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Thermoresponsive Gelatin/Monomethoxy Poly(Ethylene Glycol)–Poly(d,l-lactide) Hydrogels: Formulation, Characterization, and Antibacterial Drug Delivery

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Purpose

The primary objective of this study was to prepare novel thermoresponsive binary component hydrogels composed of gelatin and monomethoxy poly(ethylene glycol)–poly(d,l-lactide) (MPEG–PDLLA) diblock copolymer and to obtain optimal formulations capable of forming gels upon a narrow temperature range between body temperature and room temperature.

Methods

MPEG–PDLLA diblock copolymers with a lower critical solution temperature (LCST) feature were synthesized by using a ring-opening polymerization method. The starting weight ratio of MPEG/DLLA was varied to obtain a series of copolymers with a wide range of molecular weight and hydrophilicity. The copolymers were characterized by 1H nuclear magnetic resonance (1H NMR) and thermogravimetric analysis. MPEG (2K)–PDLLA (1:4) was chosen to construct hydrogels with gelatin. To obtain optimal thermoresponsive formulation, various hydrogels were formulated and quantified in terms of sol–gel phase transition kinetics and rheological properties. Selected hydrogels were studied as drug carrier for gentamicin sulfate.

Results

Gelatin/MPEG–PDLLA hydrogels underwent gelation in less than 15 min when 30 wt.% MPEG (2K)–PDLLA (1:4) was mixed with 10, 50, or 100 mg/mL gelatin. Hydrogels showed rapid gelation when 100 mg/mL gelatin was mixed with 15, 20, or 25 wt.% MPEG–PDLLA as temperature fell from 37°C to room temperature. The viscosity of hydrogels depended on the frequency applied in the rheological tests, the environment temperature, and the concentration of both polymer components. The time needed for 50% gentamicin sulfate release was 5 days or longer at room temperature, and the release lasted up to 40 days. 1H NMR confirmed that MPEG–PDLLA hydrolyzed under in vitro situations.

Conclusions

The incorporation of a second polymer component MPEG–PDLLA into the gelatin hydrogel could modify the thermal characteristic of gelatin and the resulting binary component hydrogels obtained different thermal characteristics from the individual polymer components. Formulation of gelatin/MPEG–PDLLA hydrogels could be varied for obtaining such gels that can undergo gelation promptly upon a narrow temperature change.

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References

  1. K. Y. Lee D. J. Mooney (2001) ArticleTitleHydrogels for tissue engineering Chem. Rev. 101 1869–1879 Occurrence Handle1:CAS:528:DC%2BD3MXjvFSqu7w%3D Occurrence Handle11710233

    CAS  PubMed  Google Scholar 

  2. A. S. Hoffman (2002) ArticleTitleHydrogels for biomedical applications Adv. Drug Deliv. Rev. 54 3–12 Occurrence Handle10.1016/S0169-409X(01)00239-3 Occurrence Handle1:CAS:528:DC%2BD38XhvVWg Occurrence Handle11755703

    Article  CAS  PubMed  Google Scholar 

  3. Y. Qiu K. Park (2001) ArticleTitleEnvironment-sensitive hydrogels for drug delivery Adv. Drug Deliv. Rev. 53 321–339 Occurrence Handle10.1016/S0169-409X(01)00203-4 Occurrence Handle1:CAS:528:DC%2BD3MXovFyrtbg%3D Occurrence Handle11744175

    Article  CAS  PubMed  Google Scholar 

  4. N. A. Peppas P. Bures W. Leobandung H. Ichikawa (2000) ArticleTitleHydrogels in pharmaceutical formulations Eur. J. Pharm. Biopharm. 50 27–46 Occurrence Handle1:CAS:528:DC%2BD3cXjslyju7Y%3D Occurrence Handle10840191

    CAS  PubMed  Google Scholar 

  5. M. W. Davis J. P. Vacanti (1996) ArticleTitleToward development of an implantable tissue engineered liver Biomaterials 17 365–372 Occurrence Handle10.1016/0142-9612(96)85575-X Occurrence Handle1:CAS:528:DyaK28XovVSmtA%3D%3D Occurrence Handle8745334

    Article  CAS  PubMed  Google Scholar 

  6. Q. Hou P. A. De Bank K. M. Shakesheff (2004) ArticleTitleInjectable scaffolds for tissue regeneration J. Mater. Chem. 14 1915–1923 Occurrence Handle10.1039/b401791a Occurrence Handle1:CAS:528:DC%2BD2cXlt1alsbg%3D

    Article  CAS  Google Scholar 

  7. B. Jeong Y. H. Bae D. S. Lee S. W. Kim (1997) ArticleTitleBiodegradable block copolymers as injectable drug-delivery systems Nature 388 860–862 Occurrence Handle1:CAS:528:DyaK2sXlslajur8%3D Occurrence Handle9278046

