Research Update on Bioreactors Used in Tissue Engineering

doi:10.1007/s12204-021-2293-5

Abstract

Abstract: Owing to the paucity of donor organs and their acute rejection by the immune system after transplantation, advanced organ failure is one of the major challenges faced by the medical community. Static culturing used for synthesising tissues and organs cannot simulate the in vivo mechanical and biochemical signals; therefore, such artificial organs fail to maintain effective functional activity following transplantation. Tissue engineering can overcome these hurdles by successfully enabling regeneration of tissues and organs in vitro. Bioreactors are pivotal in the development and generation of engineered biological products. They simulate the in vivo microenvironment of tissue growth while also providing various mechanical stimuli and biochemical signals to stem cells to effectively generate transplantable organs or tissues. Various designs and types of bioreactors, their applications, and future research prospects are summarised, which promote functional tissue engineering.

Key words: bioreactor, organoid, stem cell, tissue engineering

摘要： Owing to the paucity of donor organs and their acute rejection by the immune system after transplantation, advanced organ failure is one of the major challenges faced by the medical community. Static culturing used for synthesising tissues and organs cannot simulate the in vivo mechanical and biochemical signals; therefore, such artificial organs fail to maintain effective functional activity following transplantation. Tissue engineering can overcome these hurdles by successfully enabling regeneration of tissues and organs in vitro. Bioreactors are pivotal in the development and generation of engineered biological products. They simulate the in vivo microenvironment of tissue growth while also providing various mechanical stimuli and biochemical signals to stem cells to effectively generate transplantable organs or tissues. Various designs and types of bioreactors, their applications, and future research prospects are summarised, which promote functional tissue engineering.

关键词: bioreactor, organoid, stem cell, tissue engineering

CLC Number:

R 318

WANG Wenhao, (王文豪), DENG Qian(邓迁), LI Tao (李涛), LIU Yuehua (刘月华), LIU Yang (刘洋), SUN Yeye (孙叶叶), DENG Changxu (邓昌旭), ZHOU Xiaojun (周小军), MA Zhenjiang (马振江), QIANG Lei (强磊), WANG Jinwu, (王金武), DAI Kerong, (戴尅戎). Research Update on Bioreactors Used in Tissue Engineering[J]. J Shanghai Jiaotong Univ Sci, 2021, 26(3): 272-283.

