Journal Home > Volume 9 , Issue 1

Recently, substrate stiffness has been involved in the physiology and pathology of the nervous system. However, the role and function of substrate stiffness remain unclear. Here, we review known effects of substrate stiffness on nerve cell morphology and function in the central and peripheral nervous systems and their involvement in pathology. We hope this review will clarify the research status of substrate stiffness in nerve cells and neurological disorder.

Full text
About this article

Substrate stiffness in nerve cells

Show Author's information Weijin SiJihong Gong( )Xiaofei Yang( )
Key Laboratory of Cognitive Science, Hubei Key Laboratory of Medical Information Analysis and Tumor Diagnosis & Treatment, Laboratory of Membrane Ion Channels and Medicine, College of Biomedical Engineering, South-Central Minzu University, Wuhan 430074, China


Recently, substrate stiffness has been involved in the physiology and pathology of the nervous system. However, the role and function of substrate stiffness remain unclear. Here, we review known effects of substrate stiffness on nerve cell morphology and function in the central and peripheral nervous systems and their involvement in pathology. We hope this review will clarify the research status of substrate stiffness in nerve cells and neurological disorder.

Keywords: neurological diseases, synapse, pathology, substrate stiffness, nerve cell, neurite


Barriga EH, Franze K, Charras G, et al. Tissue stiffening coordinates morphogenesis by triggering collective cell migration in vivo. Nature 2018, 554(7693): 523–527.
Niu CJ, Fisher C, Scheffler K, et al. Polyacrylamide gel substrates that simulate the mechanical stiffness of normal and malignant neuronal tissues increase protoporphyin IX synthesis in glioma cells. J Biomed Opt 2015, 20(9): 098002.
Ulrich TA, de Juan Pardo EM, Kumar S. The mechanical rigidity of the extracellular matrix regulates the structure, motility, and proliferation of glioma cells. Cancer Res 2009, 69(10): 4167–4174.
Jiang FX, Lin DC, Horkay F, et al. Probing mechanical adaptation of neurite outgrowth on a hydrogel material using atomic force microscopy. Ann Biomed Eng 2011, 39(2): 706–713.
Previtera ML, Firestein BL. Glutamate affects dendritic morphology of neurons grown on compliant substrates. Biotechnol Prog 2015, 31(4): 1128–1132.
Previtera ML, Langhammer CG, Firestein BL. Effects of substrate stiffness and cell density on primary hippocampal cultures. J Biosci Bioeng 2010, 110(4): 459–470.
Previtera ML, Langhammer CG, Langrana NA, et al. Regulation of dendrite arborization by substrate stiffness is mediated by glutamate receptors. Ann Biomed Eng 2010, 38(12): 3733–3743.
Sur S, Newcomb CJ, Webber MJ, et al. Tuning supramolecular mechanics to guide neuron development. Biomaterials 2013, 34(20): 4749–4757.
Abe K, Baba K, Huang LG, et al. Mechanosensitive axon outgrowth mediated by L1-laminin clutch interface. Biophys J 2021, 120(17): 3566–3576.
Kostic A, Sap J, Sheetz MP. RPTPalpha is required for rigidity-dependent inhibition of extension and differentiation of hippocampal neurons. J Cell Sci 2007, 120(Pt 21): 3895–3904.
Chen WH, Cheng SJ, Tzen JTC, et al. Probing relevant molecules in modulating the neurite outgrowth of hippocampal neurons on substrates of different stiffness. PLoS One 2013, 8(12): e83394.
Koch D, Rosoff WJ, Jiang JJ, et al. Strength in the periphery: growth cone biomechanics and substrate rigidity response in peripheral and central nervous system neurons. Biophys J 2012, 102(3): 452–460.
