Paul E. Chasan, M.D. La Jolla, Calif.
Background
The debate over the legitimacy of silicone as a safe tool for soft tissue augmentation has spanned well over half a century. Proponents state that injection of questionable purity and/or massive quantities have produced unfavorable outcomes. They claim that in experienced hands with “injectable-grade” silicone, there are very few problems. Despite these claims, the literature is replete with disastrous outcomes following silicone fluid injection, often many years after the initial treatment. The unanswered question remains: are the risks worth the potential benefits of silicone oil as a permanent filler?
Chemistry
Silicone describes a large family of silicon containing synthetics. Siloxane is a mnemonic acronym derived from the names of its chemical constituents: Silicon, Oxygen, and Methane. The variety used for medical applications are polydimethylsiloxanes (PDMS). The relative polymerization and chain length of the compound determines its viscosity, as measured by centistokes (1 centistoke equals the viscosity of water). By their nature, silicones are heavily contaminated with heavy metals, short length volatile polymers, and other impurities, which require an extensive purification process depending on the specifications. For example, some of the specifications of Silikon-1000 are an ave. molecular weight of 38,000 – 48,000, less than 50 particles per ml (at less than 10 microns) and less than 5 particles per ml (at less than 25 microns), and less than 0.001% heavy metals. Some of the techniques used to purify silicone include fractionization with solvents, baking, a wet film still, and filtration. Typically, silicones are sterilized by a dry heat terminal sterilization process.
Nomenclature
Dow Corning 200 Fluids – polydimethylsiloxanes (PDMS) of different viscosities. Generally used for industrial purposes. Available in 20 kg pails and 200 kg drums. The product is not tested or represented as suitable for medical or pharmaceutical uses.
Dow Corning 360 Medical Fluids – PDMS available in 5 standard viscosities: 20,100, 350, 1000, and 12,500 centistokes. It is the same as the Dow Corning 200 fluid, except that more rigid quality control procedures were established to remove heavy metals, low-chain-length polymers, and other impurities. It is supplied in 1, 40, and 440 lb. containers.
Dow Corning MDX 4-4011 – The designation of the Dow Corning 360 Medical Fluid, 350 centistokes, which was further purified and sterilized and used for the FDA study ND #2702 in 1965 to evaluate injectable PDMS for soft tissue augmentation. It was packaged by Philadelphia Laboratories in 1 and 50 cc ampules and certified as sterile by the packager.
Centistoke – a measure of viscosity where 1 centistoke equals the viscosity of water.
Weber-Christian Disease – Idiopathic lobular panniculitis characterized recurrent inflammatory subcutaneous nodules. The acute process is self-limiting, and resolution results in atrophy of the surrounding subcutaneous fat, leaving a depression. The nodules are usually symmetric, most commonly involving the thighs and lower legs, but may also involve the arms, trunk, and face. Malaise, fever, and arthralgias frequently occur. The etiology is unknown.
The Beginnings of Silicone
Johann Berzelius was a Swedish chemist who was the first to isolate elemental silicon in 1824. F.S. Kipping at Nottingham University first synthesized silicone in the late 1800’s utilizing the new Grignard reagent. This method of producing organosilicones is still in use today. He was primarily interested in the pure chemistry of silicones, not their applications. He described the silicone polymers as sticky messes which had no uses and called them “uninviting glues”. From 1899 to 1944, he published 54 papers on the subject of silicon-carbon chemistry. The first polydimethylsiloxanes (PDMS) were first made in the late 1930’s by Frank Hyde, an organic chemist working with Corning Glass Works at the Mellon Institute for industrial Research. By 1939, it appeared that silicones would make excellent lubricants. Hyman Rickover, then head of the electrical section of the Bureau of Ships for the Navy, was impressed with the use of fiberglass tape covered with silicone resin, known as 990A resin. His comment after examining the tape was “now you’ve got something, I want it tomorrow”. As the demand for larger volumes of silicone were needed, based on Rickover’s demand and its potential as an industrial product, Corning Glass sought the assistance of Dow Chemical to further its product development and produce large volumes of silicones. The Dow Corning Corporation was founded in 1943. The first product was used by the United States Air Force to prevent ignition failure at high altitude allowing an aircraft to remain at 35,000 feet for up to 8 hours; without the aid of the compound, it could only remain at that altitude for just a few minutes. It made possible the flight of airplanes, such as the B-17, to England and North Africa at a time when the United States was beginning to lose many aircraft through submarine attacks on the shipping convoys that carried our airplanes across the sea. Subsequent products that followed were used for dampening vibrations in instruments, non-melting grease for spark plugs, and antifoaming agents that prevented bubbles from forming in motor oil at high altitudes. Dow Corning explored non-defense applications of silicone, eventually creating more than 5,000 products. One of the first products to reach wide usage was a silicone liquid used to insulate electrical transformers.
