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Temporal Delivery Of Polypeptide Biomaterials For Accelerated Wound Healing And Tissue Repair
Deepanjan Ghosh1, Suneel Kumar2, Francois Berthiaume2, David J. DiCaudo3, Jacquelyn Kilbourne1, Kaushal Rege1.
1Arizona State University, Tempe, AZ, USA, 2Rutgers University, Piscataway, NJ, USA, 3Mayo Clinic, Scottsdale, AZ, USA.

BACKGROUND: Impairment of cutaneous wound healing is a common complication faced during diabetic mellitus and is a huge burden to the US healthcare system. Complexity of repair process, monotherapies and delivery challenges limit the effectiveness of current treatment strategies. Here, we demonstrate that temporal delivery of polypeptide biomaterials augments individual stages of wound repair and accelerates closure of acute and slow healing diabetic wounds.
METHODS: Single full-thickness 5 mm excisional splinted wounds were made on the dorsal skin surface to better mimic human wound healing mediated by granulation and not contraction of wound edges.
RESULTS: A combination of silk fibroin protein and soluble exogenous histamine, a vasoactive amine was more effective at wound closure in a splinted model compared to individual treatments and Tegaderm dressing in Balb/c and diabetic and obese db/db mice. 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. Kinetics of wound closure indicated the transition time from which the combination resulted in significantly higher efficacy compared to Tegaderm. Delivery of the second therapeutic polypeptide - growth factor nanoparticles (GFNPs) -one day before the transition from inflammation to proliferative phases resulted in further acceleration of wound closure. This sequential delivery of stromal-derived growth factor (SDF1) or basic fibroblast growth factor (bFGF) nanoparticles after silk+histamine treatment enhanced wound closure compared to the simultaneous treatment of the polypeptide treatments. In addition to wound closure, the ultimate tensile strength (UTS) of the healed tissue was also significantly higher for the combination compared to individual treatments, and the sequential treatment demonstrated the highest efficacy. In the case of diabetic wounds, GFNPs delivery in a sequential manner resulted in reepithelialization 2 days prior to control groups and also ~20% improvement in healed skin strength.
CONCLUSIONS: These findings demonstrate that multifactor therapies treatment (silk fibroin dressing, exogenous histamine, and GFNPs) is a promising treatment option for enhancing wound healing and that they outperform clinically approved polyurethane wound dressing.


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