The ABM CDT is a partnership between The Universities of Manchester and Sheffield. ALL APPLICATIONS should however, be submitted via the Manchester application system only.
In this project we team up with Terumo Aortic to produce next generation vascular grafts. A great need exists for conduits for small-diameter (<6 mm) vascular grafts. Autologous blood vessels represent the current gold standard, but these are of limited availability, may be of poor quality and their extraction causes donor site morbidity. Synthetic grafts, while available, are inferior to autografts.
In this project, Tissue Engineered Blood Vessels (TEVBs) will be grown in the lab for use as vascular grafts. Additionally, we will use state-of-the-art manufacturing techniques to produce the biomaterials templates, we have already established protocols in combining additive manufacturing and casting to produce tubular tissue engineering scaffolds with an inherent 10-50 µm porosity via using a biodegradable emulsion-based resin. [2,3,7-9] The scaffolds will be produced in elastic, biodegradable polymers such as polyglycerol sebacate or polycaprolactone. We will seed these scaffolds with smooth muscle cells and culture them in a bioreactor. As the scaffold degrades, it leaves behind a vessel composed of only cells/ECM. These vessels can then be decellularised, rendering them non-antigenic, leaving a shaped, physiologically relevant, matrix of ECM proteins suitable for implantation (successfully demonstrated in ).
This project will (1) optimise the vessel culture and decellularisation, (2) explore the production of TEBVs with tubular scaffolds, (3) examine the interaction between the decellularised vessels and vascular endothelial cells (ECs) in vitro. Achieving this will allow further translation of this technology with our industrial collaborator.
Globally, cardiovascular disease is the number one cause of death. Treatment by surgical intervention is commonplace and there is a great need for suitable blood vessels for use in bypass surgery and the creation of vascular access conduits. Currently, utilising autologous veins or arteries represents the gold standard for vascular grafting. However, these vessels are of limited availability, may be of poor quality and their extraction causes donor site morbidity. Synthetic vascular grafts are also available, constructed from materials such as polytetrafluoroethylene (PTFE). Although these grafts have shown satisfactory performance as large and medium diameter vessels, they remain inferior to autografts for small diameter applications (<6 mm).
Tissue engineering offers a potential alternative to autologous vessels or synthetic vascular grafts. Tissue engineered blood vessels (TEBVs) may be grown in vitro for implantation as bypass grafts, vessel replacements or vascular access conduits. These vessels could offer superior performance to synthetic grafts and could be obtained without the need for invasive autograft harvest. Prominent research groups have made great strides towards producing TEBVs with some products currently undergoing clinical trials . However, these technologies only offer the ability to generate uniform tubular blood vessels and they would be very difficult to adapt to producing more complex shapes due to their sheet-based manufacturing process. This project will aim beyond the current state-of-the-art in tissue engineered blood vessels to manufacture flexible, porous biodegradable materials in complex geometries (e.g. tapers, bifurcations or valves).
Main questions to be answered
Manufacturing of inherently porous biodegradable materials: The Claeyssens group has substantial expertise in light-based additive manufacturing of biocompatible polymers and we will adopt our current 3D printing-enabled manufacturing of flexible (polyglycerol sebacate or polycaprolactone-based) materials to this project.[2,3,7-9] To enable maximum cell ingrowth we will use our in-house emulsion templated resins, which are inherently porous on the 10-50 µm length scale.
Bioreactor-based cell culture on the shaped porous constructs: Once we have established an effective printing protocol, we will rapidly advance to cell culture on the constructs. For this we will use in-house developed bioreactors built by stereolithography. We will explore smooth muscle cell ingrowth and extracellular matrix (ECM) deposition both in static and pulsed flow conditions. The influence of the flow regime on the amount of ECM production and composition (collagen/elastin ratio) will be assessed and optimised.
Decellullarisation protocol: After in lab cell culture on the constructs will be decellullarised. We have optimised a number of decellullarisation protocols which will be explored on these in-lab engineered tissues. Once decellullarised their properties (mechanical: burst pressure, suturability, elasticity, biological: subsequent cell adhesion/growth, ECM composition) will be determined, and future clinical translation will be explored with the industrial collaborator.