Ibuprofen-conjugated hyaluronate/polygalacturonic acid hydrogel for the prevention of epidural fibrosis

Abstract

The formation of fibrous tissue is part of the natural healing response following a laminectomy. Severe scar tissue adhesion, known as epidural fibrosis, is a common cause of failed back surgery syndrome. In this study, by combining the advantages of drug treatment with a physical barrier, an ibuprofen-conjugated crosslinkable polygalacturonic acid and hyaluronic acid hydrogel was developed for epidural fibrosis prevention. Conjugation was confirmed and measured by 1D ¹H NMR spectroscopy. In vitro analysis showed that the ibuprofen-conjugated polygalacturonic acid–hyaluronic acid hydrogel showed low cytotoxicity. In addition, the conjugated ibuprofen decreased prostaglandin E₂ production of the lipopolysaccharide-induced RAW264.7 cells. Histological data in in vivo studies indicated that the scar tissue adhesion of laminectomized male adult rats was reduced by the application of our ibuprofen-conjugated polygalacturonic acid-hyaluronic acid hydrogel. Its use also reduced the population of giant cells and collagen deposition of scar tissue without inducing extensive cell recruitment. The results of this study therefore suggest that the local delivery of ibuprofen via a polygalacturonic acid-hyaluronic acid-based hydrogel reduces the possibility of epidural fibrosis.

Keywords

Epidural fibrosis hyaluronic acid polygalacturonic acid injectable hydrogel ibuprofen

Get full access to this article

View all access options for this article.

References

Robertson

. Role of peridural fibrosis in the failed back: a review. Eur Spine J 1996; 5(Suppl 1): S2–S6.

Kendall

Feghali-Bostwick

. Fibroblasts in fibrosis: novel roles and mediators. Front Pharmacol 2014; 5: 123–123.

Darby

Hewitson

. Fibroblast differentiation in wound healing and fibrosis, Int Rev Cytol Academic Press, 2007, pp. 143–179.

Diegelmann

Evans

. Wound healing: an overview of acute, fibrotic and delayed healing. Front Biosci 2004; 9: 283–289.

Sandoval

Hernandez-Vaquero

. Preventing peridural fibrosis with nonsteroidal anti-inflammatory drugs. Eur Spine J 2008; 17: 451–455.

Pohjolainen

Jekunen

Autio

. Treatment of acute low back pain with the COX-2-selective anti-inflammatory drug nimesulide: results of a randomized, double-blind comparative trial versus ibuprofen. Spine (Phila Pa 1976) 2000; 25: 1579–1585.

Sharma

Levenson

Bell

. Suppression of lipopolysaccharide-stimulated cytokine/chemokine production in skin cells by sandalwood oils and purified α-santalol and β-santalol. Phytother Res 2014; 28: 925–932.

Tsai

W-C

Hsu

C-C

Chang

H-N

. Ibuprofen upregulates expressions of matrix metalloproteinase-1, -8, -9, and -13 without affecting expressions of types I and III collagen in tendon cells. J Orthop Res 2010; 28: 487–491.

Tsai

W-C

Hsu

C-C

Chen

CPC

. Ibuprofen inhibition of tendon cell migration and down-regulation of paxillin expression. J Orthop Res 2006; 24: 551–558.

10.

Tsai

W-C

Tang

F-T

Hsu

C-C

. Ibuprofen inhibition of tendon cell proliferation and upregulation of the cyclin kinase inhibitor p21CIP1. J Orthop Res 2004; 22: 586–591.

11.

Redpath

Marques

CMG

Dibden

. Ibuprofen and hydrogel-released ibuprofen in the reduction of inflammation-induced migration in melanoma cells. Br J Dermatol 2009; 161: 25–33.

12.

Castellsague

Riera-Guardia

Calingaert

. Individual NSAIDs and upper gastrointestinal complications. Drug Saf 2012; 35: 1127–1146.

13.

Michels

Collins

Reynolds

. Over-the-counter ibuprofen and risk of gastrointestinal bleeding complications: a systematic literature review. Curr Med Res Opin 2012; 28: 89–99.

14.

Rahman

Summers

Richter

. Comparison of techniques for decompressive lumbar laminectomy: the minimally invasive versus the “classic” open approach. Minim Invasive Neurosurg 2008; 51: 100–105.

15.

Ewert

Ahmad

Bouxsein

. Non-viral gene delivery with cationic liposome-DNA complexes. Meth Mol Biol 2008; 433: 159–175.

16.

Chang

Gallego-Perez

Zhao

. Dielectrophoresis-assisted 3D nanoelectroporation for non-viral cell transfection in adoptive immunotherapy. Lab Chip 2015; 15: 3147–3153.

17.

Chang

Bertani

Gallego-Perez

. 3D nanochannel electroporation for high-throughput cell transfection with high uniformity and dosage control. Nanoscale 2016; 8: 243–252.

18.

Gallego-Perez

Otero

Czeisler

. Deterministic transfection drives efficient nonviral reprogramming and uncovers reprogramming barriers. Nanomedicine 19 December 2015. pii: S1549-9634(15)00595-X.

19.

Tan

Nourbakhsh

Capo

. Effects of nonsteroidal anti-inflammatory drugs on flexor tendon adhesion. J Hand Surg 2010; 35: 941–947.

20.

Nishimura

Nakamura

diZerega

. Ibuprofen inhibition of postsurgical adhesion formation: a time and dose response biochemical evaluation in rabbits. J Surg Res 1984; 36: 115–124.

21.

Velasco

Danoux

Redondo

. pH-sensitive polymer hydrogels derived from morpholine to prevent the crystallization of ibuprofen. J Control Release 2011; 149: 140–145.

