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Hydrogels as drug-delivery platforms: physicochemical barriers and solutions

    Lamees B Alkayyali

    Queen’s University Belfast, School of Pharmacy, The Drug Delivery & Biomaterials Group, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UK

    ,
    Osama A Abu-Diak

    Queen’s University Belfast, School of Pharmacy, The Drug Delivery & Biomaterials Group, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UK

    ,
    Gavin P Andrews

    Queen’s University Belfast, School of Pharmacy, The Drug Delivery & Biomaterials Group, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UK

    &
    David S Jones

    * Author for correspondence

    Queen’s University Belfast, School of Pharmacy, The Drug Delivery & Biomaterials Group, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UK.

    Published Online:https://doi.org/10.4155/tde.12.48

    The properties of hydrogels, in particular their high biocompatibility and water sorption uptake, make hydrogels very attractive in drug delivery and biomedical devices. These favorable features of hydrogels are compromised by certain structural limitations such as those associated with their low mechanical strength in the swollen state. This review highlights the most important challenges that may seriously affect the practical implementation of hydrogels in clinical practice and the solutions that may be applied to overcome these limitations.

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

    References

    • Berger J, Reist M, Mayer JM, Felt O, Gurny R. Structure and interactions in covalently and ionically crosslinked chitosan hydrogels for biomedical applications. Eur. J. Pharm. Biopharm.57,19–34 (2004).▪ Presents a critical analysis of covalently and ionically crosslinked chitosan hydrogels and related networks for medical/pharmaceutical applications.
    • Peppas NA, Bures P, Leobandung W, Chikqwa H. Hydrogels in pharmaceutical formulations. Eur. J. Pharm. Biopharm.50,27–46 (2000).▪▪ Describes the applications of hydrogels in the pharmaceutical field, hydrogel characterization and classification, and drug-release mechanisms.
    • Hoffman AS. Hydrogels for biomedical applications. Adv. Drug Deliv. Rev.43,3–12 (2002).
    • Lin CC, Metters AT. Hydrogels in controlled release formulations: network design and mathematical modelling. Adv. Drug Deliv. Rev.58,1379–1408 (2006).▪ Focuses on the challenges associated with mathematical modeling of drug release from different types of hydrogels.
    • Jagur-Grodzinski J. Polymeric gels and hydrogels for biomedical and pharmaceutical applications. Polym. Adv. Technol.21,27–47 (2010).
    • Costa-Junior ES, Barbosa-Stancioli EF, Mansur AP, Vasconcelos WL, Mansur HS. Preparation and characterization of chitosan/poly(vinyl) alcohol chemically crosslinked blends for biomedical applications. Carbohydr. Polym.76,472–481 (2009).
    • Amsden B. Solute diffusion within hydrogels: mechanisms and models. Macromolecules31,8382–8395 (1998).
    • Peppas NA, Mikos AG. Preparation methods and structure of hydrogels. In: Hydrogels in Medicine and Pharmacy (Volume 1). Peppas NA (Ed.). CRC Press, Boca Raton, FL, USA, 1–27 (1986).
    • Anseth KS, Bownman, CN, Brannon-Peppas L. Mechanical properties of hydrogels and their experimental determination. Biomaterials17,1647–1657 (1996).▪ Highlights the importance of investigating the mechanical properties of hydrogels in assessing their in vivo applications.
