linkages, the minimum block size is a single linkage of the appropriate degradability for the function. More preferably, the block size is two to forty groups; most preferably, three to twenty. The reactive groups may be considered as a block for some purposes; the typical number of units in such a block is one, but may be two to five.

As used herein, a carbonate is a functional group with the structure —O—C(O)—O—. The carbonate starting material can be cyclic, such as trimethylene carbonate (TMC), or can be linear, such as dimethylcarbonate (CH3O—C(O)—OCH3). After incorporation into the polymerizable macromer, the carbonate will be present at least in part as R—O—C(═O)—O—R′, where R and R′ are other components of the macromer.

As used herein, a dioxanone is a repeating unit with the structure —O—C(O)—R—O—, where R is a straight, branched or cyclic alkyl group. An example of a cyclic dioxanone is 1,4-dioxan-2-one, 1,4-dioxan-2-one is a preferred dioxanone.

As used herein, a hydrogel is a substance formed when an organic polymer (natural or synthetic) is cross-linked via covalent, ionic, or hydrogen bonds to create a three-dimensional open-lattice structure which entraps water molecules to form a gel.

As used herein, “water-soluble” is defined as a solubility of at least one gram/liter in an aqueous solution at a temperature in the range of about 0° C. and 50° C. Aqueous solutions can include small amounts of water-soluble organic solvents, such as dimethylsulfoxide, dimethylformamide, alcohols, acetone, and/or glymes.

Types of Block Copolymers

In general terms, the macromers are block co-polymers that comprise a biodegradable block, a water-soluble block, and at least one polymerizable group. Preferably, the macromers comprise at least 1.02 polymerizable groups on average, and, more preferably, include at least two polymerizable groups per macromer, on average. Average numbers of polymerizable groups can be obtained, for example, by blending macromers with different amounts of polymerizable groups.

The individual polymeric blocks can be arranged to form different types of block copolymers, including di-block, tri-block, and multi-block copolymers. The polymerizable blocks can be attached directly to biodegradable blocks or indirectly via water-soluble nondegradable blocks, and are preferably attached so that the polymerizable groups are separated from each other by a biodegradable block. For example, if the macromer contains a water-soluble block coupled to a biodegradable block, one polymerizable group may be attached to the water-soluble block and another attached to the biodegradable block. Preferably, both polymerizable groups would be linked to the water-soluble block by at least one degradable linkage.

The di-block copolymers include a water-soluble block linked to a biodegradable block, with one or both ends capped with a polymerizable group. The tri-block copolymers can include a central water-soluble block and outside biodegradable blocks, with one or both ends capped with a polymerizable group. Alternatively, the central block can be a biodegradable block, and the outer blocks can be water-soluble. The multiblock copolymers can include one or more of the water-soluble blocks and biocompatible blocks coupled together in a linear fashion. Alternatively, the multiblock copolymers can be brush, comb, dendritic or star copolymers. If the backbone is formed of a water-soluble block, at least one of the branches or grafts attached to the backbone is a biodegradable block. Alternatively, if the backbone is formed of a biodegradable block, at least one of the branches or grafts attached to the backbone is a water-soluble block, unless the biodegradable block is also water-soluble. In another embodiment, a multifunctional compound, such as a polyol, can be coupled to multiple polymeric blocks, at least one of which is water-soluble and at least one of which is biodegradable.

In general, any formulation of the macromer which is intended to be biodegradable must be constructed so that each polymerizable group is separated from each other polymerizable group by one or more linkages which are biodegradable. Non-biodegradable materials are not subject to this constraint.

Those skilled in the art will recognize that the individual polymeric blocks may have uniform compositions, or may have a range of molecular weights, and may be combinations of relatively short chains or individual species which confer specifically desired properties on the final hydrogel, while retaining the required characteristics of the macromer. The lengths of oligomers referred to herein may vary from single units (in the biodegradable portions) to many, subject to the constraint of preserving the overall water-solubility of the macromer.

In the discussion below and the examples, macromers are often designated by a code of the form xxKZn. xxK represents the molecular weight of the backbone polymer, which is polyethylene glycol (“PEG”) unless otherwise stated, in thousands of Daltons. Z designates the biodegradable linkage, using a code wherein where L is for lactic acid, G is for glycolic acid, D is for dioxanone, C is for caprolactone, T is for trimethylene carbonate, and n is the average number of degradable groups in the block. The molecules are terminated with acrylic ester groups, unless otherwise stated. This is sometimes also indicated by the suffix A2.

While the preferred biodegradable groups (in addition to carbonate or dioxanone) are hydroxy acids, orthoesters, anhydrides, or other synthetic or semisynthetic degradable linkages, natural materials may be used in the biodegradable sections when their degree of degradability is sufficient for the intended use of the macromer. Such biodegradable groups may comprise natural or unnatural amino acids, carbohydrate residues, and other natural linkages. Biodegradation time will be controlled by the local availability of enzymes hydrolyzing such linkages. The availability of such enzymes may be ascertained from the art or by routine experimentations.

Water soluble regions

Suitable water-soluble polymeric blocks include those prepared from poly(ethylene glycol), poly(ethylene oxide), partially or fully hydrolyzed poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), poly(ethylene oxide)-co-poly(propylene oxide) block copolymers (poloxamers and meroxapols), poloxamines, carboxymethyl cellulose, hydroxyalkylated celluloses such as hydroxyethyl cellulose and methylhydroxypropyl cellulose, polypeptides, polynucleotides, polysaccharides or carbohydrates such as Ficoll® polysucrose, hyaluronic acid, dextran, heparan sulfate, chondroitin sulfate, heparin, or alginate, and proteins such as gelatin, collagen, albumin, or ovalbumin. Preferably, the water-soluble polymeric blocks are made from poly (ethylene glycol) or poly(ethylene oxide).

The soluble polymer blocks may be intrinsically biodegradable or may be poorly biodegradable or effectively non-biodegradable in the body. In the latter two cases, the soluble blocks should be of sufficiently low molecular weight to allow excretion. The maximum molecular weight to allow excretion in human beings (or other species in which use is intended) will vary with polymer type, but will often be about 40,000 daltons or below. Water-soluble natural polymers and synthetic equivalents or derivatives, including polypeptides, polynucleotides, and degradable polysaccharides, can be used.

The water-soluble blocks can be a single block with a molecular weight of at least 600, preferably 2000 or more, and more preferably at least 3000 Daltons. Alternatively, the water-soluble blocks can be two or more water-soluble blocks which are joined by other groups. Such joining groups can include biodegradable linkages, polymerizable linkages, or both. For example, an unsaturated dicarboxylic acid, such as maleic, fumaric, or aconitic acid, can be esterified with degradable groups as described below, and such linking groups can be conjugated at one or both ends with hydrophilic groups such as polyethylene glycols. In another embodiment, two or more PEG molecules can be joined by biodegradable linkages including carbonate linkages, and subsequently be end-capped with polymerizable groups.

Biodegradable Blocks.

The biodegradable blocks are preferably hydrolyzable under in vivo conditions. At least one biodegradable region is a carbonate or dioxanone linkage. Additional biodegradable polymeric blocks can include polymers and oligomers of hydroxy acids or other biologically degradable polymers that yield materials that are non-toxic or present as normal metabolites in the body. Preferred poly(hydroxy acid)s are poly(glycolic acid), poly(DL-lactic acid) and poly(L-lactic acid). Other useful materials include poly(amino acids), poly(anhydrides), poly(orthoesters), and poly(phosphoesters). Polylactones such as poly(epsilon-caprolactone), poly(delta-valerolactone), poly(gamma-butyrolactone) and poly(beta-hydroxybutyrate), for example, are also useful.

Biodegradable regions can be constructed from monomers, oligomers or polymers using linkages susceptible to biodegradation, such as ester, peptide, anhydride, orthoester, and phosphoester bonds.

By varying the total amount of biodegradable groups, and selecting the ratio between the number of carbonate or dioxanone linkages (which are relatively slow to hydrolyze) and of lower hydroxy acid linkages (especially glycolide or lactide, which hydrolyze relatively rapidly), the degradation time of hydrogels formed from the macromers can be controlled.

Carbonates and Dioxanones

Any carbonate can be used to make the macromers. Preferred carbonates are aliphatic carbonates, for maximum biocompatibility. For example, trimethylene carbonate and dimethyl carbonate are examples of aliphatic carbonates. Lower dialkyl carbonates are joined to backbone polymers by removal by distillation of alcohols formed by equilibration of dialkyl carbonates with hydroxyl groups of the polymer.

More preferred carbonates are the cyclic carbonates, which can react with hydroxy-terminated polymers without release of water. Suitable cyclic carbonates include ethylene carbonate (1,3-dioxolan-2-one), propylene carbonate (4-methyl-1,3-dioxolan-2-one), trimethylene carbonate (1,3-dioxan-2-one) and tetramethylene carbonate (1,3-dioxepan-2-one). Under some reaction conditions, it is possible that orthocarbonates may react to give carbonates, or that carbonates may react with polyols via orthocarbonate intermediates, as described in Timberlake et al, U.S. Pat. No. 4,330,481. Thus, certain orthocarbonates, particularly dicyclic orthocarbonates, can be suitable starting materials for forming the carbonate-linked macromers.

Alternatively, suitable diols or polyols, including backbone polymers, can be activated with phosgene to form chloroformates, as is described in the art, and these active compounds can be mixed with backbone polymers containing suitable groups, such as hydroxyl groups, to form macromers containing carbonate linkages.

All of these materials are “carbonates” as used herein.

Suitable dioxanones include dioxanone (p-dioxanone; 1,4-dioxan-2-one; 2-keto-1,4-dioxane), and the closely related materials 1,4-dioxolan-2-one, 1,4-dioxepan-2-one and 1,5-dioxepan-2-one. Lower alkyl, for example C1-C4 alkyl, derivatives of these compounds are also contemplated, such as 2-methyl p-dioxanone (cyclic O-hydroxyethyl ether of lactic acid).

Polymerizable Groups.

The term “polymerizable group” is defined as a reactive functional group that has the capacity to form additional covalent bonds resulting in macromer interlinking. Polymerizable groups specifically include groups capable of polymerizing via free radical polymerization and groups capable of polymerizing via cationic or heterolytic polymerization. Suitable groups include, but are not limited to, ethylenically or acetylenically unsaturated groups, isocyanates, epoxides (oxiranes), sulfhydryls, succinimides, maleimides, amines, imines, amides, carboxylic acids, sulfonic acids and phosphate groups. (Aliphatic hydroxy groups are not considered to be reactive groups for the chemistry disclosed herein, except in formulations which also contain groups capable of covalent crosslinking with such hydroxyls.) Ethylenically unsaturated groups include vinyl groups such as vinyl ethers, N-vinyl amides, allyl groups, unsaturated monocarboxylic acids, unsaturated dicarboxylic acids, and unsaturated tricarboxylic acids. Unsaturated monocarboxylic acids include acrylic acid, methacrylic acid and crotonic acid. Unsaturated dicarboxylic acids include maleic, fumaric, itaconic, mesaconic or citraconic acid. Unsaturated tricarboxylic acids include aconitic acid. Polymerizable groups may also be derivatives of such materials, such as acrylamide, N-isopropylacrylamide, hydroxyethylacrylate, hydroxyethylmethacrylate, and analogous vinyl and allyl compounds. Reactive group forming compounds will preferably be available in a stable activated form, to allow simple incorporation into the macromer. Examples of such materials are (meth)acrylyl chloride, acrylic anhydride, and allyl glycidyl ether. The polymerizable groups are preferably located at one or more ends of the macromer. In a less preferred embodiment, the polymerizable groups can be located within the macromer.

Polymerization is initiated by any convenient reaction, including photopolymerization, chemical or thermal free-radical polymerization, redox reactions, cationic polymerization, and chemical reaction of active groups (such as isocyanates, for example.) Polymerization is preferably initiated using photoinitiators. Photoinitiators that generate a free radical or a cation on exposure to UV light are well known to those of skill in the art. Free-radicals can also be formed in a relatively mild manner from photon absorption of certain dyes and chemical compounds. The polymerizable groups are preferably polymerizable by free radical polymerization. The preferred polymerizable groups are acrylates, diacrylates, oligoacrylates, methacrylates, dimethacrylates, oligomethacrylates, cinnamates, dicinnamates, oligocinnamates, and other biologically acceptable photopolymerizable groups.

These groups can be polymerized using photoinitiators that generate free radicals upon exposure to light, including UV (ultraviolet) and IR (infrared) light, preferably long-wavelength ultraviolet light (LWUV) or visible light. LWUV and visible light are preferred because they cause less damage to tissue and other biological materials than short-wave UV light. Useful photoinitiators are those which can be used to initiate polymerization of the macromers without cytotoxicity and within a short time frame, minutes at most and most preferably seconds.

Exposure of dyes, preferably in combination with co-catalysts such as amine, to light, preferably visible or LWUV light, can generate free radicals. Light absorption by the dye causes the dye to assume a triplet state, and the triplet state subsequently reacts with the amine to form a free radical which initiates polymerization, either directly or via a suitable electron transfer reagent or co-catalyst, such as an amine. Polymerization can be initiated by irradiation with light at a wavelength of between about 200-1200 nm, most preferably in the long wavelength ultraviolet range or visible range, 320 nm or higher, and most preferably between about 365 and 550 nm.

Numerous dyes can be used for photopolymerization. Suitable dyes are well known to those of skill in the art. Preferred dyes include erythrosin, phloxime, rose bengal, thionine, camphorquinone, ethyl eosin, eosin, methylene blue, riboflavin, 2,2-dimethyl-2-phenylacetophenone, 2-methoxy-2-phenylacetophenone, 2,2-dimethoxy-2-phenyl acetophenone, other acetophenone derivatives, and camphorquinone. Suitable cocatalysts includes amines such as N-methyl diethanolamine, N,N-dimethyl benzylamine, tri-ethanol amine, triethylamine, dibenzyl amine, N-benzylethanolamine, N-isopropyl benzylamine. Triethanolamine is a preferred cocatalyst.

Suitable chemical, thermal and redox systems may initiate the polymerization of unsaturated groups by generation of free radicals in the initiator molecules, followed by transfer of these free radicals to the unsaturated groups to initiate a chain reaction. Peroxides and other peroxygen compounds are well-known in this regard, and may be considered as chemical or thermal initiators. Azobisbutyronitrile is a chemical initiator. A combination of a transition metal, especially iron, with a peroxygen and preferably a stabilizing agent such as glucuronic acid allows generation of free radicals to initiate polymerization by a cycling redox reaction.

Combinations of chemical or redox systems with photo-initiated systems have been demonstrated to be effective in WO 96/29370, and are a preferred initiation system for many applications of the macromers of the present invention.

It is also possible to use the macromers with other types of linking reactions. For example, a macromer could be constructed with amine termination, with the amine considered as an active group; and another macromer could be constructed with isocyanate termination, with the isocyanate as the active group. On mixing, the materials will spontaneously react to form a gel. Alternatively, an isocyanate-terminated macromer could be polymerized and crosslinked with a mixture of diamines and triamines. Such a reaction is more difficult to control than a photoinitiated reaction, but could be preferred for high volume extracorporeal production of gels for implantation, perhaps as drug delivery systems. Other pairs of reactants include maleimides with amines or sulfhydryls, or axiranes with amines, sulfhydryls or hydroxyls.

Preferred Macromers

Preferably, the macromers contain between about 0.3% and 20% by weight of carbonate residues or dioxanone residues, more preferably, between about 0.5% and 15% carbonate or dioxanone residues, and most preferably, about 1% to 5% carbonate or dioxanone residues. In those embodiments where hydroxy acid residues are desired, the macromer contains between about 0.1 and 10 residues per residue of carbonate or dioxanone, more preferably between about 0.2 and 5, and most preferably one or more such residue per macromer.

