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Research & Initiatives

以點擊化學原理合成膠原蛋白液晶彈性體以用於骨仿生材料與骨組織微流道晶片之開發
Collagen Liquid Crystal Elastomers for Bone Biomimetic Materials and Bone-on-a-Chip Development (NSTC 112-2314-B-309-001)​
 
本研究應用膠原蛋白液晶彈性體水凝膠於三維細胞培養，以開發骨組織微流道晶片，模擬正常骨組織並發展骨質疏鬆症之體外人類模型。本研究將人類骨髓間質幹細胞與人類CD14+單核細胞共培養(co-culture)於膠原蛋白液晶彈性體水凝膠，並整合於微流道系統，以模擬具有間質液(interstitial fluid flow)之動態骨組織微環境，探討環境中的機械刺激，如表面硬度與流體剪應力(fluid shear stress)，對機械傳導(mechanotransduction)與成骨分化的影響。另一方面，由於膠原蛋白液晶彈性體水凝膠中的介晶單元(mesogenic unit)具有一般生醫材料所沒有的刺激響應(stimuli-responsive)特性，其排列可能會因為細胞與細胞外基質之交互作用，或細胞所誘發之基質重塑(matrix remodeling)而改變，可藉成骨分化過程中細胞外基質生成與礦物質沈積所造成的光學性質變化，發展具細胞感測功能的響應型骨仿生材料，並拓展骨組織微流道晶片(bone-on-a-chip)的功能多樣性。為進一步建置骨質疏鬆症微流道晶片(osteoporosis-on-a-chip)，本研究透過合成高孔隙率之膠原蛋白液晶彈性體水凝膠，於促進蝕骨作用的條件下培養細胞，以模擬骨質疏鬆症之骨組織結構與微環境，並以美國食品藥物管理局核准之促骨新生藥物進行測試，以評估其效能與技術限制。本研究所建置之體外人類骨組織與骨質疏鬆症疾病模型，可作為藥物開發與疾病模式之非動物性替代方案，為液晶彈性體在組織工程與精準醫療的應用提供創新的發展方向。
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Taking advantage of the versatility and stimuli-responsiveness of collagen-based liquid crystal elastomer (LCE) hydrogel synthesized by the amine‒acrylate click chemistry of aza-Michael addition, this study aims at establishing bone-on-a-chip and osteoporosis-on-a-chip microfluidic systems with three-dimensional (3D) osteoblast/osteoclast co-culture to create a bone-stimulating microenvironment that mimics normal bone tissue as well as to construct an in vitro human disease model for osteoporosis. The 3D osteoblast/osteoclast co-culture is developed by co-culturing human bone marrow-derived mesenchymal stem cells (hBMSCs) with human CD14+ monocytes on collagen-based LCE hydrogel, which is integrated into a microfluidic system to establish a bone-on-a-chip platform mimicking the microenvironment of bone tissue in the presence of interstitial fluid flow. The bone-on-a-chip microfluidic device enables mechanical stimuli from the environment, such as surface stiffness and fluid shear stress, and the correlation of mechanotransduction with osteogenic differentiation on collagen-based LCE hydrogel to be investigated. On the other hand, collagen-based LCE hydrogel is stimuli-responsive to cell‒matrix interaction or cell-mediated matrix remodeling, such as the synthesis of extracellular matrix and mineral deposition during osteogenic differentiation both in the presence and absence of fluid shear stress, allowing novel biosensing functionalities unachievable with conventional bone scaffolds or biomaterials to be built into the bone-on-a-chip platform to signal the growth and differentiation status of the 3D osteoblast/osteoclast co-culture. Furthermore, we propose to transform the bone-on-a-chip platform into an in vitro human disease model of osteoporosis-on-a-chip featuring both the structure and microenvironment of the osteoporotic bone by synthesizing porous collagen-based LCE hydrogel to support 3D osteoblast/osteoclast co-culture in an osteoclastogenic state, followed by validation with FDA-approved bone anabolics to assess its efficacy and limitations. The microfluidic bone-on-a-chip and osteoporosis-on-a-chip models developed with collagen-based LCE hydrogel are considered promising platforms as alternatives to animal testing for future application in precision medicine for drug treatment and disease modeling customized to the patient.
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開發液晶生物感測器以應用於癌症生物標記免疫偵測與蛋白質定量分析
Liquid Crystal Biosensors for Cancer Biomarker Immunodetection and Quantitative Protein Analysis (MOST 106-2314-B-309-001; 109-2320-B-309-001; 110-2320-B-309-001)

 

本研究開發以液晶為基礎之無標記免疫偵測技術，採用大雙折射率之液晶，並透過配相膜之改質，大幅提高液晶免疫偵測之靈敏度。藉由光譜分析、介電頻譜技術與液晶光電性質之量測，本研究突破液晶生物感測無法精準量化之技術瓶頸，以膽固醇型液晶、藍相液晶、染料型液晶、雙頻液晶、液晶與高分子複合材料、向列型溶致彩色液晶等作為感測媒介，驗證以液晶為基礎之免疫偵測與蛋白質定量技術之可行性。本研究在液晶‒玻璃界面的生物感測技術領先國外其他研究團隊，可為液晶的生醫應用提供創新的發展方向，有利於延伸我國優越的液晶顯示技術於生醫光電與精準健康產業。