    • 10  Davis TP, Huglin MB. Effect of composition on properties of copolymeric N-vinyl-2–7 pyrrolidone /methylmethacrylate hydrogels and organogels. Polymer31,513–519 (1990).
    • 11  Vogel MK, Cross RA, Bixler HJ, Guzman RJ. Medical uses for polyelectrolyte complexes. J. Macromol. Sci. Chem.4,675–692 (1970).
    • 12  Bhattarai N, Gunn J, Zhang M. Chitosan-based hydrogels for controlled, localized drug delivery. Adv. Drug Deliv. Rev.62,83–99 (2010).
    • 13  Drury JL, Dennis RG, Mooney DJ. The tensile properties of alginate hydrogels. Biomaterials25,3187–3199 (2004).
    • 14  Jeffrey L, Hinkley A, Morgret LD, Gehrke SH. Tensile properties of two responsive hydrogels. Polymer45,8837–8843 (2004).
    • 15  Svensson A, Nicklasson E, Harrah T et al. Bacterial cellulose as a potential scaffold for tissue engineering of cartilage. Biomaterials26,419–431(2005).
    • 16  Awad HA, Quinn Wickham M, Leddy HA, Gimble JM, Guilak F. Chondrogenic differentiation of adipose-derived adult stem cells in agarose, alginate and gelatine scaffolds. Biomaterials25,3211–3222 (2004).
    • 17  Ranta-Eskola AJ. Use of the hydraulic bulge test in biaxial tensile testing. Int. J. Mech. Sci.21,457–465 (1979).
    • 18  Tsakalakos T. The bulge test: a comparison of the theory and experiment for isotropic and anisotropic films. Thin Solid Films75,293–305 (1981).
    • 19  Mirshams RA, Pothapragada RM. Correlation of nanoindentation measurements of nickel made using geometrically different indenter tips. Acta Mater.54,1123–1134 (2006).
    • 20  De Groot CJ, Van Luyn MJA, Van Dijk-Wolthuis WNE et al.In vitro biocompatibility of biodegradable dextran-based hydrogels tested with human fibroblasts. Biomaterials22,1197–1203 (2001).
    • 21  Jatav, VS, Singh, H, Singh, SK. Recent trends on hydrogel in human body. Int. J. Res. Pharm. Biomed. Sci.2,442–447 (2011).
    • 22  Pal K, Banthia AK, Majumdar DK. Polymeric hydrogels: characterization and biomedical applications – a mini review. Designed Monomers Polym.12,197–220 (2009).
    • 23  Biazar E, Roveimiab Z, Shahhosseini G, Khataminezhad M, Zafari M, Majdi A. Biocompatibility evaluation of a new hydrogel dressing based on polyvinylpyrrolidone/polyethylene glycol. J. Biomed. Biotechnol. doi:10.1155/2012/343989 (2012) (Epub ahead of print).
    • 24  Danielsson C, Ruault S, Simoneth M, Neuenschwander P, Freya P. Polyesterurethane foam scaffold for smooth muscle cell tissue engineering. Biomaterials27,1410–1415 (2006).
    • 25  Sajeesh S, Bouchemal K, Sharma CP, Vauthier C. Surface-functionalized polymethacrylic acid based hydrogel microparticles for oral drug delivery. Eur. J. Pharm. Biopharm.74,209–218 (2010).
    • 26  Liang L, Xu XD, Chen CS et al. Evaluation of the biocompability of novel peptide hydrogel in rabbit eye. J. Biomed. Mater. Res. B Appl. Biomater.93,324–332 (2010).
    • 27  Patel VR, Amji MM. Preparation and characterization of freeze-dried chitosan and poly(ethylene oxide) hydrogels for site-specific antibiotic delivery in the stomach. Pharm. Res.13,588–593 (1996).
    • 28  Yamaguta T, Morishita M, Kavimandan NJ et al. Characterisation of insulin protection properties of complexation hydrogels in gastric and intestinal enzyme fluids. J. Control Release112,343–349 (2006).
    • 29  Alvarez-Lorenzo C, Yanez F, Concheiro A. Ocular drug delivery from molecularly-imprinted contact lenses. J. Drug Deliv. Sci. Technol.20,237–248 (2010).
    • 30  Xinming l, Yingde C, Lloyd AW et al. Uptake and release of dexamethasone phosphate from silicone hydrogel and group I, II, and IV hydrogel contact lenses. Cont. Lens Anterior Eye31,57–64 (2008).
    • 31  Andrade-Vivero P, Fernandez-Gabriel E, Alvarez-Lorenzo C, Concheiro A. Improving the loading and release of NSAIDs from pHEMA hydrogels by copolymerization with functionalized monomers. J. Pharm. Sci.96,802–813 (2007).
    • 32  Gulsen D, Chauhan A. Dispersion of microemulsion drops in HEMA hydrogel: a potential ophthalmic drug delivery vehicle. Int. J. Pharm.292,95–117 (2005).
    • 33  Carlfors J, Edsman K, Perterson R, Jonving K. Rheological evaluation of Gelrite in situ gels for ophthalmic use. Eur. J. Pharm. Sci.6,113–119 (1998).
    • 34  Moriyama K, Yui N. Regulated insulin release from biodegradable dextran hydrogels containing polyethylene glycol. J. Control Release42,237–248 (1996).
    • 35  Megeed Z, Cappello J, Ghandehari H. In vitro and in vivo evaluation of recombinant silk-elastin like hydrogels for cancer gene therapy. J. Control Release94,433–445 (2004).
    • 36  Quick D, Anseth K. DNA delivery from photocrosslinked PEG hydrogels: encapsulation efficiency, release profiles, and DNA quality. J. Control Release96,341–351 (2004).
    • 37  Lei P, Padmashali RM, Andreadis ST. Cell-controlled and spatially arrayed gene delivery from fibrin hydrogels. Biomaterials30,3790–3799 (2009).
    • 38  Wieland JA, Houchin-Ray TL, Shea LD. Non-viral vector delivery from PEG hyaluronic acid hydrogels. J. Control Release120,233–241 (2007).
    • 39  Lei Y, Huwan S, Sharif-Kashani P, Chen Y, Kavehpour P, Segura T. Incorporation of active DNA/cationic polymer polyplexes into hydrogel scaffolds. Biomaterials31,9106–9116 (2010).
    • 40  Nguyen KT, West JL. Photopolymerizable hydrogels for tissue engineering applications. Biomaterials23,4307–4314 (2002).
    • 41  Mann BK, Bobin AS, Tsai AT, Schmedien RH, West JL. Smooth muscle cell growth in photopolymerized hydrogels with cell adhesive and proteolytically degradable domains: synthetic ECM analogs for tissue engineering. Biomaterials22,30–45 (2001).
    • 42  Ferreira P, Coelho JFJ, Dos Santos KSCR, Ferreira EI, Gil MH. Thermal characterization of chitosan-grafted membranes to be used as wound dressings J. Carbohydr. Chem.25,233–251 (2006).
    • 43  West JL, Hubbell JA. Separation of the arterial wall from blood contact using hydrogel barriers reduces intimal thickening after balloon injury in the rat: the roles of hydrogel medial and luminal factors in arterial healing. Proc. Natl Acad. Sci.93,13188–13193 (1996).
    • 44  Hoare TR, Kohane DS. Hydrogels in drug delivery: progress and challenges. Polymer49,1993–2007 (2008).▪▪ Highlights the challenges to improve the clinical applicability of hydrogels for drug delivery and provides solutions to achieve this goal.
    • 45  Long D, Van Luyen D. Chitosan-carboxymethylcellulose hydrogel as supports for cell immobilization. J. Macromol. Sci. Pure Appl. Chem. A33,1875–1884 (1996).
    • 46  Tsao TC, Chang CH, Lin YY et al. Antibacterial activity and biocompatibility of a chitosan–c-poly(glutamic acid) polyelectrolyte complex hydrogel. Carbohydr. Res.345,1774–1780 (2010).
