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Facial Surgery
https://doi.org/10.1093/asj/sjac122
www.aestheticsurgeryjournal.com
University of Groningen, Groningen, the Netherlands. Dr Dijkstra
is a professor, Department of Rehabilitation Medicine, University
Medical Center Groningen, University of Groningen, Groningen, the
Netherlands.
Corresponding Author:
Dr Martin C.Harmsen, Department of Pathology and Medical Biology,
University of Groningen, University Medical Center Groningen,
Hanzeplein 1-EA11, 9713 GZ Groningen, the Netherlands.
E-mail: m.c.harmsen@umcg.nl
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Review Article
Supplementation of Facial Fat Grafting to
Increase Volume Retention: ASystematic
Review
JanAartM.Schipper, MD ; LindaVriend, MD ; AartjeJ.Tuin, MD, DMD,
PhD; PieterU.Dijkstra, PT, MT, PhD; RutgerH.Schepers, MD, DMD,
MSc, PhD; BerendvanderLei, MD, PhD; JohanJansma, MD, DMD,
MSc, PhD, FEBOMFS; and MartinC.Harmsen, PhD
Abstract
Background: For decades, facial fat grafting has been used in clinical practice for volume restoration. The main challenge
of this technique is variable volume retention. The addition of supplements to augment fat grafts and increase volume re-
tention has been reported in recent years.
Objectives: The aim of this systematic review was to investigate which supplements increase volume retention in facial
fat grafting as assessed by volumetric outcomes and patient satisfaction.
Methods: Embase, Medline, Ovid, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, and
Google Scholarwere searched up to November 30, 2020. Only studies assessing volume after facial fat grafting with sup-
plementation in human subjects were included. Outcomes of interest were volume or patient satisfaction. The quality of
the studies was assessed with the Eective Public Health Practice Project tool.
Results: After duplicates were removed 3724 studies were screened by title and abstract. After reading 95 full-text articles, 27
studies were eligible and included for comparison. Supplementation comprised of platelet-rich plasma, platelet-rich fibrin, adipose
tissue–derived stromal cells or bone marrow–derived stromal cells, cellular or tissue stromal vascular fraction, or nanofat. In 13 out
of 22 studies the supplemented group showed improved volumetric retention and 5 out of 16 studies showed greater satisfaction.
The scientific quality of the studies was rated as weak for 20 of 27 studies, moderate for 6 of 27 studies, and strong for 1 study.
Conclusions: It remains unclear if additives contribute to facial fat graft retention and there is a need to standardize
methodology.
Level of Evidence: 4
Editorial Decision date: May 5, 2022; online publish-ahead-of-print May 16, 2022.
© 2022 The Aesthetic Society.
Dr Schipper is a medical doctor and Dr Harmsen is a professor of
cardiovascular regenerative medicine, Department of Pathology and
Medical Biology, University of Groningen, University Medical Center
Groningen, Groningen, the Netherlands. Dr Tuin is an oral and
maxillofacial surgeon in training and Drs Schepers and Jansma are
oral and maxillofacial surgeons, Department of Oral and Maxillofacial
Surgery, University Medical Center Groningen, University of
Groningen, Groningen, the Netherlands. Dr Vriend is a medical
doctor and Dr van der Lei is a professor, Department of Plastic
and Reconstructive Surgery, University Medical Center Groningen,
This is an Open Access article distrib-
uted under the terms of the Creative
Commons Attribution-NonCommercial
License (https://creativecommons.org/
licenses/by-nc/4.0/), which permits
non-commercial re-use, distribution, and
reproduction in any medium, provided
the original work is properly cited. For
commercial re-use, please contact jour-
nals.permissions@oup.com
Facial Surgery
Aesthetic Surgery Journal
2022, 1–17
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Fat grafting has been performed in clinical practice since
the end of the 19th century.1 It has been used to restore
volume loss due to trauma, aging, congenital defects, or for
aesthetic reasons, predominantly in the face, breasts, and
buttock. Facial fat grafting can be performed easily, safely,
and with minimum donor-site morbidity and complications.2
However, not all transplanted tissue is retained at the ac-
ceptor site. Long-term volume retention rates vary widely
between 25% and 80%.3-5 Additionally, multiple surgical
procedures are often required to obtain the desiredvolume.
Lipografting is a form of tissue transplantation, albeit
of fragmented adipose tissue. These fragments consist
of multiple large lipid-laden adipocytes that are structur-
ally supported by connective tissue and perfused with a
highly developed microvasculature. Adipocytes are about
4-fold less numerous than stromal vascular cells, yet com-
prise about 90% of the total volume of fat.6 Upon trans-
plantation (ie, fat grafting), the survival and regeneration
of adipocytes are pivotal to retaining the grafted volume.7
Ischemia may cause apoptotic loss of adipocytes, and thus
suppression of apoptosis in fat grafts might improve graft
volume retention. For graft survival, it is essential to form
a rapid connection between local vasculature and capil-
laries that literally stick out from the tissue clumps in the
fat graft. Thus angiogenic stimulation by fat graft supple-
ments is warranted. Any adipocytes lost from ischemic
insult require replenishment through proliferation of pre-
adipocytes (adipose tissue–derived stromal cells [ASCs])
and their dierentiation and maturation into adipocytes,
which would be supported by promitogenic factors in sup-
plements. Finally, metabolic maintenance is important be-
cause adipocyte volume, ie, the storage of the high-energy
triglycerides, varies with the body’s metabolic demand.
Weight loss is associated with loss of adipocyte volume
and consequently with reduced graft volume.8 Although
repeated fat grafting does build up sucient volume, this
is an undesirable burden for the patient. Therefore, sup-
plements that augment suppression of apoptosis, stimu-
late proliferation, and enhance angiogenesis are desired.
