regen Magazine 2015

regen.

ISSUE 6 - SEPTEMBER 2015

GETTING REGENERATIVE THERAPIES TO THE MARKET

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FOREWARD:

Joining the regenmed dots – another year of Regener8 connections

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Partnering to build the global regenmed industry

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The pathway to innovation for regenerative therapies

Regener8’s early career researchers’ network – one year on

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Building clarity and consensus in the business of regenerative medicine and cell therapies

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Progress in the fabrications of bioactive cements and pre-set scaffolds for bone tissue regeneration

Focussing on technology, innovation and the future

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The power of partnership

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Five years of successful research translation and commercialisation

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The use of DBM and cellularised DBM in rotator cuff repair

Building the platform for world leading regenerative medicine

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Urinary tract application for a bladder – derived natural acellular matrix

Small bowel replacement and regeneration

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Islet transplantation for a sustainable cure for type 1 diabetes – all they need is the air that they breathe

Manufacturing bone tissue using resorbable calcium phosphate microspheres loaded with autologous stem cells:

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Working with universities to realise the potential of new discoveries

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Camregen scaffolds for cardiac repair

Regener8 Annual Conference sponsors

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Regener8 membership benefits

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Tissue engineering X systems engineering

CONTACT INFORMATION Regener8, X102 Medical and Biological Engineering, University of Leeds, Leeds, LS2 9JT E: regener8@horizonworks.co.uk Contact details for key members of the Regener8 team can be found on our website at www.regener8.ac.uk Regener8 cannot be held responsible for any inaccuracies that may occur, individual products or services advertised, member news or late entries. No part of this publication may be reproduced, scanned or digitally stored without prior written permission from Regener8.

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OVERVIEW

Dr Mike Raxworthy, Operations Director at Regener8.

UNIQUE OPPORTUNITIES FROM WORLD-CLASS PARTNERSHIPS

By Dr Mike Raxworthy, Operations Director, Regener8.

One of the most satisfying things about sitting down each year to write this overview for Regen, is to see the progress made over the previous 12 months and to review the outlook for the next couple of years. It is clear in looking back that regenerative medicine as a whole has continued to emerge – as a technology, an industry, a sub-sector and a community. RegenMed is well along the path to becoming established rather than just emergent!

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OVERVIEW Regenerative medicine continues to be a proud member of the ‘8 Great Technologies’ club and to enjoy support though funding schemes managed by Innovate UK and the Research Councils. The UK Strategy for Regenerative Medicine has led to the establishment of five UK Regenerative Medicine Platform Hubs which have so far received investment of around £20 million and which currently engage with 18 companies.

Centres for Doctoral Training have been set up or extended in Manchester, Leeds and Loughborough (with Keele and Nottingham) over the past 18 months. In the case of the Leeds centre, for instance, 10 companies are currently engaged. This support is clearly able to span early- and mid-stage translation.

Regener8 – with its extensive national profile – has over 260 industry members (including some 25 outside the UK). And late stage translation is being realised though investment funding attracted recently by ReNeuron, Cell Therapy Ltd, Orthox and Tissue Regenix among others.

A distinct classification Regener8 and our strategic alliance partners at the Medical Technologies IKC have for the last several years sought to focus on regenerative therapies that can be brought to market via the medical device route.

Regenerative devices as a distinct class or sub-class are now receiving increasing recognition. One of the tracks at the MEIbioeng15 conference will focus on regenerative devices and describes them as ‘regenerative therapies which can be delivered to the market and patient as class three medical devices (or human tissue products). These are cost effective healthcare interventions, with shorter translation pathways and with lower development costs than other forms of regenerative and cell therapies’. The field has also been the subject of a recent Innovate UK scoping workshop.

Regener8 Executive Director John Fisher, speaking at the Innovate UK workshop, made the point that implants, biomaterials or scaffolds that deliver tissue regeneration and repair and that can be translated through the medical device regulatory pathway make up an industry that could be worth an estimated £1 billion to the UK beyond 2020.

The global market for new products and for products using these technologies to replace existing approaches is estimated to be £75 billion by 2020.

Regener8 and the Medical Technologies IKC will continue to explore technologies and approaches such as point of care manufacturing technologies, minimally-manipulated cell therapies, and the clinical development of biologic and synthetic scaffolds as regenerative device opportunities which will complement higher risk/longer leadtime approaches in regenerative medicine and cell therapies.

Recent funding of £3 million awarded to the IKC will be used in part to deliver 40 industry-lead and academicinspired Proof of Concept (PoC) projects through targeted national calls to further strengthen and promote translation in the regenerative devices field.

A vibrant interface As outlined above, the regenerative medicine industry base becomes progressively stronger. This is illustrated by the two keynote presentations at this year’s Regener8 conference (or dedicated Regener8 track at the MEIbioeng15 conference). Professor Anthony Hollander’s presentation on ‘cell bandage’ technology illustrates the steps required to translate a technology from its beginnings at the University of Bristol into a company, Azellon Ltd, set up to commercialise the therapeutic approach to repair soft tissues. Cell Bandage uses the patient’s own bone marrow stem cells delivered via a scaffold to repair meniscal tears. Azellon has received funding from Innovate UK, has worked with the Cell Therapy Catapult and unlocked funds from private investors to progress Cell Bandage to its current stage of translation (phase IIa clinical trial). Professor Hollander comments that, “meeting the challenges and hurdles in science, regulation, financing has taught us a huge amount about how to develop a cell therapy in the commercial setting and will continue to do so in the future.”

John Ferris from Cytori Therapeutics provides the other keynote: Cytori has recently established a base in the UK as part of an initiative to attract businesses developing advanced manufacturing processes. Cytori’s approach is to harvest autologous adipose-derived regenerative cells from patients during surgery and then re-implant to treat cardiovascular disease and other conditions. John Ferris notes that, “to succeed, companies have to learn how to navigate a landscape which seems to be beset with challenges in every direction. The ultimate goal is to offer an innovative device or therapy, which is reimbursed by governmental and private health insurance schemes.

Getting there can be an interesting journey.”

Other invited and submitted presentations in the Regener8 track (The Delivery of Regenerative Medicine: Getting Regenerative Therapies to the Patient and the Market) illustrate the strength and breadth of academic and clinical groups and industry working to translate novel technologies and approaches along the pathway to commercialisation in order to realise patient benefits.

A connected landscape Regener8’s roots are in the N8 group of research-intensive universities in the North of England. Although now a national centre, the N8 Research Partnership grouping remains an important ally for Regener8. We are pleased to see the steps being made to create a Northern Powerhouse and continue to discuss opportunities with the N8 to leverage the strengths in medical technology and regenerative medicine that can be brought to bear via Regener8 and our wider group of collaborators from academia and industry. At this time when there is considerable discussion about regional investment, Regener8 and IKC Medical Technologies, both initiated some eight years ago in emerging areas of technology in the North of England, have shown how centres with national and international reach and international excellence can be grown from initial collaborations with

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OVERVIEW

The Regener8 and IKC Medical Technologies team, from left to right: Dr Mike Raxworthy, Operations Director, Regener8 and Medical Technologies IKC team members: Fiona Kingscott, IP and Contracts Manager, Jane Wilcox, Reporting and Information Systems Manager, Dr Jo Dixon-Hardy, Director of Medical Technology Innovation, Dr Graeme Howling, Technology Innovation Manager and Rowan Grant, National Outreach Manager.

a small number of universities and industry partners. The additional external funding leveraged to match publiclyfunded research, and private funding into industry for new products (over £200 million across the partners) has potential to deliver the £1 billion/year industry in the UK referred to earlier which will benefit the whole of the UK. Regener8’s national status allows us to explore an ongoing collaborative partnership with the Cell Therapy Catapult as we seek to bring together the complementary technologies championed by these two centres and to add value in doing so. Beyond the UK, we continue to enjoy the progress in translating regenerative approaches being made by the Center for Commercialisation of Regenerative Medicine in Canada and look forward to establishing a more formal relationship when conditions allow and the opportunity arises.

A strong centre Recent funding successes from the EPSRC to secure the next phase of the work of the Medical Technologies IKC (Regenerative Devices) and from HEFCE’s Catalyst scheme to develop capability in MedTech innovation in the wider region mean that Regener8 will continue to operate out of a strong centre from which it can exert a national reach and influence. We expect to be able to announce the conditions and process for the first PoC funding call under the EPSRC scheme later this year.

An optimistic outlook Regener8’s Early Career Researcher network continues

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to thrive and, following an overview of activity given at last year’s annual conference, ECRs have participated in a number of industry visits organised by Regener8. Visits have been made to the Smith & Nephew Research Centre, Xiros and the Cell Therapy Catapult. A second ECR careers event has been added as part of the MEIbioeng15 meeting to examine individual strengths, motivation and the means of deciding on an ‘ideal’ career direction.

As we look at the quality of scientists and engineers emerging from training with our partner and collaborative organisations, as well as the infrastructure and connected landscape to support them, there is every cause to be optimistic about the future of regenerative therapies.

