Intradiscal delivery of celecoxib-loaded microspheres restores intervertebral disc integrity in a preclinical canine model

Tellegen, Anna R.; Rudnik-Jansen, Imke; Beukers, Martijn; Miranda-Bedate, Alberto; Bach, Frances C.; Jong, W. De; Woike, Nina; Mihov, George; Thies, Jens; Meij, Björn P.; Creemers, Laura B.; Tryfonidou, Marianna A.

doi:10.1016/j.jconrel.2018.08.019

Cited by 52 publications

(56 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Certainly, this system fails to reproduce complex immunologic interactions. However, intradiscal injection of Etanercept in patients already demonstrated beneficial effects which were partially reproducible in our bioreactor system (Tellegen et al, 2018).…”

Section: Strengths and Limitationsmentioning

confidence: 59%

Preclinical ex-vivo Testing of Anti-inflammatory Drugs in a Bovine Intervertebral Degenerative Disc Model

Gehlen

Heizmann

et al. 2020

Front. Bioeng. Biotechnol.

View full text Add to dashboard Cite

Discogenic low back pain (LBP) is a main cause of disability and inflammation is presumed to be a major driver of symptomatic intervertebral disc degeneration (IDD). Anti-inflammatory agents are currently under investigation as they demonstrated to alleviate symptoms in patients having IDD. However, their underlying anti-inflammatory and regenerative activity is poorly explored. The present study sought to investigate the potential of Etanercept and Tofacitinib for maintaining disc homeostasis in a preclinical intervertebral disc (IVD) organ culture model within IVD bioreactors allowing for dynamic loading and nutrient exchange. Bovine caudal IVDs were cultured in a bioreactor system for 4 days to simulate physiological or degenerative conditions: (1) Phy-physiological loading (0.02-0.2 MPa; 0.2 Hz; 2 h/day) and high glucose DMEM medium (4.5 g/L); (2) Deg+Tumor necrosis factor α (TNF-α)-degenerative loading (0.32-0.5 MPa; 5 Hz; 2 h/day) and low glucose DMEM medium (2 g/L), with TNF-α injection. Etanercept was injected intradiscally while Tofacitinib was supplemented into the culture medium. Gene expression in the IVD tissue was measured by RT-qPCR. Release of nitric oxide (NO), interleukin 8 (IL-8) and glycosaminoglycan (GAG) into the IVD conditioned medium were analyzed. Cell viability in the IVD was assessed using lactate dehydrogenase and ethidium homodimer-1 staining. Immunohistochemistry was performed to assess protein expression of IL-1β, IL-6, IL-8, and collagen type II in the IVD tissue. Etanercept and Tofacitinib downregulated the expression of IL-1β, IL-6, IL-8, Matrix metalloproteinase 1 (MMP1), and MMP3 in the nucleus pulposus (NP) tissue and IL-1β, MMP3, Cyclooxygenase-2 (COX2), and Nerve growth factor (NGF) in the annulus fibrosus (AF) tissue. Furthermore, Etanercept significantly reduced the IL-1β positively stained cells in the outer AF and NP regions. Tofacitinib significantly reduced IL-1β and IL-8 positively stained cells in the inner AF region. Both, Etanercept and Tofacitinib reduced the GAG loss to the level under physiological culture condition. Etanercept and Tofacitinib are able to neutralize the proinflammatory and catabolic environment in the IDD organ culture model. However, combined anti-inflammatory and anabolic treatment may be required to constrain accelerated IDD and relieving inflammation-induced back pain.

show abstract

Section: Strengths and Limitationsmentioning

confidence: 59%

Preclinical ex-vivo Testing of Anti-inflammatory Drugs in a Bovine Intervertebral Degenerative Disc Model

Gehlen

Heizmann

et al. 2020

Front. Bioeng. Biotechnol.

View full text Add to dashboard Cite

show abstract

“…Power analysis was done to detect differences between TAA as bolus and TAA released by MSs. Our previous results demonstrated that an n of 6 allows for detection of differences in synovial inflammation, cartilage degeneration, and bone changes of given intervention (Tellegen et al, ). However, in treatment groups “MS‐TAA 1.0 mg” and “MS‐TAA 1.6 mg,” one rat was killed before the end of the study, leading to a reduction in n value of 5.…”

Section: Methodsmentioning

confidence: 99%

Local controlled release of corticosteroids extends surgically induced joint instability by inhibiting tissue healing

