公开(公告)号：US20030236320A1

公开(公告)日：2003-12-25

申请号：US10403942

申请日：2003-03-28

Applicant: Metabolix, Inc.

Inventor： David P. Martin ,  Frank Skraly ,  Simon F. Williams

IPC: C08K003/00

CPC classification number: C08G63/912 ,  A61K9/1647 ,  A61K47/593 ,  A61K47/6957 ,  A61L15/26 ,  A61L17/10 ,  A61L17/12 ,  A61L24/0042 ,  A61L26/0019 ,  A61L26/009 ,  A61L27/18 ,  A61L27/34 ,  A61L27/58 ,  A61L29/06 ,  A61L31/06 ,  A61L31/148 ,  C08G63/06 ,  C08G63/64 ,  C08G63/6852 ,  C08G63/6882 ,  C08J9/26 ,  C08J2201/0444 ,  C08J2201/0482 ,  C08J2367/04 ,  C08K5/0033 ,  C12N5/0068 ,  C12N2533/30 ,  C12P7/625 ,  C08L67/04

Abstract: Biocompatible polyhydroxyalkanoate compositions with controlled degradation rates have been developed. In one embodiment, the polyhydroxyalkanoates contain additives to alter the degradation rates. In another embodiment, the polyhydroxyalkanoates are formed of mixtures of monomers or include pendant groups or modifications in their backbones to alter their degradation rates. In still another embodiment, the polyhydroxyalkanoates are chemically modified. Methods for manufacturing the devices which increase porosity or exposed surface area can be used to alter degradability. For example, as demonstrated by the examples, porous polyhydroxyalkanoates can be made using methods that creates pores, voids, or interstitial spacing, such as an emulsion or spray drying technique, or which incorporate leachable or lyophilizable particles within the polymer. Examples describe poly(4HB) compositions including foams, coatings, meshes, and microparticles. As demonstrated by the examples, these polyhydroxyalkanoate compositions have extremely favorable mechanical properties, as well as are biocompatible and degrade within desirable time frames under physioogical conditions. These polyhydroxyalkanoate materials provide a wider range of polyhydroxyalkanoate degradation rates than are currently available. Methods for processing these materials, particularly for therapeutic, prophylactic or diagnostic applications, or into devices which can be implanted or injected, are also described.

Abstract translation: 已经开发了具有受控降解速率的生物相容性聚羟基链烷酸酯组合物。 在一个实施方案中，聚羟基链烷酸酯含有改变降解速率的添加剂。 在另一个实施方案中，聚羟基链烷酸酯由单体的混合物形成或包括侧链基团或其主链中的修饰以改变其降解速率。 在另一个实施方案中，聚羟基链烷酸酯被化学改性。 用于制造增加孔隙率或暴露表面积的装置的方法可用于改变降解性。 例如，如通过实施例所证明的，多孔聚羟基链烷酸酯可以使用产生孔，空隙或间隙的方法，例如乳液或喷雾干燥技术，或者在聚合物内含有可浸出或可冷冻干燥的颗粒。 实例描述了包括泡沫，涂层，网格和微粒的聚（4HB）组合物。 如实施例所示，这些聚羟基链烷酸酯组合物具有非常有利的机械性能，并且在生理条件下在期望的时间范围内是生物相容的和降解的。 这些聚羟基链烷酸酯材料提供比目前可获得的更广泛的聚羟基链烷酸酯降解速率。 还描述了用于处理这些材料的方法，特别是用于治疗，预防或诊断应用，或可植入或注射的装置。

公开(公告)号：US20030211131A1

公开(公告)日：2003-11-13

申请号：US10434334

申请日：2003-05-07

Applicant: Metabolix, Inc. ,  Tepha, Inc.

Inventor： David P. Martin ,  Frank A. Skraly

IPC: A61F002/02 ,  C12N001/20 ,  C12P007/00

CPC classification number: C12P7/625 ,  Y10T428/31507

Abstract: Genetically engineered organisms for production of PHA copolymers containing 2-hydroxyacid monomers and the methods of making and using thereof have been developed. The copolymers containing 2-hydroxyacid monomers can be synthesized via biosynthesis by the action of a PHA polymerase in a living cell. By changing the genetic background of the cells, one can control specific metabolic pathways allowing control of the level of glycolic acid co-monomer in the PHA polymer.

