Click Chemistry for Immobilized Bone Morphogenetic Protein

固定化骨形态发生蛋白的点击化学

基本信息

批准号：
7159096
负责人：
Shrikumar Ambujakshan Nair
金额：
$ 24.03万
依托单位：
AFFINERGY ,INC
依托单位国家：
美国
项目类别：
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/7159096
关键词：
biomaterial development /preparation bone fracture bone morphogenetic proteins cell differentiation cell line chemical addition collagen cytotoxicity high performance liquid chromatography matrix assisted laser desorption ionization osteoblasts peptide chemical synthesis peptide library phage display photoelectron spectrometry slow release drug surface coating wound healing

项目摘要

DESCRIPTION (provided by applicant): Project Summary/Abstract: There are over 6.3 million fractures each year in the United States of which approximately 700,000 are difficult to heal. The available treatment options for fractures that do not heal or are slow to heal are limited. Bone morphogenetic proteins are growth factors that stimulate new bone production and have received FDA approval for bone fracture repair and spinal fusion. For most clinically approved uses of BMPs, a resorbable collagen sponge is used as the delivery matrix to retain BMP at the site of repair. Low affinity of BMP for the collagen results in the rapid diffusion of BMP and as a result, supraphysiological levels of BMP are required to promote healing. Affinergy develops peptidic macromolecules, interfacial biomaterials (IFBMs) that modulate the critical interface between biological surfaces to initiate and specify interfacial biologic activities. The IFBMs under investigation are composed of different peptide modules that have affinity for BMP and the collagen sponge. A limitation of the technology is the ability to construct many different IFBMs to facilitate rapid screening for subsequent in vivo evaluation. [3+2] cyclo-addition or "click chemistry" will be used to prepare IFBMs since this takes advantage of our modular approach and allows for higher total yields through the coupling of shorter peptides (<25 mers). As a model system we will identify, synthesize, and characterize IFBMs that bind a regenerated collagen sponge and a growth factor for sustained release of Bone Morphogenetic Protein (BMP) to improve bone healing at a fracture site. The specific aims are: Aim 1: Optimize the reaction conditions for coupling peptides of varying molecular weights and sequences using click-chemistry. Aim 2: Screen a library of synthesized IFBMs from peptides identified using phase display and determine binding affinity in vitro to BMP-2. Aim 3: Evaluate the in-vitro ability of BMP-IFBM coated collagen sponges with varying BMP affinities to induce osteoblast differentiation in a C3H10T1/2 mouse mesenchymal cell line. The goal of this SBIR is to demonstrate that IFBMs can be used with a resorbable material to control the delivery of growth factors to bone injuries with the intent of improving healing and clinical outcomes. Project Narrative: There are over 6.3 million fractures each year in the United States of which approximately 700,000 are difficult to heal. Bone morphogenetic proteins (BMPs) are growth factors that stimulate new bone production and have received FDA approval. Currently, a resorbable collagen sponge is used as a delivery matrix for BMP. Low affinity of BMP for the sponge results in poor delivery profiles requiring supraphysiological levels of BMP to promote healing. In this proposal, we describe a novel peptide based approach to enhance the affinity of BMP-2 to the sponge and postulate that this improvement will result in sustained release of BMP resulting in improved bone healing.

描述（由申请人提供）：项目概要/摘要：美国每年有超过 630 万例骨折，其中约 70 万例难以愈合。对于不愈合或愈合缓慢的骨折，可用的治疗方案是有限的。骨形态发生蛋白是刺激新骨生成的生长因子，已获得 FDA 批准用于骨折修复和脊柱融合。对于大多数临床批准的 BMP 用途，可吸收胶原海绵用作递送基质，以将 BMP 保留在修复部位。 BMP 对胶原蛋白的低亲和力导致 BMP 快速扩散，因此需要超生理水平的 BMP 来促进愈合。 Affinergy 开发肽大分子、界面生物材料 (IFBM)，可调节生物表面之间的关键界面，以启动和指定界面生物活性。正在研究的 IFBM 由不同的肽模块组成，这些模块对 BMP 和胶原海绵具有亲和力。该技术的一个限制是能够构建许多不同的 IFBM 以促进快速筛选以进行后续的体内评估。 [3+2]环加成或“点击化学”将用于制备 IFBM，因为这利用了我们的模块化方法，并通过较短肽（<25 mers）的偶联实现了更高的总产量。作为模型系统，我们将识别、合成和表征 IFBM，该 IFBM 结合再生胶原海绵和生长因子，以持续释放骨形态发生蛋白 (BMP)，从而改善骨折部位的骨愈合。具体目标是：目标 1：使用点击化学优化不同分子量和序列的肽偶联的反应条件。目标 2：从使用相显示鉴定的肽中筛选合成的 IFBM 文库，并确定体外与 BMP-2 的结合亲和力。目标 3：评估具有不同 BMP 亲和力的 BMP-IFBM 涂层胶原海绵在 C3H10T1/2 小鼠间充质细胞系中诱导成骨细胞分化的体外能力。该 SBIR 的目标是证明 IFBM 可以与可吸收材料一起使用来控制生长因子向骨损伤的输送，从而改善愈合和临床结果。项目叙述：美国每年有超过 630 万例骨折，其中约 70 万例难以愈合。骨形态发生蛋白 (BMP) 是刺激新骨生成的生长因子，已获得 FDA 批准。目前，可吸收胶原海绵被用作 BMP 的递送基质。 BMP 对海绵的低亲和力导致输送特性较差，需要超生理水平的 BMP 来促进愈合。在本提案中，我们描述了一种基于肽的新型方法来增强 BMP-2 对海绵的亲和力，并假设这种改进将导致 BMP 持续释放，从而改善骨愈合。