Individualized tissue‐engineered veins as vascular grafts: A proof of concept study in pig

Abstract

Personalized tissue engineered vascular grafts are a promising advanced therapy medicinal product alternative to autologous or synthetic vascular grafts utilized in blood vessel bypass or replacement surgery. We hypothesized that an individualized tissue engineered vein (P‐TEV) would make the body recognize the transplanted blood vessel as autologous, decrease the risk of rejection and thereby avoid lifelong treatment with immune suppressant medication as is standard with allogenic organ transplantation. To individualize blood vessels, we decellularized vena cava from six deceased donor pigs and tested them for cellular removal and histological integrity. A solution with peripheral blood from the recipient pigs was used for individualized reconditioning in a perfusion bioreactor for seven days prior to transplantation. To evaluate safety and functionality of the individualized vascular graft in vivo, we transplanted reconditioned porcine vena cava into six pigs and analyzed histology and patency of the graft at different time points, with three pigs at the final endpoint 4–5 weeks after surgery. Our results showed that the P‐TEV was fully patent in all animals, did not induce any occlusion or stenosis formation and we did not find any signs of rejection. The P‐TEV showed rapid recellularization in vivo with the luminal surface covered with endothelial cells. In summary, the results indicate that P‐TEV is functional and have potential for use as clinical transplant grafts.

Personalized tissue-engineered arteries as vascular graft transplants: A safety study in sheep

“…Tissue engineering, as a part of regenerative medicine, has great potential to cater the patients in need of reconstructive surgery and organ transplantation. As a model for this field, we recently showed that personalized tissue engineered veins could be transplanted to vena cava in a porcine model with efficient recellularization and full patency after one month [ 14 ]. On the artery side of vascular surgery, there is a great need of small-diameter blood vessels since the available grafts on the market suffer from problems with patency and infections [ 30 , [40] , [41] , [42] ].…”

“…We have previously shown with ROTEM analysis that our reconditioned vascular grafts have better hemocompatibility with reduced activation of the intrinsic coagulation pathway, increased clotting and clot formation time and decreased alpha angle compared with native and decellularized scaffolds [ 14 ]. Recellularization of the personalized veins grafts, produced with the same procedure, starts as early as three days after transplantation and is very efficient to repopulate the tissue already two weeks post-surgery [ 14 ]. After 4 months in vivo , personalized tissue engineered arteries showed recellularization of the deeper layers of the vascular grafts ( Fig.…”

“…Reconditioning of artery scaffolds were performed as previously described [ 14 ]. Briefly, decellularized arteries were connected to a reconditioning bioreactor and perfused with PBS + AA for 24 and 1 h with 50 IU/mL heparin (Leo Pharma) in PBS + 0,5 × AA.…”

“…Perfusion of functional organs with whole blood or blood-derived solutions preceding transplantation has been shown favorable for maintaining organ physiology and functionality [ 12 , 39 ]. We have previously shown that reconditioned tissue engineered veins, perfused with the recipient’s own peripheral blood after decellularization, were safe and functional with efficient recellularization in vivo and full patency in a pig model of vena cava transplantation over one month [ 14 ]. The rationale for this method is that autologous blood components from the recipient can attach to the surface of the decellularized scaffold to mask exposed extracellular matrix to make the graft more autologous and thereby prime for exposure to the blood stream and prevent rejection and thrombotic events and facilitate rapid cellularization in vivo after transplantation.…”

Uterus bioengineering as a future alternative to uterus transplantation

“…With modifications, these and other perfusion systems specifically developed for ex vivo pig, sheep and human uterus perfusion [62][63][64][65], will likely prove to be of significant value for future whole uterus recellularization protocols. During this extended in vitro recellularization time, multiple cell types will need to be applied in sequence, including endothelial cells for the vasculature reconstruction [66,67].…”