Abstract translation: 已经开发了用于生产含有2-羟基酸单体的PHA共聚物的基因工程生物及其制备和使用方法。 含有2-羟基酸单体的共聚物可以通过PHA聚合酶在活细胞中的作用通过生物合成来合成。 通过改变细胞的遗传背景，人们可以控制特异性代谢途径，从而控制PHA聚合物中乙醇酸共聚单体的含量。

公开(公告)号：US20040053381A1

公开(公告)日：2004-03-18

申请号：US10642026

申请日：2003-08-15

Applicant: Metabolix, Inc.

Inventor： Simon F. Williams ,  David P. Martin ,  Tillman Gerngross ,  Daniel M. Horowitz

IPC: C12P007/62 ,  C08G063/78 ,  C08G063/82 ,  C08G063/87

CPC classification number: C12P7/625 ,  A61B17/06166 ,  A61B42/00 ,  A61K47/593 ,  A61K47/6957 ,  A61L15/26 ,  A61L17/10 ,  A61L27/18 ,  A61L27/34 ,  A61L29/06 ,  A61L31/06 ,  C08G63/06 ,  C08G63/6852 ,  C08G63/6882 ,  C08G63/912 ,  C12N5/0068 ,  C12N2533/30 ,  Y10S977/775 ,  Y10T428/139 ,  C08L67/04

Abstract: Polyhydroxyalkanoates (PHAs) from which pyrogen has been removed are provided for use in numerous biomedical applications. PHAs which have been chemically modified to enhance physical and/or chemical properties, for targeting or to modify biodegradability or clearance by the reticuloendothelial system (RES), are described. Methods for depyrogenating PHA polymers prepared by bacterial fermentation processes are also provided, wherein pyrogens are removed from the polymers without adversely impacting the polymers' inherent chemical structures and physical properties. PHAs with advantageous processing characteristics, including low melting points and/or solubility in non-toxic solvents, are also described. PHAs are provided which are suitable for use in in vivo applications such as in tissue coatings, stents, sutures, tubing, bone and other prostheses, bone or tissue cements, tissue regeneration devices, wound dressings, drug delivery, and for diagnostic and prophylactic uses. Properties which are selected for include degradability, elasticity, inclusion of functional groups or derivatized groups, which can in turn be used to attach targeting agents, and bioadhesion.

Abstract translation: 已经除去热原的聚羟基链烷酸酯（PHA）被提供用于许多生物医学应用。 已经化学改性以增强物理和/或化学性质的PHA用于通过网状内皮系统（RES）靶向或修饰生物降解性或清除的PHA。 还提供了通过细菌发酵方法制备的去氢原位PHA聚合物的方法，其中热原从聚合物中除去而不会不利地影响聚合物固有的化学结构和物理性质。 还描述了具有有利处理特性的PHA，包括低熔点和/或在无毒溶剂中的溶解度。 提供适用于体内应用的PHA，例如在组织涂层，支架，缝线，管，骨和其他假体，骨或组织水泥，组织再生装置，伤口敷料，药物递送以及用于诊断和预防用途 。 选择的性质包括降解性，弹性，包含官能团或衍生基团，其又可用于附着靶向剂，以及生物粘附。

公开(公告)号：US20040137586A1

公开(公告)日：2004-07-15

申请号：US10773916

申请日：2004-02-06

Applicant: Metabolix, Inc.

Inventor： Gjalt W. Huisman ,  Frank Skraly ,  David P. Martin ,  Oliver P. Peoples

IPC: C07H021/04 ,  C12P007/62 ,  C12N009/10 ,  C12N009/16

CPC classification number: C12N9/0008 ,  C08G63/06 ,  C12N9/1029 ,  C12N9/1096 ,  C12N15/8243 ,  C12P7/625

Abstract: The gene encoding a 4-hydroxybutyryl-Co A transferase has been isolated from bacteria and integrated into the genome of bacteria also expressing a polyhydroxyalkanoate synthase, to yield an improved production process for 4HB-containing polyhydroxyalkanoates using transgenic organisms, including both bacteria and plants. The new pathways provide means for producing 4HB containing PHAs from cheap carbon sources such as sugars and fatty acids, in high yields, which are stable. Useful strains are obtaining by screening strains having integrated into their genomes a gene encoding a 4HB-CoA transferase and/or PHA synthase, for polymer production. Processes for polymer production use recombinant systems that can utilize cheap substrates. Systems are provided which can utilize amino acid degradation pathways, null-ketoglutarate, or succinate as substrate.

