Gao Xu, You Zhifeng, Li Yue, Kang Xinyi, Yang Wen, Wang Huiru, Zhang Ting, Zhao Xinhao, Sun Yifu, Shen He, Dai Jianwu
Department of Orthopaedic Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, P. R. China; Key Laboratory for Nano-Bio Interface Research, Division of Nanobiomedicine, Suzhou Institute of NanoTech and NanoBionics, Chinese Academy of Sciences, Suzhou, 215123, P. R. China.
Key Laboratory for Nano-Bio Interface Research, Division of Nanobiomedicine, Suzhou Institute of NanoTech and NanoBionics, Chinese Academy of Sciences, Suzhou, 215123, P. R. China.
Acta Biomater. 2023 Jan 1;155:235-246. doi: 10.1016/j.actbio.2022.11.015. Epub 2022 Nov 13.
Transplantation of allogeneic adult spinal cord tissues (aSCTs) to replace the injured spinal cord, serves as a promising strategy in complete spinal cord injury (SCI) repair. However, in addition to allograft immune rejection, damage-associated molecular pattern (DAMP)-mediated inflammatory microenvironments greatly impair the survival and function of transplants. In this study, we aimed to regulate the immune microenvironment after aSCT implantation by developing a functional hybrid gelatin and hyaluronic acid hydrogel (F-G/H) modified with cationic polymers and anti-inflammatory cytokines that can gelatinize at both ends of the aSCT to glue the grafts for perfect matching at defects. The F-G/H hydrogel exhibited the capacities of DAMP scavenging, sustainably released anti-inflammatory cytokines, and reduced lymphocyte accumulation, thereby modulating the immune response and enhancing the survival and function of aSCTs. When the hydrogel was used in combination with a systemic immunosuppressive drug treatment, the locomotor functions of SCI rats were significantly improved after aSCTs and F-G/H transplantation. This biomaterial-based immunomodulatory strategy may provide the potential for spinal cord graft replacement for treating SCI. STATEMENT OF SIGNIFICANCE: In this study, we aimed to regulate the immune microenvironment by developing a functional hybrid gelatin and hyaluronic acid hydrogel (F-G/H) modified with cationic polymers and anti-inflammatory cytokines that can gelatinize at both ends of the aSCT to glue the grafts for perfect matching at defects. We found that with the treatment of F-G/H hydrogel, the aSCT survival and function was significantly improved, as a result of reducing recruitment and activation of immune cells through TLR- and ST-2- related signaling. With the combination of immunosuppressive drug treatment, the locomotor functions of SCI rats were significantly improved after aSCTs and F-G/H transplantation. Findings from this work suggest the potential application of the F-G/H as a biomaterial-based immunoregulatory strategy for improving the therapeutic efficiency of the transplanted spinal cord graft for spinal cord injury repair.
移植同种异体成年脊髓组织（aSCTs）以替代受损脊髓，是完全性脊髓损伤（SCI）修复中一种很有前景的策略。然而，除了同种异体移植免疫排斥外，损伤相关分子模式（DAMP）介导的炎症微环境极大地损害了移植组织的存活和功能。在本研究中，我们旨在通过开发一种功能性混合明胶和透明质酸水凝胶（F-G/H）来调节aSCT植入后的免疫微环境，该水凝胶用阳离子聚合物和抗炎细胞因子修饰，可在aSCT两端凝胶化以黏合移植物，使其在缺损处完美匹配。F-G/H水凝胶具有清除DAMP、持续释放抗炎细胞因子以及减少淋巴细胞聚集的能力，从而调节免疫反应并增强aSCTs的存活和功能。当水凝胶与全身免疫抑制药物治疗联合使用时，SCI大鼠在接受aSCTs和F-G/H移植后的运动功能得到显著改善。这种基于生物材料的免疫调节策略可能为脊髓移植替代治疗SCI提供潜力。重要性声明：在本研究中，我们旨在通过开发一种功能性混合明胶和透明质酸水凝胶（F-G/H）来调节免疫微环境，该水凝胶用阳离子聚合物和抗炎细胞因子修饰，可在aSCT两端凝胶化以黏合移植物，使其在缺损处完美匹配。我们发现，通过F-G/H水凝胶治疗，aSCT的存活和功能得到显著改善，这是通过TLR和ST-2相关信号通路减少免疫细胞的募集和激活实现的。与免疫抑制药物治疗联合使用时，SCI大鼠在接受aSCTs和F-G/H移植后的运动功能得到显著改善。这项工作的发现表明，F-G/H作为一种基于生物材料的免疫调节策略，有可能提高移植脊髓移植物治疗脊髓损伤修复的治疗效率。
