Received: 10 March 2023 | Accepted: 16 April 2023

DOI: 10.1111/jocd.15795

ORIGINAL ARTICLE

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

1
CM Clinic, Palma de Mallorca, Spain
2
Clínica Le Boost, Madrid, Spain
Abstract
3
Department of Biochemistry, University Background: Various injection algorithms have been proposed in the past which are
of Valencia, Valencia, Spain in line with the three aesthetic principles: upper face first, lateral face first, and deep
4
Department of Dermatology, Hospital
regions first. However, increasing evidence is provided that the upper midface can be
Universitario 12 de Octubre, Madrid,
Spain targeted with superficial soft tissue filler injections alone too.
5
Clínica Kiré, Murcia, Spain Objective: To investigate in a prospective split-­face study design whether superficial
6
Clínica Dr Gomariz, Murcia, Spain
or deep upper midfacial injections provide superior aesthetic outcomes.
7
Department of Hand, Plastic and
Aesthetic Surgery, Ludwig-­Maximilians-­
Methods: A total of n = 20 study participants (100% females; age 43.95 (11.7) years;
University Munich, Munchen, Germany BMI 22.92 (2.6) kg/m2) were treated with superficial soft tissue filler injections on
8
Department of Clinical Anatomy, Mayo side of their face and deep injections on the contralateral side with a mean volume of
Clinic School of Medicine, Rochester,
Minnesota, USA 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
Correspondence
Sebastian Cotofana Department of nasolabial, crow's feet, and upper cheek fullness severity scores.
Clinical Anatomy, Mayo Clinic College of Results: No adverse events related to safety or product tolerability were observed
Medicine and Science, Mayo Clinic, Stabile
Building 9-­38, 200 First Street, Rochester, during the entire study period. All semiquantitative scores improved statistically sig-
Minnesota, 55905, USA. nificantly after the observational period (p < 0.001) but displayed no difference be-
Email: cotofana.sebastian@mayo.edu
tween the two applied injection techniques (p > 0.05).
Funding information Conclusion: The results of this split-­face study revealed that both the superficial and
Merz Pharmaceuticals
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.

KEYWORDS
biomechanics, facial anatomy, hyaluronic acid injection, minimally invasive procedures

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.

J Cosmet Dermatol. 2023;00:1–10.  wileyonlinelibrary.com/journal/jocd | 1

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2 MARTÍN et al.
1 | I NTRO D U C TI O N
In a recent publication, the term facial biomechanics was introduced
1
by Cotofana and colleagues. 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
3
addition to the already established deep injections.
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 | M ATE R I A L S A N D M E TH O DS
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
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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, planned to 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).

MARTÍN et al.
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.
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
12
cheek”)
• “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.
|
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3
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 | R E S U LT S
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.
 |
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
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F I G U R E 2 3D images of a 29-­year-­old
female study participant showing the
change of volume at 7 weeks follow-­up
when compared to baseline. She received
a superficial injection on the left side and
a deep injection on the right side for both
the initial and the touch-­up injection.
F I G U R E 3 3D images of a 56-­year-­old
female study participant showing the
change of volume at 7 weeks follow-­up
when compared to baseline. She received
a superficial injection on the left side and
a deep injection on the right side for both
the initial and the touch-­up injection.
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 < 0.001 for both deep and superficial injections
(Figure 6).
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MARTÍN et al. 5

F I G U R E 4 3D images of a 56-­year-­old
female study participant showing the skin
vector displacement at 7 weeks follow-­up
when compared to baseline. She received
a superficial injection on the left side and
a deep injection on the right side for both
the initial and the touch-­up injection.

F I G U R E 5 Bar graphs showing the

“crow's feet at rest scale” (0–­4, best
to worst) as evaluated by independent
observers before treatment, after
treatment, at 3 weeks follow-­up, and at
7 weeks follow-­up. Scores are compared
between deep (orange) and superficial
(blue) injections.

F I G U R E 6 Bar graphs showing the

“upper cheek fullness scale” (0–­4, best
to worst) as evaluated by independent
observers before treatment, after
treatment, at 3 weeks follow-­up, and at
7 weeks follow-­up. Scores are compared
between deep (orange) and superficial
(blue) injections.