In a preferred embodiment, the macromer includes a core, an extension on each end of the core, and an end cap on each extension. The core is a hydrophilic polymer or oligomer; each extension is a biodegradable oligomer comprising one or more carbonate or dioxanone linkage; and each end cap comprises one or more functional groups capable of cross-linking the macromers. In a particularly preferred embodiment, the core includes hydrophilic poly(ethylene glycol) oligomers with a molecular weight between about 400 and 40,000 Da; each extension includes 1 to 10 residues selected from carbonate and dioxanone, and optionally further included between one and five hydroxyacid residues, preferably alpha-hydroxy acid residues; wherein the total of all residues in the extension is sufficiently small to preserve water-solubility of the macromer, being typically less than about 20% of the weight of the macromer, more preferably 10% or less.

Preferably, each end cap includes a polymerizable group. The preferred groups are free-radical (homolytically) polymerizable. More preferably, they are ethylenically-unsaturated (i.e., containing carbon-carbon double bonds), with a preferred molecular weight between about 50 and 300 Da, which are capable of cross-linking and/or polymerizing the macromers. A preferred embodiment incorporates a core consisting of poly(ethylene glycol) oligomers of molecular weight about 25,000 Da; extensions including polycarbonate or poly(dioxanone) oligomers with a molecular weight of about 200 to 1000 D, alone or in combination with extensions formed of hydroxy acid oligomers; and end caps consisting of acrylate moieties (which are about 55 Da molecular weight).

Macromer Synthesis

The macromers can be synthesized using means well known to those of skill in the art. General synthetic methods are found in the literature, for example in U.S. Pat. No. 5,410,016 to Hubbell et al., U.S. Pat. No. 4,243,775 to Rosensaft et al., and U.S. Pat. No. 4,526,938 to Churchill et al.

For example, a polyethylene glycol backbone can be reacted with trimethylene carbonate (TMC) or a similar carbonate in the presence of a Lewis acid catalyst, such as stannous octoate, to form a TMC-polyethylene glycol terpolymer. The TMC-PEG polymer may optionally be further derivatized with additional degradable groups, such as lactate groups. The terminal hydroxyl groups can then be reacted with acryloyl chloride in the presence of a tertiary amine to end-cap the polymer with acrylate end-groups. Similar coupling chemistry can be employed for macromers containing other water-soluble blocks, biodegradable blocks, and polymerizable groups, particularly those containing hydroxyl groups.

When polyethylene glycol is reacted with TMC and a hydroxy acid in the presence of an acidic catalyst, the reaction can be either simultaneous or sequential. As shown in the examples below, the simultaneous reaction will produce an at least partially random copolymer of the three components. Sequential addition of a hydroxy acid after reaction of the PEG with the TMC will tend to produce an inner copolymer of TMC and one or more PEGs, which will statistically contain more than one PEG residue linked by linkages derived from TMC, with hydroxy acid largely at the ends of the (TMC, PEG) region. There is a tendency for TM and other carbonate groups to re-arrange by “back-biting” during synthesis, which is why multiple PEG molecules can become incorporated in the same macromer. When the hydroxy acid contains a secondary hydroxyl, as in lactic acid, then the tendency towards rearrangement is reduced.

In principle, the degradable blocks or regions could be separately synthesized and then coupled to the backbone regions. In practice, this more complex reaction does not appear to be required to obtain useful materials.

Sequential Addition

In a preferred embodiment, sequential addition of biodegradable groups to a carbonate-containing macromer can be used to enhance biodegradability of the macromer after capping with reactive end groups.

Upon reaction of, for example, trimethylene carbonate (TMC) with polyethylene glycol (PEG), the TMC linkages in the resulting copolymers have been shown to form end linked species of PEG, resulting in segmented copolymers, i.e. PEG units coupled by one or more adjacent TMC linkages. The length of the TMC segments can vary, and is believed to exhibit a statistical distribution. Coupling may also be accomplished via the carbonate subunit of TMC. These segmented PEG/TMC copolymers form as a result of transesterification reactions involving the carbonate linkages of the TMC segments during the TMC polymerization process when a PEG diol is used as an initiator. Similar behavior is expected if other polyalkylene glycol initiators were used. The end-linking may begin during the reaction of the TMC with the PEG, and completion of the end linking and attainment of equilibrium is observable by a cessation of increase of the viscosity of the solution.

If the product of this first reaction step is then reacted with a reactive end-capping material, such as acryloyl chloride, a significant percentage of the macromer end groups can be PEG hydroxyls, resulting in the attachment of the reactive groups directly to one end of a non-biodegradable PEG molecule. Such a reaction of the PEG/TMC segmented copolymers can be prevented by adding additional segments of other hydrolyzable co-monomers (e.g. lactate, glycolate, 1,4-dioxanone, dioxepanone, caprolactone) on either end of the PEG/TMC segmented copolymer. Some scrambling of the comonomer segments with the PEG/TMC prepolymer is expected, but this can be minimized by using proper reaction conditions. The basic PEG/TMC segmented copolymer or the further reacted PEG/TMC/comonomer segmented terpolymer is then further reacted to form crosslinkable macromers by affixing reactive end groups (such as acrylates) to provide a macromer with reactive functionality. Subsequent reaction of the end groups in an aqueous environment results in a bioabsorbable hydrogel. Similar segmented structures would be expected if another polyalkylene glycol (PAG) were used, for example a poloxamer.

The copolymers and macromers can have tailorable solubility and solution viscosity properties. The hydrogels can have tailorable modulus and degradation rate. For a given solution concentration in water, the viscosity is affected by the degree of end linking, the length of the TMC (and other hydrophobic species) segments, and the molecular weight of the starting PAG. The modulus of the hydrogel is affected by the molecular weight between crosslinks. The hydrogel degradation rate can be modified by adding a second, more easily hydrolyzed comonomer (e.g. lactate, glycolate, 1,4-dioxanone) as a segment on the ends of the basic PAG/TMC copolymer prior to adding the crosslinkable end group to form the macromer.

Some of these structures described herein are depicted below. PEG, lactate and acrylate units are used solely for purposes of illustration.

SOME BASIC STRUCTURES:

(CH2—CH2—O)x═PEG repeat unit═(PEG)x

(CO—(CH2)3—O)y═TMC repeat unit═(TMC)y

(CO—CH(CH3)—O)z═Lactate repeat unit═(LA)z

—CO—CH═CH2═Acrylate end group═AA

SEGMENTED PEG/TMC COPOLYMER:

HO—(CO—(CH2)3—O)y—[(CH2—CH2—O)x—(CO—(CH2)3—O)y]n—H

or HO—(TMC)y—[(PEG)x—(TMC)y]n—H

SEGMENTED PEG/TMC/Lactate TERPOLYMER:

HO—(CH(CH3)—CO)z—O—(CO—(CH2)3—O)y—[(CH2—CH2—O)x—(CO—(CH2)3—O)y]n—(CO—C H(CH3)—O)z—H

or HO—(LA)z—(TMC)y—[(PEG)x—(TMC)y]n—(LA)z—H

SEGMENTED PEG/TMC MACROMER (acrylated):

CH2═CH—CO—O—(CO—(CH2)3O)y—[(CH2—CH2—O)x—(CO—(CH2)3—O)y]n—CO—CH═CH2

or AA—(TMC)y—[(PEG)x—(TMC)y]n—AA

SEGMENTED PEG/TMC/Lactate TERPOLYMER MACROMER (acrylated):

AA—(LA)z—(TMC)y—[(PEG)x—(TMC)y]n—(LA)z—AA

Applications for the Macromers.

Sealing Leaks in Tissue

A preferred application of the polymers is in a method of sealing leaks, for example, leaks of gases and/or bodily fluids (such as blood, cerebrospinal fluid, urine and bile), in tissue such as lung, urethra, ureter, gastrointestinal tract, reproductive tract, liver, spleen, dura, and the spinal cord. The method involves priming the surface of the tissue with a polymerization initiator, applying a macromer solution that also contains one or more polymerization initiators to the surface of the tissue to be coated, and then polymerizing the macromer. Preferably, the polymerization initiator comprises a photoinitiator.

Applying the initiator to surface of the tissue before adding the macromer solution polymerizes the macromer at the interface between the solution and the tissue surface. This “interfacial polymerization” provides excellent adherence of the resulting polymer to the tissue surface. Providing an initiator in the macromer solution allows a relatively thick, for example 1 mm to 10 mm, layer of polymer to be formed on the tissue surface. Relatively thick polymer layers may be required to effectively seal some types of tissue, for example, lung tissue or dura, depending on the size of the leak.

An advantage of the macromers when prepared with at least one carbonate group is that during the synthesis of the macromer, short blocks of non-biodegradable but excretable polymer, such as polyethylene oxide chains of up to about 40,000 D, can become linked by carbonate groups so give higher molecular weights to the macromers while preserving the biodegradability to secretable products of the macromer. It is believed that the higher molecular weights increase the elasticity of the final hydrogel. This is an important and useful property when the polymer must be readily and repeatedly stretched, as in a sealant layer applied to lung tissue. High elasticity can also be provided by linking nondegradable blocks with other polyfunctional linkers, such as dicarboxylic acids. However, since the synthetic chemistry required to make such macromers can be more complex than the simple reactions required for carbonate-based linking, this method is less preferred.

Prevention of Surgical Adhesions

Another preferred application is a method of reducing formation of adhesions after a surgical procedure in a patient. The method involves coating damaged tissue surfaces in a patient with an aqueous solution of a light-sensitive free-radical polymerization initiator and a macromer solution as described above. The coated tissue surfaces are exposed to light sufficient to polymerize the macromer. The light-sensitive free-radical polymerization initiator may be a single compound (e.g., 2,2-dimethoxy-2-phenyl acetophenone) or a combination of a dye and a cocatalyst (e.g., ethyl eosin or eosin Y, and triethanolamine).

Controlled delivery of incorporated agents.

Another preferred application involves locally applying an incorporated agent, such as a prophylactic, therapeutic or diagnostic agent, to tissue surfaces of a patient. The method includes the steps of mixing an agent to be incorporated with an aqueous solution including a suitable polymerization initiator, such as a light-sensitive free-radical polymerization initiator, and a macromer, to form a coating mixture. Tissue surfaces are coated with the coating mixture and the macromer is polymerized, for example, by exposure of the coating mixture to an effective amount of light of an appropriate wavelength.

Any of a variety of therapeutic, prophylactic or diagnostic agents can be delivered using these methods. Examples include synthetic and natural inorganic and organic compounds such as proteins (100 amino acid residues or more), peptides (less than 100 amino acid residues), carbohydrates, lipids, nucleic acid molecules, and small synthetic materials such as ethical drugs, having therapeutic, prophylactic or diagnostic activities. Nucleic acid molecules include genes, antisense molecules which bind to complementary DNA to inhibit transcription, aptamers, triple helix forming oligomers and ribozymes. The agents to be delivered can have a variety of biological activities. Diagnostic agents such as radiolabelled compounds, enzymatically labeled compounds, fluorescently labeled compounds, and other detectable agents can also be incorporated. Compounds with a wide range of molecular weights can be incorporated, for example, between 100 and 500,000 grams or more per mole.

Therapeutic or prophylactic compounds (“drugs”) of particular interest are those whose efficacy in treatment of a localized medical condition is increased by local delivery of the compound at or near the site of the localized medical condition. Examples of classes of such drugs are those which inhibit the formation or re-formation of scars or adhesions; those which prevent unwanted proliferation of vascular tissue or other luminal tissue; and growth factors, cytokines, etc. which only needs to be effective locally.

Imaging agents which may be utilized include commercially available agents used in positron emission tomography (PET), computer assisted tomography (CAT), single photon emission computerized tomography, x-ray, fluoroscopy, and magnetic resonance imaging (MRI).

Examples of suitable materials for use as contrast agents in MRI include the gadolinium chelates currently available, such as diethylene triamine pentacetic acid (DTPA) and gadopentotate dimeglumine, as well as iron, magnesium, manganese, copper and chromium.

Examples of materials useful for CAT and x-rays include iodine based materials for intravenous administration, such as ionic monomers typified by diatrizoate and iothalamate, non-ionic monomers such as ioparnidol, isohexol, and ioversol, non-ionic dimers, such as iotrol and iodixanol, and ionic dimers, for example, ioxagalte.

Hydrogels incorporating these agents can be detected using standard techniques available in the art and commercially available equipment.

The macromers are particularly useful for delivering hydrophilic and/or labile materials. Because the macromer is water-soluble, water can penetrate the polymer and dissolve or extract incorporated hydrophilic materials. Labile materials can be incorporated without exposure of the material to organic solvents which would destroy biological activity. Hydrophobic materials may also be incorporated, if the rate of dissolution of the hydrophobic material and/or the gel matrix is sufficiently rapid to release the material at a therapeutically-effective rate. In all cases, the polymerized hydrogel will tend to protect the therapeutic material from attack by biological activities of the subject, such as enzyme activity.

In a variation of the method for controlled drug delivery, the macromers are polymerized with incorporated agent on the surface of tissue or a medical device.

The macromers may be polymerized to form devices in the shape of particles, sheets, rods, or nano or microcapsules.

Preferred Macromers

Preferably, the macromers contain between about 0.3% and 20% by weight of carbonate residues or dioxanone residues, more preferably, between about 0.5% and 15% carbonate or dioxanone residues, and most preferably, about 1% to 5% carbonate or dioxanone residues. In those embodiments where hydroxy acid residues are desired, the macromer contains between about 0.1 and 10 residues per residue of carbonate or dioxanone, more preferably between about 0.2 and 5, and most preferably one or more such residue per macromer.

In a preferred embodiment, the macromer includes a core, an extension on each end of the core, and an end cap on each extension. The core is a hydrophilic polymer or oligomer; each extension is a biodegradable oligomer comprising one or more carbonate or dioxanone linkage; and each end cap comprises one or more functional groups capable of crosslinking the macromers. In a particularly preferred embodiment, the core includes hydrophilic poly(ethylene glycol) oligomers with a molecular weight between about 400 and 40,000 Da; each extension includes 1 to 10 residues selected from carbonate and dioxanone, and optionally further includeds between one and five hydroxyacid residues, preferably alpha-hydroxy acid residues; wherein the total of all residues in the extensions is sufficiently small to preserve water-solubility of the macromer, being typically less than about 20% of the weight of the macromer, more preferably 10% or less.

Preferably, each end cap includes a polymerizable group. The preferred groups are free-radical (homolytically) polymerizable. More preferably, they are ethylenically-unsaturated (i.e., containing carbon-carbon double bonds), with a preferred molecular weight between about 50 and 300 Da, which are capable of cross-linking and/or polymerizing the macromers. A preferred embodiment incorporates a core consisting of poly(ethylene glycol) oligomers of molecular weight about 25,000 Da; extensions including polycarbonate or poly(dioxanone) oligomers with a molecular weight of about 200 to 1000 D, alone or in combination with extensions formed of hydroxy acid oligomers; and end caps consisting of acrylate moieties (which are about 55 Da molecular weight).

Tissue Adhesives.

The macromers, and hydrogels formed therefrom, can also be used to adhere tissue surfaces in a patient. The macromer is mixed with a suitable polymerization initiator system, such as a photoinitiator or photoinitiator/amine mixture, to form an aqueous mixture. The mixture is applied to a tissue surface to which tissue adhesion is desired. The tissue surface is contacted with the tissue with which adhesion is desired, forming a tissue junction. The macromers are then polymerized at the tissue junction.

Such a technique can be used to hold surgically severed tissue in apposition during the healing process, thereby replacing or supplementing the use of sutures, staples, etc. In addition, such a gel may also be used to form a protective barrier.

Tissue Coatings.

In a particularly preferred application of these macromers, an ultra thin coating is applied to the surface of a tissue, most preferably the inside surface of a blood vessel. Such coatings can be used to treat or prevent stenosis or restenosis of blood vessels. A polymerization initiator, preferably a photoinitiator, is applied to the surface of the tissue, allowed to stain the tissue, and, optionally, the excess photoinitiator is removed by dilution or rinsing. After the initiator has been applied to the tissue, the macromer solution is applied and the macromer is polymerized. As demonstrated below, this method is capable of creating a uniform polymeric coating of between about one and 300 microns in thickness, more preferably about ten to 200 microns, most preferably 20 to 80 microns, which does not evoke thrombosis during its residence at the site.

