Background/Objective

Intervertebral disc (IVD) degeneration (IVDD) that greatly affected by regional biomechanical environment is a major cause of low back pain. Injectable hydrogels have been commonly studied for treatment of IVDD due to their capability of mimicking extracellular matrix structure to support cellular behavior and clinical prospects in minimally invasive treatment. However, most hydrogels suffer from complicated chemistry, potential uncertainty and toxicity from in-situ gelation, and mismatch with IVD mechanical environment that limit their therapeutic effects or clinical translation in IVDD or intervertebral disc defect repair. For IVD lesion repair, the study aims to develop a novel hydrogel with shear-thinning enabled injectability, high bio-safety, and mechanical properties adaptable to the IVD environment, using a simple chemistry and method. And therapeutic efficacy of the novel hydrogel in the treatment of IVDD or intervertebral disc defect will be revealed.

Methods

A glycerol cross-linked PVA gel (GPG) was synthesized based on multiple H-bonds formation between glycerol molecules and PVA chains. The rheological and mechanical properties were tested. The swelling ratio was measured. The micro-architecture was observed through scanning and transmission electron microscopes. Nucleus pulposus (NP) cells were cultured in GPG-coated plates or silicone chambers treated under hydrostatic or dynamic loading in vitro, and examined for proliferation, vitality, apoptosis, expression of catabolic and anabolic markers. GPG was injected in needle puncture (IDD) or NP discectomy (NPD) models in vivo, and examined through magnetic resonance imaging, micro-computed tomography scanning and histological staining.

Results

GPG had a highly porous structure consisting of interconnected pores. Meanwhile, the GPG had NP-like viscoelastic property, and was able to withstand the cyclic deformation while exhibiting a prominent energy-dissipating capability. In vitro cell tests demonstrated that, the hydrogel significantly down-regulated the expression of catabolic markers, maintained the level of anabolic markers, preserved cell proliferation and vitality, reduced apoptotic rate of NP cells under pathologically hydrostatic and dynamic loading environments compared to cells cultured on untreated plate or silicone chamber. In vivo animal studies revealed that injection of GPG efficiently maintained NP structural integrity, IVD height and relative water content in IDD models, and stimulated the fibrous repair in NPD models.

Conclusion

This study showed that GPG, with high injectability, NP-like viscoelastic characteristics, good energy-dissipating properties and swelling capacities, preserved NP cells vitality against pathological loading, and had therapeutic effects on IVD repair in IDD and NPD models.

The translational potential of this article

Effective clinical strategy for treatment of intervertebral disc degeneration (IVDD) is still lacking. This study demonstrates that injection of a hydrogel with nucleus pulposus-matched viscoelastic property could remarkably prevent the IVDD progress. Prepared with simple chemistry and procedure, the cell/drug-free GPG with high bio-safety and shear-thinning enabled injectability bears great translational potential for the clinical treatment of IVDD via a minimally invasive approach.

中文翻译：

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具有与髓核匹配的粘弹性特性的可注射水凝胶可防止椎间盘退变

 背景/目标

椎间盘（IVD）退变（IVDD）受局部生物力学环境影响较大，是腰痛的主要原因。可注射水凝胶因其模仿细胞外基质结构以支持细胞行为和微创治疗的临床前景而被广泛研究用于 IVDD 的治疗。然而，大多数水凝胶具有复杂的化学性质、原位凝胶化的潜在不确定性和毒性，以及与 IVD 机械环境的不匹配，限制了其在 IVDD 或椎间盘缺损修复中的治疗效果或临床转化。对于 IVD 病变修复，该研究旨在使用简单的化学和方法开发一种新型水凝胶，具有剪切稀化可注射性、高生物安全性和适应 IVD 环境的机械性能。新型水凝胶治疗 IVDD 或椎间盘缺损的疗效将被揭示。

 方法

基于甘油分子和PVA链之间形成的多个氢键合成了甘油交联PVA凝胶(GPG)。测试了流变性能和机械性能。测量溶胀率。通过扫描和透射电子显微镜观察微结构。髓核 (NP) 细胞在体外静水或动态负载下处理的 GPG 包被板或硅胶室中培养，并检查增殖、活力、凋亡、分解代谢和合成代谢标志物的表达。 GPG被注射到体内针刺（IDD）或NP椎间盘切除（NPD）模型中，并通过磁共振成像、微型计算机断层扫描和组织学染色进行检查。

 结果

GPG 具有由相互连接的孔组成的高度多孔结构。同时，GPG具有类NP的粘弹性，能够承受循环变形，同时表现出突出的耗能能力。体外细胞测试表明，与培养的细胞相比，水凝胶在病理静水和动态负载环境下显着下调分解代谢标志物的表达，维持合成代谢标志物的水平，保留细胞增殖和活力，降低NP细胞的凋亡率未经处理的板或硅胶室。体内动物研究表明，注射GPG可有效维持IDD模型中的NP结构完整性、IVD高度和相对含水量，并刺激NPD模型中的纤维修复。

 结论

本研究表明，GPG 具有高可注射性、类似 NP 的粘弹性特性、良好的耗能特性和膨胀能力，可在病理负荷下保持 NP 细胞的活力，并对 IDD 和 NPD 模型中的 IVD 修复具有治疗作用。

本文的翻译潜力

治疗椎间盘退变（IVDD）的有效临床策略仍然缺乏。这项研究表明，注射具有与髓核匹配的粘弹性特性的水凝胶可以显着阻止 IVDD 进展。这种无细胞/药物的 GPG 采用简单的化学和程序制备而成，具有高生物安全性和剪切稀化注射能力，对于通过微创方法进行 IVDD 临床治疗具有巨大的转化潜力。