Organs-on-a-Chip: A Fast Track for Engineered Human Tissues in Drug Development

Cell stem cell, Journal Year: 2018, Volume and Issue: 22(3), P. 310 - 324

Published: March 1, 2018

Language: Английский

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3D In Vitro Model (R)evolution: Unveiling Tumor–Stroma Interactions

Trends in cancer, Journal Year: 2020, Volume and Issue: 7(3), P. 249 - 264

Published: Nov. 19, 2020

Complex tumor–stroma interactions, a key feature of most solid tumors, drive tumor progression, metastasis, and drug resistance, ultimately lead to treatment failure.Clinically relevant 3D in vitro models are necessary recapitulate the complex interactions between stromal cells, provide tools better understand molecular mechanisms as well for testing anticancer therapies.Novel bioengineered models, organoid systems, microfabrication technologies, such bioprinting, have delivered innovations towards more advanced platforms modeling vitro. The microenvironment which malignant cells grow is crucial cancer progression. physical biochemical characteristics this niche involved controlling cell differentiation, proliferation, invasion, metastasis. It therefore essential how interact communicate with their surrounding tissue – so-called stroma interplay regulates disease To mimic (TME), widely used because they can incorporate different patient-derived tissues/cells allow longitudinal readouts, thus permitting deeper understanding interactions. These excellent bridge gap oversimplified 2D systems unrepresentative animal models. We present an overview state-of-the-art studying focus on why TME target therapy. composition (TME, see Glossary) major factors that aggravate growth leading poor clinical outcomes [1.Avnet S. et al.Pre-clinical interaction mesenchymal induction stemness.Front. Oncol. 2019; 9: 305Crossref PubMed Scopus (9) Google Scholar, 2.Mitchell M.J. al.Engineering sciences oncology: challenges opportunities.Nat. Rev. Cancer. 2017; 17: 659-675Crossref (132) 3.Asghar W. microenvironments 3-D models.Mater. Today. 2015; 18: 539-553Crossref (168) 4.Langhans S.A. Three-dimensional culture discovery repositioning.Front. Pharmacol. 2018; 6Crossref (370) 5.Rodenhizer D. al.The current landscape models: what hallmarks accessible discovery?.Adv. Healthc. Mater. 7e1701174Crossref (31) Scholar]. There increasing evidence activated disease-defining factor, highlighting it important player invasion/extravasation, migration, angiogenesis, resistance [6.Mcmillin D.W. role tumour-stromal modifying response: Drug Discov. 2013; 12: 217-228Crossref (282) Scholar,7.Maman Witz I.P. A history exploring context.Nat. 359-376Crossref (144) Scholar], stem maintenance [8.Batlle E. Clevers H. Cancer revisited.Nat. Med. 23: 1124-1134Crossref (838) immunosurveillance evasion Scholar,9.De Palma M. al.Microenvironmental regulation tumour angiogenesis.Nat. 457-474Crossref (627) Scholar,10.Valkenburg K.C. al.Targeting improve therapy.Nat. Clin. 15: 366-381Crossref stroma, nonneoplastic part TME, composed abundant extracellular matrix (ECM) multiple support [2.Mitchell including cancer-associated fibroblasts (CAFs), endothelial pericytes, immune [such lymphocytes, neutrophils, dendritic (DCs), monocytes] prevalent types (Figure 1). Other less include myeloid-derived suppressor (MDSCs) (MSCs) [7.Maman platelets [9.De Scholar,11.Yan Jurasz P. microenvironment: from tumors leukemia.Biochim. Biophys. Acta, Mol. Cell Res. 2016; 1863: 392-400Crossref (90) actively among themselves, ECM by secreting chemokines, (GFs), enzymes, vesicles, miRNAs regulate expression genes proteins influence metabolic pathways related [12.Ramamonjisoa N. Ackerstaff Characterization non-invasive preclinical imaging.Front. 7: 28-37Crossref (45) As such, some either promote or suppress depending upon cellular context [13.Bellomo C. al.Transforming factor β regulator stemness metastasis.Br. J. 115: 761-769Crossref (109) Hence, much has been accurately vivo. In field research, especially drugs, many experiments still performed cocultures, xenografts, syngeneic mouse Nevertheless, too simple unable complexity dynamic TME. Cells flat plastic surface monolayer, result loss signaling changes responses stimuli [14.Duval K. al.Modeling physiological events vs. culture.Physiology. 