Collagen-Binding Peptidoglycans Inhibit MMP Mediated Collagen Degradation and Reduce Dermal Scarring

Scarring of the skin is a large unmet clinical problem that is of high patient concern and impact. Wound healing is complex and involves numerous pathways that are highly orchestrated, leaving the skin sealed, but with abnormal organization and composition of tissue components, namely collagen and proteoglycans, that are then remodeled over time. To improve healing and reduce or eliminate scarring, more rapid restoration of healthy tissue composition and organization offers a unique approach for development of new therapeutics. A synthetic collagen-binding peptidoglycan has been developed that inhibits matrix metalloproteinase-1 and 13 (MMP-1 and MMP-13) mediated collagen degradation. We investigated the synthetic peptidoglycan in a rat incisional model in which a single dose was delivered in a hyaluronic acid (HA) vehicle at the time of surgery prior to wound closure. The peptidoglycan treatment resulted in a significant reduction in scar tissue at 21 days as measured by histology and visual analysis. Improved collagen architecture of the treated wounds was demonstrated by increased tensile strength and transmission electron microscopy (TEM) analysis of collagen fibril diameters compared to untreated and HA controls. The peptidoglycan's mechanism of action includes masking existing collagen and inhibiting MMP-mediated collagen degradation while modulating collagen organization. The peptidoglycan can be synthesized at low cost with unique design control, and together with demonstrated preclinical efficacy in reducing scarring, warrants further investigation for dermal wound healing

Prevention of Collagen-Induced Platelet Binding and Activation by Thermosensitive Nanoparticles

Peripheral artery disease is an atherosclerotic occlusion in the peripheral vasculature that is typically treated via percutaneous transluminal angioplasty. Unfortunately, deployment of the angioplasty balloon damages the endothelial layer, exposing the underlying collagen and allowing for the binding and activation of circulating platelets, which initiate an inflammatory cascade leading to eventual restenosis. Here, we report on the development of poly(NIPAm-MBA-AMPS-AAc) nanoparticles that have a collagen I-binding peptide crosslinked to their surface allowing them to bind to exposed collagen. Once bound, these particles mask the exposed collagen from circulating platelets, effectively reducing collagen-mediated platelet activation. Using collagen I-coated plates, we demonstrate that these particles are able to bind to collagen at concentrations above 0.5 mg/mL. Once bound, these particles inhibit collagen-mediated platelet activation by over 60%. Using light scattering and zeta potential measurements, we investigated the potential of the nanoparticles as a drug delivery platform. We have verified that the collagen-binding nanoparticles retain the temperature sensitivity common to poly(NIPAm)-based nanoparticles while remaining colloidally stable in aqueous environments. We also demonstrate that they are able to passively load and release anti-inflammatory cell penetrating peptides. Combined, we have developed a collagen-binding nanoparticle that has dual therapy potential, preventing collagen-mediated platelet activation while delivering water-soluble therapeutics directly to the damaged area