diferenca preenchimento superficial vs profundo

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J Cosmet Dermatol. 2023;00:1–10.  | 1wileyonlinelibrary.com/journal/jocd
Received: 10 March 2023  | Accepted: 16 April 2023
DOI: 10.1111/jocd.15795 
O R I G I N A L A R T I C L E
Superficial versus deep injections of the upper 
midface— A prospective interventional split- face study
Javier Murillo Martín MD1 | Juan Maria Revelles MD2 | Nerea Martínez Aznar3 | 
Lidia Maroñas Jiménez MD4 | Jose Barbosa Orellana MD5 | Miguel Ángel Gomariz MD6 | 
Michael Alfertshofer MD7  | Sebastian Cotofana MD PhD8
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, 
provided the original work is properly cited.
© 2023 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.
1CM Clinic, Palma de Mallorca, Spain
2Clínica Le Boost, Madrid, Spain
3Department of Biochemistry, University 
of Valencia, Valencia, Spain
4Department of Dermatology, Hospital 
Universitario 12 de Octubre, Madrid, 
Spain
5Clínica Kiré, Murcia, Spain
6Clínica Dr Gomariz, Murcia, Spain
7Department of Hand, Plastic and 
Aesthetic Surgery, Ludwig- Maximilians- 
University Munich, Munchen, Germany
8Department of Clinical Anatomy, Mayo 
Clinic School of Medicine, Rochester, 
Minnesota, USA
Correspondence
Sebastian Cotofana Department of 
Clinical Anatomy, Mayo Clinic College of 
Medicine and Science, Mayo Clinic, Stabile 
Building 9- 38, 200 First Street, Rochester, 
Minnesota, 55905, USA.
Email: cotofana.sebastian@mayo.edu
Funding information
Merz Pharmaceuticals
Abstract
Background: Various injection algorithms have been proposed in the past which are 
in line with the three aesthetic principles: upper face first, lateral face first, and deep 
regions first. However, increasing evidence is provided that the upper midface can be 
targeted with superficial soft tissue filler injections alone too.
Objective: To investigate in a prospective split- face study design whether superficial 
or deep upper midfacial injections provide superior aesthetic outcomes.
Methods: A total of n = 20 study participants (100% females; age 43.95 (11.7) years; 
BMI 22.92 (2.6) kg/m2) were treated with superficial soft tissue filler injections on 
side of their face and deep injections on the contralateral side with a mean volume of 
0.78 cc. Outcome was evaluated at 7 weeks follow- up for midfacial, and lower facial 
volume, for medial and lateral facial skin vector displacement, and for improvement of 
nasolabial, crow's feet, and upper cheek fullness severity scores.
Results: No adverse events related to safety or product tolerability were observed 
during the entire study period. All semiquantitative scores improved statistically sig-
nificantly after the observational period (p  0.05).
Conclusion: The results of this split- face study revealed that both the superficial and 
the deep cannula injection technique for midface volumization statistically signifi-
cantly improve the midfacial volume, reduce nasolabial fold and crow's feet severity. 
No statistically significant difference was observed between the two injection tech-
niques when compared via semiquantitative and objective outcome evaluation after 
7 weeks follow- up.
K E Y W O R D S
biomechanics, facial anatomy, hyaluronic acid injection, minimally invasive procedures
www.wileyonlinelibrary.com/journal/jocd
https://orcid.org/0000-0002-4892-2376
mailto:
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mailto:cotofana.sebastian@mayo.edu
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2  |    MARTÍN et al.
