Development of a Cellular Assay as a Personalized Model for Testing Chronic Wound Therapeutics.

ABSTRACT

Exudates of nonhealing wounds contain drivers of pathogenicity. We utilized >800 exudates from nonhealing and healing wounds of diverse etiologies, collected by 3 different methods, to develop a wound-specific, cell-based functional biomarker assay. Human dermal fibroblast proliferation served as readout to (i) differentiate between healing and nonhealing wounds, (ii) follow the healing process of individual patients, and (iii) assess the effects of therapeutics for chronic wounds ex vivo. We observed a strong correlation between wound chronicity and inhibitory effects of individual exudates on fibroblast proliferation, with good diagnostic sensitivity (76-90%, depending on the sample collection method). Transition of a clinically nonhealing to a healing phenotype restored fibroblast proliferation and extracellular matrix formation while reducing inflammatory cytokine production. Transcriptional analysis of fibroblasts exposed to ex vivo nonhealing wound exudates revealed an induction of inflammatory cytokine and chemokine pathways and the unfolded protein response, indicating that these changes may contribute to the pathology of nonhealing wounds. Testing the wound therapeutics, PDGF and silver sulfadiazine, yielded responses in line with clinical experience and indicates the usefulness of the assay to search for and profile new therapeutics.