SMART STEP - Stepwise Translational Pathway for Smart Material Cell Therapy
Lead Research Organisation:
University of Cambridge
Department Name: Surgery
Abstract
Diseases of bones and joints have the fourth greatest impact on the health of the world population, considering both death and disability. Injured cartilage that does not heal by itself leads to osteoarthritis, a disease that destroys the surfaces of the joints. It brings about severe joint pain and reduced function, making it difficult to walk and sleep. The current National guidelines for treatment of osteoarthritis (NICE) offer treatment options limited mainly to symptom relief with pain-killers and physiotherapy, and recommend only one surgical procedure, joint replacement with an artificial prosthesis, indicated in advanced disease with joint failure. This involves major surgery, which is costly and invasive. The artificial joints rarely restore a full range of movement and, most importantly, they do not last forever. This is a major limitation for young individuals and very active people. There is therefore a medical need for the development of new treatments that can prevent or cure osteoarthritis at the early stages. Instead of using prostheses, regenerative medicine offers to repair the joints with the patients' own cells, which are grown in the laboratory and then implanted back in the knee to repair the cartilage. Unfortunately, growing cells from each patient is costly and cumbersome, and must be repeated for every single patient. An industrial production of large batches is difficult. Thus, for its costs and challenging manufacturing this technology is not routinely available.
The mission of our consortium is to regenerate fully functional and pain-free joints by implanting biological devices into cartilage lesions in key-hole surgery. The questions we want to address are how to 1) make a consistent and effective biological device (not metal or plastic); 2) make it available off-the-shelf; 3) make it easy to administer to patients.
Our consortium sets out to link leading academic clinicians and scientists, in the UK (Universities of Cambridge, Aberdeen, Nottingham, Oxford and Queen Mary London) and The Netherlands (Universities of Rotterdam and Nijmegen), to bring together multiple disciplines such as engineering, biology, and material science, with the ultimate goal of clinical delivery to patient benefit. Our focus is on repair and regeneration of cartilage to prevent or alleviate symptoms in patients with early osteoarthritis, and ultimately provide a lifelong solution to restore a normal working pain-free joint, thereby avoiding joint replacement.
Recent studies, largely from our laboratories, have identified special repair cells, called stem cells, which are naturally present in the joint of adult individuals and have capacity to form the repair cartilage tissue, when natural healing occurs. We have also identified chemical and physical means to artificially activate these cells within the joint. Therefore we now want to build special scaffold materials, which can be inserted into the cartilage wound and, through their physical characteristics or through the release of chemical substances, can attract the repair stem cells. Once these cells enter the scaffold material, they will proliferate and will find adequate stimuli to form cartilage. The scaffold material will be degraded over time, leaving a cartilage repair tissue that is exclusively made by the patient's own cells.
The research programme will go from bench to bedside and will respond to the needs of the healthcare providers, such as the NHS, and the expectations of the industry to develop novel treatments for osteoarthritis. These treatments will take the form of key-hole and minor surgery, which can be used throughout the NHS. Our goal is to make those treatments easily affordable, easy to apply and deliverable in day case, ultimately available to all patients without requirement for specialist centres.
The mission of our consortium is to regenerate fully functional and pain-free joints by implanting biological devices into cartilage lesions in key-hole surgery. The questions we want to address are how to 1) make a consistent and effective biological device (not metal or plastic); 2) make it available off-the-shelf; 3) make it easy to administer to patients.
Our consortium sets out to link leading academic clinicians and scientists, in the UK (Universities of Cambridge, Aberdeen, Nottingham, Oxford and Queen Mary London) and The Netherlands (Universities of Rotterdam and Nijmegen), to bring together multiple disciplines such as engineering, biology, and material science, with the ultimate goal of clinical delivery to patient benefit. Our focus is on repair and regeneration of cartilage to prevent or alleviate symptoms in patients with early osteoarthritis, and ultimately provide a lifelong solution to restore a normal working pain-free joint, thereby avoiding joint replacement.
Recent studies, largely from our laboratories, have identified special repair cells, called stem cells, which are naturally present in the joint of adult individuals and have capacity to form the repair cartilage tissue, when natural healing occurs. We have also identified chemical and physical means to artificially activate these cells within the joint. Therefore we now want to build special scaffold materials, which can be inserted into the cartilage wound and, through their physical characteristics or through the release of chemical substances, can attract the repair stem cells. Once these cells enter the scaffold material, they will proliferate and will find adequate stimuli to form cartilage. The scaffold material will be degraded over time, leaving a cartilage repair tissue that is exclusively made by the patient's own cells.
