Engineering growth factor microenvironments - a new therapeutic paradigm for regenerative medicine

Lead Research Organisation: University of Glasgow
Department Name: School of Engineering

Abstract

Growth factors are molecules within our body that participate in many physiological process that are key during development as they control stem cell function. These molecules thus have the potential to drive the regeneration of tissues in a broad range of medical conditions, including in musculoskeletal (bone repair), haematological (bone marrow transplantation) and cardiovascular (infarction, heart attack) diseases. Growth factors are currently produced commercially and are used regularly in clinical applications. However, they are very power cell signalling molecules and dose is critical as balance between effect and safety has to be considered. To date the use of growth factors in regenerative medicine has been only partially successful and even controversial. The growth factors are rapidly broken down and cleared by the body. This makes prolonged delivery (as is required to effect repair) a problem and typically higher than wanted doses are administered to get around this. While their help in regeneration is undoubted, collateral side effects can be catastrophic e.g. tumour formation.
We have developed new technology that directly addresses these concerns as it uses materials (that can be topically implanted) to deliver low, but effective, growth factor doses; this programme is about the safe use of growth factors in clinical applications. This will not only reduce risks for patients who currently receive growth factor treatments, but will open up therapies that can include co-transplantation with stem cells to a wider range of patients as doctors would not have to keep these therapies back for cases of most pressing need. This increased use would minimise costs as growth factors are very expensive and reduced dose would save money per treatment.

Our approach is unique and this programme grant will allow us to enhance the UK's world leading position through innovative bioengineering. We know that stem cells have huge regenerative potential and that growth factors provide exquisite stem cell control - both are currently untapped. We will engineer new materials to enable growth factor technology, and critically stem cell technologies, where traditional approaches are falling very short of the mark.

Planned Impact

Laboratory
We will produce a range of new techniques, tools and technologies that will find broad application in laboratories. This will include:
-Novel cell culture platforms specifically designed around the needs to stem cells rather than fastidious cells. A dynamic phenotype is important for the use of stem cells. However, in culture this results in a rapid loss of stem cell phenotype and presents scale up challenges for autologous therapies.
- Our precision measurement and sensing research will enable non-invasive, label free approaches.

Industry/Pharma
The potential for growth factor (GF) driven regeneration in clinic is massive. However, it is currently limited due to lack of ability to administer these powerful drugs with efficiency and safety. Despite safety concerns, products are still widely used and the market still flourishes. If safety concerns can be addressed and efficiency of action increased, the market would clearly expand from a >£1B market to a multi-£B market. We identify SMEs/stake holders within each of our grand challenges: musculoskeletal (Taragenyx, Locate Therapeutics, Nanokick), haematology (SNBTS) and cardiovascular (Clyde Bioscences) and we have the Senior Director of Johnson & Johnson Medical Device Innovation as an advisor. These partners will help us to realise this market potential.
Further:
- Our ability to control stem cells will go beyond laboratory and find use in biotechnology for industrial scale stem cell expansion.
- Our 3D environments will find use in drug screening and gene therapies coming out of the Pharma sector. This will be replace much expensive animal testing allowing a cheaper Pharma workflow through selection of better drug leads for animal testing.
- Building in vivo sensors/ clinical sensors for diagnostics, toxicology and delivery visualisation.

Health Service Providers
Our strategy involves dramatic reduction of the GF dose (~ 500 times) which will increases cost-effectiveness of these very expensive signalling molecules (e.g. BMP treatment, which can cost up to £3k per patient). This new technology will dramatically reduce the cost of these therapies and this will facilitate the larger range of conditions that GFs can be used in as we address safety issues. It will further open up new delivery systems for prolonged administration saving further surgical procedures and we will also aim to discover other, cheaper, drugs (metabolites) that can further reduce growth factors costs through synergistic action.

Patients
The research will have clear impact on patients. It will remove safety issues from growth factor use and will thus increase the range of conditions growth factors can be used in. Further, the public now expect stem cell technologies to be made available but platforms for stem cell growth and delivery are not currently easily ready. We can deliver these platform technologies to facilitate wider uptake of stem cell treatments by health service providers through increasing quality of stem cell therapies and driving down costs. Further, our approaches are amenable to personalised/stratified approaches. Patients stem cells can be tested for optimal response to different growth factors on our surfaces and, indeed their own proteins and growth factors will be compatible with our technologies. Non invasive diagnostics and monitoring will also be developed.

