- Email: [email protected]
Breast implants: The next generation
Eugene P. Goldberg, PhD, and Mutaz B. Habal, MD, FRCSC
here is an important need for safe and effective mammary prostheses for augmentation and reconstructive plastic surgery. However, a moratorium for general clinical use of silicone gel breast implants (SGBIS) was imposed by the Food and Drug Administration (FDA) in 1992 because of inadequate safety data. Data were not available at that time for large cohort prospective or retrospective studies concerning such potential problems as local complications, shell rupture, and the frequency of additional surgeries. As a consequence, to satisfy the desire by patients for cosmetic augmentation, there has been a dramatic growth in the use of FDA-accepted saline implants (SIs) during the past decade (to more than 200,000 per year). This has been concurrent with the widespread removal of gel implants. Although SIs have been approved by the FDA for two U.S. companies, the relatively high prevalence of SI complications and their aesthetic deficiencies (approaching a total of 60% within 5 years, based on FDA submission data) has continued to foster much more research concerning: (1) the reasons for breast implant problems; (2) the possible general reintroduction of improved gel implants; and (3) the development of new and significantly improved prostheses. The discussion presented here is, therefore, intended to focus attention on the most important gel and saline implant deficiencies and comment on some future biomaterials and device design opportunities which might afford a new generation of improved implants.
Background A variety of clinical problems were reported for silicone gel breast implants (SGBIS) during the 30 years of use before the 1992 FDA moratorium. An adequate body of scientific, physical, and chemical property data and large cohort prospective or retrospective clinical studies were lacking, thereby resulting in the action of the FDA to withdraw these cosmetic implants from general use in the U.S. lo The need for breast prostheses has consequently resulted in the use of saline implants and more research since 1992 concerning the behavior of SGBIs. One objective has been to provide a better scientific basis for risk-benefit assessments by plastic surgeons and patients for revisions and new augmentations. Research in this field has greatly benefited from the collaboration of biomaterials scientists and plastic surgeons. In light of historical problems and recent developments, this section considers the opportunities for new and improved implants.
From the Biomaterials Center, Department Materials Science & Engineering, University of Florida, Gainesville, FL, USA. Address reprint requests to Mutaz B. Habal, MD, Tampa Bay Craniofacial Center, 801 west M. L. King Blvd, Tampa, FL 33603-3301. Copyright 2003, Elsevier Science (USA). All rights reserved. 1071-0949/03/0901-0101$35.00/0 doi:lO.l053/otpr.2003.125470
Operative
Techniques
in Plastic and Reconstructive
Surgery,
Silicone Gel bnplants. SGBIs are unique prostheses in that a crosslinked silicone elastomer shell was designed to contain lightly crosslinked silicone gels. In fact, this “gel” was actually a composition that contained as much as 85% to 95% uncrosslinked silicone fluid comprised of low molecular weight and oligomeric polydimethylsiloxane. Basic principles of polymer science predict that such silicone “gel” fluids will: (1) diffuse readily into and through the elastomer shell with continuous release of silicone fluid into surrounding tissues (the so-called “bleed”), and (2) that the swelling of the shell by silicone fluid will significantly reduce the mechanical strength properties of the shell. In the first large cohort retrospective failure analysis for explanted SGBIs (for more than 8000 explants from 35 studies), reported in 1999, a significant statistical correlation was found between gel implant duration and elastomer shell failure (25% failure within 3.9 years and 71.6% at 18.9 years).3 In addition, the results indicated a high prevalence of reoperative procedures (33% within 6 years). The earliest reports of mechanical testing of SGBIs involved experimental compression of the entire prosthesis to determine the breaking strength or “breaking pressure.“+*5 These tests were primarily intended to model the compressive forces associated with “closed capsulotomy,” a technique that was commonly used to break up the fibrous scar tissue responsible for capsular contracture. There was sufficient concern about prosthesis rupture using this procedure that it was generally abandoned during the late 19SOs. In this regard, the early ex-vivo mechanical tests suggested that there was also considerable variation among various prostheses and even lot to lot variations from the same manufacturer. In general, low breaking strengths for explanted prostheses were measured when compared with new unimplanted controls.+J In more recent studies, comparisons were made between manufacturer’s data6 and the mechanical properties of explanted and unimplanted control shells.r-11 These studies showed that the mechanical strength properties of explanted SGBI shells are generally much poorer than either unimplanted controls or the data reported by manufacturers.6 Phillips and co-workers first concluded that there was a correlation between the strength of explanted shells and the implantation time, suggesting a decrease in silicone shell mechanical properties with time.10 The decrease in mechanical strength, because of swelling of the silicone elastomer shell with silicone oil, has been suggested as a significant cause of the high prevalence of rupture for SGBI implants.3~8J” As early as 1971, implant manufacturers had data showing that filling silicone implant shells with gel caused the implant shell to swell and drastically reduce shell mechanical strength properties.i3J3 This deterioration in mechanical strength clearly had the potential to greatly influence the ultimate performance of these devices. Despite early adverse experience with thin shells (as thin as 0.003”) during the 1980s some manufacturers once again produced gel implants with thinner
Vol 9, No 1: pp 3-9
3
Fig 1. An example of an implant after 20 years of implantation, showing intracapsular contents with total disruption of the external shell and moderate calcification.
