Medical implants including laminates of poly-4-hydroxybutyrate and copolymers thereof

Abstract

Methods to produce laminates including layers of constructs made from P4HB and copolymers thereof have been developed. These laminates may be used as medical implants, or further processed to make medical implants. The laminates are produced at a temperature equal to or greater than the softening points of the P4HB or copolymers thereof. The layers may include oriented forms of the constructs. Orientation can be preserved during lamination so that the laminate is also oriented, when the laminates are formed at temperatures less than the de-orientation temperatures of the layers. The laminate layers may include, for example, films, textiles, including woven, knitted, braided and non-woven textiles, foams, thermoforms, and fibers. The laminates preferably include one or more oriented P4HB films.

1 . An implant comprising:
 a poly-4-hydroxybutyrate (P4HB) laminated structure comprising a first layer comprising P4HB or a P4HB copolymer, and a second layer comprising P4HB or a P4HB copolymer, wherein each of the first and second layers of the laminated structure are at least partially mono-axially or biaxially oriented.   
     
     
         2 . The implant of  claim 1 , wherein the laminated structure is not porous. 
     
     
         3 . (canceled) 
     
     
         4 . The implant of  claim 1 , wherein each of the first and second layers are selected from the group consisting of film, sheet, tape, mesh, and woven and nonwoven fabrics. 
     
     
         5 . (canceled) 
     
     
         6 . The implant of  claim 1 , wherein the implant has one or more properties selected from the group consisting of tensile strength that is greater than 45 MPa, tensile modulus that is greater than 55 MPa, burst strength that is greater than 1 N, and elongation to break that is between 10% and 500%. 
     
     
         7 . The implant of  claim 1  wherein the laminate is formed using one or more conditions selected from the group consisting of a temperature equal to or greater than the softening temperature of P4HB, a temperature less than the de-orientation temperature of oriented P4HB, a pressure greater than 5 kPa, and a vacuum. 
     
     
         8 . The implant of  claim 1  wherein a tackifier is used to prepare the laminate structure. 
     
     
         9 . The implant of  claim 1  wherein the laminated structure is perforated. 
     
     
         10 . The implant of  claim 9  wherein the perforations are randomly located throughout the laminate. 
     
     
         11 . The implant of  claim 9  wherein the laminate is perforated by machining or laser drilling. 
     
     
         12 . The implant of  claim 4  wherein the structure comprises a knitted, woven or non-woven mesh made of P4HB laminated to a film made of P4HB. 
     
     
         13 . The implant of  claim 4  wherein one or more layers have been annealed prior to lamination. 
     
     
         14 . The implant of  claim 13  wherein the layer is annealed under tension. 
     
     
         15 . The implants of  claim 1  wherein the laminated structure has been cut, shaped, formed into a tube or plug, molded, thermoformed, stretched, or formed into an anatomical shape, three-dimensional shape, or asymmetric shape. 
     
     
         16 . The implant of  claim 1  further comprising one or more polymers selected from the group consisting of poly(lactide); poly(glycolide); poly(lactide-co-glycolide); poly(lactic acid); poly(glycolic acid); poly(lactic acid-co-glycolic acid); polycaprolactone; poly(orthoester); polyanhydride; poly(phosphazene); polyhydroxyalkanoate (including poly-3-hydroxybutyrate (PHB), poly-3-hydroxybutyrate-co-3-hydroxyvalerate (PHBV), and P4HB copolymers); synthetically or biologically prepared polyesters (including polyesters with one or more monomeric units selected from the group consisting of: glycolic, lactic; trimethylene carbonate, p-dioxanone and beta-caprolactone); poly(lactide-co-caprolactone); polycarbonate; tyrosine polycarbonate; polyamides (including synthetic and natural polyamides, polypeptides, and poly(amino acids)); polyesteramide; poly(dioxanone); poly(alkylene alkylate); polyether; polyethylene glycol (PEG); polyethylene oxide (PEO); polyvinyl pyrrolidone (PVP); polyurethane; polyetherester; polyacetal; polycyanoacrylate; poly(oxyethylene)/poly(oxypropylene) copolymer; polyketal; polyphosphate; phosphorous-containing polymer; polyphosphoester; polyalkylene oxalate; polyalkylene succinate; poly(maleic acid); chitin; chitosan; modified chitosan; collagen; silk; biocompatible polysaccharide; biocompatible block or random copolymers; hydrophilic or water soluble polymers; block polymers of PEG with one or more polymers selected from the group consisting of poly(lactide), poly(lactide-co-glycolide, and polycaprolcatone; and block polymers of PVP with one or more polymers selected from the group consisting of poly(lactide), poly(lactide-co-glycolide and polycaprolcatone. 
     