Silicone was then tested on rats and monkeys and found to be chemically inert. John Holter, an engineer whose baby had hydrocephalus, developed the silicone hydrocephalic shunt in the early 1950’s. The first shunt was placed in 1955, and by 1962, four thousand shunts had been placed. In 1959 Dow Corning established the Center for Aid to Medical Research (CAMR) as a source for in-house and independent medical research. Dow Corning supplied the silicone implants for Gerow and Cronin in the early 1960’s, eventually leading to the introduction of their product in 1964.
The Misuse of Silicone
When World War II was over, American Army quartermasters noticed drums of the transformer insulating fluid (Dow Corning 200 fluid) disappearing from the docks of Yokahama Harbor in Japan. The silicone was being injected into prostitutes who sought a more “western” appearance for the American servicemen. This practice spread to the United States, primarily in California, Las Vegas, and Texas. A Newsweek article in 1963 quotes a Las Vegas physician as injecting over 200 patients’ breasts. Carol Doda became famous for her large breasts after being injected with silicone in 1964. There were obvious problems with migration, therefore attempts were made to improve success by mixing the silicone with “scarring agents” or “adulterants”. This caused a significant inflammatory response, and this practice was quickly abandoned. The most popular was the Sakurai formula, which included the addition of vegetable (olive oil) and mineral oils. Dr. Sakurai was a Japanese physician who then moved to Beverly Hills to “perfect” his technique. Thousands of women underwent injection of massive amounts of silicone oil in their breasts. This practice was often performed by lay people and never regulated. This silicone product (Dow Corning 200 fluid) that was used was used for industrial purposes and never intended for injection.
In 1962, Dow Corning 360 Medical Fluid was introduced with specifications of higher purity, but not designed for injection. It was intended for medical use in coating needles, oral drug delivery systems, and immersion therapy for burn patients, but never intended for injection. Dow Corning 360 Medical Fluid was readily available. Sources included local hospitals Hubbard tanks for the treatment of burns and veterinary supplies. Injection of silicone into the breasts of entertainers in Nevada was rampant and with disastrous results. By 1975, the Nevada legislature passed a law criminalizing the use of injectable silicone.
