Tissue homeostasis in in-situ tissue engineered vascular access grafts
Patients diagnosed with end-stage renal disease require hemodialysis to clean their blood and remove excessive fluids. An arteriovenous (AV)-graft connecting an artery with a vein is often used to ensure sufficient blood flow and easy access points for the dialysis machine (figure A). However, vascular access grafts often occlude due to thrombosis with venous neo-intimal hyperplasia being the underlying pathology in most of the cases, representing the main cause of morbidity among dialysis patients. The creation of living, self-healing grafts via Tissue Engineering (TE) is hypothesized to circumvent these drawbacks. Our goal is to create living grafts ‘in-situ’, starting from an implanted synthetic vascular scaffold that is gradually replaced by endogenous tissue produced by cells recruited into the scaffold (figure B).
The aim of this project is to investigate later stage tissue formation and remodeling in a vascular access graft under physiological hemodynamic circumstances. The hemodynamic environment in an AV-graft is characterized by high blood flows (> 300 ml/min) and large pressure drops (80-90 mmHg), resulting in high wall shear stresses and gradients of circumferential stresses over the length of the graft. It is hypothesized that by tuning the microstructure of the graft (i.e. scaffold anisotropy) and graft degradation rate, tissue formation and remodeling can be controlled under these harsh hemodynamic conditions.
To systematically investigate the relative contribution of graft anisotropy and graft degradation to tissue remodeling and architecture, a 3D in vitro platform will be designed that mimics the in vivo circumstances in an AV-graft (figure C). The graft, composed of an electrospun supramolecular polymer, will be seeded with vascular smooth muscle cells representing the situation after cell infiltration. The outcomes will be used to create the optimal micro-environment for the cell that needs to maintain tissue homeostasis. This knowledge is fundamental for creating AV-grafts with long-term functionality.