3D In Vitro Glioma-Neuron-Astrocyte Biomimetic Composites Recapitulate Key Molecular Mechanisms Linked to Glioblastoma Multiforme Pathophysiology

IF 18.5 1区 材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY Advanced Functional Materials Pub Date : 2025-01-23 DOI:10.1002/adfm.202419211
Mateo S. Andrade Mier, Esra Türker, Jessica Faber, Mike Friedrich, Zan Lamberger, Jeannette Weigelt, Panthipa Suwannakot, Benedikt Gantert, Abhinav Singh, Vanessa Moessler, Annemarie Sodmann, Nicoletta Murenu, Joachim Schenk, Natascha Schaefer, Torsten Blunk, Aldo R. Boccaccini, Tessa C. Lühmann, Jörg Tessmar, Jeremy M. Crook, Eva Tomaskovic-Crook, Paul D. Dalton, Gregor Lang, Robert Blum, Reiner Strick, Silvia Budday, Katrin G. Heinze, Carmen Villmann
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Abstract

Glioblastoma multiforme is the most devastating brain tumor without cure. Although in vitro and in vivo research on glioblastoma multiforme have demonstrated its complexity, including interactions with brain cells and the tumor microenvironment, 3D models resembling those key features and allowing to study therapeutic interventions of this aggressive tumor are scarce. Here, a 3D glioblastoma model is developed that establishes a tumor microenvironment including a hyaluronic acid-based hydrogel cross-linked with laminin, both of which are key components of the brain's extracellular matrix. This hydrogel mimics the mechanical properties of the brain's extracellular matrix at the macroscopic and mesoscopic levels, as evaluated by stiffness, viscosity using rheological and nanoindentation measurements. The ultra-soft hydrogel with a storage modulus of 100 Pa is reinforced by 3D printed microfiber scaffolds which allow the setup of a multicellular 3D model including primary cortical neurons and astrocytes and glioblastoma cells. Tumor microenvironment interactions are characterized through nanoindentation and confocal shadow imaging with the 3D in vitro disease model resembling in vivo properties of glioblastoma tumor entities characterized by functional interactions with the surrounding astrocytes and neurons and the tumor's hijacking capability using neuronal signaling to promote its own proliferation.

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3D体外胶质瘤-神经元-星形胶质细胞仿生复合材料概括了与胶质母细胞瘤多形性病理生理相关的关键分子机制
多形性胶质母细胞瘤是无法治愈的最具破坏性的脑肿瘤。尽管多形性胶质母细胞瘤的体外和体内研究已经证明了其复杂性,包括与脑细胞和肿瘤微环境的相互作用,但类似这些关键特征并允许研究这种侵袭性肿瘤的治疗干预措施的3D模型很少。在这里,开发了一个3D胶质母细胞瘤模型,建立了一个肿瘤微环境,包括与层粘连蛋白交联的基于透明质酸的水凝胶,两者都是大脑细胞外基质的关键成分。这种水凝胶在宏观和介观水平上模拟了大脑细胞外基质的机械特性,通过流变学和纳米压痕测量来评估其刚度、粘度。储存模量为100 Pa的超软水凝胶由3D打印的微纤维支架加强,可以建立多细胞3D模型,包括初级皮质神经元、星形胶质细胞和胶质母细胞瘤细胞。肿瘤微环境相互作用通过纳米压痕和共聚焦阴影成像表征,三维体外疾病模型与胶质母细胞瘤肿瘤实体的体内特性相似,其特征是与周围星形胶质细胞和神经元的功能相互作用以及肿瘤利用神经元信号促进自身增殖的劫持能力。
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来源期刊
Advanced Functional Materials
Advanced Functional Materials 工程技术-材料科学:综合
CiteScore
29.50
自引率
4.20%
发文量
2086
审稿时长
2.1 months
期刊介绍: Firmly established as a top-tier materials science journal, Advanced Functional Materials reports breakthrough research in all aspects of materials science, including nanotechnology, chemistry, physics, and biology every week. Advanced Functional Materials is known for its rapid and fair peer review, quality content, and high impact, making it the first choice of the international materials science community.
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