Willits RK, Skornia SL. Effect of collagen gel stiffness on neurite extension. J Biomater Sci Polym Ed 2004, 15(12): 1521–1531.
Cheng CM, LeDuc PR, Lin YW. Localized bimodal response of neurite extensions and structural proteins in dorsal-root ganglion neurons with controlled polydimethylsiloxane substrate stiffness. J Biomech 2011, 44(5): 856–862.
Man AJ, Davis HE, Itoh A, et al. Neurite outgrowth in fibrin gels is regulated by substrate stiffness. Tissue Eng Part A 2011, 17(23/24): 2931–2942.
Nichol RH 4th, Catlett TS, Onesto MM, et al. Environmental elasticity regulates cell-type specific RHOA signaling and neuritogenesis of human neurons. Stem Cell Reports 2019, 13(6): 1006–1021.
Jiang FX, Yurke B, Schloss RS, et al. Effect of dynamic stiffness of the substrates on neurite outgrowth by using a DNA-crosslinked hydrogel. Tissue Eng Part A 2010, 16(6): 1873–1889.
Flanagan LA, Ju YE, Marg B, et al. Neurite branching on deformable substrates. Neuroreport 2002, 13(18): 2411–2415.
Jiang FX, Yurke B, Firestein BL, et al. Neurite outgrowth on a DNA crosslinked hydrogel with tunable stiffnesses. Ann Biomed Eng 2008, 36(9): 1565–1579.
Thompson AJ, Pillai EK, Dimov IB, et al. Rapid changes in tissue mechanics regulate cell behaviour in the developing embryonic brain. eLife 2019, 8: 39356.
Koser DE, Thompson AJ, Foster SK, et al. Mechanosensing is critical for axon growth in the developing brain. Nat Neurosci 2016, 19(12): 1592–1598.
Kayal C, Moeendarbary E, Shipley RJ, et al. Mechanical response of neural cells to physiologically relevant stiffness gradients. Adv Healthcare Mater 2020, 9(8): 1901036.
Rosso G, Young P, Shahin V. Mechanosensitivity of embryonic neurites promotes their directional extension and schwann cells progenitors migration. Cell Physiol Biochem 2017, 44(4): 1263–1270.
Chan CE, Odde DJ. Traction dynamics of filopodia on compliant substrates. Science 2008, 322(5908): 1687–1691.
Athamneh AIM, Suter DM. Quantifying mechanical force in axonal growth and guidance. Front Cell Neurosci 2015, 9: 359.
Franze K. Integrating chemistry and mechanics: the forces driving axon growth. Annu Rev Cell Dev Biol 2020, 36: 61–83.
Geiger B, Spatz JP, Bershadsky AD. Environmental sensing through focal adhesions. Nat Rev Mol Cell Biol 2009, 10(1): 21–33.
Gomez TM, Letourneau PC. Actin dynamics in growth cone motility and navigation. J Neurochem 2014, 129(2): 221–234.
Rocha DN, Carvalho ED, Relvas JB, et al. Mechanotransduction: exploring new therapeutic avenues in central nervous system pathology. Front Neurosci 2022, 16: 861613.
Georges PC, Miller WJ, Meaney DF, et al. Matrices with compliance comparable to that of brain tissue select neuronal over glial growth in mixed cortical cultures. Biophys J 2006, 90(8): 3012–3018.
Tanaka A, Fujii Y, Kasai N, et al. Regulation of neuritogenesis in hippocampal neurons using stiffness of extracellular microenvironment. PLoS One 2018, 13(2): e0191928.
Wen YQ, Gao XH, Wang AP, et al. Substrate stiffness affects neural network activity in an extracellular matrix proteins dependent manner. Colloids Surf B Biointerfaces 2018, 170: 729–735.
Zhang QY, Zhang YY, Xie J, et al. Stiff substrates enhance cultured neuronal network activity. Sci Rep 2014, 4: 6215.
Yu Y, Liu SS, Wu XA, et al. Mechanism of stiff substrates up-regulate cultured neuronal network activity. ACS Biomater Sci Eng 2019, 5(7): 3475–3482.
Bizanti A, Chandrashekar P, Steward R Jr. Culturing astrocytes on substrates that mimic brain tumors promotes enhanced mechanical forces. Exp Cell Res 2021, 406(2): 112751.