1  |  INTRODUC TION
In a recent publication, the term facial biomechanics was introduced 
by Cotofana and colleagues.1 The authors used this term to describe 
movements of facial soft tissues occurring during various facial ex-
pressions and during facial aging. Their results were supported by 
previous anatomic and ultrasound studies which have identified that 
superficial facial fat compartments are significantly more mobile than 
deep facial fat compartments.2– 4 This is in alignment with currently 
accepted treatment algorithms that predominantly target deep = su-
praperiosteal fascial layers to reshape and revolumize various facial 
regions including the midface. These observations are also in line with 
the previously established treatment principles for minimally invasive 
facial aesthetic procedures which were confirmed in independent clin-
ical studies: lateral face first, upper face first, and deep layers first.1,5– 7
Despite its global acceptance, the latter principle however (deep 
layers first) is being challenged by anatomic findings which investi-
gated the superficial facial fat compartments individually and have 
reported that some superficial fat compartments move more (super-
ficial nasolabial and jowl) whereas others are stable (superficial me-
dial cheek and superficial lateral cheek) when experimentally tested 
and related to the underlying bone. Especially the superficial medial 
cheek fat compartment (which is also termed malar fat pad) seems 
to not undergo positional changes which might make this fat com-
partment also a target for superficial soft tissue filler injections in 
addition to the already established deep injections.3
From a safety standpoint, both planes can be considered “safer” 
injection planes because no major vessel can be found within the 
superficial fatty layer and in the deep plane, the small branches pres-
ent arise predominantly from the external carotid artery without im-
mediate connection to the ophthalmic artery circulation.8
From an aesthetic outcome standpoint, it might be interesting to 
evaluate which of the two targeted planes (superficial or deep) pro-
vide a better surface projection with consecutive improvement of 
upper cheek fullness and nasolabial fold severity if the same product 
and product volume is utilized.
Therefore, the objective of this study to investigate in a split- face 
study design the aesthetic outcome and the 3- dimensional local and 
regional effects of minimally invasive soft tissue filler injections of 
the upper midface if the superficial versus deep fascial planes are 
targeted using the same hyaluronic acid- based product and adminis-
tering the same volume.
2  |  MATERIAL S AND METHODS
2.1  |  Study sample
The investigated study sample consisted of 20 female volunteers of 
100% Caucasian (Spanish) ethnic background. The mean age was 
43.95 (11.9) years [range: 28– 65], and the mean body mass index 
(BMI) was 22.92 (2.7) kg/m2 [range: 20.02– 26.89]. Study participants 
were recruited for this study via online advertisements and adhered 
to the following inclusion criteria: female gender, age between 25 
and 65 years, Fitzpatrick skin type I– IV, body mass index between 20 
and 27, bilateral, symmetrical, moderate- to- severe midfacial volume 
loss,9 moderate- to- severe jawline contouring loss,10 desire for vol-
ume loss correction, fully vaccinated for SARS- CoV2 at least 2 weeks 
prior to the start of the study, and willingness to comply with the 
treatment algorithm and the follow- up visits. Prior to the inclusion 
in this study all participants had to provide written and informed 
consent for the use of their demographic and imaging related data.
Patients were not included in this study if they were pregnant 
or breastfeeding, had reported hypersensitivity to hyaluronic acid 
or lidocaine/anesthesia, had active skin disease (e.g., infection, ec-
zema, dermatitis, psoriasis, acne, and rosacea) in the treatment area 
(= midface), had autoimmune disorder or cancer (unspecified), previ-
ous treatment in midface with nonpermanent soft tissue filler and/or 
neuromodulators in last 12 and 6 months, respectively, had previous 
facial surgery (unspecified), had scars or permanent- or semiperma-
nent fillers in their midface, plannedto undergo any other aesthetic 
treatment in the midface during the duration of the study, or had 
COVID- 19 symptoms or a confirmed positive infection.
This study was performed in adherence to the Declaration of 
Helsinki (1996), and in accordance with regional laws and good clin-
ical practice for studies in human subjects.11 The study was con-
ducted between September 2021 and June 2022, and all treatments 
were performed at REDACTED by the same injector to assure con-
sistency during the treatment process. The study received ethics 
approval under the number of REDACTED.
