Theme 5: Tissue Engineering for Regenerative Medicine

A special Regenerative Medicine project

The demand for effective skeletal repair will continue to grow steadily in line with increasing world populations and, in particular, age-related trauma. Accordingly, in late 2012 New Zealand’s University of Auckland initiated what became a four-country four-year project bringing together experts from a range of disciplines to establish a platform for enhancing skeletal regeneration research.

It was recognised that musculoskeletal degeneration and complications from injuries are eligible for treatment by regenerative approaches that aim to repair, restore or rejuvenate skeletal elements and associated tissues using stem cells and biocompatible scaffolds. Ideally, scaffolds with integrated bioactive factors that support the differentiation of stem cells into tissue-specific cells should be able to respond to environmental cues. Moreover, scaffold biomaterials should facilitate the tissue-implant interface and could comprise titanium rods with bulk polymers and self-assembling short peptides.

The project, funded by the European Union (EU) and named skelGEN, brought together leading EU and New Zealand experts in the field of orthopaedic research. This consortium aimed, through a multidisciplinary approach, to develop novel regenerative medical solutions for the human skeleton, including bones, cartilage and tendons. An important underlying driver for the consortium was, by the generation of new knowledge, to contribute to a shift from clinical management to effective skeletal repair.

The consortium, led by University of Leeds, comprised academics/researchers in universities in the EU [four in the UK, two in Portugal and one in The Netherlands] and New Zealand [two].

The programme was made up of four distinct but interrelated work packages: (1)Stem cells: Basic translational stem cell biology – from lab bench to clinic; (2)Scaffolds: Making tissue-specific scaffolds translational; (3)Computational modelling: Predictive modelling to build an understanding of the mechanisms of cell, scaffold and tissue regeneration interactions; and (4)Evaluation: Standardising evaluation with regenerative medicine – basic through to translational for both in vitro and in vivo, inclusive of clinical.

Skeletal tissue engineering

Researchers initially standardised protocols for the isolation, characterisation and expansion of skeletal stem cells from different sources. In addition, they developed several biomanufacturing platforms for the design and production of tissue-specific porous scaffolds. These were designed to deliver the supporting material and growth factors for the directed differentiation of skeletal stem cells into bioengineered bone, cartilage or ligament.

Researchers visualised construct topology, performed mechanical evaluation and immunogenicity testing, and evaluated biomaterial scaffolds in vitro. Studies in various animal models validated the biocompatibility and potential clinical efficacy of the generated constructs.

The overall tissue engineering approach was assisted by the use of computational modelling. This tool allowed the integrated understanding of stem cell behaviour, cell growth and nutrient requirements, and gases dynamics (e.g. O2 ingress to and CO2 egress from peripheral and deep constructs) during the tissue regeneration process. The aim was to understand the mechanisms of cell and tissue regeneration as well as the cells-scaffold interaction in the three-dimensional setting.

Clinical translation

The next step towards clinical translation of candidate medical devices was mediated through contacts with orthopaedic surgeons and industry experts. Importantly, all partners believed that the engagement of research scientists with clinicians in the early stages of research and development towards clinical translation would have significant impact on the success of skelGEN. It was envisioned that this early involvement would include product conceptualisation, design and specification; clinical trialling; counsel in clinical utility; and contribution to the evidence base for cost-effectiveness. It would also bring an ability to interpret and articulate the connections between product development and market/clinical need, and to identify any incongruities (therefore opportunities) that might arise within the rhythm of a surgical procedure.

The skelGEN initiative set a platform for such engagement to be pursued with vigour.

In research related to that undertaken in skelGEN doctors and researchers at the University of Southampton employed a construct made of bone and titanium in hip surgery. Patient-specific, the implant was designed and developed using computer-aided design (CAD) and manufacturing technology. Doctors used bone stem cells to replace bone loss and encourage tissue regeneration behind and around the implant. This cutting-edge technology was and is expected to significantly improve the outcomes for patients.

Industry involvement

A number of carefully selected companies became involved during the course of the project. It was anticipated that they would provide expertise in moving eventual skelGEN products towards commercialisation. Click below to view slide presentations made by three of these companies, and by the author, at a consortium meeting in Portugal in October 2015:

The future

Bypassing political and ethical concerns, skelGEN partners envisioned that innovations in stem cell therapy coupled with advances in biomaterials/scaffolds and greater understanding of interactions with growth factors will significantly advance the field of Regenerative Medicine. An understanding of regulatory pathways and the ability to negotiate these successfully for the sophisticated products having their genesis in the skelGEN initiative will be an important challenge.

Go-to persons for skelGEN

Prof Jillian Cornish, University of Auckland

j.cornish@auckland.ac.nz

Prof Xuebin Yang, University of Leeds

X.B.Yang@leeds.ac.uk