Dermal implants: Safety of products injected for soft tissue augmentation

Dermal implants: Safety of products injected for soft tissue augmentation

Dermatologic surgery Dermal implants: Safety of products injected for soft tissue augmentation David P. Clark, MD,a C. William Hanke, MD,b and Neil A...

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Dermatologic surgery

Dermal implants: Safety of products injected for soft tissue augmentation David P. Clark, MD,a C. William Hanke, MD,b and Neil A. Swanson, MDc

Columbia, Missouri, Indianapolis, Indiana, and Ann Arbor, Michigan Soft tissue augmentation is a frequently performed outpatient operation. Products available for soft tissue augmentation vary in chemistry, clinical indications, and toxicity. This review examines safety and efficacy data for collagen implants (Zyderm and Zyplast), gelatin matrix implants (Fibrel), and injectablesilicone. Soft tissue augmentation requires excellent technique to achieve excellent clinical efficacy. When used appropriately, the available products for soft tissue augmentation have few complications or adverse reactions. (J AM ACAD DERMATOL 1989;21:992-8.)

For centuries physicians have attempted to augment skin by injecting a variety of agents into the dermis and subcutaneous tissue. Local and systemic toxicity has limited the use of most substances. Since the introduction of injectable collagen (Zyderm I) in 1981, however, more than 350,000 patients have safely received intradermal injections for soft tissue augmentation. Intense interest in long-lasting agents has resulted in the development of new products such as glutaraldehyde crosslinked bovine collagen implant (Zyplast) and gelatin matrix implant (Fibrel), and the reconsideration of older agents such as silicone. The clinical efficacy of injectable agents depends on proper patient selection and technique. This review does not address clinical indications, injection technique, or longevity of soft tissue augmentation inasmuch as these topics are well covered elsewhere. Rather, we will discuss the safety and toxicity of available injectable agents used to correct soft tissue deficiencies. COLLAGEN IMPLANTS

In 1981 the Food and Drug Administration approved purified reconstituted bovine collagen From the Division of Dermatology, University of Missouri, School of Medicine," the Department of Dermatology, Indiana University School of Medicine,' and the Department of Dermatology, University'of Michigan School of Medicine.' Reprint requests: David P. Clark; MD, Division of Dermatology, University of Missouri, School of Medicine, Columbia, MO

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(Zyderm; Collagen Corp., Palo Alto, Calif.) for use as an injectable medical device to augment soft tissues. Since the introduction of Zyderm I, Zyderm II and Zyplast Implant have been approved for clinical use. More than 4 million collagen injections have been safely administered since 1981. Current interest in injectable collagen includes defining broader clinical applications and development of new products. 1-3 Chemistry Bovine dermal collagen is solubilized, purified, and reconstituted in a neutral solution into an injectable form (collagen in solution). The collagen fibrils are harvested and resuspended in phosphatebuffered saline containing 0.3% lidocaine. Zyderm I and II are prepared in an identical manner and differ in the final collagen concentration; I is 35 mg/ml and II is 65 mg/ml.r" Zyplast Implant is prepared in a similar manner except that glutaraldehyde is added during processing.7 Chemical characterization of collagen in solution reveals it to be 95% type I collagen in the triple helical conformation. Collagen in solution is free of noncollagenous proteins; reconstitution and redissolution depletes the mixture of imperfect collagen molecules.' The collagen used in Zyderm I and Zyplast Implant has a relatively small fiber diameter and few degraded collagen molecules. These properties permit even flow and extrusion through a 3D-gauge needle." Resistance of Zyderm I to biologic resorption, or persistence, has been evaluated in animal models.