The Early Clinical Trials
In 1964, The Federal Food and Drug Administration stated that a silicone, when injected into the tissues is a “New Drug”. Therefore, in 1965, Dow Corning filed a “Notice of Claimed Investigational Exemption for a new drug” ND #2702. This was a non-blinded single treatment prospective study. The Dow Corning 360 Medical Fluid specifically designated for this FDA approved study for soft tissue augmentation was designated MDX 4-4011. This 350 Centistoke viscosity fluid had even higher purification specifications and was sterilized. The principle investigators included Thomas Rees (NYU), Franklin Ashley (UCLA), Reed Dingman (Univ. of Michigan), Milton Edgerton (Johns Hopkins), Dicran Goulian (Cornell), and Norman Orentreich. Of the 1,333 patients treated, 709 were treated for such conditions as wrinkles and acne scars, and only 408 were followed sufficiently to allow any data to be collected. There was only one reported complication: migration of the silicone in the leg of a polio patient that received a large quantity of silicone. In 1973, Rees et. al. published their experience over 10 years with MDX 4-4011 on 73 patients with hemifacial or bilateral facial atrophy. They showed good to excellent results in 68 patients and minimal complications, however, there was follow up data on only 3 patients at 1, 3, and 7 years. It is interesting to note that the authors cautioned that individual doses should be kept small, but the total amount injected ranged from 3.5 ml to 55.5 ml. The passage of the 1976 Medical Device Amendment to the Food, Drug, and Cosmetic Act charged the FDA with identifying certain drugs that would be classified as devices. That same year, the FDA suspended ND #2702 citing inadequate follow up, lack of case reports, and numerous patients who left the protocol. In 1977, Dow Corning submitted an amended ND #2702 which received FDA approval: a 3-year clinical study up to 300 patients to evaluate safety and effectiveness of liquid silicone on the most severe facial deformities such as Romberg’s disease and Weber-Christian Disease. In 1979, the ND #2702 had been transferred to the bureau of Devices and redesignated IDE L0002702. Between 1979 and 1981, 600 patients were enrolled. Only 144 patients had any meaningful follow up. The only documented complications from this study were in 3 patients; two had a diagnosis of Weber-Christian disease. A 66 yo woman, with a diagnosis of Weber-Christian disease, received a total of 12 cc of MDX 4-4011 in her cheeks over a 4 year period. She also had rheumatoid arthritis and atypical mycobacteria were cultured from her facial lesions one year prior to her silicone injections. Inflammatory episodes began 11 years after her last injection. She required debridement and a latissimus musculocutaneous free flap reconstruction. According to the treating physician, “it was impossible to be certain if this was a reactivation of Weber-Christian disease or a reaction to the silicone”. The two other complications occurred 5 months and 16 months after the last injection, but have little clinical information. Before the PMA was submitted, the FDA requested an interim report on the status of the protocol, which Dow Corning filed in 1990. The FDA reviewed the report and found that there was no follow up greater than 4 years, no objective measurements of improvement, and insufficient pre and post-operative pictures. By November 1991, the hearings on the safety of breast implants had begun. The much larger breast implant issue had eclipsed Dow Corning’s interest in injectable silicone. No attempt was made to correct these deficiencies, and Dow Corning elected not to pursue a formal PMA application. By 1992, the IDE became invalid. The company’s position per Arthur Rathjen, director of medical research for Dow Corning, was: “it was not for any reason of safety nor effectiveness of the product for facial treatments. The primary influence behind the decision was derived from Dow Corning’s inability to devise a workable system of controls that would preclude misuse of the product”.
Support Against the Use of Silicones
In 1977, Wilke published his results on the treatment of 92 patients for a total of 230 treatments with injectable grade silicone (MDX 4-4011(1966-1970)/Koken Co.- silicone Japan (1970-1976)) over a 10-year period. He reported 13 granulomas and noted that 8 of these occurred with in the first year after treatment with a very high incidence in the glabella (20%). Five of the granulomas resolved spontaneously, and he also did report “worthwhile improvement in many patients”. In 1978, Pearl reported 5 complications associated with silicone injections which resulted in significant inflammatory reactions in the face. Only one of the patients was injected with injectable grade silicone. The main focus of the paper was a treatment regimen using systemic steroids starting with 60 mg/day of prednisone. They state that “all of our patients who have been treated with this regimen are now improved and in acceptable condition, both functionally and cosmetically, though they continue to suffer mild symptoms from the low dose prednisone therapy and from the residual silicone”. Another case of facial swelling 6 months after injection of an unknown grade of silicone from Italy is reported in 1993 from Switzerland. It is interesting to note that she had received injections to the nose, glabella, and cheeks, but developed only left cheek swelling one week after her last injection. In 1996, Rappaport, Vinnik, and Zarem presented an extensive literature review and reported 54 patients over a 26 year period with problems associated with silicone injections occurring 0.5 to 28 years after injection. Notable is the preponderance of complications occurring in the glabella and cheeks, and only 3 in the lips (two thickened upper lips and one nodule). They summarize with the following statement: “While the incidence of complications may be low, when they do occur, they are devastating and cannot be resolved satisfactorily”. A recent article (Oct. 2005) describes the salvage of 23 patients treated with either injected silicone oil or silicone prosthetic blocks over the last 15 years. 19 of the patients were treated with presumed silicone injections, and 13 were treated for larger cheek deficiencies. These would have required larger doses of silicone. One of the most impressive pictures was a case report of a 60 year-old woman with hemifacial atrophy that had silicone injections as a child, putting her in the pre MDX 4-4011 period.
