A Comparison of Cell-Enriched Fat Transfer to Conventional Fat Grafting after Aesthetic Procedures Using a Patient Satisfaction Survey

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1 CLINICAL ARTICLES A Comparison of Cell-Enriched Fat Transfer to Conventional Fat Grafting after Aesthetic Procedures Using a Patient Satisfaction Survey Brian Mailey, MD,* Salim Saba, MD,* Jennifer Baker, MD,* Christopher Tokin, MD,* Sean Hickey, MD,* Ryan Wong, MD,* Anne M. Wallace, MD,* and Steven R. Cohen, MD*Þ Introduction: The role of regenerative cells in adult human fat is still unfolding. At present, limited clinical studies comparing patient satisfaction with cellenriched fat transfer (CEFT) to conventional autologous fat transfer (AFT) for aesthetic indications have been performed. Herein, we present our data obtained from patient satisfaction questionnaires. Methods: Patients undergoing fat grafting received AFT or CEFT. Study participants were surveyed for overall satisfaction, symmetry, deformity, scarring, and pigmentation. Hospital charts were reviewed for complications, and patient survey responses between the groups were compared. Results: Between January 2009 and September 2011, 36 patients had 6-months follow-up and were mailed surveys. Of these, 17 (12 CEFT and 5 AFT) returned completed Patient Satisfaction Rating surveys. At a median follow-up time of 10.7 months, the overall mean satisfaction rate was 5.2 of 6 (5.3 vs 5.0 for CEFT and AFT, respectively, P = 0.42). There were no significant differences about deformity (5.1 vs 4.7, P = 0.50), symmetry (4.5 vs 5.0, P = 0.48), or scarring (5.3 vs 4.5, P = 0.23). However, pigmentation was improved in the CEFT vs the AFT groups (P G 0.001). No patients in the AFT group noted skin pigmentation improvement, whereas 7 of 12 receiving CEFT noted improvement in skin pigmentation. Conclusions: Cell-enriched fat transfer to the face and body of aesthetic patients produces high satisfaction rates. Our preliminary data demonstrates similar satisfaction with regard to symmetry, scarring, and deformity in patients treated with CEFT versus AFT, without any complications. Unexpectedly, a clinical and statistical improvement in pigmentation was seen for patients treated with CEFT over AFT. Further studies need to be done to better understand this phenomenon. Key Words: fat graft, regenerative cell, stem cell, patient survey, pigmentation, patient satisfaction (Ann Plast Surg 2013;70: 410Y415) Autologous fat grafting for recontouring soft tissue defects began surging in popularity in the 1980s. 1,2 Early experiences focused on craniofacial soft tissue augmentation 3 ; however, reconstructive surgeons quickly expanded applications of autologous fat transfer (AFT) to include reconstruction of congenital anomalies, traumatic Received November 7, 2012, and accepted for publication, after revision, November 15, From the *Division of Plastic Surgery, School of Medicine, University of California San Diego; and Faces+, San Diego, CA. Presented at 62nd Annual Meeting of California Society of Plastic Surgeons, May 27, 2012, Coronado, CA. Note from the CSPS Scientific committee: The CSPS Scientific Committee has reviewed this manuscript and it is to be published in the special CSPS edition set for April Conflicts of interest and sources of funding: Dr Cohen is a consultant for Cytori Therapeutics. No portion of this study was funded by Cytori or any other agency; this was an investigator-initiated study. This work was supported by the Plastic Surgery Foundation. Reprints: Steven R. Cohen, MD, FACES+, 4510 Executive Center Dr, Suite #200, San Diego, CA scohen@facesplus.com. Copyright * 2013 by Lippincott Williams & Wilkins ISSN: /13/7004Y0410 DOI: /SAP.0b013e31827e5353 sequelae, and oncologic resections. 4Y9 Aesthetic surgeons have also used fat as an injectable for soft tissue rejuvenation. 10 Inherent properties of fat, namely, safety, technical ease, autologous nature, and possibility of altering outcomes by repeat intervention make it an ideal material for reconstruction. Despite excellent immediate results, traditional fat-filling procedures claim inconsistent long-term durability with up to 70% of the initially implanted tissue volume reabsorbed. 11,12 We now know that aspirated adipose tissue consists of 2 components, namely, lipid inclusion containing adipocytes and stromal cells containing a cellular compartment. 13 Recently, these inherent properties of the preinjected fat have been proposed as the explanation for differences in final graft survival. 