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Current Drug Delivery

Editor-in-Chief

ISSN (Print): 1567-2018
ISSN (Online): 1875-5704

Research Article

Ketorolac Tromethamine Loaded Nano-Spray Dried Nanoparticles: Preparation, Characterization, Cell Viability, COL1A1 Gene Simulation and Determination of Anti-inflammatory Activity by In vivo HET-CAM Assay

Author(s): A.A. Öztürk*, T. Çevikelli, E.K. Tilki, U.M. Güven and H.T. Kıyan

Volume 20, Issue 6, 2023

Published on: 01 February, 2023

Page: [830 - 840] Pages: 11

DOI: 10.2174/1567201820666230125144133

Price: $65

Abstract

Background: Ketorolac tromethamine (KT) is a non-steroidal anti-inflammatory drug from the heteroaryl acetic acid derivatives family. The most widely used new nanotechnological approaches for topical drug delivery are polymeric nanoparticles (NPs).

Objective: Successful results have been obtained with low doses in many treatments, such as cancer, antimicrobial, pain, made with nanoparticle formulations of drug active ingredients.

Methods: NPs were prepared using Nano Spray-Dryer. The cytotoxicity of the optimum formulation in BJ (ATCC® CRL-2522™) human fibroblast cells was determined by the WST- 1 method and the gene activity was elucidated by mRNA isolation and real-time polymerase chain reaction (RT-PCR). The in vivo HET- CAM assay was performed for anti-inflammatory activity.

Results: NPs presented PDI values lower than 0.5, and therefore particle size distribution was decided to be monodisperse. Positive zeta potential values of NPs highlighted the presence of the cationic ammonium group of Eudragit® RS 100. The release rates observed from KT-NP coded formulations after 24 hours were 78.4% ± 2.9, demonstrating extended release from all formulations, relative to pure KT. The lowest concentration of KT-NP increased fibroblast cell proliferation higher than the highest concentration of KT. The 5-fold increased effect of KT-NP formulation on collagen gene expression compared to KT is also related to the enhanced anti-inflammatory effect in line with the in vivo HET-CAM assay results.

Conclusion: With the obtained cell viability, gene expression, and HET-CAM results, it has the hope of a successful nano-topical formulation, especially in both wound healing and anti-inflammatory treatment.

