Inflammatory Responses to Biomaterials

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ments of implanted biomaterials, may cause implant failure. In the case ... long-term biomedical implants, including breast prostheses, joint replacements ...
BASIC SCIENCE Review Article

Inflammatory Responses to Biomaterials LIPING TANG, P H D , AND JOHN W. EATON, P H D

of silicone-filled mammary prostheses, the extravasation of silicone gel has been held responsible for a number of complications, including silicone granuloma, synovitis, connective-tissue disease, and lymphadenopathy. In some instances, material-mediated inflammatory responses may even cause degradation of the material itself (via oxidative products released by implant-associated inflammatory cells). Overall, there is insufficient knowledge of the determinants and mechanisms of host: implant responses. A clear understanding of tissue:biomaterial interactions will be required both to explain the pathogenesis of many implantmediated complications and to aid in the development of more biocompatible materials for implantable devices. (Key words: Biomaterials; Fibrinogen; Inflammation) Am J Clin Pathol 1995;103:466-471.

Immediately after implantation, hydrophobic polymeric materials, such as polyetherurethanes, polyethylene, polydimethylsiloxane (Silastic, Dow Corning, Midland, MI) and Dacron (Bard, Billerica, MA) acquire a layer of host proteins.4,5 Plasma or interstitial fluid proteins rapidly collide with the material surface, bind and appear to "melt" into the surface. This melting behavior is probably a result of progressive denaturation of the protein as it increasingly contacts the hydrophobic surface of the implant. After a few hours, proteins adsorbed to most biomaterial surfaces cannot be removed even with powerful detergents.6'7 Therefore, the implant is spontaneously coated with a chaotic layer of denatured and partially denatured proteins. Because proteins adsorb so rapidly to the mateEARLY HOST:IMPLANT INTERACTIONS A N D rial surface, host inflammatory cells and fibroblastic cells probACUTE INFLAMMATORY RESPONSES ably never make contact with the material surface per se.8"10 This protein layer influences, or even dictates, further somatic On implantation, biomaterials, like any foreign body, trigger responses to the implant, and is an important determinant of acute inflammatory responses reflected by an accumulation of the biocompatibility of the implant. 1 3 phagocytic cells. " However, unlike foreign bodies that arrive Among proteins that most readily adsorb to polymeric imin the body by misadventure (such as drive-by shootings), bioplants, albumin, immunoglobulin G, and fibrinogen usually material implants are relatively inert, unreactive, and nonpredominate."' 2 Adsorbed albumin is unlikely to mediate toxic. Therefore, it is difficult to understand how such implants subsequent inflammatory responses because albumin-coated are detected by the body and how this detection might eventuimplants tend not to attract inflammatory cells (ie, the surfaces ate in an inflammatory response. In considering the mechaare reported to be "passivated"). 51314 Given this, one might nisms involved in such responses, an appropriate place to start suspect that spontaneous binding of immunoglobulin G or suris in the very early interactions between material surfaces and face-mediated complement activation would be likely pro-insurrounding host proteins. flammatory mechanisms. After all, immobilized IgG and components of activated complement are powerful mediators of phagocyte activation and inflammatory responses.15"21 FurFrom the Division ofExperimental Pathology, Department ofPathol- thermore, perhaps the best known example of biomaterial-meogy and Laboratory Medicine, Albany Medical College, Albany, New diated phagocyte activation is the hemodialysis-induced tranYork. sient neutropenia that may arise secondary to complement activation by the dialysis membrane. 22 However, the acute inManuscript received January 31, 1995; accepted February 3, 1995. flammatory response to implanted materials is normal in both Address reprint requests to Dr. Eaton: Division of Experimental Paseverely hypogammaglobulinemic mice (with severe combined thology, A-81, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208. immunodeficiency) and in complement-depleted mice (treated

Implanted medical devices are of increasing importance in the practice of medicine. Excluding dental implants and contact lenses, more than 3 million people in the United States have long-term biomedical implants, including breast prostheses, joint replacements, vascular grafts, pacemakers, and catheters. Unfortunately, despite the inert and non-toxic nature of most biomaterials, adverse reactions such as device-mediated inflammation, fibrosis, coagulation, and infection are frequent and sometimes life-threatening. This brief review is an attempt to summarize the current knowledge of the causes and consequences of inflammatory reactions to implanted biomaterials.

