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The Future of Facial Fat Grafting

Brooker, Jack E., MD*; Rubin, J. Peter, MD*,†,‡; Marra, Kacey G., PhD*,†,‡

Journal of Craniofacial Surgery: May 2019 - Volume 30 - Issue 3 - p 644–651
doi: 10.1097/SCS.0000000000005274
Original Articles
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SDC

Fat grafting was first described in the early 20th century but for many years remained a relatively underused technique due to the unreliability of long-term volume expansion. Significant improvements in reliability have been made in the last 2 decades and there is a large body of literature pertaining to extraction, processing and injection methods to obtain more lasting effects. However, volume loss and graft resorption remain a major challenge in the long term and lead to unpredictability in results. Enriching adipose graft with stromal vascular fraction, ex vivo cultured adipose stem cells and platelet-derived growth factor among others is one method under active investigation which may assist graft survival through a range of mechanisms including increased angiogenesis. Breaking adipose graft into smaller fragments such that engrafted cells have greater access to donor-site oxygenation and nutrition is another method which in theory may promote survival. Presently, adipose grafting in the face is usually for the addition of volume to fill defects. However, the stem-cell containing fraction of adipose grafting (stromal vascular fraction) appears to exert a rejuvenating effect on overlying skin and soft tissue when administered alone. The application of these low-volume injections represents a significant shift in thinking away from mere volume expansion. These techniques have been tested in a range of animal models and some human studies. In this review, the authors provide a broad overview of present research and highlight both limitations in previous research and current areas of investigation.

*Department of Plastic Surgery

Department of Plastic Surgery, Department of Bioengineering, McGowan Institute of Regenerative Medicine

Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA.

Address correspondence and reprint requests to Kacey G. Marra, PhD, Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15213; E-mail: marrak@upmc.edu

Received 29 August, 2018

Accepted 22 September, 2018

The authors report no conflicts of interest.

Autologous fat grafting has been has been practiced for over 100 years, having first been described for the use of tuberculosis-induced changes to facial contours.1 The growth of fat grafting in the area of facial reconstruction was at first slow but over time gathered new applications. The use of fat grafting in the obliteration of frontal sinus described in the 1950s remains the gold standard today.2–4 In the 1980s and early 1990s, the use of fat grafts in cosmetic filling was described by multiple surgeons5–7; however, results often demonstrated a high degree of resorption and their reports garnered relatively little attention at the time.8 One 5-year study utilizing magnetic resonance imaging (MRI) to track the fate of facial fat grafts found that 49% of the original graft resorbed in the first 3 months, increasing to 55% by the first 6 months.9 The first demonstration of long-term survival in fat grafting was reported in the mid-1990s when Coleman reported his trials in the nasolabial fold.10,11 Unlike previous authors, Coleman did not extract the fat from the donor area at high negative pressure, break up the adipose tissue, or implant into the recipient area at high positive pressure. Instead fat was transferred in “parcels” such that cells had their own nutritional source upon implantation.10 This fat grafting procedure is now used in a wide range of clinical scenarios including aesthetic surgery, craniofacial abnormalities, posttumor resection reconstruction and trauma reconstruction.8 Additionally, fat grafting has been used for the surgical correction of a number of congenital craniofacial anomalies, including hemifacial microsomia and Parry-Romberg syndrome.12,13 Although initially seen as an autologous filler, interest soon grew in the apparent regenerative effects of engrafted lipoaspirate on overlying skin.14,15 Tissue overlying the grafts appeared to improve in the first year postoperatively; pore size decreased, wrinkles softened, skin pigmentation changes regressed.14 As a result the use of fat grafting has also been reported in scar resolution secondary to acne and burns.1,16 Rigotti et al contend that radiation scarring is due to anoxia and poor vascularity and contend that tissue healing in refractory scars relies on the stem-cell population within the graft secreting angiogenic factors which leads to microvascularization and oxygenation.17 There are several key advantages which render fat grafting attractive to plastic and reconstructive surgeons. Autologous fat grafting is versatile, lacks immunogenicity and is readily available in most patients.18 Patient satisfaction has generally been high with fat grafting, even when multiple procedures are required.19 Complications are also relatively low compared to prosthetics and fillers and include hematoma, ecchymosis, and resorption.19 Resorption remains a major challenge even with Coleman's improved method for harvesting and grafting; retention rates during the 1990s ranged from 20% to 90% while more recent studies report that resorption rates still vary from 20% to 60%.8 The sheer unreliability of long-term retention is itself a significant drawback to the use of facial fat grafting.

