Background: Immunomodulatory properties of bisphosphonates (BP) are suggested to contribute to the development of medication-associated osteonecrosis of the jaw (MRONJ). Furthermore, bisphosphonate-derived immune modulation might contribute to the anti-metastatic effect observed in breast cancer patients. Macrophages are potential candidates for the mediation of immunomodulatory effects of bisphosphonates. The study aimed to investigate the influence of bisphosphonates alone and in combination with surgical trauma on systemic macrophage polarization (M1 vs. M2) using an in vivo rat model. Methods: A total of 120 animals were divided into four groups. Groups 2 and 4 were treated with 8 × 40 μg/kg body weight of the BP Zoledronate i.p. (week 0–7). Groups 3 and 4 were exposed to surgical trauma (week 8, tooth extraction + tibia fracture), whereas in Group 1 neither medication nor surgical trauma was applied. After 8, 10, 12 and 16 weeks, skin, lung and spleen were immunohistochemically examined for macrophage polarization via expression analysis of CD68, CD163 and iNOS using a tissue microarray (TMA). Results: A significant shift of macrophage polarization towards M1 was observed in skin, spleen and lung tissue of animals, with and without surgical trauma, treated with BP when compared to those without BP application. Surgical trauma did not cause a significant increase towards M1 polarization. Conclusions: BP application leads to a systemic pro-inflammatory situation in vivo, independent of surgical trauma, as evidenced by the shift in macrophage polarization towards M1 in various somatic tissues. This provides a possible explanation for the clinically observed anti-tumor effect of bisphosphonates and might also contribute to pathogenesis of MRONJ.
This study aimed to investigate accuracy in different sectional planes of the TMA Grand Master (3DHISTECH) Workstation in various soft tissue samples collected from Wistar rats. A total of 108 animals were sacrificed and 963 tissue specimens collected from 12 soft-tissue types. A total of 3307 tissue cores were punched and transferred into 40 recipient TMA blocks. Digital image analysis was performed. Core loss showed a significant correlation with tissue type and was highest in skin tissue (p < 0.001), renal medulla and femoral artery, nerve, and vein bundle (p < 0.01). Overall, 231 of 3307 tissue cores (7.0%) were lost. Hit rate analysis was performed in 1852 punches. The target was hit completely, partially and missed totally by 89.4%, 7.2% and 2.2%. A total of 54.5% of punches had good accuracy with less than 200 µm deviation from the centre of the targeted region and 92.6% less than 500 µm. Accuracy decreases with greater sectional depth. In the deepest sectional plane of roughly 0.5 mm median depth, almost 90% of cores had a deviation below 500 µm. Recommendations for automated TMA creation are given in this article. The ngTMA®-method has proven accurate and reliable in different soft tissues, even in deeper sectional layers.
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