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Computational modeling for the optimization of a cardiogenic 3D bioprocess of encapsulated embryonic stem cells

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Abstract

We present a computational fluid dynamics (CFD)-based model aimed at the identification of optimized culture conditions promoting efficient cardiogenesis of hydrogel-bead-encapsulated embryonic stem cells (ESCs) within a rotating bioreactor. The numerical approach, integrating diffusion, convection, and multiphase fluid dynamics calculations, allowed to evaluate (i) the microgravity motion of the floating beads, (ii) the O2 delivery to the cells, also (iii) taking into account the cellular O2 consumption, as a function of different rotation speeds of the breeding chamber. According to our results, a 25 rpm rotation (i) enhances an adequate mixing of the cell carriers, avoiding sedimentation and excessive packing, also maintaining a quite homogeneous distribution of the suspended beads and (ii) imparts a proper cellular O2 supply, providing cells close to a normoxia condition. The bioreactor working conditions derived from the numerical analysis allowed the attainment of in vitro long-term cell viability maintenance, supporting efficient large-scale generation of ESC-derived cardiomyocytes (ESC-DCs) through a chemical-based conditioning bioprocess. In conclusion, we demonstrated the feasibility of using CFD-based tools, as a reliable and cost-effective strategy to assist the design of a 3D cardiogenic bioprocess.

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References

  • Akmal M, Anand A, Anand B, Wiseman M, Goodship AE, Bentley G (2006) The culture of articular chondrocytes in hydrogel constructs within a bioreactor enhances cell proliferation and matrix synthesis. J Bone Joint Surg Br 88(4): 544–553

    Article  Google Scholar 

  • Balakrishnan B, Jayakrishnan A (2005) Self-cross-linking biopolymers as injectable in situ forming biodegradable scaffolds. Biomaterials 26(18): 3941–3951

    Article  Google Scholar 

  • Bauwens C, Yin T, Dang S, Peerani R, Zandstra PW (2005) Development of a perfusion fed bioreactor for embryonic stem cell-derived cardiomyocyte generation: oxygen-mediated enhancement of cardiomyocyte output. Biotechnol Bioeng 20;90(4):452–461

    Google Scholar 

  • Cameron VA, Ellmers LJ (2003) Natriuretic peptides during development of the fetal heart and circulation. Endocrinology 144(6): 2191–2194

    Article  Google Scholar 

  • Carpenedo RL, Sargent CY, McDevitt TC (2007) Rotary suspension culture enhances the efficiency, yield, and homogeneity of embryoid body differentiation. Stem Cells 25(9): 2224–2234

    Article  Google Scholar 

  • Cochran DM, Fukumura D, Ancukiewicz M, Carmeliet P, Jain RK (2006) Evolution of oxygen and glucose concentration profiles in a tissue-mimetic culture system of embryonic stem cells. Ann Biomed Eng 34(8): 1247–1258

    Article  Google Scholar 

  • Consolo F, Fiore GB, Truscello S, Caronna M, Morbiducci U, Montevecchi FM, Redaelli A (2009) A computational model for the optimization of transport phenomena in a rotating hollow-fiber bioreactor for artificial liver. Tissue Eng Part C Methods 15(1): 41–55

    Article  Google Scholar 

  • Curcio E, Salerno S, Barbieri G, De Bartolo L, Drioli E, Bader A (2007) Mass transfer and metabolic reactions in hepatocyte spheroids cultured in rotating wall gas-permeable membrane system. Biomaterials 28: 5487–5497

    Article  Google Scholar 

  • Dang SM, Kyba M, Perlingeiro R, Daley GQ, Zandstra PW (2002) Efficiency of embryoid body formation and hematopoietic development from embryonic stem cells in different culture systems. Biotechnol Bioeng 78: 442–453

    Article  Google Scholar 

  • Drew DA, Lahey RT (1993) In particulate two-phase flow. Butterworth-Heinemann, Boston, pp 509–566

    Google Scholar 

  • Eckmann L, Freshney M, Wright EG, Sproul A, Wilkie N, Pragnell IB (1988) A novel in vitro assay for murine haematopoietic stem cells. Br J Cancer Suppl 9: 36–40

    Google Scholar 

  • Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292: 154–156

    Article  Google Scholar 

  • Filipczyk AA, Passier R, Rochat A, Mummery CL (2007) Regulation of cardiomyocyte differentiation of embryonic stem cells by extracellular signalling. Cell Mol Life Sci 64(6): 704–718

    Article  Google Scholar 

  • FLUENT User’s Guide Manual. ANSYS Inc., USA

  • Freed LE, Vunjak-Novakovic G (1997) Microgravity tissue engineering. In Vitro Cell Dev Biol Anim 33(5): 381–385

