Professor Nikolaj Gadegaard
- Professor (Biomedical Engineering)
I graduated from Copenhagen University in 1998 with a BSc degree in chemistry and MSc in physics. After a brief position as research assistant at Risø National Laboratory in Denmark I continued my PhD studies in biophysics graduating in 2002. This was followed by a post doc in the Centre for Cell Engineering at the University of Glasgow. In 2003 I received a personal fellowship from the Royal Society of Edinburgh and was appointed lecturer in 2006, senior lecturer in 2010, reader in 2012 and professor in 2014. In 2013 I was visiting professor at University of California Santa Barbara.
I have published more than 120 papers in peer review journals, many of significant impact. Most notably is the work on the interplay between nanotopography and stem cells published in a series of papers in Nature Materials together with Prof. Matthew Dalby:
- The control of human mesenchymal cell differentiation using nanoscale symmetry and disorder
- Nanoscale surfaces for the long-term maintenance of mesenchymal stem cell phenotype and multipotency
- Harnessing nanotopography and integrin–matrix interactions to influence stem cell fate
My main research interest is surface engineering aimed at biological applications. This involves the design and fabrication of well-defined nanotopographies mainly using high-resolution electron beam lithography (EBL). The topography fabrication requires new methodologies for realising large area (>1 cm2) patterning with sub-100 nm features and pattern transfer technologies. I have developed new techniques for preparing well-defined nanostructured surfaces with dimensions as small as 30 nm and surfaces with different geometrical arrangements. Biological experiments require large number of samples which is realised through various pattern transfer technologies. For large volume pattern transfer I have been particularly interested in developing the possibilities of injection moulding for sub-100 nm surface features. Topographical analysis of fabricated surfaces is important and is carried out by combining high resolution electron microscopy and atomic force microscopy (AFM). I lead all fabrication activities of micro- and nanofabrication for cell and tissue engineering applications in the Centre for Cell Engineering.
Micro- and Nanofabrication, injection moulding, biomaterials, polymers, interface characterisation
McMurray, R.J., Gadegaard, N., Tsimbouri, P.M., Burgess, K.V., McNamara, L.E., Tare, R., Murawski, K., Kingham, E., Oreffo, R.O.C., and Dalby, M.J. (2011) Nanoscale surfaces for the long-term maintenance of mesenchymal stem cell phenotype and multipotency. Nature Materials, 10(8), pp. 637-644. (doi:10.1038/nmat3058)
Hendry, E., Carpy, T., Johnston, J., Popland, M., Mikhaylovskiy, R.V., Lapthorn, A., Kelly, S.M., Barron, L.D., Gadegaard, N., and Kadodwala, M. (2010) Ultrasensitive detection and characterization of biomolecules using superchiral fields. Nature Nanotechnology, 5(11), pp. 783-787. (doi:10.1038/nnano.2010.209)
Yang, J., Rose, F.R.A.J., Gadegaard, N., and Alexander, M. (2009) A high-throughput assay of cell-surface interactions using topographical and chemical gradients. Advanced Materials, 21(3), pp. 300-304. (doi:10.1002/adma.200801942)
Fleming, C., Long, D. L., McMillan, N., Johnston, J., Bovet, N., Dhanak, V., Gadegaard, N., Kogerler, P., Cronin, L., and Kadodwala, M. (2008) Reversible electron-transfer reactions within a nanoscale metal oxide cage mediated by metallic substrates. Nature Nanotechnology, 3(4), pp. 229-233. (doi:10.1038/nnano.2008.66)
FAKIR, ERC; 2015-2020
Synergistic microenvironments for non-union bone defects. UK Regenerative Medicine Platform (UKRMP) - MRC; 2014 - 2017
Mapping the mesoscale structural landscape using "sculpted" chiral plasmonic fields, EPSRC; 2016-2019
Biosensors and Diagnostics 4 (ENG4036) - Course coordinator
Scaffolds and Tissues M (ENG5282) - Course coordinator
Introduction to Research in Nanoscience and Nanotechnology (ENG5144)
Potential PhD projects
Development of a microfluidic probe for high-content single cell analysis
The golden standard in assessment of cellular function and state is by biochemical analysis such as qPCR, ELISA etc. Usually these measurements are based on whole cell populations of 1000s to 1000000s of cells. As there is a natural variance between cells, it is therefore of interest to analyse samples from smaller populations to single cells. As the analysis generally is acquired from a Petri dish or similar it is difficult to reduce the number of cells without reducing the concentration of the analysis too. However, with the use of a microfluidic probe, it is possible to sample directly in a Petri dish from a select population. Using this method it will be possible to sample from micro-array samples for higher throughput.
In this project you will develop a microfluidic probe platform based on an inverted microscope. This will involve the design of new probes and manipulation mechanics. Once assembled, it will be applied on a range of cell system to validate the process.
The project has partners at IBM Zurich.
Imaging Plasmonic Polarimetry
We have demonstrated the ability to measure the structure of biological molecules using nanopatterned surfaces with unique plasmonic properties. When these plasmonic surfaces are exposed to light, they generate optical activity which is highly sensitive to the surrounding environment. These fields are capable of detecting binding events to proteins and are also able to detect the structural nature of the proteins. We are now able to measure these changes using a reflective polarimeter. In this project the candidate will build and test an imaging system for superpolarimetry which will enable spatial detection from a patterned substrate. Once the instrument has been build it will be calibrated against more established methods and finally tested with known biological samples.
