Macrophages are a critical driver of neovessel formation in tissue-engineered vascular grafts (TEVGs), but also contribute to graft stenosis, a leading clinical trial complication. Macrophage depletion via liposomal delivery of clodronate, a first-generation bisphosphonate, mitigates stenosis, but simultaneously leads to a complete lack of tissue development in TEVGs. This result and the associated difficulty of utilizing liposomal delivery means that clodronate may not be an ideal means of preventing graft stenosis. Newer generation bisphosphonates, such as zoledronate, may have differential effects on graft development with more facile drug delivery. We sought to examine the effect of zoledronate on TEVG neotissue formation and its potential application for mitigating TEVG stenosis. Thus, mice implanted with TEVGs received zoledronate or no treatment and were monitored by serial ultrasound for graft dilation and stenosis. After two weeks, TEVGs were explanted for histological examination. The overall graft area and remaining graft material (polyglycolic-acid) were higher in the zoledronate treatment group. These effects were associated with a corresponding decrease in macrophage infiltration. In addition, zoledronate affected the deposition of collagen in TEVGs, specifically, total and mature collagen. These differences may be, in part, explained by a depletion of leukocytes within the bone marrow that subsequently led to a decrease in the number of tissue-infiltrating macrophages. TEVGs from zoledronate-treated mice demonstrated a significantly greater degree of smooth muscle cell presence. There was no statistical difference in graft patency between treatment and control groups. While zoledronate led to a decrease in the number of macrophages in the TEVGs, the severity of stenosis appears to have increased significantly. Zoledronate treatment demonstrates that the process of smooth muscle cell-mediated neointimal hyperplasia may occur separately from a macrophage-mediated mechanism.

中文翻译：

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唑来膦酸盐改变组织工程血管移植物的自然进展

巨噬细胞是组织工程血管移植物 (TEVG) 中新血管形成的关键驱动因素，但也导致移植物狭窄，这是一种主要的临床试验并发症。通过第一代双膦酸盐氯膦酸盐的脂质体递送来消耗巨噬细胞可减轻狭窄，但同时导致 TEVG 完全缺乏组织发育。这一结果和使用脂质体递送的相关困难意味着氯膦酸盐可能不是预防移植物狭窄的理想方法。新一代双膦酸盐，如唑来膦酸盐，可能对移植物的发育产生不同的影响，药物递送更容易。我们试图检查唑来膦酸盐对 TEVG 新组织形成的影响及其在减轻 TEVG 狭窄方面的潜在应用。因此，植入 TEVG 的小鼠接受唑来膦酸盐或不治疗，并通过连续超声监测移植物扩张和狭窄。两周后，取出 TEVG 进行组织学检查。唑来膦酸盐治疗组的总移植面积和剩余的移植材料（聚乙醇酸）较高。这些影响与巨噬细胞浸润的相应减少有关。此外，唑来膦酸盐影响 TEVG 中胶原蛋白的沉积，特别是总胶原蛋白和成熟胶原蛋白。这些差异可能部分解释为骨髓内白细胞的消耗，随后导致组织浸润性巨噬细胞数量的减少。来自唑来膦酸盐治疗小鼠的 TEVG 表现出显着更大程度的平滑肌细胞存在。治疗组和对照组之间的移植物通畅率没有统计学差异。虽然唑来膦酸盐导致 TEVG 中巨噬细胞数量减少，但狭窄的严重程度似乎显着增加。唑来膦酸盐治疗表明平滑肌细胞介导的新内膜增生过程可能与巨噬细胞介导的机制分开发生。