Biofabrication of a 3D bone tissue analogue with immunomodulatory factors to induce neovascularization and osteogenesis

Over 50,000 bone procedures performed annually in the UK involve autografts (1). Serious limitations in autologous-grafts, such as limited tissue supply, donor site morbidity, potential for infection or disease transmission and poor osseointegration, has led to many bone tissue engineering approaches (2). However, a major challenge of critically-sized 3D engineered tissues is the lack of adequate vascular supply which results in cell necrosis and tissue failure.
We have developed bone marrow derived mesenchymal-stem-cells (MSC) spheroids that form calcium rich nodules (3) and an endothelial and MSC coculture methodology in collagen gel for the prevascularisation of engineered constructs (4) that combined with natural hydrogels induce angiogenesis and osteogenesis. When a biomaterial is implanted a response is initiated by the host tissue which could result in persistent inflammation. This in turn results in impaired healing and repair. Therefore the osteo- and angio-immunomodulatory properties of biomaterials can affect the outcomes of bone regeneration (5). Increasing evidence suggest that the inflammatory cytokines secreted by macrophages are necessary for mediating tissue-biomaterial integration.
Here we aim to biofabricate vascularised-bone-constructs by embedding cellular spheroids/organoids of osteoprogenitor-cells (bone marrow derived mesenchymal-stem-cells) in a natural hydrogel (collagen, gelatin or alginate). In that, ECs and MSCs in collagen gel will be bioprinted using the suspended layer additive manufacture (SLAM) method for the creation of a suspended vascular network. These will be cultured with or without active osteo-immunomodulatory factors released by macrophages to increase bone regeneration.

There are numerous beneficiaries of this Advanced Biomedical Materials CDT. Firstly and of short term impact are the PhD students themselves. They will receive extensive research specific and professional/transferable skills training throughout the 4 years of the programme. They will have access to state of the art facilties and world leading academics, industry and clinicians. The training and potential placements are designed to maximise the impact of their research in terms of dissemination and movement of their research along the translation pathway.

Longer term benefits are that this distinct cohort will become the future UK Biomedical Materials leaders and be able to use their bespoke training and network within the cohort to collaborate on future worldwide funding opportunities and drive UK research in this area.

UK and international academics will benefit as they will gain the next generation of highly skilled postdoctoral researchers with knowledge and expertise not only in their specific research area but of industry, regulatory and clinical aspects.

UK and international industry will benefit - in the short term they will gain academic based research to further develop products and in the longer term have a pool of highly skilled graduates.

Clinicians will benefit from collaborative research and also the development of new and novel products to enhance the treatment of a variety of trauma and disease based needs from biomaterials.

The public will benefit as end users as patients that will have their quality of life improved from the products developed in the CDT and will be educated in novel technologies and materials to repair the human body. The UK economy will benefit from the reduced healthcare costs associated with the new and improved medical products developed in this CDT and subsequently from the trained graduates. The UK economy will also benefit from the increased revenue from medical sales products from the UK industrial partners we will be working with.

The impact of this CDT will be realised by direct academic, clinical and industrial engagement with the students allowing efficient and state of the at training and fast translation of developing products. Students will also be trained in knowledge exchange and will use these skills to disseminate their research to, and liaise with, the key stakeholders - the academic, industrial, clinical and public sectors. We will ensure widening participation routes are addressed in this CDT in order to include equality and diversity not only in our initial CDT student cohort but in future researcher generations to come.