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Human Histology and Persistence of Various Injectable Filler Substances for Soft Tissue Augmentation


Abstract and Figures

An increasing number of soft tissue filler substances have been introduced to the beauty market outside the U.S. which lack experimental and clinical data in support of their claim. Ten commercially available filler substances were examined for biocompatibility and durability: 0.1 cc of each substance was injected deep intradermally into the volar forearm of one of the authors and observed for clinical reaction and permanence. At 1, 3, 6, and 9 months the test sites were excised, histologically examined, and graded according to foreign body reactions classification. Collagen (Zyplast) was phagocytosed at 6 months and hyaluronic acid (Restylane) at 9 months. PMMA microspheres (Artecoll) had encapsulated with connective tissue, macrophages, and sporadic giant cells. Silicone oil (PMS 350) was clinically inconspicuous but dissipated into the tissue, causing a chronic foreign body reaction. Polylactic acid microspheres (New-Fill) induced a mild inflammatory response and had disappeared clinically at 4 months. Dextran microspheres (Reviderm intra) induced a pronounced foreign body reaction and had disappeared at 6 months. Polymethylacrylate particles (Dermalive) induced the lowest cellular reaction but had disappeared clinically at 6 months. Polyacrylamide (Aquamid) was well tolerated and remained palpable to a lessening degree over the entire testing period. Histologically, it dissipated more slowly and was kept in place through fine fibrous capsules. Polyvinylhydroxide microspheres suspended in acrylamide (Evolution) were well tolerated, slowly diminishing over 9 months. Calcium hydroxylapatite microspheres (Radiance FN) induced almost no foreign body reaction but were absorbed by the skin at 12 months. Host defense mechanisms react differently to the various filler materials, but all substances—resorbable or nonresorbable—appeared to be clinically and histologically safe, although all exhibit undesirable side effects. Since the mechanism of late inflammation or granuloma formation is still unknown, early histological findings are not useful in predicting possible late reactions to filler substances.
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Human Histology and Persistence of Various Injectable Filler
Substances for Soft Tissue Augmentation
Gottfried Lemperle, M.D., Ph.D.,
Vera Morhenn, M.D.,
and Ulrich Charrier, M.D
San Diego, CA, USA
Frankfurt, Germany
Abstract. An increasing number of soft tissue filler sub-
stances have been introduced to the beauty market outside
the U.S. which lack experimental and clinical data in sup-
port of their claim. Ten commercially available filler sub-
stances were examined for biocompatibility and durability:
0.1 cc of each substance was injected deep intradermally
into the volar forearm of one of the authors and observed
for clinical reaction and permanence. At 1, 3, 6, and 9
months the test sites were excised, histologically examined,
and graded according to foreign body reactions classifica-
tion. Collagen (Zyplast) was phagocytosed at 6 months and
hyaluronic acid (Restylane) at 9 months. PMMA micro-
spheres (Artecoll) had encapsulated with connective tissue,
macrophages, and sporadic giant cells. Silicone oil (PMS
350) was clinically inconspicuous but dissipated into the
tissue, causing a chronic foreign body reaction. Polylactic
acid microspheres (New-Fill) induced a mild inflammatory
response and had disappeared clinically at 4 months.
Dextran microspheres (Reviderm intra) induced a pro-
nounced foreign body reaction and had disappeared at 6
months. Polymethylacrylate particles (Dermalive) induced
the lowest cellular reaction but had disappeared clinically at
6 months. Polyacrylamide (Aquamid) was well tolerated
and remained palpable to a lessening degree over the entire
testing period. Histologically, it dissipated more slowly and
was kept in place through fine fibrous capsules. Polyvinyl-
hydroxide microspheres suspended in acrylamide (Evolu-
tion) were well tolerated, slowly diminishing over 9 months.
Calcium hydroxylapatite microspheres (Radiance FN) in-
duced almost no foreign body reaction but were absorbed
by the skin at 12 months.Host defense mechanisms react
differently to the various filler materials, but all substanc-
es—resorbable or nonresorbable—appeared to be clinically
and histologically safe, although all exhibit undesirable side
effects. Since the mechanism of late inflammation or gran-
uloma formation is still unknown, early histological find-
ings are not useful in predicting possible late reactions to
filler substances.
Key words: Dermal filler substances—Soft tissue augmen-
Fill-Radiance FN—Restylane—Reviderm intra
In recent decades, dermal filler substances consisting
of highly viscous fluids [33,40,53] or polymer parti-
cle suspensions [21,37] have been injected beneath
wrinkles and acne scars [8,31]. These substances are
useful for the correction of congenital or traumatic
facial, bony, and soft tissue defects [10], and in pa-
tients suffering from scleroderma, Romberg’s disease,
facial wasting, or lipodystrophy following AIDS
treatment [2,11,57]. Additional indications are uni-
lateral paralysis of vocal cords [12,24,28], augmen-
tation of the lip and soft palate in cleft lip patients,
anophthalmic orbits [10], or enophthalmus. Other
potential applications as bulking agents are lower
esophageal sphincter in gastroesophageal reflux pa-
tients [22,48], and bladder neck or anal sphincter in
patients suffering from urinary [5] or fecal inconti-
nence [27,63].
Animal studies [38] and clinical trials [15,19] have
shown good acceptance and short- and long-term
Presented at the 33rd Annual Meeting of the Association of
German Plastic Surgeons in Heidelberg, Germany, Sep-
tember 21, 2002
Correspondence to Gottfried Lemperle, M.D., Ph.D.,
Division of Plastic Surgery, University of California, San
Diego; email:
Aesth. Plast. Surg. 27:354–366, 2003
DOI: 10.1007/s00266-003-3022-1
efficacy in accordance with the chemical structure
and surface characteristics of the microparticles.
Resorbable materials such as collagen, hyaluronic
acid [19,36,49], polymethylacrylate (PMA) [6], dex-
tran [20], or polylactic acid [2] are removed by
phagocytosis over a period of 3–12 months de-
pending on the amount and type of bulking agent
implanted. Permanent fillers such as paraffin [33],
fluid silicone [11,17], Teflon [34], or silicone particles
[21] have an irregular surface and cannot be phag-
ocytosed but may eventually form foreign body
granulomas due to ‘‘frustrated macrophages’’ [20].
Microspheres below the size of 15 microns [44,61]
are generally phagocytosed and may be transported
to local lymph nodes. Larger microspheres from
nonresorbable polymers with a smooth surface
[35,38,51] are encapsulated with fibrous tissue and
escape phagocytosis. Clinically, all injected fluids
[45,59] and particles [54,56] have been shown to
cause foreign body granulomas in a small percent-
age of patients. Until the mechanism of granuloma
formation is fully understood, the chance of devel-
opment is not predictable.
The ideal soft tissue filler substance for wrinkles,
skin defects, and sphincter
is biocompatible and safe
is stable at the implantation site
keeps its volume and remains pliable
does not cause protrusion of the skin or mucosa
induces minimal foreign body reaction
will not be removed by phagocytosis
has no migration potential to distant locations
does not cause foreign body granuloma.
As a percentage of wet weight, the human skin is
composed of collagen (27–39%), elastin (0.2–0.6%),
glycosaminoglycans (0.03–0.3%), and 60–72%water.
The goal of this study was to confirm histocompati-
bility and permanence of various filler substances
under investigation. For some products there exist no
published scientific reports on biocompatibility, his-
tology, or clinical studies.
Materials and Methods
During the past 4 years, four 0.1-cc blebs of 10 dif-
ferent dermal filler substances have been injected deep
intradermally into the volar skin of a forearm, next to
an existing scar. The injection sites were inspected
weekly and clinical changes were recorded and pho-
tographed. Each raw of the different implants was
excised after 1, 3, 6, or 9 months. At least four sec-
tions were cut from each implantation site at different
levels for histological examination. The sections were
stained with hematoxilin–eosin or Masson trichrome
and evaluated in Frankfurt. An independent pathol-
ogist (U.C.) was blinded, receiving the histological
slices numbered only, and being unaware of the ma-
terial involved.
