This paper introduces the concept of “skin bed preparation” prior to surgical procedures. Following the theory of chronic wound bed preparation and adapting the skin model to one of chronic wound changes related to extrinsic and intrinsic factors, a topical formulation aimed at recycling the extracellular matrix (ECM) from accumulated waste products is evaluated and discussed. The clearance of these products and stimulation of new replacements has the potential to change the regenerative milieu of the skin so that when procedures are carried out, cellular signaling and cross-talk at the dermal level are improved and healing is optimized. By introducing a combination of peptides and other synergistic active agents, a sequence of clearance, regeneration, and remodeling is initiated. This is confirmed and validated by a series of biopsies and clinical studies that demonstrate changes in the ECM as early as 2 to 3 weeks after application. Clinical studies related to resurfacing procedures show accelerated healing and improved symptomatic relief compared with standard of care by preconditioning the skin 2 weeks prior to the procedure. A similar approach is suggested as a potential advantage for invasive surgical procedures based on similar scientific principles elucidated on in the text.