Our December Researcher in Focus is Dr. Tom Flanagan of the School of Medicine, University College Dublin. Tom is a lecturer in Human Anatomy and leads the Tissue Engineering Research Group at the School. The focus of Tom’s research group is the use of tissue engineering to develop living, cardiovascular devices to treat children and adults with heart defects. As Tom explains “Tissue Engineering aims to repair or replace damaged and defective organs by combining cells from the patient with temporary degradable biomaterials that will guide the growth of a new living tissue structure”.
Tom is funded by the National Children’s Research Centre through our Paediatric Research Project Grant scheme to work on the project “Mending Broken Hearts: Living, Growing Heart Valve Devices for Children”. Approximately 1% of all babies are born with congenital heart disease (CHD). In children with CHD, a defect in a valve of the heart is one of the most common problems. Heart valves (mitral, tricuspid, aortic, and pulmonary valves) are thin flaps of tissue that open and close as the muscles of the heart contract and relax. The opening and closing of these valves is responsible for the characteristic “Lub Dub” sound of our heartbeat. These valves control the flow of blood through the chambers of our heart, maintaining a one-way direction of blood flow. Any compromise to this flow means that the heart must work harder, which can place significant strains on the heart and cause it to fail.
In Ireland, about 650 children are born with structural abnormalities of the heart every year (translating to about 1.5 million children worldwide), many of whom will require surgical reconstruction of the heart, as well as artificial heart valve implantation. For these children, the only replacement valve options are mechanical valves or preserved biological valves. As these valves do not grow as the child’s heart grows, children with defects in the valves of their heart will require multiple valve replacements and surgeries over the course of their childhood and adolescence.
Together with co-principal investigators, Professor Damien Kenny (Paediatric Cardiologist at Children’s Health Ireland, Crumlin) and Professor Massimo Caputo (Paediatric Cardiac Surgeon, University of Bristol), as well as a multi-disciplinary team of collaborators, Tom aims to develop an implantable valve that promotes tissue development, leading to a living valve tissue that will grow as the child’s surrounding heart grows. “We propose to develop a novel tissue-engineered heart valve by mimicking the normal valve structure”.
The project also aims to remove the need for invasive open heart surgeries for valve implantation by mounting it on a novel, bio-degradable 3-D printed valve stent that will allow minimally-invasive implantation. “The proposed valve will be deliverable to the child’s heart on a novel biodegradable 3-D printed valve stent through a catheter using keyhole surgery”
As Tom explains “The ultimate goal is to remove the need for successive valve implantation procedures in children due to outgrowth of an implant. The type of device that we are trying to develop within this project has the potential to change the landscape of paediatric valve intervention procedures, by reducing morbidity, reducing the number of high-risk surgical procedures endured by the infant patient and consequently, the associated healthcare costs, while significantly improving the quality of life of these children”.
This project builds on insights into the structure of heart valves gained during Tom’s early research career. Previously, heart valves were thought to be simple flaps of tissue, but several groups including Tom’s have shown that they have a distinct microscopic structure and contain populations of cells that are unique to heart valves. These features are critical for the normal functioning of the valve. Knowledge of the unique structural and cellular features of heart valves provides Tom with a blueprint for the development of living, growing heart valve devices. Tom and his colleagues have been applying these blueprints over the last number of years to test various natural and synthetic materials that can be used to construct new heart valve replacements, as well as examining the potential for various patient-derived cells to populate and remodel these materials into implantable tissues.
Tom links his interest in the cardiovascular field to the death of his father, when Tom was just a child. “My father was referred for triple heart-bypass surgery at just 50 years of age, back in the late 1980s. Sadly, he suffered complications during the surgery, and we lost him that day. The loss of a parent at such a young age can have a profound effect on any child; children of that age have so many questions – and I always questioned how this could happen to my own father”.