shells and gels with very high uncrosslinked silicone oil content. Such changes were intended to provide a more natural aesthetic quality. However, the thin shells were weak and these so-called 2”d generation SGBIs have since been shown to exhibit an extraordinarily high rate of rupture. More engineering design work and silicone materials research on shells and gels was clearly necessary to better define the minimum strength requirements for prolonged safe performance of SGBIs (Fig 1). Studies from this laboratory and reports by many other research groups point to a general time-dependent reduction in tensile strength, tear strength, and elongation (ductility) for all types of explanted elastomer shells. This adverse change in properties has made mammary prostheses vulnerable to the forces exerted on them from cyclic stresses incurred during use. Deterioration in strength has clearly been a major factor in the relatively high rupture/failure rate that has been reported in recent years.3 The 1991 and 1992 FDA Breast Implant Advisory Panel reviews led to the FDA decision to place a moratorium on the general clinical use of SGBIs for augmentation but continued general approval for saline implants. The basis for this moratorium was the lack of adequate clinical safety data from the major manufacturers to support approval of the gel implant PMA submissions requested by the FDA during the late 198Os.l However, gel implant use was allowed for reconstructive surgery and for a limited number of augmentation procedures under strict protocols intended to provide safety data from prospective 5-year clinical studies. This gel implant history, coupled with the confusion concerning the potential for immunologic complications that might be attributed to silicone gels, had the following consequences: 1. Cessation of gel implant augmentation in 1992 from a previous rate of about 150,000&r. 2. Revision surgery for removal of gel implants estimated at more than 35,000 in 1994 and reaching about 5O,OOO/yr thereafter, with saline implant replacement in a majority of cases. 3. Rapid growth in the use of saline implants to a current level of 2OO,OOO/yr, although data for prospective clinical safety trials were not available until the time of the FDA review of saline PMAs from manufacturers in May 2000.15 4. FDA approval of saline implant PMAs for two U.S. manufacturers in 2000. However, clinical results reported by manufacturers for prospective studies of 4 to 5 years suggested a high prevalence of saline implant complications necessitat-
4
ing a high rate of additional surgeries within 5 years of primary implantati0n.l” 5. Development and offshore clinical use of implants designed with nonsilicone fillings such as aqueous polyvinylpyrrolidine (PVP) solutions and vegetable oils. These were touted as safer than silicone gel-filled implants, more radiolucent, and more aesthetically pleasing. Unfortunately, widespread reports of clinical problems in the UK for the vegetable oil implants, implicating oil leakage and oil degradation complications, forced a halt to clinical use and initiation of many revisions beginning in the UK in March 1999.17 In addition, a PMA application to the FDA for aqueous PVP-filled implants was not approved. During the past decade there has been a proliferation of papers concerning many key aspects of gel implant chemical, physical, and biological properties, as well as more reliable data for noninvasive diagnostic methods, to determine implant status. In particular, MRI has evolved to the point where diagnosis of gel leakage and shell rupture may be obtained with a relatively high degree of certainty (Fig 2) .18J9 Because “gels” were predominantly silicone fluid when first introduced in the 196Os, the gel implant was in fact a type of continuous silicone fluid release device. The physiologic consequence of continuous infusion of small amounts of silicone fluid throughout the life of the device into the implant recipient was essentially unknown and untested, and even the recent literature does little to clearly clarify this question. However, from pathological examination of tissues surrounding implants, there is compelling evidence that a local chronic inflammatory response may often occur. In view of the renewed interest in approving SGBIs, an understanding of the following questions will be essential for designing new and improved mammary prostheses: 1. The effects and variability of perJoi7ncuice because of the nunlerous and frequently changed implant designs? In this regard, there is an excellent comprehensive review of breast implant designs and historical development by Middleton and McNamara.19 Some specific examples of potential problems associated with the numerous designs include: (a) the consequences of frequent changes in shell thickness and the wide variations in shell thickness within even a single implant (in the range 0.003 to 0.020”), (b) performance of single versus double lumen structures, (c) the effect of the variety of shell surface textures, and (d) the stability and in vivo effectiveness of phenylsiloxane and perfluorosiloxane
Fig 2. Ruptured implant using a special coil magnetic nance scan.
reso-
GOLDBERG AND HABAL
Fig 3. (A) Patient was referred to us two years after implantation elsewhere with deformed breasts. (B) lntraoperative view of the collapsed implant; saline was the filler. (C) The removed implant was totally empty. (D) We filled the implant from the valve to demonstrate the leak; it was a small mechanical shell in the body away from the seam as predicted most of the time; the blue dye used was everywhere in the tissue.
silicone oil diffusion barrier coatings on interior shell surfaces and the variations in these coatings from the standpoint of adhesion to the shell, thickness, and mechanical properties. In general, one may conclude that more uniform and thicker silicone shells (in the 0.020 to 0.025” thickness range), with minimal defects, would be advantageous. 2. The effects of the myriad chmzges in silicone polymers, catalysts, and manu.jactw-ing procedures? Some key questions concern: (a) the composition of the “gels” (especially the large amount of uncrosslinked fluid), (b) the lot-to-lot and batch-to-batch variability of silicone shell and gel crosslinking and properties, and (c) the extent of routine testing of
the final assembled and sterilized product. In particular, soft gels with near 100% crosslinking would be desirable. behavior? This may remain a controversial 3. Irnnnlnological question for implants that release silicone fluids until larger and better epidemiological studies than those reported to date further clarify this issue.‘” of several well lznowlt adverse 4. The severity and j-equelcy events: Capsular Contractul-e, Pain, Disfigurement, Silicone Leakage (Bleed) and Migration, Chronic Irflmmnation, Infection, Iniplant Deterioration, Loss of Sllell Integrity (Rupture), and Revision Szu-gely? With regard to these and related gel implant safety issues, the November 2000 FDA website doc-
Fig 4. (A) Successful saline-filled implant in the registry at our Center 5 years after implantation ruptured after 1 year). (B) Mammogram of the implanted breast. BREAST IMPLANTS
(the original saline implant
5
Fig 5. (A) Successful implant that was a replacement for a ruptured silicone implant 5 years after reimplantation. The silicone implant was present for 12 years before failure. This suggests that all implants may need annual evaluation and scrutiny for a maintenance program and replacement when needed. (B) Mammogram of the same patient.
ument, “Breast Implant Risks,” discusses all of these potential risks plus those associated with calcium deposits, reduced nipple and breast sensation, tissue atrophy and implant extrusion, hematoma, and infection. However, the FDA statement, as well as most product inserts and descriptive product information, provide little or no quantitative clinical results on which to base better informed judgements of risks versus benefits.
The Importance of
ammary Implants
There is an obvious need for mammary implants as evidenced by the increasing willingness of patients to incur the expense and surgical risks required to alter appearance. Since 1992, breast implant procedures for cosmetic augmentation have once again become one of the fastest growth areas of plastic surgery using saline implants.15 In part because of product liability concerns, only two major breast implant manufacturers have emerged (InamedMcGhan and Mentor) to supply saline implants in the U.S., a market that is now about 200,000 implants per year. The incentive for companies in this field is the recent rate of growth of about 14% per year, with the prospect of maintaining a steady state business of $500 million per year selling saline implants at ca. $500 each and even more for gel implants (only generally available now offshore) at ca. $800 to $1000 each. From an overall economic standpoint, it should be noted that the total cost for one augmentation in the U.S. is now ca. $5000, encompassing surgeon fees (average $3100) plus other surgery-related expenses.
Mechanistic Aspects of Mammary Implant Complications Ruyttcre. It is reasonable to interpret the many literature reports on both gel and saline mammary implant complications as supportive of the view that formation of hard fibrous capsules, which often produce pain and disfigurement, remains a major reason for most revisions. Implant rupture or deflation (of salines) is a second major problem. Based on most studies to date, the mechanism for implant rupture or gross leakage of gel is almost surely the progressive cyclic mechanical stress-induced creation and enlargement of tears, especially in weak-
6
ened silicone fluid swollen silicone elastomer shells. These tears (for both saline and gel implants) are most readily initiated at sites of folds and/or defects in the shells (ie, bubbles, particulate contamination, and abrupt changes in thickness) where stresses are concentrated (Figs 3, 4, 5). For saline implants, the lack of internal silicone gel lubrication of fold surfaces may actually serve to exacerbate this mechanism for abrasive mechanical damage and tearing. Diagnostic Noninvasive MRI. Most of our understanding of implant rupture has come from surgically removed explants. Although the meta-analysis of implant failure from numerous explant studies has provided the best retrospective data for time-dependent rupture, such analyses have left questions concerning the status of all remaining implants. One criticism of failure analyses based on explantation has been that women who present for explant surgery may represent an atypical or selected subpopulation of the total population of undiagnosed and asymptomatic implanted women. However, the noninvasive MRI investigation, reported by Brown and co-workers in 2000 (sponsored by the NIH and the FDA Office of Women’s Health), afforded good scientific evidence that current MRI techniques can be reliable. Furthermore, explant analyses correlate well with the MRI results.ls Available large cohort explant studies may, therefore, be quite useful for judging the probable status of implants in all implanted women. The study by Brown and co-workers encompassed an unreferred population of 344 women with 687 gel implants. It indicated a prevalence of rupture of 55% affecting 69% of the women. If implants rated as suspicious for rupture were included, another 7% is added for a prevalence of 62% affecting 77% of women. These authors concluded that a conservative estimate of the median implant age to rupture for gel implants was 10.8 years. Two other significant findings were: (a) evidence for a high prevalence of silicone migration beyond the fibrous capsule surrounding the implants (observed for 21% of women in the study), and (b) a greater tendency for submuscular implants to rupture compared with subglandular placement. Fibrous Capsule Formation The phenomenon of fibrous capsule formation and contraction results from the normal cascade of wound healing events (ie, GOLDBERG AND HABAL
tissue release of cytokines, fibrin deposition, mobilization and infiltration of macrophage and fibroblasts, fibrinolysis and deposition by fibroblasts of the capsular collagenous “scar tissue”). This is a normal postoperative response to tissue damage and the presence of a “foreign body,” the implant. Modification of implant surface topography, ionicity, and hydrophilicity may help alter the extent of fibroblast-associated collagen deposition. However, it is likely that the most promising approach to inhibiting formation of thick contractile capsules will be local delivery of biological agents such as anti-inflammatory and/or cytotoxic drugs, or TGF inhibitors through their incorporation into and controlled release from implant surface coatings.
