General Considerations on Soft Tissue Augmentation:

On first examination, it would appear that small focal and permanent increases in skin volume would be easy to achieve. More than half a century of anecdotes describing adverse reactions and disfigurement suggest otherwise. Many techniques have been investigated but all have been long term failures. Age-related wrinkles, pit-type scarring from certain diseases or trauma and focal lipid losses (lipodystrophy) motivate the search for substances suitable for augmentation and contour modification of soft tissue. Subtle diseases and morbidity surround the use of soft tissue augmentation by insertion, implantation or injection of material is associated with risks and frequently results in only temporary volume augmentation. Moreover, the esthetic effects are not stable and alterations of contour and dimension of the correction can deteriorate over time leading to grossly unpleasing results.

Injection of soft tissue with oily substances of any kind is particularly subject to these limitations and has been associated with severe long term sequelae. Even the injection of natural fatty tissue removed from one site and transposed to another in the same individual and without preservation of the complex ultrastructure of the fatty tissue is afflicted with the same problems. The reinjection of material removed through liposuction or excision, homogenized to an oily emulsion, is not suited for treatment of tissue defects. The substance is resorbed or may lead to granulomata with calcification. The technique used for volumes much larger than a fraction of a ml can also entail major hazards.

Injected oily substances can injure a user without suffering gross degradation or the release of toxic debris into the surrounding tissue. The process of injecting small pockets or droplets of oily material triggers a natural body response which causes the foreign substance to become encapsulated. The process is comparatively rapid and is generally associated with inflammatory activity at the interface between the foreign substance and the natural tissue.

Capsules inevitably form around sites where foreign substances are injected. The more irritating and incompatible the substance is, the more rapidly the process takes place. For many types of oily substances, this process, a form of fibrosis, continues for many years, sometimes leading to large composite masses of oils and fibrous tissue termed ‘granuloma’. Newly-formed capsular tissue surrounding fluids of this kind is not stable. It undergoes dehydration from the impeded irrigation of the site. Shrinkage and necrosis generally takes place over the longer term giving the site a hard tumor-like consistency.

Capsules and granuloma-like tissue are ideal sites for microbiological colonization. Direct injection of any substance through skin is almost always accompanied by a small number of viable micro-organisms, even under ideal circumstances. This is primarily a result of the natural skin flora which often exists to a significant depth and which will resist disinfection by all commonly used topical disinfectant/sterilants. Once contaminated by viable entities, the oily pocket will form an ideal environment where the micro-organisms can remain dormant for many years. The thick capsules that form around such areas with the low fluid mobility through the site makes the viable entity nearly impregnable to conventional antimicrobials including oral and intravenous antibiotics.

The direct injection of oils intended to form microcapsules and deliberate granulomata for contour correction can induce local and systemic problems which may resemble natural phenomena of an infective or inflammatory nature. It can magnify pre-existing adverse reactions and induce unusual forms of disease and deformity. The explanation for the injurious processes lies in the basic physiology and anatomy of soft tissue in mammalians. In essence, the problems associated with this approach to soft tissue augmentation are a direct consequence of an inappropriately designed technique which is attractive because of its ease, simplicity and low cost but is not compatible with healthy tissue. Whereas it may lead to a cosmetically gratifying effect over the short term, it causes the modified area to undergo changes that make the site vulnerable to disease, ultimately leading to loss of tissue in the affected area.

Purity of the Product - A Key Area of Concern:

Purity of compounds used in contact with the body is a basic requirement. There may be practical limitations but purification of any material intended for medical application is essential. Injectable products are even more demanding. Permanently implanted oily substances for augmentation of volume in soft tissue have the most demanding requirements.

There is the issue of mobility or dispersal which further complicates purity requirements. If a liquid is injected into the site in the form of a single pocket or a large number of smaller spaces, two courses can take place. The substance can remain as a stable pocket at the cost of forming a hard, impermeable barrier which prevents the substance from migrating into the surroundings. The oil, its impurities and its derivatives can also undergo slow diffusion through fatty tissue and eventually reappear as dissolved or dispersed molecules entrained within micelles of fat which make up a fraction of the blood stream. In such a form, the material can be easily distributed to sites far removed from the injection.

