Biodegradable Poly(<scp>d</scp>,<scp>l</scp>-lactide-<i>co</i>-ε-caprolactone) Electrospun Scaffolds Outperform Antifibrotic-Loaded Meshes in an <i>in Vivo</i> Tissue Regeneration Model

Wound healing is a complex and dynamic process of replacing missing cellular structures and tissue layers. Clinical practice includes the application of a sterile bandage to promote healing and to restrain infection, like the commercial nonbiodegradable meshes. However, while inert, nontoxic, and nonimmunogenic, they can cause calcification, fibrosis, and inflammation, potentially hindering the healing process in the long term. To address this challenge and enhance wound healing, we developed a totally biodegradable electrospun poly(d,l-lactide-<i>co</i>-ε-caprolactone) (PDLLCL) drug delivery system that incorporates two already FDA-approved antifibrotics, pirfenidone (PIRF) and triamcinolone acetonide (TA). The PDLLCL meshes, fabricated via electrospinning, exhibited homogeneity and complete degradation after 120 days, consistent with the wound healing process. <i>In vitro</i>, functional analysis on RAW 264.7 macrophages revealed no cytotoxicity and an immunomodulatory effect of PIRF and TA compared with the positive control (lipopolysaccharides, LPS) and the PDLLCL meshes alone. Lastly, subcutaneous <i>in vivo</i> assessment on a rabbit model, following the ISO 10993-6 standard, showed that our tailored made PDLLCL meshes were able to lower both irritation and fibrosis indexes from 2 weeks to 4 weeks of implantation, highlighting the beneficial effect of biodegradable polymers. However, we saw no significant positive effect on the incorporation of antifibrotics <i>in vivo</i> for irritation and fibrosis indexes. This underscores the potential of PDLLCL meshes as a possible alternative for wound healing, reducing the use of intermittent antifibrotic agents during the healing process.