    Article  Google Scholar 

  • Galbusera F, Cioffi M, Raimondi MT, Pietrabissa R (2007) Computational modelling of combined cell population dynamics and oxygen transport in engineered tissue subject to interstitial perfusion. Comput Methods Biomech Biomed Eng 10: 279

    Article  Google Scholar 

  • Gerecht S, Burdick JA, Ferreira LS, Townsend SA, Langer R, Vunjak-Novakovic G (2007) Hyaluronic acid hydrogel for controlled self-renewal and differentiation of human embryonic stem cells. Proc Natl Acad Sci USA 104(27): 11298–11303

    Article  Google Scholar 

  • Gerecht-Nir S, Cohen S, Itskovitz-Eldor J (2004) Bioreactor cultivation enhances the efficiency of human embryoid body (hEB) formation and differentiation. Biotechnol Bioeng 86(5): 493–502

    Article  Google Scholar 

  • Horton RE, Millman JR, Colton CK, Auguste DT (2009) Engineering microenvironments for embryonic stem cell differentiation to cardiomyocytes. Regen Med 4(5): 721–732

    Article  Google Scholar 

  • Hwang YS, Randle WL, Bielby RC, Polak JM, Mantalaris A (2006) Enhanced derivation of osteogenic cells from murine embryonic stem cells after treatment with HepG2-conditioned medium and modulation of the embryoid body formation period: application to skeletal tissue engineering. Tissue Eng 12(6): 1381–1392

    Article  Google Scholar 

  • Hwang YS, Cho J, Tay F, Heng JY, Ho R, Kazarian SG, Williams DR, Boccaccini AR, Polak JM, Mantalaris A (2009) The use of murine embryonic stem cells, alginate encapsulation, and rotary microgravity bioreactor in bone tissue engineering. Biomaterials 30(4): 499–507

    Article  Google Scholar 

  • Kehat I, Kenyagin-Karsenti D, Snir M, Segev H, Amit M, Gepstein A et al (2001) Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest 108: 407–414

    Google Scholar 

  • Khaoustov VI, Darlington GJ, Soriano HE, Krishnan B, Risin D, Pellis NR, Yoffe B (1999) Induction of three-dimensional assembly of human liver cells by simulated microgravity. In Vitro Cell Dev Biol-Animal 35: 501–509

    Article  Google Scholar 

  • Kwon O, Devarakonda SB, Sankovic JM, Banerjee RK (2008) Oxygen transport and consumption by suspended cells in microgravity: a multiphase analysis. Biotech Bioeng 99(1): 99–107

    Article  Google Scholar 

  • Li CS, Wang L, Jiang H, Acevedo J, Chang AC, Loudon WG (2009) Stem cell engineering for treatment of heart diseases: potentials and challenges. Cell Biol Int 33: 255

    Article  Google Scholar 

  • Maltsev VA, Rohwedel J, Hescheler J, Wobus AM (1993) Embryonic stem cells differentiate in vitro into cardiomyocytes representing sinusnodal, atrial and ventricular cell types. Mech Dev 44: 41–50

    Article  Google Scholar 

  • Murry CE, Soonpaa MH, Reinecke H, Nakajima H, Nakajima HO, Rubart M, Pasumarthi KB, Virag JI, Bartelmez SH et al (2004) Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 428: 664–668

    Article  Google Scholar 

  • Niebruegge S, Nehring A, Bär H, Schroeder M, Zweigerdt R, Lehmann J (2008) Cardiomyocyte production in mass suspension culture: embryonic stem cells as a source for great amounts of functional cardiomyocytes. Tissue Eng Part A 14(10): 1591–1601

    Article  Google Scholar 

  • Niebruegge S, Bauwens CL, Peerani R, Thavandiran N, Masse S, Sevaptisidis E, Nanthakumar K, Woodhouse K, Husain M, Kumacheva E, Zandstra PW (2009) Generation of human embryonic stem cell-derived mesoderm and cardiac cells using size-specified aggregates in an oxygen-controlled bioreactor. Biotechnol Bioeng 1;102(2):493–507

    Google Scholar 

  • Pollack SR, Meaney DF, Levine EM, Litt M, Johnston ED (2000) Numerical model and experimental validation of microcarrier motion in a rotating bioreactor. Tissue Eng 6(5): 519–530

    Article  Google Scholar 

  • Raimondi MT, Boschetti F, Falcone L, Migliavacca F, Remuzzi A, Dubini G (2004) The effect of media perfusion on three-dimensional cultures of human chondrocytes: integration of experimental and computational approaches. Biorheology 41: 401

    Google Scholar 

  • Randle WL, Cha JM, Hwang YS, Chan KL, Kazarian SG, Polak JM, Mantalaris A. (2007) Integrated 3- dimensional expansion and osteogenic differentiation of murine embryonic stem cells. Tissue Eng 13(12): 2957–2970

    Article  Google Scholar 

  • Reiser PJ, Portman MA, Ning HH, Moravec CS (2001) Human cardiac myosin heavy chain isoforms in fetal and failing adult atria and ventricles. Am J Physiol Heart Circ Physiol 280: 1814–1820

    Google Scholar 

  • Rojas A, De Val S, Heidt AB, Xu SM, Bristow J, Black BL (2005) Gata4 expression in lateral mesoderm is downstream of BMP4 and is activated directly by Forkhead and GATA transcription factors through a distal enhancer element. Development 132(15): 3405

    Article  Google Scholar 

  • Rubart M, Field LJ (2006) Cardiac repair by embryonic stem-derived cells. Handb Exp Pharmacol 174: 73–100

    Article  Google Scholar 

  • Rungarunlert S, Techakumphu M, Pirity MK, Dinnyes A (2009) Embryoid body formation from embryonic and induced pluripotent stem cells: benefits of bioreactors. World J Stem Cells 31;1(1):11–21

    Google Scholar 

  • Sasaki D, Shimizu T, Masuda S, Kobayashi J, Itoga K, Tsuda Y, Yamashita JK, Yamato M, Okano T (2009) Mass preparation of size-controlled mouse embryonic stem cell aggregates and induction of cardiac differentiation by cell patterning method. Biomaterials 30(26): 4384–4389

    Article  Google Scholar 

  • Schiller L, Naumann Z (1935) A drag coefficient correlation. Ver Deutsch Ing, pp 77–318

  • Sengers BG, van Donkelaar CC, Oomens CW, Baaijens FP (2005) Computational study of culture conditions and nutrient supply in cartilage tissue engineering. Biotechnol Prog 21: 1252

    Article  Google Scholar 

  • Shi WJ, Wang H, Pan GJ, Geng YJ, Guo YQ, Pei DQ (2006) Regulation of the pluripotency marker Rex-1 by Nanog and Sox2. J Biol Chem 281(33): 23319–23325

    Article  Google Scholar 

  • Siti-Ismail N, Bishop AE, Polak JM, Mantalaris A (2008) The benefit of human embryonic stem cell encapsulation for prolonged feeder-free maintenance. Biomaterials 29(29): 3946–3952

    Article  Google Scholar 

  • Spaulding GF, Jessup JM, Goodwin TJ (1993) Advances in cellular construction. J Cell Biochem 51: 249

    Article  Google Scholar 

  • Wobus AM, Wallukat G, Hescheler J (1991) Pluripotent mouse embryonic stem cells are able to differentiate into cardiomyocytes expressing chronotropic responses to adrenergic and cholinergic agents and Ca2+ channel blockers. Differentiation 48: 173–182

    Article  Google Scholar 

  • Wolf DA, Schwarz RP (1992) Experimental measurement of the orbital paths of particles sedimenting within a rotating viscous fluid as influenced by gravity. NASA Technical Paper 3200

  • Yaniv YH (2009) Rheological Characterization of Alginate Microbead Gels and Suspensions. PhD dissertation thesis. North Carolina State University

  • Yirme G, Amit M, Laevsky I, Osenberg S, Itskovitz-Eldor J (2008) Establishing a dynamic process for the formation, propagation, and differentiation of human embryoid bodies. Stem Cells Dev 17: 1227–1242

    Article  Google Scholar 

  • Zhang F, Pasumarthi KB (2008) Embryonic stem cell transplantation: promise and progress in the treatment of heart disease. BioDrugs 22(6): 361–374

    Article  Google Scholar 

  • Zhang H, Williams-Dalson W, Keshavarz-Moore E, Shamlou PA (2005) Computational-fluid-dynamics (CFD) analysis of mixing and gas-liquid mass transfer in shake flasks. Biotechnol Appl Biochem 41(Pt 1): 1

    Google Scholar 

  • Zimmermann WH, Eschenhagen T (2007) Embryonic stem cells for cardiac muscle engineering. Trends Cardiovasc Med 17: 134–140

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Bioengineering, Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133, Milan, Italy

    F. Consolo & A. Redaelli

  2. Department of Mechanics, Politecnico di Torino, Corso Duca delgi Abruzzi 24, 10129, Turin, Italy

    C. Bariani, F. Montevecchi & U. Morbiducci

  3. Department of Chemical Engineering, Imperial College London, London, SW7 2AZ, UK

    A. Mantalaris

Authors
  1. F. Consolo
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  2. C. Bariani
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  3. A. Mantalaris
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  4. F. Montevecchi
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  5. A. Redaelli
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  6. U. Morbiducci
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Correspondence to F. Consolo.

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Consolo, F., Bariani, C., Mantalaris, A. et al. Computational modeling for the optimization of a cardiogenic 3D bioprocess of encapsulated embryonic stem cells. Biomech Model Mechanobiol 11, 261–277 (2012). https://doi.org/10.1007/s10237-011-0308-0

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  • DOI: https://doi.org/10.1007/s10237-011-0308-0

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