Selective COX-2 Inhibitors: Comparison
Please note this is a comparison between Version 3 by Camila Xu and Version 2 by Camila Xu.

Knee osteoarthritis (OA) is a condition that leads to pain and is mainly characterized by cartilage degradation.

  • DMOADs
  • intra-articular injection
  • knee osteoarthritis
  • selective COX-2 inhibitors.

1. Introduction

Knee osteoarthritis (OA) is a condition that leads to pain and is mainly characterized by cartilage degradation [1]. Currently, drug treatments provide symptomatic pain relief but no effective treatment exists to slow down progression of OA-related cartilage damage [1]. Pain-killing drug therapies include non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs provide pain relief by blocking cyclooxygenase (COX)-dependent prostanoid synthesis. Prostanoids are an important family of signaling molecules present in synovial fluid [2]. At least two COX isoforms have been described, COX-1 and COX-2, the latter being considered as the inflammatory isoform [3]. Selective COX-2 inhibitors have been developed to specifically target the inflammatory COX-2 while circumventing inhibition of the COX-1 isoform. While selective COX-2 inhibitors may provide an effective means for pain relief, targeting the inflammatory COX-2 may be also a promising approach to inhibit cartilage degradation and thereby slow down knee OA progression [3]. This hypothesis is supported by the accumulating evidence showing that inflammation precedes OA disease progression [3,4][3][4].[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49]

From the anti-nerve growth factor clinical trials it became clear that next to a substantial improvement in pain, patients also displayed structural OA disease progression [5]. This emphasizes the importance of treatment strategies not only providing pain relief, which will lead to a vicious self-perpetuating cycle of joint overloading and OA progression, but also providing the ability for disease modification.

The actions of non-selective COX inhibitors on cartilage degradation in vitro and in vivo have been excellently reviewed in the past [6]. Moreover, ex vivo and in vivo actions of the selective COX-2 inhibitor celecoxib on cartilage degradation, synovial inflammation and osteoclast metabolism have also been reviewed and date back to 2011 [7]. Recently, an updated review of studies published until 2016 has been conducted on the OA disease-modifying actions of celecoxib on different OA tissues. This review confirms the contradictive reports regarding the chondroprotective actions of celecoxib both ex vivo and in vivo. Based on these reviews, it still remains obscure whether selective COX-2 inhibitors can be used in vivo to protect cartilage and slow down the progression of knee OA. One of the explanations of the contradictive reports found in the literature regarding the potential of selective COX-2 inhibitors may be related to the route of administration. Specifically, scarcely vascularized tissues such as cartilage and meniscus, which are important participants in knee OA, may be modified differentially after systemic oral treatment compared to intra-articular treatment [8,9][8][9]. To date, the role of the route of administration on the chondroprotective effects of selective COX-2 inhibitors remains unclear.

2. Discussion

The main finding of this systematic review is that the administration route plays a major role in determining chondroprotective actions of selective COX-2 inhibitors. The intra-articular administration route may be promising, since studies using bolus intra-articular administration of selective COX-2 inhibitors show chondroprotective effects. On the other hand, conflicting evidence exists when selective COX-2 inhibitors are incorporated into a drug delivery system. While preclinical studies point out to a potential chondroprotective role of COX-2 inhibitors, clinical studies did not investigate the intra-articular administration route and failed to confirm chondroprotective actions of systemically administered selective COX-2 inhibitors.

Discrepancies in chondroprotective actions of selective COX-2 inhibitors observed in the preclinical studies may be related to the route of administration. While six of the fourteen studies using systemic administration failed to demonstrate chondroprotective actions of selective COX-2 inhibitors, all studies that applied intra-articular bolus injections demonstrated chondroprotective actions. Interestingly, all clinical studies included in this systematic review evaluated chondroprotective actions using the systemic administration route. Since these studies failed to demonstrate chondroprotective actions, it will be of interest to investigate the chondroprotective actions of selective COX-2 inhibitors using the intra-articular administration route for clinical studies. We did not encounter studies comparing chondroprotective effects of systemic versus intra-articularly administration of selective COX-2 inhibitors, but we believe this will be of interest to investigate in the future.

