无机活性材料在类器官研究领域的应用

doi:10.15541/jim20250007

摘要/Abstract

摘要： 类器官作为模拟相应组织/器官结构和功能的体外三维（3D）模型,在生物医学领域显示出广阔的应用前景。类器官的构建需要对干细胞的行为以及多细胞相互作用进行调控,而无机活性材料具有良好的生物相容性和生物活性,可以调节细胞行为、细胞-细胞和细胞-基质之间的相互作用,在疾病诊疗和再生医学等领域得到了广泛研究,因而,有望用于类器官的构建、生长和发育的调控。本文综述了无机活性材料在类器官研究中的作用,强调了其在类器官培养和实际应用方面的研究进展。我们首先概述了类器官构建策略的基本步骤,介绍了代表性无机活性材料的生物学功能,特别是与类器官构建关键步骤相适配的功能;重点阐释了无机活性材料促进类器官生长和发育的关键作用机制,包括对关键信号通路的作用、基质材料的调控以及细胞能量的代谢等。此外,我们还探讨了类器官作为辅助工具在促进无机活性材料的研究和应用方面的作用;最后展望了利用无机活性材料提供多种物理和生化调控信号的特性进一步推进类器官基础研究和应用研究的策略。

关键词: 类器官, 无机活性材料, 类器官发育, 生物活性离子, 综述

Abstract: As an effective in vitro three-dimensional (3D) model, organoids can simulate the structure and function of corresponding tissues/organs, demonstrating broad application prospects in the biomedical field. The construction of organoids relies on the behavior's regulation of stem cells and multicellular interactions. Inorganic bioactive materials possess excellent biocompatibility and bioactivities, showing wide application in the field of bio-medical research. Therefore, they can potentially regulate cell behaviors and cell-cell/cell-matrix interactions in constructing in organoids. In this review, we explored the role of inorganic bioactive materials in organoid research, emphasizing their contribution to organoid development and applications. We summarized the critical steps of organoid construction strategies. Subsequently, the biological functions of inorganic bioactive materials, particularly those compatible with key steps in organoid construction, were systematically elucidated. We also emphasized the key mechanisms by which inorganic bioactive materials promote organoid development and application, including their effects on key signaling pathways, regulations of matrix material properties and cellular energy metabolism. In addition, we reviewed application of organoids as auxiliary tools to promote the application of inorganic bioactive materials. Finally, we looked forward to strategies for further advancing organoid research by regulating various physical and biochemical clues provided by inorganic bioactive materials.

Key words: organoid, inorganic bioactive material, organoids development, review

中图分类号:

TQ174

马文平, 韩雅卉, 吴成铁, 吕宏旭. 无机活性材料在类器官研究领域的应用[J]. 无机材料学报, DOI: 10.15541/jim20250007.

MA Wenping, HAN Yahui, WU Chengtie, LU Hongxu. Application of Inorganic Bioactive Materials in Organoid Research[J]. Journal of Inorganic Materials, DOI: 10.15541/jim20250007.