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"Wet-weight" recovery and labeled collagen studies demonstrate a direct relationship between collagen concentration and persistence. 9 After injection, Zyderm I undergoes condensation and therefore the tissue concentration of collagen increase. Of collagen implanted in guinea pigs and rats, 20% to 30% was mobilized from the treatment site during the first 6 days. 5,8 The rapid degradation of Zyderm I led to methods for increasing resistance to enzymatic digestion. The addition of glutaraldehyde in low concentration to purified bovine collagen resulted in increased physical stability. Concentrations of glutaraldehyde as low as 0.0075% (wt/vol) produced significant collagen cross-linking and resistance to proteolytic degradation.'? Persistence studies in animals show decreased mobilization and a marked decrease in biologic degradation.v"

Clinical aspects Extensive data on adverse clinical reactions have accumulated since the introduction of collagen implant products in 1981.1-4, 11-16 Adverse clinical reactions can be divided into normal cutaneous responses, local test site reactions, treatment site reactions, and systemic toxicity. Normal cutaneous responses to collagen implants. Almost all patients receiving collagen implants experience some transient treatment site erythema, which in 95% to 97% of cases involves only trauma to the site and not a hypersensitivity reaction. This erythema frequently occurs within the first 30 minutes after injection and resolves within 24 hours, rarely persisting as long as 96 hours." This normal tissue response is not accompanied by induration or other systemic symptoms. Local test site reactions. Approximately 1% to 5% of patients who receive a Zyderm I skin test will experience a test site reaction1,2,3,17 characterized by erythema, induration, and occasional pruritus; 70% of these reactions occur within the first 72 hours, an additional 10% in 7 days, and the remainder within 4 weeks. Positive test site reactions are transient and last an average of 4 months. Treatment site reactions. Of patients with a nonreactive skin test result 1% to 4% will have an adverse treatment site reaction after their first Zyderm I treatment,!,2,3,18 These adverse reactions are identical to those caused by a Zyderm I skin test. Although data suggest that Zyplast Implant causes fewer treatment site hypersensitivity reactions, the time course of onset and resolution of these reactions are similar to those seen in Zyderm I,19 Recurrent intermittent swelling at the treatment site is a rare adverse reaction, which is accompanied by

Dermal implants 993 erythema and induration in approximately one half the cases and may last up to 3 years. This recurrent swelling occasionally can be initiated by exercise, ingestion of alcohol, or other causes of vasodilation. 16 Adverse reactions at the treatment site also may be due to mechanical factors. Overcorrection (i.e., the placement of excess collagen in the papillary dermis) is a common problem, particularly for inexperienced practitioners. Overcorrection with Zyderm I occasionally results in ridges whereas Zyplast Implant may "bead." Because of the physical differences in the collagen products, Zyplast Implant placed in the papillary dennis often will produce this unwanted response. Rarely an area of superficial necrosis will occur at the treatment site. This unusual complication is not associated with anti collagen antibodies and is limited to the treatment sites." Mechanical obstruction of superficial vesselsis the presumed cause of the necrosis, and healing may be accompanied by scarring and pigmentary change. Occasionally bruising occurs because of mechanical damage to the superficial vessels. This superficial ecchymosis usually resolves within 7 days and rarely causes pigmentary change.3,16,20 Systemic reactions. In one instance an embolus of collagen entered the ophthalmic artery after an attempted correction of glabellar frown lines. This single case report of partial vision loss resulting from arterial occlusion is the only systemic complication associated with bovine collagen implants." Although numerous complaints of arthralgias, malaise, and headache have been investigated, no reproducible, statistically significant systemic complication has been documented to be due to Zyderm I or Zyplast Implant injections.1,3,lS-17

Immunology of collagen implants Collagen biomaterials have been used extensively in medical treatment with established safety and minimal host reactivity.' Bovine collagen implants are mildly immunogenic when injected into human soft tis-

sues." A local hypersensitivity reaction at the skin test or treatment site is a reliable predictor of systemic hypersensitivity reactions. Of patients who have localized hypersensitivity reactions, 90% will have circulating antibodies against bovine collagen.v'" 22, 23 IgG antibodies to bovine collagen are found in the serum of patients with test-site hypersensitivity reactions to injectable collagen. 3,15,18,24,25 These IgG antibodies react with multiple antigenic sites on Zyderm 1.18,24The antibody response is species-specific to bovine collagen and does not cross-react with other animal or human collagens.25-28 Before treatment 8.4% of patients have anticollagen antibodies as measured by enzyme-linked immunosorbent assay (ELISA).18 Those with pretreatment anticol-

