Recent technical advances in fat grafting and the development of surgical devices such as liposuction cannulae have made fat grafting a relatively safe and effective procedure. However, new guidelines issued by the American Society of Plastic Surgeons in 2009 announced that fat grafting to the breast is not a strongly recommended procedure, as there are limited scientific data on the safety and efficacy of this particular type of fat transfer. Recent progress by several groups has revealed that multipotent adult stem cells are present in human adipose tissue. This cell population, termed adipose-derived stem cells (ADSC), represents a promising approach to future cell-based therapies, such as tissue engineering and regeneration. In fact, several reports have shown that ADSC play a pivotal role in graft survival through both adipogenesis and angiogenesis. Although tissue augmentation by fat grafting does have several advantages in that it is a noninvasive procedure and results in minimal scarring, it is essential that such a procedure be supported by evidence-based medicine and that further basic scientific and clinical research is conducted to ensure that fat grafting is a safe and effective procedure.
Fat grafting for the purpose of small contour correction, such as wrinkle augmentation in the aging face and hand rejuvenation, is considered an effective procedure in cosmetic surgery because it is a minimally invasive option for patients and results in negligible scarring.1,2 Fat grafting in these areas achieves natural-looking structural changes that may be longer-lasting compared with biodegradable and synthetic materials such as hyaluronic acid. However, in 1987, the American Society of Plastic and Reconstructive Surgeons (ASPRS) Ad-Hoc Committee on New Procedures determined that fat grafting to the breast region would impede breast cancer detection and should therefore be avoided.3 This position was supported by several subsequent studies that revealed severe complications related to fat grafting for the purpose of breast augmentation.4-6
Recent advances and innovations in surgical techniques and diagnostic radiology, as well as advances in our understanding of adipose tissue physiology, are affecting physicians’ ability to perform fat grafting of the breast. In particular, technical advances in fat grafting of the body, the development of devices such as liposuction cannulae and injectors, and emerging research related to multipotent adult stem cells that are present in human adipose tissue (adipose-derived stem cells, or ADSC) appear to justify strong support for the procedure. However, the mechanisms underlying the survival of injected fat and the fate of ADSC remain largely unknown. As such, additional studies are needed before cosmetic surgeons can safely and reliably perform fat grafting of the body, particularly to the breast.
In this article, we present a historical review of fat grafting and the current consensus on the procedure, with emphasis on the breast. We also highlight the characteristics and role of ADSC in clinical applications. Finally, we project some future directions in fat grafting as a cosmetic procedure.
Historical Perspective on Lipoinjection
Fat grafting, or lipoinjection, is a process in which fat cells from one area of the body are transferred to another. It is commonly employed for enhancement of the face or hands. Neuber first described fat grafting for the correction of a depressed facial scar in 1893.7 In 1895, fat grafting to the breast was first described to correct a postmastectomy defect.8 An extensive survey of published articles in the PubMed database revealed that 3345 and 5355 scientific articles used the terms fat grafting and fat injection, respectively (Figure 1). The articles included not only those in the field of plastic surgery and aesthetic surgery, but also other medical fields.9-12 When we narrowed the search using the terms fat grafting, breast and fat injection, breast, the number of references extracted were 348 and 210, respectively (Figure 2). The number of publications containing any of the four terms has increased in recent years, which suggests that scientific interest in fat grafting and lipoinjection is increasing across medical fields.
Normal Mature Adipocyte Physiology
Any physician who deals with adipose tissue as an injectable material should have a thorough understanding of the basic physiology of the material. Normal human adipocytes are typically 70 to 90 µm in diameter. In obese individuals, lipid droplets accumulate in the cytoplasm and the size of the adipocyte increases to approximately 130 µm in diameter. In addition to size, adipocyte number also increases in obese individuals, as evidenced by the fact that mature adipocytes and preadipocytes undergo mitosis.13 Individual adipocytes are in direct contact with adjacent capillary vessels, which indicates that adipose tissue is a highly vascularized tissue. In free fat grafting, as with skin grafting, direct diffusion of nutrients from plasma in the surrounding bed and subsequent revascularization usually occur within 48 hours and are essential for graft survival. If the local environment does not undergo revascularization, the grafted fat tissue eventually experiences necrosis, which might be the cause of several complications associated with fat grafting.