Saline Implants Following the FDA gel implant moratorium in 1992, the FDA allowed saline implants to remain available for general clinical use. However, PMAs with appropriate 4- to S-year prospective clinical data were requested for review by the FDA in May 2000 for proof of safety. PMAs from two companies, Mentor and McGhan (Inamed), were approved. However, the clinical data presented suggested a relatively high prevalence of complications for saline implants. One prospective clinical study for almost 2000 SIs indicated the need for revisions for 27% of patients within 3 years as a result of complications such as pain, infection, rupture, or deflation. PMA data submitted to the FDA by one manufacturer (PMA #P940038)16 also showed a high complication rate for both aesthetic and surgical outcomes. These data included one S-year clinical study (1990) encompassing 468 augmentation and 25 reconstruction patients, and another study was restricted to augmentation (1995) for 901 patients with data available for only 3 to 4 years. The 1990 Aug/Recon Study had a total for “any complication” of 46% within 1 year and 68% at 5 years. Similarly, the larger 1995 Augmentation Study showed an “any complication” total of 48% within 1 year and 60% at 4 years. Examples of saline implant complications at 4 years from both the 1990 and 1995 prospective studies (from Table 2 of the PMA) were: Pain (15 to 17%), Capsular Contracture (9 to ll%), Wrinkling (11 to 24%)) Asymmetry (11 to 12%)) Malposition (6 to 8%), Palpability/Visibility (9 to 15%), Irritation/ Inflammation (2 to 3%), Leakage and Deflation (6 to 9%), and Loss of Nipple Sensation (10 to 11%). Another important observation was the rate of Implant Related Secondary Surgeries reported for the Augmentation Population (22-26% at 4 years-PMA Table 5) and the Reconstruction Population (40% at 4 years-PMA Table 6). The complications noted in these prospective SI studies, coupled with inherent aesthetic problems (wrinkling and poor match to tissue softness) have renewed considerable interest in qualifying a new generation of improved gel implants for general clinical use.
The Next Generation of Mammary Implants Future Needs and Opportunities for Saline and Gel lnzplants. To provide a perspective for future developments, the foregoing discussion has placed some emphasis on the deficiencies and safety considerations for both gel and saline breast implants. It is equally important to emphasize the fact that breast implants remain an essential cosmetic implant for satisfying the needs of a large population of women. A key point is the need to insure that there are incentives to improve the aesthetic quality and BREAST IMPLANTS
safety of these implants and that there are more clearly defined and reasonable expectations for their performance and life. According to American Society of Plastic and Reconstuctive Surgery estimates, saline devices are now being implanted at a rate of about 2OO,OOO/yr, with many used for replacement of a large number of gel implants removed each year.l5 Because gel implants may still be regarded as aesthetically superior, the high prevalence of aesthetic and surgical complications for SIs reported to the FDA may well stimulate the reintroduction of gel implants with improved properties. A major problem for future innovations is the reluctance of manufacturers to invest in risky and expensive new product development, especially given the history of product liability litigation in this field. However, with more advanced design engineering and materials development, better manufacturing control, and improved testing, it is possible that a new generation of gel implants may yet emerge as a safer and more aesthetically pleasing alternative to current saline and previous silicone gel devices. In particular, there is likely to be an opportunity for approval of silicone gel implants in the U.S., especially for implants with thicker and stronger silicone elastomer shells and more highly crosslinked silicone gels. Recent Non-Silicone
Gel Develo~rnents
Sqybean Oil and Aqueous Polvviilyll)-i-olidonc Gel Replacements. The use of a vegetable oils, ie, soybean oil, was touted during the past decade as an improved nonsilicone filling for silicone shells. Unfortunately, clinical experience in Europe and the UK has resulted in reports of numerous complications for the soybean oil implants. Concern by the UK/Medical Devices Agency (MDA) resulted in withdrawal of these prostheses from the market in March 1999.17 As many as 8000 implants may have been used during 1995 to 1999 in the UK and reported complications have included: (1) degradation of the soybean oil to rancid oxidation products with potentially toxic properties, and (2) diffusion, leakage, or “bleed” of the oil through the silicone shell, accompanied by emulsification of this oil to droplets that could induce inflammation in tissues. Because these problems might have been anticipated from the basic chemical and physical properties of such vegetable oils, future fluids and gels will obviously require more caution and more extensive animal testing before human clinical use. The fate of implants filled with aqueous polyvinylpyrrolidone (PVP) solutions is unclear at this time. Aqueous PVP has been used as a blood plasma expander, it is relatively biostable, and the polymer is cleared by the renal system at molecular weights below 40,000. Appropriate concerns include: (1) osmolarity differences between the implant fluid and the surrounding tissues, with consequent osmotic pressure “pumping” of water and some metabolites in and out of silicone shells; (2) the potential for infectious complications inside the implant in the aqueous PVP solution; and (3) the unknown consequences of shell rupture spilling large volumes of PVP solution into breast tissue. Answers to these questions will be needed. Next Generation:
Bionzaterinls CotIce@
Despite the large research and development costs and product liability issues, patient demand and a large lucrative market potential suggest that new ideas will continue to be evaluated. New biomaterials and device design ideas will be needed as well as more sophisticated manufacturing methods and quality as-
7
surance testing. Some representative ideas concerning new directions for such developments are noted here. Gels. In the past, silicone gels have not been highly crosslinked polymer gels. Instead, the results of a 1979 Battelle Institute study for the FDA (Report 233 to 77-038/Task 6) and research from our laboratory have shown that so-called silicone “gels” have actually been composed primarily of silicone fluid in a variety of compositions which have contained only 5 to 20% crosslinked silicone polymer swollen by 80 to 95% of silicone fluid. Improvements in silicone gels should therefore include: (1) inhibition of silicone fluid swelling and weakening of shells, and (2) prevention of the release of silicone fluid into tissues by diffusion through the shell. These objectives may be achieved by: (a) developing “soft” but fully crosslinked silicone gels (with low cross-link densities), or (b) replacement with stable nonsilicone gels. Examples of nonsilicone gels that would be less likely to diffuse through the shell and which would retain structural integrity even on shell failure might include biostable crosslinked hydrogels (ie, compositions derived from poly(N-vinyl-pyrollidone) [PVP] or poly(hydroxyethylmethacrylate) [PHEMA]), or foamed polymers (ie, foamed low modulus plastics derived from polypropylene, fluorocarbon elastomers, or even foamed silicone elastomers). Potential water diffusion problems due to local osmolarity problems would have to be carefully investigated for even hydrogels prepared in iso-osmolar saline. The long-term chemical and physical stability of such hydrogels and foams will also require appropriate testing, especially to show that such shell fillers are mechanically stable under cyclic mechanical stress and that no low molecular weight toxic degradation products can form. Local drug delivery by incorporation of antibiotics (to prevent