Rudnik-Jansen

Tellegen

Pouran

et al. 2019

British J Pharmacology

View full text Add to dashboard Cite

Background and PurposeCorticosteroids are intra‐articularly injected to relieve pain in joints with osteoarthritis (OA) or acute tissue damage such as ligament or tendon tears, despite its unverified contraindication in unstable joints. Biomaterial‐based sustained delivery may prolong reduction of inflammatory pain, while avoiding harmful peak drug concentrations.Experimental ApproachThe applicability of prolonged corticosteroid exposure was examined in a rat model of anterior cruciate ligament and medial meniscus transection (ACLT + pMMx) with ensuing degenerative changes.Key ResultsIntra‐articular injection of a bolus of the corticosteroid triamcinolone acetonide (TAA) resulted in enhanced joint instability in 50% of the joints, but neither instability‐induced OA cartilage degeneration, synovitis, nor the OA‐related bone phenotype was affected. However, biomaterial microsphere‐based extended TAA release enhanced instability in 94% of the animals and induced dystrophic calcification and exacerbation of cartilage degeneration. In healthy joints, injection with TAA releasing microspheres had no effect at all. In vitro, TAA inhibited cell migration out of joint tissue explants, suggesting inhibited tissue healing in vivo as mechanisms for enhanced instability and subsequent cartilage degeneration.Conclusions and ImplicationsWe conclude that short‐term TAA exposure has minor effects on surgically induced unstable joints, but its extended presence is detrimental by extending instability and associated joint degeneration through compromised healing. This supports a contraindication of prolonged corticosteroid exposure in tissue damage‐associated joint instability, but not of brief exposure.

show abstract

“…In a classcial pre-clinical study a controlled release system for the COX-2 inhibitor celecoxib (cyclooxygenase-2) was tested in a dog model for IVDD (Tellegen et al, 2018). Since celecoxib prevented IVDD progression and reduced inflammation, follow-up studes will be conducted in a clincal study aiming to eliviate the chronic pain associated with low back pain.…”

Section: Intervertebral Disc Degenerationmentioning

confidence: 99%

“…There are several research groups which have a track record of developing preclinical large animal models, some of which have managed to translate their research into clinical applications ( Kang et al, 2010 , 2013 ; Mcilwraith et al, 2011 , 2012 ; Godwin et al, 2012 ; Smith et al, 2013 ; Bach et al, 2017 ; Whitehouse et al, 2017 ; Goldberg et al, 2018 ; Tellegen et al, 2018 ; Broeckx et al, 2019 ; Tellegen et al, 2019 ). This − by no means exhaustive − list clearly demonstrates the collective efforts of the veterinary community to provide large animal models to be used in translational projects.…”

Section: Introductionmentioning

confidence: 99%

Large Animal Models in Regenerative Medicine and Tissue Engineering: To Do or Not to Do

Ribitsch

Baptista

Consiglio

et al. 2020

Front. Bioeng. Biotechnol.

146

110

View full text Add to dashboard Cite

Rapid developments in Regenerative Medicine and Tissue Engineering has witnessed an increasing drive toward clinical translation of breakthrough technologies. However, the progression of promising preclinical data to achieve successful clinical market authorisation remains a bottleneck. One hurdle for progress to the clinic is the transition from small animal research to advanced preclinical studies in large animals to test safety and efficacy of products. Notwithstanding this, to draw meaningful and reliable conclusions from animal experiments it is critical that the species and disease model of choice is relevant to answer the research question as well as the clinical problem. Selecting the most appropriate animal model requires in-depth knowledge of specific species and breeds to ascertain the adequacy of the model and outcome measures that closely mirror the clinical situation. Traditional reductionist approaches in animal experiments, which often do not sufficiently reflect the studied disease, are still the norm and can result in a disconnect in outcomes observed between animal studies and clinical trials. To address these concerns a reconsideration in approach will be required. This should include a stepwise approach using in vitro and ex vivo experiments as well as in silico modeling to minimize the need for in vivo studies for screening and early development studies, followed by large animal models which more closely resemble human disease. Naturally occurring, or spontaneous diseases in large animals remain a largely untapped resource, and given the similarities in pathophysiology to humans they not only allow for studying new treatment strategies but also disease etiology and prevention. Naturally occurring disease models, particularly for longer lived large animal species, allow for studying disorders at an age when the disease is most prevalent. As these diseases are usually also a concern in the chosen veterinary species they would be beneficiaries of newly developed therapies. Improved awareness of the progress

show abstract

Intradiscal delivery of celecoxib-loaded microspheres restores intervertebral disc integrity in a preclinical canine model

Cited by 52 publications

References 50 publications

Preclinical ex-vivo Testing of Anti-inflammatory Drugs in a Bovine Intervertebral Degenerative Disc Model

Preclinical ex-vivo Testing of Anti-inflammatory Drugs in a Bovine Intervertebral Degenerative Disc Model

Local controlled release of corticosteroids extends surgically induced joint instability by inhibiting tissue healing

Large Animal Models in Regenerative Medicine and Tissue Engineering: To Do or Not to Do

Contact Info

Product

Resources

About