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PMMA-Microspheres (Artecoll) for Long-Lasting Correction of Wrinkles:
Refinements and Statistical Results
Gottfried Lemperle, M.D., Ph.D., Nelly Gauthier-Hazan, M.D., and Martin Lemperle, M.D.
Frankfurt am Main, Federal Republic of Germany
Abstract. The corium is diminished to about half of its thick-
ness in skin defects and wrinkles. All biological materials that
increase the thickness of the corium are resorbed within a cer-
tain time. Therefore, a lasting effect can be achieved only with
nonresorbable synthetic substances. Artecoll consists of micro-
spheres of 30–40 m in diameter, of exceptional surface
smoothness, purity, and homogeneity related to PMMA. These
microspheres are suspended in atelocollagen which serves as a
vehicle for subdermal implantation. Due to its smooth surface
and consequential lack of electrical charges, each single micro-
sphere is immediately encapsulated with the patient’s own col-
lagen fibers, thus preventing dislocation. Within 3 months, col-
lagen (making up 75% of Artecoll) is replaced by the body’s
own connective tissue. The microspheres (25% of Artecoll)
serve merely as a stimulus to the fibroblasts. Indications for
Artecoll are all facial folds, lip- and philtrum augmentation,
chin- and malar augmentation, dark-shadowed eyelids, enoph-
thalmos, bony defects in face and hands, nipple reconstruction
and augmentation, and urinary incontinence. Questionnaires
were sent to all patients who had received Artecoll in 1993 and
1994. Of a total of 950 questionnaires sent, 515 were returned
by September 1995. Satisfaction was rated ‘‘very good’’ in
29%, ‘‘good’’ in 38%, ‘‘satisfactory’’ in 23%, and ‘‘no differ-
ence’’ in 8% of the patients. The question, ‘‘Would you repeat
the treatment again?’’ was answered by 91% of the patients
with ‘‘yes.’’ The overall complication rate was 3%. Strictly
subdermal implantation will prevent longer lasting redness or
visibility of the Artecoll.
Key words: Nonresorbable synthetic fillants—(Artecoll) mi-
crospheres—Fibroblast growth stimulants
More types of therapy are available for facial wrinkles
than for any other physiological aging process. Small
wrinkles such as crow’s feet, perioral lines, and wrinkled
cheeks can be effectively treated with dermabrasion,
chemical peel, or CO
2
-laser resurfacing (15). Striking
folds like glabellar frowns, nasolabial folds (Fig. 1) or
depressed corners of the mouth have to be surgically
stretched or lined with certain tissues. Since all biologi-
cal tissues such as fat, dermis, collagen, and even bone,
cartilage, or tendon will be resorbed at sites where they
are not naturally formed, synthetic biomaterials have to
be used for permanent leveling. Silicone granules (Bio-
plastique) are known to cause granulomas (1) because of
their irregular surface and accumulation of electrical
charges. Goretex (SAM-facial implant) has an excellent
biocompatibility and seems good for lip augmentation
(11). However, larger pieces placed under nasolabial
folds will eventually show their margins and may need to
be trimmed or removed. Silicone fluid, (6) although eas-
Presented at the New York City Biennial ISAPS Congress,
September 1995.
Correspondence to Prof. Dr. G. Lemperle at Frankfurt Clinic
for Plastic and Reconstructive Surgery, Finkenhofstr. 15, D-
60322 Frankfurt am Main, Federal Republic of Germany
Fig. 1. Cross-section through a nasolabial fold showed normal
thickness of epidermis, but diminished thickness of dermis to
about
1
⁄
4
of its normal thickness.
Aesth. Plast. Surg. 22:356–365, 1998
© 1998 Springer-Verlag New York Inc.
ily and effectively applied beneath wrinkles, may even-
tually cause chronic inflammation or migration (4).
Therefore, when collagen preparations were intro-
duced in 1982, we envisioned a nonresorbable material
in powder form which could be added to the collagen
solution as a mean to be implanted (13). For more than
100 years collagen has been used in surgery in the form
of catgut to be resorbed during the wound healing pro-
cess. Implanted under wrinkles and folds, it resorbs
within 4 weeks to 4 months depending on the single
volume (2). Among the various injectable biomaterials in
powder form which have been in use for many decades,
Polymethyl-metacrylate- (PMMA) microspheres used as
bone cement (Palacos) showed the least number of tissue
reactions during animal experiments (13).