infection) and anti-inflammatory drugs (to inhibit thick capsule formation) are additional possibilities for such implants. Slzells. There are few likely immediate alternatives to silicone elastomers. In the near term, new approaches for improving silicone strength properties (tensile, tear, and cyclic flex fatigue stress cracking) should be sought. Two approaches may be: (1) improvements in silica fillers (which now, at about 20% loading, affect a lo-fold increase in strength over unfilled silicone), and (2) fiber reinforcement of silicone elastomers perhaps based on stable low modulus polymer fibers (ie, polypropylene, woven Dacron, or fluorocarbon polymers) that could increase strength and reduce tear propagation. Crosslinked polyester polyurethanes have 3 to 4 times the strength of the best available silicones but are not likely to have adequate long-term biostability. Newer, more stable polyurethane elastomers may represent a class of biomaterials that will ultimately find application for much stronger implant shells. Higher strength, biostable, and less permeable shell elastomers may also be sought in the future from among new metallocene catalyzed polypropylene rubber and from fluorocarbon copolymer elastomers. Testing. The successful development of new implants will not only require advanced biopolymer technology but also more sophisticated testing for proof of mechanical and biological safety. Specifications and quality assurance testing will need to be based on better estimates of in vivo functional performance. Computer design engineering and modeling techniques used today for some medical device developments and for aircraft and automotive components will need to be used. These methods include finite element analysis to insure safe
8
design stresses, and cyclic stress fatigue testing of the final product (to establish safe stress levels versus number of cycles in use; ie, S/N plots). It will also be appropriate to require animal implant evaluations for proof of safety and performance before human clinical studies.
Conclusions Patient demand insures that breast implant surgery will remain a major factor in the practice of plastic surgery.‘l For the near future, the next generation of mammary implants are most likely to be based on stronger silicone shells with better barrier coatings. Shells will also need to be thicker (at least 0.020” and more uniform and extracted to remove residual silicone monomer and oligomers). Improved gels should be soft and pliable but fully crosslinked, and foamed gel compositions will deserve consideration. Longer term, with adequate economic incentives for manufacturers, a true next generation may evolve from research and development with newer nonsilicone shell and gel biomaterials. It will also be essential to continually improve the quality of informed consent with consideration of periodic MRI if deemed appropriate to insure long-term safety for specific patients. This monitoring of potential long-term complications is now commonplace for many implants including: (1) hip joints, which exhibit abrasive wear and often need replacement at 8 to 10 years, (2) small diameter vascular grafts, which often occlude because of thrombogenic events and intimal hyperplasia within 1 to 2 years, and (3) intraocular implants following cataract surgery, which often require laser capsulotomy within 1 year to correct posterior capsule opacification.
References 1. Deliberations of the 1991-1992 FDA Advisory Panel on Breast Implants 2. Kessler DA, Merkatz RB, Shapiro R: A call for higher standards for breast implants. J Am Med Assoc 270:2607-2608, 1993 3. Marotta JS, Widenhouse CW, Habal MB, Goldberg EP: Silicone qel implant failure and frequency of additional surgeries: Analysis of 35 studies reporting examination of more than 8000 explants. J Biomed Mater Res (Appl Biomater) 48:354-364, 1999 4. Peters W: The mechanical properties of breast prostheses. Annals Plastic Surg 6:179-l 81, 1981 5. van Rappard J, Sonneveld G, van Twisk R, Borghouts J: Pressure resistance of silicone breast implants as a function of implantation time. Ann Plastic Surg 21566569, 1988 6. Morey S, North J: Final report on low bleed mammary implants: Technical report to Dow Corning Wright from Battelle Research Inst, Columbus, Ohio 1986 7. Brandon H, Young V, Wolf C, Jerina K: Mechanical analysis of explanted breast implants. Fifth World Biomaterials Congress, Toronto, Canada, 1996 8. Lockwood M: Strength, strain, energy and toughness of silicone breast implant shells. MS thesis, U. Illinois, Champaign-Urbana, IL, 1995 9. Marotta J_,Amety D, Widenhouse C, Martin P, Goldberg EP: Degradation of physical properties of silicone gel breast implants and high rates of implant failures. Trans Twenty-Fourth Annual Meeting Sot Biomaterials, 1998, p 374 10. Phillips J, decamera D, Lockwood M, Grebner W: Strength of silicone breast implants. Plastic Reconstr Surg 97:1215-1225, 1996 11. Wolf C, Brandon H, Young V, Jerina K, Srivastava A: Physical and chemical analysis of explanted breast implants. Current Topics Microbiol lmmunol 210:25-38, 1996 12. Goldberg
EP, Widenhouse
C, Marotta J, Martin P: Failure of silicone
GOLDBERG
AND HABAL
gel breast implants: Analysis of literature data for 1652 explanted prostheses. Plastic Reconstr Surg 100:281-284, 1997 13. Manikian M: Long term physical property evaluation of Silastic mammary prosthesis. Dow Corning report, Midland, MI 1971
imaging in a population of women in Birmingham, AL. AJR: 175: 1057-1064, 2000 (b) Brown SL, Pennelo G, Berg WA, Soo MS,
15. Data reported in 2000 by Am Sot Plastic Surg and MedTech insight Nov./Dee. 2000, pp 211-214
Middleton MS: Silicone gel breast implant rupture, extracapsular silicone, and health status in a population of women. J Rheumatol 28:996-1003, 2001 19. Middleton MS, Mcnamara MP: Breast implant classification. RSNA Online, 1999 20. Hennekens CH, Lee IM, Cook NR, et al: Self-reported breast im-
16. McGhan Medical Corp., PMA #940038 to FDA, May, 2000 17. BBC Health News, March 8, 1999 18. (a) Brown SL, Middleton MS, Berg WA, Soo MS, Pennelio G: Prevalence of rupture of silicone gel breast implants revealed on MR
plants and connective A retrospective cohort 21. Habal MB: Key issues Issues Plast Cosmetic
14. Peters S: Physical properties versus time for Silastic-ll prosthesis. Dow Corning report, Hemlock, MI, 1981
BREAST IMPLANTS
and standard
tissue diseases in female health professionals: study. JAMA 27.5616-621, 1996 in the status of silicone breast implants. Key Surg 16:39-61, 1999
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here is an important need for safe and effective mammary prostheses for augmentation and reconstructive plastic surgery. However, a moratorium for general clinical use of silicone gel breast implants (SGBIS) was imposed by the Food and Drug Administration (FDA) in 1992 because of inadequate safety data. Data were not available at that time for large cohort prospective or retrospective studies concerning such potential problems as local complications, shell rupture, and the frequency of additional surgeries. As a consequence, to satisfy the desire by patients for cosmetic augmentation, there has been a dramatic growth in the use of FDA-accepted saline implants (SIs) during the past decade (to more than 200,000 per year). This has been concurrent with the widespread removal of gel implants. Although SIs have been approved by the FDA for two U.S. companies, the relatively high prevalence of SI complications and their aesthetic deficiencies (approaching a total of 60% within 5 years, based on FDA submission data) has continued to foster much more research concerning: (1) the reasons for breast implant problems; (2) the possible general reintroduction of improved gel implants; and (3) the development of new and significantly improved prostheses. The discussion presented here is, therefore, intended to focus attention on the most important gel and saline implant deficiencies and comment on some future biomaterials and device design opportunities which might afford a new generation of improved implants.
