Lecture 8: Physical Hydrogels

Transcription

1 BEH.462/3.962J Mlecular Principles f Bimaterials Spring 2003 Lecture 8: Physical Hydrgels Last Day: Tday: Reading: Overview f bimedical applicatins f hydrgels Structure f cvalent hydrgels Thermdynamics f hydrgel swelling Bnding in physical hydrgels Structure and thermdynamics f blck cplymer hydrgels L.E. Brmberg and E.S. Rn, Temperature-respnsive gels and thermgelling plymer matrices fr prtein and peptide delivery, Adv. Drug Deliv. Rev., 31, 197 (1998) Assciative frces in physical hydrgels Crss-link structure in physical hydrgels Driving assciative frces: 1. Hydrphbic assciatins/ Van der Waals frces i. LCST plymers, hydrphbic-hydrphilic blck cplymers 2. Micellar packing 3. Hydrgen bnding (Rubner) 4. Inic bnding (later lecture) 5. crystallizing segments 6. Cmbinatins f the abve interactins Peptide interactins (e.g. ciled cils)(1) Stability requires cperative bnding interactins(2) (Guenet, Thermreversible gelatin f plymers and biplymers) Individual nn-cvalent bnds are relatively weak: Strength f cvalent bnd: Hydrphbic assciatin: Inic bnd: Hydrgen bnd in water: Cperativity: lwered energy barrier fr secnd and subsequent bnds after first has frmed Used in bilgical assciatins Lecture 8 Physical gels 1 f 12

2 BEH.462/3.962J Mlecular Principles f Bimaterials Spring 2003 Alpha helix, beta nn-cperative interactins: Unstable, n gelatin cperative interactins: sheet Stable interactins, gel frms General characteristics f physical gel bimaterials Dehydratin f hydrphbes/hydrphbic assciatin Examples: PEO-b-PPO-b-PEO, PPO-b-PEO-b-PPO (cmmercially knwn as Plurnics (BASF)) 2 Similar assciative prperties frm PLGA-PEG-PLGA cplymers and PEG- PLGA-PEG cplymers water Example blcks: Ply(ethylene glycl) (PEG) Hydrphilic B blcks Hydrphbic A blcks Ply(prpylene xide) (PPO) Ply(butylene xide) (PBO) PEO PPO PEO CH 3 O CH 3 O O O CH 3 O CH 3 O O O HO-(CH-C-O-CH-C-O-) x -(CH 2 -C-O-CH 2 -C-O) y -(CH 2 -CH 2 -O) z -(CH-C-O-CH-C-O-) x -(CH 2 -C-O-CH 2 -C-O) y -H PLGA PEG PLGA Lecture 8 Physical gels 2 f 12

3 BEH.462/3.962J Mlecular Principles f Bimaterials Spring 2003 Ply(N-isprpylacrylamide) rdered water mlecules (minimize water-hydrphbe cntacts) Dehydratin allws water t disrder (entrpically-driven) S = S dehydrated - S hydrated > 0 Hydrxyprpylmethyl cellulse (natural biplymer) Hydrxyprpyl grups dehydrate t assciate and frm a gel Micellar packing Examples: Plurnics PEO-PPO-PEO blck cplymers Cubic lipid gel phases(3) (Landau and Rsenbusch 1996(4)) Lecture 8 Physical gels 3 f 12

4 BEH.462/3.962J Mlecular Principles f Bimaterials Spring 2003 PEO PPO PEO 5 mm (micellar crystal figure frm website, Matthew, Bhatia, and Rberts; 5mm hydrgel shwn abve is a cmpsite bx frmed by Sciperi printer frm Plurnic F-127 and PPF-c-PEG Hydrgen bnding Hydrgen bnds can frm between H and C, N, O, and F Examples: Ply(vinyl alchl) Ply(vinyl alchl)/peo blends Plymers that can frm hydrgen bnded gels(5): Ply(vinyl alchl) Gelatin (natural biplymer) Frm Sigma prduct sheet: Gelatin is a hetergeneus mixture f water-sluble prteins f high average mlecular weights, present in cllagen. The prteins are extracted by biling skin, tendns, ligaments, bnes, etc. in water. Type A used as a stabilizer, thickener and texturizer in fds; in the manufacture f rubber substitutes, adhesives, cements, lithgraphic and printing inks, plastic cmpunds, artificial silk, phtgraphic plates and films, matches, and light filters fr Lecture 8 Physical gels 4 f 12

