Localized Growth Factor Therapy for Surgical Hernia Repair

用于疝气修复手术的局部生长因子疗法

• 批准号: 7998296
• 负责人: Bruce Lamb
• 金额: $ 91.04万
• 依托单位: AFFINERGY ,INC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-14 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7998296
• 关键词: Abdomen; Adhesions; Affinity; Amino Acids; Animal Model; Animals; Area; Autologous; Binding; Biocompatible; Biocompatible Materials; Biological Assay; Blood Platelets; Caring; Cells; Characteristics; Chemicals; Chemistry; Clinical; Collagen; Complication; Data; Dermal; Development; Development Plans; Dose; Drug Formulations; Drug Kinetics; Ensure; Excipients; FDA approved; Failure; Fascia; Fibroblasts; Foreign Bodies; Future; Generations; Goals; Growth; Growth Factor; Harvest; Healed; Hernia; Human; Implant; Infection; Left; Life; Link; Marketing; Mediating; Medical Device; Medical Technology; Metals; Modeling; Modification; Normal tissue morphology; Operative Surgical Procedures; Outcome; Pain; Pathway interactions; Patients; Peptide Synthesis; Peptides; Performance; Phage Display; Pharmaceutical Preparations; Phase; Plasma; Plastics; Platelet-Derived Growth Factor; Polypropylenes; Property; Proteins; Recombinant Growth Factor; Recombinant Proteins; Recurrence; Relative (related person); Repair Material; Research; Rights; Rodent; Rodent Model; Route; Safety; Series; Simulate; Site; Source; Sterility; Sterilization; Surface; Surgeon; Suture Techniques; System; Techniques; Technology; Testing; Therapeutic Agents; United States; Ursidae Family; Wound Healing; base; biomaterial compatibility; clinical efficacy; commercialization; cost; critical period; design; experience; flexibility; follow-up; healing; implantation; improved; in vivo; innovation; interfacial; novel; platelet-derived growth factor BB; product development; programs; protein aminoacid sequence; prototype; public health relevance; repaired; research study; response; soft tissue; success; synthetic peptide

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. .

描述（由申请人提供）：美国每年进行超过700，000例疝修补手术，尽管最近取得了进展，但复发率仍然很高。在疝修补术中，采用生物相容性补片加强腹部筋膜已在很大程度上取代了高张力疝修补技术。目前，优选的生物材料包括耐用的合成网片，其承受永久性异物的所有缺陷;或其他胶原基网片，其是生物可吸收的，但以不可接受的高速率失效，导致复发性疝。因此，外科医生只能选择异物或弱修复。我们的目标是将我们的位点特异性递送技术应用于当前生物材料的改进，缩短初始修复和内源性伤口愈合之间的关键期。使用噬菌体展示技术，我们分离了选择性结合PDGF-BB和TGF-β 3的肽序列，以及作为合成肽的具有亚微摩尔相对亲和力的基于胶原的外科修复材料。在我们的I期研究计划中，我们将这些肽连接起来，产生一种双功能分子，能够在胶原基网状材料表面局部保留生物活性剂量的生长因子。本文介绍的技术提供了一种独特的方法，可持续保留生长因子并将其输送至手术部位，而不会改变胶原基可吸收疝修补补片的结构组成。拟议的II期研究计划将继续商业化我们领先的PDGF-BB：胶原肽作为胶原基修复补片的涂层。TGF-β 3：胶原蛋白肽将在后续产品开发计划中进行类似的测试和优化工作。首先，我们将利用我们在肽化学和序列优化方面的丰富经验，设计一种有效的中试规模肽合成策略，每批能够产生> 500 mg的肽。在这些合成工作的同时，将开始使用自体收获的生长因子来源（如富含血小板的血浆）对Affinergy的PDGF：胶原结合肽进行测试。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：胶原蛋白和肽随后将接受监管批准所需的一系列生物相容性试验。还将在模拟长期储存后和暴露于广泛使用的灭菌技术后检查肽的稳定性和功能。最后，将使用补片植入后软组织愈合的啮齿动物模型，在胶原修复补片上使用肽递送的PDGF-BB，以确定药代动力学和伤口愈合率。这些数据将为我们的肽的体内功效提供第一个证据，并且对于监管提交和伙伴关系发展至关重要。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，更新了我们的产品线，并将我们的核心能力扩展到关键领域，以促进我们作为一家创新医疗技术公司的持续增长。 公共卫生相关性：提高手术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愈合代表了一种潜在的改进，但由于缺乏临床可行的递送机制，这些分子仍然未得到充分利用。该提案旨在进一步商业化一种新的肽连接系统，用于在基于胶原蛋白的外科修复补片上局部保留生长因子。我们认为，该主要产品概念通过向胶原补片中添加生长因子而不改变其理想特性，有可能增强外科疝修补术后的愈合。然而，我们还寻求将我们的技术扩展到使用来自富血小板血浆的自体生长因子，以提供合作伙伴关系的灵活性，并加快我们的市场路线。由于疝修补术是全球最常见的外科手术之一，因此该产品将显著改善临床结局。.