Tunable Hydrogels pp 227-251 | Cite as
Gradient Hydrogels
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Abstract
Gradient hydrogels represent a pivotal and expanding direction of three-dimensional cell culture. Since various types of gradients play an important role in physiological and pathological processes in vivo, recreation of these gradients in vitro allows a better understanding of cellular behavior, intercellular and cell–matrix interactions. Moreover, gradient hydrogels can advance the creation of functionally improved and physiologically relevant tissue engineered constructs. Another application of gradient hydrogels is the optimization of the 3D in vitro microenvironment (e.g., in terms of hydrogel stiffness or concentration of adhesion ligands). Tunable hydrogels provide researchers with a versatile toolbox to manufacture such gradients in vitro. In this chapter different types of in vivo and in vitro gradients in hydrogels will be presented. Equipment and methods for various gradient fabrications will be discussed. Furthermore, methods of gradient characterizations in hydrogels will be reported. As one of the most recent developments, the influence of low oxygen concentration on cells, as well as the creation and characterization of oxygen gradients in hydrogels will be described. In the last part, achievements in the creation of multiple combinatorial gradients will be presented. The aim of this chapter is to give the reader an overview on existing techniques and biological importance of gradient hydrogels in basic science as well as in applied research.
Graphical Abstract
Keywords
Gradient hydrogel fabrication Gradient hydrogels Hydrogel characterization In vitro gradient systems In vivo gradients Oxygen gradients Stiffness gradientsNotes
Acknowledgements
This work was supported by the German Research Foundation (DFG Project 398007461 488 “3D Dual-Gradient Systems for Functional Cell Screening”).
References
- 1.Morgan TH (1901) Regeneration and liability to injury. Science 14(346):235–248PubMedGoogle Scholar
- 2.Wartlick O, Kicheva A, González-Gaitán M (2009) Morphogen gradient formation. Cold Spring Harb Perspect Biol 1(3):a001255PubMedPubMedCentralGoogle Scholar
- 3.Child C (1912) Studies on the dynamics of morphogenesis and inheritance in experimental reproduction. IV. Certain dynamic factors in the regulatory morphogenesis of Planaria dorotocephala in relation to the axial gradient. J Exp Zool 13(1):103–152Google Scholar
- 4.Fathollahipour S, Patil PS, Leipzig ND (2018) Oxygen regulation in development: lessons from embryogenesis towards tissue engineering. Cells Tissues Organs 205(5–6):350–371PubMedPubMedCentralGoogle Scholar
- 5.Xia T, Liu W, Yang L (2017) A review of gradient stiffness hydrogels used in tissue engineering and regenerative medicine. J Biomed Mater Res A 105(6):1799–1812PubMedGoogle Scholar
- 6.Wu J et al (2012) Gradient biomaterials and their influences on cell migration. Interf Focus 2(3):337–355Google Scholar
- 7.Laasanen MS et al (2003) Biomechanical properties of knee articular cartilage. Biorheology 40(1–3):133–140PubMedGoogle Scholar
- 8.Wang Y et al (2018) Bioengineered systems and designer matrices that recapitulate the intestinal stem cell niche. Cell Mol Gastroenterol Hepatol 5(3):440–453.e1PubMedPubMedCentralGoogle Scholar
- 9.Katz NR (1992) Metabolic heterogeneity of hepatocytes across the liver acinus. J Nutr 122(3 Suppl):843–849PubMedGoogle Scholar
- 10.Erickson K et al (2003) Effect of longitudinal oxygen gradients on effectiveness of manipulation of tumor oxygenation. Cancer Res 63(15):4705–4712PubMedGoogle Scholar