In clinical applications, the cellular fate of grafted fat is usu-
ally not assessed, yet this does not preclude investigation
of the influence of supplements on graftvolume.
To increase graft retention, supplementation with sev-
eral autologous components has been investigated.
Blood-derived products, eg, platelet-rich plasma (PRP) and
platelet-rich fibrin (PRF),9,10 are a source of concentrated
platelets, growth factors, and cytokines which could in-
duce better graft retention by promoting angiogenesis
and reducing apoptosis.11 Adipose tissue–derived com-
ponents, eg, ASCs, cellular and tissue stromal vascular
fraction (cSVF, tSVF),12,13 and nano- and microfat,14-16 have
shown proangiogenic action through paracrine factors
which could induce better graft vascularization, reduce
apoptosis, and increase proliferation.17,18 Furthermore,
enzymatic cell-assisted lipografting made addition of cSVF
or cultured ASC to fat grafting popular.4, 19-20 However, be-
cause cell-assisted lipografting requires enzymatic diges-
tion of SVF and the use of animal-derived enzymes such
as collagenase it is restricted by legislation in many coun-
tries,21 and hence new nonenzymatic, fast, intraoperative,
mechanical dissociation procedures have been developed
to produce tSVF.22,23 PRP or PRF are also easily obtained
by centrifugation of blood with or without anticoagulant.24
These supplementations are believed to improve retention
through either increased survival of the grafted cells by re-
ducing/preventing cell apoptosis, or by restoring hyper-
trophy or increasing vascularization at the injectionsite.
Currently, the number of clinical studies investigating
supplemented fat grafting is increasing rapidly, and multiple
new supplementation therapies are being developed.25
These developments warrant systematic evaluation of the
clinical available evidence. The current systematic reviews
on fat graft supplementation are heterogeneous because
they include human and animal studies for various indi-
cations.26,27 The aim of this systematic review was there-
fore to investigate the ecacy of human facial fat grafting
based on quantitative volumetric outcome measures and
patient satisfaction assessments.
METHODS
Protocol and Registration
This manuscript follows the Preferred Reporting Items for
Systematic Reviews and Meta-analysis (PRISMA) state-
ment.28 The study was registered in Prospero (register
code: CRD42020179975).
Search Strategy and Information Sources
A systematic literature search was conducted in the elec-
tronic medical databases Embase (Elsevier, Amsterdam,
the Netherlands), MEDLINE (National Library of
Medicine, Bethesda, MD), Ovid (Wolters Kluwer, Alphen
aan den Rijn, the Netherlands), Web of Science Core
Collection (Clarivate Analytics, London, UK), Cochrane
Central Register of Controlled Trials (CENTER; London,
UK), and Google Scholar (Google, Mountain View, CA)
from inception to November 30, 2020. Search strategy
was based on the PICO (population, intervention, com-
parison, outcome) framework and combined terms related
to fat graft transplantation (ie, lipofilling, fat transplantation,
adipose tissue transplantation, adipose tissue grafting,
volume retention) plus a supplementation therapy (ie, PRP,
ASCs, SVF, nanofat, microfat).29 In databases where a the-
saurus was available (Embase and MEDLINE), papers were
searched by thesaurus terms and by title and/or abstract.
2 Aesthetic Surgery Journal
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Schipper et al 3
The searches were adapted corresponding to each data-
base (Supplemental Table 1, available online at www.
aestheticsurgeryjournal.com, and Figure 1). Reference
lists of included studies were analyzed to identify relevant
studies missed in the searches.
Eligibility Criteria
Studies were included if they clinically evaluated the
effects of fat grafting in combination with a supple-
ment, for instance the addition of PRP, ASCs, or SVF,
on volume restoration in the face or patient satisfac-
tion. Only studies injecting in the adipose tissue plane
in the face were included. Studies were excluded when
no volumetric outcome was reported, as were studies
reporting on other body parts than the face only. If
studies described multiple body parts and data of
the face were separately described, the study was in-
cluded. (Systematic) reviews, case studies, conference
abstracts, letters to the editor, and animal and in vitro
studies were also excluded. No publication date restric-
tion was applied.
Study Selection and Data
Collection Process
Two reviewers (J.S., L.V.) independently assessed titles,
abstracts, and full texts. Disagreement between reviewers
was discussed until consensus was reached. In the case
of persistent disagreement, a senior author (M.H.) gave a
binding verdict.
Data Extraction
All data were extracted by the same 2 reviewers and con-
sisted of 5 categories: study characteristics, treatment
characteristics, complications, volumetric assessment of
fat graft (retention), and patient satisfaction.
Complications were categorized as minor (erythema,
mild edema, hematoma, local pain at incision site, and
oily cyst) and major complications (infection, tissue loss,
skin necrosis, fibrosis, severe edema, pain spreading
beyond injection site, cellulitis, fat embolus, and em-
bolus causing blindness). For supplemented fat grafting
therapy, data outcomes of interest were time between
harvesting and injection, injected volumes, supplement
dosing, cell yield or PRP concentration, isolation pro-
cedures, repeated treatments, and characterization of
supplementation therapy. For volumetric outcomes, data
from objective and subjective volume measurement
tools and follow-up points were extracted. When studies
reported fat graft resorption as an outcome measure, re-
tention was calculated as inverse resorption (100% – x%).
For each volume retention reported, a fold-change was
calculated (%supplemented fat divided by % fat). A dif-
ference was reported when there was a statistically sig-
nificant dierence (P < 0.05).
Risk of Bias in Individual Studies
The 2 reviewers independently assessed risk of bias with
the Eective Public Health Practice Project tool (EPHPP).30
This tool enables quality assessment of dierent types of
Figure 1. Flow diagram of study selection.