The research programme will go from bench to bedside and will respond to the needs of the healthcare providers, such as the NHS, and the expectations of the industry to develop novel treatments for osteoarthritis. These treatments will take the form of key-hole and minor surgery, which can be used throughout the NHS. Our goal is to make those treatments easily affordable, easy to apply and deliverable in day case, ultimately available to all patients without requirement for specialist centres.
Technical Summary
Joint surface defects are disabling and predispose to osteoarthritis, a leading cause of disability for which there is no cure.
Cellular products, such as autologous chondrocytes, suffer from high costs of production and sub-optimal consistency of manufacturing due to the individual isolation, in vitro expansion, and quality controls of autologous cells.
We intend to form a knowledge and technology framework for the development and preclinical testing of cell-free bioactive devices capable of recruiting chondrogenic stem cells present in the joint and inducing cartilage formation. Such devices will represent off-the-shelf, affordable, life-long biological solutions for joint surface defects and the prevention of post-traumatic osteoarthritis.
Novel material technology allows adaptation of the physical characteristics of the biomaterials to interfere with mechanosensitive signalling pathways that influence cell-fate decisions, proliferation and differentiation. In addition, biomaterials will be engineered to expose, in a controlled way, growth factors that will enhance their cartilage formation.
Following in vitro screening in chondrogenesis models, such technologies will be tested, for safety and efficacy, in small and then large animal models of joint surface defect (mice and sheep, respectively) as well as on human cells transplanted in a surrogate potency assay for cartilage formation.
The effects of inflammation and proteolytic activity of the joint environment will be tested.
A robust management and monitoring structure will ensure optimal use of resources and animals, and coordinate a broad variety of expertise, spanning material sciences, cell biology, rheumatology, orthopaedics, tissue engineering, imaging, and clinical trial methodology, and ensure a seamless delivery of the programme.
The early involvement of the TSB Cell Therapy Catapult, industrial partners, and the regulatory agencies will facilitate the transition to the clinical phase.
Cellular products, such as autologous chondrocytes, suffer from high costs of production and sub-optimal consistency of manufacturing due to the individual isolation, in vitro expansion, and quality controls of autologous cells.
We intend to form a knowledge and technology framework for the development and preclinical testing of cell-free bioactive devices capable of recruiting chondrogenic stem cells present in the joint and inducing cartilage formation. Such devices will represent off-the-shelf, affordable, life-long biological solutions for joint surface defects and the prevention of post-traumatic osteoarthritis.
Novel material technology allows adaptation of the physical characteristics of the biomaterials to interfere with mechanosensitive signalling pathways that influence cell-fate decisions, proliferation and differentiation. In addition, biomaterials will be engineered to expose, in a controlled way, growth factors that will enhance their cartilage formation.
Following in vitro screening in chondrogenesis models, such technologies will be tested, for safety and efficacy, in small and then large animal models of joint surface defect (mice and sheep, respectively) as well as on human cells transplanted in a surrogate potency assay for cartilage formation.
The effects of inflammation and proteolytic activity of the joint environment will be tested.
A robust management and monitoring structure will ensure optimal use of resources and animals, and coordinate a broad variety of expertise, spanning material sciences, cell biology, rheumatology, orthopaedics, tissue engineering, imaging, and clinical trial methodology, and ensure a seamless delivery of the programme.
The early involvement of the TSB Cell Therapy Catapult, industrial partners, and the regulatory agencies will facilitate the transition to the clinical phase.
Planned Impact
Impact summary
The final aim of this application is to develop and validate cell free bioactive scaffold(s) which, when implanted into a cartilage defect, will be able to recruit mesenchymal stem cells present in the joint and induce cartilage formation in situ without the need for the ex vivo cell manipulations characteristic of current approaches (implantation of autologous chondrocytes or stem cells) that make them economically unsustainable, cumbersome and unattractive for the industry and therefore not routinely used in the UK (NICE report 2008).
Therefore the potential beneficiaries will include:
Society and Patients
- With the progressive trend towards an ageing population, well-being, ability to work, and independence are becoming a priority over the mere length of life. This is a particularly acute problem for focal defects and post-traumatic osteoarthritis. Osteoarthritis is the first cause of disability allowance in the UK and a leading cause of disability worldwide. Therefore a biological, life-long therapy that reduces or eliminate disability will benefit the patients who will recover their independence and ability to live a fulfilling, productive life, and the society, because it will reduce the financial burden of disability.