- 11.Dewhirst MW et al (1999) Quantification of longitudinal tissue pO2 gradients in window chamber tumours: impact on tumour hypoxia. Br J Cancer 79(11–12):1717–1722PubMedPubMedCentralGoogle Scholar
- 12.Remensnyder JP, Majno G (1968) Oxygen gradients in healing wounds. Am J Pathol 52(2):301–323PubMedPubMedCentralGoogle Scholar
- 13.Knighton DR, Silver IA, Hunt TK (1981) Regulation of wound-healing angiogenesis-effect of oxygen gradients and inspired oxygen concentration. Surgery 90(2):262–270PubMedGoogle Scholar
- 14.Cheema U et al (2008) Spatially defined oxygen gradients and vascular endothelial growth factor expression in an engineered 3D cell model. Cell Mol Life Sci 65(1):177–186PubMedGoogle Scholar
- 15.Radisic M et al (2006) Oxygen gradients correlate with cell density and cell viability in engineered cardiac tissue. Biotechnol Bioeng 93(2):332–343PubMedGoogle Scholar
- 16.Jing X et al (2019) Role of hypoxia in cancer therapy by regulating the tumor microenvironment. Mol Cancer 18(1):157PubMedPubMedCentralGoogle Scholar
- 17.Lewis DM et al (2016) Intratumoral oxygen gradients mediate sarcoma cell invasion. Proc Natl Acad Sci 113(33):9292–9297PubMedGoogle Scholar
- 18.Pedron S, Becka E, Harley BA (2015) Spatially gradated hydrogel platform as a 3D engineered tumor microenvironment. Adv Mater 27(9):1567–1572PubMedGoogle Scholar
- 19.Schreml S et al (2014) Luminescent dual sensors reveal extracellular pH-gradients and hypoxia on chronic wounds that disrupt epidermal repair. Theranostics 4(7):721PubMedPubMedCentralGoogle Scholar
- 20.Niethammer P et al (2009) A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish. Nature 459(7249):996–999PubMedPubMedCentralGoogle Scholar
- 21.Moeendarbary E et al (2017) The soft mechanical signature of glial scars in the central nervous system. Nat Commun 8(1):14787PubMedPubMedCentralGoogle Scholar
- 22.Seo J et al (2018) High-throughput approaches for screening and analysis of cell behaviors. Biomaterials 153:85–101PubMedGoogle Scholar
- 23.Smith Callahan LA (2018) Gradient material strategies for hydrogel optimization in tissue engineering applications. High-throughput 7(1):1PubMedCentralGoogle Scholar
- 24.Wong JY et al (2003) Directed movement of vascular smooth muscle cells on gradient-compliant hydrogels. Langmuir 19(5):1908–1913Google Scholar
- 25.Lavrentieva A et al (2020) Fabrication of stiffness gradients of GelMA hydrogels using a 3D printed micromixer. Macromol Biosci 20(7):2000107Google Scholar
- 26.Selimovic S et al (2011) Generating nonlinear concentration gradients in microfluidic devices for cell studies. Anal Chem 83(6):2020–2028PubMedPubMedCentralGoogle Scholar
- 27.Hadden WJ et al (2017) Stem cell migration and mechanotransduction on linear stiffness gradient hydrogels. Proc Natl Acad Sci 114(22):5647–5652PubMedGoogle Scholar
- 28.Liu Z et al (2012) Covalently immobilized biomolecule gradient on hydrogel surface using a gradient generating microfluidic device for a quantitative mesenchymal stem cell study. Biomicrofluidics 6(2):024111PubMedCentralGoogle Scholar
- 29.Sant S et al (2010) Biomimetic gradient hydrogels for tissue engineering. Can J Chem Eng 88(6):899–911PubMedPubMedCentralGoogle Scholar
- 30.He J et al (2010) Rapid generation of biologically relevant hydrogels containing long-range chemical gradients. Adv Funct Mater 20(1):131–137PubMedPubMedCentralGoogle Scholar
- 31.Lee D et al (2019) Fabrication of hydrogels with a stiffness gradient using limited mixing in the hele-Shaw geometry. Exp Mech 59(9):1249–1259Google Scholar
