Towards Bespoke Bio-Hybrid Prosthesis - Manufacturing bio-inductive interfaces in 3D
Lead Research Organisation:
University of Leeds
Department Name: Mechanical Engineering
Abstract
There have been a number of exciting research developments in the field of bio-integrated and neural connected limb prosthetics. However, it has been shown that the range and lifetime of functionality is limited due to failures at both nerve and muscle interfaces, leading to signal loss and mechanical failure, respectively. Our vision is to challenge the mind-set of limb prosthesis being a disparate and mismatched entity to one where it may be truly interactive and integrated with the residual anatomy and physiology. Our envisaged prosthesis will respond to biological feedback via a tissue engineered abiotic/biotic conduit between the artificial prosthetic and remaining biological muscle and nerves. This will provide the natural and full range of communication and feedback with afferent and efferent connections to the neural system with an emphasis on integration and long-term reliability. This will be achieved through exploration and understanding the fundamental engineering and manufacture of bespoke 3D coupling constructs that encourage and facilitate the robust integration and interface with tissue-engineered skeletal muscle and nerves, and their ancillary structures. The researching will entail developing a new manufacturing process, and the associated sciences, through a multidisciplinary team comprising of manufacturing engineering, biological science and chemistry. Considerations for industrial scale-up, good manufacturing practice (GMP) and regulatory requirements are integrated throughout. The work will be conducted in partnership with a world-leading UK prosthetic manufacturing company along with clinical engagement.
Planned Impact
The proposed research is expected to generate significant clinical impact by addressing the key scientific and manufacturing challenges around interfacing biological components with electromechanical systems such as advanced limb prosthetics. The research will provide significant commercial, technological and scientific impact as it will enable, via a novel multi-systems manufacturing approach, new realms of functionality and personalisation in medical devices. Patient benefit will be allied with benefit to our industrial partner, Blatchford, and UK industry by developing new business models, innovative products and the creation of new supply chains. This proposal concerns limb prostheses, although several core technical accomplishments will be relevant to a myriad of other industrial areas.
This research will contribute to UK society and economy by benefitting the medical device industry, healthcare providers, medical professionals and patients. The resultant impact addresses the national priority areas of rehabilitation by facilitating superior forms of prostheses integration and performance. It will impact in a multitude of diverse ways by enhancing quality of life and health, raising the effectiveness of healthcare services and increasing economic competitiveness both directly, through device industry, and indirectly by allowing patients to more fully engage in occupational and social activity. Medium term benefits will be evident to those involved in the target areas of orthopaedics and rehabilitation, long term benefits will apply more broadly. Specific groups will include:
- Patients - Approximately 5000-6000 limb amputations occur in the UK every year, and an estimated 1 million globally which equates to one case every 30 seconds. Patients experiencing limb-loss or deficiency will be primary beneficiaries through increased function and capability, and resulting enhanced quality of life and health. Indirect economic advantages include a reduced tax burden, increased working capacity, less time off work and reduced travel to and from hospital.
- A wider range of medical conditions can also potentially benefit through the ability to create living tissue neural interfaces that can support the bidirectional flow of signalling between the body and external electrical mechanical and sensory devices. The ability to route signals in and out of the bodies neural networks or bypass damaged and severed nerve areas will open up new avenues for treatments and research. Potential conditions could include retinal eye implants, paraplegics, motor neuron disease, or other neurological disorders. Animal testing may be reduced by providing new methods to study neural interfaces.
- Healthcare Providers - our national health service will benefit economically from greater efficiency and reduced treatment costs helping them to meet the populations' growing expectations within ever tighter financial constraints. Surgical and clinical revision rates could be reduced. A significant current issue in prostheses, namely volume loss and muscle atrophy, may be reduced or eliminated due to the integration and utilisation of residual function. This can be an ongoing issue for prosthesis users, and results in significant further treatment and revision.
- Prosthetics industry will directly benefit from the increased scientific understanding and developments concerning interfacing the artificial with the residual biological elements. In particular, our project partner Blatchford, the UK's No.1 prosthetics company and our industrial project partner, view the fundamental research from this project as key to unlocking the future potential of prosthetics. Blatchford currently provide over 30% of all NHS prosthetic and orthotics services and also run the MOD clinic at Headley Court.
