Clinical Vascular Tissue Engineering Under GMP Conditions

Abstract

Tissue-engineered products intended for clinical use are classified as medicinal products under European Union (EU) regulations and must therefore be manufactured in compliance with Good Manufacturing Practice (GMP). GMP is a highly rigorous framework that impacts all stages of production. Following a successful clinical program of in vitro endothelialization of vascular grafts for peripheral vascular reconstruction—conducted over 35 years and involving 442 patients—we demonstrated that endothelialized grafts implanted in femoro-popliteal and femoro-crural positions significantly improve long-term patency rates compared to non-endothelialized grafts. After the implementation of updated EU regulations, a dedicated GMP facility was established. After obtaining GMP certification for our in-hospital facility, production of autologous endothelialized grafts resumed in September 2020. Patients with peripheral arterial disease lacking suitable autologous saphenous veins for surgical reconstruction were eligible for treatment with endothelialized grafts. The endothelialization process comprises two stages: first, a short segment of subcutaneous vein is harvested from the patient to establish endothelial cell cultures. These cultures are expanded to produce sufficient cell quantities, which are then seeded confluently onto fibrin matrix-coated expanded polytetrafluoroethylene (ePTFE) grafts prior to implantation. A total of 82 patients received GMP-compliant endothelialized grafts, implanted in the femoro-popliteal (n=69) or femoro-crural (n=13) positions. In 43% of cases, the grafts were used in re-do procedures. Primary patency rates were 92% at 1 year, 87% at 2 years, and 84% at 3 years. Manufacturing tissue-engineered products under GMP conditions for clinical application is challenging but achievable. The clinical outcomes from our previous long-term endothelialization program were successfully replicated. Additionally, we have recently initiated the production of matrix-associated chondrocyte transplantation (MACT) products for cartilage and bone reconstruction.