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In recent years, Ireland has become established as one of the leading countries in Europe for regenerative medicine research and the development of related technologies, with several active research groups located throughout the country.
Particularly strong clusters are found in Dublin and Galway, most notably at the RCSI, Trinity College Dublin (TCD) and NUI Galway. These groups work closely with industry to bring technologies to the clinic for the benefit of patients and society.
The field of regenerative medicine includes the application of advanced biomaterials in tissue engineering and the use of cellular therapeutics such as allogeneic or autologous stem cells to restore and regenerate cells, tissues and organs of the body that are lost or impaired as a result of ageing, disease or trauma. It is a highly interdisciplinary field and typically includes inputs from experts in fields including materials science, engineering, pharmacy and the life sciences, in addition to different areas of clinical medicine.
<h3 class=”subheadMIstyles”>Tissue regeneration</h3>
Some of the regenerative medicine areas where Ireland is particularly strong include the application of advanced materials for tissue regeneration and drug delivery. For example, AMBER, an exciting €58 million Science Foundation Ireland (SFI) and industry-funded venture, brings together a multidisciplinary team from CRANN and the Trinity Centre for Bioengineering in TCD, with researchers and clinicians from the RCSI Tissue Engineering Research Group (TERG), and is focused on developing the next generation of materials and medical technologies in partnership with industry (currently, 31 companies are partners on collaborative projects).
As an example, a number of technologies from AMBER-TERG researchers in the RCSI have been patented, resulting in the spin-out in 2011 of a high-potential start-up, SurgaColl Technologies. The first product from the group commercialised by SurgaColl, HydroxyColl, a collagen-hydroxyapatite porous scaffold biomaterial developed for use as a bone graft substitute received regulatory approval (CE mark) in November 2015 and is currently in clinical use.
A second product, ChondroColl, a multi-layered scaffold for cartilage repair, is expected to receive regulatory approval in 2017. Human clinical translation of the latter technology is being carried out in partnership with Prof Cathal Moran, Professor of Orthopaedics in TCD and Consultant Surgeon in the Sports Surgery Clinic, and Prof John O’Byrne, Abraham Colles Professor of Orthopaedics in the RCSI and Consultant Surgeon in Cappagh National Orthopaedic Hospital.
Both of these technologies are biodegradable, natural, polymer-based scaffolds, whose composition directs host cells to repair bone and joint tissue without the need for growth factors or <em>in vitro</em> cell culture. It is hoped that the ChondroColl product will delay the need for more invasive surgery, including the requirement for total joint replacements, especially in athletes and younger patients.
However, for more complex joint injuries, the application of next-generation processing techniques such as 3D bioprinting of cells and biomolecules and cutting-edge additive manufacturing processes offers a major opportunity to develop next-generation devices and therapeutics. Irish researchers such as Prof Danny Kelly, Director of the Trinity Centre for Bioengineering and AMBER Principal Investigator, are at the forefront of this initiative, with other researchers in University College Dublin (UCD), University of Limerick and the RCSI also actively involved in this major growth area.
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<strong>Prof Fergal O’Brien</strong>
From a regulatory perspective, cell-free biomaterials offer the opportunity for more rapid translation to the clinic if relatively simple in composition and manufactured from products already in clinical use. However, for large, multifaceted injuries, additional factors such as stem cells, genes or growth factors may be required to enhance the regenerative capacity of such biomaterials.
There is an active body of research ongoing in this area in AMBER and other Irish centres, including the Galway-based CÚRAM Centre for medical devices, which brings together researchers from NUI Galway, the RCSI, University College Cork and UCD, and aims to rapidly translate novel transformative products to the patient’s bedside. These advanced regenerative templates enhance the regenerative process by incorporating growth factors, proteins and other small biomolecules into the damaged tissue, altering the physiological environment and advancing the rate of repair. This is a major growth area in regenerative medicine and has been exploited clinically to deliver (for example) platelet-derived growth factor for the promotion of wound healing (Regranex), and bone-morphogenetic proteins for bone formation (Medtronic’s Infuse).
However, despite approval of some products by regulatory bodies such as the FDA, complications have hampered the clinical use of many drug-loaded biomaterials, predominantly due to poor release kinetics of the biomolecule causing significant side-effects. Therefore, much ongoing research is focused on advanced delivery systems, such as the use of nanoparticles embedded within macroporous biomaterials, which aim to achieve controlled delivery of the biomolecule at a rate sufficient to elicit a therapeutic response while minimising side-effects.