Coating Medical Devices

The surface of medical devices can be coated with the macromers using interfacial polymerization, bulk polymerization, or both, as discussed above. Coating layers applied using interfacial polymerization or a combination of interfacial and bulk polymerization typically adhere more strongly to the medical devices than those prepared using only bulk polymerization.

The present invention will be more fully understood by reference to the following non-limiting examples.

Example 1: General Synthesis of Macromers: Melt Method.

Methods analogous to those described in U.S. Pat. No. 4,526,938 to Churchill et al. were used to form derivatized PEG by the melt method. Polyethylene glycol (PEG) was obtained commercially. The molecular weight listed on the label was assumed to be the molecular weight of the material. The PEG was optionally dissolved in methanol and purified by passage over an ion exchange resin, and dried.

Purified or as-supplied PEG was charged to a reactor, optionally with a small amount of xylene, and heated for five to six hours at about 110° C. (note: all temperatures herein are in degrees Celsius) under vacuum to complete removal of water. After cooling under vacuum, the flask was placed in a glove bag, the materials for forming the biodegradable linkages (including T (trimethylene carbonate) and L (lactide)) were added to the PEG, and the temperature was raised to about 160-165° C. under an argon blanket.

After dissolution of the reactants in the melted PEG, a catalyst, typically stannous octoate, was added, the temperature was raised to 185° C., and ring-opening addition was allowed to proceed for about 3 hours, with stirring under argon. The PEG—(T,L) intermediate could be further reacted at this stage, but typically was freed of unreacted monomers by precipitation in hexane, recovery and drying.

The purified intermediate, for example, PEG—(TnLm), where “n” is the number of T groups and “m” is the number of L groups, or the original reaction mixture without purification, was taken up in toluene, and an agent capable of adding unsaturated linkages, such as acryloyl chloride, was added, typically in excess, under mild heating (e.g., about 50° C.) and in the presence of an acid-neutralizing agent such as triethylamine. Suitable reactant ratios were found to be 1 ml acryloyl chloride and 1.8 ml triethylamine per 30 grams of PEG. The endcapped macromer, PEG-(T, L)-A2, was purified by precipitation in hexane, recovered and dried. Stabilizer was optionally added at this stage. The extent of incorporation of monomers was determined by NMR.

A similar procedure was used to prepare other macromers. PEG—(Tn)—A2, PEG—(Dn, Gm)—A2, where D is dioxanone and G is glycolide, and like materials were formed by similar procedures. Synthesis of macromers based on other starting hydrophilic blocks follows similar procedures, with adjustment in precipitation conditions as required. In a synthesis with multi-hydroxy compounds, such as polyvinyl alcohol, the water would be removed azeotropically under mild reflux in, e.g., toluene; and the degradable linkages are preferably synthesized by polymerization onto the hydroxy compound as described above, although such blocks could be added as preformed activated acrylated blocks, for example, using a carbodiimide derivative of the acylated poly(degradable linkage), if greater control were required.

Example 2: Synthesis of PEG-TMC and PEG-TMC-Lactide Macromers.

35K(T8)A2 (“35KT” in the examples below) was made from purified PEG of nominal molecular weight 35,000 by the melt procedure as described above. T was charged into the reactor at a nominal molar ratio of 13:1 to the PEG to obtain this result. The final actual acrylate incorporation averaged 1.6 per PEG molecule, or about 2 acrylates per macromer.

35K(T7L2)A2 (“35KTL”) contained about 7 T units (6.88 measured) and 2 lactate units (1.86 measured) as synthesized. (Note that there are 2 lactate units per lactide molecule.) T and L were charged at nominal molar ratios of 10:1 and 3:1 relative to PEG.

20K(T30L15)A2 contained about 30 T units and 15 lactide units per 20,000 D PEG molecule. The actual acrylate to PEG ratio was 1.42.

Example 3: Seal pressure text on latex to measure strength and elasticity

Poly(ethylene glycol)-lactide-trimethylene carbonate terpolymers endcapped with acrylate esters were evaluated using a seal pressure test apparatus to determine the failure pressure for coatings prepared using the macromers.

One of the materials tested had a poly(ethylene glycol) molecular weight of 20,000 Daltons (“20 kD”), a lactate incorporation of 13.8 and a trimethylene carbonate incorporation of 16.0, with nominal acrylation of 2 per macromer (“20KTL”). Also tested were 35 kD PEG esterified with about 8 TMC linkages and then endcapped with acrylates (“35KT”), and 35 kD PEG esterified with about 8 TMC and about 8 lactate groups (“35KTL”), both also acrylated. The reagents applied were “primer” and “sealant”. The complete system contained both a photoinitiation system (Eosin Y/triethanolamine) and a redox initiation system (ferrous gluconate/fructose, plus t-butylhydroperoxide after mixing) which did not cause significant polymerization of the macromer until both mixed (primer and sealant) and activated by light.

Primer solution contained Eosin Y (2000 ppm, w/w), 5000 ppm ferrous gluconate, 10,000 ppm (1%) fructose, 30,000 ppm NaCl, and 30% w/w of 3.5KL5 macromer (made according to U.S. Pat. No. 5,410,016). Primer was applied to a 2 cm×2 cm piece of latex film (from a latex examination glove; about 1 mm thick) with a 6 mm diameter hole created in the center. A toroidal Teflon® fluoropolymer template with a 1 cm. diameter central hole was placed on the latex film to control the area of application of the sealant, by limiting its spread.

Sealant solution contained macromer (in this example, 10% or 20% w/w of one of the macromers described above) dissolved in an aqueous solution containing isotonic saline, 90 mM triethanolamine as buffer and electron transfer component, Eosin Y (20 ppm) as a photoinitiator, 4000 ppm vinylcaprolactam as comonomer, and 125 ppm t-butylhydroperoxide as part of the light-sensitized redox initiation system. Two drops of sealant were dispensed inside the template above the hole and then carefully mixed in with the primer, using a brush. Three more drops of sealant were dispensed, and then the area was illuminated with visible light from a xenon arc lamp (450-550 nm) at an intensity of 100 mW/cm2 for 40 seconds. Samples were laced in phosphate buffered saline (pH 7.4) at 37° C. for different times (t=0, 4 hours, 1 days, 3 days, 6 days and 10 days).

Samples were evaluated at each time point using a seal pressure test apparatus to determine the failure pressure. The test apparatus was a modified membrane holder, in which the latex sample was clamped at the edges between gaskets. Pressure was then applied to the side of the latex away from the polymer seal, and the pressure required to rupture the seal was measured.

FIG. 1 shows the results obtained with five different sealant materials. The seal pressure decreases over the course of time, presumably due to a combination of swelling of the hydrogel due to hydration and programmed degradation of the hydrogel.

Example 4: Bioabsorption in-vivo

Poly(ethylene glycol)-trimethylene carbonate copolymers, optionally containing lactate, and endcapped with acrylate esters, were evaluated. Two of the materials described with Example 3 were used (20KTL and 35KT). The macromers were polymerized using visible light illumination from a xenon arc lamp (450-550 nm) at an intensity of 100 mW/cm2 in a sealant solution containing macromer, eosin, triethanolamine, vinylcaprolactam, t-butylhydroperoxide and saline as in Example 3. Macromer concentration was 10% for 20KTL and 20% for 35KT.

The absorption of the sealant was determined by subcutaneous implants in rats. Five female Sprague Dawley rats (250-300 g) were used in this study. The animals were anesthetized by intramuscular (“IM”) injection of 3.2 ml/kg mixture of Ketamine (52.4 mg/kg), Xylazine (2.8 mg/kg), Acepromazine (0.7 mg/kg). Four 1 cm longitudinal incisions were made through the skin on the back. Two incisions were made on each side of the spinal column, spaced 1 cm off the midline and 2 cm apart. A 2×2 cm pocket was created at each incision site by blunt dissection. Preformed hydrogel disks were prepared using sterile technique. One hundred microliters of sealant solution was placed in the bottom of one well of a standard 24-well tissue culture plate, and was illuminated for 40 sec at 100 mW/cm2, producing a thin disc about 18 mm. in diameter. One disk was placed in each subcutaneous pocket. Incisions were then closed with surgical staples. Animals were euthanized at intervals by CO2 inhalation. Incisions were opened and gross observations were recorded. Each site was harvested and analyzed by gel permeation chromatography for mass loss.

FIGS. 2A and 2B show that the 20KTL based hydrogels were completely absorbed in 20 days in vivo (FIG. 2A), whereas the 35KT based hydrogels were partially absorbed (60% weight loss) in 154 days (FIG. 2B). This illustrates the significant effect of rapidly-degrading linkages such as lactate groups.

Example 5: Sealing of Dural Leak in Canine Craniotomy

A poly(ethylene glycol)-trimethylene carbonate-lactate copolymer endcapped with acrylate ester (20KTL, from Example 2) was evaluated for its ability to seal fluid leaks in membranes in vivo. The poly(ethylene glycol) molecular weight used was 20,000 Da. The lactate incorporation was 13.8 and the trimethylene carbonate incorporation was 16.0. The macromer was fully acrylated.

The performance of the sealant was evaluated in a dural incision injury model in three mongrel canines. The animals were pre-anesthetized, intubated and maintained on isoflurane gas anesthesia. With the head elevated, a bilateral craniotomy was created. Two dural incisions, each 2 cm. long, were made, one on the left side and one on the right side. Incisions were closed using 3 simple interrupted 4-0 to 6-0 silk sutures spaced approximately 5 mm apart. Cerebrospinal fluid (CSF) pressure was raised by inflating the lungs to 20 cm H2O and the leak was assessed. All incisions were found to leak, as expected from the closure.

The control side (left) received no additional closure of the incision. For the treatment side (right), the primer (a low-viscosity solution; described in example 4) was applied and mixed with the fluid on the tissue interface. The sealant (10% w/w solution of 20KTL (described above) with other materials as in Example 4) was layered over the primer, and the primer and sealant were mixed with a brush. Illumination for 40 sec. with a visible xenon arc lamp (450-550 nm) at an intensity of 100 mW/cm2 was then performed to complete the polymerization.

The leaks were re-verified by raising the CSF pressure by inflating the lungs to 20 cm H2O. Leakage was observed on the control side, but not on the experimental side. The bone flaps were replaced and the incision was repaired.

All animals were euthanized at 21 days and the craniotomy was re-opened. Adhesions between the dura and the bone flap were recorded, and the dura repair sites were inspected for evidence of CSF fluid leaks. Dural repair sites were dissected free from underlying cortical tissue and the presence of adhesions noted. The tissues were harvested, rinsed in saline, and fixed in 10% neutral buffered formalin. Hematoxylin and eosin stained histological sections were taken.

At the time of explant, the control sites showed a slight fibrosis present between the dura mater and calvarium. No inflammation was detected. The sealant was not apparent in two out of three animals and only small amounts were present in the third animal. The dural edges were approximated. Defects in the bone (resulting from the surgery) were filled with fibro-osseous tissue at 21 days, in both control and treated sites. Normal healing appeared to be taking place, both visually and histologically.

EXAMPLE 6. Solution Synthesis

Macromers can also be made by synthesis in solution. While requiring additional waste disposal, the solution synthesis is more easily controlled (compared to the melt synthesis of Example 1 or 2), and is preferred for most applications. This example also illustrates the practice of sequential addition of monomers; the method is also useful for simultaneous addition of monomers.

35KTLA was made by dissolving 75 g of 35kD (nominal) PEG in toluene to 20% w/w concentration, and was dried by nitrogen purge for 3 hours at 108° C. 3.06 G TMC (14 mole equivalents per PEG) and 0.024 g stannous octoate catalyst were added, and the solution was held at 108° C. for 4 hours with stirring. Then 0.46 g (1.5 equiv.) lactide was added, and stirring continued for 2 hrs. Then 300 ml toluene was added to give about a 10% wt/vol solution of polymer. After cooling the solution to about 50°, 4.6 g of triethylamine and 2.5 ml of acryloyl chloride were added. The solution was stirred for 20 min. at about 50. Acrylated macromer was recovered by precipitation and optionally filtration as described in Ex. 1 and 2. The resulting polymer contained 5 TMC residues and 1.2 lactate residues per PEG molecule, and ratios of lactate:acrylate of 0.6.

EXAMPLE 7. In Vitro Degradation

35KTLA2 was synthesized as described in Example 6. The completed macromer had a TMC:PEG molar ratio of 3.57; an acrylate: PEG ratio of 1.52; a lactate: PEG ratio of 1.39; and contained 766 ppm TMC. On gel permeation chromatography, the macromer was 48.1% “monomer” (one PEG unit per macromer molecule), 46.3% “dimer” two PEG units per macromer molecule), 5.4% “trimer” and 0.1% higher oligomer.

Discs of the macromer were made as described in example 4 and were incubated in phosphate-buffered saline, pH 7.4, at 37° and 57°. At 57°, half of the mass was lost at about 140 hrs, while at 37°, half the mass was lost at about 42 days. Mass loss was determined by rinsing the specimen, drying to constant weight, and correcting for the amount of buffer and salt present.

EXAMPLE 8. Dioxanone-containing Macromers

Dioxanone (1,4-dioxan-2-one; p-dioxanone) was synthesized from DEG (diethylene glycol) essentially according to U.S. Pat. No. 2,807,629, Example 1. Two kilograms of DEG were mixed with 40 g. copper chromite (Aldrich) and heated at about 230° for 4 hours under nitrogen purge, which displaced generated hydrogen. Dioxanone and DEG were distilled from the mixture under vacuum at about 50° pot temperature. DEG was partially removed by extraction in cold (4°) diethyl ether. The partially purified material was dissolved in chloroform and applied to a silica column equilibrated in chloroform. Dioxanone was recovered in the initial fractions.

Macromer 35KDA was made by drying overnight (vacuum, 110°) 15 g of 35K PEG, 1.7 g dioxanone, and 0.01 g of catalyst (stannous octoate). This is a ratio of 21:1 D:PEG. Samples were also made at other amounts of D (1.0 g, 18:1, 0.84 g, 15:1, 1.34 g, 24:1). Vials were sealed and heated at 150 for 5 hrs. Samples were dissolved in chloroform; optionally precipitated in ether; and acrylated as described in previous examples. NMR showed final molar ratios in the synthesized polymer of D/PEG, 1.82; Ac/PEG, 1.64.

Macromer 35KDLA: To a mixture of 15 g PEG, 0.84 g Dioxanone and 0.01 g catalyst was also added 0.39 g d,l-lactide. A mixture was dried, then incubated at 185° overnight; dissolved in chloroform and precipitated in ether, filtered and vacuum-dried; and acrylated with excess acryloyl chloride and triethylamine.