A refined vision and purpose We have outlined how regenerative devices can be translated at lower cost and reduced time compared to other regenerative approaches such as cell and molecular therapies and have the potential to deliver real economic as well as healthcare benefits before 2025. Eight years on from starting our journey with IKC Medical Technologies and Regener8, the most recent market data indicates a 10 per cent year-on-year growth and a £75 billion/year global market by 2020. Convergence of the UK’s traditional strength in medical engineering technology with emerging regenerative technologies provides a strong platform on which to develop new and enhanced products to meet this growing clinical need in an ageing population For more information on Regener8, visit www.regener8.ac.uk

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REGENER8 ANNUAL MEETING 2015

THE DELIVERY OF REGENERATIVE MEDICINE: GETTING REGENERATIVE THERAPIES TO THE PATIENT AND THE MARKET

By Dr Mike Raxworthy, MEIbioeng Track Lead.

The 8th Regener8 Annual meeting – this year brought to you in partnership with the MEIbioeng15 conference, Engineering Future Benefits for Patients - continues our practice of bringing together experts involved in the translation of regenerative therapies. We are proud to welcome two prestigious keynote speakers: Professor Anthony Hollander, now at the University of Liverpool and Azellon Ltd and part of the team that successfully created and transplanted the first ever tissue-engineered windpipe; and John Ferris, from Cytori Therapeutics, a leading company in the development of cell therapies based on autologous adipose-derived cells.

Both keynotes will consider the journey from early lab studies through to the challenges and hurdles involved in developing regenerative therapies and devices in a commercial setting: Anthony Hollander on using Cell Bandage to treat and promote better short-term recovery for meniscal tears, and prevent or delay osteoarthritis in damaged knees (see page 14); John Ferris on the processing, use, regulation and adoption of adipose-derived regenerative cells for orthopaedic and wound management indications (see page 16).

Regener8 has also invited two speakers to complement the excellent submitted/selected content of the two sessions. Cells and Scaffolds will look at natural and synthetic scaffolds and the exciting technology being developed to produce and validate these biomaterials in preclinical and clinical settings. Professor Mohsen Miraftab

from the University of Bolton will discuss the application of polymer electrospinning to introduce novel properties into prosthetic vascular grafts.

The session on Processing and Delivery of Cell-based Therapies Dr Mike Raxworthy, will move through understanding Operations Director, and reducing inherent risks in the manufacture and administration of Regener8. autologous cell therapies, to the challenges of applying regenerative strategies to CNS disorders and the need for delivery systems to be developed in parallel with the cell therapy treatment. Dr Melanie Coathup from UCL will conclude the meeting with data on how stem cell treatment could augment the fixation of orthopaedic implants thereby providing a useful commentary on the potential of a regenerative device approach.

In keeping with our core principles, the Regener8 conference will seek to operate at the interface of industry and academia so that the most promising ideas and candidates for the treatment of priority clinical needs are presented for analysis and a collaborative approach to overcoming translational challenges. Delegates can look forward to new insights, new and renewed contacts and improved connections into the regenerative medicine landscape.

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ANNUAL CONFERENCE

INTRODUCING THIS YEAR’S KEYNOTE SPEAKERS…

John Ferris

Professor Anthony Hollander

Senior Director, European Business Development, Cytori Ltd

Head of The Institute of Integrative Biology and Professor of Stem Cell Biology, the University of Liverpool

John Ferris is employed by Cytori Therapeutics, a leading regenerative medicine company based in San Diego, California. He has served as Director of European Business Development since 2006.

The main responsibilities of the role include the commercialisation of Cytori’s Celution® system for the isolation and concentration of adipose derived regenerative cells. The Celution system is CE marked for use in a wide range of clinical indications including plastic and reconstructive surgery, wound healing and the treatment of soft tissue wasting disorders.

John has worked in the medical industry since 1983 in different sales and marketing position starting in the pharmaceutical industry.

Since 1987, he has been in the medical device sector, including 12 years in orthopaedics with DePuy International.

He earned a BA (Honours) from the University of Newcastle upon Tyne in 1979. He currently lives in North Yorkshire.

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Professor Anthony Hollander graduated with a first Class degree in Pharmacology from The University of Bath and a PhD in Pathology from the University of Bristol.

He then spent three years at an internationally renowned cartilage laboratory at McGill University in Montreal before returning to the UK to take up an Arthritis Research UK Fellowship and a Lectureship at The University of Sheffield.

He was appointed as the Arthritis Research UK Professor of Rheumatology and Tissue Engineering at the University of Bristol in September 2000 and he was Head of The School of Cellular and Molecular Medicine in Bristol from 2009 to 2013.

Professor Hollander was appointed as Head of The Institute of Integrative Biology and Professor of Stem Cell Biology at The University of Liverpool in June 2014.

He has more than 100 publications and he has received approximately £7 million of peer-reviewed funding over the past 10 years from the UK Government, medical charities, EU framework programmes and biotechnology companies.

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INVITED SPEAKERS

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TECHNOLOGY AND INNOVATION

Dr Ruth McKernan, Chief Executive, Innovate UK.

DEVELOPING THE UK’S NETWORK OF MEDICAL CATAPULTS

By Dr Ruth McKernan, Chief Executive, Innovate UK.

The UK is building a world-class network of medical Catapult centres, co-ordinated by the UK’s innovation agency, Innovate UK, to tackle some of the biggest challenges in healthcare.

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TECHNOLOGY AND INNOVATION The latest development is that the northwest of England is to host a new Catapult centre in Medicines Technologies at Alderley Park in Cheshire. In July, I was privileged to accompany the Chancellor of the Exchequer, George Osborne when he announced the £5 million funding in 2015-16 to kick-start the project.

It builds on plans to put science and innovation at the heart of building the government’s Northern Powerhouse, ensuring that the region maximises the state-of-the-art facilities at Alderley Park. The best of the UK’s businesses, scientists, clinicians and engineers will be working side-byside in the new Catapult.

The vision is for a network of medical Catapult centres, focused on different aspects of research and translation that underpin all phases of making medicines.

The Medicines Technologies Catapult will conduct early pre-clinical work bringing together a growing base of new technologies to support early biomedical research companies in the UK, particularly in in vitro and in vivo safety testing.

The Precision Medicine Catapult will lead the clinical work focusing on personalising medical treatments to individuals and specific patient group. The third in the trio of medicines catapults covers the new and futuristic approaches of cell and gene therapy, which are carried out at the Cell Therapy Catapult. At all these centres research and business will work seamlessly to support the UK’s burgeoning prowess in developing new medicines.

At the same time the Chancellor made his Alderley Park announcement, he also revealed that the headquarters of the Precision Medicine Catapult will be located in Cambridge, with regional centres of excellence in the north of England, Northern Ireland, Scotland, Wales and southern England.

The Cambridge headquarters is well-located close to facilities such as the Wellcome Trust Sanger Institute, a leader in the human genome project and the European Bioinformatics Institute, part of the European Molecular Biology Laboratory. Clinical trials rarely occur in just one location and when it comes to precision medicine, patients will be all around the country so it is important that this Catapult operates a distributed model with centres of excellence throughout the UK. Precision medicine uses diagnostic tests or data-based insights to understand a patient’s disease more precisely.

Clinicians can then select treatments which are more predictable, safer and more cost-effective.

By combining accurate diagnosis with rules-based therapies and effective service delivery, precision medicine is expected to transform medicine in the coming decades, improving outcomes for patients and the healthcare system. A value of £14 billion has been put on the global market for tests, therapies and solutions, and this is expected to grow to £50 billion - £60 billion in 2020.

The Precision Medicine Catapult is focused on making

the UK the most compelling location in the world for the development and delivery of this new targeted approach.

The country has a competitive position in precision medicine, based on its scientific excellence and £1 billion of research infrastructure investment from the Government over recent years. By focusing on the main bottlenecks to product delivery, the Precision Medicine Catapult will work with the precision medicine community to build a thriving industry generating economic and healthcare benefits.

Established in April 2015, in its first year of operations the Precision Medicine Catapult is developing and testing its plans for tackling the industry bottlenecks - around business models, test development, clinical trial networks, data services and healthcare service delivery.

“These three complementary Catapults should keep the UK at the forefront of a sector we have long excelled in.”

- Dr Ruth McKernan.

The first of our medical catapults - Cell Therapy Catapult - was established in 2012 as a centre of excellence in innovation, with the core purpose of building a worldleading cell therapy industry in the UK. Its mission is to drive the growth of the industry by helping organisations across the world translate early stage research into commercially viable and investable therapies.

Located high above London, on the 12th floor of Guy’s Hospital, are the facilities of the Cell Therapy Catapult (see page 12 for an interview with its Chief Scientific Officer).

An innovative space for collaboration and state-of-the-art labs are available to help assist our partners achieve their goals for therapy development and commercialisation. The 1,200m2 facility includes process and assay development laboratories designed to mimic manufacturing suites, enabling the development of cell therapies from the laboratory to commercial scale. A key design feature is a viewing area between the laboratories and office space, encouraging interaction and visits.

This all means that the UK will have a world-class network of medicines Catapults – Medicines Technologies, Precision Medicine and the Cell Therapy Catapult. Together, these three complementary Catapults should keep the UK at the forefront of a sector we have long excelled in and act as a magnet for inward investment.

For more information, visit www.catapult.org.uk

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INTERVIEW

INSIDE THE CELL THERAPY CATAPULT… Interview with Professor Johan Hyllner

Professor Johan Hyllner is the Chief Scientific Officer of the Cell Therapy Catapult, which was established in 2012 as an independent centre of excellence to advance the growth of the UK cell and gene therapy industry, by bridging the gap between scientific research and fullscale commercialisation.

In this in-depth interview, we find out more about Johan’s role, the Cell Therapy Catapult’s activities… and the challenges facing the industry.