3.2.3 | Nasolabial fold severity scale
Immediately after the treatment, the score changed from its base-
line value (see above) to (deep vs. superficial) 2.28 (0.6) versus 2.40
(0.6) with p = 0.039. After 3 weeks follow-­up the scores were (deep
vs. superficial) 2.09 (0.5) versus 2.09 (0.6) and p = 0.957 indicating
no statistical difference between facial sides. After 7 weeks follow-
­up the scores were (deep vs. superficial) 1.83 (0.4) versus 1.83 (0.4)
with p = 1.00 indicating no statistical difference between facial sides.
Follow-­up visits (3 and 7 weeks) revealed a statistically significant im-
provement in the upper cheek fullness scale when compared to base-
line with all p < 0.001 for both deep and superficial injections (Figure 7).
 |
6 MARTÍN et al.
3.3 | Objective outcome assessment
3.3.1 | Midfacial volume
Immediately after the treatment, the midfacial volume increased fol-
lowing the deep versus superficial injections by 1.90 (1.5) cc versus
1.72 (1.5) cc with p = 0.616. After 7 weeks follow-­up the midfacial
volume increase was for the deep versus superficial injections 2.19
(1.2) cc versus 1.94 (1.3) cc with p = 0.332 (Figure 8).
3.3.2 | Lower facial volume
Immediately after the treatment, the lower facial volume decreased
following the deep versus superficial injections by −0.11 (0.9) cc ver-
sus −0.02 (1.0) cc with p = 0.478. After 7 weeks follow-­up the lower
facial volume decrease was for the deep versus superficial injections
−0.10 (1.1) cc versus −0.05 (1.0) cc with p = 0.837 (Figure 9).
3.3.3 | Medial midface repositioning
Immediately after the treatment, the vertical skin vector displace-
ment for the medial midface was for the deep versus superficial in-
jection −0.05 (0.5) mm versus −0.01 (0.4) mm with p = 0.841. After
7 weeks the vertical skin vector displacement for the medial midface
was for the deep versus superficial injection −0.04 (0.5) mm versus
−0.22 (0.6) mm with p = 0.126 (Figure 10).
3.3.4 | Lateral midface repositioning
Immediately after the treatment, the vertical skin vector displace-
ment for the lateral midface was for the deep versus superficial in-
jection 0.08 (0.7) mm versus −0.07 (0.8) mm with p = 0.334. After
7 weeks the vertical skin vector displacement for the medial midface
was for the deep versus superficial injection −0.03 (0.7) mm versus
−0.52 (0.9) mm with p = 0.723. (Figure 11).
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F I G U R E 7 Bar graphs showing the
“nasolabial fold severity scale” (0–­4, best
to worst) as evaluated by independent
observers before treatment, after
treatment, at 3 weeks follow-­up, and at
7 weeks follow-­up. Scores are compared
between deep (orange) and superficial
(blue) injections.
3.4 | Global assessment improvement scale (GAIS)
3.4.1 | Patient GAIS
The aesthetic improvement following the treatment as assessed at
7 weeks by the patients on a scale from 1 to 5, best to worst was for
the deep injections 1.74 (0.9) whereas it was for the superficial injec-
tions 1.84 (1.0) with p = 0.671.
3.4.2 | Observer GAIS
The aesthetic improvement following the treatment as assessed at
7 weeks by the four observers on a scale from 1 to 5, best to worst
was for the deep injections 2.04 (0.6) whereas it was for the superfi-
cial injections 2.04 (0.4) with p = 0.902.
3.4.3 | Treating physician GAIS
The aesthetic improvement following the treatment as assessed
at 7 weeks by the treating physician on a scale from 1 to 5, best to
worst was for the deep injections 2.16 (0.8) whereas it was for the
superficial injections 2.21 (0.8) with p = 0. 317.
3.4.4 | Adverse events
No adverse events related to safety or product tolerability were ob-
served during the entire study period.
4 | DISCUSSION
The results of this prospective, interventional split-­face study re-
vealed that both injection techniques (superficial and deep product
administration) have provided safe aesthetic treatments; no adverse
events related to safety or product tolerability were observed during
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MARTÍN et al. 7

F I G U R E 8 Bar graphs showing

volumetric changes in the midface (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 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.