Developing a functional hepatic niche using nanopatterning and hepatic stem cells
Conventional hepatic culture models for drug discovery assays mostly use rodent primary hepatocytes or human immortalized cell lines, which rapidly lose polarity and phenotype and are not representative of normal liver tissue. These models often lack the functional repertoire of primary human hepatocytes (PHHs) including the ability to metabolize drugs (CYP450 activity). However, PHHs have a short culture life-span, exhibit phenotypic variability and instability in culture with intermittent supply and high unit costs. Hence alternative culture models are in great demand and a promising direction is the recent development of HepaRG cells. These are progenitors with the potential to differentiate into the different cell types found in the liver.
The aim of this project is to study the effect of micro- and nanopatterning on a hepatocyte stem cell line, HepaRG. These are human derived cells and are available in a proliferative and differentiated state, depending on what we would like to study. The cells will be cultured and imaged on the difference nanotopographies as well as novel mechanically compliant substrates and their size, density and shape measure together with P450 activity as well as other makers. These parameters will then be correlated with metabolic activity measured using mass spectrometry.
Nanopatterns identified to provide stable hepatocyte cultures will then be used to study the effect paracetamol toxity, another benchmarking compound. The impact on the cultures will be assessed is a similar manner as above. Successful patterns will then be taken forward to study influence on HepaRG cells.
Superresolution and correlative microscopy to study cell adhesion on nanopatterned substrates
As cells adhere to surfaces, they for focal adhesions which link the cells mechanically to their surroundings but also provide important signalling too. With the invention of superresolution microscopy it has become possible to study the proteins involved in these adhesions at a molecular level. The improvement in detail is typically 10 times with a resolution of about 20 nm.
At the same time semiconductor technologies have made it possible to control patterns with a precision similar to the size of the proteins. This opens up the possibilities to potentially manipulate the adhesions at a molecular level. These interactions can be visualised with a combination of superresolution and scanning electron microscopy, known as correlative microscopy.
In this project you will use advanced microscopy and genetically engineered cells to investigate the adhesion formation on a range of nanopatterned surfaces. The aim will be to correlate the formation of the focal adhesions with the design parameters with a view to produce engineered materials for regenerative medicine. This project is part of an ERC funded 5 year programme.
Measuring nanoNewton forces from cancer cells during metastasis
As cells migrate in the body, they exert force on their environment. The magnitude of such forces is in the nanoNewton range and can be measure in vitro (in a Petri dish) in various ways. One method is to have a bed of regularly spaced flexible pillars on which the cells are migrating. By tracking the movement of these pillars and knowing their mechanical properties it is possible to calculate direction and magnitude of forces the cells are exerting on the substrates. This is highly relevant for cancer cells during metastasis.
In this project, the aim is to manufacture such micropillars and study the forces from different cancer cell types. Here cells with varying degrees of malignancy will be measured and correlated to the forces measured. You will also construct a model for intravasation, mimicking the metastasis from the tumour, and measure the force as the cells “squeeze” through the endothelium.
Collaborators on the project are the Beatson Institute, Columbia University (New York) and the Mechanobiology Institute in Singapore.
Development of nanoscale mechanotaxis arrays for cell engineering
There is clear evidence that eukaryotic cells are influence by surface topography. Their response goes from the micrometer range, comparable to a single cell, down into the nanometer range. Over the past 10 years or more, we have demonstrated that highly ordered nanopatterns prepared by electron beam lithography profoundly influence cell adhesion, migration and proteome. More recently we discovered that bone marrow derived stem cells can be made to either differentiate to bone forming cells or retain multipotency in prolonged culture. This is driven by minute changes in the surface topography (<50 nm) and we have shown that the metabolic profiles for the cells on the different surfaces are distinctly different.
The aim of this project will be to develop new substrates with the emphasis on mechanical properties. It is well-known that the mechanical properties of the substrate on which stem cells are seeded will influence their fate. Where most work has been carried out on gels or elastomers, this project will develop a process whereby solid substrate can be manufactured to have similar mechanical properties at the surface.
The project will involve a close collaboration with Columbia University in New York City.
Advanced manufacturing of medical implants and devices
Injection moulding is the preferred technology used to make large quantities of plastic parts - often with complex shape and surface texture. One of the reasons behind the success of the injection moulding process is the speed of manufacture where parts can be made in seconds in a fully automatic process. This is driven by the rapid cooling of the injected polymer into the tool cavity. However, as the complexity of the parts increases, the process is challenged as the polymer may freeze too rapidly to take the shape or dimensions of the tool. As a means to compensate for the rapid cooling yet still benefitting from the automatic process variothermal injection moulding has been developed. Here the tooling is kept about the Tg (glass transition temperature) of the polymer which maintains the liquid state of the polymer. Once the tool is filled it is then cooled below Tg before the parts is removed. This adds additional processing time but enables the manufacture of complex parts.
This project will develop tooling technologies for faster mastering through the use of 3D printing and direct laser writing. The project will also develop variothermal heating on the injection moulding equipment available within the research group. This project will involve collaboration with several companies and international partners.