- Autologous chondrocyte implantation is burdened by the costly and cumbersome manufacturing of the patient-by-patient different autologous cells, which makes manufacturing and potency inconsistent, and often requires re-intervention. Recent data from a prospective clinical trial (Vanlauwe et al 2009 AJSM) clearly indicate that a large proportion of this variability resides in the manufacturing. The standardized, upscalable manufacturing of bioactive cell-free biomaterials will ensure better consistency and minimize or even eliminate batch-to-batch variability.
The industry and patients
- The high production costs of cell therapy reduce dramatically the revenue margins and restrict the markets for such cellular products, particularly in the current economic climate when the NHS and other healthcare providers struggle justifying the use of such expensive solutions. Bioactive, cell-free biomaterials will be significantly cheaper, due to robust industrial manufacturing, and therefore more affordable for healthcare providers and more accessible to patients.
Care providers
- Besides the financial strain associated with the production costs, the use of cellular products is also associated with a major logistical strain: due to the very short half-life (usually <5 days), there is relatively little flexibility allowed for the availability of surgeons, theatre, equipment etc. Failure of any of these components means having to obtain a new cartilage biopsy with an additional surgery and repeat the process all over again doubling costs and morbidity.
Veterinary surgeons
- Some animals, including Sports horses and racing dogs, are prone to develop cartilage defects, which often ends their career. There is therefore a substantial market and clinical need for such kind of products in veterinary medicine.
The final aim of this application is to develop and validate cell free bioactive scaffold(s) which, when implanted into a cartilage defect, will be able to recruit mesenchymal stem cells present in the joint and induce cartilage formation in situ without the need for the ex vivo cell manipulations characteristic of current approaches (implantation of autologous chondrocytes or stem cells) that make them economically unsustainable, cumbersome and unattractive for the industry and therefore not routinely used in the UK (NICE report 2008).
Therefore the potential beneficiaries will include:
Society and Patients
- With the progressive trend towards an ageing population, well-being, ability to work, and independence are becoming a priority over the mere length of life. This is a particularly acute problem for focal defects and post-traumatic osteoarthritis. Osteoarthritis is the first cause of disability allowance in the UK and a leading cause of disability worldwide. Therefore a biological, life-long therapy that reduces or eliminate disability will benefit the patients who will recover their independence and ability to live a fulfilling, productive life, and the society, because it will reduce the financial burden of disability.
- Autologous chondrocyte implantation is burdened by the costly and cumbersome manufacturing of the patient-by-patient different autologous cells, which makes manufacturing and potency inconsistent, and often requires re-intervention. Recent data from a prospective clinical trial (Vanlauwe et al 2009 AJSM) clearly indicate that a large proportion of this variability resides in the manufacturing. The standardized, upscalable manufacturing of bioactive cell-free biomaterials will ensure better consistency and minimize or even eliminate batch-to-batch variability.
The industry and patients
- The high production costs of cell therapy reduce dramatically the revenue margins and restrict the markets for such cellular products, particularly in the current economic climate when the NHS and other healthcare providers struggle justifying the use of such expensive solutions. Bioactive, cell-free biomaterials will be significantly cheaper, due to robust industrial manufacturing, and therefore more affordable for healthcare providers and more accessible to patients.
Care providers
- Besides the financial strain associated with the production costs, the use of cellular products is also associated with a major logistical strain: due to the very short half-life (usually <5 days), there is relatively little flexibility allowed for the availability of surgeons, theatre, equipment etc. Failure of any of these components means having to obtain a new cartilage biopsy with an additional surgery and repeat the process all over again doubling costs and morbidity.
Veterinary surgeons
- Some animals, including Sports horses and racing dogs, are prone to develop cartilage defects, which often ends their career. There is therefore a substantial market and clinical need for such kind of products in veterinary medicine.
Publications
Zelinka A
(2022)
Cellular therapy and tissue engineering for cartilage repair.
in Osteoarthritis and cartilage
Von Loga IS
(2020)
Does Pain at an Earlier Stage of Chondropathy Protect Female Mice Against Structural Progression After Surgically Induced Osteoarthritis?
in Arthritis & rheumatology (Hoboken, N.J.)
