Subcutaneous Surgical Rat Models for the Evaluation of Tissue-Engineered Heart Valve Immunogenicity: A Systematic Review

Background: Tissue engineered heart valves are being designed as alternative valvular conduits to standard bioprostheses with the potential to meet the requirements of an ideal valvular prosthesis: non-thrombogenicity, non-immunogenicity, long-lasting, and capability of growth, repair, and remodelling upon implantation. Assessments of immunogenicity are required before in vivo testing in large animals may be undertaken. Rats are a cost-effective model that are widely used for such assessments. However, it is unclear whether the surgical rat models used for examining tissue immunogenicity are homogenous in their design. Methods: Systematic searches were conducted in the PubMed, Scopus, and Web of Science databases for articles in which the immunogenicity of tissue engineered heart valves was examined using subcutaneous surgical rat models. Assessments were made of the animal, surgical, and donor scaffold characteristics used in such models. The heterogeneity of the various characteristics was then evaluated qualitatively. Results: In total, 54 articles were qualitatively assessed in this systematic review. The donor scaffold characteristics were homogenous. Whereas, the animal and surgical characteristics were heterogenous and infrequently reported. The collective data suggest that an agreed subcutaneous rat model might consist of implanting four, 1 cm2, tissue engineered heart valve samples in the dorsal aspect of 6-week-old, Sprague Dawley, rats. Conclusions: Rat subcutaneous implantation may be undertaken to assess the immunogenicity of tissue engineered heart valves before proceeding to in vivo studies in large animal models. There is significant heterogeneity in the characteristics of the subcutaneous rat models that have been used, to date. Most studies insufficiently report the techniques used. Funding Information: This work was supported by funding gratefully received from the Green Lane Research and Education Fund (Greenlane Research and Education Fund, Grafton, Auckland, New Zealand), and the National Heart Foundation of New Zealand (National Heart Foundation of New Zealand, Ellerslie, Auckland, New Zealand). S.W. received a postgraduate scholarship from the National Heart Foundation of New Zealand, M.G. received and Green Lane Research and Education Fund Postgraduate Scholarship, and C.A. received a University of Auckland summer research scholarship. Declaration of Interests: The authors declare that they have no conflicts of interest related to this work.