Adipose tissue is derived from the mesoderm with cellular components including endothelial cells, mesenchymal stem cells, fibroblasts, macrophages, pericytes and muscle cells which, after lipoaspiration, can be broken down (usually with collagenase) and separated by centrifuge.20 Adipose-derived stem cells (ASCs) are mesenchymal stem cells (MSC) with many properties similar to bone-marrow-derived stem cells (BMSC) and bear the relevant immunologic cell surface markers (CD105, CD73, CD29, CD44, CD90) (25).21 The ASCs are multipotent, like BMSCs, and can differentiate into multiple cell lines.22 The ASCs are capable of differentiating into mesenchymal phenotypes.22 These include mesenchymal tissue such as chondrocytes and osteocytes as well as nonmesenchymal cell phenotypes; cardiomyocytes, neurons, and endothelial cells have all been reported.22–25

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NEAR FUTURE APPLICATIONS

Nanofat Grafting

It has been suggested that stromal cells and preadipocytes represent the surviving population of cells in a graft as their metabolic rates are lower than mature adipose cells rendering them more resistant to the burden of hypoxia which follows grafting.27 Consequently, the concept of nanofat grafting is rapidly developing. Tonnard et al described their results in 2013. Their study involved the complete emulsification of abdominal fat such that no viable adipocytes were evident. This strategy is not intended for volume augmentation, but rather to both mechanically concentrate the ASCs and also create a more flowable graft material that can be applied with a narrow gauge injection cannula or needle. Emulsification was achieved by passing fat between two 10cc syringes connected by a luer-lok followed by filtration through a nylon cloth. The effluent collected was considered the “nanofat” sample. Nonmulsified fat was also used as a control (referred to as microfat if taken via a small multiport cannula with sharp 1-mm side-holes or macrofat if taken via a standard 3-mm cannula). Histologic staining confirmed the presence of viable adipocytes in macrofat and microfat samples and the absence of these in the nanofat sample. The stromal vascular fraction (SVF) was separated from the lipoaspirates and cultured for 7 days after which CD34 positive cells were identified. Neither the morphology (fibroblast in nature) nor the CD43 positive cells to SVF ratio differed significantly between nanofat, microfat, and macrofat lipoaspirates. A further 10 days in an adipogenic medium yielded cells which were round and lipid filled (again no difference was seen between the 3 lipoaspirate types either in quantity or quality). Grafting occurred in 67 patients, of which the greatest facial indication was perioral skin rejuvenation, followed by glabellar skin and dark lower eyelids.28 Three patients with images were selected by Tonnard et al which are displayed in Figure 1.

FIGURE 1

FIGURE 1

Uyulmaz and colleagues published their experience in a total of 52 patients with scars (n = 40), discoloration (n = 6), and wrinkles (n = 6) treated with nanofat injections. The processing method was the same as that described by Tonnard et al. The average volume of injected lipoaspirate was 4.6 mL. Pre- and postoperative photographs were judged by a panel of 3 physicians; a plastic surgeon, a general surgeon and a dermatologist who graded their outcomes independently as good, satisfactory or no change. In 66% of patients they judged the outcome to be good, with only 7% receiving a “no change” rating. Scars were judged to be highly improved (88% receiving a “good” grading) while wrinkles and discoloration had more equivocal results though as noted above, the sample sizes of these last 2 categories were small.29 Selected patient images before and after nanofat injection are shown in Figure 2.

FIGURE 2

FIGURE 2

Nanofat grafting represents a shift in thinking as regards the application of fat grafting.28 Traditional grafting relies on the volume which can be achieved through the implantation of mature adipose tissue. Long-term viability relies on the maintenance of this tissue vitality though the preservation of tissue architecture and the insertion of small “packets” to ensure vascularization and preservation of volume and consistency. Nanofat grafting relies on none of this, but instead utilizes the stem-cell population within the SVF to achieve rejuvenation of native tissue, resolution of scars, and reversal of aging signs. In the regulatory framework, this mechanical processing is still considered minimal manipulation and falls under the umbrella of a surgical procedure.