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Implanted biomedical devices are of increasing importance in modern medical care. However, surprisingly little is known of the factors that determine biocompatibility of the materials used in these devices. These materials, although generally inert and non-toxic, can mediate a variety of adverse reactions, including inflammation, fibrosis, coagulation, and infection. This brief review focuses on the inflammatory responses (including fibrosis) that commonly occur around implanted biomaterials. Host proteins that spontaneously associate with implant surfaces are important determinants of the acute inflammatory response. In this regard, adsorbed fibrinogen appears particularly pro-inflammatory. Chronic inflammatory processes, in many cases in response to fragments of implanted biomaterials, may cause implant failure. In the case

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Inflammatory Responses to Biomaterials

CHRONIC INFLAMMATORY RESPONSES Chronic inflammatory responses, accompanied by macrophage and/or foreign body giant cell accumulation, have been observed around many types of biomaterial implants and have been associated with various adverse complications affecting both the host and the implant itself. At least part of the chronic inflammation may arise from interactions between the proteincoated surfaces of the biomaterial and host tissues and phagocytes, such as macrophages and foreign body giant cells. In addition, as exemplified by the special case of hip prostheses, inflammatory responses to fragments of implanted material are also of pathologic significance. Inflammatory

Reactions

to Total Hip

Replacements

Artificial hips, constructed of metallic and polymeric materials, have been implanted in millions of patients with endTABLE 1. HOST AND SURFACE CONDITIONS AFFECTING MONOCYTE/MACROPHAGE AND NEUTROPHIL ACCUMULATION ON EXPERIMENTAL INTRAPERITONEAL IMPLANTS IN MICE*

Conditions

Phagocyte Accumulation

Normal host Uncoated

Albumin coated Plasma coated Serum coated Serum +fibrinogencoated Hypocomplementemic host Uncoated Hypogammaglobulinemia host Afibrinogenemic host Uncoated Fibrinogen coated * Data from references 9 and 10.

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FIG. I. Cross-section of polyester terephthalate sample implanted intraperitoneally in a Swiss Webster mouse for 18 hours. The implant surface (Bottom) has artifactually dissected away from the cell layer. Note thefibroblastoidcell on the right directly adjacent to a polymorphonuclear neutrophil (Left), reflecting the potential for both inflammatory and fibrotic reactions to such implants. The variables which govern the proportionate recruitment offibroblasticvs. inflammatory cells to such implants are not yet known. Electron micrograph courtesy of Dr. M. Ma.

stage hip and knee degeneration over the past 30 years.24 Perhaps the major drawback of this procedure is that the rate of implant failure and reoperation after 10 years is between 10% and 30%. Unfortunately, such revision surgery often turns out to be difficult and yields poorer results than the primary arthroplasty. 25 Aseptic loosening is the predominant cause of total hip implant failure.26"28 Although purely mechanical causes for this loosening have been suggested, it appears that osteolytic changes are more often responsible. 2930 These implant-associated osteolytic changes probably involve inflammatory reactions.f The weight of evidence suggests that inflammation triggered by very small implant-derived material fragments, especially microscopic pieces of the ultrahigh density polyethylene (HDP), is a most important factor promoting osteolytic bone loss (especially of the proximal portion of the femur in total hip replacements).31"34 These fragments are not only numerous, but evidently ineluctable. One estimate is that the average wear rate for HDP of 0.1 mm per year generates 20 million particles per day, 7 billion particles per year. The HDP fragments are thought to arise from so-called third-body wear involving fragments of polymethylmethacrylate (PMMA) cement (used to fix the device),35 metal,36 or hydroxyapatite particles (HA). 37,38 At the femorakacetabular interface these particles foster abra-

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t There are important, non-inflammatory causes of active bone resorption, including the often asymmetric distribution of mechanical stress on the long bone. In this case, resorption is more likely to occur in remaining bone which now lacks the persistent gravitational and exertional pressures which ordinarily prevent osteoclastic activity. More direct, traumatic damage to the implant-associated bone can also arise from poorfixationof the implant.

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with cobra venom factor).9 Thus, these experimental results suggest that neither surface-bound IgG nor complement activation is required to initiate acute inflammatory responses to implants. Surprisingly, the host protein of greatest importance in acute inflammatory responses to implanted polymers appears to be fibrin(ogen). Materials pre-coated with fibrinogen or plasma (but not albumin or serum) elicit large numbers of phagocytic cells when implanted intraperitoneally or subcutaneously. Perhaps most convincingly, mice pre-treated with ancrod (a snake venom thrombin analog that will deplete circulating fibrinogen) fail to mount an inflammatory response to implanted material unless the material is pre-coated with either plasma or purified fibrinogen (Table 1).'° Fibrinogen readily adsorbs to most biomaterials, and probably denatures, which possibly exposes previously hidden epitopes. The interaction of these presently unknown epitopes with inflammatory cells (perhaps initially mast cells23) leads to the eventual accumulation of large numbers of both neutrophils and monocyte/macrophages on implant surfaces. These phagocytes, perhaps with the collaboration of a subset of mobile fibroblast-like cells (Fig. 1), may initiate the long-term inflammatory and fibrotic responses seen around chronic implants.

