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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Barcelona-Estaje E (2021) You Talking to Me? Cadherin and Integrin Crosstalk in Biomaterial Design. in Advanced healthcare materials

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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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Bjørge IM (2020) Cell Behavior within Nanogrooved Sandwich Culture Systems. in Small (Weinheim an der Bergstrasse, Germany)

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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)

 
Description In the last 4 years, we have progressed significantly in the objectives of the grant towards the following achievements:

1. Development of a new microscope based on Raman spectroscopy that allows chemical characterisation of thick tissues (e.g. bone) without the need of chemical labelling

2. New materials that will be used as active bioinks in 3D printing applications, to develop in vitro models

3. Novel developments in in vitro tissue models, in particular the bone marrow, which will lead to understand diseases such as leukaemia and search for novel treatments

4. New materials to grow cardiomyocytes more efficiently, so that they maintain their natural electrical activity and so can be used in the future for regenerative medicine applications or models to test cardiotoxicity in vitro
Exploitation Route The outcomes will be taken forward by other research groups which will benefit from the fundamental knowledge generated and also by industry.
Sectors Healthcare,Manufacturing, including Industrial Biotechology

 
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. In addition, we have developed new hydrogels in collaboration with the company CellInk (Sweden). The development of the hydrogels was done both in their labs in Sweden and in Glasgow. We have just filed a patent (September 2021) and are currently negotiating licensing of the technology to the company.
First Year Of Impact 2020
Sector Healthcare
Impact Types Societal,Economic

 
Description (HEALIKICK) - A modular strategy for the repair of critical sized bone fractures
Amount € 5,243,536 (EUR)
Funding ID 874889 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 05/2020 
End 05/2025
 
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 Elasticity Spectra as a Tool to Investigate Actin Cortex Mechanics 
Description  
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? Yes  
URL http://researchdata.gla.ac.uk/id/eprint/1033
 
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 Nanotopography reveals metabolites that maintain the immunomodulatory phenotype of mesenchymal stromal cells during large-scale expansion 
Description  
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? Yes  
URL http://researchdata.gla.ac.uk/id/eprint/973
 
Title Nanovibrational Stimulation of Mesenchymal Stem Cells Induces Therapeutic Reactive Oxygen Species and Inflammation for Three- Dimensional Bone Tissue Engineering 
Description  
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? Yes  
URL http://researchdata.gla.ac.uk/id/eprint/1037
 
Title Nanovibrational mesenchymal stem cell stimulation allows detection of highly osteo-specific bioactive metabolites that can be modified for enhanced potency 
Description Interest in bioactive, or activity, metabolites is growing. For adult stem cells in particular, the ability to target desired phenotypes with specificity and potency is important for provision of cellular therapies and also for drug discovery for tissue regeneration. Metabolomics provides a powerful tool for the discovery of bioactive metabolites, but bioinformatic pipelines are hindered by the quality of the input signal that drives the process being studied. For example, with mesenchymal stem cell (MSC) differentiation to bone forming osteoblasts, dexamethasone and bone morphogenetic protein 2 are commonly used stimuli in the lab and in clinic respectively. However, both can result in the artefactual production of adipocytes as well as osteoblasts and this could confound bioactive metabolite identification. Here, we use nanovibrational stimulation of MSCs to promote osteogenesis without adipogenesis and show that this can be used to identify bioactive metabolites with high osteogenic specificity. Further, these metabolites can have their structure-function relationship examined to provide both specificity and enhanced potency as we illustrate within this new work. 
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? Yes  
URL http://researchdata.gla.ac.uk/id/eprint/952
 
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  
 
Title Composition for 3D tissue culture 
Description A new family of hydrogels to be used as bioinks. These are functional bioinks that incorporate extracellular matrix proteins in synthetic hydrogels. 
IP Reference GB 2113077.8 
Protection Patent application published
Year Protection Granted 2021
Licensed No
Impact We are curently negotiating licensing of the patent to CellInk