Immune Dysfunction in Medication-Related Osteonecrosis of the Jaw: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Beatrix Zheng and Version 1 by Federico Mussano.

The pathogenesis of medication-related osteonecrosis of the jaw (MRONJ) is multifactorial and there is a substantial consensus on the role of antiresorptive drugs (ARDs), including bisphosphonates (BPs) and denosumab (Dmab), as one of the main determinants. The time exposure, cumulative dose and administration intensity of these drugs are critical parameters to be considered in the treatment of patients, as cancer patients show the highest incidence of MRONJ. BPs and Dmab have distinct mechanisms of action on bone, but they also exert different effects on immune subsets which interact with bone cells, thus contributing to the onset of MRONJ.

  • medication-related osteonecrosis of the jaw
  • osteoclast
  • osteoblast

1. Introduction

Osteonecrosis of the jaw (ONJ) is a multifaceted disease that has been known since 2003 in patients exposed to BPs (bisphosphonate-related ONJ (BRONJ)), but was renamed medication-related ONJ (MRONJ) [1] after the observation of cases due to the receptor activator of the nuclear factor κB ligand (RANKL) antibody, denosumab (Dmab), and other drugs [2,3,4][2][3][4]. Indeed, due to the continuous evolution in cancer treatment, MRONJ has been associated in smaller measure to antiangiogenic and cyclin inhibitor drugs [2,5][2][5].
To date, there is still open discussion about the definition, diagnosis, staging and treatment strategy of MRONJ [5,6,7,8,9,10][5][6][7][8][9][10]. The pathogenesis of MRONJ appears multifactorial [11]. MRONJ has the peculiarity of occurring in the jaw (often, albeit not exclusively, at a tooth extraction site), but not in other bones. A possible reason is the strong mechanical stimulation to which jaws are subjected that leads to a high bone turnover rate, which is approximately 3- to 6-times faster than those observed in long bones of beagle dogs [12,13][12][13].
There is a substantial consensus on the important role of antiresorptive drugs (ARDs), such as BPs and Dmab, in the pathogenesis of MRONJ [1,4,14][1][4][14]. With regard to zoledronic acid (Zol), which is an amino-bisphosphonate (N-BP), and denosumab (Dmab), time exposure, cumulative dose and administration intensity are all parameters that increase MRONJ risk. Of course, MRONJ reduces the quality of life of the affected patients [15]; thus, measures aimed to reduce the disease risk that contribute to patients’ oral health have been adopted by clinicians.
The coexistence of more factors increases the risk for MRONJ, which is higher for oncologic than osteoporotic patients likely due to the higher and more frequent doses of ARDs that can lead to an intense suppression of bone turnover [16]. One of the main causes of MRONJ is represented by the inhibition of osteoclast (OC) and osteoblast (OB) activity due to the ARDs, which causes suppressed bone turnover with compromised bone healing [17]. Microcirculation dysfunctions with angiogenesis inhibition [18], mucosal damage secondary to toxic exposure of the bone, bacterial infection and immune dysfunction all come together to lead to MRONJ [17,19][17][19].

2. An Immunosuppressed Milieu Favors ONJ Induced by ARDs

Both N-BPs and Dmab cause an immune dysfunction in MRONJ patients [20,21,22][20][21][22] by hindering their capability to respond properly to immunological stress independently of the oral microbiome [23]. It is also noteworthy that a large number of patients that develop MRONJ have other disease conditions or partake in many pharmacological treatments (chemotherapy, steroids, antiviral drugs, etc.), which may contribute to their immune system impairment [23,24][23][24].