Complications After Free Fat Grafting to the Breast
There have been several reports of complications associated with free fat grafting to the breast.4-6 Complications include fat necrosis, oil cyst formation, indurations in either the subcutis or breast parenchyma, calcification, and severe breast deformity (Figures 3,4). Such complications seem to be due in part to a lack of knowledge of proper lipoinjection technique on the part of the physician who performed the procedure.5 However, even when fat grafting was performed by well-trained physicians, calcifications in the grafts were difficult to distinguish from breast tumors, thus potentially masking the detection of breast cancer.
Positions of the American Society of Plastic Surgeons and the American Society for Aesthetic Plastic Surgery
After the announcement of the ASPRS Ad Hoc Committee on New Procedures in 19873 and until 2005, most physicians refrained from performing fat grafting to the breast. During this period of time, most of the published articles related to fat grafting reported complications associated with the technique.4,6
However, as fat grafting techniques became more refined and breast cancer detection methods more sophisticated, physicians began to develop improved fat grafting techniques.14,15 In 2007, the American Society of Plastic Surgeons (ASPS) and the American Society for Aesthetic Plastic Surgery (ASAPS) announced that fat grafting for breast augmentation was not recommended, based on the lack of available clinical data on the safety and efficacy of the procedure and concerns that the procedure might interfere with the accurate detection of cancer. Subsequently, in 2009, the ASPS announced a new position on fat transfer, fat grafting, and fat injection to the body, which was based on a review of the literature and numerous patients who underwent fat grafting (238 of whom underwent fat grafting to the breast).16 The ASPS task force concluded that fat grafting could be considered for breast augmentation and the correction of defects associated with medical conditions and previous breast operations. However, it cautioned that the results are largely dependent on technique and surgeon expertise. In addition, because the lifetime of fat grafts is unknown, additional treatment might be necessary to obtain the desired effect. Although no scientific evidence was found that specifically addressed patient selection, physicians were advised to exercise caution when considering high-risk patients, such as those with risk factors for breast cancer (ie, BRCA-1, BRCA-2, and/or a personal or familial history of breast cancer), when determining whether a patient is an appropriate candidate for autologous fat grafting to the breast. The largest reported series to date, by Delay et al,17 demonstrated safety and efficacy with an acceptable complication rate.
Structural Fat Grafting
The concept of “structural fat grafting,” as proposed by Coleman and Saboeiro,14 is theoretically reasonable when considering the mechanism of free tissue grafting. In other words, smaller grafts with higher surface-area-to-volume ratios have an advantage over larger grafts, as a greater proportion of the graft is in contact with the graft bed (although too small a graft volume is associated with resorption). In their original case series of fat grafting to the breast, Coleman and Saboeiro placed approximately 0.2 mL of fat tissue mainly in the subcutaneous tissue, subglandular space, and within the pectoralis major muscle with each withdrawal of the injection cannula. Several subsequent reports demonstrated the usefulness of such a procedure and introduced minor modifications.15,18,19 However, a substantial limitation of these studies was that the postoperative evaluations were performed primarily by microscopic examination, not by quantitative assessment with mammography, ultrasonography, or magnetic resonance imaging (MRI).
Due to recent advances, diagnostic imaging technology can provide a relatively precise distinction between microcalcifications associated with fat grafting and those associated with breast cancer. According to Carvajal and Patiño,20 of 20 patients who underwent free fat injections to the breast for cosmetic purposes and exhibited mammographic abnormalities (including microcalcifications and radiolucent oil cysts), 17 were designated as Breast Imaging Reporting and Data System (BI-RADS) category II (“benign findings”; nothing further is required other than routine screening), whereas three patients were designated as BI-RADS III (“probably benign findings”; short-interval mammographic follow-up is suggested to monitor the stability of the lesion).21 These latter three patients were subsequently examined by digital mammography and reclassified as BI-RADS II.20 However, the authors also concluded by stating that the technique of free fat injection for breast augmentation should not be performed in patients with a family history of breast cancer because of the side effect of calcification in the breast parenchyma.
