Still confused

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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