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Medicinal Biotechnology for Disease Modeling, Clinical Therapy, and Drug Discovery and Development

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Introduction to Biotech Entrepreneurship: From Idea to Business

Abstract

Over the past decades, stem cell technology has revolutionalized medical biotechnology due to the unlimited self-renewal ability and differentiation capacity of stem cells to generate cells and tissues of the entire human body. Many efforts have focused on providing cutting-edge stem cell therapies in order to repair or replace damaged cells or tissues, hoping to ultimately cure devastating diseases. Undoubtedly, this novel technology guarantees a serial entrepreneur’s confidence in the future prospects of stem cell-based products and services. Here, we describe the state of the art of several applications of adult stem cells, as well as of embryonic and induced pluripotent stem cells in biotechnology that represent entrepreneurial opportunities. Although the contribution of stem cells to medical research is enormous, several hurdles still have to be overcome, including ethical and regulatory issues, functional maturation of stem cell progenitors, stringent manufacturing guidelines, immune rejection, and tumorigenicity.

Nevertheless, key studies applying microfluidic technology, “organ-in-a-dish” and 3D bioprinting have been published, reporting the successful development of human pluripotent stem cell-based healthy and disease models for deciphering pathological mechanisms, drug discovery and toxicity screening, and regenerative medicine. Interestingly, because of the increasing amount of newly identified targets, assistance from computational chemistry and bioinformatics became indispensable to reduce the quantity of molecules that need to be tested in vitro or in vivo. In the past years, a boom in companies and start-ups all over the world occurred, focusing on bioinformatics and machine learning. Furthermore, biotechnological applications are highly applied in the veterinary medicine nowadays, and stem cell-based biotechnology is opening an exciting era in human therapeutics. In conclusion, scientists with strong entrepreneur mind-set are crucial to generate economic value in medicinal biotechnology. Thus, we need to educate next generation of scientists in entrepreneurship and work directly with institutions and funding agencies to guarantee a successful translational process in hiring and training our next generation of students.

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References

  • Adachi M, Hoshino Y, Izumi Y, Takagi S (2016) Immunohistochemical detection of a potential molecular therapeutic target for canine hemangiosarcoma. J Vet Med Sci 78:649–656

    Article  CAS  PubMed  Google Scholar 

  • An R, Hoffman MD, Donoghue MA, Hunt AJ, Jacobson SC (2008) Water-assisted femtosecond laser machining of electrospray nozzles on glass microfluidic devices. Opt Express 16:15206–15211

    Article  CAS  PubMed  Google Scholar 

  • Andersen P, Tampakakis E, Jimenez DV, Kannan S, Miyamoto M, Shin HK, Saberi A, Murphy S, Sulistio E, Chelko SP, Kwon C (2018) Precardiac organoids form two heart fields via Bmp/Wnt signaling. Nat Commun 9:3140

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ashammakhi N, Elkhammas EA, Hasan A (2017) Glomerulus-on-a-chip life up. Transplantation 101:E343–E344

    Article  PubMed  Google Scholar 

  • Bandak B, Yi L, Roper MG (2018) Microfluidic-enabled quantitative measurements of insulin release dynamics from single islets of Langerhans in response to 5-palmitic acid hydroxy stearic acid. Lab Chip 18:2873–2882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barkauskas CE, Chung MI, Fioret B, Gao X, Katsura H, Hogan BL (2017) Lung organoids: current uses and future promise. Development 144:986–997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barnard JB, Richardson S, Sheldon S, Fildes J, Pravica V, Hutchinson IV, Leonard CT, Yonan N (2006) The Mdr1/Abcb1 gene, a high-impact risk factor for cardiac transplant rejection. Transplantation 82:1677–1682

    Article  CAS  PubMed  Google Scholar 

  • Baron MG, Mintram KS, Owen SF, Hetheridge MJ, Moody AJ, Purcell WM, Jackson SK, Jha AN (2017) Pharmaceutical metabolism in fish: using A 3-D hepatic in vitro model to assess clearance. PLoS One 12:E0168837

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Barry R, Diggle T, Terrett J, Soloviev M (2003) Competitive assay formats for high-throughput affinity arrays. J Biomol Screen 8:257–263

    Article  CAS  PubMed  Google Scholar 

  • Beebe D, Wheeler M, Zeringue H, Walters E, Raty S (2002) Microfluidic technology for assisted reproduction. Theriogenology 57:125–135

    Article  CAS  PubMed  Google Scholar 

  • Beer M, Kuppalu N, Stefanini M, Becker H, Schulz I, Manoli S, Schuette J, Schmees C, Casazza A, Stelzle M, Arcangeli A (2017) A novel microfluidic 3D platform for culturing pancreatic ductal adenocarcinoma cells: comparison with in vitro cultures and in vivo xenografts. Sci Rep 7:1325

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bein A, Shin W, Jalili-Firoozinezhad S, Park MH, Sontheimer-Phelps A, Tovaglieri A, Chalkiadaki A, Kim HJ, Ingber DE (2018) Microfluidic organ-on-a-chip models of human intestine. Cell Mol Gastroenterol Hepatol 5:659–668

    Article  PubMed  PubMed Central  Google Scholar 

  • Ben-Shaul S, Landau S, Merdler U, Levenberg S (2019) Mature vessel networks in engineered tissue promote graft-host anastomosis and prevent graft thrombosis. Proc Natl Acad Sci U S A 116:2955–2960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bian S, Zhang L, Duan L, Wang X, Min Y, Yu H (2014) Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model. J Mol Med 92:387–397

    Article  CAS  PubMed  Google Scholar 

  • Bian S, Repic M, Guo Z, Kavirayani A, Burkard T, Bagley JA, Krauditsch C, Knoblich JA (2018) Genetically engineered cerebral organoids model brain tumor formation. Nat Methods 15:631–639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Birgersdotter A, Sandberg R, Ernberg I (2005) Gene expression perturbation in vitro – a growing case for three-dimensional (3D) culture systems. Semin Cancer Biol 15:405–412

    Article  PubMed  Google Scholar 

  • Bollard CM, Heslop HE (2016) T cells for viral infections after allogeneic hematopoietic stem cell transplant. Blood 127:3331–3340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brown JA, Pensabene V, Markov DA, Allwardt V, Neely MD, Shi M, Britt CM, Hoilett OS, Yang Q, Brewer BM, Samson PC, Mccawley LJ, May JM, Webb DJ, Li D, Bowman AB, Reiserer RS, Wikswo JP (2015) Recreating blood-brain barrier physiology and structure on chip: a novel neurovascular microfluidic bioreactor. Biomicrofluidics 9:054124

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Brown JA, Codreanu SG, Shi M, Sherrod SD, Markov DA, Neely MD, Britt CM, Hoilett OS, Reiserer RS, Samson PC, Mccawley LJ, Webb DJ, Bowman AB, Mclean JA, Wikswo JP (2016) Metabolic consequences of inflammatory disruption of the blood-brain barrier in an organ-on-chip model of the human neurovascular unit. J Neuroinflammation 13:306

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Buchan NS, Rajpal DK, Webster Y, Alatorre C, Gudivada RC, Zheng C, Sanseau P, Koehler J (2011) The role of translational bioinformatics in drug discovery. Drug Discov Today 16:426–434

    Article  CAS  PubMed  Google Scholar 

  • Cao Y, Vacanti JP, Paige KT, Upton J, Vacanti CA (1997) Transplantation of chondrocytes utilizing a polymer-cell construct to produce tissue-engineered cartilage in the shape of a human ear. Plast Reconstr Surg 100:297–302. Discussion 303–4