Dispersed material which enters the blood stream does not remain. It is normally metabolized or somehow excreted. The process can be rapid or very protracted extending sometimes for as much as several months to reduce the concentration by half. Silicones are habitually dispersed as emulsions stabilized by natural surface-active agents such as blood proteins. They are not easily metabolized and excretion is slow. Typical mechanisms of disposal include direct physico-chemical transport much in the same way as paraffin oil. The substances are fat-liking and can diffuse through dense, poorly vascularized fibrofatty material. Dispersal in the form of fine emulsions takes place when fatty tissue is metabolized. Silicones are then entrained into biological fluids as fine mixed particles. Further cleavage of the particles to smaller debris which is more water-dispersible than the starting material takes place with time.

Eventually natural disposal mechanisms which would normally break the substance to soluble entities, a process termed ‘phagocytosis’, will occur. Silicone molecules are not easily 'digested' and many cycles of repeated unsuccessful phagocytosis leads to accumulation of inflammatory cells such as macrophages in the injected area. These entities rapidly accelerate the destruction of tissue leading to large quantities of heterogeneous, partly degraded biological material adjacent to the foreign material. Close to the skin, all of these processes culminate in formation of inhomogeneities. With time, these areas may necrose and the tissue may exfoliate, exposing the healthy underlying tissue. For deeper injections, the material cannot be disposed of through attrition of the surface layer and thus a partly necrotic zone becomes incorporated into the tissue below the skin surface.

Mechanical consequences and unesthetic sequelae include deformity from uncontrolled tissue remodelling, fibrosis from chronic inflammation, mechanically induced tissue damage (ischemia, necrosis), exfoliation of surface skin, color and consistency changes as well as discomfort and pain. For deep injection sites, compression of proximal blood vessels also leads to ischemia and secondary necrotic phenomena with dissemination of denatured tissue into the affected area. Some of these situations lead to abscesses with release of damaging biological substances formed as a result of fermentation and decay of biological substances in closed or poorly irrigated spaces. Calcification may occur in late stages.

Cultures demonstrating common pathogens in biopsy tissue from such sites do not habitually reveal large populations of fast-growing entities. Conversely, long term cultures often reveal colonization by slow growing micro-organisms such as mycobacteria. Secondary granuloma-forming activity occasionally takes place when the population of these micro-organisms reaches substantial levels. This further exacerbates the poor esthetics of the site and may magnify the volume of the augmentation leading to benign but unsightly tumor-like sites.

Other more subtle health problems can result from disturbances of a fragile biological environment. Some problems are simply the result of increasing the volume of a space that cannot contain it. Other injuries have complex explanations that have to do with pharmacological and immunological effects which take place in the space which contains the foreign substance surrounded by its semi-permeable tissue capsule.

Hypodermic syringes core out tissue as they are inserted. They form cylindrical plugs which enter the lumen of the needle. When the injection takes place, these ‘cores’ of skin tissue are expelled and are mixed with the oily injectable. Skin is difficult to sterilize in depth and surviving micro-organisms are almost always present within cores of tissue. These act as innoculae and further complicate the oil-injected environments. It is virtually impossible to maintain sterility in an office environment where such procedures are conducted. The procedures introduce large populations of micro-organisms which would normally be controlled by modern anti-infectives. However, antibiotics require access to the affected site as well as good irrigation to achieve their effects. These conditions are rarely met in areas where large quantities of foreign substances and capsular tissue exist. Even if ideal injectable substances for tissue augmentation were available, the implantation procedures would require extreme forms of sterility control which could only be met under institutional environments.

Injection sites which contain dense distribution of finely hydrophobic substances are susceptible to tenacious infective processes which may not have immediately discernible consequences other than superficial irritation or erythema. Microbiological activity can be silent, taking place over several years, producing small serous pockets filled with metabolites and foreign impurities which are slowly released into the deeper tissue and a portion will be entrained into body fluids systemically.

There are variations amongst patients which make some more vulnerable than others to deficient products and technologies, in particular those with repeated injections into the same site. Factors such as age, general health condition, occupational history and vulnerable phenotype are other examples of special problem patients. Individuals with perceived needs for small volume soft tissue augmentation fall mostly within these categories.

Technical Realities of Tissue Augmentation Injectables:

Hydrophobic oils have been used for tissue augmentation almost from the outset. The approach was predicated on the belief that compatibility with the tissue and the permanency of the correction would be most easily achievable if the oils did not mix easily with water. At first natural oils of plant origin were injected. Later, the more inert purified paraffins such as Nujol™, a commonly available laxative, were employed. In the late-forties, siloxanes ( "silicones") were developed as insulating oils and specialty lubricants. They came to the attention of the medical community shortly after World War II. Many processes were used to make these substances but medical applications were not an initial concern.