the entire study period. Despite being a split-­face study, which ad-
ministered the product in two different fascial planes (superficial vs.
deep), no statistically significant side differences were observed at
the end of the 7 weeks observational period when the aesthetic im-
provement was rated via the GAIS by the patient (p = 0.671), by the
four observers (p = 0.902), or when rated by the treating physician
(p = 0.317). This indicates that despite the product was administered
in two separate planes the aesthetic outcome showed no statisti-
cally significant differences independent of who rated the outcome
after 7 weeks. However, it has to be noted that the outcome was
evaluated in repose and not under dynamic conditions like smiling.16
Assessing the outcome also under dynamic condition could have
 |
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 < 0.001. This indi-
cates that the cannula injection techniques performed are effective
in improving the locale volume (= Upper cheek fullness scale: from
2.8/2.9 to 1.7/1.6) but have also regional effects. This can be seen
in the correction of the Crow's feet at rest scale (from 2.5/2.6 to
1.8/1.9) and in the improvement of the Nasolabial fold severity scale
(from 2.5/2.5 to 1.8/1.8). The regional effects can be explained by
the layered arrangement of the facial anatomy.17 The fascial layers
of the upper and lateral midface (where the product was initially
administered) are connected with each other via the 3-­dimensional
superficial musculo-­aponeurotic system (SMAS) which can trans-
mit soft tissue changes to another region even if those regions are
apart.18,19 Injections along the zygomatic arch are located lateral to
the line of ligaments5,6,20 and can therefore precondition and thus
improve medially located facial regions like the nasolabial fold even
if the nasolabial fold was not targeted a priori.1 The improvement
of the lateral orbital region can be explained by the fact that the
orbicularis oculi muscle is integrated into the SMAS and therefore
changes to the SMAS affect the tension between the muscle and
skin resulting ultimately in reduced wrinkle severity in the circum-
ference of the lateral orbit. 21
In addition to the performed multiobserver semiquantitative
outcome scoring, objective facial regional analyses were conducted
via 3-­dimensional photography.6,13 The results revealed that the in-
crease in midfacial volume when compared to the facial status be-
fore the treatment was (deep vs. superficial) 2.19 cc versus 1.94 cc
at the 7 weeks follow-­up. This is remarkable because only 0.78 cc
of product were administered but the volume increase was 181%
for the deep and 149% for the superficial injection. This can be ex-
plained by the rheologic properties of the product. The product is
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F I G U R E 1 1 Bar graphs showing skin
repositioning in the lateral 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.
able to bind water due to its specific water binding abilities and thus
increase the local volume of the infiltrated midfacial soft tissues. 22
The injected product has a G-­prime which is stable enough to el-
evate the overlying soft tissues. 23–­25 Elevated soft tissues form a
tent-­like formation around the product, and this allows for a greater
surface projection that just the volume of the administered prod-
uct itself. 26 This product behavior is supported by the fact that the
increase in surface projection was observed immediately after the
treatment and continued until the 7 weeks follow-­up period. It can
be speculated that this effect might continue even further but fu-
ture studies need to investigate this trend specifically with a longer
follow-­up period.
Despite not statistically significant (p = 0.616 and p = 0.332),
a slight trend was visible in which the deep injection effected a
greater surface projection than the superficial injection technique.
This is plausible because the deep injection technique elevates more
soft tissues than the superficial technique; this can be compared to
the bottom diameter of a large (= deep injection technique) versus
a small (= superficial injection technique) tent: a larger tent has a
greater overall surface than a small tent. This effect is additionally
supported by volume measurements conducted in the lower face
which have revealed that midfacial volume increase promotes lower
facial volume decrease. This is in line with a previous publication27
and provides an explanatory model for the effects seen in the lower
face. The volume decrease in the lower face was (deep vs. superfi-
cial) −0.10 cc versus −0.05 cc after 7 weeks follow-­up with p = 0.837
between facial sides. This indicates that the decrease in lower facial
volume was slightly larger for the deep injection which is supported
by the fact that more facial soft tissues were repositioned with the
deep versus the superficial injection technique.
A similar effect was observed when analyzing objective skin
vector displacement which is also in line with the results presented
above. A deep injection can elevate the entire soft tissue envelope
as a coherent unit whereas the superficial injection technique can
cause a disconnection between the fascial layers separating su-
perficial from deeper fascial planes. This is most likely caused by
the administered product which creates a new layer between the

