公开(公告)号：US08703449B2

公开(公告)日：2014-04-22

申请号：US13250492

申请日：2011-09-30

申请人： David P. Martin ,  Frank A. Skraly

发明人： David P. Martin ,  Frank A. Skraly

IPC分类号： C12P7/62 ,  C12N1/20 ,  C12N15/00 ,  C12Q1/00 ,  C12N9/04 ,  C12N9/10 ,  C12N9/02 ,  C07H21/04

CPC分类号： C12P7/625 ,  Y10T428/31507

摘要： 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.

摘要翻译： 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：US20110190866A1

公开(公告)日：2011-08-04

申请号：US13057974

申请日：2009-07-17

申请人： Klaus-Peter Schmitz ,  Detlef Behrend ,  Katrin Sternberg ,  Niels Grabow ,  David P. Martin ,  Simon F. Williams

发明人： Klaus-Peter Schmitz ,  Detlef Behrend ,  Katrin Sternberg ,  Niels Grabow ,  David P. Martin ,  Simon F. Williams

IPC分类号： A61F2/84 ,  A61F2/82 ,  B05D7/00

CPC分类号： A61L31/18 ,  A61F2/82 ,  A61F2210/0004 ,  A61F2250/0067 ,  A61L31/10 ,  A61L31/148 ,  A61L31/16 ,  A61L2300/606 ,  C08L67/04

摘要： Absorbable stents and absorbable stent coatings have been developed with improved properties. These devices preferably comprise biocompatible copolymers or homopolymers of 4-hydroxybutyrate, and optionally poly-L-lactic acid and other absorbable polymers and additives. Compositions of these materials can be used to make absorbable stents that provide advantageous radial strengths, resistance to recoil and creep, can be plastically expanded on a balloon catheter, and can be deployed rapidly in vivo. Stent coatings derived from these materials provide biocompatible, uniform coatings that are ductile, and can be expanded without the coating cracking and/or delarmnating and can be used as a coating matrix for drug incorporation.

摘要翻译： 可吸收支架和可吸收支架涂层已经开发出具有改进的性能。 这些装置优选包含4-羟基丁酸酯和任选的聚-L-乳酸和其它可吸收的聚合物和添加剂的生物相容性共聚物或均聚物。 这些材料的组合物可用于制造提供有利的径向强度，抵抗反冲和蠕变的可吸收支架，可以在球囊导管上塑性膨胀，并且可以在体内迅速部署。 衍生自这些材料的支架涂层提供生物相容性均匀的延展性涂层，并且可以在没有涂层开裂和/或脱胶的情况下扩展，并且可以用作药物掺入的涂层基质。

公开(公告)号：US20080132602A1

公开(公告)日：2008-06-05

申请号：US11931850

申请日：2007-10-31

申请人： Said Rizk ,  David P. Martin ,  Kicherl Ho ,  Simon F. Williams

发明人： Said Rizk ,  David P. Martin ,  Kicherl Ho ,  Simon F. Williams

IPC分类号： A61F2/02 ,  A61F2/82

CPC分类号： A61L27/34 ,  A61L27/18 ,  A61L31/10 ,  B29C55/005 ,  B29C55/04 ,  B29C55/12 ,  B29K2067/00 ,  B29K2067/046 ,  B29K2995/006 ,  C08L67/04

摘要： Continuous processing methods for making absorbable polymeric films with one or more of the following properties: high toughness, low modulus, high tensile strength, and thickness less than 10 mm, more preferably less than 1 mm, and more preferably less than 100 μm, have been developed. In the preferred embodiment, the polymer is a polyhydroxyalkanoate, and in the most preferred embodiment, the polymer comprises 4-hydroxybutyrate. A particularly preferred embodiment is a film of poly-4-hydroxybutyrate or copolymer thereof, wherein the film has a tensile strength greater than 5.5 kgf/mm2, tensile modulus less than 181 kgf/mm2, and elongation at break from 10-500%, wherein the film is derived by a continuous process such as melt extrusion or solvent casting, followed by orientation to more than 25% of the film's original length in one or more directions. These can be used for a variety of purposes including fabrication of medical devices.

摘要翻译： 用于制造具有以下特性中的一种或多种的可吸收聚合物膜的连续加工方法：高韧性，低模量，高拉伸强度和小于10mm，更优选小于1mm，更优选小于100μm的厚度具有 已经开发 在优选的实施方案中，聚合物是聚羟基链烷酸酯，并且在最优选的实施方案中，聚合物包含4-羟基丁酸酯。 特别优选的实施方案是聚-4-羟基丁酸酯或其共聚物的膜，其中所述膜的拉伸强度大于5.5kgf / mm 2，拉伸模量小于181kgf / mm 2， 2℃，断裂伸长率为10-500％，其中该膜通过连续方法如熔体挤出或溶剂浇铸得到，然后在一个或多个膜中定向至超过膜的原始长度的25％ 方向。 这些可以用于各种目的，包括制造医疗器械。

公开(公告)号：US07179883B2

公开(公告)日：2007-02-20

申请号：US11020896

申请日：2004-12-22

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

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

IPC分类号： C08G63/08

CPC分类号： 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

摘要： 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.

