Subscribe to RSS
DOI: 10.1055/s-0042-100469
Engineering Approaches for Understanding Osteogenesis: Hydrogels as Synthetic Bone Microenvironments
Publication History
received 27 October 2015
accepted 05 January 2016
Publication Date:
14 April 2016 (online)
Abstract
The microenvironment, which can be considered the sum of all the components and conditions surrounding a particular cell, is critical to moderating cellular behavior. In bone, interactions with the microenvironment can influence osteogenic differentiation, and subsequent extracellular matrix deposition, mineralization, and bone growth. Beyond regenerative medicine purposes, tissue engineering tools, namely cell-scaffold constructs, can be used as models of the bone microenvironment. Hydrogels, which are hydrophilic polymer networks, are popularly used for cell culture constructs due to their substantial water content and their ability to be tailored for specific applications. As synthetic microenvironments, a level of control can be exerted on the hydrogel structure and material properties, such that individual contributions from the scaffold on cellular behavior can be observed. Both biochemical and mechanical stimuli have been shown to modulate cellular behaviors. Hydrogels can be modified to present cell-interactive ligands, include osteoinductive moieties, vary mechanical properties, and be subject to external mechanical stimulation, all of which have been shown to affect osteogenic differentiation. Following “bottom-up” fabrication methods, levels of complexity can be introduced to hydrogel systems, such that the synergistic effects of multiple osteogenic cues can be observed. This review explores the utility of hydrogel scaffolds as synthetic bone microenvironments to observe both individual and synergistic effects from biochemical and mechanical signals on osteogenic differentiation. Ultimately, a better understanding of how material properties can influence cellular behavior will better inform design of tissue engineering scaffolds, not just for studying cell behavior, but also for regenerative medicine purposes.
-
References
- 1 Black CRM, Goriainov V, Gibbs D, Kanczler J, Tare RS, Oreffo ROC. Bone tissue engineering. Curr Mol Bio Rep 2015; 1: 132-140
- 2 Amini AR, Laurencin CT, Nukavarapu SP. Bone tissue engineering: recent advances and challenges. Crit Rev Biomed Eng 2012; 40: 363-408
- 3 Langer R, Vacanti JP. Tissue engineering. Science 1993; 260: 920-926
- 4 MacNeil S. Progress and opportunities for tissue-engineered skin. Nature 2007; 445: 874-880
- 5 Esch MB, King TL, Shuler ML. The role of body-on-a-chip devices in drug and toxicity studies. Annu Rev Biomed Eng 2011; 13: 55-72
- 6 Lutolf MP, Hubbell JA. Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering. Nat Biotechnol 2005; 23: 47-55
- 7 Hynes RO. The extracellular matrix: not just pretty fibrils. Science 2009; 326: 1216-1219
- 8 Alvarez K, Nakajima H. Metallic scaffolds for bone regeneration. Materials 2009; 2: 790-832
- 9 Singh R, Lee PD, Jones JR, Poologasundarampillai G, Post T, Lindley TC, Dashwood RJ. Hierarchically structured titanium foams for tissue scaffold applications. Acta Biomater 2010; 6: 4596-4604
- 10 Yuan H, Yang Z, Li Y, Zhang X, De Bruijn JD, De Groot K. Osteoinduction by calcium phosphate biomaterials. J Mater Sci Mater Med 1998; 9: 723-726
