SMART STEP - Stepwise Translational Pathway for Smart Material Cell Therapy

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.

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.

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.