George Hamilton

The Mechanical Behavior of Vascular Grafts: A Review

The development of intimal hyperplasia (IH) near the anastomosis of a vascular graft to artery is directly related to changes in the wall shear rate distribution. Mismatch in compliance and diameter at the end-to-end anastomosis of a compliant artery and rigid graft cause shear rate disturbances that may induce intimal hyperplasia and ultimately graft failure. The principal strategy being developed to prevent IH is based on the design and fabrication of compliant synthetic or innovative tissue-engineered grafts with viscoelastic properties that mirror those of the human artery. The goal of this review is to discuss how mechanical properties including compliance mismatch, diameter mismatch, Young’s modulus and impedance phase angle affect graft failure due to intimal hyperplasia.

Small calibre polyhedral oligomeric silsesquioxane nanocomposite cardiovascular grafts: Influence of porosity on the structure, haemocompatibility and mechanical properties

There is a significant worldwide demand for a small calibre vascular graft for use as a bypass or replacement conduit. An important feature in determining the success of a graft is the wall structure, which includes porosity, pore size and pore interconnectivity, as these play a crucial role in determining the long-term patency of a bypass graft. In this study we fabricate a small diameter (<5mm) vascular graft from polyhedral oligomeric silsesquioxane-poly(carbonate urea)urethane (POSS-PCU) via an extrusion, phase inversion method using an automated, custom built machine. Through the dispersion of a porogen, sodium bicarbonate (NaHCO(3)), in controlled concentrations (0-55%) we were able to produce grafts with well-defined pore morphologies. The impact of NaHCO(3) concentration on the structure of the graft wall and its influence on the mechanical and haemocompatibility properties are evaluated here. Scanning electron microscopy and mercury porosimetry were used to characterise graft structure. Atomic force microscopy elucidated any changes in surface morphology. The addition of NaHCO(3) improved the pore interconnectivity and increasing the concentration of NaHCO(3) led to grafts with rougher surfaces and larger pore sizes. The ultimate tensile strength and suture retention decreased with increasing concentrations of NaHCO(3), while graft compliance increased. To evaluate haemocompatibility platelets and peripheral blood mononuclear cells (PBMC) were incubated on a range of different graft samples. Platelet adhesion, PBMC surface receptor expression (CD14, CD86, CD69 and HLA-DR) and cytokine release (PF4, IL-1β, IL-6, IL-10, TNFα) were all measured. Increasing numbers of platelets adhered to grafts produced with no NaHCO(3), which exhibited a smooth surface morphology, and PBMC adherent on these grafts expressed higher levels of CD14 and CD86. Whilst the different graft samples induced varying levels of cytokine secretion in vitro, no distinct pattern suggesting a non-trivial relationship was observed.

An assessment of covalent grafting of RGD peptides to the surface of a compliant poly(carbonate-urea)urethane vascular conduit versus conventional biological coatings: its role in enhancing cellular retention.

The aim of sodding prosthetic grafts with endothelial cells (EC) is to establish a functioning antithrombogenic monolayer of EC. Application of basement membrane proteins improves EC adherence on ePTFE grafts. Their addition to a biodurable compliant poly(carbonate-urea)urethane graft (CPU) was studied with respect to EC adherence. Preclot, fibronectin, gelatin, and collagen were coated onto CPU. RGD peptide, heparin, and both RGD and heparin were chemically bonded to CPU. Human umbilical vein EC (HUVEC) labeled with 111-Indium oxine were sodded (1.8 x 10(6) EC/cm(2)) onto native and the modified CPU. The grafts were washed after 90 min and EC retention determined. The experiments were repeated six times. EC retention on native CPU was 1.0 +/- 0.2 x 10(5) EC/cm(2). The application of preclot, fibronectin, gelatin, and collagen did not improve EC retention, which was 0.8 +/- 0.1, 0.4 +/- 0.1, 0.3 +/- 0.08, and 0.5 +/- 0.2 x 10(5) EC/cm(2), respectively. Bonding RGD, heparin, and both RGD and heparin significantly improved EC retention to 1.9 +/- 0.6, 1.7 +/- 0.5, and 2.6 +/- 0.6 x 10(5) EC/cm(2), respectively (p < 0.01). Bonding of RGD, heparin, and both RGD and heparin accelerates and enhances EC retention onto CPU. Simple coating of basement membrane proteins confers no advantage over native CPU.

