Localized Growth Factor Therapy for Surgical Hernia Repair

描述(由申请人提供)：在美国，每年有超过700,000例腹股沟疝修补术，尽管最近取得了进展，但复发率仍然很高。在疝修补术中，使用生物相容性网片来加强腹筋膜在很大程度上已经取代了高压缝合技术。目前，首选的生物材料包括耐用的合成网片，它可以承受永久性异物的所有缺陷；或者其他胶原基网片，它可以被生物吸收，但失败率高得令人无法接受，会导致复发的疝气。因此，外科医生只能选择异物或软弱的修复。我们的目标是将我们的特定部位输送技术应用于改进现有的生物材料，缩短从最初修复到内源性伤口愈合的关键时期。利用噬菌体展示技术，我们分离了选择性结合PDGF-BB和TGF-β3的多肽序列，以及具有亚微摩尔相对亲和力的胶原基外科修复材料作为合成肽。在我们的第一阶段研究计划中，我们将这些多肽连接起来，生成了一种双功能分子，能够将具有生物活性的生长因子剂量局部保留在胶原基网状材料的表面。这里介绍的技术提供了一种独特的方法，可以保持生长因子的保留并将其输送到手术部位，而不会改变基于胶原蛋白的可吸收疝修补网的结构组成。拟议的第二阶段研究计划将继续将我们领先的PDGF-BB：胶原肽作为胶原基修复网状涂层的商业化。在后续的产品开发计划中，这种转化生长因子-？3：胶原蛋白多肽将进行类似的一系列测试和优化工作。首先，我们将利用我们在多肽化学和序列优化方面的丰富经验，设计出一种高效的中试规模的多肽合成策略，每批能够产生500毫克的多肽。在这些合成工作的同时，将开始使用自体获取的生长因子来源，如富含血小板的血浆，对AffinEnergy的PDGF：胶原结合多肽进行测试。这些努力的成功将消除未来对拥有重组生长因子专有权的合作伙伴的任何需求。PDGF-BB：胶原蛋白和多肽随后将接受监管批准所需的生物相容性测试。还将对多肽在模拟长期储存和暴露后的稳定性和功能进行广泛使用的灭菌技术(S)。最后，网片植入后软组织愈合的啮齿动物模型将被用来建立药物动力学和伤口愈合率，使用多肽递送的PDGF-BB在胶原修复网片上。这些数据将为我们的多肽在体内的有效性提供第一个证据，并将对监管提交和合作伙伴关系的发展至关重要。我们认为，拟议的第二阶段研究计划加快了该产品进入市场的速度，刷新了我们的产品线，并将我们的核心能力扩展到关键领域，使我们作为一家创新的医疗技术公司继续增长。 公共卫生相关性：提高疝修补术后的愈合率将减少疼痛、不适和后续护理。将生物制剂引入软组织修复是一种潜在的改进，但由于缺乏临床上可行的递送机制，这些分子仍未得到充分利用。这项提议旨在进一步商业化一种新的多肽连接系统，用于在以胶原为基础的外科修复网上局部保留生长因子。我们相信，这种主要的产品概念有可能通过在不改变其预期特性的情况下向胶原网状物中添加生长因子来促进腹股沟修补手术后的愈合。然而，我们也寻求将我们的技术扩展到从富血小板血浆中使用自体生长因子，以提供合作灵活性，并加快我们进入市场的道路。由于疝修补术是世界上最常见的外科手术之一，该产品将显著改善临床结果。。

DESCRIPTION (provided by applicant): Over 700,000 surgical hernia repairs are performed each year in the United States and despite recent advances, a significant rate of recurrence persists. The incorporation of biocompatible mesh to strengthen the abdominal fascia has largely replaced high-tension suturing techniques in hernia repair. Currently, the preferred biomaterials include durable synthetic mesh, which bears all the pitfalls of a permanent foreign body; or other collagen-based meshes, which are bioabsorbable but fail at an unacceptably high rate causing recurrent hernias. Surgeons are therefore left to choose either a foreign body or a weak repair. Our goal is to apply our site-specific delivery technology toward the improvement of current biomaterials, shortening the critical period between initial repair, and endogenous wound healing. Using phage display technology, we have isolated peptide sequences which selectively bind PDGF-BB and TGF-¿3 and collagen-based surgical repair materials with sub-micromolar relative affinity as synthetic peptides. During our Phase I research program, we have linked these peptides to generate a bifunctional molecule, capable of localized retention of biologically active doses of growth factor on the surface of collagen-based mesh materials. The technology presented here provides a unique means of sustaining the retention and delivery of growth factors to a surgical site, without altering the structural composition of collagen-based resorbable hernia repair mesh. The proposed Phase II research plan will continue the commercialization of our leading PDGF-BB:collagen peptide as a coating for collagen-based repair mesh. The TGF-¿3:collagen peptide will be put through a similar battery of tests and optimization efforts during a follow-up product development plan. First, we will employ our extensive experience in peptide chemistry and sequence optimization to devise an efficient pilot-scale peptide synthesis strategy capable of generating > 500 mg of peptide per batch. In parallel with these synthesis efforts, testing will begin on Affinergy's PDGF:collagen binding peptide using autologously harvested sources of growth factor, such as platelet rich plasma. Success in these efforts would remove any future need for a partner with proprietary rights to a recombinant growth factor. The PDGF-BB:collagen and peptide will then be subjected to the battery of biocompatibility testing required for regulatory approval. Peptide will also be examined for stability and function after simulated long-term storage and after exposure widely-used sterilization technique(s). Finally, a rodent model for soft tissue healing after mesh implantation will be used to establish both pharmacokinetics and wound healing rates using peptide-delivered PDGF-BB on collagen repair mesh. These data will provide the first evidence for in vivo efficacy of our peptide, and will be essential for regulatory submissions and partnership development. We feel that the proposed Phase II research plan accelerates the entrance of this product to market, refreshes our product pipeline and extends our core capabilities into critical areas for our continued growth as an innovative medical technology company. PUBLIC HEALTH RELEVANCE: Improving the rate of healing after surgical hernia repair would reduce pain, discomfort and follow-up care. The introduction of biologics into soft tissue healing represents a potential improvement, but due to a lack of clinically viable delivery mechanisms, these molecules remain under-utilized. This proposal aims to further the commercialization of a novel peptide linkage system for the local retention of growth factors on a collagen-based surgical repair mesh. We believe that this primary product concept has the potential to enhance healing after surgical hernia repair by adding growth factors to collagen meshes without altering their desireable properties. However, we also seek to extend our technology to the use of autologous growth factors from platelet rich plasma, to provide partnership flexibility, and accelerate our route to market. Because hernia repair is one of the most common surgical procedures world-wide, this product will provide substantially improved clinical outcomes. .