Thorup AS
(2020)
ROR2 blockade as a therapy for osteoarthritis.
in Science translational medicine
Thorup AS
(2022)
In vivo potency assay for the screening of bioactive molecules on cartilage formation.
in Lab animal
Thorup AS
(2021)
Lessons from joint development for cartilage repair in the clinic.
in Developmental dynamics : an official publication of the American Association of Anatomists
Thorup A
(2021)
OP0200 BLOCKING ROR2 IMPROVES CARTILAGE INTEGRITY AND PROVIDES PAIN RELIEF IN OSTEOARTHRITIS
in Annals of the Rheumatic Diseases
Thomas B
(2018)
Neutrophil extracellular vesicles have a cartilage protective effect during inflammatory arthritis
in Osteoarthritis and Cartilage
Tanase CE
(2019)
Targeted protein delivery: carbodiimide crosslinking influences protein release from microparticles incorporated within collagen scaffolds.
in Regenerative biomaterials
Symons RA
(2022)
Targeting the IL-6-Yap-Snail signalling axis in synovial fibroblasts ameliorates inflammatory arthritis.
in Annals of the rheumatic diseases
Description | British Orthopaedic Association guidance on Orthobiologics |
Geographic Reach | National |
Policy Influence Type | Participation in a guidance/advisory committee |
Impact | I cannot assess the size of the effect, but note that this national guidance is available on website for the British Orthopaedic Association as a resource for patients: to explain the evidence and conclusion about use of this type of treatment. |
URL | https://www.boa.ac.uk/resources/injectable-orthobiologic-treatments-for-osteoarthritis.html |
Description | ARUK Funded Research: The role of Agrin loss in the establishment and treatment of OA pain |
Amount | £596,000 (GBP) |
Organisation | Versus Arthritis |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 12/2017 |
End | 11/2022 |
Description | Is Agrin necessary for cartilage health? |
Amount | £35,000 (GBP) |
Funding ID | M380-F1 |
Organisation | Rosetrees Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2016 |
End | 06/2018 |
Description | Public engagement funding - Muscling In |
Amount | £13 (GBP) |
Organisation | Queen Mary University of London |
Department | Centre for Public Engagement |
Sector | Academic/University |
Country | United Kingdom |
Start |
Description | UKRMP Hub: The Engineered Cell Environment. |
Amount | £4,218,389 (GBP) |
Funding ID | MR/R015635/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2018 |
End | 03/2024 |
Title | Devise an MRI scoring system for pre clinical osteochondral defects |
Description | Describe an MRI scoring system for pre clinical osteochondral defects |
Type Of Material | Physiological assessment or outcome measure |
Year Produced | 2019 |
Provided To Others? | No |
Impact | This work will be published shortly |
Title | Model of osteochondral defect regeneration |
Description | Several years ago we optimised a model of osteochondral healing in mice. While this model has been useful to study spontaneous healing of cartilage and bone, it was unsuitable to test how exogenous molecules alter this process because the defect was so small that nothing could be injected. We have now generated a new model where a much larger and much better controlled defect is generated in the femoral condyle of immunocompetent mice and such defects can be filled with a gel containing either cells or bioactive molecules. This new model is much more sensitive to change than the previous one and has enabled to study in vivo the function of GCP2 in cartilage. This model is also being used in our laboratory to study the function of other molecules in cartilage repair. |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Year Produced | 2017 |
Provided To Others? | Yes |
Impact | This model enables investigators to study the effect of exogenous bioactive molecules on cartilage and bone repair. |
Title | Osteochondral defect repair in mice |
Description | This model enables to perform gain and loss of function experiments testing whether a certain substance/gene is required for osteochondral healing or it its supplementation enhances osteochondral healing and enables the use of lineage tracking to see the effect of the intervention in specific cell lines. A 2mm deep and 1mm wide osteochondral defect is generated on the lateral femoral chondyle in mice. A bioactive substance can be inoculated in the defect embedded in a collagen gel. |
Type Of Material | Data analysis technique |
Year Produced | 2016 |
Provided To Others? | No |
Impact | This technology has enables us to show that agrin supplementation enhances cartilage repair by recruiting GDF5-positive joint stem cells. We also tested additional 2 molecules. The data will be submitted for publication in the next 12 months. |
Description | UK Regenerative Medicine Platform Stage II Disease-focused |
Organisation | University of Cambridge |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Preclinical mouse models for cell lineage tracing in cartilage repair. |
Collaborator Contribution | Functional biomaterials for cartilage repair |
Impact | Eldridge SE, Barawi A, Wang H, Roelofs AJ, Kaneva M, Guan Z, Lydon H, Thomas BL, Thorup A, Fernandez BF, Caxaria S, Strachan D, Ali A, Shanmuganathan K, Pitzalis C, Whiteford JR, Henson F, McCaskie AW, De Bari C, Dell'Accio F. Agrin induces long term osteochondral regeneration by supporting repair morphogenesis. Sci Transl Med. 2020; 12 (559): 1-15. Multidisciplinary collaboration including clinicians, chemists, biologists, vets and expertise in small and large preclinical animal models. |
Start Year | 2014 |
