Lecture 7: Hydrogel Biomaterials: Structure And Physical .
BEH.462/3.962J Molecular Principles of BiomaterialsSpring 2003Lecture 7: Hydrogel Biomaterials: Structure and Physical ChemistryLast Day:programmed/regulated/multifactor controlled release for drug delivery and tissueengineeringToday:Applications of hydrogels in bioengineeringCovalent hydrogels structure and chemistry of biomedical gelsThermodynamics of hydrogel swellingReading:N.A. Peppas et al., ‘Physicochemical foundations and structural design of hydrogels inmedicine and biology,’ Annu. Rev. Biomed. Eng., 2, 9-29 (2000).Supplementary Reading:P.J. Flory, ‘Principles of Polymer Chemistry,’ Cornell University Press, Ithaca, pp. 464469, pp. 576-581 (Statistical thermodynamics of networks and network swelling)Applications of hydrogels in bioengineering Hydrogels: insoluble network of polymer chains that swell in aqueous solutionsGels can be classified by the type of crosslinker:1 Covalent covalent junctions Physicalnon-covalent junctionsLecture 7 – Hydrogels 11 of 15
BEH.462/3.962J Molecular Principles of BiomaterialsSpring 2003Physical gels: example- Hydrophobicinteractions in physical gelswaterPhysical gels are formed by noncovalentcross-linksExample blocks:Poly(ethylene glycol) (PEG)Hydrophilic B blocksHydrophobic A blocks Poly(propylene oxide) (PPO)Poly(butylene oxide) (PBO)Key properties of gels for bioengineering applications:1. in situ formability2. degradability3. responsive swelling4. tissue-like structure/properties In situ formability Gelation of liquid solutions by: Irradiation with light Temperature change (e.g. 4 C to 37 C) Cross-linking enzymes Presence of divalent saltsON BOARD:In situ formation hν Heat Crosslinking by enzymes Introduction of divalentcations (e.g. Ca , Mg )Lecture 7 – Hydrogels 12 of 15
BEH.462/3.962J Molecular Principles of BiomaterialsSpring 2003Key properties of hydrogels for bioengineeringapplications: example: ÔprintableÕgels T(Landers et al. 2002)Chilled/heatedprinting headsprovide 4-70 CdispensingTemperature-controlled stage (Irvine lab)DegradabilityON BOARD:Degradability Hydrolysis Enzymatic attackGel with degradable crosslinks or network chains Eliminible/metabolizableWater-soluble fragmentsResponsive swelling Temperature-, pH-, and molecule-responsive swelling Basis of sensors and ‘smart’ materials (to be covered later)Lecture 7 – Hydrogels 13 of 15
BEH.462/3.962J Molecular Principles of BiomaterialsSpring 2003ON BOARD:Responsive swelling pH T c (change in concentration of a molecule Tissue-like structure/properties Form swollen networks similar to collagen, elastin, proteoglycansGeneral areas of application in bioengineering: Controlled releaseON BOARD:Controlled release Tissue barriers (Hubbell2,3) Prevent thrombosis (vessel blocked by coagulating platelets) and restenosis (re-narrowing of bloodvessel after operation) in vessels after vascular injury/angioplasty/etc. Prevent tissue-tissue adhesion after an operationTissue barriers and conformal coatings1)Adsorbedlayer ofphotoinitiatorBloodvessel3)vesselPhotoinitiator solution2)Two layers ofhydrogelformed in situGreen laserPEG-diacrylate solutionLecture 7 – Hydrogels 1(An and Hubbell 2000)4 of 15
BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003TE scaffolds/cell encapsulation/immunoisolation4,5Poly(methyl es:1. Perfect connectivity forcell migration2. Improved nutrienttransport3. No Ôdead crospheresO.D. Velev and A.M. Lenhoff, Curr.Opin. Coll. Interf. Sci. 5, 56 (2000)Hydrogel Ôinverse opalsÕOptical micrograph/20 µm poresFluorescence micrograph/60 µm pores60 µm Biosensors (to be covered later)Contact lensesLecture 7 – Hydrogels 15 of 15