- 32.Zinkovska N, Smilek J, Pekar M (2020) Gradient hydrogels—the state of the art in preparation methods. Polymers 12(4):966PubMedCentralGoogle Scholar
- 33.Jeon NL et al (2000) Generation of solution and surface gradients using microfluidic systems. Langmuir 16(22):8311–8316Google Scholar
- 34.Du Y et al (2010) Convection-driven generation of long-range material gradients. Biomaterials 31(9):2686–2694PubMedGoogle Scholar
- 35.Song F et al (2015) Nanocomposite hydrogels and their applications in drug delivery and tissue engineering. J Biomed Nanotechnol 11(1):40–52PubMedGoogle Scholar
- 36.Gadjanski I (2017) Recent advances on gradient hydrogels in biomimetic cartilage tissue engineering. F1000 Res 6Google Scholar
- 37.Oh SH et al (2016) Wide-range stiffness gradient PVA/HA hydrogel to investigate stem cell differentiation behavior. Acta Biomater 35:23–31PubMedGoogle Scholar
- 38.Ko H et al (2019) A simple layer-stacking technique to generate biomolecular and mechanical gradients in photocrosslinkable hydrogels. Biofabrication 11(2):025014PubMedPubMedCentralGoogle Scholar
- 39.Foxman EF, Kunkel EJ, Butcher EC (1999) Integrating conflicting chemotactic signals: the role of memory in leukocyte navigation. J Cell Biol 147(3):577–588PubMedPubMedCentralGoogle Scholar
- 40.Lo C-M et al (2000) Cell movement is guided by the rigidity of the substrate. Biophys J 79(1):144–152PubMedPubMedCentralGoogle Scholar
- 41.Piraino F et al (2012) Multi-gradient hydrogels produced layer by layer with capillary flow and crosslinking in open microchannels. Lab Chip 12(3):659–661PubMedGoogle Scholar
- 42.Jeon O et al (2013) Biochemical and physical signal gradients in hydrogels to control stem cell behavior. Adv Mater 25(44):6366–6372PubMedPubMedCentralGoogle Scholar
- 43.Bailey BM, Nail LN, Grunlan MA (2013) Continuous gradient scaffolds for rapid screening of cell–material interactions and interfacial tissue regeneration. Acta Biomater 9(9):8254–8261PubMedPubMedCentralGoogle Scholar
- 44.Hu C et al (2017) Microfluidic platforms for gradient generation and its applications. Biochem Anal Biochem 6(320):2161Google Scholar
- 45.Burdick JA, Khademhosseini A, Langer R (2004) Fabrication of gradient hydrogels using a microfluidics/photopolymerization process. Langmuir 20(13):5153–5156PubMedGoogle Scholar
- 46.Loessberg-Zahl J et al (2019) Flow focusing through gels as a tool to generate 3D concentration profiles in hydrogel-filled microfluidic chips. Lab Chip 19(2):206–213PubMedGoogle Scholar
- 47.Yamada M et al (2006) A microfluidic flow distributor generating stepwise concentrations for high-throughput biochemical processing. Lab Chip 6(2):179–184PubMedGoogle Scholar
- 48.Idaszek J et al (2019) 3D bioprinting of hydrogel constructs with cell and material gradients for the regeneration of full-thickness chondral defect using a microfluidic printing head. Biofabrication 11(4):044101PubMedGoogle Scholar
- 49.Motealleh A et al (2019) 3D printing of step-gradient nanocomposite hydrogels for controlled cell migration. Biofabrication 11(4):045015PubMedGoogle Scholar
- 50.Sun Y et al (2020) 3D bioprinting dual-factor releasing and gradient-structured constructs ready to implant for anisotropic cartilage regeneration. Sci Adv 6(37):eaay1422PubMedGoogle Scholar
- 51.Tse J, Engler A (2011) Stiffness gradients mimicking. VivoGoogle Scholar
- 52.Marklein RA, Burdick JA (2010) Spatially controlled hydrogel mechanics to modulate stem cell interactions. Soft Matter 6(1):136–143Google Scholar