The role of immune responses and inflammation in the onset and/or progression of MRONJ has been recently reported since a massive infiltration of lymphocytes mixed with inflammatory cells within tissue affected by MRONJ has been documented [25]. Moreover, it has been found that N-BPs increased the production of acute general inflammatory mediators in vitro [26] and in vivo [27], modifying the immune cell subset of patients [28[28][29],29], but they did not change inflammatory bone markers. Tooth extraction is comparable, for some aspects, to a bone fracture, where inflammation and fracture healing are parallel processes, because both need a focus and a resolution. Initially, at the damage site, the T-cell subset releases cytokines, such as IL-17, which directly support the proliferation and differentiation of local mesenchymal stem cells into OBs. Later, another specific subgroup of T cells blocks the secretion of pro-inflammatory factors to allow for lesion healing. In pathological conditions, the over production of IL-17 elicits an opposite effect on OBs by inhibiting their differentiation and activity, and by promoting OC bone resorption [30,31][30][31]. Thus, the correct cross-talk among immune cells and bone cells is fundamental to avoid both bone and immune alterations [32]. In mice treated with Zol, tooth extraction increases inflammatory cytokine levels and osteocyte apoptosis in the extraction site, promoting osteonecrosis [33]. These data confirm other previously published data, showing that the serum level of inflammatory cytokines was increased in MRONJ patients and that the administration of anti-inflammatory cytokines, such as antitumor necrosis factor-α (TNFα) and anti-interleukin 6 (IL-6), were effective in preventing a cytokine storm induced by N-BPs [33]. Recently, it has been reported in a murine model that the administration of either anti-inflammatory or antibiotic drugs significantly blocked Zol-induced osteonecrosis following tooth extraction [34], suggesting that this type of treatment should be considered to prevent MRONJ onset.

3. Bacterial Infections as Both Cause and Consequence of Immune Dysfunction in MRONJ

The role of commensal oral microbiota and bacterial infections, either associated or not to tissue damage induced by invasive dental procedures, in MRONJ is debated [35]. It is noteworthy that the jawbone is the peculiarly susceptible to infections compared to other bones, which are not as easily exposed to microorganisms as they occur in the oral cavity. Breaching the mucosal barrier during or after antiresorptive treatment may cause infection and hinder the healing process, thus leading to bone necrosis [36,37][36][37]. The most common surgical procedure associated with the onset of osteonecrosis is tooth extraction [6]. After N-BP treatment, bacteria are known to stimulate bone resorption [38,39][38][39]. A growing number of scientific papers have suggested the possible role of Actinomyces species [40[40][41],41], which are ubiquitous Gram-positive, non-spore-forming bacteria, that were found in more than 80% of bone samples from MRONJ patients in two retrospective studies [37,42][37][42]. Bacterial microfilms that are detectable in N-BP-related sites of osteonecrosis may stimulate OC activity on the bone surface, supporting the concept that microorganisms may directly contribute to bone necrosis [43,44][43][44].
Several studies highlighted oral cavity infection as a major event that stimulates a chronic inflammatory immune response, with the increase in cytokines leading to the upregulation of β-defensin 3 [45]. Defensins are antimicrobial peptides (AMPs) that are important in the innate immunity response against microbial pathogens [46], and they exert a protective action on oral cavity integrity against the invasion by microbes [47]. In the animal model, it has been reported that infectious osteomyelitis and ARD administration synergize in promoting MRONJ, with an increased release of pro-inflammatory cytokines. The same authors suggested that ”pro-inflammatory cytokines may represent therapeutic targets to prevent osteonecrosis induced by infectious osteomyelitis in patients treated with anti-resorptive therapy” [48,49][48][49]. Increased levels of β-defensins were also described in osteomyelitis of the jaw compared to uninfected healthy jaws, while in infected osteoradionecrosis (ORN), their levels were significantly reduced [50]. This observation suggests that, in MRONJ, bone displays not only necrotic characteristics similar to the ORN samples, but it shows the previously described aspect of bone affected by bacterial infections [51]. Thus, Stockman et al. concluded that “The increased expression of human β-defensins in bone samples of N-BP-induced ONJ can be interpreted as a sign of unimpaired metabolic activity and can therefore be seen as a reaction of vital bone to microbial invasion” [50]. Furthermore, β-defensins are expressed by OBs, stimulating their proliferation and differentiation process [52], and, in patients with infection, the level of expression of β-defensin-2 by OBs has been found to increase, suggesting that antimicrobial peptides play a central role in the prevention of bone infection. Looking at patients treated with immunosuppressive drugs, an increased susceptibility to bone infection seems to occur due to decreasing antimicrobial peptide expression levels [53]. Considering all these data and the fact that an intrinsic basal level of β-defensin 3 expression is independent of exposure to bacterial stimuli, it is still unclear whether AMP expression contributes to the MRONJ pathogenesis or if it is simply an after-effect of the disease [54].

