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Preclinical Evaluation of an Autologous Stem Cell-Based Tissue-Engineered Vascular Graft in a Pig Model

Navyash Gupta, Lorenzo Soletti, Alejandro Nieponice, Burhan Gharaibeh, Gerhardt Konig, Jianjun Guan, Yi Hong, Johnny Huard, William R. Wagner, David A. Vorp.
University of Pittsburgh, Pittsburgh, Pa.

OBJECTIVES: Limited autologous vascular graft availability and poor patency rates of synthetic small diameter grafts remain a concern. A tissue engineered approach, including adequate cell source, scaffold, seeding, and culture methods can potentially solve these limitations. We report our progress in the development of a stem cell-based tissue engineered vascular graft (TEVG) and its preliminary evaluation in a pig model.

METHODS: Compound (bi-layered), synthetic, biodegradable, elastomeric tubular scaffolds comprised of a porous medial layer and an external, reinforcing layer were developed and morphological and mechanical characterization was performed. Autologous muscle-derived stem cells (MDSCs) were obtained from striated muscle biopsies and transfected with the LacZ promoter gene. Scaffolds were bulk-seeded with 30x106 MDSCs using a rotational vacuum seeding device and placed in spinner flask culture at 15 rpm for 24 hrs. Cellular integration was assessed via nuclear and cytoskeletal staining. Constructs were implanted in domestic pigs as carotid interposition (n=3) or carotid-IJ vein grafts (n=2) [Figure 1] for 1 month. Angiogram, gross pathology, histology, and SEM were performed at the time of explant.

RESULTS: The scaffolds showed firm adhesion with no delamination of the two layers. Ultimate tensile stress was 8.3±1.7 MPa, compliance: 6.2±0.6%/100 mmHg, and suture retention force: 345±0.33 grams. Uniform distribution of MDSCs was noted within the wall of the constructs after seeding (efficiency: 91±2%). Intraop, the TEVGs were easily suturable and withstood physiological arterial pressure without leaking. Macroscopically, all TEVGs were patent with no dilation. Microscopically, the constructs showed extensive remodeling with cell infiltration and collagen matrix deposition. Intimal hyperplasia was observed primarily at the anastamotic sites. LacZ+ cells were shown to be engrafted in the remodeled construct.

CONCLUSIONS: We have demonstrated the feasibility of a preclinical, autologous approach in a pig model in the systemic circulation or as AV fistula after a short culture period with in vivo remodeling is compatible with clinical translation. Further work will evaluate a higher cell number integrated into the scaffolds to decrease intimal hyperplasia and longer time points.

AUTHOR DISCLOSURES: N. Gupta, None; L. Soletti, None; A. Nieponice, AHA Postdoctoral Fellowship 0525585U; B. Gharaibeh, None; G. Konig, None; J. Guan, None; Y. Hong, None; J. Huard, None; W.R. Wagner, NIH BRP #RO1 HL069368; D.A. Vorp, NIH BRP #RO1 HL069368.