    • 47  Shaha HK, Conkieb JA, Tait RC, Johsona JR, Wisona CG. A novel biodegradable and reversible polyelectrolyte platform for topical-colonic delivery of pentosan polysulphate. Int. J. Pharm.404,124–132 (2011).
    • 48  Chellat F, Tabrizian M, Dumitriu S et al.In vitro and in vivo biocompatibility of chitosan–xanthanpolyionic complex. J. Biomed. Mater. Res.51,107–116 (2000).
    • 49  Sakiyama T, Takata H, Kikuchi M, Nakanishi K. Polyelectrolyte complex gel with high pH-sensitivity prepared from dextran sulphate and chitosan. J. Appl. Polym. Sci.73,2227–2233 (1999).
    • 50  Feng X, Pelton R. Carboxymethyl cellulose: polyvinylamine complex hydrogel swelling. Macromolecules40,1624–1630 (2007).
    • 51  Piyakulawat P, Praphairaksit N, Chantarasiri N, Muangsin N. Preparation and evaluation of chitosan/carrageenan beads for controlled release of sodium diclofenac. AAPS Pharm. Sci. Tech.8(4),E97 (2007).
    • 52  Beauchamp RO, St Clair MB, Fennell TR, Clarke DO, Morgan KT. A critical review of the toxicology of glutaraldehyde. Crit. Rev. Toxicol.22,143–174 (1992).
    • 53  Murata-Kamiya N, Kamiya H, Kaji H, Kasai H. Mutational specificity of glyoxal, a product of DNA oxidation, in the lacI gene of wild-type Escherichia coli. Mutat. Res.377,255–262 (1997).
    • 54  Mi FL, Tan YC, Liang HF, Sung HW. In vivo biocompatibility and degradability of a novel injectable-chitosan-based implant. Biomaterials23,181–191 (2002).
    • 55  Ying L, Sun JA, Jiang GQ, Jia Z, Ding FX. In vitro evaluation of lysozyme-loaded microspheres in thermosensitive methylcellulose-based hydrogel. J. Chem. Eng.15,566–572 (2007).
    • 56  Ito T, Yen Y, Highley CB, Bellas E, Benitez CA, Kohane DS. The prevention of peritoneal adhesions by in situ cross-linking hydrogels of hyaluronic acid and cellulose derivatives. Biomaterials28,975–985 (2007).
    • 57  Mastekova R, Chalupova Z, Sklubalova Z. Stimuli sensitive hydrogels in controlled and sustained drug delivery. Micina39,19–24 (2003).▪ Reviews the main stimuli-sensitive hydrogels and their uses as drug-delivery systems.
    • 58  Katchalsky A, Michaeli I. Polyelectrolyte gels in salt solution. J Polym. Sci.15,69–86 (1955).
    • 59  Qiu Y, Park K. Environment-sensitive hydrogels for drug delivery. Adv. Drug Deliv. Rev.53,321–339 (2001).
    • 60  Kim B, Lim SH, Ryoo W. Preparation and characterization of pH-sensitive anionic hydrogel microparticles for oral protein-delivery applications. J. Biomater. Sci. Polym. Ed.20,427–436 (2009).
    • 61  Mahkam M. New interpolymers as hydrogels for oral protein delivery application. J. Drug. Target17(1),29–35 (2009).
    • 62  Nho YC, Park SE, Kim HI, Hwang TS. Oral delivery of insulin using pH-sensitive hydrogels based on polyvinyl alcohol grafted with acrylic acid/methacrylic acid by radiation. Nucl. Instrum. Methods Phys. Res. B236,283–288 (2005).
    • 63  Mundargi RC, Rangaswamy R, Aminabhavi TM. Poly(N-vinylcaproloactam-co-methacrylic acid) hydrogel microparticles for oral insulin delivery. J. Microencapsul.28,384–394 (2011).
    • 64  Gupta KM, Barnes SR, Tangaro RA et al. Temperature and pH sensitive hydrogels: an approach towards smart semen-triggered vaginal microbicidal vehicles. J. Pharm. Sci.96,670–681 (2007).
    • 65  Chang JY, Oh YK, Choi HG, Kim YB, Kim CK. Rheological evaluation of thermosensitive and mucoadhesive vaginal gels in physiological conditions. Int. J. Pharm.241,155–163 (2002).