Improved chondroprotection of intra-articular injections with selective COX-2 inhibitor compared to a saline control condition may be related to increased bioavailability of the drug in the knee joint compared to systemic administrations. In addition, in a total joint disease such as knee OA [38[38][39][40][41],39,40,41], intra-articular administration of drugs may be more effective compared to systemic treatment due to the presence of scarcely vascularized tissues such as cartilage and meniscus [8]. Since COX-2 inhibitors can have an effect on all joint tissues, it is unclear whether the chondroprotective effect is a direct result of COX-2 inhibition in chondrocytes or an effect of COX-2 inhibition of other joint tissues.

Others and we failed to show a reduction of OA-related cartilage damage by celecoxib, when incorporated in an intra-articular drug delivery system [28,29][28][29]. It is a possibility that prolonged release of celecoxib may counteract potential chondroprotective effects due to increased loading of the affected joint indirectly caused by the analgesic effects of COX-2 inhibitors. These findings corroborate earlier observations in clinical studies, in which patients treated with anti-NGF demonstrated an increase in OA-related cartilage damage possibly due to joint overloading [5].

COX-2 inhibitors are expected to have anti-inflammatory effects by inhibiting the synthesis of prostanoids. Prostanoid subtypes are considered as inflammatory mediators [2]  [2] and are involved in cartilage degradation [3], but also in other pathophysiologic OA processes in different joint tissues such as synovial fibrosis and chondrocyte hypertrophy [42,43][42][43]. However, also anti-inflammatory actions of certain prostanoid subtypes have been shown [2], and therefore identifying downstream targets of the COX-2 pathway may further aid in anti-inflammatory treatment for knee OA. Inflammatory processes have been suggested to precede knee OA [4][44] [4,44] and to be involved in structural disease progression [4]. A window of opportunity may exist, in which modulating the inflammatory status of the knee joint via intra-articular treatment with selective COX-2 inhibitors may lead to OA disease modification. The initiation of treatment may thus be important for the treatment outcome. The studies performed by Wen et al. [24] [24] and Dai et al. [20] [20] did not start treatment shortly after surgery and demonstrated chondroprotective actions of orally administered COX-2 inhibitors. It can be hypothesized that inhibiting inflammation directly after inducing a joint trauma may compromise cartilage regeneration, since inflammation is part of the early phases of natural tissue regeneration after a trauma [45]. This may explain why studies in surgical OA models fail to show chondroprotective effects when starting treatment directly after surgery. Moreover, the lack of a chondroprotective effect in clinical studies may be related to the stage of disease. Patients with knee OA are diagnosed in a stadium when the disease has progressed towards its end-stage [46], and it can be hypothesized that at this stage the disease is in an irreversible stadium where drug-based disease modification is not effective anymore. In addition, knee OA is a heterogeneous disease showing variability in the rate of disease progression in human subjects [47], while also the existence of distinct OA subtypes has been suggested [18[18][48],48], suggesting that patient-tailored drug treatment needs to be developed. Finally, the outcome measurements of clinical studies, such as joint space narrowing on conventional radiography, may not be sensitive enough. With the ongoing advancements in cartilage imaging [49], advanced techniques such as 7-tesla MRI imaging [49] [49] may provide a more sensitive means to evaluate multiple outcome domains relevant to the clinical and pathophysiological aspects of disease modifying osteoarthritis drug (DMOAD)-mediated disease modification.


