Biocompatibility of Microparticles

into Soft Tissue Fillers

Klaus Laeschke, DDS

The increasing need for long-lasting injectable soft tissue fillers for the treatment of
wrinkles and folds requires a critical discussion of the biocompatibility on a scientific
background. Since biological fillers made of collagen and hyaluronic acid will be resorbed
over time, copolymer biomaterials with microparticles have been developed in recent years.
The microparticles followed special and essential demands because of the interaction with
the tissue. In search of an ideal soft tissue filler substance, a variety of biomaterials with
microparticles suspended have been created for injecting into dermal defects, into the
urethra of patients with urinary incontinence, and in patients with vocal cord insufficiency.
The particles differ in chemical composition, surface structure, surface charge, and particle
size and evoke different host reactions, accordingly.
Semin Cutan Med Surg 23:214-217 © 2004 Elsevier Inc. All rights reserved.

T he ideal injectable material for wrinkle treatment should

not only offer esthetic results and a long-lasting effect, it
should be safe and biodegradable, with minimal complica-
Depending on their chemical structure and surface char-
acteristics, most resorbable biological materials and synthet-
ics such as polymethyl acrylate, polylactic acid, or dextrano-
tions and no risk of migration. mere initiate a temporary foreign body reaction which may
For that reason, there are some requirements (Table 1) and es- last up to several months.9,10
sential demands (Table 2) for microparticles into soft tissue fillers. Nonresorbable or permanent materials tend to chronic in-
flammation and granuloma formation37 (Table 3).
Chemical Composition
The chemical composition of the microparticles is important Migration of particles in the dermal compartment
because of the possibility to biodegrade. If they are made
● Implanted particles of ● They have to be
from a synthetic process like metal, ceramic, polymethyl
biomaterials cannot phagocytosed by
methacrylate, or other polymers, they cannot degrade after migrate actively macrophages and migrated
the implantation time into the soft tissue. Biomaterial copol- to lymph nodes or liver
ymers, made by a process of fermentation, can have a wide
variety of composition and properties. In addition, their sur- Migration of particles in the dermal compartment
face may be modified physically and biochemically.
Water sorption in biomaterials is very important to the ● The critical particle Extracellular “migration” by
size to avoid this mechanical forces (muscle
function of the polymers, such as hydrogels or dextranomere
phenomenon is 80 to movement, gravity) is
particles.3,4 Water content may also lead to absorption of ions 120 ␮m correctly called
and other molecules, as enzymes, which cause the biodegra- “dislocation”
dation of the microparticles.
The chemical composition of the microparticles is impor-
tant for biodegradation: biomaterials degraded after time
Biocompatibility I
without any adverse reaction and synthetic hard micropar-
ticles are not degradable and do not stay permanent in the ● Microparticles with smooth surfaces and regular shape
tissue. create the best tissue augmentation in the form of
fibroblast and collagen fibers surrounding the
microspheres
● A monolayer of macrophages surrounded the surface of
Institut for Skin Care Concept, Friedenstr. 29, 56427 Siershahn, Germany. this type of microparticles
Address reprint requests to Klaus Laeschke, DDS, Institut for Skin Care Concept,
● This is a sign of optimal biocompatibility
Friedenstr. 29, 56427 Siershahn, Germany.E-mail: matridex@aol.com.

214 1085-5629/04/$-see front matter © 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.sder.2004.09.005
Biocompatibility of microparticles into soft tissue fillers 215

Table 1 Requirements for Injectable Soft Tissue Fillers Con- Table 2 Essential Demands for Particulate Material
taining Microparticles
● Spherical microspheres or microbeads
Biocompatibility ● Minimum diameter 40 ␮m
● Chemical composition ● Smooth, homogeneous surface
● Surface structure ● Liquid medium with excellent biocompatibility
● Surface charge
● Particle size

Surface Charge
Biocompatibility II The presence of an implant grossly changed the local dielec-
● Microparticles with rough surface and irregular shape tric environment, thus affecting local intermolecular interac-
create a foreign body granuloma as a dominant tions.10,13,18 This influences the cell attachment to the im-
characteristic of the long-term biological response. planted materials (Tables 5 and 6). Eppley and colleagues
demonstrated that different charged surfaces stimulate differ-
ent cell regeneration. They used dextranomeres as a micro-
Conclusion particle due to the chemical possibility to get charged sur-
● The biocompatibility of implant materials is based upon faces.3,4 Microparticles made from dextranomeres have two
the “fibrous capsule” that envelops the implant different charged surfaces: negatively charged, such as the
● No chronic inflammation cation exchanger CM Sephadex, which induces new bone
● The microparticles are well embedded in “new” collagen formation by stimulating osreogenesis; and positively
● No long-term biological response charged, such as the anion exchanger DEAE Sephadex,
which induces new collagen fibers by stimulating collagen-
esis.
It is not clear why positive charges preferentially attract
Surface Structure macrophages nor why and how macrophages are activated by
positively charged DEAE Sephadex microparticles.
Although the chemical composition of the implant micropar-
In tissue culture, macrophages migrate toward posi-
ticle would seem to be of primary importance, its physical
tively charged particles and this positively charged mate-
form is equally critical in determining biocompatibility
rial invokes a favorable wound-healing response in rat
(Tables 3 and 4). A variety of physicochemical factors affect
incisional wounds.
phagocytosis, including particle size, shape, contact angles,
Also, in humans, positively charged DEAE Sephadex mi-
and surface charge.38
croparticles stimulate collagenesis. The microparticles were
A simple experiment with rods of 1 mm in diameter, but
embedded in new collagen fibers without chronic inflamma-
different shapes, implanted into rats showed that triangular
tion after the implantation.20-22,36
implants with sharp edges caused significantly higher cellular
response (chronic inflammation) than square or round im-
plants.
There is also a statistically significant difference between
Phagocytosis of Particles
rough and smooth surfaces of the microparticles and the Phagocytosis, the process by which macrophages recog-
interaction of the tissue with the microparticles. nize and try to destroy injected biomaterial, is an essential