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study design. Studies were given an overall final rating as
strong, moderate, or weak based on ratings of study design,
selection bias, confounders, data blinding, data collection,
and dropouts. According to the EPHPP tool, “strong studies”
had no weak rating, “moderate studies” had 1 weak rating
and “weak studies” had 2 or more weak ratings.
RESULTS
Study Selection
In total, 3724 studies were identified. After title and abstract
screening, 95 studies remained for full-text assessment of
eligibility criteria (Figure 1). A total of 27 studies were in-
cluded; 68 studies were excluded for the following reasons:
10 studies were excluded because the fat graft was not sup-
plemented;
23,31-39 19 studies were excluded because fat graft
retention was not assessed by volumetric or patient satisfac-
tion measurements;
40-59 3 studies were excluded because
the study methods or intervention were not evaluable due
to insucient description;
60-62 8 studies were excluded be-
cause these were conference abstracts;
63-69 13 studies were
excluded because these concerned trial registrations;
70-82 1
study was excluded because the supplementation therapy
was not carried out in the face, but in other body parts;
83 in
1 study the injection site was not adipose tissue but product
was injected within the muscles of the face (facial muscular
plane);
84 12 studies were excluded because they did not de-
scribe human subjects or clinical results;
85-95 no translation
of 1 study was available (Russian).96
Study Characteristics
The studies included were published between 2008 and
2020 (Table 1). Follow up ranged from 6 to 60months and
a total of 1117 participants were described in the studies
(range, 6 to 236 per study). The mean age of the partici-
pants ranged between 6 and 61.5years old and 73% of
all patients were female (range, 33%-100%). Five studies
had a female sex bias due to the inclusion of female parti-
cipants only.97-101 Eight studies reported mean BMI, which
ranged from 17 to 32kg/m². Indications for supplemented
fat grafting were with underlying pathology (48%) or cos-
metic (without underlying pathology) with (19%) or without
facelift (33%). Indications with underlying pathology
were craniofacial deformity (31%), scars (23%), (hemi)fa-
cial lipoatrophy (15%), Parry-Romberg syndrome (15%),
or a combination of these indications (15%). The majority
(13/27) of the studies supplemented fat grafts with PRP/
PRF. Three studies reported multiple supplements.102-104
Studies were categorized by type of supplement (PRP,
SVF, and cellular components) for analysis of supplement
characteristics, volumetric, and patient satisfaction out-
comes (Supplemental Table 2, available online at www.
aestheticsurgeryjournal.com, and Tables 2, 3).
Study Design and Quality
Study designs included randomized controlled trials
(n = 6),67,99,101,105-107 controlled trials (n = 6),4,19,108-111 cohort
studies (2 groups with pre- and posttreatment evalu-
ation, n = 6),34,103,104,108,112,113 cohort studies (1 group with
pre- and posttreatment evaluation, n = 8)98,100,114-119 and a
retrospective study (n = 1)45 (Table 4). Confounding factors
were not controlled for in 8 studies.42,44,108,110,114,116-118 The
reliability and validity of outcome measurements were
weak in 12 studies.4,19,44,67,105,108,110,113-116,119 Four studies re-
ported dropouts and reported the number of participants
who completed the follow up.101,105,107,118 Based on the
EPHPP guidelines, 20 studies had an overall final rating
of weak, 6 studies were rated as moderate, and only 1
study was rated as strong (4%).106 Data pooling and meta-
analysis was not possible due to heterogeneity across
studies in terms of clinical features, eg, population char-
acteristics, indications, supplementation strategies, and
additional interventions (facelift, additional injections), and
methodologic characteristics, eg, assessment tools, study
design, and followup.
Characteristics of Supplementation
Strategies
The mean injected total volume ranged from 6.8 to
100mL. The volume-to-volume ratio of PRP-to-fat ranged
from 1:2 to 1:9. In SVF-supplemented therapies, 2 out of 14
studies reported the ratio of supplementation. Repeated
supplemented fat graft injections were performed in 11
studies and concerned merely supplementation with
SVF and cellular components.19,34,108-113,115,117,118 Aminority
of studies reported supplement concentrations: platelet
concentration in PRP or PRF was 0.8 × 109 to 3.6 × 109/
mL (mean [standard deviation], 2.6 [1.3] × 109/mL), and the
number of nucleated cells in cSVF or tSVF was 0.3 × 105
to 100 × 105 cells.112,107,109 Some studies reported a con-
centration range of fat-supplemented therapy and the
single addition of bone marrow–derived stromal cells
(BMSCs) ranged from 3 to 86 × 108 at a volume ratio
of 2:1 of BMSC:fat graft.113 Most studies performed
intraoperative isolation procedures of the supplemen-
tation therapy. Two studies cultured ASCs for 14days109
and 14 to 28days34 before supplementing fat grafts but
the volume ratio was not reported.34,109 Only 4 studies re-
ported the lag time between preparation of supplements
to administration to the patient or the time (range) to pre-
pare the supplements.106,108-110 Three studies described
the characterization of supplements; nanofat plus PRF,
ASCs, cSVF.19,106,109 The shared joint analyzed markers in-
cluded expression of mesenchymal cell markers (CD73,
CD90, and CD105) albeit that these are not restricted
to mesenchyme, integrin β1 (CD29), and the absence of
leukocyte markers (CD45).