Artecoll (14) consists of 25% microspheres of 30–40
m diameter (Fig. 2) suspended in 75% atelocollagen
(Resoplast). The collagen is phagocytized by macro-
phages within 1–4 months. In the same period of time,
each single microsphere is encapsulated with collagen
fibers secreted by the body’s own fibroblasts (Fig. 3).
The microspheres serve merely as a stimulus for connec-
tive tissue formation. The amount of connective tissue
depends on the individual’s typical scar formation, but
appears to be closely related to the prior content of bo-
vine atelocollagen, e.g., 75% (Fig. 4).
Material
Artecoll (Rofil Medical International, Breda, The Neth-
erlands) isa1in3suspension of Polymethyl-metacrylate
(PMMA)-microspheres of 30–40 m diameter in a 3.5%
collagen solution. Atelocollagen (Resoplast, Rofil) is de-
rived from the hide of calves from a pharmaceutical herd
in southern Germany, fed solely with milk and grass. No
feed additives such as animal meal are used, and no
foreign cattle are brought into this herd. Therefore, this
herd is absolutely free of Bovine Spongiforme Enceph-
alopathy (BSE). Furthermore, during the manufacturing
process, the collagen is subjected to a viral inactivation
procedure by treatment with 1N-sodium hydroxide for 1
h at 20°C. This method is internationally recognized not
only for the complete inactivation of BSE causative
agents, but also for a multitude of other viruses, which
cannot be detected by routine testing methods. Removal
of the immunizing endings of the molecule guarantees
low antigenicity of the atelocollagen. Filtration through
0.2-m pores removes any possible bacteria.
German collagen has been tested in a controlled study
on the left forearm of 200 patients. Except from short-
lasting redness in six patients, no allergic reactions of the
acute or late type were observed. One patient who had
been allergic to Zyderm 10 years earlier showed an acute
allergic reaction to Resoplast as well.
The uniformity of the microspheres is achieved by a
complicated process of straining. An ultrasound-bath re-
moves all dust and irregular particles from the micro-
spheres. Washing in Tween 80 makes the microspheres
suspendable in the watery collagen solution. Lidocaine
0.3% is added in order to diminish pain after implanta-
tion. The gel state of the PMMA-collagen suspension is
stable at room temperature but, preferably, should be
kept in the refrigerator. The collagen gel melts at 50°C as
the microspheres sink to the bottom. Simple heating by
turning the syringe several times under warm tap water
brings the microspheres back into suspension. The gel
state of the suspension is regained by lowering the tem-
perature of the running tap water.
Technique of Artecoll Implantation
If a patient is not yet sure about Artecoll or whether she
would like the effect of augmentation of the lip or the
wrinkles, a trial implant with collagen should be recom-
mended.
Artecoll should be implanted subdermally at the junc-
tion between the dermis and the subcutaneous fat (Fig.
5). The gray of the needle should never shine through
the skin (Fig. 15). Should this occur, the needle should be
withdrawn immediately and implantation restarted at
1
⁄
10
of a millimeter deeper. Should blanching be observed
following a too superficial injection, the implant should
be flattened by applying strong pressure using the finger
nail. Younger patients, generally have a tendency toward
more scar formation than elderly patients. Therefore,
overcorrection in elderly patients is harmless, especially
when Artecoll is distributed in a fanlike manner beneath
the wrinkle. The best candidates are those between 40
and 50 years of age without surplus skin, i.e., without
need for a frontal, facial, or midfacial lift.
Using a short 27G-needle Artecoll requires stronger
pressure than pure collagen implants. The addition of
25% PMMA-microspheres increases greatly the viscosity.
The best distribution beneath a wrinkle can be achieved
by moving the needle back and forth several times while
maintaining constant pressure throughout the injection
procedure. The volume of Artecoll to be implanted de-
pends on the extent and number of wrinkles. Overcor-
rection is almost impossible since the junction between
dermis and subcutaneous fat allows only a limited
amount of implanted material. The volume of the absorb-
able collagen (75%) in Artecoll is approximately propor-
tional to the growth of connective tissue expected in
patients with normal tissue reactions (Fig. 4). A second
or even third implantation may become necessary after a
few months. This technique results in the material being
distributed under the fold and up to 3 mm into the neigh-
boring areas in a partly parallel, partly fan-shaped manner.
