Wednesday, October 29, 2003 - 7:00 AM
3602

Modification of Fibrous Capsule Formation Around Implants Using TempostatinTM (Halofuginone)

Kevin C. Olbrich, PhD, Ricardo A. Meade, MD, William Bruno, MD, Burton M. Sundin, MD, Lior Heller, MD, Detlev Erdmann, MD, Bruce Klitzman, PhD, and L. Scott Levin, MD.

Fibrous capsule formation around implants remains a common and problematic complication of reconstructive and aesthetic surgery. Although the etiology of capsule formation may not be fully understood, the end result is the deposition of a dense collagen-rich capsule surrounding the implant. This capsule can cause undesirable aesthetic results, capsular contracture, and even implant failure.

The purpose of this study was to determine if TempostatinTM (halofuginone, or HF), a highly selective small molecule inhibitor of stromal cell activation, migration and collagen type I synthesis, is effective at preventing excessive deposition of collagen around implanted materials.

Four silastic disks (6-mm diameter x 2-mm thick) were implanted subcutaneously into dorsum of 19 adult male Sprague-Dawley rats. The rats were randomized into 4 groups: Group A received rodent chow supplemented with 10 ppm HF for 2 months, Group B received the HF chow for 1 month followed by normal chow for 1 month, Group C received normal chow for 1 month followed by HF chow for 1 month, and Group D (control) only received normal rodent chow. At the end of the study, the rats were euthanized and the implants and capsules were harvested. Blood samples were taken and HF levels were confirmed by HPLC. No systemic or local side effects of HF were noted, and all animals gained weight at a similar rate.

Tissue samples were fixed and stained with Masson's Trichrome. Microscopic images of the capsule region near the implants were captured under standard illumination with a color CCD camera. The color information from each capsule image was quantified using digital colorimetric analysis. The collagen index, determined from the colorimetric analysis, served as a semi-quantitative assessment of collagen content. The collagen index ranged from an average of -0.83 ± 0.05 (n=11) for muscle to 1.04 ± 0.06 (n=18) in fascia of control animals. Gross morphological observation of each slide indicated a trend towards reduced fibrocellular reaction and reduced trichrome staining in adjacent subcutaneous tissue and overlying dermis of treated animals.

The collagen index value for group A averaged -0.27 ± 0.09 (n=6), group B was 0.30 ± 0.09 (n=5), group C was 0.01 ± 0.10 (n=4), and group D (control) was 0.26 ± 0.10 (n=4). ANOVA indicated at least one significant difference with a p < 0.05. Dunnett's test (using group D as the control) indicated that group A (HF for 2 months) was significantly lower than the control group (p<0.05). There was a small, but not significant decrease in the ratio for group C (normal chow for 1 month + HF chow for 1 month). These results suggest that TempostatinTM is effective at inhibiting the deposition of collagen within the capsule that forms around implanted silicone. Additionally, the reduction of the collagen index in group C and in the capsule and adjacent dermis of treated animals suggests that this drug is effective at reducing the collagen content of pre-existing structures.

The ability of TempostatinTM to safely inhibit pathologic fibrocellular reactions and type I collagen synthesis has been demonstrated in a variety of fibrosis related diseases. Early phase I human studies suggest that this drug has demonstrated minimal side-effects and a good safety record. Its ability to inhibit collagen deposition in new and pre-existing fibrous capsules suggests that it may be a useful adjunct to minimize the formation of capsules around implants.