32: 266-277Crossref (478) 15.Mabry K.M. al.Microarray analyses quantify advantages hydrogel maintaining native valvular interstitial phenotype.Biomaterials. 74: 31-41Crossref (57) 16.Melissaridou effect cultures response, EMT profile features head neck cancer.Cancer Int. 19: 1-10Crossref (58) Moreover, do not conserve original shape polarization (Table By contrast, usually expensive, complex, difficult work with, associated ethical problems. also challenging analyze effects often representative human-specific events, limits applicability these [3.Asghar Scholar,17.Sung K.E. Beebe D.J. Microfluidic cancer.Adv. Deliv. 2014; 79: 68-78Crossref (107) multicellular overcome limitations experimental tractability relevance. reproduce mechanical cues development, morphology, cell–cell/cell–ECM stiffness, specific gradients [4.Langhans Scholar,14.Duval Scholar,18.Jensen Teng Y. Is time start transitioning culture?.Front. Biosci. 2020; 33Crossref (80) However, only one component cells. Thus, although new being developed, yet achieved. recent advances potential (i) discovery, (ii) be testing, (iii) enable development personalized treatments Scholar].Table 12D versus Culture MethodsCharacteristics2D3DRefsCell morphologyAltered shape, elongated; epithelial polarityThe natural preserved; aggregates[15.Mabry Scholar]Gene expressionCell adhesion-, proliferation-, survival-related modifiedAccurate representation gene patterns[16.Melissaridou Scholar,85.Riedl A. al.Comparison vs reveals differences AKT–mTOR–S6K responses.J. Sci. 130: 203-218Crossref (184) Scholar,86.Luca A.C. al.Impact phenotype, expression, EGFR inhibition colorectal lines.PLoS One. 8e59689Crossref (185) Scholar]Cell proliferation differentiationCell differentiation occurs at unnaturally rapid paceCells differentiated; realistic interactions[15.Mabry interactionsDeprived cell–cell cell–ECM no niches createdCell junctions common communication[14.Duval Scholar]Tumoral heterogeneityBasic; all receive same amount nutrients; inaccurate replication TMEBetter approximation TME; nutrients equally supplied[4.Langhans Scholar,51.Costa E.C. al.3D spheroids: techniques analysis.Biotechnol. Adv. 34: 1427-1441Crossref (216) Scholar]Response stimuliInaccurate cuesCells environment directions properly represent vivo stimuli[16.Melissaridou Scholar]ReproducibilityHighly replicableDifficult replicate conditions[4.Langhans Scholar]Analysis quantificationEasy interpretation results; long-term culturesDifficult data, when spheroid/organoid conformation[4.Langhans Scholar]CostCheaper large-scale studiesMore expensive techniques[18.Jensen Scholar] Open table tab This review presents within cell/ECM-based assays, cell-based microfluidics. each platform discussed, followed critical analysis novel should address establish clinically components almost control behavior external stimuli. Dynamic adhesion, cytoskeletal organization, Scholar,19.Bonnans al.Remodelling disease.Nat. Biol. 786-801Crossref (1636) For example, stiffness (desmoplasia), alongside establishment blood vessel network, contributes hypoxia epithelial-derived [19.Bonnans Scholar,20.Emon B. al.Biophysics metastasis mini review.Comput. Struct. Biotechnol. 16: 279-287Crossref (83) Furthermore, secretion hypoxia-inducible (HIFs) induces macrophage fibroblast recruitment hypoxic regions primary tumor, increased remodeling angiogenesis [21.Gilkes D.M. al.Hypoxia matrix: drivers metastasis.Nat. 14: 430-439Crossref (657) formation abnormal stimulates progression starts activation CAFs, contribute fibrosis alignment building up collagen fibers (mediated primarily LOX enzymes) [22.Hamidi Ivaska Every step way: integrins 533-548Crossref (354) addition, deregulated supports transformation hyperplasia Matrix metalloproteinases (MMPs) degradation metastatic sites Scholar,22.Hamidi every carcinogenesis function receptors mechanotransduction, instance, correlated overexpression β1 focal adhesion kinase RhoA/Rho-associated protein integrin-mediated fibronectin CAFs directional migration [23.Erdogan al.Cancer-associated aligning fibronectin.J. 216: 3799-3816Crossref (179) architecture over demonstrate spatiotemporal dynamics targets promising effective therapies. Given both tumor-inducing assays developed manipulate physiologically setting. An ideal scaffold appropriate proliferation/differentiation, generation closely context, cultured biomaterials, decellularized tissues, scaffolds based ceramics synthetic and/or polymers. Hydrogel-based typically preferred owing possibility tailoring properties 2). Scaffolds produced polymeric biomaterials polyethylene glycol (PEG), polycaprolactone (PCL), poly(hydroxyethylmethacrylate) (PHEMA), poly(lactic-co-glycolic acid) (PLGA), (such hydroxyapatite bioglass) [24.Feng al.Expansion breast fibrous scaffolds.Integr. 