Lasers in Surgery and Medicine
Evaluation of the In Vivo Effects of Various Laser, Light, or
Ultrasound Modalities on Human Skin Treated With a
Collagen and Polymethylmethacrylate Microsphere Dermal
Filler Product
Douglas C. Wu, MD, PhD,1 Jwala Karnik, MD,2 Tara Margarella, DO,2 Vivien L. Nguyen, PharmD,2
Antoanella Calame, MD,3 and Mitchel P. Goldman, MD1
1
Goldman Butterwick Groff Fabi and Wu, Cosmetic Laser Dermatology, 9339 Genesee Avenue Suite 300, San Diego,
California 92121
2
Suneva Medical, Inc., 5385 Hollister Ave Ste 100, Santa Barbara, California 93111
3
Compass Dermatopathology, Inc., 7300 Girard Ave, La Jolla, California 92037
Background: Bellafill1 is a soft tissue dermal filler
composed of non-resorbable polymethylmethacrylate
(PMMA) microspheres, suspended in a water-based carrier
gel composed of 3.5% bovine collagen. It has been approved
by the FDA for the correction of nasolabial folds and
atrophic facial acne scars. Energy-based therapies are
used for facial rejuvenation and treatment of acne
scarring. However, little has been published about the
effects of energy devices on previously placed PMMA. This
prospective, in vivo clinical study evaluated the safety and
histopathological effects of a number of different laser,
light, and ultrasound treatment modalities on PMMA-
collagen filler previously injected into human tissue.
Methods: Following a negative reaction to the bovine
collagen skin test, the abdomen of one subject (with
planned mini-abdominoplasty) was divided into a grid
with 32 treatment sections. Seventeen treatment areas
received subdermal injections of PMMA-collagen product
(0.1–0.2 cc in each area). The subject was assessed for
adverse events at each post-treatment office visit. Eighty
days post-injection, 30 treatment sections were treated
with laser, light, or ultrasound therapy (16 of the 17
PMMA-collagen treated areas, with two of those areas
receiving a combination of therapies, and an additional 14
areas receiving laser therapy alone). One PMMA-collagen
treated area was not exposed to any energy devices, and
one remaining treatment area received no treatment of
any kind, representing an internal control. Sixty days
following energy device treatment, the tissue was excised
in a planned mini-abdominoplasty procedure and sent for
histological examination.
Results: The subject experienced no adverse events
during the study. No histological changes in PMMA
microspheres were observed in any treatment area. An
expected lymphohistiocytic response was identified in all
areas where PMMA microspheres were present.
Conclusion: Laser, light, and ultrasound treatments can
safely be administered following a PMMA-collagen injec-
tion. Lasers Surg. Med. ß 2016 Wiley Periodicals, Inc.
ß 2016 Wiley Periodicals, Inc.
Key words: polymethylmethacrylate; PMMA; Bellafill;
laser; ultrasound; acne scarring; filler; resurfacing;
abdominoplasty; soft tissue augmentation
INTRODUCTION
In October 2006, polymethylmethacrylate (PMMA)-
collagen filler (Bellafill1, Suneva Medical, Inc.; San Diego,
CA) was FDA-approved for the correction of nasolabial
folds and atrophic facial acne scars [1]. It is a soft tissue
filler comprised of inert, non-resorbable PMMA micro-
spheres suspended in a non-cross linked, biocompatible,
3.5% bovine collagen vehicle with 0.3% lidocaine, and other
buffers. Specifically, each syringe of product contains by
volume 80% collagen gel and 20% smooth, round PMMA
microspheres 30–50 m in diameter. This is theorized as the
ideal size band for the PMMA microspheres, as it is large
enough to escape phagocytosis by macrophages in the
tissue, but small enough to be delivered through a
26-gauge needle [2]. The smaller the microspheres, the
larger their combined total surface area in a given volume
and, therefore, the greater the promotion of collagen
deposition. Thus, larger microspheres (e.g., 100 m in
diameter) would promote less connective tissue build-up
because of the resulting smaller total surface area per
volume [2].
Conflict of Interest Disclosures: All authors have completed
and submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest and none were reported.
Contract grant sponsor: Suneva Medical, Inc.

