Thayer School of Engineering at Dartmouth, Hanover, NH, 03755, USA.
Department of Surgery, Geisel School of Medicine at Dartmouth, Hanover, NH, 03755, USA.
Sci Rep. 2017 Aug 30;7(1):10093. doi: 10.1038/s41598-017-10671-w.
The poor efficacy of systemic cancer therapeutics in pancreatic ductal adenocarcinoma (PDAC) is partly attributed to deposition of collagen and hyaluronan, leading to interstitial hypertension collapsing blood and lymphatic vessels, limiting drug delivery. The intrinsic micro-regional interactions between hyaluronic acid (HA), collagen and the spatial origins of mechanical stresses that close off blood vessels was investigated here. Multiple localized pressure measurements were analyzed with spatially-matched histochemical images of HA, collagen and vessel perfusion. HA is known to swell, fitting a linear elastic model with total tissue pressure (TTP) increasing above interstitial fluid pressure (IFP) directly with collagen content. However, local TTP appears to originate from collagen area fraction, as well as increased its entropy and fractal dimension, and morphologically appears to be maximized when HA regions are encapsulated by collagen. TTP was inversely correlated with vascular patency and verteporfin uptake, suggesting interstitial hypertension results in vascular compression and decreased molecular delivery in PDAC. Collagenase injection led to acute decreases in total tissue pressure and increased drug perfusion. Large microscopic variations in collagen distributions within PDAC leads to microregional TPP values that vary on the hundred micron distance scale, causing micro-heterogeneous limitations in molecular perfusion, and narrows viable treatment regimes for systemically delivered therapeutics.
在胰腺导管腺癌 (PDAC) 中，全身性癌症疗法的疗效不佳部分归因于胶原蛋白和透明质酸的沉积，导致间质高压使血管和淋巴管塌陷，限制了药物输送。在这里，我们研究了透明质酸 (HA)、胶原蛋白之间的固有微观区域相互作用以及机械应力的空间起源，这些机械应力会使血管关闭。对 HA、胶原蛋白和血管灌注的空间匹配组织化学图像进行了多次局部压力测量分析。已知透明质酸会膨胀，符合总组织压力 (TTP) 随着胶原蛋白含量的增加而直接高于间质液压力 (IFP) 的线性弹性模型。然而，局部 TTP 似乎来自于胶原蛋白面积分数，以及增加了其熵和分形维数，并且当 HA 区域被胶原蛋白包裹时，形态上似乎达到最大值。TTP 与血管通畅性和维替泊芬摄取呈负相关，表明间质高压导致血管压缩和 PDAC 中分子输送减少。胶原酶注射导致总组织压力急性下降和药物灌注增加。PDAC 内胶原蛋白分布的大微观变化导致微区域 TPP 值在数百微米的距离尺度上变化，导致分子灌注的微观异质性限制，并缩小了系统性输送治疗剂的可行治疗方案。
