Microfluidic / Organ-on-chip

一行要約

Microfluidic organ-on-chip (OOC) は PDMS / glass チャネル内で複数細胞種を 3D 配置し、生理的 shear flow / 共培養 / 薬物 perfusion を模擬する microphysiological system (MPS)。Brain met / EV 領域では特に BBB-on-chip (endothelial cell + astrocyte + pericyte の co-culture) が drug permeability prediction や CNS-active TKI / ADC の transport 研究で活用、tumor-on-chip が TIL infiltration / immune trafficking under flow を 2D dish では再現困難な dynamic で解析。Patient-derived organoid を chip に統合した personalized drug screening も発展中。

原理

Chip 設計

(1) Soft lithography で PDMS マイクロチャネル製造 (10 µm-1 mm channel)。(2) 複数 channel を多孔質膜 / hydrogel で隔てて co-culture (apical / basal compartment)。(3) 培地 perfusion で physiological shear stress (1-20 dyn/cm²) を付与。(4) live-cell imaging compatible (透明 PDMS), 出口で metabolite / cytokine / EV 採取可能。

主要モデル

• BBB-on-chip: brain endothelial cell + astrocyte + pericyte の 3-cell co-culture, TEER (transendothelial electrical resistance) > 1500 Ω·cm² で in vivo BBB に近い barrier
• Lung-on-chip: alveolar epithelial cell + endothelial cell + air-liquid interface + breathing motion (Wyss Institute Huh 2010 Science)
• Tumor-on-chip: tumor spheroid + stromal cell + immune cell + perfusion, TIL trafficking / CAR-T cytotoxicity 観察
• Patient-derived organoid-on-chip: PDO を chip に integrate、personalized drug screening
• EV-on-chip: 血管モデル下で EV uptake / transit を physiological flow で観察

主要エビデンス / 適用領域

• BBB drug permeability prediction: osimertinib / lorlatinib / tucatinib 等 CNS-active TKI の BBB transport quantification
• TIL trafficking: tumor microenvironment chip で T-cell extravasation, CAR-T migration を flow 条件下で観察
• EV transit across BBB: tumor-derived EV の brain met pre-metastatic niche priming
• ADC linker permeability: payload release / bystander effect を perfusion 環境で評価
• Lung-on-chip ARDS / IPF model: 非腫瘍呼吸器疾患モデル
• Personalized therapy: PDO-chip で drug response prediction (oncology trial precursor)

適用分野と限界

• 強み: 生理的 shear / 共培養 / dynamic exposure の再現、live-imaging、low cell input、animal model 代替で ethical / cost
• 限界: PDMS は疎水性物質吸着 (特定薬物 PK 評価不正確), throughput は plate 比劣る, immune system complexity (lymph node, BM hematopoiesis) 完全再現困難, standardization 不足, regulatory framework (drug discovery use) 開発中

Open Questions

• Multi-organ “body-on-chip”: 複数 organ chip 連結で systemic PK / tox 予測
• Personalized drug screening: PDO-chip clinical decision support の prospective validation
• Vascularized tumor-on-chip with blood-flow + immune cell + drug
• Standardization / regulatory: FDA Modernization Act 2.0 で MPS を animal study 代替する pathway 整備

関連エンティティ

• 補完手法: Organoid / PDX / Tissue-clearing-3D-imaging / Multiplex-IF-imaging
• 関連細胞: Endothelial-cell / Astrocyte / Reactive-astrocyte / Pericyte / CD8-T-cell / CAR-T-cell
• 関連薬剤: Osimertinib / Lorlatinib / ADC / CAR-T-therapy
• 関連経路: BBB-neurovascular-unit-pathway
• 関連概念: BBB-disruption-in-brain-metastasis / Brain-metastasis-immune-microenvironment / EV-organotropism

関連論文

Basic-Brain metastasis

• Liu et al. CancerPathogTher 2024 — Experimental models for cancer brain metastasis
• Pardridge et al. JCerebBloodFlowMetab 2012 — Drug transport across the blood-brain barrier
• Rabas et al. NatRevCancer 2024 — Cancer-induced systemic pre-conditioning of distant organs building a niche for metastatic cells
• Dunbar et al. TrendsCancer 2025 — Regulation of metastatic organotropism

Basic-Extracellular vesicles

• Jung et al. ACSSens 2026 — Wash-free digital detection of tumor extracellular vesicles via plasmonic droplet microfluidics
• Garcia et al. CancerLett 2023 — Fernandez-Exosome-like systems Nanotechnology to overcome challenges for targeted cancer therapies
• Moon et al. Cells 2022 — Exosome as a delivery vehicle for cancer therapy
• Ma et al. CurrProtoc 2021 — Characterization and functional analysis of tumor-derived microparticles
• Liu et al. JNanobiotechnology 2026 — Overcoming blood-brain barrier and chemoresistance in glioblastoma by angiopep-2-modified NK cell-derived extracellular
• Gong et al. NatMater 2024 — Tumour-derived small extracellular vesicles act as a barrier to therapeutic nanoparticle delivery
• Chaudhari et al. NatRevBioeng 2026 — The status of extracellular vesicles a drug carriers and therapeutics
• Chiu et al. Small 2016 — A single-cell assay for time lapse studies of exosome secretion and cell behaviors

Basic-Neutrophil and myeloid cell

• Kang et al. ACSNano 2017 — Nanoparticles coated with neutrophil membranes can effectively treat cancer metastasis
• Xu et al. CancerImmunolRes 2020 — Chemotherapeutic tumor microparticles elicit a neutrophil response targeting malignant pleural effusions

Basic-Others

• Lucotti et al. FrontOncol 2020 — Platelets and metastasis New implications of an old interplay
• Rennick et al. NatNanotechnol 2021 — Key principles and methods for studying the endocytosis of biological and nanoparticle therapeutics

Basic-Tumor microenvironment

• Zhuo et al. CancerCell 2026 — A conserved re-epithelialization program underlies malignancy in pancreatic ductal adenocarcinoma

Clinical-NSCLC-Driver negative

• Jabbour et al. JAMAOncol 2020 — Phase 1 trial of pembrolizumab administered concurrently with chemoradiotherapy for locally advanced non-small cell

Clinical-Novel modalities

• Andersson-Rolf et al. NatRevMolCellBiol 2026 — New developments and applications of human organoids

Clinical-Thymic

• Caruso et al. TrendsCancer 2023 — Thymic expression of immune checkpoint molecules and their implication for response to immunotherapies

合成 (Outputs)

• bbb-permeability-cns-drug-selection