Macrophages are primary immune cells that play a crucial role in tissue regeneration during the early stages of biomaterial implantation. They create a microenvironment that facilitates cell infiltration, angiogenesis, and tissue remodeling. In the field of vascular tissue engineering, numerous studies have been conducted to modulate the macrophage phenotype by designing various biomaterials, which in turn enhances the regenerative capacity and long-term patency of vascular grafts. However, the mechanism underlying the different phenotypes of macrophages involved in the tissue regeneration of vascular grafts remains unclear. In this study, vascular grafts loaded with various macrophage phenotypes were developed, and their effects were evaluated both in vivo and in vitro. The RAW 264.7 macrophages (M0) were initially treated with LPS or IL-4/IL-10 and polarized into M1 and M2 phenotypes. Subsequently, M0, M1, and M2 macrophages were seeded onto electrospun PCL scaffolds to obtain macrophage-loaded vascular grafts (PCL-M0, PCL-M1, and PCL-M2). As prepared vascular grafts were implanted into the mouse carotid artery for up to one month. The results indicate that the loading of M2 macrophages effectively enhances the patency rate and neotissue formation of vascular grafts. This is achieved through the development of a well-defined endothelium and smooth muscle layer. RNA sequencing was used to investigate the mechanisms of action of different macrophages on tissue regeneration. The study found that M1 macrophages inhibited tissue regeneration by mediating angiogenesis and chronic inflammation through upregulation of VEGFa, IL-1β, and IL-6 expression. In contrast, M2 macrophages regulate the immune microenvironment by upregulating the expression of IL-4 and TGF-β, thereby promoting tissue regeneration. In conclusion, our study demonstrates how different macrophage phenotypes contribute to the initial inflammatory microenvironment surrounding vascular grafts, thereby modulating the biological process of vascular remodeling. STATEMENT OF SIGNIFICANCE: Regulating the biophysical and biochemical characteristics of biomaterials can induce macrophage polarization and enhance vascular remodeling. In previous work, we fabricated a vascular graft with a macroporous structure that promoted macrophage infiltration and polarization into a pro-regenerative phenotype. To illustrate the mechanism, we established a new mouse model and evaluated the effects of different macrophages on vascular regeneration. The study revealed that tuning macrophage phenotype can impact the initial inflammatory microenvironment by secreting cytokines, which can increase the patency rate and regenerative capacity of vascular grafts. These findings provide essential theoretical support for the development of immunoregulatory scaffolds for vascular and other tissue regeneration.

The unique ability of piezoelectric materials to generate electricity spontaneously has attracted widespread interest in the medical field. In addition to the ability to convert mechanical stress into electrical energy, piezoelectric materials offer the advantages of high sensitivity, stability, accuracy and low power consumption. Because of these characteristics, they are widely applied in devices such as sensors, controllers and actuators. However, piezoelectric materials also show great potential for the medical manufacturing of artificial organs and for tissue regeneration and repair applications. For example, the use of piezoelectric materials in cochlear implants, cardiac pacemakers and other equipment may help to restore body function. Moreover, recent studies have shown that electrical signals play key roles in promoting tissue regeneration. In this context, the application of electrical signals generated by piezoelectric materials in processes such as bone healing, nerve regeneration and skin repair has become a prospective strategy. By mimicking the natural bioelectrical environment, piezoelectric materials can stimulate cell proliferation, differentiation and connection, thereby accelerating the process of self-repair in the body. However, many challenges remain to be overcome before these concepts can be applied in clinical practice, including material selection, biocompatibility and equipment design. On the basis of the principle of electrical signal regulation, this article reviews the definition, mechanism of action, classification, preparation and current biomedical applications of piezoelectric materials and discusses opportunities and challenges for their future clinical translation.

