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功能高分子材料促进脊髓损伤后再生修复的研究进展

孙秀敏 庞卯 冯丰 刘斌 戎利民 何留民

孙秀敏, 庞卯, 冯丰, 刘斌, 戎利民, 何留民. 功能高分子材料促进脊髓损伤后再生修复的研究进展[J]. 功能高分子学报, 2021, 34(4): 301-319. doi: 10.14133/j.cnki.1008-9357.20210118001
引用本文: 孙秀敏, 庞卯, 冯丰, 刘斌, 戎利民, 何留民. 功能高分子材料促进脊髓损伤后再生修复的研究进展[J]. 功能高分子学报, 2021, 34(4): 301-319. doi: 10.14133/j.cnki.1008-9357.20210118001
SUN Xiumin, PANG Mao, FENG Feng, LIU Bin, RONG limin, HE Liumin. Research Progress of Functional Polymer for Spinal Cord Regeneration[J]. Journal of Functional Polymers, 2021, 34(4): 301-319. doi: 10.14133/j.cnki.1008-9357.20210118001
Citation: SUN Xiumin, PANG Mao, FENG Feng, LIU Bin, RONG limin, HE Liumin. Research Progress of Functional Polymer for Spinal Cord Regeneration[J]. Journal of Functional Polymers, 2021, 34(4): 301-319. doi: 10.14133/j.cnki.1008-9357.20210118001

功能高分子材料促进脊髓损伤后再生修复的研究进展

doi: 10.14133/j.cnki.1008-9357.20210118001
基金项目: 国家重点研发计划项目(2017YFA0105403);国家自然科学基金(31870964,32071354);中国博士后科学基金(2020TQ0378,2020M680137)
详细信息
    作者简介:

    孙秀敏(1984—),女,博士后,研究方向为神经组织工程和脊髓损伤再生修复。E-mail: ermine2005@163.com

    何留民,博士,长期专注于纳米医学与神经再生研究,在功能性自组装短肽纳米水凝胶的设计、聚合物功能化改性以及纳米支架多级信号诱导神经再生等方面进行了深入的研究。主持多项国家自然科学基金及省部级项目。先后入选“广东特支计划”科技创新青年拔尖人才计划、广州市珠江科技新星、广东省高等学校优秀青年教师培养计划。以第一作者/通讯作者在包括Biomaterials、ACS Appl Mater Interfaces、Acta Biomater、J Mater Chem等学术期刊上发表SCI论文40余篇,被引近2 000次。以第一发明人授权中国发明专利2件,成功转让1件。自2015年起受邀在全国生物材料大会担任神经修复材料分会主席并作邀请报告

    通讯作者:

    何留民,E-mail: helm9@mail.sysu.edu.cn

  • 中图分类号: O63

Research Progress of Functional Polymer for Spinal Cord Regeneration

  • 摘要: 脊髓损伤后损伤区域神经纤维束的破坏,导致损伤区域以下长久的感觉和运动功能丧失。损伤区域恶劣的微环境是脊髓损伤难以修复的一大问题,大量的炎症细胞聚集、细胞死亡、抑制因子的分泌等,进一步导致损伤区域神经细胞的二次死亡、胶质细胞过度增生、胶原纤维沉积等。不利的微环境不仅限制轴突的再生,同时损伤神经干细胞的功能,不利于神经干细胞向损伤区域迁移并向神经元分化。虽然近期的研究证明脊髓损伤后轴突在合适的基质环境下能够再生,但完全恢复目前还没有可行措施。近年来,高分子生物材料在脊髓损伤修复研究中取得了一定进展,可以发挥多种功能:减少空洞和瘢痕组织的形成,为再生轴突的生长提供支撑作用;调控细胞行为,诱导神经细胞生长和分化;抑制炎症细胞的非特异性渗入进而改善脊髓损伤区域的微环境;作为载体负载和释放药物、细胞和生物活性因子。本文结合本课题组的研究从生物材料种类、支架类型、微环境构建以及因子负载等方面在脊髓损伤修复中的应用研究进行了综述,为生物材料用于脊髓损伤的治疗提供基础研究方向。

