Inorganic Biomaterials on Regulating Neural Cell Function and Innervated Tissue Regeneration: A Review

doi:10.15541/jim20250001

Abstract

Abstract:

In regard to the crucial role of nerves in tissue regeneration, developing tissue engineering scaffolds with neural-activities has attracted more attention. Recently, inorganic biomaterials have been extensively used in regulating neural cell functions and innervated tissue regeneration due to their advantages of highly controllable chemical compositions, micro/nano topographical structures, and excellent physicochemical properties. This review firstly introduces the typical used inorganic biomaterials for neural regulation, including bioceramics and electroactive materials, and then elaborates on their biological effects of enhancing neural cell viabilities and functions through modulating cell behaviors, regulating immune microenvironment, and constructing electroactive microenvironment. Subsequently, recent progress of inorganic biomaterials on various innervated tissue regeneration, such as spinal cord, peripheral nerves, skin, skeletal muscles, and cavernous tissues, is summarized. Finally, the current challenges and future perspectives of inorganic biomaterials in innervated tissue regeneration are discussed.

Key words: inorganic biomaterial, bioceramic, electroactive material, tissue regeneration, innervation, review

CLC Number:

TQ174

ZHANG Hongjian, ZHAO Ziyi, WU Chengtie. Inorganic Biomaterials on Regulating Neural Cell Function and Innervated Tissue Regeneration: A Review[J]. Journal of Inorganic Materials, 2025, 40(8): 849-859.

Figures/Tables 6

Fig. 1 Inorganic biomaterials promoting innervated skin regeneration through enhancing cellular functions[57-58,60] (a) Spindle zinc silicate nanoparticles promoting neuro-vascularized wound healing via releasing bioactive Zn and Si ions[57]; (b) Cu-CS containing wound dressing promoting cutaneous neural networks reconstructions and wound healing[58]; (c) Sprayable magnesium silicate particles containing hydrogel promoting vascularized and innervated skin regeneration[60]. Colorful figures are available on website

Fig. 2 3D bioprinted Li-Ca-Si bioceramics containing neural constructs for innervated tissue regeneration[62] (a) SEM images of the Li-Ca-Si bioceramic microspheres; (b) Immunofluorescence images and semi-quantitative analysis of Li-Ca-Si bioceramic microspheres inducing the neuronal differentiation and maturation of neural stem cells (NSCs); (c) Li-Ca-Si bioceramic microspheres inducing the neuronal differentiation and maturation of NSCs through activating PI3K-AKT signal pathway; (d) Optical images and their weight of the regenerated muscles; (e) Representative images of H&E and Masson staining assays. Colorful figures are available on website

Fig. 3 Sprayable Mg-gallate metal-organic framework-based hydrogel promoting innervated and vascularized wound healing through immune-modulatory approaches[67] (a) Schematic illustrations of synthesis and application of sprayable hydrogel; (b) Enzyme-catalytic behaviors of hydrogel to scavenging ROS; (c) In vivo representative images of the wounds; (d) Representative immunofluorescent images of the regenerated nerves and vessels in the wound area. Colorful figures are available on website

Fig. 4 GeP nanosheet-based conductive hydrogel inducing the neuronal differentiation of NSCs[69] (a) Preparation of GeP@PDA nanosheets; (b-d) Conductivity (b), Nyquist curves (c) and impedance spectra (d) of hydrogel; (e) Representative immunostaining images of NSCs under different treatments. Colorful figures are available on website

Fig. 5 Ultrasound-triggered wireless electrical stimulation nanopatch promoting neural differentiation[75] (a) Scheme of the nanopatch of stimulating neural cells; (b) Cell viability of nanopatch under different LIPUS stimulation intensities; (c) EdU fluorescence images of cells treated with different groups and corresponding statistical analysis; (d) Representative immunostaining images of β3-tubulin of neurons and corresponding statistical analysis of neurite length. Colorful figures are available on website

Fig. 6 Inorganic biomaterials enhancing neural cell functions and innervated tissue regeneration through modulating cellular behaviors, regulating immune microenvironment and building electroactive microenvironment