摘要翻译： 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：US07081357B2

公开(公告)日：2006-07-25

申请号：US10773916

申请日：2004-02-06

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

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

IPC分类号： C12P7/62 ,  C12N15/53 ,  C12N15/54

CPC分类号： C12N9/0008 ,  C08G63/06 ,  C12N9/1029 ,  C12N9/1096 ,  C12N15/8243 ,  C12P7/625

摘要： The gene encoding a 4-hydroxybutyryl-CoA 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, α-ketoglutarate, or succinate as substrate.

摘要翻译： 已经从细菌中分离出编码4-羟基丁酰辅酶A转移酶的基因，并整合到也表达聚羟基链烷酸酯合成酶的细菌的基因组中，以产生使用包括细菌和植物在内的转基因生物体的含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：US07025980B1

公开(公告)日：2006-04-11

申请号：US09661773

申请日：2000-09-14

申请人： Simon F. Williams ,  David P. Martin

发明人： Simon F. Williams ,  David P. Martin

IPC分类号： A61F2/02

CPC分类号： C12P7/625 ,  A61L27/18 ,  C08L67/04

摘要： Polyhydroxyalkanoate materials are provided which are suitable for repair of soft tissue, augmentation, and as viscosupplements in animals, particularly humans. The materials comprise liquid polyhydroxyalkanoate polymer compositions or polyhydroxyalkanoate microdispersions. Devices also are provided for storage and delivery of the polyhydroxyalkanoate compositions in vivo. Methods are provided for repairing or augmenting soft tissue in animals using the materials. In a preferred embodiment, the method include the steps of (a) selecting the animal soft tissue to be repaired or augmented; and (b) placing an injectable, liquid polyhydroxyalkanoate polymer or a polyhydroxyalkanoate microdispersion into the animal soft tissue, preferably using a minimally-invasive method such as injection. In another embodiment, the liquid polyhydroxyalkanoate polymer compositions or polyhydroxyalkanoate microdispersions are used as viscosupplements.

公开(公告)号：US06623730B1

公开(公告)日：2003-09-23

申请号：US09661948

申请日：2000-09-14

申请人： Simon F. Williams ,  David P. Martin

发明人： Simon F. Williams ,  David P. Martin

IPC分类号： A61K31765

CPC分类号： A61K31/19 ,  A61K31/765

摘要： Oligomers and polymer compositions are provided which comprise GHB and produce GHB after administration in vivo. Devices for the storage and delivery of these polymers and oligomers are also provided. These oligomers and polymer compositions are useful in a variety of applications. The compositions can be used therapeutically, for example, in the treatment of patients with narcolepsy, chronic schizophrenia, catatonic schizophrenia, atypical psychoses, chronic brain syndrome, neurosis, alcoholism, drug addiction and withdrawal, Parkinson's disease and other neuropharmacological illnesses, hypertension, ischemia, circulatory collapse, radiation exposure, cancer, and myocardial infarction. Other uses for the compositions include anesthesia induction, sedation, growth hormone production, heightened sexual desire, anorectic effects, euphoria, smooth muscle relaxation, muscle mass production, and sleep, including rapid eye movement sleep. In a still further embodiment, the oligomers and polymers may be used to produce absence seizures.

摘要翻译： 提供含有GHB并在体内施用后产生GHB的低聚物和聚合物组合物。 还提供了用于储存和递送这些聚合物和低聚物的装置。 这些低聚物和聚合物组合物可用于各种应用中。 组合物可用于治疗例如发作性睡病，慢性精神分裂症，紧张性精神分裂症，非典型精神病，慢性脑综合征，神经症，酒精中毒，药物成瘾和戒断，帕金森病和其他神经药理学疾病，高血压，缺血的患者的治疗 ，循环衰竭，放射线暴露，癌症和心肌梗死。 组合物的其它用途包括麻醉诱导，镇静，生长激素生成，性欲升高，厌食症，欣快，平滑肌松弛，肌肉量产和睡眠，​​包括快速眼动睡眠。 在另一个实施方案中，低聚物和聚合物可以用于产生不发作的发作。

公开(公告)号：US06548569B1

公开(公告)日：2003-04-15

申请号：US09535146

申请日：2000-03-24

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

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

IPC分类号： C08L6704

CPC分类号： 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

摘要： 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.

