For decades, it has been assumed that the foreign body response (FBR) to biomedical implants is primarily a reaction to the chemical and mechanical properties of the implant. Here, we show for the first time that a third independent variable, allometric tissue-scale forces (which increase exponentially with body size), can drive the biology of FBR in humans. We first demonstrate that pathological FBR in humans is mediated by immune cell-specific Rac2 mechanotransduction signaling, independent of implant chemistry or mechanical properties. We then show that mice, which are typically poor models of human FBR, can be made to induce a strikingly human-like pathological FBR by altering these extrinsic tissue forces. Altering these extrinsic tissue forces alone activates Rac2 signaling in a unique subpopulation of immune cells and results in a human-like pathological FBR at the molecular, cellular, and local tissue levels. Finally, we demonstrate that blocking Rac2 signaling negates the effect of increased tissue forces, dramatically reducing FBR. These findings highlight a previously unsuspected mechanism for pathological FBR and may have profound implications for the design and safety of all implantable devices in humans.

中文翻译：

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异速组织尺度力激活机械反应免疫细胞以驱动对生物医学植入物的病理异物反应

几十年来，人们一直认为生物医学植入物的异物反应 (FBR) 主要是对植入物的化学和机械特性的反应。在这里，我们首次展示了第三个自变量，异速生长组织尺度力（随身体大小呈指数增长），可以驱动人类 FBR 的生物学。我们首先证明人类病理性 FBR 是由免疫细胞特异性Rac2机械转导信号介导的，与植入物化学或机械特性无关。然后，我们表明，通常是人类 FBR 的较差模型的小鼠，可以通过改变这些外在组织力来诱导明显类似于人类的病理性 FBR。单独改变这些外在组织力会激活Rac2在独特的免疫细胞亚群中发出信号，并在分子、细胞和局部组织水平上产生类似人类的病理性 FBR。最后，我们证明阻断Rac2信号会抵消组织力增加的影响，从而显着降低 FBR。这些发现突出了以前未曾预料到的病理性 FBR 机制，并可能对人类所有可植入设备的设计和安全性产生深远影响。