Synthesis of Hyaluronic acid-Tyramine Microgels for Sustained Protein Release

Microgels are hydrophilic polymer matrix with high water content suitable for encapsulation and delivery of biomolecules. In this study, hyaluronic acid (HA) microgels were synthesized using a water in oil emulsion method. First, hyaluronic acid was modified with tyramine, and then the microemulsion was produced by homogenizing the polymer solution in isooctane as an oil phase. HA microdroplets were crosslinked via enzymatic method by addition of horseradish peroxidase (enzyme) and hydrogen peroxide, and stable microgels were produced in a mild crosslinking reaction. According to the results, larger microgels were achieved by increasing the initial polymer concentration. Two sample proteins, Bovine serum albumin (BSA) and lysozyme, were incorporated in the polymer network to investigate the encapsulation efficiency of the microgels. The results demonstrated that the proposed method has a high efficiency for protein encapsulation (> 70%). The release profiles showed that lysozyme, as a cationic protein, was released in a sustained manner over a period of two weeks. However, BSA, as a negatively charged protein, showed a faster release rate. The simple method of microgel fabrication, besides the sustained release of the encapsulated proteins, makes the HA microgels a promising vehicle for delivery of cationic proteins.

[1]  P. Podešva,et al.  Tunable uptake/release mechanism of protein microgel particles in biomimicking environment , 2017, Scientific Reports.

[2]  H. Weinans,et al.  Nanoemulsion-induced enzymatic crosslinking of tyramine-functionalized polymer droplets. , 2017, Journal of materials chemistry. B.

[3]  Shewaye Lakew Mekuria,et al.  Polysaccharide based nanogels in the drug delivery system: Application as the carrier of pharmaceutical agents. , 2016, Materials science & engineering. C, Materials for biological applications.

[4]  A. van den Berg,et al.  Enzymatic Crosslinking of Polymer Conjugates is Superior over Ionic or UV Crosslinking for the On-Chip Production of Cell-Laden Microgels. , 2016, Macromolecular bioscience.

[5]  Andrés J. García,et al.  Methods for Generating Hydrogel Particles for Protein Delivery , 2016, Annals of Biomedical Engineering.

[6]  R. Haag,et al.  Enzymatically crosslinked dendritic polyglycerol nanogels for encapsulation of catalytically active proteins. , 2015, Soft matter.

[7]  J. Rong,et al.  Hyaluronan microgel as a potential carrier for protein sustained delivery by tailoring the crosslink network. , 2014, Materials science & engineering. C, Materials for biological applications.

[8]  K. Park,et al.  Enzymatically in situ shell cross-linked micelles composed of 4-arm PPO-PEO and heparin for controlled dual drug delivery. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[9]  Glenn D Prestwich,et al.  Hyaluronic acid-based hydrogels functionalized with heparin that support controlled release of bioactive BMP-2. , 2012, Biomaterials.

[10]  Myron Spector,et al.  Modulation of mesenchymal stem cell chondrogenesis in a tunable hyaluronic acid hydrogel microenvironment. , 2012, Biomaterials.

[11]  Todd Hoare,et al.  Injectable microgel-hydrogel composites for prolonged small-molecule drug delivery. , 2011, Biomacromolecules.

[12]  H. Bysell,et al.  Microgels and microcapsules in peptide and protein drug delivery. , 2011, Advanced drug delivery reviews.

[13]  Xinqiao Jia,et al.  Heparin-decorated, hyaluronic acid-based hydrogel particles for the controlled release of bone morphogenetic protein 2. , 2011, Acta biomaterialia.

[14]  H. Park,et al.  Stability investigation of hyaluronic acid based nanoemulsion and its potential as transdermal carrier , 2011 .

[15]  J. Feijen,et al.  Injectable chitosan-based hydrogels for cartilage tissue engineering. , 2009, Biomaterials.

[16]  M. Kurisawa,et al.  An injectable hyaluronic acid-tyramine hydrogel system for protein delivery. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[17]  M. Kurisawa,et al.  An injectable enzymatically crosslinked hyaluronic acid- hydrogel system with independent tuning of mechanical strength and gelation rate. , 2008, Soft matter.

[18]  J. Kobler,et al.  Hyaluronic acid-based microgels and microgel networks for vocal fold regeneration. , 2006, Biomacromolecules.

[19]  Antonios G Mikos,et al.  Dual growth factor delivery from degradable oligo(poly(ethylene glycol) fumarate) hydrogel scaffolds for cartilage tissue engineering. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[20]  V. Sinha,et al.  Biodegradable microspheres for protein delivery. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[21]  J. Prausnitz,et al.  Lysozyme Net Charge and Ion Binding in Concentrated Aqueous Electrolyte Solutions , 1999 .

[22]  Zhiyuan Zhong,et al.  Enzyme-mediated fast in situ formation of hydrogels from dextran-tyramine conjugates. , 2007, Biomaterials.

[23]  Weiliam Chen,et al.  Hyaluronan microspheres for sustained gene delivery and site-specific targeting. , 2004, Biomaterials.

[24]  A. Takahara,et al.  Bovine serum albumin adsorption onto immobilized organotrichlorosilane surface: influence of the phase separation on protein adsorption patterns. , 1998, Journal of biomaterials science. Polymer edition.