Skin‐Integrated Electrogenetic Regulation of Vasculature for Accelerated Wound Healing

Abstract Neo‐vascularization plays a key role in achieving long‐term viability of engineered cells contained in medical implants used in precision medicine. Moreover, strategies to promote neo‐vascularization around medical implants may also be useful to promote the healing of deep wounds. In this context, a biocompatible, electroconductive borophene–poly(ε‐caprolactone) (PCL) 3D platform is developed, which is called VOLT, to support designer cells engineered with a direct‐current (DC) voltage‐controlled gene circuit that drives secretion of vascular endothelial growth factor A (VEGFA). The VOLT platform consists of a 3D‐printed borophene‐PCL honeycomb‐shaped matrix decorated with borophene‐PCL nanofibers by electrospinning. The honeycomb structure provides mechanical stability, while the nanofibers facilitate the adhesion, migration, and proliferation of the engineered cells. The cells incorporate a DC‐powered reactive oxygen species (ROS)‐sensing gene circuit wired to an engineered synthetic promoter that triggers secretion of VEGFA to promote vascularization in the adjacent extracellular matrix. Cells engineered with this gene circuit and enclosed in the VOLT matrix, termed the VOLT_VEGFA system, can be simply triggered using off‐the‐shelf AA batteries, utilizing the established ability of a brief DC bias to generate non‐cytotoxic levels of ROS. For proof‐of‐concept, a subcutaneous wound‐healing model in rats is chosen. Electrostimulation of a VOLT_VEGFA implant (5 V, 20 s per day) induced secretion of VEGFA, and significantly accelerated neovascularization and granulation tissue formation, resulting in faster wound closure compared with non‐stimulated controls. Complete re‐epithelialization and dermal regeneration are observed within 15 days of application.