The review presented by Mizuno and Hyakusoku discusses the interesting clinical history of fat grafting to the breast, as well as the physiology and basic science concepts behind its application and results. The authors note that the first known fat transfer was completed by Neuber in 1893, where fat grafts from the arm were transplanted to fill facial soft tissue defects following tuberculosis.1 Two years later, Czerny first described fat transfer to surgically correct a breast deformity resulting from operative intervention on chronic cystic mastitis.2 Significant postoperative resorption and minimal graft survival was reported in 1950, leading to the subsequent decline of autologous fat transfers in the face and breast.3

Refined techniques and improved outcomes, however, renewed interest in fat transfer in the 1980s in the field of facial reconstruction.4 In contrast, fat grafting remained unpopular in clinical use for breast reconstruction, particularly when the American Society of Plastic and Reconstructive Surgeons (ASPRS) Ad-Hoc Committee on New Procedures released the statement in 1987 that the committee “unanimously deplored the use of fat injection in breast augmentation.”5 Despite this statement, techniques improved with research using low negative-pressure syringes to minimize cellular trauma and centrifugation to separate out adipocytes.6,7 In 2007, the ASPRS and the American Society for Aesthetic Plastic Surgery (ASAPS) relaxed their positions and recommended caution against fat injection in the breast but jointly encouraged research efforts to improve “the safety and efficacy of the procedure.”5,8 Along with this national support, the authors point out a significant increase in the number of articles published on this topic since then. Promising results in clinical level III and IV data studies exist, but these procedures are extremely surgeon dependent and may have prolonged operative times.

Despite limited data, autologous tissue remains an attractive option for breast reconstruction and augmentation, as it eliminates the complications associated with breast implants and synthetic materials. Although there is an increase in interest, less consensus exists in breast fat transfer than in craniofacial fat transfer due to concern regarding increased difficulty of breast cancer surveillance after fat transfer. However, any surgical recontouring procedures of the breast parenchyma can result in postoperative microcalcifications. The evidence of post–breast reduction microcalcifications is well documented,9,10 and similar radiographic findings are seen after fat transfer.11

Aside from the issue of breast cancer surveillance, the actual long-term survival of transferred adipocytes remains unknown. In craniofacial fat transfer procedures, it has been difficult to demonstrate long-term changes in anatomic areas of laxity.12 Other areas, such as the forehead and infraorbital regions (as well as less mobile cosmetic defects and scars), have demonstrated greater longevity.13 According to a recent report by Mojallal et al,14 patients had the greatest satisfaction after fat grafting in the malar eminence and the worst results in fat grafting to the lips. To improve on these outcomes, Coleman et al15,16 have refined their fat grafting technique with improved instruments and centrifugation and demonstrated promising outcomes.

However, even with optimized techniques in the most experienced hands (e.g., 10-year report in 880 patients by Delay et al17), fat transfer to the breast largely remains controversial with variable outcomes. Considering these current limitations, tissue engineering strategies with autologous adipose-derived stromal cells (ADSC) may offer more attractive solutions. These multipotent cells can potentially address some of the current deficiencies known in autologous fat transfer.18 Numerous studies have discussed the ability of human ADSC to differentiate into multiple mesenchymal lineages, including bone and fat.19 Furthermore, several scientists have demonstrated the inverse relationship between adipocyte and osteoblast differentiation.20

For each differentiation pathway, specific genes and cell surface receptors have been implicated to drive the multipotent cells to one lineage over another. For example, PPAR-gamma receptor activation has been shown to drive cells to adipogenic differentiation.21 In addition, several Hox genes have been recently identified to be overexpressed during adipogenesis.22,23 Other genes such as TAZ have been shown to activate the Runx-2 transcription factor and stimulate osteogenesis while inhibiting adipogenesis.24 In terms of clinical translation strategies, we foresee specifically targeting these genes and other critical cell surface receptors to induce adipogenesis. We can improve the current outcomes and durability of autologous tissue transfer to the breast by stimulating the multipotent cells to differentiate into adipocytes in a coordinated physiologic environment to increase cell/tissue survival.

Beyond improving our techniques on a cellular level, recent advances in material sciences have expanded the opportunities for application of ADSC in reconstruction. Active collaboration between bioengineers and clinicians has fostered the development of three-dimensional constructs tailored to address specific soft tissue contour demands with an appropriate scaffold. Several materials such as Matrigel (BD Biosciences, Franklin Lakes, New Jersey), alginate, and collagen sponges have been explored, but lack a strong structural support.25 Others have focused on polyethylene glycol-based hydrogels, which demonstrate slower degradation rates and improved durability.25 In vivo implantation of human mesenchymal cells seeded onto such hydrogels has been shown to promote adipogenic differentiation when placed subcutaneously in rats.26 Importantly, these constructs maintained their entire volume and shape during the four-week follow-up time.

In a limited clinical study, Yoshimura et al27 employed autologous fat as a scaffold and seeded the fat with freshly isolated ADSC to treat facial lipoatrophy. These scaffold-based designs could be extremely useful when trying to customize a breast reconstruction or augmentation for patients with greatly varying deformities and anatomies.

As Mizuno and Hyakusoku clearly summarize, the technique, indications, and interest in autologous fat transfer continue to expand exponentially. Ultimately, the potential cell-based strategies with ADSC to generate fat tissue will be very different from the current fat grafting methods. As clinicians and scientists, we have the obligation to continue to question and test our methods. Our ultimate goal should be to both improve our patient outcomes and also to understand the basic science underlying the clinical interventions. We believe that the real breakthrough in breast reconstruction techniques with autologous tissue will not come by incremental improvements to technical aspects such as liposuction cannulas or injection syringes. Instead, novel strategies need to be explored to identify and isolate the specific fat precursors from ADSC and coordinate a physiologic induction of adipose tissues in the native environment. Although critics often raise the concern over implanting too many ADSC, too little rather than too much donor tissue is the usual challenge in tissue reconstruction. ADSC-seeded biomaterial constructs may provide a new direction for autologous fat transfer, such as de novo assembly of natural three-dimensional adipose tissues.28

Disclosures

The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

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