References 72

	[1]
	LANCASTER M A, KNOBLICH J A. Organogenesis in a dish: Modeling development and
	disease using organoid technologies [J]. Science, 2014, 345(6194): 1247125.
[2]	VAN
	DE WETERINGM, FRANCIES H E, FRANCIS J M, et al. Prospective derivation of a
	living organoid biobank of colorectal cancer patients [J]. Cell, 2015, 161(4):
93	3-945.
[3]	ZHAO
	J J, GRIFFIN M, CAI J, et al. Bioreactors for tissue engineering: An update
[J]	Biochemical Engineering Journal, 2016, 109: 268-281.
	[4]
	PEARCE D, FISCHER S, HUDA F, et al. Applications of computer modeling and
	simulation in cartilage tissue engineering [J]. Tissue Engineering and
	Regenerative Medicine, 2020, 17(1): 1-13.
	[5]
	MANDENIUS C F. Advances in micro-bioreactor design for organ cell studies [J].
	Bioengineering, 2018, 5(3): 64.
[6]	CHEN
	H Z, LI Z H. Bioreactor engineering [J]. Progress in Biotechnology, 1998,
18	(4): 46-49 (in Chinese).
	[7]
	PURNELL B A, LAVINE M. Approximating organs [J]. Science, 2019, 364(6444):
94	6-947. [8] TUVESON D, CLEVERS H. Cancer modeling meets human organoid
	technology [J]. Science, 2019, 364(6444): 952-955.
[9]	LI D
	Q, DAI K R. Application progress of the bioreactor in tissue engineering [J].
	International Journal of Orthopaedics, 2008, 29(1): 8-10 (in Chinese).
	[10]
	DING C M, QIAO Z G, JIANG W B, et al. Regeneration of a goat femoral head using
	a tissue-specific, biphasic scaffold fabricated with CAD/CAM technology [J].
	Biomaterials, 2013, 34(28): 6706-6716.
	[11]
	WEISS P, TAYLOR A C. Reconstitution of complete organs from single-cell
	suspensions of chick embryos in advanced stages of differentiation [J].
	Proceedings of the National Academy of Sciences of the United States of
	America, 1960, 46(9): 1177-1185.
	[12]
	MONTESANO R, SCHALLER G, ORCI L. Induction of epithelial tubular morphogenesis
	in vitro by fibroblast-derived soluble factors [J]. Cell, 1991, 66(4): 697-711.
	[13]
	CHOI H, SONG J, PARK G, et al. Modeling of autism using organoid technology
[J]	Molecular Neurobiology, 2017, 54(10): 7789-7795.
	[14]
	TAKEBE T, KOBAYASHI S, KAN H, et al. Human elastic cartilage engineering from
	cartilage progenitor cells using rotating wall vessel bioreactor [J].
	Transplantation Proceedings, 2012, 44(4): 1158-1161.
	[15]
	YOON H H, BHANG S H, SHIN J Y, et al. Enhanced cartilage formation via
	three-dimensional cell engineering of human adipose-derived stem cells [J].
	Tissue Engineering Part A, 2012, 18(19/20): 1949-1956.
[16]	LIU
	L Q, WU W, TUO X Y, et al. Novel strategy to engineer trachea cartilage graft
	with marrow mesenchymal stem cell macroaggregate and hydrolyzable scaffold [J].
	Artificial Organs, 2010, 34(5): 426-433.
	[17]
	SONG K D, YAN X Y, ZHANG Y, et al. Numberical simulation of fluid flow and
	three-dimensional expansion of tissue engineering seed cells in large scale
	inside a novel rotating wall hollow fiber membrane bioreactor [J]. Bioprocess
	and Biosystems Engineering, 2015, 38(8): 1527-1540.
	[18]
	XING H, LEE H, LUO L J, et al. Extracellular matrixderived biomaterials in
	engineering cell function [J]. Biotechnology Advances, 2020, 42: 107421.
[19]	LI
	K, ZHANG C, QIU L, et al. Advances in application of mechanical stimuli in
	bioreactors for cartilage tissue engineering [J]. Tissue Engineering Part B:
	Reviews, 2017, 23(4): 399-411. [20] P¨ORTNER R, NAGEL-HEYER S, GOEPFERT C, et al.
	Bioreactor design for tissue engineering [J]. Journal of Bioscience and
	Bioengineering, 2005, 100(3): 235- 245.
	[21]
	AHMED S, CHAUHAN V M, GHAEMMAGHAMI A M, et al. New generation of bioreactors
	that advance extracellular matrix modelling and tissue engineering [J].
