Laughter Melissa R, Bardill James R, Ammar David A, Pena Brisa, Calkins David J, Park Daewon
Department of Bioengineering, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado 80045, United States.
Department of Ophthalmology, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado 80045, United States.
ACS Biomater Sci Eng. 2018 Sep 10;4(9):3374-3383. doi: 10.1021/acsbiomaterials.8b00803. Epub 2018 Jul 23.
In general, neurons belonging to the central nervous system (CNS), such as retinal ganglion cells (RGCs), do not regenerate. Due to this, strategies have emerged aimed at protecting and regenerating these cells. Neurotrophic factor (NTF) supplementation has been a promising approach but is limited by length of delivery and delivery vehicle. For this study, we tested a polymeric delivery system (sulfonated reverse thermal gel or SRTG) engineered to deliver cilliary neurotrophic factor (CNTF), while also being injectable. A rat optic nerve crush (ONC) model was used to determine the neuroprotective and regenerative capacity of our system. The results demonstrate that one single intravitreal injection of SRTG-CNTF following ONC showed significant protection of RGC survival at both 1 and 2 week time points, when compared to the control groups. Furthermore, there was no significant difference in the RGC count between the eyes that received the SRTG-CNTF following ONC and a healthy control eye. Intravitreal injection of the polymer system also induced noticeable axon regeneration 500 m downstream from the lesion site compared to all other control groups. There was a significant increase in Müller cell response in groups that received the SRTG-CNTF injection following optic nerve crush also indicative of a regenerative response. Finally, higher concentrations of CNTF released from SRTG-CNTF showed a protective effect on RGCs and Müller cell response at a longer time point (4 weeks). In conclusion, we were able to show a neuroprotective and regenerative effect of this polymer SRTG-CNTF delivery system and the viability for treatment of neurodegenerations.
一般来说,属于中枢神经系统(CNS)的神经元,如视网膜神经节细胞(RGCs),不会再生。因此,出现了旨在保护和再生这些细胞的策略。补充神经营养因子(NTF)一直是一种有前景的方法,但受到递送时间长度和递送载体的限制。在本研究中,我们测试了一种经设计用于递送睫状神经营养因子(CNTF)的聚合物递送系统(磺化反向热凝胶或SRTG),同时该系统也是可注射的。使用大鼠视神经挤压(ONC)模型来确定我们系统的神经保护和再生能力。结果表明,与对照组相比,ONC后单次玻璃体内注射SRTG-CNTF在1周和2周时间点均显示出对RGC存活的显著保护作用。此外,ONC后接受SRTG-CNTF的眼睛与健康对照眼之间的RGC计数没有显著差异。与所有其他对照组相比,玻璃体内注射聚合物系统还在损伤部位下游500 m处诱导了明显的轴突再生。视神经挤压后接受SRTG-CNTF注射的组中,Müller细胞反应显著增加,这也表明了再生反应。最后,从SRTG-CNTF释放的更高浓度的CNTF在更长时间点(4周)对RGCs和Müller细胞反应显示出保护作用。总之,我们能够证明这种聚合物SRTG-CNTF递送系统的神经保护和再生作用以及治疗神经退行性疾病的可行性。