A Stem Cell and Tissue Engineering Perspective on Microfluidic Chips

Yıl 2024, Cilt: 27 Sayı: 2, 429 - 433, 27.03.2024

Gülşah Torkay , Ayça Bal Öztürk

https://doi.org/10.2339/politeknik.1094010

Cited By: 2

Öz

Microfluidic systems, which can be easily modified and integrated into many studies, have been the focus of attention of researchers in recent years. Thanks to microfluidic chips, controlled and optimized cell culture studies can be performed with less solution and continuous perfusion. In recent years, culturing the stem cells which has attracted the attention of regenerative medicine, alone or together with other cells and differentiating these cells in the desired direction, are frequently studied in chip systems. Adding hydrogels or decellularized organ matrices to these systems that will mimic the intercellular environment conditions gives results closer to in vivo. There are many studies showing that all the behaviors of the stem cells, including the differentiation, change considerably due to the material from which the chips are produced, the surface modifications, the flow rate, the medium content, the mechano-chemical properties of the hydrogels used, and electrical, chemical or mechanical stimulations. It is predicted that microfluidic chip systems will add a new dimension to personalized medicine, drug toxicity experiments, point-of-care rapid diagnostic kits, and many basic science researches in the future, and will be one of the more reliable and inexpensive potential methods, especially by replacing animal experiments. All these reasons make chip systems the focus of research. In this study; The fabrication, advantages, disadvantages, and applications of microfluidic chip systems in tissue engineering are discussed.

Anahtar Kelimeler

microfluidic systems, lab-on-chip, organ-on-chip, tissue engineering, stem cell

Mikroakışkan Çiplere Kök Hücre ve Doku Mühendisliği Perspektifinden Bakış

Öz

Kolayca modifiye edilebilir ve pek çok çalışmaya entegre edilebilir özellikleriyle mikroakışkan sistemler son yıllarda araştırmacıların ilgi odağındadır. Mikroakışkan çipler sayesinde daha az solüsyon ve sürekli perfüzyon ile kontrollü ve optimize hücre kültürü çalışmaları yapılabilmektedir. Son yıllarda özellikle rejeneratif tıbbın ilgisini çeken kök hücrelerin tek başına veya diğer hücrelerle birlikte kültürlenmesi ve kullanılan kök hücrelerin istenilen yönde farklılaştırılması çip sistemlerinde sıklıkla çalışılmaktadır. Bu sistemlere hücreler arası ortam koşullarını taklit edecek hidrojellerin veya hücrelerinden arındırılmış organ matrislerinin de ilave edilmesi in vivo'ya daha yakın sonuçlar vermektedir. Çiplerin üretildiği malzeme, yüzey modifikasyonları, akış hızı, besi yeri içeriği, kullanılan hidrojellerin mekano-kimyasal özellikleri, elektriksel, kimyasal ya da mekanik uyarımlar neticesinde kök hücrelerin farklılaşmaları da dahil tüm davranışlarının oldukça değiştiğini gösteren birçok çalışma mevcuttur. Mikroakışkan çip sistemlerinin ilerleyen zamanlarda kişiselleştirilmiş tıp, ilaç toksisite deneyleri, hasta-yanı hızlı tanı kitleri ve birçok temel bilim araştırmasına yeni bir boyut kazandıracağı, özellikle hayvan deneylerinin yerini alarak daha güvenilir ve ucuz potansiyel yöntemlerin başında geleceği öngörülmektedir. Tüm bu sebepler çip sistemlerini araştırma odağı yapmaktadır. Bu çalışmada; mikroakışkan çip sistemlerinin üretimi, avantajları, dezavantajları ve doku mühendisliği alanındaki uygulamaları tartışılmıştır.