Claims (40)

1. A method for forming a polymeric, biocompatible coating on tissue comprising:
a) applying to the tissue surface a polymerization initiator capable of initiating polymerization via free radical or cationic polymerization;
b) applying to the initiator-coated surface a solution of a biodegradable, polymerizable macromer with a solubility of at least one gram/liter in aqueous solutions at a temperature in the range between about 0 and 50° C. comprising at least one water soluble region, at least one degradable region, and at least one functional group capable of being polymerized via free radical or cationic polymerization, wherein the polymerizable regions are separated from each other by at least one degradable region and wherein at least one degradable region is a carbonate or dioxanone region; and
c) polymerizing the macromer.
2. The method of claim 1, wherein the macromer solution further comprises a polymerization initiator capable of initiating polymerization via free radical or cationic polymerization.
3. The method of claim 1, wherein the tissue is coated to prevent leakage of gases or bodily fluids from the tissue.
4. The method of claim 1, wherein the tissue is coated to prevent adhesion of the tissue to other tissue.
5. The method of claim 1, wherein the tissue is coated and adhered to other tissue during polymerization.
6. The method of claim 1 wherein the macromer solution further comprises a prophylactic, therapeutic or diagnostic agent.
7. The method of claim 1 wherein the initiator binds to the tissue, further comprising removing unbound initiator prior to application of the macromer solution.
8. A method for making a device for controlled release of a prophylactic, therapeutic or diagnostic agent comprising:
a) mixing a prophylactic, therapeutic or diagnostic agent with a solution of a biodegradable, polymerizable macromer with a solubility of at least one gram/liter in aqueous solutions at a temperature between about 0 and 50° C. comprising at least one water soluble region, at least one degradable region, and at least one functional group capable of being polymerized via free radical or cationic polymerization, wherein the polymerizable regions are separated from each other by at least one degradable region and wherein at least one degradable region is a carbonate or dioxanone region; and
b) polymerizing the macromer to incorporate the agent within the resulting polymer.
9. The method of claim 8 wherein the polymer is formed into a shape selected from the group consisting of particles, sheets, rods, and nano or microcapsules.
10. The method of claim 8 wherein the macromer is polymerized in situ in or on a living tissue.
11. The method of claim 8 wherein the controlled release device is formed on the surface of a medical device.
12. The method of claim 11 wherein the device is coated after implantation into the body.
13. The method of claim 11 wherein the device is coated prior to implantation.
14. A method for increasing the elasticity of a hydrophilic polymer gel comprising incorporating one or more carbonate linkages into a reactive polymer before gelation by reaction of the reactive groups, wherein the resulting polymer has a solubility in water of at least one gram/liter of an aqueous solution at a temperature in the range between about 0 and 50° C., is biodegradable, and wherein each reactive group is separated from each other reactive group by at least one degradable linkage.
15. The method of claim 14 wherein the carbonate linkage is prepared from trimethylene carbonate.
16. The method of claim 14, wherein two or more polymer blocks are linked by linkages comprising carbonate groups to obtain a higher molecular weight of reactive macromer without compromise of biodegradability.
17. A method for improving the biodegradability of a carbonate-comprising chemically-reactive macromer, the method comprising:
a) reacting a carbonate with a biocompatible compound which has a solubility of at least one gram/liter in aqueous solutions at a temperature in the range between about 0 and 50° C., wherein the biocompatible compound comprises at least two hydroxyl groups to form a carbonate-comprising precursor, the reaction continuing for a sufficient time to ensure completion of the reaction and attainment of equilibrium among reacting species, and the carbonate providing a first biodegradable linkage;
b) adding to the carbonate-comprising precursor an excess of a first reagent to form a second biodegradable linkage, wherein the first reagent comprises a biodegradable moiety other than a carbonate; and then
c) adding to the carbonate-comprising precursor a second reagent which forms at least one chemically-reactive group, thereby forming the chemically-reactive macromer,
wherein the chemically reactive group of step c) is attached to the macromer via the biodegradable moiety of step b).
18. The method of claim 17, wherein the carbonate is a cyclic aliphatic carbonate.
19. The method of claim 17 in which the polymer is a polyalkylene glycol.
20. The method of claim 17 in which the first reagent comprises a residue of a hydroxycarboxylic acid.
21. The method of claim 20 which the hydroxycarboxylic acid residue is an alpha-hydroxy acid.
22. The method of claim 21 in which the acid is selected from lactic acid, lactide, and lactoyl chloride.
23. The method of claim 17 wherein the chemically-reactive group of step c) comprises at least one component selected from the group consisting of ethylenically unsaturated groups, acetylenically unsaturated groups, isocyanates, oxiranes, sulfhydryls, succinimides, maleimides, amines, imines, carboxylic acids, sulfonic acids, and phosphoric acids.
24. A polymer comprising a biodegradable macromer comprising at least one water soluble region, at least one degradable region, and at least one functional, polymerizable group, wherein the polymerizable groups are separated from each other by at least one degradable region, and wherein at least one degradable region is a carbonate
or dioxanone
region.
25. The polymer of claim 24, further comprising a prophylactic, therapeutic, or diagnostic agent.
26. The polymer of claim 24, wherein the polymer is a hydrogel.
27. The polymer of claim 24, wherein the polymer is formed into a shape selected from the group consisting of particles, sheets, rods, and nano or microcapsules.
28. The polymer of claim 24, wherein the polymer is a tissue sealant.
29. The polymer of claim 24, wherein the water soluble region is selected from the group consisting of poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), poly(ethylene oxide)-co-poly(propylene oxide) block copolymers, polysaccharides, carbohydrates, proteins, and combinations thereof.
30. The polymer of claim 29, wherein the water soluble region is poly(ethylene glycol).
31. The polymer of claim 24, wherein at least one biodegradable region is selected from the group consisting of poly(hydroxy acids), poly(lactones), poly(amino acids), poly(anhydrides), poly(orthoesters), and poly(phosphoesters).
32. The polymer of claim 31, wherein the biodegradable region is a poly(hydroxy acid) selected from the group consisting of poly(glycolic acid), poly(D,L-lactic acid) and poly(L-lactic acid).
33. The polymer of claim 31, wherein the biodegradable region is a poly(lactone) selected from the group consisting of poly(epsilon-caprolactone), poly(delta-valcrolactone) and poly(gamma-butyrolactone).
34. The polymer of claim 24, wherein the carbonate linkage is prepared from a cyclic aliphatic carbonate.
35. The polymer of claim 24, wherein the carbonate linkage is prepared from trimethylene carbonate.
36. The polymer of claim 24, wherein the one or more reactive polymerizable group(s) are selected from the group consisting of ethylenically or acetylenically unsaturated groups, isocyanates, epoxides (oxiranes), sulfhydryls, succinimides, maleimides, amines, imines, amides, carboxylic acids, sulfonic acids, and phosphate groups.
37. The polymer of claim 36, wherein the one or more reactive polymerizable group(s) are ethylenically-unsaturated groups.
38. The polymer of claim 37, wherein the ethylenically-unsaturated group is selected from the group consisting of vinyl groups, allyl groups, unsaturated monocarboxylic acids, diacrylates, oligoacrylates, unsaturated dicarboxylic acids, and unsaturated tricarboxylic acids.
39. The polymer of claim 24, wherein the macromer comprises carbonate or dioxanone residues in range from about 0.3% to 20 % (by weight).
40. The polymer of claim 24, wherein the water soluble region forms the core of the macromer.
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040091462A1 (en) * 2002-08-20 2004-05-13 Lin Steve T. Composition for the carrying and delivery of bone growth inducing material and methods for producing and applying the composition
US20090017097A1 (en) * 2007-07-09 2009-01-15 Sawhney Amarpreet S Hydrogel polymeric compositions and methods
US20090062821A1 (en) * 2007-08-31 2009-03-05 Phillips Plastics Corporation Composite scaffold structure
US20110142936A1 (en) * 2009-12-15 2011-06-16 Patrick Campbell Implants and biodegradable fiducial markers
US8409606B2 (en) 2009-02-12 2013-04-02 Incept, Llc Drug delivery through hydrogel plugs
US8961501B2 (en) 2010-09-17 2015-02-24 Incept, Llc Method for applying flowable hydrogels to a cornea

Families Citing this family (117)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6743248B2 (en) 1996-12-18 2004-06-01 Neomend, Inc. Pretreatment method for enhancing tissue adhesion
US20040176801A1 (en) * 1997-03-12 2004-09-09 Neomend, Inc. Pretreatment method for enhancing tissue adhesion
US8003705B2 (en) 1996-09-23 2011-08-23 Incept Llc Biocompatible hydrogels made with small molecule precursors
US20030191496A1 (en) * 1997-03-12 2003-10-09 Neomend, Inc. Vascular sealing device with microwave antenna
US6994686B2 (en) 1998-08-26 2006-02-07 Neomend, Inc. Systems for applying cross-linked mechanical barriers
CA2291622C (en) 1997-06-06 2007-09-04 Anna Gutowska Reversible geling co-polymer and method of making
WO1999034833A9 (en) * 1998-01-07 2005-03-17 Shearwater Polymers Inc Degradable heterobifunctional poly(ethylene glycol) acrylates and gels and conjugates derived therefrom
US20040228794A1 (en) * 1998-04-10 2004-11-18 Battelle Memorial Institute Therapeutic agent carrier compositions
US6165193A (en) * 1998-07-06 2000-12-26 Microvention, Inc. Vascular embolization with an expansible implant
US6458147B1 (en) 1998-11-06 2002-10-01 Neomend, Inc. Compositions, systems, and methods for arresting or controlling bleeding or fluid leakage in body tissue
US6830756B2 (en) * 1998-11-06 2004-12-14 Neomend, Inc. Systems, methods, and compositions for achieving closure of vascular puncture sites
US7279001B2 (en) * 1998-11-06 2007-10-09 Neomend, Inc. Systems, methods, and compositions for achieving closure of vascular puncture sites
US7351249B2 (en) * 1998-11-06 2008-04-01 Neomend, Inc. Systems, methods, and compositions for achieving closure of suture sites
US6899889B1 (en) 1998-11-06 2005-05-31 Neomend, Inc. Biocompatible material composition adaptable to diverse therapeutic indications
US6949114B2 (en) 1998-11-06 2005-09-27 Neomend, Inc. Systems, methods, and compositions for achieving closure of vascular puncture sites
US6371975B2 (en) 1998-11-06 2002-04-16 Neomend, Inc. Compositions, systems, and methods for creating in situ, chemically cross-linked, mechanical barriers
JP2002531217A (en) 1998-12-04 2002-09-24 チャンドラシェカー ピー. パサック, Biocompatible crosslinked polymer
JP4548623B2 (en) * 1999-02-24 2010-09-22 多木化学株式会社 Biological material
US6423818B1 (en) * 1999-07-30 2002-07-23 Takehisa Matsuda Coumarin endcapped absorbable polymers
US6794485B2 (en) * 2000-10-27 2004-09-21 Poly-Med, Inc. Amorphous polymeric polyaxial initiators and compliant crystalline copolymers therefrom
JP3565758B2 (en) * 2000-03-09 2004-09-15 株式会社日立製作所 For treating a tumor sensitizer
EP1263801B1 (en) * 2000-03-13 2006-05-24 BioCure, Inc. Tissue bulking and coating compositions
US6652883B2 (en) 2000-03-13 2003-11-25 Biocure, Inc. Tissue bulking and coating compositions
CA2403218C (en) 2000-03-13 2011-10-18 Biocure, Inc. Embolic compositions
US20030104347A1 (en) * 2000-03-21 2003-06-05 Yuichi Mori Coating material for living organism tissue, coated product from living organism tissue and method of coating living organism material
EP1142596A1 (en) * 2000-04-03 2001-10-10 Universiteit Gent Compositions of crosslinkable prepolymers for use in therapeutically active biodegradable implants
US7682648B1 (en) 2000-05-31 2010-03-23 Advanced Cardiovascular Systems, Inc. Methods for forming polymeric coatings on stents
US6673385B1 (en) * 2000-05-31 2004-01-06 Advanced Cardiovascular Systems, Inc. Methods for polymeric coatings stents
EP1992317B1 (en) * 2000-08-30 2012-02-29 Johns Hopkins University Devices for intraocular drug delivery
US7087244B2 (en) * 2000-09-28 2006-08-08 Battelle Memorial Institute Thermogelling oligopeptide polymers
US6841617B2 (en) * 2000-09-28 2005-01-11 Battelle Memorial Institute Thermogelling biodegradable aqueous polymer solution
JP3392411B1 (en) * 2000-10-11 2003-03-31 ポハン アイアン アンド スチール カンパニー リミテッド Copolymer and a manufacturing method thereof comprising an alkylene carbonate
DE60135784D1 (en) * 2000-11-28 2008-10-23 Genzyme Corp The viscosity-increasing polymeric formulations of polyalkylene glycol
EP1347756B1 (en) 2000-12-27 2006-03-08 Genzyme Corporation Controlled release of anti-arrhythmic agents from a biodegradable hydrogel for local application to the heart
JP2004527281A (en) * 2001-02-14 2004-09-09 ジェンザイム・コーポレーション Biocompatible fleece for hemostasis and tissue engineering
US7700819B2 (en) 2001-02-16 2010-04-20 Kci Licensing, Inc. Biocompatible wound dressing
US7763769B2 (en) 2001-02-16 2010-07-27 Kci Licensing, Inc. Biocompatible wound dressing
US20020192182A1 (en) * 2001-03-12 2002-12-19 Stephen Massia Polysaccharide-based polymerizable hydrogels
US6994722B2 (en) 2001-07-03 2006-02-07 Scimed Life Systems, Inc. Implant having improved fixation to a body lumen and method for implanting the same
US8252040B2 (en) 2001-07-20 2012-08-28 Microvention, Inc. Aneurysm treatment device and method of use
US7572288B2 (en) 2001-07-20 2009-08-11 Microvention, Inc. Aneurysm treatment device and method of use
US8715312B2 (en) * 2001-07-20 2014-05-06 Microvention, Inc. Aneurysm treatment device and method of use
US6790455B2 (en) 2001-09-14 2004-09-14 The Research Foundation At State University Of New York Cell delivery system comprising a fibrous matrix and cells
DE10152407A1 (en) * 2001-10-24 2003-05-08 Aesculap Ag & Co Kg Composition of at least two biocompatible chemically crosslinkable components
WO2003070805A1 (en) * 2002-02-15 2003-08-28 Nektar Therapeutics Al, Corporation Hydrolytically degradable alkylene oxide based polymers
US6932833B1 (en) * 2002-04-01 2005-08-23 Bobby W. Presley Method and barrier for limiting fluid movement through a tissue rent
US7329414B2 (en) * 2002-05-03 2008-02-12 Biopsy Sciences, Llc Biodegradable polymer for marking tissue and sealing tracts
US7148315B2 (en) * 2002-10-23 2006-12-12 Ethicon, Inc. Monomer addition techniques to control manufacturing of bioabsorbable copolymers
US7223826B2 (en) * 2003-01-30 2007-05-29 3M Innovative Properties Company Amide-functional polymers, compositions, and methods
US20040151691A1 (en) * 2003-01-30 2004-08-05 Oxman Joel D. Hardenable thermally responsive compositions
US20040185013A1 (en) * 2003-01-30 2004-09-23 Burgio Paul A. Dental whitening compositions and methods
WO2004087777A3 (en) * 2003-03-28 2004-12-16 Univ Carnegie Mellon Degradable polymers
US8246974B2 (en) * 2003-05-02 2012-08-21 Surmodics, Inc. Medical devices and methods for producing the same
WO2004098565A3 (en) * 2003-05-02 2005-03-03 Aron B Anderson Implantable controlled release bioactive agent delivery device
EP1626748B1 (en) * 2003-05-13 2012-07-11 Medtronic, Inc. Moisture curable materials for delivery of agents, methods, and medical devices
EP1629028B1 (en) * 2003-05-21 2012-06-20 The Polymer Technology Group Permselective structurally robust membrane material
US7687586B2 (en) * 2003-05-21 2010-03-30 Isense Corporation Biosensor membrane material
US20080267901A1 (en) * 2003-07-03 2008-10-30 Dirk Wybe Grijpma Biocompatible Polymer Networks
US7790141B2 (en) * 2003-08-11 2010-09-07 Pathak Holdings, Llc Radio-opaque compounds, compositions containing same and methods of their synthesis and use
US20050208095A1 (en) * 2003-11-20 2005-09-22 Angiotech International Ag Polymer compositions and methods for their use
CN100497437C (en) 2003-11-17 2009-06-10 中国科学院过程工程研究所 Preparation method of polyethylene carboxylic acid and its use
EP1725590A4 (en) * 2004-03-05 2013-08-07 Univ Carnegie Mellon Atom transfer radical polymerization process
EP1727883B1 (en) * 2004-03-24 2012-02-29 Archer-Daniels-Midland Company Vegetable based dioxanone derivatives, synthesis and uses thereof
JP4977600B2 (en) * 2004-04-20 2012-07-18 ジェンザイム・コーポレーション Mesh implants for surgery
US20050281866A1 (en) * 2004-05-24 2005-12-22 Genzyme Corporation Adherent polymeric compositions
US20050271727A1 (en) * 2004-06-07 2005-12-08 Callisyn Pharmaceuticals, Inc. Biodegradable and biocompatible crosslinked polymer hydrogel prepared from PVA and/or PEG macromer mixtures
CA2572603C (en) * 2004-06-29 2013-01-15 Biocure, Inc. Spinal disc nucleus pulposus implant
ES2395732T3 (en) 2004-08-02 2013-02-14 Samyang Corporation multi-block polymer composition capable of biodegradable sol-gel transition
US8348971B2 (en) * 2004-08-27 2013-01-08 Accessclosure, Inc. Apparatus and methods for facilitating hemostasis within a vascular puncture
EP1836227B1 (en) * 2004-12-29 2010-05-19 Luigi Ambrosio Biodegradable, super absorbent polymer hydrogels and a method for their preparation
US20060149363A1 (en) * 2005-01-06 2006-07-06 Scimed Life Systems, Inc. Optimally expanded, collagen sealed ePTFE graft with improved tissue ingrowth
WO2006086510A3 (en) * 2005-02-09 2007-05-10 Ahmad R Hadba Synthetic sealants
US9290617B2 (en) * 2005-07-06 2016-03-22 Molly S. Shoichet Method of biomolecule immobilization on polymers using click-type chemistry
WO2007025086A3 (en) 2005-08-23 2007-06-07 Krzysztof Matyjaszewski Atom transfer radical polymerization in microemulsion and true emulsion polymerization
WO2007025310A1 (en) * 2005-08-26 2007-03-01 Carnegie Mellon University Polymerization process with catalyst reactivation
US8241656B2 (en) * 2005-09-21 2012-08-14 Surmodics, Inc Articles including natural biodegradable polysaccharides and uses thereof
US20070112115A1 (en) * 2005-11-15 2007-05-17 Shalaby Shalaby W Inorganic-organic hybrid micro-/nanofibers
US20070149641A1 (en) * 2005-12-28 2007-06-28 Goupil Dennis W Injectable bone cement
US20070237803A1 (en) * 2006-04-11 2007-10-11 Medtronic Vascular, Inc. Biodegradable Biocompatible Amphiphilic Copolymers for Coating and Manufacturing Medical Devices
WO2008057163A3 (en) * 2006-10-09 2008-07-24 Krzysztof Matyjaszewski Preparation of functional gel particles with a dual crosslink network
CN102552967B (en) 2006-12-15 2015-08-12 生命连结有限公司 Gelatin - transglutaminase haemostatic dressing and the sealing material
US8133484B2 (en) 2006-12-15 2012-03-13 Lifebond Ltd Hemostatic materials and dressing
US8865797B2 (en) * 2007-05-23 2014-10-21 Carnegie Mellon University Hybrid particle composite structures with reduced scattering
US8252880B2 (en) 2007-05-23 2012-08-28 Carnegie Mellon University Atom transfer dispersion polymerization
US8133553B2 (en) 2007-06-18 2012-03-13 Zimmer, Inc. Process for forming a ceramic layer
US8309521B2 (en) 2007-06-19 2012-11-13 Zimmer, Inc. Spacer with a coating thereon for use with an implant device
JP5734650B2 (en) * 2007-06-25 2015-06-17 マイクロベンション インコーポレイテッド The self-expanding prosthesis
US20110230973A1 (en) * 2007-10-10 2011-09-22 Zimmer, Inc. Method for bonding a tantalum structure to a cobalt-alloy substrate
US8608049B2 (en) * 2007-10-10 2013-12-17 Zimmer, Inc. Method for bonding a tantalum structure to a cobalt-alloy substrate
KR100927533B1 (en) * 2007-10-23 2009-11-17 한남대학교 산학협력단 Poly hydroxy ethyl aspartic amide-poly p - oxa nongong polymers and methods for their preparation
EP2217251A4 (en) * 2007-11-02 2010-11-10 Genzyme Corp Methods of augmenting or repairing soft tissue
US20090187256A1 (en) * 2008-01-21 2009-07-23 Zimmer, Inc. Method for forming an integral porous region in a cast implant
US20090198286A1 (en) * 2008-02-05 2009-08-06 Zimmer, Inc. Bone fracture fixation system
US8745133B2 (en) * 2008-03-28 2014-06-03 Yahoo! Inc. System and method for optimizing the storage of data
US20090294049A1 (en) * 2008-06-02 2009-12-03 Medtronic Vascular, Inc. Biodegradable Adhesive Hydrogels
WO2009153748A3 (en) * 2008-06-18 2010-09-30 Lifebond Ltd Methods and devices for use with sealants
US20110086014A1 (en) * 2008-06-18 2011-04-14 Ishay Attar Method for enzymatic cross-linking of a protein
EP2310459B1 (en) 2008-06-18 2014-10-22 Lifebond Ltd Improved cross-linked compositions
EP2334686A4 (en) * 2008-08-28 2012-05-02 Harvard College Cortistatin analogues and syntheses therof
WO2010111708A1 (en) 2009-03-27 2010-09-30 Carnegie Mellon University Preparation of functional star macromolecules
US9265633B2 (en) 2009-05-20 2016-02-23 480 Biomedical, Inc. Drug-eluting medical implants
US20110319987A1 (en) * 2009-05-20 2011-12-29 Arsenal Medical Medical implant
US8992601B2 (en) 2009-05-20 2015-03-31 480 Biomedical, Inc. Medical implants
US8888840B2 (en) * 2009-05-20 2014-11-18 Boston Scientific Scimed, Inc. Drug eluting medical implant
JP5820370B2 (en) 2009-05-20 2015-11-24 アーセナル メディカル, インコーポレイテッド Medical implants
US9309347B2 (en) 2009-05-20 2016-04-12 Biomedical, Inc. Bioresorbable thermoset polyester/urethane elastomers
US9066991B2 (en) 2009-12-22 2015-06-30 Lifebond Ltd. Modification of enzymatic crosslinkers for controlling properties of crosslinked matrices
CN101864069B (en) * 2010-06-10 2012-02-22 武汉大学 Biodegradable hydrogel and synthesis method thereof
US9232805B2 (en) 2010-06-29 2016-01-12 Biocure, Inc. In-situ forming hydrogel wound dressings containing antimicrobial agents
CN103118713B (en) 2010-08-05 2016-06-01 生命连结有限公司 Dry composition and adhesive wound dressing
EP2619243B1 (en) * 2010-09-21 2015-11-11 Total Research & Technology Feluy One-step, one-pot process for preparing multiblock and gradient copolymer
US9644042B2 (en) 2010-12-17 2017-05-09 Carnegie Mellon University Electrochemically mediated atom transfer radical polymerization
JP6199883B2 (en) 2011-12-05 2017-09-20 インセプト・リミテッド・ライアビリティ・カンパニーIncept,Llc Medical organogel processes and compositions
US9533297B2 (en) 2012-02-23 2017-01-03 Carnegie Mellon University Ligands designed to provide highly active catalyst complexes
WO2013181498A1 (en) 2012-06-01 2013-12-05 Surmodics, Inc. Apparatus and method for coating balloon catheters
US9827401B2 (en) 2012-06-01 2017-11-28 Surmodics, Inc. Apparatus and methods for coating medical devices
CN104119486B (en) * 2014-06-27 2017-02-08 重庆阮氏塑业有限公司 A composite material and preparation of a polycarbonate