Support For the Use of Silicones
Orentreich performed further purification of the Dow Corning 360 medical grade silicone and used minute amounts at each session, coining the terms “injectable-grade” silicone and “microdroplet technique” respectively. Using his technique with injectable-grade silicone, Orentreich has claimed thousands of treatments without complications. Specifically, he contends “1400 patients without serious flaw under continuous study”. In 1984, Arohnsohn described his treatment of 4,862 patients over a 22 year period and concludes, “There is absolutely no evidence to date that shows that the subcutaneous injection of minute amounts of pure silicone into suitable areas spaced over a long interval of time leads to any systemic physiologic problems”. It is interesting to note that he used both 100 and 350 centistoke silicone oils and sterilized them himself by autoclaving 250 cc bottles at 250 degrees F for 20 minutes. Also, for the first 538 patients, he added an adulterant, either oleic acid or sesame oil as a 1% solution. He abandoned the use of the adulterant as he saw erythema and/or skin nodules. Early in his series, he noted silicone migration which disappeared when he began using microdroplet technique. No follow up data was included in this study. Webster et. al. reports extremely favorable results in 2,811 facial treatments in 235 patients over a 20 year period. In another paper, he reports favorable outcomes in 347 patients for a total of 1,937 treatments used in post-rhinoplasty deformities over a period of 20 years. Of those patients 100 were followed for an average of 76 months to assess erythema over the injection site in which 10% developed compared with 3% in the control group. In 1986, Webster et. al. reported on 17,000 treatments since 1962, but does not have any data on how many patients were followed or the length of time they were followed. In 1971, Ashley presented hundreds of animal studies and followed 90 patients for 3 months with excellent results. He did mention that it was important to use small volumes at each session. His average volume per injection was 4 cc which was considered a small volume in the early 1970’s. He was the first to utilize higher viscosity silicones up to 1000 centistokes, noting that large volumes of low viscosity silicones tended to migrate where the higher viscosity silicones did not migrate. In 1972, Rees and Ashley presented their findings in a ten year study treating 73 patients with facial deformities using MDX 4-4011 with universally good results. Their treatment volumes ranged from 3.5 to 55.5 ml. In another report, Rees demonstrated spectacular results in the treatment of facial lipodystrophies in 9 patients without complications; again, these patients were followed for an unspecified amount of time. Berger reported his ten year experience with injectable silicone with favorable results in 1975, but does not mention how many patients were treated or how long they were followed. Edgerton and Wells reported their ten year experience using MDX 4-4011 in 200 patients over a ten year period in 1974; again, there is insufficient follow up data. Their only complication was a subcutaneous nodule in a patient with calf augmentation. They concluded that by carefully controlling patient selection, indications, and the technique of injection, most of the dangers of liquid silicone injection may be circumvented. In 1982, Milojevic reported on 1677 facial injections performed in Yugoslavia, but there is no mention as to the number of patients treated or the length of follow up. They had only two granulomas 4 and 5 weeks after injection respectively. Both resolved with evacuation. In 1990, Duffy performed an extensive review of injectable silicone and reported on 2,000 results utilizing microdroplet technique, much like Orentreich, over a 6 year period with only minor or transient problems noted. Clark, et. al. in 1989 reviewed the safety of silicone injections and concluded that “past problems associated with silicone soft tissue augmentation are related primarily to the use of impure product, excess volumes, or inappropriate location. In 1997, Maas reported on 7 patients with complications from injectable materials. Six of the seven patients in which the materials tested were found not to been injected with silicone; the substances recovered were paraffin, methacrylate, and Teflon paste.
