Laboratorio de Neurobiología, Instituto de Neurociencias. Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain.
Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC-Universidad de Zaragoza, C/ Pedro Cerbuna, 12, 50009 Zaragoza, Spain; Aragonese Foundation for Research and Development (ARAID), Av. Ranillas, 1-D, 50018 Zaragoza, Spain.
Acta Biomater. 2024 Oct 15;188:157-168. doi: 10.1016/j.actbio.2024.09.002. Epub 2024 Sep 7.
Cell therapy is a promising strategy for treating neurological pathologies but requires invasive methods to bypass the blood-brain barrier restrictions. The nose-to-brain route has been presented as a direct and less invasive alternative to access the brain. The primary limitations of this route are low retention in the olfactory epithelium and poor cell survival in the harsh conditions of the nasal cavity. Thus, using chitosan-based hydrogel as a vehicle is proposed in this work to overcome the limitations of nose-to-brain cell administration. The hydrogel's design was driven to achieve gelification in response to body temperature and a mucosa-interacting chemical structure biocompatible with cells. The hydrogel showed a < 30 min gelation time at 37 °C and >95 % biocompatibility with 2D and 3D cultures of mesenchymal stromal cells. Additionally, the viability, stability, and migration capacity of oligodendrocyte precursor cells (OPCs) within the hydrogel were maintained in vitro for up to 72 h. After the intranasal administration of the OPCs-containing hydrogel, histological analysis showed the presence of viable cells in the nasal cavity for up to 72 h post-administration in healthy athymic mice. These results demonstrate the hydrogel's capacity to increase the residence time in the nasal cavity while providing the cells with a favorable environment for their viability. This study presents for the first time the use of thermosensitive hydrogels in nose-to-brain cell therapy, opening the possibility of increasing the delivery efficiency in future approaches in translational medicine. STATEMENT OF SIGNIFICANCE: This work highlights the potential of biomaterials, specifically hydrogels, in improving the effectiveness of cell therapy administered through the nose. The nose-to-brain route has been suggested as a non-invasive way to directly access the brain. However, delivering stem cells through this route poses a challenge since their viability must be preserved and cells can be swept away by nasal mucus. Earlier attempts at intranasal cell therapy have shown low efficiency, but still hold promise to the future. The hydrogels designed for this study can provide stem cells with a biocompatible environment and adhesion to the nasal atrium, easing the successful migration of viable cells to the brain.
细胞疗法是治疗神经病理学的一种有前途的策略，但需要侵入性方法来绕过血脑屏障的限制。鼻内途径被提出是一种直接且侵入性较小的替代方法来进入大脑。该途径的主要限制是在嗅上皮中的保留率低，并且在鼻腔的恶劣条件下细胞存活率差。因此，在这项工作中，提出使用壳聚糖基水凝胶作为载体来克服鼻内细胞给药的限制。水凝胶的设计旨在实现对体温的凝胶化反应，并具有与细胞相容的粘膜相互作用的化学结构。水凝胶在 37°C 下的凝胶化时间小于 30 分钟，并且与 2D 和 3D 间充质基质细胞培养物的生物相容性大于 95%。此外，寡突胶质细胞前体细胞（OPC）在水凝胶中的活力、稳定性和迁移能力在体外维持长达 72 小时。在鼻内给予含 OPC 的水凝胶后，组织学分析显示在健康无胸腺小鼠中，给药后长达 72 小时鼻腔内仍存在存活细胞。这些结果表明，该水凝胶能够增加在鼻腔中的停留时间，同时为细胞提供有利于其活力的环境。这项研究首次展示了在鼻内细胞治疗中使用温敏水凝胶，为未来转化医学中提高递送效率开辟了可能性。意义声明：这项工作突出了生物材料，特别是水凝胶，在提高通过鼻腔给药的细胞治疗效果方面的潜力。鼻内途径被提议作为一种非侵入性的方法来直接进入大脑。然而，通过该途径递送干细胞具有挑战性，因为必须保持其活力，并且细胞可能会被鼻腔粘液冲走。早期的鼻内细胞治疗尝试显示效率较低，但仍有未来的潜力。本研究设计的水凝胶可以为干细胞提供生物相容性环境和与鼻腔心房的附着，便于有活力的细胞成功迁移到大脑。