994 Clark et al. lagen antibodies are assumed to have been sensitized to bovine collagen through dietary exposure: McCoy et al." suggested that' patients with significant pretreatment anticollagen antibody levels are approximately six: times more likely to have an adverse treat ment reaction. Most patients with a positive Zyderm I skin test reaction will have evidence of anticollagen antibodies. Anticollagen antibodies after initial exposure, however, develop in a small number of patients whose skin tests are clinically negative.P-" If skin test data are doubtful, serologic examination can be more sensitive and should beconsidered before further treatment. Results of clinical trials and postmarketing experience suggest that the immunogenicity of cross-linked collagen, Zyplast Implant, is less than to Zyderm 1. In a series of 809 patients only 0.9% had a hypersensitivity reaction to Zyplast Implant." Patients with hypersensitivity to Zyplast Implant, however, do have circulating anticollagen antibodies." After treating 62 patients with Zyplast Implant, Elson" reported no hypersensitivity reactions. He noted hypersensitivity only at Zyderm l-treated sites in subjects treated with both Zyderm I and Zyplast Implant and no reaction at sites treated only with Zyplast Implant in these same patients." Systemic symptoms have been related to Zyderm 1. Patients with malaise, arthralgia, and swelling without test site reactivity do not have evidence of circulating antibodies.IS, IB Eight cases of rheumatologic disease have been reported in more than 350,000 patients treated with injectable collagen." The three reports of rheumatoid arthritis represent a prevalence of disease lower than predicted from the population at risk. Similarly, the two cases of dermatomyositis and one case of polymyositis are within the prevalence range of the general popul ation. 19. 28, 32

Histologic findings Microscopic investigations of injectable collagen have dealt with three major areas: animal studies, studies of normal treatment sites, and studies of treatment site reactions. Extensive histologic studies have been carried out in animals and humans injected with Zyderm I and Zyplast Implant.4, 10,23. 33 Initial studies in rodents engrafted with bovine collagen demonstrated a mild tissue reaction. Rats injected with Zyderm I have a mild inflammatory response that first appears at 12 to 72 hours and clears in I week. The collagen graft was gradually colonized by fibroblasts and blood vessels and reabsorbed in 3 months. Investigators who compared Zyplast Implant with Zyderm I in animal models found significant differences, Zyplast Implant demonstrated far slower resorp-

Journal of the American Academy of Dermatology

tion and, unlike Zyderm T, was replaced by collagen. Zyplast Implants were characterized by a sparse lymphohistiocytic infiltrate. By 6 months the graft was invaded by large fibroblasts, and evidence of new collagen production was found. Zyplast Implants in animals were reabsorbed in 12 months.v-" Microscopic evaluations of collagen implants have noted two findings unique to animal models. Dermal calcification frequently develops in rodents injected with bovine collagen, and marked neovascularization around the collagen grafts also developed in animals.' Dermal collagen grafts placed in human beings cause a transient perivascular, periappendageallymphohistiocytic infiltrate. Clefts and crevices associated with a scant fibroblast infiltration develop within the intradermal Zyderm I. Although Zyderm grafts are reabsorbed by 3 months, authors disagree about residual microscopic changes. Burke et al.22 found that the Zyderm grafts were replaced by granulation tissue whereas others could not demonstrate host granulation tissue. Investigators have not found calcification or neovascularization in human collagen grafts,16,3S Kligman" noted that Zyplast Implant produced a much more intense lymphohistiocytic infiltrate than Zyderm I. He reported that the host inflammatory response was greater in younger subjects and directly correlated with the fibroblast response. Zyplast Implant collagen grafts persisted up to 12 months whereas Zyderm I was reabsorbed by 3 months. " Stegman and co-workers have intensively studied and reviewed the histology of human treatment site reactions to Zyderm 1. 16 As previously discussed, treatment site reactions appear between 1 week and 2 months after injection. Of patients with an adverse treatment site reaction (e.g., erythema or induration) one third will show histologic findings indistinguishable from those of normal treatment sites. The remaining two thirds will have evidence of granuloma formation. Both "diffuse" granuloma formation and "palisading" foreign body granuloma have been identified.16,36·39 The diffuse type frequently is found in treatment-site biopsy specimens at 2 to 4 weeks. Treatment sites at 2 to 3 months often have a palisading foreign body reaction. " Residual Zyderm I routinely is identified in the mid or reticular dermis of granulomatous tissue-site reactions.P-" Treatment site reactions after Z yplast Implant administration are microscopically identical to Zyderm I reactions. Both types of granulomas have been identified in Zyderm reactions, and the time course of the adverse reactions are similar." Recurrent intermittent swelling at the treatment site has been noted. Analysis of the treatment site biopsy specimen 2 years after injection demonstrated scant foci of collagen implant in the reticular dermis and subcuta-

