Pro-angiogenic Collagen Implants

促血管生成胶原蛋白植入物

• 批准号: 6833595
• 负责人: Joseph M Backer
• 金额: $ 18.38万
• 依托单位: SIBTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6833595
• 关键词: angiogenesis; binding proteins; bioengineering /biomedical engineering; biomaterial compatibility; biomaterial development /preparation; biotechnology; cell line; chemical kinetics; collagen; gel; medical implant science; phosphorylation; protein structure function; recombinant proteins; slow release drug; tissue support frame; vascular endothelial growth factors; wound healing; angiogenesis; binding proteins; bioengineering /biomedical engineering; biomaterial compatibility; biomaterial development /preparation; biotechnology; cell line; chemical kinetics; collagen; gel; medical implant science; phosphorylation; protein structure function; recombinant proteins; slow release drug; tissue support frame; vascular endothelial growth factors; wound healing

DESCRIPTION (provided by applicant): The overall goal of this project is to develop a pro-angiogenic wound-healing implant. New tissue that replaces a wound should be vascularized through a process known as angiogenesis. Vascular endothelial growth factor (VEGF) is the major pro-angiogenic factor and its presence at the wound site stimulates healing. Systemic delivery of a highly labile VEGF is difficult and can lead to undesirable side effects. Unfortunately, there is no effective technology for local delivery of VEGF to the wound sites. Current synthetic biodegradable matrices are not easily adaptable for formulation and controlled release of protein therapeutics. On the other hand, natural collagen-based dermal regeneration implants, such as Apligraft TM (Organogenesis), do not hold protein therapeutics because of the required porosity of these materials. Thus, the challenge is to create a biocompatible porous scaffold capable of controlled release of VEGF. Significantly, a similar problem exists for other protein therapeutics that require slow and sustained release. In this project we propose to test feasibility of a novel approach to this problem. We propose to immobilize VEGF inside of a porous matrix in non-covalent complexes with a standardized "adapter" protein integrated into the matrix. The complexes are formed as a result of interactions between adapter protein and a standardized "docking tag" genetically fused to VEGF. Thus, instead of controlling release of VEGF via degradation of a matrix, we propose to achieve a sustained release via slow dissociation of VEGF from these complexes. An innovative humanized adapter/docking tag system suitable for slow release has been recently developed in our company and tested in vitro and in vivo. This system includes a 107-aa adapter protein that can be immobilized on a desired scaffold and a 15-aa "docking" tag fused to a targeting protein. Both docking tag and adapter are parts of human ribonuclease I, and therefore are not expected to be significantly immunogenic. Furthermore, the current version of adapter is engineered to contain a unique cysteine residue for covalent linking to the scaffold. In Phase I of this project, we will test feasibility of this approach with two collagen-based scaffolds: a traditional collagen gel and a recently described electrospun collagen mat. We will establish if adapter immobilized in matrices retains affinity to tagged VEGF, determine the kinetics of VEGF uptake and release, and select the best candidate for pre-clinical development in Phase II. Importantly, technology developed in this project may be used as a platform for other protein therapeutics in need of slow and sustained release.

描述（由申请人提供）： 该项目的总体目标是开发促血管生成的伤口治疗植入物。替代伤口的新组织应通过称为血管生成的过程进行血管。血管内皮生长因子（VEGF）是主要的促血管生成因子，其在伤口部位的存在刺激了愈合。 高度不稳定的VEGF的全身传递很困难，可能导致不良的副作用。不幸的是，没有有效的技术可以将VEGF局部运送到伤口部位。当前的合成生物降解矩阵不容易适应蛋白质疗法的制剂和受控释放。 On the other hand, natural collagen-based dermal regeneration implants, such as Apligraft TM (Organogenesis), do not hold protein therapeutics because of the required porosity of these materials.因此，挑战是创建一个能够控制释放VEGF的生物相容性多孔支架。值得注意的是，其他需要缓慢释放的蛋白质治疗剂也存在类似的问题。 在这个项目中，我们建议测试针对此问题的新方法的可行性。 We propose to immobilize VEGF inside of a porous matrix in non-covalent complexes with a standardized "adapter" protein integrated into the matrix.这些复合物是由于适配器蛋白与标准化的“对接标签”之间的相互作用而形成的，将其遗传融合到VEGF上。 Thus, instead of controlling release of VEGF via degradation of a matrix, we propose to achieve a sustained release via slow dissociation of VEGF from these complexes. An innovative humanized adapter/docking tag system suitable for slow release has been recently developed in our company and tested in vitro and in vivo. This system includes a 107-aa adapter protein that can be immobilized on a desired scaffold and a 15-aa "docking" tag fused to a targeting protein.对接标签和适配器都是人类核糖核酸酶I的一部分，因此预计不会显着免疫原性。此外，当前版本的适配器经过设计，可以包含独特的半胱氨酸残留物，用于与脚手架的共价链接。 In Phase I of this project, we will test feasibility of this approach with two collagen-based scaffolds: a traditional collagen gel and a recently described electrospun collagen mat. We will establish if adapter immobilized in matrices retains affinity to tagged VEGF, determine the kinetics of VEGF uptake and release, and select the best candidate for pre-clinical development in Phase II. Importantly, technology developed in this project may be used as a platform for other protein therapeutics in need of slow and sustained release.