How would you describe as a typical week as Chief Scientific Officer of the Cell Therapy Catapult?

In a typical week I would spend two days engaging with the research community and having meetings with them, primarily in the UK, but also internationally. I would then spend a day in internal strategic meetings and also in meetings with people working in the laboratory, and two days ‘at the desk’ communicating, writing and also studying the most recent advances in our area.

What do you think are the most notable achievements of the Cell Therapy Catapult over the past 12 months?

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INTERVIEW The relationships we have built with the stakeholders in the cell therapy field - this is demonstrated by successful projects that we have with SMEs like ReNeuron and successful Horizon2020 or EU applications with academia and industry. All of that is part of our strategic plan.

There has been an increased use of our expertise by companies and lastly, there is the new cell therapy manufacturing centre that we have commenced building in Stevenage. In the UK there are several good phase one and phase two manufacturing organisations, but there were no manufacturing centres for larger scale studies or commercial manufacturing, so that is why we applied to the Government and received the funding to create the centre.

The Cell Therapy Catapult has been very active in recruitment recently – what capabilities have been added to the organisation as a result?

When I started the Cell Therapy Catapult, we had 16 employees and now we have more than 100, which is an enormous growth. In the last three years we have really brought in expertise in process development and analytical development in areas like stem cells and immune cells, and also expertise in clinical and regulatory affairs. We have a business development team, particularly in health economics – that is something that many academics and people in industry appreciate.

What are the key challenges facing the cell therapy/ regenerative medicine industry today?

Firstly, there are manufacturing-related challenges – bringing the product from the lab bench in an up scaled manner to a medicinal product.

The clinical and regulatory area is also extremely important because it’s not only new to people here but it is also somewhat new to the regulators.

The business model for autologists or allogeneic therapies is another thing we are working on with collaborators.

And lastly, health economics and reimbursement is a question for all of us – these therapies have to be economically viable.

What is the Cell Therapy Catapult’s long term aim?

It’s to bring health and wealth to the UK by being part of building an industry based on the excellent science base in the UK. Why do you think academics and businesses should become involved with the Cell Therapy Catapult?

The Cell Therapy Catapult provides a chance to accelerate their ideas. We have built our teams around the barriers to bringing ideas to the clinic. Some companies and universities will have expertise in some of these areas but maybe not in others - we have gathered together 100 experts and that is a great resource to tap into.

What do you see as the role of partnerships and external collaborations in cell therapy?

We are a flexible organisation and can work in a variety of ways. We have core projects that we have control over ourselves where we work with partners to bring the therapies to the clinic. We have one project with Imperial College and UCL where we have started our first clinical trials at Great Ormond St Hospital.

We are also a people service organisation and several overseas companies and UK companies have started to use us for specific missions – it could be regulatory affairs, it could be health economics.

Regener8 – through its members and partner organisations – has a range of technologies and expertise to contribute in such areas as tissue scaffolds, near patient processing of autologous cells, surgical delivery technologies, preclinical simulation and stratification – what opportunities do you see for such capabilities to be combined with the outputs of the Cell Therapy Catapult?

I think that all of these capabilities are vital elements in a variety of cell therapies. I really believe there is a good fit with the Cell Therapy Catapult and all of these areas are exactly the sort of things that we are very keen on.

We do work with tissue scaffolds – for instance we are working on a trachea and oesophagus project and we are very keen on further evolving the 3D technologies base.

Working with a UK company we have developed a device to deliver cells into the skin.

The Regener8 ECRs recently took part in a successful visit to the Cell Therapy Catapult – what advice would you give to an aspiring scientist or engineer considering a career in the cell therapy industry?

I wouldn’t hesitate to recommend working in this field to someone.

There is an incredible UK commitment to the eight great technologies and regenerative medicine is one of them. It is driven by excellent science but the politicians and the public are behind it in a way that is unique.

We are seeing increased investment by the pharma companies into specific areas of cell therapies. It is really evolving right now and being part of this evolution is very inspiring.

Finally, what developments would please you most over the next 12 months?

That we, together with our partners, deliver on the 20 plus projects that we are currently running and also that new projects and collaborations are created.

For more information on the Cell Therapy Catapult, visit ct.catapult.org.uk

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INNOVATION

CELL BANDAGE – USING STEM CELLS TO REPAIR KNEE INJURIES Regen takes a closer look at the work of Professor Anthony Hollander, keynote speaker at the Regener8 Annual Meeting 2015.

“You have a meniscal tear,” are words to fear. Over a million people a year in the US and Europe suffer this painful knee injury. The standard treatment, removing the damaged cartilage, often leads to osteoarthritis and even knee replacement.

An innovative cell therapy could change all that – thanks to grant funding and support from Innovate UK which has helped it move out of the lab and into clinical trials.

The Cell Bandage uses a patient’s own stem cells as an internal ‘bandage’ to encourage cell growth and allow the tear to repair itself. It’s been developed by Azellon – a spin out from the University of Bristol’s Department of Molecular and Cellular Medicine.

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INNOVATION The initial idea came from a series of projects on cartilage repair led by Professor Anthony Hollander, founder of Azellon and now head of the Institute of Integrative Biology at the University of Liverpool.

“We knew we could grow cartilage in the lab, the problem was how to get it into the patient. The answer was a structural ‘bio-scaffold’ that could grow stem cells harvested from a patient’s own bone marrow,” said Professor Hollander.

He realised its potential benefits for orthopaedics and set up Azellon in 2007 to develop the Cell Bandage concept.

He spent two years trying to raise funding from private investors.

“We hit a brick wall. Investors were interested, but reluctant to commit funds at such an early stage. They wanted proof that the idea could be commercialised,” he said.

Getting to clinical trials In 2008 Innovate UK awarded grant funding of £555,000 towards a two-year £1 million collaborative project to develop the Cell Bandage to Azellon and its partners – the University of Bristol and University College London.

The project took the Cell Bandage from prototype to clinical evaluation in a small number of patients. However, anything to do with cell therapies is complicated. “It’s been a long road. Not only did we have to commercialise a lab-based process, but we also had to navigate a complex regulatory process to get the product licensed for clinical trial,” said Professor Hollander.

“Innovate UK were there when we ran into technical problems. Our monitoring officer was extremely helpful,” Professor Hollander commented.

In 2013 the Cell Bandage began its first small clinical trial.

There’s still some way to go before it will be repairing damaged knees, but results are positive so far.

“If it works as well as we hope, it will promote better short-term recovery for meniscal tears and also prevent or delay osteoarthritis in the damaged knee,” said Professor Hollander.

The technology could be used to treat a wide range of other injuries.

“The credibility the Cell Bandage project gained as a result of Innovate UK backing played a critical role in unlocking funds from private investors. Regenerative medicine won’t work without support from organisations like Innovate UK and the Catapult”, he said.

Despite the challenges along the way, Anthony remains enthusiastic about the future for the Cell Bandage and for cell therapy.

“We’re showing it can be done and we’re creating British expertise in developing cell therapies,” said Professor Hollander.

Article and image used with kind permission of Innovate UK. Pictured left: Professor Anthony Hollander.

“The credibility the Cell Bandage project gained as a result of Innovate UK backing played a critical role in unlocking funds from private investors. Regenerative medicine won’t work without support from organisations like Innovate UK and the Catapult” - Professor Anthony Hollander.

“The Cell Bandage is a just delivery mechanism – in principle it could be used to heal any soft tissues that need to be integrated,” he added.

Supporting cell therapy Azellon has also been working with the Cell Therapy Catapult – set up in 2012 by Innovate UK to help cell therapy organisations translate early stage research into commercially viable and investable therapies. Professor Hollander believes the Catapult, and Innovate UK, play a pivotal role in his sector.

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RESEARCH

CLINICAL TRIALS WITH ADIPOSEDERIVED REGENERATIVE CELLS

By John Ferris, Senior Director, European Business Development, Cytori Ltd.

Cells are the living, fundamental building blocks of all tissues and organs and are critical in maintaining homeostasis and restoring function in injury, disease and aging. Human adipose tissue is a unique reservoir of multiple cell types including stem cells, mesenchymal and endothelial progenitor cells, important leukocyte subtypes, lymphatic cells, pericytes and vascular smooth muscle cells that can contribute to the healing process. This heterogeneous cell population referred to as AdiposeDerived Regenerative Cells or ADRCs is a natural and abundant part of a patient’s own adipose tissue.

ADRCs have been investigated and shown to exert therapeutic impact within both acute and chronic conditions via several principal mechanisms of action. Preclinical studies suggest that ADRCs have the potential to modulate inflammation, promote angiogenesis and reduce cell death, which all may contribute to healing and repair in a broad range of medical conditions.

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RESEARCH Rigorous, well-designed, controlled studies sponsored by research institutions and industry are central in developing a strong evidence portfolio for patients, health care providers, regulatory agencies and for payers. This data will facilitate bringing new options to patients where there are poorly met medical needs. With this objective in mind, multiple studies have been and are being conducted administering ADRCs for a variety of medical disorders.

Several of the investigational clinical studies are described in the following paragraphs.

Scleroderma The FDA has granted approval to begin the STAR Trial, a randomized, double blind, placebo-controlled, phase III pivotal clinical trial of 80 patients with impaired hand function from scleroderma. The trial will evaluate the safety and efficacy of a single administration of ADRCs in patients with scleroderma affecting the hands1. The primary endpoint of the study is the Cochin Hand Function Score, a validated measure of hand function. Other key efficacy endpoints include assessments of Raynaud’s Phenomena and health-related quality of life. After all patients have completed 48 weeks of follow-up, patients in the placebo group will be eligible for crossover to the active arm of the trial. The trial is anticipated to begin enrollment in 2015.

