Potential of acellular biological scaffold coated with chemokines and cytokines as tissue engineered small artery grafts

Millions of coronary or peripheral artery bypass grafts are performed yearly worldwide by cardiac and vascular surgeons using patient's own veins from the leg (SVG) or synthetic grafts. However, >50% of these grafts get blocked after 5-10 years, with common infections at the harvesting sites and frequent hospital re-admissions. Patient's own arteries are used only in 1:5 cases due to shortage of available artery, despite >95% of these do not get blocked after 15 years. Using arterial grafts made in the lab provides hope for future patients. Our previous research suggests that implanting biological tubes made from pig or cow material into a pig graft experimental model leads to encouraging but sub-optimal results. This is an exciting development, but we need to improve the lining of the graft to reduce the occurrence of blockages. Our goal is to improve the grafts by coating the biological scaffolds with proteins able to attract cells and create a suitable lining which stops blockage by blood clots and cell growth. Our plan will allow us to achieve grafts more similar to real arteries which avoid the use of the patients own leg vein and induce the patients blood cells to create an optimal graft. This would pave the road to bringing this new technology to the bedside in 5-10 years, while saving large amount of resources to the health services and greatly improving patient's well-being and outcome.

Millions of coronary and peripheral artery bypass procedures are undertaken yearly worldwide using autologous saphenous veins (SVG) or synthetic grafts. However, >50% of these grafts get blocked after 5-10 years. Moreover, vein graft occlusion is more frequent in diabetic patients than non-diabetics. Infections at the harvesting sites, hospital re-admissions, and revascularizations are also common, which further reduces the success of the grafts. Arterial conduits are used only in ~20% of all cases, despite a >95% patency rate at 15-20 years and reduced long-term mortality. Bioengineering of small arterial conduits is a possible alternative approach to improve SVG patency. Our pilot suggests that implanting acellular biological grafts in a porcine carotid artery leads to in situ arterial bioengineering by host cells, although with a sub-optimal three-layered wall, asymmetric cell recruitment and matrix remodeling. In this application, we aim to improve our results by modulating cell recruitment and differentiation within the graft by coating scaffolds with chemokines and cytokines (monocyte chemoattractant protein-1 (MCP-1), fractalkine, pleiotrophin and tumour necrosis factor-alpha (TNF-alpha)). We hypothesize that the use of these chemokines will attract monocytes and the cytokines will promote differentiation into endothelial-like cells and produce more structured and functional arterial-like grafts. We will develop the coated acellular grafts and test their performance in vitro (bio-reactor) and in vivo (porcine carotid artery implantation). Our laboratories are highly experienced with in vitro and in vivo models of grafting and tissue engineering which are essential for the success of this project. The creation of this off-the-shelf graft will avoid the use of autologous vein which will save surgical time and money as well as eliminating the risk of infection and discomfort of the leg in addition to improving the function of the graft.

1. Academic beneficiaries
Despite decades of research, the failure rate for autologous saphenous vein grafts is unacceptably high and patients also experience undesirable complications at the site of vein harvest in the leg. Creating an acellular graft that undergoes in situ remodelling to generate an arterial-like graft, has the potential for a profound impact on the future of research in this field. Our findings may facilitate a new approach in which off the shelf grafts which avoid the use of autologous vein, can be utilised which had low thrombus and occlusion rates. In this way, we will advance our collective knowledge of in situ remodelling of grafts and establish improved alternatives to autologous grafts.
This study will have global reach as cardiovascular disease and bypass graft failure are prevalent across the world. It is of particular note that the rates of cardiovascular disease in Malaysia are higher than many countries in the world. Moreover, the rates of cardiovascular disease and vein graft failure are significantly higher in diabetics than non-diabetic patients.
2. Patient benefit
Ultimately, is successful this approach will reduce vein graft failures and infection at the site of vein harvest in patients undergoing bypass grafting for reducing the symptoms of coronary artery disease and peripheral artery disease. This will enhance patient recover times, general well being and outcome.
3. Healthcare policy makers at governmental level
The cost of implantation of grafts that fail and infections at the harvesting site can only be estimated, but given the volume of bypass grafts performed, it is unequivocally dramatic. The clear translatable aim of this study is to assess whether coated acellular biological scaffolds can provide an off the shelf alternative to the less than optimal autologous saphenous vein and synthetic scaffold grafts. Should this new approach to grafting prove successful, a strong case could be made for testing in longer term pre-clinical models and humans, ultimately resulting in improved effectiveness of our public
services and ultimately improved health of our population. Due to the reduced surgical intervention i.e. no need to harvest saphenous vein, the procedure will be shorter thereby reducing the cost. Additionally, the improved outcome of the patient and graft will reduce the healthcare costs and likelihood of future reintervention.
4. Commercial Exploitation
The ultimate goal of this research is to develop a novel graft scaffold, initially for coronary artery disease but also applicable to peripheral artery diease. Given the vast patient population that this graft would potentially serve, the prospect would be exceptionally attractive to industry. Our group in Bristol has first-hand experience of pioneering novel devices in pre-clinical models at TBRC and driving them through commercial realisation. The University of Bristol Research Enterprise Department is available to offer advice with regards patents and licencing.
5. Deliver highly trained researchers
Through hands-on training delivered by world class supervisors, we are confident that this project, at this institution, with this project, will deliver provide high quality training to 2 M.Med.Science research students from Malaysia. This will act as a catalyst for their academic careers. Moreover, this novel project will enable the technician based in Bristol to gain new skills in project management, collaboration and laboratory skills which will facilitate their career progression.
6. Promoting collaboration
This research project is an ideal opportunity for collaboration between the two Univerisities. There is considerable advantage to the interaction and sharing of knowledge at the level of discovery science, translational science and clinical benefit. For example, the University of Bristol's preclinical translational research centre will be accessible to the Universiti Kebangsaan Malaysia for additional studies.