22.

Francis

Baby

Kumar

. Poly(N-isopropylacrylamide) hydrogel: effect of hydrophilicity on controlled release of ibuprofen at different pH. J Appl Polym Sci 2012; 124: 5079–5088.

23.

Kim

Luu

Chang

. Incorporation and controlled release of a hydrophilic antibiotic using poly(lactide-co-glycolide)-based electrospun nanofibrous scaffolds. J Control Release 2004; 98: 47–56.

24.

Vacanti

Cheng

Hill

. Localized delivery of dexamethasone from electrospun fibers reduces the foreign body response. Biomacromolecules 2012; 13: 3031–3038.

25.

Tseng

Y-Y

Liao

J-Y

Chen

W-A

. Biodegradable poly([D,L]-lactide-co-glycolide) nanofibers for the sustainable delivery of lidocaine into the epidural space after laminectomy. Nanomedicine 2013; 9: 77–87.

26.

Malkoc

Gallego-Perez

Nelson

. Controlled neuronal cell patterning and guided neurite growth on micropatterned nanofiber platforms. J Micromech Microeng 2015; 25: 125001–125001.

27.

Liu

Zhu

. Mitomycin C-polyethylene glycol controlled-release film inhibits collagen secretion and induces apoptosis of fibroblasts in the early wound of a postlaminectomy rat model. Spine J 2010; 10: 441–447.

28.

Qiu

Park

. Environment-sensitive hydrogels for drug delivery. Adv Drug Delv Rev 2012; 64(Suppl): 49–60.

29.

Hoare

Kohane

. Hydrogels in drug delivery: progress and challenges. Polymer 2008; 49: 1993–2007.

30.

Akeson

Massie

Huang

. Topical high-molecular-weight hyaluronan and a roofing barrier sheet equally inhibit postlaminectomy fibrosis. Spine J 2005; 5: 180–190.

31.

Schimizzi

Massie

Murphy

. High-molecular-weight hyaluronan inhibits macrophage proliferation and cytokine release in the early wound of a preclinical postlaminectomy rat model. Spine J 2006; 6: 550–556.

32.

Kato

Haro

Komori

. Evaluation of hyaluronic acid sheet for the prevention of postlaminectomy adhesions. Spine J 2005; 5: 479–488.

33.

Ito

Yeo

Highley

. The prevention of peritoneal adhesions by in situ cross-linking hydrogels of hyaluronic acid and cellulose derivatives. Biomaterials 2007; 28: 975–983.

34.

Lin

C-Y

Peng

H-H

Chen

M-H

. In situ forming hydrogel composed of hyaluronate and polygalacturonic acid for prevention of peridural fibrosis. J Mater Sci Mater Med 2015; 26: 1–12.

35.

Yeo

Highley

Bellas

. In situ cross-linkable hyaluronic acid hydrogels prevent post-operative abdominal adhesions in a rabbit model. Biomaterials 2006; 27: 4698–4705.

36.

Yeo

Adil

Bellas

. Prevention of peritoneal adhesions with an in situ cross-linkable hyaluronan hydrogel delivering budesonide. J Control Release 2007; 120: 178–185.

37.

Pouyani

Prestwich

. Functionalized derivatives of hyaluronic acid oligosaccharides: drug carriers and novel biomaterials. Bioconjugate Chem 1994; 5: 339–347.

38.

Revel

Loty

. A quantitative model of post-laminectomy scar formation: effects of a nonsteroidal anti-inflammatory drug. Spine (Phila Pa 1976) 1995; 20: 557–563; discussion 79–80.

39.

Kapitsinou

Jaffe

Michael

. Preischemic targeting of HIF prolyl hydroxylation inhibits fibrosis associated with acute kidney injury. Am J Physiol Renal Physiol 2012, pp. F1172–F1179.

40.

Schnell

Kawano

Porte

. Effects of ibuprofen on the viability and proliferation of rainbow trout liver cell lines and potential problems and interactions in effects assessment. Environ Toxicol 2009; 24: 157–165.

41.

Kobayashi

Sun

Terao

. Production of prostanoids via increased cyclo-oxygenase-2 expression in human amnion cells in response to low molecular weight hyaluronic acid fragment. Biochim Biophys Acta 1998; 1425: 369–376.

42.

Lemos

Grespan

Vieira

. Prostaglandin mediates IL-23/IL-17-induced neutrophil migration in inflammation by inhibiting IL-12 and IFNγ production. Proc Natl Acad Sci USA 2009; 106: 5954–5959.

43.

Tajima

Murata

Aritake

. Lipopolysaccharide induces macrophage migration via prostaglandin D2 and prostaglandin E2. J Pharmacol Exp Ther 2008; 326: 493–501.

44.

Cilli

Khan

. Prostaglandin E2 affects proliferation and collagen synthesis by human patellar tendon fibroblasts. Clin J Sport Med 2004; 14: 232–236.

45.

Hui

Dannenberg

Sung

JJY

. Prostaglandin E2 inhibits transforming growth factor β1-mediated induction of collagen α1(I) in hepatic stellate cells. J Hepatol 2004; 41: 251–258.

46.

Lardinois

Vogt

Yang

. Non-steroidal anti-inflammatory drugs decrease the quality of pleurodesis after mechanical pleural abrasion. Eur J Cardiothoracic Surg 2004; 25: 865–871.

47.

Wilgus

Vodovotz

Vittadini

. Reduction of scar formation in full-thickness wounds with topical celecoxib treatment. Wound Repair Regener 2003; 11: 25–34.