    Article  CAS  PubMed  Google Scholar 

  • Carpenter S (2007) Science careers. Carving a career in translational research. Science 317:966–967

    Article  PubMed  Google Scholar 

  • Chang CM, Chang WH, Wang CH, Wang JH, Mai JD, Lee GB (2013) Nucleic acid amplification using microfluidic systems. Lab Chip 13:1225–1242

    Article  CAS  PubMed  Google Scholar 

  • Chang SY, Weber EJ, Ness KV, Eaton DL, Kelly EJ (2016) Liver and kidney on chips: microphysiological models to understand transporter function. Clin Pharmacol Ther 100:464–478

    Article  CAS  PubMed  Google Scholar 

  • Chen YW, Huang SX, De Carvalho A, Ho SH, Islam MN, Volpi S, Notarangelo LD, Ciancanelli M, Casanova JL, Bhattacharya J, Liang AF, Palermo LM, Porotto M, Moscona A, Snoeck HW (2017) A three-dimensional model of human lung development and disease from pluripotent stem cells. Nat Cell Biol 19:542–549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chin MH, Mason MJ, Xie W, Volinia S, Singer M, Peterson C, Ambartsumyan G, Aimiuwu O, Richter L, Zhang J, Khvorostov I, Ott V, Grunstein M, Lavon N, Benvenisty N, Croce CM, Clark AT, Baxter T, Pyle AD, Teitell MA, Pelegrini M, Plath K, Lowry WE (2009) Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell 5:111–123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chirullo B, Ammendola S, Leonardi L, Falcini R, Petrucci P, Pistoia C, Vendetti S, Battistoni A, Pasquali P (2015) Attenuated mutant strain of Salmonella typhimurium lacking the znuabc transporter contrasts tumor growth promoting anti-cancer immune response. Oncotarget 6:17648–17660

    Article  PubMed  PubMed Central  Google Scholar 

  • Cho M, Chung S, Jung JH, Rhie GE, Jeon JH, Seo TS (2014) Combination of biobarcode assay with on-chip capillary electrophoresis for ultrasensitive and multiplex biological agent detection. Biosens Bioelectron 61:172–176

    Article  CAS  PubMed  Google Scholar 

  • Chong JJ, Yang X, Don CW, Minami E, Liu YW, Weyers JJ, Mahoney WM, Van Biber B, Cook SM, Palpant NJ, Gantz JA, Fugate JA, Muskheli V, Gough GM, Vogel KW, Astley CA, Hotchkiss CE, Baldessari A, Pabon L, Reinecke H, Gill EA, Nelson V, Kiem HP, Laflamme MA, Murry CE (2014) Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature 510:273–277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Conant G, Lai BFL, Lu RXZ, Korolj A, Wang EY, Radisic M (2017) High-content assessment of cardiac function using heart-on-a-chip devices as drug screening model. Stem Cell Rev 13:335–346

    Article  Google Scholar 

  • Crapo PM, Gilbert TW, Badylak SF (2011) An overview of tissue and whole organ decellularization processes. Biomaterials 32:3233–3243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Crespo M, Vilar E, Tsai SY, Chang K, Amin S, Srinivasan T, Zhang T, Pipalia NH, Chen HJ, Witherspoon M, Gordillo M, Xiang JZ, Maxfield FR, Lipkin S, Evans T, Chen S (2017) Colonic organoids derived from human induced pluripotent stem cells for modeling colorectal cancer and drug testing. Nat Med 23:878–884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cugola FR, Fernandes IR, Russo FB, Freitas BC, Dias JL, Guimaraes KP, Benazzato C, Almeida N, Pignatari GC, Romero S, Polonio CM, Cunha I, Freitas CL, Brandao WN, Rossato C, Andrade DG, Faria Dde P, Garcez AT, Buchpigel CA, Braconi CT, Mendes E, Sall AA, Zanotto PM, Peron JP, Muotri AR, Beltrao-Braga PC (2016) The Brazilian Zika virus strain causes birth defects in experimental models. Nature 534:267–271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dauth S, Maoz BM, Sheehy SP, Hemphill MA, Murty T, Macedonia MK, Greer AM, Budnik B, Parker KK (2017) Neurons derived from different brain regions are inherently different in vitro: a novel multiregional brain-on-a-chip. J Neurophysiol 117:1320–1341

    Article  CAS  PubMed  Google Scholar 

  • Dendukuri D, Gu SS, Pregibon DC, Hatton TA, Doyle PS (2007) Stop-flow lithography in a microfluidic device. Lab Chip 7:818–828

    Article  CAS  PubMed  Google Scholar 

  • Duelen R, Sampaolesi M (2017) Stem cell technology in cardiac regeneration: a pluripotent stem cell promise. EBioMedicine 16:30–40

    Article  PubMed  PubMed Central  Google Scholar 

  • Duffy DC, Mcdonald JC, Schueller OJ, Whitesides GM (1998) Rapid prototyping of microfluidic systems in poly(dimethylsiloxane). Anal Chem 70:4974–4984

    Article  CAS  PubMed  Google Scholar 

  • Dutta D, Heo I, Clevers H (2017) Disease modeling in stem cell-derived 3D organoid systems. Trends Mol Med 23:393–410

    Article  CAS  PubMed  Google Scholar 

  • Dye BR, Dedhia PH, Miller AJ, Nagy MS, White ES, Shea LD, Spence JR (2016) A bioengineered niche promotes in vivo engraftment and maturation of pluripotent stem cell derived human lung organoids. Elife:5

    Google Scholar 

  • Ebert AD, Yu J, Rose FF Jr, Mattis VB, Lorson CL, Thomson JA, Svendsen CN (2009) Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457:277–280

    Article  CAS  PubMed  Google Scholar 

  • Edmondson R, Broglie JJ, Adcock AF, Yang L (2014) Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors. Assay Drug Dev Technol 12:207–218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eisenstein M (2018) Organoids: the body builders. Nat Methods 15:19

    Article  CAS  Google Scholar 

  • Felder M, Trueeb B, Stucki AO, Borcard S, Stucki JD, Schnyder B, Geiser T, Guenat OT (2019) Impaired wound healing of alveolar lung epithelial cells in a breathing lung-on-a-chip. Front Bioeng Biotechnol 7:3

    Article  PubMed  PubMed Central  Google Scholar 

  • Feng Y, Chen CS, Ho J, Pearce D, Hu S, Wang B, Desai P, Kim KS, Zhu H (2018) High-throughput chip assay for investigating Escherichia Coli interaction with the blood-brain barrier using microbial and human proteome microarrays (dual-microarray technology). Anal Chem 90:10958–10966

    Article  CAS  PubMed  Google Scholar 

  • Ferrebee JW, Thomas ED (1960) Transplantation of marrow in man. Arch Intern Med 106:523–531

    Article  CAS  PubMed  Google Scholar 

  • Figeys D, Aebersold R (1998) High sensitivity analysis of proteins and peptides by capillary electrophoresis-tandem mass spectrometry: recent developments in technology and applications. Electrophoresis 19:885–892

    Article  CAS  PubMed  Google Scholar 

  • Figeys D, Gygi SP, Mckinnon G, Aebersold R (1998) An integrated microfluidics-tandem mass spectrometry system for automated protein analysis. Anal Chem 70:3728–3734

    Article  CAS  PubMed  Google Scholar 

  • Fiorotto R, Amenduni M, Mariotti V, Fabris L, Spirli C, Strazzabosco M (2019) Liver diseases in the dish: ipsc and organoids as a new approach to modeling liver diseases. Biochim Biophys Acta Mol Basis Dis 1865(5):920–928