	Biotechnology Letters, 2019, 41(1): 1-25.
	[22]
	BRUNNER M, FRICKE J, KROLL P, et al. Investigation of the interactions of
	critical scale-up parameters (pH, pO2 and pCO2) on CHO batch performance and
	critical quality attributes [J]. Bioprocess and Biosystems Engineering, 2017,
40	(2): 251-263.
	[23]
	ZHENG C, ZHUANG C, CHEN Y T, et al. Improved process robustness, product
	quality and biological efficacy of an anti-CD52 monoclonal antibody upon pH shift
	in Chinese hamster ovary cell perfusion culture [J]. Process Biochemistry,
20	18, 65: 123-129.
	[24]
	GRILO A L, MANTALARIS A. Apoptosis: A mammalian cell bioprocessing perspective
[J]	Biotechnology Advances, 2019, 37(3): 459-475.
	[25]
	NIENOW A W, SCOTT W H, HEWITT C J, et al. Scale-down studies for assessing the
	impact of different stress parameters on growth and product quality during
	animal cell culture [J]. Chemical Engineering Research and Design, 2013,
91	(11): 2265-2274.
[26]	LIU
	H J, MACQUEEN L A, USPRECH J F, et al. Microdevice arrays with strain sensors
	for 3D mechanical stimulation and monitoring of engineered tissues [J].
	Biomaterials, 2018, 172: 30-40.
[27]	LYNCH
	M E, FISCHBACH C. Biomechanical forces in the skeleton and their relevance to
	bone metastasis: Biology and engineering considerations [J]. Advanced Drug
	Delivery Reviews, 2014, 79/80: 119-134.
	[28]
	MAJMUNDAR A J, WONG W J, SIMON M C. Hypoxia-inducible factors and the response
	to hypoxic stress [J]. Molecular Cell, 2010, 40(2): 294-309.
	[29]
	SIEBER S, MICHAELIS M, G¨UHRING H, et al. Importance of osmolarity and oxygen
	tension for cartilage tissue engineering [J]. BioResearch Open Access, 2020, 9(1):
10	6-115. [30] LUSHCHAK V I, BAGNYUKOVA T V, HUSAK V V, et al. Hyperoxia results
	in transient oxidative stress and an adaptive response by antioxidant enzymes
	in goldfish tissues [J]. The International Journal of Biochemistry & Cell
	Biology, 2005, 37(8): 1670-1680.
	[31]
	SHAEGH S A M, DE FERRARI F, ZHANG Y S, et al. A microfluidic optical platform
	for real-time monitoring of pH and oxygen in microfluidic bioreactors and
	organ-on-chip devices [J]. Biomicrofluidics, 2016, 10(4): 044111.
	[32]
	GOMEZ N, WIECZOREK A, LU F, et al. Culture temperature modulates half antibody
	and aggregate formation in a Chinese hamster ovary cell line expressing a
	bispecific antibody [J]. Biotechnology and Bioengineering, 2018, 115(12):
29	30-2940.
[33]	LEE
	Y Y, WONG K T K, TAN J, et al. Overexpression of heat shock proteins (HSPs) in
	CHO cells for extended culture viability and improved recombinant protein
	production [J]. Journal of Biotechnology, 2009, 143(1): 34-43.
	[34]
	BEDOYA-L´OPEZ A, ESTRADA K, SANCHEZFLORES A, et al. Effect of temperature
	downshift on the transcriptomic responses of Chinese hamster ovary cells using
	recombinant human tissue plasminogen activator production culture [J]. PLoS
	One, 2016, 11(3): e0151529.
	[35]
	GOMEZ N, SUBRAMANIAN J, JUN O Y, et al. Culture temperature modulates
	aggregation of recombinant antibody in CHO cells [J]. Biotechnology and
	Bioengineering, 2012, 109(1): 125-136.
	[36]
	SWIDEREK H, AL-RUBEAI M. Functional genomewide analysis of antibody producing
	NS0 cell line cultivated at different temperatures [J]. Biotechnology and Bioengineering,
20	07, 98(3): 616-630.
	[37]
	MULUKUTLA B C, YONGKY A, LE T, et al. Regulation of glucose metabolism - A
	perspective from cell bioprocessing [J]. Trends in Biotechnology, 2016, 34(8):
63	8-651.
[38]	YUAN
	H X, XIONG Y, GUAN K L. Nutrient sensing, metabolism, and cell growth control
[J]	Molecular Cell, 2013, 49(3): 379-387.
[39]	GOSWAMI
