Improving brain repair by neural stem cells using engineered scaffolds

Clinical trials are not too far away for neural stem cells in neurodegenerative diseases, such as stroke and Huntington's Disease. Neural stem cells are immature brain cells that have the capacity to replace mature brain cells that have been lost following disease or injury. These stem cells have now been successfully isolated and grown in culture, first from mouse, but more recently from human tissue. If neural stem cells are transplanted into the brains of experimental animals with lesions that mimic these degenerative disorders, they repair brain structure and restore function. Human neural stem cells have now been grown to clinical grade, so if they prove safe, clinical trials can be undertaken to discover whether they actually work for real patients. Although we are approaching clinical trials, the fact is that we do not yet know how best to transplant the cells. In the animal studies, we simply inject them as a suspension, hoping that they will integrate efficiently into the damaged brain. Apart from the fact that this approach is inefficient, it is difficult to justify in human patients because it requires us to inject the cells into undamaged tissue next to the areas of damage, rather than into the damaged areas themselves. The danger is that the injection will do further damage. We have to learn how to inject cells into the damaged tissue itself. The problem is that following a stroke, for example, this damaged tissue looses all structure and becomes largely fluid filled. Our studies indicate that cells do not work very well if injected into such an environment. Almost certainly we can do better by supporting them in a matrix scaffold that will insure that the cells go precisely where we need them and holds them in place while they work their way into the damaged tissue. We also hope we might be able to achieve more fundamental tissue repair by giving the cells structure right from the start. In this project, tissue engineers and neurobiologists will work together to develop cell-scaffold combinations that will optimise the repair potential of neural stem cells.

There is a reasonable prospect that neural stem cells will reach clinical trials in the near future for stroke and other neurodegenerative disorders. This optimism is based on the increasing evidence for efficacy in pre-clinical animal studies and the success in growing clinical-grade human neural stem cell lines from fetal material. This prospect highlights the limitations of our current approach to tissue regeneration in the brain whereby cell suspensions are injected directly into brain tissue. Such grafts only work if injected into relatively undamaged tissue, and work poorly if made into the fluid filled cavities that result from tissue loss in stroke. Unsurprisingly, although new cells are formed and host tissue function improved, there is little tissue reconstruction with current approaches and the cavities remain unreduced. In this proposal, a multidisciplinary team of tissue engineers and neurobiologists will develop cell-scaffold matrices for injection into stroke-lesioned rodent brain. We will attempt to overcome three distinct but overlapping problems. First, we will optimise the use of MRI (magnetic resonance imaging) for the delivery of brain grafts. This is a necessary objective if cavities are to be reproducibly targeted for injections. Second, we will devise 'cell-scaffold matrices' to optimise the integration of neural stem cells into host tissue following injection into stroke cavities. Our objective is to get neural stem cell integration comparable with that seen with intra-parenchymal grafts. Third, we will investigate the possibility of getting true brain tissue reconstruction in cavities by manipulating cell-scaffold matrices and assaying neovascularisation and tissue integrity.