Ultrabright Plasmonic-Fluor Nanosensor-Enabled Noninvasive Management of Pediatric Nephrotic Syndrome

小儿肾病综合征（NS）是一种以蛋白尿、低白蛋白血症和肾功能进行性丧失为特征的儿童期肾脏疾病。此外，类固醇耐药NS（约占儿科人群终末期肾病的10%）可能需要长期使用免疫抑制剂，这可能导致肾毒性。儿科静脉穿刺的艰巨困难，以及单次抽血和2个月内允许的最大抽血量限制很小，特别是在新生儿、婴儿和幼儿中，限制了对NS活动期肾功能的密切监测。此外，尿试纸测试作为半定量且不总是可靠的测定，是评价治疗反应的粗略方法。它也无法评估可能因容量收缩、常规使用利尿剂和血管紧张素转换酶抑制剂以及药物引起的急性肾毒性而损害的肾功能。因此，开发一种创新的、无痛的、免容量抽取的、高灵敏度的生物诊断平台对于改善小儿NS患者的临床护理是势在必行的。 富含生物分析物的真皮间质液（ISF）为实现无痛和有效的生物诊断技术提供了新的机会。然而，ISF的临床应用受到当前技术的限制。我们的目标是开发我们新发明的超亮等离子体荧光（PF）微针（MN）技术（PF-MN），作为一种超灵敏和微创诊断工具，用于在床旁和家中快速采样和定量ISF血尿素氮（BUN）和肌酐（Cr）。为了实现我们的研究目标，我们将利用高度可重复的遗传性NS小鼠模型。在该临床前模型中，我们的目标是通过使用对MN进行的PF增强竞争性免疫测定来确定真皮ISF中BUN和Cr的浓度。此外，我们将关联它们的浓度来自MN采样的ISF，提取的ISF和血清。 我们的开创性提案的成功完成可能会导致新生儿和儿科诊断的范式转变。这也将为未来在儿童NS患者中的转化研究铺平道路。

Pediatric nephrotic syndrome (NS), characterized by proteinuria, hypoalbuminemia and progressive loss of kidney function, is a debilitating childhood kidney disease. In addition, steroid-resistant NS, accounting for about 10% of end- stage kidney disease in the pediatric population, may require long-term use of immunosuppressants that can cause nephrotoxicity. The daunting difficulty in pediatric venipuncture, as well as the small volume limit of maximum blood draw allowed for a single draw and within 2 months, especially in neonates, infants and young children, has limited close monitoring of kidney function in the active phase of NS. Moreover, urine dipstick test, as a semi-quantitative and not- always-reliable assay, is a crude way of evaluating the treatment response. It is also unable to assess the kidney function that may be compromised by volume contraction, routine use of diuretics and angiotensin-converting enzyme inhibitors, and drug-induced renal toxicity acutely. Thus, development of an innovative, pain-free and volume extraction-free, and highly sensitive biodiagnostic platform is imperative to improve the clinical care for pediatric NS patients. Bioanalyte-rich dermal interstitial fluid (ISF) provides a novel opportunity to achieve painless and effective biodiagnostic technologies. However, the clinical utility of ISF is limited by the current technology. Our goal is to develop our newly invented ultrabright plasmonic-fluor (PF)-enabled microneedle (MN) technology (PF-MN) as an ultrasensitive and minimally-invasive diagnostic tool for rapid sampling and quantification of ISF blood urea nitrogen (BUN) and creatinine (Cr) in point-of-care settings and at home. To accomplish our research goals, we will utilize a highly reproducible hereditary NS mouse model. In this preclinical model, we aim to determine concentrations of BUN and Cr in the dermal ISF by using PF-enhanced competitive immunoassay performed on MN. Furthermore, we will correlate their concentrations derived from MN-sampled ISF, extracted ISF and serum. A successful completion of our pioneering proposal may lead to a paradigm-shift in the newborn and pediatric diagnostics. It will also pave the way for future translational study in pediatric NS patients.