	J, SINSKEY A J, STELLER H, et al. Apoptosis in batch cultures of Chinese
	Hamster Ovary cells [J]. Biotechnology and Bioengineering, 1999, 62(6):
63	2-640.
	[40]
	CABODEVILLA A G, S´ANCHEZ-CABALLERO L, NINTOU E, et al. Cell survival during
	complete nutrient deprivation depends on lipid droplet-fueled β- oxidation of
	fatty acids [J]. Journal of Biological Chemistry, 2013, 288(39): 27777-27788.
	[41]
	ZAGARI F, JORDAN M, STETTLER M, et al. Lactate metabolism shift in CHO cell
	culture: The role of mitochondrial oxidative activity [J]. New Biotechnology, 2013,
30	(2): 238-245. [42] REINHART D, DAMJANOVIC L, KAISERMAYER C, et al. Benchmarking
	of commercially available CHO cell culture media for antibody production [J].
	Applied Microbiology and Biotechnology, 2015, 99(11): 4645- 4657.
	[43]
	KISHISHITA S, KATAYAMA S, KODAIRA K, et al. Optimization of chemically defined
	feed media for monoclonal antibody production in Chinese hamster ovary cells
[J]	Journal of Bioscience and Bioengineering, 2015, 120(1): 78-84.
	[44]
	CHANG C H, LIN F H, LIN C C, et al. Cartilage tissue engineering on the surface
	of a novel gelatin-calciumphosphate biphasic scaffold in a double-chamber
	bioreactor [J]. Journal of Biomedical Materials Research Part B: Applied
	Biomaterials, 2004, 71B(2): 313-321.
	[45]
	VUKASOVIC A, ASNAGHIM A, KOSTESIC P, et al. Bioreactor-manufactured cartilage
	grafts repair acute and chronic osteochondral defects in large animal studies [J].
	Cell Proliferation, 2019, 52(6): e12653.
	[46]
	DURAINE G D, ATHANASIOU K A. ERK activation is required for hydrostatic
	pressure-induced tensile changes in engineered articular cartilage [J]. Journal
	of Tissue Engineering and Regenerative Medicine, 2015, 9(4): 368-374.
	[47]
	TOYODA T, SEEDHOM B B, YAO J Q, et al. Hydrostatic pressure modulates
	proteoglycan metabolism in chondrocytes seeded in agarose [J]. Arthritis & Rheumatism,
20	03, 48(10): 2865-2872.
	[48]
	CORREIA C, PEREIRA A L, DUARTE A R, et al. Dynamic culturing of cartilage
	tissue: The significance of hydrostatic pressure [J]. Tissue Engineering Part
	A, 2012, 18(19/20): 1979-1991.
	[49]
	CANDIANI G, RAIMONDI M T, AURORA R, et al. Chondrocyte response to high
	regimens of cyclic hydrostatic pressure in 3-dimensional engineered constructs [J].
	The International Journal of Artificial Organs, 2008, 31(6): 490-499.
[50]	ZHI
	W, ZHANG C, DUAN K, et al. A novel porous bioceramics scaffold by accumulating
	hydroxyapatite spherulites for large bone tissue engineering in vivo. II. Construct
	large volume of bone grafts [J]. Journal of Biomedical Materials Research Part
	A, 2014, 102(8): 2491-2501.
[51]	HAN
	D, DAI K R. Prefabrication of a vascularized bone graft with beta tricalcium
	phosphate using an in vivo bioreactor [J]. Artificial Organs, 2013, 37(10): 884-893.
[52]	REN
	L, YANG P F, WANG Z, et al. Biomechanical and biophysical environment of bone
	from the macroscopic to the pericellular and molecular level [J]. Journal of
	the Mechanical Behavior of Biomedical Materials, 2015, 50: 104-122.
[53]	LI
	D Q, TANG T T, LU J X, et al. Effects of flow shear stress and mass transport
	on the construction of a large-scale tissue-engineered bone in a perfusion
	bioreactor [J]. Tissue Engineering Part A, 2009, 15(10): 2773-2783.
	[54]
	MYGIND T, STIEHLER M, BAATRUP A, et al. Mesenchymal stem cell ingrowth and
	differentiation on coralline hydroxyapatite scaffolds [J]. Biomaterials, 2007,
28	(6): 1036-1047. [55] NOKHBATOLFOGHAHAEI H, BOHLOULI M, PAKNEJAD Z, et al.
	Bioreactor cultivation condition for engineered bone tissue: Effect of various
	bioreactor designs on extra cellular matrix synthesis [J]. Journal of
