Toward Developing Immunocompetent Diabetic Foot Ulcer-on-a-Chip Models for Drug Testing

Bioengineering of skin has been significantly explored, ranging from the use of traditional cell culture systems to the most recent organ-on-a-chip (OoC) technology that permits skin modeling on physiological scales among other benefits. This article presents key considerations for developing physiologically relevant immunocompetent diabetic foot ulcer (DFU) models. Diabetic foot ulceration affects hundreds of millions of individuals globally, especially the elderly, and constitutes a major socioeconomic burden. When DFUs are not treated and managed in a timely manner, 15-50% of patients tend to undergo partial or complete amputation of the affected limb. Consequently, at least 40% of such patients die within 5 years postamputation. Currently, therapeutic strategies are actively sought and developed. However, present-day preclinical platforms (animals and in vitro models) are not robust enough to provide reliable data for clinical trials. Insights from published works on immunocompetent skin-on-a-chip models and bioengineering considerations, presented in this article, can inform researchers on how to develop robust OoC models for testing topical therapies such as growth factor-based therapies for DFUs. We propose that immunocompetent DFU-on-a-chip models should be bioengineered using diseased cells derived from individuals; in particular, the pathophysiological contribution of macrophages in diabetic wound healing, along with the typical fibroblasts and keratinocytes, needs to be recapitulated. The ideal model should consist of the following components: diseased cells embedded in reproducible scaffolds, which permit endogenous "diseased" extracellular matrix deposition, and the integration of the derived immunocompetent DFU model onto a microfluidic platform. The proposed DFU platforms will eventually facilitate reliable and robust drug testing of wound healing therapeutics, coupled with reduced clinical trial failure rates. Impact statement Current animal and cell-based systems are not physiologically relevant enough to retrieve reliable results for clinical translation of diabetic foot ulcer (DFU) therapies. Organ-on-a-chip (OoC) technology offers desirable features that could finally enable the vision of modeling DFU for pathophysiological studies and drug testing at a microscale. This article brings together the significant recent findings relevant to developing a minimally functional immunocompetent DFU-on-a-chip model, as wound healing cannot occur without a proper functioning immune response. It looks feasible in the future to recapitulate the stagnant inflammation in DFU (thought to impede wound healing) using OoC, diseased cells, and an endogenously produced extracellular matrix.