Rapid Endothelialization Research Articles

A bilayer vascular scaffold with spatially controlled release of growth factors to enhance in situ rapid endothelialization and smooth muscle regeneration

When transplanting a scaffold to repair defected vascular tissues, there is a critical need to achieve in-situ rapid endothelialization together with the circumferential alignment and ingrowth of smooth muscle cells. To this end, we hereby design and fabricate a bilayer vascular scaffold with spatially controlled release of growth factors. The lumen of such a scaffold was made of electrospun poly(l-lactide-co-caprolactone) and collagen (PLCL/COL) nanofibers loaded with uniform heparin and vascular endothelial growth factors (VEGF), while its outer layer was composed of circumferentially aligned, PLCL/COL nanofiber yarns loaded with graded platelet derived growth factors (PDGF) increasing from the outermost toward the interior of the scaffold. With the controlled release of VEGF and PDGF from the scaffold, we showed a continuous greater release percentage (ca. 15%) of VEGF relative to PDGF over a duration of almost one month in vitro. At two-month post implantation in a rat abdominal aorta defect model, we observed rapid endothelialization at the luminal surface and orientated smooth muscles infiltrating inside the vascular wall. In particular, loose connective tissues rich in collagen fibers were produced at the outermost layer of the vascular scaffold, indicating the capability of such kind of vascular scaffold for in-situ vascular repair or regeneration.

Primary Results of the EVOLVE Short DAPT Study: Evaluation of 3-Month Dual Antiplatelet Therapy in High Bleeding Risk Patients Treated With a Bioabsorbable Polymer-Coated Everolimus-Eluting Stent.

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In vivo endothelialization and neointimal hyperplasia assessment after rabbit carotid endarterectomy with bovine pericardium.

BackgroundPrevious studies have reported that the use of a patch in carotid endarterectomy (CEA) surgery can reduce the rate of restenosis and perioperative complications. The goal of this study was to compare the short- and medium-term outcomes of endothelialization and neointimal hyperplasia of patch closure (PC) angioplasty in CEA with direct closure (DC) in a rabbit model. A bovine pericardial patch (BPP) was used in the PC procedures.MethodsTwo carotid arteries were dried by air flow to simulate endarterectomy and selected for PC and DC in each rabbit. Different animals were sacrificed at 1, 2, 3, 4, and 8 weeks after the procedure. The endarterectomized segments were extracted and examined microscopically with histopathological and immunohistochemical analysis, and electron-microscopy measurements.ResultsIn all, 19 rabbits were included in this study; 3 rabbits were placed in a 2-week postoperative group and 4 rabbits were placed in the 1-, 3-, 4-, and 8-week postoperative group respectively. Hematoxylin-eosin (HE) staining showed neointima on the PC side at an early stage (1-week postoperatively), and intimal hyperplasia could be seen on both sides. Immunohistochemical analysis showed that Ki-67 was higher on the PC side than on the DC side at an early stage (1,661.5±1,122.9 cells/mm2, P=0.060). In the 2-week postoperative group, von Willebrand factor (vWF) was higher on the DC side (−377.0±155.6 cells/mm2, P=0.052). Alpha-smooth muscle actin (α-SMA) values were comparable on both sides (P>0.05). Electron microscopy measurements showed that functional endothelial cells exhibited a cobblestone-like morphology and were nicely elongated in the direction of blood flow.ConclusionsThe use of BPP in PC angioplasty during CEA can maintain stability and also provide rapid endothelialization. PC with BPP has comparable ability of efficient endothelialization with DC, but is more likely to have early endothelialization.

Coronary stent CD31-mimetic coating favours endothelialization and reduces local inflammation and neointimal development in vivo.

