权利要求：
We claim:
1. A method for fabricating a three-dimensional object made from poly- 4-hydroxybutyrate or copolymer thereof, wherein the object is fabricated by a computer aided additive manufacturing approach.
2. The method of claim 1, wherein the object is printed with print lines, wherein the dimensions of the print lines are within 25% of the expected dimensions of the print lines, and more preferably within 10% of the expected dimensions of the print lines.
3. The method of claim 1, wherein the object is printed continuously without interruption of the printing process.
4. The method of claim 1, wherein cells are incorporated into the object during or after printing.
5. The method of claim 1 wherein the object is fabricated by a method selected from the group comprising: (i) fused filament fabrication, (ii) fused pellet deposition, (iii) melt extrusion deposition, (iv) selective laser melting, (v) printing of slurries and solutions using a coagulation bath, and (vi) printing using a binding solution and granules of powder.
6. The method of claim 5, wherein the object is fabricated from a filament of poly-4-hydroxybutyrate polymer, or copolymer or blend thereof, the method comprising: providing an apparatus for use in fused filament fabrication, the apparatus comprising (a) a heat sink, (b) a melt tube, (c) a heating block and nozzle, (d) a transition zone between the heat sink and heating block, (e) a movable stage, and (f) a computer programmed with 3D CAD data for the object that can control the position of the nozzle and stage, wherein, the melt tube extends through the heat sink, transition zone, and through the heat block to the nozzle, wherein, the filament is received into the melt tube, melted, and conveyed from the nozzle to fabricate the object, and wherein, the temperature of the filament in the melt tube at the top of the heat sink is between -50 °C and 42 °C, more preferably between 0 °C and 35 °C, and even more preferably between 15 °C and 30 °C.
7. The method of claim 6, wherein the temperature of the filament in the melt tube at the bottom of the heat sink is between 15 °C and 42 °C, more
preferably between 20 °C and 35 °C, and even more preferably between 25 °C and 32 °C.
8. The method of claims 6 and 7, wherein the temperature of the filament in the melt tube in the transition zone is between 15 °C and 100 °C, more preferably between 30 °C and 95 °C, and even more preferably between 42 °C and 92 °C.
9. The method of any one of claims 6-8, wherein the temperature of the nozzle is between 180 °C to 300 °C, more preferably between 220 and 280 °C, and even more preferably between 250 °C and 270 °C.
10. The method of any one of claims 6-9, wherein the length of the transition zone between the bottom of the heat sink and the top of the heating block is between 1 mm to 10 mm, more preferably between 1.5 mm and 8 mm, and even more preferably between 2 to 3 mm.
11. The method of any one of claims 6-10, wherein the nozzle has an opening with a diameter of 0.1 mm to 5 mm, and more preferably 0.15 mm to 1 mm.
12. The method of any one of claims 6-11, wherein the apparatus further comprises a feeding mechanism to drive the filament into the melt tube so it passes through the heat sink, transition zone and heat block, and exits as a molten filament through the nozzle.
13. The method of claim 12, wherein the filament is unoriented or partially oriented.
14. The method of and one of claims 6-13, wherein the apparatus further comprises one or more of the following: (i) a source of compressed gas directed at the heat sink to cool the heat sink and a deflector to divert the gas from the fabricated object, and (ii) a cooling fluid to chill the heat sink.
15. The method of any one of claims 6-14, wherein the apparatus further comprises a movable stage, and optionally a movable nozzle, that allows the melted filament to be deposited from the nozzle to fabricate a two or three- dimensional object preferably wherein the stage, and optionally the nozzle, are controlled by computer-aided manufacturing (CAM), and preferably
wherein the temperature of the stage is uniform and maintained at 2-65 °C, preferably 15-30 °C, and even more preferably 18-22 °C.
16. The method of any one of claims 6-15, wherein the weight average molecular weight of the polymer or copolymer decreases less than 25% during melting and fabrication of the object.
17. The method of claim 6, wherein the filament is made by pultrusion, preferably at a temperature of -50 to 30 °C, or wherein the filament is made by extrusion or spinning, preferably melt spinning or wet spinning.
