公开(公告)号：US07247609B2

公开(公告)日：2007-07-24

申请号：US10325021

申请日：2002-12-18

申请人： Matthias Lütolf ,  Jason Schense ,  Jeffrey A. Hubbell ,  Anna Jen

发明人： Matthias Lütolf ,  Jason Schense ,  Jeffrey A. Hubbell ,  Anna Jen

IPC分类号： A01N37/18

CPC分类号： A61L27/225 ,  A61K38/00 ,  A61L27/227 ,  C07K14/635 ,  C07K2319/00

摘要： Proteins are incorporated into protein or polysaccharide matrices for use in tissue repair, regeneration and/or remodeling and/or drug delivery. The proteins can be incorporated so that they are released by degradation of the matrix, by enzymatic action and/or diffusion. As demonstrated by the examples, one method is to bind heparin to the matrix by either covalent or non-covalent methods, to form a heparin-matrix. The heparin then non-covalently binds heparin-binding growth factors to the protein matrix. Alternatively, a fusion protein can be constructed which contains a crosslinking region such as a factor XIIIa substrate and the native protein sequence. Incorporation of degradable linkages between the matrix and the bioactive factors can be particularly useful when long-term drug delivery is desired, for example in the case of nerve regeneration, where it is desirable to vary the rate of drug release spatially as a function of regeneration, e.g. rapidly near the living tissue interface and more slowly farther into the injury zone. Additional benefits include the lower total drug dose within the delivery system, and spatial regulation of release which permits a greater percentage of the drug to be released at the time of greatest cellular activity.

摘要翻译： 将蛋白质掺入用于组织修复，再生和/或重塑和/或药物递送的蛋白质或多糖基质中。 可以掺入蛋白质，使其通过降解基质，通过酶作用和/或扩散来释放。 如实施例所示，一种方法是通过共价或非共价方法将肝素与基质结合，形成肝素基质。 然后肝素将肝素结合生长因子非共价结合到蛋白质基质上。 或者，可以构建融合蛋白，其包含交联区域，例如因子XIIIa底物和天然蛋白质序列。 当需要长期药物递送时，例如在神经再生的情况下，在基质和生物活性因子之间引入可降解的键可能是特别有用的，其中期望在空间上改变作为再生的功能的药物释放速率 ，例如 快速靠近生物组织界面，并进一步向进入损伤区更慢。 额外的益处包括递送系统内的总药物剂量越少，释放的空间调节，允许在最大的细胞活动时释放更多百分比的药物。

公开(公告)号：US06607740B1

公开(公告)日：2003-08-19

申请号：US09695466

申请日：2000-10-24

申请人： Jeffrey A. Hubbell ,  Jason Schense

发明人： Jeffrey A. Hubbell ,  Jason Schense

IPC分类号： C12N910

CPC分类号： A61L31/046 ,  A61F2310/00377 ,  A61L24/106 ,  A61L27/225 ,  A61L27/227 ,  C07K2319/00 ,  C12N5/0068 ,  C12N2533/56

摘要： The invention provides fibrin-based, biocompatible materials useful in promoting cell growth, wound healing, and tissue regeneration. These materials are provided as part of several cell and tissue scaffolding structures that provide particular application for use in wound-healing and tissue regenerating. Methods for preparing these compositions and using them are also disclosed as part of the invention. A variety of peptides may be used in conjunction with the practice of the invention, in particular, the peptide IKVAV, and variants thereof. Generally, the compositions may be described as comprising a protein network (e.g., fibrin) and a peptide having an amino acid sequence that comprises a transglutaminase substrate domain (e.g., a factor XIIIa substrate domain) and a bioactive factor (e.g., a peptide or protein, such as a polypeptide growth factor), the peptide being covalently bound to the protein network. Other applications of the technology include their use on implantable devices (e.g., vascular graphs), tissue and cell scaffolding. Other applications include use in surgical adhesive or sealant, as well as in peripheral nerve regeneration and angiogenesis.

