A recombinant matrix to improve autologous tissue grafts

改善自体组织移植的重组基质

• 批准号: 9908609
• 负责人: Scott Thomas Hollenbeck
• 金额: $ 25.46万
• 依托单位: INSOMA BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-11 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9908609
• 关键词: Address; Adipocytes; Adipose tissue; American; Animal Model; Area; Autologous; Beds; Birth; Body Temperature; Cells; Cellular Infiltration; Cicatrix; Clinical; Data; Deformity; Development; Elastin; Engraftment; Evaluation; Extracellular Matrix Proteins; Fat necrosis; Fatty acid glycerol esters; Fibrosis; Filler; Fractals; Functional disorder; Gel; Goals; Graft Survival; Harvest; Health; Histologic; Histology; Human; Hyaluronan; Hydrogels; In Vitro; Infection; Inflammation; Injectable; Injections; Life; Light; Liquid substance; Malignant Neoplasms; Mammaplasty; Mastectomy; Measures; Metabolic; Molecular; Monitor; Names; Natural regeneration; Nature; Necrosis; Nude Mice; Nutrient; Operative Surgical Procedures; Outcome; Patients; Phase; Phase Transition; Plastic Surgeon; Plastic Surgical Procedures; Polymers; Procedures; Process; Production; Property; Protein Engineering; Protocols documentation; Recombinant Proteins; Recombinants; Research; Risk; Small Business Technology Transfer Research; Solid; Structure; Suspensions; Technology; Temperature; Testing; Time; Tissue Grafts; Tissue Harvesting; Tissues; Trauma; United States National Institutes of Health; University Hospitals; Vascularization; Weight; Work; X-Ray Computed Tomography; Xenograft Model; biomaterial compatibility; blood vessel development; capsule; clinical implementation; clinically relevant; confocal imaging; cost; improved; improved outcome; in vivo; in vivo evaluation; innovation; neovascular; novel; reconstruction; recruit; regenerative; repaired; restoration; scaffold; soft tissue; subcutaneous; success; tissue reconstruction

Abstract The objective of this proposal is to validate a new regenerative tissue matrix which studies to date indicate may be possible of redefining the limits of autologous fat grafting. This objective is motivated by the currently limited surgical options available to the 6 million patients undergoing reconstructive plastic surgery each year to treat body disfigurement and dysfunction. A core component of many reconstructive procedures is filling a void with tissue, and the use of autologous fat grafts, with their innate biocompatibility and low procedural risk, has gained popularity. Despite their increase in favorable outcomes, obtaining consistent results has proved a significant challenge. For example, patients undergoing post-mastectomy breast reconstruction require an average of greater than 2 surgeries for procedural completion because of insufficient available volume of soft tissue or resorption due to insufficient vascularization. While attempts have been made to improve initial graft success rates by combining autologous tissue with synthetic polymers or patient-derived decellularized tissue, these attempts have met with minimal success due to lack of intrinsic bioactivity, high cost, or long processing times. Recombinant protein polymers are an unexplored but promising alternative, whereby mimics of naturally occurring extracellular matrix proteins can be recombinantly synthesized at high yield with molecular level control of their properties—a precision far superior to synthetic polymers. Motivated by this clear clinical need, this proposal seeks to optimize and test a recently developed innovative biomatrix —Fractomer— composed of an artificial recombinant protein designed to mimic native elastin. The Fractomer biomatrix is thermally responsive, allowing it to be injected as a liquid, but to rapidly phase transition in vivo to form a porous, fractal network at body temperature. Preliminary studies have shown that this matrix is biocompatible, with minimal inflammation, no fibrous capsule formation, excellent tissue integration, and the rapid formation of the branching neovascular networks essential for tissue graft success. Our central hypothesis is that the Fractomer matrix can stability integrate with and increase the effective volume of adipose tissue, maximizing graft success while reducing the required amount of autologous tissue. The following research strategy will be pursued in clinically relevant small animal models as a precursor to clinical implementation: purified fat prepared from human lipoaspirate at Duke University Hospital will be mixed with a Fractomer solution at different ratios in athymic mice, and monitored for up to 6 months. The cellular composition and long term stability of the Fractomer matrix will be directly compared with both fat grafting and commercial hyaluronan gels with the goal of demonstrating permanent retention of higher graft volumes. Graft weight, volume, and cellular composition—as determined by a combination of computed tomography and histology—will be used to evaluate graft success. The technology proposed here offers a basis for solving the fundamental issues associate with fat graft reliability, and, if successful, would significantly reduce the necessity of secondary surgical procedures.

摘要 该提案的目的是验证一种新的再生组织基质，迄今为止的研究表明， 有可能重新定义自体脂肪移植的界限。这一目标的动机是目前有限的 每年为600万接受重建整形手术的患者提供手术选择， 身体缺陷和功能障碍。许多重建程序的核心组成部分是填补空白， 组织，以及使用自体脂肪移植物，其固有的生物相容性和低手术风险，已经获得了 人气尽管他们在有利的结果增加，获得一致的结果已被证明是一个显着的 挑战.例如，接受乳房切除术后乳房重建的患者平均需要 由于可用软组织体积不足，完成手术的手术次数超过2次，或 由于血管化不足而导致的吸收。虽然已经尝试改善初始移植成功率 通过将自体组织与合成聚合物或患者来源的脱细胞组织组合， 由于缺乏固有的生物活性、高成本或长的处理时间，尝试的成功率很低。 重组蛋白质聚合物是一种未开发但有前途的替代品， 存在的细胞外基质蛋白可以在分子水平控制下以高产率重组合成 其性能的精确性远远优于合成聚合物的上级。基于这种明确的临床需求， 该提案旨在优化和测试最近开发的创新生物基质-Fractomer-由一种 设计来模拟天然弹性蛋白的人工重组蛋白。Fractomer生物基质是热响应的， 允许其作为液体注射，但在体内快速相变以形成多孔的分形网络， 体温初步研究表明，这种基质是生物相容的，炎症最小， 无纤维囊形成，组织整合良好，分支新生血管快速形成 组织移植成功所必需的网络。我们的中心假设是Fractomer矩阵可以稳定 整合并增加脂肪组织的有效体积，最大限度地提高移植成功率，同时减少 所需数量的自体组织。以下研究策略将在临床相关的小型 动物模型作为临床应用的先驱：从杜克的人脂肪抽吸物制备的纯化脂肪 将在无胸腺小鼠中以不同比例将University Hospital与Fractomer溶液混合，并监测 最多6个月。将直接比较Fractomer基质的细胞组成和长期稳定性 脂肪移植和商业透明质酸凝胶，目的是证明永久保留 更高的移植体积。移植物重量、体积和细胞组成--由以下因素的组合确定 计算机断层扫描和组织学-将用于评估移植物的成功。这里提出的技术 为解决与脂肪移植可靠性相关的基本问题提供了基础，如果成功， 大大减少了二次手术的必要性。