BEH.462/3.962J Molecular Principles of BiomaterialsSpring 2003Structure of covalent hydrogel biomaterialsChemical and physical structureStructure and swelling of hydrogel materialsÔineffectivenetworkchainÕ x x xx solutiondilution elswellingNetworks formed by stitching together monomers in aqueous solutions via cross-linkers that are multifunctional unitso Draw an example of a crosslinker: bisacrylamide networks from hydrophilic vinyl monomers hydroxyethyl methacrylate poly(ethylene glycol) methacrylate acrylic acid acrylamide, N-isopropylacrylamide Common crosslinkers: PEGDMA, EGDMA bis-acrylamideHydrogels undergo swelling in analogy to dilution of free polymer chains in solutiono Difference lies in limit to ‘dilution’ when chains are cross-linked together (ENTROPIC)Poly(2-hydroxyethyl methacrylate) hydrogels6 One of the first biomedical hydrogels; applied to contact lenses in late 1950sLecture 7 – Hydrogels 16 of 15
BEH.462/3.962J Molecular Principles of BiomaterialsSpring 2003PEGDMA-co-PHEMACH3CH3 CH3CH3-CH2-CH-CH2-C-CH2-CH-CH2-CHC OC O C OC OOOOOCH2CH2 CH2CH2CH2CH2 CH2CH2OOHOHOHCH2CH2OC O-CH2-CH-CH2-C-CH2-CH-CH2-CHC OC OC OOOOCH2CH2CH2CH2CH2CH2OHOHOH(Chielline et al.7)Interpenetrating networks Useful for obtaining gels with properties in between two different materialso E.g. mix a swelling polymer with a temperature- or pH-responsive polymer to obtain networks that have adefined amount of swelling in response to changes in temperature or pHxInterpenetrating networksxxxoxSem-interpenetrating networks: second component is entangled with first network but not cross-linkedBiological recognition of hydrogels Inclusion of peptide-functionalized co-monomers allows hydrogels to have tailored biological recognitionproperties similar to solid degradable polymerso Promoting cell adhesion:Incorporating biological recognition:adhesion sequence PEGNR6 fibroblast adhesion on (no cell adhesion on ligand-free hydrogels)Lecture 7 – Hydrogels 17 of 15
BEH.462/3.962J Molecular Principles of BiomaterialsoSpring 2003Promoting remodeling/cell migration through synthetic networks: collagenase sequencePEGPEG-GWGLGPAGK- . Mann, A.S. Gobin, A.T. Tsai, R.H.Schmedlen, J.L. West, Biomaterials 22,3045 (2001)Example synthesis strategy: photoencapsulation of live cells5 Photoencapsulation: expose solution of cells, prepolymer/cross-linker/monomer, and photoinitiator to light toinitiate free radical polymerizationIn sterile culture media: hν Cyclohexyl phenyl ketone:UV hν Provides very rapid polymerization (2-20 seconds typical), at neutral pH and room temp. – 37 C‘soft’ UV photoinitiators are common and non-toxic (illuminate at 365 nm)Lecture 7 – Hydrogels 18 of 15
BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003Cells can be entrapped with highviability4,8:UV lampliquidgelExample Biomedical Hydrogel Materials6Formed from hydrophilic biocompatible polymers, often polymers that can be safely eliminated by the body if the gelbreaks down.CH 3CH CC OORGeneral methacrylatesLecture 7 – Hydrogels 19 of 15
BEH.462/3.962J Molecular Principles of BiomaterialsSpring 2003Chemical structure of biodegradable hydrogelsMechanism I: (non-degradable water-soluble polymers with degradable cross-links) Degradable cross-linkso e.g. dextran hydrogels9 bacterial exo-polysaccharide branched polymer composed of α-1,6-linked D-glucopyranose residues with a low % of α-1,2 and 1,3side chainsDextran with polylactide crosslinks: hydrolyzable crosslinks9 dextran can be functionalized with methacrylate and then crosslinked in the presence of a smallamount of vinyl monomer:ddegradable gels show first swelling then dissolution as cross-links are hydrolyzed:Lecture 7 – Hydrogels 110 of 15