     
         17 . The implant of  claim 1  further comprising one or more agents selected from the group consisting of therapeutic, diagnostic, prophylactic or neutraceutical agent, filler, plasticizer, nucleant, porogen, contrast agent, radiopaque marker and radioactive substance. 
     
     
         18 . The implant of  claim 1  wherein the implant is used for soft or hard tissue repair, regeneration or replacement. 
     
     
         19 . The implant of  claim 18  wherein the implant is selected from the group consisting of a patch, wound healing device, bandage, wound dressing, burn dressing, ulcer dressing, skin substitute, hemostat, tracheal reconstruction device, organ salvage device, dural patch or substitute, nerve regeneration or repair device, hernia repair device, hernia mesh, hernia plug, device for temporary wound or tissue support, tissue engineering scaffold, guided tissue repair/regeneration device, anti-adhesion membrane or barrier, tissue separation membrane, retention membrane, sling, device for pelvic floor reconstruction, urethral suspension device, device for treatment of urinary incontinence, bladder repair device, bulking or filling device, bone marrow scaffold, bone plate, fixation device for an implant, ligament repair device or augmentation device, anterior cruciate ligament repair device, tendon repair device or augmentation device, rotator cuff repair device, meniscus repair or regeneration device, articular cartilage repair device, osteochondral repair device, spinal fusion device, stent, including coronary, cardiovascular, peripheral, ureteric, urethral, urology, gastroenterology, nasal, ocular, or neurology stents and stent coatings, stent graft, cardiovascular patch, catheter balloon, vascular closure device, intracardiac septal defect repair device, atrial septal defect repair devices, PFO (patent foramen ovale) closure devices, left atrial appendage (LAA) closure device, pericardial patch, vein valve, heart valve, vascular graft, myocardial regeneration device, periodontal mesh, guided tissue regeneration membrane for periodontal tissue, ocular cell implant, imaging device, cochlear implant, anastomosis device, cell seeded device, cell encapsulation device, controlled release device, drug delivery device, plastic surgery device, breast lift device, mastopexy device, breast reconstruction device, breast augmentation device, breast reduction device, devices for breast reconstruction following mastectomy with or without breast implants, facial reconstructive device, forehead lift device, brow lift device, eyelid lift device, face lift device, rhytidectomy device, thread lift device, rhinoplasty device, device for malar augmentation, otoplasty device, neck lift device, mentoplasty device, cosmetic repair device, and device for facial scar revision. 
     
     
         20 . The implant of  claim 1  wherein the implant has been sterilized by ethylene oxide, electron beam irradiation, or gamma irradiation. 
     
     
         21 . A process for forming the implant of  claim 1 , wherein the first and second layers are bonded together under heat and pressure to form the laminated structure. 
     
     
         22 . The process of  claim 21 , wherein the layers are heated to (i) a temperature equal to or greater than the softening temperature of P4HB, (ii) a temperature less than the de-orientation temperature of oriented P4HB, or (iii) a temperature equal to or greater than the softening temperature of P4HB, but less than the orientation temperature of oriented P4HB. 
     
     
         23 . The process of  claim 21 , wherein the layers are heated to (i) a temperature equal to or greater than the softening temperature of the P4HB copolymer, (ii) a temperature less than the de-orientation temperature of the oriented P4HB copolymer, or (iii) a temperature equal to or greater than the softening temperature of the P4HB copolymer, but less than the orientation temperature of the oriented P4HB copolymer. 
     
     
         24 . The process of  claim 21  wherein a pressure greater than 5 kPa is used to bond the layers together. 
     
     
         25 . The process of  claim 21  wherein a vacuum is applied during the lamination process. 
     
     
         26 . The process of  claim 21  wherein the layers are laminated using press laminating, coextrusion, coinjection, or a continuous process. 
     
     
         27 . The process of  claim 21  wherein pressure sensitive adhesive is used to bond two or more of the layers together. 
     
     
         28 . A method of using the implant of  claim 1 , wherein the implant is implanted in the body or applied topically to the surface of the body. 
     
     
         29 . The implant of  claim 1 , wherein the first layer comprises a P4HB blend or a P4HB copolymer blend, and wherein the second layer comprises a P4HB blend or a P4HB copolymer blend.