Dilip Thomas, a doctoral candidate at the Science Foundation Ireland Centre for Research in Medical Devices (CÚRAM) at NUI Galway, has been awarded first place in the category of ‘Best Preclinical Study’ at the Journal of Wound Care Awards 2017. The Journal of Wound Care (JWC) Awards recognise excellence in research that aims explore new frontiers in wound-care therapies. The award also sets a high standard in recognising the quality and rigorous methodology in the execution of the pre-clinical study to obtain both meaningful and high-impact output. The research for which Thomas was awarded focused on the development of a next-generation stem cell therapy for the treatment of peripheral arterial disease (PAD). PAD affects blood supply to the lower extremities due to narrowing of the arteries that supply blood to the limbs. Sedentary lifestyle and factors such as smoking, diabetes, high blood pressure, cholesterol and other age-associated diseases contribute to the progression of PAD. The global prevalence of PAD increased by 24% from 2000 to 2010, i.e. from 164 million to 202 million. In Europe alone, 40 million cases were reported in 2010 (Fowkes F.G.R et al, 2013). Although early stages of this disease can be treated using by-pass procedures, studies have shown approximately 30% of the patients are deemed unfit for by-pass and are classified as ‘no-option’ critical limb ischemia (CLI) patients. The lack of sufficient blood supply from non-healing ulcers and tissue damage leads to foot amputation in a third of the CLI patient population. No-option CLI patients suffer from poor quality of life due to high treatment cost and inevitable limb amputation within a year. One of the early and critical events in wound healing is the establishment of a robust blood-supply network. Delivery of stem cells have emerged as an effective therapy due to its potential in secreting beneficial factors that help in restoring blood supply and accelerating wound healing. However, due to poor retention of the stem cells, the therapeutic factors produced by these stem cell ‘micro-factories’ gets diluted and renders the treatment ineffective.

Advanced biomaterials in tissue engineering

Advanced biomaterials used in the field of tissue engineering offer multiple strategies to overcome the loss of cell after injection. Thomas’ research explored the use of embedding-based cell immobilisation technology to ‘restrain and retrain’ stem cells in microscale hydrogels (also referred as ‘microgels’), which are high water bearing, jelly-like materials that resemble properties of soft tissues in our body. This immobilisation method sets the stage not only for recapitulating ideal cell environment for higher stem cell function, but also dramatically increase their ability to survive post implantation in a pre-clinical model. The microgels used in the preclinical study composed of human mesenchymal stem cells from the bone marrow trapped in a matrix of collagen – a predominant structural protein found in body tissues. For the first time in encapsulation methodologies, the study demonstrates that tuning the microgel properties by modulating collagen concentrations in a shape-controlled spherical format, results in an altered stem-cell phenotype that promote higher release of therapeutic factors which aid in wound healing. The microgels were tested as a local implantable device in a pre-clinical limb ischemia model developed in-house. The microgels not only accelerated formation of new blood vessels in the limb, but also led to amputation and necrosis-free survival. A major clinically attractive aspect of the preclinical study was the use of a low-stem cell dose (up to 20 times lower than standard) in the microgels for tissue repair. Hence as a therapy in a clinical setting, microgels would not only help faster tissue repair, but also provide treatment for more patients. The research adds to the current knowledge in cell-encapsulation strategies by highlighting how entrapment of stem cells, and subsequent cell maturation within the engineered microgels enhance the release of therapeutic cargo by the stem cells for regeneration of new blood vessels. The development on microgel-based stem cell therapy will encourage research into newer functional materials to be used in combination with stem cells to improve our understanding of the underlying mechanisms that trigger wound healing in diseased states. Subsequently, this will lead newer therapies in wound repair. Thomas’ research has already taken a translational path with a feasibility grant awarded by Science Foundation Ireland (SFI). The idea is to move from bench-side to bedside by developing a microfluidic device that can generate microgels embedded with stem cells in a high-throughput manner. The research success to date and the promise to further develop this technology is due to integration of key expertise and shared goals in an interdisciplinary environment within CURAM, where biomaterial technology has been used to enable existing stem-cell-based therapies for debilitating vascular diseases such as CLI.

Q&A with Dilip Thomas

1. Please describe the work you have done which resulted in you winning a JWC award. My pre-clinical research and innovation is centred around the development and testing of a biomaterial-based stem cell delivery device as a therapeutic strategy for 'no option' CLI patients. In order to enhance the therapeutic efficacy of stem cells, cells were encapsulated in collagen ‘microgels’ – to promote high cell survival and retention. I demonstrated that tuning the properties of the microgels, prime and enhance the angiogenic capacity of stem cells via paracrine release of trophic factors, when delivered to an ischemic, slow-healing wound (Thomas et.al, 2014). 2. How do you think winning this award will affect your work in the future? The recognition of my work by the JWC highlights the impact of research to healthcare professionals, translational scientists and peers in the area of wound care. The award also certifies a high standard based on the quality of work to obtain further funding from research agencies. From the research and translational standpoint, future work will focus on understanding the mechanism of action whilst compiling safety and toxicology data for the first-in-human clinical trial. 3. How has winning this award changed people’s perception of your role? Winning the award for the Best Pre-Clinical Study is a testament to the training, expertise and execution of a well-formulated study design. There is an increased appreciation of not only the pre-clinical findings, but also the feasibility and timeframe to conduct a thorough study from in vitro to in vivo. 4. What is the most important aspect of your work and why? The most important aspect of my research is the use of biomaterials and manipulation of stem cells in a physiologically relevant, three-dimensional matrix derived from tissues. Working with cells in this microenvironment allows to limit the discrepancy in therapeutic effect moving from bench-to-bedside. 5. What do you most enjoy about your work? Working in a multidisciplinary, translation focussed environment that also promotes cross-pollination of ideas and collaborations. 6. What are the main challenges you face? One of the major challenges was pertaining to the development of a pre-clinical animal model and its relevance to the pathophysiology of CLI observed in humans. Even though the animal models will never match the co-morbidities of human diseases, reproducing the most relevant clinical symptoms and defined study end-points can provide meaningful indicators of an effective therapy. 7. What advice would you give to wound-care practitioners and researchers aspiring to achieve positive change within the field? In this new age of personalised medicine, to achieve a positive change in the field, it is imperative to drive research with a ‘patient-centric’ approach; first, identifying the key clinical problem and then working backwards to device a tailored solution which will ensure quality and efficacy by design. Dilip Thomas received a BSc in Biotechnology at the University of Mumbai, India and an MSc in Biochemical Engineering at University College London. His research interests include the development of novel functionalised biomaterials, microencapsulation and transplantation of progenitor cells to promote angiogenesis in ischemic animal models. He is a a doctoral candidate at the Science Foundation Ireland Centre for Research in Medical Devices (CÚRAM) at NUI Galway.