    Article  CAS  PubMed  Google Scholar 

  • Folch A, Toner M (2000) Microengineering of cellular interactions. Annu Rev Biomed Eng 2:227–256

    Article  CAS  PubMed  Google Scholar 

  • Fontanarosa PB, Deangelis CD (2002) Basic science and translational research in JAMA. JAMA 287:1728

    Article  PubMed  Google Scholar 

  • Foquet M, Korlach J, Zipfel W, Webb WW, Craighead HG (2002) DNA fragment sizing by single molecule detection in submicrometer-sized closed fluidic channels. Anal Chem 74:1415–1422

    Article  CAS  PubMed  Google Scholar 

  • Forbester JL, Goulding D, Vallier L, Hannan N, Hale C, Pickard D, Mukhopadhyay S, Dougan G (2015) Interaction of Salmonella Enterica serovar typhimurium with intestinal organoids derived from human induced pluripotent stem cells. Infect Immun 83:2926–2934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Forsythe SD, Devarasetty M, Shupe T, Bishop C, Atala A, Soker S, Skardal A (2018) Environmental toxin screening using human-derived 3D bioengineered liver and cardiac organoids. Front Public Health 6:103

    Article  PubMed  PubMed Central  Google Scholar 

  • Freedman BS, Brooks CR, Lam AQ, Fu H, Morizane R, Agrawal V, Saad AF, Li MK, Hughes MR, Werff RV, Peters DT, Lu J, Baccei A, Siedlecki AM, Valerius MT, Musunuru K, Mcnagny KM, Steinman TI, Zhou J, Lerou PH, Bonventre JV (2015) Modelling kidney disease with crispr-mutant kidney organoids derived from human pluripotent epiblast spheroids. Nat Commun 6:8715

    Article  CAS  PubMed  Google Scholar 

  • Fukumoto J, Kolliputi N (2012) Human lung on a chip: innovative approach for understanding disease processes and effective drug testing. Front Pharmacol 3:205

    PubMed  Google Scholar 

  • Gabriel E, Ramani A, Karow U, Gottardo M, Natarajan K, Gooi LM, Goranci-Buzhala G, Krut O, Peters F, Nikolic M, Kuivanen S, Korhonen E, Smura T, Vapalahti O, Papantonis A, Schmidt-Chanasit J, Riparbelli M, Callaini G, Kronke M, Utermohlen O, Gopalakrishnan J (2017) Recent Zika virus isolates induce premature differentiation of neural progenitors in human brain organoids. Cell Stem Cell 20:397–406 E5

    Article  CAS  PubMed  Google Scholar 

  • Gao J, Xu J, Locascio LE, Lee CS (2001) Integrated microfluidic system enabling protein digestion, peptide separation, and protein identification. Anal Chem 73:2648–2655

    Article  CAS  PubMed  Google Scholar 

  • Garcez PP, Loiola EC, Madeiro Da Costa R, Higa LM, Trindade P, Delvecchio R, Nascimento JM, Brindeiro R, Tanuri A, Rehen SK (2016) Zika Virus impairs growth in human neurospheres and brain organoids. Science 352:816–818

    Article  CAS  PubMed  Google Scholar 

  • Gherghiceanu M, Barad L, Novak A, Reiter I, Itskovitz-Eldor J, Binah O, Popescu LM (2011) Cardiomyocytes derived from human embryonic and induced pluripotent stem cells: comparative ultrastructure. J Cell Mol Med 15:2539–2551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gilbert TW, Sellaro TL, Badylak SF (2006) Decellularization of tissues and organs. Biomaterials 27:3675–3683

    CAS  PubMed  Google Scholar 

  • Gkatzis K, Taghizadeh S, Huh D, Stainier DYR, Bellusci S (2018) Use of three-dimensional organoids and lung-on-a-chip methods to study lung development, regeneration and disease. Eur Respir J 52

    Google Scholar 

  • Glasgow IK, Zeringue HC, Beebe DJ, Choi SJ, Lyman JT, Chan NG, Wheeler MB (2001) Handling individual mammalian embryos using microfluidics. IEEE Trans Biomed Eng 48:570–578

    Article  CAS  PubMed  Google Scholar 

  • Gori M, Simonelli MC, Giannitelli SM, Businaro L, Trombetta M, Rainer A (2016) Investigating nonalcoholic fatty liver disease in a liver-on-a-chip microfluidic device. PLoS One 11:E0159729

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Grix T, Ruppelt A, Thomas A, Amler AK, Noichl BP, Lauster R, Kloke L (2018) Bioprinting perfusion-enabled liver equivalents for advanced organ-on-a-chip applications. Genes (Basel) 9

    Google Scholar 

  • Guo Y, Li Z, Su W, Wang L, Zhu Y, Qin J (2018) A biomimetic human gut-on-a-chip for modeling drug metabolism in intestine. Artif Organs 42:1196–1205

    Article  CAS  PubMed  Google Scholar 

  • Han C, Sun X, Liu L, Jiang H, Shen Y, Xu X, Li J, Zhang G, Huang J, Lin Z, Xiong N, Wang T (2016) Exosomes and their therapeutic potentials of stem cells. Stem Cells Int 2016:7653489

    PubMed  Google Scholar 

  • Hardy RE, Ikpeazu EV (1989) Bone marrow transplantation: a review. J Natl Med Assoc 81:518–523

    CAS  PubMed  PubMed Central  Google Scholar 

  • He Y, Zhang YH, Yeung ES (2001) Capillary-based fully integrated and automated system for nanoliter polymerase chain reaction analysis directly from cheek cells. J Chromatogr A 924:271–284

    Article  CAS  PubMed  Google Scholar 

  • Heo I, Dutta D, Schaefer DA, Iakobachvili N, Artegiani B, Sachs N, Boonekamp KE, Bowden G, Hendrickx APA, Willems RJL, Peters PJ, Riggs MW, O'connor R, Clevers H (2018) Modelling cryptosporidium infection in human small intestinal and lung organoids. Nat Microbiol 3:814–823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Herland A, Van Der Meer AD, Fitzgerald EA, Park TE, Sleeboom JJ, Ingber DE (2016) Distinct contributions of astrocytes and pericytes to neuroinflammation identified in a 3D human blood-brain barrier on a chip. PLoS One 11:E0150360

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hopwood AJ, Hurth C, Yang J, Cai Z, Moran N, Lee-Edghill JG, Nordquist A, Lenigk R, Estes MD, Haley JP, Mcalister CR, Chen X, Brooks C, Smith S, Elliott K, Koumi P, Zenhausern F, Tully G (2010) Integrated microfluidic system for rapid forensic DNA analysis: sample collection to DNA profile. Anal Chem 82:6991–6999

    Article  CAS  PubMed  Google Scholar 

  • Hu H, Gehart H, Artegiani B, LÖpez-Iglesias C, Dekkers F, Basak O, Van Es J, Chuva De Sousa Lopes SM, Begthel H, Korving J, Van Den Born M, Zou C, Quirk C, Chiriboga L, Rice CM, Ma S, Rios A, Peters PJ, De Jong YP, Clevers H (2018) Long-term expansion of functional mouse and human hepatocytes as 3D organoids. Cell 175(1591–1606):E19

    Google Scholar 

  • Huh D, Hamilton GA, Ingber DE (2011) From 3D cell culture to organs-on-chips. Trends Cell Biol 21:745–754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huh D, Leslie DC, Matthews BD, Fraser JP, Jurek S, Hamilton GA, Thorneloe KS, Mcalexander MA, Ingber DE (2012) A human disease model of drug toxicity-induced pulmonary edema in a lung-on-a-chip microdevice. Sci Transl Med 4:159ra147