    CAS  PubMed  Google Scholar 

  8. B. Jeong Y. K. Choi Y. H. Bae G. Zentner S. W. Kim (1999) ArticleTitleNew biodegradable polymers for injectable drug delivery systems J. Control. Release 62 109–114 Occurrence Handle10.1016/S0168-3659(99)00061-9 Occurrence Handle1:CAS:528:DyaK1MXmsV2qsr4%3D Occurrence Handle10518642

    Article  CAS  PubMed  Google Scholar 

  9. Y. Tabata Y. Ikada (1998) ArticleTitleProtein release from gelatin matrixes Adv. Drug Deliv. Rev. 31 287–301 Occurrence Handle10.1016/S0169-409X(97)00125-7 Occurrence Handle1:CAS:528:DyaK1cXhvVSjsb4%3D Occurrence Handle10837630

    Article  CAS  PubMed  Google Scholar 

  10. E. S. Gil S. M. Hudson (2004) ArticleTitleStimuli-responsive polymers and their bioconjugates Prog. Polym. Sci. 29 1173–1222 Occurrence Handle10.1016/j.progpolymsci.2004.08.003 Occurrence Handle1:CAS:528:DC%2BD2cXps1OksLo%3D

    Article  CAS  Google Scholar 

  11. G. J. Martinez-diaz D. Nelson W. C. Crone W. J. Kao (2003) ArticleTitleMechanical and chemical analysis of gelatin-based hydrogel degradation Macromol. Chem. Phys. 204 1898–1908 Occurrence Handle1:CAS:528:DC%2BD3sXovVahsLg%3D

    CAS  Google Scholar 

  12. Y. Otani Y. Tabata Y. Ikada (1996) ArticleTitleRapidly curable biological glue composed of gelatin and poly(l-glutamic acid) Biomaterials 17 1387–1391 Occurrence Handle10.1016/0142-9612(96)87279-6 Occurrence Handle1:CAS:528:DyaK28Xks1elt7w%3D Occurrence Handle8830964

    Article  CAS  PubMed  Google Scholar 

  13. J. L. Zilinski W. J. Kao (2004) ArticleTitleTissue adhesiveness and host response of in situ photopolymerizable interpenetrating networks containing methylprednisolone acetate J. Biomed. Mater. Res., A 68 392–400

    Google Scholar 

  14. J. A. Burmania G. J. Martinez-Diaz W. J. Kao (2003) ArticleTitleSynthesis and physicochemical analysis of interpenetrating networks containing modified gelatin and poly(ethylene glycol) diacrylate J. Biomed. Mater. Res., A 67 224–234

    Google Scholar 

  15. J. A. Burmania K. R. Stevens W. J. Kao (2003) ArticleTitleCell interaction with protein-loaded interpenetrating networks containing modified gelatin and poly(ethylene glycol) diacrylate Biomaterials 24 3921–3930 Occurrence Handle10.1016/S0142-9612(03)00270-9 Occurrence Handle1:CAS:528:DC%2BD3sXkvFels7s%3D Occurrence Handle12834587

    Article  CAS  PubMed  Google Scholar 

  16. K. R. Stevens N. J. Einerson J. A. Burmania W. J. Kao (2002) ArticleTitleIn vivo biocompatibility of gelatin-based hydrogels and interpenetrating networks J. Biomater. Sci., Polym. Ed. 13 1353–1366 Occurrence Handle10.1163/15685620260449741 Occurrence Handle1:CAS:528:DC%2BD3sXhtVWrtLY%3D

    Article  CAS  Google Scholar 

  17. M. Changez K. Burugapalli V. Koul V. Choudhary (2003) ArticleTitleThe effect of composition of poly(acrylic acid)-gelatin hydrogel on gentamicin sulphate release: in vitro Biomaterials 24 527–536 Occurrence Handle10.1016/S0142-9612(02)00364-2 Occurrence Handle1:CAS:528:DC%2BD38XoslSqsbw%3D Occurrence Handle12437947

    Article  CAS  PubMed  Google Scholar 

  18. M. C. Tate D. A. Shear S. W. Hoffman D. G. Stein M. C. LaPlaca (2001) ArticleTitleBiocompatibility of methylcellulose-based constructs designed for intracerebral gelation following experimental traumatic brain injury Biomaterials 22 1113–1123 Occurrence Handle10.1016/S0142-9612(00)00348-3 Occurrence Handle1:CAS:528:DC%2BD3MXisVWju70%3D Occurrence Handle11352091