Min SK, Jung SM, Ju JH, et al. Regulation of astrocyte activity via control over stiffness of cellulose acetate electrospun nanofiber. In Vitro Cell Dev Biol -Animal 2015, 51(9): 933–940.
Wilson CL, Hayward SL, Kidambi S. Astrogliosis in a dish: substrate stiffness induces astrogliosis in primary rat astrocytes. RSC Adv 2016, 6(41): 34447–34457.
Moshayedi P, da F Costa L, Christ A, et al. Mechanosensitivity of astrocytes on optimized polyacrylamide gels analyzed by quantitative morphometry. J Phys: Condens Matter 2010, 22(19): 194114.
Rosso G, Liashkovich I, Young P, et al. Schwann cells and neurite outgrowth from embryonic dorsal root ganglions are highly mechanosensitive. Nanomed Nanotechnol Biol Med 2017, 13(2): 493–501.
Rosso G, Wehner D, Schweitzer C, et al. Matrix stiffness mechanosensing modulates the expression and distribution of transcription factors in Schwann cells. Bioeng Transl Med 2021, 7(1): e10257.
Xu ZY, Orkwis JA, Harris GM. Preparation of tunable extracellular matrix microenvironments to evaluate schwann cell phenotype specification. JoVE 2020(160), .
Urbanski MM, Kingsbury L, Moussouros D, et al. Myelinating glia differentiation is regulated by extracellular matrix elasticity. Sci Rep 2016, 6: 33751.
López-Fagundo C, Bar-Kochba E, Livi LL, et al. Three-dimensional traction forces of Schwann cells on compliant substrates. J R Soc Interface 2014, 11(97): 20140247.
Gu Y, Ji YW, Zhao YH, et al. The influence of substrate stiffness on the behavior and functions of Schwann cells in culture. Biomaterials 2012, 33(28): 6672–6681.
Ong W, Marinval N, Lin JQ, et al. Biomimicking fiber platform with tunable stiffness to study mechanotransduction reveals stiffness enhances oligodendrocyte differentiation but impedes myelination through YAP-dependent regulation. Small 2020, 16(37): 2003656.
Lourenço T, de Faria JP, Bippes CA, et al. Modulation of oligodendrocyte differentiation and maturation by combined biochemical and mechanical cues. Sci Rep 2016, 6: 21563.
Bollmann L, Koser DE, Shahapure R, et al. Microglia mechanics: immune activation alters traction forces and durotaxis. Front Cell Neurosci 2015, 9: 363.
Reimer M, Zustiak SP, Sheth S, et al. Intrinsic response towards physiologic stiffness is cell-type dependent. Cell Biochem Biophys 2018, 76(1): 197–208.
Elkin BS, Ilankovan A, Morrison B 3rd. Age-dependent regional mechanical properties of the rat hippocampus and cortex. J Biomech Eng 2010, 132(1): 011010.
Arani A, Murphy MC, Glaser KJ, et al. Measuring the effects of aging and sex on regional brain stiffness with MR elastography in healthy older adults. NeuroImage 2015, 111: 59–64.
Coelho A, Sousa N. Magnetic resonance elastography of the ageing brain in normal and demented populations: a systematic review. Hum Brain Mapp 2022, 43(13): 4207–4218.
Lv H, Kurt M, Zeng N, et al. MR elastography frequency-dependent and independent parameters demonstrate accelerated decrease of brain stiffness in elder subjects. Eur Radiol 2020, 30(12): 6614–6623.
Sack I, Beierbach B, Wuerfel J, et al. The impact of aging and gender on brain viscoelasticity. NeuroImage 2009, 46(3): 652–657.
Christ AF, Franze K, Gautier H, et al. Mechanical difference between white and gray matter in the rat cerebellum measured by scanning force microscopy. J Biomech 2010, 43(15): 2986–2992.
Murphy MC, Huston J 3rd, Jack CR Jr, et al. Decreased brain stiffness in Alzheimer’s disease determined by magnetic resonance elastography. J Magn Reson Imaging 2011, 34(3): 494–498.
ElSheikh M, Arani A, Perry A, et al. MR elastography demonstrates unique regional brain stiffness patterns in dementias. AJR Am J Roentgenol 2017, 209(2): 403–408.
