Engineering self-assembling silk hydrogels for the delivery of stem cells
Lead Research Organisation:
University of Strathclyde
Department Name: Inst of Pharmacy and Biomedical Sci
Abstract
Context of the research: Stroke is the number one cause of disability in the UK, with an estimated 150,000 new cases annually. Following the acute onset of stroke, lack of oxygen leads to massive neuronal cell death within minutes and progressive brain damage over the following hours and days. A therapeutic intervention that would retard or even halt stroke progression would benefit stroke survivors. In this context, stem cell-based therapies are currently being assessed in patients. However, delivering those cells safely and effectively to the area in the brain where they are needed most is challenging. There is the need to develop delivery systems that can place, retain, support and protect applied stem cells to maximise their therapeutic potential.
Aims and objectives: Ensuring that a delivery system can fulfil all these needs is not trivial and requires careful selection of the most suitable strategy. The overall aim is to develop a biopolymer solution that can be loaded with stem cells and injected into the stroked brain, which could subsequently transition into a gel that retains, supports and protects the applied stem cell load at the target site. The programme's two main objectives include: 1. Develop protocols that permit the biopolymer's triggered transition from a solution to a gel and to underpin this by robust sample characterisation. 2. Examine the biopolymer's ability to support and protect applied stem cells.
Potential applications and benefits: Achieving the vision of this proposal will have significant potential to contribute to the nation's health and wellbeing through the development of new, better and affordable stem cell delivery systems-a need that is currently unmet. Unlocking this potential through the provision of better delivery technologies has significant promise for substantial economic impact in the UK, from which a range of sectors and their key role in the economy will benefit, e.g. UK biotechnology industry research and development spending is approximately 780 million p.a. with around 1,000 manufacturers revenues of 8 billion p.a. and projected growth of 4.4% p.a.
Aims and objectives: Ensuring that a delivery system can fulfil all these needs is not trivial and requires careful selection of the most suitable strategy. The overall aim is to develop a biopolymer solution that can be loaded with stem cells and injected into the stroked brain, which could subsequently transition into a gel that retains, supports and protects the applied stem cell load at the target site. The programme's two main objectives include: 1. Develop protocols that permit the biopolymer's triggered transition from a solution to a gel and to underpin this by robust sample characterisation. 2. Examine the biopolymer's ability to support and protect applied stem cells.
Potential applications and benefits: Achieving the vision of this proposal will have significant potential to contribute to the nation's health and wellbeing through the development of new, better and affordable stem cell delivery systems-a need that is currently unmet. Unlocking this potential through the provision of better delivery technologies has significant promise for substantial economic impact in the UK, from which a range of sectors and their key role in the economy will benefit, e.g. UK biotechnology industry research and development spending is approximately 780 million p.a. with around 1,000 manufacturers revenues of 8 billion p.a. and projected growth of 4.4% p.a.
Planned Impact
Achieving the vision of this proposal will deliver economic benefits and impact companies in a range of sectors including the biotechnology and pharmaceutical industries. The programme also has substantial potential to contribute to the nation's health and wellbeing.
Economic Impact: The proposal has substantial potential to contribute to wealth creation through the exploitation and commercialisation of novel self-assembling hydrogels. In addition to the potential for spin-out formation or licensing opportunities, access to skills and know-how will contribute to increased opportunities for inward investment in biotechnology and pharmaceutical companies. This is based on a skilled talent base and advanced material processing and application capabilities.
Societal Impact: The proposal has substantial potential to deliver long term benefits to society through improvements in quality of life, health, international development and policy. The need for cell delivery systems is at a critical bottleneck in regard to tissue engineering and regenerative medicine-disciplines that are pivotal to advanced therapeutic strategies for an aging population. While this proposal focuses on developing a delivery method in the stroke setting, similar challenges apply to many other patient populations (e.g. myocardial infarct, macular degeneration). Within the lifecycle of this project, we will directly and immediately impact general society with our dissemination strategies and planned outreach and engagement activities (e.g. Glasgow Science Festival, the Explorathon). These activities are important for raising general awareness and educating the general public on the promise of tissue engineering and its underlying material science. In the long term, the application and adoption of the proposed technology has the potential to improve the nation's health.
The PI already has a track record of success within the industry (see track record), is mentored by Professor Gavin Halbert and has close links with the CMAC National Facility, which allows him to further refine his skill set to positively affect the economy and society.