Immediately following injection the implant should be
spread and modeled by applying mild pressure with the
finger tips. To keep an even distribution of Artecoll, the
implant site should be firmly taped (Transpore, 3M) for
about 3 days. Strong mimic muscle movement can form
nodules from the flat implant, especially in the lips and
corners of the mouth.
Artecoll can be dislodged from the subdermal area of
implantation into deeper layers by pronounced facial
mimicry within the first 3 days following implantation
diminishing the expected result. For this reason, new
357G. Lemperle et al.
Fig. 2. PMMA-microspheres of 30–40 m in diameter and absolute surface smoothness.
Fig. 3. Histology of Artecoll 3 months after implantation demonstrates encapsulation of all microspheres with body’s own connective
tissue. No foreign body reaction.
Fig. 4. Computer calculation of the
relation of microspheres to connective
tissue in eight histological pictures at
different time intervals. The initial
volume of 75% collagen is almost totally
replaced by connective tissue.
Fig. 5. Artecoll has to be implanted
strictly subdermally. A blanching effect
must be avoided, since this may cause
visible granulations (see Fig. 14).
358 PMMA-Microspheres (Artecoll) for Treatment of Wrinkles
implantations should be supported with a transparent
tape for about 3 days.
Local anesthetics are necessary only for implantation
into the orbit or for augmentation of upper and lower lip.
Here, 1 ml of 2% or 1% Lidocaine solution should be
injected along the mucosa of the labiogingival folds to
achieve a field block. Patients with low pain thresholds
may receive a topical anesthetic (EMLA-creme), applied
30–60 min before implantation.
Patients who never had collagen treatment should re-
ceive a test injection of Artecoll or Resoplast in the fore-
arm to exclude sensitivity 4 weeks prior to Artecoll treat-
ment. Patients with atrophic skin (Fig. 16) and flaccid
skin are poor candidates for Artecoll since the implant
may shine through, may be palpable, or may even be
visible as rubber-like nodules following implantation.
Patients
A third clinical study was designed to get subjective and
objective data from 320 patients with a total of 950 sub-
dermal Artecoll implants into different pairs of wrinkles
during 1993 and 1994. By September 1995, 515 ques-
tionnaires had been returned from 290 patients. All data
were computerized, and patient’s assessments were sta-
tistically analyzed. Roughly 20% of all questions and
answers referred to each of the following categories: gla-
bellar frowns, nasolabial folds, depressed corners of the
mouth, lip augmentation, and ‘‘other’’ wrinkles (Fig. 6).
‘‘Other’’ implantation sites included forehead wrinkles,
dark-shadowed eyelids, perioral lines, horizontal chin
folds, and acne scars. Of the 515 pairs of wrinkles, 61%
had been treated once, 27% twice, 11% three times, and
1% four times.
Results
The questionnaire contained 27 questions concerning
aesthetic result and acute side effects such as pain, swell-
ing, and redness. Furthermore, the change of volume,
dislocation, new folds, and side effects like nodules, itch-
Fig. 7. Patients assessment on the effect of
implantation after 1 year or more.
Fig. 6. Locations of Artecoll implantation
in Study III.
359G. Lemperle et al.
ing, pain by pressure, discoloration, unevenness, and un-
pleasant feelings were ascertained. The last five answers
referred to the subjective and objective judgment of the
patient, which were then compared with the notes of the
implantor and the ‘‘before’’ and ‘‘after’’ photographs.
A number of patients reported an improvement of the
depth of the wrinkles in time. As it is observed in elderly
patients with facial palsy or post CVA, most wrinkles
disappeared on the paralyzed side of the face, meaning,
that even in old age the dermis in a fold is able to recover
up to its previous thickness. The same mechanism may
be true for facial folds which cannot be moved to the
same extent as before Artecoll implantation.
After at least 1 year following Artecoll implantation,
77% of the patients reported an ‘‘optimal or clear im-
provement,’’ 19% saw ‘‘little improvement,’’ and 4%
‘‘no improvement’’ in the treated wrinkles.