5 BEH.462/3.962J Mlecular Principles f Bimaterials Spring 2003 mercury lamps; in textiles; t inhibit crystallizatin in bacterilgy and prepare cultures; in PCR hybridizatin in mlecular bilgy; in the pharmaceutical industry as a suspending agent, encapsulating agent and tablet binder; and in veterinary applicatins as a plasma expander and hemstatic spnge. Percec: frm hydrgels by H-bnding between water-insluble shrt chains and lng water-sluble chains (Percec and Bera(6)) Inic bnding Examples: Sdium alginate(7) (Grant, Mrris, FEBS Lett. 32, 195 (1973)) Crsslinked by divalent catins, frming salt bridges Sensitive t salt cncentratin in physilgical lcatins Crsslinked by blending with catinic plymer E.g. chitsan, plylysine Used extensively fr gentle cell encapsulatin Lecture 8 Physical gels 5 f 12

6 BEH.462/3.962J Mlecular Principles f Bimaterials Spring 2003 n Alginate (plysaccharide) + catinic plymer + divalent catins e.g. chitsan (catinic plysaccharide), plylysine +- Ca Salt bridge Divalent catins Crystallizing segments Examples: Istactic Plyvinyl alchl (Merrill/Bray(8)) Istactic Ply(methacrylic acid) ON BOARD: Prtein interactins Examples: Avidin crss-linked particle netwrks(9) Assciating alpha helices (Wang et al.): ciled-cil peptide crss-links Lecture 8 Physical gels 6 f 12

7 BEH.462/3.962J Mlecular Principles f Bimaterials Spring 2003 Lecture 8 Physical gels 7 f 12

8 BEH.462/3.962J Mlecular Principles f Bimaterials Spring 2003 Structure f Assciating Blck Cplymer Hydrgels 4 Plurnics (trade name, BASF) are an imprtant class f hydrphbically-assciating blck cplymers: FDA apprved fr use in viv Starting at relatively lw cncentratins, Hydrphilic-hydrphbic blck cplymers frm micelles upn passing a critical cncentratin (cmc) r temperature (cmt) 2 ON BOARD: unimers micelles ŌflwerÕmicelle Increasing c, T Cre-shell micelle Hydrphbic blck Hydrphilic blck At higher cncentratins, micelles verlap and gelatin can ccur: Micelles pack tgether Interactins between micelles depend n structure f blck cplymer: Intermicelle physical crss-links Entanglement f packed micelle crnas Lecture 8 Physical gels 8 f 12

9 BEH.462/3.962J Mlecular Principles f Bimaterials Spring 2003 Experiments by Hattn grup at MIT: PEO-PPO-PEO micellizatin at different temperatures measured by adding a hydrphbic dye that absrbs UV light when bund in a hydrphbic envirnment (e.g. micelle cre) but nt free in slutin Transitin range: micelles in equilibrium with unimers Blck length determines gel structure (Chu 1996) Lecture 8 Physical gels 9 f 12

10 BEH.462/3.962J Mlecular Principles f Bimaterials Spring 2003 Relatin between structure and applicatins in biengineering Cubic phase gels studied mst ften (plurnic F-127 at cncentratins circa 20% w/vl) Applied t: Hydrgel scafflds fr tissue engineering f cartilage(10) Drug delivery Cubic phase gels erde by surface disslutin Prvides zer-rder drug release(11) Cubic phase gel drug depts Micelle drug nancarriers nm Drugs can be incrprated int micelles as nan-carriers E.g. Kim et al. PEO-PLGA-PEO blck cplymers fr drug delivery (Nature paper)(12) Thermdynamics f Hydrphbic Assciatin vs. H-Bnding Gels 2,5 LCST plymers(5) Amphiphilic cplymers like PEO/PPO blck cplymers assciate n increasing temperature They belng t a class f materials exhibitin LCST (lwer critical slutin temperature) behavir LCST materials phase separate frm their slvent with increasing temperature, in cntrast t the mre cmmn UCST materials, that phase separate at lw temperatures: UCST ON BOARD: LCST T PS T P + S P + S PS 0 Mle % B Mle % B 100 PS = plymer slutin P + S = tw-phase regin: plymer-rich, plymer-pr Lecture 8 Physical gels 10 f 12

