Artificial Vascular Grafts Research Articles

Precise Preparation of a Multilayer Tubular Cell Sheet with Well-Aligned Cells in Different Layers to Simulate Native Arteries

Compared with artificial vascular grafts, bottom-up tubular cell sheets (TCSs) without scaffolds have shown promise for patients with cardiovascular disease. However, TCS therapy also faces the challenges of lengthy maturation time, elaborate operation, and weak mechanical strength. In this work, a structured small-diameter vascular graft (SDVG), consisting of three layers of TCSs, with different cell types and arrangements, was fabricated using layer-by-layer assembly of naturally formed TCSs and further cell culture. To this end, a surface-patterned collagen-coated cylindrical substrate was designed for the efficient harvesting of naturally formed and well-aligned TCSs. The patterned collagen (type I) layer facilitated the adhesion and orientation of cells, and a continuous tubular cell monolayer was naturally formed after approximately 4 days in cell culture. Biocompatible near-infrared (NIR) light was used to trigger the photothermal phase transition of the collagen coated on the cylindrical substrate to dissociate the collagen layer. As a result, an intact TCS could be harvested within a few minutes. These naturally formed and well-aligned TCSs exhibited outstanding free-standing performance without rugosity, facilitating their operability and practical application. A ring tensile test showed that orientation was critical for improving the mechanical properties of TCSs. The layer-by-layer assembly of SDVGs not only is easy to manipulate and has a short preparation time but also overcomes the bottleneck of forming a hierarchically structured vascular graft. This approach shows promise for repairing damaged blood vessels.

Resealable Antithrombotic Artificial Vascular Graft Integrated with a Self-Healing Blood Flow Sensor.

Coronary artery bypass grafting is commonly used to treat cardiovascular diseases by replacing blocked blood vessels with autologous or artificial blood vessels. Nevertheless, the availability of autologous vessels in infants and the elderly and low long-term patency rate of grafts hinder extensive application of autologous vessels in clinical practice. The biological and mechanical properties of the resealable antithrombotic artificial vascular graft (RAAVG) fabricated herein, comprising a bioelectronic conduit based on a tough self-healing polymer (T-SHP) and a lubricious inner coating, match with the functions of autologous blood vessels. The self-healing and elastic properties of the T-SHP confer resistance against mechanical stimuli and promote conformal sealing of suturing regions, thereby preventing leakage (stable fixation under a strain of 50%). The inner layer of the RAAVG presents antibiofouling properties against blood cells and proteins, and antithrombotic properties, owing to its lubricious coating. Moreover, the blood-flow sensor fabricated using the T-SHP and carbon nanotubes is seamlessly integrated into the RAAVG via self-healing and allows highly sensitive monitoring of blood flow at low and high flow rates (10- and 100 mL min-1, respectively). Biocompatibility and feasibility of RAAVG as an artificial graft were demonstrated via ex vivo, and in vivo experiment using a rodent model. The use of RAAVGs to replace blocked blood vessels can improve the long-term patency rate of coronary artery bypass grafts.

Abstract Number ‐ 127: Poly(vinyl alcohol) grafts of brain aneurysms with patient‐specific morphologies