5: 768-777Crossref (50) Scholar,25.Long T.J. al.Prostate xenografts engineered precision-porous poly(2-hydroxyethyl methacrylate) hydrogels tumorigenesis dormancy escape.Biomaterials. 35: 8164-8174Crossref (20) Synthetic polymers ability modulate them required. modified peptides, RGD (Arg-Gly-Asp) peptides fibrinogen, adsorption [5.Rodenhizer hybrid combine soft [26.Rijal G. Li research.Biomaterials. 81: 135-156Crossref (99) PEG heparin were culturing prostate functionalized peptide motifs RGD, GFOGER (collagen I), IKVAV (laminin-111) [27.Taubenberger A.V. growth, invasion microenvironments.Acta Biomater. 36: 73-85Crossref (75) choice physical/chemical conditions determine will react substrate play outcome 2A,B). Natural collagen, fibrin, alginate, chitosan sourced tissues [28.Grolman J.M. al.Rapid extrusion microenvironments.Adv. 27: 5512-5517Crossref (69) 29.Rebelo S.P. al.3D-3-culture: tool unveil plasticity microenvironment.Biomaterials. 163: 185-197Crossref (66) 30.Hume R.D. al.Tumour invasiveness response chemotherapeutics adipocyte invested anisotropic scaffolds.Sci. Rep. 8: 12658Crossref (5) Alternatively, (dECM) offers advantage recreating environments without compromising tissue-specific ECM, thereby generating structural similar those [31.Ferreira L.P. al.Decellularized bioengineering physiomimetic models.Trends 38: 1397-1414Abstract Full Text PDF (14) Scholar,32.Lü W.D. al.Development acellular three-dimensional engineering.PLoS 9e103672Crossref (54) Most commonly substitutes, Matrigel, undefined highly variable affect results reproducibility model [33.Drost Organoids research.Nat. 407-418Crossref (400) close resemblance structure, easily replicated dECM-based after cellularization. dECMs alternatives vitro, individual whole [34.Gill B.J. West J.L. Modeling engineering repurposed frontiers biology.J. Biomech. 47: 1969-1978Crossref (59) decellularization process, however, its ensure intactness detergents enzymes. With considerations mind, modifications scaffold-based optimized modeling. (TMS) using methods biophysical/biochemical [35.Rijal versatile system screening.Sci. 3e1700764Crossref (53) consists multilayered prepared mammary tissue. compartmental fashion intracellular biomarkers confirming correct proliferation. TMS mimics structure while providing simple-to-use screening approach, was seeded adipocytes [30.Hume allowed examination pores aligned perpendicular surface, reflecting organizes spatial configuration. into compared two lines overexpressing Wnt1 Her2. presence types, promoted reducing overall number migratory demonstrating heterogeneity proper ECM-mimicking offer inexpensive analyzable tunable instructive One study showed significant difference levels affecting remodeling, namely processes resulted radio- chemoresistance Matrigel culture, highlights reproduction findings [36.Zschenker O. al.Genome-wide but DNA repair.PLoS 2012; 7e34279Crossref (93) applied produce bioprinted induce assembly spheroids, microfluidic platforms, explained detail next sections. use fabrication paved way bioprinting create well-defined architecture, composition, high 2C) [37.Langer E.M. phenotypes bioprinting.Cell 26: 608-623Abstract printing emerging approach patterning facilitates temporal distribution Common extrusion-, inkjet-, stereolithography-based laser-assisted electrospinning-based (Box 1) [38.Heinrich M.A. bioprinting: benches translational applications.Small. 15e1805510Crossref process must avoid damaging pressure/heat sensitive fluids, living Therefore, biomaterial consider biocompatibility, shape-fidelity material, level instructiveness required.Box 1Microfabrication Techniques Produce Constructs DevicesOver past decades, improved design cell-laden constructs. Each technologies application-specific depends type bioink [40.Moroni L. al.Biofabrication stra