Correspondence to: Douglas C. Wu, MD, PhD, Goldman
Butterwick Groff Fabi and Wu, Cosmetic Laser Dermatology,
9339 Genesee Avenue Suite 300, San Diego, CA 92121.
E-mail: dwu@clderm.com
Accepted 14 August 2016
Published online in Wiley Online Library
(wileyonlinelibrary.com).
DOI 10.1002/lsm.22580
2 WU ET AL.

Migration of the microspheres out of the implant into the
surrounding fine network of collagen fibers in the deep
dermal layer is prevented by two features of PMMA-
collagen. First, the bovine collagen embeds the micro-
spheres and prevents them from clumping, thereby
allowing tissue ingrowth at an early stage [2] (Fig. 1).
Following injection, the PMMA microspheres elicit an
initial, low-grade foreign body reaction, which presumably
stimulates the fibroblasts to generate collagen [3]. Over
time, the injected bovine collagen is enzymatically
degraded and it is thought that new collagen is formed
as fibroblasts, collagen, and capillaries fill the interstitial
spaces between the microspheres. Human histology
studies show that the bovine collagen is resorbed by
3 months with evidence of new collagen growth as early as
1 month [4]. During this gradual process, the PMMA
microspheres become fully encapsulated and integrated
into the dermis to become part of the tissue within 3–6
months post-injection [2]. Secondly, the 30–50 m size
prevents the microspheres from entering into the inter-
stices between deep dermal fibers, which have a diameter
of approximately 10–15 m [2].
The safety and effectiveness of PMMA-collagen in the
correction of nasolabial folds and acne scars have been well
established [5–10]. Other dermatologic treatments such as
laser, light, and ultrasound devices also play important
roles in treating both aging skin and acne scars. Several
studies have been conducted evaluating the effect of laser
and light treatments on hyaluronic acid fillers and other
soft tissue fillers [11–13]. However, there is little in the
published literature regarding the effect of laser treatment
on injected PMMA-collagen dermal filler. This is of
particular importance due to the increasing use
of combination treatment modalities for the treatment of
acne scarring. The following study was designed to
evaluate the safety and histopathologic effects of various
laser, light, and ultrasound treatment modalities on
PMMA microspheres previously injected into human
abdominal tissue.
METHODS
This Institutional Review Board (IRB)-approved open-
label pilot study was conducted in accordance with the
Declaration of Helsinki and the International Conference

Fig. 1. (A) PMMA microspheres surrounded by homogenized bovine collagen matrix immediately
after injection (H&E, 200); (B) trichrome staining highlighting the homogenized bovine collagen
(200); (C) approximately 5 months post-injection the intact PMMA microspheres (sample 7, see
Table 2) are surrounded by lymphohistiocytic inflammation and collagen, which is highlighted with
a trichrome stain (D) (200).
 EFFECTS OF VARIOUS LASER, LIGHT, OR ULTRASOUND MODALITIES 3

on Harmonization at a single center in a single subject with
planned mini-abdominoplasty. The subject was seen by the
Investigator at Baseline (Visit 1), Day 28 (Visit 2), D
ay 42 (Visit 3), Day 108 (Visit 4), Day 115 (Visit 5), Day 122
(Visit 6), Day 138 (Visit 7), and Day 168 (Visit 8).
Photographs were taken of the treatment area at Visits
2 through 8. Safety was assessed at each post PMMA-
collagen treatment visit.
At Visit 1, prior to screening and enrollment, the subject
underwent the informed consent process and signed
an IRB-approved informed consent/HIPPA, California
Experimental Subject’s Bill of Rights, and Photo Consent
and Release Forms. To participate, the potential subject
was required to meet the inclusion and exclusion criteria
(Table 1). After verification that the subject fulfilled the
inclusion and exclusion criteria, skin testing for sensitivity
to bovine collagen was conducted consistent with the
PMMA-collagen skin test product labeling [14].
The Subject returned 28 days after placement of the skin
test for final interpretation (Visit 2). Following a negative

TABLE 1. Inclusion/Exclusion Criteria

Inclusion Criteria

 Female or Male in good general health greater than 21 years of age.

