Evaluation of synthetic vascular grafts in a mouse carotid grafting model

Current animal models for the evaluation of synthetic grafts are lacking many of the molecular tools and transgenic studies available to other branches of biology. A mouse model of vascular grafting would allow for the study of molecular mechanisms of graft failure, including in the context of clinically relevant disease states. In this study, we comprehensively characterise a sutureless grafting model which facilitates the evaluation of synthetic grafts in the mouse carotid artery. Using conduits electrospun from polycaprolactone (PCL) we show the gradual development of a significant neointima within 28 days, found to be greatest at the anastomoses. Histological analysis showed temporal increases in smooth muscle cell and collagen content within the neointima, demonstrating its maturation. Endothelialisation of the PCL grafts, assessed by scanning electron microscopy (SEM) analysis and CD31 staining, was near complete within 28 days, together replicating two critical aspects of graft performance. To further demonstrate the potential of this mouse model, we used longitudinal non-invasive tracking of bone-marrow mononuclear cells from a transgenic mouse strain with a dual reporter construct encoding both luciferase and green fluorescent protein (GFP). This enabled characterisation of mononuclear cell homing and engraftment to PCL using bioluminescence imaging and histological staining over time (7, 14 and 28 days). We observed peak luminescence at 7 days post-graft implantation that persisted until sacrifice at 28 days. Collectively, we have established and characterised a high-throughput model of grafting that allows for the evaluation of key clinical drivers of graft performance.Alex H.P. Chan, Richard P. Tan, Praveesuda L. Michael, Bob S.L. Lee, Laura Z. Vanags, Martin K.C. Ng, Christina A. Bursill, Steven G. Wis

Development of a Tissue-Engineered Lymphatic Graft Using Nanocomposite Polymer for the Treatment of Secondary Lymphedema

Damage of the lymphatic vessels, commonly due to surgical resection for cancer treatment, leads to secondary lymphedema. Tissue engineering approach offers a possible solution to reconstruct this damage with the use of lymphatic graft to re-establish the lymphatic flow, hence preventing lymphedema. The aim of this study is to develop a tissue-engineered lymphatic graft using nanocomposite polymer and human dermal lymphatic endothelial cells (HDLECs). A nanocomposite polymer, the polyhedral oligomeric silsequioxane-poly(carbonate-urea)urethane (POSS-PCU), which has enhanced mechanical, chemical, and physical characteristics, was used to develop the lymphatic graft. POSS-PCU has been used clinically for the world's first synthetic trachea, lacrimal duct, and is currently undergoing clinical trial for coronary artery bypass graft. Two designs and fabrication methods were used to manufacture the conduits. The fabrication method, the mechanical and physical properties, as well as the hydraulic conductivity were tested. This is followed by in vitro cell culture analysis to test the cytocompatibility of HDLEC with the polymer surface. Using the casted extrusion method, the nanocomposite lymphatic graft demonstrates desirable mechanical property and hydraulic conductivity to re-establish the lymphatic flow. The conduit has high tensile strength (casted: 74.86 ± 5.74 MPa vs. coagulated: 31.33 ± 3.71 MPa; P < 0.001), favorable kink resistance, and excellent suture retention property (casted vs. coagulated, P < 0.05). Cytocompatibility study showed that the POSS-PCU scaffold supports the attachment and growth of HDLECs. This study demonstrates the feasibility of developing a tissue-engineered lymphatic graft using the nanocomposite polymer. It displays excellent mechanical property and cytocompatibility to HDLECs, offering much promise for clinical applications and as a new treatment option for secondary lymphedema

Endothelium-specific activation of AMP-activated protein kinase alleviates diabetes-induced impairment in endothelial repair in mice

Poster Session 1: Basic Science - Abstract no. 101published_or_final_versionThe 16th Medical Resarch Conference (MRC), The University of Hong Kong, Hong Kong, China, 22 January 2011. In Hong Kong Medical Journal, 2011, v. 17, suppl. 1, p. 43, abstract no. 6