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Inflammation Associated With Silicone Materials Polymers made of polydimethylsiloxane have been used in many different forms, such as oils, gels, and solid silicone elastomer (Silastic).5253 Although these silicones themselves are quite inert and unreactive, they have been at least indirectly implicated in a number of adverse reactions when implanted. Silicone Gels and Liquids Silicone gels have been widely used forfillingmammary implants and Kaufman prostheses (for the treatment of urinary incontinence after prostatectomy). In the case of breast prostheses containing silicone gel, the gel has been found to leak through the Silastic envelope or be released on traumatic rupture of breast implants.52"58 The released gel may then deposit within the fibrotic capsule that typically forms around the breast implant, where it may incite the formation of foreign body giant cells.56,5759"63 The spread of gel particles to adjacent lymph nodes has also been found,55,64 and spread to more distant sites, such as the antecubital fossa, upper arm, chest, shoulder, and as far as the groin.65"69 Despite this metastatic spread of silica gels, there is presently no clear indication as to whether the gel is important in triggering important inflammatory responses. There are reports associating gel particles with lymphadenopathy and connective tissue diseases,55,64 but a recent study on the latter yielded negative results.70 Silicone liquid is commonly used as an antifoam agent in cardiopulmonary bypass surgery.52,53 Hematogenous dissemination of this silicone oil has been seen in patients undergoing

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cardiopulmonary bypass into almost all organs of the body.53 To date, little is known of the possible long-term consequences. Silicone Elastomer (Silastic) This material has been used as the casing for mammary implants, for joint (usually,finger)prostheses and for roller pump tubing. Silicone fragments released from pump tubing have been found in the blood and eventually accumulate in the liver of hemodialysis patients.7'"77 No serious consequences of this accumulation have yet been found. However, the silicone elastomer used in joint prostheses also generates small particles which spread to surrounding tissues. These have been implicated in a silicone synovitis in adjacent synovium.78"80 Further spread of these particles to the lymphatics has been claimed to be associated with lymphadenopathy, fever, and even lymphoma.59,81,82 Silicone gel and material fragments have also been purported to mediate seronegative and seropositive synovitis.83,84 Although immunologic reactions have been invoked to explain some of these effects of silicones,52 the mechanisms underlying silicone-mediated inflammatory responses are still not well defined. Indeed, in many cases (particularly those involving litigation), there is a lack of solid information supporting cause-and-effect relationships. Effects of Inflammatory Processes on Biomaterials During chronic inflammatory responses to implants, products generated by adherent inflammatory cells may damage the implant and/or react with the biomaterial to generate toxic catabolites. For example, some types of polyetherurethane used as insulation for cardiac pacemaker leads have been found to develop surface defects after implantation. This process, termed "environmental stress cracking," appears to require the presence of adherent and viable inflammatory cells.85 The explanation may be that phagocyte-derived oxidants (especially hypochlorous acid and derivatives of nitric oxide) react with polyetherurethane and cause the oxidative degradation of the polymer.86 Inflammatory responses may also play an important role in the degradation of polyurethane foams that have been coated on some type of Silastic breast implants to minimize capsule contraction.87 Inflammatory reactions have been observed surrounding these foam coatings,87,88 and are associated with degradation of the foam after only 1 to 3 months when implanted in animals.87 Although factors such as mechanical stress, spontaneous hydrolysis, and enzymatic attack have been suggested to contribute to foam destruction,86 possible phagocyte-mediated oxidative attack has not yet been investigated. Furthermore, some studies indicate that the polyurethane foam may break down into reactive monomers (2,4and 2,6-toluenediisocyanate), which can be converted into their corresponding diamines in vitro and in vivo.90'9* One of these, 2,4-toluenediamine, has been shown to be a mutagen and to produce liver cancer in rats.92 These observations have prompted the removal of polyurethane-coated breast implants from the market. INFLAMMATION vs FIBROSIS Fibrous capsule formation around biomaterial implants is considered a "normal" response. However, this foreign body response can be problematic when the capsule starts to contract around the implant. Capsule contracture is the most common