AimsThe rapid endothelialization of bare metal stents (BMS) is counterbalanced by inflammation-induced neointimal growth. Drug-eluting stents (DES) prevent leukocyte activation but impair endothelialization, delaying effective device integration into arterial walls. Previously, we have shown that engaging the vascular CD31 co-receptor is crucial for endothelial and leukocyte homeostasis and arterial healing. Furthermore, we have shown that a soluble synthetic peptide (known as P8RI) acts like a CD31 agonist. The aim of this study was to evaluate the effect of CD31-mimetic metal stent coating on the in vitro adherence of endothelial cells (ECs) and blood elements and the in vivo strut coverage and neointimal growth.Methods and resultsWe produced Cobalt Chromium discs and stents coated with a CD31-mimetic peptide through two procedures, plasma amination or dip-coating, both yielding comparable results. We found that CD31-mimetic discs significantly reduced the extent of primary human coronary artery EC and blood platelet/leukocyte activation in vitro. In vivo, CD31-mimetic stent properties were compared with those of DES and BMS by coronarography and microscopy at 7 and 28 days post-implantation in pig coronary arteries (n = 9 stents/group/timepoint). Seven days post-implantation, only CD31-mimetic struts were fully endothelialized with no activated platelets/leukocytes. At day 28, neointima development over CD31-mimetic stents was significantly reduced compared to BMS, appearing as a normal arterial media with the absence of thrombosis contrary to DES.ConclusionCD31-mimetic coating favours vascular homeostasis and arterial wall healing, preventing in-stent stenosis and thrombosis. Hence, such coatings seem to improve the metal stent biocompatibility.

Preclinical assessment of a modified Occlutech left atrial appendage closure device in a porcine model

Left atrial appendage (LAA) closure is being developed as an alternative for stroke prevention in patients with atrial fibrillation that cannot tolerate long-term oral anticoagulation. To assess the feasibility, safety, and performance of a novel modified Occlutech LAA closure device in a preclinical porcine model, the modified Occlutech modified Occlutech Plus LAA closure device was implanted in 12 female pigs (25–39 kg body weight) under fluoroscopic and transesophageal echocardiography (TEE) guidance. Procedural and technical success, as well as safety of LAA closure, were evaluated peri-procedurally and after 4, 8, and 12 weeks. Moreover, after 4, 8 and, 12 weeks animals were sacrificed for pathological analysis (e.g., thrombus formation, device ingrowth, endothelialization, and inflammation). All LAA closure devices were successfully implanted. On follow-up, no serious adverse events such as device-associated thrombus or translocalization/embolization were observed. A clinically non-significant pericarditis was observed in 4 animals at the time of autopsy. Endothelialization of the device was visible after 4 weeks, advanced after 8 weeks and completed after 12 weeks. Immunohistochemistry showed low amounts of inflammatory infiltration on the edges of the device. The results of this study indicate that implantation of a modified Occlutech LAA closure device is feasible with rapid endothelialization and low inflammatory infiltration in a porcine model. Human data are needed to further characterize safety and efficacy.

Mechanically tuned vascular graft demonstrates rapid endothelialization and integration into the porcine iliac artery wall

Mechanical properties of vascular grafts likely play important roles in healing and tissue regeneration. Healthy arteries are compliant at low pressures but stiffen rapidly with increasing load, ensuring sufficient volumetric expansion without overstretching the vessel. Commercial synthetic vascular grafts are stiff and unable to expand under physiologic loads, which may result in altered hemodynamics, deleterious cellular responses, and compromised clinical performance. The goal of this study was to develop an Elastomeric Nanofibrillar Graft (ENG) with artery-tuned nonlinear compliance and compare its healing responses to conventional expanded polytetrafluoroethylene (ePTFE) grafts in a porcine iliac artery model. Human and porcine iliac arteries were mechanically characterized, and an ENG with similar properties was created by utilizing residual strains within electrospun nanofibers. The ENG was tested for implantation suitability and implanted onto n = 5 domestic swine iliac arteries, with control ePTFE grafts implanted onto the contralateral iliac arteries. After two weeks in vivo, all iliac arteries and grafts remained patent with no signs of thrombosis or dilation. The mechanically tuned ENG implants exhibited a more confluent CD31-positive cell monolayer (1.53 ± 0.73 µm2/mm vs 0.52 ± 0.55 µm2/mm, p = 0.042) on the graft lumenal surface and a higher fraction of αSMA-positive cells (16.2 ± 8.6% vs 1.4 ± 0.7%, p = 0.018) within the graft wall than the ePTFE controls. Despite heavy cellular infiltration, the ENG retained its artery-like mechanical characteristics after two weeks in vivo. These short-term results demonstrate potential advantages of mechanically tuned biomimetic vascular grafts over standard ePTFE grafts. Statement of SignificanceOff-the-shelf synthetic vascular grafts are often the only option available for treating advanced stages of vascular disease. Despite significant efforts devoted to improving their biochemical characteristics, synthetic peripheral arterial grafts continue to demonstrate poor clinical outcomes leading to costly reinterventions. Here, we hypothesized that a synthetic vascular graft with elastomeric mechanical properties tuned to a healthy peripheral artery promotes better healing responses than a synthetic stiff graft. To test this hypothesis, we developed an Elastomeric Nanofibrillar Graft (ENG) with artery-tuned mechanical properties and compared its performance to a commercial ePTFE graft in a preclinical porcine iliac artery model. Our results suggest that mechanically tuned ENGs can offer better healing responses, potentially leading to better clinical outcomes for peripheral arterial repairs.

