Capturing the Cell

 

Biological cells are the fundamental unit of life, and in many areas of biology and medicine it is essential to be able to study and manipulate them. Because of their tiny size, however, working with individual cells can be very challenging and so they are usually dealt with in very large numbers. But now, thanks to the efforts of Dr Maan Alkaisi, a research scientist at the University of Canterbury’s Department of Electrical and Computer Engineering and Principal Investigator of the MacDiarmid Institute, studying individual cells may become much easier.

Dr Alkaisi and his colleagues have been involved in the development of an innovative new technique for studying individual biological cells, known as ‘Biochip’. A Biochip consists of a silicon platform containing thousands of tiny cavities the exact size and shape of biological cells. Cells contained within the cavities can be examined and manipulated one at a time. “Biologists usually deal with thousands or even millions of cells and use statistical methods to study their response to different hormones or treatments,” says Dr Alkaisi. “I was wondering whether having the capability to deal with individual cells would help. It turns out that yes, it is helpful, especially if you treat individual cells and look at their response to various stimuli.”

Cells captured inside the Biochip cavities can be examined using atomic force microscope imaging – a technique with very high resolution, allowing biologists to look at the cell’s most intricate details. The atomic force microscope also has the advantage that it can image living cells in an aqueous environment, unlike the traditional electron microscope.

As well as capturing and holding cells, the Biochip also separates them according to their size or type. Using a phenomenon known as dielectrophoresis, biological cells are either attracted to or repelled from electrodes in the platform depending on the ion concentration in their membranes. Each cell has unique dielectric properties and if a cell either is responding to certain kinds of treatments or hormones or has been affected with a disease, the concentration of ions in their membrane changes. Therefore, the method has the potential to help in diagnosis of diseases, and in evaluating the effects of different treatments.

To make a Biochip, lithography is used to etch tiny cavities the sizes of typical biological cells on a silicon substrate patterned with micron sized inter-digitated gold electrodes. A high level of accuracy is needed to make such intricate structures, and the platforms are made with the help of a MA6 mask aligner acquired by the MacDiarmid Institute.

The project is in collaboration with fellow MacDiarmid Institute Principal Investigator, Professor John Evans, of the Christchurch School of Medicine, and to date the platform has been used for imaging pituitary cells from the pituitary gland, to help study fertility treatments. More applications are possible for the future. “Recently we started applying this technique for looking at cancer cells,” says Dr Alkaisi. “The ability to image individual cancer cells at very high resolution should help in early diagnosis. This possibility for early diagnosis of diseases is what really attracted me to this field.”

But this is not the end of the story for the potential of Biochip. “There is a new development that is even more exciting in this field,” says Dr Alkaisi. “When you bring people from biology, lithography and electronics together you will end up with something that’s really novel.”

That something is ‘bioImprint’, another new technique that Dr Alkaisi and his PhD student James Muys have developed. BioImprint uses the Biochip to make a replica of a biological cell. First, a cast of the biological cell is made, then the mould is filled. The result is a replica in exactly the same shape of the original cell, down to nanoscale details.

“The advantage of this technique is that we have a replica of a cell at each stage of its life,” Dr Alkaisi explained. “After subsequent treatments the cell membrane will change, and we can capture this change permanently. Then we can look at this replica using again the atomic force microscope or any other suitable imaging technique.”

At present, Dr Alkaisi is applying this technique to the study of cancer cells. “The topography of cancer cells is very important, and we can compare these to healthy cells, or we can compare cells that have just started to be infected with ones that have been affected for a long time,” he explained. “This will help in building a database for cell behaviour and response to different treatments and also in studying these events at early stages at an individual cell level.”

Another potential use of the bioImprint is for educational purposes. Because living cells continually change, it is not easy to obtain cells at different stages on cue, for example for laboratory classes. Using the bioImprint, exact replicas of cells could be made at different stages, which medical schools could use to show students during classes, without the need to have live cells. The method could also be useful for studying dangerous organisms, avoiding the need for contact with live viruses. “There are other applications that we are planning to investigate,” says Dr Alkaisi.

 

 

Left:  The BioChip concept: cells have become trapped within cavities by the dielectrophoresis effects induced through the interdigitated electrodes. The trapped cell can be scanned and analysed by the atomic force microscope tip.

 

BioImprint has recently been patented, and this idea has led a team of PhD students including James Muys and David Melville to be one of the finalists in ‘Nanochallenge’, an international business competition (see the relevant article in this issue). “We are very excited about this,” says Dr Alkaisi, “if our team wins this prize it will be a major achievement, but just being one of the finalists is something we are very happy about.”

As well as his own research, Dr Alkaisi has also recently established the MacDiarmid Institute’s ‘Bionanonetwork’, to coordinate the research activities in the field of bio-nanotechnology within the MacDiarmid institute and to establish links with other relevant groups in New Zealand. Bio-nanotechnology involves the application of physical science techniques to biological and medical applications.

Like Dr Alkaisi, a number of researchers at the MacDiarmid institute are currently involved in this field, with different projects scattered among the different themes and universities. The central aims of the Bionanonetwork are to increase exchange of experience and skills, to ensure an efficient use of resources, uncover new funds and to facilitate student training and exchange. There are currently 28 members, 14 of them from within the MacDiarmid institute and 14 from outside the MacDiarmid Institute. A web site has been set up at .

The inaugural Bionanonetwork meeting was held on 16 June in Christchurch. The meeting was attended by 30 people representing three different themes from the MacDiarmid institute, plus 12 other research centres outside the institute. The aims of the meeting were to explore collaboration, coordinate research work, share experience, and form stronger research groups. Dr Alkaisi considers the meeting, and the Bionanonetwork itself to have been very successful, and more meetings are planned for the future.