A classification of foreign body reactions, estab-
lished by Duranti et al. [19], was applied to each
histological slide. The grading was performed on at
least four slices of the same specimen.
Grade I: slight reaction with a few inflammatory
Grade II: clear inflammatory reaction with one or
two giant cells
Grade III: fibrous tissue with inflammatory cells,
lymphocytes, and giant cells
Grade IV: granuloma with encapsulated implants
and clear foreign body reaction
The following commercially available filler mate-
rials were bought and injected in Europe:
1. Zyplast, a suspension of 3.5%crosslinked bovine
collagen, purchased from Collagen Aesthetics,
Inc., Fremont, CA
2. Restylane, a suspension of 2.0%crosslinked
hyaluronic acid (HA) produced biotechno-
logically from Streptococcus equi [36,47,50] in
saline, purchased from Q-Med AB, Uppsala,
3. Artecoll, a suspension of 20%microspheres (40
lm) of polymethylmethacrylate (PMMA) in
3.5%bovine collagen solution [35,37], obtained
from Artes Medical Inc., San Diego, CA
4. PMS 350, medical grade silicone fluid (dimeth-
ylpolysiloxane) of 350 centistoke viscosity, pur-
chased from Vikomed, Meinerzhagen, Germany
5. New-Fill, which comes as a powder of poly-L-
lactic acid (L-PLA) microspheres (2–50 lm) to
prepare a 4.5%suspension in 2.7%methylcellu-
lose [2], purchased from Biotech Industry S.A.,
6. Reviderm intra, a suspension of 2.5%dextran
microspheres (40 lm Sephadex) [20] in 2.0%hy-
aluronic acid (2.5 MDa) of bacterial origin
(Rofilan), obtained from Rofil Medical Interna-
tional N.V. (RMI), Breda, The Netherlands
7. Dermalive, a 240%suspension of hydroxyethyl-
methacrylate (HEMA) fragments in 1.14%
crosslinked hyaluronic acid of bacteriological
origin [6], purchased from Dermatech S.A., Paris,
8. Aquamid, a clear 5%crosslinked gel from poly-
acrylamide (PAAG) [42], purchased from Con-
tura International S.A., Montreux, Switzerland
9. Evolution, a suspension of 6%polyvinylhidrox-
ide (PVOH) microspheres (5–80 lm) in 2.5%
polyacrylamide gel, purchased from Laboratoires
ProCytech, Bordeaux, France
10. Radiance FN, a suspension of 30%calcium
hydroxylapatite microspheres (25-40 lm) in a
carboxymethyl-cellulose gel [9], purchased from
BioForm Inc., Franksville, WI
G. Lemperle et al. 355
All four implant sites in the human forearm could
easily be identified after 1 and 3 months; however,
not all implants could be visualized after 6 and 9
months. In the latter cases, the whole area was ex-
cised and sectioned 5–10 times in order to identify
microscopic traces of the implant.
The tissue sections obtained from human skin
showed the presence of many macrophages and in-
vading capillaries at the circumference of the im-
plants at 1 month. This process goes along with slow
resorption of the crosslinked eosinophilic opaque
material with gradual and scarce infiltration of in-
flammatory cells, and little or no deposition of
structures, which resemble new collagen fibers at 3
months [32]. At 6 months, no residue of cell-free
Zyplast could be found in the human skin. The his-
tological reactions were evaluated according to the
Duranti scale (Fig. 1).
The clear hyaluronic acid gel induced erythema and
swelling in the human skin for 2 days. Clinically,
Restylane and all other tested crosslinked hyaluronic
acid products disappeared from the skin within 4
months. Histologically, the blue stained hyaluronic
acid showed little foreign body reaction (Fig. 2) but
was slowly degraded by macrophages. Some macr-
ophages and rare giant cells were apparent in the
human skin at 3 months [19]. Clusters of these cells
could still be found after 6 months; however, no
residue could be identified at 9 months.
At 1 month, each individual microsphere was sepa-
rated from adjacent microspheres by a thin layer of
eosinophilic material representing collagen fibers
(Fig. 3). The implants were discrete and well cir-
cumscribed within the soft tissue. The peripheral re-
gions of these foci had infiltrated to a depth of 2–3
microspheres and contained macrophages (1 per ap-
proximately 15 beads) and few multinucleated giant
cells. The centers of the lesions were cell free and
separated through fibrin fibers only. At 3 and 6
months, isolated giant cells extended deeper into the
lesions (Fig. 4).
The implanted denatured collagen appeared to be
resorbed at 3 months. New collagen deposits, evident
at 1 month, increased the spaces between individual
microspheres. The number of inflammatory cells was
small at all times and indicates that collagen and
microspheres induce a minimal immunogenic re-
The relative size of the palpable Artecoll lesions in
human skin remained unchanged over 9 months
(Fig. 5), suggesting that dissipation of microspheres
into the surrounding soft tissue or migration to
adjacent lymph nodes does not occur (Fig. 3).
PMS 350 Silicone Fluid
PMS 350 is a colorless oil with a low viscosity, 350
times that of water (1 centistoke = viscosity of wa-
ter), but with high chemical stability. Immediately
after injection, PMS 350 dispersed into the sur-
rounding tissue in form of millions of microdroplets
(Fig. 6). At 1 month, each microdroplet, about 20–
100 microns in size, was encapsulated by a monolayer
of fibroblasts and collagen fibers. Macrophages and
giant cells, which phagocytosed the foamy, translu-
cent, bifringent material, were found at 3 and 6
months. Asteroid bodies in the cytoplasma of macr-
ophages and giant cells were typically seen after
phagocytosis of the silicone fluid. At 9 months, gra-
nulomatous nodules in the dermis and subcutaneous
tissue were surrounded by strands of fibrous tissue.
The PLA implants were well palpable for the first 3
months but had disappeared from the human skin at
4 months. In the refrigerator, PLA microspheres with
diameters between 2 and 50 lm, were still recogniz-
able as microspheres 2 weeks after suspension, and
were partly hydrolyzed and deformed at 1 and 3
Histologically, a fine capsule could be observed
around the implant throughout. At 3 months, the
microspheres had remained spherical and were sur-
rounded by macrophages and some lymphocytes
(Fig. 7). At 6 months, most microspheres showed a
porous surface structure, were fissured and sometimes
deformed, and were surrounded by macrophages and
small giant cells. Their pseudopodia infiltrated the
surface of some microspheres but did not degrade the
activity of these cells. The PLA was likely dissolved by
hydrolysis and extracellular enzymes [3,60] and sub-
sequently broken down by macrophages. At 9
months, the degradation of PLA microspheres was
completed. At 9 months, no remnant of cicatricial fi-
brosis was found after total disappearance of PLA
residues in the human skin. This finding illustrates the
excellent biocompatibility of PLA.
Reviderm intra
The injection of dextran beads caused swelling and
redness, which continued for 10 days—possibly due
356 Histology and Persistence of Filler Substances
Fig. 1. The Duranti-classification reflects the extent of
histological foreign body reaction at certain times. Class 2
is determined by a few giant cells.
Fig. 2. Restylane at 1 month. Minor cellular reaction of the
surrounding tissue, scattered macrophages and giant cells,
no immune response, and good biocompatibility. HE ·100.
Fig. 3. Artecoll at 1 month. The two strands of implants
here have a diameter of a 26 G needle and are still packed in
a fibrin network with some macrophages and giant cells.
Masson trichrome ·20.
Fig. 4. Artecoll at 6 month. All microspheres are encap-
sulated by connective tissue and some macrophages. Dur-
anti Grade II. Masson trichrome ·400.