One-Year COMBO Stent Outcomes in Acute Coronary Syndrome: from the COMBO Collaboration.

The COMBO biodegradable polymer sirolimus-eluting stent includes endothelial progenitor cell capture (EPC) technology for rapid endothelialization, which may offer advantage in acute coronary syndromes (ACS). We sought to analyze the performance of the COMBO stent by ACS status and ACS subtype. The COMBO collaboration (n = 3614) is a patient-level pooled dataset from the MASCOT and REMEDEE registries. We evaluated outcomes by ACS status, and ACS subtype in patients with ST segment elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI) versus unstable angina (UA). The primary endpoint was 1-year target lesion failure (TLF), composite of cardiac death, target vessel myocardial infarction, or clinically driven target lesion revascularization. Secondary outcomes included stent thrombosis (ST). We compared 1965 (54%) ACS and 1649 (46.0%) non-ACS patients. ACS presentations included 40% (n = 789) STEMI, 31% (n = 600) NSTEMI, and 29% (n = 576) UA patients. Risk of 1-year TLF was greater in ACS patients (4.5% vs. 3.3%, HR 1.51 95% CI 1.01-2.25, p = 0.045) without significant differences in definite/probable ST (1.1% vs 0.5%, HR 2.40, 95% CI 0.91-6.31, p = 0.08). One-year TLF was similar in STEMI, NSTEMI, and UA (4.8% vs 4.8% vs. 3.7%, p = 0.60), but definite/probable ST was higher in STEMI patients (1.9% vs 0.5% vs 0.7%, p = 0.03). Adjusted outcomes were not different in MI versus UA patients. Despite the novel EPC capture technology, COMBO stent PCI was associated with somewhat greater risk of 1-year TLF in ACS than in non-ACS patients, without significant differences in stent thrombosis. No differences were observed in 1-year TLF among ACS subtypes.

Fabrication and assessment of chondroitin sulfate-modified collagen nanofibers for small-diameter vascular tissue engineering applications

Chondroitin sulfate (ChS) has shown promising results in promoting cell proliferation and antithrombogenic activity. To engineered develop a dual-function vascular scaffold with antithrombosis and endothelialization, ChS was tethered to collagen to accelerate the growth of endothelial cells and prevent platelet activation. First, ChS was used to conjugate with collagen to generate glycosylated products (ChS-COL) via reductive amination. Then, the fabricated ChS-COL conjugates were electrospun into nanofibers and their morphologies and physicochemical characteristics, cell-scaffold responses and platelet behaviors upon ChS-COL nanofibers were comprehensively characterized to evaluate their potential use for small-diameter vascular tissue-engineered scaffolds. The experimental results demonstrated that the ChS modified collagen electrospun nanofibers were stimulatory of endothelial cell behavior, alleviated thrombocyte activation and maintained an antithrombotic effect in vivo in 10-day post-transplantation. The ChS-COL scaffolds encouraged rapid endothelialization, thus probably ensuring the antithrombotic function in long-term implantation, suggesting their promise for small-diameter vascular tissue engineering applications.