References

  1. Marx, R.E. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: A growing epidemic. J. Oral Maxillofac. Surg. 2003, 61, 1115–1117.
  2. Fusco, V.; Santini, D.; Armento, G.; Tonini, G.; Campisi, G. Osteonecrosis of jaw beyond antiresorptive (bone-targeted) agents: New horizons in oncology. Expert Opin. Drug. Saf. 2016, 15, 925–935.
  3. Nicolatou-Galitis, O.; Schiodt, M.; Mendes, R.A.; Ripamonti, C.; Hope, S.; Drudge-Coates, L.; Niepel, D.; Van den Wyngaert, T. Medication-related osteonecrosis of the jaw: Definition and best practice for prevention, diagnosis, and treatment. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 2019, 127, 117–135.
  4. Eguia, A.; Bagan-Debon, L.; Cardona, F. Review and update on drugs related to the development of osteonecrosis of the jaw. Med. Oral Patol. Oral Cir. Bucal 2020, 25, e71–e83.
  5. Yarom, N.; Shapiro, C.L.; Peterson, D.E.; Van Poznak, C.H.; Bohlke, K.; Ruggiero, S.L.; Migliorati, C.A.; Khan, A.; Morrison, A.; Anderson, H.; et al. Medication-Related Osteonecrosis of the Jaw: MASCC/ISOO/ASCO Clinical Practice Guideline. J. Clin. Oncol. 2019, 37, 2270–2290.
  6. Ruggiero, S.L.; Dodson, T.B.; Fantasia, J.; Goodday, R.; Aghaloo, T.; Mehrotra, B.; O’Ryan, F.; American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw—2014 update. J. Oral Maxillofac. Surg. 2014, 72, 1938–1956.
  7. Bedogni, A.; Fusco, V.; Agrillo, A.; Campisi, G. Learning from experience. Proposal of a refined definition and staging system for bisphosphonate-related osteonecrosis of the jaw (BRONJ). Oral Dis. 2012, 18, 621–623.
  8. Fusco, V.; Santini, D.; Campisi, G.; Bertoldo, F.; Lanzetta, G.; Ibrahim, T.; Bertetto, O.; Numico, G.; Addeo, A.; Berruti, A.; et al. Comment on Medication-Related Osteonecrosis of the Jaw: MASCC/ISOO/ASCO Clinical Practice Guideline Summary. JCO Oncol. Pract. 2020, 16, 142–145.
  9. Otto, S.; Pautke, C.; Van den Wyngaert, T.; Niepel, D.; Schiodt, M. Medication-related osteonecrosis of the jaw: Prevention, diagnosis and management in patients with cancer and bone metastases. Cancer Treat. Rev. 2018, 69, 177–187.
  10. Campisi, G.; Mauceri, R.; Bedogni, A.; Fusco, V. Re: AAOMS Position Paper on Medication-Related Osteonecrosis of the Jaw-2022 Update. J. Oral Maxillofac. Surg. 2022, 80, 1723–1724.
  11. Reid, I.R. Osteonecrosis of the jaw: Who gets it, and why? Bone 2009, 44, 4–10.
  12. Huja, S.S.; Fernandez, S.A.; Hill, K.J.; Li, Y. Remodeling dynamics in the alveolar process in skeletally mature dogs. Anat. Rec. A Discov. Mol. Cell. Evol. Biol. 2006, 288, 1243–1249.
  13. Allen, M.R.; Burr, D.B. The pathogenesis of bisphosphonate-related osteonecrosis of the jaw: So many hypotheses, so few data. J. Oral Maxillofac. Surg. 2009, 67, 61–70.
  14. Hanley, D.A.; Adachi, J.D.; Bell, A.; Brown, V. Denosumab: Mechanism of action and clinical outcomes. Int. J. Clin. Pract. 2012, 66, 1139–1146.
  15. Bensi, C.; Giovacchini, F.; Lomurno, G.; Eramo, S.; Barraco, G.; Tullio, A. Quality of life in patients affected by medication-related osteonecrosis of the jaws: A systematic review. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 2021, 132, 182–189.