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[1]
Ozturk, A. Design of cefaclor monohydrate containing nanoparticles with extended antibacterial effect by nano-spray dryer: A nanoenglobing study. J. Res. Pharm, 2020, 24(1), 100-111.
[2]
Öztürk, K. Eroğlu, H.; Çalış S. Novel advances in targeted drug delivery. J. Drug Target., 2018, 26(8), 633-642.
[http://dx.doi.org/10.1080/1061186X.2017.1401076] [PMID: 29096554]
[3]
Öztürk, A.A. Aygül, A.; Şenel, B. Influence of glyceryl behenate, tripalmitin and stearic acid on the properties of clarithromycin incorporated solid lipid nanoparticles (SLNs): Formulation, characterization, antibacterial activity and cytotoxicity. J. Drug Deliv. Sci. Technol., 2019, 54, 101240.
[http://dx.doi.org/10.1016/j.jddst.2019.101240]
[4]
Öztürk, A.A.; Yenilmez, E.; Özarda, M.G. Clarithromycin-loaded poly (lactic-co-glycolic acid)(PLGA) nanoparticles for oral administration: Effect of polymer molecular weight and surface modification with chitosan on formulation, nanoparticle characterization and antibacterial effects. Polymers, 2019, 11(10), 1632.
[http://dx.doi.org/10.3390/polym11101632] [PMID: 31600969]
[5]
Naz, M.Y.; Fatima, H.; Shukrullah, S.; Aslam, H.; Ullah, S.; Assiri, M.A. A review of multifunction smart nanoparticle based drug delivery systems. Curr. Pharm. Des., 2022, 28(36), 2965-2983.
[http://dx.doi.org/10.2174/1381612828666220422085702] [PMID: 35466867]
[6]
Fadilah, N.I.M.; Isa, I.L.M.; Zaman, W.S.W.K.; Tabata, Y.; Fauzi, M.B. The effect of nanoparticle-incorporated natural-based biomaterials towards cells on activated pathways: A systematic review. Polymers, 2022, 14(3), 476.
[http://dx.doi.org/10.3390/polym14030476] [PMID: 35160466]
[7]
Alamdari, S.G.; Amini, M.; Jalilzadeh, N.; Baradaran, B.; Mohammadzadeh, R.; Mokhtarzadeh, A.; Oroojalian, F. Recent advances in nanoparticle-based photothermal therapy for breast cancer. J. Control. Release, 2022, 349, 269-303.
[http://dx.doi.org/10.1016/j.jconrel.2022.06.050] [PMID: 35787915]
[8]
Afshari, A.R.; Sanati, M.; Mollazadeh, H.; Kesharwani, P.; Johnston, T.P.; Sahebkar, A. Nanoparticle-based drug delivery systems in cancer: A focus on inflammatory pathways. In: Seminars in Cancer Biology. 2022.
[9]
Ekinci, M. Öztürk, A.A.; Santos-Oliveira, R.; İlem-Özdemir, D. The use of Lamivudine-loaded PLGA nanoparticles in the diagnosis of lung cancer: Preparation, characterization, radiolabeling with 99mTc and cell binding. J. Drug Deliv. Sci. Technol., 2022, 69, 103139.
[http://dx.doi.org/10.1016/j.jddst.2022.103139]
[10]
Chakraborty, A.; Haque, S.M.; Dey, D.; Mukherjee, S.; Ghosh, B. Phytogenic silver nanoparticles from tissue-cultured Kaempferia angustifolia — an underutilized medicinal herb: A comparative antibacterial study on urinary pathogens. J. Genet. Eng. Biotechnol., 2022, 20(1), 131.
[http://dx.doi.org/10.1186/s43141-022-00414-4] [PMID: 36074190]
[11]
Babaie, S.; Taghvimi, A.; Hong, J.H.; Hamishehkar, H.; An, S.; Kim, K.H. Recent advances in pain management based on nanoparticle technologies. J. Nanobiotechnology, 2022, 20(1), 290.
[http://dx.doi.org/10.1186/s12951-022-01473-y] [PMID: 35717383]
[12]
Abdelghany, T.M.; Al-Rajhi, A.M.; Almuhayawi, M.S.; Abada, E.; Al Abboud, M.A.; Moawad, H. Green fabrication of nanocomposite doped with selenium nanoparticle–based starch and glycogen with its therapeutic activity: Antimicrobial, antioxidant, and anti-inflammatory in vitro. Biomass Convers. Biorefin., 2022, 1-13.
[13]