- 11 Nicolson PC, Vogt J. Soft contact lens polymers: an evolution. Biomaterials 2001; 22: 3273-3283
- 12 Hoare TR, Kohane DS. Hydrogels in drug delivery: progress and challenges. Polymer 2008; 49: 1993-2007
- 13 Madaghiele M, Demitri C, Sannino A, Ambrosio L. Polymeric hydrogels for burn wound care: Advanced skin wound dressings and regenerative templates. Burn Trauma 2014; 2: 153-161
- 14 Drury JL, Mooney DJ. Hydrogels for tissue engineering: scaffold design variables and applications. Biomaterials 2003; 24: 4337-4351
- 15 Shapiro JM, Oyen ML. Hydrogel composite materials for tissue engineering scaffolds. JOM 2013; 65: 505-516
- 16 Oyen ML, Ferguson VL. Bone as a composite material. In: Öchsner A, Ahmed W. (eds.) Biomechanics of hard tissues: modeling, testing, and materials. Weinheim, Germany: Wiley-VCH Verlag; 2010: 101-122
- 17 Rho JY, Kuhn-Spearing L, Zioupos P. Mechanical properties and the hierarchical structure of bone. Med Eng Phys 1998; 20: 92-102
- 18 Weiner S, Wagner HD. The material bone: structure-mechanical function relations. Annu Rev Mater Sci 1998; 28: 271-298
- 19 Currey JD. Bones: structure and mechanics. Princeton: Princeton University Press; 2002
- 20 Schaffler MB, Burr DB. Stiffness of compact bone: effects of porosity and density. J Biomech 1988; 21: 13-16
- 21 Murugan R, Ramakrishna S. Development of nanocomposites for bone grafting. Compos Sci Technol 2005; 65: 2385-2406
- 22 Goldstein SA. The mechanical properties of trabecular bone: dependence on anatomic location and function. J Biomech 1987; 20: 1055-1061
- 23 Bonucci E. Basic composition and structure of bone. In: An YA, Draughn RA. (eds.) Mechanical testing of bone and the bone-implant interface. Boca Raton: CRC Press; 1999: 3-21
- 24 Oyen ML. The materials science of bone: Lessons from nature for biomimetic materials synthesis. MRS Bull 2008; 33: 49-55
- 25 Bianco P, Riminucci M, Gronthos S, Robey PG. Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells 2001; 19: 180-192
- 26 Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 1997; 276: 71-74
- 27 Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003; 423: 337-342
- 28 Schaffler MB, Kennedy OD. Osteocyte signaling in bone. Curr Osteoporos Rep 2012; 10: 118-125
- 29 Jaiswal N, Haynesworth SE, Caplan AI, Bruder SP. Osteogenic differentiation of purified, culture-expanded human mesenchymal stem cells in vitro. J Cell Biochem 1997; 64: 295-312
- 30 Meirelles LS, Nardi NB. Murine marrow-derived mesenchymal stem cell: isolation, in vitro expansion, and characterization. Br J Haematol 2003; 123: 702-711
- 31 Hayashi O, Katsube Y, Hirose M, Ohgushi H, Ito H. Comparison of osteogenic ability of rat mesenchymal stem cells from bone marrow, periosteum, and adipose tissue. Calcif Tissue Int 2008; 82: 238-247
- 32 Kern S, Eichler H, Stoeve J, Klüter H, Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 2006; 24: 1294-1301
- 33 Sudo H, Kodama HA, Amagai Y, Yamamoto S, Kasai S. In vitro differentiation and calcification in a new clonal osteogenic cell line derived from newborn mouse calvaria. J Cell Biol 1983; 96: 191-198
- 34 LeGeros RZ. Properties of osteoconductive biomaterials: calcium phosphates. Clin Orthop Relat Res 2002; 395: 81-98
- 35 Roach HI. Why does bone matrix contain non-collagenous proteins? The possible roles of osteocalcin, osteonectin, osteopontin and bone sialoprotein in bone mineralisation and resorption. Cell Biol Int 1994; 18: 617-628