Heparinization and hybridization of electrospun tubular graft for improved endothelialization and anticoagulation

Constructing biomimetic structure and immobilizing antithrombus factors are two effective methods to ensure rapid endothelialization and long-term anticoagulation for small-diameter vascular grafts. However, few literatures are available regarding simultaneous implementation of these two strategies. Herein, a nano-micro-fibrous biomimetic graft with a heparin coating was prepared via a step-by-step in situ biosynthesis method to improve potential endothelialization and anticoagulation. The 4-mm-diameter tubular graft consists of electrospun cellulose acetate (CA) microfibers and entangled bacterial nanocellulose (BNC) nanofibers with heparin coating on dual fibers. The hybridized and heparinized graft possesses suitable pore structure that facilitates endothelia cells adhesion and proliferation but prevents infiltration of fibrous tissue and blood leakage. In addition, it shows higher mechanical properties than those of bare CA and hybridized CA/BNC grafts, which match well with native blood vessels. Moreover, this dually modified graft exhibits improved blood compatibility and endothelialization over the counterparts without hybridization or heparinization according to the testing results of platelet adhesion, cell morphology, and protein expression of von Willebrand Factor. This novel graft with dual modifications shows promising as a new small-diameter vascular graft. This study provides a guidance for promoting endothelialization and blood compatibility by dual modifications of biomimetic structure and immobilized bioactive molecules.

Comparison of in Vascular Bioreactors and In Vivo Models of Degradation and Cellular Response of Mg-Zn-Mn Stents.

Traditional in vitro evaluation criteria of magnesium (Mg)-based stents cannot reflect the degradation process in vivo, due to the interdependence and interference between biodegradable properties and bioenvironment. The current direct and indirect evaluation approaches of in vitro biocompatibility do not have a hydrodynamic environment and vascular biological structure existing in vivo. Herein, we designed a vascular bioreactor to provide an ex vivo culture environment for vessels, which reveals the degradation behavior of Mg-Zn-Mn stent and the effect of its degradation on cells. We reported that rabbit carotid arteries could maintain native morphology and viability in the bioreactor under the best condition within a flow rate of 5.4 mL min-1 and a culture time of one week. With this culture condition, Mg-Zn-Mn stents were implanted into the arteries in the bioreactors and compared with in vivo rabbit models. The arteries maintained cell survival in the bioreactor, but the cell attachment was absent on the stent struts, associated with a fast degradation. Conversely, the stents achieved a rapid and complete endothelialization in vivo for two weeks. This study could provide a correlation and difference of the degradation behavior and cellular response to the degradation of Mg-based stent between ex vivo and in vivo approaches.

A biomimetic basement membrane consisted of hybrid aligned nanofibers and microfibers with immobilized collagen IV and laminin for rapid endothelialization

A biomimetic basement membrane consisted of hybrid aligned nanofibers and microfibers with immobilized collagen IV and laminin for rapid endothelialization

Improved Performance of Bacterial Nanocellulose Conduits by the Introduction of Silk Fibroin Nanoparticles and Heparin for Small-Caliber Vascular Graft Applications.