BEH.462/3.962J Molecular Principles of BiomaterialsSpring 2003Mechanism III: Co-encapsulation of degradation catalysto e.g. dextran hydrogels9 encapsulating dextranase enzyme polymerization is carried out in the presence of protein to be delivered and a bacterial dextranase:dextranase breaks down the dextran chains over time, releasing protein degradation/protein release rate depends on amount of enzyme encapsulatedThermodynamics of hydrogel swellingDerivation of the free energy of polymer chains cross-linked in the presence of solvent Theory originally developed by Flory and Rehner for solid rubber networks exposed to solvent10,11Adapted to describe hydrogels in biomedical applications by Bray and Merrill12Description of the modelPolymer and solvent (water) are modeled assegments of equal volume- polymer chains arecomposed of connected segmentsEnergy of contacts: ω12(Flory13)Model parametersµ1bathchemical potential of water in external bath ( µ10)µ1chemical potential of water in the hydrogelµ10chemical potential of pure water in standard state w12pair contact interaction energy for polymer with waterzmodel lattice coordination numberxnumber of segments per polymer moleculeLecture 7 – Hydrogels 111 of 15
BEH.462/3.962J Molecular Principles of eφ1φ2,sφ2,r Spring 2003Molecular weight of polymer chains before cross-linkingMolecular weight of cross-linked subchainsnumber of water molecules in swollen gelpolymer-solvent interaction parameterBoltzman constantabsolute temperature (Kelvin)molar volume of solvent (water)molar volume of polymerspecific volume of solvent (water)specific volume of polymertotal volume of polymertotal volume of swollen hydrogeltotal volume of relaxed hydrogelnumber of subchains in networknumber of ‘effective’ subchains in networkvolume fraction of water in swollen gelvolume fraction of polymer in swollen gelvolume fraction of polymer in relaxed gelSubchains, Mc, and ‘effective’ chainsAAssume cross-links are randomly placed; on average, allare equidistantν number of subchains in cross-linked networkeffectiveÕsubchains: tethered at bothνe number of ÔendsM MW of original chainsMc MW of subchains MW between cross-linksExample: assume polymer chains have a molecularweight M 4A and each ÔsubchainÕhas molecular weightA:ν 24νe 12Two useful relationships:ν V2/vsp,2Mcνe ν(1 - 2(Mc/M))Lecture 7 – Hydrogels 112 of 15
BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003Physical picture of the equilibrium described:o Polymer chains are cross-linked in watero Relaxed network is moved to a large bath of water and swells to a new equilibriumVrCross-linking(relaxed)Expansion factor: ααxαyαz α3 Vs/Vr (V2 n1vm,1)/Vrφ2,s V2/(V2 n1vm,1)φ2,r V2/VrVsswellingvolume fraction of polymer in swollen gelvolume fraction of polymer in relaxed gelDerivation of the equilibrium properties We want to calculate the change in free energy as the network is cross-linked and first exposed to a surroundingsolvent bath that can trigger solvent to enters/leave the hydrogelThe free energy of the system can be written as a contribution from mixing and an elastic retracting energy: Gtotal Gmix GelAt equilibrium, the chemical potentials of solvent inside and outside the gel are equal:Eqn 1µ1bath µ1Eqn 2µ10 µ1Eqn 3 ( Gtotal ) 0 (µ1) total (µ1) mix (µ1 ) el dn1 T ,P chemical potential of bath is water’s standard state (µ1)mix and (µ1)el will depend on the degree of swelling and thus allow us to calculate the swelling if we know thephysicochemical parameters of the system Determining the contribution from mixing:o Based on Flory’s original lattice liquid modelLecture 7 – Hydrogels 113 of 15