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neous tissue. The residual implant was accompanied by fibroblasts, numerous polymorphonuclear neutrophils, lymphocytes, eosinophils, and histiocytes.w"

Conclusion Available bovine collagen implants are effective with little associated toxicity. Widespread use has failed to identify any significant systemic toxicity. Local treatment site reactions are most frequent. Pretreatment skin tests will identify a small number (l % to 5%of patients) with preexisting antibodies to bovine collagen. One to two patients in 100 would be expected to have a self-limited treatment site reaction after a negative skin test reaction. Adverse reactions resulting from mechanical factors can be reduced but not eliminated by careful technique. The major problem with current collagen implants is reabsorption. Zyplast Implant appears to be an improvement over Zyderm I; however, development of longer-lasting agents is needed. GELATIN MATRIX IMPLANT Gelatin matrix. implant, marketed as Fibrel (Serono Diagnostics, Inc., Norwell, Mass.), has been recently approved for soft tissue augmentation. This agent which is injected intradermally, is a combination of gelatin powder and e-aminocaproic acid reconstituted with a mixture of 0.9% sodium chloride for injection (U.S.P.) and the patient's plasma in a 1:1 ratio. The mechanism of gelatin matrix implant action is unknown, but it is hypothesized that it elevates the depression and serves as a template for the subsequent deposition of new collagen. The injection injury initiates the wound healing process, and the e-aminocaproic acid stabilizes fibrin and enhances new collagen synthesis. The patient's plasma, used to reconstitute the gelatin powder complex, supplies supplemental fibrinogen and clotting factors.

Clinical studies In the United States 288 patients (840 scars) have been treated with gelatin matrix implant for elevation of scars." In approximately half the patients, a two-thirds improvement in scars occurred. Clinical correction appeared to last at least 1 year.

Adverse reactions Of the 321 patients who had initial skin tests with the gelatin matrix implant product, 1.9% had positive results. In the treatment group whose initial skin tests were negative, 8% had treatment site reactions. These treatment site reactions were characterized by transient erythema, swelling, and nodules. Although 75% of the treatment-site reactions resolved in less than 2 weeks,

Dermal implants 995 20% of the patients had reactions, primarily nodules, that lasted longer than 1 month. In the initial 288 patients treated with gelatin matrix implant, no significant systemic effects were noted. In a small subset of patients examined prospectively for immunologic abnormalities, 12% were found to have pretreatment antibodies to bovine collagen. Although this prevalence of antibovine collagen antibody levels is higher than most studies in normal populations, the antibody titers did not increase significantly after treatment. In one patient with an initially negative titer, a twofold rise in antibovine collagen antibodies developed 8 weeks after treatment.

