Summary The most common complications of irradiated implant-based mammary reconstruction are fibrosis and capsular contracture. The indications for postmastectomy adjuvant radiotherapy have considerably broadened. Facing an increased number of patients who will require radiotherapy, most guidelines recommend delaying reconstruction after radiotherapy to prevent long-term fibrotic complications. Does radiotherapy permanently alter cellular properties which will adversely affect implant-based reconstruction? If so, is there a benefit in delaying reconstruction after radiotherapy? Our in vitro model simulates two implant-based mammary reconstruction approaches: the irradiated implant and the delayed implant reconstructions by using an implant inset beneath healthy non-irradiated tissue post radiotherapy. We performed cell culture of fibroblasts and endothelial cells to simulate these two surgical conditions. Irradiated fibroblasts simulate the capsular tissue seen around the breast implant. The delayed reconstruction approach is simulated by non-irradiated fibroblasts conditioned with supernatant culture media obtained from irradiated endothelial cells. Irradiation induced fibrosis through fibroblast differentiation into myofibroblasts, as demonstrated by increased α-smooth-muscle actin levels in fibroblasts. This constitutes the basis for scar tissue contraction observed in irradiated implant-based breast reconstruction. Irradiation of endothelial cells induced irreversible cell cycle arrest known as senescence and secretion of the profibrotic connective tissue growth factor. Non-irradiated fibroblasts conditioned with culture media obtained from irradiated endothelial cells exhibited myofibroblast differentiation and the expression of fibrotic phenotype akin to capsular contracture. Our results demonstrate that radiotherapy causes irreversible cellular changes, which permanently alter the microenvironment in favor of fibrosis. Given that these changes are permanent, delaying reconstruction does not present an advantage in preventing capsular contracture.