  16. Peng, J.; Wang, H.; Liu, Z.; Xu, Z.L.; Wang, M.X.; Chen, Q.M.; Wu, M.L.; Ren, X.L.; Liang, Q.H.; Liu, F.P.; et al. Real-world study of antiresorptive-related osteonecrosis of jaw based on the US food and drug administration adverse event reporting system database. Front. Pharmacol. 2022, 13, 1017391.
  17. Marx, R.E.; Sawatari, Y.; Fortin, M.; Broumand, V. Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: Risk factors, recognition, prevention, and treatment. J. Oral Maxillofac. Surg. 2005, 63, 1567–1575.
  18. Walter, C.; Pabst, A.; Ziebart, T.; Klein, M.; Al-Nawas, B. Bisphosphonates affect migration ability and cell viability of HUVEC, fibroblasts and osteoblasts in vitro. Oral Dis. 2011, 17, 194–199.
  19. Otto, S.; Pautke, C.; Martin Jurado, O.; Nehrbass, D.; Stoddart, M.J.; Ehrenfeld, M.; Zeiter, S. Further development of the MRONJ minipig large animal model. J. Craniomaxillofac. Surg. 2017, 45, 1503–1514.
  20. Francisconi, C.F.; Vieira, A.E.; Azevedo, M.C.S.; Tabanez, A.P.; Fonseca, A.C.; Trombone, A.P.F.; Letra, A.; Silva, R.M.; Sfeir, C.S.; Little, S.R.; et al. RANKL Triggers Treg-Mediated Immunoregulation in Inflammatory Osteolysis. J. Dent. Res. 2018, 97, 917–927.
  21. Park, S.; Kanayama, K.; Kaur, K.; Tseng, H.C.; Banankhah, S.; Quje, D.T.; Sayre, J.W.; Jewett, A.; Nishimura, I. Osteonecrosis of the Jaw Developed in Mice: Disease Variants Regulated by gammadelta T Cells in Oral Mucosal Barrier Immunity. J. Biol. Chem. 2015, 290, 17349–17366.
  22. Zhu, W.; Xu, R.; Du, J.; Fu, Y.; Li, S.; Zhang, P.; Liu, L.; Jiang, H. Zoledronic acid promotes TLR-4-mediated M1 macrophage polarization in bisphosphonate-related osteonecrosis of the jaw. FASEB J. 2019, 33, 5208–5219.
  23. Kalyan, S. It May Seem Inflammatory, but Some T Cells Are Innately Healing to the Bone. J. Bone Miner. Res. 2016, 31, 1997–2000.
  24. Kalyan, S.; Quabius, E.S.; Wiltfang, J.; Monig, H.; Kabelitz, D. Can peripheral blood gammadelta T cells predict osteonecrosis of the jaw? An immunological perspective on the adverse drug effects of aminobisphosphonate therapy. J. Bone Miner. Res. 2013, 28, 728–735.
  25. Salesi, N.; Pistilli, R.; Marcelli, V.; Govoni, F.A.; Bozza, F.; Bossone, G.; Venturelli, V.; Di Cocco, B.; Pacetti, U.; Ciorra, A.; et al. Bisphosphonates and oral cavity avascular bone necrosis: A review of twelve cases. Anticancer Res. 2006, 26, 3111–3115.
  26. Muratsu, D.; Yoshiga, D.; Taketomi, T.; Onimura, T.; Seki, Y.; Matsumoto, A.; Nakamura, S. Zoledronic acid enhances lipopolysaccharide-stimulated proinflammatory reactions through controlled expression of SOCS1 in macrophages. PLoS ONE 2013, 8, e67906.
  27. Norton, J.T.; Hayashi, T.; Crain, B.; Cho, J.S.; Miller, L.S.; Corr, M.; Carson, D.A. Cutting edge: Nitrogen bisphosphonate-induced inflammation is dependent upon mast cells and IL-1. J. Immunol. 2012, 188, 2977–2980.
  28. Rossini, M.; Adami, S.; Viapiana, O.; Fracassi, E.; Ortolani, R.; Vella, A.; Zanotti, R.; Tripi, G.; Idolazzi, L.; Gatti, D. Long-term effects of amino-bisphosphonates on circulating gammadelta T cells. Calcif. Tissue Int. 2012, 91, 395–399.
