Ultrasound-mediated gene delivery for orthopaedic tissue regeneration
Lead Research Organisation:
University of Leeds
Department Name: Mechanical Engineering
Abstract
Due to demographic changes resulting in an ageing society in developed countries around the world it is expected that musculoskeletal tissue defects and disease incidence will continuously increase. Musculoskeletal health is particularly important in the elderly population due to the significant impact on mobility, quality of life, mortality and morbidity. Furthermore, there is increasing demand for advanced orthopaedic interventions that reduce hospitalisation timeframes and accelerate rehabilitation not only in elderly patients but also in trauma care of younger patient populations. Generally, it is recognised that there is a significant need and opportunity for novel therapies in orthopaedics that accelerate healing and approach regeneration from a more biological angle to offer true functional regeneration in a cost-effective and safe manner and are inspired by nature (biomimetic).
Current approaches for the treatment of musculoskeletal defects rely on the application of donor tissue (e.g. iliac crest) leading to donor site morbidity or biological approaches using recombinant protein growth factors at supraphysiologic doses which can cause adverse effects and are expensive. The approaches investigated in the proposed research project utilise the delivery of genetic instructions to endogenous cells at the defect site in vivo in order to force target cells to produce regenerative factors in a controlled, sustained manner in situ. In line with safety, straightforward deployability and translation requirements, the current project therefore aims to employ a physical, non-viral and minimally invasive gene delivery approach, that can deliver true spatiotemporal control over drug delivery in vivo; ultrasound-mediated gene delivery (sonoporation). The main research question of the proposed project is if this method can be tailored to match or outperform current standard methods of stem cell transplantation, autologous tissue grafting and growth factor application for orthopaedic regeneration. This project is of true multidisciplinary nature incorporating biological (synthetic biology, gene therapy, stem cell biology, orthopaedic regeneration, in vitro and in vivo models) with physical sciences (physical drug delivery, ultrasound) and materials research (microbubble contrast agents, biological support scaffolds) addressing a clear clinical need. It will lead to therapeutic methods with wide ranging applicability in orthopaedic regeneration, ultimately benefiting patients and health care providers by delivering safe, efficient and cost-effective means of treatment that have the potential to significantly decrease hospitalisation time and accelerate rehabilitation.
AIMS
Development and benchmarking of novel ultrasound-mediated gene therapy approaches for orthopaedic regeneration (innovation in medical and biological engineering).
Comprehensive preclinical evaluation in ectopic and orthotopic models in vivo (joint replacement and tissue re-engineering).
OBJECTIVES
Identification of 2 clear therapeutic targets for intervention using available health economic, systematic review and clinical advisory input at the beginning of the project (focusing on highest priority unmet clinical challenges in musculoskeletal regeneration).
Tailoring of available prototype technology to clinical target needs (adaptation to accelerated translation).
Evaluation of effectiveness of the approach for induction of differentiation in clinically relevant cellular models in vitro (proof of concept novel regenerative therapy for musculoskeletal defects).
reclinical benchmarking of developed approaches in in vivo models for tissue induction and/or regeneration in comparison to clinical standard (e.g. vs. autologous tissue grafting, BIO DBM Stryker).
Current approaches for the treatment of musculoskeletal defects rely on the application of donor tissue (e.g. iliac crest) leading to donor site morbidity or biological approaches using recombinant protein growth factors at supraphysiologic doses which can cause adverse effects and are expensive. The approaches investigated in the proposed research project utilise the delivery of genetic instructions to endogenous cells at the defect site in vivo in order to force target cells to produce regenerative factors in a controlled, sustained manner in situ. In line with safety, straightforward deployability and translation requirements, the current project therefore aims to employ a physical, non-viral and minimally invasive gene delivery approach, that can deliver true spatiotemporal control over drug delivery in vivo; ultrasound-mediated gene delivery (sonoporation). The main research question of the proposed project is if this method can be tailored to match or outperform current standard methods of stem cell transplantation, autologous tissue grafting and growth factor application for orthopaedic regeneration. This project is of true multidisciplinary nature incorporating biological (synthetic biology, gene therapy, stem cell biology, orthopaedic regeneration, in vitro and in vivo models) with physical sciences (physical drug delivery, ultrasound) and materials research (microbubble contrast agents, biological support scaffolds) addressing a clear clinical need. It will lead to therapeutic methods with wide ranging applicability in orthopaedic regeneration, ultimately benefiting patients and health care providers by delivering safe, efficient and cost-effective means of treatment that have the potential to significantly decrease hospitalisation time and accelerate rehabilitation.
AIMS
Development and benchmarking of novel ultrasound-mediated gene therapy approaches for orthopaedic regeneration (innovation in medical and biological engineering).
Comprehensive preclinical evaluation in ectopic and orthotopic models in vivo (joint replacement and tissue re-engineering).
OBJECTIVES
Identification of 2 clear therapeutic targets for intervention using available health economic, systematic review and clinical advisory input at the beginning of the project (focusing on highest priority unmet clinical challenges in musculoskeletal regeneration).
Tailoring of available prototype technology to clinical target needs (adaptation to accelerated translation).
Evaluation of effectiveness of the approach for induction of differentiation in clinically relevant cellular models in vitro (proof of concept novel regenerative therapy for musculoskeletal defects).
reclinical benchmarking of developed approaches in in vivo models for tissue induction and/or regeneration in comparison to clinical standard (e.g. vs. autologous tissue grafting, BIO DBM Stryker).
