The Interplay Between Stiffness and Hyperglycemia on Diabetic Foot Ulcer Wound Closure

Introduction: Diabetic foot ulcers are open wounds with impaired wound closure at the bottom of the foot. Although diabetic plantar skin is stiffer, which should enhance fibroblast mechanotransduction, fibroblasts still fail to migrate effectively. This suggests impaired wound closure is driven by another factor; hyperglycemia (≥11.1 mM glucose), which alters fibroblast mechanotransduction. Purpose: To mimic diabetic foot ulcers by developing a 2D circular in vitro wound closure model system to investigate fibroblast mechanoresponses under diabetic plantar skin stiffness and hyperglycemia. Methods: Polydimethylsiloxane was used as a substrate, fabricated at 57 kPa and 90 kPa for normal and diabetic plantar skin stiffnesses, respectively. Cell culture media contained a 5.5 mM glucose concentration simulating normal blood glucose or an altered 11.1 mM glucose concentration simulating hyperglycemia. Results: Time-lapse fluorescent imaging of wound assays reveals a restrictive effect of higher stiffness on migrating fibroblasts under normal glucose conditions, and a biphasic response to hyperglycemic conditions. Fibroblasts migrating on softer substrates mimicking normal plantar skin stiffness and under hyperglycemia have decreased velocity as predicted. Whereas cells migrating on stiffer substrates mimicking diabetic plantar skin stiffness and under hyperglycemia demonstrate increased cell velocity, overcoming the higher stiffness's restrictive effect. Despite faster cell velocities on higher stiffness, wounds under normal glucose conditions still close faster than those under hyperglycemic conditions. Conclusion: This research establishes a wound closure model demonstrating significantly slower wound closure in diabetic plantar skin with higher stiffness and hyperglycemic glucose levels compared to normal plantar skin with softer stiffness and normal glucose levels. Supplementary Information: The online version of this article (10.1007/s12195-025-00877-8) contains supplementary material, which is available to authorized users.