Pre-Clinical Development of a Fetal Micropacemaker

描述(申请人提供)：我们已经开发了一种新型的微起搏器，以解决胎儿完全性心脏传导阻滞的关键问题。这种情况在胎儿中是一种危及生命的紧急情况，如果胎儿积水在很小的胎龄就发展起来，几乎总是致命的。目前在这些病例中还没有有效的治疗方案，在胎儿心脏上植入带电极的宫外起搏器的尝试总是失败，因为铅从胎儿运动中移位。这种新颖的设计是一种独立的单腔微起搏器，可以在没有外部导线的情况下经皮植入胎儿体内，允许随后的胎儿运动，而不会有电极移位的风险。这样的设计和应用是可能的，因为胎儿干预技术的进步允许在超声波和胎儿镜检的指导下，通过母体腹部和胎儿胸壁经皮放置起搏系统。通过成功的胎儿起搏，胎儿积水有望完全恢复，存活至足月，生活接近正常。该装置的功能原型已经建立，用成年兔子进行的动物试验提供了关于电子和机械设计策略的关键方面的令人信服的数据。此外，该装置最近还被联邦药品管理局授予人道主义使用装置称号。该项目的下一个转换步骤需要成功地将一个功能装置植入胎羊，以在相关的临床前动物模型中证明概念的证据。一种新的包装系统将被开发出来，并在体外进行测试，该系统旨在保护电路免受体液的影响。该装置将被植入一系列胎羊体内，并将在怀孕期间定期确认对胎儿心肌的脑室刺激。微起搏器由一个微型的、可商业购买的可充电锂离子电池供电，可以为2-3周的起搏提供电力。因此，我们还将设计和建造一个感应充电系统，允许电池每周从母亲以外的地方充电。这一研究项目只有通过具有不同经验和技能的调查人员团队之间的多学科合作才能实现。这些技能的范围从设备的设计和制造，到对发育中心脏的特定电气和起搏特性的了解，再到对胎儿外科干预的熟练程度。Ramen Chmait医生是一位胎儿外科医生，他成功和安全地对胎儿进行了许多外科手术和干预。亚尼夫·巴尔-科恩医生专门研究儿科心律失常，并拥有心脏起搏设备的专业知识。杰拉尔德·勒布博士在微型设备技术方面拥有丰富的经验，此前曾开发出一种FDA批准的可注射设备来刺激骨骼肌。迈克尔·西尔卡医生是世界知名的儿科电生理学家，在胎儿心律失常方面具有专长。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，这将对该设备的植入和后续治疗至关重要。 公共卫生相关性：胎儿完全性心脏传导阻滞是一种危及生命的紧急情况，如果胎儿在很小的胎龄就出现积水，几乎总是致命的。目前在这些病例中还没有有效的治疗方案，在胎儿心脏上植入带电极的宫外起搏器的尝试总是失败，因为铅从胎儿运动中移位。这项研究的目标是设计、制造和测试一种自给自足、电池供电的微起搏器，它可以从母亲外部经皮植入胎儿体内，并根据需要通过无线电波充电，直到分娩。

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. PUBLIC HEALTH RELEVANCE: Complete heart block in the fetus is a life-threatening emergency, 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 goal of this research is to design, build and test a self-contained, battery-powered micropacemaker that can be percutaneously implanted into the fetus from outside the mother and recharged by radio waves as needed until delivery.