Bioengineering of pharma ready bone marrow models for cancer drug screening

Studentship strategic priority area:Biomaterials & Tissue Engineering. Keywords:HSCs, MSCs, niche, biomaterials

The therapeutic potential of stem cells is well known due to their properties of self-renewal and ability to become different types of cells in the body.The most successful application of stem cells has been the use of hematopoietic stem cells (HSCs) from the bone marrow in bone marrow transplants.However, the full potential of these cells cannot be exploited due to limited cell numbers.Expansion of these cells out of the body is therefore of great interest.Mesenchymal stem cells (MSCs) are another type of stem cell that reside in the bone marrow with immense therapeutic potential in tissue repair.These offer support to and regulate HSCs. Out with the body however, MSCs fail to adequately support and grow HSCs.This is believed to be due to lack of regulatory signals that are normally supplied to the HSCs and MSCs within the bone marrow microenvironment; termed the bone marrow niche.

Biomaterials have been of great interest in the field of tissue engineering to try and mimic aspects of the 3D environment of tissues.They can provide support for cell growth, allow the study of fundamental mechanisms, and provide drug screening models. Biomaterials can be either natural or synthetic polymers and can be modified/functionalized to present proteins or soluble factors to mimic different tissue environments.Their chemical, mechanical and topological properties can therefore be engineered and altered to help direct stem cell fate for a desired outcome or to promote cell maintenance/expansion.In our laboratories, recent work has demonstrated how MSCs can be maintained and supported using low stiffness collagen hydrogels on PEA coated surfaces functionalised with extracellular matrix protein fibronectin and growth factor BMP-2 out with the body to mimic aspects of the bone marrow niche. This 3D niche model could support MSC niche characteristics and promote maintenance of HSCs outside the body. In this new project, the student will aim to adapt and simplify this model to create a drug screening tool for cancer drugs. The student will aim to create an encapsulated biomaterial-based HSC supportive environment with the use of alginate microbeads from industrial partner Atelerix Ltd. Coupled with microfluidics and an appropriate biomaterial-based 3D niche environment, this could ultimately provide an easy to use off-the-shelf bone marrow model for drug screening. This can then be utilized as a predictive tool to assess cancer drug toxicity/side effects. This is important due to the lack of available in vitro screening models in this area.

The student will obtain lab-based skills in the generation and functionalisation of biomaterials and hydrogels for 3D cell culture. In addition, skills will be obtained in the culture of stem cells, flow cytometry, microscopy and microfluidics. In addition to lab-based skills training the student will join a thriving lab with links to both the clinic and industry. The student will receive world-class multidisciplinary training as part of their doctorate training programme which will equip them well in their future career paths. These multidisciplinary skills and training provided are therefore in line with the EPSRC strategy to invest in and promote alignments between academia and industry for innovative research and leadership training. In addition, this project highlights a new growth area for the application of biomaterial methods to provide off-the-shelf drug screening models. After all, this could be an important first step in the development of non-animal technologies. Finally, this project is in line with the research vision of 21st century products whereby it is possible that current and future advancements of biomaterial engineering could be what we need to invest in to push in vitro model development, 3D tissue engineering and the development of non-animal technologies forward.

Humanised, 3D tissue models are finding interest due to current overly-simplified immortal cell lines and non-human in vivo models providing poor prediction of drug safety, dosing and efficacy; 43% of drug fails are not predicted by traditional screening and move into phase I clinical trials1. Phase I sees a 48% success rate, phase II a 29% success rate and phase III a 67% success rate [1]. The drug development pipeline is pressurised due to adoption of high throughput screening / combinatorial libraries. However, while R&D spend has increased to meet this growing screening programme, success, measured by launched drugs, remains static [2]. This poor predictive power of the >1 million animals used in the UK each year drives the 12-15 year, £1.85B pipeline, for each new drug launch [3]. Contract research organisations (CROs) are also similarly hit by these problems.

Drive to reduce animal experimentation in toxicology and outright banning of animal testing for e.g. cosmetics in the UK has driven companies to outsource or to adopt the limited number of regulator approved NAT models for e.g. skin [4,5].

Another key area that uses 3D tissues is the field of advanced therapeutic medicinal products (ATMPs), i.e. tissue engineering/regenerative medicine. Regulation is a major ATMP bottleneck. It is thus noteworthy that regulators, such as the UKs Medicines and Healthcare Products Regulatory Agency (MHRA), are receptive to the inclusion of NAT-based data in investigative medicinal product dossiers [6].

The lifETIME CDT will directly address these issues through nurturing of a cohort training not only in the research skills required to conceive and design new NATs, but also in skills based on:

- GMP and manufacture.
- Commercialisation and entrepreneurship.
- Regulation.
- Drug discovery and toxicology - a focus on the end product.
- Policy.
- Public engagement.

Our NAT graduate community will impact on:

- Pharma - access to skills that develop tools to unlock their drug discovery and testing portfolios. By helping train graduates who can create and deploy NATs, they will increase efficiency of drug development pipelines.

- ATMP manufacturers - the same skills and tools used to deliver NAT innovation will help to deliver tissue engineered / combination product ATMPs.

- CROs - access to skills to create platform tools providing more sophisticated approaches to the diverse research challenges they face.

- Catapult Centres - access to skills that provide innovation that can be deployed across the broader healthcare sector.

- Regulatory agencies e.g. MHRA - better education for the next generation of scientists on development of investigational new drug / medicinal product dossiers to speedup approvals.

- Clinicians and NHS - access to more medicines more quickly through provision of highly skilled scientists, manufacturers and regulators. NATs will help drive the stratified/personalised medicine revolution and understand safety and efficacy parameters in human-relevant tissues. Clinicians will also benefit from development of ATMP-based regenerative medicine.

- Patients - benefit from skills for faster and more economically streamlined development of new medicines that will improve lifespan and healthspan.

- Public and Society - benefit from the economic growth of a thriving drug development industry. Benefits will be direct, via jobs creation and access to wider and more targeted healthcare products; and indirect, via increased economic benefit of patients returning to work and increased tax revenues, that in turn feed back into the healthcare systems.


[1]. Cook. Nat Rev Drug Discov 13, 419-431 (2014).
[2]. Pammolli. Nat Rev Drug Discov 10, 428-438 (2011).
[3]. DiMasi. Health Econ 47, 20-33 (2016).
[4]. Cotovio. Altern Lab Anim 33, 329-349 (2005).
[5]. Kandarova. Altern Lab Anim 33, 351-367 (2005).
[6]. https://goo.gl/i6xbmL