摘要翻译： 本发明提供了用于促进细胞生长，伤口愈合和组织再生的基于纤维蛋白的生物相容性材料。 提供这些材料作为几种细胞和组织脚手架结构的一部分，其提供用于伤口愈合和组织再生的特定应用。 制备这些组合物并使用它们的方法也作为本发明的一部分公开。 多种肽可以与本发明的实践结合使用，特别是肽IKVAV及其变体。 通常，组合物可以被描述为包括蛋白质网络（例如，纤维蛋白）和具有包含转谷氨酰胺酶底物结构域（例如，因子XIIIa底物结构域）和生物活性因子（例如肽或其衍生物）的氨基酸序列的肽 蛋白质，例如多肽生长因子），肽共价结合蛋白质网络。 该技术的其他应用包括它们在可植入装置（例如血管图），组织和细胞支架上的使用。 其他应用包括用于手术粘合剂或密封剂，以及在周围神经再生和血管生成中。

公开(公告)号：US06331422B1

公开(公告)日：2001-12-18

申请号：US09057052

申请日：1998-04-08

申请人： Jeffrey A. Hubbell ,  Jason Schense

发明人： Jeffrey A. Hubbell ,  Jason Schense

IPC分类号： C12N910

CPC分类号： A61L31/046 ,  A61F2310/00377 ,  A61L24/106 ,  A61L27/225 ,  A61L27/227 ,  C07K2319/00 ,  C12N5/0068 ,  C12N2533/56

摘要： The invention provides fibrin-based, biocompatible materials useful in promoting cell growth, wound healing, and tissue regeneration. These materials are provided as part of several cell and tissue scaffolding structures that provide particular application for use in wound-healing and tissue regenerating. Methods for preparing these compositions and using them are also disclosed as part of the invention. A variety of peptides may be used in conjunction with the practice of the invention, in particular, the peptide IKVAV, and variants thereof. Generally, the compositions may be described as comprising a protein network (e.g., fibrin) and a peptide having an amino acid sequence that comprises a transglutaminase substrate domain (e.g., a factor XIIIa substrate domain) and a bioactive factor (e.g., a peptide or protein, such as a polypeptide growth factor), the peptide being covalently bound to the protein network. Other applications of the technology include their use on implantable devices (e.g., vascular graphs), tissue and cell scaffolding. Other applications include use in surgical adhesive or sealant, as well as in peripheral nerve regeneration and angiogenesis.

摘要翻译： 本发明提供了用于促进细胞生长，伤口愈合和组织再生的基于纤维蛋白的生物相容性材料。 提供这些材料作为几种细胞和组织脚手架结构的一部分，其提供用于伤口愈合和组织再生的特定应用。 制备这些组合物并使用它们的方法也作为本发明的一部分公开。 多种肽可以与本发明的实践结合使用，特别是肽IKVAV及其变体。 通常，组合物可以被描述为包括蛋白质网络（例如，纤维蛋白）和具有包含转谷氨酰胺酶底物结构域（例如，因子XIIIa底物结构域）和生物活性因子（例如肽或其衍生物）的氨基酸序列的肽 蛋白质，例如多肽生长因子），肽共价结合蛋白质网络。 该技术的其他应用包括它们在可植入装置（例如血管图），组织和细胞支架上的使用。 其他应用包括用于手术粘合剂或密封剂，以及在周围神经再生和血管生成中。

公开(公告)号：US20050065281A1

公开(公告)日：2005-03-24

申请号：US10494905

申请日：2002-11-07

申请人： Mathias Lutolf ,  Jason Schense ,  Anna Jen ,  Jeffrey Hubbell

发明人： Mathias Lutolf ,  Jason Schense ,  Anna Jen ,  Jeffrey Hubbell

IPC分类号： A61L27/00 ,  A61K47/48 ,  A61L27/18 ,  A61L27/26 ,  A61L27/52 ,  A61L31/04 ,  C08G65/329 ,  C08G65/332 ,  C08G65/334 ,  C08G81/00 ,  C08H1/00 ,  C08L71/02

CPC分类号： C08L71/02 ,  A61K47/60 ,  A61K47/6903 ,  A61L27/18 ,  A61L27/26 ,  A61L27/52 ,  A61L31/041 ,  C08G65/329 ,  C08G65/3322 ,  C08G65/334 ,  C08L2203/02 ,  C08L2666/02

摘要： Biomaterial comprises a three dimensional polymeric network obtainable from the reaction of at least a first and second precursor molecule. The first precursor molecule is at least a trifunctional, branched component comprising at least three arms substantially similar in molecular weight and the second precursor molecule is at least a bifunctional component The ratio of equivalent weight or the functional groups of the first and second precursor molecule is in a range of between 0.9 and 1.1. The molecular weight of the arms of the first precursor molecule. the molecular weight of the second precursor molecule and the functionality of the branching points are selected so that the water content of the polymeric networks is between the equilibrium weight % and 92 weitht of the total weight of the polymeric network after completion of water uptake. The present invention teaches a way to improve characteristics of synthetic matrices which are useful for wound healing applications.