Language: Английский

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Towards a deeper understanding of the vaginal microbiota

Nature Microbiology, Journal Year: 2022, Volume and Issue: 7(3), P. 367 - 378

Published: March 4, 2022

Language: Английский

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Tumor microenvironment: barrier or opportunity towards effective cancer therapy

Journal of Biomedical Science, Journal Year: 2022, Volume and Issue: 29(1)

Published: Oct. 17, 2022

Abstract Tumor microenvironment (TME) is a specialized ecosystem of host components, designed by tumor cells for successful development and metastasis tumor. With the advent 3D culture advanced bioinformatic methodologies, it now possible to study TME’s individual components their interplay at higher resolution. Deeper understanding immune cell’s diversity, stromal constituents, repertoire profiling, neoantigen prediction TMEs has provided opportunity explore spatial temporal regulation therapeutic interventions. The variation TME composition among patients plays an important role in determining responders non-responders towards cancer immunotherapy. Therefore, there could be possibility reprogramming overcome widely prevailing issue immunotherapeutic resistance. focus present review understand complexity comprehending future perspective its as potential targets. later part describes sophisticated models emerging valuable means extensive account tools profile predict neoantigens. Overall, this provides comprehensive current knowledge available target TME.

Language: Английский

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Tumor-on-a-chip: from bioinspired design to biomedical application

Microsystems & Nanoengineering, Journal Year: 2021, Volume and Issue: 7(1)

Published: June 21, 2021

Cancer is one of the leading causes human death, despite enormous efforts to explore cancer biology and develop anticancer therapies. The main challenges in research are establishing an efficient tumor microenvironment vitro exploring means for screening drugs reveal nature treatments. possesses human-specific biophysical biochemical factors that difficult recapitulate conventional planar cell models vivo animal models. Therefore, model limitations have hindered translation basic findings clinical applications. In this review, we introduce recent progress tumor-on-a-chip devices research, medicine assessment, biomedical applications detail. emerging platforms integrating 3D culture, microfluidic technology, tissue engineering successfully mimicked pivotal structural functional characteristics microenvironment. advances studies detailed analyzed review. This review should be valuable further understanding mechanisms evolution process, drugs, developing therapies, it addresses potential opportunities predicting drug treatment.

Language: Английский

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Exosome-mediated microRNA-497 delivery for anti-cancer therapy in a microfluidic 3D lung cancer model

Lab on a Chip, Journal Year: 2020, Volume and Issue: 20(3), P. 548 - 557

Published: Jan. 1, 2020

Non-small cell lung cancer (NSCLC) is one of the leading causes death from worldwide. The delivery and controlled regulation miRNAs via exosomes known as a potential therapeutic approach in treatment cancer. In this study, human cell-derived were used vehicles for miRNAs, we investigated their anti-tumor anti-angiogenic effects on NSCLCs that cultured 2D 3D microfluidic devices. We demonstrated contained miRNA-497 (miR-497) effectively suppressed tumor growth expression associated genes, i.e., yes-associated protein 1 (YAP1), hepatoma-derived factor (HDGF), cyclin E1 (CCNE1), vascular endothelial factor-A (VEGF-A), A549 cells. Also, level VEGF-A-mediated angiogenic sprouting was decreased drastically umbilical vein cells (HUVECs) device. To mimic vivo-like microenvironment NSCLC, co-cultured with HUVECs single device, miR-497-loaded delivered to both types As result, tube formation migration dramatically compared control. This indicated miR-497 has synergistic inhibitory target angiogenesis, so exosome-mediated miRNA therapeutics combined technology could be predictive, cost-efficient translational tool development targeted therapy.

