(622f) Temporal Delivery of Polypeptide Nanoparticles for Accelerated Wound Healing and Tissue Repair

Complexity of repair process, low potency of monotherapies and delivery challenges limit the effectiveness of current wound healing treatment strategies, particularly in chronic and diabetic wounds. Growth factors, engineered cells and skin grafts have been investigated for promoting wound healing. However, little attention has been given to the critical role of augmenting early-stage processes in order to set the stage for effective execution of subsequent proliferation and remodeling phases of tissue repair. Here, we demonstrate that temporal delivery of a combination of bioactives that modulate and augment individual phases of healing leads to improved healing outcomes compared to sequential delivery. Histamine, a small-molecule chemoattractant of cells that mediate early stages of tissue repair, was delivered to full-thickness 5 mm excisional splinted wounds in the dorsal skin of immunocompetent BALB/c mice and genetically obese and diabetic db/db mice. Delivery of histamine along with silk fibroin dressing resulted in effective wound closure and improved healed skin strength in both Balb/c and db/db mice compared to Tegaderm dressing alone. Histological and immunohistochemistry analyses showed silk dressing-histamine treatment reduced dermal gap, promoted angiogenesis (CD31+), myofibroblast-mediated wound contraction (aSMA+), and higher TGF-β1 expression which are hallmarks of improved healing outcomes. Growth factors play key roles in different stages of tissue repair, especially in later stages i.e. proliferation, but their availability is limited due to dysfunctional healing response and proteolytic degradation in case of chronic wounds. We have used recombinant methods to generate growth factor nanoparticles (GFNPs) based on a growth factor-elastin-like polypeptide (GF-ELPs) fusion platform. Nanoparticles of basic fibroblast growth factor (bFGF-ELP) and stromal-derived growth factor 1 (SDF1-ELP), with hydrodynamic diameters from 300-400 nm, demonstrated higher stability and bioavailability in wound fluid compared to growth factors alone. Temporally sequential delivery of SDF1-ELP or bFGF-ELP nanoparticles immediately prior to the transition phase following histamine delivery resulted in improved biomechanical and biochemical outcomes of tissue repair compared to simultaneous delivery or individual treatments acting alone. These findings demonstrate that multifactor therapeutics (silk fibroin dressing, exogenous histamine, and GFNPs) are promising for improved outcomes in wound healing and tissue repair, including in diabetic and obese mice, and outperform clinically approved polyurethane wound dressing. A fundamental understanding of tissue repair kinetics and associated temporal delivery of therapeutics can lead to faster healing and improved tissue repair outcomes, thus reducing the propensity for re-opening, progression to intractable phenotypes and surgical site infections, all of which can have remarkable outcomes in the clinic.