Conclusion Gelatin matrix implant appears to be an effective agent for soft tissue augmentation. Because few patients have been treated, however, further clinical data are required. SILICONE The term silicone, used first by F. S, Kipping early in this century to designate certain polymers containing silica (Si02) ,41 defines a variety of liquid, gel, and solid polymer products. Silicone in liquid and elastomer (solid) forms is used widely in medicine. Silicone elastomers are found in implanted prosthetic devices, intravenous fluid tubing, and contact lenses." Silicone liquid, dimethylpolysiloxane, has been used for soft tissue augmentetion.v":" Silicone first was used to augment soft tissues in the 1940s. Initial studies in animals and human beings suggested that silicone was chemically inert and had low biologic reactivity.v" Widespread use of silicone in breast augmentation, however, led to numerous complications. 4J, 50, 51 Frequently, problems were due to adulterants added to the silicone in a misguided attempt to increase the dermal reaction and to "fix" the silicone in a fibrous capsule.f Complications also occurred when patients received excessive volumes of silicone and silicone with varied vlscosity.s'- 49, 53 In 1964 the Food and Drug Administration ruled silicone to be a "new drug." Although the use of silicone in Europe and the Orient was unaffected, clinical use in the United States was limited to a few treatment protocols and a few experienced investigators.t'<" After the reclassification of silicone, use of injectable silicone was outlawed in Nevada, and medical-grade silicone became unavailable. Recently interest in injectable silicone has grown. Selmanowitz and Orentreich" and others 49, s4 have championed the use of small-dose liquid silicone injections for elimination of age-related wrinkles and correction of fa-

Journal of the American Academy of Dermatology

996 Clark et al. cialscarring.This renewed interest has caused a re-evaluation of the risks associated with injectable liquid silicone. Chemistry Dimethylsiloxane is a large molecule consisting of repetitive (-[CH3]2SiO-)x units. The viscosity of the silicone polymer family is dependent on the degree of polymerization. The viscosity of medical-grade silicone is 350 centistokes. The designation of medical-grade silicone refers to particle purity, sterile preparation, and constant viscosity." It is clear, colorless, odorless, and unaffected by storage. Medical-grade silicone (MDX 44011; Dow Corning, Midland, Mich.) is characterized by high water repellency, low surface tension, low volatility, heat stability, and the ability to remain in liquid form indefinitely." Toxicity Toxicity studies of silicone must be divided into those dealing with the elastomer products and liquid silicone. This review deals primarily with injectable silicone and will not further consider elastomer silicone toxicity. Animal studies. Animal studies of silicone toxicity demonstrated medical-grade silicone to be a near-inert compound with little toxicity unless the volume of silicone physically impinged on vital structures. 41,54.55,58 Although numerous animal studies in mice, rats, guinea pigs, rabbits, dogs, and monkeys suggest that silicone has very little systemic effect, large subcutaneous injections result in phagocytosis of silicone and subsequent recovery in other organs. 56.58 Massive silicone ingestion, 20.0 gm/kg, does not cause any discernible local or systemic effect," Intravenous and intraarterial injection resulted in death by embolism." The intravenous action of silicone was dose-dependent. Animals tolerated repeated intravenous injections of small quantities of silicone, but death occurred when a large volume was usOO. 41 Human studies. Human toxicity data are difficult to evaluate because reports of complications resulting from silicone lack information about silicone purity and viscosity. Almost all contemporary reports deal with silicone injections that involve injection of unknown quantities of nonmedical-grade silicone.v'" Injection of pure medical-grade silicone in small amounts, less than 1 ml per session, carries little risk,41.48 Webster and co-workers" reported 17,000 injections with few complications. Treatment-site reactions include erythema, ecchymosis, hyperpigmentation, texture problems (i.e., uneven contour), and excessive elevation. Selmanowitz and Orentreich" have noted that most treatment-site problems occur when silicone is deposited in the papillary dermis rather than in the reticular dermis at the level of the subcutaneous fat." Overcorrection can result in a beaded appearance that can last indefinitely.