This research will contribute to UK society and economy by benefitting the medical device industry, healthcare providers, medical professionals and patients. The resultant impact addresses the national priority areas of rehabilitation by facilitating superior forms of prostheses integration and performance. It will impact in a multitude of diverse ways by enhancing quality of life and health, raising the effectiveness of healthcare services and increasing economic competitiveness both directly, through device industry, and indirectly by allowing patients to more fully engage in occupational and social activity. Medium term benefits will be evident to those involved in the target areas of orthopaedics and rehabilitation, long term benefits will apply more broadly. Specific groups will include:
- Patients - Approximately 5000-6000 limb amputations occur in the UK every year, and an estimated 1 million globally which equates to one case every 30 seconds. Patients experiencing limb-loss or deficiency will be primary beneficiaries through increased function and capability, and resulting enhanced quality of life and health. Indirect economic advantages include a reduced tax burden, increased working capacity, less time off work and reduced travel to and from hospital.
- A wider range of medical conditions can also potentially benefit through the ability to create living tissue neural interfaces that can support the bidirectional flow of signalling between the body and external electrical mechanical and sensory devices. The ability to route signals in and out of the bodies neural networks or bypass damaged and severed nerve areas will open up new avenues for treatments and research. Potential conditions could include retinal eye implants, paraplegics, motor neuron disease, or other neurological disorders. Animal testing may be reduced by providing new methods to study neural interfaces.
- Healthcare Providers - our national health service will benefit economically from greater efficiency and reduced treatment costs helping them to meet the populations' growing expectations within ever tighter financial constraints. Surgical and clinical revision rates could be reduced. A significant current issue in prostheses, namely volume loss and muscle atrophy, may be reduced or eliminated due to the integration and utilisation of residual function. This can be an ongoing issue for prosthesis users, and results in significant further treatment and revision.
- Prosthetics industry will directly benefit from the increased scientific understanding and developments concerning interfacing the artificial with the residual biological elements. In particular, our project partner Blatchford, the UK's No.1 prosthetics company and our industrial project partner, view the fundamental research from this project as key to unlocking the future potential of prosthetics. Blatchford currently provide over 30% of all NHS prosthetic and orthotics services and also run the MOD clinic at Headley Court.
Organisations
Publications
Wilkinson NJ
(2019)
Aerosol Jet Printing for the Manufacture of Soft Robotic Devices
Wilkinson NJ
(2019)
A Review of Aerosol Jet Printing - A Non-Traditional Hybrid Process for Micro Manufacturing
in The International Journal of Advanced Manufacturing Technology
Wilkinson N
(2020)
Electrohydrodynamic and Aerosol Jet Printing for the Copatterning of Polydimethylsiloxane and Graphene Platelet Inks
in Advanced Materials Technologies
Wilkinson N
(2019)
A review of aerosol jet printing-a non-traditional hybrid process for micro-manufacturing
in The International Journal of Advanced Manufacturing Technology
Smith MAA
(2018)
Digitally-Driven Micro Surface Patterning by Hybrid Manufacturing
Smith MAA
(2023)
A digitally driven manufacturing process for high resolution patterning of cell formations.
in Biomedical microdevices
Smith M.A.A.
(2020)
Digitally-driven micro surface patterning by hybrid manufacturing
in Solid Freeform Fabrication 2018: Proceedings of the 29th Annual International Solid Freeform Fabrication Symposium - An Additive Manufacturing Conference, SFF 2018
Rimington RP
(2021)
Bioengineered model of the human motor unit with physiologically functional neuromuscular junctions.
in Scientific reports
Rimington RP
(2018)
Feasibility and Biocompatibility of 3D-Printed Photopolymerized and Laser Sintered Polymers for Neuronal, Myogenic, and Hepatic Cell Types.
in Macromolecular bioscience
Rimington RP
(2017)
Biocompatible 3D printed polymers via fused deposition modelling direct C2C12 cellular phenotype in vitro.
