Shukla Shashank, Shukla Anita
School of Engineering, Center for Biomedical Engineering, Institute for Molecular and Nanoscale Innovation, Brown University, Providence, RI, USA.
J Mater Chem B. 2018 Oct 28;6(40):6444-6458. doi: 10.1039/c8tb00980e. Epub 2018 Sep 19.
Hydrogels are used extensively in wound management. Many wounds are highly susceptible to infection and hydrogels can provide localized antibacterial delivery to treat and prevent this infection. There are several key considerations in designing antibacterial hydrogels for wound therapy, including preserving activity of encapsulated antibacterial agents, controlling drug release timescales and concentrations, and having the ability to conform to various wound configurations. In this work, we have used gellan, a U.S. Food and Drug Administration approved food additive, to develop antibiotic loaded hydrogels focusing on these criteria. These hydrogels were formed to exhibit a range of mechanical properties, which were investigated using oscillatory rheology. We denoted hydrogels formed using 1% w/v gellan and 1 mM CaCl"ointment" hydrogels and those formed using 4% w/v gellan and 7 mM CaCl"sheet" hydrogels. Vancomycin, a broad-spectrum antibiotic against Gram-positive bacteria, was encapsulated in these hydrogels both directly and/or in graphitized carbon black nanoparticles (CNPs). We found that vancomycin released from both sheet and ointment hydrogels at therapeutically effective concentrations over 9 days with CNPs and 6 days without CNPs. Applying the Ritger-Peppas and Peppas-Sahlin semi-empirical drug release models to sheet hydrogels, we determined that Fickian diffusion dominates release while case II relaxation also has a small contribution. The sheet hydrogels exhibited a larger overall release of the drug (83.6 ± 1.6% compared to 67.0 ± 2.6% for ointments), which was attributed to the larger swelling resulting from osmotic pressure differences between the hydrogel formulations and the release buffer. We also suggest that final drug release amounts are influenced by intermolecular interactions between vancomycin and gellan, which were observed via quartz crystal microbalance with dissipation monitoring. Lastly, we examined the potential for future in vivo translation. We demonstrated in vitro growth inhibition of Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus in the presence of these hydrogels, demonstrating that vancomycin activity is preserved upon encapsulation. We also showed that these hydrogels are non-toxic to important wound healing cells including fibroblasts and mesenchymal stem cells.
水凝胶在伤口处理中得到广泛应用。许多伤口极易感染，水凝胶可提供局部抗菌递送以治疗和预防这种感染。在设计用于伤口治疗的抗菌水凝胶时，有几个关键考虑因素，包括保持封装抗菌剂的活性、控制药物释放时间尺度和浓度，以及能够适应各种伤口形态。在这项工作中，我们使用了结冷胶（一种美国食品药品监督管理局批准的食品添加剂）来开发专注于这些标准的载抗生素水凝胶。这些水凝胶形成后表现出一系列机械性能，使用振荡流变学对其进行了研究。我们将使用1% w/v结冷胶和1 mM氯化钙形成的水凝胶称为“软膏”水凝胶，将使用4% w/v结冷胶和7 mM氯化钙形成的水凝胶称为“薄片”水凝胶。万古霉素是一种针对革兰氏阳性菌的广谱抗生素，它被直接和/或包裹在石墨化炭黑纳米颗粒（CNPs）中封装在这些水凝胶中。我们发现，万古霉素从薄片和软膏水凝胶中释放，在有CNPs时在9天内以治疗有效浓度释放，在没有CNPs时在6天内释放。将Ritger - Peppas和Peppas - Sahlin半经验药物释放模型应用于薄片水凝胶，我们确定菲克扩散主导释放，而情况II松弛也有小的贡献。薄片水凝胶表现出更大的药物总体释放量（83.6 ± 1.6%，而软膏为67.0 ± 2.6%），这归因于水凝胶配方与释放缓冲液之间渗透压差异导致的更大溶胀。我们还表明最终药物释放量受万古霉素与结冷胶之间分子间相互作用的影响，这通过带有耗散监测的石英晶体微天平观察到。最后，我们研究了未来体内转化的潜力。我们证明在这些水凝胶存在下对金黄色葡萄球菌（S. aureus）和耐甲氧西林金黄色葡萄球菌具有体外生长抑制作用，表明万古霉素在封装后活性得以保留。我们还表明这些水凝胶对包括成纤维细胞和间充质干细胞在内的重要伤口愈合细胞无毒。