Anahtar Kelimeler

mikroakışkan sistemler, çip-üstü-lab, çip-üstü-organ, doku mühendisliği, kök hücre

Kaynakça

• [1] Terry S.C., Jerman J.H. and Angell J.B., "A gas chromatographic air analyzer fabricated on a silicon wafer." IEEE transactions on electron devices, 26.12, (1979).
• [2] Buhlmann C., Preckel T., Chan S., Luedke G. and Valer, M., “A new tool for routine testing of cellular protein expression: integration of cell staining and analysis of protein expression on a microfluidic chip-based system”, Journal of biomolecular techniques: JBT, 14.2:119, (2003).
• [3] Shen S., Tian C., Li T., Xu J., Chen S. W., Tu Q., Wang, J. et al., “Spiral microchannel with ordered micro-obstacles for continuous and highly-efficient particle separation” Lab on a Chip, 17:21 3578-3591, (2017).
• [4] Yin B. F., Wan X. H., Yang M. Z., Qian C. C. and Sohan A. S. M., “Wave-shaped microfluidic chip assisted point-of-care testing for accurate and rapid diagnosis of infections” Military Medical Research, 9:1 1-13, (2022).
• [5] Hu B., Li J., Mou L., Liu Y., Deng J., Qian W., Jiang X. et al., “An automated and portable microfluidic chemiluminescence immunoassay for quantitative detection of biomarkers”, Lab on a Chip, 17.13: 2225-2234, (2017).
• [6] Sista R., Hua Z., Thwar P., Sudarsan A., Srinivasan V., Eckhardt A., Pamula V., et al., “Development of a digital microfluidic platform for point of care testing”, Lab on a Chip, 8:12 2091-2104, (2008).
• [7] Hong J. W., Chen Y., Anderson W. F. and Quake S. R. “Molecular biology on a microfluidic chip”, Journal of Physics: Condensed Matter, 18:18 S691, (2006).
• [8] Yin H., and Marshall D., “Microfluidics for single cell analysis”, Current opinion in biotechnology, 23:1 110-119, (2012).
• [9] Zhang J., Wei X., Zeng R., Xu F. and Li X., “Stem cell culture and differentiation in microfluidic devices toward organ-on-a-chip”, Future science OA, 3:2 FSO187, (2017).
• [10] Zhang Q., and Austin R. H., “Applications of microfluidics in stem cell biology”, BioNanoScience, 2:4 277-286, (2012).
• [11] Giulitti S., Pellegrini M., Zorzan I., Martini P., Gagliano O., Mutarelli M., Martello G. et al., “Direct generation of human naive induced pluripotent stem cells from somatic cells in microfluidics.” Nature cell biology, 21:2 275-286, (2019).
• [12] Zhong J. F., Chen Y., Marcus J. S., Scherer A., Quake S. R., Taylor C. R., and Weiner L. P., “A microfluidic processor for gene expression profiling of single human embryonic stem cells”, Lab on a Chip, 8:1 68-74, (2008).
• [13] Gagliano O., Elvassore N., and Luni C., “Microfluidic technology enhances the potential of human pluripotent stem cells”, Biochemical and biophysical research communications, 473:3 683-687, (2016).
• [14] Kamei K. I., Guo S., Takahashi H., Gschweng E., Suh C., Wang X., Tseng H. R., et al., “An integrated microfluidic culture device for quantitative analysis of human embryonic stem cells”, Lab on a Chip, 9:4 555-563, (2009).
• [15] Hasani-Sadrabadi M. M., Hajrezaei S. P., Emami S. H., Bahlakeh G., Daneshmandi L., Dashtimoghadam E., Tayebi L., et al., “Enhanced osteogenic differentiation of stem cells via microfluidics synthesized nanoparticles”, Nanomedicine: Nanotechnology, Biology and Medicine, 11:7 1809-1819, (2015).
• [16] Cosson S. and Lutolf M. P., “Hydrogel microfluidics for the patterning of pluripotent stem cells”, Scientific reports, 4:1 1-6, (2014).
• [17] Saldin L. T., Cramer M. C., Velankar S. S., White L. J. and Badylak S. F., “Extracellular matrix hydrogels from decellularized tissues: Structure and function”, Acta biomaterialia, 49 1-15, (2017).
• [18] Miki T., Ring A. and Gerlach J., “Hepatic differentiation of human embryonic stem cells is promoted by three-dimensional dynamic perfusion culture conditions”, Tissue Engineering Part C: Methods, 17:5 557-568, (2011).