in Lab on a chip
Description | Through this award we have created and engineered a unique lab-based fabrication system that permits the digitally-driven manufacture of micro-scale geometrical and topographical feature deposition to create attractant and non-attractant patterns. This is now being further investigated and developed for the creation of devices for the possible treatment of cancer. |
Exploitation Route | The unique manufacturing process elements are being further researched and expanded upon for wider high-value applications including cancer treatments |
Sectors | Healthcare Manufacturing including Industrial Biotechology Pharmaceuticals and Medical Biotechnology |
Description | Our work and it's impact has been recognised through a number of invited activities. These include: - A opening talk (invited) at the Royal Society for Medicine. - A opening talk (invited) at the Henry Moore Institute. This was a weekend event open to the public and provided a culmination of a 3 month exhibit on prosthetics. - The Principal Investigator has spent a week (invited) in clinical departments. - An invited talk at the IPSO Trent Prosthetics conference. - A keynote presentation role of Senior Mentor at the Newton Fund & British Council's 'Digital Hospital' workshop in Peru. - An invited presentation and meeting with Bosch. - An invited presentation for the Henry Royce Institute - The manufacturing technology concerned has continued its development, including applications for soft robotics, surgical devices, diagnosis platforms, and maxillofacial prosthetics. |
First Year Of Impact | 2016 |
Sector | Healthcare,Manufacturing, including Industrial Biotechology,Culture, Heritage, Museums and Collections |
Impact Types | Cultural Societal Economic |
Description | A Platform for Hybrid Manufacturing Process research |
Amount | £1,675,630 (GBP) |
Funding ID | EP/P027687/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 06/2017 |
End | 06/2023 |
Description | New minimally invasive technologies for the treatment of pancreatic cancer |
Amount | £1,522,147 (GBP) |
Funding ID | EP/V009818/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 04/2021 |
End | 04/2024 |
Description | Towards a 'toothbrush' sensor for passive biomarker monitoring - "Sens Or Pass" |
Amount | £229,136 (GBP) |
Organisation | Cancer Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 06/2022 |
End | 01/2024 |
Title | Supplementary information files for Leucine elicits myotube hypertrophy and enhances maximal contractile force in tissue engineered skeletal muscle in vitro |
Description | Supplementary information files for Leucine elicits myotube hypertrophy and enhances maximal contractile force in tissue engineered skeletal muscle in vitro.
The amino acid leucine is thought to be important for skeletal muscle growth by virtue of its ability to acutely activate mTORC1 and enhance muscle protein synthesis, yet little data exist regarding its impact on skeletal muscle size and its ability to produce force. We utilized a tissue engineering approach in order to test whether supplementing culture medium with leucine could enhance mTORC1 signaling, myotube growth, and muscle function. Phosphorylation of the mTORC1 target proteins 4EBP-1 and rpS6 and myotube hypertrophy appeared to occur in a dose dependent manner, with 5 and 20 mM of leucine inducing similar effects, which were greater than those seen with 1 mM. Maximal contractile force was also elevated with leucine supplementation; however, although this did not appear to be enhanced with increasing leucine doses, this effect was completely ablated by co-incubation with the mTOR inhibitor rapamycin, showing that the augmented force production in the presence of leucine was mTOR sensitive. Finally, by using electrical stimulation to induce chronic (24 hr) contraction of engineered skeletal muscle constructs, we were able to show that the effects of leucine and muscle contraction are additive, since the two stimuli had cumulative effects on maximal contractile force production. These results extend our current knowledge of the efficacy of leucine as an anabolic nutritional aid showing for the first time that leucine supplementation may augment skeletal muscle functional capacity, and furthermore validates the use of engineered skeletal muscle for highly-controlled investigations into nutritional regulation of muscle physiology. |
Type Of Material | Database/Collection of data |
Year Produced | 2017 |
Provided To Others? | Yes |
URL | https://repository.lboro.ac.uk/articles/dataset/Supplementary_information_files_for_Leucine_elicits_... |
Title | Supplementary information files for: Bioengineered model of the human motor unit with physiologically functional neuromuscular junctions |
