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Hydrogels in regenerative medicine: towards understanding structure–function relationships

† Author for correspondence

Applied Optics Group, Electrical Systems and Optics Research Division, University of Nottingham, Nottingham, NG7 2RD, UK.

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Email the corresponding author at melissa.mather@nottingham.ac.uk

Paul E Tomlins

Materials Division, National Physical Laboratory, Teddington, Middlesex, TW11 0LW, UK

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Published Online:27 Sep 2010https://doi.org/10.2217/rme.10.32

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Abstract

Hydrogels are playing an increasing role in regenerative medicine owing to their growing functional sophistication. This is being underpinned by advances in hydrogel synthesis, particularly through molecular and genetic engineering, which provide greater control of hydrogel structure and hence the emergence of hydrogels with new functionalities. In order to exploit this capability it is necessary to fully understand the relationship between hydrogel structure and function. This article will investigate the nature of hydrogel-structure relationships by: highlighting the key attributes of hydrogels that modulate their function, discussing the link between these attributes and hydrogel behavior, and identifying possible measurement strategies to elucidate them.

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Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

Bibliography

1 Kopecek J: Hydrogel biomaterials: a smart future? Biomaterials28(34),5185–5192 (2007).▪ Provides good background information on hydrogel synthesis.Crossref, Medline, CAS, Google Scholar
2 Hennink WE, Van Nostrum CF: Novel crosslinking methods to design hydrogels. Adv. Drug Deliv. Rev.54,13–36 (2002).▪ Provides good background information on hydrogel synthesis.Crossref, Medline, CAS, Google Scholar
3 Hong Y, Gong Y, Gao C, Shen J: Collagen-coated polylactide microcarriers/chitosan hydrogel composite: injectable scaffold for cartilage regeneration. J. Biomed. Mater. Res.85A,628–637 (2007).Crossref, Google Scholar
4 Hori Y, Winans AM, Huang CC, Horrigan EM, Irvine DJ: Injectable dendritic cell-carrying alginate gels for immunization and immunotherapy. Biomaterials29,3671–3682 (2008).Crossref, Medline, CAS, Google Scholar
5 Temenoff JS, Mikos AG: Injectable biodegradable materials for orthopedic tissue engineering. Biomaterials21,2405–2412 (2000).Crossref, Medline, CAS, Google Scholar
6 Hou Q, Chau DYS, Pratoomsoot C et al.: In situ gelling hydrogels incorporating microparticles as drug delivery carriers for regenerative medicine. J. Pharm. Sci.97(9),3972–3980 (2008).Crossref, Medline, CAS, Google Scholar
7 Chung IM, Enemchukwu NO, Khaja SD, Murthy N, Mantalaris A, Garcia AJ: Bioadhesive hydrogel microenvironments to modulate epithelial morphogenesis. Biomaterials29,2637–2645 (2008).Crossref, Medline, CAS, Google Scholar
8 Cushing MC, Anseth KS: Hydrogel cell cultures. Science316,1133–1134 (2007).▪ Provides a perspective on future hydrogel applications.Crossref, Medline, CAS, Google Scholar
9 Elisseeff J, Puleo C, Yang F, Sharma B: Advances in skeletal tissue engineering with hydrogels. Orthod. Craniofac. Res.8,150–161 (2005).Crossref, Medline, CAS, Google Scholar