• [19] Coluccio M. L., Perozziello G., Malara N., Parrotta E., Zhang P., Gentile F., Di Fabrizio E. et al., “Microfluidic platforms for cell cultures and investigations”, Microelectronic Engineering, 208 14-28, (2019).
• [20] Manz A., Graber N., and Widmer H. M. “Miniaturized total chemical analysis systems: A novel concept for chemical sensing” Sensors and Actuators B: Chemical, 1:1, 244–248, (1990).
• [21] Dixit C. K., “Fundamentals of Fluidics”, Microfluidics for biologists Fundamentals and Applications, Springer, Berlin, Germany, (2016).
• [22] Solanki S. and Pandey C. M. “Biological Applications of Microfluidics System Microfluidics for biologists Fundamentals and Applications, Springer, Berlin, Germany, (2016).
• [23] Amirouche F., Zhou Y. and Johnson T. “Current micropump technologies and their biomedical applications”, Microsystem technologies, 15:5 647-666, (2009).
• [24] Douville N. J., Zamankhan P., Tung Y. C., Li R., Vaughan B. L., Tai C. F., Takayama S. et al., “Combination of fluid and solid mechanical stresses contribute to cell death and detachment in a microfluidic alveolar model”, Lab on a Chip, 11:4 609-619, (2011).
• [25] Park J. Y., Yoo S. J., Hwang C. M. and Lee S. H., “Simultaneous generation of chemical concentration and mechanical shear stress gradients using microfluidic osmotic flow comparable to interstitial flow”, Lab on a Chip, 9:15 2194-2202, (2009).
• [26] Ohtani-Kaneko R., Sato K., Tsutiya A., Nakagawa Y., Hashizume K. and Tazawa H., “Characterisation of human induced pluripotent stem cell-derived endothelial cells under shear stress using an easy-to-use microfluidic cell culture system”, Biomedical microdevices, 19:4 1-10, (2017).
• [27] Fair R. B., “Digital microfluidics: is a true lab-on-a-chip possible?”, Microfluidics and Nanofluidics, 3:3 245-281, (2007).
• [28] Dimov N., “Manufacturing Methods Overview for Rapid Prototyping” Microfluidics for biologists Fundamentals and Applications, Springer, Berlin, Germany, (2016).
• [29] Martinez-Duarte R. and Madou M., “SU-8 photolithography and its impact on microfluidics” Microfluidics and Nanofluidics Handbook Fabrication, Implementation, And Applications, CRC Press, (2010).
• [30] Tsao C. W., "Polymer microfluidics: Simple, low-cost fabrication process bridging academic lab research to commercialized production." Micromachines, 7:12 225, (2016).
• [31] Tsao C. W., and DeVoe D. L., “Bonding of thermoplastic polymer microfluidics” Microfluidics and nanofluidics, 6:1 1-16, (2009).
• [32] Sano E., Mori C., Matsuoka N., Ozaki Y., Yagi K., Wada A., Torisawa Y. S. et al., “Tetrafluoroethylene-propylene elastomer for fabrication of microfluidic organs-on-chips resistant to drug absorption” Micromachines, 10:11 793, (2019).
• [33] Domansky K., Sliz J. D., Wen N., Hinojosa C., Thompson G., Fraser J. P., Ingber D. E. et al., “SEBS elastomers for fabrication of microfluidic devices with reduced drug absorption by injection molding and extrusion” Microfluidics and Nanofluidics, 21:6 1-12, (2017).
• [34] Ren K., Zhou J. and Wu H., “Materials for microfluidic chip fabrication”, Accounts of chemical research, 46:11 2396-2406, (2013).
• [35] Niculescu A. G., Chircov C., Bîrcă A. C. and Grumezescu A. M., “Fabrication and applications of microfluidic devices: A review”, International Journal of Molecular Sciences, 22:4 2011, (2021).
• [36] Sia S. K. and Whitesides G. M., “Microfluidic devices fabricated in poly (dimethylsiloxane) for biological studies”, Electrophoresis, 24:21 3563-3576, (2003).
• [37] Yang Y., Kulangara K., Sia J., Wang L. and Leong K. W, “Engineering of a microfluidic cell culture platform embedded with nanoscale features”, Lab on a Chip, 11:9 1638-1646, (2011).