11 BEH.462/3.962J Mlecular Principles f Bimaterials Spring 2003 Hmplymers can als exhibit LCST behavir E.g. ply(n-isprpylacrylamide) Sluble in water at lw temperatures, but cllapses at 32 deg. C Thermdynamically, any plymer that phase separates frm water n increasing temperature must be driven by entrpy G int thery? Assciating blck cplymers(13, 14) The assciatin f hydrphbic blcks in aqueus slutin is described by the clsed assciatin mdel Micelles frm in a transitin frm unimers directly t multimlecular structures, with n intermediate bi-mer/trimer/etc. Examining the driving frce fr cplymer self-assembly What is the free energy change fr frmatin f micelle structures? Eqn 1 G 0 = G micelle G unimer cmc / cmt = H 0 T S 0 = RT lnc cmc Fundatins f cllid Science R.J. Hunter Eqn 2 H 0 = R lnc cmc (1/T) T,P Assciatin f hydrphbic blcks driven by increasing cncentratin is exactly equivalent t assciatin driven by increasing temperature, thus: ln( c ) ln( c ) cmc = (determined experimentally) 1/ T 1/ T ( ) ( ) cmt Frm X, a plt f ln c vs 1/T cmt allws H 0 t be determined:(15) Psitive slpe f 1/T cmt plt indicates H 0 is psitive: but G 0 is negative (micellizatin is a spntaneus prcess at the cmc/cmt) Thus, assciatin is enthalpically unfavrable? Lecture 8 Physical gels 11 f 12

12 BEH.462/3.962J Mlecular Principles f Bimaterials Spring 2003 Driven by favrable entrpy change Ordered water arund hydrphbic grups is released t disrder if hydrphbic blcks assciate, and this entrpy gain utweighs the entrpy penalty fr cnfining the blcks t the micelle cre Cnsistent with directin f transitin temperature change: Any entrpically-driven prcess will ccur with increasing temperature, since G = H - TS Entrpy/hydrphbic effect-driven gelatin cntrasts with hydrgen-bnding assciatin f gels Hydrgen bnded gels break crss-links with increasing temperature (gel frmed driven by enthalpy gain n H-bnds) H-bnds weak; thermal energy can becme greater than bnding energy H-bnding transitin gels (gels dissciate with increasing temperature): Nature 349, 400 (1991) Oppsite temperature behavir- gel is dissciated/swells with increasing temperature E.g. gelatin/pva are fluid at elevated temperatures and gelled at lwer temperatures, while plurnics are fluid at lw temperature and gel at elevated temperatures References 1. Wang, C., Stewart, R. J. & Kpecek, J. (1999) Nature 397, Guenet Thermreversible Gelatin f Plymers and Biplymers, New Yrk). 3. Shah, J. C., Sadhale, Y. & Chilukuri, D. M. (2001) Adv Drug Deliv Rev 47, Landau, E. M. & Rsenbusch, J. P. (1996) Prc Natl Acad Sci U S A 93, Rn, E. S. & Brmberg, L. E. (1998) Adv Drug Deliv Rev 31, Percec, V., Bera, T. K. & Butera, R. J. (2002) Bimacrmlecules 3, Ku, C. K. & Ma, P. X. (2001) Bimaterials 22, Bray, J. C. & Merrill, E. W. (1973) Jurnal f Applied Plymer Science 17, Salem, A. K., Rse, F. R. A. J., Oreff, R. O. C., Yang, X., Davies, M. C., Mitchell, J. R., Rberts, C. J., Stlnik- Trenkic, S., Tendler, S. J. B., Williams, P. M. & Shakesheff, K. M. (2003) Advanced Materials 15, Ca, Y., Rdriguez, A., Vacanti, M., Ibarra, C., Areval, C. & Vacanti, C. A. (1998) J Bimater Sci Plym Ed 9, Zhang, L., Parsns, D. L., Navarre, C. & Kmpella, U. B. (2002) J Cntrl Release 85, Jeng, B., Bae, Y. H., Lee, D. S. & Kim, S. W. (1997) Nature 388, Chu, B. & Zhu, Z. (1996) in Nninic Surfactants: Plyxyalkylene Blck Cplymers, ed. Nace, V. M. (Marcel Dekker, New Yrk), pp Chu, B. (1995) Langmuir 11, Alexandridis, P., Hlzwarth, J. F. & Hattn, T. A. (1994) Macrmlecules 27, Lecture 8 Physical gels 12 f 12