Cardiovascular injuries cause huge morbidity and mortality worldwide. Arterial reconstructions are generally performed either by using native grafts or synthetic grafts, both of which are limited by several complications. Synthetic biodegradable polymers offer a promising platform, which may also be modified to foster in situ tissue regeneration through the recruitment of host cells. Vascular endothelial growth factor (VEGF) promotes endothelialization and neovascularization in vascular grafts, however, an overdose of VEGF may induce tumor-like vasculature, which requires alternative strategies. The objective of this study was to exploit prominin-1-derived VEGF-binding peptide (BP) to improve neovascularization and endothelialization, while stromal cell-derived factor 1-alpha (SDF-1α) peptide to encourage endogenous stem/progenitor cells mobilization and complement BP-mediated vascular remodeling. The BP and SDF-1α peptides were covalently conjugated with low molecular weight poly (ε-caprolactone) (LPCL) to afford LPCL-BP and LPCL-SDF-1α, respectively. Chemical analysis revealed successful modification of LPCL with peptides, which also displayed good cytocompatibility in vitro once blended along with high molecular weight PCL (HPCL). The bioactived vascular grafts were fabricated by blending LPCL-BP, LPCL-SDF-1α or dual peptide-polymer conjugates with HPCL. The in vivo tests of vascular grafts through rat abdominal aorta implantation model revealed that, compared with HPCL grafts, the dual peptides modified grafts exhibited superior patency and tissue regeneration at 4-week post-implantation, including stem cell recruitment, rapid endothelialization and functional SMC layer formation. Taken together, these results may have implications for the in situ regeneration of artificial blood vessels through the orchestration of host's responses and endogenous cell recruitment.

Design and fabrication of scaffolds with three-dimensional (3D) topological cues inducing regeneration of the neo-tissue comparable to native one remains a major challenge in both scientific and clinical fields. Here, we developed a well-designed vascular graft with 3D highly interconnected and circumferentially oriented microchannels by using the sacrificial sugar microfiber leaching method. The microchannels structure was capable of promoting the migration, oriented arrangement, elongation, and the contractile phenotype expression of vascular smooth muscle cells (VSMCs) in vitro. After implantation into the rat aorta defect model, the microchannels in vascular grafts simultaneously improved the infiltration and aligned arrangement of VSMCs and the oriented deposition of extracellular matrix (ECM), as well as the recruitment and polarization of macrophages. These positive results also provided protection and support for ECs growth, and ultimately accelerated the endothelialization. Our research provides a new strategy for the fabrication of grafts with the capability of inducing arterial regeneration, which could be further extended to apply in preparing other kinds of oriented scaffolds aiming to guide oriented tissue in situ regeneration.

In vivo long-term evaluation of degradable implants offers valuable information for the further design and optimization of biomaterials. In this study, we prepared one type of bilayer graft, which had an internal layer of oriented elastic degradable poly(l-lactide-ε-caprolactone) (PLCL) microfibers and an external layer of slowly degradable poly-ε-caprolactone (PCL) nanofiber. After in vivo implantation for 18 months, no aneurysm or graft rupture occurred, despite the finding that the mechanical properties of explanted PLCL grafts had decreased due to the degradation of PLCL materials. Explanted grafts maintained complete endothelialization and the degradation of PLCL improved vascular remodeling, which included the formation of a thicker media layer, denser extracellular matrix deposition, and obvious contractile and diastolic functions. Also, we found that the degradation products of PLCL tended to cause calcification, which may limit the return of vascular function to the natural artery level. Taken together, this bilayered graft showed a positive impact on vascular regeneration, while modification of bioactive or anticalcification factors should be considered for incorporation in future designs and the fabrication of small-diameter vascular grafts.

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.

