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A ready-to-use, thermoresponsive, and extended-release delivery system for the paranasal sinuses

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Abstract

A drug delivery system for the paranasal sinuses consisting of a freeze-dried thermoresponsive hydrogel with degradable microspheres, called FD-TEMPS (Freeze Dried—Thermogel, Extended-release Microsphere-based delivery to the Paranasal Sinuses), was developed. Glass transition temperatures (Tg′) of the maximally freeze concentrated solutions consisting of poly(N-isopropylacrylamide) (pNIPAAm) and polyethylene glycol (PEG) were determined by differential scanning calorimetry, which informed optimization of the thermogel formulation. By replacing low molecular weight (MW) PEG (200 Da) with a higher MW PEG (2000 Da), the resulting freeze-dried gel exhibited a brittle texture, porous structure, and low residual moisture (< 3% measured by thermal gravimetric analysis). When combined with poly(lactic-co-glycolic acid) microspheres (PLGA MSs) and freeze dried, the complete system (FD-TEMPS) exhibited enhanced shelf-stability. Specifically, the smooth, spherical morphology of the MSs and initial release kinetics were maintained following 6 weeks of storage under ambient conditions. Furthermore, FD-TEMPS remained in place after application to a simulated mucosal surface, suggesting that it could be more uniformly distributed along the sinonasal mucosa in vivo. Freeze drying enables this delivery system to be stored as a ready-to-use product for better ease of clinical translation without compromising the thermoresponsive or sustained release characteristics that would enable local delivery of therapeutics to the sinonasal mucosa.

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Acknowledgements

The work was supported by not-for-profit funding received through the Eye & Ear Foundation of Pittsburgh. The authors would like thank Dr. Dan Lamont for assistance with the thermal analysis. The graphical abstract was created with Biorender.com.

Funding

The work was supported by not-for-profit funding received through the Eye & Ear Foundation of Pittsburgh.

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Authors and Affiliations

  1. Department of Chemical Engineering, University of Pittsburgh, 940 Benedum Hall, 3700 O’Hara Street, Pittsburgh, PA, 15213, USA

    Andrea L. Schilling, Erin Cannon, Susan K. Fullerton-Shirey & Steven R. Little

  2. Department of Electrical and Computer Engineering, University of Pittsburgh, 1238 Benedum Hall, 3700 O’Hara Street, Pittsburgh, PA, 15213, USA

    Susan K. Fullerton-Shirey

  3. Department of Otolaryngology—Head and Neck Surgery, University of Pittsburgh Medical Center, 1400 Locust Street, Suite 2100, Pittsburgh, PA, 15219, USA

    Stella E. Lee & Eric W. Wang

  4. Department of Bioengineering, University of Pittsburgh, 302 Benedum Hall, 3700 O’Hara Street, Pittsburgh, PA, 15213, USA

    Steven R. Little

  5. Department of Clinical and Translational Science, University of Pittsburgh, Forbes Tower, Suite 7057, Pittsburgh, PA, 15213, USA

    Steven R. Little

  6. McGowan Institute for Regenerative Medicine, University of Pittsburgh, 450 Technology Drive, Suite 300, Pittsburgh, PA, 15219, USA

    Steven R. Little

  7. Department of Immunology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA, 15213, USA

    Steven R. Little

  8. Department of Pharmaceutical Science, University of Pittsburgh, 3501 Terrace Street, Pittsburgh, PA, 15213, USA

    Steven R. Little

Authors
  1. Andrea L. Schilling
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  2. Erin Cannon
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  3. Susan K. Fullerton-Shirey
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  4. Stella E. Lee
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  5. Eric W. Wang
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Contributions

A.L.S., S.E.L., E.W.W., and S.R.L. conceived of the presented idea. A.L.S. and E.C. carried out the experimental work with support from S.K.F. A.L.S. wrote the manuscript with input from E.C., S.K.F., S.E.L., E.W.W., and S.R.L.

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Correspondence to Steven R. Little.

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Schilling, A.L., Cannon, E., Fullerton-Shirey, S.K. et al. A ready-to-use, thermoresponsive, and extended-release delivery system for the paranasal sinuses. Drug Deliv. and Transl. Res. 12, 708–719 (2022). https://doi.org/10.1007/s13346-021-01069-3

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