Webster et al.,47,48 who used a small needle and a microdroplet method, believed that this problem can be minimized. Systemic embolization with disastrous results has been noted. Injection of liquid siliconein ophthalmic and meningeal vessels has resulted in blindness, loss of neurologic function, and death." Subcutaneous silicone injection in transsexual persons with presumed systemic absorption has resulted in acute pneumonitis and acute respiratory distress syndrome," Use of medical grade silicone for augmentation mammaplasty has been associated with acute arthritis and renal failure." Significant silicone migration, erysipelas-like reactions, and lymphatic obstruction-the major complications found in silicone injections of the breast-were not found in the three major reports of small-dose silicone used for facial rhytides. 41,47,48,64 Recently Spiera'" noted the development of scleroderma in patients previously treated with silicone for augmentation mammaplasty. Scleroderma or eosinophilic fasciitis developed in five patients 2 to 21 years after initial silicone implantation. Although the association of scleroderma and previous silicone augmentation mammaplasty has been suggested, careful studies to confirm these observations are needed.v"

Histologic findings Small amounts of silicone injected into the subcutaneous space elicits a small polymorphonuclear infiltrate followed by a scant lymphocyte response." The stromal response is primarily fibrohistiocytic with a fibrous capsule that surrounds individual globules of silicone. 67,68 Human tissue can form granulomas in response to silicone. Although silicone granulomas or siliconomas have been documented in animals and humans, foreign body giant cells and a marked granulomatous response are rare." The elastomer form of silicone induces a marked foreign body granulomatous response. Contaminants, often demonstrating birefringent granules, also will cause an exuberant tissue reaction.68 Wilke'" found granulomas in 13 of 92 patients injected with liquid silicone. Webster and coworkers, 47 in reporting more than 17,000 silicone injections, noted no granulomas. It is significant that Webster used smaller bore needles for injection and far smaller volumes per session. Animal studies suggest that volume is a critical factor in determination of tissue response.54,59,62,69 Tissue histiocytes phagocytose silicone and migrate to other organs. 58,68,69 Although histiocytic phagocytosis of silicone has been documented in both human beings and animals, no adverse consequences have resulted." This type of migration is to be distinguished from the intravascular embolic migration

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of silicone reported from hemodialysis tubing, silicone-gel prosthesis, and large-volume breast injections.":" Acute pulmonary edema, pneumonitis, hepatic fibrosis, and death have been reported after silicone emboli.A 61.70 This type of problem has not been reported when silicone has been used in small volumes.

Carcinogenesis Concern has been raised about the possiblerole of siliconeas a cause or promoter of cancer." Standard screening tests have failed to suggest a link between medical-grade silicone and cancer," Several reviews of silicone injections in animals did not reveal evidenceof carcinogenesis.41,58, 72 No convincingprospectivedata link silicone with carcinogenesisin human beings.

Conclusion Silicone is a permanent injectable material with low tissue reactivity when used in small amounts. Past problems associated with silicone soft tissue augmentation are related primarily to use of an impure product, excessive volumes, or inappropriate location, for example, the breasts. Although a chronic inflammatory response to silicone has been reported, the majority of complications associated with small-dose silicone injection are due to injection technique. Excessive elevation, superficial injection, and systemic emboli are caused by imprecise technique. The morbidity of small-dose silicone, like many medical devices, is in large measure a function of injection technique. Although controlled studies are difficult to accomplish, it appears that silicone is both safe and effectivewhen used in small amounts for appropriate indications. REFERENCES 1. Castrow FF II, Krull EA. Injectable collagen implantupdate. J AM ACAD DERMATOL 1983;9:889-93. 2. Cooperman LS, Mackinnon V, Bechler G, et al. Injectable collagen: a six-year clinical investigation. Aesthetic Plast Surg 1985;9:145-52. 3. Swanson NA, Stoner JG, Siegle RJ, et al. Treatment site reactions to Zyderm Collagen Implantation. J Dermatol Surg OncoI1983;9:377-80. 4. Knapp TR. Development of an injectable collagen for soft tissue restoration. In: Rubin LR, ed. Biomaterials in reconstructive surgery. 81. Louis: CV Mosby, 1983;882910. 5. McPherson JM, Wallace DG, Piez KA. Review: development and biochemical characterization of injectable collagen. J Dermatol Surg Onco11988;14(suppll):13-20. 6. Simpson RL. Collagen as a biomaterial. In: Rubin LA,

