We research the interactions between materials, proteins and cells and look at strategies to engineer and control cell behaviour and stem cell differentiation.

Engineering the Cellular Microenvironment

Fibronectin fibrils on a poly(ethyl acrylate) surface. Image by Virginia Llopis-Hernandez

Cells produce and encounter rich environments around them, that help them perform their very diverse functions around the body. They use it as support and to regulate their dynamic behaviour. Engineering these cellular micro environments to promote regeneration or to model tissues in vitro, involves the design of complex systems that interact with cells in a variety of ways, mimicking what happens in living beings. We study and exploit interactions between material surfaces, synthetic biocompatible materials, natural and synthetic extracellular matrix (ECM) molecules and growth factors (GFs) to understand and control cell behaviour and tissue repair.
We are pioneering work in several strategies to modulate cell behaviour and to direct stem cell fate:
– Nanovibrational stimulation to promote stem cells to differentiate into osteoblasts, and development of the ‘Nanokick Bioreactor’ to prime stem cells in vitro.
– Synthetic material-driven fibronectin fibrillogenesis, and it’s use to enhance presentation of GFs in different tissue engineering platforms.
– Introduced the concept of living biointerfaces to interact and study cell biology. We use genetically modified non-pathogenic bacteria as an in vitro functional and dynamic interface with stem cells.

X-ray preop for surgery of a non-union fracture in a veterinary patient. The patient had already undergone two previous surgeries. Holes from previously used screws are visible. Image by William Marshall

Bone Regeneration
We work in therapeutic solutions to address clinical needs in bone regeneration. Our research relies in different but complementary strategies to guide stem cell differentiation into osteogenic precursors.

The Bone Marrow Niche
Bone marrow 
transplants, where heathy HSCs are delivered
 to a recipient with e.g., leukaemia, have been
successfully used for some time, but there are significant limitations. We work to towards polymer and hydrogel systems that allow controlled presentation of growth factors (GFs) to develop synthetic niches. These will enable understanding of MSC niche functions and ultimately allow one donor to reach multiple recipients. In addition, a reliable in vitro system permitting HSC self- renewal will be invaluable to achieve gene editing therapies that can potentially be used to correct hematopoietic diseases if HSC phenotype can be maintained during in vitro manipulation.

Regeneration in the Nervous System

Astrocytes growing through a 3D synthetic polymer hydrogel to form connections with each other. Stained for immunofluorescent microscopy in green for actin, blue for nuclei and red for GFAP, an astrocyte marker. Image by Mr Douglas Venters.

Recovery of function following peripheral nerve injury is sometimes slow and often incomplete. Outcomes could be improved by an increased understanding of the molecular biology of regeneration and by translation of experimental bioengineering strategies. Micropatterned structures are studied in our lab to regulate the rate and directionality of neurite regeneration, and their effect on mTOR gene expression, neurite outgrowth and glial migration.

Effects of Surface Topography
We study the use of nanoscale order and disorder on the surface of materials in contact with cells to stimulate human MSCs to produce bone mineral in vitro, in the absence of osteogenic supplements. MSCs respond to nanoscale surface features, with changes in cell growth and differentiation mediated by alterations in cell adhesion. The interaction of nano-topographical features with integrin receptors in the cells’ focal adhesions alters how the cells adhere to materials surfaces and defines cell fate through changes in both cell biochemistry and cell morphology.

In Vitro Models of Disease

Chronic myeloid leukaemia stem cells on collagen coated transwell membrane. Image by Caroline Busch and Benjamin Tuck

A major challenge to improve current cell culture systems as in vitro models, is to exploit the versatility of biology while keeping systems simple, cheap, robust and reproducible. We develop extracellular matrix mimics, that provide the essential characteristics of a natural ECM in its ability to direct and control cell behaviour, yet with minimal complexity.

Living Biointerfaces

Co-culture of human cells and L. lactic bacteria producing recombinant human ECM protein fragments. Image by Aleixandre Rodrigo-Navarro and Jake Hay

Cells interact with the extracellular environment through a highly dynamic process that comprises different spatiotemporal stimuli at different stages. Cells cultured in vitro are often a very poor representation of in vivo behaviours because of the static nature of the culture systems used in the lab. We have devised a new approach where we utilise genetically modified non-pathogenic bacteria as a functional and dynamic interface between biomaterials and stem cells. These living interfaces consist of engineered bacteria that dynamically express functional fragments, such as fragments of extracellular matrix proteins or growth factors, on their membrane and promote cell adhesion, signalling and differentiation.