4 Aesthetic Surgery Journal
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Schipper et al 5
Table 1. Study Characteristics
Author
(year)
Design Follow up
(months)
Indication Pathologya Injection
site
Total
(n)
Ageb
(years)
Female
(n)
BMI
(kg/m2)
Comorbidities Intervention
(fat +)
Intervention
(n)
Control Control
(n)
Minor
complications
Major
complica-
tions
Bashir et al
2019
C2G 6 UP Hemifacial at-
rophy, craniofa-
cial microsomia,
posttraumatic
and postinfective
deformity
NR 37 24.9 [8.1] 28 NR NR cASC 16 Fat 21 “Most patients” Both in
control and
intervention
group: 6%
cellulitis
Bernardini
et al 2015
C1G 12 C + FL Brows,
upper
sulcus,
inferior orbit
hollow, tear
trough,
perioral
area, malar
and
zygomatic
areas, lips,
chin,
temporal
fossa
98 51 92 NR NR PRP 98 — — 4% 3% of patients
oil cyst, 1 case
requiring
surgical
removal
Castro-Govea
et al 2018
C1G 18 UP Craniosynostosis Forehead 12 6 8 NR NR cSVF 12 — — 0 0
Cervelli et al
2009
RC 18 UP Scars,
Parry-Romberg,
hemifacial
atrophy,
mandibular cyst
Zygomatic
region,
cheek,
buccal rim,
upper and
lower eyelid,
temporal
area, orbital
area
25 NR NR NR Diabetes,
hypertension,
nasal polypus,
neurologic
disease,
arteriopathy,
cardiologic
disease,
dislipidemy,
trauma
PRP 19 Fat 10 0 0
Chang et al
2013
CCT 18 UP Hemifacial
atrophy
NR 20 27.5 12 NR — cSVF 10 Fat 10 0 0
Fontdevila et
al 2014
RCT 12 UP HIV lipoatrophy Cheeks 49 46.3 [7.4] 16 24.3 [3.2] Diabetes,
hypertension,
hypercho-
lesterolemia,
hypertrigly-
ceridemia,
fibrates/statin/
antidepres-
sant/
anxiolytic/
antidiabetic
drug use
PRP 20 Fat 29 0 0
Gennai et al
2017
C1G 6 C + FL Periocular,
perioral
area
65 49.7 58 NR NR PRP 65 — — 0 0
Gentile et al
2014
C2G 12 UP Burns,
posttraumatic
scars
NR 20 NR 10 NR NR cSVFPRP 1010 Fat 10 0 0
Gentile et al
2020
C2G 60 C Zygomatic/
cheek
region,
lower
orbital area,
nasolabial
fold, lips
63 42.1d63 27 (21-
33.16)
— tSVF 33 Fat 30 Intervention
group: 9%;
control group:
13%
0
Gu et al 2018 C1G 6 UP Scars NR 20 (25
scars)
38.3 14 NR — tSVF 25 — — NR NR
Hesamirostami
et al 2019
C1G 30 C Forehead 56 40.2 52 NR NR PRP 56 — — 0 0
Jianhui et al
2014
C2G 12 UP Parry-Romberg NR 36 24.3 [6.6]d25 NR NR Intra-
operative
BMSC
10 Fat 26 0 0
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Author
(year)
Design Follow up
(months)
Indication Pathologya Injection
site
Total
(n)
Ageb
(years)
Female
(n)
BMI
(kg/m2)
Comorbidities Intervention
(fat +)
Intervention
(n)
Control Control
(n)
Minor
complications
Major
complica-
tions
Keyhan et al
2013
RCT c12 C Cheek,
cheekbone
area
25 45 17 NR — PRP 25cFat/PRF 25c0 0
Koh et al 2012 CCT 15 UP Parry-Romberg NR 10 28 5 NR — cASC 5 Fat 5 0 0
Lee et al 2012 C1G c11 C + FL Malar
eminence,
infraorbital
region,
nasolabial
fold
9 43.3 6 NR NR cSVF 9cFat 9c0 0
Li et al 2013 C2G 6 NRG Temporal,
cheek, facial
asymmetry
38 29.4 [6.6]d38 NR NR cSVF 26 Fat 12 “Most patients” 0
Ozer et al
2019
C1G 9 C NR 14 44.9 [11.9] 14 NR NR PRP 14 — — 0 0
Sasaki et al
2015
C2G 12 C + FL Midface 236 61.5d227 22.2 (16.9-
32.3)d
— PRP
cSVF
cSVF/PRP
106
929
Fat 92 “All patients” 0
Sasaki et al
2019
RCT c12 C + FL Midface 10 54.4 10 22.4 (20.5-
24.6)
— PRP 10cFat/sa-
line
10c“All patients” 0
Schendel et al
2015
C1G 17 C Temples,
malar areas,
forehead/
glabella,
eyelid area,
lips, chin
10 51.6 [9.6] 10 NR NR cSVF 10 — — 0 0
Sterodimas et
al 2011
CCT 18 UP Several
congenital or
acquired facial
tissue defects
NR 20 45.1d10 21.6dSmoking,
hypertension,
diabetes,
COPD
cSVF 10 Fat 10 “Most patients” Control
group: 10%
infection
Tanikawa et al
2013
RCT 6 UP Craniofacial
microsomia
NR 14 15.4 [5.6]d9 <25 NR cSVF 7 Fat 7 “All patients” 0
Tenna 2017 CCT 6 UP Acne scars Cheeks 30 NR NR NR — Fat/PRP/
laser
15 Fat/PRP 15 NR NR
Wei et al 2017 CCT 24 C Tempora,
geisoma,
frontal part,
palpebra
sup inf,
lacrimal
groove,
zygoma,
cheeks,
nasolabial
groove,
chin, mari-
onette lines,
submaxilla
139 28.5 NR NR NR Nanofat/PRF 62 Fat 77 0 0
Willemsen et
al 2018
RCT 12 C Temporal,
midface,
nasolabial
fold,
marionette
lines,
prejowling,
chin
25 52.1 [6.8] 32 (20-25) NR PRP 13 Fat/sa-
line
12 0 0
Yin et al 2020 RCT 50 C Forehead,
temporal,
cheek/
zygomatic,
nasolabial
fold
50 35.4 [8.2]d50 21.4 [1.9]d— cSVF 25 Fat 25 0 0
Table 1. Continued
6 Aesthetic Surgery Journal
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Schipper et al 7
Influence of Supplementation Therapies
on Fat Graft Retention
Twenty studies assessed volume retention of sup-
plemented fat grafts after 3 to 36months, of which 3
studies reported multiple supplementation groups
(PRP/cSVF, PRP/cSVF/PRP + cSVF, PRP/tSVF).102-104
Volume was measured by computed tomography (CT),
MRI, 3-dimensional (3D) surface imaging, ultrasound,
visual 2D photograph assessment, numeric rating scale
(NRS), or Likert scale. Seven studies used 3D surface
imaging to assess fat graft retention. Volume measure-
ment methods were often not validated and details of
volumetric measurements were often not described,
or described too briefly to allow for reproduction of
studies.