14Y16 In 2001, the existence of multilineage regenerative cells in adult human fat was recognized and published by Zuk et al. 17,18 These regenerative cells maintain the ability to undergo cellular differentiation and regeneration. 13 In particular, adipose-derived regenerative cells (ADRCs) have the potential to differentiate into tissue types of mesenchymal origin, namely, adipocytes, chondrocytes, osteoblasts, and myoblasts, depending on environmental influences. 19 The therapeutic potential of these multipotent cells have become of basic interest to many disparate specialties of medicine and may be the explanation for variable fat graft survival. Comparison of whole fat to lipoaspirated fat noted whole fat contained twice the number of progenitor cells. 20 These results were explained 2-fold. First, ADRCs are primarily located around large vessels, which are mostly left at the donor site during traditional liposuction. Second, some ADRCs are released into the supernatant portion of the liposuction aspirates and discarded. These important findings offer additional insight into harvest and preparation of fat grafts, and potentially support the use of lipoaspirated fat enriched with ADRC. Other promising features of fat grafting have recently been recognized. These include an increase in vascularity caused by proangiogenic factors and dermal regeneration. 21 The inherent properties of preinjected fat (ie, adipocyte maturity, extracellular scaffold, and presence of ADRC) may explain theses differences in fat graft behavior. 14,15 The emergence of commercially available devices to enrich preinjected fat with autologous ADRC has introduced a practical way of incorporating regenerative cells into clinical practice. Similar to many new technologies, regenerative cell-enriched fat has been received with both promise and skepticism. To decipher the degree of true science versus marketing-hype, several authors have reported their clinical and preclinical data. Most of the reports have been promising, 20Y22 but additional work is still needed before a consensus and exact utility for the cells can be reached. In our practice, we have offered patients undergoing fat transfer to have their fat enriched with autologous ADRC before injection since During the past 2 years, our experience using this method has been positive from both investigators and patients. The purpose of the current study was to determine and compare patient satisfaction scores in all patients undergoing fat grafting, using either the conventional, standard AFT method or a cell-enriched fat transfer (CEFT). This was conducted using a patient satisfaction survey questionnaire. We also reviewed patient charts for any systemic or Annals of Plastic Surgery & Volume 70, Number 4, April 2013

2 Annals of Plastic Surgery & Volume 70, Number 4, April 2013 Patient Survey Comparing CEFT to AFT local complications related to fat grafting or the collagenase enzyme used for the cell-enrichment process. METHODS Study Population All patients between January 2009 and September 2011 who underwent fat grafting for aesthetic purposes were considered for study. Eighty-four (54 CEFT and 30 AFT) patients underwent fat grafting procedures. Two standardized processing techniques were used: (1) a bilaminar filtration technique (AFT) and (2) a bilaminar filtration technique enriched with ADRC (CEFT). At the time of study, 36 patients had 6-months follow-up and were mailed questionnaires to return (Fig. 1). Seventeen patients returned completed surveys and were used for this study. Patients rated scores from 1 to 6 on deformity, symmetry, scarring, pigmentation, and satisfaction, with 6 being the most highly satisfied and 1 being unsatisfied. Adipose Tissue Harvesting Fat harvesting was performed under general anesthesia when done in conjunction with other aesthetic procedures (eg, facelift) or local anesthesia when done alone. Approximately twice the intended volume of the graft was harvested using standard tumescent, syringebased liposuction technique. Fat was harvested by hand with a 3-mL cannula and a 60-mL syringe. Adipose tissue was subsequently divided into 2 fractions (Fig. 2), one for extraction of ADRC and the other cleaned with the Pure Graft bilaminar filtration system (Cytori Therapeutics, San Diego, Calif ) (Fig. 2). Preparation of the Cell-Enriched Fat Graft One fraction of the lipoaspirate was added to the Celution system (Cytori Therapeutics) using a proteolytic collagenase enzyme reagent (Celase; Cytori Therapeutics) releasing the stromal vascular fraction (eg, ADRC) from adipose cells (Fig. 3). The Celution system digests adipocytes, while preserving the stromal vascular cellular fraction (eg, ADRC, endothelial cells, vascular smooth muscle cells, tissue resident macrophages, and perivascular cells) (Fig. 3). The cells were then washed to remove residual enzyme and concentrated within the closed automated system in the operating room. Total time for the digestion and enrichment process was approximately 1.5 hours. The suspension of ADRCs (È5 ml) was retrieved from the Celution system using an 18-gauge spinal needle. This aliquot of cells was then added to the second fraction of harvested fat that had been washed using the PureGraft gravity sedimentation/flotation system; this combination of the 2 fractions was then termed the CEFT (Fig. 2). The Celution system is not Food and Drug Administration approved; this study was approved through the Sharp Healthcare System institutional review board. FIGURE 1. An example of the survey mailed to all patients after fat transfer (AFT and CEFT). Patients rated scores on deformity, symmetry, scarring, skin pigmentation, and overall satisfaction with treatment results. * 2013 Lippincott Williams & Wilkins 411

3 Mailey et al Annals of Plastic Surgery & Volume 70, Number 4, April 2013 FIGURE 2. Fat is harvested with a 3-mL cannula and 60-mL syringe. Approximately half of the adipose tissue is cleaned with the PureGraft bilaminar filtration system (Cytori Therapeutics) and the other half is used to isolate ADRC. The 2 fractions are then combined to create a cell-enriched fat graft. Fat Grafting Technique (CEFT or AFT) Two-millimeter stab incisions were made at locations that could be concealed. For facial fat grafting, an 18-gauge needle was used to make needle punctures in key areas such as the temporal region, lateral eyebrows, malar regions, upper and lower eyelids, the nasolabial folds, marionette basins, labiomental grooves, prejowl regions, lips, buccal fat pads, and at the mandibular border. Pretunneling was performed with a blunt cannula, releasing scar tissue and defining tissue planes for injection. Fat injections were performed using a byron cannula attached to a Celbrush (Cytori Therapeutics), which consists of a stainless steel thumb controlled syringe adapter designed to provide microdroplet dispersion of graft (Fig. 4). The Celbrush permits small threads of fat graft to be deposited in a retrograde fashion. Delivery of the graft was accomplished using a fan-shaped pattern of injections in different trajectories to maximize the graft to native tissue surface area (Fig. 5). The range of total amount of fat grafted is from approximately 20 to 200 ml in the face at a single setting. Statistical Analysis The primary outcomes of interest were patient reported scores for satisfaction, deformity, scarring, symmetry, and pigmentation, which was calculated from questionnaire responses and reported as a mean with standard deviations or standard error of the mean, as appropriate. Patients were asked to categorically judge yes or no for improvement in scar appearance and improvement in skin pigmentation. The patient cohort was stratified into 2 groups based on receiving cell enrichment into their fat graft, with the main factor of interest being a comparison of patient reported scores between the conventional AFT group to the CEFT group. FIGURE 3. The lipofraction used for isolation of ADRC was digested using a proteolytic enzyme reagent, thereby releasing the stromal vascular fraction (eg, ADRC) from adipose cells. The enzyme digests adipocytes, while preserving the stromal vascular cellular fraction (eg, ADRC, endothelial cells, vascular smooth muscle cells, tissue resident macrophages, and perivascular cells) (Fig. 2). The cells were then washed to remove residual enzyme and concentrated within the closed automated system * 2013 Lippincott Williams & Wilkins

4 Annals of Plastic Surgery & Volume 70, Number 4, April 2013 Patient Survey Comparing CEFT to AFT FIGURE 4. The Celbrush consists of a stainless steel thumb controlled syringe adapter designed to provide microdroplet dispersion of graft by permitting small threads of fat graft to be deposited in a retrograde fashion. Fat is delivered using a fan-shaped pattern of injections in different trajectories to maximize the graft to native tissue surface area. Demographic and clinical factors were compared between groups by the W 2 test for categorical variables and Student t test for continuous variables. Satisfaction scores were also compared using similar statistical methods. All reported P values were 2-sided with values of G0.05 considered statistically significant. Statistical analyses were performed using SPSS (version 12; Chicago, IL). RESULTS Characteristics of Study Population Of the 36 surveyed patients who underwent fat transfer, 17 returned completed patient satisfaction surveys giving a 47% overall response rate (Table 1). Women comprised the majority (82%, n = 14) of patients with only 3 (18%) patients being men. The most common site of injection was the face (88%, n = 15), with only 2 patients receiving fat graft to the breast. The mean follow-up time was 10.7 months. There were no complications reported in our entire cohort. Patients reported scores for various outcomes of interest on a scale of 1 to 6. The overall response rates were very positive for symmetry (4.7/6), deformity (5.0/6), scarring (5.2/6), and overall mean satisfaction (5.2/6). For pigmentation, patients reported a score and either Yes improved or No not improved; 7 of 17 (41%) patients reported improvement (Table 1). Comparison of CEFT Versus AFT Survey Responses Of 17 returned survey questionnaires, the majority received CEFT (n = 12, 71%) and only 5 (29%) underwent conventional AFT (Table 2). The face was the most common recipient site for both the CEFT and AFT groups (83% and 100%, respectively, P = 0.45). There were no differences between groups for symmetry, scarring, deformity, or overall satisfaction (all P ). There was a statistically significant difference between groups for pigmentation (P G 0.001), where 7 of 12 patients in the CEFT group reported improvement and no patients in the conventional AFT groups reported any improvement (P G 0.001) (Table 2). Figures 6 and 7 are representative photograph of a patients before and 12 months after surgery. Patients with more severe photodamage reported even more pronounced effects. DISCUSSION Over the past decade, many investigators have explored various in vitro and in vivo effects of ADRC. 20Y22 Most reports have shown great promise, but the exact clinical significance of regenerative cells is still unclear. The safety and efficacy of ADRC-enriched fat grafting for soft tissue augmentation was reported in the RE- STORE-2 trail, where improvements in breast defects occurred using ADRC-enriched fat grafts, with stable results at 12 months. 22 This FIGURE 5. Needle punctures (18-gauge) were made at aesthetically optimal locations. Pretunneling was performed with a 1.5-mm blunt byron cannula and fat injections were performed with multiple passes in a fan-shaped pattern to maximize surface area contact between the graft and native tissue. TABLE 1. Characteristics of Study Population Factor n (% or SD) Sex Male 3 (18) Female 14 (82) Site of fat grafting Face 14 (82) Breast 2 (12) Neck 1 (6) Follow-up time, mean (SD), mo 10.7 T 5.3 Complications 0 (0) Fat grafting method AFT 5 (29) CEFT 12 (71) Patient survey response, mean (SD) Overall satisfaction 5.2 T 0.75 Symmetry 4.7 T 1.0 Scarring 5.2 T 0.83 Deformity 5.0 T 0.85 Pigmentation 3.6 T 2.8 Investigator survey response Overall satisfaction 4.3 T 0.49 Symmetry 4.6 T 0.51 Scarring 4.7 T 0.61 Deformity 4.3 T 0.49 Pigmentation 4.7 T 0.61 * 2013 Lippincott Williams & Wilkins 413

5 Mailey et al Annals of Plastic Surgery & Volume 70, Number 4, April 2013 TABLE 2. Comparison of Patient Reported Responses, AFT Versus CEFT Groups Factor CEFT, n = 12 (%) AFT, n = 5 (%) Sex Male 3 (25) 0 (0) 0.24 Female 9 (75) 5 (100) Site of fat grafting Face 10 (83) 5 (100) 0.45 Breast 2 (17) 0 (0) Follow-up time, mean (SD), mo 12.3 (1.5) 7.0 (2.1) 0.06 Complications 0 0 N/A Patient survey response (mean) Overall satisfaction Symmetry Scarring Deformity Pigmentation G0.001 study also concluded volume augmentation at 6 months can be considered permanent, with continued improvement over time in the tissue quality, as measured by an increase in skin elasticity and reduction in scar tethering. 22 Further evidence using a murine model revealed ADRC-supplemented grafts resulted in a higher capillary density and 2-fold higher fat graft retention. 21 Similar to findings of other authors, we demonstrate positive findings enriching fat with ADRC. Using a patient satisfaction survey, we found most patients receiving CEFT reported an improvement in skin pigmentation, whereas no patients in the AFT group noted any improvement. This result, albeit preliminary, may be due to improved vascularity and/or dermal regeneration. Additional studies are required to determine if this effect is preserved in larger sample sizes. The current study, to our knowledge, is the first to report skin pigmentary improvement from ADRC therapy in the literature. We recognize the small size of our cohort is a significant limitation. Several techniques have been proposed to achieve more consistent long-term outcomes with traditional fat grafting. 22 Most described techniques have focused on different processing methods before fat injection. 23 These methods have included centrifugation to remove the nonliving components (oil, blood, water, and lidocaine), 24 the use of whole fat versus suction assisted lipectomy, processing fat with nutrients, 25 anabolic hormones or the use of bioenhancers (eg, insulin, insulin growth factor, and type 1 collagen). 26 A review of the literature reveals a lack of support for any single method and despite intense interest in graft survival, a consensus for producing consistent results has not been reached; no single method of graft preparation is in widespread use. Enrichment of traditional fat grafts with ADRC may be the method for stabilizing outcomes and producing more predictable results. We found an overall high satisfaction rate for all patients in our cohort, using either conventional or cell-enriched fat. This high satisfaction rate is somewhat confounded by concomitant procedures performed in conjunction with the fat transfer (eg, facelift), as patients report satisfaction with their final overall outcome. Despite this, our results are the first report of pigmentation improvement using fat enriched with ADRC and are not likely the result of concomitant procedures, as no patients in the AFT group noted any improvement. The mechanism of action for pigmentary improvement by fat enriched with ADRCs can be explained by reports, which have shown ADRCs to have antioxidant and wound-healing effects in the skin through secretion of growth factors and by activating fibroblasts. More specifically, P FIGURE 6. A 58-year-old woman before (left) and 6-months postoperative (right) after mini facelift, with injection of 40 ml of cell-enriched fat graft. She reported skin pigmentary improvements. in culture, ADRCs have shown whitening effects by inhibiting the synthesis of melanin and the activity of tyrosinase. 27 Histologic analysis after subcutaneous injection of ADRC performed on a murine model confirmed significant increases in collagen synthesis, increased dermal thickness, collagen density, and fibroblast number, therefore promoting ADRCs as a potential therapeutic modality for aging skin. 28 Confirmation of objective in vivo clinical improvement will need to include an assessment using colorimetry, diffuse reflectance spectroscopy, or another validated measurement tool to document the existence of these changes and their true clinical significance. The treating physician, who rated scores on an identical scale, also evaluated each patient s change. These ratings were high for each modality, including deformity, symmetry, scarring, pigmentation, and satisfaction. There were no statistical differences between groups or between patient responses and are not included in this report as they added little additional information to that documented by the patient reported scores. Of note, we observed the most pronounced effects in skin improvement for patients with severe photodamage; this may represent a patient population most likely to benefit from this therapy. Our study is limited by our sample size, lack of randomization, and use of concomitant procedures at the time of fat grafting. Despite these problems, we feel the results of our study were unexpected and deserve further investigation. FIGURE 7. Before (left) and one-year after (right) face and neck lift, endoscopic brow lift with cell enriched fat transfer to the cheeks, temporal regions, lips nasolabial folds and cheeks * 2013 Lippincott Williams & Wilkins

6 Annals of Plastic Surgery & Volume 70, Number 4, April 2013 Patient Survey Comparing CEFT to AFT In conclusion, results of our study confirm previous findings regarding the safety and efficacy of ADRC-enriched fat transfer. 20Y22 No patients in our study developed complications attributed to their aesthetic procedures and patients rated their satisfaction as very high. Unexpectedly, most of patients undergoing CEFT reported improvements in overall skin pigmentation, whereas no patients in the AFT group reported any improvements. We believe this observation deserves further investigation to determine if ADRCs affect skin pigmentation in larger studies and to determine the cellular explanation. ACKNOWLEDGMENT Informed consent was received for publication of the figures in this article. REFERENCES 1. Report on autologous fat transplantation. ASPRS Ad-Hoc Committee on New Procedures, September 30, Plast Surg Nurs. 1987;7:140Y Coleman WP 3rd. Autologous fat transplantation. 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