Fig. 5. Artecoll at 10 years. The microspheres are still intact
and surrounded by collagen fibers, fibroblasts, some
macrophages, and isolated giant cells. Masson trichrome
Fig. 6. PMS 350 silicone gel at 1 month. The gel has dis-
sipated into millions of microdroplets, which are sur-
rounded by macrophages and lymphocytes. HE ·100.
G. Lemperle et al. 357
to the toxic effect of free dextranomers. Edematous
swelling of the implants continued for more than 3
months. The palpable deep dermal implant began to
disappear at 4 months and was no longer palpable at
6 months.
Histologically, the 40-lm dextran beads produced
the greatest amount of granulation tissue among all
injectables tested. At 1 month, the hydrophilic micr-
ospheres were swollen and measured up to 75 lmin
diameter (Fig. 8); some were broken apart and sur-
rounded by foamy macrophages and small giant cells.
The hyaluronic acid carrier had early separated from
the beads and was found in pools, surrounded by a
rim of giant cells (Fig. 9). At 3 months, only few
elastic fibers could be seen; instead there were great
numbers of macrophages and giant cells, which en-
veloped and tried to phagocytose the beads. The
surface of the dextran beads began to show irregu-
larities at 6 months and total disintegration at 9
months. It ranged to the top of the Duranti scale
among the resorbable implants (Fig. 10), possibly due
to the carrier from an undisclosed source of hyalu-
ronic acid (Rofilan), which has been crosslinked with
a plant extract.
The hydroxyethyl-methacrylate (HEMA) fragments
began to disappear in the human skin at 4 months
and were no longer palpable at 6 months.
Histologically, they showed the least cellular reac-
tion of all implants. The polygonal, translucent, and
irregular particles, 20–120 lm in size, which appeared
like clear broken glass gravel, were packed in clusters,
with minimal ingrowth of fibrous tissue, cells, and
blood vessels (Fig. 11). Only a fine network of elastic
fibers and occasionally macrophages were found, but
there were no apparent capillaries and no strong fi-
brous capsule. The hyaluronic acid was separated and
surrounded by macrophages, which had disappeared
at 3 months. At 9 months, only a few small clusters of
Dermalive with rounded corners and ridges, many
macrophages, and lymphoid cell clusters could be
detected. The few giant cells contained abundant as-
teroid bodies in their cytoplasma. Some pointed
particles had a tendency to irritate the surrounding
soft tissue, which showed clear evidence of low grade
inflammation. However, only about one tenth of the
implant volume consisted of cells and fibers (Fig. 11).
The clear gel of polyacrylamide was implanted into
human skin at four sites. Used in breast augmenta-
tion in Ukraine and China, it had a viscosity of 1045
centistoke. Since no anesthetic is added, the injections
into human skin caused a burning sensation for 20
sec. This was likely due to the cross-linked gel’s pH of
7.0 to 9.0. On examination, the implants revealed no
reaction and were still palpable at 9 months, but
decreasing in size.
Histologically, acrylamide gel was difficult to detect
at 1 month. The injected, non stainable transparent
gel produced only a fine fibrocellular capsule (Fig.
13), as expected from the literature [14,42]. At 3
months, no further histopathological reaction oc-
curred outside the implant site, such as foreign body
reaction. At 6 and 9 months, Aquamid had dispersed
into the skin and was surrounded by macrophages
and fibroblasts (Fig. 12). The histological reaction
resembled that of injected fluid silicone. In small
quantities, such as a slim strand beneath a wrinkle,
the gel appeared to be slowly absorbed, without vis-
ible foreign body reaction. Therefore, the manufac-
turer’s claim of ‘‘lifelong permanence’’ seems to be
dependent on the amount of implanted acrylamides.
Clinically, the implant made of polyvinylhidroxide
microspheres suspended in acrylamide gel resembles
Artecoll. It was not painful during injection as was
Aquamid. Because of evaporation through the poly-
ethylene syringe, the water content of the material
was already diminished at the time of purchase. The
implants were well visible and diminishing palpably
over the whole course of 9 months. Histological ex-
amination showed the beads, most of them 30–40 lm
in diameter, within the clear acrylamide gel (Fig. 13)
surrounded by an almost invisible fibrous capsule.
Each droplet, 3–5 mm in size, was encapsulated with
a very fine layer of fibroblast and fibers without in-
growth into the implant. No foreign body reaction
was detectable. A few single microspheres outside the
implant site were covered with a fibrin layer or had
attached macrophages and fibroblasts. At 6 and 9
months, most of the carrier gel had been absorbed
and was replaced at the outer layers by granulation
tissue. At 9 months, the implant was totally infiltrated
by macrophages, fibroblasts, and giant cells (Fig. 14),
which resembled the tissue ingrowth of PLA at 3
months. The surface of the microspheres was still
intact after 9 months.
Radiance FN
Clinically, the subdermal implants in the forearm
were swollen for 3 days. Within 1 month, the palpable
implant diminished to half its prior size and became
whitish and shining through the skin. The hard
nodules diminished further in size and disappeared
clinically at 9 months from the skin.
Histologically, Radiance microspheres stimulate
almost no foreign body reaction. The 1-month sam-
ple had to be embedded in PMMA like bone tissue
because the implant could not be cut by conventional
358 Histology and Persistence of Filler Substances
Fig. 8. Reviderm at 1 month. Most dextran beads (its
empty vacuoles) are surrounded by macrophages and giant
cells with conspicuous foamy cytoplasm. The HA carrier is
separated from the beads and surrounded by a rim of giant
cells. Masson trichrome ·100.
Fig. 7. New-Fill at 3 months. Macrophages and giant cells
are surrounding the PLA microspheres and are filled with
phagocytosed PLA material. HE ·400.
Fig. 9. The HA carrier of Reviderm
at 1 month has
separated early from the beads and is slowly phagocytosed
by a rim of multinucleated giant cells. Masson trichrome
Fig. 10. The Duranti classification reflects the extent of
histological foreign body reaction. Class 3 is defined by
infiltrating lymphocytes and giant cells. Zeraplast consists
of PMMA beads suspended in Rofilan. L40 are PLA beads
suspended in collagen.
Fig. 11. Dermalive at 3 months. The PMA particles are
packed and cause little foreign body reaction. Invading
macrophages and some giant cells gather at edges and
corners. Masson trichrome ·400.
Fig. 12. Aquamid at 6 month. The big droplets have been
dispersed into millions of mini-droplets, surrounded by fine
fibrous capsules with minimal foreign body reaction. This
picture resembles fluid silicone. HE ·100.
G. Lemperle et al. 359
methods. The beads were packed and surrounded by
some fibrin fibers but little cellular tissue. At 3
months, a method of rapid decalcification was ap-
plied prior to cutting and staining. The beads were
still packed (Fig. 15) and tissue ingrowth started from
the fine outer capsule of the implant. The main ‘‘in-
terstitium’’ still consists of fibrin fibers and few cel-
lular elements like fibroblasts and flattened
macrophages. No vascularity could be detected. At 6
months, the whole implant is surrounded by a fine
fibrous capsule and single microspheres are encap-
sulated by a thin fibroplastic stroma with flattened
cells. At 9 months, the voids are much smaller in
diameter and the microspheres deformed and slowly
adsorbed (Fig. 16). Since few macrophages were seen
it is suggested that calcium hydroxylapatite micro-
spheres are degraded by enzymatic breakdown rather
than phagocytosis.
Collagen Gel
Bovine collagen is the ‘‘gold standard’’ for all
other newly introduced injectables. To date, Zyderm
Fig. 13. Evolution at 3 months. Most PVH microspheres
are still suspended in acrylamide gel, which results in a fine
fibrous capsule without foreign body reaction. Aquamid
induces the same inconspicuous histological reaction at that
time. Masson trichrome ·100.