The Newer Silicones
In 1994, purified and sterilized high viscosity silicone oil made by Adatomed of Germany was introduced for ophthalmologic use. More recently, Alcon and Bausch and Laumb introduced a high viscosity, sterile and purified form of injectable grade silicone under the brand names Silikon 1000 and Adato-Sil-Ol 5000 respectively. These have been F.D.A. approved for ophthalmologic use.
Richard James Corporation, the manufacturer of Silikon-1000 which licenses to Alcon, introduced a new silicone fluid, Silskin, with even higher purification specifications than Silikon 1000 and is intended for use as a soft tissue filler. A F.D.A. approved trial involving Silskin started on 1/2002 with 26 patients enrolled. The patients were injected on one-half of the face with collagen and the other half with Silikon 1000 and followed for one year. The lead investigators are David Orentriech, Daniel Baker, and a dermatology group – Skin Care Physicians at Chestnut Hill (Drs. Dover, Arndt, and Kaminer). Alister Carruthers recently studied 24 patients with lipoatrophy of the face assessing their quality of life after Silikon injection. The results of both studies have not yet been published as of the writing of this manuscript.
Discussion
An extensive review of the literature on the complications of silicone injections for soft tissue augmentation of the face revealed several features: there can be impressive results and significant disasters associated with injectable silicone of the face. The majority of complications involved the cheeks, nasolabial folds, and glabella. The average time to first complication is 8 –10 years with a range of 6 months to 36 years. This extensive lag time makes it difficult to study because the history of the technique, amount, and material injected is often not available. A “material” was injected in the past and is often presumed to be silicone. The majority of complications include granulomas, nodularity, migration, and chronic cellulites. It is interesting to note that there are only a few complications involving the lips and none reported were severe. The fact that the MDX 4-4011 silicone was limited only to the initial seven “authorized’ investigators (an additional investigator was added later) and never made available for widespread use indicates that nearly all of the injected silicone was of an industrial or “medical-grade” that never produced or intended for injection. Even the MDX 4-4011 is contaminated by low molecular weight impurities by today’s standards. Unfortunately, the majority of the larger trials are no more than anecdotal reviews; there is virtually no follow up data. Generally, the only follow up end-point becomes a complication. It does seem unlikely that the six authors above that published the largest series which included over 9000 patients followed an average of 15 years would extol the benefits of soft tissue augmentation with injectable silicone if the complications were excessively high or the results weren’t acceptable. Just the litigation alone would have stopped their practices if there were a large number of significant complications. A reasonable explanation would be that they didn’t see any of their own complications for many years, but still these same practitioners were in practice for over 20 years and would see some of their patients back who did have complications. There is no question that pure injectable-grade silicone fluids that have been injected by expert hands have resulted in adverse outcomes, but they are rare. Using a conservative estimate, there are well over 100,000 patients that have had silicone injected for facial soft tissue augmentation. Yet, the number of serious complications reported is well less than 200, and many are of questionable silicones or not silicone at all, large quantities injected, unknown technique, and/or poor treatment sites. Even if there is larger under reporting bias, there are tens of thousands, the vast majority, of patients who have benefited from silicone injections. Because of the long latency before complications, there is a “ticking time-bomb” attitude towards silicone injections that makes it more difficult to study. The F.D.A. studies initially showed excellent results with few complications in spite of large volumes of silicone being injected and MDX 4-4011 having a relatively low viscosity. In fact, all studies involving MDX 4-4011 showed a low rate of complications. However, there is still a lack of long term follow up data.