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sion between the (femoral) metal and (acetabular) HDP surfaces.37-39 The HDP particles generated by this abrasion then migrate to areas where the implant and host bony tissues intersect (eg, around the prosthetic acetabular cup and the neck of the remaining femur). Long-term inflammatory reactions to these particles are evidently involved in osteolytic bone loss.40 Around prosthetic acetabula, a "transition zone" comprised of membranous material between cement and bone is characterized by an advancing front of bone resorption. This zone contains macrophages and small HDP particles (often within macrophages), and exhibits active bone resorption.4'-43 In fact, the fibrous tissues that form at implant-bone interfaces show obvious foreign body granulomatous tissue reactions, with abundant foamy histiocytes and numerous giant cells containing phagocytosed particulates from implant materials.44 In general, the larger wear particles prompt afibrousor giant cell reaction, while the smaller particles incite a macrophage phagocytosis reaction. The possible chain of events leading to periprosthetic osteolysis triggered by wear particles is suggested by some recent observations. First, conditioned medium from the tissue surrounding failed total hips initiates resorption of radiolabeled mouse calvarium in v/7ro.44,45 Second, high levels of interleukin 1, prostaglandin E2 and collagenase, which can cause bone resorption, may be generated and released by the surrounding fibrotic tissue.46"49 Finally, wear particles can stimulate macrophages to generate many proteolytic enzymes and cytokines, such as PGE2, collagenase, interleukin 1, interleukin 6, and tumor necrosis factor,50 some of which may stimulate osteoclasts in adjacent bone.29,51

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SUMMARY The field of biomedical engineering has produced some astounding successes and a number of cataclysmic failures involving medical implants. Many of the failures derive from our lack of knowledge of the basic principles of biocompatibility. As should be evident from the foregoing, we (meaning at least the authors of this review) are woefully ignorant of the processes involved in inflammatory responses to tissue-contact biomaterials. To the degree that implantable biomaterials have proved successful in many applications, luck may have played a large part. However, in the future, we need a fuller understanding of the ways in which the body responds to the insertion of biomedical implants, most of which can be viewed as large, expensive, and sometimes dangerous foreign bodies. REFERENCES 1. Marchant RE, Miller KM, Anderson JM. In vivo biocompatibility studies: V. In vivo leukocyte interactions with biomer. J Biomed Mater Res 1984:18:1169-1190. 2. Marchant RE, Anderson JM, Dilingham EO. In vivo biocompatibility studies: VII. Inflammatory responses to polyethylene and to a cytotoxic polyvinylchloride. J Biomed Mater Res 1986;20:37-50. 3. Spilizewski KL, Marchant RE, Hamlin CR. The effect of hydrocortisone acetate loaded poly(DL-lactide) films on the inflammatory responses. Journal of Controlled Release 1985;2: 197-203. 4. Baier RE, Dutton RC. Initial events in interactions of blood with a foreign surface. J Biomed Mater Res 1969; 3:191 -206. 5. Sevastianov VI. Role of protein adsorption in blood biocompatibility of polymers. CRC Critical Reviews of Biocompatibilitv 1988;4:109-154. 6. Chinn JA, Posso SE, Horbett TA, Ratner BD. Postadsorption transition in fibrinogen adsorbed to polyurethanes: Changes in antibody binding and sodium dodecyl sulfate elutability. J Biomed Mater Res 1992; 16:757-778. 7. Soderquist ME, Walton AG. Structural changes in proteins adsorbed on polymer surfaces. J Colloid Interface Sci 1980;75: 386-397. 8. Pitt WG, Park K, Cooper SL. Sequential protein adsorption and thrombus deposition on polymeric biomaterials. Journal of Colloid and Interface Science 1986; 111:343-362.