Perioperative antithrombotic management in joint replacement surgeries

Objectives To determine optimal perioperative antithrombotic management for patients with cardiac diseases undergoing joint replacement surgeries. Data sources MEDLINE and PubMed database search up to January 2013. Study selection Those dealing with perioperative antithrombotic management of patients undergoing orthopaedic operations, especially joint replacement, and also those undergoing general surgery. Various combinations of the following key words were used in our search: 'antiplatelet', 'antithrombotic', 'anticoagulant', 'coronary stent', 'perioperative', 'venous thromboembolism', 'cardiovascular', 'surgery', 'orthopaedic', 'knee replacement', 'hip replacement', 'joint replacement', and 'arthroplasty'. Data extraction Literature review, original articles, and best practice guidelines. Data synthesis Patients should be stratified according to their risk of developing arterial thromboembolism in order to decide the most appropriate perioperative antiplatelet or anticoagulant regimen for them. After recent coronary stenting, including bare-metal stents implanted within 6 weeks and drug-eluting stents implanted within 6 months, surgery should be deferred. For venous thromboembolism prophylaxis in patients already on aspirin, the dosage should be adjusted as necessary or additional low-molecular-weight heparin administered. Conclusion The perioperative management of patients with cardiac diseases in receipt of antithrombotic agents is based upon a delicate balance between the perceived risk of arterial thromboembolism and the perceived risk of perioperative bleeding. One must exercise good judgement in deciding the most appropriate perioperative antithrombotic regimen. Venous thromboembolism is also a common problem after joint replacement surgeries. For patients already on aspirin, optimal venous thromboembolism prophylaxis is still being debated.published_or_final_versio

Initial Use of Endothelial Progenitor Cells Capturing Stents in Paediatric Congenital Heart Disease

INTRODUCTION: Stenosis, mediated by neointimal hyperplasia and thrombosis, is a major limiting factor in successful stent implantation. The introduction of a stent, coated in its endoluminal surface by antihuman CD34 antibodies with endothelial progenitor cell-capturing properties, opens the possibility of promoting a rapid and normal functioning coverage by endothelium and thus avoids both an excessive cell proliferation within stent and the need for long-term dual antiplatelet therapy. These stents, developed for adult coronary artery disease, have not yet been implanted in children or in those with congenital heart disease. OBJECTIVE AND METHODS: In this paper, we describe the implantation of Genous® stents in three children with cyanotic congenital heart disease and obstructed systemic-to-pulmonary shunts. We describe the use of this stent and address its potential feasibility in paediatric congenital heart disease. RESULTS: To maintain the patency of two modified Blalock-Taussig shunts and one ductus arteriosus, four Genous® stents were implanted in three infants with cyanotic heart disease. All procedures were immediately successful, with resolution of stenosis and improvement in transcutaneous oxygen saturation from 66% ± 3.6% to 92% ± 2.6%. In the follow-up, one stent had no occlusion; however, the remaining two had partial occlusion after 5 and 5.5 months, which were successfully managed with balloon dilatation preceding elective definitive surgical correction. CONCLUSION: In our preliminary experience, we demonstrated that Genous® stent implantation was feasible in infants with complex congenital heart disease. Additional studies with larger samples and longer follow-up are required to confirm the potential benefits of this technology in this clinical setting.info:eu-repo/semantics/publishedVersio

Modelling the impact of atherosclerosis on drug release and distribution from coronary stents

Although drug-eluting stents (DES) are now widely used for the treatment of coronary heart disease, there remains considerable scope for the development of enhanced designs which address some of the limitations of existing devices. The drug release profile is a key element governing the overall performance of DES. The use of in vitro, in vivo, ex vivo, in silico and mathematical models has enhanced understanding of the factors which govern drug uptake and distribution from DES. Such work has identified the physical phenomena determining the transport of drug from the stent and through tissue, and has highlighted the importance of stent coatings and drug physical properties to this process. However, there is limited information regarding the precise role that the atherosclerotic lesion has in determining the uptake and distribution of drug. In this review, we start by discussing the various models that have been used in this research area, highlighting the different types of information they can provide. We then go on to describe more recent methods that incorporate the impact of atherosclerotic lesions

