Ultrafast Laser Phonosurgery for Biomaterial Localization in Scarred Vocal Folds

声带疤痕是发音困难等发声障碍的主要原因，估计有200万至600万人受到影响。 仅在美国。声带瘢痕是振动浅固有层(SLP)置换术的结果 有坚硬的胶原疤痕组织。SLP粘弹性能的改变对声带振动的影响 并导致发音不佳。在过去的十年里，可注射生物材料被作为一种手段进行了研究 以恢复瘢痕声带的粘弹性。不幸的是，由于阻力增加，本地化程度较差 生物材料在硬性疤痕组织中的流动会对可重复和可靠的结果产生不利影响。 为了解决这个关键问题，我们假设由聚焦在以下的超快激光脉冲产生的空洞 疤痕部位的表面将有助于生物材料的注射和在所需位置的定位。我们的基础是 假设a)超快激光在块状组织中非侵入性地进行亚表面切割的独特能力，b) 生物材料优先流经阻力最小的路径的事实，c)体外实验 结果降低了注射压力并成功地在Focus产生的空隙中定位了生物材料 疤痕组织中的超快激光脉冲，以及d)导致长时间持续的初步体内手术实验 在周围没有可检测到的纤维化(无疤痕)的健康组织中，生物材料在消融空洞内的定位 空无一物。为了证明上述假设，我们将开发喉部特定的、图像引导的超快激光探测器 并使用小(仓鼠)和大(犬)动物模型在体内测试我们的手术方法。 我们将通过三个具体目标推进我们在该项目中的目标：1)量化 超快激光消融组织及其体内空洞形成和生物材料注射技术的研究 在疤痕组织中使用桌面显微镜和经过验证的仓鼠颊囊疤痕模型，2)设计和 开发喉部特异的超快激光手术探头，将能够在大型动物身上进行亚表面消融 (并最终在人类患者中)并通过非线性显微镜提供视觉反馈和指导， 3)评价激光探头在犬声带瘢痕模型中的有效性和人体工效学 最终评估注射生物材料的本地化对声带功能改善的影响。 该项目的成功完成将导致一种新的经过临床前测试的手术工具，它将使受控 以及可注射生物材料的可重复测试，用于治疗人类患者的疤痕声带。 这个高度跨学科的项目将在消色差、微型化光学、微 制造，用于超快激光传输和非线性内窥镜的大型空芯光纤技术，高 用于区分组织的快速视频频闪图像分析和定量分析方法 用非线性显微镜进行了形态观察。

Vocal fold scarring is a major cause of voice disorders like dysphonia, affecting an estimated 2 to 6 million people in the US alone. Vocal fold scarring results from the replacement of the vibratory superficial lamina propria (SLP) with stiff collagenous scar tissue. The modified viscoelastic properties of the SLP impairs vocal fold’s vibration and results in poor phonation. Over the last decade, injectable biomaterials have been investigated as a means to restore the viscoelasticity of scarred vocal folds. Unfortunately, poor localization due to increased resistance of biomaterial flow in stiff scar tissue adversely affects repeatable and reliable outcomes. To address this critical issue, we hypothesize that voids created by ultrafast laser pulses focused below the surface at the scar site will aid biomaterial injection and localization in the desired location. We base our hypothesis on a) the unique ability of ultrafast lasers to non-invasively create sub-surface cuts in bulk tissue, b) the fact that biomaterials preferentially flow through the path of least resistance, c) ex vivo experiments that resulted in reduced injection pressures and successful biomaterial localization in voids created by focused ultrafast laser pulses in scarred tissue, and d) Preliminary in vivo surgery experiments that resulted in long lasting biomaterial localization inside the ablated voids in healthy tissue with no detectable fibrosis (no scarring) around the void. To demonstrate the said hypothesis, we will develop larynx-specific, image guided ultrafast laser probes and test our surgery method in vivo using small (hamster) and large (canine) animal models. We will advance our goals in this project through three Specific Aims: 1) quantify the healing response of tissue to ultrafast laser ablation and characterize the void formation and biomaterial injection techniques in vivo in scar tissues using a table-top microscope and a proven hamster cheek pouch scar model, 2) design and develop larynx-specific ultrafast laser surgery probes that will be capable of sub-surface ablation in large animals (and eventually in human patients) and provide visual feedback and guidance through non-linear microscopy, and 3) evaluate the efficacy and ergonomics of the laser probes in a canine vocal fold scar model in vivo to ultimately assess the impact of localization of injected biomaterials on the functional improvement of vocal folds. Successful completion of the project will result in a new pre-clinically tested surgery tool that will enable controlled and repeatable testing of injectable biomaterials for the treatment of scarred vocal folds in human patients. This highly interdisciplinary project will provide innovations in achromatic, miniaturized optics, micro- manufacturing, large air-core optical fiber technologies for ultrafast laser delivery and non-linear endoscopy, high speed videostroboscopy image analysis and quantitative analysis methods for differentiating tissue morphologies using non-linear microscopy.