BEH.462/3.962J Molecular Principles of BiomaterialsEqn 4 Spring 2003 Gmix Hmix – T SmixFree energy can be decreased by entropy gain on mixing (more configurations, Smix 0) and favorable solventpolymer interactions ( Hmix 0)CH2CHOCOCH2 Eqn 5 HH Oo drives SWELLING of hydrophilic networks in waterEnthalpy of mixing: count contacts and provide ω12 energy per contact:o ω12 accounts for energy of moving a molecule of solvent from pure water into pure polymero # contacts between 1 and 2 (total number of polymer segments in system)(# contacts with solvent) (n2x)[(number neighbors per segment)(probability that neighbor is solvent)] (n2v2)(z)(φ1) zn1φ2 Hmix z ω12x1n1φ2Define the polymer-solvent interaction parameter:Eqn 6χ z ω12x1/kBTEqn 7therefore Hmix kBTn1φ2 Eqn 8(unitless)Now derive Smix: we won’t derive it here:o Based on fundamental equation:S kBln Ω Where Ω is the number of configurations possible in the system.Lower configurational entropy if chains of network are stretched Gel 0 Eqn 9 Eqn 10 Resists chain stretching, competes against Gmix and Gion, driving network collapseFlory derived an expression for the # ways free polymer chains could be arranged on the lattice: Smix kBln(Ωsolution/Ωseparate) -kB [n1ln φ1 n2ln φ2]For a gel, the number of ‘free’ polymer chains n2 0, so: Gmix kBT[n1ln φ1 χn1φ2]The chemical potential change can be obtained by differentiating Eqn 10:Eqn 11Lecture 7 – Hydrogels 114 of 15
BEH.462/3.962J Molecular Principles of BiomaterialsSpring , K. T. & West, J. L. Photopolymerizable hydrogels for tissue engineering applications. Biomaterials 23,4307-14 (2002).An, Y. & Hubbell, J. A. Intraarterial protein delivery via intimally-adherent bilayer hydrogels. J Control Release 64,205-15 (2000).Hubbell, J. A. Hydrogel systems for barriers and local drug delivery in the control of wound healing. Journal ofControlled Release 39, 305-313 (1996).Elisseeff, J. et al. Photoencapsulation of chondrocytes in poly(ethylene oxide)-based semi-interpenetratingnetworks. Journal of Biomedical Materials Research 51, 164-171 (2000).Jen, A. C., Wake, M. C. & Mikos, A. G. Review: Hydrogels for cell immobilization. Biotechnology andBioengineering 50, 357-364 (1996).Peppas, N. A., Huang, Y., Torres-Lugo, M., Ward, J. H. & Zhang, J. Physicochemical foundations and structuraldesign of hydrogels in medicine and biology. Annu Rev Biomed Eng 2, 9-29 (2000).Chiellini, F., Petrucci, F., Ranucci, E. & Solaro, R. in Biomedical Polymers and Polymer Therapeutics (eds.Chiellini, E., Sunamoto, J., Migliaresi, C., Ottenbrite, R. M. & Cohn, D.) 63-74 (Kluwer, New York, 1999).Anseth, K. S. & Burdick, J. A. New directions in photopolymerizable biomaterials. Mrs Bulletin 27, 130-136 (2002).Hennink, W. E. et al. in Biomedical Polymers and Polymer Therapeutics (eds. Chiellini, E., Sunamoto, J.,Migliaresi, C., Ottenbrite, R. M. & Cohn, D.) 3-18 (Kluwer, New York, 2001).Flory, P. J. & Rehner Jr., J. Statistical mechanics of cross-linked polymer networks. II. Swelling. J. Chem. Phys.11, 521-526 (1943).Flory, P. J. & Rehner Jr., J. Statistical mechanics of cross-linked polymer networks. I. Rubberlike elasticity. J.Chem. Phys. 11, 512-520 (1943).Peppas, N. A. & Merrill, E. W. Polyvinyl-Alcohol) Hydrogels - Reinforcement of Radiation-Crosslinked Networksby Crystallization. Journal of Polymer Science Part a-Polymer Chemistry 14, 441-457 (1976).Flory, P. J. Principles of Polymer Chemistry (Cornell University Press, Ithaca, 1953).Lecture 7 – Hydrogels 115 of 15
Lecture 7: Hydrogel Biomaterials: Structure and Physical Chemistry . P.J. Flory, ‘Principles of Polymer Chemistry,’ Cornell University Press, Ithaca, pp. 464-469, pp. 576-581 . Prevent tissue-tissue adhesion after an operation Tissue barriers and conformal coatings
Tear is a convenient experimental setup to study time-dependent rupture of a hydrogel of complex rheology. The hydrogel is attached with two inextensible backing layers, which guide the crack to extend along the midline of the hydrogel, and localize the active deformation in a region scaled by the thickness of the hydrogel.
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