参考文献

[1] HOFER M, LUTOLF M P.Engineering organoids.Nature Reviews Materials, 2021, 6(5): 402.
[2] KRATOCHVIL M J, SEYMOUR A J, LI T L,et al. Engineered materials for organoid systems. Nature Reviews Materials, 2019, 4(9): 606.
[3] SATO T, VRIES R G, SNIPPERT H J,et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature, 2009, 459(7244): 262.
[4] BARKER N, HUCH M, KUJALA P,et al. Lgr5+ve stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell, 2010, 6(1): 25.
[5] CHO A N, JIN Y, AN Y,et al. Microfluidic device with brain extracellular matrix promotes structural and functional maturation of human brain organoids. Nature Communications, 2021, 12: 4730.
[6] MORIZANE R, LAM A Q, FREEDMAN B S,et al. Nephron organoids derived from human pluripotent stem cells model kidney development and injury. Nature Biotechnology, 2015, 33(11): 1193.
[7] TAO T T, DENG P W, WANG Y Q,et al. Microengineered multi-organoid system from hiPSCs to recapitulate human liver-islet axis in normal and type 2 diabetes. Advanced Science, 2022, 9(5): 2103495.
[8] LEWIS-ISRAELI Y R, WASSERMAN A H, GABALSKI M A,et al. Self-assembling human heart organoids for the modeling of cardiac development and congenital heart disease. Nature Communications, 2021, 12: 5142.
[9] RICHARDS D J, LI Y, KERR C M,et al. Human cardiac organoids for the modelling of myocardial infarction and drug cardiotoxicity. Nature Biomedical Engineering, 2020, 4(4): 446.
[10] DUTTA D, HEO I, CLEVERS H.Disease modeling in stem cell-derived 3D organoid systems.Trends in Molecular Medicine, 2017, 23(5): 393.
[11] CRUZ-ACUÑA R, QUIRÓS M, FARKAS A E,et al. Synthetic hydrogels for human intestinal organoid generation and colonic wound repair. Nature Cell Biology, 2017, 19(11): 1326.
[12] VLACHOGIANNIS G, HEDAYAT S, VATSIOU A,et al. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science, 2018, 359(6378): 920.
[13] BROKESH A M, GAHARWAR A K.Inorganic biomaterials for regenerative medicine.ACS Applied Materials & Interfaces, 2020, 12(5): 5319.
[14] ERMAKOV A, DAKS A, FEDOROVA O,et al.Ca²⁺-depended signaling pathways regulate self-renewal and pluripotency of stem cells. Cell Biology International, 2018, 42(9): 1086.
[15] TAWFIK I, GOTTSCHALK B, JARC A,et al. T3-induced enhancement of mitochondrial Ca²⁺ uptake as a boost for mitochondrial metabolism. Free Radical Biology and Medicine, 2022, 181: 197.
[16] HAN P P, WU C T, XIAO Y.The effect of silicate ions on proliferation, osteogenic differentiation and cell signalling pathways (WNT and SHH) of bone marrow stromal cells.Biomaterials Science, 2013, 1(4): 379.
[17] AISENBREY E A, MURPHY W L.Synthetic alternatives to Matrigel.Nature Reviews Materials, 2020, 5(7): 539.
[18] ROSSI G, MANFRIN A, LUTOLF M P.Progress and potential in organoid research.Nature ReviewsGenetics, 2018, 19(11): 671.
[19] ROOKMAAKER M B, SCHUTGENS F, VERHAAR M C,et al. Development and application of human adult stem or progenitor cell organoids. Nature Reviews Nephrology, 2015, 11(9): 546.
[20] LUKONIN I, SERRA D, CHALLET MEYLAN L,et al. Phenotypic landscape of intestinal organoid regeneration. Nature, 2020, 586(7828): 275.
[21] BOUFFI C, WIKENHEISER-BROKAMP K A, CHATURVEDI P,et al. In vivo development of immune tissue in human intestinal organoids transplanted into humanized mice. Nature Biotechnology, 2023, 41(6): 824.
[22] SORRENTINO G, REZAKHANI S, YILDIZ E,et al. Mechano-modulatory synthetic niches for liver organoid derivation. Nature Communications, 2020, 11: 3416.
[23] CLEVERS H.Modeling development and disease with organoids.Cell, 2016, 165(7): 1586.
[24] BARTFELD S, BAYRAM T, VAN DE WETERING M,et al. In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection. Gastroenterology, 2015, 148(1): 126.
[25] XU J S, PATTON D, JACKSON S K,et al. In-vitro maintenance and functionality of primary renal tubules and their application in the study of relative renal toxicity of nephrotoxic drugs. Journal of Pharmacological and Toxicological Methods, 2013, 68(2): 269.
[26] YU J Y, VODYANIK M A, SMUGA-OTTO K,et al. Induced pluripotent stem cell lines derived from human somatic cells. Science, 2007, 318(5858): 1917.
[27] ROMITTI M, TOURNEUR A, DE FARIA DA FONSECA B,et al. Transplantable human thyroid organoids generated from embryonic stem cells to rescue hypothyroidism. Nature Communications, 2022, 13: 7057.