     

  • 图  1  脊髓损伤后的病理生理示意图,细胞和细胞外基质在损伤区域沉积的过程:(a)脊髓损伤后急性期(0~72 h)损伤导致神经细胞死亡和大量炎性细胞迁移到损伤区域;(b)脊髓损伤后慢性期(损伤72 h之后),慢性空洞形成,星形胶质细胞反应性增生和细胞外基质的沉积

    Figure  1.  The schematic of SCI pathophysiology, cellular and extracellular composition of the spinal injury scar: (a) In the acute post-injury phase (0—72 h), neural cell death and the release of a number of inflammatory cell in the injury site; (b) In the chronic post-injury phase (after 72 h), a chronic cystic cavity develops, reactive astrocytes hypertrophy and extracellular deposition

    图  2  (a)脱细胞基质周围神经基质(DNM)和脱细胞脊髓基质(DSCM);(b)天然或脱细胞周围神经/脊髓组织学切片的 H&E 染色(箭头指示细胞核);(c)消化和离子平衡后的DSCM预凝胶;(d)DSCM水凝胶;(e)COLI, DNM 和 DSCM水凝胶纳米纤维结构的 SEM图像[65]

    Figure  2.  (a)Decellularized peripheral nerve matrix and decellularized spinal cord matrix; (b) Histological sections with H&E staining of the native or decellularized peripheral nerve/spinal cord, respectively (The arrows indicate cell nucleus); (c) Pre-gel solution obtained after digestion and ionic balance of DSCM in a tilted vial; (d)The appearance of DSCM-gel after sol-gel transition;(e)SEM images of the nanofibrous structure in the COLI, DNM, and DSCM hydrogels [65]

    图  3  (a):ⅰ—实心的圆柱体,ⅱ—单通道管,ⅲ—5通道管,ⅳ—有核开放性结构,ⅴ—无核开放性结构;(b)通道管模具设计线框图;(c)无核开放性结构设计模具;(d)有核开放性结构设计模具[84]

    Figure  3.  (a)ⅰ—Solid cylinder, ⅱ—Tube, ⅲ—Channel, ⅳ—Open-path without core, ⅴ—Open-path without core; (b) Wireframe view of a mold for the channel design; (c) Open-path without a core mold blueprint; (d) Open-path with core blueprint[84]

    图  4  PLLA多通道导管制备装置示意图和不同结构多通道导管横截面的SEM照片[102]

    Figure  4.  Scheme of the systematized device for fabrication of multi-channel conduits and SEM images of the multi-channel conduits cross section[102]

      LNC: NC with a ladder-like microstructure; MNC: NC with a microspherical pores and nano-fibrous pore walls; NNC: NC witha hano-fibrous microstructure

    图  5  含生长因子的F/S水凝胶的形态特征:(a)含有生长因子的RADA16-IKVAV溶液与RADA16-RGD溶液混合形成的稳定水凝胶;(b)F/S水凝胶纤维和(c~e)不同生长因子的水凝胶纤维的AFM照片[139]

    Figure  5.  Morphological characteristics of the F/S hydrogel containing growth factors: (a) Stable hydrogel was formed by combining RADA16-IKVAV solution containing growth factors and RADA16-RGD solution; (b) AFM images of F/S hydrogel fiber and (c—e) those with different growth factors [139]

    图  6  模拟脊髓结构的3D打印支架:(a)3D打印机系统装置;(b)3D打印机打印的连续层结构;(c)正常大鼠脊髓轴突NF200染色结果(上方白质中轴突高度排列成平行阵列,下方灰质中轴突为无序结构);(d)脊髓中相关功能轴突线状排列区域(束)(运动系统用绿色表示,感觉系统用蓝色表示)[147]