2.2  |  Study design
This study was designed as a prospective interventional split- face 
study with a total follow- up of 7 weeks and a touch- up interim pos-
sibility at 3 weeks. Study participants were treated on one side of 
the face (random assignment) with a deep injection, whereas the 
contralateral side was treated with a superficial injection utilizing for 
both approaches up to 1.0 cc of Belotero(R) Volume (Merz Pharma 
GmbH & Co. KGaA, Frankfurt am Main, Germany) as needed. 
(Figure 1) After 3 weeks, the aesthetic outcome was evaluated and 
a touch- up with the same injection technique was applied if the 
aesthetic correction was incomplete or asymmetric based on the 
evaluation of the treating physician. At 7 weeks, the final aesthetic 
outcome was evaluated for each side separately.
2.3  |  Injection techniques
2.3.1  |  Deep injection technique
The deep injection technique relied on the administration of an aver-
age volume of 0.78 cc (0.2) of hyaluronic acid- based (HA) soft tissue 
filler via a 22G blunt- tip cannula (TSK Laboratory Europe, Oisterwijk, 
the Netherlands) via a sequential retrograde bolus injection target-
ing the supraperiosteal plane of the zygomatic arch and of the lateral 
midface (Figure 1).
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    |  3MARTÍN et al.
2.3.2  |  Superficial injection technique
The superficial injection technique relied on the administration of 
an average volume of 0.78 cc (0.2) of hyaluronic acid- based (HA) 
soft tissue filler via a 25G blunt- tip cannula (TSK Laboratory Europe, 
Oisterwijk, the Netherlands) via a sequential retrograde fanning in-
jection targeting the subdermal plane of the zygomatic arch and of 
the lateral midface (Figure 1).
Following product administration, the correct plane (deep 
vs. superficial) of product placement was verified via ultrasound 
imaging.
2.3.3  |  Clinical outcome assessment
Clinical outcome assessment was performed via pictures by four in-
dependent observers and for each facial side separately before the 
treatment, immediately after the treatment, before the touch- up in-
jection at 3 weeks, and at the end of the follow- up period at 7 weeks. 
The following outcome variable were evaluated:
• “Crow's Feet at Rest Scale” (4- Point Likert scale ranging from 1 to 
4; 1 = “no wrinkles”, and 4 = “very severe wrinkles”)12
• “Upper Cheek Fullness Scale” (4- Point Likert scale ranging from 1 
to 4; 1 = “full upper cheek”, and 4 = “very severely sunken upper 
cheek”)12
• “Nasolabial Fold Severity Scale” (4- Point Likert scale ranging from 
1 to 4; 1 = “no folds”, and 4 = “very severe folds”)12
The aesthetic improvement was evaluated via the GAIS 
(“Global Aesthetic Improvement Scale”); a 5- Point Likert scale 
ranging from 1 to 5 with 1 = “Very much improved” and 5 = “Very 
much worsened”. Clinical evaluation of the GAIS was performed 
in person for each facial side separately by the treating physician 
and the patient and was performed on patient images by the four 
independent observers.
2.3.4  |  Objective outcome assessment
Objective outcome assessment was conducted using 3- dimensional 
(3D) imaging as described previously.6,13– 15 In brief, standardized fullface 
3D images were obtained utilizing a Vectra H2 camera system (Canfield, 
Parsippany, NJ, USA). The images were automatically aligned to the 
baseline image and differences in volume (volume change in cc) and in 
skin position (skin vector displacement in mm) were calculated following 
the internal computational algorithm of the Mirror software tool kit for 
the middle, lower, medial, and lateral facial regions (Figures 2,3,4).
2.3.5  |  Statistical analysis
Clinical scores, as assessed by the four observers, was averaged 
and the mean value was used for data presentation and statistical 
calculation. Comparisons between facial sides and between assess-
ment points was performed by nonparametric paired testing using 
Wilcoxon signed- rank test due to the small sample size. All calcula-
tions were run using SPSS Statistics 25 (IBM, Armonk, NY, USA), and 
differences were considered statistically significant at a probability 
level of ≤0.05 to guide conclusions.