Fig. 14. Evolution at 9 month. Macrophages and multi-
nucleated giant cells have phagocytosed most of the acryl-
amide carrier. At that stage, each single microsphere is
encapsulated with fibrin and some macrophages. Masson
trichrome ·400.
Fig. 15. Radiance at 3 months. The calcium microspheres are packed, the interstitium is filled with fibrin and scattered
fibroblasts and macrophages. Masson trichrome ·100.
360 Histology and Persistence of Filler Substances
and Zyplast have been the only FDA-approved
dermal filler substances in the U.S. for more than
20 years. The limited longevity of Zyderm and Zy-
plast, ease of use, low incidence of allergic reactions
(< 1 %), and safety are well established [32]. Late
granuloma formation occurs at a lower rate [26,45]
than with slowly resorbable gels and particulate
Hyaluronic Acid Fluids
Human hyaluronic acid, a polysaccharide of 4–5 kDa
molecular weight has a half-life of only 1–2 days. It
forms the cellular interstitium of the dermis and
creates volume by binding water. A human body
contains approximately 15 g HA. To avoid an early
breakdown, injectable hyaluronic acids have to be
crosslinked. The HA in Restylane has a molecular
weight of 1 ·10
Da, but 0.5%or every 200th amino
acid of the molecule is crosslinked (‘‘stabilized’’) with
a neighbor molecule. The company claims that it
contains a suspension of 1 ·10
HA particles of 40–
60 lm size in HA fluid. A similar product, Perlane, is
said to contain 8 ·10
gel particles/ml of approxi-
mately 100 lm in diameter, and Fine Lines approxi-
mately 2 ·10
gel particles/ml of 20–30 lmin
diameter. These gel particles, however, cannot been
seen under the microscope. Residues from the process
of fermentation of Streptococcus equi (>107 lg/ml
[41] may induce allergies to this bacterial protein in
certain patients. Acute and late inflammatory skin
reactions have been occasionally reported
PMMA Microspheres
These microspheres showed the most stable appear-
ance throughout the experiment. Once injected, the
PMMA microspheres cannot be broken down by
enzymes, since a methyl group in the alpha-position
stabilizes the molecule. Interestingly, the volume of
the injected collagen (80%) remained stable in the
implant over the years (Fig. 5). The microspheres act
merely as a scaffold and a stimulus for constant
connective tissue production. Here, the implant car-
rier is truly ‘‘replaced’’ by the body’s own tissue. In
contrast to other ‘‘dead’’ permanent filler substances
like acrylamide or Radiance, the ingrowth of con-
nective tissue creates a ‘‘living’’ implant.
Artecoll gives predictable results; however, at the
same time it is ‘‘non-forgiving’’ when mistakenly
implanted in an incorrect plane. To avoid technical
mistakes, introductory courses and a careful learning
curve are required. It may induce granuloma forma-
tion in very rare instances [35], as all other substances
will do in certain patients. Artecoll has a 10-year
history [35] and has been used in more than 200,000
patients worldwide outside the U.S.
Another injectable implant of PMMA micro-
spheres, 1–80 lm in diameter but suspended in Mg-
carboxy-gluconate (Metacrill), is produced and
distributed in Brazil [47].
Silicone Fluid
As we know from ruptured breast implants, silicone
gel causes the rarest foreign body reaction among the
Fig. 16. At 9 months, the Radiance microspheres appear deformed and partly degraded, probably by osteolytic enzymes and
not by phagocytosis. Masson trichrome ·100.
G. Lemperle et al. 361
filler materials. In most patients, silicone gel remains
very soft and is encapsulated by only a very thin layer
of fibroblasts. The lack of fibrous capsule formation
may lead to the displacement of larger quantities,
aided by gravity, which may migrate downwards
from the glabella to the cheeks and from the naso-
labial folds to beneath the chin. In time, the implant
can harden through ingrowth of connective tissue,
macrophages, and foreign body cells, which form a
granuloma [53].
The reputation of ‘‘medical grade’’ silicone fluid has
been damaged by five facts: (1) the use of large
quantities, e.g., in breast augmentation or facial dys-
trophies [17,18], has led to deformation; (2) the pos-
sibility of gravity induced ‘‘migration’’ in patients with
very lax skin and subcutaneous tissue; (3) the possi-
bility of late (5–20 years) granuloma (siliconoma)
formation; (4) the substitution of cheaper, non-medi-
cal-grade silicone fluids by nonprofessionals; and (5)
the lack of experience of most physicians in the
treatment of rare cases of late siliconoma. Though
difficult to remove surgically, siliconomas respond
favorably to multiple injections of corticosteroid [7] or
antimitotic agents [58]. The wrinkles and lips of
thousands of patients in Europe and Asia have been
treated successfully with the micro-droplet technique
with small amounts of medical-grade silicone fluid. On
the other hand, hundreds of women required total
mastectomy due to chronic inflammation of large
amounts of silicone oil injected directly into the breast.
As so often in medicine, success depends on the right
dosage, volume, and knowledge of side effects.
Polylactic Acid Microspheres
Polylactic acids do not occur naturally, but were first
synthesized by French chemists in 1954. PLA and
polyglycolic acid (PGA) have been used safely in
suture materials (Vicryl, Dexon), in resorbable plates
and screws, in guided bone regeneration, in ortho-
pedic, neuro-, and cranio-facial surgery, and as drug
delivery devices [60]. PLA does not stimulate the
natural production of collagen [2], but causes a for-
eign body reaction, characterized by macrophages,
giant cells, and some elastic fibers. The PLA polymer
New-Fill disappeared within 6 months, probably due
to extracellular hydrolysis, ester cleavage, and the
catalytic effect of hydrosoluble acid monomers
formed in the polymer matrix during degradation [3].
Whether the mild inflammatory response elicited by
PLA can be ascribed to degradation activity of
macrophages is not clear.
The degradation rate of PLA polymers in vivo is
said to be almost twice that in vitro [60]. Our experi-
ments with microspheres, however, have shown the
opposite. After refrigeration for 6 months, the micr-
ospheres in their fluid cellulose carrier had dissolved
totally, whereas the microspheres in living tissue were
still recognizable as round with irregular surface. The
degradation of different PLAs is affected dramatically
by the amount of glycolic units in the lactic acid chains
[60]. Degradation only appears when the molecular
weight of the PLA decreases below 20 ·10
Da. The
PLA in New-Fill has a molecular weight of 170 ·10
Da. Nine months after implantation, no polymer
residue or remnant cicatricial fibrosis were found,
confirming the good biocompatibility of PLA micro-
spheres. Since PLAs contain no animal proteins, al-
lergies are not expected; however, late granulomas
have been reported as with any other filler substance.
Dextran Microspheres
Dextrans are the substrate of chromatography col-
umns (Sephadex) used for the separation of proteins.
Dextran molecules of 40,000 and 80,000 Da are used
as plasma expanders, since dextran molecules
<20,000 Da will be filtered by the kidney. Dextran
beads of 100 lm in diameter were found intact 2 years
after implantation in the back skin of rats. Eppley et
al. [18] emphasized that the positive surface charges
of dextran beads apparently attracted macrophages.
The macrophages in turn release TGF-beta and
interleukins, which stimulate fibroblasts to produce
collagen fibers. After extensive resorption of the
dextran beads at 9 months, however, little or no
cicatricial residue could be detected at the implanta-
tion sites in these studies. Dextran beads of 100 lmin
diameter (Deflux, Q-Med, Uppsala, Sweden) are
currently used in clinical trials for the treatment of
stress urinary incontinence.
HEMA Fragments
Dermalive is a by-product of the manufacture of in-
traocular lenses and was introduced in the European
Fig. 17. Duranti classification reflects the extent of foreign
body reaction at certain times. Class 4 defines granuloma
formation. Bioplastique is a suspension of silicone particles
in PVP. Embosphere are soft microspheres of trisacryl-
gelatin used for tumor embolization [4].
