Portable, low-cost cryotherapy system that does not require consumable cryogen gas for the treatment of cervical precancerous lesions

摘要 虽然宫颈癌死亡率在高收入国家大幅下降，但宫颈癌是世界上最严重的癌症之一。 低收入和中等收入国家（LMIC）癌症死亡的主要原因。宫颈癌占 2020年有341，800人死亡，其中约90%发生在中低收入国家。治疗 癌前病变对预防癌症进展非常有效，因此关键是识别和治疗 早期病变然而，大多数提供宫颈癌筛查的低收入国家缺乏可获得的治疗 服务缺乏容易获得的治疗选择意味着将患者转诊到较大的医院， 阻碍适当的治疗，导致疾病进展为癌症。宫颈环形电切术 手术是治疗病变的金标准，它需要训练有素的临床医生和操作人员。 在LMIC诊所很少发现的环境。世界卫生组织建议对宫颈癌患者进行冷冻治疗。 但是目前冷冻治疗系统的主要缺点是它们依赖于 消耗性冷冻剂气体。获得冷冻剂气体供应是不可靠的，消耗气体成本高，并且 笨重的气瓶限制了偏远诊所的便携性。其他针对中低收入国家的备选方案已 尝试过，但由于成本高和制造商支持中断（CryoPen）， 组织坏死深度不足，无法进行完全有效的治疗（基于热的热消融）。综合起来看， 目前还没有一个单一的系统能够提供一个适合于大规模低成本军事干预的适当的、具有成本效益的解决方案 使用.使用LMIC适当的治疗方案，宫颈癌死亡率可降低33%（约300，000 到2030年。在NIH SBIR第一阶段的支持下，Ananya Health的目标是开发Ala系统，一种便携式， 用于治疗中低收入国家宫颈癌前病变的电池供电闭环冷冻治疗系统。 通过在闭环系统中再循环冷冻剂流体，ALA系统无需消耗品 冷冻剂气体可充电电池允许独立于电网可用性进行治疗。初步 研究表明，我们可以用电池在绵羊子宫组织模型上实现组织冷冻温度， 动力闭环原型对于这个建议，首先，我们将使用台式颈椎模型来进一步优化 系统参数满足既定的宫颈组织冷冻治疗要求：组织深度≥ 5 mm 在≤ 5分钟的过程中达到≤-20 °C并持续≥ 1分钟（具体目标1）。其次，我们将亲自访问两个 LMIC临床研究中心访谈并观察≥ 6名临床医生，以确定关键用户需求和系统要求 确保Ala系统设计适合初级保健机构的临床、可用性和操作需求， LMIC（具体目标2）。第一阶段的开发工作将为最终的设备测试奠定基础， 设计验证，并在第二阶段通过FDA 510（k）获得监管批准，随后广泛部署 通过全球非政府组织以及地方和区域LMIC组织伙伴关系，

Abstract While cervical cancer deaths have dramatically fallen in high-income countries, cervical cancer is one of the leading causes of cancer deaths in low- and middle-income countries (LMICs). Cervical cancer accounted for 341,800 deaths in 2020, with approximately 90% of these deaths occurring in LMICs. Treatments for precancerous lesions are highly effective for preventing cancer progression, so the key is to identify and treat lesions early. However, most low-income countries that offer cervical cancer screening lack accessible treatment services. The lack of readily accessible treatment options means referral of patients to larger hospitals, which is an obstacle to proper treatment, leading to disease progression to cancer. While loop electrosurgical excision procedure is the gold standard in the treatment of lesions, it requires highly trained clinicians and an operating environment rarely found in LMIC clinics. The World Health Organization recommends cryotherapy for cervical precancer treatment in LMICs, but the key drawback for current cryotherapy systems is their dependence on consumable cryogen gas. Access to a cryogen gas supply is unreliable, consumable gas costs are high, and heavy and bulky gas cylinders limit portability to remote clinics. Other LMIC-targeted options have been attempted, but they were poorly adopted due to high cost and discontinued manufacturer support (CryoPen) or insufficient depth of tissue necrosis for fully effective treatment (heat-based thermal ablation). Taken together, no single system exists to provide an appropriate and cost-effective solution that is suitable for widespread LMIC use. With an LMIC-appropriate treatment solution, cervical cancer mortality could be reduced by 33% (~300,000 deaths) by 2030. With NIH SBIR Phase I support, Ananya Health’s goal is developing the Ala System, a portable, battery-powered, closed-loop cryotherapy system for the treatment of cervical precancerous lesions in LMICs. By recirculating the cryogen fluid in a closed-loop system, the Ala System eliminates the need for consumable cryogen gas. The rechargeable battery allows for treatment independent of electrical grid availability. Preliminary studies have shown we can achieve tissue-freezing temperatures on an ovine uterus tissue model with a battery- powered closed-loop prototype. For this proposal, first, we will use a benchtop cervical model to further optimize system parameters to meet the established cervical tissue cryotherapy requirement: ≥5 mm depth of tissue reaches ≤-20°C for ≥1 min in a ≤5 min procedure (Specific Aim 1). Second, we will make in-person visits to two LMIC clinical sites to interview and observe ≥6 clinicians to identify critical User Needs and system requirements to ensure the Ala System design will suit the clinical, usability, and operational needs of primary care facilities in LMICs (Specific Aim 2). The development work in Phase I will lay the foundation for final device testing, user design validation, and regulatory approvals via FDA 510(k) in Phase II, followed by widespread deployment of the Ala System through global NGOs and local and regional LMIC organizational partnerships.