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Stromal Vascular Fraction-Enriched Fat Grafting

Facial fat grafting has traditionally been utilized to augment volume in the various compartments of the face.11,30 In youth, adipose tissue in the face is abundant, diffuse, and balanced; however, as the face ages, there is increasing imbalance which develops in volume; some compartments become hypertrophied while others become atrophied.30

The SVF is the product of lipoaspirate after collagenase degradation. This leads to 2 distinct phases; a floating mature adipocyte fraction and a lower, aqueous fraction containing cellular components.31 Separation of the aqueous component of the degradation product yields a heterogenous mixture of cells including ASC, endothelial precursor cells, macrophages, smooth muscle cells, lymphocytes, pericytes, and preadipocytes.31

Given the ASC and stromal stem-cell population, it was theorized that SVF enrichment of adipose tissue grafts may improve graft volume retention. A number of animal studies, some of which are summarized in Table 1, compared graft retention rates of adipose/SVF grafts to adipose grafts alone and overwhelmingly reported superior rates in the adipose/SVF cohorts. Matsumoto et al published one of the earliest studies using an immunodeficient mouse recipient model for human adipose grafts.32 It was found that the addition of SVF significantly improved graft retention rates and through immunofluorescent tagging of the SVF cells, they were able to later identify them between mature ASC in the connective tissue and some expressed Von Willebrand factor, suggesting increased angiogenesis was one part of their mechanism of action.32 Another study by Paik et al used a similar model but employed varying doses of cells ranging from 0 (control) to 10 million and found that graft retention rates at higher doses of SVF were poorer which the authors hypothesized was due to increased metabolic demand from the increased loading of stem cells which compete for nutrients with the adipocytes in the postgraft period.33 Rasmussen et al included 13 animal studies for SVF-enriched adipose grafting in their review and found a 0.65- to 2.5-fold improvement in volume retention compared to adipose grafting alone after a mean of 13 weeks.34

TABLE 1

TABLE 1

Human studies have been reported using SVF-enriched grafts to the face. In their review, Toyserkani et al included 3 studies of SVF-enriched facial fat grafting, summarized in Table 2, all of which led to significant increases in volume retention compared to fat grafting alone.35 In their meta-analysis, Zhou et al included 4 studies using SVF-enriched fat grafting to the face and found a significant overall increase in volume retention in the SVF-enriched group (71%) compared to the unenriched group (52%).36 They also found that the number of reoperations was reduced from 24.2% to 10.6%.36 Gontijo-de-Amorim et al published a prospective comparative study of 30 patients with hemifacial soft tissue volume loss from tumor excision, Parry-Romberg syndrome, and trauma.37 Fifteen patients received standard autologous fat grafting while the remaining 15 received grafting enriched with SVF. At 12 months a subset of 5 patients from each group underwent volumetric analysis by computed tomography (CT) and all had aesthetic outcomes judged by independent surgeons at 1 to 2 years.37 Example patient images (both with Parry-Romberg syndrome) prior to grafting and 2 years after grafting are shown in Figure 3, with the top patient receiving only un-enriched grafting and the bottom patient receiving SVF-enriched grafting.

TABLE 2

TABLE 2

FIGURE 3

FIGURE 3

Patients receiving SVF-enriched grafting were judged to have an “excellent” outcome by the independent surgeon panel in 82.5% of patients while those receiving graft only were judged “excellent” in 47.6% of patients. The CT volumetric analysis showed a volume loss of 24% in the un-enriched control group and 9.6% in the enriched group. Flow cytometry identified an average of 16,000 mesenchymal stem cells in each of 25 SVF pellets analyzed.37 Facial rejuvenation has also been examined using SVF-enriched grafts. Charles de Sá et al harvested abdominal fat from 6 facelift patients and extracted SVF from the lipoaspirate.38 Patients received SVF-enriched fat to the right preauricular area while expanded ASC in culture (number of passages unknown) was administered to the left preauricular area. Skin biopsies were assessed 3 months after grafting using histologic and electron microscopy analysis.38

Important considerations for the use of ASC enriched fat grafts are the regulatory constraints, especially in the United States and European Union, and the added cost of the procedure versus fat grafting alone. Unlike mechanical emulsification, deliberate separation of SVF is considered “greater than minimal” manipulation in many regions and the cell product has a higher regulatory burden.