- 53.Sunyer R et al (2012) Fabrication of hydrogels with steep stiffness gradients for studying cell mechanical response. PLoS One 7(10):e46107PubMedPubMedCentralGoogle Scholar
- 54.Norris SC, Tseng P, Kasko AM (2016) Direct gradient photolithography of photodegradable hydrogels with patterned stiffness control with submicrometer resolution. ACS Biomater Sci Eng 2(8):1309–1318PubMedGoogle Scholar
- 55.Zaari N et al (2004) Photopolymerization in microfluidic gradient generators: microscale control of substrate compliance to manipulate cell response. Adv Mater 16(23–24):2133–2137Google Scholar
- 56.Zhu D et al (2018) Mimicking cartilage tissue zonal organization by engineering tissue-scale gradient hydrogels as 3D cell niche. Tissue Eng A 24(1–2):1–10Google Scholar
- 57.Garcia S et al (2015) Generation of stable orthogonal gradients of chemical concentration and substrate stiffness in a microfluidic device. Lab Chip 15(12):2606–2614PubMedGoogle Scholar
- 58.Wang W et al (2018) A microfluidic hydrogel chip with orthogonal dual gradients of matrix stiffness and oxygen for cytotoxicity test. Biochip J 12(2):93–101Google Scholar
- 59.Iturri J, Toca-Herrera JL (2017) Characterization of cell scaffolds by atomic force microscopy. Polymers 9(8):383PubMedCentralGoogle Scholar
- 60.Ruedinger F et al (2015) Hydrogels for 3D mammalian cell culture: a starting guide for laboratory practice. Appl Microbiol Biotechnol 99(2):623–636PubMedGoogle Scholar
- 61.Deng CX, Hong X, Stegemann JP (2016) Ultrasound imaging techniques for spatiotemporal characterization of composition, microstructure, and mechanical properties in tissue engineering. Tissue Eng Part B Rev 22(4):311–321PubMedPubMedCentralGoogle Scholar
- 62.Kennedy KM et al (2015) Quantitative micro-elastography: imaging of tissue elasticity using compression optical coherence elastography. Sci Rep 5:15538PubMedPubMedCentralGoogle Scholar
- 63.Schmitz C et al (2020) Live reporting for hypoxia: hypoxia sensor–modified mesenchymal stem cells as in vitro reporters. Biotechnol Bioeng 117:3265PubMedGoogle Scholar
- 64.Rosales AM et al (2017) Hydrogels with reversible mechanics to probe dynamic cell microenvironments. Angew Chem Int Ed 56(40):12132–12136Google Scholar
- 65.Chen Y et al (2017) Receptor-mediated cell mechanosensing. Mol Biol Cell 28(23):3134–3155PubMedPubMedCentralGoogle Scholar
- 66.Cross LM et al (2018) Gradient nanocomposite hydrogels for interface tissue engineering. Nanomedicine 14(7):2465–2474PubMedGoogle Scholar
- 67.Pedron S et al (2017) Spatially graded hydrogels for preclinical testing of glioblastoma anticancer therapeutics. MRS Commun 7(3):442–449PubMedPubMedCentralGoogle Scholar
- 68.Rape AD et al (2015) A synthetic hydrogel for the high-throughput study of cell–ECM interactions. Nat Commun 6(1):1–9Google Scholar
- 69.Zhang Y et al (2017) Influence of stage cooling method on pore architecture of biomimetic alginate scaffolds. Sci Rep 7(1):1–8Google Scholar
- 70.Orsi S, Guarnieri D, Netti PA (2010) Design of novel 3D gene activated PEG scaffolds with ordered pore structure. J Mater Sci Mater Med 21(3):1013–1020PubMedGoogle Scholar
- 71.Yin Q et al (2020) Bio-inspired design of reinforced gradient hydrogels with rapid water-triggered shape memory performance. ACS Appl Polym MaterGoogle Scholar
- 72.Chen CS et al (1997) Geometric control of cell life and death. Science 276(5317):1425–1428PubMedGoogle Scholar
- 73.Hogrebe NJ, Reinhardt JW, Gooch KJ (2017) Biomaterial microarchitecture: a potent regulator of individual cell behavior and multicellular organization. J Biomed Mater Res A 105(2):640–661PubMedGoogle Scholar