    Article  CAS  PubMed  Google Scholar 

  19. A. Chenite C. Chaput D. Wang C. Combes M. D. Buschmann C. D. Hoemann J. C. Leroux B. L. Atkinson F. Binette A. Selmani (2000) ArticleTitleNovel injectable neutral solutions of chitosan form biodegradable gels in situ Biomaterials 21 2155–2161 Occurrence Handle10.1016/S0142-9612(00)00116-2 Occurrence Handle1:CAS:528:DC%2BD3cXls1Cltb0%3D Occurrence Handle10985488

    Article  CAS  PubMed  Google Scholar 

  20. C. E. Kast W. Frick U. Losert A. Bernkop-Schnurch (2003) ArticleTitleChitosan–thioglycolic acid conjugate: a new scaffold material for tissue engineering? Int. J. Pharm. 256 183–189 Occurrence Handle10.1016/S0378-5173(03)00076-0 Occurrence Handle1:CAS:528:DC%2BD3sXivVGjtrY%3D Occurrence Handle12695025

    Article  CAS  PubMed  Google Scholar 

  21. B. Jeong K. M. Lee A. Gutowska Y. H. An (2002) ArticleTitleThermogelling biodegradable copolymer aqueous solutions for injectable protein delivery and tissue engineering Biomacromolecules 3 865–868 Occurrence Handle10.1021/bm025536m Occurrence Handle1:CAS:528:DC%2BD38XjvVaju70%3D Occurrence Handle12099835

    Article  CAS  PubMed  Google Scholar 

  22. R. A. Stile K. E. Healy (2001) ArticleTitleThermo-responsive peptide-modified hydrogels for tissue regeneration Biomacromolecules 2 185–194 Occurrence Handle10.1021/bm0000945 Occurrence Handle1:CAS:528:DC%2BD3MXptFOrtA%3D%3D Occurrence Handle11749171

    Article  CAS  PubMed  Google Scholar 

  23. H.-H. Lin Y.-L. Cheng (2001) ArticleTitleIn-situ thermoreversible gelation of block and star copolymers of poly(ethylene glycol) and poly(N-isopropylacrylamide) of varying architectures Macromolecules 34 3710–3715 Occurrence Handle1:CAS:528:DC%2BD3MXivVyhs7s%3D

    CAS  Google Scholar 

  24. R. A. Stile W. R. Burghardt K. E. Healy (1999) ArticleTitleSynthesis and characterization of injectable poly(N-isopropylacrylamide)-based hydrogels that support tissue formation in vitro Macromolecules 32 7370–7379 Occurrence Handle10.1021/ma990130w Occurrence Handle1:CAS:528:DyaK1MXmsVKntrs%3D

    Article  CAS  Google Scholar 

  25. A. Lucke J. Tessmar E. Schnell G. Schmeer A. Gopferich (2000) ArticleTitleBiodegradable poly(d,l-lactic acid)–poly(ethylene glycol)–mono-methyl ether diblock copolymers: structures and surface properties relevant to their use as biomaterials Biomaterials 21 2361–2370 Occurrence Handle10.1016/S0142-9612(00)00103-4 Occurrence Handle1:CAS:528:DC%2BD3cXmslKmt78%3D Occurrence Handle11055283

    Article  CAS  PubMed  Google Scholar 

  26. J. C. Gilbert J. L. Richardson M. C. Davies K. J. Palin J. Hadgraft (1987) ArticleTitleThe effect of solutes and polymers on the gelation properties of Pluronic F-127 solutions for controlled drug delivery J. Control. Release 5 113–118 Occurrence Handle10.1016/0168-3659(87)90002-2 Occurrence Handle1:CAS:528:DyaL2sXmtVGjtbg%3D

    Article  CAS  Google Scholar 

  27. X. Zhang U. P. Wyss D. Pichora M. F. Goosen (1994) ArticleTitleBiodegradable controlled antibiotic release devices for osteomyelitis: optimization of release properties J. Pharm. Pharmacol. 46 718–724 Occurrence Handle1:CAS:528:DyaK2cXms1entb0%3D Occurrence Handle7837040

    CAS  PubMed  Google Scholar 

  28. S. S. Sampath D. H. Robinson (1990) ArticleTitleComparison of new and existing spectrophotometric methods for the analysis of tobramycin and other aminoglycosides J. Pharm. Sci. 79 428–431 Occurrence Handle1:CAS:528:DyaK3cXks1GgtLc%3D Occurrence Handle2352163

    CAS  PubMed  Google Scholar 

  29. M. J. Song D. S. Lee J. H. Ahn D. J. Kim S. C. Kim (2004) ArticleTitleThermosensitive sol–gel transition behaviors of poly(ethylene oxide)/aliphatic polyester/poly(ethylene oxide) aqueous solutions J. Polym. Sci., Part A: Polym. Chem. 42 772–784 Occurrence Handle1:CAS:528:DC%2BD2cXotFGkuw%3D%3D