Citations (99)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2155658A (en) 1936-01-08 1939-04-25 Chemische Forschungs Gmbh Surgical and medical preparations
US2210817A (en) 1939-04-19 1940-08-06 Du Pont Superpolycarbonate
US2517965A (en) 1948-03-23 1950-08-08 Pittsburgh Plate Glass Co Purification of carbonic acid esters
US2668162A (en) 1952-03-20 1954-02-02 Du Pont Preparation of high molecular weight polyhydroxyacetic ester
US2683136A (en) 1950-10-25 1954-07-06 Du Pont Copolymers of hydroxyacetic acid with other alcohol acids
US2703316A (en) 1951-06-05 1955-03-01 Du Pont Polymers of high melting lactide
US2789968A (en) 1953-12-08 1957-04-23 Eastman Kodak Co Polycarbonates from polymethylene glycol-bis
US2917410A (en) 1955-06-20 1959-12-15 American Cyanamid Co Polyglycol-polyacid ester treatment of textiles
US2962524A (en) 1957-04-18 1960-11-29 Chich
US3021310A (en) 1959-12-03 1962-02-13 Union Garbide Corp Polymerization of cyclic esters
US3030331A (en) 1957-08-22 1962-04-17 Gen Electric Process for preparing copolyesters comprising reacting a carbonyl halide with a dicarboxylic acid and a dihydroxy compound in the presence of a tertiary amine
US3046255A (en) 1957-06-20 1962-07-24 Pittsburgh Plate Glass Co Process for preparing polycarbonates
US3063988A (en) 1959-11-14 1962-11-13 Hoechst Ag Steroid-21-amino acid esters and process of preparing them
US3157622A (en) 1961-01-03 1964-11-17 Gen Electric Resinous compositions
US3161615A (en) 1957-02-05 1964-12-15 Gen Electric Resinous copolymeric polycarbonate of a mixture of dihydric phenols
US3169121A (en) 1957-08-22 1965-02-09 Gen Electric Carbonate-carboxylate copolyesters of dihydric phenols and difunctional carboxylic acids
US3223083A (en) 1960-09-09 1965-12-14 President And Directors Of Geo Method for adhesively securing together skin and other soft tissue and bone
US3268486A (en) 1963-06-28 1966-08-23 Shell Oil Co Process for preparing polyesters
US3268487A (en) 1963-12-23 1966-08-23 Shell Oil Co Process for polymerization of lactides
US3297033A (en) 1963-10-31 1967-01-10 American Cyanamid Co Surgical sutures
US3301825A (en) 1963-09-26 1967-01-31 Union Carbide Corp Polyester polycarbonate polymers
US3301824A (en) 1963-09-26 1967-01-31 Union Carbide Corp Polymers of cyclic carbonates
US3305605A (en) 1964-02-04 1967-02-21 Union Carbide Corp Compositions containing polycarbonate plasticizers
US3312753A (en) 1964-01-13 1967-04-04 Union Carbide Corp Preparation of block copolymers of a caprolactone and oxirane compound
US3379693A (en) 1964-05-28 1968-04-23 Union Carbide Corp Carbonate compositions
US3438374A (en) 1966-02-28 1969-04-15 Us Health Education & Welfare Method of bonding tissue surfaces and controlling hemorrhaging thereof using a tissue adhesive and hemostatic composition
US3442871A (en) 1966-05-04 1969-05-06 American Cyanamid Co Process for polymerizing a glycolide
US3463158A (en) 1963-10-31 1969-08-26 American Cyanamid Co Polyglycolic acid prosthetic devices
US3531561A (en) 1965-04-20 1970-09-29 Ethicon Inc Suture preparation
US3552986A (en) 1967-11-24 1971-01-05 Sun Chemical Corp Printing and coating untreated polyolefins
US3620118A (en) 1970-11-16 1971-11-16 Yoshiyuki Koishikawa Tambourine
US3626948A (en) 1968-12-23 1971-12-14 American Cyanamid Co Absorbable polyglycolic acid suture of enhanced in-vivo strength retention
US3629374A (en) 1969-04-01 1971-12-21 Union Carbide Corp Lactone/alkylene oxide copolymers as plasticizers for vinyl chloride resins
US3639503A (en) 1969-02-20 1972-02-01 Union Carbide Corp Block copolycarbonates containing polylactone blocks and cyclobutylene polycarbonate blocks
US3641200A (en) 1969-01-17 1972-02-08 Union Carbide Corp Block copolycarbonates containing polylactone blocks and dihydric phenol polycarbonate blocks
US3739773A (en) 1963-10-31 1973-06-19 American Cyanamid Co Polyglycolic acid prosthetic devices
US3784585A (en) 1971-10-21 1974-01-08 American Cyanamid Co Water-degradable resins containing recurring,contiguous,polymerized glycolide units and process for preparing same
US3795701A (en) 1972-02-07 1974-03-05 Laporte Industries Ltd Copolymers of epoxides and lactones
US3839297A (en) 1971-11-22 1974-10-01 Ethicon Inc Use of stannous octoate catalyst in the manufacture of l(-)lactide-glycolide copolymer sutures
US3865723A (en) 1972-03-21 1975-02-11 Zambon Spa Method to form stable complexes of polyanions occurring in biological liquids
US3867190A (en) 1971-10-18 1975-02-18 American Cyanamid Co Reducing capillarity of polyglycolic acid sutures
US3875937A (en) 1963-10-31 1975-04-08 American Cyanamid Co Surgical dressings of absorbable polymers
US3882192A (en) 1973-02-01 1975-05-06 Bayer Ag Polycarbonate-polyvinyl chloride moulding compositions
US3896802A (en) 1974-04-19 1975-07-29 American Cyanamid Co Flexible flocked dressing
US3937223A (en) 1974-04-19 1976-02-10 American Cyanamid Company Compacted surgical hemostatic felt
US3939049A (en) 1974-04-10 1976-02-17 The United States Of America As Represented By The United States Energy Research And Development Administration Process for radiation grafting hydrogels onto organic polymeric substrates
US3960152A (en) 1974-01-21 1976-06-01 American Cyanamid Company Surgical sutures of unsymmetrically substituted 1,4-dioxane-2,5-diones
US3966788A (en) 1973-10-16 1976-06-29 Societe Nationale Des Poudres Et Explosifs Process for the preparation of aliphatic diol polycarbonates
US3982543A (en) 1973-04-24 1976-09-28 American Cyanamid Company Reducing capillarity of polyglycolic acid sutures
US3991766A (en) 1973-05-31 1976-11-16 American Cyanamid Company Controlled release of medicaments using polymers from glycolic acid
US4033938A (en) 1974-01-21 1977-07-05 American Cyanamid Company Polymers of unsymmetrically substituted 1,4-dioxane-2,5-diones
US4045418A (en) 1975-01-28 1977-08-30 Gulf Oil Corporation Copolymers of D,L-lactide and epsilon caprolactone
US4057537A (en) 1975-01-28 1977-11-08 Gulf Oil Corporation Copolymers of L-(-)-lactide and epsilon caprolactone
US4066630A (en) 1977-01-10 1978-01-03 Air Products And Chemicals, Inc. End capped polyalkylene carbonates having improved thermal stability
US4067876A (en) 1974-10-15 1978-01-10 Paolo Ferruti High polymers containing nicotinic acid, process for their preparation and their use
US4072704A (en) 1974-08-19 1978-02-07 Basf Wyandotte Corporation Multi-block coupled polyoxyalkylene copolymer surfactants
US4079038A (en) 1976-03-05 1978-03-14 Alza Corporation Poly(carbonates)
US4093677A (en) 1975-06-10 1978-06-06 Paolo Ferruti Macromolecular materials suitable for forming antithrombogenic prosthesis and artificial organs and process for preparing same
US4104264A (en) 1977-05-05 1978-08-01 Air Products & Chemicals, Inc. End capped polyalkylene carbonates having improved thermal stablity
US4137280A (en) 1978-04-19 1979-01-30 Air Products And Chemicals, Inc. Polyalkylene carbonates as processing aids for polyvinyl chloride
US4137921A (en) 1977-06-24 1979-02-06 Ethicon, Inc. Addition copolymers of lactide and glycolide and method of preparation
US4143017A (en) 1976-02-25 1979-03-06 Hoya Lens Corporation Process of producing soft contact lenses
US4145320A (en) 1974-10-15 1979-03-20 Paolo Ferruti Polymers containing polyunsaturated acid radicals, process for their preparation and use thereof
US4145525A (en) 1977-10-03 1979-03-20 Air Products And Chemicals, Inc. End capped polyalkylene carbonates
US4166902A (en) 1974-10-14 1979-09-04 Paolo Ferruti High polymers containing nicotinic acid, process for their preparation and their use
US4169923A (en) 1974-10-15 1979-10-02 Paolo Ferruti High polymers containing nicotinic acid, process for their preparation and their use
US4179304A (en) 1978-04-03 1979-12-18 Polychrome Corporation Finger nail lacquer
US4189609A (en) 1974-08-19 1980-02-19 Basf Wyandotte Corporation Multi-block coupled polyoxyalkylene copolymer surfactants
US4211865A (en) 1976-08-10 1980-07-08 Paolo Ferruti Novel prostaglandin precursors in polymeric form
US4223011A (en) 1974-10-15 1980-09-16 Paolo Ferruti Therapeutic compositions containing polymers having polyunsaturated acid radicals
US4239861A (en) 1974-01-17 1980-12-16 Bayer Aktiengesellschaft Polyvinyl chloride-polycarbonate alloys
US4243775A (en) 1978-11-13 1981-01-06 American Cyanamid Company Synthetic polyester surgical articles
US4264752A (en) 1979-08-08 1981-04-28 Union Carbide Corporation Radiation-curable acrylated urethane polycarbonate compositions
US4297455A (en) 1977-03-22 1981-10-27 Bayer Aktiengesellschaft Process for the preparation of carbonic acid aryl esters of polyester-diols lengthened via carbonate groups and their use for the preparation of polyester-diol bis-diphenol carbonates and polyester/polycarbonates
US4300565A (en) 1977-05-23 1981-11-17 American Cyanamid Company Synthetic polyester surgical articles
US4303066A (en) 1979-06-28 1981-12-01 National Patent Development Corporation Burn dressing
US4316001A (en) 1976-05-26 1982-02-16 Societe Nationale Des Poudres Et Explosifs Anionic polymerization of heterocyclic monomers with alkali metal amide hydroxylated compound initiator
US4330481A (en) 1978-12-26 1982-05-18 The Dow Chemical Company Process for preparing polycarbonates
US4354487A (en) 1980-05-12 1982-10-19 Johnson & Johnson Fiber/absorbent polymer composites and method of forming same
US4415502A (en) 1980-08-11 1983-11-15 The Dow Chemical Co. Polycarbonate type nonionic surfactants
US4429080A (en) 1982-07-01 1984-01-31 American Cyanamid Company Synthetic copolymer surgical articles and method of manufacturing the same
US4436839A (en) 1979-08-13 1984-03-13 Akzo Nv Process for preparing polycarbonate-polyether-blockcopolymers
US4452973A (en) 1982-11-12 1984-06-05 American Cyanamid Company Poly(glycolic acid)/poly(oxyethylene) triblock copolymers and method of manufacturing the same
US4503216A (en) 1984-02-21 1985-03-05 Eastman Kodak Company Hydroxyl-terminated polyether-esters
US4511478A (en) 1983-11-10 1985-04-16 Genetic Systems Corporation Polymerizable compounds and methods for preparing synthetic polymers that integrally contain polypeptides
US4526938A (en) 1982-04-22 1985-07-02 Imperial Chemical Industries Plc Continuous release formulations
US4532929A (en) 1984-07-23 1985-08-06 Ethicon, Inc. Dry coating of surgical filaments
US4559945A (en) 1984-09-21 1985-12-24 Ethicon, Inc. Absorbable crystalline alkylene malonate copolyesters and surgical devices therefrom
US4643191A (en) 1985-11-29 1987-02-17 Ethicon, Inc. Crystalline copolymers of p-dioxanone and lactide and surgical devices made therefrom
US4653497A (en) 1985-11-29 1987-03-31 Ethicon, Inc. Crystalline p-dioxanone/glycolide copolymers and surgical devices made therefrom
US4699974A (en) 1986-08-07 1987-10-13 General Electric Company Method of preparing copolyester carbonate from cyclic aromatic polycarbonate oligomer and lactone
US4705820A (en) 1986-09-05 1987-11-10 American Cyanamid Company Surgical suture coating
US4716203A (en) 1986-09-05 1987-12-29 American Cyanamid Company Diblock and triblock copolymers
US4727134A (en) 1985-02-22 1988-02-23 General Electric Company Method for preparing cyclic polycarbonate oligomer mixtures
US4741872A (en) 1986-05-16 1988-05-03 The University Of Kentucky Research Foundation Preparation of biodegradable microspheres useful as carriers for macromolecules
US4745160A (en) 1984-06-26 1988-05-17 Imperial Chemical Industries Plc Biodegradable amphipathic copolymers
US4760117A (en) 1985-06-11 1988-07-26 General Electric Company Method for preparing copolycarbonates from cyclic polycarbonate oligomers
US4768523A (en) 1981-04-29 1988-09-06 Lifecore Biomedical, Inc. Hydrogel adhesive
EP1586349A1 (en) * 2000-12-27 2005-10-19 Focal, Inc. Controlled release of anti-arrhythmic agents