Description | Supplementary files for article: Bioengineered model of the human motor unit with physiologically functional neuromuscular junctions.Investigations of the human neuromuscular junction (NMJ) have predominately utilised experimental animals, model organisms, or monolayer cell cultures that fail to represent the physiological complexity of the synapse. Consequently, there remains a paucity of data regarding the development of the human NMJ and a lack of systems that enable investigation of the motor unit. This work addresses this need, providing the methodologies to bioengineer 3D models of the human motor unit. Spheroid culture of iPSC derived motor neuron progenitors augmented the transcription of OLIG2, ISLET1 and SMI32 motor neuron mRNAs ~ 400, ~ 150 and ~ 200-fold respectively compared to monolayer equivalents. Axon projections of adhered spheroids exceeded 1000 µm in monolayer, with transcription of SMI32 and VACHT mRNAs further enhanced by addition to 3D extracellular matrices in a type I collagen concentration dependent manner. Bioengineered skeletal muscles produced functional tetanic and twitch profiles, demonstrated increased acetylcholine receptor (AChR) clustering and transcription of MUSK and LRP4 mRNAs, indicating enhanced organisation of the post-synaptic membrane. The number of motor neuron spheroids, or motor pool, required to functionally innervate 3D muscle tissues was then determined, generating functional human NMJs that evidence pre- and post-synaptic membrane and motor nerve axon co-localisation. Spontaneous firing was significantly elevated in 3D motor units, confirmed to be driven by the motor nerve via antagonistic inhibition of the AChR. Functional analysis outlined decreased time to peak twitch and half relaxation times, indicating enhanced physiology of excitation contraction coupling in innervated motor units. Our findings provide the methods to maximise the maturity of both iPSC motor neurons and primary human skeletal muscle, utilising cell type specific extracellular matrices and developmental timelines to bioengineer the human motor unit for the study of neuromuscular junction physiology. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://repository.lboro.ac.uk/articles/dataset/Supplementary_information_files_for_Bioengineered_mo... |
Title | Supplementary information files for: Bioengineered model of the human motor unit with physiologically functional neuromuscular junctions |
Description | Supplementary files for article: Bioengineered model of the human motor unit with physiologically functional neuromuscular junctions.Investigations of the human neuromuscular junction (NMJ) have predominately utilised experimental animals, model organisms, or monolayer cell cultures that fail to represent the physiological complexity of the synapse. Consequently, there remains a paucity of data regarding the development of the human NMJ and a lack of systems that enable investigation of the motor unit. This work addresses this need, providing the methodologies to bioengineer 3D models of the human motor unit. Spheroid culture of iPSC derived motor neuron progenitors augmented the transcription of OLIG2, ISLET1 and SMI32 motor neuron mRNAs ~ 400, ~ 150 and ~ 200-fold respectively compared to monolayer equivalents. Axon projections of adhered spheroids exceeded 1000 µm in monolayer, with transcription of SMI32 and VACHT mRNAs further enhanced by addition to 3D extracellular matrices in a type I collagen concentration dependent manner. Bioengineered skeletal muscles produced functional tetanic and twitch profiles, demonstrated increased acetylcholine receptor (AChR) clustering and transcription of MUSK and LRP4 mRNAs, indicating enhanced organisation of the post-synaptic membrane. The number of motor neuron spheroids, or motor pool, required to functionally innervate 3D muscle tissues was then determined, generating functional human NMJs that evidence pre- and post-synaptic membrane and motor nerve axon co-localisation. Spontaneous firing was significantly elevated in 3D motor units, confirmed to be driven by the motor nerve via antagonistic inhibition of the AChR. Functional analysis outlined decreased time to peak twitch and half relaxation times, indicating enhanced physiology of excitation contraction coupling in innervated motor units. Our findings provide the methods to maximise the maturity of both iPSC motor neurons and primary human skeletal muscle, utilising cell type specific extracellular matrices and developmental timelines to bioengineer the human motor unit for the study of neuromuscular junction physiology. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://repository.lboro.ac.uk/articles/dataset/Supplementary_information_files_for_Bioengineered_mo... |
Description | An invited talk for the EPSRC Centre for Doctoral Training |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | An invited talk to the cohort of researchers in the EPSRC Centre for Doctoral Training describing some of our research in new manufacturing processes. Conducted 15 March 2017. |
Year(s) Of Engagement Activity | 2017 |
Description | Henry Moore institute - Opening talk at public discussion on Prosthetics |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | As part of the part of the Henry Moore Institute's event of 'The Body Extended: Sculpture and Prosthetics' (https://www.henry-moore.org/whats-on/2016/07/21/the-body-extended-sculpture-and-prosthetics) I provided the opening talk at the public event of '3DMe: Dialogues about prosthetic extensions, perceptions and representations' on Saturday 22nd October |
Year(s) Of Engagement Activity | 2016 |
URL | https://www.henry-moore.org/whats-on/2016/07/21/the-body-extended-sculpture-and-prosthetics |
Description | Industry engagement event at Blatchford (world leading rehabilitation provider with clinical expertise in prosthetics, orthotics, special seating and wheelchairs) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | Professor Harris and Dr Kay visited Blatchford on 14th February 2018 to present their research in new manufacturing processes to management and engineering teams. This resulted in questions and discussion regarding how this related to current, emerging, and future devices for rehabilitation. |
