中国神经再生研究(英文版) ›› 2024, Vol. 19 ›› Issue (3): 680-686.doi: 10.4103/1673-5374.380908

• 原著:视神经损伤修复保护与再生 • 上一篇    下一篇

壳聚糖基温敏鼠神经生长因子缓释凝胶治疗神经营养性角膜病变

  

  • 出版日期:2024-03-15 发布日期:2023-09-02

Chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor for neurotrophic keratopathy

Jie Wu1, 2, 3, #, Yulei Huang4, #, Hanrui Yu4, #, Kaixiu Li4, Shifeng Zhang4, Guoqing Qiao4, Xiao Liu5, Hongmei Duan5, Yifei Huang1, Kwok-Fai So6, 7, 8, 9, 10, Zhaoyang Yang5, *, Xiaoguang Li5, 11, 12, *, Liqiang Wang1, 2, *#br#   

  1. 1Department of Ophthalmology, the Third Medical Center, Chinese PLA General Hospital, Beijing, China; 2The PLA Medical College, Department of Nephrology, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China; 3Department of Ophthalmology, Hainan Hospital of Chinese PLA General Hospital, Sanya, Hainan Province, China; 4Medical School of Chinese PLA, Beijing, China; 5Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China; 6Guangdong-Hongkong-Macau Institute of CNS Regeneration, Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Jinan University, Guangzhou, Guangdong Province, China; 7Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, Guangdong Province, China; 8Department of Ophthalmology and State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong Special Administrative Region, China; 9Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, Guangzhou, Guangdong Province, China; 10Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China; 11School of Engineering Medicine, Beijing Key Laboratory for Biomaterials and Neural Regeneration, Beihang University, Beijing, China; 12Beijing International Cooperation Bases for Science and Technology on Biomaterials and Neural Regeneration, Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University, Beijing, China
  • Online:2024-03-15 Published:2023-09-02
  • Contact: Liqiang Wang, MD, PhD, liqiangw301@163.com (lead contact); Xiaoguang Li, PhD, lxgchina@sina.com; Zhaoyang Yang, PhD, wack_lily@163.com.
  • Supported by:
    This work was supported by PLA General Hospital Program, No. LB20201A010024 (to LW).

摘要:

神经营养性角膜病变是由各种病因引起的角膜神经缺失导致的角膜上皮的持续性缺损,伴有或不伴有基质溃疡,而神经营养性角膜病变的治疗方案却很有限。实验构建了一种具备温敏、透明、缓释的特性的鼠神经生长因子眼用凝胶--壳聚糖基温敏鼠神经生长因子缓释凝胶,发现壳聚糖基温敏鼠神经生长因子缓释凝胶能在小鼠眼表稳定释放鼠神经生长因子超过20h,且小鼠角膜去神经损伤后,壳聚糖基温敏鼠神经生长因子的治疗可以显著促进小鼠角膜神经密度及角膜知觉的恢复,且在保持局部鼠神经生长因子浓度约1300pg/mL。进一步的临床试验显示,2或3期神经营养性角膜病变患者每天接受2次壳聚糖基温敏鼠神经生长因子缓释凝胶外用治疗8周后,患眼的角膜病灶均有所缩小,且无明显不良反应,其中有3例患者在治疗结束时角膜神经出现明显再生。这项研究表明温敏鼠神经生长因子缓释凝胶可以在治疗神经营养性角膜病变角膜病变方面安全有效,为临床上难治的角膜神经再生困境提供了新的选择。

https://orcid.org/0000-0002-7216-5352 (Liqiang Wang); https://orcid.org/0000-0003-4480-3676 (Xiaoguang Li); https://orcid.org/0000-0001-8313-6998 (Zhaoyang Yang)

Abstract: Neurotrophic keratopathy is a persistent defect of the corneal epithelium, with or without stromal ulceration, due to corneal nerve deficiency caused by a variety of etiologies. The treatment options for neurotrophic keratopathy are limited. In this study, an ophthalmic solution was constructed from a chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor (CTH-mNGF). Its effectiveness was evaluated in corneal denervation (CD) mice and patients with neurotrophic keratopathy. In the preclinical setting, CTH-mNGF was assessed in a murine corneal denervation model. CTH-mNGF was transparent, thermosensitive, and ensured sustained release of mNGF for over 20 hours on the ocular surface, maintaining the local mNGF concentration around 1300 pg/mL in vivo. Corneal denervation mice treated with CTH-mNGF for 10 days showed a significant increase in corneal nerve area and total corneal nerve length compared with non-treated and CTH treated mice. A subsequent clinical trial of CTH-mNGF was conducted in patients with stage 2 or 3 neurotrophic keratopathy. Patients received topical CTH-mNGF twice daily for 8 weeks. Fluorescein sodium images, Schirmer’s test, intraocular pressure, Cochet-Bonnet corneal perception test, and best corrected visual acuity were evaluated. In total, six patients (total of seven eyes) diagnosed with neurotrophic keratopathy were enrolled. After 8 weeks of CTH-mNGF treatment, all participants showed a decreased area of corneal epithelial defect, as stained by fluorescence. Overall, six out of seven eyes had fluorescence staining scores < 5. Moreover, best corrected visual acuity, intraocular pressure, Schirmer’s test and Cochet-Bonnet corneal perception test results showed no significant improvement. An increase in corneal nerve density was observed by in vivo confocal microscopy after 8 weeks of CTH-mNGF treatment in three out of seven eyes. This study demonstrates that CTH-mNGF is transparent, thermosensitive, and has sustained-release properties. Its effectiveness in healing corneal epithelial defects in all eyes with neurotrophic keratopathy suggests CTH-mNGF has promising application prospects in the treatment of neurotrophic keratopathy, being convenient and cost effective.

Key words: chitosan, corneal reinnervation, murine nerve growth factor, neurotrophic keratopathy, thermosensitive hydrogel