- 36 Waddington RJ, Roberts HC, Sugars RV, Schonherr E. Differential roles for small leucine-rich proteoglycans in bone formation. Eur Cell Mater 2003; 6: 12-21
- 37 Weiss RE, Reddi AH. Appearance of fibronectin during the differentiation of cartilage, bone, and bone marrow. J Cell Biol 1981; 88: 630-636
- 38 Ratner BD, Hoffman AS. Synthetic hydrogels for biomedical applications. In: Andrade J. (ed.) Hydrogels for medical and related applications. Washington, DC: American Chemical Society; 1976. 31. 1-36
- 39 Lutolf MP, Raeber GP, Zisch AH, Tirelli N, Hubbell JA. Cell-responsive synthetic hydrogels. Adv Mater 2003; 15: 888-892
- 40 Burdick JA, Anseth KS. Photoencapsulation of osteoblasts in injectable RGD-modified PEG hydrogels for bone tissue engineering. Biomaterials 2002; 23: 4315-4323
- 41 Zajaczkowski MB, Cukierman E, Galbraith CG, Yamada KM. Cell-matrix adhesions on poly (vinyl alcohol) hydrogels. Tissue Eng 2003; 9: 525-533
- 42 DeLong SA, Moon JJ, West JL. Covalently immobilized gradients of bFGF on hydrogel scaffolds for directed cell migration. Biomaterials 2005; 26: 3227-3234
- 43 Mann BK, Schmedlen RH, West JL. Tethered-TGF-β increases extracellular matrix production of vascular smooth muscle cells. Biomaterials 2001; 22: 439-444
- 44 Ansorge-Schumacher MB, Slusarczyk H, Schümers J, Hirtz D. Directed evolution of formate dehydrogenase from Candida boidinii for improved stability during entrapment in polyacrylamide. FEBS J 2006; 273: 3938-3945
- 45 Baroli B. Hydrogels for tissue engineering and delivery of tissue-inducing substances. J Pharm Sci 2007; 96: 2197-2223
- 46 Hoffman AS. Hydrogels for biomedical applications. Ann NY Acad Sci 2001; 944: 62-73
- 47 Metters AT, Anseth KS, Bowman CN. Fundamental studies of a novel, biodegradable PEG-b-PLA hydrogel. Polymer 2000; 41: 3993-4004
- 48 Kim S, Healy KE. Synthesis and characterization of injectable poly (N-isopropylacrylamide-co-acrylic acid) hydrogels with proteolytically degradable cross-links. Biomacromolecules 2003; 4: 1214-1223
- 49 Shapiro JM, Oyen ML. Viscoelastic analysis of single-component and composite PEG and alginate hydrogels. Acta Mech Sinica 2014; 30: 7-14
- 50 Oyen M. Mechanical characterisation of hydrogel materials. Int Mater Rev 2014; 59: 44-59
- 51 Gong JP, Katsuyama Y, Kurokawa T, Osada Y. Double-network hydrogels with extremely high mechanical strength. Adv Mater 2003; 15: 1155-1158
- 52 Butcher AL, Offeddu GS, Oyen ML. Nanofibrous hydrogel composites as mechanically robust tissue engineering scaffolds. Trends Biotechnol 2014; 32: 564-570
- 53 Galli M, Fornasiere E, Cugnoni J, Oyen ML. Poroviscoelastic characterization of particle-reinforced gelatin gels using indentation and homogenization. J Mech Behav Biomed Mater 2011; 4: 610-617
- 54 Ingber DE. Mechanosensation through integrins: Cells act locally but think globally. Proc Natl Acad Sci USA 2003; 100: 1472-1474
- 55 Ferreira AM, Gentile P, Chiono V, Ciardelli G. Collagen for bone tissue regeneration. Acta Biomater 2012; 8: 3191-3200
- 56 Collins MN, Birkinshaw C. Hyaluronic acid based scaffolds for tissue engineering—A review. Carbohydr Polym 2013; 92: 1262-1279
- 57 Yu HS, Lee EJ, Seo SJ, Knowles JC, Kim HW. Feasibility of silica-hybridized collagen hydrogels as three-dimensional cell matrices for hard tissue engineering. J Biomater Appl 2015; 30: 338-350