In relation to cell-based therapeutics in regenerative medicine, major progress is also being made towards clinical translation in Ireland, led by teams such as the REMEDI (Regenerative Medicine Institute). The Centre for Cell Manufacturing Ireland (CCMI) at NUI Galway was Ireland’s first approved GMP facility for the manufacture of stem cells and clinical-grade preparation of small molecules and cellular therapeutics.
This purpose-built, state-of-the-art facility housed at the National Centre for Biomedical and Engineering Sciences (NCBES), was licensed to manufacture Advanced Therapeutic Medicinal Products (ATMP) for use in human clinical trials in 2014. Prof Timothy O’Brien is currently leading a trial examining the potential of intramuscular delivery of autologous mesenchymal stem cells to patients with no-option, critical limb ischaemia.
The Centre will also be used to manufacture stem cell batches for the Horizon 2020-funded ADIPOA2, phase 2 trial for osteoarthritis, led by Prof Frank Barry. A similar approach using stem cells is also being employed by Irish clinicians for the treatment of corneal injuries at the Royal Victoria Eye and Ear Hospital (RVEEH) in Dublin. The first limbal stem cell tissue transplant in Ireland was performed by Mr William Power, Consultant Ophthalmic Surgeon at the RVEEH. The process, whereby cells isolated from healthy corneal tissue are isolated and expanded to form cell sheets for surgical implantation, was authorised for clinical use by the Health Products Regulatory Authority (HPRA) in January 2016, with the first surgery taking place six months later. In addition, Dr Garry Duffy from NUI Galway and the RCSI is leading two EU consortia grants (AMCARE and DRIVE) focused on natural polymer-based delivery of stem cells and pancreatic islets to treat myocardial infarction and type 1 diabetes, respectively.
In the Irish context, the growth of ever-closer ties between academia and the pharma industry provides opportunities for significant progress in translating regenerative technologies to the clinic. Ireland is now well established as a leader in the production of pharmaceuticals worldwide, with over 120 international companies, including nine of the top 10 global pharmaceutical giants, found on the island.
Similarly, 18 of the world’s top 25 medical technology companies are also based here, with the Irish medical technology sector employing more than 29,000 people, making Ireland the largest exporter of medicinal products in the EU and an emerging global leader in this industry. Critically, a considerable proportion of the money invested by the MedTech companies located and headquartered here (existing companies invested €960 million in 2014-2015) is being allocated to innovation, research and development.
The Government has also recognised the importance of investment in this area, leading to significant funding in industry-academic partnerships by agencies such as SFI. The SFI’s Research Centres programme links scientists and engineers in partnerships across academia and industry to address crucial research questions, foster the development of new and existing Irish-based technology companies, attract industry that could make an important contribution to Ireland and its economy and expand educational and career opportunities in Ireland in science and engineering.
Furthermore, the advancing engagement between Enterprise Ireland and the Mayo Clinic in the US proposes to lead the commercialisation of in excess of 20 novel medical technologies by 2022, with the additional aim of establishing a similar number of high-quality, high-value spin-out companies in Ireland in the process. Initiatives like these will undoubtedly continue to provide major opportunities for clinical translation going forward, further enhancing our position as a global leader in the development of economical medical devices for the treatment of chronic and acute diseases.
Challenges exist, of course. As it is a relatively nascent field, the regulatory environment for translation of regenerative medicine technologies can be challenging. But in Ireland, the HPRA, which has responsibility for regulating medicines, medical devices and other health products, as well as the design and execution of clinical trials, is very willing to provide formal and informal input in these areas, even at early stages of technology development and clinical trial design.
Furthermore, as with many areas of the economy, concerns exist due to Brexit and the recent US presidential election about the risk of reduced investment into Ireland, which could slow down the recovering economy, as well as see spending cuts in health and research.
To finish on a positive note, however, this might also provide opportunities — an example being the discussions that have begun recently about possibly relocating the European Medicines Agency to Ireland from the UK, if or when Article 50 is triggered. As potentially the only native English-speaking country left in the EU, and with a host of Europe’s leading pharma and MedTech companies having a presence in Ireland, this might provide a major opportunity for further success as this exciting field continues to grow.
<em>Prof O’Brien acknowledges input from Ms Sarah Casey from the RCSI Tissue Engineering Research Group in compiling this article.</em>
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