Instructive acellular tissue engineering (IATE)

There are currently 10 million people in the UK affected by musculoskeletal disorders, which costs the National Health Service £4.76 billion annually. Alarmingly with increasing life expectancy and the demand for sustained quality of life in older years, this pressure is only expected to rise. As such, new approaches to regenerate damaged or diseased bones are greatly needed. Ideally, these technologies should improve patient outcomes while also being cost effective.
Outside of grafting bone from another part of the body, which is limited in scale and results in local morbidity, current approaches to regenerate bone typically rely on combining concentrated doses of single proteins with structural materials. However, since these approaches do not mimic the natural formation process of bone they can be sub-optimal and even result in significant side effects. Therefore, in the past decade researchers have focused on developing a new strategy, tissue engineering. This field aims to imitate natural regeneration by bringing together the three major constituents. Tissue engineering combines cells with instructive biological factors and incorporates them into a material to allow them to be delivered to the intended site. Despite many advancements in tissue engineering and promising results at a laboratory scale, very few of these technologies reach clinical use. This is typically due to cell-based products not meeting regulatory standards associated with safety and reproducibility since the behaviour of cells when implanted may be difficult to control. Furthermore, the complex process of approving biological therapies is extremely expensive and may take over 10 years. In this project, a novel bone regeneration treatment will be developed that mimics our body's own development processes. This acellular approach will lead to a safe therapy, which aims to circumnavigate the issues associated with current treatments.
Research has shown that during healthy development of bone nanosized (one billionth of a metre) particles are released from bone forming cells (osteoblasts) that act as sites to bring together all of the elements needed to create the mineral component of this tissue. These particles, termed extracellular vesicles, have been shown to be carriers of important factors (for example proteins) that may instruct and encourage bone formation. It has also been found that these vesicles may signal to other cells involved in healing processes enhancing their effect. As such, the development of a bone regeneration therapy based on delivery of such vesicles represents an exciting opportunity to recapitulate the way our bodies regenerate in a healthy state.
In this project, we will study the process by which bone cells form these regenerative vesicles and use a range of techniques to unearth further information on what they contain. This new fundamental knowledge will allow us to develop a safe therapy, which exploits and maximises the natural healing capacity of vesicles. During the programme, we will use our multidisciplinary expertise to engineer a material capable of controllably releasing vesicles along with other acellular factors known to encourage bone regeneration. This work will deliver a technology that may be locally injected into a site of bone disease or injury for which we will demonstrate its effectiveness to enhance mineral formation beyond current clinical gold standards. With our project collaborators, we will also explore the opportunity to form this material using a bioprinting process into 3D structures that will help to guide bone regeneration.
While the primary focus of this programme is to develop a novel acellular technology capable of regenerating bone, we will also examine the capacity of vesicle derived from cartilage cells. The possibility to programme vesicles to repair cartilage is very attractive since this tissue has limited self-healing capacity and is often compromised in musculoskeletal injuries

The approach developed in this project will utilise vesicles as instructive components in an injectable osteoconductive material to regenerate diseased or damaged bone tissue beyond current gold standards. This novel acellular technology is designed to mimic natural regeneration processes and as such may circumnavigate many of the issues associated with cell-based therapies. Dr Cox will receive the support of a multidisciplinary project advisory board to ensure this project will impact various stakeholders as detailed below.
Patients: this research will ultimately be of the most benefit to patients. The approach developed is distinctive in its potential to enhance mineralisation while also being naturally inspired and as such may minimise associated side effects. Given the implications of musculoskeletal disorders may be significant, including pain, threat to life and loss of function (both temporary and permanent) the multiple benefits of a technology that may enhance or speed up regeneration is very attractive from a patient perspective. Of further importance, are the costs of treating these diseases or injuries. Musculoskeletal disorders represent a significant cost burden to the NHS and have a knock on effect to the economy through loss of working days. As such, the potential of this acellular technology to be rapidly developed represents significant socioeconomic impact.
Clinicians: the findings of this project would also be of significant importance to the healthcare professionals involved in treating a range of musculoskeletal indications, including fractures or non-unions, osteointegration of medical devices, and fusion of joints such as the spine or ankle. Through engagement with surgeons on the project advisory board, advice will be sought to enable identification of an initial target indication in which the technology may have the biggest impact to both the NHS and the patient. Demonstration of in-vivo efficacy will be assessed at the end of this programme. It is also important to note that due to increases in life expectancy outgrowing improvements in device life span, revision of prosthetics is becoming more common. These secondary operations represent increased risks to patients and may reflect negatively on the reputation of the clinician who implanted the first prosthesis. As such, the instructive acellular technology developed in this programme may find particular value in improving outcomes of revision procedures by improving integration at the device/tissue interface.
Medical device sector: the novel acellular therapy developed in this project has the potential to be used as a standalone system or as an adjunct to existing medical devices to enhance osseointegration. The long-term impact of this will be improved patient outcomes and reduced medical device failures. Initial market research has indicated a clear industrial demand for such a product. Engagement with medical device companies will be facilitated throughout the project by the University's technology transfer team. Translational experts from the Medical Devices Testing and Evaluation Centre based at the Institute of Translation Medicine will also support this industrial impact. Subsequently this would be of benefit to the economy through job creation and the UK government through increased tax collection.
Educational beneficiaries: this inherently multidisciplinary project, which will achieve advancements relevant to a number of sectors, clearly has great potential from a training and education perspective. It will significantly benefit Dr Cox's career progression by establishing independence, reputation and mentoring while exposing members of her team to collaborative opportunities. The biological, materials and manufacturing advancements made also have excellent prospective to inspire future generations into the STEM subjects. Furthermore, it is an ideal opportunity to engage undergraduate students and visitors in healthcare research.