Language: Английский

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Recent advances in microfluidic platforms for single-cell analysis in cancer biology, diagnosis and therapy

TrAC Trends in Analytical Chemistry, Journal Year: 2019, Volume and Issue: 117, P. 13 - 26

Published: May 17, 2019

Language: Английский

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Organ-On-A-Chip: A Survey of Technical Results and Problems

Frontiers in Bioengineering and Biotechnology, Journal Year: 2022, Volume and Issue: 10

Published: Feb. 10, 2022

Organ-on-a-chip (OoC), also known as micro physiological systems or "tissue chips" have attracted substantial interest in recent years due to their numerous applications, especially precision medicine, drug development and screening. devices can replicate key aspects of human physiology, providing insights into the studied organ function disease pathophysiology. Moreover, these accurately be used discovery for personalized medicine. These present useful substitutes traditional preclinical cell culture methods reduce use

Language: Английский

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Tumor microenvironment signaling and therapeutics in cancer progression

Cancer Communications, Journal Year: 2023, Volume and Issue: 43(5), P. 525 - 561

Published: April 2, 2023

Abstract Tumor development and metastasis are facilitated by the complex interactions between cancer cells their microenvironment, which comprises stromal extracellular matrix (ECM) components, among other factors. Stromal can adopt new phenotypes to promote tumor cell invasion. A deep understanding of signaling pathways involved in cell‐to‐cell cell‐to‐ECM is needed design effective intervention strategies that might interrupt these interactions. In this review, we describe microenvironment (TME) components associated therapeutics. We discuss clinical advances prevalent newly discovered TME, immune checkpoints immunosuppressive chemokines, currently used inhibitors targeting pathways. These include both intrinsic non‐autonomous TME: protein kinase C (PKC) signaling, Notch, transforming growth factor (TGF‐β) Endoplasmic Reticulum (ER) stress response, lactate Metabolic reprogramming, cyclic GMP–AMP synthase (cGAS)–stimulator interferon genes (STING) Siglec also recent Programmed Cell Death Protein 1 (PD‐1), Cytotoxic T‐Lymphocyte Associated 4 (CTLA4), T‐cell immunoglobulin mucin‐3 (TIM‐3) Lymphocyte Activating Gene 3 (LAG3) checkpoint along with C‐C chemokine receptor (CCR4)‐ class chemokines 22 (CCL22)/ 17 (CCL17), type 2 (CCR2)‐ (C‐C motif) ligand (CCL2), 5 (CCR5)‐ (CCL3) axis TME. addition, review provides a holistic TME as three‐dimensional microfluidic models believed recapitulate original characteristics patient hence may be platform study mechanisms screen for various anti‐cancer therapies. further systemic influences gut microbiota reprogramming treatment response. Overall, comprehensive analysis diverse most critical highlighting newest preclinical studies underlying biology. highlight importance technologies microfluidics lab‐on‐chip research present an overview extrinsic factors, such inhabitant human microbiome, have potential modulate biology drug responses.

Language: Английский

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Mimicking tumor microenvironment by 3D bioprinting: 3D cancer modeling

Biofabrication, Journal Year: 2022, Volume and Issue: 14(3), P. 032002 - 032002

Published: May 5, 2022

Abstract The tumor microenvironment (TME) typically comprises cancer cells, vasculature, stromal components like fibroblasts, and host immune cells that assemble to support tumorigenesis. However, preexisting classic models 2D cell culture methods, 3D spheroids, organoids seem lack essential TME components. bioprinting offers enormous advantages for developing in vitro by allowing user-controlled deposition of multiple biomaterials, biomolecules a predefined architecture. This review highlights the recent developments modeling using different techniques recreate TME. bioprinters enable fabrication high-resolution microstructures reproduce intricacies. Furthermore, bioprinted can be applied as preclinical model versatile research applications biology pharmaceutical industries. These provide an opportunity develop high-throughput drug screening platforms further developed suit individual patient requirements hence giving boost field personalized anti-cancer therapeutics. We underlined various ways existing studies have tried mimic TME, hallmark events growth metastasis within showcase drug-tumor interaction utilization such medicine.

Language: Английский

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