Microfluidic Construction of Glioma Micromodels on Hydrogel Microspheres for Drug Testing

Yingrui Zhang; Zengnan Wu; Jingyang Li; Shiyu Chen; Tong Xu; Shulang Chen; Xiaorui Wang; Yanli Guo; Yi Zhang; Jin-Ming Lin

doi:10.1016/j.eng.2026.01.010

Engineering ›› :202601010 DOI: 10.1016/j.eng.2026.01.010

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Microfluidic Construction of Glioma Micromodels on Hydrogel Microspheres for Drug Testing

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Abstract

Gliomas are aggressive brain tumors associated with poor prognosis, necessitating advanced in vitro models for efficient drug screening. In this study, we develop a microfluidic glioma-on-a-microsphere model based on compartmentalized hydrogel microspheres with engineered rough surfaces. Each microsphere enables to accurately structure U251 glioma cells, M2-polarized THP-1 macrophages, and endothelial cells that can form a functional endothelial barrier on the Matrigel-modified microsphere surface. The model exhibited high cell viability, controllable molecular permeability, and upregulated expression of glioma-associated genes compared to conventional two-dimensional (2D) cultures. To validate the practicality of this platform in drug evaluation, chlorogenic acid was applied, resulting in suppressed gene expression, repolarization of macrophages toward an M1 phenotype, and significant alterations in key metabolites including tryptophan, glutamate, and lactate. Overall, this hydrogel microsphere-based glioma model offers a high-throughput and physiologically relevant platform for drug screening, disease modeling, and personalized therapeutic development.

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Microfluidic / Glioma-on-a-microsphere / Hydrogel microsphere / Glioma / Drug testing

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Yingrui Zhang, Zengnan Wu, Jingyang Li, Shiyu Chen, Tong Xu, Shulang Chen, Xiaorui Wang, Yanli Guo, Yi Zhang, Jin-Ming Lin. Microfluidic Construction of Glioma Micromodels on Hydrogel Microspheres for Drug Testing. Engineering 202601010 DOI:10.1016/j.eng.2026.01.010

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References

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[1]	Ramani A, Pasquini G, Gerkau NJ, Jadhav V, Vinchure OS, Altinisik N, et al. Reliability of high-quantity human brain organoids for modeling microcephaly, glioma invasion and drug screening. Nat Commun 2024; 15(1):10703.

[2]	Wang Z, Thakare RP, Chitale S, Mishra AK, Goldstein SI, Fan AC, et al. Identification of rocaglate acyl sulfamides as selective inhibitors of glioblastoma stem cells. ACS Cent Sci 2024; 10(8):1640-56.

[3]	Platten M, Friedrich M, Wainwright DA, Panitz V, Opitz CA. Tryptophan metabolism in brain tumors—IDO and beyond. Curr Opin Immunol 2021; 70:57-66.

[4]	Xu X, Li L, Luo L, Shu L, Si X, Chen Z, et al. Opportunities and challenges of glioma organoids. Cell Commun Signal 2021; 19(1):102.

[5]	Jayaram MA, Phillips JJ. Role of the microenvironment in glioma pathogenesis. Annu Rev Pathol 2024; 19(1):181-201.

[6]	Hovis G, Chandra N, Kejriwal N, Hsieh KJY, Chu A, Yang I, et al. Understanding the role of endothelial cells in glioblastoma: mechanisms and novel treatments. Int J Mol Sci 2024; 25(11):6118.

[7]	Zhang H, Luo YB, Wu W, Zhang L, Wang Z, Dai Z, et al. The molecular feature of macrophages in tumor immune microenvironment of glioma patients. Comput Struct Biotechnol J 2021; 19:4603-18.

[8]	Prashanth A, Donaghy H, Stoner SP, Hudson AL, Wheeler HR, Diakos CI, et al. Are in vitro human blood-brain-tumor-barriers suitable replacements for in vivo models of brain permeability for novel therapeutics? Cancers 2021; 13(5):955.

[9]	Wang Y, Tian F, Duan Y, Li Z, Chen Q, Chen J, et al. In vitro 3D cocultured tumor-vascular barrier model based on alginate hydrogel and Transwell system for anti-cancer drug evaluation. Tissue Cell 2022; 76:101796.

[10]	Maity S, Bhuyan T, Jewell C, Kawakita S, Sharma S, Nguyen HT, et al. Recent developments in glioblastoma-on-a-chip for advanced drug screening applications. Small 2025; 21(1):e2405511.

