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Improving the stability of chitosan–gelatin-based hydrogels for cell delivery using transglutaminase and controlled release of doxycycline

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Abstract

Although local cell delivery is an option to repair tissues, particularly using chitosan-based hydrogels, significant attrition of injected cells prior to engraftment has been a problem. To address this problem, we explored the possibility of stabilizing the chitosan–gelatin (CG) injectable hydrogels using (1) controlled release of doxycycline (DOX) to prevent premature degradation due to increased gelatinase activity (MMP-2 and MMP-9), and (2) transglutaminase (TG) to in situ cross-link gelatin to improve the mechanical stability. We prepared DOX-loaded PLGA nanoparticles, loaded into the CG hydrogels, measured DOX release for 5 days, and modeled using a single-compartmental assumption. Next, we assessed the influence of TG and DOX on hydrogel compression properties by incubating hydrogels for 7 days in PBS. We evaluated the effect of these changes on retention of fibroblasts and alterations in MMP-2/MMP-9 activity by seeding 500,000 fibroblasts for 5 days. These results showed that 90 % of DOX released from cross-linked CG hydrogels after 4 days, unlike CG hydrogels where 90 % of DOX was released within the first day. Addition of TG enhanced the CG hydrogel stability significantly. More than 60 % of seeded fibroblasts were recovered from the CG-TG hydrogels at day 5, unlike 40 % recovered from CG-hydrogels. Inhibition of MMP-2/MMP-9 were observed. In summary, controlled release of DOX from CG hydrogels cross-linked with TG shows a significant potential as a carrier for cell delivery.

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Acknowledgments

Financial support was provided by the Oklahoma Center for Advancement of Science and Technology (HR12-023) and by the Edward Joullian Endowment. CJT is a McNair Scholar and CA was supported by Wentz Scholarship and Niblack Scholarship.

Conflict of interest

There are no conflict of interests to disclose.

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Authors and Affiliations

  1. School of Chemical Engineering, Oklahoma State University, 208 Cordell North, Stillwater, OK, 74078, USA

    Christian J. Tormos, Carol Abraham & Sundararajan V. Madihally

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  1. Christian J. Tormos
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  2. Carol Abraham
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  3. Sundararajan V. Madihally
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Correspondence to Sundararajan V. Madihally.

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Tormos, C.J., Abraham, C. & Madihally, S.V. Improving the stability of chitosan–gelatin-based hydrogels for cell delivery using transglutaminase and controlled release of doxycycline. Drug Deliv. and Transl. Res. 5, 575–584 (2015). https://doi.org/10.1007/s13346-015-0258-7

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