Sirs,
A still
increasing number of publications in the scientific press is dealing with
saftety and efficacy of dermal fillers. As in the article of P.J. Nicolau they
mostly report individual experiences and
personel opinions and not a systematic approach to the problems and
the claim to more true scientific studies does not indicate the direction or aim of
such studies.
Up to date
we can find a reasonable systematic approach to the physical and chemical properties
of the implant matierials. But more important are the reaction of the
bioorganism and our knowledge so far is limited( ).
Material
characteristics and the biological
reactions of the bioorganism are two entities. They are not necessarily linked
in a linear way as pretended by the head line of the article cited above. That
can be easily derived by the fact that it is no possible to draw conclusions
from the type of tissue reaction or granuloma to the initiating material.
The meaning
of this observation is that the reaction of the bioorganism to a defined
material is multifold and dependend of very individual reactions of the
biorganism. Everybody is generating his own reactions towards a defined implant
material. This is a different approach to the problem of biocompatibility of
foreign materials. In case of a non-degradable material the problem is still
more complicated by the fact that the reactions of the bioorganism are not
constant during life time. The ability to tolerate a material may change in the
course of time. Observations like that are paralleled by experiences with
breast augmentation implants and orthopedic devices with respect to early and
late failure. This might also be the background for adverse reactions following
injections in a previoulsly treated area.
The features of implantation of a foreign material are very similar. Wounding is unavoidable. Wounding causes a inflammatory reaction and subsequent a scar tissue formation which normally is resolved with the maturation of the scar tissue. Once a foreign body is present at the healing site a chronic inflammatory reaction is set up and perpetuated life long characterized by a fibrotic encapsulation of the permanent foreign body.
The chronic
inflammatory reaction is initiated at the foreign body´s surface which may be
physically or chemically or both activ. Every foreign body displays a foreign
surface to the host tissue. Even a chemical inert material is physically active
because it is separated from the tissue by its surface which acts as an
interface. In a first step the foreign surface accumulates plasma derived
macromolecules (race for the surface 1) within minutes and in a second step
cellular elements like leucocytes or bacteria are attracted and retained (race
for the surface 2). The latter taking hours coincides with the early
inflammatory phase of wound healing
The
settling of cellular elements at the foreign body surface is dependent of the
macromolecular layer which can be influences by the properties of the foreign
body material. But in fact most today implant materials are derived from
industrial use and not adapted to biology and therefore behave quite randomly
in a biological environment. The adsorption of macromolecules at the surface is
more or less uniformly. The adsorption of plasma proteins, which are partly
denatured by the free surface forces or surface tension resp., is followd by
adhesion of white blood elements, usually monocytes, which flatten at the
surface and trigger the final fibrotic reaction. The flattening of the
monocytic cell types on the foreign surface is the signal starting up the
fibrotic reaction. A surface disigned biomaterial for elective or specific
adsorption preserving the structure of bound proteins and /or preventing
monocytic cells of flattening is the aim of
todays research on biomaterials but is out of sight with respect to
dermal fillers presently. This is a lesson to be learned from biomaterial
sciences and teachs a more or less uniform reaction of the bioorganism to most
of the known biomaterials in the early phase of integration. Exceptions are
biomaterials with chemical acticvity at the surface like bioglass,
hydroxylapatit and PLA or such with signaling character to the living tissue
like HA (see below).
The uniform
answer of the bioorganism to different implant materials is not a contradiction
to our clinical observations of different types of possible reactions. What we
see in practice is the result of different and individual late phase reactions
of the host independed of the implanted material. The signal set by the
flattening of the monocytic elements on the foreign surface is processed in a
different and individual way in the late phase of healing. Therfore it is not
possible to specify the implant material by describing the cellular reaction in
the phase of chronic inflammation.
Takeing that in acount it is obvious that there must
be an additional component directing the individual reaction of a patient
towards a defined biomaterial. That component may be described as a complex
reaction of multiple parallel acting systems of the bioorganism on a
time-scale, including the genetic and epigenetic status of the immune system,
individual aspects of wound healing and wound healing sites.Therefore,
achieving clinical studies on biomaterials implanted in the human body with a
high number of participants, which is in fact a condition for the commercial
distribution of an implant materials by the FDA, will
thus elicite comparable results independet of the material as a matter
of statistics.
May be the
clinical or visible results will be registered differently depending of the
kind of implant site and function like orthopedic devices, breast prostheses or
dermal fillers. But with respect to the
dependence of the reactions of the life time phase the value of that kind of
clinical studies is strongly limited by the time of follow up. In case of non
degradable materials we should request a life long follow up, even when the
foreign material has been removed after a defined period.
There are
some more concerns about non degradable filler materials and those which are
slow degradable and chemical active once. How to detect dislocation or passiv
migration driven by muscle motions,
gravitation forces and dynamics of the blood and lymphatic flow to
distant organs including lung, liver, brain ( )? In clinical studies on dermal fillers
usually observation at the bodys surface
can be examined and registered. What about highly chemical activ particles like
polylactid acid (PLA) cristals which release lactic acid at the particle
surface with a toxic pH-value of about 2?
In fact they cause a severe chronic inflammation due to the toxic
pH-value at the interface to the adjacent tissue with a subsequent extended
scaring and scar collagen formation. A comparable tissue reaction in a
glandular organ like the liver is generally named cirrhosis and not
neocollagenesis. A similar reaction in the lung following false injection or
migration may lead to fibrosis. There are no experimental data available to
exclude a happening like that.
Therefore
it is very euphemistic to name the
tissue reaction to intoxicating agents like lactid acid or the
consequences of chronic inflammation “neocollagenesis”. We should keep in mind
that a variety of products for skin treatment are pushed in the market arguing
about their ability to trigger neocollagenesis. This argumentation cannot
withstand a scientific scrutinization. Generating scar tissue which contains
predominantly scar collagen cannot be a therapeutic aim. Who by the way is
interested in adding collagen to aging skin for example in the face ? Usually
abundant collagen is resected performing a face lifting.
What we
desire is an agent or a procedure which cause a net shrink effect of the
dermis. A candidate for that purpose may be hyaluronic acid (HA) or
modifications of it ( ) . HA is known as a signaling molecule stimulating
specific receptors of a variety of cell types including fibroblasts ( ).
Therefore HA and its modifications act not only as fillers when administered in
the dermis.
In so
called semi-permanent fillers HA as well as collagen are used as a lubricant to
facilitate injection of less deformable plastic particles.We have no reliable
date to conclude that collagen or HA have a spacer function in the tissue.
Primarily they are lubricants in such preparations. In case of HA it has to
take in account its signaling character to the connective tissue. High
molecular HA has anti-inflammatory properties. In contrast collagen is known as
a structure activating platelets and thus starting infammation.
Despite
that, it is not (yet) the biomaterial influence over host tissue response, it
is still the host which predominantly influences the biomaterial´s
destiny. No doubt, more systematic
research is necessary but in a different way of thinking. Implantation of
dermal fillers is not an exception in biomaterial science and to give a
recomandation, if any, than to use exclusively nontoxic biodegradable stuff.
Draft, 1st
of December 2007
Dr. med. Johannes Reinmüller
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