    Figure  6.  3D-printed scaffold mimics the spinal cord architecture: (a) 3D-printer setup; (b) 3D printing creates a structure with one continuous layer; (c) Heavy chain neurofilament (NF200) labeling of axons in rat spinal cord (The axons in the white matter (top of the panel) are highly organized into parallel arrays traveling from rostral to caudal. The axons in the gray matter (bottom of the panel) are not linear);(d) Axonal projections in the spinal cord are linearly organized into regions (fascicles) containing axons of related function (Motor systems are shown in green and sensory systems are shown in blue)[147]

    表  1  生物材料支架负载生物活性因子的研究

    Table  1.   Investigations of biomaterial scaffolds loaded with neurotrophic factors

    Types of drug delivery strategiesBiomaterialsFactorOutcomeFrom
    Polymer micro/nanoparticlesPLGANGF and GDNFThe neurotrophins were released over 6 weeks in vitro and resulted in both tissue regeneration and functional improvements[161, 162]
    PLGAGDNFPromoted axon growth and functional improvement after SCI[163]
    Nanoparticle20 nm Nanoparticles were found along the spinal cord both rostral and caudal to the injection site, while 100 nm nanoparticles remained at the injection site[164]
    PEG nanoparticleLimit protein adsorption and macrophage engulfment[165]
    Short peptide series nanoparticleEnhance nanoparticle deliveryacross the BBB[166]
    PLGA nanoparticleChABCDegraded glial scar, promoted functional recovery and axonal regeneration[167]
    Chemical crosslinkL-lactide, L-LA and
    ε-caprolactone, ε-CL
    Load factors[168]
    Electrospun collagen nanofibers, microbial transglutaminase (mTG)NT3Proteins were loaded at an efficiency of approximately 45%—48%, a sustained release of NT3 was obtained[169]
    CollagenNT3, BDNF, bFGF, EphA4LBD and PlexinB1LBDFacilitated axonal and neuronal regeneration, remyelination and synapse formation of regenerated axons after SCI[34, 35, 37, 38]
    Physical blendFibrin gelsNT3, BDNFChABC, Rho inhibitor, gethrinPromote axonal regeneration and functional recovery[170, 171]
    Hyaluronan/methyl cellulose (HAMC) hydrogelFGF2Increased angiogenesis[172]
    Hyaluronan/methyl cellulose (HAMC) hydrogelErythropoietin(EPO)Attenuated inflammatory response and promoted neurogenesis[173]
    PCL core-shell structuresRetinoic acidSustained released of RA was obtained for at least 14 d, enhanced MSCs neuronal differentiation[174]
    PCL core-shell nanofibersAlbumin and lysozymeThe released lysozyme maintained its structure and bioactivity[175]
    PCL core-shell nanofibersPlatelet-derived growth factor (PDGF)The protein with near zero-order kinetics and preserved bioactivity[176]
    Self-assembling peptide hydrogels FAQ SAPsChABCChABC was continuously released in vitro for 42 d, favored host neural regeneration and behavioral recovery[177]
    Particle/scaffold compositesPLA-PEG-PLAPLGA microparticlesGDNFBDNFBDNF was slowly released over a 56 d period, whereas a bolus of GDNF was released around 28 d[127]
    PLA-PEG-PLA hydrogels,
    PLGA microparticles
    CNTFCNTF released from a degradable hydrogel was able to stimulate outgrowth of a significantly higher number of neurites[178]
    PLG microparticlesTGF-β1Expression of cytokines TNF-alpha, IL-12, and MCP-1 were decreased by at least 40%[179]
    HAMCPLGA micro/nanoparticleFGF2Increased the density of neovascularization in the injured area[180]
    Functional multichannel Poly(propylene fumarate)-Collagen scaffoldNT3Facilitated axonal and neuronal regeneration, remyelination and synapse formation of regenerated axons after SCI[36]
    PLLA gelatinNT3Decreased inflammatory responses and collagen/astrocytic scar formation. Promoted axonal regeneration and functional restoration[107]
    PLGA multifunctional, multichannel bridges, HA microparticlesNT3BDNFEnhance axonal growth and promote regeneration[118]
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出版历程
  • 收稿日期:  2021-01-18
  • 网络出版日期:  2021-03-31
  • 刊出日期:  2021-07-08

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