Bioactive polysaccharide-based hydrogels for growth factors delivery during tissue repair.

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

Abstract

Pathological conditions, including non-union bone defects, skin lesions, neurological disorders and inflammatory processes during cancer development are growing in occurrence due to an aging population. These problems are debilitating, costly and current approaches have limited success in alleviating suffering. The controlled delivery of biological molecules, such as growth factors (GFs) - proteins that orchestrate our development and hold the capacity to stimulate cellular growth and differentiation and that could thus drive regeneration - could provide potent tissue engineering strategies to promote tissue development and repair. However, the soluble administration of these proteins usually implies their delivery at high doses, which produces undesired, potentially serious/fatal systemic effects limiting their clinical use. In this proposal we will develop a new hydrogel, based on the acemannan polysaccharide - main bioactive component from the inner leaves of Aloe Vera - that will act as a bioactive carrier for the efficient and local delivery of GFs for tissue engineering applications. As a hydrogel, this natural carrier will increase the retention of the GFs within the healing site for a sufficient period to allow cells to migrate, proliferate and differentiate. Moreover, the inherent biological activity of the carrier (e.g. anti-inflammatory properties, antiseptic functions and potential to promote vascularisation, stimulate osteogenic differentiation), together with the released GFs, will provide a synergistic effect that will allow ultra-low dose GF delivery, several orders of magnitude lower than the ones used in current clinical technologies. Thus, this strategy will significantly improve societal health by increasing regenerative potential while reducing the life-threatening issues and high cost associated with the use of high GF doses. Also, microcarriers will be generated for their easy injection into the body through minimally invasive surgery. To do so, a novel microfluidics technology will be used as an efficient tool to generate microcarriers at higher throughput than conventional technologies, which will allow us to easily scale the technology to meet high demand levels in clinical practice. Although this proposal will focus on GF delivery during processes of bone regeneration, this new bioactive carrier will provide a versatile platform of GFs delivery with the potential to be widely used for different biomedical applications.

Planned Impact

The motivation for our research is the improvement of people's health, by developing bioengineering strategies that can be translated into clinical solutions. Pathological conditions, including non-union bone defects, skin lesions, neurological disorders and inflammatory processes during cancer development are growing in occurrence due to an aging population. These problems are debilitating and costly, and current approaches have shown limited success in alleviating suffering. In the UK there are approximately 850000 new fractures each year. A rate of 5-10% are non-union fractures and the treatment associated to these kind of fractures costs the NHS between £7,000 and £79,000 per person. Moreover, we believe that the treatment of complex fractures is a stepping stone towards more demanding and prevalent conditions such as osteoporosis and bone tissue tumors, where these innovative therapeutic concepts could lead to new tissue reconstruction techniques, personalized diagnostic tools and clinically relevant disease models.

Controlled delivery of biological molecules, such as growth factors (GFs) - proteins that can stimulate cellular growth and induce cell specialization, driving tissue regeneration - could hold up potent tissue engineering strategies to promote tissue repair and regeneration, including non-union bone defects. However, the soluble administration of these proteins usually implies their delivery at high doses, which produces undesired, potentially serious and fatal systemic effects, limiting their clinical use.

In this project we will engineer a novel delivery platform based on acemannan, a polysaccharide extracted from Aloe Vera leaves that has inherent biological properties and that will act as a bioactive carrier for the efficient delivery of functional biological molecules for tissue engineering applications. In our project, low doses of GFs released to the site of injury, together with the bioactivity of the own carrier, will provide a synergistic effect that will reduce the high GF doses required with current technologies and that lead to undesired systemic effects.

The following impacts are expected from this project:

- Knowledge. Contribution to UK's leadership position in regenerative medicine, and foundation of novel and potentially profitable engineering solutions for new drug delivery therapies. In particular, the protein delivery platform developed in this project will be available to academic researchers with an interest to efficiently deliver biological molecules for tissue engineering applications. The outcomes of the project will be submitted high-impact academic journals and to international conferences. The availability of this system, once proven and published, will drive a network of collaborators to exploit the potential applications of the platform, maximizing the impact of the project.

- People. Researchers involved in the project will acquire new multidisciplinary skills in materials science, engineering and biology, will have the opportunity to engage with clinical and industrial communities, and will have the opportunity to improve their leadership skills by supervising PhD and masters students.

- Social. This project will build a working interface between the academic research community, clinicians and industry, towards the translation of the project's breakthrough technologies into tangible products and therapies for patients suffering bone fractures.