The overall subjective judgment of the patients regard-
ing the effect of Artecoll implantation was ‘‘very good’’
in 29%, ‘‘good’’ in 38%, ‘‘satisfactory’’ in 23%, i.e., a
total of 90% of the patients were pleased with the result
(Fig. 7). ‘‘No difference’’ was noted by 8%; this was
probably due to implantation of inadequate volume or
due to excessive mimic movement of the patient follow-
ing implantation. ‘‘Worse’’ was the judgment of 1.5% of
the patients, mainly because of redness and unevenness
of the implant. The question, ‘‘Would you repeat the
treatment again?’’ was answered by 91% of the patients
with ‘‘Yes’’ (Fig. 8).
Alasting effect of Artecoll implantation for at least 1–2
years was reported by 91% of the patients; 29% felt that the
implants decreased in size, and 6% said that they increased
in size over the years. New folds or deepening of the old
fold occurred in about 20% of the implanted areas. A co-
worker whose deep glabella frowns were erraded by Arte-
coll implants 6 years ago developed a new glabellar frown
in the midline after 5 years. As mimic muscles move new
folds are created in elderly skin over the years.
Fig. 8. 91% of the patients who were
asked, ‘‘Would you repeat the treatment
with Artecoll again?’’ answered with
‘‘Yes.’’ The cause for the negative
answers of 9% of patients was ‘‘lack of
efficacy’’ or ‘‘visibility of the implant’’
(3%).;
Fig. 9. Long-term side effects. Visible nod-
ules or persistent redness were rated as
long-term side effects in a total of 3% of
the treated wrinkles.
360 PMMA-Microspheres (Artecoll) for Treatment of Wrinkles
Visible implants, mainly in nasolabial folds, horizontal
frowns, and corners of the mouth, were reported by 3%
of the patients. No transparency was reported, how-
ever, after lip augmentation or implantation beneath gla-
bella frowns, perioral lines, chin folds, and acne scars
(Fig. 9).
Palpable implants were reported by 64% of the pa-
tients, mainly after lip augmentation and implantation of
glabellar frowns and corners of the mouth. Of the pa-
tients with lip augmentations, 40% complained about
little pain on pressure, as did 15% after implantation of
Artecoll beneath glabellar frowns and perioral lines as
well as 8% after implantation beneath nasolabial folds.
An overall satisfaction was reported by 100% of the
patients after Artecoll implantation in horizontal chin
folds and acne scars, by 91% for all other treated folds,
and only by 80% for horizontal forehead furrows.
Among the ‘‘others’’ were patients with depressed scars,
acne scars, nipple augmentation, and nipple reconstruc-
tion, enophtalmos, and depressions after rhinoplasty.
Indications
The treatment of horizontal frontal frowns was judged
‘‘insufficient’’ by 35% of the patients. All had received
only one treatment. This suggests, that a second, more
superficial, implantation between the first base implant
and the wrinkle is necessary after about 3 months.
The best results and least complications were seen in
the treatment of glabellar frowns. A single intradermal
and subdermal implantation of 0.5 ml of Artecoll gives a
long-lasting and satisfying result. Overcorrection is nec-
essary, even if the implant can always be palpated.
The treatment of dark-shadowed eyelids (Fig. 10A and
B) provides a challenge since there is no other simple
treatment available. The implantation has to be strictly
epiperiostally, i.e., below the orbicularis muscle and just
above the insertion of the septum orbitale. The bone can
be felt with the tip of the needle. Moving the needle
backward, the Artecoll can be spread along the lower
orbital rim. Care has to be taken in withdrawing the
needle, since implantation into the muscle will cause a
nodule!