 Subject must sign an IRB-approved informed consent form, photographic release form, California Experimental
Subject’s Bill of Rights form, and the authorization for use and release of health and research study information
(HIPAA) form prior to any study-related procedures being performed.
 Planned mini-abdominoplasty of lower abdomen.
 Fitzpatrick skin type I–III.
 Sufficient excess skin in lower abdomen to allow for planned laser/light/ultrasound treatment area (Appendix A,
approximately 6  10 cm).
 For female subject of childbearing potential, must have had a regular menstrual cycle prior to study entry (a female is
considered of childbearing potential unless she is postmenopausal, without a uterus and/or both ovaries, or has had a
bilateral tubal ligation) and is willing to use an acceptable form of birth control during the entire course of the study
[i.e., acceptable methods of birth control are oral contraceptives, contraceptive patches/rings/implants Implanon1,
Depo-Provera1, double-barrier methods (e.g., condoms and spermicide), abstinence, and vasectomies of partner with a
documented second acceptable method of birth control should the subject become sexually active]. All systemic birth
control measures must be in consistent use at least 30 days prior to study participation and PMMA injection.
 Negative urine pregnancy test results at the time of study entry and treatment (if applicable).
 Must be willing to comply with study protocols and complete the entire course of the study.

Exclusion Criteria
 Female subjects that are pregnant (positive UPT), breast-feeding, or who are of childbearing potential and not
practicing a reliable method of birth control.
 Have any skin pathology or condition that could interfere with the evaluation of the treatment areas, worsen due to the
proposed treatment or require interfering topical, systemic or surgical therapy.
 Have recent or current history of inflammatory skin disease, infection, cancerous/pre-cancerous lesion, unhealed
wound in the study area.
 Have a history of systemic granulomatous diseases active or inactive (e.g., Sarcoid, Wegeners, TB, etc.) or connective
tissue diseases (e.g., lupus, dermatomyositis, etc.).
 Have any evidence of keloid scarring or susceptibility to keloid formation or hypertrophic scarring.
 Have a history of bleeding disorders.
 Have a known hypersensitivity or previous allergic reaction to any of the components of the study device (including
lidocaine or any amide-based anesthetic), or has a history of allergies to any bovine collagen products, including but not
limited to injectable collagen, collagen implants, hemostatic sponges, and collagen-based sutures.
 Undergo or be planning to undergo desensitization injections to meat products.
 Be unable to communicate or cooperate with the Investigator due to a language barrier (non-english speaking), poor
mental development, or impaired cerebral function.
 Have evidence of alcohol or drug abuse (Investigator opinion), or history of poor cooperation, non-compliance with
medical treatment, or unreliability.
 Have used of an investigation device, biologic or drug in the past 30 days, or is currently participating in an
experimental drug, biologic or device trial.
 Have a condition or be in a situation that, in the Investigator’s opinion, may put the subject at significant risk, may
confound the study results, or may interfere significantly with the subject’s participation in the study.
 Have a history of any previous injectable filler to the study treatment area.
4 WU ET AL.
PMMA-collagen skin test result, a 6  10 cm area of the
Subject’s lower abdomen was divided into 32 individual
rectangular treatment sections with tattoos in each corner
of the treatment rectangle. In 17 of the 32 treatment
sections, 0.1–0.2 cc of PMMA-collagen filler was injected
using the linear threading injection technique with a
26-gauge needle.
The subject returned at Visit 3 (Day 42 which was 14 days
after filler injection) for follow-up observation and safety
evaluation. At Visit 4 (Day 108 which was 80 days post filler
injection), the subject’s treatment area was anesthetized
and several energy sources of varying degrees of heat and
ablative capacity were applied to the skin’s surface.
The treatments included:
 Pulsed-dye laser (595 nm) at 10 mm spot size, 8 J/cm2,
6 ms pulse duration, DCD 50/30.
 Nd:YAG laser (1,064 nm) at 3.5 mm spot size, 200 J/cm2,
25 ms pulse duration, 30/30 cooling.
 Nd:YAG fractional nonablative laser (1,320/1,440 nm) at
14 mm spot size, 7.5/2.5 J/cm2.
 1,565 nm fractional nonablative laser at 5 mm spot size,
400/cm2 density, 40 mJ.