There is a significant difference between the technique of silicone injection today and 20 years ago. The silicone is purified and sterilized and intended for injection which, in theory, would decrease the possibility of granulomas formation and infection. It is also much more viscous which has minimized or even eliminated the issues with migration. The use of small volume injections spaced at least one month a part should reduce migration, granuloma formation, and scarring. Lastly, there are certain areas that have had large numbers of complications, such as the breast, cheeks and glabella. It is unclear whether these specific areas are actually prone to complications or that they areas that typically require large amounts of silicone oil for correction.
Summary
Injectable silicone as a soft tissue filler is a very controversial topic. Both the lay and scientific literature is replete with stories of disastrous results and disfigurement, often occurring many years after the initial injection. There are also reports of thousands of patients treated with spectacular results over long periods of time. It is probable that some of the successes that are claimed eventually had a complication if followed long enough or that they just weren’t reported. It is just as likely that poor technique and impure, low viscosity silicones contributed to many of the complications. Some of the conflicting facts are that prior to 1965, there was no silicone fluid available that was made for injection. The majority of injections were performed with Dow Corning 360 “medical grade” silicone that was never intended for soft tissue injection or augmentation. Often times, silicone wasn’t even the substance that was injected; “something” was injected in years past and was presumed to be silicone. It wasn’t until 1965, when MDX 4-4011 was introduced that a silicone intended for injection was produced, and this was given to only a few investigators involved with the F.D.A. studies. Therefore, the overwhelming majority of silicone injections performed in the last 50 years has been a grade of silicone that was never intended for injection. Furthermore, the viscosity of the silicone at 350 centistokes is less viscous than currently available silicones. The volumes of currently injected silicones are much lower than previously reported, especially when using microdroplet technique. Lastly, there are clearly areas of the face and body that tend to have a higher percentage of complications than others, i.e. breasts and glabella.
Given that there are significant potential benefits to purified, high-viscosity, injectable silicone oil, if used correctly, it would be important to elucidate those factors contributing to complications. Impure or adulterated silicone and large volumes of a low viscosity silicone would clearly be implicated in significantly increasing the rate of complications. The question is: will small amounts of a purified, high viscosity silicone, injected correctly, cause the same problems of delayed and often disfiguring granuloma as previously reported. The only way to know is a longitudinal study with appropriate follow up data; something that has not been performed to date. Before we discard the potential benefits from something as powerful as injectable silicone oil, it would be prudent to determine the specific factors leading to its complications.
Bibliography
Achauer, B.M., A serious complication following medical-grade silicone injection of the face, Plast. and Reconstr. Surg., 71(2): 251, 1983.
Aronsohn, R.B., A 22 year experience with the use of silicone injections, Am. J. Cosmet. Surg., 1:21, 1984.
Ashley, F.L., et. al., The present status of silicone fluid in soft tissue augmentation,
Plast. and Reconstr. Surg., 39(4): 411, 1967.
Ashley, F.L., Thompson, D.P., Henderson, T., Augmentation of surface contour by subcutaneous injections of silicone fluid, Plast. and Reconstr. Surg., 51(1):8, 1973.
Ashley, F.L., Braley, S., McNall, E.G., The current status of silicone injection therapy, Surgical Clinics of North America, 51(2): 501, 1971.
Bon, A., Eichmann, A., Serious long term complication following silicone injection of the face, Dermatology, 187:286, 1993.
Berger, R.A., Use of silicone injections in facial defects, Arch. Otolaryngol., 101: 525, 1975.
Blocksma, R., Braley, S., The silicones in plastic surgery, Plast. Reconstr. Surg., 35:367, 1965.
Braley, S.A., The status of injectable silicone fluid for soft tissue augmentation, Plast. and Reconstr. Surg., 47(4): 343, 1970.
