An Early Study on the Mechanisms that Allow Tissue-Engineered Vascular Grafts to Resist Intimal Hyperplasia
Abstract : Intimal hyperplasia is one of the prominent failure mechanisms for arteriovenous fistulas and arteriovenous access grafts. Human tissue-engineered vascular grafts (TEVGs) were implanted as arteriovenous grafts in a novel baboon model. Ultrasound was used to monitor flow rates and vascular diameters throughout the study. Intimal hyperplasia in the outflow vein of TEVGs was assessed at the anastomosis and at juxta-anastomotic regions via histological analysis, and was compared to intimal hyperplasia with polytetrafluoroethylene (PTFE) grafts in the baboon model and in literature reports from other animal models. Less venous intimal hyperplasia was observed in histological sections with arteriovenous TEVGs than with arteriovenous PTFE grafts. TEVGs were associated with a mild, noninflammatory intimal hyperplasia. The extent of intimal tissue that formed with TEVG placement correlated with the rate of blood flow through tissue engineered vascular grafts at 2 weeks postimplant. Outflow vein dilatation was observed with increased flow rate. Both mid-graft flow rates and outflow vein diameters reached a plateau by week 4, which suggested that venous remodeling and intimal hyperplasia largely occurred within the first 4 weeks of implant in the baboon model. Given their compliant and noninflammatory nature, TEVGs appear resistant to triggers for venous intimal hyperplasia that are common for PTFE arteriovenous grafts, including (1) abundant proinflammatory macrophage populations that are associated with PTFE grafts and (2) compliance mismatch between PTFE grafts and the outflow vein. Our findings suggest that arteriovenous TEVGs develop only a mild form of venous intimal hyperplasia, which results from the typical hemodynamic changes that are associated with arteriovenous settings.
Keywords Tissue-engineered vascular graft • Intimal hyperplasia • Arteriovenous graft · Remodeling · Blood flow rate· Noninflammatory
There are more than 347,000 patients on chronic hemodialysis . Each year, more than 100,000 new end stage renal disease patients begin therapy on hemodialysis . Native arteriovenous fistulas have recently been the first choice for access, but even with the best surgical care, fistula prevalence is only 47% in the USA . The remainder of access is dependent on arteriovenous grafts or catheters, with a preference for grafts when possible . Currently, most arteriovenous grafts that are placed for hemodialysis access are comprised of synthetic polytetrafluoroethylene (PTFE). Synthetic arteriovenous grafts suffer from significant drawbacks, which include a high rate ofinfection (9% per annum) and a propensity for occlusion due to thrombosis and intimal hyperplasia (40-60% in the first year), with a median patency of only 10 months [4—7]. PTFE grafts require frequent interventions to maintain patency throughout their lifetime, which necessitates costly surgical intervention, increased overall healthcare costs, and increased patient morbidity.
By some reports, up to 85% of PTFE graft failures result from intimal hyperplasia at either the venous anastomosis or outflow vein. Intimal hyperplasia is typically characterized by intimal thickening of the vein, which diminishes the vein lumen, decreases blood flow rate, may lead to postcannulation bleeding due to intra-graft pressurization, and eventually leads to thrombosis and occlusion . The intima is defined as the innermost layer of an artery or vein, on the luminal side of the internal elastic lamina. In a healthy vein, the intima is one cell layer thick and comprised solely of endothelial cells. With intimal hyperplasia, cells may migrate into the intima from the medial and adventitial layers of the vein and from the circulation . Once they migrate into the intima, these cells express markers for myofibroblast and smooth muscle cell phenotypes. The cells proliferate and deposit extracellular matrix proteins. The formation of new tissue in the intima can compromise blood flow.
Intimal hyperplasia is thought to be triggered by the high wall shear stresses created by AV grafts, and compliance mismatch between PTFE and the native vein. Intimal hyperplasia also has been identified in regions with turbulent flow, flow separation, low shear stress, and oscillatory shear. In addition, PTFE's synthetic composition commonly leads to inflammation at the graft placement site following implant, which promotes intimal hyperplasia formation.
Development of tissue-engineered vascular grafts may provide a new opportunity for hemodialysis patients. If designed correctly, a tissue-engineered graft has the potential to reduce incidence of failure mechanisms associated with PTFE grafts. We have recently described a new human tissue-engineered vascular graft (TEVG) with compliance between that of human vein and human artery, which obviates concern about compliance mismatch. Furthermore, our TEVGs are made of extracellular matrix proteins, which make them highly biocompatible and resistant to inflammation. These TEVGs are acellular, which allows them to be stored in simple refrigeration for up to 1 year, thereby making them readily available to patients at the time of need . We demonstrated excellent function of these TEVGs in multiple vascular settings. TEVGs placed as arteriovenous grafts in a baboon model for 1—6 months demonstrated a patency rate of 88%, without incidence of graft infection.
In this study, we evaluate intimal hyperplasia formation associated with arteriovenous placement of TEVGs. We also investigate the impact of flow rate and outflow vein remodeling on intimal hyperplasia formation.