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Jacob A, Morley M, Hawkins F, Mccauley KB, Jean JC, Heins H, Na CL, Weaver TE, Vedaie M, Hurley K, Hinds A, Russo SJ, Kook S, Zacharias W, Ochs M, Traber K, Quinton LJ, Crane A, Davis BR, White FV, Wambach J, Whitsett JA, Cole FS, Morrisey EE, Guttentag SH, Beers MF, Kotton DN (2017) Differentiation of human pluripotent stem cells into functional lung alveolar epithelial cells. Cell Stem Cell 21(472–488):E10

    Google Scholar 

  • Joachim J, Tooze SA (2018) Control of gabarap-mediated autophagy by the golgi complex, centrosome and centriolar satellites. Biol Cell 110:1–5

    Article  CAS  PubMed  Google Scholar 

  • Justice BA, Badr NA, Felder RA (2009) 3D cell culture opens new dimensions in cell-based assays. Drug Discov Today 14:102–107

    Article  CAS  PubMed  Google Scholar 

  • Karakikes I, Ameen M, Termglinchan V, Wu JC (2015) Human induced pluripotent stem cell-derived cardiomyocytes: insights into molecular, cellular, and functional phenotypes. Circ Res 117:80–88

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Keatch RP, Armoogum K, Schor SL, Pridham MS, Banks K, Khor TY, Matthew C (2002) Microengineering as a tool to study substratum modulation and cell behaviour. Biomed Tech (Berl) 47(Suppl 1 Pt 1):386–389

    Article  Google Scholar 

  • Kehat I, Khimovich L, Caspi O, Gepstein A, Shofti R, Arbel G, Huber I, Satin J, Itskovitz-Eldor J, Gepstein L (2004) Electromechanical integration of cardiomyocytes derived from human embryonic stem cells. Nat Biotechnol 22:1282–1289

    Article  CAS  PubMed  Google Scholar 

  • Khanlarkhani N, Baazm M, Mohammadzadeh F, Najafi A, Mehdinejadiani S, Sobhani A (2016) Multipotent stem cell and reproduction. J Stem Cells 11:219–229

    CAS  PubMed  Google Scholar 

  • Kilic O, Pamies D, Lavell E, Schiapparelli P, Feng Y, Hartung T, Bal-Price A, Hogberg HT, Quinones-Hinojosa A, Guerrero-Cazares H, Levchenko A (2016) Brain-on-a-chip model enables analysis of human neuronal differentiation and chemotaxis. Lab Chip 16:4152–4162

    Article  CAS  PubMed  Google Scholar 

  • Kim S, Lesherperez SC, Kim BC, Yamanishi C, Labuz JM, Leung B, Takayama S (2016) Pharmacokinetic profile that reduces nephrotoxicity of gentamicin in a perfused kidney-on-a-chip. Biofabrication 8:015021

    Article  PubMed  Google Scholar 

  • Kimura H, Ikeda T, Nakayama H, Sakai Y, Fujii T (2015) An on-chip small intestine-liver model for pharmacokinetic studies. J Lab Autom 20:265–273

    Article  CAS  PubMed  Google Scholar 

  • Kizilkurtlu AA, Polat T, Aydin GB, Akpek A (2018) Lung on a chip for drug screening and design. Curr Pharm Des 24:5386–5396

    Article  CAS  PubMed  Google Scholar 

  • Konar D, Devarasetty M, Yildiz DV, Atala A, Murphy SV (2016) Lung-on-a-chip technologies for disease modeling and drug development. Biomed Eng Comput Biol 7:17–27

    PubMed  PubMed Central  Google Scholar 

  • Kong J, Luo Y, Jin D, An F, Zhang W, Liu L, Li J, Fang S, Li X, Yang X, Lin B, Liu T (2016) A novel microfluidic model can mimic organ-specific metastasis of circulating tumor cells. Oncotarget 7:78421–78432

    PubMed  PubMed Central  Google Scholar 

  • Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, Homfray T, Penninger JM, Jackson AP, Knoblich JA (2013) Cerebral organoids model human brain development and microcephaly. Nature 501:373–379

    Article  CAS  PubMed  Google Scholar 

  • Lee J, Kim S (2018) Kidney-on-a-chip: a new technology for predicting drug efficacy, interactions, and drug-induced nephrotoxicity. Curr Drug Metab 19:577–583

    Article  CAS  PubMed  Google Scholar 

  • Lee JH, Lee JB, Shapovalova Z, Fiebig-Comyn A, Mitchell RR, Laronde S, Szabo E, Benoit YD, Bhatia M (2014) Somatic transcriptome priming gates lineage-specific differentiation potential of human-induced pluripotent stem cell states. Nat Commun 5:5605

    Article  CAS  PubMed  Google Scholar 

  • Lee H, Chae S, Kim JY, Han W, Kim J, Choi Y, Cho DW (2019) Cell-printed 3D liver-on-a-chip possessing a liver microenvironment and biliary system. Biofabrication 11:025001

    Article  PubMed  Google Scholar 

  • Lenigk R, Liu RH, Athavale M, Chen Z, Ganser D, Yang J, Rauch C, Liu Y, Chan B, Yu H, Ray M, Marrero R, Grodzinski P (2002) Plastic biochannel hybridization devices: a new concept for microfluidic DNA arrays. Anal Biochem 311:40–49

    Article  CAS  PubMed  Google Scholar 

  • Leonardi L, Mechelli L, Lepri E, Manuali E, And Vitellozzi G (2012) PMWS (Postweaning multisystemic wasting syndrome) in central italy: histopathological, immunohistochemical and ultrastructural findings. Int J Vet Sci 1(2):49–54

    Google Scholar 

  • Leonardi L, Piro F, Pannaioli V, Bellezza E, Marsili R, Angeli G, Bucci A, Moretti M, Rossi G (2015) Additive manufacturing and advanced testing techniques applied to bone reconstructive sciences in animals and humans. Congresso Aip Vet, Perugia, 15–17 June 2015

    Google Scholar 

  • Levenberg S, Rouwkema J, Macdonald M, Garfein ES, Kohane DS, Darland DC, Marini R, Van Blitterswijk CA, Mulligan RC, D’amore PA, Langer R (2005) Engineering vascularized skeletal muscle tissue. Nat Biotechnol 23:879–884

    Article  CAS  PubMed  Google Scholar 

  • Li X, Ballerini DR, Shen W (2012) A perspective on paper-based microfluidics: current status and future trends. Biomicrofluidics 6:11301–1130113

    Article  PubMed  CAS  Google Scholar 

  • Li Z, Jiang L, Tao T, Su W, Guo Y, Yu H, Qin J (2017) Assessment of cadmium-induced nephrotoxicity using a kidney-on-a-chip device. Toxicol Res (Camb) 6:372–380

    Article  CAS  Google Scholar 

  • Li Y, Hermanson DL, Moriarity BS, Kaufman DS (2018) Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Cell Stem Cell 23:181–192 E5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin JH (1995) Species similarities and differences in pharmacokinetics. Drug Metab Dispos 23:1008–1021

    CAS  PubMed  Google Scholar 

  • Lion N, Gellon JO, Jensen H, Girault HH (2003) On-chip protein sample desalting and preparation for direct coupling with electrospray ionization mass spectrometry. J Chromatogr A 1003:11–19