Bacterial nanocellulose (BNC) is a promising material for small-caliber artificial blood vessels, although promoting its anticoagulant properties with more rapid endothelialization would improve long-term patency. Silk fibroin nanoparticles (SFNP) were introduced into the luminal wall surface of BNC conduits both with and without heparin (Hep) through pressurization followed by fixation. Hep was introduced in two ways: (1) embedded within SF nanoparticles to form SF-HepNPs for construction of the BNC-SF-HepNP conduit and (2) chemically grafted onto BNC and BNC-SFNP to form BNC-Hep and BNC-SFNP-Hep conduits. Fourier transform infrared spectroscopy confirmed the formation of SF-HepNPs, although they did not incorporate into the fibrillar network due to their large size. Hep was successfully grafted onto BNC and BNC-SFNP, verified by toluidine blue staining. The hemocompatibility and cytocompatibility of the five samples (BNC, BNC-SFNP, BNC-SF-HepNP, BNC-Hep, and BNC-SFNP-Hep conduits) were compared in vitro. The heparinized BNC-Hep and BNC-SFNP-Hep conduits improved the anticoagulant properties, and BNC-SFNP-Hep promoted human umbilical vein endothelial cell proliferation but also controlled excessive human arterial smooth muscle cell proliferation, assisting rapid endothelialization and improving lumen patency. No significant inflammatory reaction or material degradation was observed after subcutaneous implantation for 4 weeks. Autogenous tissues were observed around the conduits, and cells infiltrated into the edges of all samples, the BNC-SFNP conduit causing the deepest infiltration, providing an appropriate microenvironment for angiogenesis when used in small-caliber blood vessel applications. Few inflammatory cells were found around the BNC-Hep and BNC-SFNP-Hep conduits. Thus, the anticoagulant properties of the BNC-SFNP-Hep conduit and its stimulation of endothelialization suggest that it has great potential in clinical applications as a small-caliber artificial blood vessel.

Use of Elastic, Porous, and Ultrathin Co‐Culture Membranes to Control the Endothelial Barrier Function via Cell Alignment

AbstractPorous membranes used in co‐culture enable the in vitro partitioning of cellular microenvironments, while still permitting physical and biochemical crosstalk between cells. Thus, features of the co‐culture membrane are crucial for recapitulating the physiological functions of co‐cultured cells. This study presents elastic, porous, and ultrathin membranes (EPUMs), which enhance cell–cell interactions and control cell alignment with surface topology created by stretching the membranes. The EPUM is fabricated using poly(lactide‐co‐caprolactone) as the base material, and the porous feature is endowed by a vapor‐induced phase separation process induced by the presence of hygroscopic salt. Owing to its elastic property, the membrane can be stretched, and the deformed porous structures on the membrane surfaces act as nanostructured topographical cues, resulting in cell alignment. By co‐culturing human mesenchymal stem cells (hMSCs) and human umbilical vein endothelial cells (HUVECs) on the opposite sides of the membrane, rapid endothelialization occurs through the membranes, as compared to the commercial membranes. Furthermore, the stretched membranes induce the alignment of hMSCs and HUVECs and ultimately exhibit enhanced endothelial barrier function. The co‐culture membrane developed in this study may provide an effective tool for recapitulating endothelial basement membranes with a controllable endothelial barrier function.

Expanded polytetrafluoroethylene/silk fibroin/salicin vascular graft fabrication for improved endothelialization and anticoagulation

Clinical application of small-diameter artificial vascular grafts has been hampered by intimal blockages owing to the lack of an endothelial layer and the formation of thrombosis. In this study, an expanded polytetrafluoroethylene (ePTFE) vascular graft was fabricated using a biofriendly ethanol/water mixture as a lubricant and drug carrier. Natural silk fibroin (SF) hydrogel and white willow extract salicin were embedded into ePTFE graft successfully via the ethanol/water lubricant and drug carrier as verified by Fourier-transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). The ePTFE graft functionalized by SF hydrogel improved the proliferation of human umbilical vein endothelial cell (HUVEC) due to SF’s hydrophilia and cytocompatibility as measured by the live/dead and cell counting kit-8 (CCK-8) assays. The rapid endothelialization of ePTFE graft helped reduced intimal blockages in vitro. Furthermore, the salicin-modified ePTFE graft exhibited an anticoagulation property as demonstrated by platelet adhesion and activated partial thromboplastin time (APTT) tests. These results suggest that ePTFE graft fabricated with silk fibroin and salicin can be an attractive candidate for vascular grafts.

