Novel proteomic-guided bioprinting strategies for osteochondral joint repair

The osteochondral (OC) tissue is composed of bone and cartilage zones displaying different compositional and functional properties. Bioprinting offers the possibility to generate constructs with embedded physiochemical gradients through precise 3D spatial deposition of different materials and cells. We know that biomimicry of the native ECM microenvironment is vital for the regulation of chondro- and osteogenic cell differentiation and have previously developed different acellular (polymeric and composite) and cellular (cell-laden hydrogels) constructs capable of supporting in vitro cell adhesion, proliferation and differentiation [1-2]. We have also established a printing methodology for the generation of hybrid scaffolds composed of a soft and stiff matrix and have published an efficient, reproducible 3-step protocol for generation of chondrocytes from hESCs [3-4] which we are extending to a 3D phase generating hard tissue pellets. Despite our data suggesting that stem cell differentiation is mainly governed by the mechanical and chemical composition of the ECM, very little is known about the proteome dynamics underpinning such processes [5]. Therefore, unveiling the proteomic expression of differentiating stem cells is not only important to obtain homogeneous chondro- and osteogenic cell populations, but also to modulate the physicochemical properties of bioprinted zonal implants.

Regenerative medicine aims to develop biomaterial and cell-based therapies that restore function to damaged tissues and organs. It is a priority of the University and the nation, and a central focus of the EPSRC challenge theme "Healthcare Technologies". It is also an MRC strategic priority, "Repair and replacement: to translate burgeoning knowledge in regenerative medicine into new treatment strategies". It is in recognition of the challenges associated with clinical translation of regenerative medicine that EPSRC, MRC, BBSRC and TSB jointly funded the £25m UK Regenerative Medicine Platform - UoM is a partner on all three funded national hubs: 'Engineering and exploiting the stem cell niche', 'Acellular technologies, 'Safety and efficacy'. Our Centre for Doctoral Training in Regenerative Medicine, and hub partnerships, will have major impact by delivering a cohort of highly training scientists and clinicians who can take regenerative medicine to the next level of therapeutic efficacy, and engage with these national hubs. This capability will enable the UK to retain its position as a world-leader in regenerative medicine.

Specific impacts include:

(i) Biomedical scientists, the UK regenerative medicine community and international colleagues
Major impact will be achieved by training our students in the scientific methods required to: understand how the microenvironment (niche) directs cells to remodel tissues; design (nano)materials that interact at a mechanical and biochemical level with cells and orient their behaviour; understand how inflammatory processes affect regeneration; translate this knowledge to patients.
Our students will have the outstanding opportunity of benefiting directly from, and contributing directly to all the national UK Regenerative Medicine Platform hubs.
Added value will be achieved through research collaborations and data/reagent sharing across the University of Manchester and the Manchester Academic Health Science Centre, nationally through the hubs, and internationally through our six world-leading doctoral centre partners.
The Centre's strong links with MIMIT (Manchester: Integrating Medicine and Innovative Technology; linked to CIMIT, Boston USA), which develops clinical solutions for tissue repair and related unmet clinical needs, and with the Manchester Collaborative Centre for inflammation Research, enable our students to develop new regenerative strategies that encompass inflammatory control.

(ii) Biopharma
The ability to direct the effective repair or regeneration of tissues is highly sought after by cell therapy/regenerative medicine/tissue engineering companies wishing to translate these discoveries to new therapeutic products, and to Biopharma to inform the design and delivery of niche-based biologics and MSC-based anti-inflammatory therapies. We have more than 30 industrial partners, attesting to the strength of our Centre plan.
Our students will be advised by the University of Manchester Intellectual Property (UMIP) in all aspects of commercialisation, e.g. selling/licensing of reagents, provision of research expertise, in-house assays/techniques, co-development of technologies or licensing of IP.

(iii) General Public
The Centre will be a powerful platform for the Centre students to inform the public about our regenerative medicine activities and therapeutic advances.
The students will write review articles for popular press and student science magazines; develop skills in communications and public engagement; participate in Manchester Science Week and internet fora; develop outreach materials to inform local, national and international audiences, and meet patient groups.