Biocompatibility and intradiscal application of a thermoreversible celecoxib-loaded poly-N-isopropylacrylamide MgFe-layered double hydroxide hydrogel in a canine model.
BACKGROUND
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 E2 (PGE2) 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 PGE2 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 PGE2 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 PGE2 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.
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 108, Utrecht, 3584, CM, The Netherlands. N.Willems@uu.nl.
Nicole
N
Willems
Department of Orthopedics, University Medical Center, Heidelberglaan 100, Utrecht, 3584, CX, The Netherlands. H.Y.Yang@umcutrecht.nl.
Hsiao-Yin
HY
Yang
Department of Materials Technology, TNO, De Rondom 1, Eindhoven, 5612, AP, The Netherlands. mlangelaan@gmail.com.
Marloes L P
ML
Langelaan
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 108, Utrecht, 3584, CM, The Netherlands. a.r.tellegen@uu.nl.
Anna R
AR
Tellegen
Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, Utrecht, 3508, TD, The Netherlands. g.c.m.grinwis@uu.nl.
Guy C M
GC
Grinwis
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 108, Utrecht, 3584, CM, The Netherlands. h.c.kranenburg@uu.nl.
Hendrik-Jan C
HJ
Kranenburg
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 108, Utrecht, 3584, CM, The Netherlands. f.m.riemers@uu.nl.
Frank M
FM
Riemers
Department of Orthopedics, University Medical Center, Heidelberglaan 100, Utrecht, 3584, CX, The Netherlands. s.g.m.plomp@uu.nl.
Saskia G M
SG
Plomp
Department of Materials Technology, TNO, De Rondom 1, Eindhoven, 5612, AP, The Netherlands. eric.craenmehr@tno.nl.
Eric G M
EG
Craenmehr
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 108, Utrecht, 3584, CM, The Netherlands. w.j.a.dhert@uu.nl.|Department of Orthopedics, University Medical Center, Heidelberglaan 100, Utrecht, 3584, CX, The Netherlands. w.j.a.dhert@uu.nl.
Wouter J A
WJ
Dhert
Department of Materials Technology, TNO, De Rondom 1, Eindhoven, 5612, AP, The Netherlands. nicole.papen@tno.nl.
Nicole E
NE
Papen-Botterhuis
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 108, Utrecht, 3584, CM, The Netherlands. b.p.meij@uu.nl.
Björn P
BP
Meij
Department of Orthopedics, University Medical Center, Heidelberglaan 100, Utrecht, 3584, CX, The Netherlands. l.b.creemers@umcutrecht.nl.
Laura B
LB
Creemers
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 108, Utrecht, 3584, CM, The Netherlands. m.a.tryfonidou@uu.nl.
Marianna A
MA
Tryfonidou
D000180:Acrylic Resins / Q000737:chemistry; D000818:Animals; D001672:Biocompatible Materials / Q000008:administration & dosage / Q000737:chemistry; D000068579:Celecoxib / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020100:Hydrogels / Q000008:administration & dosage / Q000737:chemistry; D006878:Hydroxides / Q000737:chemistry; D007150:Immunohistochemistry; D007279:Injections, Subcutaneous; D007403:Intervertebral Disc / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D055959:Intervertebral Disc Degeneration / Q000188:drug therapy* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012212:Rheology; D013696:Temperature
D000180:Acrylic Resins; D001672:Biocompatible Materials; D052246:Cyclooxygenase 2 Inhibitors; D003692:Delayed-Action Preparations; D020100:Hydrogels; D006878:Hydroxides; C052970:poly-N-isopropylacrylamide; C031356:hydroxide ion; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D015232:Dinoprostone