362 Histology and Persistence of Filler Substances
market in 1998. Because of a rather high incidence of
granuloma formation, it is now used mainly in the
form of Dermadeep with HEMA fragments 80–110
lm in size for deep dermal and epiperiosteal im-
plantation. Inside the implant, the HEMA particles
were packed closely, probably due to diminished
viscosity of the carrier medium hyaluronic acid. This
carrier dissipated from the particles just after im-
plantation of Dermalive and was found outside of the
clusters of particles.
The great advantage of collagen as a suspension
medium for filler substances is its high viscosity,
which keeps the particles or microspheres apart
weeks after implantation. Since little host tissue for-
mation is stimulated, more Dermalive has to be in-
jected compared to other fillers. On the other hand,
HEMA has a free OH-group, which should stimulate
macrophage activity. Endogenous esterases in serum
and liver break down HEMA. Interestingly, the
amount of tissue reaction is no indication for the rate
of granuloma formation. In the studies described
here, Dermalive evoked the least new tissue forma-
tion but clinically causes a rather high rate of gran-
uloma formation [54].
Polyacrylamide Gel
Like dextran beads, polyacrylamide is used mainly
for protein separation by molecular biologists. The
use of polyacrylamides as injectable filler materials
was initiated in 1983, and they were used clinically in
the Ukraine and China as Interfall [14] or ‘‘Amazing
Gel’’ in thousands of patients. However, to date few
clinical and scientific data have been published in
Western literature [23]. Since Interfall’s patent ex-
pired, at least seven European companies are mar-
keting polyacrylamides as dermal filler substances
(Royamid, Argiform, Bioformacryl, OutLine, Aqu-
amid, Evolution, Kosmogel). So far, they have been
injected in large quantities for breast, buttock, and
calf augmentation, in facial lipodystrophy and con-
genital malformations [14], and have been called
‘‘endoprotheses’’ [42]. If overcorrection occurs, the
fluid can be withdrawn from the implant even after
years. Reportedly, it has a half-life in the human
body of >20 years. This may be true for large
quantities; however, the injection of 0.1 cc Aquamid
was resorbed in human skin within 9 months.
The concentration of acrylamide monomers that can
be toxic was reported to be <10 ppm or 0.04%.
Side effects were enlarged lymphnodes in 10%, mi-
gration of gel in 3%, and edema in 2%. The U.S.
Environmental Protection Agency classifies acryla-
mide as a medium-hazard probable human carcino-
gen. Even if there are few published reports [30],
granuloma formation after Interfall implantation is
well known in China since 1997 [14] and has to
be expected in certain patients as with all other
Polyvinyl Gel Microspheres
The mixture of apparently slowly resorbable
nyl microspheres with a longer lasting polyacryla-
mide gel (Evolution) showed similar histological
reactions to Aquamid within the first 6 months, and
from then on was like Artecoll. Clinically and histo-
logically it showed the least reactions and remained
visible and palpable throughout the 9 months. Future
clinical experience has to show whether late side ef-
fects are as high as with acrylamides.
Calcium-Hydroxylapatite Microspheres
Ca-hydroxylapatite is the primary component of
bone and dents. In form of particles it was first used
as onlay grafts for bone regeneration in dentistry. Ca-
hydroxylapatite microspheres of 75-125 lm in dia-
meter (Coaptite) are injected as a bulking agent in
urinary incontinence. It is highly biocompatible,
causes little tissue reaction, well defined at the injec-
tion site, radio-opaque, and can therefore be used as
a tissue marker (Radiance FN). In the skin and es-
pecially in the lip, it does not ‘‘remain soft’’ but ex-
hibits a clear hardening of the implant, which resolves
over time. Since March 2002, Radiance FN can be
used ‘‘off-label’’ in the US for wrinkle treatment and
lip augmentation. Since it disappeared from the skin
within 12 months, it is a semi-permanent implant like
many others (Aquamid, Dermalive, New-Fill, Revi-
derm) and not a ‘‘near-permanent solution’’. While
Radiance is well tolerated beneath wrinkles, it should
not be recommended for lip augmentation. The
concomitant movement of the orbicularis muscle in
women during chewing compresses every injected
strand to a lump!
Histologically, the calcium hydroxylapatite micro-
spheres do not ‘‘provide a scaffold for tissue infil-
tration consistent with the form of the surrounding
tissue’’. Because of little tissue ingrowth [16, 43] and
absence of granulation tissue, triamcinolone (Kena-
log) injections into Radiance lumps will be ineffec-
tive and should be omitted. In some patients,
however, Radiance microspheres may induce a kind
of foreign body reaction - as demonstrated by one
histological picture in the company’s advertisement,
which of course will react to intralesional cortico-
In general, the histological examination of all
samples showed distinctive morphological findings
for each type of micro-implant, which can help dis-
tinguish different injected substances. The differential
diagnosis could also be of medico-legal interest be-
cause adulterated or improper substances are some-
times injected fraudulently [54]. PMA-particles
(Dermalive) showed multiple sharp edges and points
taking on a ‘‘broken glass’’ appearance, whereas
microspheres are devoid of any jagged or sharp edges
that might serve as a continued source of irritation.
G. Lemperle et al. 363
Besides well-known allergies, displacement, and
granuloma formation, another potential complica-
tion of dermal filler substances was documented only
recently [62]. Localized fat atrophies in the cheeks,
similar to those seen in facial lipodystrophy after HIV
treatment [11,57], occurred 2–3 months after the im-
plantation of Restylane or New-Fill in the nasolabial
folds of healthy patients. At 9 months, the implants
could still be identified and were interspersed with
giant cells and granulomatous tissue. The residues
were encapsulated and surrounded by fat necroses
and vacuoles. No explanation has been found for this
side effect since there is no obvious link in the
chemical structure of these two filler substances and
HIV protease inhibitors.
All injectable filler materials cause normal foreign-
body-type reactions that may develop into a foreign
body granuloma in selected patients. Its cause is still
unknown and no predictions can be made. Some of
the patients reported a severe generalized viral or
bacterial infection [37,41,53], vaccination, or local
trauma some months before the appearance of the
Granulomas occur in patients at a rate of 0.01%to
1.0%according to the chemical composition, shape,
and surface structure of the particles [38]. They occur
significantly less often after implantation of micro-
spheres with a smooth surface (Artecoll, New-Fill,
Evolution) [37,38] than after implantation of particles
with irregular surface (Bioplastique, Dermalive)
[6,54]. As would be expected, they also occur less
frequently after injection of resorbable implants
(collagen [29,45], hyaluronic acid [13,25,39-41,59])
compared to long-lasting implants [53,54].
Legal Aspects
In contrast to the FDA, Notified Bodies of the Eu-
ropean Community do not require animal or clinical
studies for the registration and approval of injectable
filler substances or surgically introduced artificial
implants. The European product quality control
systems classify injectable dermal fillers as Medical
Devices Class IIa (resorbable substances), and Class
IIb (substances that cannot be reabsorbed). The FDA
has determined that collagen is a Class III.A device
and injected particles are a Class III.B device. In
November 1997, a new provision was added to the
Federal Food, Drug, and Cosmetic Act to allow any
legally marketed, FDA-approved product to be ad-
ministered for any condition within a doctor-patient
relationship. This is called ‘‘off-label use’’ of an FDA-
approved product.
The CE mark controls only Good Manufacturing
Practice (GMP) of an injectable agent but does not
guarantee a maximum of biological safety. Therefore,
a central office similar to the FDA should be estab-
lished in Europe to which all severe clinical side ef-
fects have to be reported. Some manufacturers report
the complication rates as a percentage of treatments
(Restylane, Hylaform, Dermalive)— most probably
of syringes sold—, whereas other manufacturers re-
port the side effects as percentage of treated patients
[35]. Only a careful statistical analysis of these data
will shed some light on the true incidence of side ef-
fects for each dermal filler substance.