Background A variety of clinical problems were reported for silicone gel breast implants (SGBIS) during the 30 years of use before the 1992 FDA moratorium. An adequate body of scientific, physical, and chemical property data and large cohort prospective or retrospective clinical studies were lacking, thereby resulting in the action of the FDA to withdraw these cosmetic implants from general use in the U.S. lo The need for breast prostheses has consequently resulted in the use of saline implants and more research since 1992 concerning the behavior of SGBIs. One objective has been to provide a better scientific basis for risk-benefit assessments by plastic surgeons and patients for revisions and new augmentations. Research in this field has greatly benefited from the collaboration of biomaterials scientists and plastic surgeons. In light of historical problems and recent developments, this section considers the opportunities for new and improved implants.
From the Biomaterials Center, Department Materials Science & Engineering, University of Florida, Gainesville, FL, USA. Address reprint requests to Mutaz B. Habal, MD, Tampa Bay Craniofacial Center, 801 west M. L. King Blvd, Tampa, FL 33603-3301. Copyright 2003, Elsevier Science (USA). All rights reserved. 1071-0949/03/0901-0101$35.00/0 doi:lO.l053/otpr.2003.125470
Operative
Techniques
in Plastic and Reconstructive
Surgery,
Silicone Gel bnplants. SGBIs are unique prostheses in that a crosslinked silicone elastomer shell was designed to contain lightly crosslinked silicone gels. In fact, this “gel” was actually a composition that contained as much as 85% to 95% uncrosslinked silicone fluid comprised of low molecular weight and oligomeric polydimethylsiloxane. Basic principles of polymer science predict that such silicone “gel” fluids will: (1) diffuse readily into and through the elastomer shell with continuous release of silicone fluid into surrounding tissues (the so-called “bleed”), and (2) that the swelling of the shell by silicone fluid will significantly reduce the mechanical strength properties of the shell. In the first large cohort retrospective failure analysis for explanted SGBIs (for more than 8000 explants from 35 studies), reported in 1999, a significant statistical correlation was found between gel implant duration and elastomer shell failure (25% failure within 3.9 years and 71.6% at 18.9 years).3 In addition, the results indicated a high prevalence of reoperative procedures (33% within 6 years). The earliest reports of mechanical testing of SGBIs involved experimental compression of the entire prosthesis to determine the breaking strength or “breaking pressure.“+*5 These tests were primarily intended to model the compressive forces associated with “closed capsulotomy,” a technique that was commonly used to break up the fibrous scar tissue responsible for capsular contracture. There was sufficient concern about prosthesis rupture using this procedure that it was generally abandoned during the late 19SOs. In this regard, the early ex-vivo mechanical tests suggested that there was also considerable variation among various prostheses and even lot to lot variations from the same manufacturer. In general, low breaking strengths for explanted prostheses were measured when compared with new unimplanted controls.+J In more recent studies, comparisons were made between manufacturer’s data6 and the mechanical properties of explanted and unimplanted control shells.r-11 These studies showed that the mechanical strength properties of explanted SGBI shells are generally much poorer than either unimplanted controls or the data reported by manufacturers.6 Phillips and co-workers first concluded that there was a correlation between the strength of explanted shells and the implantation time, suggesting a decrease in silicone shell mechanical properties with time.10 The decrease in mechanical strength, because of swelling of the silicone elastomer shell with silicone oil, has been suggested as a significant cause of the high prevalence of rupture for SGBI implants.3~8J” As early as 1971, implant manufacturers had data showing that filling silicone implant shells with gel caused the implant shell to swell and drastically reduce shell mechanical strength properties.i3J3 This deterioration in mechanical strength clearly had the potential to greatly influence the ultimate performance of these devices. Despite early adverse experience with thin shells (as thin as 0.003”) during the 1980s some manufacturers once again produced gel implants with thinner
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Fig 1. An example of an implant after 20 years of implantation, showing intracapsular contents with total disruption of the external shell and moderate calcification.