Introduction Current animal models of brain aneurysms used for testing neuro‐interventional devices have highly simplistic vascular anatomy in comparison with human aneurysm‐parent vessel complexes. Poly(vinyl alcohol) (PVA) is a leading biomaterial for manufacture of artificial vascular grafts because of its biocompatibility, hemocompatibility, availability, low cost, moldability/castability, and tunable mechanical properties to match arterial compliance [1,2]. However, PVA is non‐cell adhesive and requires modification with additives to promote endothelialization of the luminal surface to maintain long‐term graft patency [1,3]. We have previously studied the biocompatibility of resorcinol bis(diphenyl phosphate) (RDP) coated clays blended with polymers and have found excellent cell adhesion and proliferation with human dermal fibroblasts as well as dental pulp stem cells [4]. Our overall goal is to develop a new in vivo model of brain aneurysms by manufacturing patient‐specific aneurysm anatomies with a blend of PVA and RDP clay and grafting them into animals. Here, we evaluate the casting of PVA in the shape of patient‐specific aneurysms. Methods 10% PVA (w/w) (99% hydrolyzed, 85–124K molecular weight, Sigma Aldrich) was dissolved in deionized water, to which 1% RDP clay (ICL Industrial Products, Be’er Sheva, Israel) was added. The PVA was crosslinked using 15% (w/w) of sodium trimetaphosphate and 30% (w/w) of sodium hydroxide, after which rheological studies (stress sweeps using a Bohlin Gemini rheometer) were conducted. In the casting procedure, negative molds of both simple tubes and complex aneurysm geometries were designed using Rhinoceros 3D software (Robert McNeel & Associates, Seattle, WA) and 3D printed in ABS plastic. The negative mold was then filled with beeswax, resulting in a positive wax mold that was dip‐coated 8 times in PVA solution, and spun on a two‐axis spinner in between each dip to ensure even coverage. After overnight drying in a fume hood, the model was placed in heated water, allowing the wax to melt out and leaving behind the luminal PVA cast. Results Rheology on the crosslinked polymers showed that the PVA/RDP blend exhibited over twice the elastic modulus of unblended PVA (Figure A). Such enhanced mechanical properties are consistent with previous studies [5]. Both simple tubular geometries and patient‐specific anatomies were able to be successfully cast using the methodology developed here (Figure B). Conclusions This proposed casting methodology demonstrates a realistic, efficient way to replicate complex aneurysm geometries with comparatively inexpensive materials and short time frame. Future endeavors will include further exploration of the PVA/RDP biocompatibility as well as completing the casting procedure with a PVA/RDP blend.

Experimental surgery as part of the development of degradable biomaterials for cardiovascular surgery

Introduction: Cardiovascular diseases are responsible for significant morbidity and mortality in the population. Artificial vascular grafts are often essential for surgical procedures in radical or palliative treatment. Many new biodegradable materials are currently under development. Preclinical testing of each new material is imperative, both in vitro and in vivo, and therefore animal experiments are still a necessary part of the testing process before any clinical use. The aim of this paper is to present the options of using various experimental animal models in the field of cardiovascular surgery including their extrapolation to clinical medicine. Methods: The authors present their general experience in the field of experimental surgery. They discuss the selection process of an optimal experimental animal model to test foreign materials for cardiovascular surgery and of an optimal region for implantation. Results: The authors present rat, rabbit and porcine models as optimal experimental animals for material hemocompatibility and degradability testing. Intraperitoneal implantation in the rat is a simple and feasible procedure, as well as aortic banding in the rabbit or pig. The carotid arteries can also be used, as well. Porcine pulmonary artery banding is slightly more difficult with potential complications. The banded vessels, explanted after a defined time period, are suitable for further mechanical testing using biomechanical analyses, for example, the inflation-extension test. Conclusion: An in vivo experiment cannot be avoided in the last phases of preclinical research of new materials. However, we try to strictly observe the 3R concept – Replacement, Reduction and Refinement; in line with this concept, the potential of each animal should be used as much as possible to reduce the number of animals.

Tannic Acid-Assisted Immobilization of Copper(II), Carboxybetaine, and Argatroban on Poly(ethylene terephthalate) Mats for Synergistic Improvement of Blood Compatibility and Endothelialization.

Due to thrombosis and intimal hyperplasia, small-diameter vascular grafts have poor long-term patency. A combination strategy based on nitric oxide (NO) and anticoagulants has the potential to address those issues. In this study, poly(ethylene terephthalate) (PET) mats were prepared by electrospinning and coated with tannic acid (TA)/copper ion complexes. The chelated copper ions endowed the mats with sustained NO generation by catalytic decomposition of endogenous S-nitrosothiol. Subsequently, zwitterionic carboxybetaine acrylate (CBA) and argatroban (AG) were immobilized on the mats. The introduced AG and CBA had synergistic effects on the improvement of blood compatibility, resulting in reduced platelet adhesion and prolonged blood clotting time. The biocomposite mats selectively promoted the proliferation and migration of human umbilical vein endothelial cells while inhibiting the proliferation and migration of human umbilical arterial smooth muscle cells under physiological conditions. In addition, the prepared mats exhibited antibacterial activity against Escherichia coli and Staphylococcus aureus. Collectively, the prepared mats hold great promise as artificial small-diameter vascular grafts.