• [38] Yılmaz, H., Altın, Y., ve Bedeloğlu, A. "Grafen Takviyeli Epoksi Nanokompozitlerin Özelliklerinin İncelenmesi". Politeknik Dergisi, 24: 1719-1727, (2021)
• [39] Waldbaur A., Rapp H., Länge K. and Rapp B. E., “Let there be chip—towards rapid prototyping of microfluidic devices: one-step manufacturing processes”, Analytical Methods, 3:12 2681-2716, (2011).
• [40] Kosack C. S., Page A. L. and Klatser P. R., “A guide to aid the selection of diagnostic tests”, Bulletin of the World Health Organization, 95:9 639, (2017).
• [41] Tsutsui H. and Ho C. M., “Cell separation by non-inertial force fields in microfluidic systems”, Mechanics research communications, 36:1 92-103, (2009).
• [42] Chen P., Feng X., Du W. and Liu B. F., “Microfluidic chips for cell sorting”, Frontiers in Bioscience, 13 2464-2483, (2008).
• [43] Chen P., Chen C., Liu Y., Du W., Feng X. and Liu B. F., “Fully integrated nucleic acid pretreatment, amplification, and detection on a paper chip for identifying EGFR mutations in lung cancer cells”, Sensors and Actuators B: Chemical, 283 472-477, (2019).
• [44] Selimović Š., Kaji H., Bae H. and Khademhosseini A., “Microfluidic systems for controlling stem cell microenvironments”, Microfluidic Cell Culture Systems, William Andrew Publishing (Elsevier), USA, (2019).
• [45] Schilling E. A., Kamholz A. E. and Yager P., “Cell lysis and protein extraction in a microfluidic device with detection by a fluorogenic enzyme assay”, Analytical chemistry, 74:8 1798-1804, (2002).
• [46] Gervais L., De Rooij N. and Delamarche E., “Microfluidic chips for point‐of‐care immunodiagnostics”, Advanced materials, 23:24 H151-H176, (2011).
• [47] Bhagat A.A.S., Bow H., Hou H.W. et al., “Microfluidics for cell separation”, Medical & Biological Engineering & Computing, 48 999–1014, (2010).
• [48] Aghlmandi A., Nikshad A., Safaralizadeh R., Warkiani M. E., Aghebati-Maleki L. and Yousefi M., “Microfluidics as efficient technology for the isolation and characterization of stem cells”, EXCLI journal, 20 426, (2021).
• [49] Wang X., Chen S., Kong M., Wang Z., Costa K. D., Li R. A. and Sun D., “Enhanced cell sorting and manipulation with combined optical tweezer and microfluidic chip technologies”, Lab on a Chip, 11:21 3656-3662, (2011).
• [50] Okşak N. and Kuruca D. S. “Hematopoetik Kök Hücre İzolasyonunda Güncel Yöntemler”, Journal of Istanbul Faculty of Medicine, 9-10, (2021).
• [51] Bilitewski U., Genrich M., Kadow S. and Mersal G., “Biochemical analysis with microfluidic systems”, Analytical and bioanalytical chemistry, 377:3 556-569, (2003).
• [52] Vorwerk S., Ganter K., Cheng Y., Hoheisel J., Stähler P. F. and Beier M., “Microfluidic-based enzymatic on-chip labeling of miRNAs”, New biotechnology, 25:2-3 142-149, (2008).
• [53] Oblath E. A., Henley W. H., Alarie J. P. and Ramsey J. M., “A microfluidic chip integrating DNA extraction and real-time PCR for the detection of bacteria in saliva”, Lab on a Chip, 13:7 1325-1332, (2013).
• [54] Kashani S. Y., Moraveji M. K., Taghipoor M., Kowsari-Esfahan R., Hosseini A. A., Montazeri L., Bonakdar S. et al., “An integrated microfluidic device for stem cell differentiation based on cell- imprinted substrate designed for cartilage regeneration in a rabbit model”, Materials Science and Engineering: C, 121 111794, (2021).
• [55] Zhong J. F., Feng Y. and Taylor C. R., “Microfluidic devices for investigating stem cell gene regulation via single-cell analysis”, Current medicinal chemistry, 15:28 2897-2900, (2008).
• [56] Lecault V., VanInsberghe M., Sekulovic S., Knapp D. J., Wohrer S., Bowden W., Hansen C. L., et al., “High-throughput analysis of single hematopoietic stem cell proliferation in microfluidic cell culture arrays”, Nature methods, 8:7 581-586, (2011).
