•Calcification may contribute to vascular graft implantation failure. An excellent anti-calcification property has been a critical factor for SDVG long-time transplantation. In this review, we ...summarized the calcification mechanisms of native vascular and the causes of SDVG calcification, which sources dECM and polymer materials.•At the same time, the different strategies to prevent or delay the calcification of SDVGs are reported.•In addition, a review of anti-calcification methods in other biomaterials was also discussed, with the hope of applying them to SDVGs.•This review might be helpful for researchers in designing the anti-calcification SDVGs.
The incidence of cardiovascular disease is on the rise, and vascular reconstruction is an effective method for treatment. Small-diameter vascular grafts (SDVGs) are commonly used in reconstructive surgery, but they face significant challenges such as rapid endothelialization, antithrombotic formation, and calcification. Little research has been conducted on post-implantation calcification, a pathological process that occurs in vascular grafts. Calcification may contribute to vascular graft implantation failure. Comprehending the basic mechanisms of vascular graft calcification is crucial to achieve long-term transplantation success. In the present review, we summarized the calcification mechanisms of native vascular and the causes of SDVG calcification, which sources decellularized extracellular matrix (dECM) and polymer materials. At the same time, different strategies to prevent or delay calcification on SDVGs are reported (optimize cross-linking method, surface modification, large pore size, reduced inflammatory response). In addition, a review of anti-calcification methods in other biomaterials was also discussed, with the hope of applying them to SDVGs. This review might be helpful for researchers in designing the anti-calcification SDVGs.
There is a growing demand for off-the-shelf tissue engineered vascular grafts (TEVGs) for the replacement or bypass of damaged arteries in various cardiovascular diseases. Scaffolds from the ...decellularized tissue skeletons to biopolymers and biodegradable synthetic polymers have been used for fabricating TEVGs. However, several issues have not yet been resolved, which include the inability to mimic the mechanical properties of native tissues, and the ability for long-term patency and growth required for in vivo function. Electrospinning is a popular technique for the production of scaffolds that has the potential to address these issues. However, its application to human TEVGs has not yet been achieved. This review provides an overview of tubular scaffolds that have been prepared by electrospinning with potential for TEVG applications.
Implanted grafts, including vascular substitutes, inevitably experience remodeling by host cells. The design of grafts capable of promoting constructive remodeling remains a challenge within ...regenerative medicine. Here, we used a biodegradable elastic polymer, poly (l-lactide-co-ε-caprolactone) (PLCL), to develop a vascular graft with circumferentially aligned microfibers. The grafts exhibited excellent handling properties and resistance to deformation. Upon implantation in rat abdominal aorta, graft-guided neoartery regeneration was achieved in a short period (4 weeks) as evidenced by rapid cell infiltration and alignment, and complete endothelialization. During vascular remodeling, a high ratio of M2/M1 macrophage was detected, and the expression of pro-inflammatory and anti-inflammatory cytokines first increased and then decreased to normal level for the follow-up period. By 12 months, the PLCL grafts were almost completely degraded and a well-integrated neoartery was formed with characteristics comparable to native arteries, such as transparent appearance, synchronous pulsation, dense and orderly extracellular matrix (ECM) arrangement, strong and compliant mechanical properties, and vasomotor response to pharmacologic agents. Taken together, our strategy represents a new avenue for guided tissue regeneration by designing the grafts to promote tissue remodeling via controlling structure, degradation and mechanical properties of the scaffolds.
•By regulating ROS balance and NO production to reduce the inflammation and promote the process of vascular remodeling.•Chelates maintain the catalysis of NO by Cu (Ⅱ) and remove excessive ROS by ...carnosine to reduce adverse effects by Cu (Ⅱ).•Car-Cu (Ⅱ) graft achieved satisfactory effects of anti-thrombotic, anti-inflammatory and pro-endothelialization.