Economic Impact: The proposal has substantial potential to contribute to wealth creation through the exploitation and commercialisation of novel self-assembling hydrogels. In addition to the potential for spin-out formation or licensing opportunities, access to skills and know-how will contribute to increased opportunities for inward investment in biotechnology and pharmaceutical companies. This is based on a skilled talent base and advanced material processing and application capabilities.
Societal Impact: The proposal has substantial potential to deliver long term benefits to society through improvements in quality of life, health, international development and policy. The need for cell delivery systems is at a critical bottleneck in regard to tissue engineering and regenerative medicine-disciplines that are pivotal to advanced therapeutic strategies for an aging population. While this proposal focuses on developing a delivery method in the stroke setting, similar challenges apply to many other patient populations (e.g. myocardial infarct, macular degeneration). Within the lifecycle of this project, we will directly and immediately impact general society with our dissemination strategies and planned outreach and engagement activities (e.g. Glasgow Science Festival, the Explorathon). These activities are important for raising general awareness and educating the general public on the promise of tissue engineering and its underlying material science. In the long term, the application and adoption of the proposed technology has the potential to improve the nation's health.
The PI already has a track record of success within the industry (see track record), is mentored by Professor Gavin Halbert and has close links with the CMAC National Facility, which allows him to further refine his skill set to positively affect the economy and society.
Publications
Gorenkova N
(2019)
In Vivo Evaluation of Engineered Self-Assembling Silk Fibroin Hydrogels after Intracerebral Injection in a Rat Stroke Model.
in ACS biomaterials science & engineering
Holland C
(2019)
The Biomedical Use of Silk: Past, Present, Future.
in Advanced healthcare materials
Phuagkhaopong S
(2021)
Silk Hydrogel Substrate Stress Relaxation Primes Mesenchymal Stem Cell Behavior in 2D.
in ACS applied materials & interfaces
Phuagkhaopong S
(2021)
Silk Hydrogel Substrate Stress Relaxation Primes Mesenchymal Stem Cell Behavior in 2D
Seib F
(2018)
Self-assembling Biomaterials
Seib F.P.
(2018)
Silk hydrogels for drug and cell delivery
Seib FP
(2018)
Reverse-engineered silk hydrogels for cell and drug delivery.
in Therapeutic delivery
Description | Context of the research: Stroke is the number one cause of disability in the UK, with an estimated 150,000 new cases annually. Following the acute onset of stroke, lack of oxygen leads to massive neuronal cell death within minutes and progressive brain damage over the following hours and days. A therapeutic intervention that would retard or even halt stroke progression would benefit stroke survivors. In this context, stem cell-based therapies are currently being assessed in patients. However, delivering those cells safely and effectively to the area in the brain where they are needed most is challenging. There is the need to develop delivery systems that can place, retain, support and protect applied stem cells to maximise their therapeutic potential. Aims and objectives: Ensuring that a delivery system can fulfil all these needs is not trivial and requires careful selection of the most suitable strategy. The overall aim is to develop gels that can be loaded with stem cells and injected into the stroked brain, supports and protects the applied stem cell load at the target site. Outcomes: We used energy to programme the transition of liquid silk to a stable gel. This method allowed us to fine tune the self-assembly process of silk gels to achieve space conformity in the absence of any silk gel swelling while supporting healthy cell growth. Embedded stem cells showed excellent health even after injection through a 30G needle, especially when the gels were in the pre-gelled state. Silk gels with physical characteristics matching brain tissue exhibited good space conformity in stroke brains. Next, the impact on stroke symptoms, interaction with the stroke scar, interference with the normal inflammatory response and cell growth in the lesion cavity were examined for several weeks. Self-assembling gels presented neither an overt stroke scar response nor adverse side effects. This study informs on an optimal stem cell gel matrix for minimally invasive application as a platform for targeting brain repair. The stroke model confirmed that self-assembling silk gels provide a favorable microenvironment as a future support matrix in the stroke cavity. |