• [57] Glotzbach J. P., Januszyk M., Vial I. N., Wong V. W., Gelbard A., Kalisky T., Gurtner G. C. et al., “An information theoretic, microfluidic-based single cell analysis permits identification of subpopulations among putatively homogeneous stem cells”, PloS one, 6:6 e21211, (2011).
• [58] Zhou Y., Basu S., Laue E. and Seshia A. A., “Single cell studies of mouse embryonic stem cell (mESC) differentiation by electrical impedance measurements in a microfluidic device”, Biosensors and Bioelectronics, 81 249-258, (2016).
• [59] Ramme A. P., Koenig L., Hasenberg T., Schwenk C., Magauer C., Faust D., Dehne E. M., et al. “Autologous induced pluripotent stem cell-derived four-organ-chip”, Future science OA, 5:8 FSO413, (2019).
• [60] Yin F., Zhu Y., Zhang M., Yu H., Chen W. and Qin J. A, “3D human placenta-on-a-chip model to probe nanoparticle exposure at the placental barrier”, Toxicology in Vitro, 54 105-113, (2019).
• [61] Lee P. J., Hung P. J. and Lee L. P., “An artificial liver sinusoid with a microfluidic endothelial‐like barrier for primary hepatocyte culture”, Biotechnology and bioengineering, 97:5 1340-1346, (2007).
• [62] Gillette B. M., Parsa H. and Sia S. K., “Microfluidics for Engineering 3D Tissues and Cellular Microenvironments”, Microfluidic Cell Culture Systems, William Andrew Publishing (Elsevier), USA, (2013).
• [63] Sadeghi S. and Elitaş M., “A simple, bubble-free cell loading technique for culturing mammalian cells on lab-on-a-chip devices”, Sabanci University, (2017).
• [64] Xiao Y., Zhang B., Hsieh A., Thavandiran N., Martin C. and Radisic M., “Microfluidic Cell Culture Techniques”, Microfluidic Cell Culture Systems, William Andrew Publishing (Elsevier), USA, (2013).
• [65] Kim L., Toh Y. C., Voldman J. and Yu H., “A practical guide to microfluidic perfusion culture of adherent mammalian cells”, Lab on a Chip, 7:6 681-694, (2007).
• [66] Mora-Boza A., Castro L. M. M., Schneider R. S., Han W. M., García A. J., Vázquez-Lasa B. and San Román J., “Microfluidics generation of chitosan microgels containing glycerylphytate crosslinker for in situ human mesenchymal stem cells encapsulation”, Materials Science and Engineering: C, 120 111716, (2021).
• [67] Kanda P., Benavente-Babace A., Parent S., Connor M., Soucy N., Steeves A., Davis D. R., et al., “Deterministic paracrine repair of injured myocardium using microfluidic-based cocooning of heart explant-derived cells”, Biomaterials, 247 120010, (2020).
• [68] Tomasi R. F. X., Sart S., Champetier T. and Baroud C. N., “Individual control and Quantification of 3D spheroids in a high-density microfluidic droplet array” Cell reports, 31:8 107670, (2020).
• [69] Shin Y., Jeon J. S., Han S., Jung G. S., Shin S., Lee S. H., Chung S., et al., “In vitro 3D collective sprouting angiogenesis under orchestrated ANG-1 and VEGF gradients”, Lab on a chip, 11:13 2175-2181, (2011).
• [70] Lyu J., Chen L., Zhang J., Kang X., Wang Y., Wu W., Tang K., et al., “A microfluidics-derived growth factor gradient in a scaffold regulates stem cell activities for tendon-to-bone interface healing”, Biomaterials Science, 8:13 3649-3663, (2020).
• [71] Özdemir, A. O., Karataş, Ç. ve Yücesu, S., "Elyaf Konfigürasyonunun Termoplastik Kompozit Levhaların Mekanik Özelliklerine Etkisi", Politeknik Dergisi, 24: 599-607, (2021)
• [72] Chin C. D., Khanna K. and Sia S. K., “A microfabricated porous collagen-based scaffold as prototype for skin substitutes”, Biomedical microdevices, 10:3 459-467, (2008).
• [73] Sheth S., Stealey S., Morgan N. Y. and Zustiak S. P., “Microfluidic Chip Device for In Situ Mixing and Fabrication of Hydrogel Microspheres via Michael-Type Addition”, Langmuir, 37:40 11793-11803, (2021).
• [74] Zamora-Mora V., Velasco D., Hernández R., Mijangos C., and Kumacheva E., “Chitosan/agarose hydrogels: Cooperative properties and microfluidic preparation”, Carbohydrate polymers, 111 348-355, (2014).
