Development of a Colorimetric Sensor for Detection of Cerebrospinal Fluid Leaks

项目摘要 Chemeleon公司是一家位于纽约的初创公司，正在开发一种新型的比色生物传感器， 脑脊液（CSF）在床旁（POC）泄漏，例如由医生诊断创伤性脑 急诊科（艾德）的创伤（TBI）患者，或急诊科的急诊医疗技术人员（EMT）。 救护车，或在脊柱和耳鼻喉科手术的术中和术后护理期间。CSF 当缓冲大脑和脊柱的液体通过周围的破裂而泄漏时， 膜。这些泄漏主要是由TBI引起的，但在脊柱手术、耳鼻喉科手术中也是一种风险。 手术、腰椎穿刺和腰椎穿刺，它们也可以是自发的。区分CSF泄漏与 对于艾德医生、EMT和外科医生来说，其他体液的泄漏是一个众所周知的问题， 单侧溢液或耳溢液，从鼻子或耳朵流出的透明水样分泌物，或与血液混合， 脊柱手术中的其他液体。目前没有针对CSF泄漏的POC诊断，现有方法 要求将患者样本送至第三方实验室，可能需要4-7天才能得出结果。治疗延迟 或误诊会大大增加危及生命的脑膜炎、感染和中风的风险。患者 发展成脑膜炎的脑脊液漏也有更高的发病率。此外，为期一周的 住院不仅会给病人带来严重的痛苦和不适，而且还会导致更高的死亡率。 医疗费用。在这个直接进入第二阶段的提案中，Chemeleon旨在通过以下方式推进CSF泄漏诊断： 开发一种新颖、廉价的生物传感器，不需要额外的设备或人员培训， 在几分钟内提供结果，使医疗专业人员能够做出时间敏感的决定。Chemeleon拥有 已经成功地开发了一种原型结合诱导纳米结构动态表面（BINDS）分析 结合CSF蛋白生物标志物β-2-转铁蛋白（b2 TR）。该BINDS平台技术集成了 具有b2 TR特异性适体受体的纳米光子报告物表面，其中b2 TR与传感器的结合 表面改变表面能量，产生肉眼可见的鲜艳颜色变化。证明 概念实验显示Chemeleon的BINDS CSF测定可在10分钟内检测1 μg/ml的b2 TR， 其高于CSF中发现的4-5 μg/ml。对于直接进入II期研究，CSF传感器将进一步 开发用于实现临床使用所需的高特异性、高灵敏度和低读出时间， 字段设置。Chemeleon将专注于（1）优化传感器性能，以快速区分CSF和鼻腔 流体和血液样品，（2）完成有效扩大规模的制造工艺，以及（3）设计和 测试一个商业体外诊断原型。Chemeleon的CSF传感器将在以下方面提供进步： 头部创伤、脊柱和耳鼻喉科手术病例的决策，并提供模块化平台 用于其他医疗诊断的发展。

PROJECT SUMMARY Chemeleon, Inc. is a NYC-based startup that is developing a novel colorimetric biosensor that rapidly diagnoses cerebrospinal fluid (CSF) leaks at the Point-of-Care (POC), such as by doctors to diagnose Traumatic Brain Injury (TBI) patients in the Emergency Department (ED), or the Emergency Medical Technician (EMT) in the ambulance, or during intraoperative and post-operative care for spinal and otolaryngological surgeries. CSF leaks occur when the fluid that cushions the brain and spine escapes through ruptures in the surrounding membranes. These leaks are largely caused by TBIs but are also a risk during spinal surgeries, otolaryngological surgeries, lumbar punctures and epidurals and they can also be spontaneous. Distinguishing CSF leaks from other bodily fluids is a well-known problem for ED doctors, EMTs and surgeons as the leaks often present as unilateral rhinorrhea or otorrhea, a clear watery discharge from the nose or ear, or as a mixture with blood and other fluids during spinal surgery. Currently there are no POC diagnostics for CSF leaks and existing methods require patient samples to be sent to third-party laboratories for results that can take 4-7 days. Treatment delays or misdiagnoses significantly increase the risk for life-threatening meningitis, infections and stroke. Patients with CSF rhinorrhea that develop meningitis have also have much higher morbidity rates. Additionally, the weeklong stay not only causes significant distress and discomfort for the patient, but also leads to radically higher healthcare costs. In this Direct-to-Phase II proposal, Chemeleon aims to advance CSF leak diagnosis by developing a novel, inexpensive biosensor that requires no additional equipment or personnel training that can provide results in minutes, enabling medical professionals to make time-sensitive decisions. Chemeleon has already successfully developed a prototype Binding-Induced Nanostructured Dynamic Surface (BINDS) Assay that binds the CSF protein biomarker, beta-2-transferrin (b2TR). This BINDS platform technology integrates nanophotonic reporter surfaces with b2TR-specific aptamer receptors, where binding of b2TR to the sensor surface alters the surface energy producing a vibrant color change that is visible to the naked eye. Proof-of- concept experiments revealed that Chemeleon’s BINDS CSF assay could detect 1 µg/ml of b2TR in 10 minutes, which is higher than the 4-5 µg/ml found in CSF. For Direct-to-Phase II studies, the CSF sensor will be further developed to achieve the high specificity, high sensitivity and low readout time required for use in clinical and field settings. Chemeleon will focus on (1) optimizing sensor performance to rapidly distinguish CSF from nasal fluid and blood samples, (2) finalizing manufacturing processes for efficient scale-up, and (3) designing and testing a commercial in vitro diagnostic prototype. Chemeleon’s CSF sensor will provide advancements in decision-making for head trauma, spinal and otolaryngological surgical cases and present a modular platform for the development of other healthcare diagnostics.