Exploitation Route | This study informs on optimal MSC-hydrogel matrix conditions for minimally invasive application as a platform for future experiments targeting brain repair. Taken together, this study provides valuable information regarding the optimal MSC-hydrogel matrix combinations for future experimental studies targeting central nervous system repair. The in vivo stroke model confirmed that self-assembling silk fibroin hydrogels provide a favorable microenvironment as a future support matrix in the stroke cavity. There are an increasing number of other investigators now pursuing similar lines of research (reviewed in e.g. Michel Modo, Brain Research Bulletin 2019, 150 136-149). Our technology has attracted substantial attention by companies (e.g. NineSigma, Japan) looking for solution providers. In summary, our findings bode well for the use of this system as a matrix for therapeutic delivery. |
Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
Description | The full impact of this award will emerge over the next decade and is thus beyond the lifecycle of this grant. However, the academic outputs of this grant are promising; this has lead to additional IAA funding to catalyse impact. The importance of material - cell interactions is now being studied (funded by the Leverhulme Trust 2019). Economic: Achieving the vision of this proposal-to develop self-assembling hydrogels for the delivery of stem cells-will, in the long term (10 years), bring economic benefits across a range of sectors including pharmaceuticals and biotechnology. Improving stem cell delivery for therapeutic applications is a market that is expected to grow significantly over the next decade. Wealth creation will occur through the exploitation and commercialisation of novel, self-assembling hydrogels. In addition to the potential for spin-out formation or licensing opportunities, access to the relevant skills and know-how (short term) will contribute to increased opportunities for investment and economic growth. The creative work generated in this grant has captured the attention of companies seeking solution providers. Societal: The proposal has substantial potential to deliver long-term benefits to society through improvements in quality of life, health, international development and policy. We have delivered immediate impact through our public engagement activities showcasing our state-of-the-art research. This has not only raised awareness of hydrogels for advanced therapies, but also stroke in general (the primary cause of disability in the UK associated with a direct £1.7B NHS healthcare cost). |
First Year Of Impact | 2017 |
Sector | Education,Healthcare,Pharmaceuticals and Medical Biotechnology |
Impact Types | Societal,Economic |
Description | EPSRC Centre for Doctoral Training in Medical Devices & Health Technologies (1 PhD with Prof. Patricia Connolly) |
Amount | £75,000 (GBP) |
Organisation | Imperial College London |
Department | EPSRC Centres for Doctoral Training |
Sector | Academic/University |
Country | United Kingdom |
Start | 10/2018 |
End | 09/2021 |
Description | Engineered substrates for the isolation and expansion of mesenchymal stem cells |
Amount | £271,000 (GBP) |
Funding ID | RPG-2019-252 |
Organisation | The Leverhulme Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2020 |
End | 01/2023 |
Description | IAA EPSRC |
Amount | £10,000 (GBP) |
Organisation | University of Strathclyde |
Sector | Academic/University |
Country | United Kingdom |
Start | 07/2017 |
End | 06/2020 |
Description | Pauline Fitzpatrick Research Award Travel Grant for EPSRC DTC candidate William Brownlee |
Amount | £500 (GBP) |
Organisation | University of Strathclyde |
Sector | Academic/University |
Country | United Kingdom |
Start | 10/2017 |
End | 11/2017 |
Description | PhD Scholarship from the Office of the Civil Service Commission for Suttinee Phuagkhaopong |
Amount | £125,000 (GBP) |
Organisation | Government of Thailand |
Sector | Public |
Country | Thailand |
Start | 10/2018 |
End | 09/2021 |
Description | Travel grant from the Biochemistry Society for EPSRC DTC candidate William Brownlee |
Amount | £500 (GBP) |
Organisation | Biochemical Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 10/2017 |
End | 11/2017 |
Title | Data for: "Self-assembling silk hydrogels integrate with host tissue and support endogenous cell proliferation after a focal cerebral ischaemic stroke" |
Description | "Data include: 1) Prizm files (.pzfx) containing row data measurements and graphs , and 2) Pictures (as .jpg or .tiff) of brain tissue sections, cutted on microtome and mounted on slides and processed through histological and immunofluorescent staining (single channel or merged channels), or a pictures of a whole clear brain sections mounted on slides. Animal weight and neurological deficit data were expressed as means ± standard error of means (SEM), t-test, one-way ANOVA with Bonferroni post-hoc test and regression analysis for infarct vs. number of Ki67+ cells were done using Prism 6 (GraphPad). A P value of <.05 was considered significant. Haematoxylin and eosin staining was performed in order to detect the silk hydrogel graft in the cavity, as well as for lesion volume measurement. The whole brain images were used as guidance to lesion/graft localisation and were taken with Sumsung Galaxy Neo camera (CMOS 16.0 MP resolution, with f/1.9 aperture). All other immunofluorescent images (4x-40x) were captured and analysed using WinFluor V3.9.1 fluorescence imaging programme (Nikon Eclipse E600). Data access pending publication (data released 06/12/18)" |