Covalent grafting of PEG and heparin improves biological performance of electrospun vascular grafts for carotid artery replacement

Rapid endothelialization of small-diameter vascular grafts remains a significant challenge in clinical practice. In addition, compliance mismatch causes intimal hyperplasia and finally leads to graft failure. To achieve compliance match and rapid endothelialization, we synthesized low-initial-modulus poly(ester-urethane)urea (PEUU) elastomer and prepared it into electrospun tubular grafts and then functionalized the grafts with poly(ethylene glycol) (PEG) and heparin via covalent grafting. The PEG- and heparin-functionalized PEUU (PEUU@PEG-Hep) graft had comparable mechanical properties with the native blood vessel. In vitro data demonstrated that the grafts are of good cytocompatibility and blood compatibility. Covalent grafting of PEG and heparin significantly promoted the adhesion, spreading, and proliferation of human umbilical vein endothelial cells (HUVECs) and upregulated the expression of vascular endothelial cell-related genes, as well as increased the capability of grafts in preventing platelet deposition. In vivo assessments indicated good biocompatibility of the PEUU@PEG-Hep graft as it did not induce severe immune responses. Replacement of resected carotid artery with the PEUU@PEG-Hep graft in a rabbit model showed that the graft was capable of rapid endothelialization, initiated vascular remodeling, and maintained patency. This study demonstrates the PEUU@PEG-Hep vascular graft with compliance match and efficacious antithrombosis might find opportunities for bioactive blood vessel substitutes.

Fluid targeted delivery of functionalized magnetoresponsive nanocomposite particles to a ferromagnetic stent

Vascular stent implantation needs a rapid endothelialization to reduce morbidity and improve patient outcomes. A promising strategy to enhance the artery wall healing is to use the site-specific drug targeting technique to deliver the required medication at the site of injury. This work presents a new concept of using permanent magnet systems to guide and target the functionalized magnetoresponsive nanocomposite clusters around the ferromagnetic stent. In our experiment, the PEG-coated magnetic clusters capture and deposition are based on the competition between the drag force and the magnetic force exerted by both the magnetic field gradient generated by the permanent external magnet and the ferromagnetic stent. Also, the ferromagnetic stent was tested for biological toxicity, and the result shown the excellent device biocompatibility. Stent magnetic particle targeting process generates an almost uniform strut coverage with PEG-coated MNP’s within the different stent segments (proximal, central, and distal segment), but visibly different between stent segments. The magnetic clusters deposition stability in time demonstrates that stent struts coverage remains quasi constant after 1 min of exposure to the flow shear stress.

Poloxamer additive as luminal surface modification to modulate wettability and bioactivities of small-diameter polyurethane/polycaprolactone electrospun hollow tube for vascular prosthesis applications

In regard of engineering small-diameter vascular graft, a stable surface treatment targeting only the tube lumen toward rapid endothelialization and anti-thrombosis without weakening or deconstructing the prosthesis remains a technical challenge. In this study, a bilayer hollow tube with a hydrophilic inner layer polyurethane/polycaprolactone/Poloxamer (PU/PCL/Poloxamer) was fabricated. Poloxamer 407 was blended with PU/PCL as a one-step surface modification to enhance the hydrophilicity and bioactive properties of the electrospun tube’s luminal surface. Hydrophobic polypropylene glycol backbones anchored poloxamer onto based polymer while hydrophilic side chains migrated to the surface to modify the behaviors of electrospun inner surface. The poloxamer blended surface, interestingly, exhibited complicated attraction and repellent behaviors regulated by the dynamic of PEG chains. Moderate grafting density (2 %–8 %) exhibited high bioactive performance of PEG tails to simultaneously modulate cells' adhesion, elongation and proliferation while restricting platelet adhesion in comparison with PU/PCL and super-hydrophilic PU/PCL/Poloxamer surface. The elevation of poloxamer content in composition resulted in a corresponding increase in both hydrophilicity and tensile strength while maintained the homogenous fibrous structure of electrospun mat. Besides, a hydrophobic outer layer PU/PCL was fabricated to prevent the leakage and permeable transmembrane phenomenon toward the sustain application in vascular engineering.

Mimicking the Nitric Oxide-Releasing and Glycocalyx Functions of Endothelium on Vascular Stent Surfaces.

