Thermoresponsive and Covalently Cross-Linkable Hydrogels for Intra-Articular Drug Delivery

David Andrew Prince; Ian J Villamagna; Aneta Borecki; Frank Beier; John R de Bruyn; Mark Hurtig; Elizabeth R Gillies

doi:10.1021/acsabm.9b00410

Thermoresponsive and Covalently Cross-Linkable Hydrogels for Intra-Articular Drug Delivery

ACS Appl Bio Mater. 2019 Aug 19;2(8):3498-3507. doi: 10.1021/acsabm.9b00410. Epub 2019 Jul 31.

Authors

David Andrew Prince¹, Ian J Villamagna^{2

3}, Aneta Borecki^{1

4}, Frank Beier^{3

5}, John R de Bruyn^{4

6}, Mark Hurtig⁷, Elizabeth R Gillies^{1

2

3

4

8}

Affiliations

¹ Department of Chemistry, The University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 5B7, Canada.
² School of Biomedical Engineering, The University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 5B9, Canada.
³ Bone and Joint Institute, The University of Western Ontario, London, Ontario N6A 3K7, Canada.
⁴ Centre for Advanced Materials and Biomaterials Research, The University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 3K7, Canada.
⁵ Department of Physiology and Pharmacology, The University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 3B7, Canada.
⁶ Department of Physics and Astronomy, The University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 3K7, Canada.
⁷ Ontario Veterinary College, Department of Clinical Studies, University of Guelph, 50 Stone Road, Guelph, Ontario N1G 2W1, Canada.
⁸ Department of Chemical and Biochemical Engineering, The University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 5B9, Canada.

PMID: 35030737
DOI: 10.1021/acsabm.9b00410

Abstract

The local delivery of drugs to joints is a recognized strategy in the treatment of osteoarthritis. Hydrogels, particularly those that can be injected as liquids but undergo gelation in the joint, are promising platforms for intra-articular drug delivery. However, their properties must be carefully designed and tuned to achieve sustained drug release, which has been a challenge with previous hydrogels. We describe here the use of a combination of noncovalent thermal gelation and covalent cross-linking with poly(caprolactone-co-lactide)(PCLA)-poly(ethylene glycol)(PEG)-PCLA triblock copolymers to achieve hydrogels with sustained drug release in joints. The hybrid cross-linking approach afforded higher viscoelastic and compression moduli compared to noncovalent cross-linking alone and enabled celecoxib as well as other drugs to be loaded without substantially compromising the mechanical properties. Celecoxib release in vitro was much slower for the hybrid cross-linked hydrogel, with only 20% released over 22 days, compared to 90% released over 22 days for a noncovalently cross-linked hydrogel. Furthermore, the burst release of celecoxib was reduced in vivo in horse joints compared to noncovalent systems, and the drug was detected in synovial fluid for a period of two months. Overall, this new hydrogel system shows significant promise as a platform for further development in intra-articular delivery.

Keywords: celecoxib; cross-linking; drug delivery; hydrogel; intra-articular; thermal gelation.