18. The method of claim 6, wherein the diameter of the filament is not more than 97% of the diameter of the melt tube, more preferably not more than 94% of the diameter of the melt tube, and the diameter of the filament is not less than 70% of the diameter of the melt tube, more preferably not less than 81.25% of the diameter of the melt tube.
19. The method of claim 6, wherein the filament is received into the melt tube at a feed rate of 0.05-0.35 mm/s, more preferably at 0.2 to 0.25 mm/s, the residence time of the filament in the melt tube is 10 s/mm3to 1,000 s/mm3, more preferably 50 s/mm3to 500 s/mm3, and wherein the average print speed is 2.5 mm/s to 7.5 mm/s.
20. The method of claim 5, wherein the object is fabricated from pellets of poly-4-hydroxybutyrate polymer, or copolymer or blend thereof, the method comprising: providing an apparatus for fused pellet deposition, the apparatus comprising (a) a heated pressurized reservoir for polymer pellets fitted at one end with a gas line, (b) a nozzle located at the opposite end of the reservoir to the gas line inlet, (c) a movable stage located underneath the nozzle, and (d) a computer programmed with 3D CAD data for the object that can control the position of the nozzle and stage, wherein, dried pellets of polymer, copolymer or blend thereof are placed in the reservoir, melted, and the molten polymer is conveyed through the nozzle to form the printed object on the stage, and wherein the diameter of the nozzle is 0.1 to 1.0 mm, the pellets are heated to a temperature of 85 to 180 °C, more preferably 120 to 150 °C, and the reservoir is pressurized to a pressure of 650 to 2,000 kPa.
21. The method of claim 5, wherein the object is fabricated from poly-4- hydroxybutyrate polymer, or copolymer or blend thereof, the method comprising: providing an apparatus for melt extrusion deposition, the apparatus comprising (a) a horizontal single screw heated barrel, with a hopper for the polymer, connected to a vertical extruder fitted with a plunger and comprising a nozzle orifice, (b) a moving stage positioned under the vertical extruder, and (c) a computer programmed with 3D CAD data for the object that can control the position of the nozzle orifice and the stage, wherein the polymer, copolymer or blend thereof is dried, placed in the hopper, and kept dry using a purge of dry gas, wherein the plunger is used to eject the polymer, copolymer or blend thereof through the nozzle orifice as small droplets onto the stage where they fuse to form the object, and wherein the temperature of the horizontal extruder is set between 150 °C and 230 °C, the residence time of the polymer, copolymer or blend in the horizontal extruder is 0.5 to 5 min/cm3, and the diameter of the nozzle orifice is from 0.1 to 0.4 mm.
22. The method of claim 21, wherein the plunger is piezoelectrically driven to create the small droplets.
23. The method of claim 21, wherein the polymer, copolymer or blend thereof is in the form of pellets, and the average diameters of the pellets are from 0.05 mm to 3 mm.
24. The method of claim 21, wherein the water content of the polymer, copolymer or blend thereof is from 1 ppm to 1,000 ppm, and more preferably from 50 ppm to 500 ppm.
25. The method of any one of claims 6, 20, and 21, wherein the object is printed with print lines, wherein the dimensions of the print lines are within 10% of the expected dimensions of the print lines.
26. The method of claim 5, wherein the object is fabricated from poly-4- hydroxybutyrate polymer, or copolymer or blend thereof, the method comprising: providing an apparatus for selective laser melting, the apparatus comprising (a) a moving powder bed, polymer powder reservoir and powder sweeper, (b) a laser source with moving lens that can focus a laser on the
polymer in the powder bed, and (c) a computer programmed with 3D CAD data for the object that can control the position of the powder bed and laser beam, wherein the laser can fuse the polymer powder and print an object as it is scanned over the surface of the polymer powder, wherein the average sizes of the granules of the polymer powder range from 0.5 to 250 pm, wherein the particle sizes of the granules of polymer powder are no more than 25% larger or smaller than the average particle sizes, wherein the weight average molecular weight of the polymer or copolymer is from 80 kDa to 500 kDa, and more preferably 80 kDa to 200 kDa, wherein the thickness of the powder prior to fusion by the laser is from 50 to 250 pm, wherein the power of the laser is from 4 to 60 Watts, and wherein the speed of movement of the laser beam is from 0.8 to 80 cm/s.
