Continuous calcium sensor patch for hypoparathyroid patients

项目摘要 甲状旁腺功能减退症（hypoPT）是一种以循环甲状旁腺激素缺乏为特征的疾病 (PTH)，细胞外钙稳态的主要激素调节剂。低钙血症的症状范围 从刺痛和肌肉痉挛和神经精神症状到癫痫发作和危及生命 喉痉挛钙和维生素D治疗可部分缓解低钙血症症状，但 也“过冲”，导致高钙血症发作，在缺乏肾钙保存的情况下， PTH影响，导致肾实质钙化和长期不可逆肾损害。事实上，慢性 在41%的低PT患者中发现了肾脏疾病，并且与低PT患者的时间比例直接相关。 高钙血症 因此，即使有今天的最佳实践，每日钙水平上下波动，导致 低钙血症和高钙血症，伴有严重和不可逆的器官损伤和死亡。低PT患者 如果能在真实的时间内了解他们的卡路里变化， 个体化、动态化治疗。我们建议开发一种传感器贴片技术， 生物相容性“水凝胶微丝”，其可以穿透皮肤，同时允许原位光学成像。 真皮间质液中分析物的荧光感测。微丝的非中空结构 水凝胶的多孔性质确保了组织液中的钙可以扩散， 进入细丝，水凝胶的大的内表面允许分析物与大量的 用于信号产生的缀合的荧光适体，并且光学透明性允许原位光学成像。 使用可佩戴的荧光计进行感测，而不需要流体提取。 我们的中心假设是，具有水凝胶微丝的皮肤贴片可以在体内重复 钙敏感在完成这些目标后，预期的结果是全面描述 性能和限制的一种基于微量元素的连续传感器的钙，并在体内的演示 在活体大鼠模型和人类受试者的间质液中进行感测。这些结果预计将有一个 重要的积极影响，因为它们将为临床试验提供强有力的原则证明， 钙传感器，最终为hypoPT患者的个体化治疗提供了新的机会， 维持钙平衡，减少不可逆的肾损伤和致命的喉痉挛。更 总的来说，该项目将推动这种微创传感技术向前迈出一步， 接近精确监测和医学的新范式。

PROJECT SUMMARY Hypoparathyroidism (hypoPT) is a disease characterized by absence of circulating parathyroid hormone (PTH), the major hormonal regulator of extracellular calcium homeostasis. Symptoms of hypocalcemia range from tingling and muscle cramps and neuropsychiatric symptoms to seizures and life-threatening laryngospasm. Treatment with calcium and vitamin D partially relieves symptoms of hypocalcemia, but can also “over-shoot,” leading to episodes of hypercalcemia, which, in the absence of the renal calcium-conserving effect of PTH, lead to renal parenchymal calcification and long-term irreversible renal damage. Indeed, chronic kidney disease is found in 41% of hypoPT patients and is directly associated with the proportion of time with hypercalcemia. As such, even with today’s best practices, the daily levels of calcium fluctuate down and up, resulting in hypocalcemia and hypercalcemia, with serious and irreversible organ damage and mortality. HypoPT patients would benefit greatly from knowing their calcemic variability in real time, giving them a chance to adjust their treatment individually and dynamically. We propose to develop a sensor patch technology featuring biocompatible “hydrogel microfilaments” that can penetrate the skin while allowing for in situ optical fluorescence sensing of analytes in dermal interstitial fluid. The non-hollow structure of the microfilaments allows for easy fabrication, the porous nature of hydrogels ensures that calcium in interstitial fluid can diffuse into the filaments, the large internal surface of hydrogel allows for analytes to interact with a large number of conjugated fluorescent aptamers for signal generation, and optical transparency allows for in situ optical sensing with a wearable fluorometer with no fluid extraction needed. Our central hypothesis is that a skin patch with hydrogel microfilaments can enable repeated in vivo calcium sensing. Upon completion of these aims, the expected outcome is a full characterization of the performance and limits of a microfilament-based continuous sensor of calcium, and demonstrations of in vivo sensing in a live rat model and in the interstitial fluid of human subjects. These results are expected to have an important positive impact because they will provide a strong proof of principle for clinical testing of a continuous calcium sensor, ultimately providing new opportunities for individualized treatment of patients with hypoPT to maintain calcium homeostasis and reduce irreversible kidney damage and deadly laryngospasm. More broadly, this project will propel this minimally invasive sensing technology a step forward towards the rapidly approaching new paradigm of precision monitoring and medicine.