Development of cardiovascular bypass grafts: endothelialization and applications of nanotechnology

There is a critical clinical need for small-diameter bypass grafts, with applications involved in the coronary artery and lower limb. Commercially available materials give rise to unfavorable responses when in contact with blood and subjected to low-flow hemodynamics and, thus, are nonideal as small-diameter bypass grafts. Optimizing the mechanical properties to match both the native artery and the graft surfaces has received keen attention. Endothelialization of bypass grafts is considered a protective mechanism where the biochemicals produced from endothelial cells exert a range of favorable responses, including antithrombotic, noninflammatory responses and inhibition of intimal hyperplasia. In situ endothelialization is most desirable. Nanotechnology approaches facilitate all aspects of endothelialization, including endothelial progenitor cell mobilization, migration, adhesion, proliferation and differentiation. ‘Surface nanoarchitecturing mechanisms’, which mimic the natural extracellular matrix to optimize endothelial progenitor cell interaction and controlled delivery of various factors in the form of nanoparticles, which can be combined with gene therapy, are of keen interest. This article discusses the development of bypass grafts, focusing on the optimization of the biological properties of mechanically suitable grafts.

Optical techniques in the assessment of peripheral arterial disease

A variety of optical techniques have been developed over the years for experimental use in vascular disease, mainly for the assessment of lower limb peripheral arterial disease (PAD). Optical techniques have several advantages over more traditional experimental approaches. Photoplethysmograph (PPG) was one of the earliest methods used for this purpose; PPG satisfies many of the conditions for a non-invasive technique to estimate skin blood flow using infrared light, not only for research but also in clinical practice. PPG is a promising, safe and easy-to-use tool for diagnosis and early screening of various atherosclerotic pathologies and could be useful for regular GP-assessment or even self-monitoring of PAD at home or during individual physical exercises. This review discusses the application of PPG in the assessment of PAD.

Vitreous cryopreservation maintains the viscoelastic property of human vascular grafts

Assess the effects of cryopreservation (cryo) and vitrification (vitro) on the viscoelastic properties of blood vessels. Human external Iliac artery vessels were harvested from liver organ donors (n=8). In each case the vessel was segmented into 3 equal parts, which were randomly placed in one of 3 categories: Fresh (stored in 4°C UW for 6 h), Cryo (Placed in 10% Dulbeccos modified Eagle medium (DMEM) and slowly frozen to −196°C), or Vitro (Placed in 40% DMEM and rapidly cooled to −196°C). A pulsatile flow circuit was used to perfuse arterial segments at physiological pulse pressure and flow. Intraluminal pressure was measured using a Millar Mikro‐tip catheter transducer, and vessel wall motion was determined with duplex ultrasonography coupled with a novel echo‐locked vessel wall tracking system. Diametrical compliance (DC), Petersons elastic modulus (Ep), and stiffness index (β) were then calculated for each of the three groups over 3 mean pressure ranging from 40 to 80 mmHg. The change in the viscous component of arterial wall (lag phase angle, θ) was calculated from hysteresis plots. No significant changes were observed in the elastic properties of fresh and vitrified vessels (P>0.05 for each of DC, Ep, and β). Similarly, variation in the wall viscosity between fresh and vitrified vessels appeared to be nonsignificant (θ = 12.60±4.04 vs. 17.60±1.14, respectively). In contrast, statistical analysis of results obtained for cryopreserved vessels to the fresh vessels showed significant reduction in elastic parameter values. There was also a significant increase in the phase angle θ of the cryopreserved vessels (θ = 24.30±6.32; P< 0.001) compared with fresh vessel. Results suggest that vitrification maintains both elastic and viscous components of the mechanical properties of vascular grafts, which is positively correlated with their functional patency. In contrast, damage caused during cryopreservation significantly affects the overall tensile strength and elasticity of the vessel (i.e., Ep and β), the dynamic properties (DC), and appears to significantly affect the viscous component of the vessel wall (θ), which is likely reduce the patency of the graft for transplantation purposes.—Thakrar, R. R., Patel, V. P., Hamilton, G., Fuller, B. J., Seifalian, A. M. Vitreous cryopreservation maintains the viscoelastic property of human vascular grafts. FASEB J. 20, 874–881 (2006)

Prospective Assessment of Lower-Extremity Peripheral Arterial Disease in Diabetic Patients Using a Novel Automated Optical Device:

A new optical device based on the photoplethysmograph (PPG) method and an innovative algorithm for the assessment of lower-extremity peripheral arterial disease was investigated prospectively in patients with type II diabetes. This new functional PPG (fPPG) technique uses a cuffless functional test to assess diabetic peripheral arterial disease without operator dependency and the incompressible arteries, issues associated with ankle brachial pressure index (ABPI) measurement. Diabetic patients (n = 24; 47 legs; age, 70 ± 3 years) were recruited from the vascular clinic, and controls (n = 15; 30 legs; age, 66 ± 5 years) were recruited from the orthopedic outpatient clinic. All underwent resting ABPI, fPPG, and duplex angiography (DA) as “gold standard.” fPPG requires the placement of an optical probe on the toe for acquisition of pulsatile arterial perfusion for a period of 30 seconds with the leg in supine and raised at 45° positions. The data were analyzed, and indices were generated by an automated computer system. In those with diabetes, fPPG correlated significantly with DA (r = −.68, P < .01) and ABPI (r = −.65, P < .01). We also found a significant correlation between ABPI and DA (r = .81, P < .01). The analysis of the receiver operator curve showed that optimum sensitivity and specificity for ABPI and fPPG were 80% and 93% and 83% and 71%, respectively, against DA. This method uses changes in pulsatile arterial blood volume using a simple cuffless functional test. The fPPG investigation period was much shorter (5 minutes) with independence of operator skills, whereas ABPI took longer (10-15 minutes) and required operator experience. Although the fPPG results are promising, further improvement (eg, by incorporation of functional skin color and temperature changes) is required to improve the sensitivity and specificity of the system.