The differences in histological reactions and in per-
manence lead to a classification of injectable filler
substances into five types:
1. Autologous fat rarely is permanent and its fate is
unpredictable. The mechanism for long-term
survival of fat or stem cells has yet to be un-
2. Natural filler substances such as collagen and hy-
aluronic acids are phagocytosed slowly with min-
imal histological reaction.
3. Fluid filler substances, such as fluid silicone and
acrylamides, cause little fibrosis but can dislocate
larger volumes through muscle movement and
gravity; they are considered ‘‘dead implants.’’
4. Particulate materials like PMA gravel and PLA
microspheres are packed and induce minimal for-
eign body reaction and fibrosis. They are pure
fillers and are slowly resorbed.
5. Microspheres from non-resorbable PMMA or re-
sorbable dextran are stimulants for encapsulation
and scaffolds of permanent or temporary connec-
tive tissue formation, considered ‘‘living im-
Host defense mechanisms reacted differently to
each filler material; however, all substances—resorb-
able or nonresorbable—appeared to be clinically and
histologically safe. None of the tested substances is
without undesirable effects [1,46,52,55]. Since the
cause of late inflammation or granuloma formation is
not yet known, predictions can be not be made from
early histological results for possible late reactions of
the host to an individual filler substance.
Therefore, materials must be selected according to
the needs of the individual patient. The patient
should be informed and involved in the choice of
resorbable or long-lasting filler substance. Hyaluronic
acid and new collagen products such as Cymetra,
Fascian, or CosmoDerm could not be demonstrated
to last longer than bovine collagen. The development
of a possibly disease- and allergy-free human rec-
ombinant collagen from yeast (Fibrogen, San Fran-
364 Histology and Persistence of Filler Substances
cisco) or cow milk (Cohesion Technologies, Palo
Alto) has a long way to go. The search for the perfect
permanent injectable material with maximum safety
is ongoing. Time and a centralized registry of adverse
events—similar to the registries for silicone breast
implants—will bring improvement in efficacy and
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366 Histology and Persistence of Filler Substances
... Silicone, in its liquid and gel forms, is also a widely used substance for the cosmetic correction of small wrinkles or scars of the face and volume augmentation of soft tissues [18]. Polymethylmethacrylate, on the other hand, is a rigid permanent filler composed of microspheres with the potential for longlasting results [4,17,19]. Even though the patients were unable to inform which type of dermal filler was used in the procedures, based on the microscopic findings, we suspected that the substances used were hyaluronic acid and polymethylmethacrylate. ...
... A-D Cases 1-4: asymptomatic and normalcolored fibrous submucosal nodules located in the upper and lower lips. E Case 5: painless bilateral nodules in the mucosa of the lower lip associated with marked redness surrounded by macrophages, multinucleated giant cells, and mononuclear inflammatory cells [3,6,7,19]. Conversely, cases of polymethylmethacrylate-associated foreign body reactions have been morphologically defined as numerous well-defined round-to-oval vacuoles, some of them surrounded by multinucleated giant cells. ...
... Conversely, cases of polymethylmethacrylate-associated foreign body reactions have been morphologically defined as numerous well-defined round-to-oval vacuoles, some of them surrounded by multinucleated giant cells. Multinucleated giant cells may exhibit asteroid bodies along with vasculitis [3,7,[17][18][19][20][21]. The presence of asteroid bodies was not observed in our cases; nonetheless, we identified polymethylmethacrylate by the presence of homogenous vacuoles of similar shape and size that corresponded to its microspheres, which can be at least 20 μm in diameter [17]. ...
Full-text available
Background Dermal facial fillers are increasingly popular. Published reports on the clinical and histopathologic characteristics related to adverse reactions to dermal fillers in the facial region have been relatively well documented. This study adds to the literature on adverse reactions to injected filler in the oral and maxillofacial region in a South American population. Methods A retrospective, descriptive cross-sectional study (2019–2020) was performed. The study population was a dermatology service in Venezuela. Clinical and histopathologic features of patients with adverse effects were documented. Results A total of 35 cases of adverse reactions associated with cosmetic filler procedures were diagnosed during the analyzed period; of these, six cases (17.1%) involved the oral and maxillofacial region. All cases occurred in women. The mean age at diagnosis was 59.3 years (58–73). In three cases, dermal fillers were used in different locations on the face, while three involved the lips. Five patients exhibited adverse reactions to lip filler. All six cases were histopathologically diagnosed as foreign body reactions to injected material. Four and two cases revealed microscopic features compatible with hyaluronic acid and polymethylmethacrylate, respectively. Conclusion Reflecting the dramatic increase in cosmetic procedures with soft tissue fillers, this study contributed by reporting six cases of foreign body reaction involving the oral and maxillofacial region, confirmed with biopsy and histopathology.
... On the contrary, Lowe et al. (2001) stated that dermal in ammatory reactions were rare with using hyaluronic acid llers (Hylaform and Restylane), occurring in only 0.42% of treated patients. Accordingly, they believed that the necessity of skin testing needed to be explored more [35]. ...
... Hence, it was postulated that no allergic or wound-healing response had been elicited in both groups [13]. Furthermore, Lemperle et al. (2003) and Narins et al. (2003) reported the presence of very few eosinophils around the ller, which was regarded as a normal physiological reaction [36,37]. ...
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Objectives: The present work aimed to examine the early and late histopathological changes occurring in the lower lips of rats, as a result of hyaluronic acid injection, and to determine whether it could really bring us closer to the ideal soft tissue filler material. This research highlights the importance of experimental studies on this subject since adverse reactions have been observed routinely in dental practice. Material and Methods: The present study was carried out on 36 adult male albino rats with age ranging from 2 to 3 months and weight ranging from 150 to 200g. Rats were divided into two equal groups, each consisting of 18 rats; group I (control group) and group II (experimental group). Rats in the experimental group were injected with hyaluronic acid (0.07 ml), whereas rats in the control group were injected with 0.9% sodium chloride. Each group was further subdivided into 3 subgroups: A, B and C according to the time of sacrifice at one week, one and a half months and three months respectively. Results: The results showed inflammation triggered by the injection of hyaluronic acid. On examining the specimens histologically using Hematoxylin and Eosin stains, Toluidine Blue stain and immunohistochemistry with anti-CD68 antibody, there was a significantly greater inflammatory response in the groups at early intervals with hyaluronic acid compared with the control (P<0.0001). Higher collagen formation was also observed with Masson’s Trichrome staining. Conclusions: Based on the histopathological, histochemical and immunohistochemical results of this study, undesirable effects of hyaluronic acid filler injection can be detected at early intervals following its injection. Fortunately, all the undesirable effects are transient and decrease by time, reaching levels comparable to normal. Overall, HA was well-tolerated by tissues, reflecting how this filler material possesses a biocompatible property. Clinical Relevance: This study introduces hyaluronic acid as a favorable dermal filling material to improve skin contour, and lip augmentation, reduce depression in the skin, and treatment of facial wrinkles with minimal side effects and reasonable cost.
... 35 Despite the immunologic response, the foreign body reaction is completely biocompatible, with postinjection biopsies demonstrating no residual filler material or fibrosis. 36 The effects of tissue expansion have been noted for up to 2 years, although the duration of this effect is best appreciated after multiple treatments across 1-2 months. ...
... 40 Due to their small, smooth, and uniform size, PMMA microspheres resist phagocytosis and degradation by macrophages and instead encourage connective tissue and cell growth. 36 Compared with CaHa, overcorrection with PMMA is of lesser concern as the deep-dermal layer only allows for a certain volume of filler to be implanted. Because of this characteristic, a second injection is often necessary to add a second layer on top of the original placement. ...