- 74.Xi W et al (2019) Material approaches to active tissue mechanics. Nat Rev Mater 4(1):23–44Google Scholar
- 75.Scarpa E et al (2013) A novel method to study contact inhibition of locomotion using micropatterned substrates. Biol Open 2(9):901–906PubMedPubMedCentralGoogle Scholar
- 76.Stoecklin C et al (2018) A new approach to design artificial 3D microniches with combined chemical, topographical, and rheological cues. Adv Biosyst 2(7):1700237Google Scholar
- 77.Zou J et al (2019) Highly efficient and environmentally friendly fabrication of robust, programmable, and biocompatible anisotropic, all-cellulose, wrinkle-patterned hydrogels for cell alignment. Adv Mater 31(46):1904762Google Scholar
- 78.Nerger BA, Brun P-T, Nelson CM (2020) Marangoni flows drive the alignment of fibrillar cell-laden hydrogels. Sci Adv 6(24):eaaz7748PubMedPubMedCentralGoogle Scholar
- 79.Eng G et al (2013) Assembly of complex cell microenvironments using geometrically docked hydrogel shapes. Proc Natl Acad Sci 110(12):4551–4556PubMedGoogle Scholar
- 80.Trkov S et al (2010) Micropatterned three-dimensional hydrogel system to study human endothelial–mesenchymal stem cell interactions. J Tissue Eng Regen Med 4(3):205–215PubMedPubMedCentralGoogle Scholar
- 81.Wang X et al (2009) Growth factor gradients via microsphere delivery in biopolymer scaffolds for osteochondral tissue engineering. J Control Release 134(2):81–90PubMedGoogle Scholar
- 82.O'Grady B et al (2019) Spatiotemporal control and modeling of morphogen delivery to induce gradient patterning of stem cell differentiation using fluidic channels. Biomater Sci 7(4):1358–1371PubMedPubMedCentralGoogle Scholar
- 83.Ahadian S et al (2015) Bioconjugated hydrogels for tissue engineering and regenerative medicine. Bioconjug Chem 26(10):1984–2001PubMedGoogle Scholar
- 84.DeLong SA, Moon JJ, West JL (2005) Covalently immobilized gradients of bFGF on hydrogel scaffolds for directed cell migration. Biomaterials 26(16):3227–3234PubMedGoogle Scholar
- 85.Kapur TA, Shoichet MS (2004) Immobilized concentration gradients of nerve growth factor guide neurite outgrowth. J Biomed Mater Res A 68(2):235–243PubMedGoogle Scholar
- 86.DeLong SA, Gobin AS, West JL (2005) Covalent immobilization of RGDS on hydrogel surfaces to direct cell alignment and migration. J Control Release 109(1–3):139–148PubMedGoogle Scholar
- 87.Metzger S et al (2015) Modular poly(ethylene glycol) matrices for the controlled 3D-localized osteogenic differentiation of mesenchymal stem cells. Adv Healthc Mater 4(4):550–558PubMedGoogle Scholar
- 88.Ahadian S et al (2014) Facile and rapid generation of 3D chemical gradients within hydrogels for high-throughput drug screening applications. Biosens Bioelectron 59:166–173PubMedGoogle Scholar
- 89.Zhang B, Huang J, Narayan RJ (2020) Gradient scaffolds for osteochondral tissue engineering and regeneration. J Mater Chem BGoogle Scholar
- 90.Radhakrishnan J et al (2018) Gradient nano-engineered in situ forming composite hydrogel for osteochondral regeneration. Biomaterials 162:82–98PubMedGoogle Scholar
- 91.Xiao H et al (2019) Osteochondral repair using scaffolds with gradient pore sizes constructed with silk fibroin, chitosan, and nano-hydroxyapatite. Int J Nanomedicine 14:2011PubMedPubMedCentralGoogle Scholar
- 92.Chow DC et al (2001) Modeling pO(2) distributions in the bone marrow hematopoietic compartment. I. Krogh’s model. Biophys J 81(2):675–684PubMedPubMedCentralGoogle Scholar
- 93.Bizzarri A et al (2006) Continuous oxygen monitoring in subcutaneous adipose tissue using microdialysis. Anal Chim Acta 573:48–56PubMedGoogle Scholar