	Biomedical Materials Research Part A, 2020, 108(8): 1662-1672.
	[56]
	SONG L, ZHOU Q, DUAN P, et al. Successful development of small diameter
	tissue-engineering vascular vessels by our novel integrally designed pulsatile perfusion-based
	bioreactor [J]. PLoS One, 2012, 7(8): e42569.
	[57]
	WOLF F, ROJAS GONZ´ALEZ D M, STEINSEIFER U, et al. VascuTrainer: A mobile and
	disposable bioreactor system for the conditioning of tissue-engineered vascular
	grafts [J]. Annals of Biomedical Engineering, 2018, 46(4): 616-626.
	[58]
	C¸ELEBI-SALTIK B, ¨OTEYAKA M ¨ O, G¨OKC¸ INARYAGCI B. Stem cell-based
	small-diameter vascular grafts in dynamic culture [J]. Connective Tissue
	Research, 2021, 62(2): 151-163.
	[59]
	ALEKSIEVA G, HOLLWECK T, THIERFELDER N, et al. Use of a special bioreactor for
	the cultivation of a new flexible polyurethane scaffold for aortic valve tissue
	engineering [J]. BioMedical Engineering OnLine, 2012, 11: 92.
	[60]
	K¨ONIG F, HOLLWECK T, PFEIFER S, et al. A pulsatile bioreactor for conditioning
	of tissue-engineered cardiovascular constructs under endoscopic visualization [J].
	Journal of Functional Biomaterials, 2012, 3(3): 480-496.
	[61]
	VEDEPO M C, BUSE E E, PAUL A, et al. Nonphysiologic bioreactor processing
	conditions for heart valve tissue engineering [J]. Cardiovascular Engineering and
	Technology, 2019, 10(4): 628-637.
	[62]
	CONVERSE G L, BUSE E E, NEILL K R, et al. Design and efficacy of a single-use
	bioreactor for heart valve tissue engineering [J]. Journal of Biomedical
	Materials Research Part B: Applied Biomaterials, 2017, 105(2): 249-259.
	[63]
	LADD M R, LEE S J, ATALA A, et al. Bioreactor maintained living skin matrix
[J]	Tissue Engineering Part A, 2009, 15(4): 861-868.
[64]	HUH
	M I, AN S H, KIM H G, et al. Rapid expansion and auto-grafting efficiency of
	porcine full skin expanded by a skin bioreactor ex vivo [J]. Tissue Engineering
	and Regenerative Medicine, 2016, 13(1): 31- 38.
	[65]
	JEONG C, CHUNG H Y, LIM H J, et al. Applicability and safety of in vitro skin
	expansion using a skin bioreactor: A clinical trial [J]. Archives of Plastic
	Surgery, 2014, 41(6): 661-667. [66] KAPPOS E A, ENGELS P E, TREMP M, et al. Peripheral
	nerve repair: Multimodal comparison of the long-term regenerative potential of
	adipose tissuederived cells in a biodegradable conduit [J]. Stem Cells and
	Development, 2015, 24(18): 2127-2141.
[67]	SUN
	T, NORTON D, VICKERS N, et al. Development of a bioreactor for evaluating novel
	nerve conduits [J]. Biotechnology and Bioengineering, 2008, 99(5): 1250- 1260.
	[68]
	VADIVELU R K, KAMBLE H, MUNAZ A, et al. Liquid marbles as bioreactors for the
	study of threedimensional cell interactions [J]. Biomedical Microdevices, 2017,
19	(2): 31.
	[69]
	SUHAR R A, MARQUARDT L M, SONG S, et al. Elastin-like proteins to support
	peripheral nerve regeneration in guidance conduits [J]. ACS Biomaterials
	Science & Engineering, 2020. https: //doi.org/10.1021/acsbiomaterials.0c01053
	(published online).
	[70]
	WANG T W, WU H C, WANG H Y, et al. Regulation of adult human mesenchymal stem
	cells into osteogenic and chondrogenic lineages by different bioreactor systems
[J]	Journal of Biomedical Materials Research Part A, 2009, 88A(4): 935-946.
	[71]
	BANCROFT G N, SIKAVITSAS V I, VAN DEN DOLDER J, et al. Fluid flow increases
	mineralized matrix deposition in 3D perfusion culture of marrow stromal
	osteoblasts in a dose-dependent manner [J]. PNAS, 2002, 99(20): 12600-12605.
[72]	COUET F, MANTOVANI D. A new bioreactor
	adapts to materials state and builds a growth model for vascular tissue
	engineering [J]. Artificial Organs, 2012, 36(4): 438-445.