Type Of Material | Database/Collection of data |
Year Produced | 2017 |
Provided To Others? | Yes |
Impact | . |
Title | Data for: Self-assembling silk hydrogels as a mesenchymal stem cell support matrix for stroke |
Description | Biomaterials such as silk which has self-assembling properties, is biocompatible and biodegradable show promise for improving stem cell delivery and retention for treatment of stroke. The present aims were to assess the capacity of self-assembling silk hydrogels to improve stem cell delivery in vitro and in an in vivo stroke model. Data formats: pzf Prism, Excel, images in JPJ and powerpoint |
Type Of Material | Database/Collection of data |
Year Produced | 2018 |
Provided To Others? | Yes |
Impact | Unknown |
Description | Partner HC |
Organisation | University of Strathclyde |
Department | Strathclyde Institute of Pharmacy & Biomedical Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | The award has fostered a bi-laternal partnership with Dr Hilary Carswell (University of Strathclyde). This award has strengthened the existing partnership between Seib and Carswell as evidenced by the joint supervision of the PhD candidate Osama Ibrahim working with self-assembling silk hydrogels for stem cell delivery to the stroked brain. |
Collaborator Contribution | This now provides the project with access to an international stroke expert as well as the expertise to perform experimental stroke studies in mice and rats. |
Impact | multi-disciplinary |
Start Year | 2016 |
Description | Partner MB |
Organisation | Technical University of Dresden |
Country | Germany |
Sector | Academic/University |
PI Contribution | Exploiting self-assembling silk hydrogels for human mesenchymal stem cells (MSC) delivery. Assessing performance of MSCs in these hydrogels. |
Collaborator Contribution | Provision of human mesenchymal stem cells |
Impact | Multi-disciplinary. Secondment of PI Seib at the University Hospital Dresden |
Start Year | 2016 |
Description | Partner WH |
Organisation | University of Aberdeen |
Department | Institute of Medical Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Training to reverse engineer silk and generate self-assembling silk hydrogels. Provision of materials to conduct experimental studies. |
Collaborator Contribution | Culture of primary (central nervous system) neuronal cells on/in self-assembling silk hydrogels. |
Impact | The collaboration is multi-disciplinary. This relationship has resulted in a secondment of Anna Varone (PhD candidate) in the Seib lab. |
Start Year | 2017 |
Description | BBC4 Radio Scotland |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Good Morning Scotland Sound Reel |
Year(s) Of Engagement Activity | 2017 |
Description | Explorathon 2016 (Glasgow Science Centre) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Table-top presentation targeting the 3 year to adult age group. This includes a visually stimulating display stand, interactive sections (e.g. silk in its different formats), "show and tell" pieces to engage the audience, silk cocoon painting for kids (and adults alike); see www.SeibLab.com for examples. These activities integrated results from the EPSRC project. This also included a TED-like talk. Overall, this provides fascinating examples of how an ancient material can potentially advance present and future therapies. |
Year(s) Of Engagement Activity | 2017 |
Description | Explorathon 2017 (Riverside Museum Glasgow) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Silk: An emerging high tech material for medical applications. Table-top presentation targeting the 3 year to adult age group. This includes a visually stimulating display stand, interactive sections (e.g. silk in its different formats), "show and tell" pieces to engage the audience, silk cocoon painting for kids (and adults alike); see www.SeibLab.com for examples. These activities integrated results from the EPSRC project. Overall, this provides fascinating examples of how an ancient material can potentially advance present and future therapies. |
Year(s) Of Engagement Activity | 2017 |
Description | Glasgow Science Festival |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Glasgow Science Festival |
Year(s) Of Engagement Activity | 2018 |
Description | Native Scientist Workshop at the Goethe- Institute Glasgow |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | We covered the basics of the biopolymer silk and its potential future use. |
Year(s) Of Engagement Activity | 2017 |
Description | Science Latest: Innovation (Glasgow Science Centre) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Glasgow Science Centre (>1,500 visitors). Table top presentation and media participation. |
Year(s) Of Engagement Activity | 2017 |
Description | University of Strathclyde Alumni Evening |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Alumni Evening |
Year(s) Of Engagement Activity | 2017 |