Treatment of depressed cutaneous scars with gelatin matrix implant: A multicenter study*

Twenty-two centers participated in a study to determine the efficacy and safety of gelatin matrix implant (GMI; Fibrel) in the elevation of depressed cutaneous scars. Gelatin matrix implant is an implant consisting of absorbable gelatin powder and e-aminocaproic acid, which is reconstituted with the patient's plasma before being injected intradermally beneath the scar. A total of 321 patients were evaluated after a skin sensitivity test; six of the patients (1.9%) had a positive response. After a skin test with negative results, 27 patients dropped out of the study for unrelated reasons. The remaining 288 patients were treated with the implant (total of 840 sears), many of whom have been followed up for more than 1 year. Preliminary results show that approximately half of the treated scars showed improvement of greater than 65%. The current data suggest that the improvement lasts at least up to 1 year. Adverse reactions to gelatin matrix implant injections were local and transient, and none of the patients developed major hypersensitivity responses to the treatment. The data indicate that intradermal injections of gelatin matrix implant are safe and effective in correcting the depressed scars selected for this study. (J AM ACAD DERMATOL 1987;16:1155-62.)

Despite the recent advances in various cuta- neous surgical technics for treating facial defor- mities, there has always been an intense effort to develop an ideal dermal filler for soft tissue aug- mentation. This filler should have permanence,

Accepted for publication Dec. 16, 1986. Reprint requests to: Dr. Larry Millikan, Department of Dermatology,

Tulane University, 1430 Tulane Ave., New Orleans, LA 70112. *Participants in the study include: Larry Millikan, M. D,, Department

of Dermatology, Tulane University, New Orleans, LA; Theodore Rosen, M.D., Department of Dermatology, Baylor College of Medicine, Houston, TX; Gary Monheit, M.D., Department of Dermatology, University of Alabama, Birmingham, AL; Ching Lau, Ph.D., Andover, MA; A. Melvin Alexander, M.D., De- partment of Dermatology, Howard University, Washington, DC; William Baker, M.D., Department of Dermatology, University of Washington, Seattle, WA; Ivan S. Cohen, M.D., Department of Dermatology, Yale University, New Haven, CT; Gerald Davis, M.D., Department of Dermatology, New York Medical College, New York, NY; William Dorner, M.D., Medical Department of Northeast University College of Medicine, Akron, OH; M. L. Elgart, M.D., Department of Dermatology, George Washington University Medical Center, Washington, DC; Edmond Griffin,

behave physiologically, lack side effects, and be easily administered.

Several materials have been used as dermal fill- ers. Paraffin has a high incidence of side effects and local tissue reactions. 1 The use of silicone has

M.D., Department of Dermatology, Emory University, Atlanta, GA; John V. Hugill, M.D., Fort Meyers, FL; Paul Kelly, M.D., Medical Department, University of California School of Medicine, Los Angeles, CA; Albert Lefkovitz, M.D., Department of Der- matology, Mt. Sinai School of Medicine, New York, NY; Bobby P. Lemay, M.D., Department of Otolaryngology, University of Alabama, Birmingham, AL; Michael McClellan, M.D., Depart- ment of Dermatology, Providence Medical Center, Media, PA; Harry Mittelman, M.D., Department of Dermatology, Stanford Hospital and Medical Center, Stanford, CA; William L. Poole, M.D., Department of Dermatology, University of Alabama, Bir- mingham, AL; Michael Reed, M.D., Department of Dermatology, New York University Medical Center, New York, NY; John Stans- bury, M.D., Department of Dermatology, University of Minnesota, Minneapolis, MN; George G. Tisdale, M.D., University Hospital, Birmingham, AL; Hubert C. Watkins, M.D., Department of Der- matology, Loma Linda University School of Medicine, Loma Linda, CA; and David Weinberg, M.D., Department of Derma- tology, University of California, San Francisco, CA.