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Objective As the population ages, facial plastic providers must remain aware of the treatments to prevent and reverse the external signs of aging. In the mandibular region, skin laxity and soft tissue sagging in the jawline may lead to jowling and chin ptosis along with reduced chin projection. While surgical procedures, including chin implantation, may be performed, nonsurgical procedures are becoming increasingly popular due to their temporary, noninvasive, yet effective methods. This review covers the use of hyaluronic acid, calcium hydroxylapatite, poly‐l‐lactic acid, and polymethyl methacrylate in the jawline. Methods PubMed was searched for data on the mechanism of action, pertinent anatomy, indications, contraindications, technique, and evidence supporting the safety and efficacy of the fillers. Results There are a wide variety of fillers available for use in the lower face with unique characteristics and application methods. While the advantages of injectable fillers include relatively affordable cost, minimal patient discomfort, and limited recovery times, taking measures to prevent short‐ and long‐term complications is necessary for optimal results. Conclusions Understanding the benefits and limitations of injectable fillers in the jawline can help providers appropriately counsel and treat patients.
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Purpose: To describe the efficacy and persistence of injectable calcium hydroxyapatite (CAHY) to correct orbital volume deficit in postenucleation socket syndrome. Methods: An observational study was conducted as a clinical review of all patients in the authors' practice who received injectable CAHY placed in the extraconal and intraconal space to increase orbital volume with a 10-year follow up. The amount of CAHY to be injected was defined according to the degree of orbital volume deficit. Patients previously treated with radiotherapy or with a conjunctival fornix insufficient to accommodate the external prosthesis were excluded. All the patients with at least 10 years of follow up were included in the study. Results: Thirty-one postenucleation socket syndrome patients received injectable CAHY for orbital volume augmentation, with a 10-year follow up. The mean amount of preoperative relative enophthalmos measured by Hertel's exophthalmometry was 14.16 ± 2.15. An increase in the mean orbital volume of 3.35 ± 0.91 at 6 months and 2.97 ± 1.35 at 10 years was obtained. The mean follow-up was 219 ± 18 months (range, 184-240). Patients demonstrated clinical and cosmetic improvement that was observed to continue for 10 years. The complications were peribulbar ecchymosis, 2 extrusions of the internal prosthesis, and 2 ptosis. Conclusions: Injectable CAHY provides safe, simple, repeatable, and cost-effective technique to treat volume deficiency in the enophthalmic orbit in the long term. The volume augmentation obtained with this semipermanent filler demonstrated a lasting effect in the orbit with negligible loss of volume at 10 years.
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Angiogenesis promotes rejuvenation in multiple organs, including the skin. Heat shock protein 90 (HSP90), hypoxia-inducible factor-1 alpha (HIF-1α), and vascular endothelial growth factor (VEGF) are proangiogenic factors that stimulate the activities of phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and extracellular signal-regulated kinase 1/2 (ERK1/2). Poly-D,L-lactic acid (PDLLA), polynucleotide (PN), and calcium hydroxyapatite (CaHA) are dermal fillers that stimulate the synthesis of dermal collagen. However, it is not yet known whether these compounds promote angiogenesis, which leads to skin rejuvenation. Here, we evaluated whether PDLLA, PN, and CaHA stimulate angiogenesis and skin rejuvenation using H2O2-treated senescent macrophages and endothelial cells as an in vitro model for skin aging, and we used young and aged C57BL/6 mice as an in vivo model. Angiogenesis was evaluated via endothelial cell migration length, proliferation, and tube formation after conditioned media (CM) from senescent macrophages was treated with PDLLA, PN, or CaHA. Western blot showed decreased expression levels of HSP90, HIF-1α, and VEGF in senescent macrophages, but higher expression levels of these factors were found after treatment with PDLLA, PN, or CaHA. In addition, after exposure to CM from senescent macrophages treated with PDLLA, PN, or CaHA, senescent endothelial cells expressed higher levels of VEGF receptor 2 (VEGFR2), PI3K, phosphorylated AKT (pAKT), and phosphorylated ERK1/2 (pERK1/2) and demonstrated greater capacities for cell migration, cell proliferation, and tube formation. Based on the levels of 4-hydroxy-2-nonenal, the oxidative stress level was lower in the skin of aged mice injected with PDLLA, PN, or CaHA, while the tumor growth factor (TGF)-β1, TGF-β2, and TGF-β3 expression levels; the density of collagen fibers; and the skin elasticity were higher in the skin of aged mice injected with PDLLA, PN, or CaHA. These effects were greater in PDLLA than in PN or CaHA. In conclusion, our results are consistent with the hypothesis that PDLLA stimulates angiogenesis, leading to the rejuvenation of aged skin. Our study is the first to show that PDLLA, PN, or CaHA can result in angiogenesis in the aged skin, possibly by increasing the levels of HSP90, HIF-1α, and VEGF and increasing collagen synthesis.
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Background:. As people age, the intraorbital fat may diminish and palpebral fissures may narrow, causing the eyes to increasingly tear outside in cold weather. As the bulbus recedes from the conjunctiva, a “wind trap” is formed in the lateral corner of the eye. This wind trap appears to irritate the adjacent lacrimal gland. In this article, an 84-year-old patient experienced annoying outdoor tearing despite having undergone three tarsal strip canthopexies during the past 20 years. Methods:. Retrobulbar injections of 3.5-mL high-viscous dermal fillers (Bellafill or Radiesse) pushed the eyeballs forward, aligned the bulbus with the conjunctiva, and closed the wind trap behind the lateral canthus. Magnetic resonance imaging confirmed the filler material in the posterior lateral corner of the orbit. Results:. The effect was immediate: the patient’s constant outdoor tearing had resolved after the first treatment of his senile enophthalmos. In addition, the narrow palpebral fissure had widened by 2 mm and rejuvenated his aging eyes. Conclusions:. An eyeball that has receded with age can be pushed forward with a retrobulbar injection of a long lasting dermal filler to reattach to the eyelids.
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Soft tissues diseases significantly affect patients quality of life and usually require targeted, costly and sometimes constant interventions. With the average lifetime increase, a proportional increase of age-related soft tissues diseases has been witnessed. Due to this, the last two decades have seen a tremendous demand for minimally invasive one-step resolutive procedures. Intensive scientific and industrial research has led to the recognition of injectable formulations as a new advantageous approach in the management of complex diseases that are challenging to treat with conventional strategies. Among them, collagen-based products are revealed to be one of the most promising among bioactive biomaterials-based formulations. Collagen is the most abundant structural protein of vertebrate connective tissues and, because of its structural and non-structural role, is one of the most widely used multifunctional biomaterials in the health-related sectors, including medical care and cosmetics. Indeed, collagen-based formulations are historically considered as the "gold standard" and from 1981 have been paving the way for the development of a new generation of fillers. A huge number of collagen-based injectable products have been approved worldwide for clinical use and have routinely been introduced in many clinical settings for both aesthetic and regenerative surgery. In this context, this review article aims to be an update on the clinical outcomes of approved collagen-based injectables for both aesthetic and regenerative medicine of the last 20 years with an in-depth focus on their safety and effectiveness for the treatment of diseases of the integumental, gastrointestinal, musculoskeletal, and urogenital apparatus.
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Biocompatibily of Injectable Microspheres A review of the literature Gottfried Lemperle, M.D., Ph.D. *From the Division of Plastic Surgery, University of California, San Diego, Abstract The increasing need for long lasting injectable soft tissue fillers for the treatment of wrinkles and skin defects, gastric reflux, urinary and fecal incontinence, and other indications requires a critical discussion of biocompatibility on a scientific background. Since biological fillers made of collagen will be absorbed over time, medium- and long-lasting biomaterials have been developed in recent years. Particles of irregular shape and rough surface structure initiate a foreign body reaction. In contrary, microspheres with smooth surfaces are encapsulated by fibrous tissue. A review of the literature shows, that Teflon® and silicone particles up to 65 m are engulfed by multinucleated giant cells and transported to regional lymph nodes. On the other hand, smooth, e.g. non-porous microspheres of different chemical origin are phagocytosed only up to a diameter of 15 m, e.g. the approximate size of a macrophage. Since medium size microspheres of 40 m have a surface area twice as large as microspheres of 125 m in diameter, the stimulus for associated tissue ingrowth is doubled. Therefore, approximately 75 % of the filler volume of a medium microsphere implant consists of the body’s own connective tissue, whereas only 40% of the filler volume around larger beads are made up of fibrous tissue.