Planned Impact
Regenerative Medicine been defined as "an interdisciplinary approach, spanning tissue
engineering, stem cell biology, gene therapy, cellular therapeutics, biomaterials (scaffolds and matrices),nanoscience, bioengineering and chemical biology that seeks to repair or replace damaged or diseased human cells or tissues to restore normal function, (UK Strategy for Regenerative Medicine). CDT TERM will focus on acellular therapies, scaffolds,autologous cells and regenerative devices, which can be delivered to patients as class three device interventions, thus reducing the time and cost of translation and which provide an opportunity to deliver economic growth and benefits to health in the next decade. The primary beneficiaries of CDT TERM are patients, the health service, UK industry, as well as the academic community and the students themselves. Recognising that the impact and benefit from CDT TERM will arise in the future, the statements describing impact below are supported by evidence of actual impact from our existing research and training.
Patients will benefit from regenerative interventions, which address unmet clinical needs, have improved safety and reliability, have been stratified to meet patients needs and manufactured in a cost effective manner. An example of impact arising from previous students work is a new acellular scaffold for young adult heart valve repair, which has demonstrated improved clinical outcomes at five years.
The Health Service will benefit from collaborations on research, development and evaluation of technologies, through existing partnerships with National Health Service Blood and Transplant NHSBT and the Leeds Biomedical Musculoskeletal Research Unit LMBRU. NHSBT will benefit through collaborative projects, through technology transfer, through enhancement of manufacturing processes, through pre-clinical evaluation of products and supply of trained personnel. We currently collaborate on heart valves, skin, ligaments and arteries, have licensed patents on acellular bioprocesses, and support product and process developments with pre-clinical testing and simulation. LMBRU and NHS clinicians will benefits from our collaborative research and training environment and access to our research expertise, facilities and students. Existing collaborative projects include, delivery devices for minimally manipulated stem cells and applied imaging for early OA.
Industry will benefit from supply of highly trained multidisciplinary engineers and scientists, from collaborative research and development projects, from creation and translation of IP, creation of spinout companies and through access to unique equipment, facilities and expertise. We have demonstrated: successful spin outs in form of Tissue Regenix and Credentis; successful commercialisation of a novel biological scaffolds for vascular patch repair; sustainable long term R and D and successful licensing of technology with DePuy; collaborative research with Invibio, partnering with Simulation Solutions to develop new pre-clinical simulation systems, which been adopted by regulatory agencies such as China FDA. Our graduates and researchers are employed by our industry partners.
The academic community will benefit through collaborative research and access to our facilities. We have funded collaborations with over 30 academic institutions in UK and internationally. The CDT TERM will support these collaborations and the academic partners will support student research and training. The CDT students will benefit from enhanced integrated multidisciplinary training and research, a cohort experience focused on research innovation and translation, access to our research partners, industry and clinicians. Feedback from existing students has identified the benefit of the multidisciplinary experience, the depth and breadth of excellence in our research base, the outstanding facilities and the added value of the cohort training.
engineering, stem cell biology, gene therapy, cellular therapeutics, biomaterials (scaffolds and matrices),nanoscience, bioengineering and chemical biology that seeks to repair or replace damaged or diseased human cells or tissues to restore normal function, (UK Strategy for Regenerative Medicine). CDT TERM will focus on acellular therapies, scaffolds,autologous cells and regenerative devices, which can be delivered to patients as class three device interventions, thus reducing the time and cost of translation and which provide an opportunity to deliver economic growth and benefits to health in the next decade. The primary beneficiaries of CDT TERM are patients, the health service, UK industry, as well as the academic community and the students themselves. Recognising that the impact and benefit from CDT TERM will arise in the future, the statements describing impact below are supported by evidence of actual impact from our existing research and training.
Patients will benefit from regenerative interventions, which address unmet clinical needs, have improved safety and reliability, have been stratified to meet patients needs and manufactured in a cost effective manner. An example of impact arising from previous students work is a new acellular scaffold for young adult heart valve repair, which has demonstrated improved clinical outcomes at five years.
The Health Service will benefit from collaborations on research, development and evaluation of technologies, through existing partnerships with National Health Service Blood and Transplant NHSBT and the Leeds Biomedical Musculoskeletal Research Unit LMBRU. NHSBT will benefit through collaborative projects, through technology transfer, through enhancement of manufacturing processes, through pre-clinical evaluation of products and supply of trained personnel. We currently collaborate on heart valves, skin, ligaments and arteries, have licensed patents on acellular bioprocesses, and support product and process developments with pre-clinical testing and simulation. LMBRU and NHS clinicians will benefits from our collaborative research and training environment and access to our research expertise, facilities and students. Existing collaborative projects include, delivery devices for minimally manipulated stem cells and applied imaging for early OA.
Industry will benefit from supply of highly trained multidisciplinary engineers and scientists, from collaborative research and development projects, from creation and translation of IP, creation of spinout companies and through access to unique equipment, facilities and expertise. We have demonstrated: successful spin outs in form of Tissue Regenix and Credentis; successful commercialisation of a novel biological scaffolds for vascular patch repair; sustainable long term R and D and successful licensing of technology with DePuy; collaborative research with Invibio, partnering with Simulation Solutions to develop new pre-clinical simulation systems, which been adopted by regulatory agencies such as China FDA. Our graduates and researchers are employed by our industry partners.
The academic community will benefit through collaborative research and access to our facilities. We have funded collaborations with over 30 academic institutions in UK and internationally. The CDT TERM will support these collaborations and the academic partners will support student research and training. The CDT students will benefit from enhanced integrated multidisciplinary training and research, a cohort experience focused on research innovation and translation, access to our research partners, industry and clinicians. Feedback from existing students has identified the benefit of the multidisciplinary experience, the depth and breadth of excellence in our research base, the outstanding facilities and the added value of the cohort training.
