Injectable BMP-2 Formulation for Fracture Healing

描述（由申请人提供）：两(2)个重组人骨形态发生蛋白（BMP’s）， 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 et al. 2004）。仅在美国，每年就有超过630万例骨折发生（Praemer, Furner et al. 1999）。大约15%的骨折延迟或受损愈合。然而，目前使用的临床应用需要开放手术将载体/BMP组合插入愈合部位。通过微创手术输送BMP，加速骨折愈合或治疗延迟或骨不连，将有相当大的临床效益。在本提案中，我们提出了一种开发BMP-2注射给药系统的新方法。BMP-2可注射载体的一个主要要求是在修复部位维持适当的成骨因子浓度，使成骨祖细胞能够迁移到该部位，增殖和分化。广泛的BMP-2载体已经被描述和表征，然而，没有一个载体对BMP-2具有很强的内在亲和力，足以通过注射进行适当的愈合。事实上，迄今为止研究的大多数可注射的BMP/载体组合在体内几天后会丢失50%或更多的BMP （Seeherman, Li et al. 2003）。我们利用噬菌体展示技术鉴定了一系列对BMP-2具有强亲和力的BMP-2结合肽。代表性的高亲和力BMP-2结合肽将被化学交联到I型胶原蛋白上，以产生一种可注射的结合并保留BMP-2的载体。然后研究这些结合肽在维持BMP-2从胶原基质中释放的能力，同时维持生长因子的生物活性并提高其促进体内骨形成的能力。这种类型的递送基质使用对BMP具有不同亲和力的肽，可能允许更大程度地控制BMP从基质中的释放，更快的愈合时间，并使BMP的新的临床治疗成为可能。最重要的是，一种可注射的BMP-2制剂的开发将允许用微创手术治疗骨折。生长因子骨形态发生蛋白（BMP’s）目前被用于促进骨折愈合。仅在美国，每年就有超过630万例骨折发生，其中约15%的骨折延迟或受损愈合。然而，目前使用的临床应用需要开放手术将载体/BMP组合插入愈合部位。通过微创手术输送BMP的能力将有相当大的临床效益。在这一建议中，我们提出了一种新的方法来开发BMP-2的注射递送系统，该系统可以提高BMP-2在修复部位的保留和有效性。

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.