Thrombosis and poor endothelialization of small-diameter vascular grafts (SDVGs) remain the leading cause of frequent failure, despite current tissue-engineered vascular grafts providing a feasible strategy in clinical treatment strategies for the small-diameter (<6 mm) blood vessels in management of cardiovascular disease. Copper ions are normally used to achieve the purpose of antithrombotic because they can produce nitric oxide (NO) with the catalysis of NO donors. However, copper ions also participate in the Fenton reaction to produce reactive oxygen species (ROS), which would adversely affect vascular graft remodeling. Here carnosine, an ion-chelating agent with anti-inflammatory and antioxidant properties, was used to chelate with copper ions to synthesize carnosine-Cu (II) chelate which showed effective activity of antithrombotic, anti-inflammatory, and antioxidant. Besides, our research further demonstrated that copper ions still retain the catalytic activities for producing NO after chelating with carnosine accompanied by the production of lower levels of ROS (the average fluorescence intensity of ROS decreased from 79.69 to 7.13). Furthermore, the grafts achieved excellent patency with satisfactory endothelialization (the endothelial coverage reached 80.64 %) and significantly improved deposition of collagen and glycosaminoglycan for up to 12 weeks. In general, Car-Cu (II) modified SDVGs provided a facile approach to addressing the problems of thrombus and poor endothelialization in SDVGs for the clinic, which is significant in cardiovascular regenerative medicine.
Diabetes has been associated with postoperative complications, such as increased risk of tissue infection and impaired tissue repair caused by destabilization of hypoxia-inducible factor-1α (HIF-1α). ...Consequently, it is imperative to fabricate anti-bacterial and pro-regenerative small-diameter vascular grafts for treating cardiovascular disease in diabetic patients. Herein, we developed electrospun cobalt ion (Co2+)-loaded poly (ε-caprolactone) (PCL) microfiber vascular grafts (PCL-Co grafts). The released Co2+ significantly increased the stabilization of HIF-1α in high-glucose (HG)-treated HUVECs (HG-HUVECs) and macrophages (HG-macrophages). This resulted in enhanced cell migration, nitric oxide production, and secretion of bioactive factors by HG-HUVECs, and polarization of HG-macrophages toward M2 phenotypes in vitro. The Co2+ also conferred anti-bacterial properties to the grafts, while not perturbing the inherent anti-bacterial activities of HG-macrophages. Following abdominal artery implantation into type 2 diabetes mellitus (T2DM) rats, PCL-Co grafts were evaluated for performance in infection (grafts pre-contaminated with Staphylococcus aureus) and prophylaxes models (grafts alone). PCL-Co grafts prevented the incidence of subsequent infection in prophylaxes model and effectively inhibited the bacterial growth in the infection model. PCL-Co grafts also significantly enhanced cellularization, vascularization, endothelialization, contractile SMC regeneration and macrophages polarization in both models. Collectively, PCL-Co grafts exhibited the potential to combat infection and improve tissue regeneration under diabetes conditions.
•A history of conventional means for filling critical size bone defects using grafting and bone regeneration techniques.•An introduction as to what materials have so far been used for the creation of ...bone substitute and vascular augmentation substitutes for a composite bone and vascular void filler.•Possible future directions that will need to be considered in the successful creation of composite vascularized bone void fillers for segmental defects.
The management of large segmental bone defects caused by trauma or disease remains clinically challenging within orthopaedics. The major impediment to bone healing with current treatment options is insufficient vascularization and incorporation of graft material. Lack of rapid adequate vascularization leads to cellular necrosis within the inner regions of the implanted material and a failure of bone regeneration. Current treatment options for critical size bone defects include the continued “gold standard” autograft, allograft, synthetic bone graft substitutes, vascularized fibular graft, induced membrane technique, and distraction osteogenesis. Bone tissue engineering (BTE) remains an exciting prospect for the treatment of large segmental bone defects; however, current clinical integration of engineered scaffolds remains low. We believe that the barrier to clinical application of bone tissue engineering constructs lies in the lack of concomitant vascularization of these scaffolds. This mini-review outlines the progress made and the significant limitations remaining in successful clinical incorporation of engineered synthetic bone substitutes for segmental defects.
Conventional synthetic vascular grafts are limited by the inability to remodel, as well as issues of patency at smaller diameters. Tissue-engineered vascular grafts (TEVGs), constructed from ...biologically active cells and biodegradable scaffolds have the potential to overcome these limitations, and provide growth capacity and self-repair. Areas covered: This article outlines the TEVG design, biodegradable scaffolds, TEVG fabrication methods, cell seeding, drug delivery, strategies to reduce wait times, clinical trials, as well as a 5-year view with expert commentary. Expert commentary: TEVG technology has progressed significantly with advances in scaffold material and design, graft design, cell seeding and drug delivery. Strategies have been put in place to reduce wait times and improve 'off-the-shelf' capability of TEVGs. More recently, clinical trials have been conducted to investigate the clinical applications of TEVGs.
