Molecular, Functional, and Microstructural Imaging of Cervical Remodeling Biomarkers

总结。 早产是全世界新生儿死亡和发病率的主要原因[1，2]，据估计 每年有1500万早产儿发生早产。与早产相关的医疗费用有 据估计，美国每年约为260亿英镑[18]。临床上最常见的风险指标是 肺结核是一种短小的宫颈，根据超声(US)成像诊断，只有37.3%的女性(低敏感度) 世卫组织将在怀孕35周时分娩，阳性预测值非常有限，为17.8%。宫颈成熟 在引产过程中(美国超过23%的怀孕)是通过给药完成的 前列腺素等药物。目前的护理标准依赖于通过测量宫颈长度和一致性 主观/定性人工检查(毕晓普评分)，确定成功的能力有限 关于引产的问题。目前，还没有可靠的、临床可移植的、非侵入性的成像设备。 能够获得有关宫颈潜在机制的定量诊断信息 肺功能不全和肺结核。同样，临床上还没有可用于客观和定量测量的仪器。 引产过程中宫颈成熟的评估。因此，迫切需要一种成像技术 一种能够在分子水平上定量显示宫颈病理生理变化的仪器， 微观结构和功能层面。为了解决这一未得到满足的临床需求，我们一直在开发一种联合 融合了光声(PA)、粘弹性(VE)和常规成像技术的多模式成像仪器 超声(US)在一个单一的经阴道探头。在这台仪器中，PA成像将提供定量 宫颈重塑的分子和微结构机制生物标志物(即胶原)的测定 网络组织、水分含量、微血管和氧合状态)；VE将评估组织的变化 颈椎重塑的生物力学生物标记物(即硬度/柔软度和粘度)； 对宫颈形态(即宫颈长度)进行成像。因为TVUS是治疗的标准成像方式 在怀孕和分娩期间监测宫颈状况，拟议的多模式成像仪器将添加 常规TVUS检查仅需3-5分钟，因此在常规检查中很容易被接受 临床实践。拟议的仪器将有两个直接的临床应用：(A)改善 检测有肺结核风险的患者，特别是没有明显短子宫颈的妇女；(B) 在宫缩诱导前对宫颈成熟状态进行客观和定量的测定 引产程序。在这项研究的结论中，所提议的技术对 评估宫颈成熟的生物标志物将进行定量评估。

Summary. Preterm birth (PTB) is the leading cause of neonatal mortality and morbidity worldwide [1, 2], with an estimated incidence of 15 million neonates born preterm annually. Healthcare costs associated with prematurity are estimated to be >$26 billion annually in the United States [18]. The most common clinical indicator of risk for PTB is a short cervix, as determined by ultrasound (US) imaging identifies only 37.3% (low sensitivity) of women who will deliver <35 weeks of gestation, with a very limited positive predictive value of 17.8%. Cervical ripening during labor induction (more than 23% of pregnancies in United States) is accomplished by administration of drugs such as prostaglandin. Current standard of care relies on measuring cervical length and consistency by subjective/qualitative manual examination (a Bishop score), which has limited ability to determine the success of labor induction. Currently, there are no reliable, clinically translatable, and non-invasive imaging instruments capable of acquiring quantitative diagnostic information about the underlying mechanisms of cervical insufficiency and PTB. Similarly, there are no clinically applicable instruments for the objective and quantitative assessment of cervical ripening during labor induction. Therefore, there is an urgent need for an imaging instrument that enables quantitative visualization of pathophysiological changes of cervix at the molecular, microstructural, and functional levels. To address this unmet clinical need, we have been developing a combined multi-modal imaging instrument that merges Photoacoustic (PA), Viscoelasticity (VE), and conventional ultrasound (US) in a single transvaginal probe. In this instrument, PA imaging will provide quantitative measurements of molecular and microstructural mechanistic biomarkers of cervical remodeling (i.e. collagen network organization, water content, microvascular and oxygenation status); VE will assess the changes in tissue biomechanical biomarkers of cervical remodeling (i.e. degree of stiffness/softness and viscosity); and US for imaging cervical morphology (i.e. cervical length). Because TVUS is the standard of care imaging modality for monitoring cervical status during pregnancy and labor, the proposed multi-modal imaging instrument will add only 3-5 minutes to conventional TVUS examination and, therefore, will be readily acceptable in the routine clinical practice. The proposed instrument will have two immediate clinical applications: (a) improving the detection of patients at risk of PTB, particularly in a subset of women without an apparent short cervix; (b) objective and quantitative determination of cervical ripening status prior to induction of contractions, as a part of labor induction procedures. At the conclusion of this study, the diagnostic efficacy of the proposed technique to assess cervical ripening biomarkers will be quantitatively evaluated.