Periprosthetic Capsule Formation and Contracture in a Rodent Model of Implant-Based Breast Reconstruction With Delayed Radiotherapy.

INTRODUCTION: Capsular contracture (CC) is the most common complication of breast implantation, with an incidence of nearly 50% in patients undergoing breast reconstruction with subsequent radiotherapy. Although the move toward submuscular (SM) device placement led to a decreased incidence of CC, subcutaneous (SQ) implantation has seen a resurgence. The purpose of this study was to use a rodent model of breast reconstruction with smooth silicone implants and delayed radiotherapy to assess the occurrence of CC in SQ versus SM implantation. METHODS: Custom 2 mL smooth round silicone implants were placed bilaterally into 12 female Sprague Dawley rats that were randomized into 4 groups of 3, with each group differing by implantation plane (SQ vs SM) and irradiation status (irradiated vs nonirradiated). Rats from the SQ group received implants bilaterally underlying the skin on the flank. Rats in the SM groups received implants bilaterally under the latissimus dorsi muscle. Irradiated rats received 20 Gy localized to each implant on postoperative day 10. One rat from each group was imaged with a micro-computed tomography scanner at baseline and at explant 3 months later, whereupon capsules from all rats were examined histologically. RESULTS: Rats in the SQ group showed evidence of contracture on gross examination and greater evidence of morphologic disruption per micro-computed tomography scan. There was no evidence of contracture or morphologic disruption in either SM group. Mean ± SD capsule thickness was 39.0 ± 9.0 µm in the SQ versus 37.6 ± 9.8 µm in the SM nonirradiated groups and 43.9 ± 14.9 µm in the SQ versus 34.3 ± 8.3 µm in the SM irradiated groups (all P > 0.05). CONCLUSIONS: In a rodent model of smooth silicone breast implantation and delayed radiotherapy, although there did not appear to be differences in capsule thickness regardless of device placement plane, SQ implants demonstrated gross evidence of CC. These data indicate that capsule thickness is only part of a larger pathogenetic picture, which should take into consideration the contribution from all peri-implant tissue.

A 3-Dimensional Biomimetic Platform to Interrogate the Safety of Autologous Fat Transfer in the Setting of Breast Cancer.

INTRODUCTION: Obesity is a known risk factor for the development and prognosis of breast cancer. Adipocytes have been identified as a source of exogenous lipids in other cancer types and may similarly provide energy to fuel malignant survival and growth in breast cancer. This relationship is of particular relevance to plastic surgery, because many reconstructions after oncologic mastectomy achieve optimal aesthetics and durability using adjunctive autologous fat transfer (AFT). Despite the increasing ubiquity and promise of AFT, many unanswered questions remain, including safety in the setting of breast cancer. Clinical studies to examine this question are underway, but an in vitro system is critical to elucidate the complex interplay between the cells that normally reside at the surgical recipient site. To study these interactions and characterize possible lipid transfer between adipocytes to breast cancer cells, we designed a 3-dimensional in vitro model using primary patient-derived tissues. METHODS: Breast adipose tissue was acquired from patients undergoing breast reduction surgery. The tissue was enzymatically digested and sorted to retrieve adipocytes and adipose stromal cells. Polydimethylsiloxane wells were filled with type I collagen-encapsulated adipocytes labeled with the fluorescent lipid dye boron dipyrromethene, as well as unlabeled adipose stromal cells. A monolayer of red fluorescently labeled MDA-MB-231 and MDA-MB-468 breast cancer cells was seeded on the surface of the construct. Lipid transfer at the interface between adipocytes and breast cancer cells was analyzed. RESULTS: Confocal microscopy revealed a dense culture of native adipocytes containing fluorescent lipid droplets in the 3-dimensional collagen culture platform. RFP-positive breast cancer cells were found in close proximity to lipid-laden adipocytes. Lipid transfer from adipocytes to breast cancer cells was observed by the presence of boron dipyrromethene-positive lipid droplets within RFP-labeled breast cancer cells. CONCLUSION: We have established a 3-dimensional model to study complex breast cancer-adipose tissue interactions. Direct transfer of fluorescently labeled lipids from adipocytes to breast cancer cells may indicate aberrant metabolism to fuel malignant growth and adaptive survival. Our novel platform can untangle the complex interplay within the breast cancer tumor microenvironment for high-throughput analysis and better elucidate the safety of AFT in postoncologic mastectomy.

In Search of a Murine Model of Radiation-Induced Periprosthetic Capsular Fibrosis.