1155

1156 MuIticenter study Journal of the

American Academy of Dermatology

Table I. Demographic data of patients treated with gelatin matrix implant

[ MeanorNo. I

Age (yr) 31.7 Weight (lb) 141.3 Height (inches) 66.8 Sex

Male 94 Female 194

Race White 254 Hispanic 13 Black 9 Oriental 4 Other 2 Unknown 6

Range

18-71 100-268 50-86

been limited because of a high incidence of side effects, including migration. 2'3 Although recent formulations (of silicone) are improved, they are neither available nor physiologic. Injectable col- lagen implant (Zyderm Collagen Implant) has gen- erated widespread interest among physicians and high expectations in patients. However, the lack of permanency of correction by Zyderm 4'5 and the significant number of reported cases of ad- verse reactions associated with it TM confirm the need to continue the search for a better filler substance.

We report here a multicenter study with an in- vestigational medical device, gelatin matrix im- plant (GMI; Fibrel, Serono Laboratories, Inc., Randolph, MA) for elevating depressed cutaneous scars.

The major components of this gelatin matrix implant consist of absorbable gelatin powder and e-aminocaproic acid. Immediately before implan- tation, the gelatin matrix implant is reconstituted with the patient 's plasma.

It is hypothesized that when gelatin matrix im- plant is injected intradermally beneath a depressed scar, the injury induces a localized wound healing process that ultimately leads to the regeneration of new soft tissue. The gelatin powder elevates the depression, and the hypothesis is that it provides a matrix to enhance blood clotting by entrapping the necessary clotting factors and serves as a tem- plate for the subsequent deposition of a new ex-

Table II . Etiologic factors underlying gelatin matrix implant-treated scars

Cause

Acne Varicella Trauma Surgery Miscellaneous bacterial skin

infection Herpes Other miscellaneous causes Unstated Total

No. of ] scars %

632 75.3 101 12.0 50 6.0 19 2.3 7 0.8

5 0.6 20 2.4

6 0.6 840 100.0

tracelhlar matrix essential for wound healing, t2 In addition, it has been reported that gelatin powder probably also acts as a chemotactic agent for monocytes t3 and fibroblasts, 14 ceils that are critical for the initiation of tissue repair, m5 The antifi- brinolytic action of e-aminocaproic acid has a fibrin-stabilizing effect. 16 In animals, it has been shown to enhance new collagen synthesis through blockage of the fibrinolytic system.t7 In theory, e-aminocaproic acid should have similar activity at the injection site in man. The patient's plasma is used as a diluent to provide a source of supple- mental fibrinogen and other blood clotting factors.

The data reported in this study show that Fibrel is an effective dermal filler in patients with de- pressed scars.

MATERIALS AND METHODS

Gelatin matrix implant (Fibrel) is a medical device currently under clinical evaluation for its effectiveness and safety in the elevation of depressed cutaneous scars. The components are a lyophilized mixture of 100 mg of absorbable gelatin powder and 125 mg of e-aminocaproic acid. Immediately before implantation, the lyophilized mixture is reconstituted with 0.5 ml of the patient's plasma and 0.5 ml of 0.9% NaC1 USP. Gelatin matrix implant is supplied in a syringe within a sterile kit containing the components necessary for plasma dilution, reconstitution, and treatment.

S tudy design

Candidates with depressed cutaneous scars that were elevatable on manual stretching of the scar borders were selected for the study. Fibrotic scars (very tough and

Volume 16 Number 6 June 1987

Treatment of scars with gelatin matrix implant 1157

Fig. 1. Before gelatin matrix implant (Fibrel) at week 0. Fig. 2. After gelatin matrix implant at week 24. Fig. 3. Before gelatin matrix implant at week 0. Fig. 4. After gelatin matrix implant at week 36.

firm on palpation) and "icepick" scars were excluded from treatment. In addition, patients with the following conditions were excluded from this study:

1. A history of keloids 2. Known sensitivity to gelatin and/or ~-aminocaproic

acid 3. Bleeding disorders 4. A history of cardiac, renal, or hepatic disease 5. A history of autoimmune disease 6. Pregnancy lactation

In addition, patients receiving anticoagulant or va- sodilator therapy or any other medication, as well as those with an illness that could alter the effect of gelatin matrix implant or that could interfere with the inter- pretation of the study data, were excluded.