Objective: Exosomes (Exos) are membrane-encased vesicles derived by nearly all cell types for intercellular communication and regulation. They also received attention for their use as natural therapeutic platforms and drug delivery system. Classically activated M1 macrophages suppress tumor growth by releasing pro-inflammatory factors. This study investigated the suitability of M1-exosomes (M1-Exos) as drug carrier and their effect on the NF-κB signal pathway and further detected whether macrophages repolarization can potentiate the antitumor activities of chemotherapeutics. Methods: M1-Exos were isolated from M1-macrophages by ultracentrifugation and characterized by transmission electron, nanoparticle tracking analysis, dynamic light scattering and western blot. Then M1-Exos were used as Paclitaxel (PTX) carriers to prepare a nano-formulation (PTX- M1-Exos). A relatively simple slight sonication method was used to prepare the drug delivery system (PTX-M1-Exos). The cytotoxicity of PTX-M1-Exos on cancer cells was detected by MTT and flow cytometry in vitro. 4T1 tumor bearing mice were used to perform the therapeutic effect of PTX-M1-Exos in vivo. Results: The expression of caspase-3 in breast cancer cells was increased when co-incubated with macrophages in the presence of M1-Exos in vitro. The production of pro-inflammatory cytokines was increased after exposure of macrophages in M1-Exos. M1-Exos provided a pro-inflammatory environment which enhanced the anti-tumor activity via caspase-3 mediated pathway. The treatment of M1-Exos to the tumor bearing mice exhibit anti-tumor effects in vivo. Meanwhile, the treatment of PTX-M1-Exos demonstrated higher anti-tumor effects than the M1-Exos or PTX group. Conclusion: The results in our study indicate that the M1-Exos act as the carrier to deliver PTX into the tumor tissues, and also enhance the anti-tumor effects of chemotherapeutics in tumor bearing mice.

Here, we present a protocol to fabricate macroporous PCL vascular graft and describe an evaluation protocol by using a rat model of abdominal aorta replacement.The electrospun vascular grafts often possess relatively small pores, which limit cell infiltration into the grafts and hinder the regeneration and remodeling of the neo-arteries.In this study, PCL vascular grafts with thicker fibers (5 -6 µm) and larger pores (~30 µm) were fabricated by using a modified processing technique.The long-term performance of the graft was evaluated by implantation in a rat abdominal aorta model.Ultrasound analysis showed that the grafts remained patent without aneurysm or stenosis occurring even after 12 months of implantation.Macroporous structure improved the cell ingrowth and thus promoted tissue regenerated at 3 months.More importantly, there was no sign of adverse remodeling, such as calcification within the graft wall after 12 months.Therefore, electrospun PCL vascular grafts with modified macroporous processing hold potential to be an artery substitute for long-term implantation.

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.

Small diameter vascular grafts have been promising substitutes for bypass surgery to treat cardiovascular disease. However, no ideal product is available in the clinic. In order to design improved, next generation vascular grafts, it is essential to understand the cellular and molecular mechanisms underlying tissue regeneration after vascular graft implantation. Two diverse microenvironments, circulating blood and the surrounding tissue, are involved in the regeneration process after vascular graft implantation in situ. However, their regenerative functions are not completely understood. To elucidate their roles in regeneration, we used electrospinning to fabricate four types of tubular scaffolds with a structure consisting of a microfiber layer (fiber diameter ∼ 6 μm) and a nanofiber layer (fiber diameter < 1 μm): microfiber scaffold, nanofiber scaffold, outer microfiber bilayer scaffold and inner microfiber bilayer scaffold. In the outer microfiber scaffold, cells from the surrounding tissue were allowed into the scaffold but not cells from the circulating blood while it was opposite in the inner microfiber scaffold. The processes of endothelium formation, smooth muscle cell regeneration, neo-tissue formation and vascularization of these scaffolds were analyzed with a rat left common carotid artery replacement model. Our data showed that smooth muscle cells' regeneration and vascularization were different among the four types of scaffolds. The thickest neo-tissue and α-SMA+ cell layers were detected in the microfiber scaffold group while the thinnest in the nanofiber scaffold group, and thicker neo-tissue and α-SMA+ cell layers were found in the outer microfiber bilayer scaffold group compared to the inner microfiber bilayer scaffold group. In addition, vascularization in the outer microfiber bilayer scaffold group and microfiber group was dramatically better than the inner microfiber bilayer scaffold group and the nanofiber group. Furthermore, we demonstrated that the regenerated SMCs were associated with the CD206+ macrophages in the graft wall. In all, the microfiber scaffold showed the best neo-tissue regeneration in vivo. These results indicate that the surrounding tissue contributes more to vascular regeneration than circulating blood. This finding gives a significant design clue that modulating the vascular surrounding tissue will be an alternative strategy for designing advanced and feasible small diameter vascular grafts.