• [75] Yoon S. H., Kim Y. K. and Mofrad M. R., “Mechanobiological Approaches for the Control of Cell Motility” Microfluidic Cell Culture Systems, William Andrew Publishing (Elsevier), USA, (2013).
• [76] Ridley A. J., Schwartz M. A., Burridge K., Firtel R. A., Ginsberg M. H., Borisy G., Horwitz A. R., et al., “Cell migration: integrating signals from front to back”, Science, 302:5651 1704-1709, (2003).
• [77] Yoon S. H., Kim Y. K., Han E. D., Seo Y. H., Kim B. H. and Mofrad M. R., “Passive control of cell locomotion using micropatterns: the effect of micropattern geometry on the migratory behavior of adherent cells”, Lab on a Chip, 12:13 2391-2402, (2012).
• [78] Chung B. G. and Choo J., “Microfluidic gradient platforms for controlling cellular behavior”, Electrophoresis, 31:18 3014-3027, (2010).
• [79] Van Norman G. A., “Limitations of animal studies for predicting toxicity in clinical trials: is it time to rethink our current approach?”, JACC: Basic to Translational Science, 4:7 845-854, (2019).
• [80] Dickson I., “Multispecies liver-on-a-chip for improved drug toxicity testing”, Nature Reviews Gastroenterology & Hepatology, 17:1 4-4, (2020).
• [81] Marx U., Andersson T. B., Bahinski A., Beilmann M., Beken S., Cassee F. R., Roth A., et al., “Biology-inspired microphysiological system approaches to solve the prediction dilemma of substance testing”, Altex, 33:3 272, (2016).
• [82] Mastikhina O., Moon B. U., Williams K., Hatkar R., Gustafson D., Mourad O., Nunes S. S., et al., “Human cardiac fibrosis-on-a-chip model recapitulates disease hallmarks and can serve as a platform for drug testing”, Biomaterials, 233 119741, (2020).
• [83] Ehrlich A., Duche D., Ouedraogo G. and Nahmias Y., “Challenges and opportunities in the design of liver-on-chip microdevices”, Annual review of biomedical engineering, 21 219-239, (2019).
• [84] Satoh W., Takahashi S., Sassa F., Fukuda J. and Suzuki H., “On-chip culturing of hepatocytes and monitoring their ammonia metabolism”, Lab on a Chip, 9:1 35-37, (2009).
• [85] Kang Y. B., Eo J., Bulutoglu B., Yarmush M. L. and Usta O. B., “Progressive hypoxia‐on‐a‐chip: An in vitro oxygen gradient model for capturing the effects of hypoxia on primary hepatocytes in health and disease”, Biotechnology and bioengineering, 117:3 763-775, (2020).
• [86] Danoy M., Poulain S., Jellali R., Gilard F., Kato S., Plessy C., Leclerc E., et al., “Integration of metabolomic and transcriptomic profiles of hiPSCs-derived hepatocytes in a microfluidic environment”, Biochemical Engineering Journal, 155 107490, (2020).
• [87] Kang Y. B., Sodunke T. R., Lamontagne J., Cirillo J., Rajiv C., Bouchard M. J. and Noh M., “Liver sinusoid on a chip: Long‐term layered co‐culture of primary rat hepatocytes and endothelial cells in microfluidic platforms”, Biotechnology and bioengineering, 112:12 2571-2582, (2015).
• [88] Lauschke V. M., Shafagh R. Z., Hendriks D. F. and Ingelman‐Sundberg M., “3D primary hepatocyte culture systems for analyses of liver diseases, drug metabolism, and toxicity: Emerging culture paradigms and applications”, Biotechnology journal, 14:7 1800347, (2019).
• [89] Ortega-Prieto A. M., Skelton J. K., Cherry C., Briones-Orta M. A., Hateley C. A. and Dorner M., “Liver-on-a-Chip Cultures of Primary Hepatocytes and Kupffer Cells for Hepatitis B Virus Infection”, MyJoVE Corporation, (2016).
• [90] Santiago P. A., de Campos Giordano R. and Suazo C. A. T., “Performance of a vortex flow bioreactor for cultivation of CHO-K1 cells on microcarriers”, Process Biochemistry, 46:1 35-45, (2011).
• [91] Park E. S., Brown A. C., DiFeo M. A., Barker T. H. and Lu H., “Continuously perfused, non-cross-contaminating microfluidic chamber array for studying cellular responses to orthogonal combinations of matrix and soluble signals” Lab on a Chip, 10:5 571-580, (2010).