Family Cites Families (140)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2517985A (en) * 1948-06-22 1950-08-08 Malcom A Davis Chimney for liquid fuel burners
BE593044A (en) 1959-07-17
US3063968A (en) * 1960-06-15 1962-11-13 Gen Aniline & Film Corp Polymerization of 2-p-dioxanone
DE1205141B (en) * 1964-07-25 1965-11-18 Schmidt Gebr Metallwarenfab Multivibrator with two complementary transistors
GB1332505A (en) 1970-10-16 1973-10-03 Ethicon Inc Sutures and other surgical aids
US3736646A (en) 1971-10-18 1973-06-05 American Cyanamid Co Method of attaching surgical needles to multifilament polyglycolic acid absorbable sutures
GB1414600A (en) 1974-02-08 1975-11-19 Ethicon Inc Plasticised polyester sutures
DE2454189C3 (en) * 1974-11-15 1980-08-14 Hoechst Ag, 6000 Frankfurt
US3981766A (en) * 1975-02-21 1976-09-21 E. I. Du Pont De Nemours And Company Method of controlling fungi and bacteria in paper products
DE2640436A1 (en) * 1976-09-08 1978-03-09 Plaubel Feinmechanik & Optik Means for releasably locking the spreizscheren by interconnected parts of scissor braces cameras
DE2850824C2 (en) 1978-05-17 1995-03-16 American Cyanamid Co Surgical articles and methods for their preparation
JPH0440508B2 (en) * 1979-05-25 1992-07-03 Towa Kogyo Kk
US4632929A (en) * 1985-01-17 1986-12-30 Usv Pharmaceutical Corp. Method of hypertensive treatment using phenyl-alkylene-2-pyridyl derivatives
DE3575568D1 (en) * 1984-02-17 1990-03-01 Nuovo Consor Sanitar Nazionale Polymers polycondensation products between 1,10-bis (2-hydroxyethylthio) decane, polyoxyethylene (s) or polyoxypropylene (s) and dicarboxylic acid (s).
EP0152824B1 (en) 1984-02-17 1988-07-13 Nuovo Consorzio Sanitario Nazionale Compounds having hypolipemizing activity
US4846165A (en) 1986-11-26 1989-07-11 Dentsply Research & Development Corp. Wound dressing membrane
US5177120A (en) 1984-07-31 1993-01-05 Dentsply Research & Development Corp. Chain extended urethane diacrylate and dental impression formation
US5061281A (en) 1985-12-17 1991-10-29 Allied-Signal Inc. Bioresorbable polymers and implantation devices thereof
US5364700A (en) 1985-12-27 1994-11-15 Amoco Corporation Prepregable resin composition and composite
EP0230281A3 (en) 1986-01-16 1988-09-14 G. Cremascoli S.P.A. Synthetic material apt to stably adsorb high quantities of heparin and process for the production thereof
US5160745A (en) 1986-05-16 1992-11-03 The University Of Kentucky Research Foundation Biodegradable microspheres as a carrier for macromolecules
FR2602423B1 (en) 1986-08-08 1989-05-05 Ethypharm Sa Method of preparing a medicament based on fenofibrate, drug obtained by this method
US4781183A (en) 1986-08-27 1988-11-01 American Cyanamid Company Surgical prosthesis
DE3779838D1 (en) 1986-09-05 1992-07-23 American Cyanamid Co Coating for surgical filaments.
US4882168A (en) 1986-09-05 1989-11-21 American Cyanamid Company Polyesters containing alkylene oxide blocks as drug delivery systems
US4857602A (en) 1986-09-05 1989-08-15 American Cyanamid Company Bioabsorbable surgical suture coating
DE3785716D1 (en) 1986-09-23 1993-06-09 American Cyanamid Co Bioresorbable coating for surgical articles.
US4788979A (en) 1986-09-23 1988-12-06 American Cyanamid Company Bioabsorbable coating for a surgical article
US5147698A (en) 1986-09-30 1992-09-15 Minnesota Mining And Manufacturing Company Pressure sensitive adhesive film article having high moisture vapor transmission rate
US5009224A (en) 1986-09-30 1991-04-23 Minnesota Mining And Manufacturing Company Method for attaching a pressure-sensitive film article having high moisture vapor transmission rate
DE3641692A1 (en) 1986-12-06 1988-06-09 Boehringer Ingelheim Kg Catalyst-free resorbable homopolymers and copolymers
US5389677B1 (en) 1986-12-23 1997-07-15 Tristrata Inc Method of treating wrinkles using glycalic acid
DE3700193A1 (en) 1987-01-06 1988-07-14 Bayer Ag Sequenced constructed based copolymers of cyclic carbonates and esters
US4826945A (en) 1987-06-09 1989-05-02 Yissum Research Development Company Biodegradable polymeric materials based on polyether glycols, processes for the preparation thereof and surgical articles made therefrom
NL8701548A (en) 1987-07-01 1989-02-01 Tno A polymer network, a process for the preparation thereof, as well as, their use for coating and / or impregnating or for the manufacture of ophthalmic lenses, as well as a molded article, in whole or in part composed of such a polymer network.
DE69031483T2 (en) 1989-08-02 1998-02-05 Univ North Carolina A process for cross-linking collagen thereby generated product
US5447966A (en) 1988-07-19 1995-09-05 United States Surgical Corporation Treating bioabsorbable surgical articles by coating with glycerine, polalkyleneoxide block copolymer and gelatin
US4804691A (en) 1987-08-28 1989-02-14 Richards Medical Company Method for making a biodegradable adhesive for soft living tissue
US4788879A (en) 1987-09-17 1988-12-06 Ulrich Dana L Apparatus for hand operation of throttle and brake pedal, and methods of constructing and utilizing same
US5145945A (en) 1987-12-17 1992-09-08 Allied-Signal Inc. Homopolymers and copolymers having recurring carbonate units
US5120802A (en) 1987-12-17 1992-06-09 Allied-Signal Inc. Polycarbonate-based block copolymers and devices
US5274074A (en) 1987-12-17 1993-12-28 United States Surgical Corporation Medical devices fabricated from homopolymers and copolymers having recurring carbonate units
US5066772A (en) 1987-12-17 1991-11-19 Allied-Signal Inc. Medical devices fabricated totally or in part from copolymers of recurring units derived from cyclic carbonates and lactides
US5256764A (en) 1987-12-17 1993-10-26 United States Surgical Corporation Medical devices fabricated from homopolymers and copolymers having recurring carbonate units
US5152781A (en) 1987-12-17 1992-10-06 Allied-Signal Inc. Medical devices fabricated from homopolymers and copolymers having recurring carbonate units
US4891263A (en) 1987-12-17 1990-01-02 Allied-Signal Inc. Polycarbonate random copolymer-based fiber compositions and method of melt-spinning same and device
US4916193A (en) 1987-12-17 1990-04-10 Allied-Signal Inc. Medical devices fabricated totally or in part from copolymers of recurring units derived from cyclic carbonates and lactides
WO1989005664A1 (en) 1987-12-17 1989-06-29 Allied-Signal Inc. Medical devices fabricated from homopolymers and copolymers having recurring carbonate units
US4920203A (en) 1987-12-17 1990-04-24 Allied-Signal Inc. Medical devices fabricated from homopolymers and copolymers having recurring carbonate units
US5067961A (en) 1988-02-18 1991-11-26 Autogenesis Technologies, Inc. Non-biodegradable two phase corneal implant and method for preparing same
US4969912A (en) 1988-02-18 1990-11-13 Kelman Charles D Human collagen processing and autoimplant use
DE3808836A1 (en) 1988-03-17 1989-09-28 Bayer Ag Thermoplastic polycarbonate mixtures containing aliphatic polycarbonates
JPH04500377A (en) 1988-06-03 1992-01-23 Italfarmaco Spa
US4867602A (en) 1988-06-17 1989-09-19 Courtoise Robert L Attachment for cleaning and refacing concrete joints
US5296627A (en) 1988-06-20 1994-03-22 Ppg Industries, Inc. Ethylenically unsaturated poly(alkyleneoxy) surfactants
US5051272A (en) 1988-07-19 1991-09-24 United States Surgical Corporation Method for improving the storage stability of a polymeric article susceptible to hydrolytic degradation and resulting article
US5502158A (en) 1988-08-08 1996-03-26 Ecopol, Llc Degradable polymer composition
US4938763B1 (en) 1988-10-03 1995-07-04 Atrix Lab Inc Biodegradable in-situ forming implants and method of producing the same
US5116929A (en) 1988-10-14 1992-05-26 Enichem Synthesis S.P.A. Copolyester-diol polycarbonates, process for producing them and their use
US5378801A (en) 1988-11-01 1995-01-03 Reichert; Dieter Continuous process for the preparation of resorable polyesters and the use thereof
CA2002016A1 (en) 1988-11-21 1990-05-21 Koji Miyake Manufacturing method, continuous manufacturing method, product and manufacturing apparatus of absorbent composite
US5137800A (en) 1989-02-24 1992-08-11 Stereographics Limited Partnership Production of three dimensional bodies by photopolymerization
US5100992A (en) 1989-05-04 1992-03-31 Biomedical Polymers International, Ltd. Polyurethane-based polymeric materials and biomedical articles and pharmaceutical compositions utilizing the same
US5043398A (en) 1989-05-12 1991-08-27 Hoechst Celanese Corporation Grafting of functional compounds onto functional oxymethylene polymer backbones, with diisocyanate coupling agents, and the graft polymers thereof
US5226877A (en) 1989-06-23 1993-07-13 Epstein Gordon H Method and apparatus for preparing fibrinogen adhesive from whole blood
US4997722A (en) 1989-07-10 1991-03-05 Edward Adler Composition and method for improving adherence of copper foil to resinous substrates
US5076807A (en) 1989-07-31 1991-12-31 Ethicon, Inc. Random copolymers of p-dioxanone, lactide and/or glycolide as coating polymers for surgical filaments
DE69031063D1 (en) 1989-10-16 1997-08-21 Kanegafuchi Chemical Ind A process for the preparation of olefin-terminated polyester with
US5146945A (en) 1989-12-06 1992-09-15 Westinghouse Electric Corp. Seal ring retainer and guide ring for valve plug
US5104957A (en) 1990-02-28 1992-04-14 Autogenesis Technologies, Inc. Biologically compatible collagenous reaction product and articles useful as medical implants produced therefrom
US5201764A (en) 1990-02-28 1993-04-13 Autogenesis Technologies, Inc. Biologically compatible collagenous reaction product and articles useful as medical implants produced therefrom
US5019094A (en) 1990-05-09 1991-05-28 Ethicon, Inc. Crystalline copolymers of p-dioxanone and poly(alkylene oxides)
JP3125009B2 (en) 1990-06-08 2001-01-15 アストラゼネカ・アクチエボラーグ Apparatus for introducing a substance into a body cavity of a patient
US5540677A (en) 1990-06-15 1996-07-30 Rare Earth Medical, Inc. Endoscopic systems for photoreactive suturing of biological materials
US5360892A (en) 1990-06-26 1994-11-01 Arch Development Corporation Water and UV degradable lactic acid polymers
US5563238A (en) 1993-08-05 1996-10-08 Arch Development Corporation Water and UV degradable lactic acid polymers
US5252701A (en) 1990-07-06 1993-10-12 American Cyanamid Company Segmented absorbable copolymer
US5324307A (en) 1990-07-06 1994-06-28 American Cyanamid Company Polymeric surgical staple
NL9001641A (en) 1990-07-19 1992-02-17 Stamicarbon A process for making polymeric products of cyclic esters.
US5209776A (en) 1990-07-27 1993-05-11 The Trustees Of Columbia University In The City Of New York Tissue bonding and sealing composition and method of using the same
US5512091A (en) 1990-08-13 1996-04-30 Steiner; Carol A. Associative polymer hydrogels
US5403626A (en) 1990-09-27 1995-04-04 Sam Yang Co., Limited Process for preparing hydrophilic polymer films and apparatus thereof
US5529914A (en) 1990-10-15 1996-06-25 The Board Of Regents The Univeristy Of Texas System Gels for encapsulation of biological materials
US5573934A (en) 1992-04-20 1996-11-12 Board Of Regents, The University Of Texas System Gels for encapsulation of biological materials
US5410016A (en) 1990-10-15 1995-04-25 Board Of Regents, The University Of Texas System Photopolymerizable biodegradable hydrogels as tissue contacting materials and controlled-release carriers
JP2928892B2 (en) 1990-11-27 1999-08-03 三洋化成工業株式会社 Surgical adhesive
US5219895A (en) 1991-01-29 1993-06-15 Autogenesis Technologies, Inc. Collagen-based adhesives and sealants and methods of preparation and use thereof
US5156613A (en) 1991-02-13 1992-10-20 Interface Biomedical Laboratories Corp. Collagen welding rod material for use in tissue welding
US5525646A (en) 1991-03-04 1996-06-11 Lundgren; Dan Bioresorbable material and an article of manufacture made of such material for medical use
US5308887A (en) 1991-05-23 1994-05-03 Minnesota Mining & Manufacturing Company Pressure-sensitive adhesives
DE69213937D1 (en) 1991-06-14 1996-10-24 Mediolanum Farmaceutici Srl Polycarbonates and their use for presentation bio-degradable matrices
US5232648A (en) 1991-07-19 1993-08-03 United States Surgical Corporation Bioabsorbable melt spun fiber based on glycolide-containing copolymer
WO1993002639A1 (en) 1991-08-06 1993-02-18 Autogenesis Technologies, Inc. Injectable collagen-based compositions for making intraocular lens
JP3011768B2 (en) 1992-02-28 2000-02-21 ボード オブ リージェンツ,ザ ユニバーシティ オブ テキサス システム Tissue contacting materials and the photopolymerizable biodegradable hydrophilic gels as controlled release carriers
US5352515A (en) 1992-03-02 1994-10-04 American Cyanamid Company Coating for tissue drag reduction
US5476516A (en) 1992-03-13 1995-12-19 Albert Einstein College Of Medicine Of Yeshiva University Anticalcification treatment for aldehyde-tanned biological tissue
US5372585A (en) 1992-04-09 1994-12-13 Tiefenbrun; Jonathan Instrument and associated method for applying biologically effective composition during laparoscopic operation
US5589563A (en) 1992-04-24 1996-12-31 The Polymer Technology Group Surface-modifying endgroups for biomedical polymers
US5366756A (en) 1992-06-15 1994-11-22 United States Surgical Corporation Method for treating bioabsorbable implant material
US5385606A (en) 1992-07-06 1995-01-31 Kowanko; Nicholas Adhesive composition and method
WO1994004607A1 (en) 1992-08-13 1994-03-03 Zeneca Limited Polymer compositions
US5631336A (en) 1992-08-27 1997-05-20 Consiglio Nazionale Delle Ricerche Chain-terminated N-vinyl lactam polymers and graft-copolymers and methods for making same
JP3258326B2 (en) 1992-10-02 2002-02-18 カーギル, インコーポレイテッド Paper and a manufacturing method thereof coated with a melt-stable lactide polymer
US5278200A (en) 1992-10-30 1994-01-11 Medtronic, Inc. Thromboresistant material and articles
US5397816A (en) 1992-11-17 1995-03-14 Ethicon, Inc. Reinforced absorbable polymers
US5468253A (en) 1993-01-21 1995-11-21 Ethicon, Inc. Elastomeric medical device
CA2114290C (en) 1993-01-27 2006-01-10 Nagabushanam Totakura Post-surgical anti-adhesion device
JP3399573B2 (en) 1993-01-29 2003-04-21 株式会社ジーシー Tooth surface processing kit
JP3091618B2 (en) 1993-01-29 2000-09-25 信越化学工業株式会社 Ring-opening polymerization and ring-opening polymerization enzyme catalyst
US5459177A (en) 1993-03-09 1995-10-17 Sun Medical Co., Ltd. Adhesive for soft tissue and kit thereof
US5552452A (en) 1993-03-15 1996-09-03 Arch Development Corp. Organic tissue glue for closure of wounds
US5310599A (en) 1993-05-06 1994-05-10 E. I. Du Pont De Nemours And Company Method for making polymers of alpha-hydroxy acids
US5412067A (en) 1993-05-10 1995-05-02 Mitsui Toatsu Chemicals, Inc. Preparation process of polyester
US5522841A (en) 1993-05-27 1996-06-04 United States Surgical Corporation Absorbable block copolymers and surgical articles fabricated therefrom
US5403347A (en) 1993-05-27 1995-04-04 United States Surgical Corporation Absorbable block copolymers and surgical articles fabricated therefrom
US5403826A (en) 1993-05-28 1995-04-04 Abbott Laboratories Nutritional product for persons infected with human immunodeficiency virus
US5502087A (en) 1993-06-23 1996-03-26 Dentsply Research & Development Corp. Dental composition, prosthesis, and method for making dental prosthesis
FR2707878B1 (en) 1993-07-21 1997-02-14
US5359026A (en) 1993-07-30 1994-10-25 Cargill, Incorporated Poly(lactide) copolymer and process for manufacture thereof
US5530038A (en) 1993-08-02 1996-06-25 Sun Medical Co., Ltd. Primer composition and curable composition
DE59410329D1 (en) 1993-08-06 2003-11-06 Novartis Ag Photo-linked polymers
DE4332310C1 (en) 1993-09-23 1994-10-20 Heraeus Kulzer Gmbh Syringe for the metered dispensing of viscous material, especially of dental material
DE69425669T2 (en) 1993-11-05 2001-05-03 Asta Medica Ag A process for preparing high molecular weight polyester polycarbonates
US5391707A (en) 1993-12-10 1995-02-21 United States Surgical Corporation Process for the production of dioxanone
RU2136319C1 (en) 1993-12-23 1999-09-10 Джонсон энд Джонсон Медикал, Инк. Biologically absorbable surgical hemostatic and method of preparation thereof
JP3414029B2 (en) 1994-03-04 2003-06-09 ダイセル化学工業株式会社 Monodisperse polymers and methods for their preparation
US5629384A (en) 1994-05-17 1997-05-13 Consiglio Nazionale Delle Ricerche Polymers of N-acryloylmorpholine activated at one end and conjugates with bioactive materials and surfaces
DE4426129A1 (en) 1994-07-22 1996-01-25 Bayer Ag Di (meth) acrylates with cyclic carbonate
US5525647A (en) 1994-08-01 1996-06-11 American Dental Association Health Foundation Method and device for controllably affecting the reaction of dental adhesives
US5478921A (en) 1994-08-25 1995-12-26 United States Surgical Corporation Method of purifying bioabsorable polymer
US5650234A (en) 1994-09-09 1997-07-22 Surface Engineering Technologies, Division Of Innerdyne, Inc. Electrophilic polyethylene oxides for the modification of polysaccharides, polypeptides (proteins) and surfaces
US5607686A (en) 1994-11-22 1997-03-04 United States Surgical Corporation Polymeric composition
US5698213A (en) 1995-03-06 1997-12-16 Ethicon, Inc. Hydrogels of absorbable polyoxaesters
US5612052A (en) 1995-04-13 1997-03-18 Poly-Med, Inc. Hydrogel-forming, self-solvating absorbable polyester copolymers, and methods for use thereof
US5527864A (en) 1995-08-08 1996-06-18 Suggs; Laura J. Poly(propylene fumarate-co-ethylene oxide)
US5665428A (en) 1995-10-25 1997-09-09 Macromed, Inc. Preparation of peptide containing biodegradable microspheres by melt process
US5633342A (en) 1995-10-27 1997-05-27 Chronopol, Inc. Method for the synthesis of environmentally degradable block copolymers
US5658995A (en) 1995-11-27 1997-08-19 Rutgers, The State University Copolymers of tyrosine-based polycarbonate and poly(alkylene oxide)
US5837752A (en) 1997-07-17 1998-11-17 Massachusetts Institute Of Technology Semi-interpenetrating polymer networks
JP4839488B2 (en) 2007-12-07 2011-12-21 Necカシオモバイルコミュニケーションズ株式会社 The video playback apparatus and method with subtitles, program