- 58 Alsberg E, Anderson KW, Albeiruti A, Franceschi RT, Mooney DJ. Cell-interactive alginate hydrogels for bone tissue engineering. J Dent Res 2001; 80: 2025-2029
- 59 Hersel U, Dahmen C, Kessler H. RGD modified polymers: biomaterials for stimulated cell adhesion and beyond. Biomaterials 2003; 24: 4385-4415
- 60 Maheshwari G, Brown G, Lauffenburger DA, Wells A, Griffith LG. Cell adhesion and motility depend on nanoscale RGD clustering. J Cell Sci 2000; 113: 1677-1686
- 61 Kantlehner M, Schaffner P, Finsinger D, Meyer J, Jonczyk A, Diefenbach B, Nies B, Hölzemann G, Goodman SL, Kessler H. Surface coating with cyclic RGD peptides stimulates osteoblast adhesion and proliferation as well as bone formation. ChemBioChem 2000; 1: 107-114
- 62 Hsiong SX, Boontheekul T, Huebsch N, Mooney DJ. Cyclic arginine-glycine-aspartate peptides enhance three-dimensional stem cell osteogenic differentiation. Tissue Eng Part A 2008; 15: 263-272
- 63 Wang X, Yan C, Ye K, He Y, Li Z, Ding J. Effect of RGD nanospacing on differentiation of stem cells. Biomaterials 2013; 34: 2865-2874
- 64 Comisar WA, Kazmers NH, Mooney DJ, Linderman JJ. Engineering RGD nanopatterned hydrogels to control preosteoblast behavior: a combined computational and experimental approach. Biomaterials 2007; 28: 4409-4417
- 65 Mehta M, Madl CM, Lee S, Duda GN, Mooney DJ. The collagen I mimetic peptide DGEA enhances an osteogenic phenotype in mesenchymal stem cells when presented from cell-encapsulating hydrogels. J Biomed Mater Res A 2015; 103: 3516-3525
- 66 Becerra-Bayona S, Guiza-Arguello V, Qu X, Munoz-Pinto DJ, Hahn MS. Influence of select extracellular matrix proteins on mesenchymal stem cell osteogenic commitment in three-dimensional contexts. Acta Biomater 2012; 8: 4397-4404
- 67 Trappmann B, Gautrot JE, Connelly JT, Strange DGT, Li Y, Oyen ML, Stuart MAC, Boehm H, Li B, Vogel V, Spatz JP, Watt FM, Huck WTS. Extracellular-matrix tethering regulates stem-cell fate. Nat Mater 2012; 11: 642-649
- 68 Wen JH, Vincent LG, Fuhrmann A, Choi YS, Hribar KC, Taylor-Weiner H, Chen S, Engler AJ. Interplay of matrix stiffness and protein tethering in stem cell differentiation. Nat Mater 2014; 13: 979-987
- 69 Kempen DHR, Lu L, Hefferan TE, Creemers LB, Maran A, Classic KL, Dhert WJA, Yaszemski MJ. Retention of in vitro and in vivo BMP-2 bioactivities in sustained delivery vehicles for bone tissue engineering. Biomaterials 2008; 29: 3245-3252
- 70 Park YS, David AE, Park KM, Lin C-Y, Than KD, Lee K, Park JB, Jo I, Park KD, Yang VC. Controlled release of simvastatin from in situ forming hydrogel triggers bone formation in MC3T3-E1 cells. AAPS J 2013; 15: 367-376
- 71 Tanigo T, Takaoka R, Tabata Y. Sustained release of water-insoluble simvastatin from biodegradable hydrogel augments bone regeneration. J Control Rel 2010; 143: 201-206
- 72 Su WT, Chou WL, Chou CM. Osteoblastic differentiation of stem cells from human exfoliated deciduous teeth induced by thermosensitive hydrogels with strontium phosphate. Mater Sci Eng C Mater Biol Appl 2015; 52: 46-53
- 73 Yamamoto M, Tabata Y, Hong L, Miyamoto S, Hashimoto N, Ikada Y. Bone regeneration by transforming growth factor β1 released from a biodegradable hydrogel. J Control Rel 2000; 64: 133-142
- 74 Burdick JA, Mason MN, Hinman AD, Thorne K, Anseth KS. Delivery of osteoinductive growth factors from degradable PEG hydrogels influences osteoblast differentiation and mineralization. J Control Rel 2002; 83: 53-63