3  |  RESULTS
3.1  |  General description
3.1.1  |  Baseline comparisons
At baseline (before the treatment) no statistically significant differ-
ence was detected between facial sides for the crow's feet score (1– 
4, best to worst) (deep vs. superficial) 2.51 (0.5) versus 2.56 (0.5) with 
p = 0.234, for the upper cheek fullness score (1– 4, best to worst) 2.80 
(0.4) versus 2.86 (0.4) with p = 0.132, and for the nasolabial fold se-
verity (1– 4, best to worst) 2.45 (0.7) versus 2.46 (0.6) with p = 0.762.
F I G U R E 1  Illustrations showing the 
deep and superficial injection technique 
with the respective entry points and 
injection points utilizing a cannula.
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4  |    MARTÍN et al.
3.1.2  |  Touch- up evaluations
After the 3 weeks follow- up evaluation, 60% (12 out of 20 study 
participants) of those treated with the deep injection technique re-
quired a touch- up treatment with an average volume of 0.24 (0.1) 
cc, whereas 40% (8 out of 20 study participants) of those treated 
with the superficial injection technique required a touch- up treat-
ment with an average volume of 0.24 (0.1) cc. Despite a difference 
in frequencies was observed (60% deep vs. 40% superficial) no sta-
tistically significant difference was detected when performing a chi- 
square test with p = 0.206.
3.2  |  Clinical outcome assessment
3.2.1  |  Crow's feet at rest scale
Immediately after the treatment, the score changed from its base-
line value (see above) to (deep vs. superficial) 2.41 (0.4) versus 2.51 
(0.5) with p = 0.035. After 3 weeks follow- up the scores were (deep 
vs. superficial) 2.24 (0.4) versus 2.28 (0.4) and p = 0.470 indicating no 
statistical difference between facial sides. After 7 weeks follow- up 
the scores were (deep vs. superficial) 1.83 (0.4) versus 1.87 (0.3) with 
p = 0.317 indicating no statistical difference between facial sides. 
Follow- up visits (3 and 7 weeks) revealed a statistically significant im-
provement in the crow's feet at rest score when compared to baseline 
with all p ≤ 0.002 for both deep and superficial injections (Figure 5).
3.2.2  |  Upper cheek fullness scale
Immediately after the treatment, the score changed from its base-
line value (see above) to (deep vs. superficial) 2.39 (0.4) versus 2.41 
(0.4) with p = 0.317. After 3 weeks follow- up the scores were (deep 
vs. superficial) 1.94 (0.3) versus 1.90 (0.4) and p = 0.429 indicating no 
statistical difference between facial sides. After 7 weeks follow- up 
the scores were (deep vs. superficial) 1.67 (0.3) versus 1.59 (0.3)with 
p = 0.109 indicating no statistical difference between facial sides. 
Follow- up visits (3 and 7 weeks) revealed a statistically significant 
improvement in the upper cheek fullness scale when compared to 
baseline with all p deep (orange) and superficial (blue) 
injections.
F I G U R E 9  Bar graphs showing 
volumetric changes in the lower face 
(in cc) as measured in the 3D analysis 
software between before and after 
treatment and between before treatment 
and at 7 weeks follow- up. Scores are 
compared between deep (orange) and 
superficial (blue) injections.
F I G U R E 1 0  Bar graphs showing skin 
repositioning in the medial face (in mm) 
as measured in the 3D analysis software 
between before and after treatment and 
between before treatment and 7 weeks 
follow- up. Scores are compared between 
deep (orange) and superficial (blue) 
injections.
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8  |    MARTÍN et al.
potentially indicated a difference between superficial and deep 
product administration which was not conducted for this study; this 
must be regarded as a limitation of this investigation.
When analyzing the outcome after 7 weeks following the initial 
treatment, it was revealed that independent of the plane initially tar-
geted (superficial vs. deep) all semiquantitative scores (Crow's feet 
at rest scale, Upper cheek fullness scale, Nasolabial fold severity 
scale) statistically significantly improved with all p and objective outcome evaluation.