Jiang, W.; He, S.; Su, D.; Ye, M.; Zeng, Q.; Yuan, Y. Synthesis, characterization of tuna polypeptide selenium nanoparticle, and its immunomodulatory and antioxidant effects in vivo. Food Chem., 2022, 383, 132405.
[http://dx.doi.org/10.1016/j.foodchem.2022.132405] [PMID: 35168050]
[14]
Yasamineh, S.; Kalajahi, H.G.; Yasamineh, P.; Yazdani, Y.; Gholizadeh, O.; Tabatabaie, R.; Afkhami, H.; Davodabadi, F. farkhad, A.K.; Pahlevan, D.; Firouzi-Amandi, A.; Nejati-Koshki, K.; Dadashpour, M. An overview on nanoparticle-based strategies to fight viral infections with a focus on COVID-19. J. Nanobiotechnology, 2022, 20(1), 440.
[http://dx.doi.org/10.1186/s12951-022-01625-0] [PMID: 36209089]
[15]
Goyal, R.; Macri, L.K.; Kaplan, H.M.; Kohn, J. Nanoparticles and nanofibers for topical drug delivery. J. Control. Release, 2016, 240, 77-92.
[http://dx.doi.org/10.1016/j.jconrel.2015.10.049] [PMID: 26518723]
[16]
Öztürk, A.A.; Arpagaus, C. Nano spray-dried drugs for oral administration: A review. Assay Drug Dev. Technol., 2021, 19(7), 412-441.
[http://dx.doi.org/10.1089/adt.2021.053] [PMID: 34550790]
[17]
Öztürk, A.A. Yenilmez, E.; Arslan, R.; Şenel, B.; Yazan, Y. Dexketoprofen trometamol-loaded Kollidon® SR and Eudragit® RS 100 polymeric nanoparticles: Formulation and in vitro - in vivo evaluation. Lat. Am. J. Pharm., 2017, 36(11), 2153-2165.
[18]
Sinha, V.R.; Kumar, R.V.; Singh, G. Ketorolac tromethamine formulations: An overview. Expert Opin. Drug Deliv., 2009, 6(9), 961-975.
[http://dx.doi.org/10.1517/17425240903116006] [PMID: 19663721]
[19]
Bryant, A.E.; Aldape, M.J.; Bayer, C.R.; Katahira, E.J.; Bond, L.; Nicora, C.D.; Fillmore, T.L.; Clauss, T.R.W.; Metz, T.O.; Webb-Robertson, B.J.; Stevens, D.L. Effects of delayed NSAID administration after experimental eccentric contraction injury – A cellular and proteomics study. PLoS One, 2017, 12(2), e0172486.
[http://dx.doi.org/10.1371/journal.pone.0172486] [PMID: 28245256]
[20]
Hadagali, M.D.; Chua, L.S. The anti-inflammatory and wound healing properties of honey. Eur. Food Res. Technol., 2014, 239(6), 1003-1014.
[http://dx.doi.org/10.1007/s00217-014-2297-6]
[21]
Hamdan, S.; Pastar, I.; Drakulich, S.; Dikici, E.; Tomic-Canic, M.; Deo, S.; Daunert, S. Nanotechnology-driven therapeutic interventions in wound healing: Potential uses and applications. ACS Cent. Sci., 2017, 3(3), 163-175.
[http://dx.doi.org/10.1021/acscentsci.6b00371] [PMID: 28386594]
[22]
Zhang, J.M.; An, J. Cytokines, inflammation, and pain. Int. Anesthesiol. Clin., 2007, 45(2), 27-37.
[http://dx.doi.org/10.1097/AIA.0b013e318034194e] [PMID: 17426506]
[23]
Öztürk, A.A. Yenilmez, E.; Şenel, B.; Kıyan, H.T.; Güven, U.M. Effect of different molecular weight PLGA on flurbiprofen nanoparticles: Formulation, characterization, cytotoxicity, and in vivo anti-inflammatory effect by using HET-CAM assay. Drug Dev. Ind. Pharm., 2020, 46(4), 682-695.
[http://dx.doi.org/10.1080/03639045.2020.1755304] [PMID: 32281428]
[24]
Öztürk, A.A. Namlı İ Güleç, K.; Kıyan, H.T. Diclofenac sodium loaded PLGA nanoparticles for inflammatory diseases with high anti-inflammatory properties at low dose: Formulation, characterization and in vivo HET-CAM analysis. Microvasc. Res., 2020, 130, 103991.
[http://dx.doi.org/10.1016/j.mvr.2020.103991] [PMID: 32105668]
[25]
Öztürk, A.A. Kıyan, H.T. Treatment of oxidative stress-induced pain and inflammation with dexketoprofen trometamol loaded different molecular weight chitosan nanoparticles: Formulation, characterization and anti-inflammatory activity by using in vivo HET-CAM assay. Microvasc. Res., 2020, 128, 103961.