Patent Citations (100)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2155658A (en) 1936-01-08 1939-04-25 Chemische Forschungs Gmbh Surgical and medical preparations
US2210817A (en) 1939-04-19 1940-08-06 Du Pont Superpolycarbonate
US2517965A (en) 1948-03-23 1950-08-08 Pittsburgh Plate Glass Co Purification of carbonic acid esters
US2683136A (en) 1950-10-25 1954-07-06 Du Pont Copolymers of hydroxyacetic acid with other alcohol acids
US2703316A (en) 1951-06-05 1955-03-01 Du Pont Polymers of high melting lactide
US2668162A (en) 1952-03-20 1954-02-02 Du Pont Preparation of high molecular weight polyhydroxyacetic ester
US2789968A (en) 1953-12-08 1957-04-23 Eastman Kodak Co Polycarbonates from polymethylene glycol-bis
US2917410A (en) 1955-06-20 1959-12-15 American Cyanamid Co Polyglycol-polyacid ester treatment of textiles
US3161615A (en) 1957-02-05 1964-12-15 Gen Electric Resinous copolymeric polycarbonate of a mixture of dihydric phenols
US2962524A (en) 1957-04-18 1960-11-29 Chich
US3046255A (en) 1957-06-20 1962-07-24 Pittsburgh Plate Glass Co Process for preparing polycarbonates
US3030331A (en) 1957-08-22 1962-04-17 Gen Electric Process for preparing copolyesters comprising reacting a carbonyl halide with a dicarboxylic acid and a dihydroxy compound in the presence of a tertiary amine
US3169121A (en) 1957-08-22 1965-02-09 Gen Electric Carbonate-carboxylate copolyesters of dihydric phenols and difunctional carboxylic acids
US3063988A (en) 1959-11-14 1962-11-13 Hoechst Ag Steroid-21-amino acid esters and process of preparing them
US3021310A (en) 1959-12-03 1962-02-13 Union Garbide Corp Polymerization of cyclic esters
US3223083A (en) 1960-09-09 1965-12-14 President And Directors Of Geo Method for adhesively securing together skin and other soft tissue and bone
US3157622A (en) 1961-01-03 1964-11-17 Gen Electric Resinous compositions
US3268486A (en) 1963-06-28 1966-08-23 Shell Oil Co Process for preparing polyesters
US3301825A (en) 1963-09-26 1967-01-31 Union Carbide Corp Polyester polycarbonate polymers
US3301824A (en) 1963-09-26 1967-01-31 Union Carbide Corp Polymers of cyclic carbonates
US3875937A (en) 1963-10-31 1975-04-08 American Cyanamid Co Surgical dressings of absorbable polymers
US3297033A (en) 1963-10-31 1967-01-10 American Cyanamid Co Surgical sutures
US3463158A (en) 1963-10-31 1969-08-26 American Cyanamid Co Polyglycolic acid prosthetic devices
US3739773A (en) 1963-10-31 1973-06-19 American Cyanamid Co Polyglycolic acid prosthetic devices
US3268487A (en) 1963-12-23 1966-08-23 Shell Oil Co Process for polymerization of lactides
US3312753A (en) 1964-01-13 1967-04-04 Union Carbide Corp Preparation of block copolymers of a caprolactone and oxirane compound
US3305605A (en) 1964-02-04 1967-02-21 Union Carbide Corp Compositions containing polycarbonate plasticizers
US3379693A (en) 1964-05-28 1968-04-23 Union Carbide Corp Carbonate compositions
US3531561A (en) 1965-04-20 1970-09-29 Ethicon Inc Suture preparation
US3438374A (en) 1966-02-28 1969-04-15 Us Health Education & Welfare Method of bonding tissue surfaces and controlling hemorrhaging thereof using a tissue adhesive and hemostatic composition
US3442871A (en) 1966-05-04 1969-05-06 American Cyanamid Co Process for polymerizing a glycolide
US3552986A (en) 1967-11-24 1971-01-05 Sun Chemical Corp Printing and coating untreated polyolefins
US3626948A (en) 1968-12-23 1971-12-14 American Cyanamid Co Absorbable polyglycolic acid suture of enhanced in-vivo strength retention
US3641200A (en) 1969-01-17 1972-02-08 Union Carbide Corp Block copolycarbonates containing polylactone blocks and dihydric phenol polycarbonate blocks
US3639503A (en) 1969-02-20 1972-02-01 Union Carbide Corp Block copolycarbonates containing polylactone blocks and cyclobutylene polycarbonate blocks
US3629374A (en) 1969-04-01 1971-12-21 Union Carbide Corp Lactone/alkylene oxide copolymers as plasticizers for vinyl chloride resins
US3620118A (en) 1970-11-16 1971-11-16 Yoshiyuki Koishikawa Tambourine
US3867190A (en) 1971-10-18 1975-02-18 American Cyanamid Co Reducing capillarity of polyglycolic acid sutures
US3784585A (en) 1971-10-21 1974-01-08 American Cyanamid Co Water-degradable resins containing recurring,contiguous,polymerized glycolide units and process for preparing same
US3839297A (en) 1971-11-22 1974-10-01 Ethicon Inc Use of stannous octoate catalyst in the manufacture of l(-)lactide-glycolide copolymer sutures
US3795701A (en) 1972-02-07 1974-03-05 Laporte Industries Ltd Copolymers of epoxides and lactones
US3865723A (en) 1972-03-21 1975-02-11 Zambon Spa Method to form stable complexes of polyanions occurring in biological liquids
US3882192A (en) 1973-02-01 1975-05-06 Bayer Ag Polycarbonate-polyvinyl chloride moulding compositions
US3982543A (en) 1973-04-24 1976-09-28 American Cyanamid Company Reducing capillarity of polyglycolic acid sutures
US3991766A (en) 1973-05-31 1976-11-16 American Cyanamid Company Controlled release of medicaments using polymers from glycolic acid
US3966788A (en) 1973-10-16 1976-06-29 Societe Nationale Des Poudres Et Explosifs Process for the preparation of aliphatic diol polycarbonates
US4239861A (en) 1974-01-17 1980-12-16 Bayer Aktiengesellschaft Polyvinyl chloride-polycarbonate alloys
US3960152A (en) 1974-01-21 1976-06-01 American Cyanamid Company Surgical sutures of unsymmetrically substituted 1,4-dioxane-2,5-diones
US4033938A (en) 1974-01-21 1977-07-05 American Cyanamid Company Polymers of unsymmetrically substituted 1,4-dioxane-2,5-diones
US3939049A (en) 1974-04-10 1976-02-17 The United States Of America As Represented By The United States Energy Research And Development Administration Process for radiation grafting hydrogels onto organic polymeric substrates
US3937223A (en) 1974-04-19 1976-02-10 American Cyanamid Company Compacted surgical hemostatic felt
US3896802A (en) 1974-04-19 1975-07-29 American Cyanamid Co Flexible flocked dressing
US4072704A (en) 1974-08-19 1978-02-07 Basf Wyandotte Corporation Multi-block coupled polyoxyalkylene copolymer surfactants
US4189609A (en) 1974-08-19 1980-02-19 Basf Wyandotte Corporation Multi-block coupled polyoxyalkylene copolymer surfactants
US4166902A (en) 1974-10-14 1979-09-04 Paolo Ferruti High polymers containing nicotinic acid, process for their preparation and their use
US4223011A (en) 1974-10-15 1980-09-16 Paolo Ferruti Therapeutic compositions containing polymers having polyunsaturated acid radicals
US4145320A (en) 1974-10-15 1979-03-20 Paolo Ferruti Polymers containing polyunsaturated acid radicals, process for their preparation and use thereof
US4067876A (en) 1974-10-15 1978-01-10 Paolo Ferruti High polymers containing nicotinic acid, process for their preparation and their use
US4169923A (en) 1974-10-15 1979-10-02 Paolo Ferruti High polymers containing nicotinic acid, process for their preparation and their use
US4045418A (en) 1975-01-28 1977-08-30 Gulf Oil Corporation Copolymers of D,L-lactide and epsilon caprolactone
US4057537A (en) 1975-01-28 1977-11-08 Gulf Oil Corporation Copolymers of L-(-)-lactide and epsilon caprolactone
US4093677A (en) 1975-06-10 1978-06-06 Paolo Ferruti Macromolecular materials suitable for forming antithrombogenic prosthesis and artificial organs and process for preparing same
US4143017A (en) 1976-02-25 1979-03-06 Hoya Lens Corporation Process of producing soft contact lenses
US4079038A (en) 1976-03-05 1978-03-14 Alza Corporation Poly(carbonates)
US4316001A (en) 1976-05-26 1982-02-16 Societe Nationale Des Poudres Et Explosifs Anionic polymerization of heterocyclic monomers with alkali metal amide hydroxylated compound initiator
US4211865A (en) 1976-08-10 1980-07-08 Paolo Ferruti Novel prostaglandin precursors in polymeric form
US4066630A (en) 1977-01-10 1978-01-03 Air Products And Chemicals, Inc. End capped polyalkylene carbonates having improved thermal stability
US4297455A (en) 1977-03-22 1981-10-27 Bayer Aktiengesellschaft Process for the preparation of carbonic acid aryl esters of polyester-diols lengthened via carbonate groups and their use for the preparation of polyester-diol bis-diphenol carbonates and polyester/polycarbonates
US4104264A (en) 1977-05-05 1978-08-01 Air Products & Chemicals, Inc. End capped polyalkylene carbonates having improved thermal stablity
US4300565A (en) 1977-05-23 1981-11-17 American Cyanamid Company Synthetic polyester surgical articles
US4157437A (en) 1977-06-24 1979-06-05 Ethicon, Inc. Addition copolymers of lactide and glycolide and method of preparation
US4137921A (en) 1977-06-24 1979-02-06 Ethicon, Inc. Addition copolymers of lactide and glycolide and method of preparation
US4145525A (en) 1977-10-03 1979-03-20 Air Products And Chemicals, Inc. End capped polyalkylene carbonates
US4179304A (en) 1978-04-03 1979-12-18 Polychrome Corporation Finger nail lacquer
US4137280A (en) 1978-04-19 1979-01-30 Air Products And Chemicals, Inc. Polyalkylene carbonates as processing aids for polyvinyl chloride
US4243775A (en) 1978-11-13 1981-01-06 American Cyanamid Company Synthetic polyester surgical articles
US4330481A (en) 1978-12-26 1982-05-18 The Dow Chemical Company Process for preparing polycarbonates
US4303066A (en) 1979-06-28 1981-12-01 National Patent Development Corporation Burn dressing
US4264752A (en) 1979-08-08 1981-04-28 Union Carbide Corporation Radiation-curable acrylated urethane polycarbonate compositions
US4436839A (en) 1979-08-13 1984-03-13 Akzo Nv Process for preparing polycarbonate-polyether-blockcopolymers
US4354487A (en) 1980-05-12 1982-10-19 Johnson & Johnson Fiber/absorbent polymer composites and method of forming same
US4415502A (en) 1980-08-11 1983-11-15 The Dow Chemical Co. Polycarbonate type nonionic surfactants
US4768523A (en) 1981-04-29 1988-09-06 Lifecore Biomedical, Inc. Hydrogel adhesive
US4526938A (en) 1982-04-22 1985-07-02 Imperial Chemical Industries Plc Continuous release formulations
US4429080A (en) 1982-07-01 1984-01-31 American Cyanamid Company Synthetic copolymer surgical articles and method of manufacturing the same
US4452973A (en) 1982-11-12 1984-06-05 American Cyanamid Company Poly(glycolic acid)/poly(oxyethylene) triblock copolymers and method of manufacturing the same
US4511478A (en) 1983-11-10 1985-04-16 Genetic Systems Corporation Polymerizable compounds and methods for preparing synthetic polymers that integrally contain polypeptides
US4503216A (en) 1984-02-21 1985-03-05 Eastman Kodak Company Hydroxyl-terminated polyether-esters
US4745160A (en) 1984-06-26 1988-05-17 Imperial Chemical Industries Plc Biodegradable amphipathic copolymers
US4532929A (en) 1984-07-23 1985-08-06 Ethicon, Inc. Dry coating of surgical filaments
US4559945A (en) 1984-09-21 1985-12-24 Ethicon, Inc. Absorbable crystalline alkylene malonate copolyesters and surgical devices therefrom
US4727134A (en) 1985-02-22 1988-02-23 General Electric Company Method for preparing cyclic polycarbonate oligomer mixtures
US4760117A (en) 1985-06-11 1988-07-26 General Electric Company Method for preparing copolycarbonates from cyclic polycarbonate oligomers
US4643191A (en) 1985-11-29 1987-02-17 Ethicon, Inc. Crystalline copolymers of p-dioxanone and lactide and surgical devices made therefrom
US4653497A (en) 1985-11-29 1987-03-31 Ethicon, Inc. Crystalline p-dioxanone/glycolide copolymers and surgical devices made therefrom
US4741872A (en) 1986-05-16 1988-05-03 The University Of Kentucky Research Foundation Preparation of biodegradable microspheres useful as carriers for macromolecules
US4699974A (en) 1986-08-07 1987-10-13 General Electric Company Method of preparing copolyester carbonate from cyclic aromatic polycarbonate oligomer and lactone
US4705820A (en) 1986-09-05 1987-11-10 American Cyanamid Company Surgical suture coating
US4716203A (en) 1986-09-05 1987-12-29 American Cyanamid Company Diblock and triblock copolymers
EP1586349A1 (en) * 2000-12-27 2005-10-19 Focal, Inc. Controlled release of anti-arrhythmic agents