Informed consent was obtained from each patient before enrollment in this study. In addition, each patient

was given an intradermal skin test with 0.05 ml of reconstituted gelatin matrix implant diluted 1: 1000 with 0.9% NaC1 USP.

A positive skin test result was defined as erythema, induration, tenderness, swelling, or inflammation of the test site lasting more than 5 hours or appearing more than 24 hours after implantation. Four weeks later, if there had been no sensitivity reaction, each patient re- ceived a gelatin matrix implant treatment beneath a maximum of four scars. A second implant could be applied to any scar judged to have responded subop- timally 2 weeks after the first injection. Thereafter, periodic evaluations of the response of each scar to gelatin matrix implant treatment were conducted at pre- determined intervals for 1 year.

The efficacy of gelatin matrix implant treatment was evaluated by three independent technics: the physician's

1158 Multicenter study

Journal of the American Academy of

Dermatology

Fig. 5. Before gelatin matrix implant at week 0. Fig. 6. After gelatin matrix implant at week 36. Fig. 7. Before gelatin matrix implant at week 0. Fig. 8. After gelatin matrix implant at week 52.

and patient's global evaluations of improvement and computerized scar volume determinations (photogram- metric measurements of scar molds).

The physician's evaluation was graded according to the following response categories:

1. No improvement 2. Slight improvement (1% to 33%) 3. Moderate improvement (33% to 64%) 4. Marked improvement (65% to 95%) 5. Complete improvement (96% to 100%) 6. Slight overcorrection (1% to 32%) 7. Moderate overcorrection (33% to 64%)

8. Marked overcorrection (65% to 95%) 9. Very marked overcorrection (>95%)

The patient response categories were the same, ex- cept that the patients did not evaluate the overcorrection response.

The third technic involved the preparation of a mold impression of each scar before implantation and at each subsequent evaluation point. Scar volume was deter- mined from stereologic measurements performed by projecting a set of parallel lines onto the scar mold and viewing it at an angle from the perpendicular. The straight lines of the grid were curved over the raised

Volume 16 Number 6 June 1987

Treatment of scars with gelatin matrix implant 1159

Table III . Scar response to gelatin matrix implant: Physician evaluations

Posttreatment week

Response 1 2 [ 4 I , , 8 12 I 24 3 6 , , 5 2

1. None 35 23 22 23 52 53 30 3 2. Slight 152 163 112 125 127 103 92 25 3. Moderate 260 251 200 219 215 192 145 49 4. Marked 158 197 262 219 211 159 111 42 5. Complete 91 121 151 125 114 90 55 16 6. Slight overcorrection 53 35 15 5 3 3 0 0 7. Moderate overcorrection 33 12 6 0 0 0 0 0 8. Marked overcorrection 3 0 0 0 0 0 0 0 9. Very marked overcorrection 1 0 0 0 0 0 0 0

area of the scar mold. They were automatically tracked by computer, and the area under the curved lines was integrated to obtain the total volume.* These data were then converted to the same rating scale used by the physician.

Injection procedure Each scar area was cleansed with alcohol. A local

anesthetic could be administered before the injection procedure (optional). If necessary, an intradermal pocket was created beneath each depressed scar by un- dermining the scar with the custom 20-gauge needle supplied with the kit. Gelatin matrix implant was then injected through this needle until a slight overcorreCtion appeared. If undermining was not required, the implant was injected beneath the scar with the standard 21- gauge needle provided in the kit or with another needle of suitable gauge (22 to 27 gauge).

RESULTS

Twenty-two centers participated in this study, representing different geographical areas in the continental United States with respect to popula- tion, climate, and environment.

Study population

Out of a total of 321 patients who were evaluated after the skin sensitivity test, six (1.9%) had a positive response. After a negative skin test result, 27 patients were dropped from the study for un-

*Frobin W, Hierholzer E. Applications of human biostereometrlcs (NATD). Journal of the Society of Photo Optical Instrumentation Engineers 1978;166:39-44.

related reasons. Each of the remaining 288 patients received gelatin matrix implant beneath one to four scars. The demographic data of this patient pop- ulation, which included 94 men and 194 women with a mean age of 31.7 years, are presented in Table I.