[http://dx.doi.org/10.1016/j.mvr.2019.103961] [PMID: 31758946]
[26]
Öztürk, A.A.; Gündüz, A.B.; Ozisik, O. Supervised machine learning algorithms for evaluation of solid lipid nanoparticles and particle size. Comb. Chem. High Throughput Screen., 2019, 21(9), 693-699.
[http://dx.doi.org/10.2174/1386207322666181218160704] [PMID: 30569864]
[27]
Yurtdas, K.G.; Ozturk, A. Levocetirizine dihydrochloride-loaded chitosan nanoparticles: Formulation and in vitro evaluation. Turk. J. Pharm. Sci., 2020, 17(1), 27-35.
[http://dx.doi.org/10.4274/tjps.galenos.2018.34392] [PMID: 32454757]
[28]
Öztürk, A.A. Namlı İ Güleç, K.; Görgülü, Ş. Design of lamivudine loaded nanoparticles for oral application by nano spray drying method: A new approach to use an antiretroviral drug for lung cancer treatment. Comb. Chem. High Throughput Screen., 2020, 23(10), 1064-1079.
[http://dx.doi.org/10.2174/1386207323666200325155020] [PMID: 32209039]
[29]
Öztürk, A.A.; Güven, U.M. Cefaclor monohydrate loaded microemulsion formulation for topical application: Characterization with new developed UPLC method and stability study. J. Res. Pharm., 2019, 23(3), 426-440.
[http://dx.doi.org/10.12991/jrp.2019.150]
[30]
Öztürk, A.A.; Güven, U.M.; Yenilmez, E. Flurbiprofen loaded gel based topical delivery system: Formulation and in vitro characterization with new developed UPLC method. ACTA Pharmaceutica Sciencia, 2018, 56(4), 81-105.
[31]
Dikmen, M.; Öztürk, S.E.; Cantürk, Z.; Ceylan, G.; Karaduman, AB.; Yamaç, M Anticancer and antimetastatic activity of Hypomyces chrysospermus, a cosmopolitan parasite in different human cancer cells. Mol. Biol. Rep., 2020, 47(5), 3765-3778.
[http://dx.doi.org/10.1007/s11033-020-05468-6] [PMID: 32378168]
[32]
Engür, S.; Dikmen, M. The evaluation of the anti-cancer activity of ixazomib on Caco2 colon solid tumor cells, comparison with bortezomib. Acta Clin. Belg., 2017, 72(6), 391-398.
[http://dx.doi.org/10.1080/17843286.2017.1302623] [PMID: 28327055]
[33]
Dikmen, M.; Canturk, Z.; Tilki, E.K.; Engur, S. Evaluation of antiangiogenic and antimetastatic Effects of Penicillium chrysogenum Secondary Metabolites. Indian J. Pharm. Sci., 2017, 79(1), 49-57.
[http://dx.doi.org/10.4172/pharmaceutical-sciences.1000200]
[34]
Fathalla, Z.M.A.; Khaled, K.A.; Hussein, A.K.; Alany, R.G.; Vangala, A. Formulation and corneal permeation of ketorolac tromethamine-loaded chitosan nanoparticles. Drug Dev. Ind. Pharm., 2016, 42(4), 514-524.
[http://dx.doi.org/10.3109/03639045.2015.1081236] [PMID: 26407208]
[35]
Archna, SSG.; Mishra, MK; Prasad, RK Formulation and characterization of ketorolac tromethamine nanoparticle with eudragit RS-100 and RL-100 by nano precipitation method. Int. J. Res., 2017, 17, 17-23.
[36]
Goerne, L.; López García, M.; Rodríguez Grada, G.; Ortiz Pérez, I.; Gómez López, E.; Lemus, A. Obtaining of sol-gel ketorolac-silica nanoparticles: Characterization and drug release kinetics. J. Nanomater., 2013, Article ID 450483.
[37]
Mohammadi, G.; Mirzaeei, S.; Taghe, S.; Mohammadi, P. Preparation and evaluation of Eudragit® L100 nanoparticles loaded impregnated with KT tromethamine loaded PVA-HEC insertions for ophthalmic drug delivery. Adv. Pharm. Bull., 2019, 9(4), 593-600.
[http://dx.doi.org/10.15171/apb.2019.068] [PMID: 31857963]
[38]
Morsi, N.; Ghorab, D.; Refai, H.; Teba, H. Preparation and evaluation of alginate/chitosan nanodispersions for ocular delivery. Int. J. Pharm. Pharm. Sci., 2015, 7(7), 234-240.
[39]
Jadhav, P.A.; Yadav, A.V. Design, development and characterization of ketorolac tromethamine polymeric nanosuspension. Ther. Deliv., 2019, 10(9), 585-597.