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Cultured ASC-Enriched Fat Grafting

The ASCs represent a more homogenous population of cells compared to SVF after culturing.48,49 A number of animal studies specifically examined ASC enrichment have been reported. For example, Zhang et al harvested adipose from donor rats and extracted the SVF before culturing in fetal bovine serum.42 The ASCs were isolated and expanded to passage 4, mixed with adipose grafts and injected into recipient rats. CD34 staining was greater at 14 days in the ASC-enriched grafts and volume retention was greater at 3 months than nonenriched grafts.50 Piccinno et al utilized a rabbit model and harvested SVF from animals from which they then isolated ASC via 4 sequential passages.43 These ASCs were mixed with hyaluronic acid and autologous adipose grafts and implanted. The ASC-enriched grafts showed greater vascularity and reduced necrosis at 14 days and after 3 months; ASC-enriched grafts also showed significantly greater volume retention.43 Moseley et al published one of the few studies in mice comparing both cultured ASC and fresh ASC-enriched grafts in mice. Both were reported to be superior in volumetric retention and qualitative appearance (abundance of adipocytes and lower fibrosis than controls) and the transgenic ASCs were still present upon immunohistochemical staining at 6 months.44 Rasmussen et al reviewed 11 animal studies using cultured ASC with 8 reporting significant improvement in volume retention over adipose grafting alone.34 In general, the studies reported greater vascularity and decreased necrosis cysts on histology in the ASC-enriched grafts.34

Human studies with ex vivo expanded ASC are less numerous than those for SVF-enriched adipose grafts; however, a number do exist. Kølle et al performed the first randomized controlled trial whereby patients underwent 2 separate liposuction procedures, 1 to harvest adipose for injection, and the other for isolation of ASCs.54 The 2nd aspiration was split into 2, with 20 million ASCs added to 1 half only. The ASC-enriched and un-enriched grafts were then randomly injected into the posterior part of the right and left upper arm. Volume was measured by MRI at the time of engraftment and 121 days later where the ASC-enriched graft was found to have a retention of 80.9% versus 16.3% for the un-enriched graft.54

Koh et al applied this to the face in 5 subjects with Parry-Romberg syndrome, with 5 further subjects receiving microfat injections only as controls.55 Donor fat was obtained from abdominal lipoaspirates and cultured for 14 days whereupon microfat in the experimental group was enriched with 1 × 107 cells. Patients underwent CT volumetric analysis at 6 months which showed a 2.51-fold fat uptake rate in the experimental versus control group. Figure 4 shows the front-on views taken preoperatively, 6 months postoperatively, and 12 postoperatively showing long-term retention though no control group images were included by Koh et al.

FIGURE 4

FIGURE 4

At present at least 1 human trail examining the utility of ex vivo expanded ASC in facial fat grafting is currently underway with no results posted at the time of writing (NCT03258164). Barriers to clinical application of this technology include not only the time and resource intensive process of ex vivo expansion of primary stem cells but also regulatory hurdles as well. Currently, human cell based therapies are allowed to be marketed only with FDA approval unless they meet certain stringent parameters including minimal manipulation, something which all ex vivo expanded cultures have undergone.64 At present a significant amount of rigorous evidence from controlled trials will be required before this technology can be effectively marketed.

More radical utilization of ASC has been reported in the repair of osseous craniofacial defects. Multiple in vivo studies in rats, rabbits, and mice have been reported some of which are summarized in Table 1. These studies have shown inconsistent results, with some showing considerable efficacy using implantable matrices seeded with undifferentiated with ASC, while others have shown that only osteo-induced ASC are effective. A clinical report of ASC-seeded matrices describes injection into the calvarial defect scarred by infection in a 7-year-old girl and another report describes treatment in the hemimaxilla of a 65-year-old male.65,66 This area of ASC utilization in the head and neck will require considerably more clinical evidence before it becomes a standard reconstructive option.

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Platelet-Rich Plasma Enrichment

Platelet-rich plasma (PRP), released from the α-granules of platelets, contains numerous growth factors including platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-β) and vascular endothelial cell growth factor (VEGF).67 Liao et al reviewed the field of PRP enrichment in fat grafting, identifying 5 animal studies published to date which together suggested an improvement in graft volume maintenance.68 The authors hypothesize that this improvement is due to PRPs nutrient effect through the plasma component; enhancing adipogenesis through a range of growth factors including PDGF, platelet-derived angiogenesis factor (PDAF), and VEGF; stimulating the proliferation and differentiation of preadipocytes and ASCs.68 Liao and colleagues’ own study employed human-derived ASCs and expanded the cells in one of four culture mediums: ASCs cultured in general culture medium alone; ASCs in general culture medium +5%, 10%, 15%, or 20% PRP; ASCs cultured in adipogenic differentiation medium alone; ASCs cultured in adipogenic medium +5%, 10%, 15%, or 20% PRP.69 It was found that PRP significantly increased ASC proliferation while inhibiting adipogenic differentiation even in adipogenic media which appeared to be mediated through the bone morphogenetic protein receptor and the fibroblast growth factor receptor.69

