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

摘要 虽然高收入国家的宫颈癌死亡率大幅下降，但宫颈癌是 低收入和中等收入国家(LMIC)癌症死亡的主要原因。宫颈癌占比 2020年有341,800人死亡，其中约90%发生在低收入国家。治疗 癌前病变对防止癌症进展非常有效，因此关键是识别和治疗 早期损伤。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介到更大的医院，这是 阻碍适当治疗，导致疾病进展为癌症。而环状电刀切除 程序是治疗病变的金标准，它需要训练有素的临床医生和手术 在LMIC诊所中很少见的环境。世界卫生组织建议冷冻治疗宫颈 LMIC的癌前治疗，但目前冷冻治疗系统的主要缺点是它们依赖于 可消耗的制冷剂气体。获得制冷剂气体供应不可靠，可消耗气体成本很高，以及 笨重笨重的气瓶限制了偏远诊所的便携性。其他针对LMIC的选项包括 尝试过，但由于成本高和不再提供制造商支持(CryoPen)或 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)。加在一起， 不存在单一的系统来提供适用于广泛的LMIC的适当且经济高效的解决方案 使用。使用适合LMIC的治疗方案，宫颈癌死亡率可以降低33%(约30万 死亡)，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，一种便携式的， 电池供电的闭环式冷冻治疗系统用于治疗LMICs中的宫颈癌前病变。 通过在闭环系统中循环制冷剂流体，ALA系统消除了对消耗品的需求 低温气体。可充电电池允许与电网可用性无关的治疗。初步 研究表明，我们可以用电池在绵羊子宫组织模型上达到组织冻结温度- 动力闭环式样机。对于这一方案，首先，我们将使用台式颈椎模型来进一步优化 满足既定宫颈组织冷冻治疗要求的系统参数：≥组织深度5 mm 在≤5分钟程序中达到≥1分钟的≤-20°C(特定目标1)。第二，我们将亲自访问两个 访问和观察≥6临床医生以确定关键用户需求和系统要求的LMIC临床站点 确保ALA系统设计符合以下地区初级保健机构的临床、可用性和运营需求 LMICs(特定目标2)。第一阶段的开发工作将为最终的设备测试、用户 在第二阶段通过FDA 510(K)进行设计验证和监管批准，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，建立ALA系统。

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.