Description | British Orthopaedic Research Society Public Lecture "From Steel to Stem Cells: Regenerative Therapies in Orthopaedic Surgery" - Face to Face and Livestream |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | This was am in person and livestream public lecture. Purpose to describe the importance of bone and joint disease, and how treatment has developed from joint replacement to cell therapy, with examples of translational research work. |
Year(s) Of Engagement Activity | 2022 |
URL | https://borsoc.org.uk/2022/05/09/bors-public-lecture-from-steel-to-stem-cells-regenerative-therapies... |
Description | Cambridge Science Festival talk |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Cambridge Science Festival talk |
Year(s) Of Engagement Activity | 2018 |
Description | Doors Open Day, Institute of Medical Sciences |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Several hundred people visited our research institute. In 2018, the number of visitors was >220. In one-on-one conversations with team members, they learned about arthritis and the research that our team is doing to try to harness the regenerative potential of stem cells. This sparked several interesting discussions regarding the extent of tangible progress that has been made in the use of stem cells for therapy, whether it is safe and effective for the treatment of arthritis, and what some of the hurdles/challenges are. There was also particular interest in risk factors and what people themselves can do to try to prevent arthritis, and visitors were provided with a range of brochures from ARUK (now Versus Arthritis) to take home that contained further information about prevention and management of arthritis, which were popular and highly appreciated. |
Year(s) Of Engagement Activity | 2017,2018 |
URL | http://www.doorsopendays.org.uk/places/aberdeen-city/university-of-aberdeen-institute-of-medical-sci... |
Description | Katie Chambers, Frances Balkwill, Suzanne Eldridge - Centre for Public Engagement Large Award, "Muscling in! |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | Suzanne Eldridge, Employed by me on the UKRMP grant, was awarded a Large Public Engagement grant award from QMUL Centre for Public Engagement (PI F. Balkwill, S. Eldridge and K. Chambers co-I) in 2015 (http://www.qmul.ac.uk/publicengagement/activities/items/164606.html and http://www.qmul.ac.uk/lifesciences/news-events/news/2015/164893.html). In partnership with the Centre of Cell Suzanne worked with approximately 250 children across four schools in an area of social deprivation (Tower Hamlets) to create and deliver a new school science show, 'Muscling in!' which communicates the physiology of the musculoskeletal system of the human body and engaged pupils with her research on osteoarthritis (key stage 2&3). The show now runs as a permanent educational show at the Centre of the Cell and receives bookings from schools nationally and internationally. Suzanne Eldridge was recently shortlisted as one of three finalists for the QMUL 'Interact Award - Engagement and Enterprise Awards 2017' (video summary can be found at 2.15min https://www.youtube.com/watch?v=lmOdYS5PV3k). |
Year(s) Of Engagement Activity | 2015,2016 |
URL | http://www.qmul.ac.uk/publicengagement/activities/items/164606.html |
Description | Lecture |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | The consortium was mentioned (other programmes discussed) as a research programme in the talk "From Steel to Stem Cells" - to Cambridge Alumni in Leeds |
Year(s) Of Engagement Activity | 2017 |
Description | Open Day |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | The Open Day was to showcase all research activities within the interdisciplinary Aberdeen Centre for Arthritis and Musculoskeletal Health. This was a fantastic opportunity to engage with patients and public (in addition to students) and explain in lay terms the research that we do and the potential for benefit to patients, their families and the whole society. |
Year(s) Of Engagement Activity | 2017 |
Description | Public Lecture: Cambridge Science Festival |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Title: Movement Matters Explaing about new treatment for osteoarthritis and translational research e.g. SMARTSTEP |
Year(s) Of Engagement Activity | 2018 |
Description | Public lecture on stem cells |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Free one-hour public lecture at the Aberdeen Science Centre on the topic: Stem cells: Can we harness their healing potential? The lecture discussed some of the recent success stories of stem cell therapy extensively covered in the media, as well as challenges still ahead. Some of our own research activities and recent findings aimed at addressing these challenges were highlighted. The lecture was followed by a question and answer session with touched upon some of the ethical issues surrounding stem cell research and therapy, and informal one-on-one follow-on discussions. |
Year(s) Of Engagement Activity | 2017 |
URL | http://aberdeensciencecentre.org/stuff-worth-knowing/ |
Description | VVIP visit |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Professional Practitioners |
Results and Impact | The Aberdeen Centre for Arthritis and Musculoskeletal Health hosted a visit of HRH the Duchess of Rothesay and Chancellor of the University of Aberdeen at the Institute of Medical Sciences. The visit was organised by Arthritis Research UK and National Osteoporosis Society to showcase the clinical and research activities taking place at the University of Aberdeen and NHS Grampian. |
Year(s) Of Engagement Activity | 2017 |