Biostimulatory nanofiber-hydrogel composite for soft tissue remodeling

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.