AUTHOR CONTRIBUTIONS
J.M.M., J.M.R., N.M.A., L.M.J., J.B.O., M.A.G., M.A., and S.C. have 
made substantial contributions to conception and design, or acquisi-
tion of data, or analysis and interpretation of data. J.M.M., J.M.R., 
N.M.A., L.M.J., J.B.O., M.A.G., M.A., and S.C. have been involved in 
drafting the manuscript or revising it critically for important intellec-
tual content and given final approval of the version to be published. 
Each author has participated sufficiently in the work to take public 
responsibility for appropriate portions of the content and agreed to 
be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are ap-
propriately investigated and resolved.
FUNDING INFORMATION
This study received financial support by Merz Pharma España S.L.
CONFLIC T OF INTERE S T S TATEMENT
M.A. and S.C. declared no conflicts of interest with respect to the 
research, authorship, and publication of this article. All other authors 
provide consulting and speaking services for Merz Pharma España 
S.L. and/or its affiliates, and use Merz Aesthetics products in their 
offices.
DATA AVAIL ABILIT Y S TATEMENT
The data that support the findings of this study are available from 
the corresponding author upon reasonable request.
E THIC S S TATEMENT
The study received ethics approval under the number of: 21/574- 
EC_P (Madrid, Spain).
ORCID
Michael Alfertshofer https://orcid.org/0000-0002-4892-2376 
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How to cite this article: Martín JM, Revelles JM, Aznar NM, 
et al. Superficial versus deep injections of the upper 
midface— A prospective interventional split- face study. J 
Cosmet Dermatol. 2023;00:1-10. doi:10.1111/jocd.15795
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https://doi.org//10.1097/DSS.0000000000002236
https://doi.org//10.1097/DSS.0000000000002236
https://doi.org//10.1111/ddg.13737
https://doi.org//10.1111/ddg.13737
https://doi.org//10.1097/PRS.0000000000001837
https://doi.org//10.1111/jocd.13245
https://doi.org//10.1016/j.jpra.2018.01.001
https://doi.org//10.4161/derm.21923
https://doi.org//10.1097/gox.0000000000002172
https://doi.org//10.1002/jbm.a.30623
https://doi.org//10.1097/PRS.0000000000005524
https://doi.org//10.1097/PRS.0000000000007857
https://doi.org/10.1111/jocd.15795
	Superficial versus deep injections of the upper midface—­A prospective interventional split-­face study
	Abstract
	1|INTRODUCTION
	2|MATERIALS AND METHODS
	2.1|Study sample
	2.2|Study design
	2.3|Injection techniques
	2.3.1|Deep injection technique
	2.3.2|Superficial injection technique
	2.3.3|Clinical outcome assessment
	2.3.4|Objective outcome assessment
	2.3.5|Statistical analysis
	3|RESULTS
	3.1|General description
	3.1.1|Baseline comparisons
	3.1.2|Touch-­up evaluations
	3.2|Clinical outcome assessment
	3.2.1|Crow's feet at rest scale
	3.2.2|Upper cheek fullness scale
	3.2.3|Nasolabial fold severity scale
	3.3|Objective outcome assessment
	3.3.1|Midfacial volume
	3.3.2|Lower facial volume
	3.3.3|Medial midface repositioning
	3.3.4|Lateral midface repositioning
	3.4|Global assessment improvement scale (GAIS)
	3.4.1|Patient GAIS
	3.4.2|Observer GAIS
	3.4.3|Treating physician GAIS
	3.4.4|Adverse events
	4|DISCUSSION
	5|CONCLUSION
	AUTHOR CONTRIBUTIONS
	FUNDING INFORMATION
	CONFLICT OF INTEREST STATEMENT
	DATA AVAILABILITY STATEMENT
	ETHICS STATEMENT
	REFERENCES