Growth Factor Coated Sutures for Improved Tendon Repair

生长因子涂层缝线可改善肌腱修复

• 批准号: 8039685
• 负责人: Hanne Gron
• 金额: $ 2.46万
• 依托单位: AFFINERGY ,INC
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-28 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8039685
• 关键词: Affinity; Age; Animal Model; Animals; Bacteriophages; Binding; Biocompatible; Biocompatible Materials; Biological; Biological Assay; Biology; Biotin; Caring; Cell Proliferation; Cells; Chemistry; Chronic; Clinical; Collagen; Complex; Data; Development; Differentiation and Growth; Drug Formulations; Drug Kinetics; Effectiveness; Evaluation; Exhibits; Failure; Frequencies; GDF5 gene; Generations; Growth Factor; Harvest; Healed; Immobilization; In Vitro; Injury; Joints; Lead; Libraries; Ligation; Link; Mechanical Stimulation; Mechanics; Metals; Modeling; Operative Surgical Procedures; Outcome; Pain; Patients; Peptide Synthesis; Peptides; Phage Display; Phase; Physicians; Polymers; Population; Preparation; Process; Recording of previous events; Rehabilitation therapy; Reporting; Research; Research Contracts; Rodent Model; Solutions; Specificity; Speed; Sterilization; Streptavidin; Surface; Surgical sutures; Symptoms; System; Technology; Tendon Injuries; Tendon structure; Testing; Therapeutic; Therapeutic Uses; Time; Tissues; To specify; Treatment Efficacy; Ultrasonography; Universities; Visit; Wound Healing; base; biomaterial compatibility; bone morphogenetic protein 2; commercialization; cost; design; efficacy testing; growth differentiation factor 5; growth differentiation factor 7; healing; improved; in vivo; innovation; interest; interfacial; member; novel; product development; professor; programs; protein aminoacid sequence; prototype; public health relevance; repaired; research study; residence; scale up; targeted delivery

DESCRIPTION (provided by applicant): Of the nearly 5 million patients who visit a physician for tendon pain each year in the US, approximately 200,000 go on to have a surgical repair. And while surgical repair has a high-rate of symptom relief, recovering patients are routinely immobilized for several months. Increased tendon strength, during shorter time courses has been reported in animal models using the localized delivery of growth factors with surgical tendon repair. In particular, the growth and differentiation factors 5 and 7 (GDF5 and GDF7) are required for proper tendon formation, and have been shown to dramatically improve healing when applied to damaged tendon tissue. Here we propose the manufacture of a peptide-based coating, permitting the loading of these growth factors to the sutures used during surgical repair of tendon tissue to promote their sustained release. Using phage display technology, Affinergy has screened libraries expressing billions of peptide sequences, searching for those peptides which bind biologic therapeutics and synthetic materials. From previously identified peptides, several were identified which bind to suture materials, however GDF7/5 binding peptides were not immediately available from those already synthesized. Therefore a new round of phage display biopanning was performed with immobilized GDF7 as a target. For this round of phage display, a focused phage library was used, originally designed to find peptides specific for BMP-2, another TGF-¿ superfamily member. This library revealed several peptide sequences capable of binding GDF7 with sub ¿M affinity. After identifying these sequences, a conjugation strategy, attaching suture- and GDF7-binding peptides through a biotin:streptavidin system, was used to test their potential efficacy as a bifunctional linker molecule. These conjugates were capable of retaining bioactive GDF7 to a suture surface, as well as sustaining its release to surrounding cells. Finally, these peptides were synthesized as one continuous linear peptide, to generate a bifunctional peptide, which did not exhibit similar affinity compared to the streptavidin conjugate linkers. New IFBM formulations are therefore proposed, which replicate the peptide composition and orientation of the streptavidin conjugated molecules. Early optimization of IFBMs using new linkage chemistries and orientations have resulted in bifunctional peptides which enhance GDF7 attachment to suture surfaces. We are therefore eager to initiate additional optimization activities to further enhance these peptides. These data provide initial proof-of-concept evidence that bioactive GDF7 can be delivered on the surface of sutures through a novel GDF7:suture binding peptide. Exploring the in vivo function, and initiating product development is now essential to determine the therapeutic efficacy and commercial viability of this growth factor delivery platform. PUBLIC HEALTH RELEVANCE: With the most active senior generation in history rapidly emerging, the need for innovative therapeutics to treat problematic joints and tendons continues to grow. Here we present data from the successful completion of our Phase I research program, developing a peptide-based suture coating for the controlled delivery of growth and differentiation factors (GDFs) to surgically repaired tendons. The prototype coating developed in Phase I will be further optimized in Phase II, using new peptide conjugation and ligation chemistries devised by Affinergy. We will also further validate our peptide coatings in preparation for an in vivo animal model of surgical tendon repair. These animal studies will provide the first evidence for the efficacy and feasibility of our peptides for the localized delivery of GDF on suture after surgical repair.

描述（由申请人提供）：在美国，每年有近 500 万名因肌腱疼痛就医的患者，其中约 20 万人继续接受手术修复，而手术修复的症状缓解率和恢复率很高。据报道，在动物模型中，通过手术肌腱修复局部输送生长因子，可在较短的时间内增强肌腱强度，特别是生长因子 5 和分化因子 7。 （GDF5 和 GDF7）是正确的肌腱形成所必需的，并且已被证明在应用于受损肌腱组织时可以显着改善愈合。在这里，我们建议制造基于肽的涂层，从而允许将这些生长因子加载到所用的缝合线上。在肌腱组织的手术修复过程中，Affinergy 使用噬菌体展示技术筛选了表达数十亿肽序列的库，从先前鉴定的生物治疗剂和合成材料中寻找那些结合的肽。肽，鉴定出几种与缝合材料结合的肽，但是不能立即从已合成的肽中获得 GDF7/5 结合肽，因此以固定化 ​​GDF7 作为目标进行新一轮噬菌体展示生物淘选。使用了聚焦噬菌体库，最初设计用于寻找 BMP-2（另一种 TGF-¿）特异的肽该文库揭示了几种能够与 sub ¿ 结合 GDF7 的肽序列。鉴定这些序列后，使用通过生物素：链霉亲和素系统连接缝线和 GDF7 结合肽的缀合策略来测试它们作为双功能连接分子的潜在功效。最后，这些肽被合成为一种连续的线性肽，以产生一种双功能肽，与其他肽相比，它没有表现出类似的亲和力。因此，我们提出了新的 IFBM 配方，该配方复制了链霉亲和素缀合分子的肽组成和方向。因此，我们渴望启动额外的优化活动来进一步增强这些肽，这些数据提供了初步的概念验证证据，证明生物活性 GDF7 可以在表面传递。通过新型 GDF7：缝合线结合肽来探索缝合线的功能，并启动产品开发对于确定该生长因子递送平台的治疗功效和商业可行性至关重要：与最活跃的老年人群相关。随着历史的迅速发展，对治疗有问题的关节和肌腱的创新疗法的需求不断增长，在这里，我们展示了成功完成第一阶段研究项目的数据，该项目开发了一种基于肽的缝合线涂层，用于控制输送。在第一阶段开发的原型涂层将在第二阶段进一步优化，使用 Affinergy 设计的新肽缀合和连接化学方法，以准备进一步验证我们的肽涂层。这些动物研究将为我们的肽在手术修复后缝合处局部递送 GDF 的有效性和可行性提供第一个证据。