The Use of Therapeutic Peptides in Combination with Full-Thickness Skin Columns to Improve Healing of Excisional Wounds

Split-thickness skin grafting (STSG) is the standard of care for skin replacement therapy. While STSG is a well-established technique, it has several limitations at both the donor and recipient sites. Full-thickness skin column (FTSC) grafting is an alternative approach that involves the orthogonal harvesting of small skin columns containing the epidermis, dermis, and associated skin appendages. Peptides have been shown to promote wound repair through various reparative and regenerative mechanisms. In this study, we aimed to evaluate the extent to which FTSCs and the matrix-derived peptide TSN6, individually or in combination, influenced the rate and quality of healing, as assessed by metrics such as epithelialization, epithelial thickness, and the presence of adnexal structures. TSN6 peptide and its scrambled form was synthetized in a laboratory and mixed with a carboxymethylcellulose (CMC) hydrogel. Up to 16 standardized full-thickness excisional wounds (∅ 5 cm) were created on the dorsum of two anesthetized pigs. FTSC biopsies (∅ 1.5 mm) were harvested from donor sites located on the rump of the pig at a ratio of up to eight 1.5 mm-diameter skin columns/1 cm2. Subsequently, the wounds were randomized to receive either (1) FTSC + TSN6, (2) FTSC + scrambled peptide, (3) FTSC alone, and (4) blank CMC hydrogel. Healing was monitored for 14 or 28 days. After euthanasia, the wounds were excised and processed for histology. Additionally, non-invasive imaging systems were utilized to assess wound healing. By day 14, wounds treated with FTSC or FTSC + TSN6 were significantly more re-epithelialized compared to those treated with blank CMC hydrogel. By day 28, all FTSC-transplanted wounds were fully re-epithelialized. Notably, wounds treated with FTSC + TSN6 exhibited improved healing quality, characterized by a thicker neo-epidermis and increased rete ridges at day 28 post-transplantation. All FTSC-transplanted wounds healed better than the untransplanted controls. The TSN6 peptide further improved healing quality when applied in combination with FTSCs, particularly by enhancing epidermal maturation.