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As the liquid crystal display (LCD) market becomes increasingly saturated and faces strong competition from emerging display technologies such as OLED and MicroLED, the applications of liquid crystal materials have become more diversified. This trend calls for broader interdisciplinary collaboration to develop new products and markets, one promising direction being the development of biomedical sensing technologies. At present, most liquid crystal-based biosensing methods rely on qualitative analysis through observation of liquid crystal optical textures and therefore lack precise quantitative capability. In addition, most liquid crystal biosensing techniques reported in the literature employ thermotropic liquid crystals as the sensing medium, among which the nematic liquid crystal 5CB (4-cyano-4′-pentylbiphenyl) is the most widely used.

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To expand the applications of liquid crystals in biosensing, this research has continuously developed different types of thermotropic liquid crystals and liquid crystal phases as sensing media for biosensors, including cholesteric liquid crystals, blue-phase liquid crystals, dual-frequency liquid crystals, dye-doped liquid crystals, and liquid crystal–polymer composites. In recent years, to develop liquid crystal biosensors with real-time detection capability, the scope of sensing media has been further extended to lyotropic liquid crystals, particularly nematic lyotropic chromonic liquid crystals, as environmentally friendly and biocompatible sensing materials. By integrating transmission spectroscopy, haze measurement, dielectric spectroscopy, and electro-optical characterization of liquid crystals, this research has overcome the technical bottleneck that previously limited precise quantification in liquid crystal biosensing, and has developed label-free immunodetection techniques based on liquid crystals. In addition, by adopting strategies such as using liquid crystals with high birefringence, modifying alignment films, and applying electric fields, the sensitivity of liquid crystal-based biodetection has been significantly enhanced, thereby verifying the feasibility of liquid crystal-based immunodetection and quantitative protein analysis. This research has established a leading position internationally in biosensing at the liquid crystal–glass interface, providing an innovative direction for biomedical applications of liquid crystals and helping extend Taiwan’s strengths in liquid crystal display technology into the biomedical photonics and precision health industries.

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Representative publications

  1. M.-J. Lee**, J.-T. Hsieh, C.-T. Chang, Y.-C. Wu, P.-Y. Chan, C.‑M. Chien, and W. Lee*. 2026. Highly sensitive sunset yellow-based optical and dielectric biosensing of SARS-CoV-2 nucleocapsid protein in saliva. Colloids Surf. B Biointerfaces 257: 115128 (**first and corresponding author; SCIE, 7/79, Biophysics, 2024 IF 5.6).

  2. T.-K. Chang#, Y.-Y. Tseng#, P.-C. Wu, M.-J. Lee*, and W. Lee*. 2023. Optical and flexoelectric biosensing based on a hybrid-aligned liquid crystal of anomalously small bend elastic constant. Biosens. Bioelectron. 232: 115314 (#The authors contributed equally to this work; *corresponding author; SCIE, 3/111, Chemistry, Analytical, 2024 IF 10.5).

  3. H. Shaban, J.-T. Hsieh, M.-J. Lee*, and W. Lee*. 2023. Label-free optical and electrical immunoassays based on lyotropic chromonic liquid crystals: Implications of real-time detection and kinetic analysis. Biosens. Bioelectron. 223: 115011 (*corresponding author; SCIE, 3/111, Chemistry, Analytical, 2024 IF 10.5).

  4. T.-K. Chang, P.-C. Tung, M.-J. Lee*, and W. Lee*. 2022. A liquid-crystal aptasensing platform for label-free detection of a single circulating tumor cell. Biosens. Bioelectron. 216: 114607 (*corresponding author; SCIE, 3/111, Chemistry, Analytical, 2024 IF 10.5).

  5. B.-S. Chen, M.-J. Lee*, and W. Lee*. 2022. Multimodal spectrometric and dielectric biosensing with an ionic-surfactant-doped liquid crystal. Sens. Actuator B-Chem. 365: 131912 (*corresponding author; SCIE, 2/79, Instruments & Instrumentation, 2024 IF 7.7).

  6. M.-J. Lee**, C.-P. Pai, P.-C. Wu, and W. Lee*. 2021. Label-free single-substrate quantitative protein assay based on optical characteristics of cholesteric liquid crystals. J. Mol. Liq. 331: 115756 (**first and corresponding author; SCIE, 6/39, Physics, Atomic, Molecular & Chemical, 2024 IF 5.2).