    Article  CAS  PubMed  Google Scholar 

  • Liu RH, Lenigk R, Druyor-Sanchez RL, Yang J, Grodzinski P (2003) Hybridization enhancement using cavitation microstreaming. Anal Chem 75:1911–1917

    Article  CAS  PubMed  Google Scholar 

  • Liu C, Oikonomopoulos A, Sayed N, Wu JC (2018) Modeling human diseases with induced pluripotent stem cells: from 2D to 3D and beyond. Development 145(5), pii: dev 156166

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ma C, Zhao L, Zhou EM, Xu J, Shen S, Wang J (2016) On-chip construction of liver lobule-like microtissue and its application for adverse drug reaction assay. Anal Chem 88:1719–1727

    Article  CAS  PubMed  Google Scholar 

  • Maitre JL (2017) Mechanics of blastocyst morphogenesis. Biol Cell 109:323–338

    Article  PubMed  Google Scholar 

  • Mak IW, Evaniew N, Ghert M (2014) Lost in translation: animal models and clinical trials in cancer treatment. Am J Transl Res 6:114–118

    PubMed  PubMed Central  Google Scholar 

  • Mandai M, Watanabe A, Kurimoto Y, Hirami Y, Morinaga C, Daimon T, Fujihara M, Akimaru H, Sakai N, Shibata Y, Terada M, Nomiya Y, Tanishima S, Nakamura M, Kamao H, Sugita S, Onishi A, Ito T, Fujita K, Kawamata S, Go MJ, Shinohara C, Hata KI, Sawada M, Yamamoto M, Ohta S, Ohara Y, Yoshida K, Kuwahara J, Kitano Y, Amano N, Umekage M, Kitaoka F, Tanaka A, Okada C, Takasu N, Ogawa S, Yamanaka S, Takahashi M (2017) Autologous induced stem-cell-derived retinal cells for macular degeneration. N Engl J Med 376:1038–1046

    Article  CAS  PubMed  Google Scholar 

  • Marban E (2018) The secret life of exosomes: what bees can teach us about next-generation therapeutics. Journal of the american college of cardiology 71:193–200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mariani J, Coppola G, Zhang P, Abyzov A, Provini L, Tomasini L, Amenduni M, Szekely A, Palejev D, Wilson M, Gerstein M, Grigorenko EL, Chawarska K, Pelphrey KA, Howe JR, Vaccarino FM (2015) Foxg1-dependent dysregulation of gaba/glutamate neuron differentiation in autism spectrum disorders. Cell 162:375–390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Mechinaud F, Balduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, Grupp SA (2018) Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med 378:439–448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mccauley KB, Hawkins F, Serra M, Thomas DC, Jacob A, Kotton DN (2017) Efficient derivation of functional human airway epithelium from pluripotent stem cells via temporal regulation of WNT signaling. Cell Stem Cell 20:844–857 E6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mccracken KW, Cata EM, Crawford CM, Sinagoga KL, Schumacher M, Rockich BE, Tsai YH, Mayhew CN, Spence JR, Zavros Y, Wells JM (2014) Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature 516:400–404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mcgonigle P, Ruggeri B (2014) Animal models of human disease: challenges in enabling translation. Biochem Pharmacol 87:162–171

    Article  CAS  PubMed  Google Scholar 

  • Mertz L (2016) Omics tech, gut-on-a-chip, and bacterial engineering: new approaches for treating inflammatory bowel diseases. IEEE Pulse 7:9–12

    PubMed  Google Scholar 

  • Miller AJ, Dye BR, Ferrer-Torres D, Hill DR, Overeem AW, Shea LD, Spence JR (2019) Generation of lung organoids from human pluripotent stem cells in vitro. Nat Protoc 14:518–540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miro G, Ruperez C, Checa R, Galvez R, Hernandez L, Garcia M, Canorea I, Marino V, Montoya A (2014) Current status of L. infantum infection in stray cats in the madrid region (Spain): implications for the recent outbreak of human leishmaniosis? Parasites and Vectors 7:112

    Article  PubMed  PubMed Central  Google Scholar 

  • Moffat JG, Vincent F, Lee JA, Eder J, Prunotto M (2017) Opportunities and challenges in phenotypic drug discovery: an industry perspective. Nat Rev Drug Discov 16:531–543

    Article  CAS  PubMed  Google Scholar 

  • Moretti A, Bellin M, Welling A, Jung CB, Lam JT, Bott-Flugel L, Dorn T, Goedel A, Hohnke C, Hofmann F, Seyfarth M, Sinnecker D, Schomig A, Laugwitz KL (2010) Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N Engl J Med 363:1397–1409

    Article  CAS  PubMed  Google Scholar 

  • Morrison C (2018) Boom: 2018’s Biotech Ipos. Nat Rev Drug Discov 18:3–6

    Article  PubMed  CAS  Google Scholar 

  • Morrison JI, Loof S, He P, Simon A (2006) Salamander limb regeneration involves the activation of a multipotent skeletal muscle satellite cell population. J Cell Biol 172:433–440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moslem M, Olive J, Falk A (2018) Stem cell models of schizophrenia, what have we learned and what is the potential? Schizophr Res pii: S0920-9964(18)30719-9

    Google Scholar 

  • Murphy SV, Atala A (2014) 3D bioprinting of tissues and organs. Nat Biotechnol 32:773–785

    Article  CAS  PubMed  Google Scholar 

  • Muscari C, Giordano E, Bonafe F, Govoni M, Guarnieri C (2014) Strategies affording prevascularized cell-based constructs for myocardial tissue engineering. Stem Cells Int 2014:434169

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nakayama KH, Batchelder CA, Lee CI, Tarantal AF (2010) Decellularized rhesus monkey kidney as a three-dimensional scaffold for renal tissue engineering. Tissue Eng Part A 16:2207–2216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Neuville A, Renaud L, Luu TT, Minde MW, Jettestuen E, Vinningland JL, Hiorth A, Dysthe DK (2017) Xurography for microfluidics on a reactive solid. Lab Chip 17:293–303

    Article  CAS  PubMed  Google Scholar 

  • Ni Z, Knorr DA, Clouser CL, Hexum MK, Southern P, Mansky LM, Park IH, Kaufman DS (2011) Human pluripotent stem cells produce natural killer cells that mediate anti-HIV-1 activity by utilizing diverse cellular mechanisms. J Virol 85:43–50

    Article  CAS  PubMed  Google Scholar 

  • Ni Z, Knorr DA, Bendzick L, Allred J, Kaufman DS (2014) Expression of chimeric receptor Cd4zeta by natural killer cells derived from human pluripotent stem cells improves in vitro activity but does not enhance suppression of HIV infection in vivo. Stem Cells 32:1021–1031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nie YZ, Zheng YW, Miyakawa K, Murata S, Zhang RR, Sekine K, Ueno Y, Takebe T, Wakita T, Ryo A, Taniguchi H (2018a) Recapitulation of hepatitis B virus-host interactions in liver organoids from human induced pluripotent stem cells. EBioMedicine 35:114–123

    Article  PubMed  PubMed Central  Google Scholar 

  • Nie YZ, Zheng YW, Ogawa M, Miyagi E, Taniguchi H (2018b) Human liver organoids generated with single donor-derived multiple cells rescue mice from acute liver failure. Stem Cell Res Ther 9:5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nowakowski TJ, Pollen AA, Di Lullo E, Sandoval-Espinosa C, Bershteyn M, Kriegstein AR (2016) Expression analysis highlights AXL as a candidate Zika virus entry receptor in neural stem cells. Cell Stem Cell 18:591–596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nugraha B, Buono MF, Von Boehmer L, Hoerstrup SP, Emmert MY (2019) Human cardiac organoids for disease modeling. Clin Pharmacol Ther 105:79–85

    Article  PubMed  Google Scholar 

  • Ogawa M, Ogawa S, Bear CE, Ahmadi S, Chin S, Li B, Grompe M, Keller G, Kamath BM, Ghanekar A (2015) Directed differentiation of cholangiocytes from human pluripotent stem cells. Nat Biotechnol 33:853–861

    Article  CAS  PubMed  Google Scholar 

  • Ott HC, Matthiesen TS, Goh SK, Black LD, Kren SM, Netoff TI, Taylor DA (2008) Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Nat Med 14:213–221

    Article  CAS  PubMed  Google Scholar 

  • Pampaloni F, Reynaud EG, Stelzer EH (2007) The third dimension bridges the gap between cell culture and live tissue. Nat Rev Mol Cell Biol 8:839–845

    Article  CAS  PubMed  Google Scholar 

  • Park J, Lee BK, Jeong GS, Hyun JK, Lee CJ, Lee SH (2015) Three-dimensional brain-on-a-chip with an interstitial level of flow and its application as an in vitro model of Alzheimer’s disease. Lab Chip 15:141–150

    Article  CAS  PubMed  Google Scholar 

  • Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindborg SR, Schacht AL (2010) How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat Rev Drug Discov 9:203–214

    Article  CAS  PubMed  Google Scholar 

  • Pawlak M, Schick E, Bopp MA, Schneider MJ, Oroszlan P, Ehrat M (2002) Zeptosens’ protein microarrays: a novel high performance microarray platform for low abundance protein analysis. Proteomics 2:383–393

    Article  CAS  PubMed  Google Scholar 

  • Peela N, Truong D, Saini H, Chu H, Mashaghi S, Ham SL, Singh S, Tavana H, Mosadegh B, Nikkhah M (2017) Advanced biomaterials and microengineering technologies to recapitulate the stepwise process of cancer metastasis. Biomaterials 133:176–207

    Article  CAS  PubMed  Google Scholar 

  • Perestrelo AR, Aguas AC, Rainer A, Forte G (2015) Microfluidic organ/body-on-a-chip devices at the convergence of biology and microengineering. Sensors (Basel) 15:31142–31170

    Article  Google Scholar 

  • Petersen TH, Calle EA, Zhao L, Lee EJ, Gui L, Raredon MB, Gavrilov K, Yi T, Zhuang ZW, Breuer C, Herzog E, Niklason LE (2010) Tissue-engineered lungs for in vivo implantation. Science 329:538–541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pillekamp F, Haustein M, Khalil M, Emmelheinz M, Nazzal R, Adelmann R, Nguemo F, Rubenchyk O, Pfannkuche K, Matzkies M, Reppel M, Bloch W, Brockmeier K, Hescheler J (2012) Contractile properties of early human embryonic stem cell-derived cardiomyocytes: beta-adrenergic stimulation induces positive chronotropy and lusitropy but not inotropy. Stem Cells Dev 21:2111–2121

    Article  CAS  PubMed  Google Scholar 

  • Pjescic I, Tranter CA, Haywood JC, Paidipalli M, Ganveer A, Haywood SE, Tham J, Crews ND (2011) Real-time damage monitoring of irradiated DNA. Integr Biol (Camb) 3:937–947

    Article  CAS  Google Scholar 

  • Pollen AA, Bhaduri A, Andrews MG, Nowakowski TJ, Meyerson OS, Mostajo-Radji MA, Di Lullo E, Alvarado B, Bedolli M, Dougherty ML, Fiddes IT, Kronenberg ZN, Shuga J, Leyrat AA, West JA, Bershteyn M, Lowe CB, Pavlovic BJ, Salama SR, Haussler D, Eichler EE, Kriegstein AR (2019) Establishing cerebral organoids as models of human-specific brain evolution. Cell 176:743–756 E17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prodanov L, Jindal R, Bale SS, Hegde M, Mccarty WJ, Golberg I, Bhushan A, Yarmush ML, Usta OB (2016) Long-term maintenance of a microfluidic 3D human liver sinusoid. Biotechnol Bioeng 113:241–246

    Article  CAS  PubMed  Google Scholar 

  • Punde TH, Wu WH, Lien PC, Chang YL, Kuo PH, Chang MD, Lee KY, Huang CD, Kuo HP, Chan YF, Shih PC, Liu CH (2015) A biologically inspired lung-on-a-chip device for the study of protein-induced lung inflammation. Integr Biol (Camb) 7:162–169

    Article  CAS  Google Scholar 

  • Qian F, Huang C, Lin YD, Ivanovskaya AN, O'hara TJ, Booth RH, Creek CJ, Enright HA, Soscia DA, Belle AM, Liao R, Lightstone FC, Kulp KS, Wheeler EK (2017) Simultaneous electrical recording of cardiac electrophysiology and contraction on chip. Lab Chip 17:1732–1739

    Article  CAS  PubMed  Google Scholar 

  • Raies AB, Bajic VB (2016) In silico toxicology: computational methods for the prediction of chemical toxicity. Wiley Interdiscip Rev Comput Mol Sci 6:147–172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Raja WK, Mungenast AE, Lin YT, Ko T, Abdurrob F, Seo J, Tsai LH (2016) Self-organizing 3D human neural tissue derived from induced pluripotent stem cells recapitulate Alzheimer’s disease phenotypes. PLoS One 11:E0161969

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Reininger-Mack A, Thielecke H, Robitzki AA (2002) 3D-biohybrid systems: applications in drug screening. Trends Biotechnol 20:56–61

    Article  CAS  PubMed  Google Scholar 

  • Robertson JA (2001) Human embryonic stem cell research: ethical and legal issues. Nat Rev Genet 2:74–78

    Article  CAS  PubMed  Google Scholar 

  • Robinton DA, Daley GQ (2012) The promise of induced pluripotent stem cells in research and therapy. Nature 481:295–305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rossant J (2007) Stem cells and lineage development in the mammalian blastocyst. Reprod Fertil Dev 19:111–118

    Article  CAS  PubMed  Google Scholar 

  • Rowe RG, Daley GQ (2019) Induced pluripotent stem cells in disease modelling and drug discovery. Nat Rev Genet 20:377–388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saeidnia S, Gohari AR, Manayi A (2016) Reverse pharmacognosy and reverse pharmacology; two closely related approaches for drug discovery development. Curr Pharm Biotechnol 17:1016–1022

    Article  CAS  PubMed  Google Scholar 

  • Saheli M, Sepantafar M, Pournasr B, Farzaneh Z, Vosough M, Piryaei A, Baharvand H (2018) Three-dimensional liver-derived extracellular matrix hydrogel promotes liver organoids function. J Cell Biochem 119:4320–4333

    Article  CAS  PubMed  Google Scholar 

  • Sampaolesi M, Blot S, D'antona G, Granger N, Tonlorenzi R, Innocenzi A, Mognol P, Thiibaud JL, Galvez BG, Barthelemy I, Perani L, Mantero S, Guttinger M, Pansarasa O, Rinaldi C, Cusella De Angelis MG, Torrente Y, Bordignon C, Bottinelli R, Cossu G (2006) Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs. Nature 444:574–579

    Article  CAS  PubMed  Google Scholar 

  • Samuel R. 40 Cycle PCR using human genomic DNA in less than 1 minute. Proceedings of microtas, 2016, Dublin, Theatr Irel

    Google Scholar 

  • Sato T, Clevers H (2013) Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications. Sciencei 340:1190–1194

    Article  CAS  Google Scholar 

  • Sato T, Vries RG, Snippert HJ, Van De Wetering M, Barker N, Stange DE, Van Es JH, Abo A, Kujala P, Peters PJ, Clevers H (2009) Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459:262–265

    Article  CAS  PubMed  Google Scholar 

  • Schuster TG, Cho B, Keller LM, Takayama S, Smith GD (2003) Isolation of motile spermatozoa from semen samples using microfluidics. Reprod Biomed Online 7:75–81

    Article  PubMed  Google Scholar 

  • Schwach V, Passier R (2016) Generation and purification of human stem cell-derived cardiomyocytes. Differentiation 91:126–138

    Article  CAS  PubMed  Google Scholar 

  • Schwamborn JC (2018) Is Parkinson’s disease a neurodevelopmental disorder and will brain organoids help us to understand it? Stem Cells Dev 27:968–975

    Article  PubMed  Google Scholar 

  • Scrivener E, Barry R, Platt A, Calvert R, Masih G, Hextall P, Soloviev M, Terrett J (2003) Peptidomics: a new approach to affinity protein microarrays. Proteomics 3:122–128

    Article  CAS  PubMed  Google Scholar 

  • Sendi H, Mead I, Wan M, Mehrab-Mohseni M, Koch K, Atala A, Bonkovsky HL, Bishop CE (2018) Mir-122 inhibition in a human liver organoid model leads to liver inflammation, necrosis, steatofibrosis and dysregulated insulin signaling. PLoS One 13:E0200847

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Skardal A, Murphy SV, Devarasetty M, Mead I, Kang HW, Seol YJ, Shrike Zhang Y, Shin SR, Zhao L, Aleman J, Hall AR, Shupe TD, Kleensang A, Dokmeci MR, Jin Lee S, Jackson JD, Yoo JJ, Hartung T, Khademhosseini A, Soker S, Bishop CE, Atala A (2017) Multi-tissue interactions in an integrated three-tissue organ-on-a-chip platform. Sci Rep 7:8837

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Soloviev M, Barry R, Scrivener E, Terrett J (2003) Combinatorial peptidomics: a generic approach for protein expression profiling. J Nanobiotechnol 1:4

    Article  Google Scholar 

  • Sonnen KF, Merten CA (2019) Microfluidics as an emerging precision tool in developmental biology. Dev Cell 48:293–311

    Article  CAS  PubMed  Google Scholar 

  • Sumi T, Tsuneyoshi N, Nakatsuji N, Suemori H (2008) Defining early lineage specification of human embryonic stem cells by the orchestrated balance of canonical WNT/beta-catenin, Activin/Nodal and BMP signaling. Development 135:2969–2979

    Article  CAS  PubMed  Google Scholar 

  • Sung NS, Crowley WF Jr, Genel M, Salber P, Sandy L, Sherwood LM, Johnson SB, Catanese V, Tilson H, Getz K, Larson EL, Scheinberg D, Reece EA, Slavkin H, Dobs A, Grebb J, Martinez RA, Korn A, Rimoin D (2003) Central challenges facing the national clinical research enterprise. JAMA 289:1278–1287

    Article  PubMed  Google Scholar 

  • Taapken SM, Nisler BS, Newton MA, Sampsell-Barron TL, Leonhard KA, Mcintire EM, Montgomery KD (2011) Karotypic abnormalities in human induced pluripotent stem cells and embryonic stem cells. Nat Biotechnol 29:313–314

    Article  CAS  PubMed  Google Scholar 

  • Taguchi A, Nishinakamura R (2017) Higher-order kidney organogenesis from pluripotent stem cells. Cell Stem Cell 21:730–746 E6

    Article  CAS  PubMed  Google Scholar 

  • Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676

    Article  CAS  PubMed  Google Scholar 

  • Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872

    Article  CAS  PubMed  Google Scholar 

  • Tan HY, Trier S, Rahbek UL, Dufva M, Kutter JP, Andresen TL (2018) A multi-chamber microfluidic intestinal barrier model using Caco-2 cells for drug transport studies. PLoS One 13:E0197101

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Teh SY, Lin R, Hung LH, Lee AP (2008) Droplet microfluidics. Lab Chip 8:198–220

    Article  CAS  PubMed  Google Scholar 

  • Themeli M, Kloss CC, Ciriello G, Fedorov VD, Perna F, Gonen M, Sadelain M (2013) Generation of tumor-targeted human t lymphocytes from induced pluripotent stem cells for cancer therapy. Nat Biotechnol 31:928–933

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147

    Article  CAS  PubMed  Google Scholar 

  • Tulloch NL, Muskheli V, Razumova MV, Korte FS, Regnier M, Hauch KD, Pabon L, Reinecke H, Murry CE (2011) Growth of engineered human myocardium with mechanical loading and vascular coculture. Circ Res 109:47–59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Turco MY, Gardner L, Kay RG, Hamilton RS, Prater M, Hollinshead MS, Mcwhinnie A, Esposito L, Fernando R, Skelton H, Reimann F, Gribble FM, Sharkey A, Marsh SGE, O'rahilly S, Hemberger M, Burton GJ, Moffett A (2018) Trophoblast organoids as a model for maternal-fetal interactions during human placentation. Nature 564:263–267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ugolini GS, Visone R, Cruz-Moreira D, Mainardi A, Rasponi M (2018) Generation of functional cardiac microtissues in a beating heart-on-a-chip. Methods Cell Biol 146:69–84

    Article  PubMed  Google Scholar 

  • Unger MA, Chou HP, Thorsen T, Scherer A, Quake SR (2000) Monolithic microfabricated valves and pumps by multilayer soft lithography. Science 288:113–116

    Article  CAS  PubMed  Google Scholar 

  • Uygun BE, Soto-Gutierrez A, Yagi H, Izamis ML, Guzzardi MA, Shulman C, Milwid J, Kobayashi N, Tilles A, Berthiaume F, Hertl M, Nahmias Y, Yarmush ML, Uygun K (2010) Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix. Nat Med 16:814–820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Villenave R, Wales SQ, Hamkins-Indik T, Papafragkou E, Weaver JC, Ferrante TC, Bahinski A, Elkins CA, Kulka M, Ingber DE (2017) Human gut-on-a-chip supports polarized infection of coxsackie B1 virus in vitro. PLoS One 12:E0169412

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Vriend J, Nieskens TTG, Vormann MK, Van Den Berge BT, Van Den Heuvel A, Russel FGM, Suter-Dick L, Lanz HL, Vulto P, Masereeuw R, Wilmer MJ (2018) Screening of drug-transporter interactions in A 3D microfluidic renal proximal tubule on a chip. AAPS J 20:87

    Article  PubMed  Google Scholar 

  • Vyas D, Baptista PM, Brovold M, Moran E, Gaston B, Booth C, Samuel M, Atala A, Soker S (2017) Self-assembled liver organoids recapitulate hepatobiliary organogenesis in vitro. Hepatology 67(2):750–761

    Article  CAS  Google Scholar 

  • Waheed S, Cabot JM, Macdonald NP, Lewis T, Guijt RM, Paull B, Breadmore MC (2016) 3D printed microfluidic devices: enablers and barriers. Lab Chip 16:1993–2013

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Vaidya B, Farquar HD, Stryjewski W, Hammer RP, Mccarley RL, Soper SA, Cheng YW, Barany F (2003) Microarrays assembled in microfluidic chips fabricated from poly(methyl methacrylate) for the detection of low-abundant DNA mutations. Anal Chem 75:1130–1140