 Thulium fiber fractional nonablative laser (1,927 nm) at
treatment level 5, 20 mJ, eight passes.
 Dual laser 1,550/1,927 (Erbium doped 1,550 nm and
Thulium fiber 1,927 nm) at treatment level 4, 40 mJ for
four passes then treatment level 5, 20 mJ for four passes.
 10,600 nm CO2 Fractional Ablative Lasers:
 Active Fx, Lumenis Inc., San Jose, CA (broad,
superficial ablation) at CPG 3-6-3, 125 mJ, 450 Hz.
 Deep Fx, Lumenis Inc., San Jose, CA (deep ablative
columns, used at standard and 40% above standard
energy settings) at 20% density and 25 mJ (standard)
or 35 mJ (high).
 Fraxel Re:pair, Solta Medical, Hayward, CA (deep
ablative columns, used at standard and 40% above
standard energy settings) at 20% coverage and 50 mJ
(standard) or 70 mJ (high).
 2,940 nm Erbium:YAG non-fractionated ablative laser
at 100 m depth, 50 ablate/50 coagulation, 12.5 mJ.
 Intense pulsed light source (M22 or Lumenis 1, Lumenis
Inc., San Jose, CA) at double pulse 3.5 ms pulse width
with 20 ms pulse delay, 6 mm spot crystal, 560 nm cutoff,
35 J/cm2.
 Transcutaneous microfocused ultrasound device (Ulth-
erapy, Ulthera Inc., Mesa, AZ) 4–4.5 transducer.
Thirty of the 32 treatment sections received laser, light, or
ultrasound therapy (see Table 2). Fourteen of the 17 PMMA-
collagen treated sections received single energy treatments,
two PMMA-collagen treated sections received combination
therapies (one with a combination of Ulthera/Deep FX
35 mJ and the other Ulthera/Fraxel Restore 1,550 nm) and
one remaining PMMA-collagen treated section was not
exposed to any energy device. For comparison, 14 treatment
sections were treated with energy alone, and one area
remained untreated, for internal control.
The subject returned for additional follow-up observa-
tion and safety evaluations at Visits 5, 6, and 7.
At Visit 8 (60 days after energy device treatments),
the subject underwent scheduled mini-abdominoplasty.
After marking the area of surgical excision, the subject’s
abdomen was cleansed with 4% chlorhexidine gluconate
before being draped in sterile fashion. To induce a state
of conscious sedation, 2 mg of midazolam and 50 mg of
fentanyl were administered intravenously. Tumescent
anesthesia was then applied to the surgical site utilizing
a solution of 500 mg of lidocaine, 0.5 mg of epinephrine,
10 mEq of sodium bicarbonate in 1 L of normal saline. A
#15 surgical blade was used to excise full thickness
abdominal tissue including epidermis, dermis, and
subcutaneous fat layers. This excision included the
grid that had been previously treated with PMMA
microspheres and energy devices in its entirety.
Following excision, surgical undermining of the free
edges was performed and light hemostasis was achieved
via hyfrecation. Primary closure was carried out in a
two stage process with deep interrupted Vicryl 3–0
sutures to approximate the wound followed by running
superficial subcuticular 4–0 Proline for final closure.
The excised tissue was collected intact and preserved in
10% formaldehyde in preparation for histological exam-
ination. The tissue was submitted in its entirety to the
pathology laboratory, where 8 mm punch biopsies were
collected from each of the 32 tattoo-marked treatment
sites. The formalin-fixed punch biopsies were bisected,
processed, paraffin-embedded, and stained with hema-
toxylin and eosin for histologic evaluation, which
was performed by a dermatopathologist blinded to
the specific treatments performed at the 32 different
sites (Table 2).
RESULTS
The depth of injection was typically at the deep dermis/
subcutaneous junction as shown in Table 3. On histological
analysis, PMMA microspheres were detected at depths
ranging from 0.5–1.75 cm. The areas assessed were taken
from a single contiguous piece of abdominal skin measur-
ing 4  8 cm and so skin thickness throughout this small
surface area was likely to be uniform.
The subject experienced no adverse events due to
PMMA-collagen treatment. Laser and energy device
treatments were well tolerated and followed expected
recovery trajectories. The areas marked by prolonged post-
inflammatory hyperpigmentation correlated to the use of
deep fractionated CO2 at settings intentionally adjusted to
40% greater than what would normally be selected for
clinical application (Fig. 2). There were no complications
due to the mini-abdominoplasty procedure.
PMMA microspheres were identified in the deep dermis
and upper subcutis in each of the 17 PMMA-collagen
treatment sections. Laser, light, and ultrasound treat-
ments showed no sign of interaction with the PMMA
microspheres. No histological changes in PMMA micro-
spheres were observed in any treatment area, and no
TABLE 2. Treatment Grid