[11]	Han X, Cai C, Deng W, Shi Y, Li L, Wang C, et al. Landscape of human organoids: ideal model in clinics and research. Innovation 2024; 5(3):100620.

[12]	Sun L, Wang Y, Bian F, Xu D, Zhao Y. Bioinspired optical and electrical dual-responsive heart-on-a-chip for hormone testing. Sci Bull 2023; 68(9):938-45.

[13]	Kim TY, Choi JW, Park K, Kim S, Kim JF, Park TE, et al. Lubricant-coated organ-on-a-chip for enhanced precision in preclinical drug testing. Small 2024; 20(43):e2402431.

[14]	Wu Z, Zheng Y, Lin L, Lin Y, Xie T, Liao W, et al. Open aerosol microfluidics enable orthogonal compartmentalized functionalization of hydrogel particles. Matter 2024; 7(10):3645-57.

[15]	Wang J, Zhang X, Chen H, Ren H, Zhou M, Zhao Y. Engineered stem cells by emerging biomedical stratagems. Sci Bull 2024; 69(2):248-79.

[16]	Li B, Zhang L, Yin Y, Chen A, Seo BR, Lou J, et al. Stiff hydrogel encapsulation retains mesenchymal stem cell stemness for regenerative medicine. Matter 2024; 7(10):3447-68.

[17]	Shao C, Liu Y, Chi J, Wang J, Zhao Z, Zhao Y. Responsive inverse opal scaffolds with biomimetic enrichment capability for cell culture. Research 2019; 2019:9783793.

[18]	Mohajeri M, Eskandari M, Ghazali ZS, Ghazali HS. Cell encapsulation in alginate-based microgels using droplet microfluidics; a review on gelation methods and applications. Biomed Phys Eng Express 2022; 8(2):022001.

[19]	Namgung B, Ravi K, Vikraman PP, Sengupta S, Jang HL. Engineered cell-laden alginate microparticles for 3D culture. Biochem Soc Trans 2021; 49(2):761-73.

[20]	Rojek KO, C´wiklińska M, Kuczak J, Guzowski J. Microfluidic formulation of topological hydrogels for microtissue engineering. Chem Rev 2022; 122(22):16839-909.

[21]	Wu Z, Zheng Y, Lin L, Xing G, Xie T, Lin J, et al. Construction of multiplexed assays on single anisotropic particles using microfluidics. ACS Cent Sci 2025; 11(2):294-301.

[22]	Wang X, Zhang D, Singh YP, Yeo M, Deng G, Lai J, et al. Progress in organ bioprinting for regenerative medicine. Engineering 2024; 42:121-42.

[23]	Tendulkar S, Mirmalek-Sani SH, Childers C, Saul J, Opara EC, Ramasubramanian MK. A three-dimensional microfluidic approach to scaling up microencapsulation of cells. Biomed Microdevices 2012; 14(3):461-9.

[24]	Finklea FB, Tian Y, Kerscher P, Seeto WJ, Ellis ME, Lipke EA. Engineered cardiac tissue microsphere production through direct differentiation of hydrogel-encapsulated human pluripotent stem cells. Biomaterials 2021; 274:120818.

[25]	Deng S, Zhao X, Zhu Y, Tang N, Wang R, Zhang X, et al. Efficient hepatic differentiation of hydrogel microsphere-encapsulated human pluripotent stem cells for engineering prevascularized liver tissue. Biofabrication 2022; 15(1):015016.

[26]	Novosel EC, Kleinhans C, Kluger PJ. Vascularization is the key challenge in tissue engineering. Adv Drug Deliv Rev 2011; 63(4-5):300-11.

[27]	Tang Y, Yu Z, Lu X, Fan Q, Huang W. Overcoming vascular barriers to improve the theranostic outcomes of nanomedicines. Adv Sci 2022; 9(13):e2103148.

[28]	Wang X, Jin L, Liu W, Stingelin L, Zhang P, Tan Z. Construction of engineered 3D islet micro-tissue using porcine decellularized ECM for the treatment of diabetes. Biomater Sci 2023; 11(16):5517-32.

[29]	Zheng Y, Wu Z, Hou Y, Li N, Zhang Q, Lin JM. Microfluidic engineering of crater-terrain hydrogel microparticles: toward novel cell carriers. ACS Appl Mater Interfaces 2023; 15(6):7833-40.

[30]	Xu T, Zhang Y, Chen S, Wu Z, Meng XL, Zhang Y, et al. Biomimetic microparticles with myocardial and endocardial integration for drug toxicity studies. Anal Chem 2025; 97(19):10369-77.