- Economic. With this project we will contribute to the economic competitiveness of the United Kingdom, through translation and commercialisation of scientific knowledge ultimately leading to new commercial treatments.
 
Description During this award, we have designed and developed new hydrogel systems based on synthetic and natural polymers combined with a natural polysaccharide, extracted from the Aloe Vera plant. This polysaccharide presents intrinsic immunomodulatory properties, resulting in bioactive carriers for efficient delivery of biological molecules and cells. The system provides a versatile platform with tunable physicochemical properties for the controlled delivery of growth factors and cells for various tissue engineering applications. It has demonstrated potential to enhance biological responses in vitro, including viability, proliferation and migration of different cell types. Additionally, it has shown potential to direct mesenchymal stem cell differentiation. We are currently working on the preparation of several manuscripts for the publication of these results.

This work has opened new research questions. In future research grants we will aim to investigate the signaling pathways that trigger the enhanced cell response observed in our bioactive hydrogel system. We have developed new protocols for the synthesis of these novel hydrogels, and we have started exploring various applications of the hydrogel platform in collaboration with other academic partners.

During this award, my team has gained a significant expertise in the design and synthesis of new hydrogels, as well as in a wide range of characterisation techniques.
Exploitation Route The findings from this award have enabled me to initiate new collaborations with national and international academic partners, expanding the applications of the system in the field of tissue engineering and regenerative medicine. This work has led to new research questions and the preliminary results obtained serve as the basis for current grants in preparation. Besides disseminating our results in national and international conferences, we have started discussions with clinicians, including the lead clinician of the Care of Burns in Scotland, the consultant plastic surgeon David McGill. Additionally, we have also started collaborations with industry, including Cell Guidance Systems, which has shown interest in using our hydrogel system as a carrier for their PODs technology.
Sectors Healthcare

Pharmaceuticals and Medical Biotechnology

 
Description During this award, we have designed and developed two new hydrogel systems based on synthetic and natural polymers combined with a natural polysaccharide, extracted from the Aloe Vera plant. This polysaccharide presents intrinsic immunomodulatory properties, resulting in bioactive carriers for efficient delivery of biological molecules and cells. The system provides a versatile platform with tunable physicochemical properties for the controlled delivery of growth factors and cells for various tissue engineering applications. It has demonstrated potential to enhance biological responses in vitro, including viability, proliferation and migration of different cell types. Additionally, it has shown potential to direct mesenchymal stem cell differentiation. We are currently working on the preparation of several manuscripts for the publication of these results. The findings from this award have enabled me to initiate new collaborations with academic partners at the Polytechnic University of Valencia (Spain), the University of Adelaide (Australia), the University of Strathclyde, and the University of Glasgow (UK), expanding the applications of the system in the field of tissue engineering and regenerative medicine. This work has led to new research questions and the preliminary results obtained serve as the basis for current grants in preparation. Besides disseminating our results in national and international conferences, we have started discussions with clinicians, including the lead clinician of the Care of Burns in Scotland, the consultant plastic surgeon David McGill. Additionally, we have also started collaborations with industry, including Cell Guidance Systems, which has shown interest in using our hydrogel system as a carrier for their PODs technology.
First Year Of Impact 2023
Sector Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Societal

 
Description College (ECR) Scholarship Application - Euan Urquhart
Amount £54,500 (GBP)
Funding ID Internal application Reference: 00855042 
Organisation University of Glasgow 
Sector Academic/University
Country United Kingdom
Start 09/2021 
End 03/2025
 
Description EPSRC DTP Scholarship 2023 - Zarina Issabekova
Amount £63,000 (GBP)
Funding ID Internal application Ref (from University of Glasgow): 01214389 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 09/2023 
End 03/2027
 
Description Bioactive hydrogels to promote vascularisation - with Dr. Patricia Rico 
Organisation Polytechnic University of Valencia
Country Spain 
Sector Academic/University 
PI Contribution Development and characterisation of the hydrogel system, and in vitro evaluation. We visited the collaborator's lab to conduct the in vivo vascularisation studies.
Collaborator Contribution Expertise in a model to assess the potential of our hydrogel system in promoting vascularisation. Provided access to all the resources needed to conduct the work during a placement in her lab.
Impact The results obtained from this study will be included in a manuscript currently under preparation, and will also serve as preliminary findings for the preparation of a joint grant proposal. Multidisciplinary collaboration: materials science and engineering, cell biology.
Start Year 2023
 