Construction of PCL-collagen@PCL@PCL-gelatin three-layer small diameter artificial vascular grafts by electrospinning

The demand for artificial vascular grafts in clinical applications is increasing, and it is urgent to design a tissue-engineered vascular graft with good biocompatibility and sufficient mechanical strength. In this study, three-layer small diameter artificial vascular grafts were constructed by electrospinning. Polycaprolactone (PCL) and collagen (COL) were used as the inner layer to provide good biocompatibility and cell adhesion, the middle layer was PCL to improve the mechanical properties, and gelatin (GEL) and PCL were used to construct the outer layer for further improving the mechanical properties and biocompatibility of the vascular grafts in the human body environment. The electrospun artificial vascular graft had good biocompatibility and mechanical properties. Its longitudinal maximum stress reached 2.63 ± 0.12 MPa, which exceeded the maximum stress that many natural blood vessels could withstand. The fiber diameter of the vascular grafts was related to the proportion of components that made up the vascular grafts. In the inner structure of the vascular grafts, the hydrophilicity of the vascular grafts was enhanced by the addition of COL to the PCL, and human umbilical vein endothelial cells (HUVECs) adhered more easily to the vascular grafts. In particular, the cytocompatibility and proliferation of HUVECs on the scaffold with an inner structure PCL:COL = 2:1 was superior to other ratios of vascular grafts. The vascular grafts did not cause hemolysis of red blood cells. Thus, the bionic PCL-COL@PCL@PCL-GEL composite graft is a promising material for vascular tissue engineering.

Feasibility of using artificial vascular grafts in one-orifice venoplasty for middle hepatic vein reconstruction during living donor liver transplantation

Feasibility of using artificial vascular grafts in one-orifice venoplasty for middle hepatic vein reconstruction during living donor liver transplantation

Matrix Regeneration Ability In Situ Induced by a Silk Fibroin Small-Caliber Artificial Blood Vessel In Vivo.

The success of a small-caliber artificial vascular graft in the host in order to obtain functional tissue regeneration and remodeling remains a great challenge in clinical application. In our previous work, a silk-based, small-caliber tubular scaffold (SFTS) showed excellent mechanical properties, long-term patency and rapid endothelialization capabilities. On this basis, the aim of the present study was to evaluate the vascular reconstruction process after implantation to replace the common carotid artery in rabbits. The new tissue on both sides of the SFTSs at 1 month was clearly observed. Inside the SFTSs, the extracellular matrix (ECM) was deposited on the pore wall at 1 month and continued to increase during the follow-up period. The self-assembled collagen fibers and elastic fibers were clearly visible in a circumferential arrangement at 6 months and were similar to autologous blood vessels. The positive expression rate of Lysyl oxidase-1 (LOXL-1) was positively correlated with the formation and maturity of collagen fibers and elastic fibers. In summary, the findings of the tissue regeneration processes indicated that the bionic SFTSs induced in situ angiogenesis in defects.

The loading of C-type natriuretic peptides improved hemocompatibility and vascular regeneration of electrospun poly(ε-caprolactone) grafts

