中国神经再生研究(英文版) ›› 2025, Vol. 20 ›› Issue (12): 3539-3552.doi: 10.4103/NRR.NRR-D-24-00422

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

用于神经材料测试的多细胞脑细胞片横断损伤模型

  

  • 出版日期:2025-12-15 发布日期:2025-03-17

A macro-transection model of brain trauma for neuromaterial testing with functional electrophysiological readouts

Jessica Wiseman1, 2, #, Raja Haseeb Basit1, 3, #, Akihiro Suto4 , Sagnik Middya5 , Bushra Kabiri1 , Michael Evans6 , Vinoj George4 , Christopher Adams1 , George Malliaras5 , Divya Maitreyi Chari1, *   

  1. 1 School of Medicine, Keele University, Newcastle-under-Lyme, UK;  2 Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK;  3 Academic Department of Surgery, Queen Elizabeth Hospital & University of Birmingham, Edgbaston, UK;  4 Guy Hilton Research Center, School of Pharmacy & Bioengineering, Keele University, Newcastle-under-Lyme, UK;  5 Electrical Engineering Division, Department of Engineering, University of Cambridge, Cambridge, UK;  6 School of Life Sciences, Keele University, Newcastle-under-Lyme, UK
  • Online:2025-12-15 Published:2025-03-17
  • Contact: Divya Maitreyi Chari, DPhil, d.chari@keele.ac.uk.
  • Supported by:
    This study was supported by awards from the EPSRC Centre for Doctoral Training in Regenerative Medicine (EP/L014904/1; to JW); an NHS bursary (to RHB); and an EPSRC Healthcare Technologies award (EP/T013885/1; to DMC).

摘要:

由于缺乏临床再生疗法,穿透性神经损伤的功能恢复受到阻碍。生物材料疗法通过免疫调节、结构支撑和输送治疗性生物分子,有望成为神经修复的医用材料。然而,神经组织工程研究的一个瓶颈是缺乏用于治疗测试的简便和病理模拟模型。实验利用二维、高密度多细胞皮质脑片,在体外开发了一种简便的损伤(大切口/划痕伤口)模型。该模型涵盖了参与损伤后病理反应的主要神经细胞类型。重要的是,实验观察到损伤灶的标志性病理反应,包括细胞瘢痕、免疫细胞浸润、前体细胞迁移和短程轴突萌发。为了评估该模型在生物材料筛选方面的潜力,实验通过测试磁性微粒的递送情况,发现损伤激活的免疫细胞对引入的磁性微粒有很高的吸收率,这与体内的研究结果一致。最后,实验证明了在脑片中(在多电极阵列装置中)创建可重现的创伤性损伤是可行的,其特征是损伤部位的局灶性电尖峰丢失,为长期电生理学加组织学检测(长达 35 天)提供了可能性。总之,实验在体外模拟二维多细胞皮层脑细胞片的横断损伤,可结合细胞和电生理学检测损伤/修复情况。这种简化脑损伤模型的病理模拟性和适应性有利于再生神经学中生物材料疗法的测试,并可提供功能性电生理数据。

https://orcid.org/0000-0002-7095-8578 (Divya Maitreyi Chari)

关键词: 体外建模, 横断损伤, 多电极阵列接口, 神经材料, 创伤性脑损伤, 纳米颗粒, 划痕试验

Abstract: Functional recovery in penetrating neurological injury is hampered by a lack of clinical regenerative therapies. Biomaterial therapies show promise as medical materials for neural repair through immunomodulation, structural support, and delivery of therapeutic biomolecules. However, a lack of facile and pathology-mimetic models for therapeutic testing is a bottleneck in neural tissue engineering research. We have deployed a two-dimensional, high-density multicellular cortical brain sheet to develop a facile model of injury (macrotransection/ scratch wound) in vitro. The model encompasses the major neural cell types involved in pathological responses post-injury. Critically, we observed hallmark pathological responses in injury foci including cell scarring, immune cell infiltration, precursor cell migration, and shortrange axonal sprouting. Delivering test magnetic particles to evaluate the potential of the model for biomaterial screening shows a high uptake of introduced magnetic particles by injury-activated immune cells, mimicking in vivo findings. Finally, we proved it is feasible to create reproducible traumatic injuries in the brain sheet (in multielectrode array devices in situ) characterized by focal loss of electrical spiking in injury sites, offering the potential for longer term, electrophysiology plus histology assays. To our knowledge, this is the first in vitro simulation of transecting injury in a two-dimensional multicellular cortical brain cell sheet, that allows for combined histological and electrophysiological readouts of damage/repair. The patho-mimicry and adaptability of this simplified model of brain injury could benefit the testing of biomaterial therapeutics in regenerative neurology, with the option for functional electrophysiological readouts.

Key words: in vitro modelling, multielectrode array interfacing, nanoparticles, neuromaterials, scratch assay, transecting injury, traumatic brain injury