[28] LEE J, SUTANI A, KANEKO R,et al. In vitro generation of functional murine heart organoids via FGF4 and extracellular matrix. Nature Communications, 2020, 11: 4283.
[29] WANG S Y, WANG X, TAN Z L,et al. Human ESC-derived expandable hepatic organoids enable therapeutic liver repopulation and pathophysiological modeling of alcoholic liver injury. Cell Research, 2019, 29(12): 1009.
[30] TAKAHASHI K, TANABE K, OHNUKI M,et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 2007, 131(5): 861.
[31] DRAKHLIS L, BISWANATH S, FARR C M,et al. Human heart-forming organoids recapitulate early heart and foregut development. Nature Biotechnology, 2021, 39(6): 737.
[32] FRENZ-WIESSNER S, FAIRLEY S D, BUSER M,et al. Generation of complex bone marrow organoids from human induced pluripotent stem cells. Nature Methods, 2024, 21(5): 868.
[33] YOON S J, ELAHI L S, PAȘCA A M,et al. Reliability of human cortical organoid generation. Nature Methods, 2019, 16(1): 75.
[34] GIGER S, HOFER M, MILJKOVIC-LICINA M,et al. Microarrayed human bone marrow organoids for modeling blood stem cell dynamics. APL Bioengineering, 2022, 6(3): 036101.
[35] PRONDZYNSKI M, BERKSON P, TREMBLEY M A,et al. Efficient and reproducible generation of human iPSC-derived cardiomyocytes and cardiac organoids in stirred suspension systems. Nature Communications, 2024, 15: 5929.
[36] BERGENHEIM F, FREGNI G, BUCHANAN C F,et al. A fully defined 3D matrix for ex vivo expansion of human colonic organoids from biopsy tissue. Biomaterials, 2020, 262: 120248.
[37] HUCH M, KNOBLICH J A, LUTOLF M P,et al. The hope and the hype of organoid research. Development, 2017, 144(6): 938.
[38] LIU H T, WANG Y Q, CUI K L,et al. Advances in hydrogels in organoids and organs-on-a-chip. Advanced Materials, 2019, 31(50): 1902042.
[39] POLING H M, WU D, BROWN N,et al. Mechanically induced development and maturation of human intestinal organoids in vivo. Nature Biomedical Engineering, 2018, 2(6): 429.
[40] HOMAN K A, GUPTA N, KROLL K T,et al. Flow-enhanced vascularization and maturation of kidney organoids in vitro. Nature Methods, 2019, 16(3): 255.
[41] DE BOER J, SIDDAPPA R, GASPAR C,et al. Wnt signaling inhibits osteogenic differentiation of human mesenchymal stem cells. Bone, 2004, 34(5): 818.
[42] WEI P F, JING W, YUAN Z Y,et al. Vancomycin- and strontium-loaded microspheres with multifunctional activities against bacteria, in angiogenesis, and in osteogenesis for enhancing infected bone regeneration. ACS Applied Materials & Interfaces, 2019, 11(34): 30596.
[43] CHEN L, DENG C J, LI J Y,et al. 3D printing of a lithium-calcium-silicate crystal bioscaffold with dual bioactivities for osteochondral interface reconstruction. Biomaterials, 2019, 196: 138.
[44] WANG S, HASHEMI S, STRATTON S,et al. The effect of physical cues of biomaterial scaffolds on stem cell behavior. Advanced Healthcare Materials, 2021, 10(3): 2001244.
[45] WANG P Y, CLEMENTS L R, THISSEN H,et al. Screening mesenchymal stem cell attachment and differentiation on porous silicon gradients. Advanced Functional Materials, 2012, 22(16): 3414.
[46] GJOREVSKI N, SACHS N, MANFRIN A,et al. Designer matrices for intestinal stem cell and organoid culture. Nature, 2016, 539: 560.
[47] MA W P, ZHENG Y, YANG G Z,et al. A bioactive calcium silicate nanowire-containing hydrogel for organoid formation and functionalization. Materials Horizons, 2024, 11(12): 2957.
[48] DAS S R, UZ M, DING S W,et al. Electrical differentiation of mesenchymal stem cells into schwann-cell-like phenotypes using inkjet-printed graphene circuits. Advanced Healthcare Materials, 2017, 6(7): 1601087.
[49] SHENG R Y Y, MU J, CHERNOZEM R V,et al. Fabrication and characterization of piezoelectric polymer composites and cytocompatibility with mesenchymal stem cells. ACS Applied Materials & Interfaces, 2023, 15(3): 3731.
[50] LIU Z R, WAN X Y, 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.
[51] ZHANG H J, QIN C, SHI Z, ,et al. Bioprinting of inorganic-biomaterial/neural-stem-cell constructs for multiple tissue regeneration. Bioprinting of inorganic-biomaterial/neural-stem-cell constructs for multiple tissue regeneration and functional recovery. National Science Review, 2024, 11(4): nwae035.
[52] DU L, QIN C, ZHANG H J,et al. Multicellular bioprinting of biomimetic inks for tendon-to-bone regeneration. Advanced Science, 2023, 10(21): 2301309.
[53] HE D, LI H Y.Biomaterials affect cell-cell interactionsin vitro in tissue engineering. Journal of Materials Science & Technology, 2021, 63: 62.