摘要翻译： 生物材料包括可从至少第一和第二前体分子的反应获得的三维聚合物网络。 第一前体分子是至少三官能的支化组分，其包含分子量基本上相似的至少三个臂，第二前体分子至少是双功能组分。第一和第二前体分子的当量重量或官能团的比例是 在0.9到1.1的范围内。 第一前体分子的臂的分子量。 选择第二前体分子的分子量和支化点的官能度，使得聚合物网络的水含量在完成吸水后聚合物网络的总重量的平衡重量％和92之间。 本发明教导了一种改善可用于伤口愈合应用的合成基质的特性的方法。

公开(公告)号：US20070264227A1

公开(公告)日：2007-11-15

申请号：US11735263

申请日：2007-04-13

申请人： Matthias Lutolf ,  Jason Schense ,  Anna Jen ,  Marina Capone ,  Jeffrey Hubbell

发明人： Matthias Lutolf ,  Jason Schense ,  Anna Jen ,  Marina Capone ,  Jeffrey Hubbell

IPC分类号： A61K31/74

CPC分类号： C07C317/04 ,  A61K47/60 ,  A61K47/6903 ,  A61L27/18 ,  A61L27/52 ,  C08G65/329 ,  C08L71/02 ,  C08L2666/02

摘要： Biomaterials containing a three-dimensional polymeric network formed from the reaction of a composition containing at least a first synthetic precursor molecule having n nucleophilic groups and a second precursor molecule having m electrophilic groups wherein the sum of n+m is at least five and wherein the sum of the weights of the first and second precursor molecules is in a range from about 8 to about 16% b weight of the composition, preferably from about 10 to about 15%, more preferably from about 12 to about 14.5% by weight of the composition. In one embodiment, the first and second precursor molecules are polyethylene glycols functionalized with nucleophilic and electrophilic groups, respectively. In a preferred embodiment, the nucleophilic groups are amino and/or thiol groups and the electrophilic groups are conjugated, unsaturated groups. The ratio of the equivalent weights of the electrophilic groups (second precursor molecule) and the nucleophilic groups (first precursor molecule) is in the range of between 0.7 and 1.1, more preferably between 0.8 and 1.0. The first and/or second precursor molecule may be covalently bound to one or more molecules selected from the group consisting of cell adhesion peptides, growth factors, and growth factor-like peptides.

摘要翻译： 包含由包含至少具有n个亲核基团的第一合成前体分子和具有m个亲电子基团的第二前体分子的组合物的反应形成的三维聚合物网络的生物材料，其中n + m的总和至少为5，并且其中 第一和第二前体分子的重量的总和在组合物的约8至约16重量％的范围内，优选约10至约15重量％，更优选约12至约14.5重量％ 组成。 在一个实施方案中，第一和第二前体分子是分别用亲核基团和亲电子基团官能化的聚乙二醇。 在优选的实施方案中，亲核基团是氨基和/或硫醇基团，亲电基团是共轭的，不饱和基团。 亲电子基团（第二前体分子）和亲核基团（第一前体分子）的当量重量比在0.7和1.1之间，更优选在0.8和1.0之间。 第一和/或第二前体分子可以共价结合到选自细胞粘附肽，生长因子和生长因子样肽的一种或多种分子。

公开(公告)号：US20070179093A1

公开(公告)日：2007-08-02

申请号：US11679807

申请日：2007-02-27

申请人： Matthias Lutolf ,  Jason Schense ,  Jeffrey Hubbell ,  Anna Jen

发明人： Matthias Lutolf ,  Jason Schense ,  Jeffrey Hubbell ,  Anna Jen

IPC分类号： A61K38/36 ,  A61K38/29 ,  C07K14/635 ,  C07K14/745

CPC分类号： A61L27/225 ,  A61K38/00 ,  A61L27/227 ,  C07K14/635 ,  C07K2319/00

摘要： Proteins are incorporated into protein or polysaccharide matrices for use in tissue repair, regeneration and/or remodeling and/or drug delivery. The proteins can be incorporated so that they are released by degradation of the matrix, by enzymatic action and/or diffusion. As demonstrated by the examples, one method is to bind heparin to the matrix by either covalent or non-covalent methods, to form a heparin-matrix. The heparin then non-covalently binds heparin-binding growth factors to the protein matrix. Alternatively, a fusion protein can be constructed which contains a crosslinking region such as a factor XIIIa substrate and the native protein sequence. Incorporation of degradable linkages between the matrix and the bioactive factors can be particularly useful when long-term drug delivery is desired, for example in the case of nerve regeneration, where it is desirable to vary the rate of drug release spatially as a function of regeneration, e.g. rapidly near the living tissue interface and more slowly farther into the injury zone. Additional benefits include the lower total drug dose within the delivery system, and spatial regulation of release which permits a greater percentage of the drug to be released at the time of greatest cellular activity.