- 75 Holloway JL, Ma H, Rai R, Burdick JA. Modulating hydrogel crosslink density and degradation to control bone morphogenetic protein delivery and in vivo bone formation. J Control Rel 2014; 191: 63-70
- 76 Lu S, Lam J, Trachtenberg JE, Lee EJ, Seyednejad H, van den Beucken JJJP, Tabata Y, Wong ME, Jansen JA, Mikos AG, Kasper FK. Dual growth factor delivery from bilayered, biodegradable hydrogel composites for spatially-guided osteochondral tissue repair. Biomaterials 2014; 35: 8829-8839
- 77 Watson BM, Vo TN, Engel PS, Mikos AG. Biodegradable, in situ-forming cell-laden hydrogel composites of hydroxyapatite nanoparticles for bone regeneration. Ind Eng Chem Res 2015; 54: 10206-10211
- 78 Wu AT, Aoki T, Sakoda M, Ohta S, Ichimura S, Ito T, Ushida T, Furukawa KS. Enhancing osteogenic differentiation of MC3T3-E1 cells by immobilizing inorganic polyphosphate onto hyaluronic acid hydrogel. Biomacromolecules 2014; 16: 166-173
- 79 Hammoudi TM, Rivet CA, Kemp ML, Lu H, Temenoff JS. Three-dimensional in vitro tri-culture platform to investigate effects of crosstalk between mesenchymal stem cells, osteoblasts, and adipocytes. Tissue Eng Part A 2012; 18: 1686-1697
- 80 Visser J, Gawlitta D, Benders KE, Toma SM, Pouran B, van Weeren PR, Dhert WJ, Malda J. Endochondral bone formation in gelatin methacrylamide hydrogel with embedded cartilage-derived matrix particles. Biomaterials 2015; 37: 174-182
- 81 Lai WY, Li YY, Mak SK, Ho FC, Chow ST, Chooi WH, Chow CH, Leung AY, Chan BP. Reconstitution of bone-like matrix in osteogenically differentiated mesenchymal stem cell-collagen constructs: A three-dimensional in vitro model to study hematopoietic stem cell niche. J. Tissue Eng 2013; 4 2041731413508668
- 82 Liu Y, Chan JKY, Teoh SH. Review of vascularised bone tissue-engineering strategies with a focus on co-culture systems. J Tissue Eng Regen Med 2015; 9: 85-105
- 83 Discher DE, Janmey P, Wang Yl. Tissue cells feel and respond to the stiffness of their substrate. Science 2005; 310: 1139-1143
- 84 Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage specification. Cell 2006; 126: 677-689
- 85 Kim TH, An DB, Oh SH, Kang MK, Song HH, Lee JH. Creating stiffness gradient polyvinyl alcohol hydrogel using a simple gradual freezing-thawing method to investigate stem cell differentiation behaviors. Biomaterials 2015; 40: 51-60
- 86 Tan S, Fang JY, Yang Z, Nimni ME, Han B. The synergetic effect of hydrogel stiffness and growth factor on osteogenic differentiation. Biomaterials 2014; 35: 5294-5306
- 87 Chatterjee K, Lin-Gibson S, Wallace WE, Parekh SH, Lee YJ, Cicerone MT, Young MF, Simon CG. The effect of 3D hydrogel scaffold modulus on osteoblast differentiation and mineralization revealed by combinatorial screening. Biomaterials 2010; 31: 5051-5062
- 88 Cameron AR, Frith JE, Gomez GA, Yap AS, Cooper-White JJ. The effect of time-dependent deformation of viscoelastic hydrogels on myogenic induction and Rac1 activity in mesenchymal stem cells. Biomaterials 2014; 35: 1857-1868
- 89 Chaudhuri O, Gu L, Darnell M, Klumpers D, Bencherif SA, Weaver JC, Huebsch N, Mooney DJ. Substrate stress relaxation regulates cell spreading. Nat Commun 2015; 6: 6364
- 90 Karageorgiou V, Kaplan D. Porosity of 3D biomaterial scaffolds and osteogenesis. Biomaterials 2005; 26: 5474-5491