Out of the 9 studies in which the graft was sup-
plemented with PRP, 2 showed a difference between
groups.103,120 One study showed a 30% increase of
volume compared to the control, ie, conventional fat
grafting.103 The other study showed a difference of 5%
less retention in the PRP group compared to the con-
trol group, in which PRF was used as a control.120 In 4
out of 9 PRP studies there was no difference between
groups.99,101,105,111 In the other 3 studies no statistical
tests were performed or could not be performed due to
the absence of controls.45,104,114
The 2 studies investigating supplementation of culture-
expanded ASCs both showed a dierence when com-
pared with the conventional fat graft.34,109 The volume
retention varied from 1.5-fold higher109 to 3-fold higher.34
Seven out of 9 studies with cSVF as supplement showed
a statistically significant increased volume compared with
the conventional fat graft (1.2- to 1.9-fold).97,103,104,106-108,119
Two studies showed no increased volume. One study
without a control group reported a retention of 68%.100 In 1
study no dierence between groups was found. Only 6 pa-
tients were included in that study and surgeons assessed
volume visually from 2D photographs.4
One study investigating tSVF supplementation showed
improved outcomes.112 A 2-fold increase in volume in
the supplemented group was found, but the measure-
ment methods on MRI were not described.112 The only
study describing PRP and cSVF mixed as a supplement
showed significantly increased volume retention (70%).103
However, the mix of PRP and cSVF did not result in addi-
tional volume increase compared with cSVF (73%) or PRP
(69%) alone.
Influence of Supplementation Therapies
on Patient Satisfaction
Patient satisfaction or patient-reported outcome
measures (PROMs) are considered the key out-
come measurement of facial aesthetic procedures.121
Validated and reliable outcome measures, eg, the
FACE-Q questionnaire, are readily available.122,123
Sixteen studies assessed patient satisfaction with the
FACE-Q, the Patient and Observer Assessment Scale
(POSAS), the Global Aesthetic Improvement Scale
(GAIS), a visual analog scale (VAS), the Likert scale,
or an NRS. The FACE-Q, GAIS, and POSAS are the
only validated outcome measures and were used in
4 studiesonly.
To evaluate the dierences in patient satisfaction be-
tween procedures in a controlled trial, the satisfaction
for both the intervention and the control group should
be evaluated and statistically tested for dierences. Nine
studies performed these “between-group” comparisons,
Author
(year)
Design Follow up
(months)
Indication Pathologya Injection
site
Total
(n)
Ageb
(years)
Female
(n)
BMI
(kg/m2)
Comorbidities Intervention
(fat +)
Intervention
(n)
Control Control
(n)
Minor
complications
Major
complica-
tions
Yoshimura et
al 2008
CCT 13 UP Parry-Romberg
and lupus
lipoatrophy
NR 6 42.5 [8.0]d4 NR NR cSVF 3 Fat 3 “All patients” Control
group: 33%
necrotized
tissue
requiring
surgical
removal
Where indicated, values are mean [standard deviation] or mean (range); NR, not reported; COPD, chronic obstructive pulmonary disease. Study design: RCT, ran-
domized controlled trial; CCT, controlled clinical trial; Cohort 2G, cohort study (2 groups, pre- + postoperative); Cohort 1G, cohort study (1 group pre- + postoperative);
Retrospective, retrospective study. Indication: UP, underlying pathology, meaning with underlying disease, trauma, or congenital volume loss; C, cosmetic, meaning
with no underlying pathology or facial disease, such as fat grafting for facial rejuvenation; C + FL, cosmetic with concomitant facelift. Enrichments, PRP, platelet-
rich plasma; PRF, platelet-rich fibrin; cSVF, cellular stromal vascular fraction; tSVF, tissue stromal vascular fraction; cASC, cultured adipose-derived stromal cell;
BMSC, bone marrow–derived stromal cell.aIn the cosmetic group, there is no pathology present (ie, facial rejuvenation).bWhen decimals are reported, these are
rounded to 1 decimal place.cSplit-face design: in the studies using a split-face design: the patients themselves serve as both intervention group (one half of the face)
and control group (the other half of the face).dWhen data are presented per group, the pooled value is calculated. —, not present in the study reported (eg, no control
group was present or no complications occurred in the study).
