Biostimulatory nanofiber-hydrogel composite for soft tissue remodeling

项目摘要 颅颌面软组织的修复是颅颌面重建外科面临的一个重大挑战。软组织损失， 先天性面部差异、肿瘤切除术、创伤和炎性疾病影响着数百万患者 每年.目前面部软组织损失的解决方案-自体的和基于假体的-遭受 严重的局限性。自体移植的解决方案，如组织瓣和脂肪移植，受到供体部位缺陷的阻碍 和不可预测的生存，往往需要重复的操作，以实现充分的恢复。相比之下， 假体溶液如水凝胶填充物或聚酯植入物受到有限体积和持续时间的困扰， 修复，和纤维化，设备暴露，和感染。迫切需要一种经过设计的， 现成的解决方案，可立即恢复缺失的软组织体积，同时促进自然软组织 随着时间的推移而发展和重塑。这种方法可以创造出完整的血管化软组织 将大大减轻颅面患者的护理负担。我们最近发明了一种生物刺激 纳米纤维-水凝胶复合材料（NHC），由化学定义的聚酯纤维和透明质酸组成 (HA)水凝胶组分，其能够诱导宿主细胞浸润、组织的促再生调节 反应，以及注射部位逐渐重塑为血管化软组织。我们的长期目标是 将NHC与患者自身细胞结合使用，作为颅面软组织的再生细胞疗法 缺陷这项研究的总体目标是设计具有高生物刺激活性的NHC 与同种异体细胞相结合，并定义了控制软组织的材料特性和细胞反应 在遗传上易处理的和已建立的翻译模型中重塑。在具体目标1中，我们将设计 优化的纳米纤维-水凝胶复合物（NHC）作为生物刺激基质以促进免疫调节， 血管生成和组织重塑，并定义它们的结构-功能关系。在第二阶段，我们将 检查成脂祖细胞对宿主细胞浸润和调节的增强作用， 血管生成和软组织重塑。在具体目标3中，我们 在兔的较大体积临床前模型中使用优化的 生物刺激性NHC和脂肪祖细胞的组合。这项研究将产生一个新的系列的小康- 货架生物刺激NHC基质能够重塑成血管化的软组织，阐明了强调 通过定义生物材料、自体细胞和宿主组织反应之间的相互作用， 提供对未来临床实用性的见解。颅颌面部的生物材料和自体细胞移植 软组织修复有望显著改善临床结果-最小化发病率，降低成本， 以及扩大治疗的可及性。

PROJECT SUMMARY Restoration of craniofacial soft tissues is a major challenge in reconstructive surgery. Soft tissue losses from congenital facial differences, oncologic resection, trauma, and inflammatory diseases affect millions of patients each year. Current solutions to facial soft tissue losses – both autologous and prosthetic-based – suffer from serious limitations. Autologous solutions such as tissue flaps and lipotransfer are hampered by donor site defects and unpredictable survival, often necessitating repeated operations to achieve adequate restoration. By contrast, prosthetic solutions such as hydrogel fillers or polyester implants are plagued by limited volume and duration of restoration, and by fibrosis, device exposure, and infection respectively. There is a critical need for an engineered, off-the-shelf solution that immediately restores missing soft tissue volume while encouraging natural soft tissue development and remodeling over time. Such an approach to creating well integrated, vascularized soft tissue would greatly decrease the burden of care for craniofacial patients. We recently created a biostimulatory nanofiber-hydrogel composite (NHC), comprised of chemically defined polyester nanofiber and hyaluronic acid (HA) hydrogel components, that is capable of inducing host cell infiltration, pro-regenerative conditioning of tissue responses, and progressive remodeling of the injection site into vascularized soft tissue. Our long-term goal is to use NHC in conjunction with the patient’s own cells as a regenerative cell therapy for craniofacial soft tissue defects. The overall objective for this proposed study is to engineer NHC with high biostimulatory activity coupled with allogeneic cells and define the materials properties and cellular responses governing soft tissue remodeling in genetically tractable and established translational models. In Specific Aim 1, we will engineer optimized nanofiber-hydrogel composites (NHC) as biostimulatory matrices to promote immunomodulation, angiogenesis, and tissue remodeling and define their structure-function relationships. In Specific Aim 2, we will examine the potentiation effects of adipogenic progenitor cells on host cell infiltration and conditioning, angiogenesis, and soft tissue remodeling when co-delivered with biostimulatory NHC. In Specific Aim 3, we will demonstrate soft tissue remodeling capacity in a larger volume preclinical model in rabbits using an optimized combination of biostimulatory NHC and adipose progenitor cells. This study will yield a new series of off-the- shelf biostimulatory NHC matrices capable of remodeling into vascularized soft tissue, elucidate the underlining mechanisms by defining the interplay between biomaterials, autologous cells, and host tissue responses, and offer insights into future clinical utility. The proposed biomaterials and autologous cell approach to craniofacial soft tissue restoration promises to significantly improve clinical outcomes – minimizing morbidity, reducing cost, and expanding accessibility to treatment.