10 Ferreira LS, Gerecht S, Fuller J, Shieh HF, Vunjak-Novakovic G, Langer R: Bioactive hydrogel scaffold for controllable vascular differentiation of human embryonic stem cells. Biomaterials28,2706–2717 (2007).Crossref, Medline, CAS, Google Scholar
11 Mano JF, Silva GA, Azevedo HS et al.: Natural origin biodegradable systems in tissue engineering and regenerative medicine: present status and some moving trends. J. R. Soc. Interface4,999–1030 (2007).Crossref, Medline, CAS, Google Scholar
12 Rahaman MN, Mao JJ: Stem cell-based composite tissue constructs for regenerative medicine. Biotechnol. Bioeng.91(3),261–284 (2005).Crossref, Medline, CAS, Google Scholar
13 Uriel S, Huang JJ, Moya ML et al.: The role of adipose protein derived hydrogels in adipogenesis. Biomaterials29,3712–3719 (2008).Crossref, Medline, CAS, Google Scholar
14 Hou Q, De Bank PA, Shakesheff KM: Injectable scaffold for tissue regeneration. J. Mater. Chem.14,1915–1923 (2004).Crossref, CAS, Google Scholar
15 Boyd LM, Carter AJ: Injectable biomaterials and vertebral endplate treatment for repair and regeneration of the intervertebral disc. Euro. Spine J.15(3),414–421 (2006).Crossref, Medline, Google Scholar
16 Gao J, Dennis JE, Solchaga LA, Goldberg VM, Caplan AI: Repair of osteochondral defect with tissue engineered two phase composite material of injectable calcium phosphate and hyaluronan sponge. Tissue Eng.8(5),827–837 (2002).Crossref, Medline, CAS, Google Scholar
17 Kopecek J: Smart and genetically engineered biomaterials and drug delivery systems. European J. Pharm. Sci.20,1–16 (2003).▪ Provides good background information on hydrogel synthesis.Crossref, Medline, CAS, Google Scholar
18 Um SH, Lee JB, Park N, Kwon SY, Umbach CC, Luo D: Enzyme-catalyzed assembly of DNA hydrogel. Nat. Mater.5,797–801 (2006).Crossref, Medline, CAS, Google Scholar
19 Yang H, Liu H, Kang H, Tan W: Engineering target-responsive hydrogels based on aptamer-target interactions. J. Am. Chem. Soc.130(20),6320–6321 (2008).Crossref, Medline, CAS, Google Scholar
20 Lutolf MP, Hubbell JA: Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering. Nat. Biotechnol.23(1),47–55 (2005).Crossref, Medline, CAS, Google Scholar
21 Bruck SD: Aspects of three types of hydrogels for biomedical applications. J. Biomed. Mater. Res.7,387–404 (1973).Crossref, Medline, CAS, Google Scholar
22 Furth ME, Atala A, Van Dyke ME: Smart biomaterials for tissue engineering and regenerative medicine. Biomaterials28,5068–5073 (2007).▪ Provides a perspective on future hydrogel applications.Crossref, Medline, CAS, Google Scholar
23 Almany L, Seliktar D: Biosynthetic hydrogel scaffolds made from fibrinogen and polyethylene glycol for 3D cell cultures. Biomaterials26,2467–2477 (2005).Crossref, Medline, CAS, Google Scholar
24 Cushing MC, Liao J, Jaeggli P, Anseth KS: Material-based regulation of the myofibroblast phenotype. Biomaterials28,3378–3387 (2007).▪▪ Potential for hydrogel control of phenotype.Crossref, Medline, CAS, Google Scholar
25 Zhao X, Zhang S: Designer self-assembling peptide materials. Macromol. Biosci.7,13–22 (2007).▪▪ Examples of self-assembling hydrogels.Crossref, Medline, Google Scholar
26 Peyton SR, Kim PD, Ghajar CM, Seliktar D, Putnam AJ: The effects of matrix stiffness and RhoA on the phenotypic plasticity of smooth muscle cells in a 3D biosynthetic hydrogel system. Biomaterials29,2597–2607 (2008).▪▪ Potential for hydrogel control of phenotype.Crossref, Medline, CAS, Google Scholar