Year(s) Of Engagement Activity | 2018 |
Description | Invited presentation to a EPSRC programme grant project meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Other audiences |
Results and Impact | I was invited to make a presentation on our research in new manufacturing processes to a large of researchers working on miniaturised ingestible devices in the EPSRC programme grant EP/K034537/1 / EP/K034537/2. Conducted 12th October 2017. |
Year(s) Of Engagement Activity | 2017 |
Description | Invited speaker at Henry Royce Institute |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Invited speaker at the Henry Royce Institute for their Biomedical Materials Showcase: Biofabrication and 3D Printing for Biomedical Applications, 30 November 2021 |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.royce.ac.uk/events/showcase-biofabrication-3d-printing/ |
Description | Invited talk at Italian Institute of Technology |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Russell Harris gave a invited talk at the Italian Institute of Technology entitled 'Digitally-driven manufacturing processes for healthcare' |
Year(s) Of Engagement Activity | 2022 |
Description | Invited talks at Max Planck Institute for Intelligent Systems |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Prof Harris was invited to present his manufacturing research at the Max Planck Institute for Intelligent Systems in Stuttgart Germany. This was followed by a tour of the Institute to meet their researchers and view their extensive portfolio of research projects. The next day Prof Harris presented to their community of around 200 PhD researchers at their annual retreat in Michelsberg. |
Year(s) Of Engagement Activity | 2019 |
URL | https://future-manufacturing-processes.leeds.ac.uk/news/invited-talks-at-max-planck-institute-for-in... |
Description | Invited visit and presentation at Bosch Research Campus |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Prof Harris, along with his colleague Prof Valdastri (https://www.stormlabuk.com), were invited to visit Bosch at their new research campus in Renningen. They presented their shared vision across Manufacturing Processes and Robotics with Bosch's senior research leaders. This included illustrating our recent research projects and discussing where there may be avenues to mutually build new innovations around this. The new facility at Renningen is an outstanding environment where industrial research and innovation may flourish. More details can be found here https://www.bosch-presse.de/pressportal/de/en/research-campus-in-renningen-176321.html |
Year(s) Of Engagement Activity | 2019 |
URL | https://future-manufacturing-processes.leeds.ac.uk/news/invited-visit-to-bosch-research-campus/ |
Description | Presenter and Senior Mentor at Newton Funds event 'Digital Hospitals' in Peru |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | In June 2019, Professor Harris was invited to act as a senior mentor at a digital manufacturing and medicine event in Peru entitled "Digital Hospitals". The four day event provided UK and Peru based researchers with an opportunity for unique dialogue, training and debate about the use of novel digital design and manufacturing techniques across several healthcare areas. Specialists from various UK educational and Peruvian institutions were invited to present their respective research, and show how their manufacturing innovations can benefit global healthcare. Prof Harris said 'I was impressed by the research that I saw being conducted in Peru. It also allowed me to recognise some of the unique challenges they face as a region in medical and manufacturing technologies. I hope that we may be able to form further collaborative activities to assist one another and widen the impact of these technology fields'. More details can be found in the local language at https://puntoedu.pucp.edu.pe/noticias/medicina-de-vanguardia/ |
Year(s) Of Engagement Activity | 2019 |
URL | https://future-manufacturing-processes.leeds.ac.uk/news/invited-specialist-at-digital-hospitals-even... |
Description | RAEng Research Day talk |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | Invited talk on Hybrid Manufacturing at Royal Academy of Engineering Research Day |
Year(s) Of Engagement Activity | 2017 |
Description | Research demonstration for visit of EPSRC Healthcare Technologies team and SAT |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Supporters |
Results and Impact | Research demonstration for visit of EPSRC Healthcare Technologies team and SAT |
Year(s) Of Engagement Activity | 2022 |
Description | Russell Harris invited talk at TIPS/ISPO/BACPAR 2019 in Manchester |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Prof Harris was invited to speak at the TIPS/ISPO/BACPAR 2019 at the Lowry, in Manchester. This event covers topics including rehabilitation medicine, research, practice, prosthetics, orthotics, engineering, physiotherapy, occupational therapy, neuroscience, assistive devices and technologies. The invitation reflects the growing recognition of the value of new manufacturing processes can make to these important applications. |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.ispo.org.uk/events-tipsispobacpar2019/ |