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The authors compared clinical outcomes to determine whether acellular dermal matrix altered the capsular tissue architecture in irradiated and nonirradiated breasts following matrix–assisted expander reconstruction.Part I included all 27 patients who underwent bilateral tissue expander reconstruction with acellular dermal matrix between 2007 and 2012 and subsequent unilateral radiation therapy. Part II included a subset of patients with capsular biopsy specimens taken at the time of implant exchange for histologic analysis. Specimens included irradiated and nonirradiated acellular dermal matrix and irradiated and nonirradiated native capsule. Clinical outcomes were analyzed in relation to capsule architecture and acellular dermal matrix performance.In part I, mean follow-up was 28 months. Grade III/IV contractures were identified in nine patients (all on the irradiated side), and 12 developed noncontracture complications (75 percent on the irradiated side). Nine patients were unable to continue with implant reconstruction and required salvage with autologous tissue. In part II, postirradiation biopsy specimens were taken of the peri-implant capsule in six patients at the time of secondary surgery. Elastin content and the total cellular infiltrate were significantly greater in the irradiated versus nonirradiated native capsules (p = 0.0015). Conversely, the irradiated matrix capsule was composed of similar amounts of cellular infiltrate and collagen as the nonirradiated matrix capsules and nonirradiated native capsules. Irradiated acellular dermal matrix showed the least amount of alpha-smooth actin staining but a similar number of blood vessels.Acellular dermal matrix appears to limit the elastosis and chronic inflammation seen in irradiated implant reconstructions and is potentially beneficial in these patients.Therapeutic, III.