Sol to scaffold: Novel hybrid formulations for 3D biofabrication of in vitro tissue models

Ricky Wildman (University of Nottingham) 4th supervisor.

Background
Degenerative skeletal diseases such as severe osteoporosis and osteoarthritis affect more than 200 million people worldwide. Current strategies of joint replacements leads to removal of cartilage and healthy bone tissue and have limited life so there is a need to move from tissue replacement to tissue regeneration.

Recent advances in bioprinting have made printing of complex 3D structures possible [1, 2]. Despite the advancements in 3D printing, a central hurdle remains to develop ink formulations (bioinks) with enhanced printability, high cell viability and of suitable mechanical strength for specific tissue growth [3]. In this project, soft-chemistry-bio-friendly processing conditions will be developed to synthesise a platform of novel organic-inorganic hybrid bioinks. These will then be 3D printed in the form of customised patient specific constructs containing appropriate cells and biomolecules for in vitro maturation into functional tissue to study complex diseases. They may also lead to implantable functional tissue precursors.

Hybrids consisting of organic and inorganic interpenetrating networks built-up from molecular precursors are highly versatile with properties better than the sum of their constituents [4-7]. Here, similar to bioactive glasses (implanted in >1.5 million people to date) the inorganic network of the hybrids will be silica-based therefore as well as increasing the stiffness of the gels, the silica is expected to provide a therapeutic benefit as in bioactive glasses [7]. However, unlike conventional bioactive glasses and hybrids which employ toxic reagents and harsh processing conditions, the proposed project aims to produce cell-friendly inks that could deliver a cargo of cells and biomolecules while printed allowing complex functional tissues to be produced.

Hypothesis
At present, hydrogels from natural biopolymers are predominantly used for 3D bioprinting. These have several limitations, in particular; batch-to-batch variation, low shape fidelity, limited strength and uncontrolled degradation [3] representing a significant bottle-neck in this research topic. This project will test the hypothesis that novel hybrid materials synthesised here will lead to step changes in 3D bioprinting of in vitro tissue mimics to study and better understand complex diseases.

Experimental Methods and Research Plan
In this project we propose to employ bottom-up soft-chemistry process to synthesise organic-inorganic hybrid bioinks using cell-friendly reagents which will then be 3D printed using jetting or extrusion methods. The specific objectives are to:
1) Employ sol-gel processing to synthesise organic-inorganic hybrid bioinks whose stiffness could be modulated through i) selection of polyol-modified-silanes and organic precursors, ii) their specific compositions and iii) chemical bonding for the different target tissues.
2) Bio-print these inks in a 3D structure optimised for the different tissues according to oxygen and nutrient diffusion requirements.
3) To perform in vitro cell culture to maturation into functional tissues such as bone and cartilage.

The materials and tissue constructs developed will be studied using the UK’s National facilities available in Harwell Campus, including the Lasers for Science Facility housed within the Research Complex as well as the Diamond Light Source.

Expected Outcomes and Impact
• The project will allow 3D printing of tissue engineered constructs that are currently not possible with biopolymers alone; through the development of a novel platform of organic-inorganic hybrid formulations.
• The project presents an opportunity to create a series of synthetic cell microenvironments (ECM-mimic) for 3D-cell culture and 3D-printing markets in drug development leading to market disturbing outcomes.
• This project would produce a significant step change in the careers of the researchers involved and also be adopted by several other research groups and industries leading to clinical use.

Person Specification
Applicants should have a strong background in biomaterials, and ideally a background in organic-inorganic chemistry. They should have a commitment to research in tissue engineering and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in biomedical sciences/engineering.