Biocompatibility and intradiscal application of a thermoreversible celecoxib-loaded poly-N-isopropylacrylamide MgFe-layered double hydroxide hydrogel in a canine model

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Introduction

Chronic low back pain due to intervertebral disc (IVD) degeneration is associated with increased levels of inflammatory mediators. Current medical treatment consists of oral anti-inflammatory drugs to alleviate pain. In this study, the efficacy and safety of a novel thermoreversible poly-N-isopropylacrylamide MgFe-layered double hydroxide (pNIPAAM MgFe-LDH) hydrogel was evaluated for intradiscal controlled delivery of the selective cyclooxygenase (COX) 2 inhibitor and anti-inflammatory drug celecoxib (CXB).

Methods

Degradation, release behavior, and the ability of a CXB-loaded pNIPAAM MgFe-LDH hydrogel to suppress prostaglandin E ₂ (PGE ₂) levels in a controlled manner in the presence of a proinflammatory stimulus (TNF-α) were evaluated in vitro. Biocompatibility was evaluated histologically after subcutaneous injection in mice. Safety of intradiscal application of the loaded and unloaded hydrogels was studied in a canine model of spontaneous mild IVD degeneration by histological, biomolecular, and biochemical evaluation. After the hydrogel was shown to be biocompatible and safe, an in vivo dose–response study was performed in order to determine safety and efficacy of the pNIPAAM MgFe-LDH hydrogel for intradiscal controlled delivery of CXB.

Results

CXB release correlated to hydrogel degradation in vitro. Furthermore, controlled release from CXB-loaded hydrogels was demonstrated to suppress PGE ₂ levels in the presence of TNF-α. The hydrogel was shown to exhibit a good biocompatibility upon subcutaneous injection in mice. Upon intradiscal injection in a canine model, the hydrogel exhibited excellent biocompatibility based on histological evaluation of the treated IVDs. Gene expression and biochemical analyses supported the finding that no substantial negative effects of the hydrogel were observed. Safety of application was further confirmed by the absence of clinical symptoms, IVD herniation or progression of degeneration. Controlled release of CXB resulted in a nonsignificant maximal inhibition (approximately 35 %) of PGE ₂ levels in the mildly degenerated canine IVDs.

Conclusions

In conclusion, this study showed biocompatibility and safe intradiscal application of an MgFe LDH-pNIPAAM hydrogel. Controlled release of CXB resulted in only limited inhibition of PGE ₂ in this model with mild IVD degeneration, and further studies should concentrate on application of controlled release from this type of hydrogel in animal models with more severe IVD degeneration.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0727-x) contains supplementary material, which is available to authorized users.

Related collections

Most cited references 39

Record: found
Abstract: found
Article: found

Is Open Access

The role of interleukin-1 in the pathogenesis of human Intervertebral disc degeneration

Christine Le Maitre, Anthony J. Freemont, Judith Hoyland (2005)

In this study, we investigated the hypotheses that in human intervertebral disc (IVD) degeneration there is local production of the cytokine IL-1, and that this locally produced cytokine can induce the cellular and matrix changes of IVD degeneration. Immunohistochemistry was used to localize five members of the IL-1 family (IL-1α, IL-1β, IL-1Ra (IL-1 receptor antagonist), IL-1RI (IL-1 receptor, type I), and ICE (IL-1β-converting enzyme)) in non-degenerate and degenerate human IVDs. In addition, cells derived from non-degenerate and degenerate human IVDs were challenged with IL-1 agonists and the response was investigated using real-time PCR for a number of matrix-degrading enzymes, matrix proteins, and members of the IL-1 family. This study has shown that native disc cells from non-degenerate and degenerate discs produced the IL-1 agonists, antagonist, the active receptor, and IL-1β-converting enzyme. In addition, immunopositivity for these proteins, with the exception of IL-1Ra, increased with severity of degeneration. We have also shown that IL-1 treatment of human IVD cells resulted in increased gene expression for the matrix-degrading enzymes (MMP 3 (matrix metalloproteinase 3), MMP 13 (matrix metalloproteinase 13), and ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs)) and a decrease in the gene expression for matrix genes (aggrecan, collagen II, collagen I, and SOX6). In conclusion we have shown that IL-1 is produced in the degenerate IVD. It is synthesized by native disc cells, and treatment of human disc cells with IL-1 induces an imbalance between catabolic and anabolic events, responses that represent the changes seen during disc degeneration. Therefore, inhibiting IL-1 could be an important therapeutic target for preventing and reversing disc degeneration.