Efficacy

A total of 840 scars were treated with gelatin matrix implant. The causes of these scars are sum- marized in Table II. The two etiologic factors cited most often were acne (75%) and varicella (12%). Of the 836 scars evaluable for efficacy, 499 (59.7%) received two treatments, 2 weeks apart. The efficacy data are summarized in Table Ii i (phy- sicians' evaluation), Table IV (patients' evalua- tion), and Table V (photogrammetric evaluation).

Figs. 1 to 8 are photographic examples of scars before and after treatment with gelatin matrix implant.

In the physicians' evaluations, the percentages of scars showing greater than 65% improvement over pretreatment were 43%, 42%, 38%, and 43% at weeks 1, 24, 36, and 52, respectively (Tables III and VI). The data suggest that scars with marked improvement or greater maintain the effect for at least 1 year.

The patients' improvement response data closely paralleled the physicians' responses as shown in Tables IV and VI. Patient ratings of the percentages of scar sites showing greater than 65% improvement were approximately 40% throughout the evaluation.

1160 Multicenter study Journal of the

American Academy of Dermatology

Table IV. Scar response to gelatin matrix implant: Patient evaluations

I Posttreatment week

I 24 r 1. None 76 70 45 56 88 94 81 14 2. Slight 183 183 107 139 120 115 82 20 3. Moderate 238 231 208 185 189 169 109 42 4. Marked 199 201 250 207 216 149 122 46 5. Complete 93 121 160 133 105 82 51 20

Table V. Scar response to gelatin matrix implant: Photogrammetric evaluations

Response 1 I 2 I 1. None 51 34 2. Slight 61 41 3. Moderate 133 103 4. Marked 202 226 5. Complete 53 83 6. Slight overcorrecti0n 77 149 7. Moderate overcorrection 17 8 8. Marked overcorrection 12 10 9. Very marked overcorrection 15 6

Posttreatment week

24 32 45 46 28 9 21 44 40 28 21 4 76 68 70 62 34 10

204 156 176 123 72 21 98 87 71 55 3l 16

171 139 122 76 22 11 11 9 I0 8 0 I 3 5 7 4 1 0 6 5 6 2 1 0

Photogrammetric measurements of scar vol- umes produced data indicating a greater level of improvement after gelatin matrix implant treat- ment. These evaluations showed that more than 60% of the treated scars maintain at least a 65% improvement over baseline (Tables V and VI).

Adverse experiences

Of 840 scars treated, 67 (8%) were reported to have developed localized adverse effects that were minor and transient. Scars with more than one adverse effect were counted only once. At 40 of these scar sites the adverse experiences were con- sidered by the physician as related to the implant. At 17 scar sites the relationship of the treatment to the. adverse experience was uncertain. Adverse reactions at six scar sites were considered probably to be related to the procedure rather than to the implant itself. At the remaining four scar sites the adverse effects encountered were not considered to be related to the device. The adverse experiences

most commonly reported were erythema, swell- ing, and nodules at the treatment site. Of 40 scars that had adverse effects related to the implant, 30 adverse effects (75%) lasted less than 2 weeks. In two scar sites (5%) swelling lasted 2 to 4 weeks, and in eight scar sites (20%) nodules were present from 1 month to several months.

Of the 288 patients treated with gelatin matrix implant, five (1.7 %) reported nonlocalized adverse experiences. A vagal reaction (fainting) occurred during the implant procedure in one patient, and nausea was reported in another patient. Two pa- tients reported headaches that were considered by the physician to be causally related to the gelatin matrix implant procedure.

There was no evidence of a major systemic or local hypersensitivity reaction in the 288 patients treated. Based on this sample, the 95% confidence limits for a major hypersensitivity response to gel- atin matrix implant are 0% to 1%.

Clinical laboratory data, including data obtained

Volume 16 Number 6

June 1987 Treaonent of scars with gelatin matrix implant 1161

Table VI. Percentage of scars with greater than 65% improvement after treatment with gelatin matrix implant*

Physician Patient Photogrammetric evaluation evaluation evaluation

Wk 1 43% (339/786) 37% (292/789) 61% (376/621) Wk 24 42% (249/597) 38% (231/609) 66% (268/404) Wk 36 38% (166/433) 39% (173/445) 61% (127/210) Wk 52 43% (58/135) 47% (66/142) 68% (49/72)

*These percentages represent a ratio of the number of scars that showed marked improvement or better and the total number of scars evaluated at times specified. The numbers of scars that show marked improvement or better are a summation of categories 4 to 9 in Tables II1 and V and categories 4 and 5 in Table IV.

from hematologic and blood chemistry studies and urinalysis, showed no clinically significant devia- tions from the normal range, thus providing further evidence to support the safety of gelatin matrix implant.

DISCUSSION

The purpose of this multicenter study is to de- termine the efficacy and safety of gelatin matrix implant in the elevation of depressed cutaneous scars. Forty-nine of the 288 patients treated in this study have been followed up for at least 1 year. The results in this interim report clearly show that gelatin matrix implant is well tolerated and effec- tive in elevating the majority of selected depressed cutaneous scars. In scars with a satisfactory re- sponse, the data show that 85% of those scars followed up for 1 year maintained the desired im- provement. More than half of the original patients are enrolled in an ongoing long-term follow-up study to further evaluate the duration of im- provement.

It is interesting to note that photogrammetric measurements of scar volumes produced data in- dicating a consistently greater level of posttreat- ment correction of scars in comparison with phy- sicians' and patients' responses. This finding sug- gests that the subjective evaluation by physicians and patients may not be the most accurate param- eter to use in determining the degree of im- provement.

Safety monitoring in all centers included phys- ical examinations, monitoring of vital signs, and clinical laboratory tests. Some isolated incidents

of out-of-range values were noted in the clinical laboratory tests, but these values showed no ap- parent trends and were not considered to be related to treatment with gelatin matrix implant. In most cases, adverse experiences relating to the implant were mild and transient, and they consisted pri- marily of erythema, swelling, nodules, and pru- ritus at the injection site.

One of the common concerns about the use of an implant is the possibility of initiating an im- munologic reaction. However, one theoretical ad- vantage of gelatin matrix implant is that gelatin powder has an extremely low degree of immu- nogenicity. ~8 Serum samples taken from 4 of 115 patients (3.5%) at 24 or 36 weeks after treatment showed antibodies to bovine collagen types I and III; one patient had circulating immunocomplexes. In a subset of patients examined prospectively for immunologic parameters, 7 of 56 patients (12.5%) revealed antibodies to bovine collagen types I and III before treatment. These antibodies did not in- crease by more than two titers after treatment. This finding was not considered significant. Only one of the 49 patients (2%) with a negative baseline developed antibodies 8 weeks after treatment with gelatin matrix implant. Details of the immunologic studies will be reported elsewhere.

Data presented in this report clearly indicate that intradermal injection of gelatin matrix implant is safe and effective in correcting selected depressed cutaneous scars. Since gelatin matrix implant can produce a long-lasting desired effect, it should be a valuable addition to the limited number of ma- terials available for soft tissue augmentation.

1162 Multicenter study Journal of the

American Academy of Dermatology

REFERENCES

1. Domonkos A, Arnold H, Odom R. Andrews' diseases of the skin. Clinical dermatology, ed 7. Philadelphia: WB Saunders, 1982:52.

2. Selmanowitz VJ, Orentreich N. Medical grade fluid sil- icone [monograph review]. J Dermatol Surg Oncol 1977;3:597.

3. Piechotta F. Silicone fluid, attractive and dangerous: col- lective review and summary of experience. Aesthetic Hast Surg 1979;3:347.

4. Klein A, Rish DC. Substances for soft tissue augmen- tation: collagen and silicone. J Dermatol Surg Oncol 1985;11:337-9.

5. Cohen IK, Peacock Jr EE, Chvapil M. Zyderm. Hast Reeonstr Surg 1984;73:857-8.

6. Brooks N. A foreign body granuloma produced by an injectable collagen implant at a test site. J Dermatol Surg Oncol 1982;8:111-4.

7. Swanson NA, Stoner JG, Siegie RJ, Solomon AR. Treat- ment site reactions to Zyderm collagen implantation. J Dermatol Surg Oncol 1983;9:73l.