Impaired or damaged blood vessels can occur at all levels in the hierarchy of vascular systems from large vasculatures such as arteries and veins to meso‐ and microvasculatures such as arterioles, ...venules, and capillary networks. Vascular tissue engineering has become a promising approach for fabricating small‐diameter vascular grafts for occlusive arteries. Vascularized tissue engineering aims to fabricate meso‐ and microvasculatures for the prevascularization of engineered tissues and organs. The ideal small‐diameter vascular graft is biocompatible, bridgeable, and mechanically robust to maintain patency while promoting tissue remodeling. The desirable fabricated meso‐ and microvasculatures should rapidly integrate with the host blood vessels and allow nutrient and waste exchange throughout the construct after implantation. A number of techniques used, including engineering‐based and cell‐based approaches, to fabricate these synthetic vasculatures are herein explored, as well as the techniques developed to fabricate hierarchical structures that comprise multiple levels of vasculature.
Impaired or damaged blood vessels can be repaired by tissue engineering approaches. Significant advances have been made in fabricating tissue‐engineered vascular grafts to replace autologous and commercially available grafts. However, persistent hurdles include the provision of sophisticated hierarchical vasculature. Herein, techniques used to fabricate tissue‐engineered vascular graft, mesovasculature, microvasculature, and hierarchical vasculatures are reviewed.
Endothelialization and antithrombosis are the keys for small‐diameter vascular grafts to reduce thromboembolism and intimal hyperplasia and achieve revascularization. Nitric oxide (NO) is an ...essential antiplatelet, proendothelialization, and vasodilating agent. Meanwhile, owing to its good biocompatibility, collagen is long considered a feasible material for manufacturing small‐diameter vascular grafts. However, thrombosis and poor mechanical strength remain major drawbacks. A collagen methacrylamide‐co‐selenocysteine (Col‐MA‐Se) composite capable of catalyzing NO release is synthesized here. The Col‐MA‐Se composite improves the blood compatibility of collagen and stimulates the migration and growth of endothelial cells, which suggests that the Col‐MA‐Se composite is suitable for small‐diameter vascular grafts. The prepared composite is then incorporated with polycaprolactone (PCL) to prepare small‐diameter vascular grafts that satisfying basic mechanical requirements for transplantation, followed by a comprehensive exploration of its mechanical strength, endothelial cell response, and platelet behavior. Results confirm the successful construction of collagen/PCL vascular grafts capable of releasing NO and affording rapid endothelialization and antithrombosis, which indicate their promising application prospects for vascular regeneration.
In this study, selenocysteine (SeCA) is successfully coupled with collagen to prepare a collagen methacrylamide‐co‐SeCA (Col‐MA‐Se) composite catalyzing NO release from NO donors into the blood. Small‐diameter vascular grafts that met the mechanical strengths requirement for transplantation are prepared by incorporating polycaprolactone into the Col‐MA‐Se composite. Graft‐catalyzed NO release also promotes the adhesion and proliferation of endothelial cells.
Vascular grafts often exhibit low patency rates in clinical settings due to the pathological environment within the patients requiring the surgery. Mesenchymal stem cell (MSC)-derived small ...extracellular vesicles (sEVs) have attracted increasing attention. These sEVs contain many potent signaling molecules that play important roles in tissue regeneration, such as microRNA and cytokines. In this study, a sEVs-functionalized vascular graft was developed, and in vivo performance was systematically evaluated in a rat model of hyperlipidemia. Electrospun poly (ε-caprolactone) (PCL) vascular grafts were first modified with heparin, to enhance the anti-thrombogenicity. MSC-derived sEVs were loaded onto the heparinized PCL grafts to obtain functional vascular grafts. As-prepared vascular grafts were implanted to replace a segment of rat abdominal artery (1 cm) for up to 3 months. Results showed that the incorporation of MSC-derived sEVs effectively inhibited thrombosis and calcification, thus enhancing the patency of vascular grafts. Furthermore, regeneration of the endothelium and vascular smooth muscle was markedly enhanced, as attributed to the bioactive molecules within the sEVs, including vascular endothelial growth factor (VEGF), miRNA126, and miRNA145. More importantly, MSC-derived sEVs demonstrated a robust immunomodulatory effect, that is, they induced the transition of macrophages from a pro-inflammatory and atherogenic (M1) phenotype to an anti-inflammatory and anti-osteogenic (M2c) phenotype. This phenotypic switch was confirmed in both in vitro and in vivo analyses. Taken together, these results suggest that fabrication of vascular grafts with immunomodulatory function can provide an effective approach to improve vascular performance and functionality, with translational implication in cardiovascular regenerative medicine.
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