A preferred indication are single crow’s feet in a thick
skin just as crow’s feet in a thin and flaccid skin are an
absolute contraindication. A perfect indication for Arte-
coll are depressions of the dorsum of the nose after rhi-
noplasty or irregularities of the nostrils and a negative
nasolabial angle. Here, the possibility of implanting a
small dosis of Artecoll epiperiostally or into the nostril
(Fig. 11A and B) easily satisfies the patient. An open
roof or the visible border of a silicone implant can also be
corrected easily so. So far, no infection after Artecoll
implantation has been seen. Augmentation of a saddle
nose or a rather flat dorsum in the Asian nose is possible
in a two- or three-step procedure; during the first treat-
ment 2 ml of Artecoll should be sufficient. The dorsum
of the nose has to be modeled by the patient her/himself
throughout the first 3 days after implantation. Artecoll
has the advantage over other biomaterials of full in-
growth of connective tissue and the possibility of further
augmentation or later correction.
Augmentation of malar bones or of a receding chin
with Artecoll is possible, however, 5–10 ml of Artecoll
may be required; therefore, prefabricated implants may
be more economical. Still, Artecoll is ideal for correcting
malpositioned or asymmetric implants.
The nasolabial folds (Fig. 12A and B) are best sup-
ported by criss-cross implantations like the armament of
concrete building structures. Care must be taken not to
implant too superficially, otherwise the implant is visible
(Fig. 14), as this was the most common complaint in our
survey. A second implantation is often necessary, espe-
cially in the corner of the mouth and in the upper part of
the nasolabial fold. Here, a triangle of Artecoll must be
implanted subdermally around the nostrils.
For most women lip augmentation was the most re-
warding therapy (Fig. 13A and B). In the elderly, the
filling of the white roll and cupids bow prevents further
development of radial lip lines, and augmenting the lost
philtrum may give the lip a more youthful look. Artecoll
is not indicated in other lip defects because it may be-
come hard. Under no circumstances should the ‘‘droplet
technique’’ be applied in the lip.
Some patients complained of burning of the lips dur-
ing the first few days. Hypersensitivity to pressure lasted
for several months, even if kissing was not a problem.
Other patients reported dry lips and increased scaling,
some of them were forced to massage their lips over
several months. Especially young patients had difficulty
biting into an apple or opening their mouth at the dentist,
because of tension or pain during the first 3 months.
Herpes labialis developed in three patients who had been
susceptible to it. Therefore, this problem should be dis-
cussed with the patient beforehand and prevented by
Acyclovir.
In order to increase the pouting effect, a second row of
Artecoll can be implanted under the mucosa close to the
frontal teeth. Care has to be taken in long upper lips,
since too much Artecoll may increase the volume of the
red of the lip but hide the frontal teeth. Should this hap-
pen, an upper lip lift through a bullhorn excision is very
effective.
Perioral lines are best treated by lip augmentation
along the upper and lower white roll. Between the border
of the red of the lip and the underlying muscle is a natural
pocket, which can usually be filled easily under pressure
with 0.5 ml of Artecoll. Thereafter, the remaining radial
lines can be underlined with Artecoll from above made
more even by the criss-cross method of implantation.
In order to treat depressed or negative corners of the
mouth, one can start with a horizontal augmentation of
the lower white roll, about 1 cm in length from the cor-
ners, and sometimes even of the upper white roll. There-
after, 5–10 horizontal implantations should be added
caudally and eventually combined with criss-cross im-
plantations. There is a danger of implanting too superfi-
cially! If the implant is too close to or in the muscle,
nodule formation may result! Therefore, Artecoll should
be implanted in two sessions.
361G. Lemperle et al.
Fig. 10. (A) Dark-shadowed lower lids. (B)
Two years after treatment with 0.5 ml
Artecoll on each side. The implants are still
palpable like soft rubber on the orbital rim.
Fig. 11. (A) Collapsed nostrils after
rhinoplasty. (B) After removal of the
cartilaginous supra tip deformity and
implantation of Artecoll (four times about 0.2
ml) into the nostrils.
Fig. 12. (A) Nasolabial folds and deep
perioral wrinkles. (B) Three years after
implantation with 1.5 ml Artecoll.
Fig. 13. (A) Small upper lip in a 30-year-old
patient. (B) The same patient 3 years after
implantation of 1.8-ml Artecoll in three
sessions (augmentation of the cupids bow and
implantation along the border of the red of
the lip to mucosa).
362 PMMA-Microspheres (Artecoll) for Treatment of Wrinkles
The horizontal chin fold and single oblique folds along
the skin folding lines of the cheek do present a problem.
