Abstract：
The combination of hydrogels and magnetic nanoparticles, scarcely explored to date, offers a wide range of possibilities for innovative therapies. Herein, we have designed hybrid 3D matrices integrating natural polymers, such as collagen, chitosan (CHI) and hyaluronic acid (HA), to provide soft and flexible 3D networks mimicking the extracellular matrix of natural tissues, and iron oxide nanoparticles (IONPs) that deliver localized heat when exposed to an alternating magnetic field (AMF). First, colloidally stable nanoparticles with a hydrodynamic radius of ∼20 nm were synthesized and coated with either CHI (NPCHI) or HA (NPHA). Then, collagen hydrogels were homogeneously loaded with these coated-IONPs resulting in soft (E0 ∼ 2.6 kPa), biodegradable and magnetically responsive matrices. Polymer-coated IONPs in suspension preserved primary neural cell viability and neural differentiation even at the highest dose (0.1 mg Fe/mL), regardless of the coating, even boosting neuronal interconnectivity at lower doses. Magnetic hydrogels maintained high neural cell viability and sustained the formation of highly interconnected and differentiated neuronal networks. Interestingly, those hydrogels loaded with the highest dose of NPHA (0.25 mgFe/mg polymer) significantly impaired non-neuronal differentiation with respect to those with NPCHI. When evaluated under AMF, cell viability slightly diminished in comparison with control hydrogels magnetically stimulated, but not compared to their counterparts without stimulation. Neuronal differentiation under AMF was only affected on collagen hydrogels with the highest dose of NPHA, while non-neuronal differentiation regained control values. Taken together, NPCHI-loaded hydrogels displayed a superior performance, maybe benefited from their higher nanomechanical fluidity. STATEMENT OF SIGNIFICANCE: Hydrogels and magnetic nanoparticles are undoubtedly useful biomaterials for biomedical applications. Nonetheless, the combination of both has been scarcely explored to date. In this study, we have designed hybrid 3D matrices integrating both components as promising magnetically responsive platforms for neural therapeutics. The resulting collagen scaffolds were soft (E0 ∼ 2.6 kPa) and biodegradable hydrogels with capacity to respond to external magnetic stimuli. Primary neural cells proved to grow on these substrates, preserving high viability and neuronal differentiation percentages even under the application of a high-frequency alternating magnetic field. Importantly, those hydrogels loaded with chitosan-coated iron oxide nanoparticles displayed a superior performance, likely related to their higher nanomechanical fluidity.
摘要：
水凝胶和磁性纳米颗粒的组合，迄今为止几乎没有探索过，为创新疗法提供了广泛的可能性。在这里，我们设计了结合天然聚合物的混合3D矩阵，如胶原蛋白，壳聚糖（CHI）和透明质酸（HA），提供模拟天然组织的细胞外基质的柔软和灵活的3D网络，和氧化铁纳米颗粒（IONP），当暴露于交变磁场（AMF）时传递局部热量。首先,合成了具有〜20nm流体动力学半径的胶体稳定纳米颗粒，并用CHI（NPCHI）或HA（NPHA）涂覆。然后，胶原水凝胶均匀地负载有这些涂覆的IONP，导致柔软(E0~2.6kPa)，可生物降解和磁响应的基质。与裸露的IONP相比，即使在最高剂量（0.1mgFe/mL）下，悬浮液中的聚合物包被的IONP仍保留了原代神经细胞活力和神经分化，不管涂层，甚至在较低剂量下增强神经元互连性。磁性水凝胶保持高神经细胞活力并维持高度互连和分化的神经元网络的形成。有趣的是,相对于具有NPCHI的那些水凝胶，那些负载有最高剂量的NPHA（0.25mgFe/mg聚合物）的水凝胶显着损害了非神经元分化。当在AMF下评估时，与磁刺激的对照水凝胶相比，细胞活力略有下降，但不能与没有刺激的同行相比。AMF下的神经元分化仅对NPHA最高剂量的胶原水凝胶有影响，而非神经元分化恢复了控制值。一起来看,NPCHI负载水凝胶显示出优越的性能，也许受益于它们更高的纳米机械流动性。重要性声明：水凝胶和磁性纳米颗粒无疑是生物医学应用的有用生物材料。尽管如此，迄今为止，几乎没有探索过两者的结合。在这项研究中,我们设计了混合3D矩阵，将这两个组件整合为有前途的磁响应平台，用于神经治疗。所得胶原支架为柔软（E0～2.6kPa）和可生物降解的水凝胶，具有响应外部磁刺激的能力。原代神经细胞被证明在这些基质上生长，即使在高频交变磁场的应用下，也能保持较高的活力和神经元分化百分比。重要的是,那些负载有壳聚糖包覆的氧化铁纳米颗粒的水凝胶表现出优越的性能，可能与它们较高的纳米机械流动性有关。