Adipose-Derived Stem Cells
We now turn to a potential new evolution in medicine, stem cell biology, and the related field of regenerative medicine. Multipotent stem cells exist within a variety of tissues, including bone marrow, adipose tissue, synovial membranes, and amniotic membranes.22-25 Adipose tissue in particular represents an abundant and accessible source of ADSC, which can differentiate along multiple mesodermal lineages, including the adipogenic,25-28 osteogenic,25,28,29 and chondrogenic,25,28,30 as well as the myogenic lineage leading to skeletal muscle,25,28,31,32 smooth muscle,33,34 and cardiomyocytes.35 ADSC have also been shown to possess the potential to differentiate into nonmesodermal lineages, including neuron-like cells,36,37 endothelial cells,38,39 epithelial cells,40 hepatocytes,41,42 pancreatic cells,43 and hematopoietic supporting cells.44,45
One of the implications of the increased incidence of obesity in modern populations is that subcutaneous adipose tissue is abundant and readily accessible. Harvesting of adipose tissue by liposuction is technically easy, minimally invasive, and associated with little patient discomfort and donor site morbidity. Furthermore, small amounts of adipose tissue (100-200 mL) can be obtained under local anesthesia. Studies have shown that 1 g of adipose tissue yields approximately 5 × 103 stem cells,46 which is 100 to 500 times greater than the number of mesenchymal stem cells (MSC) in 1 g of bone marrow.47 Thus, adipose tissue is a potentially rich source of stem cells.
ADSC secrete potent growth factors such as vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), FGF-2, and insulin-like growth factor 1 (IGF-1).38,48,49 The secretion of VEGF, HGF, or both by ADSC can be induced by exposure of the cells to hypoxia,49 differentiation factor,50 or tumor necrosis factor–α.51 ADSC have also been shown to enhance tissue survival52 and protect tissue from ischemia reperfusion injury.53
Adsc in Fat Grafting
The identification of several potentially beneficial therapeutic properties of ADSC54,55 has led to a novel technique of fat grafting in conjunction with ADSC therapy for breast augmentation.56 In theory, this type of approach could accomplish several goals, including (1) the direct differentiation of ADSC into adipocytes as a reservoir for adipose tissue turnover; (2) the direct differentiation of ADSC into endothelial cells and the subsequent increase in blood supply to the grafted fat tissue, thereby decreasing the rate of graft resorption; (3) the release of angiogenic growth factors by ADSC and the induction of angiogenesis; (4) protection of the graft from ischemic reperfusion injury by ADSC; and (5) acceleration of wound healing at the recipient site.57,58 Despite these potential benefits of combined therapy, however, many aspects of the mechanism of injected fat survival, the way to control ADSC differentiation, and the fate of ADSC remain unknown.
As stated above, in general, ADSC can differentiate into a variety of the lineages under the lineage-specific culture conditions. If such differentiated ADSC are used to regenerate tissues, we theoretically might be able to control ADSC prior to transplantation. However, undifferentiated ADSC are also known to recognize the microenvironment in which ADSC were transplanted in vivo and differentiate into the appropriate cell lineage, in order to adjust themselves to their circumstances.52,57,59 In free fat grafting in conjunction with ADSC, ischemic condition within the grafted fat may control and regulate differentiation toward endothelial cells and the release of the angiogenic growth factors, which can augment the vascular supply to the adipocytes. However, there are little data on the implementation of this procedure and few clinical studies. Thus, a comparative analysis of ADSC in fat grafting has yet to be carried out. Future high-quality, controlled, multicenter studies are needed.
Although free fat grafting or lipoinjection to the breast has gradually gained acceptance over the past several years, such a procedure is not recommended by the ASPS 2009 guidelines. At present, basic science and clinical investigators are actively engaged in research in the field of adipose tissue and ADSC. Additional data are needed to ensure that in the future, fat grafting or lipoinjection is performed in a safe and effective manner.
The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.
The authors received no financial support for the research and/or authorship of this article.