Non-Patent Citations (43)

* Cited by examiner, † Cited by third party
Title
ACS Meeting Briefs, "Carbonate Copolymers: New branch of epoxybutene tree," C&EN p. 59 (1997).
Aida, et al., "Alternating Copolymerization of Carbon Dioxide and Epoxide Catalyzed by the Aluminum Porophyrin-Quaternary Organic Salt or-Triphenylphosphine System. Synthesis of Polycarbonate with Well-Controlled Molecular Weight," Macromolecules 19:8-13 (1986).
Bailey, et al., "Synthesis of Poly-epsilon-Caprolactone via a Free Radical Mechanism. Free Radical Ring-Opening Polymerization of 2-Methylene-1,3-Dioxepane," Journal of Polymer Science 20:3021-3030 (1982).
Barrows, "Degrading implant materials: A review of synthetic absorbable polymers and their applications," Clinical Materials 1:233-257 (1986).
Chen, et al., "Novel Graft Copolymers of a Temperature-Sensitive Polymer Grafted to a pH-Sensitive, Bioadhesive Polymer for Controlled Drug Delivery," 21st Annual Meeting of the Society of Biomaterials (1995).
Cima, et al., "Hepatocyte Responses to PEO-Tethered Carbohydrates Depend on Tether Conformation," 21st Annual Meeting of the Society of Biomaterials 147 (1995).
Constancis, et al., "Colcys as Surgical Adhesives, Ex Vivo Characterization of Mechanical and Adhesive Properties," 21st Annual Meeting of the Society of Biomaterials 258 (1995).
Dumanian, et al., "A New Photopolymerizable Blood Vessel Glue that Seals Human Vessel Anastomoses Without Augmenting Thrombogenicity," Plastic and Reconstructive Surgery 95(5):901-907 (1995).
Dupont, et al., "Collagen Gel Sealant (Glue) Based On Controlled Oxidized Collagen Ex Vivo and In Vivo Characterization," 21st Annual Meeting of the Society of Biomaterials 242 (1995).
Frenkel, et al., "A Collagen Bilayer Implant for Articular Cartilage Repair in a Rabbit Model," 21st Annual Meeting of the Society of Biomaterials 305 (1995).
Gagnieu, et al., "Colcys: New Crosslinkable Atelocollagens Synthesis and physico-chemical properties of highly grafted polymers," 21st Annual Meeting of the Society of Biomaterial 256 (1995).
Gershkovich, et al., "Post-Surgical Adhesion Prevention with Bioresorbable Gels of Amine Modified Hyaluronic Acid," 21st Annual Meeting of the Society of Biomaterials 66 (1995).
Hata, et al., "Enzymatic Polymerization of 2-Hydroxyethylmethacrylate for Artificial Embolization," The Third Word Biomaterials Congress 301 (1988).
Herbert, et al., "Polytetramethylene Oxide Blended With Polyurethane Reduces Platelet Adhesion", 21st Annual Meeting of the Society of Biomaterials 271 (1995).
Hsu, et al., "Study On Aqueous Polymerizations Of Vinyl Monomers Initated By Metal Oxidant-Chelating Agent Redox Initators", J. Polymer Science: Part A: Polymer Chem. 31:3213-3222 (1993).
Inoue, "Copolymerization of Carbon Dioxide and Epoxide: Functionality of the Copolymer," J, Macromol. Sci. Chem. A13(5):651-664 (1979).
Inoue, "Copolymerization of Carbon Dioxide," Department of Synthetic Chemistry, Faculty of Engineering, University of Tokyo, 1-42 (1974).
Inoue, et al., "Synthesis and Thermal Degradation of Carbon Dioxide-Epoxide Copolymer," Applied Polymer Symposium 26:257-267 (1975).
Kawaguchi, et al., "Examination of Biodegradability of Poly(ethylene carbonate) and Poly(propylene carbonate) in the Peritoneal Cavity in Rats," Chem. Pharm. Bull. 31(4):1400-1403 (1983).
Kawaguchi, et al., "Release Profiles of 5-Fluorouracil and Its Derivative from Polycarbonate Matrices in Vitro," Chem. Pharm. Bull. 30(4):1517-1520 (1982).
Keul, et al., "Anionic ring-opening polymerization of 2,2-dimethyltrimethylene carbonate," Makromol. Chem. 187:2579-2589 (1986).
Kobayashi, et al., "Water-curable Biodegradable prepolymers," Journal of Biomedical Materials Research 25:1481-1494 (1991).
Kojima, et al., "Preparation and Evaluation in Vitro of Polycarbonate Microspheres Containing Local Anesthetics," Chem. Pharm. Bull. 32(7):2795-2802 (1984).
Kricheldorf, et al., "Polylactones. 16. Cationic of Polymerization of Trimethylene Carbonate and Other Cyclic Carbonates," J. Macromol. Sci.-Chem. A26(4):631-644 (1989).
Kricheldorf, et al., "Polymers of Carbonic Acid 12<SUP>a)</SUP>-Spontaneous and Hematin-Initiated Polymerzations of Trimethylene Carbonate and Neopentylene Carbonate," Macromol. Chem. Phys. 197:1043-1054 (1996).
McPherson, et al., "Sealing Analysis of the Prevention of Protein Adsorption by Grafted PEO Chains," 21st Annual Meeting of the Society of Biomaterials 224 (1995).
Miller, et al., "Prevention of Post-Surgical Tendon Adhesions Using Hyaluronic Acid Systems," 21st Annual Meeting of the Society of Biomaterials 382 (1995).
Moore, et al., An Injectable Biodegradable Drug Delivery System Based on Acrylic Terminated Poly (_-Caprolactone), 21st Annual Meeting of the Society of Biomaterials 186 (1995).
Mouritzen, et al., "The effect of fibrin glueing to seal bronchial and alveolar leakages after pulmonary resections and decortications," Eur. J. Cardio-thorac Surg. 7(2):75-80 (1993).
Müller, et al., "Lithium and Potassium Alcoholates of Poly(ethylene-glycol)s as Initiators for the Anionic Polymerization of 2,2-Dimethyltrimethylene Carbonate, Synthesis of AB and ABA Block Copolymers," Euro. Polym. J. 27(12):1323-1330 (1991).
Pemberton, et al., "Polymerization of vinyl acetate using visible radiaition a dye-reducing agent sensitizer: 2. Kinetic studies and polymerization mechanism," Polymer 25:543-549 (1984).
Pemberton, et al., "Polymerization of vinyl acetate using visible radiation and a dye-reducing agent sensitizer: 1. Pre-initation and initiation reactions involving ethyl eosin and ascorbic acid," Polymer 25:536-542 (1984).
Reed, "In Vivo and In Vitro Studies of Biodegradable Polymers for Use in Medicine," Thesis submitted in accordance with the requirements of the University of Liverpool for the degree of Doctor of Philosophy (Jul. 1978).
Rimpler, "Gluing-a challenge in surgery," Int. J. Adhesion and Adhesives 16:17-20 (1996).
Roby, et al., "Absorbable Sutures Based on Glycolide/Trimethylene Carbonate Copolymers," 21st Annual Meeting of the Society of Biomaterials 216 (1985).
Sawhney, et al., "Optimization of photopolymerized bioerodible hydrogel properties for adhesion prevention," Journal of Biomedical Materials Research 28(7):831-838 (1994).
Sierra, et al., "Skullbase Cerebrospinal Fluid Leakage Control With a Fibrin-based Composite Tissue Adhesive," 21st Annual Meeting of the Society of Biomaterials 247 (1995).
Takanashi, et al., "Functional Polycarbonate by Copolymerization of Carbon Dioxide and Epoxide: Synthesis and Hydrolysis," Makromol. Chem. 183:2085-2092 (1982).
Tardy, et al., "New Surgical Sealant (Glue) Based on Controlled Oxidized Collagen-Design and Physico-Chemical Characterization," 21st Annual Meeting of the Society of Biomaterials 254 (1995).
Tiollier, et al., "Colcys as Surgical Adhesives-In Vivo Characterization and Biocompatability," 21st Annual Meeting of the Society of Biomaterials (1995).
Tiollier, et al., "Novel Development of Collagen/Gelatin Surgical Adhesives for Surgical Soft Tissue Applications," 21st Annual Meeting of the Society of Biomaterials 257 (1995).
Tomizawa et al., "Polyepoxy Compound Cross-Linked Cotton Type Collagen Hemostat,"21st Annual Meeting of the Society of Biomaterials 273 (1995).
Truong, et al., "In Vitro Conditions for Accelerated Hydrolysis of Bioabsorbable Fibers," 21st Annual Meeting of the Society of Biomaterials 436 (1995).

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040091462A1 (en) * 2002-08-20 2004-05-13 Lin Steve T. Composition for the carrying and delivery of bone growth inducing material and methods for producing and applying the composition
US20090017097A1 (en) * 2007-07-09 2009-01-15 Sawhney Amarpreet S Hydrogel polymeric compositions and methods
US9370485B2 (en) 2007-07-09 2016-06-21 Incept, Llc Hydrogel polymeric compositions and methods
US9125807B2 (en) 2007-07-09 2015-09-08 Incept Llc Adhesive hydrogels for ophthalmic drug delivery
US9775906B2 (en) 2007-07-09 2017-10-03 Incept Llc Hydrogel polymeric compositions and methods
US20090062821A1 (en) * 2007-08-31 2009-03-05 Phillips Plastics Corporation Composite scaffold structure
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US8563027B2 (en) 2009-02-12 2013-10-22 Incept, Llc Drug delivery through hydrogel plugs
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US8383161B2 (en) 2009-12-15 2013-02-26 Incept, Llc Radioopaque covalently crosslinked hydrogel particle implants
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