Atherosclerotic renal artery stenosis: association with emerging vascular risk factors.

Background: The established risk factors for atherosclerotic renal artery stenosis (ARAS) include hypertension, diabetes mellitus, dyslipidemia, obesity,smoking, old age and family history. In the last few years, several emerging risk factors have been proposed as predictors of ARAS, namely homocysteine, fibrinogen, C-reactive protein, lipoprotein(a) and creatinine. Methods: We searched Pubmed/Medline for studies investigating the prognostic value of each of these emerging risk factors in ARAS. Results: Creatinine and C-reactive protein seem to be the most promising predictors of ARAS, whereas the prognostic value of homocysteine, lipoprotein(a) and fibrinogen is not yet fully determined. Conclusion: The establishment of a definite role for these emerging risk factors could result in earlier recognition and/or better management of ARAS with potential regression/slowing down of progression of stenosis. Modifying these markers may also improve the therapeutic approach of the associated systemic atherosclerosis in these high-risk patients. Future trials should focus on the effect of different classes of drugs (e.g. statins and fibrates) on the levels of the emerging risk factors and the association with ARAS progression.

Are Statins an Option in the Management of Abdominal Aortic Aneurysms

Medline was searched for studies investigating the perioperative and long-term results that derive from statin use in patients with abdominal aortic aneurysm and the clinical and experimental evidence dealing with aneurysm expansion. Data suggest that statins improve the perioperative and long-term outcomes of aneurysm operations and may also reduce expansion rates. International guidelines recommend the use of statins in these patients because abdominal aortic aneurysms are considered as a coronary heart disease equivalent. These guidelines do not appear to have been widely implemented. Preliminary results suggest that statins might play a role in the management of abdominal aortic aneurysms. Verification of these results in large-scale trials may hold implications for a more comprehensive approach of patients with abdominal aortic aneurysms as well as population-wide aneurysm screening programs. Irrespective of the role of statins on aneurysm expansion rates, it is important to ensure that all abdominal aortic aneurysm patients receive statin therapy to improve perioperative and long-term morbidity and mortality.

Nanotopography and plasma treatment: redesigning the surface for vascular graft endothelialisation

INTRODUCTION Vascular graft materials in clinical use, such as polytetrafluoroethylene (PTFE) and Dacron, do not endothelialise and have low patency rates. The importance of an endothelial cell layer on the luminal surface of a vascular graft is well-known with surface topography and chemistry playing an important role. The aim of this study was to investigate the potential of plasma treatment and topographical structures on the luminal graft surface to enhance the self-endothelialisation potential of a nanocomposite vascular graft. METHODS POSS-PCU is a polycarbonate urea urethane (PCU) with a nanoparticle, polyhedral oligomeric silsesquioxane (POSS) incorporated within it. Planar, microgrooved, and nanopit patterned polymer films were fabricated using photolithography, electron beam lithography, reactive ion etching, and replication by solvent casting. Films were then exposed to oxygen plasma treatment at different powers for a fixed time (40 W, 60 W, 80 W/60 seconds). Effects of plasma treatment were assessed using scanning electron microscopy, atomic force microscopy and water contact angle analysis. Human umbilical vein endothelial cell (HUVEC) proliferation and morphology were characterised using immunostaining, live/dead staining, and Coomassie blue staining. RESULTS Successful embossing of the micro- and nanostructures was confirmed. Oxygen plasma treatment of the different samples showed that increasing power significantly increased the hydrophilicity of the samples (p < .0001). Improved HUVEC adhesion was seen on plasma modified compared with untreated samples (p < .0001). Coomassie blue staining showed that after 5 days, cells started to form monolayers and live/dead staining showed the cells were viable. Immunostaining showed that HUVECs expressed nitric oxide synthase on all topographies with focal adhesions appearing more pronounced on nanopit surfaces, showing retention of morphology and function. CONCLUSION These encouraging results indicate a future important role for plasma treatment and nanotopography in the development of endothelialised vascular grafts.