Perivascular Endothelial Implants Inhibit Intimal Hyperplasia in a Model of Arteriovenous Fistulae: A Safety and Efficacy Study in the Pig

Abstract

Vascular access complications are a major problem in hemodialysis patients. Native arteriovenous fistulae, historically the preferred mode of access, have a patency rate of only 60% at 1 year. The most common mode of failure is due to progressive stenosis at the anastomotic site. We have previously demonstrated that perivascular endothelial cell implants inhibit intimal thickening following acute balloon injury in pigs and now seek to determine if these implants provide a similar benefit in the chronic and more complex injury model of arteriovenous anastomoses. Side-to-side femoral artery-femoral vein anastomoses were created in 24 domestic swine and the toxicological, biological and immunological responses to allogeneic endothelial cell implants were investigated 3 days and 1 and 2 months postoperatively. The anastomoses were wrapped with polymer matrices containing confluent porcine aortic endothelial cells (PAE; n = 14) or control matrices without cells (n = 10). PAE implants significantly reduced intimal hyperplasia at the anastomotic sites compared to controls by 68% (p <0.05) at 2 months. The beneficial effects of the PAE implants were not due to differences in the rates of reendothelialization between the groups. No significant immunological response to the allogeneic endothelial cells that impacted on efficacy was detected in any of the pigs. No apparent toxicity was observed in any of the animals treated with endothelial implants. These data suggest that perivascular endothelial cell implants are safe and reduce early intimal hyperplasia in a porcine model of arteriovenous anastomoses.

Tissue-engineered endothelial and epithelial implants differentially and synergistically regulate airway repair

“…Endothelial cells (ECs) embedded within a 3D denatured collagen matrix secrete antiproliferative, antithrombotic, and antiinflammatory agents that promote vascular repair even when such constructs are placed far from the lumen within the vascular adventitia. Luminal inflammation, occlusive thrombosis, and intimal hyperplasia can be controlled by allo-and xenogeneic matrix-embedded (ME) ECs in a manner indistinct from native endothelium and without eliciting a significant immune response (1)(2)(3)(4)(5)(6)(7)(8). The challenge posed is whether endothelial implants recapitulate the endothelium lining as an epithelium or add to the regulation by perfusing vessels of the vasa vasorum, which are principally comprised of ECs.…”

Tissue Engineering Therapy for Cardiovascular Disease

“…Side-to-side arteriovenous fistulae were created with femoral arteries and veins in pigs. 74 Intimal thickening, observed within the venous segment at 1 and 2 months, was significantly reduced in the EC-treated animals compared with control animals.…”

Paracrine Regulation from Tissue Engineered Constructs

“…Once it was shown that paracrine-mediated regulation is disrupted in injury to the native endothelium [14][15][16], it was further suggested that implants containing healthy donor endothelial cells could restore the host intrinsic regulatory power and induce normal vascular repair [17][18][19][20][21][22]. Denatured collagen matrices that promoted endothelial cell attachment and regulatory phenotype were used to matrixembed endothelial cells [23].…”