Continuous calcium sensor patch for hypoparathyroid patients

项目总结 甲状旁腺功能减退症是一种以循环甲状旁腺激素缺乏为特征的疾病。 甲状旁腺素(PTH)，细胞外钙稳态的主要激素调节因子。低钙血症症状范围 从刺痛、肌肉痉挛和神经精神症状到癫痫发作和生命危险 喉痉挛。钙和维生素D的治疗部分缓解了低钙血症的症状，但可以 也叫“过量”，导致高钙血症的发作，在缺乏肾脏钙保存的情况下 甲状旁腺素的作用，导致肾实质钙化和长期不可逆的肾损害。的确，是慢性的 在41%的低PT患者中发现了肾脏疾病，并与 高钙血症。 因此，即使在当今的最佳实践中，每日的钙水平也会起伏不定，导致 低钙血症和高钙血症，并伴有严重和不可逆转的器官损害和死亡。低PT患者 将大大受益于实时了解他们的钙质变化，让他们有机会调整他们的 单独和动态治疗。我们建议开发一种传感器贴片技术，具有以下特点 生物相容的“水凝胶微丝”，可以穿透皮肤，同时允许就地光学 真皮间质液中分析物的荧光传感。微丝的非中空结构 由于易于制造，水凝胶的多孔性确保了间质液体中的钙可以扩散 进入细丝，水凝胶的大内表面允许分析物与大量的 共轭荧光适配子用于信号产生，光学透明度允许原位光学 使用可穿戴式荧光计进行传感，无需提取流体。 我们的中心假设是，带有水凝胶微丝的皮肤贴片可以在体内重复 钙感应。在完成这些目标后，预期的结果是充分描述 基于微丝的连续钙传感器的性能和局限性及其在体内的应用 在活体大鼠模型和人类受试者的间质液体中进行传感。这些结果预计将有一个 重要的积极影响，因为它们将为连续的临床测试提供强有力的原则证明 钙传感器，最终为低PT患者的个体化治疗提供了新的机会 维持钙平衡，减少不可逆转的肾脏损伤和致命的喉痉挛。更多 总的来说，该项目将推动这种微创传感技术向快速 迈向精准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.