Pre-Clinical Development of a Fetal Micropacemaker

描述（由申请人提供）：我们开发了一种新型微起搏器，以解决胎儿完全性心脏传导阻滞的关键问题。这种情况是一个危及生命的紧急情况下，胎儿，几乎总是致命的，如果水肿胎儿发展在一个年轻的孕龄。在这些情况下，目前没有有效的治疗方案，并且尝试在胎儿心脏上植入带有电极的子宫外起搏器总是由于电极导线从胎动中移位而失败。这种新颖的设计是一种独立的单腔微起搏器，可以在没有外置电极导线的情况下永久植入胎儿体内，允许随后的胎动而没有电极脱位的风险。这种设计和应用是可能的，因为胎儿介入的进步允许在超声和胎儿镜引导下通过母体腹部和胎儿胸壁经皮放置起搏系统。成功的胎儿起搏，水肿胎儿完全恢复，生存到足月，并接近正常的生活。该设备的功能原型已经建成，并使用成年兔子的动物试验提供了令人信服的数据，电子和机械设计策略的关键方面。此外，该器械最近被联邦药品管理局授予人道主义使用器械称号。该项目的下一个转化步骤需要将功能性器械成功植入胎羊体内，以证明相关临床前动物模型的概念验证。将开发一种旨在保护电路免受体液影响的新型包装系统，并进行体外测试。将该器械植入一系列胎羊中，并在妊娠期间定期确认胎羊心肌的心室刺激。微型起搏器由小型市售可充电锂离子电池供电，可提供2-3周的起搏电力。因此，我们还将设计和建造一个感应充电系统，允许电池每周从母体外部充电。这个研究项目只有通过具有不同经验和技能的研究人员团队之间的多学科合作才有可能。这些范围从设备设计和制造到发育中心脏的特定电气和起搏特性的知识，再到胎儿手术干预的熟练程度。Ramen Chmait博士是一名胎儿外科医生，他成功地安全地对胎儿进行了许多外科手术和干预。Yaniv Bar-Cohen博士擅长儿科心律失常，并拥有心脏起搏设备的专业知识。Gerald Loeb博士在微型器械技术方面拥有丰富的经验，此前曾开发出一种经FDA批准的可注射器械，用于刺激骨骼肌。Michael Silka博士是世界著名的儿科电生理学家，在胎儿的儿科心律紊乱方面具有专业知识。Ja Pruetz博士在胎儿心脏成像和胎儿心血管生理学方面拥有独特的专业知识，这对于该设备的植入和随访至关重要。

DESCRIPTION (provided by applicant): We have developed a novel micropacemaker to address the critical problem of complete heart block in the fetus. This condition is a life-threatening emergency in a fetus, and is nearly always fatal if hydrops fetalis develops at a young gestational age. There are currently no effective treatment options in these cases, and attempts to implant an extra-uterine pacemaker with electrodes on the fetal heart have invariably failed due to lead dislodgement from fetal movement. The novel design is a self-contained single-chamber micropacemaker that can be percutaneously implanted into the fetus without exteriorized leads, allowing for subsequent fetal movement without risk of electrode dislodgement. Such a design and application is possible because of advances in fetal intervention that allow percutaneous placement of the pacing system through the maternal abdomen and fetal chest wall under ultrasound and fetoscopic guidance. With successful fetal pacing, a complete recovery from hydrops fetalis is expected with survival to term and a nearly normal life. A functional prototype of the device has been built, and animal testing using adult rabbits has provided compelling data regarding key aspects of the electronic and mechanical design strategies. In addition, the device was recently awarded a Humanitarian Use Device designation from the Federal Drug Administration. The next translational step of the project requires the successful implantation of a functional device into a fetal sheep to demonstrate proof of concept in a relevant pre-clinical animal model. A novel packaging system intended to protect the circuitry from bodily fluids will be developed and tested in vitro. The device will the be implanted in a series of fetal sheep, and ventricular stimulation of the fetal myocardium will be confirmed at regular intervals during gestation. The micropacemaker is powered by a tiny, commercially available, rechargeable lithium ion cell which can provide power for 2-3 weeks of pacing. Therefore, we will also design and build an inductive recharging system that allows the cell to be recharged weekly from outside the mother. This research project is only possible through a multidisciplinary collaboration among a team of investigators with diverse experience and skills. These range from device design and fabrication to knowledge of specific electrical and pacing properties of the developing heart to proficiency in fetal surgical interventions. Dr. Ramen Chmait is a fetal surgeon who has successfully and safely performed numerous surgical procedures and interventions on fetuses. Dr. Yaniv Bar-Cohen specializes in pediatric heart rhythm disorders and has expert knowledge of cardiac pacing devices. Dr. Gerald Loeb has extensive experience with miniature device technology and has previously developed an FDA-approved, injectable device to stimulate skeletal muscle. Dr. Michael Silka is a world-renowned pediatric electrophysiologist with expertise in pediatric heart rhythm disorders in fetuses. Dr. Ja Pruetz has unique expertise in fetal cardiac imaging and fetal cardiovascular physiology, which will be vital for the implantation and follow-up of the device.