  29. Welton, J.L.; Morgan, M.P.; Marti, S.; Stone, M.D.; Moser, B.; Sewell, A.K.; Turton, J.; Eberl, M. Monocytes and gammadelta T cells control the acute-phase response to intravenous zoledronate: Insights from a phase IV safety trial. J. Bone Miner. Res. 2013, 28, 464–471.
  30. Uluckan, O.; Jimenez, M.; Karbach, S.; Jeschke, A.; Grana, O.; Keller, J.; Busse, B.; Croxford, A.L.; Finzel, S.; Koenders, M.; et al. Chronic skin inflammation leads to bone loss by IL-17-mediated inhibition of Wnt signaling in osteoblasts. Sci. Transl. Med. 2016, 8, 330ra337.
  31. Pollinger, B.; Junt, T.; Metzler, B.; Walker, U.A.; Tyndall, A.; Allard, C.; Bay, S.; Keller, R.; Raulf, F.; Di Padova, F.; et al. Th17 cells, not IL-17+ gammadelta T cells, drive arthritic bone destruction in mice and humans. J. Immunol. 2011, 186, 2602–2612.
  32. Ono, T.; Okamoto, K.; Nakashima, T.; Nitta, T.; Hori, S.; Iwakura, Y.; Takayanagi, H. IL-17-producing gammadelta T cells enhance bone regeneration. Nat. Commun. 2016, 7, 10928.
  33. Soma, T.; Iwasaki, R.; Sato, Y.; Kobayashi, T.; Nakamura, S.; Kaneko, Y.; Ito, E.; Okada, H.; Watanabe, H.; Miyamoto, K.; et al. Tooth extraction in mice administered zoledronate increases inflammatory cytokine levels and promotes osteonecrosis of the jaw. J. Bone Miner. Metab. 2021, 39, 372–384.
  34. Soma, T.; Iwasaki, R.; Sato, Y.; Kobayashi, T.; Ito, E.; Matsumoto, T.; Kimura, A.; Miyamoto, K.; Matsumoto, M.; Nakamura, M.; et al. Osteonecrosis development by tooth extraction in zoledronate treated mice is inhibited by active vitamin D analogues, anti-inflammatory agents or antibiotics. Sci. Rep. 2022, 12, 19.
  35. Du, W.; Yang, M.; Kim, T.; Kim, S.; Williams, D.W.; Esmaeili, M.; Hong, C.; Shin, K.H.; Kang, M.K.; Park, N.H.; et al. Indigenous microbiota protects development of medication-related osteonecrosis induced by periapical disease in mice. Int. J. Oral Sci. 2022, 14, 16.
  36. Shibahara, T. Antiresorptive Agent-Related Osteonecrosis of the Jaw (ARONJ): A Twist of Fate in the Bone. Tohoku J. Exp. Med. 2019, 247, 75–86.
  37. Russmueller, G.; Seemann, R.; Weiss, K.; Stadler, V.; Speiss, M.; Perisanidis, C.; Fuereder, T.; Willinger, B.; Sulzbacher, I.; Steininger, C. The association of medication-related osteonecrosis of the jaw with Actinomyces spp. infection. Sci. Rep. 2016, 6, 31604.
  38. Nair, S.P.; Meghji, S.; Wilson, M.; Reddi, K.; White, P.; Henderson, B. Bacterially induced bone destruction: Mechanisms and misconceptions. Infect. Immun. 1996, 64, 2371–2380.
  39. Meghji, S.; Crean, S.J.; Hill, P.A.; Sheikh, M.; Nair, S.P.; Heron, K.; Henderson, B.; Mawer, E.B.; Harris, M. Surface-associated protein from Staphylococcus aureus stimulates osteoclastogenesis: Possible role in S. aureus-induced bone pathology. Br. J. Rheumatol. 1998, 37, 1095–1101.
  40. De Ceulaer, J.; Tacconelli, E.; Vandecasteele, S.J. Actinomyces osteomyelitis in bisphosphonate-related osteonecrosis of the jaw (BRONJ): The missing link? Eur. J. Clin. Microbiol. Infect. Dis. 2014, 33, 1873–1880.