Endothelium can secrete vasoactive mediators and produce specific extracellular matrix, which contribute jointly to the thromboresistance and regulation of vascular cell behaviors. From a bionic point of view, introducing endothelium‐like functions onto cardiovascular stents represents the most effective means to improve hemocompatibility and reduce late stent restenosis. However, current surface strategies for vascular stents still have limitations, like the lack of multifunctionality, especially the monotony in endothelial‐mimic functions. Herein, a layer‐by‐layer grafting strategy to create endothelium‐like dual‐functional surface on cardiovascular scaffolds is reported. Typically, a nitric oxide (NO, vasoactive mediator)‐generating compound and an endothelial polysaccharide matrix molecule hyaluronan (HA) are sequentially immobilized on allylamine‐plasma‐deposited stents through aqueous amidation. In this case, the stents could be well‐engineered with dual endothelial functions capable of remote and close‐range regulation of the vascular microenvironment. The synergy of NO and endothelial glycocalyx molecules leads to efficient antithrombosis, smooth muscle cell (SMC) inhibition, and perfect endothelial cell (EC)‐compatibility of the stents in vitro. Moreover, the dual‐functional stents show efficient antithrombogenesis ex vivo, rapid endothelialization, and long‐term prevention of restenosis in vivo. Therefore, this study will provide new solutions for not only multicomponent surface functionalization but also the bioengineering of endothelium‐mimic vascular scaffolds with improved clinical outcomes.

Endothelial progenitor cells as the target for cardiovascular disease prediction, personalized prevention, and treatments: progressing beyond the state-of-the-art.

Stimulated by the leading mortalities of cardiovascular diseases (CVDs), various types of cardiovascular biomaterials have been widely investigated in the past few decades. Although great therapeutic effects can be achieved by bare metal stents (BMS) and drug-eluting stents (DES) within months or years, the long-term complications such as late thrombosis and restenosis have limited their further applications. It is well accepted that rapid endothelialization is a promising approach to eliminate these complications. Convincing evidence has shown that endothelial progenitor cells (EPCs) could be mobilized into the damaged vascular sites systemically and achieve endothelial repair in situ, which significantly contributes to the re-endothelialization process. Therefore, how to effectively capture EPCs via specific molecules immobilized on biomaterials is an important point to achieve rapid endothelialization. Further, in the context of predictive, preventive, personalized medicine (PPPM), the abnormal number alteration of EPCs in circulating blood and certain inflammation responses can also serve as important indicators for predicting and preventing early cardiovascular disease. In this contribution, we mainly focused on the following sections: the definition and classification of EPCs, the mechanisms of EPCs in treating CVDs, the potential diagnostic role of EPCs in predicting CVDs, as well as the main strategies for cardiovascular biomaterials to capture EPCs.

Evaluation of remodeling and regeneration of electrospun PCL/fibrin vascular grafts in vivo.

The success of artificial vascular graft in the host to obtain functional tissue regeneration and remodeling is a great challenge in the field of small diameter tissue engineering blood vessels. In our previous work, poly(ε-caprolactone) (PCL)/fibrin vascular grafts were fabricated by electrospinning. It was proved that the PCL/fibrin vascular graft was a suitable small diameter tissue engineering vascular scaffold with good biomechanical properties and cell compatibility. Here we mainly examined the performance of PCL/fibrin vascular graft in vivo. The graft showed randomly arranged nanofiber structure, excellent mechanical strength, higher compliance and degradation properties. At 9 months after implantation in the rat abdominal aorta, the graft induced the regeneration of neoarteries, and promoted ECM deposition and rapid endothelialization. More importantly, the PCL/fibrin vascular graft showed more microvessels density and fewer calcification areas at 3 months, which was beneficial to improve cell infiltration and proliferation. Moreover, the ratio of M2/M1macrophage in PCL/fibrin graft had a higher expression level and the secretion amount of pro-inflammatory cytokines started to increase, and then decreased to similar to the native artery. Thus, the electrospun PCL/fibrin tubular vascular graft had great potential to become a new type of artificial blood vessel scaffold that can be implanted in vivo for long term.