Table 1. Continued
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Table 2. Volume Outcomes
Author (year) Outcome
assessment
Follow up
(months)
Intervention
% retention
Control
% retention
Fold change Dierence in retentionb
(intervention compared with
control)
PRP/PRF
Bernardini
etal 2015
VA of volume 6 Good result (63%),
excellent result (37%)
— –
Cervelli etal
2009
VA of volume 18 65% 26% 2.5 —
Fontdevila
etal 2014
CT 12 NR NR –0.3mL (−1.1 to –0.5mL)a (NS)
Gentile etal
2014
MRI 12 69% 39% 1.8 -
Keyhan etal
2013
Linear measurements
of photographs
12 82% (PRP) 87% (PRF) ND 5% ↑ (PRF) (P < 0.05)
Sasaki etal
2015
3D SI 12 69% [40%] 38% [13%] 1.8 31% ↑ (P < 0.01)
Sasaki etal
2019
3D SI 12 24% [10%] 21% [1%] 1.1 3% ↑ NS
Tenna etal US 12 0.7cm improvement 0.6cm improvement 1.1 0.1cm ↑ NS
Willemsen
etal 2018
VA of nasolabial fold 12 NR NR ND NS
ASCs
Bashir etal
2019
US 6 95% [4%] 31% [13%] 3.1 64% ↑ (P < 0.001)
Koh etal
2012
3D SI 6 79% 53% 1.5 26% ↑ (P = 0.002)
cSVF
Chang etal
2013
CT 6 68% [2%] 59% [1%] 1.2 10% ↑ (P < 0.001)
Gentile etal
2014
MRI 12 63% 39% 1.6 24% ↑ (P < 0.0001)
Lee etal
2012
NRS (1-10) 3 Malar eminence 7
(6-8)
Infraorbital region
7 (6-9)
Nasolabial fold 8
(7-9)c
Malar eminence 6 (5-7)
Infraorbital region 6 (5-6)
Nasolabial fold 6 (5-8)c
Malar 1.2
Infraorbital 1.2l
Nasolabial 1.3
Malar eminence 1↑ (P = 0.015)
Infraorbital region 1↑
(P = 0.010)
Nasolabial fold 2↑ (P = 0.017)
Li etal 2013 CT 6 65% [10%] 46% [9%] 1.4 18% ↑ (P < 0.01)
Sasaki etal
2015
3D SI 12 73% [50%] 38% [13%] 1.9 35% ↑ (P < 0.01)
Schendel
etal 2015
3D SI 12 68% — ND —
Tanikawa
etal 2013
CT 6 88% [13%] 54% [20%] 1.6 34% ↑ (P = 0.002)
Yin etal
2020
3D SI (handheld) 6 78% [12%] 56% [10%] 1.4 21% ↑ (P < 0.001)
Yoshimura
etal 2008
LS (1-4) 12 NR NR ND NS
8 Aesthetic Surgery Journal
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Schipper et al 9
but only 6 of these 9 studies performed statistical testing.
Patient satisfaction assessment was sometimes performed
together (or in the same room) with the operating sur-
geon,116 which may have induced interviewer bias and so-
cial desirability bias. Other studies omitted to describe the
conditions under which measurements were performed
and how results were obtained.102,104,112 Follow up was
sometimes not reported or ranged considerably within
studies (3-30months).109,112,113,118
Overall, patients reported high satisfaction rates after
both conventional and supplemented facial fat grafting.
Statistical tests were performed in 8 out of 16 stud
ies.98,101,102,110-112,117,119 Six of these 8 studies statistically
tested for dierences between the intervention and con-
trol group, of which 3 reported improved satisfaction in the
intervention group.101,102,110-112,117,119 Two PRP studies showed
no significant improvement, of which the study of Tenna
etal compared PRP with or without laser.101,111 One cSVF
study showed significant improvement and 1 cSVF showed
no significant improvement.110,119 Two tSVF studies showed
significant improvement.102,112
Complications
Minor complications occurred in 9 out of 27 studies. Three
out of these 9 studies also reported major complications
occurring in the acceptor site. Major complications were
reported in the groups supplemented with ASCs and PRP
and were also reported in the control groups (conventional
fat grafting). Overall, bruising and swelling were the most
common minor complications reported. Of the studies that
reported major complications Bernardini etal reported 3
cases of oily cysts that required surgical removal.114 Bashir
etal reported 2 cases of cellulitis: 1 in the intervention and
1 in the control group.34 Yoshimura etal reported a case of
necrotized tissue in the control group that was surgically
removed.4
DISCUSSION
Our study systematically reviewed the current literature
to assess the ecacy of supplemented clinical facial
fat grafting on volume retention. Our main results are
that: (1) few studies include volumetric data or patient
satisfaction; (2) these studies are heterogeneous with
respect to (a) age, (b) injection frequency, (c) injection
volume, (d) type of supplement, (e) mixing ratio of fat and
supplement, (f) imaging, (g) concomitant interventions,
(h) follow-up time, (i) outcome parameters, and (j) use
of controls; and therefore (3) the low number of studies
and their high heterogeneity did not allow for a proper
meta-analysis.
The results showed that of all supplements, culture-
derived ASCs were most effective at retaining injected
fat volume, whereas addition of PRP, or mixtures of PRP
and cSVF did not affect volume retention. Some of our
reviewed papers assessed complications and found
virtually none, irrespective of supplements. This cor-
roborates previous studies that show fat grafting to be
safe.2,124
A major shortcoming in virtually all analyzed papers is
the near lack of properly described standardized proced-
ures, and the reporting of interassay and intraassay vari-
ation. This causes several of the studies to be subjective
rather than objective and unfortunately reduces the value
of the outcomes.
Volume retention is the goal of facial fat grafting but is
also a highly challenging parameter to measure and mon-
itor. Several studies used validated imaging methods, in-
cluding CT and MRI scanning or 3D surface imaging. It was
Author (year) Outcome
assessment
Follow up
(months)
Intervention
% retention
Control
% retention
Fold change Dierence in retentionb
(intervention compared with
control)
tSVF
Gentile etal
2020
MRI 36 61% [5%] 31% [5%] 2 30% ↑ (P < 0.0001)
PRP + cSVF
Sasaki etal
2015
3D SI 12 70% [35%] 38% [13%] 1.8 31% ↑ (P < 0.01)
Where indicated, values are mean [standard deviation] or (range). —, no test was performed, or no quantification was described; NR, not reported; NS, not sig-
nificant. Outcome assessment: NRS, numeric rating scale; US, ultrasound; CT, computed tomography; LS, Likert scale; VA, visual assessment; SI, surface imaging.
