Division of Pharmaceutical Biosciences, Drug Research Program, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland.
Circuits and Systems Research Unit, University of Oulu, 90014 Oulu, Finland.
J Control Release. 2021 Jun 10;334:367-375. doi: 10.1016/j.jconrel.2021.04.032. Epub 2021 Apr 28.
Hydrogels, natural and synthetic origin, are actively studied for their use for implants and payload carriers. These biomaterials for delivery systems have enormous potential in basic biomedical research, drug development, and long-term delivery of biologics. Nanofibrillated cellulose (NFC) hydrogels, both natural and anionic (ANFC) ones, allow drug loading for immediate and controlled release via the slow drug dissolution of solid drug crystals into hydrogel and its subsequent release. This property makes NFC originated hydrogels an interesting non-toxic and non-human origin material as drug reservoir for long-term controlled release formulation or implant for patient care. A compelling tool for studying NFC hydrogels is Raman spectroscopy, which enables to resolve the chemical structures of different molecules in a high-water content like hydrogels, since Raman spectroscopy is insensitive to water molecules. That offers real time investigation of label-free drugs and their release in high-water-content media. Despite the huge potential of Raman spectroscopy in bio-pharmaceutical applications, the strong fluorescence background of many drug samples masking the faint Raman signal has restricted the widespread use of it. In this study we used a Raman spectrometer capable of suppressing the unpleasant fluorescence background by combining a pulsed laser and time-resolved complementary metal-oxide-semiconductor (CMOS) single-photon avalanche diode (SPAD) line sensor for the label-free investigation of Metronidazole and Vitamin C diffusivities in ANFC. The results show the possibility to modulate the ANFC-based implants and drug delivery systems, when the release rate needs to be set to a desired value. More importantly, the now developed label free real-time method is universal and can be adapted to any hydrogel/drug combination for producing reliable drug diffusion coefficient data in complex and heterogeneous systems, where traditional sampling-based methods are cumbersome to use. The wide temporal range of the time-resolved CMOS SPAD sensors makes it possible to capture also the fluorescence decay of samples, giving rise to a combined time-resolved Raman and fluorescence spectroscopy, which provides additional information on the chemical, functional and structural changes in samples.
水凝胶，无论是天然的还是合成的，都因其在植入物和有效载荷载体中的应用而受到广泛研究。这些用于输送系统的生物材料在基础生物医学研究、药物开发以及生物制剂的长期输送方面具有巨大的潜力。纳米原纤化纤维素 (NFC) 水凝胶，无论是天然的还是阴离子的 (ANFC)，都允许通过固体药物晶体在水凝胶中的缓慢药物溶解及其随后的释放来进行药物负载和即时控制释放。这种特性使 NFC 衍生的水凝胶成为一种有趣的无毒且非人体来源的材料，可作为药物储库，用于长期控制释放制剂或用于患者护理的植入物。研究 NFC 水凝胶的一个引人注目的工具是拉曼光谱，它能够解析高含水量（如水凝胶）中不同分子的化学结构，因为拉曼光谱对水分子不敏感。这为在高含水量介质中对无标记药物及其释放进行实时研究提供了可能。尽管拉曼光谱在生物制药应用中具有巨大的潜力，但许多药物样本的强烈荧光背景掩盖了微弱的拉曼信号，限制了它的广泛应用。在这项研究中，我们使用了一种拉曼光谱仪，该光谱仪通过结合脉冲激光和时间分辨互补金属氧化物半导体 (CMOS) 单光子雪崩二极管 (SPAD) 线传感器，能够抑制令人不快的荧光背景，用于对 ANFC 中的甲硝唑和维生素 C 扩散率进行无标记研究。结果表明，当需要将释放速率设置为所需值时，可以对基于 ANFC 的植入物和药物输送系统进行调制。更重要的是，现在开发的无标记实时方法是通用的，可以适应任何水凝胶/药物组合，以在复杂和异质系统中产生可靠的药物扩散系数数据，在这些系统中，传统的基于采样的方法使用起来很繁琐。时间分辨 CMOS SPAD 传感器的宽时间范围使得也能够捕获样品的荧光衰减，从而产生时间分辨拉曼和荧光光谱的组合，这为样品的化学、功能和结构变化提供了额外的信息。