  1. Hunter, D.J.; Felson, D.T. Osteoarthritis. BMJ 2006, 332, 639–642. [Google Scholar] [CrossRef]
  2. Ricciotti, E.; FitzGerald, G.A. Prostaglandins and inflammation. Arterioscler Thromb Vasc. Biol. 2011, 31, 986–1000. [Google Scholar] [CrossRef]
  3. Martel-Pelletier, J.; Pelletier, J.P.; Fahmi, H. Cyclooxygenase-2 and prostaglandins in articular tissues. Semin. Arthritis Rheum. 2003, 33, 155–167. [Google Scholar] [CrossRef]
  4. Ayral, X.; Pickering, E.H.; Woodworth, T.G.; Mackillop, N.; Dougados, M. Synovitis: A potential predictive factor of structural progression of medial tibiofemoral knee osteoarthritis—Results of a 1 year longitudinal arthroscopic study in 422 patients. Osteoarthritis Cartilage 2005, 13, 361–367. [Google Scholar] [CrossRef]
  5. Miller, R.E.; Block, J.A.; Malfait, A.M. Nerve growth factor blockade for the management of osteoarthritis pain: What can we learn from clinical trials and preclinical models? Curr. Opin. Rheumatol. 2017, 29, 110–118. [Google Scholar] [CrossRef]
  6. Ding, C. Do NSAIDs affect the progression of osteoarthritis? Inflammation 2002, 26, 139–142. [Google Scholar] [CrossRef]
  7. Zweers, M.C.; De Boer, T.N.; Van Roon, J.; Bijlsma, J.W.; Lafeber, F.P.; Mastbergen, S.C. Celecoxib: Considerations regarding its potential disease-modifying properties in osteoarthritis. Arthritis Res. Ther. 2011, 13, 239. [Google Scholar] [CrossRef]
  8. Buckwalter, J.A.; Mankin, H.J. Articular cartilage: Tissue design and chondrocyte-matrix interactions. Instr. Course Lect. 1998, 47, 477–486. [Google Scholar]
  9. Makris, E.A.; Hadidi, P.; Athanasiou, K.A. The knee meniscus: Structure-function, pathophysiology, current repair techniques, and prospects for regeneration. Biomaterials 2011, 32, 7411–7431. [Google Scholar] [CrossRef]
  10. Hooijmans, C.R.; Rovers, M.M.; De Vries, R.B.; Leenaars, M.; Ritskes-Hoitinga, M.; Langendam, M.W. SYRCLE’s risk of bias tool for animal studies. BMC Med. Res. Methodol 2014, 14, 43. [Google Scholar] [CrossRef]
  11. Van der Kraan, P.M.; Buma, P.; Van Kuppevelt, T.; Van den Berg, W.B. Interaction of chondrocytes, extracellular matrix and growth factors: Relevance for articular cartilage tissue engineering. Osteoarthritis Cartilage 2002, 10, 631–637. [Google Scholar] [CrossRef]
  12. Mastbergen, S.C.; Marijnissen, A.C.; Vianen, M.E.; Zoer, B.; Van Roermund, P.M.; Bijlsma, J.W.; Lafeber, F.P. Inhibition of COX-2 by celecoxib in the canine groove model of osteoarthritis. Rheumatology 2006, 45, 405–413. [Google Scholar] [CrossRef]
  13. Huh, J.E.; Baek, Y.H.; Kim, Y.J.; Lee, J.D.; Choi, D.Y.; Park, D.S. Protective effects of butanol fraction from Betula platyphyla var. japonica on cartilage alterations in a rabbit collagenase-induced osteoarthritis. J. Ethnopharmacol 2009, 123, 515–521. [Google Scholar] [CrossRef]
  14. Fukai, A.; Kamekura, S.; Chikazu, D.; Nakagawa, T.; Hirata, M.; Saito, T.; Hosaka, Y.; Ikeda, T.; Nakamura, K.; Chung, U.; et al. Lack of a chondroprotective effect of cyclooxygenase 2 inhibition in a surgically induced model of osteoarthritis in mice. Arthritis Rheum. 2012, 64, 198–203. [Google Scholar] [CrossRef]
  15. Ou, Y.; Tan, C.; An, H.; Jiang, D.; Quan, Z.; Tang, K.; Luo, X. Selective COX-2 inhibitor ameliorates osteoarthritis by repressing apoptosis of chondrocyte. Med. Sci. Monit. 2012, 18, BR247–BR252. [Google Scholar] [CrossRef]