The cardiovascular system has fascinated Tom ever since: “We are particularly vulnerable to our cardiovascular system, and we really depend on it working adequately every day. Major advances in biomedical engineering have provided life-saving and life-changing solutions addressing cardiovascular disease; indeed, vascular stents were implanted for the first time in Ireland only 6 months after my father died, and even stents have gone through several major cycles of advancement since then. Tissue engineering, already a field with 25-30 years behind it, promises many exciting developments, but particularly in treating children who require these life-changing devices to grow as their bodies grow”
Tom recently took part in this year’s ‘Abseil for Crumlin’ to raise funds for NCRC/CMRF.
Tom’s research group are very grateful for the support of NCRC and CMRF in driving their research programme in paediatric cardiovascular devices. “Our colleagues at the NCRC and CMRF are a wonderful group of people with an admirable vision – to change the lives of sick children for the better – and we are delighted to be associated with them”.
Further information on the work of Tom and his colleagues can be found here:
UCD webpage: https://people.ucd.ie/thomas.flanagan
Research group Twitter account: @UCDTissueEng
Woods I, Black A, Jockenhoevel S, Flanagan TC (2019) Harnessing topographical and biochemical cues to enhance elastogenesis by pediatric cells for cardiovascular tissue engineering applications. Biochem Biophys Res Commun, 30, 156-62. (Pubmed)
Liu MM, Flanagan TC, Jockenhoevel S, Black A, Lu CC, French AT, Argyle DJ, Corcoran BM (2018) Development and evaluation of a tissue-engineered fibrin-based canine mitral valve three-dimensional cell culture system. J Comp Pathol, 160, 23-33. (Pubmed)
Brougham CM, Levingstone T, Shen N, Cooney GM, Jockenhoevel S, Flanagan TC, O’Brien FJ (2017) Freeze-drying as a novel biofabrication method for achieving a controlled microarchitecture within large, complex natural biomaterial scaffolds. Adv Healthc Mater, 6, 1700598. (Pubmed)
Brougham CM, Levingstone T, Jockenhoevel S, Flanagan TC, O’Brien FJ (2015) Incorporation of fibrin into a collagen-glycosaminoglycan matrix results in a scaffold with improved mechanical properties and enhanced capacity to resist cell-mediated contraction. Acta Biomaterialia, 26, 205-14. (Pubmed)
Woods I, Flanagan TC (2014) Electrospinning of biomimetic scaffolds for tissue-engineered vascular grafts: threading the path. Expert Review of Cardiovascular Therapy, 12, 815-32. (Pubmed)
Koch S, Flanagan TC, Sachweh JS, Tanios F, Schnoering H, Deichmann T,Ella V, Kellomaki M, Gronloh N, Gries T, Tolba RH, Schmitz-Rode T, Jockenhoevel S (2010) Fibrin-polylactide-based tissue-engineered vascular graft in the arterial circulation. Biomaterials, 31, 4731-4739. (Pubmed)
Flanagan TC, Sachweh JS, Frese J, Schnoering H, Gronloh N, Koch S, Tolba RH, Schmitz-Rode T, Jockenhoevel S (2009) In vivo remodelling and structural characterization of fibrin-based tissue-engineered heart valves in the adult sheep model. Tissue Engineering Part A, 15, 2965-2976. (Pubmed)
Tschoeke B, Flanagan TC, Koch S, Sri Harwoko M, Deichmann T, Ella V, Sachweh JS, Kellomaki M, Gries T, Schmitz-Rode T, Jockenhoevel S (2009) Tissue-engineered small-calibre vascular graft based on a novel biodegradable composite fibrin-polylactide scaffold. Tissue Engineering Part A, 15, 1909-1918. (Pubmed)
Flanagan TC, Cornelissen C, Koch S, Tschoeke B, Sachweh JS, Schmitz-Rode T, Jockenhoevel S (2007) The in vitro development of autologous fibrin-based tissue engineered heart valves through optimised dynamic conditioning. Biomaterials, 28, 3388-3397. (Pubmed)
Flanagan TC, Wilkins B, Black A, Jockenhoevel S, Smith TJ, Pandit AS (2006) A collagen-glycosaminoglycan co-culture model for heart valve tissue engineering applications. Biomaterials 27, 2233-2246. (Pubmed)