1 2 3 4 5 6 7 8
Bellafill BF & CO2 BF & CO2 BF & CO2 BF & CO2 BF & CO2 BF & Erbium: BF &
fractional fractional fractional fractional fractional YAG ablative Transcutaneous
ablative laser ablative laser ablative laser ablative ablative laser laser (2,940 nm) Microfocused
(10,600 nm; (10,600 nm; (10,600 nm; laser (10,600 nm; Re: Ultrasound
Active Fx, Deep Fx, Deep Fx, (10,600 nm; pair, 70 mJ)
125 mJ) 25 mJ) 35 mJ) Re:pair,
50 mJ)
9 10 11 12 13 14 15 16
BF & Ulthera/ CO2 fractional O2 fractional CO2 fractional CO2 CO2 fractional Erbium:YAG Transcutaneous
Deep FX ablative laser ablative laser ablative laser fractional ablative laser ablative laser Microfocused
35 mj (10,600 nm; (10,600 nm; (10,600 nm; ablative (10,600 nm; Re: (2,940 nm) Ultrasound
Active Fx, Deep Fx, Deep Fx, laser pair, 70 mJ)
125 mJ) 25 mJ) 35 mJ) (10,600 nm;
Re:pair,
50 mJ)
17 18 19 20 21 22 23 24
BF & Ulthera/ BF & Intense BF & Pulsed-dye BF & Fraxel Dual BF & Nd:YAG BF & Nd:YAG BF & Erbium- BF & Thulium
Fraxel Pulsed Light laser (595 nm) laser (1,550/ laser fractional laser doped fiber fiber fractional
Restore 15/50 (560–1,200 nm) 1,927 nm) (1,064 nm) (1,320/ fractional laser laser (1,927 nm)
1,440 nm) (1,565 nm)
25 26 27 28 29 30 31 32
Intense Pulsed Pulsed-dye laser Fraxel Dual laser Nd:YAG Nd:YAG Erbium-doped Thulium fiber
Light (560– (595 nm) (1,550/ laser fractional laser fiber fractional fractional laser
1,200 nm) 1,927 nm) (1,064 nm) (1,320/ laser (1,565 nm) (1,927 nm)
1,440 nm)
EFFECTS OF VARIOUS LASER, LIGHT, OR ULTRASOUND MODALITIES
5
6 WU ET AL.

TABLE 3. Histologic Findings

Histologic
Bellafill Bellafill Level of evidence of
microspheres microspheres Inflammationa bellafill energy
Sample Treatment present (Y/N) Intact (Y/N) (Y/N) microspheres treatmentsb

1 BF Y Y Y Sq N
2 BF & CO2 fractional ablative Y Y Y Sq Y
laser (10,600 nm; Active
Fx, 125 mJ)
3 BF & CO2 fractional ablative Y Y Y D, Sq Y
laser (10,600 nm; Deep Fx,
25 mJ)
4 BF & CO2 fractional ablative Y Y Y D/Sq, Sq Y
laser (10,600 nm; Deep Fx,
35 mJ)
5 BF & CO2 fractional ablative Y Y Y D/Sq, Sq Y
laser (10,600 nm; Re:pair,
50 mJ)
6 BF & CO2 fractional ablative Y Y Y Sq Y
laser (10,600 nm; Re:pair,
70 mJ)
7 BF & Erbium:YAG ablative Y Y Y D/Sq, Sq Y
laser (2,940 nm)
8 BF & Transcutaneous Y Y Y D/Sq, Sq Y
Microfocused Ultrasound
9 BF & Ulthera/Deep FX 35mj Y Y Y D/Sq, Sq Y
10 CO2 fractional ablative laser N N/A N N/A Y
(10,600 nm; Active Fx,
125 mJ)
11 CO2 fractional ablative laser N N/A N N/A Y
(10,600 nm; Deep Fx,
25 mJ)
12 CO2 fractional ablative laser N N/A N N/A Y
(10,600 nm; Deep Fx,
35 mJ)
13 CO2 fractional ablative laser N N/A N N/A Y
(10,600 nm; Re:pair,
50 mJ)
14 CO2 fractional ablative laser N N/A N N/A Y
(10,600 nm; Re:pair,
70 mJ)
15 Erbium:YAG ablative laser N N/A N N/A Y
(2,940 nm)
16 Transcutaneous N N/A N N/A Y
Microfocused Ultrasound
17 BF & Ulthera/Fraxel Restore Y Y Y Deep Sq Y
15/50
18 BF & Intense Pulsed Light Y Y Y Sq Y
(560–1,200 nm)
19 BF & Pulsed-dye laser Y Y Y Sq Y
(595 nm)
20 BF & Fraxel Dual laser Y Y Y D/Sq, Sq Y
(1,550/1,927 nm)
21 BF & Nd:YAG laser Y Y Y Sq Y
(1,064 nm)
22 BF & Nd:YAG fractional Y Y Y D/Sq, Sq Y
laser (1,320/1,440 nm)
 EFFECTS OF VARIOUS LASER, LIGHT, OR ULTRASOUND MODALITIES 7