Table 3 Injectable Microparticles

Chemical Name Trademark Particle Size Particle Form Carrier
Polytetrafluoroethylene Permanent Polytef 1-100 Spherical Glycerine
Bioplastique 16-409 Spherical PVP
Polydimethysiloxane
Polymethylmethacrylate Artecoll 36 Spherical Collagen
Polyvinylhydroxide Evolution n.n. n.n. Acrylamide
Polyethylmethacrylate Dermalive* 55 Fragments xHA

Resorbable
New fill* 46 Fragments Cellulose
Polylactic acid
Dextranomere uncharged Reviderm 50 Spherical HA
Dextranomere charged Deflux 80-120 Spherical xHA
Matridex 80-120 Spherical xHA
xHA ⴝ crosslinked hyaluronic acid; fragments ⴝ particles with sharp edges and irregular.
*Resorption time of the particles more than 24 months.
216 K. Laeschke

Table 4 Shape and Surface Structure of Microparticles Table 6 Surface Charge

Irregular shape ⴙ rough Regular/spherical shape ⴙ ● All living cells and most biomaterials possess a surface
surface structure smooth surface resulted charge (zeta-potential)
resulted in: in: ● This influences cell attachment to implanted materials
foreign body reaction Fibrous tissue with ● The presence of an implant changes the local dielectric
collagenesis environment

part of host defense. According to their chemical compo- Discussion

sition and surface charge, the body reacts either with pro-
tein attachment and consequent encapsulation with fi- The biocompatibility of implant materials is based on the
brous tissue or with an attempt to phagocytose the “fibrous capsule” that envelops the implant.
particles.34,35 The types of cells present or absent from the interface
Macrophage activity is affected by the physiochemical characterize the nature of the reaction. For example, the ab-
state, such as particle size, chemical structure, and surface sence of lymphocytes at the material interface and from the
charge22,23,24 (Table 7). perivascular region of nearby capillaries implies that the
polymer does not elicit an immune response.
Macrophages and multinucleated giant cells are the dom-
inant characteristics of the long-term biological response to
Migration of Particles rough surfaces and particles with irregular shape and surface.
Migration of particles is a main issue of artificial joint Both cell types eliminate foreign body material from the tis-
replacement surgery as well as of injectable bulking agents sue. Since most of the injected irregular particles are too big
in urology. In this context, however, migration appears to for phagocytosis and subsequent transport, a chronic rejec-
be a misnomer. Particles of biomaterials cannot actively tion process is set in motion, which lasts until the implant is
removed.
migrate within the body, but have to be phagocytosed by
In contrast to the rough and irregular surface, a monolayer
macrophages migrating to lymph nodes or liver, respec-
of macrophages surrounded by a zone of fibrous tissue is
tively. When trapped in the lung, they have to be injected
found at the surface of a smooth and charged walled implant
accidentally into a venous plexus at the injection site.
or an absolute smooth microsphere. This is the sign of opti-
Of course, extracellular “migration” of particles by me-
mal biocompatibility. These microspheres are enveloped
chanical forces such as muscle movement, skin folding, and
with fibrocytes, which remain in a steady state with the im-
gravity is a well-known phenomenon, but should be cor-
plant.
rectly called “dislocation.”25,26,32
It seems as if substances with positively charged micro-
Microspheres from irregular particles between 4 and
spheres are able to create the best tissue augmentation in the
40 ␮m in diameter were detected in the lungs and other
form of fibroblast and collagen fibers surrounding the micro-
organs. The main particle size to avoid this phenomenon is
spheres.
80 to 120 ␮m, or so-called “critical particle size” (Table 8).
The usual migration of macrophages with phagocytosed
particles is toward the lymph nodes or liver.39
Henly stated that particles smaller than 80 ␮m have a Uncited References
tendency to migrate.40 Dewan injected silicon particles (Mac- This section comprises references that occur in the refer-
roplastique) into rats, but found no foreign material at distant ence list but not in the body of the text. Please posi-
sites after 3 months; however, a marked local foreign body tion each reference in the text or delete it. Any refer-
granuloma reaction was noted.41 ences not dealt with will be retained in this sec-
Stenberg and colleagues show a lack of distant migration tion:1,2,5-8,11,12,14-17,19,27-31,32,33.
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Table 7 Surface Charge When Injected
● Neutral beads Only foreign body reaction without
Table 5 Surface Structure
new tissue formation
● Particles with rough ● Particles with smooth surface ● Negatively CM Stimulating osteogenesis, new
surface induce: induce: beads bone formation, craniofacial
1. Foreign body 1. Fibroblast adhesion repair
reaction/giant cells 2. Collagen synthesis ● Positively DEAE Stimulating collagenesis, new
2. Rapid attachment beads collagen-rich connective tissue,
of macrophages no migration of the beads
Biocompatibility of microparticles into soft tissue fillers 217

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