This trial is based on a previously published trial (SCLERADEC) conducted at Hospital de la Conception in France that demonstrated significant improvement in hand function, pain, Raynaud’s Phenomena and healthrelated quality of life in patients with scleroderma affecting the hands. Cytori is co-sponsoring a confirmatory study (SCLERADEC II) in France, which is a multi-centre, randomized, double-blind, placebo-controlled evaluating ADRCs for the same indication.

Osteoarthritis ACT-OA is a US Food and Drug Administration (FDA) approved phase II clinical trial in patients with osteoarthritis affecting the knees. The objective of this randomized, double-blind, and placebo controlled study is to evaluate the safety and efficacy (symptom relief, knee function, and activity level) of ADRCs at multiple time points through 48 weeks. Enrollment of 94 patients has been completed and data is expected in 2016.

Thermal Burn and Radiation Injury The Biomedical Advanced Research Development Authority (BARDA), under the US Department of Health and Human Services along with the FDA, has a contract to fund research, development, regulatory, clinical, and other tasks for the use of ADRCs in thermal burn and radiation injuries. The full contract is for funding up to $106 million and dependent upon key milestones being achieved.

Urinary Incontinence In Japan, a clinical trial with ADRCs for male urinary incontinence following radical prostatectomy will begin

this year. This trial is based on a previously published feasibility trial conducted at Nagoya University in Japan2. The investigators reported improvements in urinary leakage, urethral closing pressure, and qualityof-life in men with urinary incontinence following radical prostatectomy for prostate cancer. The primary funding and support of the trial will come from the Japanese Ministry of Health, Labor and Welfare and Nagoya University.

Chronic Heart Failure PRECISE is a 27 patient safety and feasibility study in Europe determining the safety and feasibility of ADRCs in chronic ischemia patients on maximal medical therapy without other options for revascularization. Data from the PRECISE trial demonstrated the feasibility of obtaining and delivering ADRCs to patients with significant heart disease. The data provided early indications of efficacy that provided the rationale for the ATHENA trials in the US. Acute Myocardial Infarction The APOLLO Trial is a 14 patient study in Europe designed to assess the safety and feasibility of ADRCs in patients with ST-elevation myocardial infarction (STEMI). The study demonstrated the feasibility of intracoronary injections of ADRCs in STEMI patients.

Breast Reconstruction The RESTORE-2 study is a Phase IV (post-market) European study that evaluated safety and efficacy of ADRCs for breast deformities post segmental breast resection (lumpectomy) with or without radiation therapy.

This prospective, single-arm, open-label, multi-centre study enrolled 71 patients with defects ranging from 25150 mL at seven European clinical centers. The procedure was shown to be safe and well tolerated. The efficacy data demonstrated high degrees of patient (75 per cent) and investigator (85 per cent) satisfaction following cell enriched fat grafting for breast defects post-breast conservation therapy3.

Cytori is a leader in providing patients and physicians around the world with medical technologies that harness the potential of adult regenerative cells from adipose tissue. Our ongoing clinical work is contributing to knowledge and hopefully advances in the field of regenerative medicine through offering new research options to clinicians in the investigation of difficult to treat conditions.

For more information, visit www.cytori.com REFERENCES 1 Granel, B, et al. Safety, tolerability and potential efficacy of injection of autologous adipose-derived stromal vascular fraction in the fingers of patients with systemic sclerosis: an open-label phase I trial. Ann Rheum Dis. 2014;0:1–8.

2 Gotoh, M, et al. Regenerative treatment of male stress urinary incontinence by periurethral injection of autologous adiposederived regenerative cells: 1-year outcomes in 11 patients. Intl Journal of Urology. 2013; 10.1111;1–7.

3 Perez-Cano R, Vranckx JJ, Lasso JM, Calabrese C, Merck B, Milstein

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INTERVIEW

HARNESS THE POWERHOUSE FOR ADVANCING LIFE SCIENCES COLLABORATIONS January 2015 saw Dr Peter Simpson take up his role as Director of the N8 Research Partnership – the collaboration body of the North’s eight most research-intensive universities, Durham, Lancaster, Leeds, Liverpool, Manchester, Newcastle, Sheffield and York.

Here, he talks to Regen about the N8 universities’ strengths in life sciences, the changing face of industry’s relationship with academia, and how deep collaboration can deliver real impact.

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Stepping into his new role following eight years at AstraZeneca, where he led life sciences research departments and project teams, Dr Peter Simpson brings with him deep insight into the industrial research landscape; and how the mind-set of major BioIndustry companies is changing.

He refers to a ‘sea change’ over the last six years in the desire of industry to work much more openly and transparently with academia. “The new industry collaboration model with universities focusses on knowledge exchange, mutual learning and long-term partnership, rather than a financially based ‘service’ model,” he says. Peter has observed this transformation at first hand. “Taking AstraZeneca as an example, it has moved from being a very closed shop to offering an excellent open innovation platform which is encouraging partnerships with academia around the world,” says Dr Simpson. “There is a similar story for many life sciences multinationals, notably several with a major presence in the North. This is clear from Croda to Unilever, and from

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INTERVIEW MedImmune to Procter & Gamble - they are increasingly motivated to build deep collaboration with their academic partners.”

The BioIndustry’s openness to collaboration dovetails, the N8 Director believes, with the growing strength of Northern England’s life sciences sector. The N8 includes four of the Global Top 100 universities in life sciences among its institutions, and has generated over 220 patents in the last 10 years, creating more than 250 spin-offs.

“The North of England is emerging as one of Europe’s most vibrant hubs for the life sciences industry, already supporting 1000 businesses and 38,000 high skilled jobs,” says Peter. “This existing capability is coupled with exciting innovation opportunities within the Northern Powerhouse, such as Health North and the Connected Health Cities initiative. N8 academics have been recognised for their industry-facing expertise, for example taking leadership roles within eight of the Biotechnology and Biological Sciences Research Council (BBSRC)’s Networks in Industrial Biotechnology & Bioenergy. These networks are delivering academic insights that fit the real world problems of their industry partners.”

Dr Simpson enthuses: “There is growing understanding of the role that life sciences can play as a major part of the Northern Powerhouse, which, in order to deliver economic rebalancing, will be driven by science and innovation. A key thing I see is the commitment from academics in N8 universities to do research with relevance. They want real world impact, and already work in close collaboration with industry - there is no ‘ivory tower’ mentality.

“There is a match between the transformation of how the BioIndustry is now wanting to work with academia, and the desire of N8 academics to deliver on real world problems through collaboration. We are in a sweet spot here in the North at the moment – both sectors want to work together to deliver impact.”

He continues: “Within MedTech specifically, I see an interdisciplinary opportunity. The next stage of Medtech innovation requires complementary types of knowledge and expertise to be brought together to create successful products with clinical impact. This needs commercial and clinical insights from AHSNs and industry; crosssectoral relationships between large companies, SMEs and academia; combinations of cell expertise and medical technology expertise, data analytics, materials expertise and clinical access, which also need to be brought together. Very few organisations are going to have the bandwidth and expertise to do it all themselves, so there needs to be deep cross-disciplinary, cross-sectoral collaboration.”

Regener8, he believes, is playing a key role in bringing the strands of academia, multinationals and SMEs together, fostering partnerships and nurturing the environment for future growth. And it’s not just on a regional or national level that Regener8 can make its mark. “Regener8 is a successful and credible model for academic/industry collaboration, as you can see from the number of national and international companies that are involved,” Dr Simpson

points out. “It fosters collaboration between players in different sectors, is an effective means of knowledge exchange, and also demonstrates that keen desire to have translational impact and commercial relevance.

“Regener8 is playing a national role within regenerative medicine. The UK has been a leader in the early days of regenerative medicine research, but needs to sustain that leadership, as the regenerative medicine field grows commercially and therapeutically.

“I am very supportive of what Regener8 and what other collaboration organisations in the UK sector are doing, to make sure that the UK stays at the forefront of translational and commercialisation of regenerative medicine research.” Life sciences, Dr Simpson asserts, will be a fundamental part of the N8 Research Partnership’s strategy moving forward. “Combine the N8’s life sciences knowledge base, industry-facing behaviours, with the eight universities’ strengths in disciplines such as disease biology, medical engineering, and advanced materials, and the opportunities are tantalising.”

He points to the world class expertise in centres across the N8 such as the UKRMP Safety and Efficacy Hub in Liverpool’s MRC Centre for Drug Safety Science; the Medical Advanced Manufacturing Research Centre in Sheffield; Manchester’s Collaborative Centre for Inflammation Research in partnership with AstraZeneca and GSK; the NIHR Newcastle Biomedical Research Centre in Ageing; Lancaster’s investment in its Health Innovation Campus; York’s Health Economics Consortium; Durham’s expertise in Metals in Biology; and Leeds’s own Institute of Medical and Biological Engineering, as examples of the N8’s life sciences research capabilities.

And the fact that The Sir Henry Royce Institute for Materials Research and Innovation – an international beacon for advanced-materials science – will have its £235 million main research centre at the University of Manchester, as well as satellite centres at the N8 Universities of Sheffield, Leeds and Liverpool, is yet further evidence of the N8’s increasing influence and potential to attract industry partners.