  16. Ashkavand, Z.; Malekinejad, H.; Amniattalab, A.; Rezaei-Golmisheh, A.; Vishwanath, B.S. Silymarin potentiates the anti-inflammatory effects of Celecoxib on chemically induced osteoarthritis in rats. Phytomedicine 2012, 19, 1200–1205. [Google Scholar] [CrossRef]
  17. Moon, S.J.; Park, J.S.; Jeong, J.H.; Yang, E.J.; Park, M.K.; Kim, E.K.; Park, S.H.; Kim, H.Y.; Cho, M.L.; Min, J.K. Augmented chondroprotective effect of coadministration of celecoxib and rebamipide in the monosodium iodoacetate rat model of osteoarthritis. Arch. Pharm. Res. 2013, 36, 116–124. [Google Scholar] [CrossRef]
  18. Panahifar, A.; Jaremko, J.L.; Tessier, A.G.; Lambert, R.G.; Maksymowych, W.P.; Fallone, B.G.; Doschak, M.R. Development and reliability of a multi-modality scoring system for evaluation of disease progression in pre-clinical models of osteoarthritis: Celecoxib may possess disease-modifying properties. Osteoarthritis Cartilage 2014, 22, 1639–1650. [Google Scholar] [CrossRef]
  19. Li, Z.; Meng, D.; Li, G.; Xu, J.; Tian, K.; Li, Y. Celecoxib Combined with Diacerein Effectively Alleviates Osteoarthritis in Rats via Regulating JNK and p38MAPK Signaling Pathways. Inflammation 2015, 38, 1563–1572. [Google Scholar] [CrossRef]
  20. Dai, M.W.; Chu, J.G.; Tian, F.M.; Song, H.P.; Wang, Y.; Zhang, Y.Z.; Zhang, L. Parathyroid hormone(1-34) exhibits more comprehensive effects than celecoxib in cartilage metabolism and maintaining subchondral bone micro-architecture in meniscectomized guinea pigs. Osteoarthritis Cartilage 2016, 24, 1103–1112. [Google Scholar] [CrossRef]
  21. Tu, M.; Yang, M.; Yu, N.; Zhen, G.; Wan, M.; Liu, W.; Ji, B.; Ma, H.; Guo, Q.; Tong, P.; et al. Inhibition of cyclooxygenase-2 activity in subchondral bone modifies a subtype of osteoarthritis. Bone Res. 2019, 7, 29. [Google Scholar] [CrossRef]
  22. Jones, M.D.; Tran, C.W.; Li, G.; Maksymowych, W.P.; Zernicke, R.F.; Doschak, M.R. In vivo microfocal computed tomography and micro-magnetic resonance imaging evaluation of antiresorptive and antiinflammatory drugs as preventive treatments of osteoarthritis in the rat. Arthritis Rheum. 2010, 62, 2726–2735. [Google Scholar] [CrossRef]
  23. Nagy, E.; Vajda, E.; Vari, C.; Sipka, S.; Farr, A.M.; Horvath, E. Meloxicam ameliorates the cartilage and subchondral bone deterioration in monoiodoacetate-induced rat osteoarthritis. PeerJ 2017, 5, e3185. [Google Scholar] [CrossRef]
  24. Wen, Z.H.; Lin, Y.Y.; Chang, Y.C.; Tang, C.C.; Hsieh, S.P.; Lee, H.P.; Sung, C.S.; Chen, W.F.; Lee, C.H.; Jean, J.H. The COX-2 inhibitor etoricoxib reduces experimental osteoarthritis and nociception in rats: The roles of TGF-beta1 and NGF expressions in chondrocytes. Eur. J. Pain. 2020, 24, 209–222. [Google Scholar] [CrossRef] [PubMed]
  25. Liu, B.; Ji, C.; Shao, Y.; Liang, T.; He, J.; Jiang, H.; Chen, G.; Luo, Z. Etoricoxib decreases subchondral bone mass and attenuates biomechanical properties at the early stage of osteoarthritis in a mouse model. Biomed Pharmacother 2020, 127, 110144. [Google Scholar] [CrossRef]
  26. Jiang, D.; Zou, J.; Huang, L.; Shi, Q.; Zhu, X.; Wang, G.; Yang, H. Efficacy of intra-articular injection of celecoxib in a rabbit model of osteoarthritis. Int. J. Mol. Sci. 2010, 11, 4106. [Google Scholar] [CrossRef]