    • 66  Kohori F, Yokoyama M, Sakai K, Okano T. Process design for efficient and controlled drug incorporation into polymeric micelle carrier systems. J. Control. Release7,155–163 (2002).
    • 67  Chen PC, Kohane DS, Park YJ, Bartlet RH, Langer R, Yang C. Injectable microparticle-gel system for prolonged and localized lidocaine release. II. In vivo anesthetic effects. J. Biomed. Mater. Res. A70,459–466 (2004).
    • 68  Whiting CJ, Voice AM, Omsted PD, McLeish TCB. Shear modulus of polyelectrolyte gels under electric field. J. Phys. Condens. Mater.13,1381–1393 (2001).
    • 69  Ramanathan S, Block LH. The use of chitosan gels as matrices for electrically-modulated drug delivery. J. Control. Release70,109–123 (2001).
    • 70  Kim SJ, Yoon SG, Lee YM, Kim SI. Electrical sensitive behaviour of poly(vinyl alchohol )/poly (diallyldimethylammonium chloride) IPN hydrogel. Sens. ActuatorsB88,286–291 (2003).
    • 71  Liu TY, Hu SH, Liu KH, Liu DM, Chen SY. Preparation and characterization of smart magnetic hydrogels and its use for drug release. J. Magn. Magn. Mater.304,397–399 (2006).
    • 72  Sutter M, Siepmann J, Hennink WE, Jiskoot W. Recombinant gelatin hydrogels for the sustained release of proteins. J. Control. Release119(3),301–312 (2007).
    • 73  Nuttleman CR, Tripodi MC, Anseth KS. Dexamethasone-functionalized gels induce osteogenic differentiation of encapsulated hMSCs. J. Biomed. Mater. Res. A76(1),183–195 (2006).
    • 74  Bouhadir K H, Kruger GM, Lee KY, Mooney DJ. Sustained and controlled release of daunomycin from cross-linked poly(aldehyde guluronate) hydrogels. J. Pharm. Sci.89(7),910–919 (2000).
    • 75  Schoenmakers RG, van de Wetering P, Elbert DL, Hubbell JA. The effect of the linker on the hydrolysis rate of drug-linked ester bonds. J. Control. Release95,291–300 (2004).
    • 76  Slaughter BV, Khurshid SS, Fisher OZ, Khademhosseini A, Peppas NA. Hydrogels in regenerative medicine. Adv. Mater.21,3307–3729 9 (2009).
    • 77  Zhang J, Peppas NA. Molecular interactions in poly (methacrylic acid)/poly (N-isopropyl acrylamide) interpenetrating polymer networks. J. Appl. Polym. Sci.82,1077–1082 (2001).
    • 78  Wang W, Wang A. Synthesis and swelling properties of pH-sensitive semi-IPN superabsorbent hydrogels based on sodium alginate-g-poly(sodium acrylate) and polyvinylpyrrolidone. Carbohydr. Polym.80,1028–1036 (2010).
    • 79  Lee WF, Chen YJ. Studies on preparation and swelling properties of the N-isopropylacrylamide/chitosan semi-IPN and IPN hydrogels. J. Appl. Polym. Sci.82,2487–2496 (2001).
    • 80  Na K, Bae YH. Self-assembled hydrogel nanoparticles responsive to tumor extracellular pH from pullulan derivative/ sulphonamide conjugate: characterization, aggregation and adriamycin release in vitro. Pharm. Res.19,681–688 (2004).
    • 81  Yeo YQ, Yang FL, Hu FQ, Du YZ, Yuan H, Yu HY. Core-modified chitosan based polymeric micelles for controlled release of doxorubicin. Int. J. Pharm.352,294–301 (2008).
    • 82  Bae JW, Go DH, Park KD, Lee SJ. Thermosensitive chitosan as an injectable carrier for local drug delivery. Macromol. Res.14,461–465 (2006).
    • 83  Rahmani-Neishaboor E, Jackson J, Burt H, Ghahary A. Composite hydrogel formulations of Stratifin to control MMP-1 expression in dermal fibroblasts. Pharm. Res.26(8),2002–2014 (2009).
    • 84  Weng L, Le HC, Lin J, Golzarian J. Doxorubicin loading and eluting characteristics of bioresorbable hydrogel microspheres: in vitro study. Int. J. Pharm.409,185–193 (2011).