摘要翻译： 将蛋白质掺入用于组织修复，再生和/或重塑和/或药物递送的蛋白质或多糖基质中。 可以掺入蛋白质，使其通过降解基质，通过酶作用和/或扩散来释放。 如实施例所示，一种方法是通过共价或非共价方法将肝素与基质结合，形成肝素基质。 然后肝素将肝素结合生长因子非共价结合到蛋白质基质上。 或者，可以构建融合蛋白，其包含交联区域，例如因子XIIIa底物和天然蛋白质序列。 当需要长期药物递送时，例如在神经再生的情况下，在基质和生物活性因子之间引入可降解的键可能是特别有用的，其中期望在空间上改变作为再生的功能的药物释放速率 ，例如 快速靠近生物组织界面，并进一步向进入损伤区更慢。 额外的益处包括递送系统内的总药物剂量越少，释放的空间调节，允许在最大的细胞活动时释放更多百分比的药物。

公开(公告)号：US20070202178A1

公开(公告)日：2007-08-30

申请号：US11739607

申请日：2007-04-24

申请人： Jason Schense ,  Hugo Schmoekel ,  Jeffrey Hubbell ,  Franz Weber

发明人： Jason Schense ,  Hugo Schmoekel ,  Jeffrey Hubbell ,  Franz Weber

IPC分类号： A61K9/00

CPC分类号： A61L31/046 ,  A61L24/0015 ,  A61L24/106 ,  A61L27/225 ,  A61L27/227 ,  A61L27/54 ,  A61L2300/236 ,  A61L2300/252 ,  A61L2300/412 ,  A61L2300/414 ,  A61L2300/45

摘要： Bioactive molecules are entrapped within a matrix for the controlled delivery of these compounds for therapeutic healing applications. The matrix may be formed of natural or synthetic compounds. The primary method of entrapment of the bioactive molecule is through precipitation of the bioactive molecule during gelation of the matrix, either in vitro or in vivo. The bioactive molecule may be modified to reduce its effective solubility in the matrix to retain it more effectively within the matrix, such as through the deglycosylation of members within the cystine knot growth factor superfamily and particularly within the TGFβ superfamily. The matrix may be modified to include sites with binding affinity for different bioactive molecules, for example, for heparin binding.

摘要翻译： 生物活性分子被包埋在基质内，用于受控递送这些化合物用于治疗性愈合应用。 基质可以由天然或合成的化合物形成。 捕获生物活性分子的主要方法是通过体外或体内在基质凝胶化过程中沉淀生物活性分子。 可以修饰生物活性分子以降低其在基质中的有效溶解度，从而更有效地将其保留在基质内，例如通过胱氨酸结生长因子超家族内，特别是在TGFbeta超家族内的成员的去糖基化。 可以修饰基质以包括对不同生物活性分子具有结合亲和力的位点，例如用于肝素结合的位点。

公开(公告)号：US20050010297A1

公开(公告)日：2005-01-13

申请号：US10841663

申请日：2004-05-07

申请人： John Watson ,  Didier Cowling ,  Jason Schense ,  Dominik Ellenrieder

发明人： John Watson ,  Didier Cowling ,  Jason Schense ,  Dominik Ellenrieder

IPC分类号： A61B17/00 ,  A61F2/00 ,  A61F2/02 ,  A61F2/28 ,  A61F2/30 ,  A61F2/44 ,  A61F2/46 ,  A61M29/00 ,  A61M31/00

CPC分类号： A61F2/4455 ,  A61B17/00234 ,  A61B2017/00004 ,  A61F2/28 ,  A61F2/30965 ,  A61F2/442 ,  A61F2/4601 ,  A61F2/4611 ,  A61F2002/2817 ,  A61F2002/2835 ,  A61F2002/30062 ,  A61F2002/30583 ,  A61F2002/4635 ,  A61F2210/0004 ,  A61F2210/0085 ,  A61F2310/00293 ,  A61F2310/00353 ,  A61F2310/00365 ,  A61F2310/00377

摘要： A medical device containing an inflatable balloon structure for use in minimally invasive surgery and minimally invasive diagnostic and therapeutic procedures are described herein. The device is delivered by a catheter and expanded using gases, liquids or liquids that solidify in situ. The inflatable balloon may be constructed from a wide variety of materials and may be reinforced by supporting structures, when necessary. The device may form an endoprosthesis in a patient. In the preferred embodiment, the device is used in spinal fusion. Optionally, the device may also be used in combination with bone graft materials and bioactive factors.