0 comments Cited 259 times – based on 0 reviews      Review now

Record: found
Abstract: found
Article: not found

Are animal models useful for studying human disc disorders/degeneration?

Mauro Alini, Stephen Eisenstein, Keita Ito … (2008)

Intervertebral disc (IVD) degeneration is an often investigated pathophysiological condition because of its implication in causing low back pain. As human material for such studies is difficult to obtain because of ethical and government regulatory restriction, animal tissue, organs and in vivo models have often been used for this purpose. However, there are many differences in cell population, tissue composition, disc and spine anatomy, development, physiology and mechanical properties, between animal species and human. Both naturally occurring and induced degenerative changes may differ significantly from those seen in humans. This paper reviews the many animal models developed for the study of IVD degeneration aetiopathogenesis and treatments thereof. In particular, the limitations and relevance of these models to the human condition are examined, and some general consensus guidelines are presented. Although animal models are invaluable to increase our understanding of disc biology, because of the differences between species, care must be taken when used to study human disc degeneration and much more effort is needed to facilitate research on human disc material.

0 comments Cited 235 times – based on 0 reviews      Review now

Record: found
Abstract: found
Article: not found

Prostaglandin E2 synthesis and secretion: the role of PGE2 synthases.

Yikyung Park, Michael Pillinger, Steven B. Abramson (2006)

Prostaglandin E2 (PGE2) is a principal mediator of inflammation in diseases such as rheumatoid arthritis and osteoarthritis. Nonsteroidal anti-inflammatory medications (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors reduce PGE2 production to diminish the inflammation seen in these diseases, but have toxicities that may include both gastrointestinal bleeding and prothrombotic tendencies. In cells, arachidonic acid is transformed into PGE2 via cyclooxygenase (COX) enzymes and terminal prostaglandin E synthases (PGES). Accumulating data suggest that the interaction of various enzymes in the PGE2 synthetic pathway is complex and tightly regulated. In this review, we summarize the synthesis and secretion of PGE2. In particular, we focus on the three isoforms of the terminal PGES, and discuss the potential of targeting PGES as a more precise strategy for inhibiting PGE2 production.

0 comments Cited 204 times – based on 0 reviews      Review now

All references

Author and article information

Contributors

Nicole Willems: N.Willems@uu.nl

Hsiao-yin Yang: H.Y.Yang@umcutrecht.nl

Marloes L. P. Langelaan: mlangelaan@gmail.com

Anna R. Tellegen: a.r.tellegen@uu.nl

Guy C. M. Grinwis: g.c.m.grinwis@uu.nl

Hendrik-Jan C. Kranenburg: h.c.kranenburg@uu.nl

Frank M. Riemers: f.m.riemers@uu.nl

Saskia G. M. Plomp: s.g.m.plomp@uu.nl

Eric G. M. Craenmehr: eric.craenmehr@tno.nl

Wouter J. A. Dhert: w.j.a.dhert@uu.nl

Nicole E. Papen-Botterhuis: nicole.papen@tno.nl

Björn P. Meij: b.p.meij@uu.nl

Laura B. Creemers: l.b.creemers@umcutrecht.nl

Marianna A. Tryfonidou: m.a.tryfonidou@uu.nl

Journal

Journal ID (nlm-ta): Arthritis Res Ther

Title: Arthritis Research & Therapy

Publisher: BioMed Central (London )

ISSN (Print): 1478-6354

ISSN (Electronic): 1478-6362

Publication date (Electronic): 20 August 2015

Publication date PMC-release: 20 August 2015

Publication date (Print): 2015

Volume: 17

Issue: 1

Electronic Location Identifier: 214

Affiliations

[ ]Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 108, Utrecht, 3584 CM The Netherlands

[ ]Department of Orthopedics, University Medical Center, Heidelberglaan 100, Utrecht, 3584 CX The Netherlands

[ ]Department of Materials Technology, TNO, De Rondom 1, Eindhoven, 5612 AP The Netherlands

[ ]Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, Utrecht, 3508 TD The Netherlands

Article

Publisher ID: 727

DOI: 10.1186/s13075-015-0727-x

PMC ID: 4545995

PubMed ID: 26290179

SO-VID: d4c3b91d-d724-47f6-8402-d4f9f3112c31

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 4 June 2015

Date accepted : 24 July 2015

Custom metadata

ScienceOpen disciplines: Orthopedics

Data availability: