3D in vitro tissue models and their potential for drug screening

Introduction: The development of one standard, simplified in vitro three-dimensional tissue model suitable to biological and pathological investigation and drug-discovery may not yet be feasible, but standardized models for individual tissues or organs are a possibility. Tissue bioengineering, while concerned with finding methods of restoring functionality in disease, is developing technology that can be miniaturized for high throughput screening (HTS) of putative drugs. Through collaboration between biologists, physicists and engineers, cell-based assays are expanding into the realm of tissue analysis. Accordingly, three-dimensional (3D) micro-organoid systems will play an increasing role in drug testing and therapeutics over the next decade. Nevertheless, important hurdles remain before these models are fully developed for HTS. Areas covered: We highlight advances in the field of tissue bioengineering aimed at enhancing the success of drug candidates through pre-clinical optimization. We discuss models that are most amenable to high throughput screening with emphasis on detection platforms and data modeling. Expert opinion: Modeling 3D tissues to mimic in-vivo architecture remains a major challenge. As technology advances to provide novel methods of HTS analysis, so do potential pitfalls associated with such models and methods. We remain hopeful that integration of biofabrication with HTS will significantly reduce attrition rates in drug development.

[1]  V. Virador,et al.  In vitro three‐dimensional (3D) models in cancer research: An update , 2013, Molecular carcinogenesis.

[2]  S. Takayama,et al.  Bioengineered three-dimensional physiological model of colonic longitudinal smooth muscle in vitro. , 2010, Tissue engineering. Part C, Methods.

[3]  Bin Liu,et al.  Increasing extracellular matrix collagen level and MMP activity induces cyst development in polycystic kidney disease , 2012, BMC Nephrology.

[4]  Martin Fussenegger,et al.  VEGF profiling and angiogenesis in human microtissues. , 2005, Journal of biotechnology.

[5]  A. Levine,et al.  Human Neuroendocrine Tumor Cell Lines as a Three-Dimensional Model for the Study of Human Neuroendocrine Tumor Therapy , 2012, Journal of visualized experiments : JoVE.

[6]  G. Peters,et al.  Postconfluent multilayered cell line cultures for selective screening of gemcitabine. , 1998, European journal of cancer.

[7]  Teruo Okano,et al.  Layered implantation of myoblast sheets attenuates adverse cardiac remodeling of the infarcted heart. , 2009, The Journal of thoracic and cardiovascular surgery.

[8]  S. Sahoo,et al.  3-D tumor model for in vitro evaluation of anticancer drugs. , 2008, Molecular pharmaceutics.

[9]  Jackie Y Ying,et al.  Three-dimensional microstructured tissue scaffolds fabricated by two-photon laser scanning photolithography. , 2010, Biomaterials.

[10]  C. Ampe,et al.  The XTT cell proliferation assay applied to cell layers embedded in three-dimensional matrix. , 2012, Assay and drug development technologies.

[11]  Yan Jin,et al.  In Vitro Construction of Scaffold-Free Bilayered Tissue-Engineered Skin Containing Capillary Networks , 2013, BioMed research international.

[12]  F. Becker,et al.  Growth and metastasis of tumor in organ culture , 1963, Cancer.

[13]  Byungkyu Kim,et al.  Cell Stiffness Is a Biomarker of the Metastatic Potential of Ovarian Cancer Cells , 2012, PloS one.

[14]  R. Knuechel,et al.  Multicellular spheroids: a three‐dimensional in vitro culture system to study tumour biology , 1998, International journal of experimental pathology.

[15]  L. Kunz-Schughart,et al.  Multicellular tumor spheroids: an underestimated tool is catching up again. , 2010, Journal of biotechnology.

[16]  Zhi-nan Chen,et al.  Human Tumor Cells Induce Angiogenesis through Positive Feedback between CD147 and Insulin-Like Growth Factor-I , 2012, PloS one.

[17]  D. Bissell,et al.  Metabolism of heme and bilirubin in rat and human small intestinal mucosa. , 1982, Journal of Clinical Investigation.

[18]  A. Rustgi Models of esophageal carcinogenesis. , 2006, Seminars in oncology.

[19]  D. Grainger,et al.  A critical evaluation of in vitro cell culture models for high-throughput drug screening and toxicity. , 2012, Pharmacology & therapeutics.

[20]  Teruo Okano,et al.  Preserved liver-specific functions of hepatocytes in 3D co-culture with endothelial cell sheets. , 2012, Biomaterials.

[21]  H. Kurahashi,et al.  Increased water intake decreases progression of polycystic kidney disease in the PCK rat. , 2006, Journal of the American Society of Nephrology : JASN.

[22]  I. Kosztin,et al.  Developmental biology and tissue engineering. , 2007, Birth defects research. Part C, Embryo today : reviews.

[23]  J. Bakhach The cryopreservation of composite tissues , 2009, Organogenesis.

[24]  V. Virador,et al.  The FASEB Journal • Research Communication Isolation , 2022 .

[25]  Mina J Bissell,et al.  The organizing principle: microenvironmental influences in the normal and malignant breast. , 2002, Differentiation; research in biological diversity.

[26]  Wolfgang Moritz,et al.  Towards automated production and drug sensitivity testing using scaffold-free spherical tumor microtissues. , 2011, Biotechnology journal.

[27]  Sophie Lelièvre,et al.  beta4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium. , 2002, Cancer cell.

[28]  S. Fey,et al.  Determination of Drug Toxicity Using 3D Spheroids Constructed From an Immortal Human Hepatocyte Cell Line , 2012, Toxicological sciences : an official journal of the Society of Toxicology.

[29]  A. Manz,et al.  Revisiting lab-on-a-chip technology for drug discovery , 2012, Nature Reviews Drug Discovery.

[30]  Hyungil Jung,et al.  Integration of intra- and extravasation in one cell-based microfluidic chip for the study of cancer metastasis. , 2011, Lab on a chip.

[31]  Mitsuo Umezu,et al.  Fabrication of functional three-dimensional tissues by stacking cell sheets in vitro , 2012, Nature Protocols.

[32]  P. Rajagopalan,et al.  3D Hepatic Cultures Simultaneously Maintain Primary Hepatocyte and Liver Sinusoidal Endothelial Cell Phenotypes , 2010, PloS one.

[33]  F. Marga,et al.  Toward engineering functional organ modules by additive manufacturing , 2012, Biofabrication.

[34]  Jamie A Davies,et al.  In vivo maturation of functional renal organoids formed from embryonic cell suspensions. , 2012, Journal of the American Society of Nephrology : JASN.

[35]  Apurva R. Patel,et al.  AlgiMatrix™ Based 3D Cell Culture System as an In-Vitro Tumor Model for Anticancer Studies , 2013, PloS one.

[36]  Ruth E. Falconer,et al.  Characterising the tumour morphological response to therapeutic intervention: an ex vivo model , 2012, Disease Models & Mechanisms.

[37]  Khajeelak Chiablaem,et al.  Effective enrichment of cholangiocarcinoma secretomes using the hollow fiber bioreactor culture system. , 2012, Talanta.

[38]  T. Kennedy,et al.  High-throughput cellular screening of engineered ECM based on combinatorial polyelectrolyte multilayer films. , 2012, Biomaterials.

[39]  K. Turksen,et al.  Using High-Throughput Immunoblotting to Identify Proteins Involved in the Differentiation of ES Cells along the Hair Follicle Lineage in Vitro , 2011, Stem Cell Reviews and Reports.

[40]  Merging photolithography and robotic protein printing to create cellular microarrays. , 2011, Methods in molecular biology.

[41]  T. Park,et al.  Integration of Cell Culture and Microfabrication Technology , 2003, Biotechnology progress.

[42]  L. Griffith,et al.  Transport‐mediated angiogenesis in 3D epithelial coculture , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[43]  Patries M Herst,et al.  Tetrazolium dyes as tools in cell biology: new insights into their cellular reduction. , 2005, Biotechnology annual review.

[44]  Brendon M. Baker,et al.  Deconstructing the third dimension – how 3D culture microenvironments alter cellular cues , 2012, Journal of Cell Science.

[45]  W. Catherino,et al.  Development and validation of a three-dimensional in vitro model for uterine leiomyoma and patient-matched myometrium. , 2012, Fertility and sterility.

[46]  R. Zengerle,et al.  Construction of a microstructured collagen membrane mimicking the papillary dermis architecture and guiding keratinocyte morphology and gene expression. , 2012, Macromolecular bioscience.

[47]  Using 3D culture to investigate the role of mechanical signaling in keratinocyte stem cells. , 2013, Methods in molecular biology.

[48]  Umut A. Gurkan,et al.  Microengineering methods for cell-based microarrays and high-throughput drug-screening applications , 2011, Biofabrication.

[49]  M. Bouvet,et al.  A rapid imageable in vivo metastasis assay for circulating tumor cells. , 2011, Anticancer research.

[50]  Roger Williams Liver Dialysis: A Review , 2011 .

[51]  J. Folkman,et al.  ISOLATION OF A TUMOR FACTOR RESPONSIBLE FOR ANGIOGENESIS , 1971, The Journal of experimental medicine.

[52]  A. Ashworth,et al.  Opportunities and challenges in ovarian cancer research, a perspective from the 11th Ovarian cancer action/HHMT Forum, Lake Como, March 2007. , 2008, Gynecologic oncology.

[53]  D. Sugarbaker,et al.  Vorinostat Eliminates Multicellular Resistance of Mesothelioma 3D Spheroids via Restoration of Noxa Expression , 2012, PloS one.

[54]  Glenn D Prestwich,et al.  A 3-D organoid kidney culture model engineered for high-throughput nephrotoxicity assays. , 2012, Biomaterials.

[55]  S. Takayama,et al.  Opportunities and challenges for use of tumor spheroids as models to test drug delivery and efficacy. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[56]  Ruth E. Cameron,et al.  A Multifunctional 3D Co-Culture System for Studies of Mammary Tissue Morphogenesis and Stem Cell Biology , 2011, PloS one.

[57]  Takanori Takebe,et al.  Vascularized and functional human liver from an iPSC-derived organ bud transplant , 2013, Nature.

[58]  E. Decullier,et al.  Cultured autologous oral mucosal epithelial cell sheet (CAOMECS) transplantation for the treatment of corneal limbal epithelial stem cell deficiency. , 2012, Investigative ophthalmology & visual science.

[59]  J. Brugge,et al.  In vitro mesothelial clearance assay that models the early steps of ovarian cancer metastasis. , 2012, Journal of visualized experiments : JoVE.

[60]  B N Chichkov,et al.  Two-photon polymerization-generated and micromolding-replicated 3D scaffolds for peripheral neural tissue engineering applications , 2012, Biofabrication.

[61]  J. Nör,et al.  RAIN-Droplet: A Novel 3-D in vitro Angiogenesis Model , 2012, Laboratory Investigation.

[62]  Mitsuo Umezu,et al.  In vitro fabrication of functional three-dimensional tissues with perfusable blood vessels , 2013, Nature Communications.

[63]  U. Demirci,et al.  Bioprinting for stem cell research. , 2013, Trends in biotechnology.

[64]  Lidong Qin,et al.  Microfluidics separation reveals the stem-cell–like deformability of tumor-initiating cells , 2012, Proceedings of the National Academy of Sciences.

[65]  D. Katti,et al.  Recapitulating tumour microenvironment in chitosan–gelatin three-dimensional scaffolds: an improved in vitro tumour model , 2012, Journal of The Royal Society Interface.

[66]  D. Panescu,et al.  Emerging Technologies , 2008, IEEE Engineering in Medicine and Biology Magazine.

[67]  Mitsuo Ochi,et al.  Rotator Cuff Regeneration Using a Bioabsorbable Material With Bone Marrow–Derived Mesenchymal Stem Cells in a Rabbit Model , 2012, The American journal of sports medicine.

[68]  A J Ryan,et al.  Development of a 3D human in vitro skin co‐culture model for detecting irritants in real‐time , 2010, Biotechnology and bioengineering.

[69]  T. Murali,et al.  Designing a multicellular organotypic 3D liver model with a detachable, nanoscale polymeric Space of Disse. , 2013, Tissue engineering. Part C, Methods.

[70]  C. V. van Blitterswijk,et al.  Spheroid culture as a tool for creating 3D complex tissues. , 2013, Trends in biotechnology.

[71]  Michael V Sefton,et al.  A modular approach to cardiac tissue engineering. , 2010, Tissue engineering. Part A.

[72]  M. Lutolf,et al.  Artificial niche microarrays for probing single stem cell fate in high throughput , 2011, Nature Methods.

[73]  Hongbin Fan,et al.  Anterior cruciate ligament regeneration using mesenchymal stem cells and silk scaffold in large animal model. , 2009, Biomaterials.

[74]  Emmanuel Gustin,et al.  Translation of a Tumor Microenvironment Mimicking 3D Tumor Growth Co-culture Assay Platform to High-Content Screening , 2013, Journal of biomolecular screening.

[75]  Michelle Keramidas,et al.  Dissecting coronary angiogenesis: 3D co-culture of cardiomyocytes with endothelial or mesenchymal cells. , 2009, Experimental cell research.

[76]  David L. Kaplan,et al.  Bioengineered 3D Human Kidney Tissue, a Platform for the Determination of Nephrotoxicity , 2013, PloS one.

[77]  M. Herlyn,et al.  The functional interplay between EGFR overexpression, hTERT activation, and p53 mutation in esophageal epithelial cells with activation of stromal fibroblasts induces tumor development, invasion, and differentiation. , 2007, Genes & development.

[78]  S. Liyanarachchi,et al.  Glioma cell migration on three-dimensional nanofiber scaffolds is regulated by substrate topography and abolished by inhibition of STAT3 signaling. , 2011, Neoplasia.

[79]  E. Polska,et al.  A novel three-dimensional bone chip organ culture , 2013, Clinical Oral Investigations.

[80]  Ronit Vogt Sionov,et al.  Organ-specific scaffolds for in vitro expansion, differentiation, and organization of primary lung cells. , 2011, Tissue engineering. Part C, Methods.