As a result of thrombosis or intimal hyperplasia, synthetic artificial vascular grafts had a low success rate when they were used to replace small-diameter arteries (inner diameter < 6 mm). C-type natriuretic peptides (CNP) have anti-thrombotic effects, and can promote endothelial cell (EC) proliferation and inhibit vascular smooth muscle cell (SMC) over-growth. In this study, poly(ε-caprolactone) (PCL) vascular grafts loaded with CNP (PCL-CNP) were constructed by electrospinning. The PCL-CNP grafts were able to continuously release CNP at least 25 days in vitro. The results of scanning electron microscopy (SEM) and mechanical testing showed that the loading of CNP did not change the microstructure and mechanical properties of the PCL grafts. In vitro blood compatibility analysis displayed that PCL-CNP grafts could inhibit thrombin activity and reduce platelet adhesion and activation. In vitro cell experiments demonstrated that PCL-CNP grafts activated ERK1/2 and Akt signaling in human umbilical vein endothelial cells (HUVECs), as well as increased cyclin D1 expression, enhanced proliferation and migration, and increased vascular endothelial growth factor (VEGF) secretion and nitric oxide (NO) production. The rabbit arteriovenous (AV)-shunt ex vitro indicated that CNP loading significantly improved the antithrombogenicity of PCL grafts. The assessment of vascular grafts in rat abdominal aorta implantation model displayed that PCL-CNP grafts promoted the regeneration of ECs and contractile SMCs, modulated macrophage polarization toward M2 phenotype, and enhanced extracellular matrix remodeling. These findings confirmed for the first time that loading CNP is an effective approach to improve the hemocompatibility and vascular regeneration of synthetic vascular grafts. Statement of significanceSmall-diameter (< 6 mm) vascular grafts (SDVGs) have not been made clinically available due to their prevalence of thrombosis, limited endothelial regeneration and intimal hyperplasia. The incorporation of bioactive molecules into SDVGs serves as an effective solution to improve hemocompatibility and endothelialization. In this study, for the first time, we loaded C-type natriuretic peptides (CNP) into PCL grafts by electrospunning and confirmed the effectiveness of loading CNP on improving the hemocompatibility and vascular regeneration of artificial vascular grafts. Regenerative advantages included enhancement of endothelialization, modulation of macrophage polarization toward M2 phenotypes, and improved contractile smooth muscle cell regeneration. Our investigation brings attention to CNP as a valuable bioactive molecule for modifying cardiovascular biomaterial.

Peripheral blood derived endothelial colony forming cells as suitable cell source for pre-endothelialization of arterial vascular grafts under dynamic flow conditions

In regenerative medicine, autologous peripheral blood derived endothelial colony forming cells (PB-derived ECFC) represent a promising source of endothelial cells (EC) for pre-endothelialization of arterial tissue engineered vascular grafts (TEVG) since they are readily attainable, can easily be isolated and possess a high proliferation potential. The aim of this study was to compare the phenotype of PB-derived ECFC with arterial and venous model cells such as human aortic endothelial cells (HAEC) and human umbilical vein endothelial cells (HUVEC) under dynamic cell culture conditions to find a suitable cell source of EC for pre-endothelialization. In this study PB-derived ECFC were cultivated over 24 h under a high pulsatile shear stress (20 dyn/cm2, 1 Hz) and subsequently analyzed. ECFC oriented and elongated in the direction of flow and expressed similar anti-thrombotic and endothelial differentiation markers compared to HAEC. There were significant differences observable in gene expression levels of CD31, CD34 and NOTCH4 between ECFC and HUVEC. These results therefore suggest an arterial phenotype for PB-derived ECFC both under static and flow conditions, and this was supported by NOTCH4 protein expression profiles. ECFC also significantly up-regulated gene expression levels of anti-thrombotic genes such as krueppel-like factor 2, endothelial nitric oxide synthase 3 and thrombomodulin under shear stress cultivation as compared to static conditions. Dynamically cultured PB-derived ECFC therefore may be a promising cell source for pre-endothelialization of arterial TEVGs.

Soft Biomimetic 3D Free-Form Artificial Vascular Graft Using a Highly Uniform Microspherical Porous Structure.

This study presents a biomimetic 3D customizable artificial vascular graft with a highly porous and uniform microscale structure. The structural features were obtained by dip coating of a highly close-packed microsphere suspension on a 3D printed sacrificial template. Considering the structured arrangement of microspherical porogens in the coating layer, the microsphere-leached constructs showed higher uniformity and porosity than the conventionally particulate-leached structures, leading to ultrasoft mechanical compliance. Considering biomechanical compatibility, the resulting elastic moduli were at the sub-MPa level, comparable with those of native vascular tissues. In addition, the developed porous graft was reinforced selectively at the edge regions using a nonporous coating to secure its practical sutureability for clinical use. The sufficiently low cytotoxicity was clinically confirmed to alleviate the stiffness mismatch issues at the anastomotic interface between the native tissue and the artificial graft, thus overcoming the relevant clinical complications. Furthermore, the overall superior properties could be implemented on the 3D printed template for patient-specific medicare, thus implying the manufacturability of patient-specific vascular grafts.

Review of Polymeric Biomimetic Small-Diameter Vascular Grafts to Tackle Intimal Hyperplasia.