shells and gels with very high uncrosslinked silicone oil content. Such changes were intended to provide a more natural aesthetic quality. However, the thin shells were weak and these so-called 2”d generation SGBIs have since been shown to exhibit an extraordinarily high rate of rupture. More engineering design work and silicone materials research on shells and gels was clearly necessary to better define the minimum strength requirements for prolonged safe performance of SGBIs (Fig 1). Studies from this laboratory and reports by many other research groups point to a general time-dependent reduction in tensile strength, tear strength, and elongation (ductility) for all types of explanted elastomer shells. This adverse change in properties has made mammary prostheses vulnerable to the forces exerted on them from cyclic stresses incurred during use. Deterioration in strength has clearly been a major factor in the relatively high rupture/failure rate that has been reported in recent years.3 The 1991 and 1992 FDA Breast Implant Advisory Panel reviews led to the FDA decision to place a moratorium on the general clinical use of SGBIs for augmentation but continued general approval for saline implants. The basis for this moratorium was the lack of adequate clinical safety data from the major manufacturers to support approval of the gel implant PMA submissions requested by the FDA during the late 198Os.l However, gel implant use was allowed for reconstructive surgery and for a limited number of augmentation procedures under strict protocols intended to provide safety data from prospective 5-year clinical studies. This gel implant history, coupled with the confusion concerning the potential for immunologic complications that might be attributed to silicone gels, had the following consequences: 1. Cessation of gel implant augmentation in 1992 from a previous rate of about 150,000&r. 2. Revision surgery for removal of gel implants estimated at more than 35,000 in 1994 and reaching about 5O,OOO/yr thereafter, with saline implant replacement in a majority of cases. 3. Rapid growth in the use of saline implants to a current level of 2OO,OOO/yr, although data for prospective clinical safety trials were not available until the time of the FDA review of saline PMAs from manufacturers in May 2000.15 4. FDA approval of saline implant PMAs for two U.S. manufacturers in 2000. However, clinical results reported by manufacturers for prospective studies of 4 to 5 years suggested a high prevalence of saline implant complications necessitat-
4
ing a high rate of additional surgeries within 5 years of primary implantati0n.l” 5. Development and offshore clinical use of implants designed with nonsilicone fillings such as aqueous polyvinylpyrrolidine (PVP) solutions and vegetable oils. These were touted as safer than silicone gel-filled implants, more radiolucent, and more aesthetically pleasing. Unfortunately, widespread reports of clinical problems in the UK for the vegetable oil implants, implicating oil leakage and oil degradation complications, forced a halt to clinical use and initiation of many revisions beginning in the UK in March 1999.17 In addition, a PMA application to the FDA for aqueous PVP-filled implants was not approved. During the past decade there has been a proliferation of papers concerning many key aspects of gel implant chemical, physical, and biological properties, as well as more reliable data for noninvasive diagnostic methods, to determine implant status. In particular, MRI has evolved to the point where diagnosis of gel leakage and shell rupture may be obtained with a relatively high degree of certainty (Fig 2) .18J9 Because “gels” were predominantly silicone fluid when first introduced in the 196Os, the gel implant was in fact a type of continuous silicone fluid release device. The physiologic consequence of continuous infusion of small amounts of silicone fluid throughout the life of the device into the implant recipient was essentially unknown and untested, and even the recent literature does little to clearly clarify this question. However, from pathological examination of tissues surrounding implants, there is compelling evidence that a local chronic inflammatory response may often occur. In view of the renewed interest in approving SGBIs, an understanding of the following questions will be essential for designing new and improved mammary prostheses: 1. The effects and variability of perJoi7ncuice because of the nunlerous and frequently changed implant designs? In this regard, there is an excellent comprehensive review of breast implant designs and historical development by Middleton and McNamara.19 Some specific examples of potential problems associated with the numerous designs include: (a) the consequences of frequent changes in shell thickness and the wide variations in shell thickness within even a single implant (in the range 0.003 to 0.020”), (b) performance of single versus double lumen structures, (c) the effect of the variety of shell surface textures, and (d) the stability and in vivo effectiveness of phenylsiloxane and perfluorosiloxane
Fig 2. Ruptured implant using a special coil magnetic nance scan.
reso-
GOLDBERG AND HABAL
Fig 3. (A) Patient was referred to us two years after implantation elsewhere with deformed breasts. (B) lntraoperative view of the collapsed implant; saline was the filler. (C) The removed implant was totally empty. (D) We filled the implant from the valve to demonstrate the leak; it was a small mechanical shell in the body away from the seam as predicted most of the time; the blue dye used was everywhere in the tissue.
silicone oil diffusion barrier coatings on interior shell surfaces and the variations in these coatings from the standpoint of adhesion to the shell, thickness, and mechanical properties. In general, one may conclude that more uniform and thicker silicone shells (in the 0.020 to 0.025” thickness range), with minimal defects, would be advantageous. 2. The effects of the myriad chmzges in silicone polymers, catalysts, and manu.jactw-ing procedures? Some key questions concern: (a) the composition of the “gels” (especially the large amount of uncrosslinked fluid), (b) the lot-to-lot and batch-to-batch variability of silicone shell and gel crosslinking and properties, and (c) the extent of routine testing of
the final assembled and sterilized product. In particular, soft gels with near 100% crosslinking would be desirable. behavior? This may remain a controversial 3. Irnnnlnological question for implants that release silicone fluids until larger and better epidemiological studies than those reported to date further clarify this issue.‘” of several well lznowlt adverse 4. The severity and j-equelcy events: Capsular Contractul-e, Pain, Disfigurement, Silicone Leakage (Bleed) and Migration, Chronic Irflmmnation, Infection, Iniplant Deterioration, Loss of Sllell Integrity (Rupture), and Revision Szu-gely? With regard to these and related gel implant safety issues, the November 2000 FDA website doc-
Fig 4. (A) Successful saline-filled implant in the registry at our Center 5 years after implantation ruptured after 1 year). (B) Mammogram of the implanted breast. BREAST IMPLANTS
(the original saline implant
5
Fig 5. (A) Successful implant that was a replacement for a ruptured silicone implant 5 years after reimplantation. The silicone implant was present for 12 years before failure. This suggests that all implants may need annual evaluation and scrutiny for a maintenance program and replacement when needed. (B) Mammogram of the same patient.
ument, “Breast Implant Risks,” discusses all of these potential risks plus those associated with calcium deposits, reduced nipple and breast sensation, tissue atrophy and implant extrusion, hematoma, and infection. However, the FDA statement, as well as most product inserts and descriptive product information, provide little or no quantitative clinical results on which to base better informed judgements of risks versus benefits.
The Importance of
ammary Implants
There is an obvious need for mammary implants as evidenced by the increasing willingness of patients to incur the expense and surgical risks required to alter appearance. Since 1992, breast implant procedures for cosmetic augmentation have once again become one of the fastest growth areas of plastic surgery using saline implants.15 In part because of product liability concerns, only two major breast implant manufacturers have emerged (InamedMcGhan and Mentor) to supply saline implants in the U.S., a market that is now about 200,000 implants per year. The incentive for companies in this field is the recent rate of growth of about 14% per year, with the prospect of maintaining a steady state business of $500 million per year selling saline implants at ca. $500 each and even more for gel implants (only generally available now offshore) at ca. $800 to $1000 each. From an overall economic standpoint, it should be noted that the total cost for one augmentation in the U.S. is now ca. $5000, encompassing surgeon fees (average $3100) plus other surgery-related expenses.
Mechanistic Aspects of Mammary Implant Complications Ruyttcre. It is reasonable to interpret the many literature reports on both gel and saline mammary implant complications as supportive of the view that formation of hard fibrous capsules, which often produce pain and disfigurement, remains a major reason for most revisions. Implant rupture or deflation (of salines) is a second major problem. Based on most studies to date, the mechanism for implant rupture or gross leakage of gel is almost surely the progressive cyclic mechanical stress-induced creation and enlargement of tears, especially in weak-
6
ened silicone fluid swollen silicone elastomer shells. These tears (for both saline and gel implants) are most readily initiated at sites of folds and/or defects in the shells (ie, bubbles, particulate contamination, and abrupt changes in thickness) where stresses are concentrated (Figs 3, 4, 5). For saline implants, the lack of internal silicone gel lubrication of fold surfaces may actually serve to exacerbate this mechanism for abrasive mechanical damage and tearing. Diagnostic Noninvasive MRI. Most of our understanding of implant rupture has come from surgically removed explants. Although the meta-analysis of implant failure from numerous explant studies has provided the best retrospective data for time-dependent rupture, such analyses have left questions concerning the status of all remaining implants. One criticism of failure analyses based on explantation has been that women who present for explant surgery may represent an atypical or selected subpopulation of the total population of undiagnosed and asymptomatic implanted women. However, the noninvasive MRI investigation, reported by Brown and co-workers in 2000 (sponsored by the NIH and the FDA Office of Women’s Health), afforded good scientific evidence that current MRI techniques can be reliable. Furthermore, explant analyses correlate well with the MRI results.ls Available large cohort explant studies may, therefore, be quite useful for judging the probable status of implants in all implanted women. The study by Brown and co-workers encompassed an unreferred population of 344 women with 687 gel implants. It indicated a prevalence of rupture of 55% affecting 69% of the women. If implants rated as suspicious for rupture were included, another 7% is added for a prevalence of 62% affecting 77% of women. These authors concluded that a conservative estimate of the median implant age to rupture for gel implants was 10.8 years. Two other significant findings were: (a) evidence for a high prevalence of silicone migration beyond the fibrous capsule surrounding the implants (observed for 21% of women in the study), and (b) a greater tendency for submuscular implants to rupture compared with subglandular placement. Fibrous Capsule Formation The phenomenon of fibrous capsule formation and contraction results from the normal cascade of wound healing events (ie, GOLDBERG AND HABAL
tissue release of cytokines, fibrin deposition, mobilization and infiltration of macrophage and fibroblasts, fibrinolysis and deposition by fibroblasts of the capsular collagenous “scar tissue”). This is a normal postoperative response to tissue damage and the presence of a “foreign body,” the implant. Modification of implant surface topography, ionicity, and hydrophilicity may help alter the extent of fibroblast-associated collagen deposition. However, it is likely that the most promising approach to inhibiting formation of thick contractile capsules will be local delivery of biological agents such as anti-inflammatory and/or cytotoxic drugs, or TGF inhibitors through their incorporation into and controlled release from implant surface coatings.