INTRODUCTION: Capsular contracture after breast reconstruction is a morbid complication, occurring in 30.0% to 47.5% of patients undergoing postoperative radiotherapy. Although it is well known that radiation increases rate of capsular contracture, there are few well-established animal models that faithfully replicate standard-of-care clinical practice, that is, prosthesis placement at the time of mastectomy followed by delayed radiotherapy. To better recapitulate current clinical practice, we developed a murine model in which the implant sites were irradiated 10 days postoperatively, rather than at time of surgery. METHODS: Hemispherical implants were created from polydimethylsiloxane and implanted bilaterally in the subcutaneous dorsa of 20 C57Bl/6 mice. Mice were randomized to 5 treatment groups, differing in irradiation dose: 0 to 40 Gy. Ten days postoperatively, irradiation was performed using 250-kVp x-rays (XRAD225Cx, Precision X-ray, North Branford, Conn). In 1 mouse per group, dosimeters were placed subcutaneously to measure the delivered absorbed dose. Thirty-one days postoperatively, the mice were sacrificed and examined grossly, and periprosthetic tissues were removed for histologic analysis of periprosthetic capsule thickness and cellular deposition. RESULTS: Total radiation dose was calculated by the treatment planning software and confirmed by the in vivo dosimeters. Physical examination of the irradiated region demonstrated evidence of local radiation delivery, including circular patterns of hair blanching and thinning directly over the implants. Furthermore, histologic analysis of the irradiated epidermis demonstrated dose-dependent radiation changes including keratin whorls and patches of uneven epidermal thickness. There was no statistically significant difference in capsule thickness among the groups. Mice in the 30 and 40 Gy groups endured complications including shortness of breath, coagulopathy, and death, signs of systemic radiation poisoning. CONCLUSIONS: There was no evidence of increased periprosthetic capsule thickness with localized irradiation, irrespective of dose up to 20 Gy. These results differ from those previously published, which demonstrated increased capsule thickness with 10 Gy irradiation. Given the evidence of local radiation delivery, we believe that the lack of increase in capsule thickness observed in our experiment is a real phenomenon and demonstrate the difficulty in creating an easily reproducible rodent model that mimics the effects of postmastectomy implant-based reconstruction and irradiation.

Comparing Outcomes after Oncoplastic Breast Reduction and Breast Reduction for Benign Macromastia.

BACKGROUND: Oncoplastic breast reconstruction improves cosmetic outcomes when compared to standard breast conservation therapy alone. The authors studied whether tailoring a breast reduction to a cancer resection affects complication rates by comparing (1) outcomes between oncoplastic and benign macromastia patients and (2) complication rates between the cancer side and the symmetrizing side of an oncoplastic reduction. METHODS: A retrospective chart review was performed on female patients who underwent either oncoplastic or benign breast reduction over 9 years by a single surgeon. Patient demographics, intraoperative data, and postoperative outcomes were gathered from the electronic medical record. Chi-square and t tests were performed when appropriate to determine significance. RESULTS: Of the 211 patients included in the study, 62 (29.4 percent) underwent oncoplastic breast reduction and 149 (70.6 percent) underwent breast reduction for benign macromastia. Total resection weight was greater in the benign group (p = 0.00). There was a higher rate of loss of nipple sensation in the oncoplastic group (p = 0.005) but no differences in any other complication. There was a higher complication rate in the oncologic breast when compared to the symmetrizing breast within the oncoplastic cohort (p = 0.039), but no differences in the rates of individual complications. CONCLUSIONS: Although the loss of nipple sensation was increased in patients undergoing oncoplastic breast reduction, all other outcomes were not significantly different between the two groups. The authors' findings indicate that oncoplastic breast reduction can be performed with a safety profile similar to that of a standard breast reduction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Three-Dimensional-Printed External Scaffolds Mitigate Loss of Volume and Topography in Engineered Elastic Cartilage Constructs.

OBJECTIVE: A major obstacle in the clinical translation of engineered auricular scaffolds is the significant contraction and loss of topography that occur during maturation of the soft collagen-chondrocyte matrix into elastic cartilage. We hypothesized that 3-dimensional-printed, biocompatible scaffolds would "protect" maturing hydrogel constructs from contraction and loss of topography. DESIGN: External disc-shaped and "ridged" scaffolds were designed and 3D-printed using polylactic acid (PLA). Acellular type I collagen constructs were cultured in vitro for up to 3 months. Collagen constructs seeded with bovine auricular chondrocytes (BAuCs) were prepared in 3 groups and implanted subcutaneously in vivo for 3 months: preformed discs with ("Scaffolded/S") or without ("Naked/N") an external scaffold and discs that were formed within an external scaffold via injection molding ("Injection Molded/SInj"). RESULTS: The presence of an external scaffold or use of injection molding methodology did not affect the acellular construct volume or base area loss. In vivo, the presence of an external scaffold significantly improved preservation of volume and base area at 3 months compared to the naked group (P < 0.05). Construct contraction was mitigated even further in the injection molded group, and topography of the ridged constructs was maintained with greater fidelity (P < 0.05). Histology verified the development of mature auricular cartilage in the constructs within external scaffolds after 3 months. CONCLUSION: Custom-designed, 3D-printed, biocompatible external scaffolds significantly mitigate BAuC-seeded construct contraction and maintain complex topography. Further refinement and scaling of this approach in conjunction with construct fabrication utilizing injection molding may aid in the development of full-scale auricular scaffolds.