Small-diameter artificial vascular grafts (SDAVG) are used to bypass blood flow in arterial occlusive diseases such as coronary heart or peripheral arterial disease. However, SDAVGs are plagued by restenosis after a short while due to thrombosis and the thickening of the neointimal wall known as intimal hyperplasia (IH). The specific causes of IH have not yet been deduced; however, thrombosis formation due to bioincompatibility as well as a mismatch between the biomechanical properties of the SDAVG and the native artery has been attributed to its initiation. The main challenges that have been faced in fabricating SDAVGs are facilitating rapid re-endothelialization of the luminal surface of the SDAVG and replicating the complex viscoelastic behavior of the arteries. Recent strategies to combat IH formation have been mostly based on imitating the natural structure and function of the native artery (biomimicry). Thus, most recently, developed grafts contain a multilayered structure with a designated function for each layer. This paper reviews the current polymeric, biomimetic SDAVGs in preventing the formation of IH. The materials used in fabrication, challenges, and strategies employed to tackle IH are summarized and discussed, and we focus on the multilayered structure of current SDAVGs. Additionally, the future aspects in this area are pointed out for researchers to consider in their endeavor.

Pre‐implantation evaluation of a small‐diameter, long vascular graft (Biotube®) for below‐knee bypass surgery in goats

There are no small-diameter, long artificial vascular grafts for below-knee bypass surgery in chronic limb-threatening ischemia. We have developed tissue-engineered vascular grafts called "Biotubes®" using a completely autologous approach called in-body tissue architecture (iBTA). This study aimed at pre-implantation evaluation of Biotube and its in vivo preparation device, Biotube Maker, for use in below-knee bypass surgery.Forty nine makers were subcutaneously embedded into 17 goats for predetermined periods (1, 2, or 3months). All makers produced Biotubes as designed without inflammation over all periods, with the exception of a few cases with minor defects (success rate: 94%). Small hole formation occurred in only a few cases. All Biotubes obtained had an inner diameter of 4 mm and a length of 51 to 52 cm with a wall thickness of 594 ± 97 μm. All Biotubes did not kink when completely bent under an internal pressure of 100 mmHg and did not leak without any deformation under a water pressure of 200 mmHg. Their burst strength was 2409 ± 473 mmHg, and suture retention strength was 1.75 ± 0.27 N, regardless of the embedding period, whereas tensile strength increased from 7.5± 1.3N at 1month to 9.7± 2.0N at 3months with the embedding period. The amount of water leakage from the needle holes prepared in the Biotube wall was approximately 1/7th of that in expanded polytetrafluoroethylene vascular grafts. The Biotubes could be easily connected to each other without cutting or anastomosis leaks. They could be stored for at least 1year at room temperature. This study confirmed that even Biotubes formed 1month after embedding of Biotube Makers had properties comparable to arteries.

Oligoglycine and fluoropolymer functionalized enzyme-responsive gene delivery surface for rapid in situ endothelialization of vascular grafts

The treatment success of small-caliber artificial vascular grafts is seriously limited by high thrombogenesis and low endothelialization. Gene transfection can effectively enhance the proliferation and migration of endothelial cells (ECs) and accelerating the formation of endothelium layer. How to efficiently and temporarily immobilize the gene complexes on the material surface, how to intelligently release them and effectively transfect ECs are still the challenges for in situ endothelialization. Herein, a matrix-metalloproteinase (MMP)-responsive gene delivery system is constructed for in situ smart release of genes from the graft surface. The fluorinated cationic polymer (F-ssPEI) is served as high-efficient and low-cytotoxic gene vector. The gene complexes are temporarily immobilized via a MMP-cleavable peptide (MCP) linker which contains a MMP-susceptible sequence as the principal part and oligoglycine sequence (Gm) with different units (m = 0, 4 and 8) as the flexible spacer arm. These gene delivery surfaces achieve the temporary immobilization, smart release and high internalization of gene complexes. The MCP(G8) group shows the highest transfection efficacy and the optimal HUVEC proliferation/migration/function. The enhanced endothelialization and contractile smooth muscle cell regeneration of grafts are achieved in vivo. The MMP-responsive gene delivery system provides an effective platform to promote regeneration of vascular graft.

