Mechanocompatible Polymer‐Extracellular‐Matrix Composites for Vascular Tissue Engineering

Abstract

Small-diameter vascular grafts developed from vascular extracellular matrix (ECM) can potentially be used for bypass surgeries and other vascular reconstruction and repair procedures. The addition of heparin to the ECM improves graft hemocompatibility but often involves chemical crosslinking, which increases ECM mechanical stiffness compared to native arteries. Herein, we demonstrate the importance of maintaining ECM mechanocompatibility, and describe a mechanocompatible strategy to immobilize heparin onto the ECM via a biodegradable elastomer. Specifically, poly (1,8-octamethylene citrate)-co-cysteine (POC-Cys) was hybridized to the ECM, forming a polymer-ECM composite that allows for heparin immobilization via maleimide-thiol “click” chemistry. Heparinized composites reduced platelet adhesion by >60% in vitro, without altering the elastic modulus of the ECM. In a rat abdominal aortic interposition model, intimal hyperplasia in heparinized mechanocompatible grafts was 65% lower when compared to ECM-only control grafts at 4 weeks. In contrast, grafts that were heparinized with carbodiimide chemistry exhibited increased intimal hyperplasia (4.2 fold) and increased macrophage infiltration (3.5 fold) compared to ECM-only control grafts. All grafts showed similar, partial endothelial cell coverage and little to no ECM remodeling. Overall, we describe a mechanocompatible strategy to improve ECM thromboresistance and highlight the importance of ECM mechanical properties for proper in vivo graft performance.

Vascular scaffolds with enhanced antioxidant activity inhibit graft calcification

“…Poly (1,8-octamethylene citrate)-co-cysteine (POC-Cys) was synthesized with 1,8 octanediol, citric acid and L-cysteine with molar ratio 1:1:0.2, as described previously,[20] and hybridized onto decellularized aorta ECM at 45°C followed by 2-β mercaptoethanol treatment as experimental group 1 (Poly-ECM). [9] Lastly, the polymer-ECM composite was reacted with N-[β-maleimidopropionic acid] hydrazide (BMPH)-heparin via click chemistry to immobilize heparin onto the Poly-ECM as experimental group 2 (Poly-ECM-Hep). [9]…”

“…[9] Lastly, the polymer-ECM composite was reacted with N-[β-maleimidopropionic acid] hydrazide (BMPH)-heparin via click chemistry to immobilize heparin onto the Poly-ECM as experimental group 2 (Poly-ECM-Hep). [9]…”

“…Bioengineered, acellular vascular grafts fabricated from biodegradable synthetic polymers such as polycaprolactone,[5] decellularized vascular extracellular matrix (ECM),[6, 7] or synthetic polymer/ECM composites[8, 9] have been evaluated as alternatives to vein and radial artery grafts, which are the current gold standard conduits for lower extremity and cardiac revascularization. Rigorous long-term safety and efficacy assessment in vivo must be completed to evaluate time-dependent durability of bioengineered vascular grafts because in vitro studies alone or short-term in vivo experiments do not capture time-dependent degeneration of the implanted material.…”

“…We previously reported the synthesis of antioxidant, citric based polymers[18, 19] and the preparation of antioxidant, citric acid-based polymer-ECM composite vascular grafts whereby the polymer coating was functionalized with heparin to enhance graft thromboresistance. [8, 9] When compared to vascular ECM grafts, the polymer-ECM composite grafts exhibited reduced neointimal hyperplasia after one month of implantation in the abdominal aorta of Sprague Dawley rats. [9].…”

“…[8, 9] When compared to vascular ECM grafts, the polymer-ECM composite grafts exhibited reduced neointimal hyperplasia after one month of implantation in the abdominal aorta of Sprague Dawley rats. [9]. Herein we report a correlation between the extent of antioxidant activity, oxidative tissue damage, and calcification in vascular grafts.…”