[http://dx.doi.org/10.4155/tde-2019-0045] [PMID: 31581882]
[40]
Salvi, V.; Pawar, P. Eudragit RL100 based moxifloxacin hydrochloride and ketorolac tromethamine combination nanoparticulate system for ocular drug delivery. Pharm. Nanotechnol., 2020, 8(2), 133-147.
[http://dx.doi.org/10.2174/2211738508666200313140902] [PMID: 32167436]
[41]
Öztürk, AA. Güven, UM; Yenilmez, E; Şenel, B Effects of different derivatives of eudragit polymer on entrapment efficiency, in vitro dissolution, release kinetics and cell viability results on extended release flurbiprofen loaded nanomedicines. Lat. Am. J. Pharm., 2018, 37(10), 1981.
[42]
Guven, UM.; Ozturk, AA. Yenilmez, E Evaluation of carvedilol-loaded Eudragit nanoparticles. MARMARA Pharm. J., 2020, 24(1), 71-81.
[43]
Yenı̇lmez, E. Desloratadine-Eudragit® RS100 nanoparticles: Formulation and characterization. Turk. J. Pharm. Sci., 2017, 14(2), 148-156.
[http://dx.doi.org/10.4274/tjps.52523] [PMID: 32454606]
[44]
El-Maghawry, E.; Tadros, M.I.; El-Kheshen, S.A.; Abd-Elbary, A. Eudragit®-S100 coated PLGA nanoparticles for colon targeting of Etoricoxib: optimization and pharmacokinetic assessments in healthy human volunteers. Int. J. Nanomedicine, 2020, 15, 3965-3980.
[http://dx.doi.org/10.2147/IJN.S244124] [PMID: 32606658]
[45]
Yurtdaş-Kırımlıoğlu, G.; Güleç, K.; Görgülü, Ş; Kıyan, H.T. Oseltamivir phosphate loaded pegylated-Eudragit nanoparticles for lung cancer therapy: Characterization, prolonged release, cytotoxicity profile, apoptosis pathways and in vivo anti-angiogenic effect by using CAM assay. Microvasc. Res., 2022, 139, 104251.
[http://dx.doi.org/10.1016/j.mvr.2021.104251] [PMID: 34520775]
[46]
Oliveira, A.M.; Guimarães, K.L.; Cerize, N.N.P.; Tunussi, A.S.; Poço, J.G.R. Nano spray drying as an innovative technology for encapsulating hydrophilic active pharmaceutical ingredients (API). J. Nanomed. Nanotechnol., 2013, 4(6)
[http://dx.doi.org/10.4172/2157-7439.1000186]
[47]
Muchtaridi, M.; Herdiana, Y.; Handaresta, D.F.; Joni, I.M.; Wathoni, N. Synthesis of nano-α mangostin based on chitosan and Eudragit S 100. J. Adv. Pharm. Technol. Res., 2020, 11(3), 95-100.
[http://dx.doi.org/10.4103/japtr.JAPTR_182_19] [PMID: 33102191]
[48]
Abdel-Mageed, H.M.; Fouad, S.A.; Teaima, M.H.; Abdel-Aty, A.M.; Fahmy, A.S.; Shaker, D.S.; Mohamed, S.A. Optimization of nano spray drying parameters for production of α-amylase nanopowder for biotheraputic applications using factorial design. Dry. Technol., 2019, 37(16), 2152-2160.
[http://dx.doi.org/10.1080/07373937.2019.1565576]
[49]
Öztürk, AA.; Yenilmez, E. Yazan, Y Dexketoprofen trometamol-loaded Eudragit® RL 100 nanoparticle formulation, characterization and release kinetics. Acta Pharmaceut. Sci., 2019, 57(1), 69-84.
[50]
Alper Öztürk, A. Namlı İ. Aygül, A. Cefaclor monohydrate-loaded colon-targeted nanoparticles for use in COVID-19 dependent coinfections and intestinal symptoms: Formulation, characterization, release kinetics, and antimicrobial activity. Assay Drug Dev. Technol., 2021, 19(3), 156-175.
[http://dx.doi.org/10.1089/adt.2020.1014] [PMID: 33728979]
[51]
Stortelers, C.; Kerkhoven, R.; Moolenaar, W.H. Multiple actions of lysophosphatidic acid on fibroblasts revealed by transcriptional profiling. BMC Genomics, 2008, 9(1), 387.
[http://dx.doi.org/10.1186/1471-2164-9-387] [PMID: 18702810]
[52]
Harris, K.L.; Bainbridge, N.J.; Jordan, N.R.; Sharpe, J.R. The effect of topical analgesics on ex vivo skin growth and human keratinocyte and fibroblast behavior. Wound Repair Regen., 2009, 17(3), 340-346.