    • 85  Collier JH, Hu BH, Ruberti JW et al. Thermally and photochemically triggered self-assembly of peptide hydrogels. J. Am. Chem. Soc.123,9463–9464 (2001).
    • 86  Liang L, Yang J, Li Q et al. A novel targeting drug delivery system based on self-assembled peptide hydrogel. J. Biomater. Nanobiotechnol.2,622–625 (2011).
    • 87  Ozbas B, Kretsinger J, Rajagopal K, Schneider JP, Pochan DJ. Salt-triggered peptide folding and consequent self-assembly into hydrogels with tunable modulus. Macromolecules37,7331–7337 (2004).
    • 88  Pochan DJ, Schneider JP, Kretsinger J, Ozbas B, Rajagopal K, Haines L. Thermally reversible hydrogels via intramolecular folding and consequent self-assembly of a de novo designed peptide. J. Am. Chem. Soc.125,11802–11803 (2003).
    • 89  Schneider JP, Pochan DJ, Ozbas B, Rajagopal K, Pakstis L, Kretsinger J. Responsive hydrogels from the intermolecular folding and self-assembly of a designed peptide. J. Am. Chem. Soc.124,15030–15037 (2002).
    • 90  Chung HJ, Park TG. Self-assembled and nanostructured hydrogels for drug delivery and tissue engineering. Nano Today4,429–437 (2009).
    • 91  Atunbas A, Lee SJ, Rajaasekaran SA, Schneider JP, Pochan DJ. Encapsulation of curcumin in self-assembling peptide hydrogels as injectable drug delivery vehicles. Biomaterials32,5906–5914 (2011).
    • 92  Silva GA, Czeisler C, Niece KL et al. Selective differentiation of neural progenitor cells by high-epitope density nanofibers. Science303,1352–1355 (2004).
    • 93  Vemula PK, Cruikshank GA, Karp JM, John G. Self-assembled prodrugs: an enzymatically triggered drug-delivery platform. Biomaterials30,383–393 (2009).
    • 94  Oh JK, Drumright R, Siegwart D, Matyjaszewski K. The development of microgels/nanogels for drug delivery applications. Prog. Polym. Sci.33,448–477 (2008).
    • 95  Kim Y, Thapa M, Hua DH, Chang KO. Biodegradable nanogels for oral delivery of interferon for norovirus infection. Antiviral Res.89,165–173 (2011).
    • 96  Sahiner N, Godbey WT, McPherson GL, John VT. Novel nanogels as drug delivery systems for poorly soluble anticancer drugs. Coll. Polym. Sci.284,1121–1129 (2006).
    • 97  Chen Y, Zheng X, Qian H, Mao Z, Ding D, Jiang X. Hollow core-porous shell structure poly(acrylic acid) nanogels with a super high capacity of drug loading. Appl. Mater. Interfaces2,3532–3538 (2010).
    • 98  Kuckling D, Vo CD, Wohlrab SE. Preparation of nanogels with temperature-responsive core and pH-responsive arms by photo-crosslinking. Langmuir18,4263–4269 (2002).
    • 99  Bhuchar N, Sunasee R, Ishihara K et al. Degradable thermoresponsive nanogels for protein encapsulation and controlled release. Bioconj. Chem.23,75–83 (2012).
    • 100  Ryu JH, Jiwpanich S, Chacko R, Bickerton S, Thaymuanava S. Surface-functionalizable polymer nanogels with facile hydrophobic guest encapsulation capabilities. J. Am. Chem. Soc.132,8246–8247 (2010).
    • 101  Cai C, Bakowsky, U, Rytting E, Schaper AK, Kissel T. Charged nanoparticles as protein delivery systems: a feasibility study using lysozyme as model protein. Eur. J. Pharm. Biopharm.69,31–42 (2008).
    • 102  Smith MH, South AM, Gaulding JC, Lyon LA. Monitoring the erosion of hydrolytically-degradable nanogels via multi angle light scattering coupled to asymmetrical flow field-flow fractionation. Anal. Chem.82,523–530 (2010).
    • 201  Nagai T, Machida Y, Suzuki Y, Ikura H: US4226848 (1980).