    Article  CAS  PubMed  Google Scholar 

  • Wang W, Wang Y, Qu C, Wang S, Zhou J, Cao W, Xu L, Ma B, Hakim MS, Yin Y, Li T, Peppelenbosch MP, Zhao J, Pan Q (2018a) The RNA genome of hepatitis E virus robustly triggers an antiviral interferon response. Hepatology 67:2096–2112

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Wang H, Deng P, Chen W, Guo Y, Tao T, Qin J (2018b) In situ differentiation and generation of functional liver organoids from human iPSCS in a 3D perfusable chip system. Lab Chip 18:3606–3616

    Article  CAS  PubMed  Google Scholar 

  • Weber EJ, Lidberg KA, Wang L, Bammler TK, Macdonald JW, Li MJ, Redhair M, Atkins WM, Tran C, Hines KM, Herron J, Xu L, Monteiro MB, Ramm S, Vaidya V, Vaara M, Vaara T, Himmelfarb J, Kelly EJ (2018) Human kidney on a chip assessment of polymyxin antibiotic nephrotoxicity. JCI Insight 3, pii: 123673

    Google Scholar 

  • Wells MF, Salick MR, Wiskow O, Ho DJ, Worringer KA, Ihry RJ, Kommineni S, Bilican B, Klim JR, Hill EJ, Kane LT, Ye C, Kaykas A, Eggan K (2016) Genetic ablation of AXL does not protect human neural progenitor cells and cerebral organoids from Zika virus infection. Cell Stem Cell 19:703–708

    Article  CAS  PubMed  Google Scholar 

  • Whitesides GM (2006) The origins and the future of microfluidics. Nature 442:368–373

    Article  CAS  PubMed  Google Scholar 

  • Wimmer RA, Leopoldi A, Aichinger M, Wick N, Hantusch B, Novatchkova M, Taubenschmid J, Hammerle M, Esk C, Bagley JA, Lindenhofer D, Chen G, Boehm M, Agu CA, Yang F, Fu B, Zuber J, Knoblich JA, Kerjaschki D, Penninger JM (2019) Human blood vessel organoids as a model of diabetic vasculopathy. Nature 565:505–510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Workman MJ, Mahe MM, Trisno S, Poling HM, Watson CL, Sundaram N, Chang CF, Schiesser J, Aubert P, Stanley EG, Elefanty AG, Miyaoka Y, Mandegar MA, Conklin BR, Neunlist M, Brugmann SA, Helmrath MA, Wells JM (2017) Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous system. Nat Med 23:49–59

    Article  CAS  PubMed  Google Scholar 

  • Yan Y, Song L, Bejoy J, Zhao J, Kanekiyo T, Bu G, Zhou Y, Li Y (2018) Modeling neurodegenerative microenvironment using cortical organoids derived from human stem cells. Tissue Eng Part A 24:1125–1137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang X, Pabon L, Murry CE (2014) Engineering adolescence: maturation of human pluripotent stem cell-derived cardiomyocytes. Circ Res 114:511–523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang X, Li K, Zhang X, Liu C, Guo B, Wen W, Gao X (2018) Nanofiber membrane supported lung-on-a-chip microdevice for anti-cancer drug testing. Lab Chip 18:486–495

    Article  CAS  PubMed  Google Scholar 

  • Ye L, Wang J, Beyer AI, Teque F, Cradick TJ, Qi Z, Chang JC, Bao G, Muench MO, Yu J, Levy JA, Kan YW (2014) Seamless modification of wild-type induced pluripotent stem cells to the natural CCR5delta32 mutation confers resistance to HIV infection. Proc Natl Acad Sci U S A 111:9591–9596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yeager A (2018) As brain organoids mature, ethical questions arise. The Scientist. https://www.the-scientist.com/features/brain-organoids-mature%2D%2Draise-ethical-questions-64533

  • Yu W, Mackerell AD Jr (2017) Computer-aided drug design methods. Methods Mol Biol 1520:85–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin I, Thomson JA (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920

    Article  CAS  PubMed  Google Scholar 

  • Zakhariants AA, Burmistrova OA, Shkurnikov MY, Poloznikov AA, Sakharov DA (2016) Development of a specific substrate-inhibitor panel (liver-on-a-chip) for evaluation of cytochrome P450 activity. Bull Exp Biol Med 162:170–174

    Article  CAS  PubMed  Google Scholar 

  • Zhang N, Tan H, Yeung ES (1999) Automated and integrated system for high-throughput DNA genotyping directly from blood. Anal Chem 71:1138–1145

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, Grimley A, Bertram R, Roper MG (2010) Microfluidic system for generation of sinusoidal glucose waveforms for entrainment of islets of Langerhans. Anal Chem 82:6704–6711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou M, Zhang X, Wen X, Wu T, Wang W, Yang M, Wang J, Fang M, Lin B, Lin H (2016) Development of a functional glomerulus at the organ level on a chip to mimic hypertensive nephropathy. Sci Rep 6:31771

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu Z, Zhang W, Leng X, Zhang M, Guan Z, Lu J, Yang CJ (2012) Highly sensitive and quantitative detection of rare pathogens through agarose droplet microfluidic emulsion PCR at the single-cell level. Lab Chip 12:3907–3913

    Article  CAS  PubMed  Google Scholar 

  • Zhu W, Qu X, Zhu J, Ma X, Patel S, Liu J, Wang P, Lai CS, Gou M, Xu Y, Zhang K, Chen S (2017) Direct 3D bioprinting of prevascularized tissue constructs with complex microarchitecture. Biomaterials 124:106–115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by Erasmus plus consortium, SupBioEnt: Supporting biotechnology students oriented toward an entrepreneurial path (# 2017-1-RO01-KA203-037304). MS is supported by CARIPLO 2015_0634, FWO (G088715 N, G060612 N, G0A8813N) and C1-KUL 3DMUSYC (#C14/17/111) grants. R.D. is a recipient of Rondoufonds voor Duchenne Onderzoek grant (EQQ-FODUCH-O2010). Y.C.C. is a recipient of C1-KUL 3DMUSYC (#C14/17/111) grant.

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Authors and Affiliations

  1. Translational Cardiomyology Laboratory, Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, Leuven, Belgium

    Robin Duelen, Marlies Corvelyn, Ilaria Tortorella, Yoke Chin Chai & Maurilio Sampaolesi

  2. Department of Veterinary Medicine, University of Perugia, Perugia, Italy

    Leonardo Leonardi

  3. Department of Development and Regeneration, Stem Cell Institute Leuven, KU Leuven, Leuven, Belgium

    Yoke Chin Chai

  4. Human Anatomy Unit, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy

    Maurilio Sampaolesi

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  1. Robin Duelen
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  2. Marlies Corvelyn
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  3. Ilaria Tortorella
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  4. Leonardo Leonardi
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  5. Yoke Chin Chai
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  6. Maurilio Sampaolesi
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Correspondence to Maurilio Sampaolesi .

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Editors and Affiliations

  1. Faculty of Biotechnology, University of Agronomic Sciences and Veterinary Medicine, Bucharest, Romania

    Florentina Matei

  2. Department of Commerce, Economic Integration and Business Administration, Romanian-American University, Bucharest, Romania

    Daniela Zirra

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Duelen, R., Corvelyn, M., Tortorella, I., Leonardi, L., Chai, Y.C., Sampaolesi, M. (2019). Medicinal Biotechnology for Disease Modeling, Clinical Therapy, and Drug Discovery and Development. In: Matei, F., Zirra, D. (eds) Introduction to Biotech Entrepreneurship: From Idea to Business. Springer, Cham. https://doi.org/10.1007/978-3-030-22141-6_5

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