Abstract translation: 已经从细菌中分离出编码4-羟基丁酰-CoA转移酶的基因，并整合到也表达聚羟基链烷酸酯合酶的细菌的基因组中，以使用包括细菌和植物在内的转基因生物来产生含4HB的聚羟基链烷酸酯的改进的生产方法。 新途径提供了从低廉的碳源（如糖和脂肪酸）生产含有PHB的4HB的方法，其产率高，稳定。 有用的菌株是通过筛选在其基因组中整合了编码4HB-CoA转移酶和/或PHA合成酶的基因的聚合物生产获得的菌株。 用于聚合物生产的方法使用可以利用廉价底物的重组体系。 提供可以利用氨基酸降解途径的系统，α-酮戊二酸或琥珀酸作为底物。

公开(公告)号：US20020187530A1

公开(公告)日：2002-12-12

申请号：US10006915

申请日：2001-11-09

Applicant: Metabolix, Inc.

Inventor： Gjalt W. Huisman ,  Frank Skraly ,  David P. Martin ,  Oliver P. Peoples

IPC: C12P007/62 ,  C12N015/74 ,  C12P021/02 ,  C12N001/21

CPC classification number: C12N9/0008 ,  C08G63/06 ,  C12N9/1029 ,  C12N9/1096 ,  C12N15/8243 ,  C12P7/625

Abstract: The gene encoding a 4-hydroxybutyryl-Co A transferase has been isolated from bacteria and integrated into the genome of bacteria also expressing a polyhydroxyalkanoate synthase, to yield an improved production process for 4HB-containing polyhydroxyalkanoates using transgenic organisms, including both bacteria and plants. The new pathways provide means for producing 4HB containing PHAs from cheap carbon sources such as sugars and fatty acids, in high yields, which are stable. Useful strains are obtaining by screening strains having integrated into their genomes a gene encoding a 4HB-CoA transferase and/or PHA synthase, for polymer production. Processes for polymer production use recombinant systems that can utilize cheap substrates. Systems are provided which can utilize amino acid degradation pathways, null-ketoglutarate, or succinate as substrate.

Abstract translation: 已经从细菌中分离出编码4-羟基丁酰-CoA转移酶的基因，并整合到也表达聚羟基链烷酸酯合酶的细菌的基因组中，以使用包括细菌和植物在内的转基因生物来产生含4HB的聚羟基链烷酸酯的改进的生产方法。 新途径提供了从低廉的碳源（如糖和脂肪酸）生产含有PHB的4HB的方法，其产率高，稳定。 有用的菌株是通过筛选在其基因组中整合了编码4HB-CoA转移酶和/或PHA合成酶的基因的聚合物生产获得的菌株。 用于聚合物生产的方法使用可以利用廉价底物的重组体系。 提供可以利用氨基酸降解途径的系统，α-酮戊二酸或琥珀酸作为底物。

公开(公告)号：US20020156150A1

公开(公告)日：2002-10-24

申请号：US10082954

申请日：2002-02-26

Applicant: Metabolix, Inc.

Inventor： Simon F. Williams ,  David P. Martin ,  Frank A. Skraly

IPC: A61F002/00

CPC classification number: A61L27/58 ,  A61F2/07 ,  A61F2210/0004 ,  A61K31/715 ,  A61L17/12 ,  A61L27/18 ,  A61L31/06 ,  A61L31/148 ,  A61L31/16 ,  A61L2300/00 ,  C08G63/06 ,  C08J9/26 ,  C08J2201/0444 ,  C08J2201/0482 ,  C08J2367/04 ,  C08K5/0033 ,  C08L67/04 ,  C12P7/625 ,  Y10S606/911