“N8 universities, individually and working collaboratively, combine the multidisciplinary strengths and collaborative mind-set needed to work effectively with industry, in regenerative medicine, MedTech, and across life sciences and beyond,” Dr Simpson says. “The N8 Research Partnership exists to help industry make these connections into academia more easily.

“In the N8 Research Partnership, we see our job very much as a catalyst – to bring together people who are experts, in different sectors, and find new ways of putting their knowledge and expertise together that are mutually beneficial to build collaborations which are more than the sum of the parts. At the heart of N8 collaborations is innovation, and impact on people and jobs.”

For more information, visit www.n8research.org.uk

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CLINICAL

AUGMENTING THE FIXATION OF ORTHOPAEDIC IMPLANTS USING STEM CELLS

By Dr Melanie Coathup, Senior Lecturer, Institute of Orthopaedics and Musculoskeletal Science (IOMS), UCL and Professor Gordon Blunn, head of the Centre for Bio-Medical Engineering, UCL and Professor at IOMS.

Massive segmental implants are used for revision procedures where there has been considerable bone stock loss or to replace bone cancers in the peripheral skeleton.

In the 1990s, the survivorship of these bone cancers was around 68 per cent at 10 years.

Bone cancers occur in a young age group and patients may be faced with multiple revision operations where the success rate of subsequent revision implants are reduced.

Using a hydroxyapatite-coated collar adjacent to the transection site of the bone leads to extra-cortical bone growth and osteointegration in this region (figure 1). This has improved the fixation and where integration occurs, the survival rate is around 98 per cent at 10 years.

However, if the implant does not become integrated the success rate reduces to 75 per cent at 10 years. Integration occurs in around 60 per cent of cases. Extra-cortical bone growth combined with osteointegration in this region leads to a reduction in stem loosening2 due to the load being transferred from the stem onto cortical bone.

We have used mesenchymal stem cells (MSCs) obtained from bone marrow in a fibrin glue to enhance fixation of these implants.

We have shown that stem cells remain viable in fibrin glue and continue to proliferate and are able to combat the negative effects of the chemotherapeutic agents on bone formation3.

A further study4 investigated the effect of spraying autologous MSCs in fibrin glue onto grooved HA-coated

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Figure 1: A: Distal femoral implant without osteointegration of the HA collar showing a gap between the shoulder of the implant and the bone. B: An integrated HA collar in a patient that had the distal femoral implant inserted at the age of seven years. At the time the radiograph was taken the patient was 19 years. The stem that was inserted was small due to the size of the patient at the time but the stem and the fixation has been protected by osteointegration of the HA collar. C: Histological section showing bone ingrowth into a single groove of a HA collar D: HA collar coated with fibrin glue and MSCs during surgery.

collars of segmental bone implants in an ovine mid-shaft tibial model.

Radiographic and histological analysis demonstrated twice the level of bone adjacent to the collars and greater osteointegration in the treated group. However, using allogenic MSCs resulted in bone formation and even resorption5.

An autogenic source of cells may be appropriate for primary or revision implants6, for patients with primary bone cancers it may be appropriate to use cells from sources other than from the patients’ own bone marrow because of the risk of expanding and introducing neoplastic cells.

Other methods have been investigated: we have used stem cells incorporated within allograft bone and shown that this increased osteoinduction7 and enhances fixation of implants when impaction allografting is used8.

For further information visit www.ucl.ac.uk/surgery/research/ioms

References 1 . Coathup et al. J Bone Joint Surg Am. 2013 Sep 4;95(17):1569-75 2 . Coathup et al. Clin Orthop RelatRes. 2015. Apr;473(4):1505-14.

3 . Lee et al. Tissue Eng. 2005 Nov-Dec;11(11-12):1727-35. 4. Kalia et al. Tissue Eng. 2006 Jun;12(6):1617-26. 5. Coathup et al. J Biomed Mater Res A. 2013 Aug;101(8):2210-8. 6. Kalia et al. Tissue Eng Part A. 2009 Dec;15(12):3689-96. 7. Korda et al. Tissue Eng Part A. 2010;16(2):675-83. 8. Korda et al. , J Orthop Res. 2008 Jun;26(6):880-5.

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NETWORKS

BUILDING EXPERTISE IN TISSUE ENGINEERING

By Professor John Hunt, UK Centre for Tissue Engineering, University of Liverpool.

The TECAS Network at their Half Year meeting June 2015

The aim of the Tissue Engineering Solutions for Cardiovascular Surgery (TECAS)-Initial Training Network (ITN) Doctoral Academy in Regenerative Engineering is to integrate the major European contributors in the field of cardiovascular tissue engineering and regenerative medicine, to generate a coherent framework of expertise which will facilitate the training and career development of early stage researchers in the field. Regener8 is an associate partner of this FPVII EU funded ITN. The network, comprised of six partners, has been focussing on the clinical needs of cardiac valve replacement/repair, myocardium reconstruction and patch graft angioplasty of the great blood vessels. The network continues to develop the expertise and technology that will lead to the manufacture of functional tissue engineering cardiovascular implants for clinical use.

This ITN provides an extensive multidisciplinary experience in training and research. Its academic, clinical and industrial partners train the new generation of competent and balanced clinicians, scientists, and engineers, who are currently in great demand by the medical devices industry and clinical sector. This is facilitated through the network’s research projects, which span the intersectoral innovation pipeline of a number of tissue engineering products and technologies, from basic science to translational research and beyond. The strategy of the TECAS ITN involves the use of functionalised 3D scaffolds, which have been seeded with either differentiated stromal cells or adult mesenchymal stem cells derived from the intended recipient, and either physically conditioned in the laboratory in bioreactors, with a view to producing biological and biomechanical functionality of the graft prior to implantation, or used unseeded with a view to attracting endogenous cell colonisation after implantation.

The TECAS Stand at the IdeenExpo2015

In July 2015 the TECAS ITN participated in the IdeenExpo 2015 in Hannover by taking up a stand in the exhibition to present interactively the use of pulsatile flow bioreactors in addition to presenting a lecture on Growing Tissues in the Lab. This followed the TECAS participation earlier this year in the Technological Transfer Fair Patras IQ 2015 in Patras, Greece, which was targeted towards developing links between academics and industrialists. Two summer schools will take place in September and October of this year in Patras and Hannover.

The TECAS network is expected to expand and is outward looking and engaging; further information is available at its webpages.

For more information, visit www.doctoralacademy.mh-hannover.de

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TECHNOLOGY

ELECTROSPINNING OF BIOMATERIALS

By Mohsen Miraftab, Professor of Fibre Science & Technology, Institute for Materials Research and Innovation, The University of Bolton.

Electrospinning is not a new technology; it was first discovered back in the 16th century but was not taken seriously until the mid-1990s when it was found that many biocompatible natural/synthetic polymers (e.g. alginate, chitosan, collagen, polylactic acid, PET and N6) could be spun into nanofibres.

2D oriented scaffolds.

When applying high voltage to a polymer liquid, nanofibres are generated as the material is drawn to negatively charged targets. The dimensions of these fibres can range from anything between 20nm to 400nm, depending on the polymer molecular weight, concentration, applied voltage, delivery rate as well as the distance between the polymer extrusion tip to the target destination. Generally, these could be controlled and optimised to ensure consistent production.

Nanofibres by definition are very fine and this leads to very high surface area in any given structure. This is of immense importance in many application areas where quick drying and/or absorption, breathability and efficient filtration is required or indeed in tissue engineering where consistent and uniform cell growth and proliferation is the intention.

The technology is very versatile and allows two and three dimensional structures to be produced in very short periods of time whilst they could be tailor-made to fit intended purposes. Fibre orientation and the landing target could be carefully arranged to allow fine engineering and precision construction.

Although the technology has matured and is now commercially available as a standalone machine, it is not as yet a mass production technique. As such the technology has been exploited in niche applications namely, in medical devices, where often small and tailor-made products are required at economically viable costs as compared to other methods e.g. drawing, template synthesis, phase separation or self-assembly.

Vascular graft.

Continuous production.

The micrographs pictured show the range of possibilities achievable via electrospinning.

For more information, visit www.bolton.ac.uk/IMRI 2D netted structures.

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3D Scaffold.

CASE STUDY

CAMREGEN SCAFFOLDS FOR CARDIAC REPAIR DR DANIEL BAX, PROFESSOR SERENA BEST (UNIVERSITY OF CAMBRIDGE)

By Dr Daniel Bax, Post-Doctoral Research Associate, University of Cambridge.

Heart disease is a leading cause of death and disability, a burden which is predicted to escalate due to an ageing population and increasing prevalence of cardiovascular disease.

Conventional fabrication

Despite this, there remains a critical need for efficacious, cost-effective treatments to stabilise and ultimately regenerate diseased cardiac tissue. For example, although multiple epicardial injections of functional cardiomyocytes can partially repair diseased myocardium, up to 90 per cent of these implanted cells die or migrate elsewhere.

Therefore the aim of the CamRegen Scaffolds for Cardiac Repair project was the development of a threedimensional cell niche for cardiac tissue regeneration which simultaneously provides mechanical support for, and structural integration with, the host tissue.

Within this context, the Proof of Concept award provided

by Regener8 has allowed us to develop innovative cross-linking parameters to apply to our collagen-based scaffolds.