Saline Implants Following the FDA gel implant moratorium in 1992, the FDA allowed saline implants to remain available for general clinical use. However, PMAs with appropriate 4- to S-year prospective clinical data were requested for review by the FDA in May 2000 for proof of safety. PMAs from two companies, Mentor and McGhan (Inamed), were approved. However, the clinical data presented suggested a relatively high prevalence of complications for saline implants. One prospective clinical study for almost 2000 SIs indicated the need for revisions for 27% of patients within 3 years as a result of complications such as pain, infection, rupture, or deflation. PMA data submitted to the FDA by one manufacturer (PMA #P940038)16 also showed a high complication rate for both aesthetic and surgical outcomes. These data included one S-year clinical study (1990) encompassing 468 augmentation and 25 reconstruction patients, and another study was restricted to augmentation (1995) for 901 patients with data available for only 3 to 4 years. The 1990 Aug/Recon Study had a total for “any complication” of 46% within 1 year and 68% at 5 years. Similarly, the larger 1995 Augmentation Study showed an “any complication” total of 48% within 1 year and 60% at 4 years. Examples of saline implant complications at 4 years from both the 1990 and 1995 prospective studies (from Table 2 of the PMA) were: Pain (15 to 17%), Capsular Contracture (9 to ll%), Wrinkling (11 to 24%)) Asymmetry (11 to 12%)) Malposition (6 to 8%), Palpability/Visibility (9 to 15%), Irritation/ Inflammation (2 to 3%), Leakage and Deflation (6 to 9%), and Loss of Nipple Sensation (10 to 11%). Another important observation was the rate of Implant Related Secondary Surgeries reported for the Augmentation Population (22-26% at 4 years-PMA Table 5) and the Reconstruction Population (40% at 4 years-PMA Table 6). The complications noted in these prospective SI studies, coupled with inherent aesthetic problems (wrinkling and poor match to tissue softness) have renewed considerable interest in qualifying a new generation of improved gel implants for general clinical use.
The Next Generation of Mammary Implants Future Needs and Opportunities for Saline and Gel lnzplants. To provide a perspective for future developments, the foregoing discussion has placed some emphasis on the deficiencies and safety considerations for both gel and saline breast implants. It is equally important to emphasize the fact that breast implants remain an essential cosmetic implant for satisfying the needs of a large population of women. A key point is the need to insure that there are incentives to improve the aesthetic quality and BREAST IMPLANTS
safety of these implants and that there are more clearly defined and reasonable expectations for their performance and life. According to American Society of Plastic and Reconstuctive Surgery estimates, saline devices are now being implanted at a rate of about 2OO,OOO/yr, with many used for replacement of a large number of gel implants removed each year.l5 Because gel implants may still be regarded as aesthetically superior, the high prevalence of aesthetic and surgical complications for SIs reported to the FDA may well stimulate the reintroduction of gel implants with improved properties. A major problem for future innovations is the reluctance of manufacturers to invest in risky and expensive new product development, especially given the history of product liability litigation in this field. However, with more advanced design engineering and materials development, better manufacturing control, and improved testing, it is possible that a new generation of gel implants may yet emerge as a safer and more aesthetically pleasing alternative to current saline and previous silicone gel devices. In particular, there is likely to be an opportunity for approval of silicone gel implants in the U.S., especially for implants with thicker and stronger silicone elastomer shells and more highly crosslinked silicone gels. Recent Non-Silicone
Gel Develo~rnents
Sqybean Oil and Aqueous Polvviilyll)-i-olidonc Gel Replacements. The use of a vegetable oils, ie, soybean oil, was touted during the past decade as an improved nonsilicone filling for silicone shells. Unfortunately, clinical experience in Europe and the UK has resulted in reports of numerous complications for the soybean oil implants. Concern by the UK/Medical Devices Agency (MDA) resulted in withdrawal of these prostheses from the market in March 1999.17 As many as 8000 implants may have been used during 1995 to 1999 in the UK and reported complications have included: (1) degradation of the soybean oil to rancid oxidation products with potentially toxic properties, and (2) diffusion, leakage, or “bleed” of the oil through the silicone shell, accompanied by emulsification of this oil to droplets that could induce inflammation in tissues. Because these problems might have been anticipated from the basic chemical and physical properties of such vegetable oils, future fluids and gels will obviously require more caution and more extensive animal testing before human clinical use. The fate of implants filled with aqueous polyvinylpyrrolidone (PVP) solutions is unclear at this time. Aqueous PVP has been used as a blood plasma expander, it is relatively biostable, and the polymer is cleared by the renal system at molecular weights below 40,000. Appropriate concerns include: (1) osmolarity differences between the implant fluid and the surrounding tissues, with consequent osmotic pressure “pumping” of water and some metabolites in and out of silicone shells; (2) the potential for infectious complications inside the implant in the aqueous PVP solution; and (3) the unknown consequences of shell rupture spilling large volumes of PVP solution into breast tissue. Answers to these questions will be needed. Next Generation:
Bionzaterinls CotIce@
Despite the large research and development costs and product liability issues, patient demand and a large lucrative market potential suggest that new ideas will continue to be evaluated. New biomaterials and device design ideas will be needed as well as more sophisticated manufacturing methods and quality as-
7
surance testing. Some representative ideas concerning new directions for such developments are noted here. Gels. In the past, silicone gels have not been highly crosslinked polymer gels. Instead, the results of a 1979 Battelle Institute study for the FDA (Report 233 to 77-038/Task 6) and research from our laboratory have shown that so-called silicone “gels” have actually been composed primarily of silicone fluid in a variety of compositions which have contained only 5 to 20% crosslinked silicone polymer swollen by 80 to 95% of silicone fluid. Improvements in silicone gels should therefore include: (1) inhibition of silicone fluid swelling and weakening of shells, and (2) prevention of the release of silicone fluid into tissues by diffusion through the shell. These objectives may be achieved by: (a) developing “soft” but fully crosslinked silicone gels (with low cross-link densities), or (b) replacement with stable nonsilicone gels. Examples of nonsilicone gels that would be less likely to diffuse through the shell and which would retain structural integrity even on shell failure might include biostable crosslinked