Direct thrombin inhibitor-bivalirudin improved the hemocompatibility of electrospun polycaprolactone vascular grafts

Synthetic artificial vascular grafts are hampered by their low patency rate in substituting small-caliber arteries (inner diameter <6 mm) because of their poor hemocompatibility . As compared to the heparin, bivalirudin (BV), a direct thrombin inhibitor, is a more reliable anticoagulant. In this study, BV-loaded polycaprolactone (PCL) grafts (PCL-BV) were fabricated by electrospinning. The loading rate of BV was approximately 87%. The PCL-BV grafts achieved the sustained release of BV for up to 30 days in vitro , but mainly released in the first 15 days. Scanning electron microscopy (SEM) and mechanical testing revealed that the BV loading did not affect the structure and mechanical properties of PCL grafts. In vitro coagulation analysis showed that the loading of the BV reduced thrombin activity, prolonged hemocompatibility parameters (activated partial thromboplastin time (APTT), prothrombin time (PT) and thromboplastin time (TT)), reduced blood coagulation, and inhibited the adhesion and activation of fibrinogen (FIB) and platelets. The assessment of vascular grafts in a rabbit arteriovenous (AV)-shunt ex vitro and carotid artery implantation in vivo indicated that BV significantly improved the antithrombogenicity and patency of PCL grafts. Overall, these results suggested that the incorporation of BV into electrospun grafts would be an effective approach to improve the hemocompatibility and patency rate of synthetic vascular grafts.

History, progress and future challenges of artificial blood vessels: a narrative review.

ABSTRACTCardiovascular disease serves as the leading cause of death worldwide, with stenosis, occlusion, or severe dysfunction of blood vessels being its pathophysiological mechanism. Vascular replacement is the preferred surgical option for treating obstructed vascular structures. Due to the limited availability of healthy autologous vessels as well as the incidence of postoperative complications, there is an increasing demand for artificial blood vessels. From synthetic to natural, or a mixture of these components, numerous materials have been used to prepare artificial vascular grafts. Although synthetic grafts are more appropriate for use in medium to large-diameter vessels, they fail when replacing small-diameter vessels. Tissue-engineered vascular grafts are very likely to be an ideal alternative to autologous grafts in small-diameter vessels and are worthy of further investigation. However, a multitude of problems remain that must be resolved before they can be used in biomedical applications. Accordingly, this review attempts to describe these problems and provide a discussion of the generation of artificial blood vessels. In addition, we deliberate on current state-of-the-art technologies for creating artificial blood vessels, including advances in materials, fabrication techniques, various methods of surface modification, as well as preclinical and clinical applications. Furthermore, the evaluation of grafts both in vivo and in vitro, mechanical properties, challenges, and directions for further research are also discussed.

CONSTRUCTION OF VASCULAR GRAFT BY 3D PRINTING USING BACTERIAL CELLULOSE FORMULATION AS BIOINK

"Currently, there is a considerable clinical demand for biocompatible and robust tissue-engineered artificial vascular graft materials. The vascular application requiring adequate mechanical strength and biocompatibility still lags at some critical points. Bacterial cellulose (BC) is well known for its use as a biomaterial in various fields due to its high biocompatibility. The most critical issue preventing the wide use of BC for 3D biomaterial printing is its insolubility in water and organic solvents. Because of this feature, the use of BC as bioink is limited. In this study, optimizing the solubility of BC with zinc sulphate, and the application of the obtained bioink with a 3D printing technique to create a model vascular graft, as well as examining it in terms of mechanical strength, were carried out for the first time in the literature. The chemical characterization of the obtained vascular graft was performed by FTIR, RAMAN and SEM analyses. The thermal behavior was analyzed by TG analysis (showing mass losses of 22.72% at 361 °C and 52.4% at 421 °C). The surface area was measured as 8.290 m2/g. The water retention capacity (WRC) was examined throughout 48 hours (after 1 h – 5%, 24 h – 9%, and 48 h – 9%). The elasticity modulus of the sample was 172.083 N/mm2 and the elongation break was 87.591%. The cytotoxicity analysis results revealed that cell viability reached 75.84% on the only resin-containing 3D-printed aorta, while it was 100% on the BC/zinc sulfate-resin composite 3D-printed aorta. The morphology of the human umbilical vein endothelial cells (HUVECs) was observed after 24, 52 and 72 h. Cell adhesion to the BC-based composite 3D printed vascular graft was determined as 89.02% after 24 h, 92.01% after 52 h, 100% after 72 h, while it reached much lower values for the only resin-containing 3D vascular graft – of 55.02% after 24 h, 56% after 48 h, and 58.04% after 72 h. Additionally, the rheological analysis indicated that the yield stress of the BC-based bioink increased with the BC content up to 20 Pa. "