27. The method of claim 26, wherein the laser is a high-powered CO2 laser.
28. The method of claim 26, wherein the focal length of the laser is 50 pm to 250 pm.
29. The method of claim 26, wherein the average size of the granules of the polymer powder range from 0.375 pm to 312.5 pm, and more preferably 3.75 pm to 62.5 pm.
30. The method of claim 27, wherein the granules are prepared by one or more of the steps comprising (i) cryo-milling and (ii) sieving.
31. The method of claim 26, wherein the object is printed with print lines, wherein the dimensions of the print lines are within 25% of the expected dimensions of the print lines.
32. The method of claim 5, wherein the object is fabricated from poly-4- hydroxybutyrate polymer, copolymer or blend thereof, the method comprising: providing an apparatus for solution printing in a coagulation bath, the apparatus comprising (a) a pressurized heated dispenser connected to a dispensing needle, (b) a movable coagulation bath, and (c) a computer programmed with 3D CAD data for the object that can control the position of the dispensing needles and coagulation bath, wherein the polymer, copolymer or blend thereof is suspended or dissolved in a solvent in the
dispenser, wherein the inner diameter of the dispensing needle is from 15 pm to 1.2 mm, and the pressure in the dispenser is from 150 to 800 kPa, wherein the coagulation bath contains a solvent selected from ethanol, methanol and water, or combinations thereof, and wherein the polymer, copolymer or blend thereof is suspended or dissolved in acetone, chloroform, dioxane or tetrahydrofuran, or mixture thereof.
33. The method of claim 32, wherein the polymer, copolymer or blend thereof is suspended or dissolved in: (a) acetone at a concentration of 0.05 to 6% w/v, more preferably 2 to 5% w/v (b) chloroform at a concentration of 0.05 to 10% w/v, more preferably 5 to 8% w/v (c) dioxane at a concentration of 0.05 to 8% w/v, more preferably 3 to 6% w/v, or (d) tetrahydrofuran at a concentration of 0.05 to 10% w/v, more preferably 5 to 8% w/v.
34. The method of claim 33, wherein the polymer suspension or solution is heated to 40 to 50 °C.
35. The method of claim 32, wherein (i) when the solvent is acetone, the coagulation solvent is water, methanol, ethanol, or a mixture thereof, (ii) when the solvent is chloroform, the coagulation solvent is methanol, ethanol, or a mixture thereof, (iii) when the solvent is dioxane, the coagulation solvent is water, ethanol, methanol or a mixture thereof, and (iv) when the solvent is tetrahydrofuran, the coagulation solvent is water, ethanol, methanol or a mixture thereof.
36. The method of claim 5, wherein the object is fabricated from poly-4- hydroxybutyrate polymer, copolymer or blend thereof, the method comprising: providing an apparatus for printing using a binding ink and polymer powder, the apparatus comprising (a) a reservoir for a binding ink that can eject droplets of ink onto a moving powder bed fitted with a polymer powder reservoir and a powder sweeper, and (b) a computer programmed with 3D CAD data for the object that can control the position of the ejected droplets and powder bed, wherein the powder is in the form of granules and the average size of the granules is from 0.5 to 250 pm, and more preferably 5 to 50 pm, wherein the polymer or copolymer has weight average molecular weight from 80 to 500 kDa, and more preferably 80 to 200 kDa, wherein the
object is printed by ejecting droplets of ink onto a layer of polymer powder with a thickness ranging from 50 to 250 pm, and wherein the binding ink is selected from chloroform, acetone, tetrahydrofuran, and dioxane.
37. The method of claim 36, wherein the granules have particle sizes no more than 25% larger or smaller than the average particle sizes.
38. The method of claim 37, wherein the granules have particle sizes from 0.375 pm to 312.5 pm.
39. The method of claim 37, wherein the granules are prepared by one or more of the steps comprising (i) cryo-milling and (ii) sieving.