摘要翻译： 本文描述了包含用于微创手术和微创诊断和治疗过程的可膨胀气囊结构的医疗装置。 该装置由导管输送，并使用现场固化的气体，液体或液体进行膨胀。 可膨胀气囊可以由各种各样的材料构成，并且可以在必要时由支撑结构加强。 该装置可以在患者体内形成内置假体。 在优选实施例中，该装置用于脊柱融合。 任选地，该装置还可以与骨移植材料和生物活性因子组合使用。

公开(公告)号：US08575101B2

公开(公告)日：2013-11-05

申请号：US13167488

申请日：2011-06-23

申请人： Jason Schense ,  John Watson ,  Isabelle Arrighi

发明人： Jason Schense ,  John Watson ,  Isabelle Arrighi

IPC分类号： A61K38/29 ,  A61K9/00 ,  C07K14/635

CPC分类号： A61K38/29 ,  A61L27/225 ,  A61L27/427 ,  A61L27/46 ,  A61L27/54 ,  A61L2300/252 ,  A61L2300/43 ,  A61L2430/02 ,  C07K14/635 ,  C07K2319/00

摘要： Supplemented matrices comprising a PTH releasably incorporated therein, optionally containing a granular material, which are used to heal bone fractures, particularly bone fractures with a risk of becoming delayed unions or non-unions, are described herein. The PTH is incorporated either through covalent linkage to the matrix or through non-covalent interaction with the matrix and/or the granules. These supplemented matrices decrease the time of healing compared to autograft and or trigger healing of bone fractures which otherwise would not heal. The matrices are biocompatible, preferably biodegradable, and can be formed in vitro or in vivo, at the time of implantation. The PTH may be a part of a fusion peptide. PTH can be incorporated into the matrices with full retention of its bioactivity. PTH can be releasably incorporated in the matrix.

摘要翻译： 本文描述了包含可释放地并入其中的PTH的补充基质，任选地含有颗粒材料，其用于治疗骨折，特别是具有变为延迟联合或非联合的风险的骨折。 通过共价连接到基质中或通过与基质和/或颗粒的非共价相互作用掺入PTH。 与自体移植相比，这些补充的基质减少愈合时间和/或触发骨折的愈合，否则不会愈合。 基质是生物相容的，优选可生物降解的，并且可以在植入时在体外或体内形成。 PTH可能是融合肽的一部分。 PTH可以并入到具有完全保留其生物活性的基质中。 PTH可以可释放地并入基质中。

公开(公告)号：US20120234718A1

公开(公告)日：2012-09-20

申请号：US13226618

申请日：2011-09-07

申请人： Jason Schense ,  Silke Mark ,  Monica Alvisi ,  Maria Angeles Martinez Vargas

发明人： Jason Schense ,  Silke Mark ,  Monica Alvisi ,  Maria Angeles Martinez Vargas

IPC分类号： B65D85/00 ,  A61K38/43 ,  A61K38/29

CPC分类号： A61L27/12 ,  A61L27/225 ,  A61L27/227 ,  A61L27/46 ,  A61L27/54 ,  A61L2300/414 ,  A61L2300/43 ,  A61L2400/06 ,  A61L2430/38

摘要： A pharmaceutical formulation for use in a spinal fusion method, comprising a composition for forming a matrix, a kit comprising the composition, a pharmaceutical product obtainable from the pharmaceutical formulation, and an interbody spinal fusion cage containing the pharmaceutical formulation or the pharmaceutical product are described herein. The composition comprises at least a first matrix material precursor component and a second matrix material precursor component that are able to crosslink to form the matrix under appropriate conditions, a bioactive factor that is biologically active for stimulating bone formation between two vertebrae and for effecting or supporting spinal fusion. The bioactive factor is PTH, optionally a PTH fusion peptide. The bioactive factor is releasably incorporated in the matrix upon crosslinking of the matrix material precursor components.

摘要翻译： 描述了用于脊柱融合方法的药物制剂，其包含用于形成基质的组合物，包含所述组合物的试剂盒，可从药物制剂获得的药物产品和包含药物制剂或药物产品的体内脊椎融合器 这里。 所述组合物包含至少第一基质材料前体组分和第二基质材料前体组分，所述第一基质材料前体组分和第二基质材料前体组分能够在合适的条件下交联以形成基质;生物活性因子，其对于刺激两个椎骨之间的骨形成有生物活性，并用于实现或支持 脊柱融合 生物活性因子是PTH，任选地是PTH融合肽。 当基质材料前体组分交联时，生物活性因子可释放地并入基质中。