Sometimes a second implantation is necessary. The same
is true for the horizontal folds of the neck. They are to be
implanted cautiously, preferably in two sessions. A flac-
cid neck is, of course, an absolute contraindication.
Complications
Acute side effects. Acute swelling after implantation
generally subsided on the following day. Bruising was
rare but lasted up to 1 week. Itching has been reported
during the first months. The ‘‘perfect result’’ began to
wane after 1–3 weeks because of resorption of the water
content of the collagen. A long-term result, therefore, can
only be expected from 3 months on, when all micro-
spheres are covered with the body’s own fibrocytes and
collagen fibers (Fig. 3).
Late side effects. Longer lasting redness after Artecoll
implantation was reported by 6.1% of the patients treated
in 1993, however, by only 0.5% of those patients treated
in 1994. Transparency of Artecoll, recorded for 9% of
the wrinkle implants in 1993, was reduced to 2.5% in
1994 (Fig. 9). In five of these patients (1%), intralesional
treatment with triamcinolone or surgical excision be-
came necessary. The decrease in the complication rate
within 1 year was due to the change to a strictly subder-
mal implantation technique in 1994.
The long-term side effects such as transparency, dis-
location and unevenness occurred primarily in the naso-
labial folds (Fig. 14) and depressed corners of the mouth
(Fig. 9).
The overall complication rate of wrinkles treated with
Artecoll in 1994 was 3.0% (six out of 201 wrinkles). An
exclusively subdermal implantation in the future will
lead to a further decrease of this rate. A blanching effect
(Fig. 15) (as is desirable in collagen implantation) should
be avoided under all circumstances in order to prevent
longer lasting redness (Fig. 16). On the other hand, pure
collagen or hyalurouic acid (12) preparations can be im-
Fig. 14. Visibility of Artecoll after faulty
intradermal implantation.
Fig. 15. The needle shines through the
skin and is positioned intradermally. This
would cause a blanching effect and should
be avoided!
Fig. 16. A very thin skin with capillary
injection is a contraindication for Artecoll
treatment. Artecoll has to be implanted
rather deep in order to avoid long-lasting
redness.
Fig. 17. The movement of the M.
orbicularis has caused two nodules from
the pressed-down implant. An injection of
triamcinolone (Kenalog) will diminish the
hypertrophic scar formation around the
single microspheres.
Fig. 18. Artecoll granuloma (less than 1%) in a 76-year-old
woman which developed 1 year after the first implantation and
3 months after the second implantation—only at locations of
the latter. No allergic reaction was noted at follow-up.
363G. Lemperle et al.
planted intradermally above the Artecoll implant in order
to improve the primary result—if the wrinkle is too su-
perficial to be erased totally with Artecoll. Likewise,
laser resurfacing of deep wrinkles can be applied directly
after Artecoll implantation, since it will be located sub-
dermally (15).
Allergic reactions. Among the 290 patients, an acute
allergic reaction occurred in one women, who had re-
ceived collagen (Zyderm) 2 years earlier. After a single
intravenous injection of 1000 mg prednisolone, all symp-
toms subsided immediately. Another patient, on the other
hand, who had had 4 years earlier a severe cellular al-
lergic reaction of the late-type IV to Zyderm, tolerated
Artecoll well following repeated testing for sensitivity.
Theoretically, an allergic reaction to PMMA is also
possible. Millions of patients, however, have tolerated
artificial dentistry, bone cement, ocular lenses, and pace-
makers without any sign of sensitivity. We are aware of
only one severe allergic reaction in a laboratory techni-
cian who had worked in PMMA dust containing mono-
mers for years (7).
Tween 80 is used for washing the PMMA-micro-
spheres and to make their hydrophobic surface suspend-
able in water (tixotropy). One out of a 1000 persons will
be allergic to Tween 80. No histological specimen taken
after Artecoll removal showed eosinophilic or lympho-
cytic cells typical for allergic reactions.
Granulomas may develop at a rate of 1 in 1000 pa-
tients. The manufacturer is aware of 10 out of over 8000
European patients (five in France, three in Germany, 1 in
the Netherlands, 1 in Switzerland) who developed nodule
formation (Fig. 17) 6 months to 2 years after Artecoll
implantation. All of them except for one 76-year-old
woman responded to intralesional triamcinolone (Kena-
log) or betamethasone (Diprosone) injections. Histology
revealed new fibroblast activity with thick bands of col-
lagen fibers as in hypertrophic scarring dispersed with
rare foreign body granulomas (Fig. 18). The cause for
this late development of nodules is not yet understood.
Discussion
The secret of PMMA-microspheres, not to evoke a for-
eign body reaction, is due to their totally smooth surface.
It is well documented that the sharp edges of poly-
urethane foam, the rough surface of silicone particles
(Bioplastique) or porous hydroxylapatite stimulate mac-
rophages and giant cells to remove this material (4). Ep-
pley et al. (5) recently showed with dextran beads in rats
that neutral or positively charged surfaces are chemotac-
tic for macrophages and fibroblasts, a cellular response
which is favorable to dermal and subcutaneous tissue
repair and augmentation. No evidence of a foreign body
or chronic inflammatory response was seen, as is typical
for materials with rough surfaces. Surface charges accu-
mulate on ridges and edges and, therefore, strongly
stimulate giant cells, which are ‘‘frustrated’’ macro-
phages (4), i.e., macrophages, which cannot achieve a
proper phagocytosis of the polymer. Positive surface
charges are important for bone substitutes, since they
enhance bone formation (7).
After implantation, all foreign materials are at once
covered with proteins. In response to the structure and
electrical charge of the surface, one or more protein lay-
ers are formed by the surrounding cells. If there are no
shearing forces, then a stable electrical field will result
(21), and the secreted proteoglycols will remain chemi-
cally and electrically inert.
The late development of granulomas in a few patients
(10 in 8000) is not yet understood. For several reasons,
Artecoll should not be implanted intramuscularly. The
constant movement of the mimic muscles may cause
hypertrophic scarring as has been shown in study II (14).
On the other hand erythematous nodules occurring at the
injection sites of pure collagen are well known and have
been described (16). They subsided very slowly despite
topical and systemic corticoid therapy and may last up to
3 years (3). Moscona (16) published a case of a severe
delayed type hypersensitivity reaction to Zyderm I. Two
years after the injection, the woman noted a sudden ap-
pearance of swelling and induration around the mouth
and lips. Biopsy showed a dense inflammatory cell in-
filtrate composed mainly of sarcoid-like granulomas
along with a focal collection of lymphocytes. The posi-
tive reaction of an erythematous nodule at the original
skin test site was due to multinucleated histiocytes in a
palisade-like array.
The Artecoll-granulomas do not show an allergic re-
action of the late-type IV, but rather a simple foreign
body reaction. Five of the eight tested patients did not
have an early or late reaction at a second skin test site.
The manufacturer prevents impurities in the PMMA mi-
crospheres through continuous electron microscopic con-
trol of all charges. Some people, however, react against
even the smoothest surfaces like that of the microspheres
(Fig. 7). Contact dermatitis on finger tips and palmar
sites of nurses and surgeons following exposure to the
monomer of acrylic cements has occasionally been re-
ported (8).
Methylmetacrylate appears to be essentially inert, but
capable of triggering macrophage activation due to the
presence of phagocytable debris particles (18). Electron
microscopic pictures of the sifted and washed PMMA-
microspheres (14) showed not a single debris (Fig. 2)
which might eventually stimulate phagocytosis. Frag-
mentation or erosion of the 40-m microspheres in time
can also be ruled out through the extensive data on bone
cements available from orthopedists (19).
Intravenous injection of inert polystyrene micro-
spheres demonstrated that 1- and 3-m spheres could be
found in monocytes and granulocytes while the 12-m
spheres were observed only outside the cells. The serum
protein levels were unchanged indicating that the spheres
did not stimulate the immune response (10). Peritoneal
macrophages in the mouse showed much less phagocy-
tosis for microspheres with nonionic hydrophilic sur-
faces than for microspheres with hydrophobic surfaces
(20).
Phagocytosis of 40-m PMMA-microspheres is an
364 PMMA-Microspheres (Artecoll) for Treatment of Wrinkles
extremely rare occurrence among all the histologic speci-
men taken after Artecoll implantation.