References 77

[1]	WAN Q Q, QIN W P, MA Y X, et al. Crosstalk between bone and nerves within bone. Advanced Science, 2021, 8(7): 2003390.
[2]	WANG X D, LI S Y, ZHANG S J, et al. The neural system regulates bone homeostasis via mesenchymal stem cells: a translational approach. Theranostics, 2020, 10(11): 4839.
[3]	ELEFTERIOU F. Impact of the autonomic nervous system on the skeleton. Physiological Reviews, 2018, 98(3): 1083. DOI PMID
[4]	BROKESH A M, GAHARWAR A K. Inorganic biomaterials for regenerative medicine. ACS Applied Materials & Interfaces, 2020, 12(5): 5319.
[5]	PEI Z, LEI H, CHENG L. Bioactive inorganic nanomaterials for cancer theranostics. Chemical Society Reviews, 2023, 52(6): 2031. DOI PMID
[6]	ZOU Y, HUANG B, CAO L, et al. Tailored mesoporous inorganic biomaterials: assembly, functionalization, and drug delivery engineering. Advanced Materials, 2021, 33(2): 2005215.
[7]	QIN C, WU C. Inorganic biomaterials-based bioinks for three-dimensional bioprinting of regenerative scaffolds. VIEW, 2022, 3(4): 20210018.
[8]	ZHAO C, LIU W, ZHU M, et al. Bioceramic-based scaffolds with antibacterial function for bone tissue engineering: a review. Bioactive Materials, 2022, 18: 383. DOI PMID
[9]	ZHOU Y, WU C, CHANG J. Bioceramics to regulate stem cells and their microenvironment for tissue regeneration. Materials Today, 2019, 24: 41.
[10]	GOU Y, QI K, WEI Y, et al. Advances of calcium phosphate nanoceramics for the osteoinductive potential and mechanistic pathways in maxillofacial bone defect repair. Nano TransMed, 2024, 3: 100033.
[11]	ZHANG Y, XU J, RUAN Y C, et al. Implant-derived magnesium induces local neuronal production of CGRP to improve bone- fracture healing in rats. Nature Medicine, 2016, 22(10): 1160.
[12]	YANG Y, WANG H, YANG H, et al. Magnesium-based whitlockite bone mineral promotes neural and osteogenic activities. ACS Biomaterials Science & Engineering, 2020, 6(10): 5785.
[13]	XU Y, XU C, HE L, et al. Stratified-structural hydrogel incorporated with magnesium-ion-modified black phosphorus nanosheets for promoting neuro-vascularized bone regeneration. Bioactive Materials, 2022, 16: 271. DOI PMID
[14]	MA Y X, JIAO K, WAN Q Q, et al. Silicified collagen scaffold induces semaphorin 3A secretion by sensory nerves to improve in-situ bone regeneration. Bioactive Materials, 2022, 9: 475.
[15]	MEI P, JIANG S, MAO L, et al. In situ construction of flower-like nanostructured calcium silicate bioceramics for enhancing bone regeneration mediated via FAK/p38 signaling pathway. Journal of Nanobiotechnology, 2022, 20(1): 162.
[16]	LI T, ZHAI D, MA B, et al. 3D printing of hot dog-like biomaterials with hierarchical architecture and distinct bioactivity. Advanced Science, 2019, 6(19): 1901146.
[17]	MA W P, YANG Z B, LU M X, et al. Hierarchically structured biomaterials for tissue regeneration. Microstructures, 2024, 4(2): 2024014.
[18]	YANG Z, XUE J, SHI Z, et al. Naturally derived flexible bioceramics: biomass recycling approach and advanced function. Matter, 2024, 7(3): 1275.
[19]	LIU Z, WAN X, WANG Z L, et al. Electroactive biomaterials and systems for cell fate determination and tissue regeneration: design and applications. Advanced Materials, 2021, 33(32): 2007429.
[20]	QIAN Y, LIN H, YAN Z, et al. Functional nanomaterials in peripheral nerve regeneration: scaffold design, chemical principles and microenvironmental remodeling. Materials Today, 2021, 51: 165.
