Molecular, Functional, and Microstructural Imaging of Cervical Remodeling Biomarkers

摘要 早产（PTB）是全球新生儿死亡和发病的主要原因[1，2]，估计 每年有1500万新生儿早产。与早产相关的医疗费用是 据估计，在美国每年超过260亿美元[18]。最常见的临床风险指标 PTB是一种短宫颈，通过超声（US）成像确定，仅37.3%（低灵敏度）的女性 妊娠期<35周的孕妇，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%的妊娠）， 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/定性手动检查（Bishop评分），其确定成功的能力有限 劳动诱导。目前，还没有可靠的、临床上可翻译的和非侵入性的成像仪器 能够获得有关宫颈癌潜在机制的定量诊断信息， 不足和PTB。同样，没有临床适用的客观和定量的工具， 在引产期间评估宫颈成熟。因此，迫切需要一种成像方法， 该仪器能够在分子水平上定量观察宫颈的病理生理变化， 微观结构和功能水平。为了解决这一未满足的临床需求，我们一直在开发一种 多模态成像仪器，融合了光声（PA）、粘弹性（VE）和常规成像技术。 超声（US）在一个单一的经阴道探头。在该仪器中，PA成像将提供定量的 测量宫颈重塑的分子和微观结构机制生物标志物（即胶原蛋白 网络组织、水含量、微血管和氧合状态）; VE将评估组织中的变化 宫颈重塑的生物力学生物标志物（即刚度/柔软度和粘性）;以及 宫颈形态学成像（即宫颈长度）。因为TVUS是标准的护理成像模式， 监测子宫颈状况在怀孕和分娩期间，拟议的多模态成像仪器将增加 常规TVUS检查仅需3-5分钟，因此在常规检查中易于接受 临床实践拟议的仪器将有两个直接的临床应用：（a）改善 检测处于PT B风险中的患者，特别是在没有明显短宫颈的女性亚组中;（B） 在宫缩诱导前客观和定量测定宫颈成熟状态，作为 劳动诱导程序。在本研究的结论中，所提出的技术的诊断功效， 评估宫颈成熟生物标志物将被定量评估。

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.