Acellular Biologic Scaffolds in Regenerative Medicine: Unacceptable Variability with Acceptable Results

Abstract: The innovation of regenerative medicine in health care is matched only by the challenges in regulating such products to ensure safety and efficacy for patients. The variability that is inherent within each step of product development, including the fidelity of basic science test methods, the relevance of preclinical models, the often-non-traditional manufacturing methods, the clinical trials, and the variability that exists within the composition of the products themselves, are unavoidable when attempting to create complex tissues and organs from biologic components that, by design, have variability as a constructive and positive attribute. Nonetheless, the control of variability has long been considered a requirement for product quality and consistency. Herein is a discussion regarding the regulation of regenerative medicine products and examples of products, especially biologic scaffold materials, that have unacceptable variability by current standards but are associated with more-than-acceptable clinical outcomes. Future considerations are suggested for the regulation of regenerative medicine products to allow for and incentivize creativity, innovation, and the commercialization of heretofore unrealized regenerative medicine solutions for unmet medical needs while also assuring safety. Lay Summary: Surgical mesh and topical wound care products composed of extracellular matrix (ECM) are safe and effective. However, by their very nature, the composition of ECM products is more variable than synthetic materials, and the methods of preparation vary markedly from one product to the next. Further, the mechanism(s) by which ECM influences the host response to affect clinical outcomes is multimodal and only partially understood. The conundrum of acceptable clinical results in the face of typically unacceptable variability in raw material composition and biologic activity presents regulatory challenges. There is a need to reevaluate the suitability of existing guidelines for regulation of ECM-based products.