A Novel Tissue Engineered Three-Dimensional Biomimetic Platform for In Vitro Study of BIA-ALCL
Matthew A. Wright1, Daniel O. Lara1, Arash Samadi1, Yoshiko Toyoda1, Karel-Bart Celie1, Runlei Zhao1, Giorgio G. Inghirami2, Kristy A. Brown3, Jason A. Spector1.
1Laboratory of Bioregenerative Medicine and Surgery, Weill Cornell Medical College, New York, NY, USA, 2Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA, 3Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
PURPOSE: Implicated in at least 16 deaths worldwide and with a lifetime risk estimated by some as high as 1 in 4000 cases of textured device implantation, breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) has garnered increasing attention from researchers and the lay press alike. However, largely because of the lack of appropriate models, the pathogenesis of this devastating complication remains poorly understood. We have developed a tissue engineered three-dimensional biomimetic breast tissue platform that utilizes patient derived tissues in order to study BIA-ALCL. METHODS: Patient-derived breast tissue was processed, and all cellular constituents including adipocytes, organoids, and stromal vascular fraction (including immune cells) were used to populate an approximately 50μL three-dimensional type I collagen extracellular matrix within 96 well plates. Two separate experiments were then performed. First, BIA-ALCL cells were seeded at a density of 200,000 cells/mL homogenously within the biomimetic platform and also in wells that contained 0.3% collagen alone without patient-derived breast cells. In addition, BIA-ALCL cells were mixed with collagen at a density of 40,000/μL and fabricated into 1μL "tumor buttons" and placed onto the bottom of each well. These buttons were then immersed within either biomimetic breast platform or 0.6% collagen-only matrix. Wells were then imaged every other day using confocal microscopy, and images were processed using Imaris™ software, analyzing for cell counts in the first experiment and for tumor cell invasion into the surrounding environment for the second experiment. RESULTS: In the first experiment, BIA-ALCL cells thrived in the biomimetic platform and grew significantly more rapidly than their counterparts in the collagen-only wells. Both groups started at an equal density of approximately 300 cells per three-dimensional confocal snapshot on day 0, and both groups demonstrated logistic growth curves. However, cells in the biomimetic platform grew nearly 50% faster and reached a higher plateau than those in the collagen-only group. On day 10 the mean cell number in the biomimetic group was 596 ± 40.8 versus 432.2 ± 32.6 in the collagen only group (p<0.0001). Analysis of the tumor buttons showed multiple instances of invasion of BIA-ALCL cells into both the surrounding biomimetic breast platform and the collagen-only matrix as early as day two and as late as day twelve. Cells traveled up to hundreds of microns into the surrounding environment in some cases. CONCLUSIONS: We have developed the first tissue engineered three-dimensional biomimetic in vitro model of BIA-ALCL to date. We believe that this novel in vitro system will allow for a better mechanistic understanding of BIA-ALCL and may eventually aid in the discovery of methods to prevent this rare, poorly understood, and potentially fatal complication of breast prosthesis placement.
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