MARTÍN et al.
superficial and the deep structures. This disconnect reduces the
connection of the superficial structures to the deep structures and
affects thus the stability of the superficial layers. As a consequence,
the superficial layers are more amenable to the effects of gravity
and can displace caudally. This skin surface displacement into more
caudal locations is confirmed by the greater magnitude of caudally
pointing (= negative) skin displacement vectors which are greater
for the superficial than for the deep injection technique (deep vs. su-
perficial): medial midface −0.04 mm versus −0.22 mm with p = 0.126;
lateral midface: −0.03 mm versus −0.52 mm with p = 0.723. Despite
not reaching statistical significance, the results are coherent and
point toward a trend.
5 | CO N C LU S I O N
The results of this split-­face study reveal that both the superficial
and the deep cannula injection technique for midface volumiza-
tion statistically significantly improve the midfacial volume, reduce
nasolabial fold and crow's feet severity. Both injection techniques
were rated by the patient, independent observers, and the treating
physician to be without side differences and to improve the over-
all aesthetic appearance of the face. No statistically significant dif-
ference was observed between the two injection techniques when
compared via semiquantitative and objective outcome evaluation.
AU T H O R C O N T R I B U T I O N S
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.
F U N D I N G I N FO R M AT I O N
This study received financial support by Merz Pharma España S.L.
C O N F L I C T O F I N T E R E S T S TAT E M E N T
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 AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from
the corresponding author upon reasonable request.
|
14732165, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jocd.15795 by CAPES, Wiley Online Library on [17/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
9
E T H I C S S TAT E M E N T
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
REFERENCES
1. Freytag DL, Alfertshofer M, Frank K, et al. Understanding fa-
cial aging through facial biomechanics—­a clinically applicable
guide for improved outcomes. Facial Plast Surg Clin North Am.
2022;30(2):125-­133.
2. Schelke L, Velthuis PJ, Lowry N, et al. The mobility of the superficial
and deep midfacial fat compartments—­an ultrasound—­based inves-
tigation. J Cosmet Dermatol. 2021;20(12):3849-­3856.
3. Schenck TL, Koban KC, Schlattau A, et al. The functional anatomy
of the superficial fat compartments of the face: a detailed imag-
ing study. Plast Reconstr Surg. 2018;141(6):1351-­1359. doi:10.1097/
PRS.0000000000004364
4. Cotofana S, Gotkin RH, Frank K, et al. The functional anatomy of
the deep facial fat compartments: a detailed imaging-­based in-
vestigation. Plast Reconstr Surg. 2019;143(1):53-­63. doi:10.1097/
PRS.0000000000005080
5. Casabona G, Frank K, Koban KC, et al. Lifting vs volumizing-­the
difference in facial minimally invasive procedures when respect-
ing the line of ligaments. J Cosmet Dermatol. 2019;18:1237-­1243.
doi:10.1111/jocd.13089
6. Freytag DL, Alfertshofer MG, Frank K, et al. The difference in facial
movement between the medial and the lateral midface: a 3D skin
surface vector analysis. Aesthet Surg J. 2021;42:1-­9. doi:10.1093/
asj/sjab152
7. Hernandez C, Zapata DU, Bermudez MP, et al. Clinical validation of
the upper face first principle—­a clinical, prospective, interventional
split-­face study. J Cosmet Dermatol. 2023;22(2):418-­425.
8. Meegalla N, Sood G, Nessel TA, Downs BW. Anatomy, head and
neck, facial arteries. 2022.
9. Carruthers J, Flynn TC, Geister TL, et al. Validated assessment
scales for the mid face. Dermatologic Surg. 2012;38(2 PART 2):320-­
332. doi:10.1111/j.1524-­4725.2011.02251.x
