Hydrogel-Forming Microneedle Arrays Allow Detection of Drugs and Glucose In Vivo: Potential for Use in Diagnosis and Therapeutic Drug Monitoring.
Hydrogel-Forming Microneedle Arrays Allow Detection of Drugs and Glucose In Vivo: Potential for Use in Diagnosis and Therapeutic Drug Monitoring.
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DOI：
10.1371/journal.pone.0145644
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Donnelly RF
中科院分区：
文献类型：
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作者：
Caffarel-Salvador E;Brady AJ;Eltayib E;Meng T;Alonso-Vicente A;Gonzalez-Vazquez P;Torrisi BM;Vicente-Perez EM;Mooney K;Jones DS;Bell SE;McCoy CP;McCarthy HO;McElnay JC;Donnelly RF
我们首次描述了使用形成水凝胶的微针（MN）阵列对体外和体内皮肤中的药物和葡萄糖进行微创提取和定量。 MN 由水解聚（甲基乙烯基醚马来酸酐）（11.1% w/w）和聚（乙二醇）10,000 道尔顿（5.6% w/w）的水性混合物制备，并通过酯化交联，在皮肤插入时通过吸收液体而膨胀。去除后，从 MN 中提取茶碱和咖啡因，并使用 HPLC 进行测定，并使用专有试剂盒对葡萄糖进行定量。使用切下的新生猪皮进行的体外研究显示，其下侧浸有生理相关的分析物浓度，分析物吸收迅速（5 分钟）。例如，插入 5 分钟后，茶碱 Franz 细胞浓度的最低 (5 μg/mL) 和最高 (35 μg/mL) 平均浓度分别为 0.16 μg/mL 和 0.85 μg/mL。将 MN 插入用 5 μg/mL 咖啡因沐浴的皮肤中 5 分钟，提取的平均浓度为 0.10 μg/mL，而将 MN 插入用 15 μg/mL 咖啡因沐浴的皮肤提取的平均浓度为 0.33 μg/mL。插入用 4 mmol/L 沐浴的皮肤 5 分钟后，检测到的平均葡萄糖浓度为 19.46 nmol/L。将水凝胶形成的 MN 插入口服 10 mg/kg 剂量的大鼠皮肤 1 小时后，提取后检测到的最高茶碱浓度为 0.363 μg/mL，而将 MN 插入口服 5 mg/kg 茶碱的大鼠皮肤 1 小时后，检测到的最大浓度为 0.063 μg/mL。在人类志愿者中，在食用 100 mg Proplus® 片剂后 1 至 2 小时内，使用 MN 检测到的咖啡因最高平均浓度为 91.31 μg/mL。摄入 75 g 葡萄糖 1 小时后检测到的最高平均血糖水平为 7.89 nmol/L，而从 MN 中提取的最高平均葡萄糖浓度为 4.29 nmol/L，在人类志愿者插入皮肤 3 小时后检测到。虽然不直接相关，但从 MN 中提取的浓度清楚地表明了大鼠和人类志愿者血液中的趋势。这项工作有力地说明了水凝胶形成的 MN 在微创患者监测和诊断中的潜力。目前正在进行进一步的研究，以减少临床插入时间并开发数学算法，从而能够直接根据 MN 测量值确定血液水平。
We describe, for the first time the use of hydrogel-forming microneedle (MN) arrays for minimally-invasive extraction and quantification of drug substances and glucose from skin in vitro and in vivo. MN prepared from aqueous blends of hydrolysed poly(methyl-vinylether-co-maleic anhydride) (11.1% w/w) and poly(ethyleneglycol) 10,000 daltons (5.6% w/w) and crosslinked by esterification swelled upon skin insertion by uptake of fluid. Post-removal, theophylline and caffeine were extracted from MN and determined using HPLC, with glucose quantified using a proprietary kit. In vitro studies using excised neonatal porcine skin bathed on the underside by physiologically-relevant analyte concentrations showed rapid (5 min) analyte uptake. For example, mean concentrations of 0.16 μg/mL and 0.85 μg/mL, respectively, were detected for the lowest (5 μg/mL) and highest (35 μg/mL) Franz cell concentrations of theophylline after 5 min insertion. A mean concentration of 0.10 μg/mL was obtained by extraction of MN inserted for 5 min into skin bathed with 5 μg/mL caffeine, while the mean concentration obtained by extraction of MN inserted into skin bathed with 15 μg/mL caffeine was 0.33 μg/mL. The mean detected glucose concentration after 5 min insertion into skin bathed with 4 mmol/L was 19.46 nmol/L. The highest theophylline concentration detected following extraction from a hydrogel-forming MN inserted for 1 h into the skin of a rat dosed orally with 10 mg/kg was of 0.363 μg/mL, whilst a maximum concentration of 0.063 μg/mL was detected following extraction from a MN inserted for 1 h into the skin of a rat dosed with 5 mg/kg theophylline. In human volunteers, the highest mean concentration of caffeine detected using MN was 91.31 μg/mL over the period from 1 to 2 h post-consumption of 100 mg Proplus® tablets. The highest mean blood glucose level was 7.89 nmol/L detected 1 h following ingestion of 75 g of glucose, while the highest mean glucose concentration extracted from MN was 4.29 nmol/L, detected after 3 hours skin insertion in human volunteers. Whilst not directly correlated, concentrations extracted from MN were clearly indicative of trends in blood in both rats and human volunteers. This work strongly illustrates the potential of hydrogel-forming MN in minimally-invasive patient monitoring and diagnosis. Further studies are now ongoing to reduce clinical insertion times and develop mathematical algorithms enabling determination of blood levels directly from MN measurements.