[31]	Pandey N, Anastasiadis P, Carney CP, Kanvinde PP, Woodworth GF, Winkles JA, et al. Nanotherapeutic treatment of the invasive glioblastoma tumor microenvironment. Adv Drug Deliv Rev 2022; 188:114415.

[32]	Azzalin A, Moretti E, Arbustini E, Magrassi L. Cell density modulates SHC 3 expression and survival of human glioblastoma cells through Fak activation. J Neurooncol 2014; 120(2):245-56.

[33]	Rechendorff K, Hovgaard MB, Foss M, Zhdanov VP, Besenbacher F. Enhancement of protein adsorption induced by surface roughness. Langmuir 2006; 22(26):10885-8.

[34]	Cho DH, Hahm JI. Protein-polymer interaction characteristics unique to nanoscale interfaces: a perspective on recent insights. J Phys Chem B 2021; 125(23):6040-57.

[35]	Yang G, Cao Y, Fan J, Liu H, Zhang F, Zhang P, et al. Rapid generation of cell gradients by utilizing solely nanotopographic interactions on a bio-inert glass surface. Angew Chem Int Ed 2014; 53(11):2915-8.

[36]	Liu D, Xu H, Zhang C, Xie H, Yang Q, Li W, et al. Erythropoietin maintains VE-cadherin expression and barrier function in experimental diabetic retinopathy via inhibiting VEGF/VEGFR2/Src signaling pathway. Life Sci 2020; 259:118273.

[37]	Wu H, Zhan T, Cui S, Chen J, Jin Q, Liu W, et al. Endothelial barrier dysfunction induced by anthracene and its nitrated or oxygenated derivatives at environmentally relevant levels. Sci Total Environ 2022; 802:149793.

[38]	Remenyik J, Biró A, Klusóczki Á, Juhász KZ, Szendi-Szatmári T, Kenesei Á, et al. Comparison of the modulating effect of anthocyanin-rich sour cherry extract on occludin and ZO-1 on Caco-2 and HUVEC cultures. Int J Mol Sci 2022; 23(16):9036.

[39]	Ryma M, Genç H, Nadernezhad A, Paulus I, Schneidereit D, Friedrich O, et al. A print-and-fuse strategy for sacrificial filaments enables biomimetically structured perfusable microvascular networks with functional endothelium inside 3D hydrogels. Adv Mater 2022; 34(28):e2200653.

[40]	Sun C, Wang Q, Zhou H, Yu S, Simard AR, Kang C, et al. Antisense MMP-9 RNA inhibits malignant glioma cell growth in vitro and in vivo. Neurosci Bull 2013; 29(1):83-93.

[41]	Li R, Zhan Y, Ding X, Cui J, Han Y, Zhang J, et al. Cancer differentiation inducer chlorogenic acid suppresses PD-L1 expression and boosts antitumor immunity of PD-1 antibody. Int J Biol Sci 2024; 20(1):61-77.

[42]	Zhou H, Chen D, Gong T, He Q, Guo C, Zhang P, et al. Chlorogenic acid sustained-release gel for treatment of glioma and hepatocellular carcinoma. Eur J Pharm Biopharm 2021; 166:103-10.

[43]	Kang Z, Li S, Kang X, Deng J, Yang H, Chen F, et al. Phase I study of chlorogenic acid injection for recurrent high-grade glioma with long-term follow-up. Cancer Biol Med 2023; 20(6):465-76.

[44]	Ye J, Yang Y, Jin J, Ji M, Gao Y, Feng Y, et al. Targeted delivery of chlorogenic acid by mannosylated liposomes to effectively promote the polarization of TAMs for the treatment of glioblastoma. Bioact Mater 2020; 5(3):694-708.

[45]	Obara-Michlewska M. The tryptophan metabolism, kynurenine pathway and oxidative stress-implications for glioma pathobiology. Neurochem Int 2022; 158:105363.

[46]	Maus A, Peters GJ. Glutamate and a-ketoglutarate: key players in glioma metabolism. Amino Acids 2017; 49(1):21-32.

[47]	Branco M, Linhares P, Carvalho B, Santos P, Costa BM, Vaz R. Serum lactate levels are associated with glioma malignancy grade. Clin Neurol Neurosurg 2019; 186:105546.

[48]	Sheng H, Liang Y, Lauschke VM, Wang Y. Organoids and organ-on-chip models for COVID-19 research and its application in modernization of traditional Chinese medicine: opportunities and challenges. Engineering 2025; 54:171-86.