27 Engler AJ, Sen S, Lee Sweeney H, Discher DE: Matrix elasticity directs stem cell lineage specification. Cell126,677–689 (2006).▪▪ Potential for hydrogel control of phenotype.Crossref, Medline, CAS, Google Scholar
28 Johnson JA, Turro NJ, Koberstein JT, Mark JE: Some hydrogels having novel molecular structures. Prog. Polym. Sci.35(3),332–337 (2010).▪ Recent update on hydrogel designs.Crossref, CAS, Google Scholar
29 Zhang X, Guo X, Yang S et al.: Double-network hydrogel with high mechanical strength prepared from two biocompatible polymers. J. Appl. Polym. Sci.112(5),3063–3070 (2009).Crossref, CAS, Google Scholar
30 Ito K: Slide-ring materials using topological supramolecular architecture. Curr. Opin. Solid State Mater. Sci.14(2),28–34 (2010).Crossref, CAS, Google Scholar
31 Schexnailder P, Schmidt G: Nanocomposite polymer hydrogels. Colloid Polym. Sci.287(1),1–11 (2009).Crossref, CAS, Google Scholar
32 Koo LY, Irvine DJ, Mayes AM, Lauffenburger DA, Griffith LG: Co-regulation of cell adhesion by nanoscale RGD organization and mechanical stimulus. J. Cell. Sci.115,1423–1433 (2002).Crossref, Medline, CAS, Google Scholar
33 Griffith LG, Swartz MA: Capturing complex 3D tissue physiology in vitro. Nat. Rev. Mol. Cell Biol.7,211–224 (2006).Crossref, Medline, CAS, Google Scholar
34 Roy I, Gupta MN: Smart polymeric materials: emerging biochemical applications. Chem. Biol.10,1161–1171 (2003).Crossref, Medline, CAS, Google Scholar
35 West JL, Hubbell JA: Photopolymerized hydrogel materials for drug delivery applications. React. Polym.25,139–147 (1995).Crossref, CAS, Google Scholar
36 Cruise GM, Scharp DS, Hubbell JA: Characterization of permeability and network structure of interfacially photopolymerized poly(ethylene glycol) diacrylate hydrogels. Biomaterials19(14),1287–1294 (1998).Crossref, Medline, CAS, Google Scholar
37 Pitt GG, Cha Y, Shah SS, Zhu KJ: Blends of PVA and PGLA: control of the permeability and degradability of hydrogels by blending. J. Control. Release19(1–3),189–199 (1992).Crossref, CAS, Google Scholar
38 Drury JL, Mooney DJ: Hydrogels for tissue engineering: scaffold design variables and applications. Biomaterials24,4337–4351 (2003).Crossref, Medline, CAS, Google Scholar
39 Li RH, Altreuter DH, Gentile FT: Transport characterization of hydrogel matrices for cell encapsulation. Biotechnol. Bioeng.50,365–373 (1999).Crossref, Google Scholar
40 Kasper FK, Seidlits SK, Tang A et al.: In vitro release of plasmid DNA from oligo(poly(etheylene glycol) fumarate) hydrogels. J. Control. Release104,521–539 (2005).Crossref, Medline, CAS, Google Scholar
41 Quick DJ, Anseth KS: DNA delivery from photocrosslinked PEG hydrogels: encapsulation efficiency, release profiles, and DNA quality. J. Control. Release96,341–351 (2004).Crossref, Medline, CAS, Google Scholar
42 Bryant SJ, Durand KL, Anseth KS: Manipulations in hydrogel chemistry control photoencapsulated chondrocyte behavior and their extracellular matrix production. J. Biomed. Mater. Res.67A,1430–1436 (2003).Crossref, CAS, Google Scholar
43 Brink KS, Yang PJ, Temenoff JS: Degradative properties and cytocompatibility of a mixed-mode hydrogel containing oligo[poly(ethylene glycol)fumarate] and poly(ethylene glycol)dithiol. Acta. Biomater.5(2),570–579 (2009).Crossref, Medline, CAS, Google Scholar
44 Hinkley JA, Morgret LD, Gehrke SH: Tensile properties of two responsive hydrogels. Polymer45(26),8837–8843 (2004).Crossref, CAS, Google Scholar