9. Tang L, Eaton JW. Fibrin(ogen) mediates acute inflammatory responses to biomaterials. J Exp Med 1993; 178:2147-2156. 10. Tang L, Lucas AH, Eaton JW. Inflammatory responses to implanted biomaterials: Role of surface-adsorbed immunoglobulin G. J Lab Clin Med 1993; 122:292-300. 11. Pankowsky DA, Ziats NP, Topham NS, Ratnoff OD. Anderson JM. Morphologic characteristics of adsorbed human plasma proteins on vascular grafts and biomaterials. J Vase Surg 1990;11:599-606. 12. Andrade JD, Hlady VL. Plasma protein adsorption: The big twelve. Ann NY Acad Sci 1987;516:158-172. 13. Kottke-Marchant K, Anderson JM, Umemura Y, Marchant RE. Effect of albumin coating on the in vitro blood compatibility of Dacron arterial prostheses. Biomaterials 1989; 10:147-155. 14. Guidon R, Snyder R, Martin L, et al. Albumin coating of a knitted polyester arterial prosthesis: An alternative to preclotting. Ann ThoracSurg 1984;37:457-465. 15. Chuang HYK, Mohammad SF, Mason RG. Prostacyclin (PG12) inhibits the enhancement of granulocyte adhesion to cuprophane induced by immunoglobulin G. Thromb Res 1980:19: 1-9. 16. Henson PM, Oades ZG. Stimulation of human neutrophils by soluble and insoluble immunoglobulin aggregates: Secretion of granule constituents and increased oxidation of glucose. J Clin Invest 1975;56:1053-1061. 17. Cheung AK, Parker CJ, Wilcox L, Janatova J. Activation of the alternative pathway of complement by cellulosic hemodialysis membranes. Kidney Int 1989;36:257-265. 18. HerzlingerGA,CummingRD. Role of complement activation in cell adhesion to polymer blood contact surfaces. Transactions of the American Society of Artificial Internal Organs 1980; 26: 165-171. 19. Shepard AD, Gelfand JA, Gallow AD. O'Donnell TF. Complement activation by synthetic vascular prostheses. J Vase Surg 1984;1:829-838. 20. Kottke-Marchant K. Anderson JM, Miller KM, Marchant RE, Lazarus H. Vascular graft-associated complement activation and leukocyte adhesion in an artificial circulation. J Biomed Mater Res 1987;21:379-397. 21. Chenoweth DE. Complement activation during hemodialysis: Clinical observations, proposed mechanisms, and theoretical implications. Artif Organs 1984:8:281-287. 22. Craddock PR, Fehr J, Dalmasso AP, Brigham KL, Jacob HS. Hemodialysis leukopenia: Pulmonary vascular leukostasis resulting from complement activation by dialyzer cellophane membrane. J Clin Invest 1977;59:879-888. 23. Tang L. Hough L, Eaton JW. Recruitment of phagocytes to implanted biomaterials is histamine-dependent. (Abstr). 21 st Annual Meeting of the Society for Biomaterials, March 18-22. 1995, San Francisco, California (in press). 24. Jasty M. Clinical reviews: Particulate debris and failure of total hip replacements. Journal of Applied Biomaterials 1993;4: 273-276. 25. Jasty M, Harris WH. Salvage total hip reconstruction in patients with major acetabular deficiency using structural femoral head allografts. J Bone Joint Surg Br 1990;72:63-67. 26. Stauffer RN. Ten-year follow-up study of total hip replacement. J Bone Joint Surg Am 1982;64:983-990. 27. Sutherland CJ, Wilde AH, Borden LS, Marks KE. A ten-year follow-up of one hundred consecutive Muller curved stem total hip arthroplasties. J Bone Joint Surg Am 1982;64:970-982. 28. Willert HG. Reaction of the articular capsule to wear products of artificial joint prostheses. J Biomed Mater Res 1977; 11:157164. 29. Mulroy RD, Harris WH. The effect of improved cementing techniques on component loosening in total hip replacement. J Bone Joint Surg Br 1990;72:757-760. 30. Schmalzried TP. Kwong LM, Jasty M, et al. The mechanism of loosening of cemented acetabular components in Total Hip Arthroplasty. Clin Ortho 1991; 274:60-78.

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complication of augmentation mammoplasty, occurring in approximately 40% of cases.93 The pathogenesis of capsule contracture is not yet understood. Although reactions to extravasated silicone gel have been implicated in this contracture,94,95 the contracture may involve inflammatory responses mediated by the implant surface. Indeed, polyurethane foam-coated implants (as previously discussed) have been found to minimize capsule contracture as compared with smooth wall (usually Silastic) implants.96"98 It is thought that ingrowth offibroustissue into the interstices of the polyurethane prevents contracture of thefibrouscapsule by dissipating long-range vectorial forces.99 It is possible that the polyurethane foam may retard contraction by heightening inflammatory responses. Products of chronic inflammation, including prostaglandin E2, have been shown to inhibit fibroblast contraction of collagen lattices in vitro.100 Alternatively, the better integration of the implant into host tissues may minimize contracture. For example, it is widely appreciated that many types of large implants that are poorly anchored tend to promote inflammatory and fibrotic reactions.