One of the earliest studies of PRP-enriched facial fat grafting was undertaken by Cervelli et al who utilized a patient and operator assessment of various aspects of facial volume and contour. It was found that PRP-enriched grafts maintained 70% of contour restoration at 18 months compared to 31% for fat grafting alone.61 Gentile and colleagues reported similar results in their study60 where 10 patients received PRP-enriched fat (5 males, 5 females, 5 with burn scars, 5 with posttraumatic scars), ten received SVF-enriched adipose tissue (discussed earlier) and 10 patients simple fat grafting. Patients receiving PRP-enriched grafting demonstrated a 69% contour restoration and volume retention at 1 year of follow-up compared to 63% with the SVF-enriched fat and 39% in the control group receiving only fat grafting.60 Pre- and postoperative of both SVF and PRP-enriched grafting are shown in Figure 5.

FIGURE 5

FIGURE 5

Sasaki published one of the largest human studies to date with 106 patients undergoing PRP-enriched facial fat grafting in addition to face lift for cosmetic purposes.57 Ninety two patients received un-enriched fat grafting while 9 patients received SVF-enriched adipose and 29 received SVF and PRP-enriched adipose. Volumetric analysis was performed using 3-dimensional photography and both PRP and SVF enriched grafts had significantly greater volume retention at 12 months compared to fat grafting alone though the combination of SVF and PRP did not yield any further improvement.57

Luck et al published one of the most comprehensive systematic reviews of PRP-enriched fat grafting.70 While not specific to the face, multiple facial grafting studies are included in the overall analysis which found that in all but 3 studies the addition of PRP augmented volume retention. Luck et al did however point out the huge methodology variation in the studies published as well as the highly variable ratio of PRP to fat studied meaning that further clinical trials will be needed before this technique becomes a fixture of clinical practice. This echoes the conclusions of Serra-Mestre et al in their 2014 review of the subject which included 3 facial grafting studies and which found significant potential for the use of PRP enrichment and a possible dose-dependent efficacy.71

Facial rejuvenation using PRP has been extensively reviewed by Motosk et al in their review on the subject.72 They identified 437 patients across 7 studies who underwent singular or multiple PRP-enriched lipofilling injections primarily in the nasolabial folds and malar regions all but one of which reported improved outcomes with the addition of PRP.72 The proangiogenic influence of PRP is the proposed mechanism for these improved outcomes.72

Finally, Picard et al in their review identified 11 human clinical studies and 7 animal studies using PRP-enriched grafting facial rejuvenation and reconstruction with 9 reporting a significant improvement in survival of adipocytes and propose vascularization as the mechanism for this.73 Based on their findings, it was recommended 20% of calcium activated PRP to enhance aesthetic and reconstructive facial fat grafts.73

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CONCLUSION

Although great strides have been made in the field of facial fat grafting in the past three decades, challenges which have dogged the field for nearly a century remain including unreliable and irregular resorption over time. A multitude of techniques have been attempted to augment the graft and improve its survival, including cultured ASC, SVF, and PRP all of which have been described in this review. While these treatment modalities are advocated by many clinicians, they have several things in common; a much greater animal-based body of evidence than clinical, significant inconsistencies in study design across human-based studies which often preclude comparisons, small sample sizes in human-based studies which limit power and a complete absence of randomized, controlled trials.

The ASCs and modified adipose tissue grafting have the capacity to fundamentally alter clinical practice and to introduce a new paradigm in head and neck reconstruction particularly in the realm of osseous healing which continue to represent some of the greatest surgical challenges. However, a much greater body of evidence in human-based trials is still needed in order for strong validation and widespread adoption in clinical practice. This review provides a fairly comprehensive summary of the many exciting possibilities which exist in the field of facial fat grafting.

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Keywords:

Adipose; craniofacial; fat; graft; stem cell

© 2019 by Mutaz B. Habal, MD.