Spinal cord repair - just add water

The Australian Stem Cell Centre is studying an alternative approach to treating spinal cord damage using acellular dermal matrix processing. Fiona Wylie spoke to the ASCC's Kathy Traienedes.

There are no effective or practical ways to repair spinal cord damage available to us today. In a recent press conference to launch a new $63 million state government neurotrauma initiative, Victorian Premier Steven Bracks cited statistics of 400 new cases of spinal cord injury every year, mainly from vehicle accidents, with few patients achieving full recovery due to the difficulty that damaged nerves have in bridging gaps in major nerve pathways.

Transected spinal nerve fibres make an attempt at regeneration, but without a suitable substrate on which to grow and spread in the right direction and towards the right nerves, most attempts are futile and short lived.

Also speaking at the session on spinal cord therapy at the AH&MRC, Dr Kathy Traianedes will introduce an alternative approach to treating spinal cord damage being undertaken at the Australian Stem Cell Centre in Melbourne (ASCC). Her presentation, 'application and development of acellular matrix technology as a biological scaffold for spinal cord repair', will outline a major new project to process and test naturally occurring acellular matrices designed to support and facilitate regeneration of nervous tissue, for eventual application in spinal cord therapy.

One of the premises of the proposed project is that a biological acellular matrix will not be rejected by the host, which is currently the major problem with either biosynthetic matrices or allograft material, and that given the right biological combinations, the matrix will actually promote regeneration of the damaged nervous tissue.

Traianedes emphasises that tissue repair is always a competition between regeneration and scar formation. "This type of therapy aims to increase and facilitate the chance of regeneration," she says.

Since the processed matrix contains no cells, the non-cellular components of the dermis, consisting primarily of extracellular matrix proteins and collagen, are relatively non-immunogenic. Alternative repair processes such as allografts and biosynthetic matrices have several inherent problems that have led to their limited success. Allograft skin elicits an immune response directed primarily against the cells of the epidermis and endothelial and fibroblast cells of the dermis.

On the other hand, explains Traianedes, "biosynthetic matrices met with limited success as they were typically formulated as a structural support with limited biocompatibility, but you need things like growth factor incorporation to guide axonal regeneration. So, getting the right cells to the right places to start the regeneration process."

Tissue repair

Traianedes is the senior scientist in the ASCC's tissue repair group and will lead the three-year program. "Pre-clinical and clinical assessment has demonstrated that this type of matrix does not produce a significant specific or non-specific inflammatory response but rather contains the information to direct normal revascularisation and normal cellular repopulation, effectively regenerating normal tissues."

This project is based on existing technology developed in the United States 13 years ago, now licensed by the ASCC for use in Australia. This patented technology, known as acellular dermal matrix processing, involves removing all cellular components from a dermal matrix sourced from cadaveric skin.

Under tonic conditions, the cellular material is extracted without destroying the underlying collagen and basement membrane. The resultant material, trademarked as AlloDerm, is then cryoprotected and freeze-dried. It can be stored pre-packaged in the fridge for up to two years, ready for immediate clinical use: just add water.

Nearly one million AlloDerm grafts have been used to treat patients in the US, mostly in cases of soft tissue damage such as burns, mucosal tissue repair, abdominal wall reconstruction, and breast reconstruction following mastectomies.

The ASCC obtained the rights to use the AlloDerm technology specifically for the arena of nerve cell damage, which has not yet been done elsewhere. A recent University of Wisconsin pre-clinical study showed processed peripheral nerve grafts of this type bridging a 2cm gap in a rat sciatic nerve over a period of about seven months. These results were very encouraging to Traianedes and her team and provide proof of principle for these acellular matrices in treating spinal cord injury.

"When presented with structurally and biochemically preserved matrix containing physiological levels of growth factors and guidance cues, the spinal cord will be able to regenerate its axons along this scaffold," she says.

Collaborations

Traianedes is being partially funded by the Spinal Cord Society of Australia, which is in turn supported by the Lions Club of Traralgon. The society donated the initial $100,000 for the program, which was used as seed funding to successfully gain a slice of the Victorian neurotrauma initiative pie to the tune of a further $413,000 grant to ASCC for this research.

The work will be conducted in collaboration with the University of Western Australia, where Professor Giles Plant and Dr Marc Ruitenberg will contribute their expertise in the experimental animal models being used to test the dermal matrix technology.

Two models will be utilised - a complete transection model and a contusion model to assess the efficacy of both dermal- and spinal cord-processed matrices. Initially the complete resection model will be used in the short term to see which matrix configuration works best. The optimal configuration will then be used, testing for any regeneration over a period of up to 12 months in both models.

"The complete resection model is used as a sort of the 'worst-case scenario'," Traienedes says. "If the matrix can bridge a complete resection, then there is increased chance of repairing the more common contusion injuries such as a crush injury after a car accident. The presence of scar in the contusion models presents a challenge in terms of tissue regrowth."

The ultimate aim is to process the skin and spinal cord tissue to provide a suitable scaffold for bridging damaged spinal cord in a bid to promote regeneration and prevent scar from forming. Rather than triggering a scarring response, the dermal matrix should allow normal tissue regeneration, restoring tissue to its original structural, functional, and physiological condition.

Different tissues

One interesting thing about AlloDerm from a scientific viewpoint, according to Traianedes, is that the same dermal graft can be used successfully for initiating regeneration in different tissue situations, such as in gingiva, skin and mucosal surfaces. She proposes that this is because the matrix is recruiting circulating stem cells rather than utilising mainly resident stem cells in surrounding tissue.

This is based on the observation that revascularistion precedes repopulation of the matrix with specific cells, thereby providing a conduit for other cells accessing the regenerating area. In fact, a major aim of this work is to address this more biological question and to define the cues for cellular repopulation on the matrix, so that can tailor-make the material appropriately and have it on hand as necessary.

The long-term plan of ASCC scientists, if this application is successful in small animal models, is to move to a large animal model and to combine the technology with other approaches for nervous system repair such as the use of stem cells seeded onto the matrix.

"There is evidence, however, that a stand-alone matrix might be sufficient in many cases, and the project will certainly be testing this premise in the first instance.

"It really is a chance to try something truly innovative with an injury that is very challenging and quite complex."