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.