  41. Schipmann, S.; Metzler, P.; Rossle, M.; Zemann, W.; von Jackowski, J.; Obwegeser, J.A.; Gratz, K.W.; Jacobsen, C. Osteopathology associated with bone resorption inhibitors—Which role does Actinomyces play? A presentation of 51 cases with systematic review of the literature. J. Oral Pathol. Med. 2013, 42, 587–593.
  42. Cerrato, A.; Zanette, G.; Boccuto, M.; Angelini, A.; Valente, M.; Bacci, C. Actinomyces and MRONJ: A retrospective study and a literature review. J. Stomatol. Oral Maxillofac. Surg. 2021, 122, 499–504.
  43. Sedghizadeh, P.P.; Stanley, K.; Caligiuri, M.; Hofkes, S.; Lowry, B.; Shuler, C.F. Oral bisphosphonate use and the prevalence of osteonecrosis of the jaw: An institutional inquiry. J. Am. Dent. Assoc. 2009, 140, 61–66.
  44. Lesclous, P.; Abi Najm, S.; Carrel, J.P.; Baroukh, B.; Lombardi, T.; Willi, J.P.; Rizzoli, R.; Saffar, J.L.; Samson, J. Bisphosphonate-associated osteonecrosis of the jaw: A key role of inflammation? Bone 2009, 45, 843–852.
  45. Gursoy, U.K.; Kononen, E. Understanding the roles of gingival beta-defensins. J. Oral Microbiol. 2012, 4, 15127.
  46. Wang, G. Human antimicrobial peptides and proteins. Pharmaceuticals 2014, 7, 545–594.
  47. Abiko, Y.; Saitoh, M.; Nishimura, M.; Yamazaki, M.; Sawamura, D.; Kaku, T. Role of beta-defensins in oral epithelial health and disease. Med. Mol. Morphol. 2007, 40, 179–184.
  48. Morita, M.; Iwasaki, R.; Sato, Y.; Kobayashi, T.; Watanabe, R.; Oike, T.; Nakamura, S.; Keneko, Y.; Miyamoto, K.; Ishihara, K.; et al. Elevation of pro-inflammatory cytokine levels following anti-resorptive drug treatment is required for osteonecrosis development in infectious osteomyelitis. Sci. Rep. 2017, 7, 46322.
  49. Shuster, A.; Reiser, V.; Trejo, L.; Ianculovici, C.; Kleinman, S.; Kaplan, I. Comparison of the histopathological characteristics of osteomyelitis, medication-related osteonecrosis of the jaw, and osteoradionecrosis. Int. J. Oral Maxillofac. Surg. 2019, 48, 17–22.
  50. Stockmann, P.; Wehrhan, F.; Schwarz-Furlan, S.; Stelzle, F.; Trabert, S.; Neukam, F.W.; Nkenke, E. Increased human defensine levels hint at an inflammatory etiology of bisphosphonate-associated osteonecrosis of the jaw: An immunohistological study. J. Transl. Med. 2011, 9, 135.
  51. Warnke, P.H.; Springer, I.N.; Russo, P.A.; Wiltfang, J.; Essig, H.; Kosmahl, M.; Sherry, E.; Acil, Y. Innate immunity in human bone. Bone 2006, 38, 400–408.
  52. Kraus, D.; Deschner, J.; Jager, A.; Wenghoefer, M.; Bayer, S.; Jepsen, S.; Allam, J.P.; Novak, N.; Meyer, R.; Winter, J. Human beta-defensins differently affect proliferation, differentiation, and mineralization of osteoblast-like MG63 cells. J. Cell. Physiol. 2012, 227, 994–1003.
  53. Varoga, D.; Tohidnezhad, M.; Paulsen, F.; Wruck, C.J.; Brandenburg, L.; Mentlein, R.; Lippross, S.; Hassenpflug, J.; Besch, L.; Muller, M.; et al. The role of human beta-defensin-2 in bone. J. Anat. 2008, 213, 749–757.
  54. Thiel, Y.; Ghayor, C.; Lindhorst, D.; Essig, H.; Weber, F.; Rucker, M.; Schumann, P. Antimicrobial peptide gene expression in medication-related osteonecrosis of the jaw. Pathol. Res. Pract. 2020, 216, 153245.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
ScholarVision Creations
Feedback