公开(公告)号：US06245537B1

公开(公告)日：2001-06-12

申请号：US09076198

申请日：1998-05-12

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

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

IPC分类号： C12P762

CPC分类号： 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

摘要： Polyhydroxyalkanoate (PHA) that contains a pyrogen such as endotoxin due to a process of producing the PHA is treated to remove the pyrogen by a process that does not affect the inherent chemical and physical properties of the PHA to obtain a biocompatible PHA. PHA produced by fermentation with a Gram negative bacteria can be treated with an oxidizing agent such as hydrogen peroxide or benzoyl peroxide to reduce the endotoxin content to less than 20 endotoxin units/gram of PHA to produce PHA that does not elicit an acute inflammatory response when implanted in an animal. The PHA may have a melting point or glass transition temperature less than 136° C., and can be chemically modified or derivatized such as by covalently coupling an attachment or targeting molecule. The PHA may be used to form various medical devices, and can be used for in vivo applications including tissue coatings, stents, sutures, tubing, bone and other prostheses, bone and tissue cements, tissue regenerating devices, wound dressings, drug delivery, and for diagnostic and prophylactic uses.

摘要翻译： 处理由于产生PHA的过程而含有热原如内毒素的聚羟基链烷酸酯（PHA），以通过不影响PHA固有的化学和物理性能以获得生物相容性PHA的方法除去热原。 通过用革兰氏阴性细菌发酵产生的PHA可以用氧化剂如过氧化氢或过氧化苯甲酰处理以将内毒素含量降低到小于20个内毒素单位/克的PHA，以产生不引起急性炎症反应的PHA 植入动物。 PHA可以具有低于136℃的熔点或玻璃化转变温度，并且可以通过共价偶联附着物或靶向分子进行化学修饰或衍生化。 PHA可以用于形成各种医疗装置，并且可以用于体内应用，包括组织涂层，支架，缝线，管，骨和其他假体，骨和组织水泥，组织再生装置，伤口敷料，药物递送和 用于诊断和预防用途。

公开(公告)号：US09125719B2

公开(公告)日：2015-09-08

申请号：US13228056

申请日：2011-09-08

申请人： David P. Martin ,  Said Rizk ,  Ajay Ahuja ,  Simon F. Williams

发明人： David P. Martin ,  Said Rizk ,  Ajay Ahuja ,  Simon F. Williams

IPC分类号： A61K9/00 ,  A61F2/00 ,  A61L27/18 ,  A61L31/06 ,  D01F6/62 ,  D01F6/84 ,  D01D5/088 ,  D01D5/16 ,  D02G3/02 ,  A61L27/48 ,  D01D5/098

CPC分类号： A61F2/0063 ,  A61F2002/0068 ,  A61L27/18 ,  A61L27/48 ,  A61L31/06 ,  B29C47/0004 ,  B29C47/0014 ,  B29C71/0072 ,  B29K2067/00 ,  B29L2031/753 ,  D01D5/088 ,  D01D5/098 ,  D01D5/16 ,  D01F6/62 ,  D01F6/625 ,  D01F6/84 ,  D02G3/02 ,  Y10T428/1362 ,  Y10T428/1369 ,  Y10T428/249922 ,  Y10T442/10 ,  Y10T442/183 ,  Y10T442/184 ,  Y10T442/2525 ,  C08L67/04

摘要： Absorbable polyester fibers, braids, and surgical meshes with prolonged strength retention have been developed. These devices are preferably derived from biocompatible copolymers or homopolymers of 4-hydroxybutyrate. These devices provide a wider range of in vivo strength retention properties than are currently available, and could offer additional benefits such as anti-adhesion properties, reduced risks of infection or other post-operative problems resulting from absorption and eventual elimination of the device, and competitive cost. The devices may also be particularly suitable for use in pediatric populations where their absorption should not hinder growth, and provide in all patient populations wound healing with long-term mechanical stability. The devices may additionally be combined with autologous, allogenic and/or xenogenic tissues to provide implants with improved mechanical, biological and handling properties.

摘要翻译： 已经开发了具有延长的强度保持性的可吸收聚酯纤维，辫子和外科网。 这些装置优选衍生自生物相容性共聚物或4-羟基丁酸酯的均聚物。 这些装置提供比目前可获得的更广泛的体内强度保持性能，并且可以提供额外的益处，例如抗粘附性质，降低的感染风险或由于吸收和最终消除装置而导致的其他手术后问题，以及 有竞争力的成本。 这些装置还可以特别适用于儿科人群，其吸收不应阻碍生长，并在所有患者群体中提供长期机械稳定性的伤口愈合。 所述装置可以另外与自体，同种异体和/或异种组织组合，以提供具有改进的机械，生物和处理性质的植入物。