Preclinical Assessment of Cardiac Valve Substitutes: Current Status and Considerations for Engineered Tissue Heart Valves

Abstract

Tissue engineered heart valve (TEHV) technology may overcome deficiencies of existing available heart valve substitutes. The pathway by which TEHVs will undergo development and regulatory approval has several challenges. In this communication, we review: (1) the regulatory framework for regulation of medical devices in general and substitute heart valves in particular; (2) the special challenges of preclinical testing using animal models for TEHV, emphasizing the International Standards Organization (ISO) guidelines in document 5840; and (3) considerations that suggest a translational roadmap to move TEHV forward from pre-clinical to clinical studies and clinical implementation.

Keywords: animal models; heart valve substitutes; preclinical studies; regulatory pathway; tissue engineered heart valves; translation.

Figure 1

Roadmap of development to clinical use of TEHV, highlighting the pre-clinical study phase emphasized in this review (red box): Initial concept design followed by in vitro testing and in vivo animal studies, with potentially iterative preclinical testing and redesign steps as indicated (e.g., materials, design, animal model, etc.). Once a final design is reached, in vivo animal testing is conducted in the high quality Good Laboratory Practice (GLP) phase for submission to regulatory authorities, i.e., the FDA or European Notified Body for approval for clinical studies. Following this limited “first in human” study, “pivotal” clinical studies should commence with careful long term followup. If pivotal studies demonstrate satisfactory safety, performance and potential efficacy, the end product typically gains approval for marketing.