45 Lee KY, Mooney DJ: Hydrogels for tissue engineering. Chem. Rev.101,1869–1879 (2001).Crossref, Medline, CAS, Google Scholar
46 Baena JR, Lendl B: Raman spectroscopy in chemical bioanalysis. Curr. Opin. Chem. Biol.8(5),534–539 (2004).Crossref, Medline, CAS, Google Scholar
47 Hench LL, West JK: The sol-gel process. Chem. Rev.90,33–72 (1990).Crossref, CAS, Google Scholar
48 Mourant JR, Yamada YR, Carpenter S, Dominque LR, Freyer JP: FTIR spectroscopy discriminates biochemical differences in mammalian cell cultures at different growth stages. Biophys. J.85,1938–1947 (2003).Crossref, Medline, CAS, Google Scholar
49 Shankar BV, Patnaik A: A new pH and thermo-responsive chiral hydrogel for stimulated release. J. Phys. Chem. B111,9294–9300 (2007).Crossref, Medline, CAS, Google Scholar
50 Khatua D, Maiti R, Dey J: A supramolecular hydrogel that responds to biologically relevant stimuli. Chem. Commun.4903–4905 (2006).Crossref, Medline, Google Scholar
51 Gadian DG, Radda GK: NMR studies of tissue metabolism. Annu. Rev. Biochem.50,69–83 (1981).Crossref, Medline, CAS, Google Scholar
52 Goheen SC, Saunders RM, Harvey SD, Olsen PC: Raman spectroscopy of 2-hydroxyethyl methacrylate-acrylamide copolymer using γ-irradiation for crosslinking. J. Raman Spectrosc.37(11),1248–1256 (2006).Crossref, CAS, Google Scholar
53 Zhang R, Tang M, Bowyer A, Eisenthal R, Hubble J: A novel pH and ionic-strength-sensitive carboxy methyl dextran hydrogel. Biomaterials26,4677–4683 (2005).Crossref, Medline, CAS, Google Scholar
54 Ju HK, Kim SY, Kim SJ, Lee YM: pH/temperature-responsive semi-IPN hydrogels composed of alginate and poly(N-isopropylacrylamide). J. Appl. Polym. Sci.83,1128–1139 (2002).Crossref, CAS, Google Scholar
55 Wang D, Williams CG, Li Q, Sharma B, Elisseeff JH: Synthesis and characterization of a novel degradable phosphate-containing hydrogel. Biomaterials24,3969–3980 (2003).Crossref, Medline, CAS, Google Scholar
56 Brinker CJ, Scherer GW: Sol–gel–glass: I. Gelation and gel structure. J. Non-Crystalline Solids70,301–322 (1985).Crossref, CAS, Google Scholar
57 Zaroslov YD, Gordeliy VI, Kuklin AI et al.: Self-assembly of polyelectrolyte rods in polymer gel and in solution: small angle neutron scattering study. Macromolecules35,4466–4471 (2002).Crossref, CAS, Google Scholar
58 Johnson WC: Secondary structure of proteins through circular dichroism spectroscopy. Annu. Rev. Biophys. Biophys. Chem.17(1),145–166 (1988).Crossref, Medline, CAS, Google Scholar
59 Jeong B, Kim SW, Bae YH: Thermosensitive sol-gel reversible hydrogels. Adv. Drug Deliv. Rev.54,37–51 (2002).Crossref, Medline, CAS, Google Scholar
60 Schexnailder P, Loizou E, Porcar L, Butler P, Schmidt G: Heterogeneity in nanocomposite hydrogels from poly(ethylene oxide) crosslinked with silicate nanoparticles. Phys. Chem. Chem. Phys.11,2760–2766 (2009).Crossref, Medline, CAS, Google Scholar
61 Jung JP, Jones JL, Cronier SA, Collier JH: Modulating the mechanical properties of self-assembled peptide hydrogels via native chemical ligation. Biomaterials29(13),2143–2151 (2008).Crossref, Medline, CAS, Google Scholar
62 Lee SJ, Kim SS, Lee YM: Interpenetrating polymer network hydrogels based on poly(ethylene glycol) macromer and chitosan. Carbohydr. Polym.41,197–205 (2000).Crossref, Google Scholar
63 Michels B, Watson G: Dynamics of micelles of poly(ethylene oxide)–poly(propylene oxide)–poly(ethylene oxide) block copolymers in aqueous solutions. Langmuir13,3111–3118 (1997).Crossref, CAS, Google Scholar