TABLE 3. (Continued)

Histologic
Bellafill Bellafill Level of evidence of
microspheres microspheres Inflammationa bellafill energy
Sample Treatment present (Y/N) Intact (Y/N) (Y/N) microspheres treatmentsb
23 BF & Erbium-doped fiber Y Y Y Sq Y
fractional laser (1,565 nm)
24 BF & Thulium fiber Y Y Y Sq Y
fractional laser (1,927 nm)
25 Yc Y Y Sq N
26 Intense Pulsed Light (560– N N/A N N/A Y
1,200 nm)
27 Pulsed-dye laser (595 nm) N N/A N N/A Y
28 Fraxel Dual laser (1,550/ N N/A N N/A Y
1,927 nm)
29 Nd:YAG laser (1,064 nm) N N/A N N/A Y
30 Nd:YAG fractional laser N N/A N N/A Y
(1,320/1,440 nm)
31 Erbium-doped fiber N N/A N N/A Y
fractional laser (1,565 nm)
32 Thulium fiber fractional N N/A N N/A Y
laser (1,927 nm)
D, Dermis; Sq, subcutaneous fat; BF, Belafill.
a
Type of inflammation present: lymphohistiocytic.
b
Histologic evidence of energy treatments included ablative and coagulative changes, blood vessel congestion, and mild fibrosis.
c
A few microspheres were present in sample 25 due to spillover from sample 17, which was immediately adjacent.

unexpected changes in the surrounding tissues were
observed (Fig. 3).
All areas that were treated with PMMA microspheres
displayed evidence of lymphohistiocytic inflammation
consistent with the proposed mechanism of action of this
soft tissue filler. Accordingly, those areas that received only
energy device treatment and no PMMA microspheres did
not show any histological evidence of a lymphohistiocytic
reaction. Histologic data from the 32 samples showed that
the PMMA microsphere implants were entirely unaffected
and indistinguishable between laser-, light-, or ultrasound-
treated sites and the untreated PMMA control site (Table 3).

