Evaluating the role of photobiomodulation in human cervical remodeling in pregnancy

摘要： 为了使胎儿足月分娩，子宫颈必须在适当的时间重塑，软化和扩张， 怀孕如果子宫颈过早重塑，妊娠有自发性早产（sPTB）的风险， 这是一种产科困境，每年影响美国十分之一的怀孕，并使婴儿面临更大的风险 新生儿死亡、终身合并症和/或成年早期死亡率。相反，如果子宫颈 缺乏或延迟宫颈重塑和扩张，怀孕可能会超过预产期， 围产期发病率/死亡率的风险和对母亲的风险，包括剖宫产率增加一倍 率到目前为止，预防宫颈过早重塑导致sPTB或不充分的治疗干预， 导致过期妊娠的宫颈重塑是有限的，并且不是完全有效的。光生物调节 (PBM)使用低水平光疗法（LLLT）目前被用于临床环境中， 蓝光PBM已被证明可诱导血管平滑肌松弛（增加组织灌注） 并且红光/红外光可以调节炎症、ECM重塑和愈合组织的机械强度。 到目前为止，我们已经证明，人类子宫颈的内口含有大量的 收缩性平滑肌（可能形成括约肌，在怀孕期间保持子宫颈关闭）， 人宫颈平滑肌细胞通过分泌促炎因子在宫颈ECM重塑中发挥作用 细胞因子和基质金属蛋白酶（MMPs）。鉴于PBM可以调节平滑肌收缩性， 炎症/ECM重塑和组织强度，在这项提案中，我们的目标是确定我们是否可以利用 使用LLLT来增强或减弱颈部平滑肌介导的收缩性， 促炎/ECM重塑途径和宫颈组织机械特性。此外，由于我们 一个多学科的研究团队包括世界级的工程师，他们在人体软组织方面具有专业知识 机械和电气工程，我们的目标是开发一种新的，无线阴道内LLLT设备（用于 随后验证非人类灵长类动物），其可以在受控时间内发射特定波长的光 时期从拟议的研究中获得的知识很有希望转化为临床护理， 预防或逆转导致sPTB的过早宫颈重塑或增加宫颈 在足月妇女中重塑/扩张。

ABSTRACT: In order for a fetus to deliver at term, the cervix must remodel, soften and dilate at the appropriate time in pregnancy. If the cervix remodels prematurely, the pregnancy is at risk for spontaneous preterm birth (sPTB), an obstetric dilemma that affects 1 in 10 pregnancies in the U.S. each year and places babies at increased risk for neonatal death, lifelong comorbidities and/or mortality in early adulthood. Conversely, if the cervix exhibits deficient or delayed cervical remodeling and dilation, the pregnancy may go past the due date which increases the risk for perinatal morbidity/mortality and risks to the mother, including a doubling in the cesarean delivery rate. To date, therapeutic interventions to prevent premature cervical remodeling leading to sPTB or inadequate cervical remodeling leading to post-term pregnancies are limited and not entirely effective. Photobiomodulation (PBM) using low level light therapy (LLLT) is currently being used in clinical settings such as wound healing as PBM with blue light has been shown to induce vascular smooth muscle relaxation (increasing tissue perfusion) and red/infrared light can modulate inflammation, ECM remodeling and mechanical strength of healing tissues. To date, we have demonstrated that the internal os of the human cervix contains a significant amount of contractile smooth muscle (that likely forms a sphincter which keeps the cervix closed during pregnancy) and human cervical smooth muscle cells play a role in cervical ECM remodeling by secreting proinflammatory cytokines and matrix metalloproteinases (MMPs). Given that PBM can modulate smooth muscle contractility, inflammation/ECM remodeling and tissue strength, in this proposal, we aim to determine if we can harness the power of light and use LLLT to enhance or attenuate cervical smooth muscle mediated contractility, proinflammatory/ECM remodeling pathways and cervical tissue mechanical properties. In addition, since our team of multidisciplinary investigators includes world class engineers with expertise in human soft tissue mechanics and electrical engineering, our goal is to develop a novel, wireless intravaginal LLLT device (for subsequent validation non-human primates) that can emit specific wavelengths of light for controlled time periods. The knowledge obtained from the proposed studies hold great promise for translation to clinical care as novel treatments to prevent or reverse premature cervical remodeling leading to sPTB or to augment cervical remodeling/dilation in women at term.