Biodegradable scaffolds seeded with bone marrow mononuclear cells (BMCs) are the earliest tissue-engineered vascular grafts (TEVGs) to be used clinically. These TEVGs transform into living blood vessels in vivo, with an endothelial cell (EC) lining invested by smooth muscle cells (SMCs); however, the process by which this occurs is unclear. To test if the seeded BMCs differentiate into the mature vascular cells of the neovessel, we implanted an immunodeficient mouse recipient with human BMC (hBMC)-seeded scaffolds. As in humans, TEVGs implanted in a mouse host as venous interposition grafts gradually transformed into living blood vessels over a 6-month time course. Seeded hBMCs, however, were no longer detectable within a few days of implantation. Instead, scaffolds were initially repopulated by mouse monocytes and subsequently repopulated by mouse SMCs and ECs. Seeded BMCs secreted significant amounts of monocyte chemoattractant protein-1 and increased early monocyte recruitment. These findings suggest TEVGs transform into functional neovessels via an inflammatory process of vascular remodeling.bone marrow | monocyte chemoattractant protein-1 | tissue engineering | neovascularization C ongenital heart disease is a leading cause of infant mortality, often requiring early surgical intervention to correct fatal cardiovascular malformations. Prosthetic vascular grafts are widely used in these reconstructive operations, but revisions are often necessary because of their inability to grow or effectively remodel within a growing child (1-3). A strategy to address this issue is the use of living tissue-engineered vascular grafts (TEVGs). Constructed from biodegradable polyester tubes seeded with autologous bone marrow mononuclear cells (BMCs), these grafts undergo extensive remodeling in animal recipients and appear to transform into living blood vessels, similar in morphology and function to the native veins into which they are interposed (4, 5). Ongoing clinical studies evaluating BMC-seeded grafts as venous conduits for congenital heart surgery report excellent safety profiles and 100% patency rates at 1-3 years of follow-up (6-8). Additionally, these grafts demonstrate growth potential, suggesting they may be more effective for the pediatric patient population than currently available vascular grafts (8,9).Although the functional efficacy and clinical utility of TEVGs are promising, little is known about how these BMC-seeded polyester tubes transform into living blood vessels in host recipients. It has been proposed that stem cells within the seeded BMC population differentiate into the endothelial cells (ECs) and smooth muscle cells (SMCs) of the developing neovessel, ultimately replacing the degrading polyester tube (10). This hypothesis, however, has not been directly examined.We recently developed a method for constructing small-diameter biodegradable synthetic scaffolds suitable for use as vascular grafts in mice (11). These tubular scaffolds are composed of the same materials and design used in clinical TEVGs...

The development of neotissue in tissue engineered vascular grafts remains poorly understood. Advances in mouse genetic models have been highly informative in the study of vascular biology, but have been inaccessible to vascular tissue engineers due to technical limitations on the use of mouse recipients. To this end, we have developed a method for constructing sub-1mm internal diameter (ID) biodegradable scaffolds utilizing a dual cylinder chamber molding system and a hybrid polyester sealant scaled for use in a mouse model. Scaffolds constructed from either polyglycolic acid or poly-l-lactic acid nonwoven felts demonstrated sufficient porosity, biomechanical profile, and biocompatibility to function as vascular grafts. The scaffolds implanted as either inferior vena cava or aortic interposition grafts in SCID/bg mice demonstrated excellent patency without evidence of thromboembolic complications or aneurysm formation. A foreign body immune response was observed with marked macrophage infiltration and giant cell formation by post-operative week 3. Organized vascular neotissue, consisting of endothelialization, medial generation, and collagen deposition, was evident within the internal lumen of the scaffolds by post-operative week 6. These results present the ability to create sub-1mm ID biodegradable tubular scaffolds that are functional as vascular grafts, and provide an experimental approach for the study of vascular tissue engineering using mouse models.

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Purpose-Use of tissue-engineered vascular grafts (TEVGs) in the repair of congenital heart defects provides growth and remodeling potential. Little is known about the mechanisms involved in neovessel formation. We sought to define the role of seeded monocytes derived from bone marrow mononuclear cells (BM-MNCs) on neovessel formation.Methods-Small diameter biodegradable tubular scaffolds were constructed. Scaffolds were seeded with the entire population of BM-MNC (n = 15), BM-MNC excluding monocytes (n = 15), or only monocytes (n = 15) and implanted as infrarenal inferior vena cava (IVC) interposition grafts into severe combined immunodeficiency/bg mice. Grafts were evaluated at 1 week, 10 weeks, or 6 months via ultrasonography and microcomputed tomography, as well as by histologic and immunohistochemical techniques.Results-All grafts remained patent without stenosis or aneurysm formation. Neovessels contained a luminal endothelial lining surrounded by concentric smooth muscle cell layer and collagen similar to that seen in the native mouse IVC. Graft diameters differed significantly between those scaffolds seeded with only monocytes (1.022 ± 0.155 mm) and those seeded without monocytes (0.771 ± 0.121 mm; P = .021) at 6 months. Complications arising from currently available vascular replacement grafts remain a significant source of morbidity and mortality when used in the repair of congenital heart defects. Of particular interest in the pediatric population is the lack of growth and remodeling of replacement conduits after implantation, thereby, necessitating further invasive revisions or reoperations as somatic growth continues. The development of tissue-engineered vascular grafts (TEVGs) provides the potential to overcome such limitations. Modeling our TEVGs on previous work [1-3], we designed a TEVG specifically for use as a conduit in congenital heart surgery where the development of a living, autologous vascular conduit with the ability to repair, remodel, and grow could be best used. Our TEVGs are made by statically seeding autologous human bone marrow-derived mononuclear cells (hBM-MNCs) onto a Conclusions-Monocytes

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Pure TVA is a safe and well-tolerated procedure with significantly less pain and faster recovery compared to traditional LA.

This pilot study examines noninvasive MR monitoring of tissue-engineered vascular grafts (TEVGs) in vivo using cells labeled with iron oxide nanoparticles. Human aortic smooth muscle cells (hASMCs) were labeled with ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles. The labeled hASMCs, along with human aortic endothelial cells, were incorporated into eight TEVGs and were then surgically implanted as aortic interposition grafts in a C.B-17 SCID/bg mouse host. USPIO-labeled hASMCs persisted in the grafts throughout a 3 wk observation period and allowed noninvasive MR imaging of the human TEVGs for real-time, serial monitoring of hASMC retention. This study demonstrates the feasibility of applying noninvasive imaging techniques for evaluation of in vivo TEVG performance.

Surgical correction of congenital heart defects often requires the use of valves, patches, or conduits to establish anatomic continuity. Homografts, xenografts, or mechanical prosthetic devices are frequently implanted during these surgical procedures. These grafts however lack growth potential, are associated with increased risk of thrombosis and infection and have limited durability, thus increasing the morbidity and mortality of their application in pediatric cardiac surgery. These limitations are being addressed through the development of living, biologic tissue-engineered valves, patches, and conduits. Pilot studies and phase 1 clinical trials are currently underway to evaluate their feasibility, safety, and efficacy. The optimal scaffold, cell source, and conditioning parameters, however, still remain to be determined and are areas of active research.