Supplements: PRP, platelet-rich plasma; PRF, platelet-rich fibrin; cSVF, cellular stromal vascular fraction; tSVF, tissue stromal vascular fraction; ASC, adipose-derived
stromal cell; BMSC, bone marrow–derived stromal cell.aFontdevila etal described no separate intervention or control volume. Only a dierence between groups
with a range was described.bDierence is described in absolute percentage points; however, for the readibility of this table we have used the percentage sign
%.Dierences are based on the original (not rounded) data, which means rounding errors can be present.cLee etal described surgeon-rated volume consistency
based on a numeric rating scale.dGu etal described the thickness using the POSAS questionnaire. The specific question about thickness is extracted.
Table 2. Continued
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Table 3. Patient Satisfaction Outcomes
Author
(publication
year)
Outcome
assessment
Follow
up
(months)
Comparisonc Comparison with
preoperative
photographs
Satisfaction
intervention
Satisfaction
control
Dierence in satisfaction
(intervention compared with
control or postoperative
compared with preoperative)
PRP/PRF
Gennai etal
2017
LS (1-4) 6 Within-group
outcome
Yes Fair to good eect (2.6) — —
Gentile etal
2014
LS (1-6) 12 Within-group
outcome
Yes nr — —
Hesamirostami
etal 2019
GAIS 12 (6-30) Within-group
outcome
Yes Moderate to excellent
improvement, 7% poor
improvement.
— —
Ozer etal
2019
FACE-Q 9 Within-group
change
— Improved from
28.4 [23.3] to
90.3 [17.5]
— 61.9↑ (P < 0.001)
Tenna etal
2017
FACE-Q 6 Between-
group
outcome
No 84%b81%bNS
Willemsen
etal 2018
VAS (1-10) 6 Between-
group
outcome
No NR NR NS
ASCs/BMSCs
Bashir etal
2019
LS (1-5) 6 Between-
group
outcome
Yes 4.3 [0.7] 2.5 [0.5] 1.8↑ NSR
Jianhui etal LS (1-3) NR Between-
group
outcome
No NR NR —
Koh etal 2012 VAS (1-5) NR Between-
group
outcome
No 4.5 3 .1 1.4↑ NSR
cSVF
Castro-Govea
etal 2018
LS of parents
(1-5)
18 Within-group
outcome
No 67% of the parents
were satisfied and 33%
were slightly satisfied
— —
Lee etal 2012 NRS (1-10) 3 Between-
group
outcome
Yes Malar eminence 7 (6-8)
Infraorbital fold 8 (7-9)
Nasolabial fold 8 (7-9)a
Malar eminence
6 (5-8)
Infraorbital fold
6 (5-7)
Nasolabial fold 7
(5-8)a
Malar eminence 1↑ (P = 0.008)
Infraorbital fold 2↑ (P = 0.010)
Nasolabial fold 1↑ (P = 0.011)
Sterodimas
etal 2011
LS (1-5) 18 Between-
group
outcome
No 4.0 b4.0 b0 NS
Yin etal 2020 LS (1-5) 6 NR No — — —
tSVF
Gentile etal
2020
LS (1-6) NR Between-
group
outcome
No 91% fully satisfied and
9% not fully satisfied
37% fully satis-
fied and 63% not
fully satisfied
(P = 0.031)
Gu etal 2018 POSAS 12 Within-group
change
Yes Preoperative 28.8 [1.0]
vs postoperative
12.2 [0.8]
— 16.6↓ (P < 0.001)d
10 Aesthetic Surgery Journal
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Schipper et al 11
surprising to note that none of the papers disclosed the
unbiased reliability, ie, inter- and intrameasurement varia-
tion, as well as inter- and intraobserver variation. This re-
duces the value of the measurements as these are prone
to subjectivebias.
With regard to the use of validated inquiries to
measure patient satisfaction and outcome, the FACE-Q,
GAIS, and POSAS have been available for several
years.121-123 Unfortunately, no more than a quarter of the
papers report utilizing these instruments. Again, com-
parisons with these instruments were not reported, but
we included these in our results. In general, statistical
testing of outcomes was neglected in more than half of
the studies. We consider this a major flaw that reduces
the value of potentially relevant clinical trials to a min-
imum. Journal editorial boards and peer-review pro-
cesses should continue to improve their standards for
statistics.
Our quest was to find published papers that reported
the benefit of supplemented fat grafting on volume re-
tention. However, we could neither corroborate nor
dispute these findings based on our current system-
atic literature analyses on supplemented clinical facial
fat grafting. This study focused on supplemented fat
grafting in the facial area, which might be a strength or
a limitation. Asystematic review on fat graft supplemen-
tation in other body parts would be interesting because
it may elucidate whether supplementation therapies
are effective and the influence of body location on fat
graft viability. One Russian study was excluded be-
cause no translation was available in the medical li-
brary. However, it is doubtful whether inclusion of this
study would have changed the general message of this
systematic review. Future studies should focus on con-
ducting well-designed randomized controlled clinical
trials to be able to establish a higher level of evidence
and to minimize inter- and intrastudy variation. Volume
outcome measurement should be performed with valid
imaging modalities and reliable volume measurement
methods. Inter- and intrameasurement variation should
be measured and reported. Imaging modalities based
on ionizing radiation, such as CT, for follow up should
be avoided. Validated patient-reported outcome ques-
tionnaires should be used and recorded both pre-
and postoperatively to minimize potential recall bias.