Optimised fabrication

Crucially, unlike the conventional fabrication process, these key modifications retain native collagen-mediated cell engagement with our highly porous, homogeneous, threedimensional scaffolds (figure 1). Through this approach we have gained primary proof of concept and fabricated scaffolds that offer a combination of excellent mechanical and degradation properties whilst simultaneously supporting improved cell behaviour.

Moreover, work on the project led to the identification of a wide variety of markets for this technology and highlighted areas, such as scaffold deployment routes for further development.

Overall, Regener8 has allowed us to optimise our scaffolds, so providing improved treatment options for cardiac repair thereby offering the potential for more rapid patient recovery with benefits of reduced hospitalisation time and cost.

Figure 1 - Confocal microscopy of cell engagement with porous 3D scaffolds produced using a conventional fabrication process (left) and the optimised fabrication process developed as part of this Regener8 project (right).

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CASE STUDY

POLYMERIC SCAFFOLDS FUNCTIONALISED FOR PERIODONTAL REPAIR UNIVERSITY OF MANCHESTER AND NEOTHERIX LTD

By Professor Julie Gough, Professor of Biomaterials and Tissue Engineering at the University of Manchester, and Project Leader.

This partnership has run a series of projects over the past six years to explore the use of a novel polymer, PVPA-AA, as an active moiety to up-regulate bone repair. Earlier work provided supportive in vitro data allowing the award of a Regener8-IKC Proof of Concept project, Polymeric Scaffolds Functionalised for Periodontal Repair. Our work aims to address clinical needs arising from periodontal disease, principally the loss of mandibular alveolar bone, consequential tooth loss and inadequate bony substrate for placement of implants.

During the course of this PoC project, we vastly increased the usability and processability of our candidate scaffold

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Human osteoblast cells grown on electrospun polycaprolactone (PCL) scaffold visualised by confocal microscopy (left) ans SEM.

material. The composition was further developed to contain nano-hydroxyapatite and a surfactant, as well as the PVPA-AA active moiety, with polycaprolactone as the carrier polymer formed into an electrospun scaffold.

Compositional advances allowed a uniform distribution of the active polymer and an increase in the compression resistance of the micro pores of the electrospun scaffold.

This latter property is critical for the intended use of the scaffold in being applied and inserted into periodontal pockets or into empty tooth sockets. The osteoconductive properties of these scaffolds were verified.

We are is now seeking funding for in vivo testing to replicate disease-specific tissue defects. Manufacturing process development will progress from research- to production scale. Toxicology, health economics and clinical trial structure will be addressed so that this further project will translate the technology through to clinical readiness.

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CASE STUDY

DEVELOPMENT AND CHARACTERISATION OF A NOVEL TISSUE SCAFFOLD VEHICLE (PHOTOTHERIX) FOR THE DELIVERY OF REGENERATIVE AND ANTIBACTERIAL STRATEGIES DR SIMON WOOD (SCHOOL OF DENTISTRY, THE UNIVERSITY OF LEEDS), DR MIKE RAXWORTHY (NEOTHERIX LTD), DR RICHARD TELFORD (CENTRE FOR CHEMICAL & STRUCTURAL ANALYSIS, THE UNIVERSITY OF BRADFORD), DR XEUBIN YANG (SCHOOL OF DENTISTRY, THE UNIVERSITY OF LEEDS) AND DR PETER IDDON (NEOTHERIX LTD)

By Dr Simon Wood, Senior Lecturer, Deputy Director of Student Education and Programme Manager for MSc and Professional Doctorate, School of Dentistry, the University of Leeds.

Human Dental Pulp Stem Cells seeded on erythrosine-loaded PGA scaffolds (day 5, Alexa Fluor 488® phalloidin, confocal microscopy).

Prevention of infection following tissue regeneration strategies is essential to a successful outcome. The aim of this successful collaboration between the Universities of Leeds and Bradford, and Neotherix Ltd has been to produce and characterise tissue regenerative scaffolds containing a photoactive antibacterial agent (PhotoTherix™) which kills bacteria when exposed to light.

Initial funding enabled Neotherix Ltd to synthesise electrospun, bioresorbable scaffolds containing a range of different photosensitisers (including erythrosine, methylene blue and toluidine blue).

Characterisation of the scaffolds at Leeds indicated that photosensitisers were released from the scaffolds over time and that these were able to kill bacteria when exposed to light.

Stability studies on a range of scaffold/photosensitiser combinations carried out at Bradford indicated that erythrosine-containing scaffolds were the most stable with respect to storage time and sterilisation.

Follow-on funding from Regener8 enabled us to perform

market analysis and to canvass key stakeholder opinion, particularly in the areas of periodontology, oral surgery and implantology (where the potential markets are >£7 billion).

Response to the technology was very positive in what is a competitive market.

While the particular emphasis of this project was on the potential for use in the dental field, the technology has the potential for more widespread use such as in the treatment of diabetic ulcers and wound management in general.

We now have a PhD student working on the project to further characterise the scaffolds in terms of stem cell growth and viability on the scaffolds and identify appropriate photosensitser/light dosimetry which will kill bacteria while maintaining stem cell viability.

This has been an excellent collaboration, enabled largely

by Regener8 funding, as it has combined different sets of expertise in basic and applied science with commercial aspects of the translational pipeline to produce a technology that has potential in the area of regenerative medicine.

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CASE STUDIES

NOVEL BIOACTIVE GLASS-IONOMER BONE CEMENTS AND GRAFT SUBSTITUTES PROFESSOR PAUL HATTON, THE UNIVERSITY OF SHEFFIELD

By Professor Paul Hatton, Professor of Biomaterials Science and Honorary NonClinical Investigator, the University of Sheffield.

Conventional glass-ionomer cements were adapted for use in bone repair in the 1980s, but since then their clinical use has been limited to middle ear surgery because of issues related to the presence of aluminium in the parent glasses used to prepare the cements.

We recently discovered that, under very specific conditions, bioactive glass compositions could be used to replace conventional aluminium-containing ionomer glasses. Both the resulting cement and pre-set biomaterial were potentially vastly superior to existing devices. Funding from the Regener8 programme has enabled our research group to optimise the compositions and demonstrate their superior biocompatibility to both conventional cements and existing commercial bioactive glasses, generating data that has been vital to stimulate commercial interest.

Moreover, the additional tasks supported by the Regener8 programme included detailed and independent market analysis that was essential to make decisions regarding the best approaches to bring this new biomaterials technology to the market for commercial and clinical benefit. As a direct result of Regener8 investment, our team at the University of Sheffield have obtained support for ongoing patent protection and are in discussions with a European manufacturer to produce the first medical device based on this technology, with clinical evaluation anticipated in early 2016.

The scientific discoveries that led to this new biomaterial were significant, most importantly because of the potential for increased and more consistent bone tissue regeneration, but without the support Regener8 it would not have been possible to move from the laboratory bench towards today’s commercial and clinical opportunities.

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Direct interface (arrowed) between new pre-set cement and vital bone tissue in a healing defect.

The scientific discoveries that led to this new biomaterial were significant, most importantly because of the potential for increased and more consistent bone tissue regeneration - Professor Paul Hatton.

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CASE STUDY

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CASE STUDIES

RESORBABLE CALCIUM PHOSPHATE MICROSPHERES FOR BONE REGENERATIVE APPLICATIONS DR IFTY AHMED, DR VIRGINIE SOTTILE, PROFESSOR DAVID GRANT AND PROFESSOR BRIGITTE SCAMMELL (ALL THE UNIVERSITY OF NOTTINGHAM).

By Dr Ifty Ahmed Associate Professor, Faculty of Engineering, The University of Nottingham.

The team at The University of Nottingham have been working on developing a minimally invasive process to repair and regenerate osteoporotic bone tissue in order to reduce trauma, especially for patients at high risk of fractures.

We wanted to manufacture fully resorbable calcium phosphate microspheres which could be loaded with stem cells to be injected directly into sites at risk of fracture.

Through funding acquired from the Regener8/IKC, proofof-concept for manufacture of bulk and porous calcium phosphate microspheres was achieved. The funding also enabled scale-up manufacture of the technology developed and incorporation of stem cells on and within the microspheres was also demonstrated (see Figure 1).

In order to advance the technology towards clinical use, the next stage developments required is a fully working minimally invasive delivery device, experimental modelling on delivering the microspheres to sites at risk of fracture and further in vitro cell culture analyses. Working with clinical collaborators, the research team also needs to establish a clinical processing route for delivery of this technology. To progress this work, the team have recently been awarded a NIHR i4i Challenge Award, in partnership with University of Leeds, Birmingham University Hospital, Ceramysis, YHEC and Surgical Dynamics Ltd. The main benefit of the IKC award was working with and having access to the Regener8/IKC team who provided guidance along the way and connected us to experienced regulatory personnel to advise on appropriate pathways. In addition, the IKC team also helped in establishing the team to apply for follow-on awards.

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Figure 1 - Calcium phosphate microspheres produced, with stem cells attached on and within and forming microsphere stem-cell agglomerates.

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ECRS career conference mike

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ACADEMIC Dr Thomas Baboolal

Regen meets four Early Career Researchers, who provide an insight into their work and experiences of the Regener8 network.

IN THE SPOTLIGHT: REGENER8 EARLY CAREER RESEARCHERS

2013 saw Regener8 launch a new membership stream for Early Career Researchers (ECRs) working in regenerative medicine and medical technologies.

