Systems-based approaches toward wound healing.

Wound healing in the pediatric patient is of utmost clinical and social importance because hypertrophic scarring can have aesthetic and psychological sequelae, from early childhood to late adolescence. Wound healing is a well-orchestrated reparative response affecting the damaged tissue at the cellular, tissue, organ, and system scales. Although tremendous progress has been made toward understanding wound healing at the individual temporal and spatial scales, its effects across the scales remain severely understudied and poorly understood. Here, we discuss the critical need for systems-based computational modeling of wound healing across the scales, from short-term to long-term and from small to large. We illustrate the state of the art in systems modeling by means of three key signaling mechanisms: oxygen tension-regulating angiogenesis and revascularization; transforming growth factor-β (TGF-β) kinetics controlling collagen deposition; and mechanical stretch stimulating cellular mitosis and extracellular matrix (ECM) remodeling. The complex network of biochemical and biomechanical signaling mechanisms and the multiscale character of the healing process make systems modeling an integral tool in exploring personalized strategies for wound repair. A better mechanistic understanding of wound healing in the pediatric patient could open new avenues in treating children with skin disorders such as birth defects, skin cancer, wounds, and burn injuries.