Braley, S.A., The use of silicones in plastic surgery: A retrospective review, Plast. and Reconstr. Surg., 51(3): 280, 1975.
Clark, D.P., Hanke, C.W., Swanson, N.A., Dermal implants: Safety of products injected for soft tissue augmentation, J. Am. Acad. Derm., 21(5): 992, 1989.
Chiu, E.S., Sharma, S., Siebert, J.W., Salvage of silicone-treated facial deformities using autologous free tissue transfer, Plast. Reconstr. Surg., 116(5):1195, 2005.
Duffy, D.M., Silicone: A critical review, Adv. Dermatol., 5: 93, 1990.
Edgerton, M.T., Wells, J.H., Indications for and pitfalls of soft tissue augmentation with liquid silicone, Plast. and Reconstr. Surg., 58(2): 157, 1976.
Maas, C.S., et. al., Complications of injectable synthetic polymers in facial augmentation, Dermatol. Surg., 23: 871, 1997.
Milojevic, B., Complications after silicone injection therapy in aesthetic plastic surgery, Aesth. Plast. Surg., 6:203, 1982.
Orentreich, D.S., Liquid injectable silicone – techniques for soft tissue augmentation, Clinics in Plastic Surg., 27(4): 595, 2000.
Orentreich, D.S., Orentreich, N.O., Injectable fluid silicone, Dermatologic Surgery: Principles and Practice, New York, Marcel Dekker Inc.: 1349, 1989.
Pearl, R.M., Laub, D.R., Kaplan, E.N., Complications following silicone injections for augmentation of the contours of the face, Plast. and Reconstr. Surg., 61(6): 888, 1978.
Rappaport, M.J., Vinnick, C., Zarem, H., Injectable Silicone: Cause of facial nodules, cellultis, ulceration, and migration, Aesth. Plast. Surg., 20: 276, 1996.
Rees, T.D., Ashley, F.L., Delgado, J.P., Silicone fluid injections for facial atrophy: A ten year study, Plast. and Reconstr. Surg., 52(2):118, 1973.
Rees, T., Ballantyne, D., Hawthorne, G., Silicone fluid research: a follow-up summary, Plast. Reconstr. Surg. 46(1):50, 1970.
Rees, T., Platt, J., Ballantyne, D., An investigation of cutaneous response to dimethylpolysiloxane
(silicone liquid) in animals and humans. A preliminary report. Plast. Reconstr. Surg. 35:131, 1965.
Rees, T., Coburn, R.J., Silicone treatment of partial lipodystrophy, J.A.M.A 230(6): 868, 1974.
Rohrich, R.J., Potter, J.K., Liquid injectable silicone: is there a role as a cosmetic soft tissue filler?, Plast. Reconstr. Surg.. 113(4):1239, 2004.
Rowe, V.K., Spencer, H., Bass,S., Toxicology studies on certain commercial silicones and hydrolysable silane intermediates, J. Industr. Hyg. and Toxicology, 30:332,1948.
Rowe, V.K., Spencer, H., Bass, H., Toxicology studies on certain commercial silicones II. Two year dietary feeding of DC Antifoam A to rats, Arch. Industr. Hyg., 1:539, 1950.
Warrick E.L., Forty years of firsts: the recollections of a Dow Corning pioneer, McGraw-Hill, 1990.
Webster, R.C., et. al., Rhinoplastic revisions with injectable silicone, Arch. Otolaryngol., 112: 269, 1986.
Webster, R.C., et. al., Injectable silicone for facial soft tissue augmentation, Arch. Otolaryngol. Head Neck Surg., 112:290, 1986.
Webster, R.C., et. al., Injectable silicone: a report of 17,000 facial treatments since 1962, Am. J. Cosmetic Surg., 3 (2): 41, 1986.
Wilke, T.F., Late development of granulomas after liquid silicone injections, Plast. and Reconstr. Surg., 60(2): 179, 1977.