Stemming time's tides: Adipose stem cell promise Early data shows ADCs engender neovascularization in fat transplants

SAN DIEGO Long-term unpredictability of volume maintenance is a well-known limitation of fat transplantation used as a filler in plastic and reconstructive surgery. The primary mechanism of tissue loss appears to be insufficient blood supply, which occurs even when the graft is transferred as small fat particles to locations near vascularized structures according to the technique described by Coleman in 1997.

Dr. Zins

When contacted for his opinion on the review, Cleveland Clinic Chairman of Plastic Surgery, James E. Zins, M.D., acknowledges that this very preliminary data is exciting and on the right track "but that we should be careful not to make more of the evidence than it is."

While the use of fetal or embryonic stem cells has been confounded by ethical issues and biological limitations such as oncogenicity, multiple sources of stem cells have been identified in the adult. Adipose tissue provides a source that is easy to harvest and has the highest concentration of stem cells — 100 to 1,000 times that of bone marrow. In addition, undifferentiated ADCs transcribe a variety of genes related to angiogenesis (Katz et al 2006).

Interestingly, ADCs injected into a tissue alone will not produce soft-tissue fill. Therefore, according to Hedrick, one strategy currently being pursued is to create an engineered filler tissue by "leveraging the stem cells' capacity to create a blood supply very quickly. Autologous ADCs are used as a supplement to the autologous free-fat graft. In theory, a blood supply is rapidly generated after implant that allows the fat graft to be sustained in situ in a much more predictable fashion than would occur otherwise."

DATA POINTS In Hedrick's study, freshly isolated autologous ADCs were mixed with minced donor fat to provide a subdermal scalp implant in athymic nude mice; control mice received an unsupplemented fat graft.

The weight of the transplant at six months after transplantation was 2.5 times greater in the ADC group compared with the control group (p = .021). In the implants that had been supplemented with ADCs, immunohistochemistry testing for stem cells with an endothelial marker demonstrated vascular support for the entire graft at six months. These data suggest that the ADCs may have implemented graft maintenance through an improvement in the graft blood supply (Mosely, Zhu, and Hedrick, 2006).

In one unpublished case study, Hedrick relates, a patient with soft-tissue involution on the ulnar aspect of one hand and who had previously failed autologous fat grafting alone, was treated with an autologous fat transplant supplemented with ADCs. After more than one year, soft-tissue volume restoration was observed (LLull, unpublished).

Also interestingly, in a small unpublished Japanese study, autologous ADC-supplemented fat implants were used to treat 23 patients with soft-tissue defects or breast augmentation. In general, the results of 26-month follow-up showed evidence of long-term graft volume maintenance. One patient experienced some fibrosis at the central area of the chest over the sternum (Yoshimura, unpublished).

REAL-TIME PROCESSING In his studies, Dr. Yoshimura obtains autologous ADCs for surgery though a multi-hour manual process that is performed under the principles of good laboratory practice. However, Cytori Therapeutics, Inc. has developed a device that can be used to extract ADCs at the bedside, the Celution System.

According to Dr. Hedrick, the Celution device sterilely disaggregates adipose tissue using a temperature and enzyme-driven process. The fat is broken up into its constituent parts: mature fat cells, supporting matrix that holds the fat together, the stem cell fraction, the free lipid fraction, and the blood fraction. Those parts that are not useful are extracted and, within approximately one hour, the surgeon has a syringe containing concentrated stem cells that can be used in the treatment of the same patient.