Crosslinking strategies for preparation of extracellular matrix-derived cardiovascular scaffolds

Abstract

Heart valve and blood vessel replacement using artificial prostheses is an effective strategy for the treatment of cardiovascular disease at terminal stage. Natural extracellular matrix (ECM)-derived materials (decellularized allogeneic or xenogenic tissues) have received extensive attention as the cardiovascular scaffold. However, the bioprosthetic grafts usually far less durable and undergo calcification and progressive structural deterioration. Glutaraldehyde (GA) is a commonly used crosslinking agent for improving biocompatibility and durability of the natural scaffold materials. However, the nature ECM and GA-crosslinked materials may result in calcification and eventually lead to the transplant failure. Therefore, studies have been conducted to explore new crosslinking agents. In this review, we mainly focused on research progress of ECM-derived cardiovascular scaffolds and their crosslinking strategies.

Keywords: calcification; cross-linking agent; extracellular matrix; scaffold; tissue engineering.

Figure 1.

Disadavantage of GA-crosslinked ECM. Histology of GA-treated aortic samples before (A) and after (B) elastase. Calcium deposition in subdermally implanted GA-treated aorta explanted at 21 days (C). Scanning electron microscopy of human endothelial cells on GA-treated bovine pericardium shows sporadic cell cadavers (D). (Reprinted with permission from Refs. [22, 50].)

Figure 2.

In vitro angiogenesis in the presence of PC at 0 (A), 0.1 (B), 0.5 (C), 1.0 (D), 1.5 (E) and 100 (F) µg/ml. Scale bar is 400 µm. (Reprinted with permission from Ref. [59].)

Figure 3.

Anti-tumor effect of PC on tumor volume (A), tumor morphology (B) and tumor weight (C). PC 10 and PC 30 are 10 and 30 mg PC/kg bodyweight, respectively. Number sign indicates P < 0.05 compared with control. (Reprinted with permission from Ref. [59].)

Figure 4.

PC-crosslinked decellularized tissue scaffolds and the crosslinking mechanism and their stability. (Reprinted with permission from Ma Bing et al. Journal of East China Normal University 2013;5:61–79. Ref. [62]. L. He et al. International Journal of Biological Macromolecules 2011;48:354–359. W.Y. Zhai et al. Journal of Biomedical Materials Research Part B: Applied Biomaterials 2014;102:1190–8.)

Figure 5.

The proliferation effect of PC on bovine aortic heart valve interstitial cells (HVICs), HUVECs and A549 cells. IR is 1.5 µg/ml irinotecan. (Reprinted with permission from Refs. [59, 62].)

Figure 6.

SEM images of the biocompatibility of PC-crosslinked decellularized arotic scaffold materials seeding with HUVECs. (Reprinted with permission from W.Y. Zhai et al. Journal of Biomedical Materials Research Part B: Applied Biomaterials 2014;102:1190–8.)

Figure 7.

The hemolysis and hemolytic rate of the PC-crosslinked decellularized bovine pericardium ECM. (Reprinted with permission from Ma Bing et al. Journal of East China Normal University 2013;5:61–79.)

Figure 8.

Mineralization of decellularized porcine aortic valves soaked in SBF. (A) Decellularized valve matrix before soaking, (B) decellularized valves after soaking for 20 days. (C) Glutaraldehyde-crosslinked decellularized valves after soaking for 20 days. (D) PC-crosslinked decellularized valves after soaking for 20 days. (Reprinted with permission from Ref. [52].)

Figure 9.

Inhibition effect of PC on ALPase activity of valvular-related cells (n 5 4). (A) VICs; (B) MSCs. OSIM, osteosynthesis inducing medium; PC, procyanidins. PC001, PC01, PC1 and PC10 represent 0.01, 0.1, 1 and 10 µg/ml PC, respectively. *P < 0.01 compared with OSIM group. (Reprinted with permission from Ref. [52].)

Figure 10.

The von Kossa staining of VICs (A–D) and MSCs (E–H) after osteoinduction (n = 4). (A) OSIM; (B) OSIM + 1 µg/ml PC; (C) OSIM + 10 µg/ml PC; (D) control; (E) OSIM; (F) OSIM + 1 µg/ml PC; (G) OSIM + 10 µg/ml PC; (H) control. OSIM, osteosynthesis-inducing medium. Bars = 150 µm. (Reprinted with permission from Ref. [52].)