[21]	ZHANG M, ZHAI X, MA T, et al. Sequential therapy for bone regeneration by cerium oxide-reinforced 3D-printed bioactive glass scaffolds. ACS Nano, 2023, 17(5): 4433. DOI PMID
[22]	KIM J W, MAHAPATRA C, HONG J Y, et al. Functional recovery of contused spinal cord in rat with the injection of optimal-dosed cerium oxide nanoparticles. Advanced Science, 2017, 4(10): 1700034.
[23]	ZHENG Y, WU J, ZHU Y, et al. Inorganic-based biomaterials for rapid hemostasis and wound healing. Chemical Science, 2022, 14(1): 29. DOI PMID
[24]	MA J, WU C. Bioactive inorganic particles-based biomaterials for skin tissue engineering. Exploration, 2022, 2(5): 20210083.
[25]	HAN D, LIU X, WU S. Metal organic framework-based antibacterial agents and their underlying mechanisms. Chemical Society Reviews, 2022, 51(16): 7138.
[26]	张兴栋, WILLIAMS D. 二十一世纪生物材料定义. 北京: 科学出版社, 2021: 25.
[27]	WU C T, CHANG J. Silicate bioceramics for bone tissue regeneration. Journal of Inorganic Materials, 2013, 28(1): 29.
[28]	WU H, HUA Y, WU J, et al. The morphology of hydroxyapatite nanoparticles regulates clathrin-mediated endocytosis in melanoma cells and resultant anti-tumor efficiency. Nano Research, 2022, 15(7): 6256.
[29]	ZHU D, LU B, YANG Q, et al. Lanthanum-doped mesoporous bioglasses/chitosan composite scaffolds enhance synchronous osteogenesis and angiogenesis for augmented osseous regeneration. Chemical Engineering Journal, 2021, 405: 127077.
[30]	GUPTA B, PAPKE J B, MOHAMMADKHAH A, et al. Effects of chemically doped bioactive borate glass on neuron regrowth and regeneration. Annals of Biomedical Engineering, 2016, 44(12): 3468. PMID
[31]	HUANG J, HUANG J, ZHANG X, et al. A bioactive multifunctional dressing with simultaneous visible monitoring of pH values and H₂O₂ concentrations for promoting diabetic wound healing. Materials Horizons, 2025, 12: 267.
[32]	HUANG J, ZHENG Y, NIU H, et al. A multifunctional hydrogel for simultaneous visible H₂O₂ monitoring and accelerating diabetic wound healing. Advanced Healthcare Materials, 2024, 13(3): 2302328.
[33]	ZHANG Z, KLAUSEN L H, CHEN M, et al. Electroactive scaffolds for neurogenesis and myogenesis: graphene-based nanomaterials. Small, 2018, 14(48): 1801983.
[34]	宁成云, 毛传斌. 电活性生物材料. 北京: 科学出版社, 2017: 1.
[35]	SHIN M, LIM J, PARK Y, et al. Carbon-based nanocomposites for biomedical applications. RSC Advances, 2024, 14(10): 7142. DOI PMID
[36]	ZHENG Y, HONG X, WANG J, et al. 2D nanomaterials for tissue engineering and regenerative nanomedicines: recent advances and future challenges. Advanced Healthcare Materials, 2021, 10(7): 2001743.
[37]	WANG X, HAN X, LI C, et al. 2D materials for bone therapy. Advanced Drug Delivery Reviews, 2021, 178: 113970.
[38]	GU G, CUI Z, DU X, et al. Recent advances in biomacromolecule-reinforced 2D material (2DM) hydrogels: from interactions, synthesis, and functionalization to biomedical applications. Advanced Functional Materials, 2024, 34(48): 2408367.
[39]	WANG Z L. Progress in piezotronics and piezo-phototronics. Advanced Materials, 2012, 24(34): 4632.
[40]	KAPAT K, SHUBHRA Q T H, ZHOU M, et al. Piezoelectric nano-biomaterials for biomedicine and tissue regeneration. Advanced Functional Materials, 2020, 30(44): 1909045.
[41]	KIM W, LEE H, LEE J, et al. Efficient myotube formation in 3D bioprinted tissue construct by biochemical and topographical cues. Biomaterials, 2020, 230: 119632.