  27. Dong, J.; Jiang, D.; Wang, Z.; Wu, G.; Miao, L.; Huang, L. Intra-articular delivery of liposomal celecoxib-hyaluronate combination for the treatment of osteoarthritis in rabbit model. Int. J. Pharm. 2013, 441, 285–290. [Google Scholar] [CrossRef]
  28. Janssen, M.; Timur, U.T.; Woike, N.; Welting, T.J.; Draaisma, G.; Gijbels, M.; van Rhijn, L.W.; Mihov, G.; Thies, J.C.; Emans, P.J. Celecoxib-loaded PEA microspheres as an auto regulatory drug-delivery system after intra-articular injection. J. Control Release. 2016, 244, 30–40. [Google Scholar] [CrossRef]
  29. Tellegen, A.R.; Rudnik-Jansen, I.; Pouran, B.; De Visser, H.M.; Weinans, H.H.; Thomas, R.E.; Kik, M.J.L.; Grinwis, G.C.M.; Thies, J.C.; Woike, N.; et al. Controlled release of celecoxib inhibits inflammation, bone cysts and osteophyte formation in a preclinical model of osteoarthritis. Drug Deliv. 2018, 25, 1438–1447. [Google Scholar] [CrossRef]
  30. Jean, Y.H.; Wen, Z.H.; Chang, Y.C.; Hsieh, S.P.; Tang, C.C.; Wang, Y.H.; Wong, C.S. Intra-articular injection of the cyclooxygenase-2 inhibitor parecoxib attenuates osteoarthritis progression in anterior cruciate ligament-transected knee in rats: Role of excitatory amino acids. Osteoarthritis Cartilage 2007, 15, 638–645. [Google Scholar] [CrossRef]
  31. Wen, Z.H.; Tang, C.C.; Chang, Y.C.; Huang, S.Y.; Chen, C.H.; Wu, S.C.; Hsieh, S.P.; Hsieh, C.S.; Wang, K.Y.; Lin, S.Y.; et al. Intra-articular injection of the selective cyclooxygenase-2 inhibitor meloxicam (Mobic) reduces experimental osteoarthritis and nociception in rats. Osteoarthritis Cartilage 2013, 21, 1976–1986. [Google Scholar] [CrossRef] [PubMed]
  32. Liu, P.; Gu, L.; Ren, L.; Chen, J.; Li, T.; Wang, X.; Yang, J.; Chen, C.; Sun, L. Intra-articular injection of etoricoxib-loaded PLGA-PEG-PLGA triblock copolymeric nanoparticles attenuates osteoarthritis progression. Am. J. Transl. Res. 2019, 11, 6775–6789. [Google Scholar] [PubMed]
  33. Tindall, E.A.; Sharp, J.T.; Burr, A.; Katz, T.K.; Wallemark, C.B.; Verburg, K.; Lefkowith, J. A 12-month, multicenter, prospective, open-label trial of radiographic analysis of disease progression in osteoarthritis of the knee or hip in patients receiving celecoxib. Clin Ther. 2002, 24, 2051–2063. [Google Scholar] [CrossRef]
  34. Sawitzke, A.D.; Shi, H.; Finco, M.F.; Dunlop, D.D.; 3rd Bingham, C.O.; Harris, C.L.; Singer, N.G.; Bradley, J.D.; Silver, D.; Jackson, C.G.; et al. The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: A report from the glucosamine/chondroitin arthritis intervention trial. Arthritis Rheum. 2008, 58, 3183–3191. [Google Scholar] [CrossRef] [PubMed]
  35. De Boer, T.N.; Huisman, A.M.; Polak, A.A.; Niehoff, A.G.; Van Rinsum, A.C.; Saris, D.; Bijlsma, J.W.J.; Lafeber, F.J.P.G.; Mastbergen, S.C. The chondroprotective effect of selective COX-2 inhibition in osteoarthritis: Ex vivo evaluation of human cartilage tissue after in vivo treatment. Osteoarthritis Cartilage 2009, 17, 482–488. [Google Scholar] [CrossRef] [PubMed]
  36. Raynauld, J.P.; Martel-Pelletier, J.; Beaulieu, A.; Bessette, L.; Morin, F.; Choquette, D.; Haraoui, B.; Abram, F.; Pelletier, J.P. An open-label pilot study evaluating by magnetic resonance imaging the potential for a disease-modifying effect of celecoxib compared to a modelized historical control cohort in the treatment of knee osteoarthritis. Semin. Arthritis Rheum. 2010, 40, 185–192. [Google Scholar] [CrossRef]
