Dichloroacetate inhibits the degeneration of decellularized cardiovascular implants.

OBJECTIVES: Intima hyperplasia is a major issue of biological cardiovascular grafts resulting in progressive in vivo degeneration that particularly decreases the durability of coronary and peripheral vascular bypasses. Previously, dichloroacetate (DCA) has been reported to prevent the formation of hyperplastic intima in injured arteries. In this study, the effect of DCA on the neointima formation and degeneration of decellularized small-caliber implants was investigated in a rat model. METHODS: Donor rat aortic grafts (n = 22) were decellularized by a detergent-based technique, surface-coated with fibronectin (50 µl ml-1, 24 h incubation) and implanted via anastomoses to the infrarenal aorta of the recipients. Rats in the DCA group (n = 12) received DCA via drinking water during the whole follow-up period (0.75 g l-1), while rats without DCA treatment served as controls (n = 10). At 2 (n = 6 + 5) and 8 (n = 6 + 5) weeks, the grafts were explanted and examined by histology and immunofluorescence. RESULTS: Systemic DCA treatment inhibited neointima hyperplasia, resulting in a significantly reduced intima-to-media ratio (median 0.78 [interquartile range, 0.51-1.27] vs 1.49 [0.67-2.39] without DCA, P < 0.001). At 8 weeks, neointima calcification, as assessed by an established von Kossa staining-based score, was significantly decreased in the DCA group (0 [0-0.25] vs 0.63 [0.06-1.44] without DCA, P < 0.001). At 8 weeks, explanted grafts in both groups were luminally completely covered by an endothelial cell layer. In both groups, inflammatory cell markers (CD3, CD68) proved negative. CONCLUSIONS: Systemic DCA treatment reduces adverse neointima hyperplasia in decellularized small-caliber arterial grafts, while allowing for rapid re-endothelialization. Furthermore, DCA inhibits calcification of the implants.

Controlled autologous recellularization and inhibited degeneration of decellularized vascular implants by side-specific coating with stromal cell-derived factor 1α and fibronectin.

Optimized biocompatibility is crucial for the durability of cardiovascular implants. Previously, a combined coating with fibronectin (FN) and stromal cell-derived factor 1α (SDF1α) has been shown to accelerate the in vivo cellularization of synthetic vascular grafts and to reduce the calcification of biological pulmonary root grafts. In this study, we evaluate the effect of side-specific luminal SDF1α coating and adventitial FN coating on the in vivo cellularization and degeneration of decellularized rat aortic implants. Aortic arch vascular donor grafts were detergent-decellularized. The luminal graft surface was coated with SDF1α, while the adventitial surface was coated with FN. SDF1α-coated and uncoated grafts were infrarenally implanted (n = 20) in rats and followed up for up to eight weeks. Cellular intima population was accelerated by luminal SDF1α coating at two weeks (92.4 ± 2.95% versus 61.1 ± 6.51% in controls, p < 0.001). SDF1α coating inhibited neo-intimal hyperplasia, resulting in a significantly decreased intima-to-media ratio after eight weeks (0.62 ± 0.15 versus 1.35 ± 0.26 in controls, p < 0.05). Furthermore, at eight weeks, media calcification was significantly decreased in the SDF1α group as compared to the control group (area of calcification in proximal arch region 1092 ± 517 µm2 versus 11 814 ± 1883 µm2, p < 0.01). Luminal coating with SDF1α promotes early autologous intima recellularization in vivo and attenuates neo-intima hyperplasia as well as calcification of decellularized vascular grafts.

Influence of Laminin Coating on the Autologous In Vivo Recellularization of Decellularized Vascular Protheses.

Decellularization of non-autologous biological implants reduces the immune response against foreign tissue. Striving for in vivo repopulation of aortic prostheses with autologous cells, thereby improving the graft biocompatibility, we examined surface coating with laminin in a standardized rat implantation model. Detergent-decellularized aortic grafts from donor rats (n = 37) were coated with laminin and systemically implanted into Wistar rats. Uncoated implants served as controls. Implant re-colonization and remodeling were examined by scanning electron microscopy (n = 10), histology and immunohistology (n = 18). Laminin coating persisted over eight weeks. Two weeks after implantation, no relevant neoendothelium formation was observed, whereas it was covering the whole grafts after eight weeks, with a significant acceleration in the laminin group (p = 0.0048). Remarkably, the intima-to-media ratio, indicating adverse hyperplasia, was significantly diminished in the laminin group (p = 0.0149). No intergroup difference was detected in terms of medial recellularization (p = 0.2577). Alpha-smooth muscle actin-positive cells originating from the adventitial surface invaded the media in both groups to a similar extent. The amount of calcifying hydroxyapatite deposition in the intima and the media did not differ between the groups. Inflammatory cell markers (CD3 and CD68) proved negative in coated as well as uncoated decellularized implants. The coating of decellularized aortic implants with bioactive laminin caused an acceleration of the autologous recellularization and a reduction of the intima hyperplasia. Thereby, laminin coating seems to be a promising strategy to enhance the biocompatibility of tissue-engineered vascular implants.