Hybrid Pericardium with VEGF‐Loaded Hyaluronic Acid Hydrogel Coating to Improve the Biological Properties of Bioprosthetic Heart Valves

Bioprosthetic heart valves (BHVs) used in the clinic are mostly fixed by glutaraldehyde and the lack of endothelialization is a major problem for glutaraldehyde‐fixed pericardia. Hyaluronic acid is a major glycosaminoglycan that exists in native heart valves. Coupled with its inherent biocompatibility, it may enhance endothelial adhesion and proliferation when associated with vascular endothelial growth factor (VEGF). In this study, an optimized system is developed to improve the endothelialization of glutaraldehyde‐fixed pericardium. A hybrid pericardium with VEGF‐loaded hyaluronic acid hydrogel coating is developed by the crosslinking of 1,4‐butanediol diglycidyl ether. The adhesion and growth potential of human umbilical vein endothelial cells (HUVECs) on pericardia, platelet adhesion, and calcification by an in vivo rat subdermal implantation model are investigated. The results show improved HUVEC adhesion and proliferation, less platelet adhesion, and less calcification for hybrid pericardium by introducing the coating of VEGF‐loaded hyaluronic acid hydrogel. Thus, the coating of VEGF‐loaded hyaluronic acid hydrogel on pericardium is a promising approach to obtain bioprosthetic valves for clinical applications with increased endothelialization and antithrombotic and anticalcification properties.     

Endothelialization and Anticoagulation Potential of Surface‐Modified PET Intended for Vascular Applications

In vascular tissue engineering, great attention is paid to the immobilization of biomolecules onto synthetic grafts to increase bio‐ and hemocompatibility—two critical milestones in the field. The surface modification field of poly(ethylene terephthalate) (PET), a well‐known vascular‐graft material, is matured and oversaturated. Nevertheless, most developed methods are laborious multistep procedures generally accompanied by coating instability or toxicity issues. Herein, a straightforward surface modification procedure is presented engineered to simultaneously promote surface endothelialization and anticoagulation properties via the covalent immobilization of gelatin through a photoactivated azide derivative. A complete physicochemical characterization and biological study including cytotoxicity and endotoxin testing are performed. In addition, biocompatibility toward small (diameter ≤ 6 mm) and/or large caliber (diameter ≥ 6 mm) vessels is assessed by micro‐ and macrovascular endothelial cell assays. Superior bio‐ and hemocompatibility properties are seen for the gelatin‐covalently modified PET surfaces compared to the conventional surface‐modification procedures based on physisorption.     

Programmable release of 2-O-d-glucopyranosyl-l-ascorbic acid and heparin from PCL-based nanofiber scaffold for reduction of inflammation and thrombosis

Reduction of inflammation and thrombosis caused by implanted devices is critical for clinical success. To this end, the strategy based on programmable release of anti-inflammatory and anti-thrombotic agents from the widely-used polycaprolactone (PCL)/gelatin nanofiber scaffold is developed. The release of 2-O-d-Glucopyranosyl-l-ascorbic Acid (AA-2G) and heparin are controlled by reactive oxygen species (ROS)-responsive poly(ethylene glycol)-based β-thioether ester copolymer (PEGDA-EDT) and mesoporous silica nanoparticles (MSN) in the nanofiber, respectively. The in vitro assay demonstrate that the scaffolds are hemocompatible with the resistance of platelet adhesion; the control release of AA-2G prevents initial inflammation and oxidation of the blood cells, and the subsequent release of heparin entitles nanofibers with long-term anti-thrombotic capability. In addition, rapid endothelialization is obtained on the surface of nanofiber scaffolds for the further enhancement of the hemocompatibility. In vivo implant evaluation convinces that the nanofiber scaffolds possess high biocompatibility with the substantial resistance for inflammation and thrombosis. Hence, our work paves a new way to develop the anti-inflammatory and anti-thrombotic tissue-engineering substrates through programmable delivery of two or multiple drugs.     

Surface Modification of Multiple Bioactive Peptides to Improve Endothelialization of Vascular Grafts

Endothelialization is an effective approach to prevent thrombus formation and enhance vascular graft survival. Surface modification of biomolecules has been proved to be effective in regulating endothelial cell behaviors. In this study, several peptides including YIGSR, RGD, and REDV sequences are covalently immobilized on the surface of electrospun silk fibroin scaffolds and the effects of combined application of these peptides on cell behaviors are studied. The results show that, compared with the scaffolds modified with single peptides, the scaffolds modified with dual peptides (YIGSR+RGD) could significantly enhance the proliferation of human umbilical vein endothelial cells (HUVECs). However, the combination of REDV+RGD or YIGSR+REDV does not promote the adhesion or proliferation of HUVECs. Notably, YIGSR‐modified scaffolds improved HUVEC migration significantly in comparison to REDV‐ or RGD‐modified groups. Moreover, its combination with either of these two peptides also presents excellent effect on cell migration. Thus, all the data suggest that the combined application of peptides might be a promising method to enhance the endothelialization of small‐diameter vascular grafts.     

Biofunctionalized Electrospun PCL‐PIBMD/SF Vascular Grafts with PEG and Cell‐Adhesive Peptides for Endothelialization

Artificial small‐caliber vascular grafts are still limited in clinical application because of thrombosis, restenosis, and occlusion. Herein, a small‐caliber vascular graft (diameter 2 mm) is fabricated from poly(ε‐caprolactone)‐b‐poly(isobutyl‐morpholine‐2,5‐dione) (PCL‐PIBMD) and silk fibroin (SF) by electrospinning technology and then biofunctionalized with low‐fouling poly(ethylene glycol) (PEG) and two cell‐adhesive peptide sequences (CREDVW and CAGW) with the purpose of enhancing antithrombogenic activity and endothelialization. The successful grafting of PEG and peptide sequences is confirmed by X‐ray photoelectron spectroscopy. The suitable surface wettability of the modified vascular graft is testified by water contact angle analysis. The surface hemocompatibility is verified by platelet adhesion assays and protein adsorption assays, and the results demonstrate that both platelet adhesion and protein adsorption on the biofunctionalized surface are significantly reduced. In vitro studies demonstrate that the biofunctionalized surface with suitable hydrophilicity and cell‐adhesive peptides can selectively promote the adhesion, spreading, and proliferation of human umbilical vein endothelial cells. More importantly, compared with control groups, this biofunctionalized small‐caliber vascular graft shows high long‐term patency and endothelialization after 10 weeks of implantation. The biofunctionalization with PEG and two cell‐adhesive peptide sequences is an effective method to improve the endothelialization and long‐term performance of synthetic vascular grafts.     

靶向性载体/基因复合物促进内皮细胞增殖

由于人工血管的表面缺乏活性内皮层,特别是小口径人工血管经常面临着长期通畅率低和再狭窄等难题,从而限制了其在临床上的应用。研究表明,通过基因复合物对内皮细胞转染可以在支架表面快速获得新生内皮层。近年来,基于靶向多肽修饰的基因载体为提高转染效率和降低载体毒性提供了有效的途径。本文详细介绍了目前用于基因转染的各种目的基因和基因载体,并以聚阳离子基因载体为基础,重点阐述了促进内皮细胞增殖的靶向性基因载体的研究进展,结合当前小口径人工血管研究进展,对采用基因转染方式实现其快速内皮化进行了分析和展望。