    CAS  Google Scholar 

  30. Y. M. Chung K. L. Simmons A. Gutowska B. Jeong (2002) ArticleTitleSol–gel transition temperature of PLGA-g-PEG aqueous solutions Biomacromolecules 3 511–516 Occurrence Handle10.1021/bm0156431 Occurrence Handle1:CAS:528:DC%2BD38XitlOks7s%3D Occurrence Handle12005522

    Article  CAS  PubMed  Google Scholar 

  31. T. Yoshida M. Takahashi T. Hatakeyama H. Hatakeyama (1998) ArticleTitleAnnealing induced gelation of xanthan/water systems Polymer 39 1119–1122 Occurrence Handle10.1016/S0032-3861(97)00266-8 Occurrence Handle1:CAS:528:DyaK1cXksFKhtw%3D%3D

    Article  CAS  Google Scholar 

  32. G. Wanka H. Hoffmann W. Ulbricht (1990) ArticleTitleThe aggregation behavior of poly(oxyethylene)–poly(oxypropylene)– poly(oxyethylene) block copolymers in aqueous solution Colloid Polym. Sci. 268 101–117 Occurrence Handle10.1007/BF01513189 Occurrence Handle1:CAS:528:DyaK3cXhvVSgtLc%3D

    Article  CAS  Google Scholar 

  33. J. W. Mwangi C. M. Ofner (2004) ArticleTitleCrosslinked gelatin matrices: release of a random coil macromolecular solute Int. J. Pharm. 278 319–327 Occurrence Handle10.1016/j.ijpharm.2004.03.024 Occurrence Handle1:CAS:528:DC%2BD2cXkslKlsr4%3D Occurrence Handle15196637

    Article  CAS  PubMed  Google Scholar 

  34. K. Terao N. Nagasawa H. Nishida K. Furusawa Y. Mori F. Yoshii T. Dobashi (2003) ArticleTitleReagent-free crosslinking of aqueous gelatin: manufacture and characteristics of gelatin gels irradiated with gamma-ray and electron beam J. Biomater. Sci., Polym. Ed. 14 1197–1208 Occurrence Handle10.1163/156856203322553437 Occurrence Handle1:CAS:528:DC%2BD3sXps1Ois7g%3D

    Article  CAS  Google Scholar 

  35. S. Yoshizawa D. Fourmy J. D. Puglisi (1998) ArticleTitleStructural origins of gentamicin antibiotic action EMBO J. 17 6437–6448 Occurrence Handle10.1093/emboj/17.22.6437 Occurrence Handle1:CAS:528:DyaK1cXnvF2jsbs%3D Occurrence Handle9822590

    Article  CAS  PubMed  Google Scholar 

  36. R. E. Botto B. Coxon (1983) ArticleTitleNitrogen-15 nuclear magnetic resonance spectroscopy of neomycin B and related aminoglycosides J. Am. Chem. Soc. 105 1021–1028 Occurrence Handle10.1021/ja00342a062 Occurrence Handle1:CAS:528:DyaL3sXovFOrtA%3D%3D

    Article  CAS  Google Scholar 

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Acknowledgments

The authors thank Ms. Amy Gustafson for testing the sol–gel phase transitions of hydrogels and for proofreading this manuscript, Professor Lian Yu and Mr. Jun Huang for the assistance with TGA tests, and Professor Daniel J. Klingenberg and Mr. Prakorn Kittipoomwong for the assistance with rheological measurements. This work was supported in part by NIH Grants HL-077825 and EB-00290.

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Author notes

  1. Hu Yang

    Present address: Department of Biomedical Engineering, School of Engineering, Virginia Commonwealth University, Richmond, Virginia, 23298, USA

Authors and Affiliations

  1. School of Pharmacy, University of Wisconsin–Madison, Madison, Wisconsin, 53705, USA

    Hu Yang & Weiyuan John Kao

  2. Department of Biomedical Engineering, College of Engineering, University of Wisconsin–Madison, Madison, Wisconsin, 53705, USA

    Weiyuan John Kao

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  1. Hu Yang
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Correspondence to Weiyuan John Kao.

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Yang, H., Kao, W.J. Thermoresponsive Gelatin/Monomethoxy Poly(Ethylene Glycol)–Poly(d,l-lactide) Hydrogels: Formulation, Characterization, and Antibacterial Drug Delivery. Pharm Res 23, 205–214 (2006). https://doi.org/10.1007/s11095-005-8417-z

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