- 94.Harrison JS et al (2002) Oxygen saturation in the bone marrow of healthy volunteers. Blood 99(1):394–394PubMedGoogle Scholar
- 95.Silver IA (1975) Measurement of pH and ionic composition of pericellular sites. Philos Trans R Soc Lond Ser B Biol Sci 271(912):261–272Google Scholar
- 96.Fermor B et al (2007) Oxygen, nitric oxide and articular cartilage. Eur Cell Mater 13:56–65PubMedGoogle Scholar
- 97.Panchision DM (2009) The role of oxygen in regulating neural stem cells in development and disease. J Cell Physiol 220(3):562–568PubMedGoogle Scholar
- 98.Dollery CT, Bulpitt CJ, Kohner EM (1969) Oxygen supply to the retina from the retinal and choroidal circulations at normal and increased arterial oxygen tensions. Investig Ophthalmol 8(6):588–594Google Scholar
- 99.Masamoto K, Tanishita K (2009) Oxygen transport in brain tissue. J Biomech Eng 131(7):074002PubMedGoogle Scholar
- 100.Zhang K, Zhu L, Fan M (2011) Oxygen, a key factor regulating cell behavior during neurogenesis and cerebral diseases. Front Mol Neurosci 4:5PubMedPubMedCentralGoogle Scholar
- 101.Bahsoun S et al (2018) The role of dissolved oxygen levels on human mesenchymal stem cell culture success, regulatory compliance, and therapeutic potential. Stem Cells Dev 27(19):1303–1321PubMedGoogle Scholar
- 102.Majmundar AJ, Wong WJ, Simon MC (2010) Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell 40(2):294–309PubMedPubMedCentralGoogle Scholar
- 103.Park KM, Gerecht S (2014) Hypoxia-inducible hydrogels. Nat Commun 5:4075PubMedPubMedCentralGoogle Scholar
- 104.Blatchley M, Park KM, Gerecht S (2015) Designer hydrogels for precision control of oxygen tension and mechanical properties. J Mater Chem B 3(40):7939–7949PubMedPubMedCentralGoogle Scholar
- 105.Sato A et al (2014) An in vitro hepatic zonation model with a continuous oxygen gradient in a microdevice. Biochem Biophys Res Commun 453(4):767–771PubMedGoogle Scholar
- 106.Lesher-Pérez SC et al (2017) Dispersible oxygen microsensors map oxygen gradients in three-dimensional cell cultures. Biomater Sci 5(10):2106–2113PubMedPubMedCentralGoogle Scholar
- 107.Sharon Gerecht DL, Park KM, Eisinger TSK (2019) WO2018017657 – Oxygen gradient hydrogel drug screeningGoogle Scholar
- 108.Boyce MW et al (2020) Generating linear oxygen gradients across 3D cell cultures with block-layered oxygen controlled chips (BLOCCs). Anal Methods 12(1):18–24PubMedGoogle Scholar
- 109.Polinkovsky M et al (2009) Fine temporal control of the medium gas content and acidity and on-chip generation of series of oxygen concentrations for cell cultures. Lab Chip 9(8):1073–1084PubMedGoogle Scholar
- 110.Erapaneedi R et al (2016) A novel family of fluorescent hypoxia sensors reveal strong heterogeneity in tumor hypoxia at the cellular level. EMBO J 35(1):102–113PubMedGoogle Scholar
- 111.Vega SL et al (2018) Combinatorial hydrogels with biochemical gradients for screening 3D cellular microenvironments. Nat Commun 9(1):1–10Google Scholar
- 112.Tong X et al (2016) Hydrogels with dual gradients of mechanical and biochemical cues for deciphering cell-niche interactions. ACS Biomater Sci Eng 2(5):845–852PubMedGoogle Scholar
- 113.Orsi G et al (2017) A new 3D concentration gradient maker and its application in building hydrogels with a 3D stiffness gradient. J Tissue Eng Regen Med 11(1):256–264PubMedGoogle Scholar
- 114.Lozano AM et al (2019) Deep brain stimulation: current challenges and future directions. Nat Rev Neurol 15(3):148–160PubMedPubMedCentralGoogle Scholar
