Extraocular Muscle (EOM) Responses to Bupivacaine Injection

描述（由申请人提供）：大多数现有的斜视治疗依赖于眼外肌（EOM）的代偿性损伤;我们正在开发一种替代方法，以加强EOM并以可控的方式改变其刚度和长度。快肌肥大（如EOM）是布比卡因（BUP）肌内注射动物的一致结果。BUP是一种局部作用的肌毒素，可导致肌纤维变性、卫星细胞激活和肌纤维再生，并持续肥大。在眼球后麻醉过程中无意中将BUP注射到人眼外肌中会导致斜视模式，建模表明这是由于肌肉作用场中的收缩性显著增加以及影响相反场的刚度略微增加。我们也有初步的结果表明，肌肉再生的长度取决于再生过程中的眼睛姿势。本课题旨在通过对兔眼的生物力学和组织学研究，以及对斜视患者的临床、MR成像、肌力和模拟研究，探讨BUP注射后眼外肌变化的类型、数量、持续性和机制。我们将BUP注射到正常和实验性麻痹的兔子眼肌中，在再生过程中，一些眼睛保持预定的姿势。我们将测量肌肉尺寸、弹性和收缩力的变化。我们将从组织学上评估肌纤维计数、大小和分离，以及结构和超微结构变化，包括瘢痕形成和纤维化。我们将改变注射体积和浓度，以确定安全产生有益效果所需的BUP剂量。我们已经开始了一项将BUP注射到成人斜视患者眼外肌中的试点试验，在水平斜视病例中取得了非常令人鼓舞的结果。这将扩展到垂直和斜肌和麻痹性疾病。我们将在注射前和注射后间隔使用磁共振成像（MRI）来验证注射部位并测量肌肉大小的变化。我们将测量和比较注射前后的双眼对准、眼球运动、扫视速度和肌肉力量，并注意任何副作用或并发症。随着剂量、注射技术和安全性数据的可用和标准化，我们将设计一项随机试验，比较BUP注射和斜视手术治疗水平斜视。控制肌肉加强BUP注射似乎准备提供一个强大的和有价值的新工具斜视管理。再生的肌肉长度减少，将模仿手术切除的效果。再生肌肉的长度增加，会产生手术无法达到的效果。充分了解动物实验中的基本肌肉变化，并准确记录各种疾病患者的肌肉大小变化和功能，对于实现这一目标至关重要。BUP注射液也有望用于治疗眼睑下垂和眼科以外的肌肉疾病。公共卫生相关性：注射局部麻醉剂布比卡因可以增加肌肉的大小和力量，并改变肌肉的长度。我们将把这一发现作为斜视或斗鸡眼手术治疗的替代方法。这种方法的扩展为许多肌肉疾病的治疗带来了巨大的希望。

Description (provided by applicant): Most existing treatments for strabismus rely on compensatory impairment of extraocular muscles (EOMs); we are developing an alternative to strengthen EOMs and alter their stiffnesses and lengths in controllable ways. Hypertrophy of fast muscle, such as EOM, is a consistent consequence of intramuscular injection of bupivacaine (BUP) in animals. BUP is a locally acting myotoxin that causes muscle fiber degeneration, satellite cell activation, and muscle fiber regeneration, continuing to hypertrophy. Inadvertent injection of BUP into human EOM during retrobulbar anesthesia causes a pattern of strabismus that modeling suggests is due to significantly increased contractility in the muscle's field of action and slightly increased stiffness affecting the opposite field. We also have preliminary results suggesting that muscles are regenerated at a length determined by eye posture during regeneration. This project aims to explore the types, amount, persistence, and mechanisms of changes in EOM after BUP injection by means of biomechanical and histological studies in rabbits, and by clinical, MR imaging, muscle force, and simulation studies in strabismus patients. We will inject BUP into normal and experimentally paralyzed rabbit eye muscles, with some eyes held in predetermined postures during regeneration. We will measure changes in muscle dimensions, elasticity, and contractile force. We will histologically assess muscle fiber counts, sizes and separations, and structural and ultrastructural changes, including scarring and fibrosis. We will vary injected volume and concentration to determine the dosage of BUP needed to safely produce beneficial effects. We have begun a pilot trial of BUP injection into EOMs of adult strabismus patients with very encouraging results in comitant horizontal cases. This will be extended to vertical and oblique muscles and to paretic disorders. We will use magnetic resonance imaging (MRI) before and at intervals after injection to verify injection sites and measure changes in muscle size. We will measure and compare binocular alignment, ocular motility, saccadic velocities, and muscle forces before and after injection, and note any side effects or complications. As data on dosage, injection technique, and safety become available and standardized, we will design a randomized trial comparing BUP injection and strabismus surgery for horizontal strabismus. Controlled muscle strengthening by BUP injection appears poised to provide a powerful and valuable new tool for strabismus management. Regenerating muscles at reduced lengths would mimic the effects of surgical resection. Regenerating muscles at increased lengths would produce effects unobtainable with surgery. Fully understanding the basic muscle changes in animal experiments and accurately documenting muscle size changes and function in patients with various disorders are both essential to this end. BUP injection also holds promise for treatment of eyelid ptosis and for muscle disorders beyond ophthalmology. PUBLIC HEALTH RELEVANCE: Injection of the local anesthetic bupivacaine can increase the size and strength, and alter the lengths of muscles. We will develop this finding as an alternative to surgical treatment for strabismus, or crossed eyes. Extension of this approach holds great promise for treatment of many muscle disorders.