[54] GAUTAM V, NAUREEN S, SHAHID N,et al. Engineering highly interconnected neuronal networks on nanowire scaffolds. Nano Letters, 2017, 17(6): 3369.
[55] MA J G, QIN C, WU J F,et al. 3D multicellular micropatterning biomaterials for hair regeneration and vascularization. Materials Horizons, 2023, 10(9): 3773.
[56] WANG X Y, GAO L, HAN Y,et al. Silicon-enhanced adipogenesis and angiogenesis for vascularized adipose tissue engineering. Advanced Science, 2018, 5(11): 1800776.
[57] GAO C D, PENG S P, FENG P,et al. Bone biomaterials and interactions with stem cells. Bone Research, 2017, 5: 17059.
[58] LUO J J, WALKER M, XIAO Y B,et al. The influence of nanotopography on cell behaviour through interactions with the extracellular matrix-A review. Bioactive Materials, 2022, 15: 145.
[59] CHEN W C, TIAN B X, LIANG J Q,et al. Matrix stiffness regulates the interactions between endothelial cells and monocytes. Biomaterials, 2019, 221: 119362.
[60] ZHANG Z, GAO S, HU Y N,et al. Ti3C2TxMXene composite 3D hydrogel potentiates mTOR signaling to promote the generation of functional hair cells in cochlea organoids. Advanced Science, 2022, 9(32): 2203557.
[61] BAO L, CUI X J, WANG X Y,et al. Carbon nanotubes promote the development of intestinal organoids through regulating extracellular matrix viscoelasticity and intracellular energy metabolism. ACS Nano, 2021, 15(10): 15858.
[62] WANG J, WU Y, LI G F,et al. Engineering large-scale self-mineralizing bone organoids with bone matrix-inspired hydroxyapatite hybrid bioinks. Advanced Materials, 2024, 36(30): 2309875.
[63] TAN Y, COYLE R C, BARRS R W, ,et al. Nanowired human cardiac organoid transplantation enables highly efficient. Nanowired human cardiac organoid transplantation enables highly efficient and effective recovery of infarcted hearts. Science Advances, 2023, 9(31): eadf2898.
[64] TIAN M, WEI J S, LV E G,et al. Drug evaluation platform based on non-destructive and real-time in situ organoid fate state monitoring by graphene field-effect transistor. Chemical Engineering Journal, 2024, 498: 155355.
[65] ROTH J G, BRUNEL L G, HUANG M S,et al. Spatially controlled construction of assembloids using bioprinting. Nature Communications, 2023, 14: 4346.
[66] POON W, ZHANG Y N, OUYANG B,et al. Elimination pathways of nanoparticles. ACS Nano, 2019, 13(5): 5785.
[67] ZHANG R, LI D, ZHAO R B,et al. Spike structure of gold nanobranches induces hepatotoxicity in mouse hepatocyte organoid models. Journal of Nanobiotechnology, 2024, 22(1): 92.
[68] BAEK A, KWON I H, LEE D H,et al. Novel organoid culture system for improved safety assessment of nanomaterials. Nano Letters, 2024, 24(3): 805.
[69] WEISS P, TAYLOR A C.Reconstitution of complete organs from single-cell suspensions of chick embryos in advanced stages of differentiation.Proceedings of the National Academy of Scinences of the United States of America, 1960, 46(9): 1177.
[70] MA P Q, CHEN Y, LAI X Y,et al. The translational application of hydrogel for organoid technology: challenges and future perspectives. Macromolecular Bioscience, 2021, 21(10): 2100191.
[71] ZHU Y L, WANG Y W, XIA G G,et al. Oral delivery of bioactive glass-loaded core-shell hydrogel microspheres for effective treatment of inflammatory bowel disease. Advanced Science, 2023, 10(18): 2207418.
[72] ZHANG H, LU Y, ZHANG R,et al. Synthesis of multifunctional plasmonic nanodarts through one-end deposition on gold nanobipyramids for tumor organoid ablation and antimicrobial applications. Advanced Functional Materials, 2024, 34(44): 2405588.
[73] ISSA R, LOZANO N, KOSTARELOS K,et al. Functioning human lung organoids model pulmonary tissue response from carbon nanomaterial exposures. Nano Today, 2024, 56: 102254.
[74] HEID S, BOCCACCINI A R.Advancing bioinks for 3D bioprinting using reactive fillers: a review.Acta Biomaterialia, 2020, 113: 1.
[75] LI R T, LIU K, HUANG X,et al. Bioactive materials promote wound healing through modulation of cell behaviors. Advanced Science, 2022, 9(10): 2105152.
[76] THUNDYIL J, PAVLOVSKI D, SOBEY C G,et al. Adiponectin receptor signalling in the brain. British Journal of Pharmacology, 2012, 165(2): 313.
[77] PUSCHHOF J, PLEGUEZUELOS-MANZANO C, CLEVERS H.Organoids and organs-on-chips: insights into human gut-microbe interactions.Cell Host & Microbe, 2021, 29(6): 867.