Description Bioactive hydrogels to promote wound healing - with Prof. Christina Bursill 
Organisation University of Adelaide
Country Australia 
Sector Academic/University 
PI Contribution We have developed a bioactive hydrogel system that promotes cell proliferation and migration. We will expand the application of the platform through this collaboration.
Collaborator Contribution Expertise in a wound healing mouse model to test the material system in vivo.
Impact Prof. Christina Bursill will host my PhD student during a placement in her lab. Multidisciplinary collaboration: materials science and engineering, cell biology.
Start Year 2024
 
Description Coagulative granular hydrogels for non-union bone fracture repair - With Dr. James Armstrong 
Organisation University of Bristol
Country United Kingdom 
Sector Academic/University 
PI Contribution In vivo characterisation of the material system by using a non-union radial bone defect model in mice.
Collaborator Contribution Development of the material system and in vitro characterisation.
Impact No outcomes yet, but we have recently submitted a project grant to Rosetrees Trust charity, which supports medical research. Multidisciplinary collaboration: Material science and engineering, cell biology
Start Year 2024
 
Description Development of new materials platforms to deliver growth factors - with Prof. Manuel Salmeron-Sanchez 
Organisation University of Glasgow
Country United Kingdom 
Sector Academic/University 
PI Contribution Development and characterisation of new hydrogels. In vitro and in vivo evaluation.
Collaborator Contribution Development and characterisation of new hydrogels.
Impact Publication of a review paper: DOI:10.1016/j.mtbio.2021.100098 Publication of three papers: DOI:10.1002/adfm.202010225, DOI: 10.1016/j.mtbio.2023.100641, DOI: 10.1002/adma.202310789 Multidisciplinary collaboration: Material science and engineering, cell biology
Start Year 2020
 
Description Development of new plant-based scaffolds for tissue engineering - with Profs. John Christie and Massimo Vassalli 
Organisation University of Glasgow
Country United Kingdom 
Sector Academic/University 
PI Contribution Expertise in characterisation techniques and biological evaluation of the scaffolds. Co-PI on a successful CDT proposal.
Collaborator Contribution Expertise in plant biology/Expertise in material characterisation. Co-PI on a successful CDT proposal.
Impact Co-PI on a successful CDT proposal. Co-supervision of a PhD student. Multidisciplinary collaboration: Material science and engineering, cell biology, plant biology.
Start Year 2021
 
Description Development of viscoelastic microgels for chondrogenic differentiation - with Dr. Marco Cantini 
Organisation University of Glasgow
Country United Kingdom 
Sector Academic/University 
PI Contribution Development of microgels with tuneable mechanical properties using droplet-based microfluidics.
Collaborator Contribution Design of the hydrogel formulations for the fine control of the mechanical properties.
Impact Co-supervision of a PhD student. Multidisciplinary collaboration: Material science and engineering, cell biology
Start Year 2022
 
Description Effect of a plant-derived polysaccharide on breast cancer cell response - with Prof. Delphine Gourdon 
Organisation University of Glasgow
Country United Kingdom 
Sector Academic/University 
PI Contribution Development of the material system, physicochemical and mechanical characterisation, and in vitro evaluation.
Collaborator Contribution Expertise in breast cancer research, mechanotransduction, and in vitro evaluation.
Impact Co-supervision of a PhD student. Multidisciplinary collaboration: Material science and engineering, cancer research, cell biology
Start Year 2022
 
Description Hydrogels incorporating a peptide platform to promote osteogenesis - with Dr. Carles Mas-Moruno 
Organisation Polytechnic University of Catalonia
Country Spain 
Sector Academic/University 
PI Contribution In vivo evaluation of the material system. Co-organisation of a symposium for the Materials Science and Engineering Congress.
Collaborator Contribution Development and characterisation of the material system and in vitro evaluation. Co-organisation of a symposium for the Materials Science and Engineering Congress.
Impact As a result of this collaboration, we organised a symposium in the Biomaterials section for the Materials Science and Engineering Congress. We are currently organising an article collection for the journal Frontiers in Biomaterials Science. Publication of a paper: DOI: 10.3389/fbioe.2023.1192436 Multidisciplinary collaboration: Material science and engineering, cell biology
Start Year 2020
 
Description Microgels as carriers for cellular therapies - with Dr. Peter Childs 
Organisation University of Strathclyde
Country United Kingdom 
Sector Academic/University 
PI Contribution We have developed a platform of microgels that act as cell carriers, and we are in charge of their synthesis and characterisation.
Collaborator Contribution Their cellular technology provides an application for our microgels as cell carriers.
Impact We are currently working on preliminary studies for a joint grant application. Multidisciplinary collaboration: materials science and engineering, cell biology.
Start Year 2023