64 Yu GE, Deng Y, Dalton S et al.: Micellisation and gelation of triblock copoly(oxyethylene/oxypropylene/oxyethylene), F127. J. Chem. Soc. Faraday Trans.88(17),2537–2544 (1992).Crossref, CAS, Google Scholar
65 Liu W, Zhang B, Lu WW et al.: A rapid temperature-responsive sol-gel reversible poly(N-isopropylacrylamide)-g-methylcellulose copolymer hydrogel. Biomaterials25,3005–3012 (2004).Crossref, Medline, CAS, Google Scholar
66 Buckin V, O’Driscoll B, Smyth C: Ultrasonic spectroscopy for material analysis. Recent advances. Spectrosc. Eur.5,20–25 (2003).Google Scholar
67 Mather ML, Collings AF, Bajenov N, Whittaker AK, Baldock C: Ultrasonic absorption in polymer gel dosimeters. Ultrasonics41(7),551–559 (2003).Crossref, Medline, CAS, Google Scholar
68 Norisuye T, Strybulevych A, Scanlon M, Page J: Ultrasonic investigation of the gelation process of poly(acrylamide) gels. Macromol. Symp.242,208–215 (2006).Crossref, CAS, Google Scholar
69 Havriliak S, Havriliak SJ: Dielectric And Mechanical Relaxation In Materials. Hanser, NY, USA (1997).Google Scholar
70 Song MJ, Lee DS, Ahn JH, Kim DJ, Kimi SC: Dielectric behavior during sol-gel transition of PEO–PPO–PEO triblock copolymer aqueous solutions. Polym. Bull.43,497–504 (2000).Crossref, CAS, Google Scholar
71 Barretta P, Bordi F, Rinaldi C, Paradossi G: A dynamic light scattering study of hydrogels based on telechelic poly(vinyl alcohol). J. Phys. Chem. B104,11019–11026 (2000).Crossref, CAS, Google Scholar
72 Addadi L, Joester D, Nudelman F, Weiner S: Mollusk shell formation: a source of new concepts for understanding biomineralization processes. Chemistry12(4),980–987 (2006).Crossref, Medline, CAS, Google Scholar
73 Liu J, He X, Pan X, Roberts CJ: Ultrasonic model and system for measurement of corneal biomechanical properties and validation on phantoms. J. Biomech.40,1177–1182 (2007).Crossref, Medline, Google Scholar
74 Masci G, Cametti C: Dielectric properties of thermoreversible hydrogels: the case of a dextran copolymer grafted with poly(n-isopropylacrylamide). J. Phys. Chem. B113(33),11421–11428 (2009).Crossref, Medline, CAS, Google Scholar
75 Kavanagh GM, Ross-Murphy SB: Rheological characterization of polymer gels. Prog. Polym. Sci.23,533–562 (1998).Crossref, CAS, Google Scholar
76 Park MJ, Char K: Phase behavior of a PEO–PPO–PEO triblock copolymer in aqueous solutions: two gelation mechanisms. Macromol. Res.10(6),325–331 (2002).Crossref, CAS, Google Scholar
77 Ramachandran S, Tseng Y, Yu YB: Repeated rapid shear-responsiveness of peptide hydrogels with tunable shear modulus. Biomacromolecules6(3),1316–1321 (2005).Crossref, Medline, CAS, Google Scholar
78 Whitesides GM, Mathias JP, Seto CT: Molecular self-assembly and nanochemistry: a chemical strategy for the synthesis of nanostructures. Science254,1312–1319 (1991).Crossref, Medline, CAS, Google Scholar
79 Gil ES, Hudson SM: Stimuli-responsive polymers and their bioconjugates. Prog. Polym. Sci.29,1173–1222 (2004).Crossref, CAS, Google Scholar
80 Yardimci H, Chung B, Harden JL, Leheny RL: Phase behavior and local dynamics of concentrated triblock copolymer micelles. J. Chem. Phys.123,244098 (2005).Crossref, Google Scholar
81 Peppas NA, Huang Y: Polymer and gels as molecular recognition agents. Pharm. Res.19(5),578–587 (2002).Crossref, Medline, CAS, Google Scholar
