Tsintou Magdalini, Dalamagkas Kyriakos, Moore Tara L, Rathi Yogesh, Kubicki Marek, Rosene Douglas L, Makris Nikos
Department of Psychiatry and Neurology Services, Center for Neural Systems Investigations, Center for Morphometric Analysis, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital; Department of Psychiatry, Psychiatry Neuroimaging Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; University College of London Division of Surgery & Interventional Science, Center for Nanotechnology & Regenerative Medicine, University College London, London, UK.
University College of London Division of Surgery & Interventional Science, Center for Nanotechnology & Regenerative Medicine, University College London, London, UK; Department of Physical Medicine and Rehabilitation, The University of Texas Health Science Center at Houston; The Institute for Rehabilitation and Research Memorial Hermann Research Center, The Institute for Rehabilitation and Research Memorial Hermann Hospital, Houston, TX, USA.
Neural Regen Res. 2021 Apr;16(4):605-613. doi: 10.4103/1673-5374.295269.
Neural tissue engineering, nanotechnology and neuroregeneration are diverse biomedical disciplines that have been working together in recent decades to solve the complex problems linked to central nervous system (CNS) repair. It is known that the CNS demonstrates a very limited regenerative capacity because of a microenvironment that impedes effective regenerative processes, making development of CNS therapeutics challenging. Given the high prevalence of CNS conditions such as stroke that damage the brain and place a severe burden on afflicted individuals and on society, it is of utmost significance to explore the optimum methodologies for finding treatments that could be applied to humans for restoration of function to pre-injury levels. Extracellular vesicles (EVs), also known as exosomes, when derived from mesenchymal stem cells, are one of the most promising approaches that have been attempted thus far, as EVs deliver factors that stimulate recovery by acting at the nanoscale level on intercellular communication while avoiding the risks linked to stem cell transplantation. At the same time, advances in tissue engineering and regenerative medicine have offered the potential of using hydrogels as bio-scaffolds in order to provide the stroma required for neural repair to occur, as well as the release of biomolecules facilitating or inducing the reparative processes. This review introduces a novel experimental hypothesis regarding the benefits that could be offered if EVs were to be combined with biocompatible injectable hydrogels. The rationale behind this hypothesis is presented, analyzing how a hydrogel might prolong the retention of EVs and maximize the localized benefit to the brain. This sustained delivery of EVs would be coupled with essential guidance cues and structural support from the hydrogel until neural tissue remodeling and regeneration occur. Finally, the importance of including non-human primate models in the clinical translation pipeline, as well as the added benefit of multi-modal neuroimaging analysis to establish non-invasive, in vivo, quantifiable imaging-based biomarkers for CNS repair are discussed, aiming for more effective and safe clinical translation of such regenerative therapies to humans.
神经组织工程、纳米技术和神经再生是不同的生物医学学科，近几十年来它们一直共同努力，以解决与中枢神经系统（CNS）修复相关的复杂问题。众所周知，由于微环境阻碍了有效的再生过程，CNS的再生能力非常有限，这使得CNS治疗方法的开发具有挑战性。鉴于中风等CNS疾病的高发病率，这些疾病会损害大脑，并给患者个人和社会带来沉重负担，探索最佳方法以找到可应用于人类的治疗方法，将功能恢复到损伤前水平至关重要。细胞外囊泡（EVs），也称为外泌体，当来源于间充质干细胞时，是迄今为止尝试过的最有前途的方法之一，因为EVs通过在纳米尺度上作用于细胞间通讯来传递刺激恢复的因子，同时避免了与干细胞移植相关的风险。与此同时，组织工程和再生医学的进展提供了使用水凝胶作为生物支架的潜力，以便提供神经修复所需的基质，以及释放促进或诱导修复过程的生物分子。本综述介绍了一个新的实验假设，即如果将EVs与生物相容性可注射水凝胶结合可能带来的益处。阐述了这一假设背后的基本原理，分析了水凝胶如何延长EVs的保留时间并使对大脑的局部益处最大化。这种EVs的持续递送将与水凝胶提供的基本引导线索和结构支持相结合，直到神经组织重塑和再生发生。最后，讨论了在临床转化流程中纳入非人灵长类动物模型的重要性，以及多模态神经成像分析在建立用于CNS修复的非侵入性、体内、可量化的基于成像的生物标志物方面的额外益处，旨在使此类再生疗法更有效、更安全地转化到人类临床应用中。
