Making Sense of Stem Cells and Fat Grafting in Plastic Surgery

The Hype, Evidence, and Evolving U.S. Food and Drug Administration Regulations

Rod J. Rohrich, M.D.; Dinah Wan, M.D.

Disclosures

Plast Reconstr Surg. 2019;143(2):417e-424e. 

In This Article

Abstract and Introduction

Abstract

Autologous fat grafting and adipose-derived stem cells are two distinct entities with two different risk profiles, and should be regulated as such. Autologous fat grafting prepared with the additional step of stromal vascular fraction isolation is considered a form of "stem cell therapy" given the high concentration of stem cells found in stromal vascular fraction. Much ambiguity existed in the distinction between autologous fat grafting and stromal vascular fraction initially, in terms of both their biological properties and how they should be regulated. The market has capitalized on this in the past decade to sell unproven "stem cell" therapies to unknowing consumers while exploiting the regulatory liberties of traditional fat grafting. This led to a Draft Guidance from the U.S. Food and Drug Administration in 2014 proposing stricter regulations on fat grafting in general, which in turn elicited a response from plastic surgeons, who have safely used autologous fat grafting in the clinical setting for over a century. After a series of discussions, the U.S. Food and Drug Administration released its Final Guidance in November of 2017, which established clear distinctions between autologous fat grafting and stromal vascular fraction and their separate regulations. By educating ourselves on the U.S. Food and Drug Administration's final stance on fat grafting and stem cell therapy, we can learn how to navigate the regulatory waters for the two entities and implement their clinical use in a responsible and informed manner.

Introduction

Although the existence of stem cells has been known for more than a century, there has been an exponential surge in public attention in the past few decades. Hematopoietic stem cells from the bone marrow were the first singular type of precursor cell to be discovered in the 1990s. These blood-forming stem cells can be extracted from bone marrow, cord blood, or peripheral blood. To this day, they remain the most extensively studied stem cell therapy, notably in the treatment of hematologic cancers and lymphoproliferative disorders. Currently, hematopoietic stem cells derived from cord blood are the only U.S. Food and Drug Administration–approved stem cell therapy.[1]

Adipose-derived Stem Cells

Mesenchymal stem cells are distinct from hematopoietic stem cells in that mesenchymal stem cells are multipotent cells with the capacity to differentiate toward adipogenic, osteogenic, chondrogenic, and myogenic lineages. Mesenchymal stem cells have traditionally been derived from bone marrow since their discovery in the 1990s. However, harvesting from this source has not been popular, given the painful extraction and low yield. In 2001, University of California, Los Angeles, researchers discovered an alternative source of mesenchymal stem cells: adipose tissue.[2] Not only is adipose tissue richer in stem cell supply, the harvest and extraction process is simpler and less invasive. This discovery of adipose-derived stem cells opened the door to a whole new realm in stem cell therapy.

Stromal Vascular Fraction

Isolation of adipose-derived stem cells from adipose tissue begins with standard fat harvest using suction-assisted lipectomy. To isolate cellular components, the lipoaspirate is enzymatically digested with collagenase to mechanically disrupt the extracellular matrix. The product is then centrifuged to obtain the stromal vascular fraction, which sits at the bottom of the tube as a high-density pellet under the aqueous and adipocyte layers. The stromal vascular fraction is the portion of the harvested fat that contains the highest concentration of stem cells.[3,4]

Cell-assisted Lipotransfer

Although a small quantity of native adipose-derived stem cells is inherently transferred in traditional fat grafting,[5] this amount is insufficient to be considered a true "cell-enriched" graft. To do so, the extra step of stromal vascular fraction isolation must be performed, which by definition requires enzymatic cell digestion with collagenase.[2,6] Cell-assisted lipotransfer is a method of autologous fat grafting supplemented with isolated stromal vascular fraction to create a cell-enriched graft higher in stem cell concentration than the traditional fat graft. Clinically, the primary advantage of cell-assisted lipotransfer is its potential to enhance adipocyte survival in autologous fat grafting.[7,8] Bench studies suggest that this benefit derives from the angiogenic properties of adipose-derived stem cells enhancing vascularity of the fat graft.[9–12] This beneficial effect has been demonstrated in animal studies showing improved long-term retention of implanted fat grafts enriched with adipose-derived stem cells[13–15] and in one experimental human trial.[16] In cell-assisted lipotransfer, stromal vascular fraction is isolated first and then reconstituted in the lipoaspirate before grafting.[4,17,18] Alternatively, the isolated stromal vascular fraction can be cultured in vitro for further cell expansion to create an even more "concentrated" form of cell-assisted lipotransfer.[2,7,19–21]

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