PFI-TT: Injectable Cellulose-Based Hydrogels for Soft Tissue Bulking

这项创新-技术转化伙伴关系（PFI-TT）项目的更广泛影响/商业潜力在于，它可能导致可注射的植物基材料的开发，以取代因疾病（即癌症）、创伤或遗传性先天缺陷而丢失的人体软组织。几种天然和合成材料已在临床上用于长期组织替代，但它们都有局限性，包括成本、安全性、效果持续时间以及在发生并发症时缺乏可逆性。在美国，每年有超过43万例组织置换手术，包括商业上可获得的半永久性填充物和脂肪移植，费用超过3.95亿美元，但结果往往不尽如人意。目前的应用旨在从植物中发现的天然糖中设计出一种稳定的、可逆的、可注射的软组织填充材料。该项目的成功完成将产生宝贵的概念验证数据，在人体试验之前，在小型动物模型中证明这些植物源性生物材料的安全性和有效性。因此，拟议的研究有可能改善患有各种需要安全和稳定的组织填充材料的疾病的个人的生活质量。该计划的重点是翻译一种新的可注射生物材料，该材料来源于植物多糖，纤维素，用于人类的长期软组织重建。衰老、创伤和疾病常常导致真皮胶原蛋白和脂肪的流失，造成软组织的缺陷。因此，有必要开发能够安全有效地恢复枯竭地区的材料。甲基纤维素（MC）是一种经fda批准的水溶性纤维素衍生物，具有生物相容性和价格低廉。与其他易受酶活性影响的天然生物材料填充物相比，人体内缺乏纤维素消化酶（纤维素酶），可以改善MC在体内的保留和机械稳定性。本研究将在小动物软组织缺损模型中研究原位胶凝MC水凝胶的长期稳定性，这种水凝胶由双热胶凝和氧化还原引发的交联机制稳定。研究设计还将探索使用纤维素酶来安全、容易地降解MC凝胶，以纠正不良后果。在不需要手术切除的情况下移除可注射的长期植入物将对临床翻译非常有益；此外，证明可逆性将在这个市场空间中提供明显的优势。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this Partnerships for Innovation - Technology Translation (PFI-TT) project is that it may lead to the development of injectable, plant-based materials to replace human soft tissues lost due to disease (i.e., cancer), trauma, or inherited birth defects. Several natural and synthetic materials have been used clinically for long-term tissue replacement, but all have limitations, which include cost, safety, duration of effect, and lack of reversibility in the event of complications. Over 430,000 tissue replacement procedures are performed in the United States annually involving commercially available semi-permanent fillers and fat grafts at a cost of over $395 million, often with unsatisfactory results. The present application aims to engineer a stable, yet reversible, injectable, soft tissue filler material from the natural sugars found in plants. Successful completion of the project will result in valuable proof-of-concept data demonstrating the safety and efficacy of these plant-derived biomaterials in a small animal model, in advance of human trials. As such, the proposed studies have the potential to improve the quality of life for individuals suffering from a variety of conditions requiring safe and stable tissue bulking materials.The proposed project focuses on translating a novel injectable biomaterial derived from the plant polysaccharide, cellulose, for long-term soft tissue reconstruction in humans. Aging, trauma, and disease often result in the loss of dermal collagen and fat, producing a deficit in the soft tissue. As a result, there is the need to develop materials that safely and effectively restore areas of depletion. Methylcellulose (MC) is an FDA-approved, water-soluble, cellulose derivative that is biocompatible and inexpensive. The absence of the cellulose-digesting enzyme, cellulase, in humans affords improved retention and mechanical stability of MC in vivo, in comparison to other natural biomaterial fillers that are susceptible to enzymatic activity. This proposal will examine the long-term stability of in situ gelling MC hydrogels stabilized by dual thermal gelation and redox-initiated crosslinking mechanisms in a small animal soft tissue deficit model. The study design will also explore the use of cellulase administration to safely and easily degrade the MC gels to correct for adverse outcomes. Removal of injectable long-term implants without the need for surgical excision would be highly beneficial for clinical translation; Moreover, demonstration of reversibility will provide a distinct advantage over competitors in this market space.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.