The network has been a great success, supporting ECRs in developing their careers, giving them guidance and helping them forge relationships with industry through, for instance, our programme of company visits to member companies.

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ACADEMIC Here, four Regener8 ECRs speak to Regen about their experience of the network…

Dr Danielle Miles Danielle is a research fellow based within the School of Chemistry and is a member of the Institute of Medical and Biological Engineering at the University of Leeds.

Her work concerns the development and evaluation of peptide hybrid hydrogels for intervertebral disc therapies, and she is a member of the ECR steering group.

Alongside characterising and optimising the hydrogels she also collaborates with engineers developing standardised in-vitro testing methodologies to examine the biomechanical performance of intervertebral disc augmentation procedures.

“Being involved with Regener8 really appealed to me as my main research interests are biomedical, applied and fingers crossed - translational. I’m hoping the networking opportunities that I will gain will be invaluable, no matter whether I stay in academia or move to industry.

“Since being a member I have been lucky enough to participate in visits to both Xiros and the Cell Therapy Catapult, both of which were fascinating. I left the Cell Therapy Catapult feeling excited and for the first time truly hopeful about the emerging cell therapy industry in the UK.”

Thomas Heathman Thomas Heathman started his career with a degree in Chemical Engineering, before working in the oil and gas industry. However, despite enjoying working in a team of talented engineers, his passion for innovation was not fulfilled.

This led him to regenerative medicine, where he saw a strong demand for engineers to develop scalable and regulatory compliant manufacturing processes.

Thomas is based at the Centre for Biological Engineering at Loughborough University, where he is completing his PhD focusing on the large scale production of human mesenchymal stem cells, with a focus on increasing product yield and consistency.

“Regener8’s industry visits to potential collaborators and employers provide us with the opportunities to not only see these industry facilities, but also to present our work and increase our industry network and exposure. I was able to present my research at the Cell Therapy Catapult, which was a fantastic opportunity to promote my research and meet a number of the influential people. I would advise all ECRs working in regenerative medicine to get involved with the Regener8 ECR network.”

Dr Amanda Barnes Dr Amanda Barnes is an EPSRC E-TERM fellow based at the University of York in the Biomedical Tissue Research Group.

Her research interests are in early stage cartilage repair through the application of biosynthetic thermoresponsive hydrogels and mesenchymal stromal cells.

Dr Thomas Baboolal Thomas is a post doc in the Mesenchymal Stem Cell Biology group at the Leeds Institute of Rheumatic and Musculoskeletal Medicine. His work is focused on the use of tissue resident stem cells to improve cartilage and bone regeneration.

This has seen him lead the development of a new medical device from conception and generation of preliminary data, securing funding for prototype manufacturing, testing and patent filing, to setting up a proof of concept clinical study and engaging with potential commercialisation partners.

“Regerer8 offers a welcome change to academia: it is a good opportunity to see how laboratory science can have real world applications. The programme has given me the unique opportunity to meet and share my work, not only with other early career scientists but also with companies working in regenerative medicine.

“I have been fortunate to visit and present my work to both Smith & Nephew and Xiros. This has provided the ECR group with valuable networking opportunities and a chance to see the work going on at these sites first hand.”

Amanda has developed her own novel hydrogel that can be used as a non-invasive injectable scaffold for defect repair. In addition, Amanda is investigating how to optimise the use of mesenchymal stromal cells and chondrocytes in the repair process, to regenerate cartilage that closely mimics the native tissue.

“Through the ECR network I have had the opportunity to visit Smith and Nephew, and the Cell Therapy Catapult.

At Smith & Nephew I presented my research and gained valuable insight and advice outside of academia.

“These visits and networking really opened my eyes to translational and industrial areas in the TERM landscape and have influenced the approach I take in my research.”

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CAREERS AND TRAINING

SUPPORTING THE TALENT PIPELINE FOR A FUTURE REGENERATIVE DEVICES INDUSTRY

By Jo Dixon-Hardy, Director of Medical Technology Innovation at the University of Leeds.

Recruiting the right people with the right blend of skills at the right time is critical for companies, especially in a period of dynamic change in the sector – and medical technology businesses expect it to become increasingly challenging in the future.

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CAREERS AND TRAINING While proficiency in science and engineering are frequently fundamental qualities for potential employees, companies are increasingly demanding that their new recruits also have the potential to be excellent and enterprising innovators. In addition, to maximise and sustain the emerging opportunity in regenerative devices, UK companies will need to access sufficient people with the right qualities.

To help companies address these wider skills needs, the Medical Technologies Innovation and Knowledge Centre (IKC) has been working closely with industrial partners for the past six years to provide a pipeline of industry-ready talent. With more than 30 of our recent young researchers progressing to careers in the sector, the value of this work in producing a pool of highly-employable people with high-level skills is now being recognised by the take-up and roll-out of IKC initiatives in innovation and career management to other scientific disciplines across the University of Leeds.

The IKC’s flagship innovation skills development programme, the Postgraduate Certificate in Innovation Management (PGCert), trains early career researchers in innovation management theory. Its action learning approach also ensures that participants embed the knowledge by applying it to their own research projects.

Mazen Al Hajjar, Senior Postdoctoral Research Fellow, notes that the process of completing the PGCert helped equip him for a challenging and successful industrial placement year with Depuy Synthes.

He comments: “Developing innovation skills and then putting them into practice to progress my own research was invaluable preparation for addressing the different day-to-day challenges I faced in the business environment.”

The programme was developed in collaboration with Leeds University Business School (LUBS), and the insights gained

by LUBS researchers through developing and piloting this with medical technology researchers have been integrated into a new MSc in Global Innovation Management.

Doctoral students, including those from the Centre for Doctoral Training in Tissue Engineering and Regenerative Medicine (CDT) are also benefitting from modules in ‘Managing for Innovation’ and ‘Innovation Management in Practice’.

Ensuring that medical technology researchers are well-equipped to secure fulfilling career pathways that make best use of their skills is a key focus for the IKC. Working in collaboration with the WELMEC Centre of Excellence in Medical Engineering, the University of Leeds Staff Development Unit and career strategist Ruth Winden, a unique programme has been developed and piloted to enable postdoctoral researchers in medical technology research areas to align their skills with the most appropriate career opportunities. Primarily aimed at researchers who are looking to move from the academic environment into industry and other sectors, the Career Architect programme teaches career management techniques and practical skills that have led to researchers

progressing to a range of roles including positions in industry, the NHS and academia, intellectual property, standards, scientific writing and medical education. This success has prompted the development of the Career Transition programme, tailored to suit the needs of final year CDT students looking to take their next career step.

“Combined with their focus, creativity and eagerness to make a difference, they are ideally placed to benefit business.”

Ruth Winden, International Career Strategist and consultant to the IKC

Piloted in the first half of 2015, it has prompted an enthusiastic response from research students: “The Career Transition programme has empowered me to discover and appreciate my strengths as a potential employee in ways I had never considered before,” says fourth year CDT student Ashley Ward, who adds, “it has helped me view things from the perspective of an employer.”

Regener8 also works closely with the IKC to influence the support provided to the medical technologies business community: the Science Industry Partnership (SIP) is a skills programme led by employers for whom science and technology is critical to their success. Operations Director of Regener8, Mike Raxworthy, sits on the programme’s Medical Technology Skills Working Group, which was established to ensure the programme provides appropriate support for the sector. The programme covers apprenticeships, traineeships and provides funding for SMEs to help cover the costs of in-work training.

The Career Architect programme and Career Transition programme welcome input from industry and other partners who offer valuable career insights and support to our researchers.

If you would like to be involved from either a business or professional perspective, please contact Jo DixonHardy, Director of Medical Technology Innovation. Email: j.e.dixon-hardy@leeds.ac.uk or tel: 0113 343 0920.

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REGENERATIVE DEVICES

EXPLORING THE ROLE OF BIOMATERIALS IN TREATING VISION LOSS

By Professor Rachel Williams, Professor of Ophthalmic Bioengineering, Department of Eye and Vision Science, the University of Liverpool.

The loss of sight is a very debilitating condition and is becoming an increasing problem as the population ages, resulting in significant loss of independence. Biomaterials have a role in various treatment options and developments in the properties of the materials have the potential to lead to improved clinical results.

One treatment strategy for age-related macular degeneration (AMD) is to transplant retinal pigment epithelial (RPE) cells under the macula as a functioning monolayer. This can be achieved by seeding cells onto an artificial substrate and transplanting the substrate and monolayer of cells as a single structure.

For this strategy to work it is necessary to establish the optimal properties of the substrate and the most appropriate source of cells. In the Department of Eye and Vision Science at the University of Liverpool we have identified two substrates, expanded polytetrafluoroethylene (ePTFE) and porous polyurethane (PU). Our group is using an NH3 gas plasma and a heptylamine plasma polymer treatment of the ePTFE to encourage the formation of a monolayer of cells.

We aim to use iris pigment epithelial cells (IPE) as iris tissue is relatively easy to obtain and affords the advantage of using cells which are less likely than the RPE to be affected by AMD and are autologous cells.

Moreover, a sub population of stem/progenitor cells within the iris may encourage their differentiation cells towards RPE. In vitro results demonstrate good monolayer formation of primary IPE on both the treated ePTFE and the PU substrates. The NH3 plasma treated ePTFE is also being investigated as a substrate for the transplantation of a conjunctival epithelium. To restore the ocular surface we require the growth of an epithelium containing both epithelial and mucin secreting goblet cells on a suitable flexible, stable membrane that is well tolerated in vivo and promotes the self-renewal potential of progenitor epithelial and mucin-producing goblet cells.