  37. Riendeau, D.; Percival, M.D.; Brideau, C.; Charleson, S.; Dubé, D.; Ethier, D.; Falgueyret, J.P.; Friesen, R.W.; Gordon, R.; Greig, G.; et al. Etoricoxib (MK-0663): Preclinical Profile and Comparison with other agents that selectively inhibit Cyclooxygenase-2. J. Pharmacol. Exp. Ther. 2001, 296, 558–566. [Google Scholar]
  38. Loeser, R.F.; Goldring, S.R.; Scanzello, C.R.; Goldring, M.B. Osteoarthritis: A disease of the joint as an organ. Arthritis Rheum. 2012, 64, 1697–1707. [Google Scholar] [CrossRef]
  39. Clockaerts, S.; Bastiaansen-Jenniskens, Y.M.; Runhaar, J.; Van Osch, G.J.; Van Offel, J.F.; Verhaar, J.A.; de Clerck, L.S.; Somville, J. The infrapatellar fat pad should be considered as an active osteoarthritic joint tissue: A narrative review. Osteoarthritis Cartilage 2010, 18, 876–882. [Google Scholar] [CrossRef]
  40. Weinberg, J.B.; Fermor, B.; Guilak, F. Nitric oxide synthase and cyclooxygenase interactions in cartilage and meniscus: Relationships to joint physiology, arthritis, and tissue repair. Subcell Biochem. 2007, 42, 31–62. [Google Scholar]
  41. De Lange-Brokaar, B.J.; Ioan-Facsinay, A.; Van Osch, G.J.; Zuurmond, A.M.; Schoones, J.; Toes, R.E.; Huizinga, T.W.J.; Kloppenburg, M. Synovial inflammation, immune cells and their cytokines in osteoarthritis: A review. Osteoarthritis Cartilage 2012, 20, 1484–1499. [Google Scholar] [CrossRef]
  42. Bastiaansen-Jenniskens, Y.M.; Wei, W.; Feijt, C.; Waarsing, J.H.; Verhaar, J.A.; Zuurmond, A.M.; Hanemaaijer, R.; Stoop, R.; van Osch, G.J.V.M. Stimulation of fibrotic processes by the infrapatellar fat pad in cultured synoviocytes from patients with osteoarthritis: A possible role for prostaglandin f2alpha. Arthritis Rheum. 2013, 65, 2070–2080. [Google Scholar] [CrossRef]
  43. Welting, T.J.; Caron, M.M.; Emans, P.J.; Janssen, M.P.; Sanen, K.; Coolsen, M.M.; Voss, L.; Surtel, D.A.; Cremers, A.; Voncken, J.; et al. Inhibition of cyclooxygenase-2 impacts chondrocyte hypertrophic differentiation during endochondral ossification. Eur. Cell Mater. 2011, 22, 420–437. [Google Scholar] [CrossRef]
  44. Felson, D.T.; Niu, J.; Neogi, T.; Goggins, J.; Nevitt, M.C.; Roemer, F.; Torner, J.; Lewis, C.E.; Guermazi, A. Synovitis and the risk of knee osteoarthritis: The MOST Study. Osteoarthritis Cartilage 2016, 24, 458–464. [Google Scholar] [CrossRef]
  45. Karin, M.; Clevers, H. Reparative inflammation takes charge of tissue regeneration. Nature 2016, 529, 307–315. [Google Scholar] [CrossRef]
  46. Glyn-Jones, S.; Palmer, A.J.; Agricola, R.; Price, A.J.; Vincent, T.L.; Weinans, H.; Carr, A.J. Osteoarthritis. Lancet 2015, 386, 376–387. [Google Scholar] [CrossRef]
  47. Karsdal, M.A.; Christiansen, C.; Ladel, C.; Henriksen, K.; Kraus, V.B.; Bay-Jensen, A.C. Osteoarthritis--a case for personalized health care? Osteoarthritis Cartilage 2014, 22, 7–16. [Google Scholar] [CrossRef]
  48. Waarsing, J.H.; Bierma-Zeinstra, S.M.; Weinans, H. Distinct subtypes of knee osteoarthritis: Data from the Osteoarthritis Initiative. Rheumatology 2015, 54, 1650–1658. [Google Scholar] [CrossRef]
  49. Oei, E.H.G.; Wick, M.C.; Muller-Lutz, A.; Schleich, C.; Miese, F.R. Cartilage Imaging: Techniques and Developments. Semin. Musculoskelet. Radiol. 2018, 22, 245–260.
Video Production Service