- 91 Wang L, Lu S, Lam J, Kasper FK, Mikos AG. Fabrication of cell-laden macroporous biodegradable hydrogels with tunable porosities and pore sizes. Tissue Eng Part C Methods 2014; 21: 263-273
- 92 Yao X, Peng R, Ding J. Cell-material interactions revealed via material techniques of surface patterning. Adv Mater 2013; 25: 5257-5286
- 93 McBeath R, Pirone DM, Nelson CM, Bhadriraju K, Chen CS. Cell shape, cytoskeletal tension, and RhoA regulate stem cell Lineage Commitment. Dev Cell 2004; 6: 483-495
- 94 Kilian KA, Bugarija B, Lahn BT, Mrksich M. Geometric cues for directing the differentiation of mesenchymal stem cells. Proc Natl Acad Sci USA 2010; 107: 4872-4877
- 95 Lee J, Abdeen AA, Huang TH, Kilian KA. Controlling cell geometry on substrates of variable stiffness can tune the degree of osteogenesis in human mesenchymal stem cells. J Mech Behav Biomed Mater 2014; 38: 209-218
- 96 Lee J, Abdeen AA, Tang X, Saif TA, Kilian KA. Geometric guidance of integrin mediated traction stress during stem cell differentiation. Biomaterials 2015; 69: 174-183
- 97 Wolff J. The Law of Bone Remodeling (translation of the German 1892 edition). Berlin: Springer; 1986
- 98 Chen JH, Liu C, You L, Simmons CA. Boning up on Wolff's Law: mechanical regulation of the cells that make and maintain bone. J Biomech 2010; 43: 108-118
- 99 Rath B, Nam J, Knobloch TJ, Lannutti JJ, Agarwal S. Compressive forces induce osteogenic gene expression in calvarial osteoblasts. J Biomech 2008; 41: 1095-1103
- 100 Sumanasinghe RD, Bernacki SH, Loboa EG. Osteogenic differentiation of human mesenchymal stem cells in collagen matrices: effect of uniaxial cyclic tensile strain on bone morphogenetic protein (BMP-2) mRNA expression. Tissue Eng 2006; 12: 3459-3465
- 101 Kapur S, Baylink DJ, Lau KHW. Fluid flow shear stress stimulates human osteoblast proliferation and differentiation through multiple interacting and competing signal transduction pathways. Bone 2003; 32: 241-251
- 102 Steinmetz NJ, Aisenbrey EA, Westbrook KK, Qi HJ, Bryant SJ. Mechanical loading regulates human MSC differentiation in a multi-layer hydrogel for osteochondral tissue engineering. Acta Biomater 2015; 21: 142-153
- 103 Liu L, Yu B, Chen J, Tang Z, Zong C, Shen D, Zheng Q, Tong X, Gao C, Wang J. Different effects of intermittent and continuous fluid shear stresses on osteogenic differentiation of human mesenchymal stem cells. Biomech Model Mechan 2012; 11: 391-401
- 104 Nii M, Lai JH, Keeney M, Han LH, Behn A, Imanbayev G, Yang F. The effects of interactive mechanical and biochemical niche signaling on osteogenic differentiation of adipose-derived stem cells using combinatorial hydrogels. Acta Biomater 2013; 9: 5475-5483
- 105 Friedland JC, Lee MH, Boettiger D. Mechanically activated integrin switch controls α5β1 function. Science 2009; 323: 642-644
- 106 Zouani OF, Kalisky J, Ibarboure E, Durrieu MC. Effect of BMP-2 from matrices of different stiffnesses for the modulation of stem cell fate. Biomaterials 2013; 34: 2157-2166
- 107 Sharma RI, Snedeker JG. Biochemical and biomechanical gradients for directed bone marrow stromal cell differentiation toward tendon and bone. Biomaterials 2010; 31: 7695-7704
- 108 Sharma RI, Snedeker JG. Paracrine interactions between mesenchymal stem cells affect substrate driven differentiation toward tendon and bone phenotypes. PLoS One 2012; 7: e31504