In addition, the material must act as a mechanical barrier preventing re-scarring and recurrent forniceal loss.

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Primary porcine corneal endothelial cells cultured for four days on a functionalised peptide gel. Scale bar: 100 microns.

The internal layer of the cornea is composed of a single layered endothelium whose main function is to pump fluid out of the cornea preventing it from swelling and therefore losing transparency. Diseases of the corneal endothelium result in significant loss of vision and are one of the commonest reasons for corneal transplantation. We are developing a synthetic corneal endothelial graft composed of a single-layered corneal endothelium on a peptide gel.

This will enable the production of many endothelial grafts from one human donor cornea. A high water content transparent gel is produced from poly-L-lysine cross-linked with multifunctional carboxylic acids.

We have shown the mechanical properties can be controlled by the nature and density of the crosslinks to produce a gel that can be handled for surgical transplantation into the eye. Free amine groups remaining on the peptide can be used to functionalise the surface to promote the attachment and growth of a monolayer of corneal endothelial cells.

For more information, visit www.liv.ac.uk/ageing-and-chronic-disease

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NETWORKS

MEDE INNOVATION: DEVELOPING EARLY CAREER RESEARCHERS

By Marlène Mengoni, Research Fellow, The Institute of Medical and Biological Engineering, University of Leeds.

Creating the next generation of researchers in medical device manufacture in the UK is a key part of MeDe Innovation’s mission.

The MeDe Early Career Researcher (ECR) Forum aims to help young academics interact with other early career researchers from the breadth of medical device manufacture to form new professional networks that may generate future innovative research ideas.

Our ECR Forum Ambassadors – an enthusiastic researcher from each academic centre – take a lead in defining and developing workshops and events in MeDe Innovation’s core research areas, influenced by ideas from the membership. Our ECR Workshop held in May, for example, was a great way to get first-hand information about MeDe Innovation projects, make connections with industry partners, and give researchers the opportunity to present on their expertise and the kinds of collaborations they would be interested in.

events to feature speakers from non-academic fields, such as policy-makers, regulators and from Government that will help ECRs shape their projects and gain a better understanding of how their research might translate into products and services.

There is a great opportunity to work with Regener8’s ECR network as the respective core areas of the groups are highly complementary.

A LinkedIn group keeps conversations going between meetings, enabling researchers to share information about conferences and prizes, and connecting researchers who want to collaborate on grant applications.

Our ECR Forum not only has membership from academia but also those in their early careers in industry. The insight from discussion and networking opportunities in a safe environment with our peers is already leading to tangible benefits for our members.

We’re planning to expand and develop the forum and its membership, influencing the curation of MeDe Innovation

For more information, visit mede-innovation.ac.uk/earlycareer-researchers

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NETWORKS

MEDE INNOVATION 2015: INNOVATION IN ORTHOPAEDIC MEDICAL DEVICE MANUFACTURE

By Professor John Fisher, Centre Director, The ESPRC Centre for Innovative Manufacturing in Medical Devices and Academic Director, Medical Technologies IKC and Executive Director, Regener8.

We formed MeDe Innovation in 2013 out of five academic and 14 company partners with the aim to transform the design, manufacture and testing of replacement joints and other medical implants.

We are focussing on addressing two key research challenges: functionally stratified design and manufacture of devices, to group patients and develop computer models that will predict which device designs best meet variations in patients, such as size, anatomy, activities and lifestyle. The second challenge is to develop new manufacturing techniques to allow devices to be produced in the clinical setting, customised to an individual patient.

We have already made several significant achievements in just two years – working with Simulation Solutions Ltd to develop new hip and knee simulators and pre-clinical testing methods that are now being sold across the UK and Asia; our new simulation methods being adopted by global orthopaedics companies; and our fundamental research into 3D printing methods for new materials is advancing, to potentially develop novel near-patient manufacturing methods.

We are continuing to build a strong and inclusive international network of industrialists, academics, clinicians

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and regulatory body representatives to deliver research that is fit for purpose and quickly ready to translate into manufacturing practice.

In the last year we held three open research workshops led by our co-investigators in Sheffield, Leeds, and Newcastle, followed by our annual conference in Nottingham (pictured above) which attracted more than 150 attendees.

Promoting innovation and new ideas is also a key objective for us. Our ‘Fresh Ideas Fund’ has provided seven teams of researchers nationwide with small grants to develop projects that identify key challenges in medical device manufacturing. The projects we’ve supported could lead to larger projects being funded by national and global funding sources.

Into 2016, we’ll continue to refine our research questions to meet our grand challenges, through targeted research workshops with our partners.

Our annual conference will take place on January 28, 2016 and we’re expecting record numbers of attendees.

To keep up to date with news and events from MeDe Innovation, visit www.mede-innovation.ac.uk/join-us

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SPONSORS

REGENER8 2015 CONFERENCE SPONSORS Appleyard Lees

Luto

Intellectual property specialists, with a multidisciplinary team of patent and trade mark attorneys. From a network of offices, Appleyard Lees provides Intellectual Property (IP) services to the whole of the UK, Europe and the rest of the world. www.appleyardlees.com

Luto specialise in producing user friendly communications through good information design. We can work with you to produce both print and digital communications, from Instructions for Use (IFU) to educational materials (videos, apps, websites). www.luto.co.uk

BioPharma Process Systems The UK’s foremost provider of freeze drying equipment and services, including equipment maintenance, R&D, characterisation and training. www.biopharma.co.uk/biopharmaprocess-systems/home Cambridge Medtech Solutions An independent technical and strategic consultancy for the design, development and industrialisation of commercially successful medical devices and enabling technologies. www.c-m-s.com Fripp Design and Research Product design and research consultancy offering product design, applied industrial design, concept design, product development and research including concept development, CAD realisation, rapid prototyping and research services. www.frippdesign.co.uk International Biomechanics - Taylor & Francis Group International Biomechanics provides a high-quality platform for researchers working on biomechanics topics to publish their work globally under a fully Open Access model. www.taylorandfrancisgroup.com

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MeDe Innovation The Centre for Innovative Manufacturing in Medical Devices researches and develops advanced design and manufacturing methods for the Class III, musculoskeletal medical device sector. www.mede-innovation.ac.uk Medical Technologies IKC Medical Technologies IKC facilitates collaboration between companies, engineers, scientists and clinicians to develop innovative technologies that help the body repair and restore function. www.medical-technologies.co.uk Peprotech World leader in supplying high quality cytokine products. www.peprotech.com The Electrospining Company Utilising the world-class electrospinning platform at the Rutherford Appleton Laboratory in Oxfordshire, UK, to develop and manufacture highly consistent fibres for incorporation into easy-to-use scaffold products. www.electrospinning.co.uk

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MEMBERS

MEMBERSHIP BENEFITS Membership of Regener8 is free and it’s easy to sign up. Regener8 members benefit from the following...

Collaborative Projects

E-newsletter

Regener8 works with members to identify specific projects, form consortia and broker funding. In some cases we can project manage where appropriate.

Regener8 members also have access to a greater pool of expertise and resource as a result of the strategic alliance between Regener8 and the Medical Technologies Innovation and Knowledge Centre (IKC). The IKC focuses on the commercialisation of medical technology, facilitating collaboration between companies, engineers, scientists and clinicians. Working in collaboration with Regener8 and the IKC provides the opportunity to: speed up route to market; ensure products and services are fit for purpose; reduce the risk of late-stage failure; and access resources to support innovation for new product development.

Our regular e-newsletter contains news and events from members and the wider regenerative medicine community and is distributed to over 900 named individuals. If you’d like to receive the Regener8 enewsletter you can sign up via the website.

Access to World Class Technology

The online events calendar on the Regener8 website is regularly updated with events that we think will be of interest to the regenerative medicine community.

Regener8 has close links with other networks across the UK and with the N8 universities (Durham, Lancaster, Leeds, Liverpool, Manchester, Newcastle, Sheffield and York), research institutes and clinical centres of excellence in regenerative medicine throughout the UK. Regener8 website The Regner8 website www.regener8.ac.uk typically attracts over 1,000 unique visitors per month and has referrals on key partner websites.

Regener8 members are featured on the Regener8 website with a profile, logo, web link and contact details.

Regener8 members can update and edit their personal or organisation details at any time by simply logging in to the site. Regener8 members can also post their own news and events to the website.

The site also features a fully searchable Expertise Directory to find Regener8 members by location and area of expertise.

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regen Magazine regen is the annual magazine for Regener8 members and the wider regenerative medicine community. Copies are distributed at Regener8 events and it is also available online on our website. Advertising packages are available.

Member Events

Annual Conference We hold an annual conference, featuring respected academic, clinical and industry speakers from the translational regenerative community.

Now established as one of the leading RegenMed events in the UK, the Regener8 Annual Conference offers networking and sales opportunities through the exhibition packages available.

Marketing and PR Opportunities Members can share their news on the Regener8 website, through the e-newsletter and in regen magazine.

For more information and to sign up as a Regener8 member, visit www.regener8.ac.uk

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Regener8, X102 Medical and Biological Engineering, University of Leeds, Leeds, LS2 9JT E: regener8@leeds.ac.uk Contact details for key members of the Regener8 team can be found on our website at

www.regener8.ac.uk