Biomaterials, Biomechanics and Tissue Engineering Group, Department Materials Science and Metallurgy, Technical University of Catalonia (UPC), Escola D'Enginyeria Barcelona Est (EEBE), C/Eduard Maristany 14, 08019, Barcelona, Spain; Barcelona Research Center in Multiscale Science and Engineering, UPC, 08019, Barcelona, Spain; Research Centre for Biomedical Engineering (CREB), UPC, 08019, Barcelona, Spain; Instituto de Investigación Sanitaria Del Principado de Asturias (ISPA), Av. de Roma S/n, Oviedo, Spain.
Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute of Science and Technology (BIST), C/Baldiri I Reixach 10-12, 08028, Barcelona, Spain.
Free Radic Biol Med. 2021 Feb 20;164:107-118. doi: 10.1016/j.freeradbiomed.2020.12.437. Epub 2021 Jan 2.
The use of oxidative stress generated by Cold Atmospheric Plasma (CAP) in oncology is being recently studied as a novel potential anti-cancer therapy. However, the beneficial effects of CAP for treating osteosarcoma have mostly been demonstrated in 2-dimensional cultures of cells, which do not mimic the complexity of the 3-dimensional (3D) bone microenvironment. In order to evaluate the effects of CAP in a relevant context of the human disease, we developed a 3D tissue-engineered model of osteosarcoma using a bone-like scaffold made of collagen type I and hydroxyapatite nanoparticles. Human osteosarcoma cells cultured within the scaffold showed a high capacity to infiltrate and proliferate and to exhibit osteomimicry in vitro. As expected, we observed significantly different functional behaviors between monolayer and 3D cultures when treated with Cold Plasma-Activated Ringer's Solution (PAR). Our data reveal that the 3D environment not only protects cells from PAR-induced lethality by scavenging and diminishing the amount of reactive oxygen and nitrogen species generated by CAP, but also favours the stemness phenotype of osteosarcoma cells. This is the first study that demonstrates the negative effect of PAR on cancer stem-like cell subpopulations in a 3D biomimetic model of cancer. These findings will allow to suitably re-focus research on plasma-based therapies in future.
冷等离体（CAP）生成的氧化应激在肿瘤学中的应用最近被研究作为一种新型的潜在抗癌疗法。然而，CAP 治疗骨肉瘤的有益效果主要在细胞的 2 维培养中得到了证实，而这些培养并不能模拟 3 维（3D）骨微环境的复杂性。为了在与人类疾病相关的背景下评估 CAP 的效果，我们使用由 I 型胶原和羟基磷灰石纳米颗粒制成的类骨支架，开发了骨肉瘤的 3D 组织工程模型。在支架内培养的人骨肉瘤细胞表现出高渗透和增殖能力，并在体外表现出成骨模拟。正如预期的那样，当用冷等离子体激活林格氏溶液（PAR）处理时，我们观察到单层和 3D 培养之间的功能行为明显不同。我们的数据表明，3D 环境不仅通过清除和减少 CAP 产生的活性氧和氮物种的量来保护细胞免受 PAR 诱导的致死作用，而且还有利于骨肉瘤细胞的干性表型。这是第一项在癌症的 3D 仿生模型中证明 PAR 对癌症干细胞样细胞亚群的负作用的研究。这些发现将使人们能够在未来适当重新关注基于等离子体的治疗研究。