10. Narins RS, Carruthers J, Flynn TC, et al. Validated assessment scales
for the lower face. Dermatologic Surg. 2012;38(2 PART 2):333-­3 42.
doi:10.1111/j.1524-­4725.2011.02247.x
11. WMA Declaration of Helsinki –­ Ethical Principles for Medical
Research Involving Human Subjects –­ WMA –­ The World Medical
Association. Available from https://www.wma.net/polic​ies-­post/
wma-­d ecla​r atio​n-­of-­h elsi​n ki-­ethic​al-­p rinc​iples​-­for-­m edic​al-­resea​
rch-­invol​ving-­human​-­subje​c ts/
12. Stella E, Petrillo A. Standard evaluation of the patient: the Merz scale;
2014:33-­50. doi:10.1007/978-­88-­470-­5361-­8 _3
13. Hernandez CA, Alfertshofer M, Frank K, et al. Quantitative mobility
analysis of the face and its relevance for surgical and non-­surgical
aesthetic facial procedures. Aesthet Plast Surg. 2022;46:2237-­2245.
doi:10.1007/s00266-­022-­02921-­8
14. Hyer JN, Murta F, Juniat VAR, Ezra DG. Validating three-­
dimensional imaging for volumetric assessment of periorbital soft
tissue. Orbit. 2021;40(1):9-­17. doi:10.1080/01676830.2020.17117
80
15. De Stefani A, Barone M, Hatami Alamdari S, et al. Validation of
Vectra 3D imaging systems: a review. Int J Environ Res Public Health.
2022;19(14). doi:10.3390/ijerph19148820
16. Cotofana S, Gotkin RH, Frank K, Lachman N, Schenck TL.
Anatomy behind the facial overfilled syndrome: the transverse
 |
10
facial septum. Dermatol Surg. 2019;46:e16-­e22. doi:10.1097/
DSS.0000000000002236
17. Cotofana S, Lachman N. Anatomy of the facial fat compart-
ments and their relevance in aesthetic surgery. JDDG J der Dtsch
Dermatologischen Gesellschaft. 2019;17(4):399-­413. doi:10.1111/
ddg.13737
18. Cotofana S, Schenck TL, Trevidic P, et al. Midface: clinical anatomy
and regional approaches with injectable fillers. Plast Reconstr Surg.
2015;136:219S-­234S. doi:10.1097/PRS.0000000000001837
19. Whitney ZB, Jain M, Zito PM. Anatomy, skin, superficial musculoapo-
neurotic system (SMAS) fascia. 2022.
20. Casabona G, Bernardini FP, Skippen B, et al. How to best utilize
the line of ligaments and the surface volume coefficient in facial
soft tissue filler injections. J Cosmet Dermatol. 2020;19(2):303-­311.
doi:10.1111/jocd.13245
21. Sandulescu T, Blaurock-­Sandulescu T, Buechner H, Naumova
EA, Arnold WH. Three-­dimensional reconstruction of the sub-
orbicularis oculi fat and the infraorbital soft tissue. JPRAS Open.
2018;16:6-­19. doi:10.1016/j.jpra.2018.01.001
22. Papakonstantinou E, Roth M, Karakiulakis G. Hyaluronic acid: a
key molecule in skin aging. Dermatoendocrinol. 2012;4(3):253-­258.
doi:10.4161/derm.21923
23. Rohrich RJ, Bartlett EL, Dayan E. Practical approach and
safety of hyaluronic acid fillers. Plast Reconstr Surg–­Glob Open.
2019;7(6):e2172. doi:10.1097/gox.0000000000002172
14732165, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jocd.15795 by CAPES, Wiley Online Library on [17/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
MARTÍN et al.
24. Falcone SJ, Palmeri DM, Berg RA. Rheological and cohesive prop-
erties of hyaluronic acid. J Biomed Mater Res A. 2006;76(4):721-­728.
doi:10.1002/jbm.a.30623
25. Stocks D, Sundaram H, Michaels J, Durrani MJ, Wortzman MS,
Nelson DB. Rheological evaluation of the physical properties of hyal-
uronic acid dermal fillers. J Drugs Dermatology. 2011;10(9):974-­980.
26. Cotofana S, Koban CK, Frank K, et al. The surface-­volume-­
coefficient of the superficial and deep facial fat compart-
ments –­ a cadaveric 3D volumetric analysis. Plast Reconstr Surg.
2019;143(6):1605-­1613. doi:10.1097/PRS.0000000000005524
27. Haidar R, DL FMD, Frank K, et al. Quantitative analysis of the lift-
ing effect of facial soft-­tissue filler injections. Plast Reconstr Surg.
2021;147:765e-­776e. doi:10.1097/PRS.0000000000007857
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