Biostimulatory nanofiber-hydrogel composite for soft tissue remodeling

项目总结 颅面软组织的修复是重建外科的一大挑战。软组织损失由 先天性面部差异、肿瘤切除、创伤和炎症性疾病影响着数百万患者 每年。目前面部软组织缺失的解决方案--包括自体和基于假体的--受到 严重的局限性。自体解决方案，如组织瓣和脂肪转移，受到供体部位缺陷的阻碍 以及不可预测的生存，往往需要反复手术才能实现充分的恢复。相反， 假体溶液，如水凝胶填充物或聚酯植入物，受到有限的体积和持续时间的困扰 分别由纤维化、器械暴露和感染引起。迫切需要一种经过精心设计的 现成的解决方案，可立即恢复丢失的软组织体积，同时鼓励天然软组织 随着时间的推移而发展和重塑。这样一种创造良好整合的、血管化的软组织的方法 将大大减轻头面部患者的护理负担。我们最近创造了一种生物刺激器 纳米纤维-水凝胶复合材料(NHC)，由化学定义的聚酯纳米纤维和透明质酸组成 (HA)水凝胶成分，能够诱导宿主细胞渗透，促进组织再生 反应，注射部位血管软组织的进行性重塑。我们的长期目标是 NHC联合患者自身细胞作为颅面软组织再生细胞疗法的实验研究 缺陷。这项拟议研究的总体目标是设计具有高生物刺激活性的NHC 与同种异体细胞结合，并定义软组织的材料特性和细胞反应 在基因上易处理的和已建立的翻译模型中的重塑。在具体目标1中，我们将设计 优化的纳米纤维-水凝胶复合材料(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，并确定它们的结构-功能关系。在具体目标2中，我们将 检测成脂前体细胞对宿主细胞渗透和调节的增强作用， 血管生成和软组织重塑，当与生物刺激NHC联合传递时。在具体目标3中，我们将 在更大体积的临床前模型中展示软组织重塑能力 生物刺激NHC和脂肪前体细胞的组合。这项研究将产生一系列新的现成 支架生物刺激NHC基质能够重塑成血管化软组织，阐明衬里 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的机制，以及 提供对未来临床应用的见解。生物材料和自体细胞入路在颅面部的应用 软组织修复有望显著改善临床结果--将发病率降至最低，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.