Maintaining vascular access (VA) patency continues to be the greatest challenge for dialysis patients. VA dysfunction, primarily due to venous neointimal hyperplasia development and stenotic lesion formation, is mainly attributed to complex hemodynamics within the arteriovenous fistula (AVF). The effect of VA creation and the subsequent geometrical remodeling on the hemodynamics and shear forces within a mature patient-specific AVF is investigated. A 3D reconstructed geometry of a healthy vein and a fully mature patient-specific AVF was developed from a series of 2D magnetic resonance image scans. A previously validated thresholding technique for region segmentation and lumen cross section contour creation was conducted in MIMICS 10.01, allowing for the creation of a 3D reconstructed geometry. The healthy vein and AVF computational models were built, subdivided, and meshed in GAMBIT 2.3. The computational fluid dynamic (CFD) code FLUENT 6.3.2 (Fluent Inc., Lebanon, NH) was employed as the finite volume solver to determine the hemodynamics and shear forces within the healthy vein and patient-specific AVF. Geometrical alterations were evaluated and a CFD analysis was conducted. Substantial geometrical remodeling was observed, following VA creation with an increase in cross-sectional area, out of plane curvature (maximum angle of curvature in AVF=30 deg), and angle of blood flow entry. The mean flow velocity entering the vein of the AVF is dramatically increased. These factors result in complex three-dimensional hemodynamics within VA junction (VAJ) and efferent vein of the AVF. Complex flow patterns were observed and the maximum and mean wall shear stress (WSS) magnitudes are significantly elevated. Flow reversal was found within the VAJ and efferent vein. Extensive geometrical remodeling during AVF maturation does not restore physiological hemodynamics to the VAJ and venous conduit of the AVF, and high WSS and WSS gradients, and flow reversal persist. It is theorized that the vessel remodelling and the continued non-physiological hemodynamics within the AVF compound to result in stenotic lesion development.

Bone graft procedures typically require surgeons to harvest bone from a second site on a given patient (Autograft) before repairing a bone defect. However, this results in increased surgical time, excessive blood loss and a significant increase in pain. In this context a synthetic bone graft with excellent histocompatibility, built in antibacterial efficacy and the ability to regenerate healthy tissue in place of diseased tissue would be a significant step forward relative to current state of the art philosophies. We developed a range of calcium-strontium-zinc-silicate glass based bone grafts and characterised their structure and physical properties, then evaluated their in vitro cytotoxicity and in vivo biocompatibility using standardised models from the literature. A graft (designated BT109) of composition 0.28SrO/0.32ZnO/0.40 SiO(2) (mol fraction) was the best performing formulation in vitro shown to induce extremely mild cytopathic effects (cell viability up to 95%) in comparison with the commercially available bone graft Novabone (cell viability of up to 72%). Supplementary to this, the grafts were examined using the standard rat femur healing model on healthy Wister rats. All grafts were shown to be equally well tolerated in bone tissue and new bone was seen in close apposition to implanted particles with no evidence of an inflammatory response within bone. Complimentary to this BT109 was implanted into the femurs of ovariectomized rats to monitor the response of osteoporotic tissue to the bone grafts. The results from this experiment indicate that the novel grafts perform equally well in osteoporotic tissue as in healthy tissue, which is encouraging given that bone response to implants is usually diminished in ovariectomized rats. In conclusion these materials exhibit significant potential as synthetic bone grafts to warrant further investigation and optimisation.

Venous neointimal hyperplasia (VNH) lesions are prone to localized development within the vascular access junction (VAJ) and efferent vein of arteriovenous (AV) fistulae and grafts. The creation of VAJ dramatically alters the local venous hemodynamics with high pulsatile flow velocities enter the vein resulting in blood-flow separation, recirculation and flow reversal. This study conducted a computational hemodynamic investigation of an idealized AV graft and realistic AV fistula which demonstrated a complex hemodynamic environment within the VAJ, producing elevated wall shear stress (WSS) magnitudes and significant spatial and temporal WSS gradients in the VAJ. These hemodynamic patterns and non-physiological WSSs are postulated to initiate VNH development at the transcriptional level. Human umbilical vein endothelial cells (HU-VEC) were exposed to elevated temporal WSS waveforms obtained from the aforementioned computational analysis, using a cone-and-plate bioreactor. Using real-time RT-PCR, early induction of MMP-2 and delayed transcriptional upregulation of MCP-1 was observed following EC exposure to VAJ high wall shear forces. These results indicate that MMP-2 and MCP-1 may be induced by high WSS present in the VAJ, suggesting a link between elevated WSS magnitudes and temporal gradients, extracellular matrix decomposition, smooth muscle cell migration and proliferation, and the subsequent VNH development in AV VAJs.

Our study demonstrates variations in perioperative management practices for patients on chronic anticoagulation therapy undergoing urological procedures. Urologists should familiarise themselves with standardised guidelines if this patient subgroup are to receive optimal perioperative management.