Abstract: Devices formed of or including biocompatible polyhydroxyalkanoates are provided with controlled degradation rates, preferably less than one year under physiological conditions. Preferred devices include sutures, suture fasteners, meniscus repair devices, rivets, tacks, staples, screws (including interference screws), bone plates and bone plating systems, surgical mesh, repair patches, slings, cardiovascular patches, orthopedic pins (including bone filling augmentation material), adhesion barriers, stents, guided tissue repair/regeneration devices, articular cartilage repair devices, nerve guides, tendon repair devices, atrial septal defect repair devices, pericardial patches, bulking and filling agents, vein valves, bone marrow scaffolds, meniscus regeneration devices, ligament and tendon grafts, ocular cell implants, spinal fusion cages, skin substitutes, dural substitutes, bone graft substitutes, bone dowels, wound dressings, and hemostats. The polyhydroxyalkanoates can contain additives, be formed of mixtures of monomers or include pendant groups or modifications in their backbones, or can be chemically modified, all to alter the degradation rates. The polyhydroxyalkanoate compositions also provide favorable mechanical properties, biocompatibility, and degradation times within desirable time frames under physiological conditions.

Abstract translation: 由生物相容性聚羟基链烷酸酯形成或包括生物相容性聚羟基链烷酸酯的设备具有受控的降解速率，优选在生理条件下小于一年。 优选的装置包括缝线，缝线紧固件，弯液面修复装置，铆钉，钉，钉，螺钉（包括干涉螺钉），骨板和骨电镀系统，外科手术网，修复贴片，吊索，心血管贴片，矫形针 材料），粘附屏障，支架，引导组织修复/再生装置，关节软骨修复装置，神经导管，肌腱修复装置，房间隔缺损修复装置，心包块，填充剂和填充剂，静脉瓣，骨髓支架，半月板再生 装置，韧带和腱移植物，眼细胞植入物，脊髓融合笼，皮肤替代物，硬脑膜替代物，骨移植物替代物，骨榫，伤口敷料和止血剂。 聚羟基链烷酸酯可以含有由单体的混合物形成的添加剂，或者在其主链中包括侧基或修饰，或者可以化学改性，以改变降解速率。 聚羟基链烷酸酯组合物还在生理条件下的期望时间范围内提供有利的机械性能，生物相容性和降解时间。

公开(公告)号：US20020173558A1

公开(公告)日：2002-11-21

申请号：US10136499

申请日：2002-05-01

Applicant: Metabolix, Inc.

Inventor： Simon F. Williams ,  David P. Martin ,  Frank A. Skraly

IPC: C08K003/00

CPC classification number: A61L27/58 ,  A61F2/07 ,  A61F2210/0004 ,  A61K31/715 ,  A61L17/12 ,  A61L27/18 ,  A61L31/06 ,  A61L31/148 ,  A61L31/16 ,  A61L2300/00 ,  C08G63/06 ,  C08J9/26 ,  C08J2201/0444 ,  C08J2201/0482 ,  C08J2367/04 ,  C08K5/0033 ,  C08L67/04 ,  C12P7/625 ,  Y10S606/911

Abstract: Devices formed of or including biocompatible polyhydroxyalkanoates are provided with controlled degradation rates, preferably less than one year under physiological conditions. Preferred devices include sutures, suture fasteners, meniscus repair devices, rivets, tacks, staples, screws (including interference screws), bone plates and bone plating systems, surgical mesh, repair patches, slings, cardiovascular patches, orthopedic pins (including bone filling augmentation material), adhesion barriers, stents, guided tissue repair/regeneration devices, articular cartilage repair devices, nerve guides, tendon repair devices, atrial septal defect repair devices, pericardial patches, bulking and filling agents, vein valves, bone marrow scaffolds, meniscus regeneration devices, ligament and tendon grafts, ocular cell implants, spinal fusion cages, skin substitutes, dural substitutes, bone graft substitutes, bone dowels, wound dressings, and hemostats. The polyhydroxyalkanoates can contain additives, be formed of mixtures of monomers or include pendant groups or modifications in their backbones, or can be chemically modified, all to alter the degradation rates. The polyhydroxyalkanoate compositions also provide favorable mechanical properties, biocompatibility, and degradation times within desirable time frames under physiological conditions.