[http://dx.doi.org/10.1111/j.1524-475X.2009.00488.x] [PMID: 19660041]
[53]
Honary, S.; Zahir, F. Effect of zeta potential on the properties of nano-drug delivery systems-a review (Part 1). Trop. J. Pharm. Res., 2013, 12(2), 255-264.
[54]
Chang, J.H.; Cho, M.A.; Son, H.H.; Lee, C.K.; Yoon, M.S.; Cho, H.H. Characterization and formation of phospholipid nanoemulsion coatings on Mg-modified sericite surface. J. Ind. Eng. Chem., 2006, 12(4), 635-638.
[55]
Campbell, R.B. Positively-charged liposomes for targeting tumor vasculature.In: Nanotechnology for cancer therapy; CRC Press: Boca Raton, 2006, pp. 613-627.
[56]
Hoeller, S.; Sperger, A.; Valenta, C. Lecithin based nanoemulsions: A comparative study of the influence of non-ionic surfactants and the cationic phytosphingosine on physicochemical behaviour and skin permeation. Int. J. Pharm., 2009, 370(1-2), 181-186.
[http://dx.doi.org/10.1016/j.ijpharm.2008.11.014] [PMID: 19073240]
[57]
Şenel, B.; Öztürk, A.A. New approaches to tumor therapy with siRNA- decorated and chitosan-modified PLGA nanoparticles. Drug Dev. Ind. Pharm., 2019, 45(11), 1835-1848.
[http://dx.doi.org/10.1080/03639045.2019.1665061] [PMID: 31491363]
[58]
Han, G.; Zhao, J.; Zhang, R.; Tian, X.; Liu, Z.; Wang, A.; Liu, R.; Liu, B.; Han, M.Y.; Gao, X.; Zhang, Z. Membrane-penetrating carbon quantum dots for imaging nucleic acid structures in live organisms. Angew. Chem. Int. Ed., 2019, 58(21), 7087-7091.
[http://dx.doi.org/10.1002/anie.201903005] [PMID: 30912239]
[59]
Krieg, T.; Aumailley, M. The extracellular matrix of the dermis: Flexible structures with dynamic functions. Exp. Dermatol., 2011, 20(8), 689-695.
[http://dx.doi.org/10.1111/j.1600-0625.2011.01313.x] [PMID: 21615511]
[60]
Gelse, K.; Pöschl, E.; Aigner, T. Collagens-Structure, function, and biosynthesis. Adv. Drug Deliv. Rev., 2003, 55(12), 1531-1546.
[http://dx.doi.org/10.1016/j.addr.2003.08.002] [PMID: 14623400]
[61]
Haws, M.J.; Kucan, J.O.; Roth, A.C.; Suchy, H.; Brown, R.E. The effects of chronic ketorolac tromethamine (toradol) on wound healing. Ann. Plast. Surg., 1996, 37(2), 147-151.
[http://dx.doi.org/10.1097/00000637-199608000-00005] [PMID: 8863973]
[62]
Reikeraas, O.; Engebretsen, L. Effects of ketoralac tromethamine and indomethacin on primary and secondary bone healing. Arch. Orthop. Trauma Surg., 1998, 118(1-2), 50-52.
[http://dx.doi.org/10.1007/s004020050310] [PMID: 9833106]
[63]
Mullis, B.H.; Copland, S.T.; Weinhold, P.S.; Miclau, T.; Lester, G.E.; Bos, G.D. Effect of COX-2 inhibitors and non-steroidal anti-inflammatory drugs on a mouse fracture model. Injury, 2006, 37(9), 827-837.
[http://dx.doi.org/10.1016/j.injury.2005.12.018] [PMID: 16497308]
[64]
Ghiselli, R.; Lucarini, G.; Ortenzi, M.; Salvolini, E.; Saccomanno, S.; Orlando, F.; Provinciali, M.; Casciani, F.; Guerrieri, M. Anastomotic healing in a rat model of peritonitis after non-steroidal anti-inflammatory drug administration. Eur. J. Histochem., 2020, 64(1), 3085.
[http://dx.doi.org/10.4081/ejh.2020.3085] [PMID: 31941266]
[65]
Wu, M.H.; Shih, M.H.; Hsu, W.B.; Dubey, N.K.; Lee, W.F.; Lin, T.Y.; Hsieh, M.Y.; Chen, C.F.; Peng, K.T.; Huang, T.J.; Shi, C.S.; Guo, R.S.; Cai, C.J.; Chung, C.Y.; Wong, C.H. Evaluation of a novel biodegradable thermosensitive keto-hydrogel for improving postoperative pain in a rat model. PLoS One, 2017, 12(10), e0186784.
[http://dx.doi.org/10.1371/journal.pone.0186784] [PMID: 29059223]

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