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.

Purpose Sheep are the standard preclinical model for assessing safety of novel replacement heart valves, yet the anatomic and pathologic effects of invasive surgery, including those involving cardiopulmonary bypass (CPB), are unknown. Thus, we aimed to determine the gross, hematologic and biochemical effects of sham mitral and aortic replacement valve procedures in sheep to establish a useful control for evaluation of novel replacement valves. Methods Six control sheep were examined without any surgical intervention. Six sham mitral valve replacements (MVR) and six sham aortic valve replacements (AVR) were performed on 12 sheep. Complete blood counts and serum biochemistry were performed throughout the study. Sheep were sacrificed with a necropsy performed at 90 days. Results Renal infarcts (RIs) were the most frequently observed lesion, averaging 4.7 in control sheep, 2.5 with MVR and 5.8 with AVR. The number of infarcts strongly correlated with total estimated area of infarcted kidney (r = .84, p < .01). Additional cardiac interventions were significantly correlated with increased numbers of RIs (r = .85, p < .01). There was no correlation between number of RIs and time on CPB, or between AVR and MVR procedures. Conclusion The sheep model for AVR and MVR requires invasive surgery and CPB, which are associated with background anatomic and pathologic changes, especially in cases with additional surgical cardiac interventions. These findings serve as a critical control for future evaluation and development of novel replacement valves in order to distinguish device-related safety issues from expected outcomes of the surgical procedure and normal background changes in sheep.

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