science

By Diliny De Alwis
Created 06/10/2009

Stem cells are discussed often in the news and arguments for or against their use are usually based around sourcing. At present, adult stem cells can be reliably obtained from healthy adult bone marrow aspirates and tissue sources such as adipose (fat) tissue where the cells are safe for use within the same (autologous) patient little risk of immunological reaction or tissue rejection. At the same time, embryonic and umbilical cord blood derived stem cells can be obtained - however, more research is as yet required although the applications for using these cells are more widespread. For the purpose of bone reconstruction, adult stem cells isolated from autologous patients have been proven to be more than adequate.

The current methods used for the reconstruction of large bone defects involves harvesting a patient's bone with increased risk of tissue death at the site of removal and risk of infection. Pieces of bone (bone grafts) may be taken from the pelvis, ribs, or skull to fill in the spaces where reconstruction is needed. Small metal screws, wires, and plates may be used to hold the bones in place. Risks following surgery are bleeding, infection, nerve damage (cranial nerve dysfunction), permanent scarring, as well as partial or total loss of bone grafts. There may also be a need for follow up surgery.

In 2009 researchers at the Helsinki University Central Hospital in Helsinki, Finland published a cutting edge journal article reporting the use of GMP derived adipose stem cells used for ectopic bone reconstruction in human patients. Up to then, most publications of bone reconstruction had been reported only in animal studies. The study, begun in 2007, on a patient who was missing part of the upper jaw bone. 200 ml of fat tissue (less than 1 cup) was obtained from the patient from which adipose derived adult stem cells were isolated and expanded under GMP (Good Manufacturing Practices) using the patient's own blood serum. Approximately 16 days later, the cells were ready for implantation via a known and trusted biomaterial, beta-tricalcium phosphate, to provide a scaffold within a titanium cage/mold for obtaining the desired shape. Initially the construct was implanted in an area of the patients upper abdomen. Eight months later the researchers returned to retrieve the young bone from the titanium cage in which it had grown and used it to repair the facial defect. The patient was discharged 10 days after the operation. Thereafter, the patient was monitored for up to 12 months. The reconstructed bone was found to integrate with the existing bone without any adverse events and further, dental implants were successfully implanted thereafter.

So given this success story, what is holding stem cell research back?

In 2009 another published journal study by researchers at the Tel Aviv University in Isreal was jumped upon by the press. The study reported cells forming a tumor four years following fetal neural stem cell transplantation. The cells used were not autologous (not from the patient) and had undergone some manipulation. Suffice it to say, the paper reports on the study of the tumor that resulted though that was not the researchers initial intent. So the question of whether manipulated stem cells are a cause of tumors after transplantation is absolutely relevant.

Animal testing and the time and quality required to conduct well developed studies is another factor. Prior to most studies, especially those carried out in the US and EU animal studies are required from small scale (mice and rabbits) to large scale (dogs and pigs) before a technology can be approved for trial in humans. The problem with this methodology is that inherent problems you would find in humans are not immediately obvious. However, questions of efficacy and obvious problems in the proposed technology will be quickly identified.

Evolving definitions is another cause for the delay. The debate is still raging on the definition of a stem cell with new terminology being introduced every year. At the moment, a stem cell can be either adult, embryonic, or umbilical cord blood derived. At the same time, iPS cells and pericytes are also new terms that may be defined as cells related to or including stem cells. Pluripotency, the stem cells ability to differentiate into different tissue types, is also under question as researchers redefine the scientific requirements for cartilage, neurons, and other tissues. This results in many schools of thought and many more proposed technologies leading industry and funding bodies to be selective in what passes and does not. Researchers who are good salespeople and who have the resources may still pass ideas that are more extravagant and time consuming. There is yet to be a suitable long term study of stem cells post transplantation to be published. Most research facilities will not wait on decades to publish results they can receive within a period of months.

Whether we like it or not, long term studies on stem cell technologies will give the answers to whether or not stem cells should be manipulated or not before being used and whether or not there is a subsequent risk of cancerous growths. Progress is slow, but hopefully some of these technologies will be made available within our lifetimes.

At present, in the case of bone construction - terminally differentiated bone cells from autologous adult stem cells appears to be a promising venture following this well developed and published study.

References:

Mesimaki K, Lindroos B, Tornwall J, Mauno J, Lindqvist C, Kontio R, Miettinen S, Suuronen R. Novel maxillary reconstruction with ectopic bone formation by GMP adipose stem cells. Int. J. Oral Maxillofac. Surg. 2009; 38: 201-209.

Amariglio N, Hirshberg A, Scheithauer BW, Cohen Y, Loewenthal R, Trakhtenbrot L, Paz N, Koren-Michowitz M, Waldman D, Leider-Trejo L, Toren A, Constantini S, Rechavi G, Donor-derived brain tumor following neural stem cell transplantation in an Ataxia Telangiectasia patient. PLoS Med 6(2): e1000029. doi:10.1371/journal.pmed.1000029