Public
Our work will be of benefit to the general public, raising interest in science, educating about the challenges faced by researchers, increasing funding for research, increasing awareness of the burden of degenerative diseases in a broad range of fields e.g.: musculoskeletal, cardiovascular, blood related conditions. We inspire the next generation of scientists and clinicians to overcome the burden of disease in this area.

Policy
We will strive to ensure that bioengineering approaches are prioritised and ready the technology for clinical uptake.

Publications

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Al-Jarsha M (2018) Engineered Coatings for Titanium Implants To Present Ultralow Doses of BMP-7. in ACS biomaterials science & engineering

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Alba-Perez A (2020) Plasma polymerised nanoscale coatings of controlled thickness for efficient solid-phase presentation of growth factors. in Materials science & engineering. C, Materials for biological applications

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Ballester-Beltrán J (2017) Confined Sandwichlike Microenvironments Tune Myogenic Differentiation. in ACS biomaterials science & engineering

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Bennett M (2018) Molecular clutch drives cell response to surface viscosity. in Proceedings of the National Academy of Sciences of the United States of America

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Cheng ZA (2019) Nanoscale Coatings for Ultralow Dose BMP-2-Driven Regeneration of Critical-Sized Bone Defects. in Advanced science (Weinheim, Baden-Wurttemberg, Germany)

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Ciccone G (2020) What Caging Force Cells Feel in 3D Hydrogels: A Rheological Perspective. in Advanced healthcare materials

 
Description Using one of the technologies developed in this grant we have contributed to treat our first veterinary patient 'Eva the dog'. Eva is a giant Munsterlander whose leg was about to be amputated due to an accident. She developed a non-union bone defect. In collaboration with veterinary surgeons at the Small Animal Hospital at the University of Glasgow, we used new polymers to present BMP-2 efficiently. Eva has had a great impact in the veterinary community, we have now secured funding to perform a clinical trial. Eva has attracted significant media attention and her case was broadcasted intensively by the BBC and other channels. In addition, and with additional support form an ERC-PoC grant, we have now treated 11 veterinary cases successfully,. This has increased the impact of the technology. We expect to use this data to support a future human application of the technology
Sector Healthcare
Impact Types Societal

 
Title Confined sandwich-like microenvironments tune myogenic differentiation 
Description  
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
 
Title Control of cell behaviour through nanovibrational stimulation: nanokicking 
Description  
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
 
Title Functionalisation of PLLA with Polymer Brushes to Trigger the Assembly of Fibronectin into Nanonetworks 
Description The dataset contains data files with original raw data and their description. The dataset has been created to help anyone interested in the work carried out in the paper 'Functionalisation of PLLA with Polymer Brushes to Trigger the Assembly of Fibronectin into Nanonetworks' to view and understand the data. 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
 
Title The molecular clutch drives cell response to surface viscosity 
Description The dataset contains data files with original raw data and their description. The dataset has been created to help anyone interested in the work carried out in this paper to view and understand the data. 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
 
Title Zinc uptake promotes myoblast differentiation via Zip7 transporter and activation of Akt signalling transduction pathway 
Description Myogenic regeneration occurs through a chain of events beginning with the output of satellite cells from quiescent state, formation of competent myoblasts and later fusion and differentiation into myofibres. Traditionally, growth factors are used to stimulate muscle regeneration but this involves serious off-target effects, including alterations in cell homeostasis and cancer. In this work, we have studied the use of zinc to trigger myogenic differentiation. We show that zinc promotes myoblast proliferation, differentiation and maturation of myofibres. We demonstrate that this process occurs through the PI3K/Akt pathway, via zinc stimulation of transporter Zip7. Depletion of zinc transporter Zip7 by RNA interference shows reduction of both PI3K/Akt signalling and a significant reduction of multinucleated myofibres and myotubes development. Moreover, we show that mature myofibres, obtained through stimulation with high concentrations of zinc, accumulate zinc and so we hypothesise their function as zinc reservoirs into the cell. 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes