Lipofilling with or without Platelet-Rich Plasma Does Not Significantly Change Overlying Skin Elasticity in This Study
Analyzed R7 parameter data (representing true elasticity) from both groups showed no significant difference before intervention (Fig. 5). The platelet-rich plasma–positive group did not differ significantly from the placebo group at any time point. Data correction for age, room temperature, humidity conditions, and baseline (preoperative) measurements resulted in similar findings.
Analyzed R5 and R6 Data Showed Comparable Values in Both Groups, at Every Follow-Up Time Point
Regression analysis of the preoperative R7 parameter as a function of age showed a negative correlation in both groups, comparable to the result shown by Ezure and Amano.21 However, after intervention, the correlation reverses (Fig. 6), which could be a sign of facial rejuvenation. Changes were most noticeable in the platelet-rich plasma–positive group: the high prediction value of the regression line (R = 0.542, p = 0.055) could suggest that the sample size in this study was not adequate. Interestingly, this reversal was only notable on the location 1 R7 paremeter, not on location 2 or with the R5 and R6 parameters.
Changes of the Nasolabial Fold
Summarized data from both groups at every follow-up time point are presented in Figure 7; lower scores represent a less prominent nasolabial fold. Grading scores showed a high level of agreement between each expert (Spearman intraclass correlation coefficient for all: r > 0.576, p < 0.001).
Preoperative scores were comparable in both groups (mean ± SD for platelet-rich plasma–negative, 2.359 ± 0.1531; platelet-rich plasma–positive, 2.622 ± 0.2388; p > 0.05). Data after 3 months and 1 year also showed comparable results, with no significant differences between both groups at any time point. Furthermore, no changes between preoperative and postoperative scores within each group were found.
Addition of Platelet-Rich Plasma Speeds Up Recovery but Does Not Increase Patient Satisfaction
Patient questionnaire–reported recovery time, derived from the number of days until return to work/social activities with or without camouflaging agents, showed a significantly faster recovery in the platelet-rich plasma–positive group (Table 2). Mean ± SD number of days until return to work/social activities with camouflaging agents was 9 days (9.133 ± 3.701 days; p < 0.01) in the platelet-rich plasma–positive group and 15 days in the control group (15.43 ± 4.949 days). Return to work/social activities without camouflaging agents supported this finding (platelet-rich plasma–positive group, 14.87 ± 4.604 days; platelet-rich plasma–negative group, 20.57 ± 6.61 days; p < 0.05). Questions regarding noticeable differences in facial volume and skin quality after 2 and 4 weeks showed no differences (p > 0.05).
Patient satisfaction and changes in volume and skin quality, reported after 6 months, proved to be similar in both groups (data not presented). Overall satisfaction was reported as “moderate.” Positive skin changes were reported by several patients in both groups, contradicted by patients that did not notice any skin changes at all. Overall, the level of recommendation of the procedure to peers was negative for both groups, mainly because of higher expectations of the effect of the procedure.
This randomized, placebo-controlled, double-blind study was undertaken to investigate the possible beneficial effects of adding platelet-rich plasma to aesthetic facial lipofilling in a well-defined healthy patient cohort. The results clearly demonstrate that the addition of platelet-rich plasma to the lipograft significantly reduces the patient’s reported recovery time. However, the addition of platelet-rich plasma to the lipograft does not significantly improve skin elasticity, produce changes in nasolabial fold depth, or change overall patient satisfaction compared with lipofilling alone. The reversal in the correlation of net elasticity as a function of patient age could suggest some form of rejuvenation by lipofilling that is enhanced by platelet-rich plasma, but lacked significance with the number of patients in this study.
Reported in vitro effects of platelet-rich plasma10 , 22–24 thus could not be reproduced in our clinical study setting, possibly because of uncontrollable patient-related confounding factors combined with a small therapeutic window for effect. Moreover, reported effects of “normal” (not stromal vascular fraction/adipose-derived stem cell enriched) lipofilling on skin rejuvenation, as has been reported and suggested to be seen in clinical studies when used in combination with face-lift surgery,2 , 9 could also not be addressed; this forces us to question what the additional effect (other than some volume enhancement) of normal lipofilling is when used during face-lift surgery.
Lipofilling Does Not Increase Skin Elasticity in the Aging Face, Even with Added Platelet-Rich Plasma
Since the comeback of lipofilling, suggestions have been made that it is “more than a filler”2 and may induce rejuvenation of the skin. However, this adipose-derived stem cell–induced effect is only well studied after deep dermal injury (e.g., thermal radiation damage, excessive scarring4 , 25–27). Surprisingly, skin rejuvenation of the normal aging skin has been described and studied histologically only by Charles-de-Sá et al.9 In this study, an increase in dermal elastin deposition was reported in biopsy specimens after normal lipofilling of the aging skin. However, to date, no controlled studies have been conducted to verify the clinical relevance of their finding. In our study, skin elasticity was determined with the Cutometer because it is a reliable and validated method of measuring skin age, and the mostly likely candidate to show changes, supported by the findings of Charles-de-Sá et al. Nevertheless, there remains minor controversy regarding the reliability of the Cutometer. A study by Nedelec et al. presented low intraclass correlation coefficients of skin elasticity measurements of dermal scars. The intraclass correlation coefficients found for normal skin elasticity measurements were, however, acceptable for the R0 (0.81), R6 (0.81), and R7 (0.78) parameters.28 We found that normal (not stromal vascular fraction/adipose-derived stem cell boosted) lipofilling with or without platelet-rich plasma did not alter skin elasticity. Reversal of the correlation between age and elasticity, however, might suggest a small effect size, and thus might not be significant with our small study population. Nevertheless, the small effect size raises questions of whether normal lipofilling is “just a filler” in aesthetic procedures in the aging face that involve only lipofilling. Improvement in outcome when lipofilling is combined with lifting procedures could be explained by the large wound surface created and adipose-derived stem cell modulation during healing, down-regulating fibrosis pathways. Recent publications on stromal vascular fraction–boosted/adipose-derived stem cell–expanded lipofilling, however, do show a significant clinical effect29 , 30 and indicate that it seems the way forward.
In theory, adding platelet-rich plasma could affect overlying skin through several pathways and cell lines. Angiopoietin-1 and angiopoietin-2, abundantly present in platelets,31 , 32 have been shown to stimulate endothelial cell growth, migration, and differentiation in cultured human dermal microvascular endothelial cells in vitro.22 , 23 Also, platelet-rich plasma lysate is a strong proliferator for adipose-derived stem cells,10 , 33 is essential for graft take,34 and is a proven down-regulator of fibrosis.26 , 35
Effects of Lipofilling with or without Platelet-Rich Plasma on Nasolabial Fold Depth
Grading of the nasolabial fold during follow-up showed no noticeable lasting effect of lipofilling or lipofilling with platelet-rich plasma on the depth of the nasolabial fold. Even though the Merz scale used in this study has been shown to successfully differentiate small-volume changes (e.g., filler injection),36 we could not determine these differences, probably because lipofilling increased the overall facial volume, not altering relative differences between facial zones. In our opinion, only in combination with a face lift may lipofilling also demonstrate its effect on the nasolabial fold: lifting probably is definitely needed as such. Furthermore, changes in facial volume are minimal because of the limited amount of lipograft that is injected, with uncertainty about the clinical impact of these minor changes if not combined with a lifting procedure. To date, only one study has been published that reported facial graft retention determined with external three-dimensional photographic reconstruction37 after aesthetic facial lipofilling. In this study, an overall retention of 32 percent was reported; however, the range and variation of reported data question its scientific merit. Moreover, the vast number of patients in this study also received some form of lifting procedure that most likely changed the distribution of facial volume and by this means influenced facial volume attributed to lipofilling, again suggesting that lipofilling should be combined with a lifting procedure in aesthetic facial rejuvenation. Even though lipograft survival in the face has been documented with magnetic resonance imaging,38 the clinical relevance of aesthetic facial lipofilling procedures without lifting procedures on facial fold depth remains to be determined.
With ongoing uncertainty about lipograft survival, several fundamental studies explored addition of platelet-rich plasma39–41 and found positive effects. Graft take might improve by platelet-rich plasma effects on adipose-derived stem cell proliferation,39 blockage of apoptosis pathways,42 and differentiation into adipocytes.43 Moreover, platelet-rich plasma lysate stimulates proliferation, migration, and tube formation of human umbilical vein endothelial cells both in vitro and in a nude mouse model.39 Platelet-rich plasma induces changes on endothelial cells that can contribute to (neo)angiogenesis of the fat graft and thereby enhance fat graft survival.44 These findings, however, fail to make a significant impact in the majority of available clinical platelet-rich plasma lipofilling studies,45 , 46 thus casting doubt on the clinical use of addition of platelet-rich plasma to lipofilling for this reason.
Platelet-Rich Plasma Speeds Up Patient Recovery
Patient-reported recovery time was significantly reduced by the addition of platelet-rich plasma in this study. This finding is in line with previous data from our retrospective study11 and current literature on aesthetic procedures such as fractional carbon dioxide laser resurfacing treatment.47 , 48
Dermal and wound closure effects observed after platelet-rich plasma injection might be explained by the effect of platelet-rich plasma on fibroblasts. An in vitro study by Ramos-Torrecillas et al.49 showed that PRP increases fibroblasts proliferation rate and induces their differentiation into myofibroblasts, thus playing a key part in wound contracture.22 Collagen I and extracellular matrix remodeling by fibroblasts is also affected by platelet-rich plasma. Fibroblasts exposed to platelet-rich plasma lysate in vitro up-regulate the expression of matrix metalloproteinase-1,24 which in turn plays a key role in collagen remodeling. Also, type I collagen expression is increased under these circumstances.50 Increased fibroblast activity, along with changes in collagen production and a potentially stronger inflammation response,51 could also play a role in our observed reduced recovery time after surgery when the lipograft was combined with platelet-rich plasma.
The Concentration Paradox: Less Is More?
A potential pitfall in evaluating the effect of platelet-rich plasma is the lack of uniform concentrations of created platelet-rich plasma. The studies of Yamaguchi et al.52 , 53 were the first publications that showed that a higher concentration of platelet-rich plasma (or more platelets) may produce counterproductive effects, possibly by unwanted cell differentiation. Most commercially available platelet-rich plasma kits capture a percentage of available platelets from whole blood, not a certain quantitative number of platelets. Considering the fact that normal human platelet counts are defined within a wide range and show large daily variations, the cumulative amount of growth factors in kit-isolated platelet-rich plasma is inconsistent.54 This variation can inadvertently influence its effect in a way as is observed in vitro on different cell types.22 Regarding cells present in the lipograft, platelet-rich plasma concentration alters adipose-derived stem cell proliferation, function, and behavior. High platelet-rich plasma concentrations increase proliferation but also change adipose-derived stem cells into a fibroblast-like phenotype, with increased collagen RNA expression and altered paracrine signaling that negatively influences endothelial vessel formation.55 , 56
Although platelet counts were normal within our well-defined healthy patient cohort, combined with comparable fat-graft, platelet-rich plasma, or placebo mixture ratios, our study is potentially biased and weakened by this concentration-dependent effect. Moreover, this phenomenon could explain the failure of clinical studies.
Local growth factor conditions after lipofilling are also issues that remain unclear; in a healthy patient, the release of platelets and proinflammatory factors because of damage caused by the lipofilling procedure itself could be of such an extent that the addition of platelet-rich plasma actually is insignificant and/or redundant or even too high.
This randomized, double-blind, placebo-controlled study clearly has shown that platelet-rich plasma significantly reduces postoperative recovery time but does not improve patient outcome when looking at skin elasticity, improvement of the nasolabial fold, or patient satisfaction. The reversal of the correlation between age and elasticity might indicate some effect on skin but requires more power in future studies. Thus far, the use of platelet-rich plasma as an additive in lipofilling has shown great promise in vitro. These beneficial effects, however, have only partially been reproduced in a clinical setting. A growing number of studies report a concentration-dependent effect of platelet-rich plasma in vitro, making optimal use in a clinical setting delicate and complex. Further studies of platelet-rich plasma interactions on both the lipograft and the receptor host site–involved cells seem to be of paramount importance to determine the optimal use and concentrations of platelet-rich plasma in a clinical setting.
This study was sponsored by Biomet, which provided the platelet-rich plasma kits free of charge, and funds to cover traveling expenses for the first author (J.C.N.W.).
Patients provided written informed consent for the use of their images.
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