Procedures for harvesting and processing should be
standardized.12,125,126 No concomitant procedures such
as a facelift or blepharoplasty should be performed
during these studies because these influence volume
outcome and patient satisfaction. We have established
a summary of recommendations for the design of future
trials in Table 5.
CONCLUSIONS
Despite multiple studies showing improved volume re-
tention and increased patient satisfaction, no clinical su-
periority of supplementations could be objectified. Future
well-designed clinical trials may elucidate whether supple-
mentation therapies enhance fat graft retention and may
increase patient satisfaction.
Supplemental Material
This article contains supplemental material located online at
www.aestheticsurgeryjournal.com.
Acknowledgments
Drs Schipper and Vriend made an equal contribution to this
work as co-first authors.
Author
(publication
year)
Outcome
assessment
Follow
up
(months)
Comparisonc Comparison with
preoperative
photographs
Satisfaction
intervention
Satisfaction
control
Dierence in satisfaction
(intervention compared with
control or postoperative
compared with preoperative)
Wei etal 2017 nr 24 Between
group
outcome
No 90% 70% 20% ↑ (P < 0.01)
Where indicated, values are mean [standard deviation] or (range). NR, not reported; NS, not significant; NSR, no significance reported, no statistical test was per-
formed/reported; —, no quantification, no intervention or control group present or no statistical test reported. Outcome assessment: NRS, numeric rating scale, with
a higher number meaning a better score; LS, Likert scale, each number represents an outcome, such as unsatisfactory-slightly satisfactory, satisfactory; VAS, visual
analog scale; FACE-Q, a validated questionnaire using a combination of Likert scales and visual analog scales; POSAS, a validated questionnaire specifically de-
signed for scars (the overall patient-reported POSAS score is reported in this table; a lower score means a greater satisfaction); GAIS, Global Aesthetic Improvement
Scale is a Likert scale, 0-4. Supplements: PRP, platelet-rich plasma; PRF, platelet-rich fibrin; cSVF, cellular stromal vascular fraction; tSVF, tissue stromal vascular frac-
tion; ASC, adipose-derived stromal cell; BMSC, bone marrow–derived stromal cell.aOverall patient satisfaction was noted from the patient satisfaction scores.bData
were manually calculated from the tables in the article.cWithin-group outcome means that no comparison to baseline or comparison to a control group was made.
Participants were asked to evaluate the outcome after surgery without evaluating the preoperative situation.dA lower score of the POSAS questionnaire means a
greater satisfaction.
Table 3. Continued
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Disclosures
The authors declared no potential conflicts of interest with re-
spect to the research, authorship, and publication of this article.
Funding
This study was funded by the Departments of Oral and
Maxillofacial Surgery, Plastic and Reconstructive Surgery, and
Table 4. Quality of the Included Studies Based on the Eective Public Health Practice Project Tool
Reference Selection bias Study Design Confounders Blinding Data Collection Dropouts Global rating
Bashir etal 2019 0 0 – 0 + – –
Bernardini etal 2015 – 0 – 0 – – –
Castro-Govea etal 2018 – 0 – 0 – – –
Cervelli etal 2009 – 0 – – – – –
Chang etal 2013 – + – 0 – – –
Fontdevila etal 2014 0 + + + – + 0
Gennai etal 2017 – 0 – – – NA –
Gentile etal 2014 – 0 + 0 0 – –
Gentile etal 2020 – 0 – – 0 – –
Gu etal 2018 – 0 – – + – –
Hesamirostami etal 2019 0 0 – – + + –
Jianhui etal 2014 – 0 – – – – –
Keyhan etal 2013 – + + 0 – – –
Koh etal 2012 – + + 0 + – –
Lee etal 2012 – 0 + 0 – – –
Li etal 2013 – 0 + 0 0 NA 0
Ozer etal 2019 – 0 + 0 + NA 0
Sasaki etal 2015 – 0 – – 0 – –
Sasaki etal 2019 – + + 0 0 – –
Schendel etal 2015 – 0 + 0 0 + 0
Sterodimas etal 2011 – + 0 0 – – –
Tanikawa etal 2013 0 + + 0 0 0 +
Tenna etal 2017 – + – 0 + – –
Wei etal 2017 – + – 0 – – –
Willemsen etal 2018 – + + 0 + 0 0
Yin etal 2020 – + + + 0 + 0
Yoshimura etal 2008 – + + 0 – – –
Totals
Weak, n (%) 23 (85%) 0 (0%) 13 (48%) 7 (26%) 12 (44%) 18 (67%) 20 (74%)
Moderate, n (%) 4 (15%) 15 (56%) 1 (4%) 18 (67%) 8 (30%) 2 (7%) 6 (22%)
Strong, n (%) 0 (0%) 12 (44%) 13 (48%) 2 (7%) 7 (26%) 4 (15%) 1 (4%)
The totals at the bottom represent the distribution of how weak, moderate and strong each criterion is. Ref, reference, +, strong, 0, moderate, –, weak.
12 Aesthetic Surgery Journal
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Schipper et al 13
Pathology and Medical Biology, University and Medical Center
Groningen, Groningen, the Netherlands.
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Recommendations
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2. Randomized
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5. Statistically testing for dierences between groups
Standardization of
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3. No concomitant procedures (eg, facelift) that can influence volume or satisfaction outcomes
4. Single injections, no repeated procedures
Measurement of
volume retention
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2. Using valid imaging modalities (without ionizing radiation)
3. Using a reliable method of volume measurement, by either reporting reliability or using a validated method of volume measure-
ment
Measurement of pa-
tient satisfaction
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2. Measuring change of PROM, including a preoperative (baseline) measurement
3. Statistically testing for dierence of PROM between intervention and control group
4. Observer/surgeon should not be present when PROM is recorded, to exclude interviewer/social desirability bias
aConsolidated Standards of Reporting Trials.bPatient-reported outcome measures.
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