Rationale: Vascular progenitor cells play key roles in physiological and pathological vascular remodelinga process that is crucial for the regeneration of acellular biodegradable scaffolds engineered as vital strategies against the limited availability of healthy autologous vessels for bypass grafting. Therefore, understanding the mechanisms driving vascular progenitor cells recruitment and differentiation could help the development of new strategies to improve tissue-engineered vessel grafts and design drug-targeted therapy for vessel regeneration. Objective: In this study, we sought to investigate the role of Dkk3 (dickkopf-3), recently identified as a cytokine promotor of endothelial repair and smooth muscle cell differentiation, on vascular progenitor cells cell migration and vascular regeneration and to identify its functional receptor that remains unknown. Methods and Results: Vascular stem/progenitor cells were isolated from murine aortic adventitia and selected for the Sca-1 (stem cell antigen-1) marker. Dkk3 induced the chemotaxis of Sca-1+ cells in vitro in transwell and wound healing assays and ex vivo in the aortic ring assay. Functional studies to identify Dkk3 receptor revealed that overexpression or knockdown of chemokine receptor CXCR7 (C-X-C chemokine receptor type 7) in Sca-1+ cells resulted in alterations in cell migration. Coimmunoprecipitation experiments using Sca-1+ cell extracts treated with Dkk3 showed the physical interaction between DKK3 and CXCR7, and specific saturation binding assays identified a high-affinity Dkk3-CXCR7 binding with a dissociation constant of 14.14 nmol/L. Binding of CXCR7 by Dkk3 triggered the subsequent activation of ERK1/2 (extracellular signal-regulated kinases 1/2)-, PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B)-, Rac1 (Ras-related C3 botulinum toxin substrate 1)-, and RhoA (Ras homolog gene family, member A)-signaling pathways involved in Sca-1+ cell migration. Tissue-engineered vessel grafts were fabricated with or without Dkk3 and implanted to replace the rat abdominal aorta. Dkk3-loaded tissue-engineered vessel grafts showed efficient endothelization and recruitment of vascular progenitor cells, which had acquired characteristics of mature smooth muscle cells. CXCR7 blocking using specific antibodies in this vessel graft model hampered stem/progenitor cell recruitment into the vessel wall, thus compromising vascular remodeling. Conclusions: We provide a novel and solid evidence that CXCR7 serves as Dkk3 receptor, which mediates Dkk3-induced vascular progenitor migration in vitro and in tissue-engineered vessels, hence harnessing patent grafts resembling native blood vessels.

Long-term results of implants in small animal models can be used to optimize the design of grafts to further promote tissue regeneration. In previous study, we fabricated a poly(ɛ-caprolactone) (PCL) bi-layered vascular graft consisting of an internal layer with circumferentially aligned microfibers and an external layer with random nanofibers. The circumferentially oriented vascular smooth muscle cells (VSMCs) were successfully regenerated after the grafts were implanted in rat abdominal aorta for 3 months. Here we investigated the long-term (18 months) performance of the bi-layered grafts in the same model. All the grafts were patent. No thrombosis, aneurysm, or stenosis occurred. The endothelium maintained complete. However, most of circumferentially oriented VSMCs migrated to luminal surface of the grafts to form a neointima with uniform thickness. Accordingly, extracellular matrix including collagen, elastin, and glycosaminoglycan displayed high density in neointima layer while with low density in the grafts wall because of the incomplete degradation of PCL. A small amounts of calcification occurred in the grafts. The contraction and relaxation function of regenerated neoartery almost disappeared. These data indicated that based on the structure design, many other factors of grafts should be considered to achieve the regenerated neoartery similar to the native vessels after long-term implantation. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2596-2604, 2018.