Fabrication and properties of L-arginine-doped PCL electrospun composite scaffolds

The article describes fabrication and properties of composite fibrous scaffolds obtained by electrospinning of the solution of poly({\epsilon}-caprolactone) and arginine in common solvent. The influence of arginine content on structure, mechanical, surface and biological properties of the scaffolds was investigated. It was found that with an increase of arginine concentration diameter of the scaffold fibers was reduced, which was accompanied by an increase of scaffold strength and Young modulus. It was demonstrated that porosity and water contact angle of the scaffold are independent from arginine content. The best cell adhesion and viability was shown on scaffolds with arginine concentration from 0.5 to 1 % wt

A polymer coated cicaprost-eluting stent increases neointima formation and impairs vessel function in the rabbit iliac artery

Drug-eluting stents have been successful in reducing in-stent restenosis but are not suitable for all lesion types and have been implicated in causing late stent thrombosis due to incomplete regeneration of the endothelial cell layer. In this study we implanted stents coated with cicaprost, a prostacyclin analogue with a long plasma half-life and antiproliferative effects on vascular smooth muscle cells, into the iliac arteries of rabbits. At 28-day follow-up we compared neointima formation within the stented vessels and vascular function in adjacent vessels, to assess if cicaprost could reduce restenosis without impairing vessel function. Arteries implanted with cicaprost eluting stents had significantly more neointima compared to bare metal stents. In adjacent segments of artery, endothelium-dependent relaxation was impaired by the cicaprost-eluting stent but vasodilation to an endothelium-independent vasodilator was maintained. We conclude that the presence of the polymer and sub-optimal release of cicaprost from the stent may be responsible for the increased neointma and impaired functional recovery of the endothelium observed. Further experiments should be aimed at optimising release of cicaprost and exploring different stent polymer coatings

537Microparticles and exosomes differentially impact on endothelial cell function in coronary artery disease

Background and Purpose: Microparticles (MPs) and exosomes are released by cells using different mechanisms. Thus, quantitative as well as qualitative changes of both particle populations, MPs and exosomes, in patients with coronary artery disease (CAD) might reflect an altered activation status of the endothelium, platelets and leukocytes. Moreover, they might exert differential effects on the target organs, such as the endothelium. Yet, alterations in both populations have not been studied side-by-side so far. The aim of the study was to compare the impact of MPs and exosomes from healthy subjects and CAD patients on endothelial cell (EC) functional characteristics. Methods: MPs and exosomes were isolated by stepwise filtration and ultracentrifugation from citrate-plasma and verified by electron microscopy and dynamic light scattering. MP and exosome fractions, as well as the vehicle (PBS), were added to human arterial ECs and EC apoptosis, number, size, capacity for in vitro-reendothelialisation after scratching, expression of adhesion molecules ICAM-1 and VCAM-1 were assessed. In parallel, platelet-, endothelial- and leukocyte-derived MPs were quantified. In a separate sub-study, the same parameters were assessed in plasma of CAD patients undergoing standard medical rehabilitation or an exercise-based cardiac rehabilitation programme. Results: MPs of healthy, but not of CAD patients supported in vitro re-endothelialisation, while exosomes had no influence. Exercise, but not standard rehabilitation improved CAD MP capacity to support in vitro rehabilitation. This was negatively correlated to the number of leukocyte- and endothelial-derived MPs, but not total or platelet MPs. EC number was negatively affected by exposure to CAD MPs. ANCOVA analysis identified disease, but not the particle type as influencing factor. Instead, apoptotic cell death was influenced by particle type, but not by the disease, and was not altered in rehabilitation. Similarly, ICAM-1 and VCAM-1 expression were enhanced on ECs after incubation with exosomes, but not with MPs, with no effect of disease or rehabilitation. Conclusion: MPs and exosomes differentially affect endothelial cell function and underlie differential modulation in disease and rehabilitation. Those findings might in the future help to optimize and monitor cardiovascular therap