Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129 Torino, Italy.
Institute for Chemical-Physical Processes, National Research Council (CNR-IPCF), Via G. Moruzzi 1, 56124, Pisa, Italy.
J Mater Chem B. 2024 Aug 28;12(34):8389-8407. doi: 10.1039/d4tb00092g.
Physical and chemical hydrogels are promising platforms for tissue engineering/regenerative medicine (TERM). In particular, physical hydrogels are suitable for use in the design of drug delivery systems owing to their reversibility and responsiveness to applied stimuli and external environment. Alternatively, the use of chemical hydrogels represents a better strategy to produce stable 3D constructs in the TERM field. In this work, these two strategies were combined to develop multi-functional formulations integrating both drug delivery potential and TERM approaches in a single device. Specifically, a novel photo-sensitive poly(ether urethane) (PEU) was developed to form supramolecular networks with α-cyclodextrins (α-CDs). The PEU was successfully synthesized using Poloxamer® 407, 1,6-diisocyanatohexane and 2-hydroxyethyl methacrylate, as assessed by infrared spectroscopy, size exclusion chromatography and proton nuclear magnetic resonance (H NMR) spectroscopy. Subsequently, PEU thermo-responsiveness was characterized through critical micelle temperature evaluation and dynamic light scattering analyses, which suggested the achievement of a good balance between molecular mass and overall hydrophobicity. Consequently, the formation of supramolecular domains with α-CDs was demonstrated through X-ray diffraction and H NMR spectroscopy. Supramolecular hydrogels with remarkably fast gelation kinetics (, few minutes) were designed using a low PEU concentration (≤5% w/v). All formulations were found to be cytocompatible according to the ISO 10993-5 regulation. Notably, the hydrogels were observed to possess mechanical properties and self-healing ability, according to rheological tests, and their fast photo-crosslinking was evidenced (<60 s) by photo-rheology. A high curcumin payload (570 μg mL) was encapsulated in the hydrogels, which was released with highly tunable and progressive kinetics in a physiological-simulated environment for up to 5 weeks. Finally, a preliminary evaluation of hydrogel extrudability was performed using an extrusion-based bioprinter, obtaining 3D-printed structures showing good morphological fidelity to the original design. Overall, the developed hydrogel platform showed promising properties for application in the emerging field of regenerative pharmacology as (i) easily injectable drug-loaded formulations suitable for post-application stabilization through light irradiation, and (ii) biomaterial inks for the fabrication of patient-specific drug-loaded patches.
物理和化学水凝胶是组织工程/再生医学（TERM）的有前途的平台。特别是，由于其对施加的刺激和外部环境的可逆性和响应性，物理水凝胶适用于药物传递系统的设计。另一方面，使用化学水凝胶代表了在 TERM 领域生产稳定的 3D 构建体的更好策略。在这项工作中，这两种策略结合在一起，开发了多功能配方，将药物传递潜力和 TERM 方法集成到单个设备中。具体来说，开发了一种新型光敏感的聚（醚尿烷）（PEU）与α-环糊精（α-CDs）形成超分子网络。通过红外光谱、尺寸排阻色谱和质子核磁共振（H NMR）光谱评估，成功地使用泊洛沙姆®407、1,6-二异氰酸己烷和 2-羟乙基甲基丙烯酸酯合成了 PEU。随后，通过临界胶束温度评估和动态光散射分析对 PEU 热响应性进行了表征，这表明分子量和整体疏水性之间达到了良好的平衡。因此，通过 X 射线衍射和 H NMR 光谱证明了与α-CDs 形成超分子结构域。通过使用低浓度的 PEU（≤5%w/v）设计了具有快速凝胶化动力学（几分钟内）的超分子水凝胶。根据 ISO 10993-5 法规，所有配方均被认为具有细胞相容性。值得注意的是，根据流变学测试，水凝胶具有机械性能和自修复能力，并且通过光流变学证明了其快速光交联（<60 s）。水凝胶中包封了高姜黄素载药量（570μg/mL），在模拟生理环境中可长达 5 周以高度可调且渐进的动力学释放。最后，使用基于挤出的生物打印机对水凝胶的挤出可加工性进行了初步评估，获得了 3D 打印结构，与原始设计具有良好的形态保真度。总的来说，所开发的水凝胶平台具有在再生药理学这一新兴领域应用的有前途的特性，（i）可注射的载药制剂，适用于通过光照射进行应用后的稳定化，（ii）生物材料墨水，用于制造针对患者的载药贴片。
