Injectable BMP-2 Formulation for Fracture Healing

用于骨折愈合的注射 BMP-2 制剂

• 批准号: 7159135
• 负责人: PAUL T HAMILTON
• 金额: $ 20.47万
• 依托单位: AFFINERGY ,INC
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7159135
• 关键词: birth; collagen; crosslink; osteogenesis; peptides

DESCRIPTION (provided by applicant): Two (2) recombinant human Bone Morphogenetic Proteins (BMP's), rhBMP-2 and rhBMP-7, are currently used in clinical applications to promote spinal fusion and fracture healing (Mont, Ragland et al. 2004). Over 6.3 million fractures occur each year in the United States alone (Praemer, Furner et al. 1999). Approximately 15% of fractures have delayed or impaired healing. The clinical applications currently in use, however, require open surgery to insert the carrier/BMP combination at the site of healing. There would be considerable clinical benefit from the ability to delivery BMP's via a minimally invasive procedure to accelerate fracture healing or treat delayed or non-unions. In this proposal, we present a novel approach for the development of an injectable delivery system for BMP-2. 1 major requirement for an injectable carrier for BMP-2 is the maintenance of an appropriate concentration of the osteogenic factor at the site of repair for sufficient time to allow bone-forming progenitor cells to migrate to the site, proliferate, and differentiate. A wide range of carriers have been described and characterized for delivery of BMP-2, however, none of them have a strong intrinsic affinity for BMP-2 sufficient for proper healing via an injectable. In fact, most injectable BMP/carrier combinations that have been explored to date lost 50% or more of the BMP after a few days in vivo (Seeherman, Li et al. 2003). We have identified a series of BMP-2 binding peptides using phage display that have strong affinity for BMP-2. Representative high affinity BMP-2 binding peptides will be chemically crosslinked to type I collagen to generate an injectable carrier that binds and retains BMP-2. These binding peptides will then be investigated for their ability to sustain the release of BMP-2 from a collagen matrix, while maintaining the growth factors bioactivity and improving its ability to promote bone formation in vivo. The development of this type of delivery matrix, which uses peptides with differing affinities for BMP, may allow for a greater degree of control of the release of BMP from the matrix, faster healing times, and enable new clinical treatments with BMP. Most importantly, the development of an injectable BMP-2 formulation would allow for the treatment of fractures with a minimally invasive procedure. Growth factors called Bone Morphogenetic Proteins (BMP's) are currently used to promote fracture healing. Over 6.3 million fractures occur each year in the United States alone and approximately 15% of fractures have delayed or impaired healing. The clinical applications currently in use, however, require open surgery to insert the carrier/BMP combination at the site of healing. There would be considerable clinical benefit from the ability to deliver BMP's via a minimally invasive procedure. In this proposal, we present a novel approach for the development of an injectable delivery system for BMP-2 that improves the retention and effectiveness of this growth factor at the site of repair.

描述（由申请人提供）：两（2）种重组人骨形态发生蛋白（BMP）rhBMP-2和rhBMP-7目前在临床应用中用于促进脊柱融合和骨折愈合（Mont，Ragland等人，2004）。仅在美国，每年就发生超过630万例骨折（Praemer，Furner等人，1999）。大约15%的骨折愈合延迟或受损。然而，目前使用的临床应用需要开放手术以在愈合部位插入载体/BMP组合。通过微创手术递送BMP的能力将具有相当大的临床益处，以加速骨折愈合或治疗延迟愈合或不愈合。在这个建议中，我们提出了一种新的方法，用于开发BMP-2的注射给药系统。对于BMP-2的可注射载体的一个主要要求是在修复部位维持适当浓度的成骨因子足够的时间，以允许骨形成祖细胞迁移到该部位、增殖和分化。已经描述和表征了用于递送BMP-2的多种载体，然而，它们中没有一种对BMP-2具有足以通过注射剂进行适当愈合的强内在亲和力。事实上，迄今为止已经探索的大多数可注射BMP/载体组合在体内几天后损失了50%或更多的BMP（Seeherman，Li等2003）。我们已经鉴定了一系列的BMP-2结合肽使用噬菌体展示，具有很强的亲和力BMP-2。代表性的高亲和力BMP-2结合肽将与I型胶原化学交联以产生结合并保留BMP-2的可注射载体。然后将研究这些结合肽维持BMP-2从胶原基质中释放的能力，同时保持生长因子的生物活性并提高其促进体内骨形成的能力。开发这种类型的递送基质，其使用对BMP具有不同亲和力的肽，可以允许更大程度地控制BMP从基质中的释放，更快的愈合时间，并且能够用BMP进行新的临床治疗。最重要的是，可注射BMP-2制剂的开发将允许用微创手术治疗骨折。生长因子称为骨形态发生蛋白（BMP）目前用于促进骨折愈合。仅在美国，每年就有超过630万例骨折发生，约15%的骨折愈合延迟或受损。然而，目前使用的临床应用需要开放手术以在愈合部位插入载体/BMP组合。通过微创手术递送BMP的能力将具有相当大的临床益处。在这项提案中，我们提出了一种新的方法，用于开发BMP-2的可注射递送系统，该系统可提高这种生长因子在修复部位的保留和有效性。