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

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.

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.