Background: Dickkopf-3 (Dkk3) is a secreted protein that may have a role in vascular diseases by promoting smooth muscle cell (SMC) differentiation and endothelial repair, two processes in which vascular stem/progenitor cells could be involved. However, the effect of Dkk3 on stem/progenitor cell migration and its specific receptor on these cells remain unknown. Methods: Vascular stem/progenitor cells (VPCs) were isolated from murine aortic adventitia and selected for the Sca-1 marker. The chemotactic ability of Dkk3 for Sca-1+ cells was tested in vitro using transwell and wound healing assays and ex vivo by the aortic ring assay. Chemokine receptors identification was carried out using Western blot (WB), siRNA-mediated knockdown, co-Immunoprecipitation (Co-IP) and saturation binding assays. To assess in vivo the role of Dkk3 in recruiting Sca-1+ cells, tissue-engineered vessel grafts, with or without Dkk3, were fabricated and implanted to replace the rat abdominal aorta. Results: We demonstrated that Dkk3 induced the chemotaxis of Sca-1+ cells in vitro , and ex vivo in culture of aortic rings derived from Sca-1-GFP transgenic mice. Flow cytometry and WB analysis revealed that Sca-1+ cells expressed CXCR7, while overexpression or knockdown of CXCR7 resulted in alterations in cell migration. Interestingly, Co-IP experiments showed the physical interaction between DKK3 and CXCR7, and specific saturation binding assays identified a high affinity Dkk3-receptor binding with a dissociation constant of 14.14 nM. Activation of CXCR7 by Dkk3 triggered the ERK1/2, PI3K/AKT, Rac1 and RhoA signalling pathways. Furthermore, when Dkk3-loaded tissue-engineered vessels were grafted to the abdominal artery of rats, the grafts showed efficient endothelization and recruitment of VPCs, which had acquired characteristics of mature SMCs. CXCR7 blocking using specific antibodies in our vessel graft model hampered stem/progenitor cell recruitment into the vessel wall, thus compromising vascular remodelling. Conclusions: We provide novel and solid evidence that CXCR7 serves as Dkk3 receptor, which mediates Dkk3-induced VPCs migration in vitro and in tissue-engineered vessels, hence harnessing patent grafts resembling native blood vessels.

Vascular graft has proven to be an effective strategy for the treatment of cardiovascular diseases. However grafts made solely from synthetic polymers cannot satisfy the clinic requirements in terms of low long-term patency, because they only provide a simple structural or physical replacement without the biological functions. In order to address the issue, we aim to fabricate vascular grafts which could mimic native extracellular matrix (ECM) in terms of both physiological structure and bio-functions. Different types of strategies and techniques have been explored to realize this purpose, including graft structure optimization, surface/interface functionalization, and controlled delivery of vascoactive molecules.Up to now, we have successfully fabricated a kind of vascular grafts with dual surface functions of anti-thrombogenicity and rapid endothelialization. Through structural optimization, the problem of limited cellularization in vascular grafts has been effectively resolved, and thus the vascular regeneration as well as the homeostasis has been improved. Furthermore, incorporation of some specific cytokines (such as Dickkopf-3) into the micro/nano- fibrous vascular grafts could enhance the migration vascular progenitor cells (VPCs) into the grafts and further induce the differentiation of them, contributing to endothelialisation and intima/media formation. In addition, vascular grafts loaded with exosomes derived from mesenchymal stem cells have been successfully prepared, and delivered exosomes exhibited immunomodulation function which is very important for the vascular regeneration and inhibition of calcification.