40. The method of any one of claims 1-39, wherein the poly-4- hydroxybutyrate or copolymer thereof further comprises one or more of the following: poly(lactide); poly(glycolide); poly(lactide-co-glycolide);
poly(lactic acid); poly(glycolic acid); poly(lactic acid-co-glycolic acid); polycaprolactone; poly(orthoester); poly anhydride; poly(phosphazene); polyhydroxyalkanoate; synthetically or biologically prepared polyester, polyester with one or more of the following monomeric units: glycolic, lactic, trimethylene carbonate, p-dioxanone, or e-caprolactone); poly(lactide- co-caprolactone); polycarbonate; tyrosine polycarbonate; polyamide;
polypeptide; polyesteramide; poly(dioxanone); poly(alkylene alkylate); polyether, polyethylene glycol, polyvinyl pyrrolidone; polyurethane;
polyetherester; polyacetal; polycyanoacrylate;
poly(oxyethylene)/poly(oxypropylene) copolymer; polyacetal, polyketal; polyphosphate; phosphorous-containing polymer; polyphosphoester;
polyalkylene oxalate; polyalkylene succinate; poly(maleic acid); chitin; chitosan; modified chitosan; polysaccharides; alginate; silk; glycerol; gelatin; hyaluronic acid and derivatives thereof; collagen; polyvinyl alcohol; and hydrogels.
41. The method of any one of claims 1-40, wherein the poly-4- hydroxybutyrate or copolymer thereof further comprises one or more of the following: nucleant, plasticizer, ceramic, contrast agent, radiopaque and/or radioactive substance.
42. A medical implant formed by the methods of any on eof claims 1-41.
43. The implant of claim 42, wherein the implant further comprises a bioactive agent or imaging agent.
44. The implant of claim 43, wherein the bioactive agent is selected from the group comprising: small-molecule drugs, anti-inflammatory agents, immunomodulatory agents, molecules that promote cell migration, molecules that promote or retard cell division, molecules that promote or retard cell proliferation and differentiation, molecules that stimulate phenotypic modification of cells, molecules that promote or retard angiogenesis, molecules that promote or retard vascularization, molecules that promote or retard extracellular matrix disposition, signaling ligands, platelet rich plasma, peptides, proteins, glycoproteins, anesthetics, hormones, antibodies, growth factors, fibronectin, laminin, vitronectin, integrins, antimicrobials, antibacterial drugs, antiviral agents, antifungal agents, anti- parisitic drugs, steroids, hydroxyapatite, silver particles, vitamins, non steroidal anti-inflammatory drugs, chitosan and derivatives thereof, alginate and derivatives thereof, collagen, sugars, polysaccharides, nucleotides, oligonucleotides, lipids, lipoproteins, hyaluronic acid and derivatives thereof, allograft material, xenograft material, ceramics, nucleic acid molecules, antisense molecules, aptamers, siRNA, and nucleic acids.