82 Pogodina NV, Lavrenko VP, Srinivas S, Winter HH: Rheology and structure of isotactic polypropylene near the gel point: quiescent and shear-induced crystallization. Polymer42(21),9031–9043 (2001).Crossref, CAS, Google Scholar
83 Budtova T, Navard P: Polyelectrolyte hydrogel swelling in a concentrated polymer solution. Macromolecules28(5),1714–1716 (1995).Crossref, CAS, Google Scholar
84 Warriner HE, Sidziak SHJ, Slack NL, Davidson P, Safinya CR: Lamellar biogels: fluid-membrane-based hydrogels containing polymer lipids. Science271,969–973 (1996).Crossref, Medline, CAS, Google Scholar
85 Mano JF: Stimuli-responsive polymeric systems for biomedical applications. Adv. Eng. Mater.10(6),515–527 (2008).Crossref, CAS, Google Scholar
86 Madhumathi K, Shalumon KT, Rani VVD et al.: Wet chemical synthesis of chitosan hydrogel–hydroxyapatite composite membranes for tissue engineering applications. Int. J. Biol. Macromol.45(1),12–15 (2009).Crossref, Medline, CAS, Google Scholar
87 Weiner AA, Moore MC, Walker AH, Shastri VP: Modulation of protein release from photocrosslinked networks by gelatin microparticles. Int. J. Pharm.360,107–114 (2008).Crossref, Medline, CAS, Google Scholar
88 Xu C, Kopecek J: Self-assembling hydrogels. Polym. Bull.58,53–63 (2007).Crossref, CAS, Google Scholar
89 Jeong B, Gutowska A: Lessons from nature: stimuli responsive polymers and their biomedical applications. Trends Biotechnol.7,305–311 (2002).Crossref, Google Scholar
90 Krsko P, Sukhishvili S, Mansfield M, Clancy R, Libera M: Electron-beam surface-patterned poly(ethylene glycol) microhydrogels. Langmuir19,5618–5625 (2003).Crossref, CAS, Google Scholar
91 Yin L, Fei L, Tang C, Yin C: Synthesis, characterization, mechanical properties and biocompatibility of interpenetrating polymer network-super-porous hydrogel containing sodium alginate. Polym. Int.56,1563–1571 (2007).Crossref, CAS, Google Scholar
92 Addadi L, Joester D, Nudelman F, Weiner S: Mollusk shell formation: a source of new concepts for understanding biomineralization processes. Chemistry12(4),980–987 (2006).Crossref, Medline, CAS, Google Scholar
93 Hoffman AS: Hydrogels for biomedical applications. Adv. Drug Deliv. Rev.43,3–12 (2002).Crossref, Google Scholar
94 Geever LM, Devine DM, Nugent MJ et al.: Lower critical solution temperature control and swelling behavior of physically crosslinked thermosensitive copolymers based on n-isopropylacrylamide. Eur. Polym. J.42,2540–2548 (2006).Crossref, CAS, Google Scholar
95 Peppas NA, Huang Y, Torres-Lugo M, Ward JH, Zhang J: Physiochemical foundations and structural design of hydrogels in medicine and biology. Annu. Rev. Biomed. Eng.2,9–29 (2000).Crossref, Medline, CAS, Google Scholar
96 Soboyejo WO, Mercer C, Allanmeh S, Nemetski B, Marcantonio N, Ricci J: Multi-scale microstructural characterization of micro-textured Ti-6Al-4V surfaces. Key Eng. Mater.198–199,203–230 (2001).Crossref, CAS, Google Scholar
97 Watson JD, Crick FHC: The structure of DNA. Cold Spring Harbor Symp. Quant. Biol.18,123–131 (1953).Crossref, Medline, CAS, Google Scholar

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Published online 27 September 2010

Published in print September 2010

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Financial & competing interests disclosure

This work is supported by the National Physical Laboratory Strategic Research Scheme. ML Mather is affiliated to the University of Nottingham (UK). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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