• [92] Bircsak K. M., DeBiasio R., Miedel M., Alsebahi A., Reddinger R., Saleh A., Gough A. et al., “A 3D microfluidic liver model for high throughput compound toxicity screening in the OrganoPlate®” Toxicology, 450 152667, (2021).
• [93] Park E. S., Brown A. C., DiFeo M. A., Barker T. H. and Lu H., “Continuously perfused, non-cross-contaminating microfluidic chamber array for studying cellular responses to orthogonal combinations of matrix and soluble signals”, Lab on a Chip, 10:5 571-580, (2010).
• [94] Ezashi T., Das P. and Roberts R. M., “Low O2 tensions and the prevention of differentiation of hES cells”, Proceedings of the National Academy of Sciences, 102:13 4783-4788, (2005).
• [95] Samal J. R., Rangasami V. K., Samanta S., Varghese O. P. and Oommen O. P., “Discrepancies on the Role of Oxygen Gradient and Culture Condition on Mesenchymal Stem Cell Fate”, Advanced Healthcare Materials, 10:6 2002058, (2021).
• [96] Merkel T. C., Bondar V. I., Nagai K., Freeman B. D. and Pinnau I., “Gas sorption, diffusion, and permeation in poly (dimethylsiloxane)”, Journal of Polymer Science Part B: Polymer Physics, 38:3 415- 434, (2000).
• [97] Shiku H., Saito T., Wu C. C., Yasukawa T., Yokoo M., Abe H., Yamada H., et al., “Oxygen permeability of surface-modified poly (dimethylsiloxane) characterized by scanning electrochemical microscopy”, Chemistry letters, 35:2 234-235, (2006).
• [98] Jensen C. and Teng Y., “Is it time to start transitioning from 2D to 3D cell culture?”, Frontiers in Molecular Biosciences, 7 33, (2020).
• [99] Halldorsson S., Lucumi E., Gómez-Sjöberg R. and Fleming R. M., “Advantages and challenges of microfluidic cell culture in polydimethylsiloxane devices”, Biosensors and Bioelectronics, 63 218- 231, (2015).
• [100] Walker G. M., Zeringue H. C. and Beebe D. J., “Microenvironment design considerations for cellular scale studies”, Lab on a Chip, 4:2 91-97, (2004).
• [101] Paguirigan A. L. and Beebe D. J., “From the cellular perspective: exploring differences in the cellular baseline in macroscale and microfluidic cultures”, Integrative Biology, 1:2 182-195, (2009).
• [102] Wang D. Y., Wu S. C., Lin S. P., Hsiao S. H., Chung T. W. and Huang Y. Y., “Evaluation of transdifferentiation from mesenchymal stem cells to neuron-like cells using microfluidic patterned co- culture system”, Biomedical Microdevices, 13:3 517-526, (2011).
• [103] Berthier E., Young E. W. and Beebe D., “Engineers are from PDMS-land, Biologists are from Polystyrenia”, Lab on a Chip, 12:7 1224-1237, (2012).
• [104] Vogt L., Ruther F., Salehi S. and Boccaccini A. R., “Poly (Glycerol Sebacate) in Biomedical Applications—A Review of the Recent Literature”, Advanced Healthcare Materials, 10:9 2002026, (2021).
• [105] Wang Y., Ameer G. A., Sheppard B. J. and Langer R., “A tough biodegradable elastomer”, Nature biotechnology, 20:6 602-606, (2002).
• [106] Wang Y., Kim Y. M. and Langer R., “In vivo degradation characteristics of poly (glycerol sebacate)”, Journal of Biomedical Materials Research Part A: An Official Journal of The Society for Biomaterials, The Japanese Society for Biomaterials, and The Australian Society for Biomaterials and the Korean Society for Biomaterials, 66:1 192-197, (2003).
• [107] Bellan L. M., Chamberlain H., Wu D. and Langer R., “Microfluidic Vascular Networks for Engineered Tissues”, Microfluidic Cell Culture Systems, William Andrew Publishing (Elsevier), USA, (2013).
• [108] Olson H., Betton G., Robinson D., Thomas K., Monro A., Kolaja G., Heller A., et al., “Concordance of the toxicity of pharmaceuticals in humans and in animals”, Regulatory Toxicology and Pharmacology, 32:1 56-67, (2000).