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BASIC SCIENCE Review Article 52. Kossovsky N, Freiman CJ. Silicon breast implant pathology: Clinical data and immunologic consequences. Arch Path Lab Med 1994; 118:686-693. 53. Travis WD, Balogh K, Abraham JL. Silicone granulomas: Report of three cases and a review of the literature. Hum Pathol 1985;16:19-27. 54. Winding O, Christensen L, Thomsen JL, et al. Si in human breast tissue surrounding silicone gel prostheses. Scand J Plast Surg 1988;22:127-130. 55. Silver RM, Sahn EE, Aleen JA, et al. Demonstration of silicon in sites of connective-tissue disease in patients with silicone-gel breast implants. Arch Dermatol 1993; 129:63-68. 56. Barker DE, Retsky MI, Schultz S. "Bleeding" of silicone from bag-gel breast implants and its clinical relation tofibrouscapsule reaction. Plast Reconstr Surg 1978;61:836-841. 57. Brody GS. Fact and fiction about breast implant "bleed." Plast Reconstr Surg 1977;60:615-616. 58. Eisenberg HV, Bartels RJ. Rupture of a silicone bag-gel breast implant by closed compression capsulotomy. Plast Reconstr Surg 1977;59:849-850. 59. Vistnes LM, Bentley JW, Fogarty DC. Experimental study of tissue response to ruptured gel-filled mammary prostheses. Plast Reconstr Surg 1977;59:31-34. 60. Wickham MG, Rudolph R, Abraham JL. Silicone identification in prostheses-associated fibrous capsules. Science 1978; 199: 437-439. 61. Rudolph R, Abraham JL. Tissue effects of new silicone mammary-type implants in rabbits. Ann Plast Surg 1980;4:14-20. 62. Montandon D. Myofibroblasts and free silicon around breast implants. Plast Reconstr Surg 1979; 63:719-720. 63. Baker JL, LeVier RR, Spielvogel DE. Positive identification of silicone in human mammary capsular tissue. Plast Reconstr Surg 1982;69:56-60. 64. Varga J, Schumacher R, Jimenez SA. Systemic sclerosis after augmentation mammoplasty with silicon implants. Ann Intern Med 1989; 111:377-383. 65. Jennings DA, Marykwas MJ, DeFranzo AJ, Argenta LC. Analysis of silicone in human breast and capsular tissue surrounding prostheses and expanders. Ann Plast Surg 1991;27:553-558. 66. Huang TT, BlackwellSJ, LewisSR. Migration of silicone gel after the "squeeze technique" to rupture a contracted breast capsule. Plast Reconstr Surg 1978;61:277-280. 67. Mason J, Apisarnthanarax P. Migratory silicone granuloma. Arch Dermatol 1981; 117:366-367. 68. Edmond JA, Versaci AD. Late complication of closed compression capsulotomy of the breast. Plast Reconstr Surg 1980;66: 478-479. 69. Capozzi A, Du Bou R, Pennisi VR. Distant migration of silicone gel from a ruptured breast implant. Plast Reconstr Surg 1978;62:302-303. 70. Gabriel SE, O'Fallon WM, Kurland LT, et al. Risk of connective tissue diseases and other disorders after breast implantation. N Engl J Med 1994;330:1697-1702. 71. Leong AS, Disney AP, Gove DW. Refractile particles in liver of hemodialysis patients. Lancet 1981; 1:889-890. 72. Leong AS, Disney AP, Gove DW. Silicone particles and hemodialysis. Lance; 1981; 2:210. 73. Leong AS, Disney AP, Gove DW. Spallation and migration of silicone from blood-pump tubing in patients on hemodialysis. N Engl J Med 1982; 306:135-140. 74. Bommer J, Ritz E, Walsherr R, Gastner M. Silicone cell inclusions causing multiorgan foreign body reaction in dialysed patients. Lancet 1981; 1:1314. 75. Bommer J, Ritz E, Walsherr R. Silicone-induced splenomegaly: Treatment of pancytopenia by splenectomy in a patient on hemodialysis. NEngl J Med 1981;305:1077-1079. 76. Parfrey PS, O'Driscoll JB, Paradinas FJ. Refractile material in the liver of hemodialysis patients. Lancet 1981; 1:1101 -1102. 77. Wolf CF. Hepatic silicone emboli due to fragmentation of roller pump tubing. Ira J Artif Organs 1981; 5:277.

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TANG AND EATON Inflammatory Responses to Biomaterials

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