[42]	HE J, HAO M, DUAN J, et al. Synergistic effect of endocellular calcium ion release and nanotopograpy of one-dimensional hydroxyapatite nanomaterials for accelerating neural stem cell differentiation. Composites Part B-Engineering, 2021, 219: 108944.
[43]	DONG X, LIU S, YANG Y, et al. Aligned microfiber-induced macrophage polarization to guide Schwann-cell-enabled peripheral nerve regeneration. Biomaterials, 2021, 272: 120767.
[44]	HAO M, ZHANG Z, LIU C, et al. Hydroxyapatite nanorods function as safe and effective growth factors regulating neural differentiation and neuron development. Advanced Materials, 2021, 33(33): 2100895.
[45]	DAI H, FAN Q, WANG C. Recent applications of immunomodulatory biomaterials for disease immunotherapy. Exploration, 2022, 2(6): 20210157.
[46]	LI L, XIAO B, MU J, et al. A MnO₂ nanoparticle-dotted hydrogel promotes spinal cord repair via regulating reactive oxygen species microenvironment and synergizing with mesenchymal stem cells. ACS Nano, 2019, 13(12): 14283.
[47]	SUN Y, ZHANG H, ZHANG Y, et al. Li-Mg-Si bioceramics provide a dynamic immuno-modulatory and repair-supportive microenvironment for peripheral nerve regeneration. Bioactive Materials, 2023, 28: 227. DOI PMID
[48]	LEVIN M. Bioelectric signaling: reprogrammable circuits underlying embryogenesis, regeneration, and cancer. Cell, 2021, 184(8): 1971. DOI PMID
[49]	MURILLO G, BLANQUER A, VARGAS-ESTEVEZ C, et al. Electromechanical nanogenerator-cell interaction modulates cell activity. Advanced Materials, 2017, 29(24): 1605048.
[50]	ZHANG X, WANG T, ZHANG Z, et al. Electrical stimulation system based on electroactive biomaterials for bone tissue engineering. Materials Today, 2023, 68: 177.
[51]	KHARE D, BASU B, DUBEY A K. Electrical stimulation and piezoelectric biomaterials for bone tissue engineering applications. Biomaterials, 2020, 258: 120280.
[52]	SEBASTIAN A, VOLK S W, HALAI P, et al. Enhanced neurogenic biomarker expression and reinnervation in human acute skin wounds treated by electrical stimulation. Journal of Investigative Dermatology, 2017, 137(3): 737.
[53]	FAN L, XIAO C, GUAN P, et al. Extracellular matrix-based conductive interpenetrating network hydrogels with enhanced neurovascular regeneration properties for diabetic wounds repair. Advanced Healthcare Materials, 2022, 11(1): 2101556.
[54]	TAN M H, XU X H, YUAN T J, et al. Self-powered smart patch promotes skin nerve regeneration and sensation restoration by delivering biological-electrical signals in program. Biomaterials, 2022, 283: 121413.
[55]	GAO J, YU X, WANG X, et al. Biomaterial-related cell microenvironment in tissue engineering and regenerative medicine. Engieering, 2022, 13: 31.
[56]	ZHANG H, WU C. 3D printing of biomaterials for vascularized and innervated tissue regeneration. International Journal of Bioprinting, 2023, 9(3): 706. DOI PMID
[57]	ZHANG H, MA W, MA H, et al. Spindle-like zinc silicate nanoparticles accelerating innervated and vascularized skin burn wound healing. Advanced Healthcare Materials, 2022, 10: 2102359.
[58]	ZHANG Z, CHANG D, ZENG Z, et al. CuCS/Cur composite wound dressings promote neuralized skin regeneration by rebuilding the nerve cell “factory” in deep skin burns. Materials Today Bio, 2024, 26: 101075.
[59]	KANG Y, LIU K, CHEN Z, et al. Healing with precision: a multi- functional hydrogel-bioactive glass dressing boosts infected wound recovery and enhances neurogenesis in the wound bed. Journal of Controlled Release, 2024, 370: 210.
