Smart materials for targeted stem cell fate and function in skeletal repair
Lead Research Organisation:
University of Edinburgh
Department Name: Sch of Chemistry
Abstract
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Technical Summary
Bone disease and injury are burgeoning in our ageing populations, leading to a high economic and social cost. Treatments for bone injury are often ineffective or inappropriate. Autograft may be limited in supply and causing morbidity at the donor site, whereas allogeneic material may be poorly osteoinductive or of unreliable efficacy and in some cases may act as an agent for the transmission of life-threatening infectious disease. To address these challenges, we propose to develop a new tissue replacement that augments bone formation through temporal and targeted delivery of chemical cues for bone induction.
To achieve this we will build on an existing collaboration between the universities of Edinburgh and Southampton focused on developing a new generation of biomaterials for bone regeneration. We will first engineer polymer nanoparticles which can carry a range of chemical cues (growth factors, small molecules, nucleic acids) and which degrade at controlled, predetermined rates. We will test this by examining release of fluorophores and by measuring uptake of released dyes by cells in in vitro assays. Next, we will use couple chemistries to tether such nanoparticles to the backbone of a variety of hard and soft tissue scaffolds. In this way, the scaffolds will provide an environment for cell in growth and will provide a reservoir of heterogeneous factors that are released at the appropriate times for the appropriate cell populations. Finally we will test the efficacy of such scaffolds in ex vivo models, such as the chorioallantoic membrane of the chick egg, and in in vivo small animal defect models. We take full advantage of the high-resolution CT imaging facilites available at Southampton to track drug delivery and tissue healing.
Our approach will provide a new technology for controlling - temporally and spatially - the delivery of factors from hard and soft tissue scaffolds. This will enable the controlled redevelopment of tissues following injury.
To achieve this we will build on an existing collaboration between the universities of Edinburgh and Southampton focused on developing a new generation of biomaterials for bone regeneration. We will first engineer polymer nanoparticles which can carry a range of chemical cues (growth factors, small molecules, nucleic acids) and which degrade at controlled, predetermined rates. We will test this by examining release of fluorophores and by measuring uptake of released dyes by cells in in vitro assays. Next, we will use couple chemistries to tether such nanoparticles to the backbone of a variety of hard and soft tissue scaffolds. In this way, the scaffolds will provide an environment for cell in growth and will provide a reservoir of heterogeneous factors that are released at the appropriate times for the appropriate cell populations. Finally we will test the efficacy of such scaffolds in ex vivo models, such as the chorioallantoic membrane of the chick egg, and in in vivo small animal defect models. We take full advantage of the high-resolution CT imaging facilites available at Southampton to track drug delivery and tissue healing.
Our approach will provide a new technology for controlling - temporally and spatially - the delivery of factors from hard and soft tissue scaffolds. This will enable the controlled redevelopment of tissues following injury.
Planned Impact
Our research project aims to bring together a multidisciplinary team to develop a new technology for improving tissue regeneration, and will have a number of academic, industrial, societal, economic and awareness impacts.
UK PLC: UK Healthcare must reap the dividend of the current 'revolution' in regenerative medicine/science. This research programme will deliver new leading-edge multi and cross-disciplinary research in exciting and highly translatable areas of biology and chemistry.
Training: A central part of our agenda is to break down traditional 'barriers' between physical and biomedical sciences. The PDRA's will benefit immensely from the interdisciplinary, translational thrust of the programme and the cross-fertilisation. They will gain a wide variety of both "hard and soft" skills that will be readily applied in a variety of employment sectors.
Business and Industry: The applicants have major interactions with industry, and have direct personal experience of spin-off/spin-out companies. As the programme progresses new commercial opportunities will undoubtedly arise - prospects in the global healthcare arena will be significant and we will look to translate our unique scaffold approaches through to the clinic in regenerative projects, programmes as appropriate including the UK Regenerative Medicine and Medical Technologies Innovation and Knowledge Centre programmes.
General: Our multidisciplinary programme will provide many opportunities for involvement in public engagement and dissemination. Research fellows will participate at the International Science Festivals and become involved in a variety of out-reach activities such as the locally run 'Researchers-in-Residence Programme' which places PDRA's in local secondary schools allowing the public to benefit, as well as engaging the next generation of scientists. We will also engage with the Cell Therapy Catapult as appropriate especially from a stem cell clinical translation perspective in the end phase of our programme again as appropriate (preclinical and early clinical development).