hydrogels (ie, compositions derived from poly(N-vinyl-pyrollidone) [PVP] or poly(hydroxyethylmethacrylate) [PHEMA]), or foamed polymers (ie, foamed low modulus plastics derived from polypropylene, fluorocarbon elastomers, or even foamed silicone elastomers). Potential water diffusion problems due to local osmolarity problems would have to be carefully investigated for even hydrogels prepared in iso-osmolar saline. The long-term chemical and physical stability of such hydrogels and foams will also require appropriate testing, especially to show that such shell fillers are mechanically stable under cyclic mechanical stress and that no low molecular weight toxic degradation products can form. Local drug delivery by incorporation of antibiotics (to prevent infection) and anti-inflammatory drugs (to inhibit thick capsule formation) are additional possibilities for such implants. Slzells. There are few likely immediate alternatives to silicone elastomers. In the near term, new approaches for improving silicone strength properties (tensile, tear, and cyclic flex fatigue stress cracking) should be sought. Two approaches may be: (1) improvements in silica fillers (which now, at about 20% loading, affect a lo-fold increase in strength over unfilled silicone), and (2) fiber reinforcement of silicone elastomers perhaps based on stable low modulus polymer fibers (ie, polypropylene, woven Dacron, or fluorocarbon polymers) that could increase strength and reduce tear propagation. Crosslinked polyester polyurethanes have 3 to 4 times the strength of the best available silicones but are not likely to have adequate long-term biostability. Newer, more stable polyurethane elastomers may represent a class of biomaterials that will ultimately find application for much stronger implant shells. Higher strength, biostable, and less permeable shell elastomers may also be sought in the future from among new metallocene catalyzed polypropylene rubber and from fluorocarbon copolymer elastomers. Testing. The successful development of new implants will not only require advanced biopolymer technology but also more sophisticated testing for proof of mechanical and biological safety. Specifications and quality assurance testing will need to be based on better estimates of in vivo functional performance. Computer design engineering and modeling techniques used today for some medical device developments and for aircraft and automotive components will need to be used. These methods include finite element analysis to insure safe
8
design stresses, and cyclic stress fatigue testing of the final product (to establish safe stress levels versus number of cycles in use; ie, S/N plots). It will also be appropriate to require animal implant evaluations for proof of safety and performance before human clinical studies.
Conclusions Patient demand insures that breast implant surgery will remain a major factor in the practice of plastic surgery.‘l For the near future, the next generation of mammary implants are most likely to be based on stronger silicone shells with better barrier coatings. Shells will also need to be thicker (at least 0.020” and more uniform and extracted to remove residual silicone monomer and oligomers). Improved gels should be soft and pliable but fully crosslinked, and foamed gel compositions will deserve consideration. Longer term, with adequate economic incentives for manufacturers, a true next generation may evolve from research and development with newer nonsilicone shell and gel biomaterials. It will also be essential to continually improve the quality of informed consent with consideration of periodic MRI if deemed appropriate to insure long-term safety for specific patients. This monitoring of potential long-term complications is now commonplace for many implants including: (1) hip joints, which exhibit abrasive wear and often need replacement at 8 to 10 years, (2) small diameter vascular grafts, which often occlude because of thrombogenic events and intimal hyperplasia within 1 to 2 years, and (3) intraocular implants following cataract surgery, which often require laser capsulotomy within 1 year to correct posterior capsule opacification.
References 1. Deliberations of the 1991-1992 FDA Advisory Panel on Breast Implants 2. Kessler DA, Merkatz RB, Shapiro R: A call for higher standards for breast implants. J Am Med Assoc 270:2607-2608, 1993 3. Marotta JS, Widenhouse CW, Habal MB, Goldberg EP: Silicone qel implant failure and frequency of additional surgeries: Analysis of 35 studies reporting examination of more than 8000 explants. J Biomed Mater Res (Appl Biomater) 48:354-364, 1999 4. Peters W: The mechanical properties of breast prostheses. Annals Plastic Surg 6:179-l 81, 1981 5. van Rappard J, Sonneveld G, van Twisk R, Borghouts J: Pressure resistance of silicone breast implants as a function of implantation time. Ann Plastic Surg 21566569, 1988 6. Morey S, North J: Final report on low bleed mammary implants: Technical report to Dow Corning Wright from Battelle Research Inst, Columbus, Ohio 1986 7. Brandon H, Young V, Wolf C, Jerina K: Mechanical analysis of explanted breast implants. Fifth World Biomaterials Congress, Toronto, Canada, 1996 8. Lockwood M: Strength, strain, energy and toughness of silicone breast implant shells. MS thesis, U. Illinois, Champaign-Urbana, IL, 1995 9. Marotta J_,Amety D, Widenhouse C, Martin P, Goldberg EP: Degradation of physical properties of silicone gel breast implants and high rates of implant failures. Trans Twenty-Fourth Annual Meeting Sot Biomaterials, 1998, p 374 10. Phillips J, decamera D, Lockwood M, Grebner W: Strength of silicone breast implants. Plastic Reconstr Surg 97:1215-1225, 1996 11. Wolf C, Brandon H, Young V, Jerina K, Srivastava A: Physical and chemical analysis of explanted breast implants. Current Topics Microbiol lmmunol 210:25-38, 1996 12. Goldberg
EP, Widenhouse
C, Marotta J, Martin P: Failure of silicone
GOLDBERG
AND HABAL
gel breast implants: Analysis of literature data for 1652 explanted prostheses. Plastic Reconstr Surg 100:281-284, 1997 13. Manikian M: Long term physical property evaluation of Silastic mammary prosthesis. Dow Corning report, Midland, MI 1971
imaging in a population of women in Birmingham, AL. AJR: 175: 1057-1064, 2000 (b) Brown SL, Pennelo G, Berg WA, Soo MS,
15. Data reported in 2000 by Am Sot Plastic Surg and MedTech insight Nov./Dee. 2000, pp 211-214
Middleton MS: Silicone gel breast implant rupture, extracapsular silicone, and health status in a population of women. J Rheumatol 28:996-1003, 2001 19. Middleton MS, Mcnamara MP: Breast implant classification. RSNA Online, 1999 20. Hennekens CH, Lee IM, Cook NR, et al: Self-reported breast im-
16. McGhan Medical Corp., PMA #940038 to FDA, May, 2000 17. BBC Health News, March 8, 1999 18. (a) Brown SL, Middleton MS, Berg WA, Soo MS, Pennelio G: Prevalence of rupture of silicone gel breast implants revealed on MR
plants and connective A retrospective cohort 21. Habal MB: Key issues Issues Plast Cosmetic
14. Peters S: Physical properties versus time for Silastic-ll prosthesis. Dow Corning report, Hemlock, MI, 1981
BREAST IMPLANTS
and standard
tissue diseases in female health professionals: study. JAMA 27.5616-621, 1996 in the status of silicone breast implants. Key Surg 16:39-61, 1999
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