Wound healing dressings are increasingly needed clinically due to the large number of skin damage annually. Nitric oxide (NO) plays a key role in promoting wound healing, thus biomaterials with NO-releasing property receive increasing attention as ideal wound dressing. In present study, we prepared a novel functional wound dressing by combining electrospun poly(ε-caprolactone) (PCL) nonwoven mat with chitosan-based NO-releasing biomaterials (CS-NO). As-prepared PCL/CS-NO dressing released NO sustainably under the physiological conditions, which was controlled by the catalysis of β-galactosidase. In vivo wound healing characteristics were further evaluated on full-thickness cutaneous wounds in mice. Results showed that PCL/CS-NO wound dressings remarkably accelerated wound healing process through enhancing re-epithelialization and granulation formation and effectively improved the organization of regenerated tissues including epidermal-dermal junction, which could be ascribed to the pro-angiogenesis, immunomodulation, and enhanced collagen synthesis provided by the sustained release of NO. Therefore, PCL/CS-NO may be a promising candidate for wound dressings, especially for the chronic wound caused by the ischemia. STATEMENT OF SIGNIFICANCE:Serious skin damage caused by trauma, surgery, burn or chronic disease has become one of the most serious clinical problems. Therefore, there is an increasing demand for ideal wound dressing that can improve wound healing. Due to the vital role of nitric oxide (NO), we developed a novel functional wound dressing by combining electrospun polycaprolactone (PCL) mat with NO-releasing biomaterial (CS-NO). The sustained release of NO from PCL/CS-NO demonstrated positive effects on wound healing, including pro-angiogenesis, immunomodulation, and enhanced collagen synthesis. Hence, wound healing process was remarkably accelerated and the organization of regenerated tissues was effectively improved as well. Taken together, PCL/CS-NO dressing may be a promising candidate for wound treatment, especially for the chronic wound caused by the ischemia.

Rapid endothelialization is a key factor that determines the success of small-diameter vascular grafts as an artery substitute in the treatment of cardiovascular diseases. Aimed to facilitate vascular regeneration, we developed a vascular scaffold loaded with resveratrol, which is a natural compound extracted from plants and showed multifaceted effects in cardiovascular protection. The tubular poly(ε-caprolactone) (PCL) scaffold was prepared by electrospinning with resveratrol in the PCL solution. In vitro assay demonstrated that resveratrol could be released from the scaffolds in a sustained and controlled manner. Cell culture results indicated that the migration of endothelial cells (ECs), nitric oxide production, and the ability of tube formation increased in the resveratrol-containing PCL scaffold groups compared with the PCL control. Meanwhile, the level of tumor necrosis factor (TNF)-α, the main proinflammatory factor secreted from macrophages, was reduced, and the messenger RNA expressions of the M2 macrophage-related genes were increased in the resveratrol-containing group. Further, in vivo implantation was performed by replacing rat abdominal aorta. We observed fast endothelialization and enhanced vascular regeneration in rats with resveratrol-containing scaffolds. The presence of resveratrol also induced a large number of M2 macrophages to infiltrate into the graft wall. Taken together, the incorporation of resveratrol into the PCL grafts enhanced the vascular regeneration by modulation of ECs and macrophages.

Long-term evaluation of vascular grafts is an essential step to facilitate clinical translation. In this study, we investigate the long-term performance of a macro-porous poly(ɛ-caprolactone) (PCL) electrospun vascular graft using the rat abdominal artery replacement model. Long-term patency, endothelialization, and smooth muscle cell regeneration were evaluated, as well as calcification and degradation. The data showed that all the grafts remained open and unobstructed. There was no evidence of aneurysm, stenosis, or calcification one year after implantation. Importantly, neo-vessel was regenerated on the luminal surface of the graft, and was composed of a complete endothelial layer and several layers of smooth muscle cells. The neo-vessel showed vascular physiological function, although not as good as that in native blood vessels, likely due to the remaining scaffold fibers. These data indicated that the PCL macro-porous electrospun vascular graft has potential to be an artery substitute for long-term implantation. Also, this work indicates that continued efforts are needed to develop advanced vascular grafts that exhibit the appropriate balance between the regeneration of the neo-vessel and the complete degradation of the graft materials. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1618-1627, 2018.