A recombinant matrix to improve autologous tissue grafts

改善自体组织移植的重组基质

• 批准号: 10652973
• 负责人: Stefan Roberts
• 金额: $ 103.59万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10652973
• 关键词: Address; Adipose tissue; Area; Autologous; Automobile Driving; Biological; Biological Products; Biomechanics; Biopsy; Body Temperature; Breast; Cancer Patient; Cannulas; Cellular Infiltration; Cicatrix; Clinical; Complex; Contracts; Contracture; Cyst; Defect; Development; Devices; Elastin; Endotoxins; Evaluation; Event; Extracellular Matrix Proteins; Family suidae; Fatty acid glycerol esters; Fermentation; Fibrosis; Foreign Bodies; Formulation; Funding; General Anesthesia; Goals; Grant; Growth; Harvest; Histologic; Implant; Inflammatory Response; Injectable; Injections; Internal Breast Prosthesis; Investments; Ki-1 Large-Cell Lymphoma; Laboratories; Length of Stay; Liquid substance; Mammaplasty; Mastectomy; Materials Testing; Methods; Modeling; Molecular; Monitor; Mus; Natural regeneration; Necrosis; Operative Surgical Procedures; Outcome; Outpatients; Patients; Phase; Phase Transition; Polymers; Porosity; Preclinical Testing; Procedures; Process; Production; Property; Protein Engineering; Proteins; Recombinant Proteins; Recombinants; Reconstructive Surgical Procedures; Recovery; Safety; Second Look Surgery; Shapes; Silicones; Small Business Innovation Research Grant; Solid; Structure; Suction Lipectomy; Surgeon; Technology; Temperature; Testing; Time; Tissue Grafts; Tissues; Toxic effect; Translations; Vascularization; biomaterial compatibility; blood vessel development; breast lumpectomy; calcification; clinical practice; clinically relevant; commercialization; comparison control; cost; cytotoxicity; efficacy testing; fat grafting; implantation; improved; in vivo; industrial production; innovation; irritation; mammary; manufacture; manufacturing organization; manufacturing process; manufacturing scale-up; mechanical properties; phase 1 study; porcine model; programs; reconstruction; repaired; research clinical testing; response; restoration; safety testing; scaffold; scale up; soft tissue; success; tissue regeneration; tissue repair

Project Summary The objective of this proposal is to further develop a new restorative tissue matrix which Phase I studies indicate is capable of expanding the utility of autologous fat grafting in breast reconstructive surgery. This objective is motivated by the need to improve the accessibility and safety of breast reconstruction for cancer patients. Breast implants dominate the field as they are easy to place and provide a defined shape. However, growing concerns over the long-term impact of implants with regards to capsular contracture, breast implant illness (BII) and breast implant associated anaplastic large cell lymphoma (BIA-ALCL) are driving many patients to seek other options. Tissue flap procedures effectively deliver large sections of fat to the defect; however, these procedures are complex, expensive, and not widely available to all patients. The long-term outcomes of successful tissue flaps are favorable but associated with significant investment in time, money, bodily scars, and effort. A third option is autologous fat, which can also be transferred as a graft using only liposuction and small injection cannulas as an outpatient procedure. Despite its potential, many surgeons feel limited in their capabilities when using fat grafts as: (1) harvesting fat with liposuction destroys its structural matrix, resulting in a shapeless slurry, and (2) many patients simply do not have enough fat to donate. To date, the technical and surgical barriers to using fat grafting for definitive breast reconstruction have not been solved. While attempts have been made to improve graft success rates by combining tissue with synthetic polymers or decellularized tissue, these attempts have shown minimal success due to a 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 synthesized at high yield with molecular level control of their properties. Motivated by this clear clinical need, this proposal seeks to advance commercialization of a recently developed innovative biomatrix —Fractomer. Fractomers are artificial proteins designed to mimic soft tissue that can be co-injected with fat to expand volume, increase long-term stability, and improve fat shape by allowing tissue ingrowth and blood vessel formation. The Phase I program focused on Fractomer’s interaction with lipoaspirate to determine biomechanical and thermal response properties ideally suited to a tissue repair matrix. In vivo studies demonstrated Fractomer’s ability to promote cellular infiltration and vascularization associated with repair and remodeling, as opposed to scar formation and fibrosis. Finally, in a murine flank fat grafting model, Fractomer enabled the retention of form, localization, and structure of fat grafts up to three months. During Phase II we will continue commercial development of Fractomer by: 1) scaling manufacturing; 2) completing necessary biocompatibility and toxicity studies as required by the FDA for Investigational Device Exemption status prior to clinical testing; and 3) testing the material’s safety and efficacy in a porcine model of mammary fat pad repair.

项目摘要 该提案的目的是进一步开发一种新的修复组织基质，I期研究表明， 可扩大自体脂肪移植在乳房再造手术中的应用。这一目标 其动机是需要提高癌症患者乳房重建的可及性和安全性。乳腺 植入物在该领域占主导地位，因为它们易于放置并提供确定的形状。然而，越来越多的关注 关于包囊挛缩、乳房植入体疾病（BII）和乳房 植入物相关性间变性大细胞淋巴瘤（BIA-ALCL）促使许多患者寻求其他选择。 组织瓣手术有效地将大块脂肪输送到缺损处;然而，这些手术是不可行的。 复杂、昂贵，并且不是所有患者都能广泛使用。成功组织瓣的远期疗效 是有利的，但与时间，金钱，身体疤痕和努力的重大投资有关。第三种选择 是自体脂肪，也可以作为移植物转移，仅使用吸脂和小注射套管， 门诊手术尽管有潜力，但许多外科医生在使用脂肪时感到能力有限 移植物：（1）用吸脂术收获脂肪破坏其结构基质，导致不成形的浆液，以及（2） 许多病人根本没有足够的脂肪可以捐献。迄今为止，使用脂肪的技术和外科障碍 用于确定性乳房再造的移植尚未解决。虽然已经尝试改进 通过将组织与合成聚合物或脱细胞组织结合来提高移植成功率，这些尝试 由于缺乏固有的生物活性、高成本或长的处理时间，显示出最小的成功。重组 蛋白质聚合物是一种未开发但有前途的替代品， 基质蛋白质可以高产率合成，并在分子水平上控制其性质。出于这一 明确的临床需求，该提案旨在推进最近开发的创新药物的商业化， 生物基质-Fractomer。Fractomers是一种人造蛋白质，旨在模拟可以共同注射的软组织 与脂肪一起扩大体积，增加长期稳定性，并通过允许组织向内生长来改善脂肪形状， 血管形成第一阶段计划的重点是Fractomer与脂肪抽吸物的相互作用，以确定 生物力学和热响应特性理想地适合于组织修复基质。体内研究 证实了Fractomer促进与修复相关的细胞浸润和血管化的能力， 重塑，而不是瘢痕形成和纤维化。最后，在小鼠侧腹脂肪移植模型中，Fractomer 使脂肪移植物的形状、定位和结构能够保持长达三个月。在第二阶段，我们将 通过以下方式继续Fractomer的商业开发：1）规模化生产; 2）完成必要的 FDA要求的试验用器械豁免状态的生物相容性和毒性研究， 临床试验;和3）在乳房脂肪垫修复的猪模型中测试材料的安全性和有效性。