Successful Surgical Management of a Tracheo-Innominate Artery Fistula in a Patient with Duchenne Muscular Dystrophy: A Case Report

Tracheo-innominate artery fistula (TIF) is a rare, life-threatening complication of tracheostomy that makes it difficult to secure the airway due to massive bleeding, constituting a medical emergency. Therefore, most successful surgical treatments include innominate artery debridement and tracheal fistula repair. Herein, we report a case of successful surgical treatment of a TIF while maintaining cerebral blood flow through an artificial vascular graft.

Klotho functionalization on vascular graft for improved patency and endothelialization

The Klotho (KL) gene is related to aging. In this study, SKL (secreted KL) and heparin were cross-linked to the acellular small intestinal submucosa (SIS). Based on this, tissue-engineered bioactive small blood vessels were constructed. The goal of this study was to determine whether the release of SKL could improve the patency of small-diameter tissue-engineered blood vessels (TEVs) through promoting cell adhesion. The recombinant human SKL protein was generated from HEK293 cells with overexpression of SKL. Then the SIS membrane was cross-linked with heparin and SKL respectively, to prepare heparin group and SKL group artificial vascular grafts. SKL treatment promoted endothelial cells proliferation and upregulated the levels of Focal adhesion kinase (FAK) phosphorylation and Ras homolog gene family, member A (RhoA). SKL effectively enhanced the endothelial cells adhesion on the SIS membrane. In vivo evaluation of SKL modified SIS grafts in rabbits exhibited increased patency rate, endothelialization, and smooth muscle regeneration. In this study, SKL-modified SIS grafts can effectively improve patency of small-diameter TEVs through enhancing cell adhesion, and it is expected to exhibit an important effect in the construction of substitutes for coronary artery bypass grafting.

Matrix stiffness exacerbates the proinflammatory responses of vascular smooth muscle cell through the DDR1-DNMT1 mechanotransduction axis.

Vascular smooth muscle cell (vSMC) is highly plastic as its phenotype can change in response to mechanical cues inherent to the extracellular matrix (ECM). VSMC may be activated from its quiescent contractile phenotype to a proinflammatory phenotype, whereby the cell secretes chemotactic and inflammatory cytokines, e.g. MCP1 and IL6, to functionally regulate monocyte and macrophage infiltration during the development of various vascular diseases including arteriosclerosis. Here, by culturing vSMCs on polyacrylamide (PA) substrates with variable elastic moduli, we discovered a role of discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase that binds collagens, in mediating the mechanical regulation of vSMC gene expression, phenotype, and proinflammatory responses. We found that ECM stiffness induced DDR1 phosphorylation, oligomerization, and endocytosis to repress the expression of DNA methyltransferase 1 (DNMT1), very likely in a collagen-independent manner. The DDR1-to-DNMT1 signaling was sequentially mediated by the extracellular signal-regulated kinases (ERKs) and p53 pathways. ECM stiffness primed vSMC to a proinflammatory phenotype and this regulation was diminished by DDR1 inhibition. In agreement with the in vitro findings, increased DDR1 phosphorylation was observed in human arterial stiffening. DDR1 inhibition in mouse attenuated the acute injury or adenine diet-induced vascular stiffening and inflammation. Furthermore, mouse vasculature with SMC-specific deletion of Dnmt1 exhibited proinflammatory and stiffening phenotypes. Our study demonstrates a role of SMC DDR1 in perceiving the mechanical microenvironments and down-regulating expression of DNMT1 to result in vascular pathologies and has potential implications for optimization of engineering artificial vascular grafts and vascular networks.