[60]	XU S, ZHANG Y, DAI B, et al. Green-prepared magnesium silicate sprays enhance the repair of burn-skin wound and appendages regeneration in rats and minipigs. Advanced Functional Materials, 2024, 34(9): 2307439.
[61]	SAMANDARI M, QUINT J, RODRIGUEZ-DELAROSA A, et al. Bioinks and bioprinting strategies for skeletal muscle tissue engineering. Advanced Materials, 2022, 34(12): 2105883.
[62]	ZHANG H, QIN C, SHI Z, et al. Bioprinting of inorganic- biomaterial/neural-stem-cell constructs for multiple tissue regeneration and functional recovery. National Science Review, 2024, 11(4): nwae035.
[63]	ZHU Y, ZHANG X, CHANG G, et al. Bioactive glass in tissue regeneration: unveiling recent advances in regenerative strategies and applications. Advanced Materials, 2025, 37(2): 2312964.
[64]	WOLTERINK R G J K, WU G S, CHIU I M, et al. Neuroimmune interactions in peripheral organs. Annual Review of Neuroscience, 2022, 45: 339. DOI PMID
[65]	LU Y Z, NAYER B, SINGH S K, et al. CGRP sensory neurons promote tissue healing via neutrophils and macrophages. Nature, 2024, 628: 604.
[66]	CUI X, WANG L, GAO X, et al. Self-assembled silk fibroin injectable hydrogels based on layered double hydroxides for spinal cord injury repair. Matter, 2024, 7(2): 620.
[67]	LIAN C, LIU J, WEI W, et al. Mg-gallate metal-organic framework-based sprayable hydrogel for continuously regulating oxidative stress microenvironment and promoting neurovascular network reconstruction in diabetic wounds. Bioactive Materials, 2024, 38: 181. DOI PMID
[68]	PENG L H, XU X H, HUANG Y F, et al. Self-adaptive all-in-one delivery chip for rapid skin nerves regeneration by endogenous mesenchymal stem cells. Advanced Functional Materials, 2020, 30(40): 2001751.
[69]	XU C, CHANG Y, WU P, et al. Two-dimensional-germanium phosphide-reinforced conductive and biodegradable hydrogel scaffolds enhance spinal cord injury repair. Advanced Functional Materials, 2021, 31(41): 2104440.
[70]	YU Q, JIN S, WANG S, et al. Injectable, adhesive, self-healing and conductive hydrogels based on MXene nanosheets for spinal cord injury repair. Chemical Engineering Journal, 2023, 452: 139252.
[71]	AN G, GUO F, LIU X, et al. Functional reconstruction of injured corpus cavernosa using 3D-printed hydrogel scaffolds seeded with HIF-1α-expressing stem cells. Nature Communications, 2020, 11: 2687. DOI PMID
[72]	WANG S, WANG Z, YANG W, et al. In situ-sprayed bioinspired adhesive conductive hydrogels for cavernous nerve repair. Advanced Materials, 2024, 36(19): 2311264.
[73]	PI W, CHEN H, LIU Y, et al. Flexible sono-piezo patch for functional sweat gland repair through endogenous microenvironmental remodeling. ACS Nano, 2024, 18(31): 20283.
[74]	CHEN P, XU C, WU P, et al. Wirelessly powered electrical- stimulation based on biodegradable 3D piezoelectric scaffolds promotes the spinal cord injury. ACS Nano, 2022, 16(10): 16513.
[75]	LIU Y, ZHANG Z, ZHAO Z, et al. An easy nanopatch promotes peripheral nerve repair through wireless ultrasound-electrical stimulation in a band-aid-like way. Advanced Functional Materials, 2024, 34(44): 2407411.
[76]	WANG L, DU J, LIU Q, et al. Wrapping stem cells with wireless electrical nanopatches for traumatic brain injury therapy. Nature Communications, 2024, 15: 7223. DOI PMID
[77]	VARADARAJAN S G, HUNYARA J L, HAMILTON N R, et al. Central nervous system regeneration. Cell, 2022, 185(1): 77. DOI PMID