Many options are available to the individual wishing to ameliorate such facial signs of aging as rhytids (fine lines, creases, and wrinkles). In response to ongoing demand, research is focusing on new and better ways to do so. In consultation with the dermatologist or cosmetic surgeon, the patient can explore these options in detail and arrive at an individualized plan. In some instances, combining procedures may be an excellent choice. Over time, senescence of the skin, elastosis, decreased collagen, and lipoatrophy lead to the loss of the face's youthful turgor and tightness, resulting in the appearance of radiating vertical lines around the lips and mouth, deepening and furrowing of the nasolabial folds, and the development of a longer and flatter upper lip leading to a thinner lip vermilion border. These changes begin to appear in a person's late 20s or early 30s, and they may become a growing concern for individuals in their 30s, 40s, and 50s [1]. People are living longer and want to achieve their best appearance for their entire life, and soft tissue augmentation is one of the few cosmetic procedures that can be used in all skin types (Fitzpatrick I-VI) [2, 3]. Figures 6.1a,b and 6.2a-d are before-and-after photos that demonstrate the results from soft tissue augmentation. This chapter focuses on procedures and products to ameliorate the fine lines, creases, and wrinkles associated with age and exposure to the elements as well as the process of revolumizing the face. For the individual desiring to rejuvenate his or her face by treating perioral signs of aging, there are many options available, including use of botulinum toxin, injectable fillers, microimplants, and combination therapy. These include soft tissue fillers that may be synthetic, animalderived, human-derived, or autologous-the latter harvested from the patient's own vein or fat. The primary action of these products and techniques is to induce collagen formation and/or occupy volume and space. The dermatologist or cosmetic surgeon can assess the patient's needs and desires and propose a course of treatment from among available products and techniques. Fillers are categorized as permanent, semipermanent, and temporary. The majority of injectable fillers are temporary, lasting from several weeks to several months, although some reportedly last 9-12 months. Many of these processes require ongoing treatment to maintain the desired appearance. Injectable microimplants are, for the most part, semipermanent, although some newer products containing microspheres are temporary. Synthetic implants are permanent, remaining in place unless removed surgically; human-derived or cadaverderived implants, while long lasting, do not appear to last indefinitely. Finally, autologous implants and injectables vary in their longevity. Each type of soft tissue filler or implant has its own advantages and disadvantages. Candidates for treatment must consider factors such as product availability, treatment complexity (number of required serial treatment sessions), necessity for local anesthesia, longevity of augmentation, contraindications, allergy testing, potential complications, cost, and technical expertise required of clinicians. General contraindications include any active disease (including diabetes) that may affect risk or outcome; disorders involving collagen, scarring, or connective tissue; lupus (dependent on type of treatment); recent treatment with isotretinoin; and clotting problems. Each type of treatment may have additional contraindications, and these are discussed in the appropriate section below. New products and techniques are being developed at a rapid pace in numerous countries. Clinical trials are in progress for many products. Product availability varies widely, and a variety of products are being used off-label. Dermatologists and cosmetic surgeons should regularly review treatment options to provide the best care possible for patients.
Migration, absorption, or toxicity of prosthetic materials has always plagued the plastic surgeon attempting to ameliorate soft-tissue deficiencies and other contour abnormalities. Our previous work to develop textured-surface breast prostheses has led to the development of micronized, inert, biphasic copolymer particles that neither migrate nor become absorbed by the body. These particles are textured, of critical dimension, and, when mixed with a bioexcretable gel vehicle, can be implanted using a special blunt-tipped cannula. Our experimentation in rabbit ears has shown that the bioexcretable gel component is rapidly phagocytized and is replaced by fibrin-like matrix within 3 days. The fibrin is then replaced by host collagen that gradually converts into a fibrotic encasement around each texturized particle. Clinical use of the substance in a variety of soft-tissue deficiencies has been generally effective, with only a few complications, when followed for 1 year. (C)1991American Society of Plastic Surgeons
background.: Several biomaterials are available for the purpose of soft tissue augmentation, but none of them has all the properties of the ideal filler material. The recent development of hyaluronic acid gels for dermal implantation give the physician new possibilities of effective treatment in this field. objective.: This study provides a clinical and histological evaluation of safety and efficacy of a cross‐linked stabilized non‐animal hyaluronic acid gel (Restylane, Q‐Med, Uppsala, Sweden) to determine its characteristics, advantages, disadvantages, and side‐effects. methods.: 158 patients were treated with facial intradermal implant of hyaluronic acid gel for augmentation therapy of wrinkles and folds, and for lip augmentation and/or recontouring. The results were evaluated in all patients by subjective judgement by the physician and the patient, and by photographic method at time 0 and after 1, 2, 4 and 8 months from the procedure. In addition, a smaller histological study was carried out in five volunteer patients for a term of 52 weeks to determine the interaction and duration of the material in human healthy skin. results.: Clinically, both the physicians' and patients' evaluations revealed very satisfactory results, with a global 78.5% and 73.4% respectively of moderate or marked improvement after eight months, independent of the treated area. The photographic evaluation revealed even better results with a 80.4% of moderate or marked improvement after 8 months. The safety evaluation showed a 12.5% of postoperative immediate adverse events, that were localized and transient. There was no evidence of major systemic side effects. Histologically, the product was shown to be long‐lasting and well tolerated as judged by histological techniques. conclusions.: Stabilized, non‐animal, hyaluronic acid gel is well tolerated and effective in augmentation therapy of soft tissues of the face. This material presents several advantages in comparison to previously used injectable biomaterials and expands the arsenal of therapeutic tools in the field of soft tissue augmentation.
Objective: To describe a syndrome of peripheral lipodystrophy (fat wasting of the face, limbs and upper trunk), hyperlipidaemia and insulin resistance in patients receiving potent HIV protease inhibitor therapy. Design: Cross-sectional study. Setting: Outpatient clinic of a university teaching hospital. Patients: HIV-infected patients either receiving at least one protease inhibitor (n = 116) or protease inhibitor-naive (n = 32), and healthy men (n = 47). Interventions and main outcome measures: Lipodystrophy was assessed by physical examination and questionnaire and body composition by dual-energy X-ray absorptiometry. Fasting triglyceride, cholesterol, free fatty acid, glucose, insulin, C-peptide and fructosamine levels, other metabolic parameters, CD4 lymphocyte counts, and HIV RNA load were also assessed. Results: HIV protease inhibitor-naive patients had similar body composition to healthy men. HIV protease inhibitor therapy was associated with substantially lower total body fat (13.2 versus 18.7 kg in protease inhibitor-naive patients; P = 0.005), and significantly higher total cholesterol and triglyceride levels. Lipodystrophy was observed clinically in 74 (64%) protease inhibitor recipients after a mean 13.9 months and 1(3%) protease inhibitor-naive patient (P = 0.0001). Fat loss occurred in all regions except the abdomen after a median 10 months. Patients with lipodystrophy experienced a relative weight loss of 0.5 kg per month and had significantly higher triglyceride, cholesterol, insulin and C-peptide levels and were more insulin-resistant than protease inhibitor recipients without lipodystrophy. Patients receiving ritonavir and saquinavir in combination had significantly lower body fat, higher lipids and shorter time to lipodystrophy than patients receiving indinavir. Three (2%) patients developed new or worsening diabetes mellitus. Conclusion: A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance is a common complication of HIV protease inhibitors. Diabetes mellitus is relatively uncommon.