  7. C.-M. Lin, P.-C. Wu, M.-J. Lee,* and W. Lee.* 2019. Label-free protein quantitation by dielectric spectroscopy of dual-frequency liquid crystal. Sens. Actuator B-Chem. 282: 158–163 (*corresponding author; SCIE, 2/79, Instruments & Instrumentation, 2024 IF 7.7).​

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促骨新生藥物與篩選平台之開發
Development of Bone-Stimulating Drugs and Screening Platforms (MOST 101-2314-B-309-001-MY3; 105-2633-B-309-001; 106-2633-B-309-001)

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目前臨床上所能應用的促骨生成藥物選擇性少，且有引發骨癌的風險。本研究首度證實多元胺類化合物可透過促進成骨基因的表現，同時抑制脂肪分化基因，使人類骨髓間葉幹細胞分化為成骨細胞。此外，利用適體(aptamer)發展骨硬化蛋白(sclerostin)抑制劑之藥物篩選平台，有助舊藥新用(drug repurposing)，加速促骨生成新藥開發，以應用於目前尚無有效療法之骨代謝疾病如骨質疏鬆症之治療。

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This research addresses the limited availability and safety concerns of clinically used bone-stimulating drugs, some of which carry a risk of inducing bone cancer. Our work was the first to demonstrate that polyamine compounds can promote osteogenic differentiation of human bone marrow-derived mesenchymal stem cells by upregulating osteogenic gene expression while suppressing adipogenic gene expression. In parallel, an aptamer-based drug screening platform targeting sclerostin was developed to facilitate drug repurposing and accelerate the discovery of new bone-stimulating agents for bone metabolic disorders such as osteoporosis, for which effective therapies remain limited.

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Representative publications

  1. C.-C. Lee#, C.-C. Chuang#, C.-H. Chen, Y.-P. Huang, C-Y. Chang, P.-Y. Tung, and M.-J. Lee*. 2024. In vitro and in vivo studies on exogenous polyamines and a-difluoromethylornithine to enhance bone formation and suppress osteoclast differentiation. Amino Acids 56: 43 (#The authors contributed equally to this work; *corresponding author; SCIE, 227/320, Biochemistry and Molecular Biology, 2024 IF 2.4).

  2. C.-C. Lee#, C.-M. Hung#, C.-H. Chen, Y.-C. Hsu, Y.-P. Huang, T.-B. Huang, and M.-J. Lee*. 2021. Novel aptamer-based small-molecule drug screening assay to identify potential sclerostin inhibitors against osteoporosis. Int. J. Mol. Sci. 22: 8320 (#The authors contributed equally to this work; *corresponding author; SCIE, 72/320, Biochemistry & Molecular Biology, 2024 IF 4.9).

  3. Y. H. Tsai#, K. L. Lin#, Y. P. Huang, Y. C. Hsu, Y. Chen, M. H. Sie, G. J. Wang, and M. J. Lee*. 2015. Suppression of ornithine decarboxylase promotes osteogenic differentiation of human bone marrow-derived mesenchymal stem cells. FEBS Letters 589: 2058–2065 (#The authors contributed equally to this work; *corresponding author; SCIE, 27/79, Biophysics, 2024 IF 3.0).

  4. M. J. Lee*, Y. Chen, Y. P. Huang, Y. C. Hsu, L. H. Chiang, T. Y. Chen and G. J. Wang. 2013. Exogenous polyamines promote osteogenic differentiation by reciprocally regulating osteogenic and adipogenic gene expression. J. Cell. Biochem. 114: 2718–2728 (*first and corresponding author; SCIE, 187/320, Biochemistry & Molecular Biology, 2024 IF 2.8).

 
開發聚乙烯亞胺官能化含碳奈米材料作為非病毒型基因傳遞載體
Polyethylenimine-Functionalized Carbon Nanomaterials as Nonviral Gene Delivery Carriers (MOST 103-2633-B-309-001)

 

本研究旨在發展含碳奈米材料作為非整合性非病毒型基因傳遞載體，以降低病毒型載體的致癌風險。本研究結果證實聚乙烯亞胺(polyethylenimine, PEI)官能化奈米碳管與石墨烯可有效傳遞小分子干擾RNA (small interfering RNA)至人類子宮頸癌細胞與乳癌細胞，達到抑制基因表現與癌細胞轉移的效果，研究成果有助新穎奈米生醫材料於癌症標靶治療與基因治療之應用。

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This research aims to develop carbon-based nanomaterials as non-integrating, nonviral gene delivery carriers to reduce the carcinogenic risks associated with viral vectors. The results demonstrated that polyethylenimine (PEI)-functionalized carbon nanotubes and graphene oxide can effectively deliver small interfering RNA (siRNA) into human cervical cancer cells and breast cancer cells, resulting in gene silencing and suppression of cancer cell migration. These findings support the potential application of novel nanobiomaterials in targeted cancer therapy and gene therapy.

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Representative publications

  1. Y. P. Huang, C. M. Hung, Y. C. Hsu, C. Y. Zhong, W. R. Wang, C. C. Chang, and M. J. Lee.* 2016. Suppression of breast cancer cell migration by small interfering RNA delivered by polyethylenimine-functionalized graphene oxide. Nanoscale Res. Lett. 11: 247.

  2. Y. P. Huang, I. J. Lin, C. C. Chen, Y. C. Hsu, C. C. Chang, and M. J. Lee.* 2013. Delivery of small interfering RNAs in human cervical cancer cells by polyethylenimine-functionalized carbon nanotubes. Nanoscale Res. Lett. 8: 267.

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