A longitudinal study (17) of human histologic speci-
men (Fig. 4) demonstrated that these microspheres are
usually well tolerated by the cellular immune sys-
tem, that they are nonantigenic, nonmigratory, and per-
manent.
The authors are grateful to Dr. Ulrich Charrier in Frankfurt/
Main for independent review of the histological specimens, and
Mrs. Lydia Kerr in Basel for a critical reading of the manu-
script.
References
1. Allen O: Response to subdermal implantation of textured
microimplants in humans. Aesth Plast Surg 16:227, 1992
2. Burke KE, Naughton G, Cassai N: A histological, immu-
nological, and electron microscopic study of bovine colla-
gen implants in the human. Ann Plast Surg 14:515, 1985
3. Clark DP, Hanke CW, Swanson NA: Dermal implants:
Safety of products injected for soft tissue augmentation. J
Amer Acad Dermatol 21:992, 1989
4. Eppley BL, Sidner RA, Sadove AM: Adequate preclinical
testing of Bioplastique injectable material? Plast Reconstr
Surg 89:157, 1992
5. Eppley BL, Summerlin D-J, Prevel CD, Sadove AM: Ef-
fect of positively charged biomaterial for dermal and sub-
cutaneous augmentation. Aesth Plast Surg 18:413, 1994
6. Hinderer UT, Escalona J: Dermal and subdermal tissue
filling with fetal connective tissue and cartilage, collagen
and silicone. Aesth Plast Surg 14:239, 1990
7. Holmes R: Personal communication
8. Jensen JS, Trap B, Skydsqaard K: Delayed contact hyper-
sensitivity and surgical glove penetration with acrylic bone
cements. Acta Orthop Scand 62:24, 1991
9. Kadunce DP, Burr R, Gress R, Kanner R, Lyon JL, Zone
JJ: Cigarette smoking: Risk factor for premature facial
wrinkling. Amer Coll Physicians 114:840, 1991
10. Kanke M, Sniecinski I, Deluca PP: Interaction of micro-
spheres with blood constituents. J Parenteral Science
Technol 37:210, 1983
11. Lassus C: Expanded PTFE in the treatment of facial
wrinkles. Aesth Plast Surg 15:167, 1991
12. Laurent TC: Structure of hyaluronic acid. In: EA Balazs,
ed.: Chemistry and Molecular Biology of the Intracellular
Matrix, Vol. II. Academic Press: New York p. 703, 1979
13. Lemperle G, Ott H, Charrier U, Hecker J, Lemperle M:
PMMA microspheres for intradermal implantation: Part I.
Animal research. Ann Plast Surg 26:57, 1991
14. Lemperle G, Hazan-Gauthier N, Lemperle M: PMMA mi-
crospheres (Artecoll) for skin and soft-tissue augmenta-
tion. Part II: Clinical investigation. Plast Reconstr Surg 96:
627, 1995
15. Lemperle G, Al Soufi A: Faltenbehandlung durch Unter-
fu¨tterung mit Artecoll und Resurfacing mit dem CO
2
-
Laser. Langenbecks Arch Chir Suppl II:1128, 1996
16. Moscona RR, Bergman R, Friedman-Birnbaum R: An un-
usual late reaction to Zyderm I injections: A challenge for
treatment. Plast Reconstr Surg 92:331, 1993
17. Nischan T: Eine klinische Studie zur intradermalen Im-
plantation von Artecoll in Falten und Hautdefekte. Thesis,
Johann Wolfgang Goethe-Universita¨t Frankfurt/Main,
1997
18. Nordstro¨m D, Santavirta S, Gristina A, Kouttinen YT: Im-
mune-inflammatory response in the totally replaced hip: a
review of biocompatibility aspects. Eur J Med 2:296, 1993
19. Stinson NE: Tissue reaction induced in Guinea-pigs by
particulate PMMA, polythene and nylon of the same size
range. Brit Exp Pathol 46:135, 1965
20. Tabata Y, Ikada Y: Effect of the size and surface charge of
polymer microspheres on their phagocytosis by macro-
phages. Biomaterials 9:356, 1988
21. Thull R: Implantable materials: Biocompatibility issues.
Symposium on Implantable Materials in Facial Aesthetic
and Reconstructive Surgery. Montreal, October 6, 1995
365G. Lemperle et al.