8. Cuein RL, Bm'ek D. Complications of injectable collagen implants. Hast Reconstr Surg 1983;72:731.

9. Barr RJ, Stegman SJ. Delayed skin test reaction to in- jectable collagen implant (Zyderm). J AM ACAO DER- MA'rOL 1984;10:652-8.

10. Labow TA, Silvers DN. Late reactions at Zyderm skin test sites. Cutis 1985;35:154-8.

i1. Barr RJ, King DF, McDonald RM, Bartlow GA. Nec- robiotic granulomas associated with bovine collagen test site injections. J AM ACAD DERMA'rOL 1982;6:867-9.

12. Clark RAF. Cutaneous tissue repair: basic biologic con- siderations. I. J AM ACAD DERMATOL 1985; 13:701-25,

13. Postlethwaite AE, Kang AH. Collagen and collagen pep- tide-induced chemotaxis of human blood monocytes. J Exp Med 1976; 143:1299-307.

14. Postlethwaite AE, Seyer JM, Kang AH. Chemotactic reaction of human fibroblasts to type I, II and II1 col- lagens and collagen-derived peptides. Proc Natl Acad Sci USA 1978;75:871-5.

15. Leibovitch SJ, Ross R. The role of the macrophage in wound repair: a study with hydrocortisone and antimac- rophage serum. Am J Pathol 1975;78:71-100.

16. Nilsson IM, Sjoerdsma A, Waldcnstron J. Antifibrino- lytic activity and metabolism of e-aminocaproic acid in man. Lancet 1960;1:1233-6.

17. Brandstedt S, Rank F, Olson PS, Wound healing and formation of granulation tissue in normal and defibri- nogenated rabbits: an experimental model and histolog- ical study. Eur Surg Res 1980;12:12-21.

18, Ring J, Messmer K. Incidence and severity of anaphy- lactoid reactions to colloid volume substitutes. Lancet 1977;1:466.

A BS TRA CTS

Occupational hand eczema and atopy

Baurle G, Homstein OP, Diepgen TL. Derm Beruf Umwelt 1985;33:161-5 (German)

Six hundred eighty-three patients with hand eczema, of whom 242 had a history of occupational eczema, were investigated for a history or stigmata of atopy. Over 50% of the occupational group had at least three indications of atopy. The nonoccupational group had similar results. All patients with occupational eczema should be investigated for atopy.

Yehudi M. Felman, M.D.

Localized cicatriciai pemphigoid of Brunsting-Perry: a clinical, histologic and immunologic study of a case and a review of the literature

Armijo M, Estella JS, Aparicio M, Soto J. Actas Dermo-Sif 1986;77:269-75 (Spanish)

The literature contains reports of forty cases of localized cicatricial pemphigoid of Bmnsting-Perry, which occurs primarily in post-mid- dle-aged men, with recurrent plaques of blistering on the face, neck, or chest that result in scarring. The authors describe a ease on the chest of a 56-year-old man. Direct immunofluorescence revealed ho-

mogeneous linear deposits of lgG, IgA, and fibrinogen at the base of the bullae and IgG, C3, aad Clq in the surrounding healthy skin and scars in the basement membrane. Treatment with dapsone, 100 mg daily, or with dapsone, 50 mg daily plus 15 mg prednisone daily, achieved the best therapeutic results.

Yehudi M. Fehnan, M.D.

Halo nevus: in situ study with monoclonal antibodies

Vignale RA, Paeiel J, Bruno J, Calandria L, De Anda G. Med Cutan Ibero Lat Am 1986;14:13-7 (Spanish)

Using immunoeytochemical methods, the inflammatory cell in- filtrates from seven halo nevi were studied. Monoclonal antibodies, Cris-1, OKT3, OKT4, OKT8, A47, Edu-l, OKT6, and anti-im- manoglobulins were employed.

The results show that the predominant cells in the inflammatory cell infiltrate were T cytotoxic/suppressor-aetivated lymphocytes. An increased number of epidermal Langerhans cells and IgM deposits in the dermoepidermal junction were also observed.

Thus, the results could postulate that self-involution of halo nevi is mediated by eytotoxic cellular immune reactions.

Yehudi M. Felman, M.D.