45. The implant of claim 44, wherein the antimicrobial agent is selected from the group comprising: rifampin; minocycline and its hydrochloride, sulfate, or phosphate salt; triclosan; chlorhexidine; vancomycin and its hydrochloride, sulfate, or phosphate salt; tetracycline and its hydrochloride, sulfate, or phosphate salt, and derivatives; gentamycin; cephalosporin antimicrobials; aztreonam; cefotetan and its disodium salt; loracarbef;
cefoxitin and its sodium salt; cefazolin and its sodium salt; cefaclor;
ceftibuten and its sodium salt; ceftizoxime; ceftizoxime sodium salt;
cefoperazone and its sodium salt; cefuroxime and its sodium salt; cefuroxime axetil; cefprozil; ceftazidime; cefotaxime and its sodium salt; cefadroxil; ceftazidime and its sodium salt; cephalexin; cefamandole nafate; cefepime and its hydrochloride, sulfate, and phosphate salt; cefdinir and its sodium salt; ceftriaxone and its sodium salt; cefixime and its sodium salt;
cefpodoxime proxetil; meropenem and its sodium salt; imipenem and its sodium salt; cilastatin and its sodium salt; azithromycin; clarithromycin; dirithromycin; erythromycin and hydrochloride, sulfate, or phosphate salts, ethylsuccinate, and stearate forms thereof, clindamycin; clindamycin hydrochloride, sulfate, or phosphate salt; lincomycin and hydrochloride, sulfate, or phosphate salt thereof, tobramycin and its hydrochloride, sulfate, or phosphate salt; streptomycin and its hydrochloride, sulfate, or phosphate salt; neomycin and its hydrochloride, sulfate, or phosphate salt; acetyl sulfisoxazole; colistimethate and its sodium salt; quinupristin; dalfopristin; amoxicillin; ampicillin and its sodium salt; clavulanic acid and its sodium or potassium salt; penicillin G; penicillin G benzathine, or procaine salt;
penicillin G sodium or potassium salt; carbenicillin and its disodium or indanyl disodium salt; piperacillin and its sodium salt; ticarcillin and its disodium salt; sulbactam and its sodium salt; moxifloxacin; ciprofloxacin; ofloxacin; levofloxacins; norfloxacin; gatifloxacin; trovafloxacin mesylate; alatrofloxacin mesylate; trimethoprim; sulfamethoxazole; demeclocycline and its hydrochloride, sulfate, or phosphate salt; doxycycline and its hydrochloride, sulfate, or phosphate salt; oxytetracycline and its
hydrochloride, sulfate, or phosphate salt; chlortetracycline and its hydrochloride, sulfate, or phosphate salt; metronidazole; dapsone;
atovaquone; rifabutin; linezolide; polymyxin B and its hydrochloride, sulfate, or phosphate salt; sulfacetamide and its sodium salt; clarithromycin; and silver ions, salts, and complexes.
46. The implant of claim 42, wherein the implant is selected from the group consisting of mesh, tube, catheter, monofilament mesh, multifilament mesh, wound healing device, bandage, wound dressing, bum dressing, ulcer dressing, skin substitute, hemostat, tracheal reconstruction device, organ salvage device, dura substitute, dura patch, nerve guide, nerve regeneration or repair device, hernia repair device, including hernia mesh, hernia plug, and devices for repair of ventral, inguinal, femoral, umbilical, incisional, epigastric and hiatal hernias, device for temporary wound or tissue support, tissue engineering scaffold, guided tissue repair/regeneration device, anti-
adhesion membrane, adhesion barrier, tissue separation membrane, retention membrane, sling, device for pelvic floor reconstruction, urethral suspension device, device for treatment of urinary incontinence, including stress urinary incontinence, device for treatment of vesicoureteral reflux, bladder repair device, sphincter muscle repair device, bulking or filling device, bone marrow scaffold, clip, clamp, screw, pin, nail, medullary cavity nail, bone plate, interference screw, tack, fastener, rivet, staple, fixation device for an implant, bone graft substitute, bone void filler, suture anchor, bone anchor, ligament repair device, ligament augmentation device, ligament graft, anterior cruciate ligament repair device, tendon repair device, tendon graft, tendon augmentation device, rotator cuff repair device, meniscus repair device, meniscus regeneration device, articular cartilage repair device, osteochondral repair device, spinal fusion device, mandibular device, cranial bone void device, maxilla implant device, craniomaxillofaciai device, device for treatment of osteoarthritis, viscosupplement, 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, including but not limited to atrial septal defect repair devices and 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, dental bone void filler, ocular cell implant, imaging device, cochlear implant, embolization device, 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 (including devices for use with breast implants), breast reduction device (including devices for removal, reshaping and reorienting breast tissue), 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, tummy tuck device, arm lift
device, rhytidectomy device, rhinoplasty device, device for malar augmentation, otoplasty device, neck lift device, mentoplasty device, cosmetic repair device, device for facial scar revision, and enclosure, pouch, holder, cover, and clamshell casings to hold implantable medical devices, including pacemakers.
47. A method of using the implant of claims 42-46, wherein the implant is implanted in the body.