Opportunistic use of silicones for tissue augmentation rose dramatically in the fifties and adverse reactions appeared from the outset. Contrary to popular belief, proponents for cosmetic injection of silicones included a significant number of physicians as well as unsanctioned individuals. During the sixties, it became common knowledge that silicones were associated with predictable adverse reactions and the technique was abandoned by the mainstream medical community. Many editorials in medical journals condemned the procedures. A small number of physicians remained committed to the technology and built practices on injections of silicones.

Clinical trials were conducted with some of these compounds. One included studies on highly purified silicone oils injected for cosmetic correction of tissue. The work, which spans the seventies, met with the same adverse reactions that had been encountered earlier with less pure forms thus demonstrating that problems were fundamental and related to the silicone derivatives themselves as opposed to minority impurities. General recognition that such products were not suited for permanent implantation, least of all as free injections in soft tissue, followed.

It was rapidly learned that these substances, when injected deeply into tissue, would injure in many ways. Initial findings centered on toxicity issues. Chemical composition controls toxicity. It also affects the degradability of the material and its ability to resist metabolism, absorption and disposal in vivo. Most silicones proposed for these applications were not acutely toxic on short term animal and human implantation tests; adverse effects took longer to be seen.

Toxicity is not the only limitation to the medical use of oily silicone derivatives. The materials are inherently difficult to purify as they have very elevated boiling points. Most are unsuited for distillation using even sophisticated equipment. Filtration is no better. It may exclude gross solid impurities but requires specialized equipment. Improvised equipment, such as conventional filtration systems based on cloth, paper or other widely found filtration media, increase the impurity content due to debris from the filtration medium.

Silicone oils require chromatographic separation techniques for adequate purification. Short path molecular distillation under near vacuum conditions, a preferred laboratory and industrial technique for purification of high boiling oils, is not available generally and is not suited for large volumes of fluid. For high molecular weight molecules, distillation is not a practical option. The yields are too small and impurities remain. The boiling temperature exceeds the temperature where thermal degradation occurs. Drastic changes in molecular structure of the material and rapid rise in impurity levels ensue. Solid degradation products such as silica can form in the presence of oxygen which is difficult to exclude from the purification stream. The purity of the final product is most strongly affected by the production methodology, the purity of the starting reagents and the atmosphere in which the reaction is conducted. Even the reaction vessels affect purity.

Silicone oils of industrial sources intended for aerospace and electronic applications are not synthesized with high purity in mind. Compatibility with short term medical and pharmaceutical applications is fortuitously achievable after simple purification but does not yield an oil suitable for long term contact with tissue.

Conventional methods of purification can only be used to remove the more labile impurities. This places the desired oily silicone-based substance as the residue where low boiling impurities are concentrated along with the desired product. Non-volatiles tend to be the most objectionable part of the mixture as they are frequently the most toxic. Treatment of the silicones to impart sterility and the absence of pyrogens further reduces purity. Sterilization is normally performed through strong heating or exposure to steam. The thermal treatments cause chemical changes in the product and create new impurities.

Adverse effects from injected hydrophobic oils, in particular silicones, have more complex mechanisms that include pharmacological, infective and immunological processes within spaces created by foreign material and the artificially formed tissue membrane. If the oil injected area has a large volume, the problem is magnified by lack of irrigation. The more remote interior of the mass is inaccessible to body fluids. Degeneration of tissue takes place at the core and culminates in necrosis and mineralization. The artificially created composite of oil and connective tissue mimics the behavior of tumors with necrotic cores.

The capsules around foreign substances are not stable. They remodel continuously causing changes in the geometry and volume of the site. Nerves, muscles and vasculature can be affected mechanically. The behavior of such spaces and the products they contain and release are decisive factors that account for problems or complicate existing diseases.

Chronic atypical intracapsular infections with release of microbiological toxins may be primary factors for systemic adverse effects. Microbiological proteins, even from non-viable debris, are active in oil mixtures. Low molecular weight silicone compounds as well as many hydrophobic substances widely used in tissue augmentation were investigated for possible commercial applications as immuno-stimulants. They behave as adjuvants, facilitating reactions to weak immunologically active substances. Many are still used in the production of biologics, in particular vaccines. Classical work on adjuvants was performed by Dow Corning staff in the early-seventies. Many silicone derivatives were investigated and found active. Some of the findings appeared in confidential memoranda circa 1974 by LeVier, Lake, Redonovich, Bennett and other Dow Corning and Dow Chemical specialists. The findings were reconfirmed by several independent workers in the nineties, including Kossovsky.