UK PLC: UK Healthcare must reap the dividend of the current 'revolution' in regenerative medicine/science. This research programme will deliver new leading-edge multi and cross-disciplinary research in exciting and highly translatable areas of biology and chemistry.
Training: A central part of our agenda is to break down traditional 'barriers' between physical and biomedical sciences. The PDRA's will benefit immensely from the interdisciplinary, translational thrust of the programme and the cross-fertilisation. They will gain a wide variety of both "hard and soft" skills that will be readily applied in a variety of employment sectors.
Business and Industry: The applicants have major interactions with industry, and have direct personal experience of spin-off/spin-out companies. As the programme progresses new commercial opportunities will undoubtedly arise - prospects in the global healthcare arena will be significant and we will look to translate our unique scaffold approaches through to the clinic in regenerative projects, programmes as appropriate including the UK Regenerative Medicine and Medical Technologies Innovation and Knowledge Centre programmes.
General: Our multidisciplinary programme will provide many opportunities for involvement in public engagement and dissemination. Research fellows will participate at the International Science Festivals and become involved in a variety of out-reach activities such as the locally run 'Researchers-in-Residence Programme' which places PDRA's in local secondary schools allowing the public to benefit, as well as engaging the next generation of scientists. We will also engage with the Cell Therapy Catapult as appropriate especially from a stem cell clinical translation perspective in the end phase of our programme again as appropriate (preclinical and early clinical development).
People |
ORCID iD |
Mark Bradley (Principal Investigator) |
Publications
Czekanska EM
(2018)
Combinatorial delivery of bioactive molecules by a nanoparticle-decorated and functionalized biodegradable scaffold.
in Journal of materials chemistry. B
Jain S
(2016)
Tetrazine-Mediated Postpolymerization Modification
in Macromolecules
Neumann K
(2016)
Nanoparticle "switch-on" by tetrazine triggering.
in Chemical communications (Cambridge, England)
Description | Nanoparticles have been used to decorate a scaffold - and allow growth-factor release to control cellular growth. Please see submitted papers for further details. For example: The combination of supportive biomaterials and bioactive factors to stimulate endogenous progenitor cells is of key interest for the treatment of conditions in which intrinsic bone healing capacities are compromised. To address this need a "scaffold-decoration platform" was developed in which a biocompatible, biotin-functionalised 3D structural polymer network was generated through a solvent blending process, and used to recruit avidin modified nanoparticles within its 3D structure through biotin-avidin conjugation. This was enabled via the generation of a suite of poly(lactic-co-glycolic acid) (PLGA) nanoparticles, encapsulating two bioactive factors, vascular endothelial growth factor (VEGF) and L-ascorbic acid 2-phosphate (AA2P) and conjugated to streptavidin to allow attachment to the bone generating scaffold. The levels of encapsulated and released VEGF and AA2P were tailored to fall within the desired range to promote biological activity as confirmed by an increase in endothelial cell tubule formation and collagen production by osteoblast cells in response to nanoparticle release of VEGF and AA2P, respectively. The release of VEGF from the scaffolds produced a significant effect on vasculature development within the chick chorioallantoic membrane (CAM) angiogenic assay. Similarly, the scaffolds showed strong biological effects in ex vivo assays indicating the potential of this platform for localised delivery of bioactive molecules with applications in both hard and soft tissue engineering. |
Exploitation Route | We are taking these forward in a number of ways with grants from the EU. |
Sectors | Chemicals Pharmaceuticals and Medical Biotechnology |
Description | team has presented work at a number of public engagement events. |
First Year Of Impact | 2016 |
Impact Types | Societal |
Description | Long term collaboration with Professor Richard Oreffo |
Organisation | University of Southampton |
Department | Bone and Joint Research Group |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We are a team that have worked together for 20+ years - us from a chemistry and materials side and Richard from a materials and biological angle. |
Collaborator Contribution | We are a team that have worked together for 20+ years - us from a chemistry and materials side and Richard from a materials and biological angle. |
Impact | See papers in list. Multidisciplinary in nature. |
Description | Smart materials for targeted stem cell fate and function in skeletal repair |
Organisation | University of Southampton |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | PhD student with Professor Richard Oreffo - supplying materials for scaffold incorporation |
Collaborator Contribution | upplying materials for scaffold incorporation |
Impact | Research is on-going |
Start Year | 2016 |
Description | Lecture to national meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Lecture to national society meeting |
Year(s) Of Engagement Activity | 2015,2016 |