Fig. 2. (A) Tattoo grid displaying area to be treated with PMMA and/or energy device on human
skin scheduled for abdominoplasty; (B) 1 week following energy device treatment; (C) 2 weeks
following energy device treatment; (D) 4 weeks following energy device treatment. Prolonged
pigmentary alteration can be seem in areas treated with ablative laser settings 40% above standard
treatment settings.
8 WU ET AL.
Fig. 3. (A) PMMA microspheres surrounded by lymphohistiocytic
inflammation (sample 1, no energy treatment, see Table 3) (H&E,
400); (B and C) intact PMMA microspheres surrounded by
lymphohistiocytic inflammation, unaltered by the energy treat-
ments—sample 22 (B) and sample 7 (C) (see Table 1) (H&E, 400).
DISCUSSION
The physician has multiple tools at his/her disposal to
treat patients’ cosmetic concerns. Dermal fillers and
energy-based devices are two of the most common types
of treatments that may be used in a single patient
sequentially and/or concurrently. A dermal filler can
provide volume and lift to depressed areas while lasers
may remove damaged skin and stimulate production of
new collagen. As opposed to the immediate gratification
seen with filler injections, skin remodeling, and rejuvena-
tion following laser procedures is a gradual process and can
take up to a year before the final result is achieved.
Combination procedures are increasing in popular-
ity [12,13,15,16]. The safety of PMMA-collagen in combi-
nation with other treatment modalities, such as laser, light
and ultrasound therapies, has been a topic of great
interest, especially since PMMA-collagen was approved
for treating acne scars. It is known that the collagen-
producing effects from laser treatments occur at approxi-
mately 658C [15,16]. The melting point of PMMA is much
higher, at 1658C. In addition, most energy-based treat-
ments do not reach the depth of the deep dermis or dermal/
subdermal junction, which is the recommended depth of
placement for PMMA-collagen. Therefore, one could
theoretically assume that using an energy-based
treatment over skin that had previously been injected
with PMMA-collagen would be safe. To our knowledge, this
has not been systematically studied. Therefore, we
undertook this rigorous analysis of gross and histological
effects of combination therapy in a study designed to
eliminate patient variability.
Following injection of PMMA-collagen into abdominal
skin, we did not see any adverse events occurring up to 80
days post-injection. The skin was then treated with
multiple different energy devices and settings, and the
skin was observed for an additional 60 days. Again, no
adverse events were observed.
Histopathological evaluation revealed no evidence of
alteration of the PMMA microspheres and no changes in
the expected lymphohistiocytic inflammatory reaction
surrounding the microspheres when the PMMA-only
treatment site was compared to the PMMA-injected sites
subjected to the different energy treatments (Table 2).
Furthermore, none of the PMMA-injected sites showed any
evidence of a foreign-body granulomatous response. The
energy treatment-induced histologic changes included
ablative and coagulative changes, heat-related blood
vessel congestion, and mild fibrosis. The microspheres
remained intact and unaltered by the various treatment
modalities. Higher energy settings caused deeper tissue
injury and increased penetration into the reticular dermis
but did not show any obvious morphologic changes or
denaturation of the PMMA microspheres.
In this experimental design, a period of 80 days was
allotted between time of PMMA microsphere implantation
and delivery of energy device treatment to allow for the
monitoring of any potential adverse events from the
PMMA microspheres alone. In routine clinical practice,
we speculate that same day treatment will likely be safe
and effective for a number of reasons. Firstly, the two
immunological responses (wound healing from laser and
foreign body to PMMA) are quite similar, following the
same stages of clot, acute/chronic inflammation, and
granulation with activation of fibroblasts. Secondly, the
lymphohistiocytic response to PMMA continues long after
 EFFECTS OF VARIOUS LASER, LIGHT, OR ULTRASOUND MODALITIES
the resolution of the acute wound healing phase of laser,
and this late phase presumably would be independent of
previous laser exposure. Thirdly, laser and PMMA
typically treat different planes of tissue which should
minimize direct interaction. Finally, PMMA microspheres
melt at a temperature of 1658C whereas most laser and
energy devices induce neocollagenesis at a tissue temper-
ature of 55–658C.
This study is the first substantial histologic evaluation
of the effect of multiple laser, light and ultrasound
treatments on pre-injected PMMA microspheres in
in vivo human tissue. There are a few limitations to
the study design. Firstly, the present study was
conducted in human abdominal skin. Laser resurfacing
and IPL treatments are commonly instituted on face,
neck, or chest skin which contains a much higher density
of dermal adnexa and has a thinner epidermis and
dermis than abdominal skin. We recognize that in vivo
human facial tissue is the optimal skin model, but is also
quite difficult to obtain. An understanding of the
difference in skin thickness across the face is an
important point to consider when using soft tissue fillers
and laser treatments [17]. Secondly, this study was done
on a single subject, whose skin reaction may not be
representative of a larger group. Combination procedures
are used regularly in aesthetic practice and merits
additional scientific study to understand the full spec-
trum of laser/filler interactions.
CONCLUSION
In summary, there was no sign of abnormal tissue
damage or injury, or alteration of the PMMA microspheres
(grossly or histologically) following any of the laser, light
and ultrasound treatment modalities tested in this study.
Based on the results of this small pilot study, laser, light
and ultrasound treatments appear to be safe following
PMMA-collagen filler implantation.
REFERENCES
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