Dermal implants 997 ed. Biomaterials in reconstructive surgery. S1. Louis: CV Mosby, 1983:109-17. 7. McPherson JM, Ledger PW, Sawamura S, et al. The preparation and physicochemical characterization of an injectable form of reconstituted, glutaraldehyde crosslinked, bovine corium collagen. J Biomed Mater Res 1986;20:93-107. 8. McPherson JM, Wallace DG, Sawamura 8J, et al. Collagen fibrillogenesis in vitro. A characterization of fibril quality as a function of assembly conditions. ColI Relat Res 1985;5:119-35. 9. McPherson JM, Sawamura 8J, Conti A. Preparation of [H3] collagen for studies of the biological fate of xenogeneic collagen implants in vivo. J Invest Dermatol1984; 86:673-7. 10. McPherson JM, Sawamura S, Armstrong R. An examination of the biologic response to injectable, glutaraldehyde cross-linkedcollagen implants. J Biomed Mater Res 1986;20:93-107. 11. Bailin PL, Bailin MD. Correction of depressed scars following Moh's surgery: the role of collagen implantation. J Dermatol Surg Onco1 1982;8:845-9. 12. Crofton BE, DeLustro FA, Koretz MM, et aI. Report on the clinical evaluation of glutaraldehyde cross-linked collagen (Keragen) implant treatment of heloma durum and heloma molle. J Foot Surg 1985;25:427-35. 13. Kaplan EN, Falces E, Tolleth H. Clinical utilization of injectable collagen. Ann Plast Surg 1983;10:437-51. 14. Knapp TR, Kaplan EN, Daniels JR. Injectable collagen for soft tissue augmentation. Plast Reconstr Surg 1977;60:398-405. 15. Siegle R, McCoy J, Shade W, et aI. Intradermal implantationofbovinecollagen: humoral response associated with clinical reactions. Arch Dermatol 1984;120:183-7. 16. Stegman SJ, Chu S, Armstrong RC. Adverse reactions to bovine collagen implant: clinical and histological features. J Dermatol Surg Oncol 1988;14(suppll):39-48. 17. Kamer FM, Churukian M. Clinical use of injectable collagen: a three year retrospective study. Arch Otolaryngol 1984;110:93-8. 18. McCoy JP Jr, Schade W, Siegle RJ, et al. Immune responses to bovine collagen implants. Significance of pretreatment serology. J AM ACAO DERMATOL 1987; 16:955-60. 19. DeLustro F, Mackinnon V, Swanson NA. Immunology of injectable collagen in human subjects. J Dermatol Surg Oncol 1988;14(suppll):49-55. 20. Cucin RL, Barek D. Complications of injectable collagen implants. Plast Reconstr Surg 1983;71:731-3. 21. DeLustro F, Condell RA, Nguyen MA, et aL A comparative study of the biologic and immunologic response to medical devices derived from bovine collagen. J Biomed Mater Res 1986;20:109. 22. Burke KE, Naughton G, Cassai NA. Histological, immunological and electron microscopic study of bovine collagen implants in the human. Ann P1ast Surg 1985;14:51522. 23. Knapp TR, Luck E, Daniels JR. Behavior of solubilized collagen as a bioimplant. J Surg Res 1977;23:96-105. 24. Ellingsworth L, DeLustro F, Brennan J, et al. The human immune response to reconstituted bovine collagen. J Immunol 1986;136:877-82. 25. DeLustro F. Reaction to injectable collagen: results in animal models and clinical use. Plast Reconstr Surg 1987;581-92. 26. Medsger TA, Dawson WN, Masi AT. The epidemiology of polymyositis. Am J Med 1970;48:715-23.

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