Murphy MC, Jones DT, Jack CR Jr, et al. Regional brain stiffness changes across the Alzheimer’s disease spectrum. Neuroimage Clin 2016, 10: 283–290.
Freimann FB, Streitberger KJ, Klatt D, et al. Alteration of brain viscoelasticity after shunt treatment in normal pressure hydrocephalus. Neuroradiology 2012, 54(3): 189–196.
Streitberger KJ, Sack I, Krefting D, et al. Brain viscoelasticity alteration in chronic-progressive multiple sclerosis. PLoS One 2012, 7(1): e29888.
Batzdorf CS, Morr AS, Bertalan G, et al. Sexual dimorphism in extracellular matrix composition and viscoelasticity of the healthy and inflamed mouse brain. Biology 2022, 11(2): 230.
Hain EG, Klein C, Munder T, et al. Dopaminergic neurodegeneration in the mouse is associated with decrease of viscoelasticity of substantia nigra tissue. PLoS One 2016, 11(8): e0161179.
Xu ZS, Lee RJ, Chu SS, et al. Evidence of changes in brain tissue stiffness after ischemic stroke derived from ultrasound-based elastography. J Ultrasound Med 2013, 32(3): 485–494.
Gerischer LM, Fehlner A, Köbe T, et al. Combining viscoelasticity, diffusivity and volume of the hippocampus for the diagnosis of Alzheimer’s disease based on magnetic resonance imaging. Neuroimage Clin 2018, 18: 485–493.
Pogoda K, Chin L, Georges PC, et al. Compression stiffening of brain and its effect on mechanosensing by glioma cells. New J Phys 2014, 16: 075002.
Sen S, Ng WP, Kumar S. Contributions of talin-1 to glioma cell-matrix tensional homeostasis. J R Soc Interface 2012, 9(71): 1311–1317.
Weickenmeier J, de Rooij R, Budday S, et al. Brain stiffness increases with myelin content. Acta Biomater 2016, 42: 265–272.
Caggiano AO, Zimber MP, Ganguly A, et al. Chondroitinase ABCI improves locomotion and bladder function following contusion injury of the rat spinal cord. J Neurotrauma 2005, 22(2): 226–239.
Huang WC, Kuo WC, Cherng JH, et al. Chondroitinase ABC promotes axonal re-growth and behavior recovery in spinal cord injury. Biochem Biophys Res Commun 2006, 349(3): 963–968.
Bradbury EJ, Moon LDF, Popat RJ, et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 2002, 416(6881): 636–640.
Ali S, Wall IB, Mason C, et al. The effect of Young’s modulus on the neuronal differentiation of mouse embryonic stem cells. Acta Biomater 2015, 25: 253–267.
Banerjee A, Arha M, Choudhary S, et al. The influence of hydrogel modulus on the proliferation and differentiation of encapsulated neural stem cells. Biomaterials 2009, 30(27): 4695–4699.
Leipzig ND, Shoichet MS. The effect of substrate stiffness on adult neural stem cell behavior. Biomaterials 2009, 30(36): 6867–6878.
Ma QQ, Yang LY, Jiang ZY, et al. Three-dimensional stiff graphene scaffold on neural stem cells behavior. ACS Appl Mater Interfaces 2016, 8(50): 34227–34233.
Saha K, Keung AJ, Irwin EF, et al. Substrate modulus directs neural stem cell behavior. Biophys J 2008, 95(9): 4426–4438.
Stukel JM, Willits RK. The interplay of peptide affinity and scaffold stiffness on neuronal differentiation of neural stem cells. Biomed Mater 2018, 13(2): 024102.
Teixeira AI, Ilkhanizadeh S, Wigenius JA, et al. The promotion of neuronal maturation on soft substrates. Biomaterials 2009, 30(27): 4567–4572.
Publication history
Rights and permissions

Publication history

Received: 14 September 2022
Accepted: 10 October 2022
Published: 27 February 2023
Issue date: March 2023


© The authors 2023.

Rights and permissions

This article is published with open access at

Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (