University of Groningen
Salivary lubrication and xerostomia
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.
Publisher's PDF, also known as Version of record
Publication date: 2020
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Vinke, J. (2020). Salivary lubrication and xerostomia. University of Groningen. https://doi.org/10.33612/diss.133408765
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
145468 Vinke BNW.indd 8
Biotribology and lubrication in the oral cavity
Biotribology is the study of lubrication, friction and wear in biological systems, for example the human oral cavity, where opposing surfaces come into close contact and where saliva plays a lubricating role. Lubrication is the ability of a certain substance (e.g., saliva) to decrease friction between contacting surfaces.
The friction between two sliding surfaces is quantified in terms of coefficient of friction (COF), i.e., the ratio of the frictional force and the normal force. COF depends on the properties of the two sliding surfaces, contact pressure, sliding velocity and the viscosity of the lubricant.
From an engineering point of view, lubrication can exist in three regimes summarized by the Stribeck curve (Figure 1). The boundary lubrication regime typically exists between sliding surfaces in contact and in absence of a fluid film, where the contact pressure is generally high, and the speed and viscosity are low. Molar surfaces are an intra-oral example of this lubrication regime, where the two surfaces are only separated by a thin layer of adsorbed proteins and glycoproteins. Elasto-hydrodynamic lubrication regime occurs in between sliding surfaces when one or both the surfaces elastically deform and give rise of a very thin fluid film. Soft oral contacts in presence of saliva is an example of such an elasto-hydrodynamic regime1–3. Pure hydrodynamic lubrication occurs when sliding surfaces are totally separated by a thick
fluid film. Both for elasto-hydrodynamic and hydrodynamic lubrication high sliding speed and high fluid viscosity are necessary. Hydrodynamic lubrication takes place in the oral cavity between soft surface in presence of large amounts of saliva. At this stage the rheology of saliva, becomes important1.
Efficacy of oral events as mastication, speech and swallowing are highly dependent on lubrication by saliva. In presence of sufficient and well-functioning saliva we take these oral functions for granted. How
Figure 1. Schematic representation of the Stribeck curve showing the relation between the COF and fluid film thickness.
have lubricating properties of saliva changed when these functions have become bothersome, for example, when one suffers from hyposalivation? The research described in this thesis focuses on intra-oral lubrication and assesses whether the salivary lubrication properties are different between healthy controls and patients suffering from xerostomia.
Saliva and glands
Human whole saliva (also named oral fluid) consists of secretions from all salivary glands (≈99% of water, ≈1% proteins and electrolytes) contaminated with gingival crevicular fluid, epithelial cell debris, food particles and microorganisms4. The major salivary glands, in particular the submandibular and parotid
glands, are the main contributors to whole saliva. Total salivary production ranges from 0.5 – 1.5 l a day 5-7. The composition and amount of saliva are predominantly influenced by the time of the day and the
type of stimulation. Saliva secretion follows circadian rhythms. Most saliva is produced during awake hours, with peak flows in the afternoon and during the meals6-8.
There are three major paired salivary glands: the parotid, submandibular and sublingual glands. The parotid glands are the largest glands and are located below and before the ear. The parotid gland secretions are transported towards the oral cavity by the major excretory duct, Stensen’s duct. The orifice of Stensen’s duct is located in the buccal mucosa adjacent to the second maxillary molar. The submandibular glands are located just below the angle of the mandible. The orifice of the major excretory duct, Wharton’s duct, can be found in the sublingual papilla, which is located in the floor of the mouth lingually from the lower anterior teeth. The sublingual glands are positioned in the floor of the mouth, lateral of the tongue. Eight to 20 small ducts (Rivini’s ducts) secrete directly at several openings in the floor of the mouth. In addition, the sublingual gland has also a major excretory duct, Bartholin’s duct, which commonly joins the Wharton’s duct4. Besides the three major paired glands, there are hundreds of
minor salivary glands, located just below the labial, buccal, palatine, lingual and pharyngeal mucosa. The main cells of the salivary glands are the acinar and ductal cells. Acinar cells form the acini and are responsible for secretion of primary saliva, which contains electrolytes and proteins. During its transportation through the ductal system, the composition of saliva is changed, amongst others by resorption and excretion of electrolytes by the striated ducts. The types of acinar cells in a salivary gland determines the nature of the secretion. Acini can be composed of mucous (main source of mucin secretion), serous (main source of water and enzymes, e.g., amylase9) or a combination of serous and
mucous (seromucous acini) acinar cells. Ductal cells alter the ionic strength of the primary saliva fluid and add proteins (e.g., lysozyme9) while transporting saliva towards the oral cavity10.
Resting whole saliva is secreted at a rate of 0.25-0.35 ml/min. The major contributor to resting saliva under minimal stimulation are the submandibular glands (seromucous), contributing to around 65% of the total secretion in awakening hours. Consecutively, the parotid glands (serous) contribute with 20%, the sublingual (mucous) and the minor salivary glands both with less than 10%11,12. Most minor salivary
glands are mixed glands (labial, buccal), but contain more mucous than serous acini. Palatal minor salivary glands are purely mucous and the von Ebner’s glands, located around circumvallate and foliate papillae, are purely serous. Just like submandibular glands, minor salivary glands continue producing mucins during the night in absence of stimuli5.
145468 Vinke BNW.indd 11
External stimuli, i.e., chewing, taste and smell, can upregulate salivary flow. Especially, the parotid glands only start producing saliva after stimulation by the mentioned stimuli. When sleeping, the contribution of the parotid glands to whole saliva reduces to about zero. Mechanical stimulation, for example, increases the contribution of parotid saliva to whole saliva to around 60%. The contribution of the submandibular glands to mechanical stimulated saliva is about 33% (>50% when stimulated with citric acid). Irrespective of the nature of the stimulus, contribution of the sublingual and minor salivary glands is about 3-4%11–13.
Sympathetic (predominantly protein secretion) and parasympathetic (predominantly water and electrolytes regulation but also protein release in some glands) innervation both result in secretion of saliva. Parasympathetic stimulation of muscarinic cholinergic receptors starts a cascade in acinar cells that
Figure 2. d the change in ionic
strength eceive acetylcholine from
the paras receptors inducing a
cascade even oride channels to transport
chloride i osmotic gradient in the
lumen, lea elatively high molarity
of sodium and chloride ions that cause the fluid to be isotonic. During transport through the ducts, striated duct cells actively remove sodium by sodium-potassium channels. Chloride passively follows by osmotic gradient differences. All this result in hypotonic saliva. Taken from Proctor and Carpenter15 with permission from S. Karger,
eventually leads to an osmotic pressure difference between the acinar lumen and the blood. This drags water into the lumen. The hypotonic character that saliva secreted into the oral cavity has, is acquired in the salivary ducts, where sodiumand chlorideare resorbed from the primary saliva and potassium is secreted10,14,15 (Figure 2).
Functions of saliva
During mastication, the molars disintegrate and grind down food while saliva is added to it to form the bolus. Saliva wets and helps in the formation of food bolus during chewing. This aides in swallowing the food. Besides that, saliva contains enzymes like amylase (parotid) and lipase (von Ebner’s) which start digesting the starch and lipids as soon as saliva becomes into contact with these substances5.
Saliva has many protective functions. The buffering capacity makes saliva able to neutralize acids. Saliva is able to re-establish remineralization of the tooth enamel through, amongst others proline-rich proteins, histatins, statherins and calcium ions16,17. Saliva also contains components that help in serving as a first
defence mechanism. Proteins (e.g., histatins, lactoferrin, cystatins, lactoperoxidase, amylase, mucin) have antimicrobial properties and can inactivate or clear viruses, bacteria and fungi from the oral cavity18–23.
The functions of saliva are summarized in Figure 3.
Another major function of saliva is lubricating the oral surfaces. Lubrication is important for speech, food processing and protection of tissue against abrasion24,25. Lubrication is facilitated by the formation
of a salivary conditioning film. The salivary conditioning film is composed of adsorbed salivary proteins, e.g., mucins, proline-rich proteins, histatins and statherins17,26–28. The composition can differ depending
on the location. Statherins17, proline-rich proteins26 and mucins29 facilitate boundary lubrication, i.e.,
during tooth-tooth contact when contact pressures can increase up to MPa range, and are abundantly
Figure 3. Functions of saliva, taken from Van Nieuw Amerongen et al.22 with permission of S. Karger AG, Basel.
145468 Vinke BNW.indd 13
present in the adsorbed pellicle on molar surfaces27. Mucins also facilitate lubrication in
Biology of mucins
Two main types of mucin glycoproteins, MG1 and MG2, encoded respectively by MUC5B and MUC7 genes, are present in human saliva. In literature, MG1 and MG2 are often directly referred to the gene which encodes them32 and in this thesis, the same nomenclature will be used. MUC7 is a short-chain
soluble protein (100-300 kDa) whereas MUC5B is a long-chain and heavy glycosylated protein (>1 MDa). The size, structure and glycosylation density of mucins are one aspect that highly determine the lubricating properties, and thus are important to elaborate on. MUC7 exists of one polypeptide chain that is rich in serine and threonine allowing for glycosylation by oligosaccharides33. Just like MUC7,
MUC5B is rich in serine and threonine rich domains, however, unlike MUC7, it also contains cysteine-rich domains which do not allow a high glycosylation density (Figure 4)34,35. At the cysteine-rich domains,
MUC5B can initiate polymerization by making disulphide bridges. This allows MUC5B to form big networks of linked proteins that gives the mucins a gel-like structure35.
The other aspect that is important for the lubrication properties of mucins are the water retention properties of the glycans35,36. Sulphate residues and sialic acid residues (N-Acetylneuraminic acid in Figure
4b) retain water the best and take care of the high lubricating properties that mucins provide. Sialic acid residues provide a negative charge providing electrostatic binding sites for the polar water molecules. Sulphated residues can retain water by H-bridges and electrostatic interaction37,38. Through these
interactions, mucin molecules are highly hydrated and thus provide hydration lubrication39,40 to surfaces
on which they adsorb.
Xerostomia, the sensation of oral dryness, is by itself not a disease, but a condition that can accompany multiple diseases and/or can be the result of treatment of a disease. Polypharmacy41,42 and head- and neck
radiotherapy43,44 are examples of iatrogenic causes. Diseases like Sjögren’s syndrome45,46 (second most
common autoimmune disease), uncontrolled diabetes mellitus47 and cystic fibrosis48 are also commonly
reported to be accompanied by xerostomia.
Commonly, xerostomia is associated with dysfunction of salivary glands, but xerostomia can also be present in patients with an abundant secretion of saliva and be absent in patients with hardly any salivary secretion. It is presumed that both a decreased salivary flow and an altered composition of saliva can underlie xerostomia49.
It has been suggested that the feeling of oral dryness is related to the residual salivary film thickness50.
The residual salivary film is the film of saliva that covers the mucosal pellicle and that remains on the mucosal surface after swallowing. This film is typically 10-70 µm thick51. Dry mouth sensation is evident
when the residual salivary film thickness drops below 10 µm which is equivalent to a dropped unstimulated salivary flow rate of <3 µl/cm2/min50.
Another reason for a reduced salivary film thickness can be a change in the water retention properties of the salivary constituents. For Sjögren’s syndrome and radiotherapy, it has been posed that the dry mouth feeling is not always just a matter of a sufficient amount of saliva, but could also be due to a change in the quality of the mucins52–56. For example, instead of the proteins levels, the water retention moieties of
salivary mucins can be affected, leading to less water resorption in the mucosal layer52,54–56.
Xerostomia is not life-threatening, but health-related quality of life (QoL) of xerostomia patients is significantly decreased and often even lower than in other chronic inflammatory diseases57–60. Frequent
complaints are oral dryness, oral tissue redness and a burning sensation, tongue fissures and a sticky tongue, ulceration of the oral mucosa, and problems with speech and food processing. Hyposalivation can also lead to higher susceptibility to oral candidiasis, enamel erosion, dental caries, and a bad breath61.
To relieve dry mouth complaints, saliva substitutes are often prescribed. A large variety of saliva substitutes exists, often in the shape of sprays, gels, rinses, toothpastes. Saliva substitutes contain a variety of ingredients varying from antimicrobial agents to food thickeners, and from vitamins to remineralizing agents. The addition of food thickeners like celluloses and other substances are used to increase viscosity, but that contributes little to lubrication62. Although, saliva substitutes are widely used to relieve symptoms
related to hyposalivation, a lot of inconsistencies arise in comparison studies and a lack of proof is given Figure 4. (a) The mucin monomer arrangement. Both the N- (left) and the C-terminal (right) consist of von Willebrand factor (vWF)-like domains. The central mucin domain consists of multiple repetitive regions that are rich in serine and threonine, and therefore highly glycosylated. Cysteine-rich domains (Cys-domains) interrupt the glycosylated regions. The scale bar represents 1000 amino acids (aa). (b) A close up of a glycosylated region showing the diversity of monosaccharides that form the glycan side chains of mucins. A schematic representation of the MUC5B glycoprotein, taken from Davies et al.35. https://pubs.acs.org/doi/full/10.1021/acs.analchem.6b03095.
Further permissions related to this material should be granted by ACS publications.
145468 Vinke BNW.indd 15
for real functionality63–65. Often, subjective surveys are being used to score and compare saliva substitutes.
Most surveys are based on dry mouth-patient perception and taste. Examples of such perception-based scoring analyses are visual-to-analogue scale, dryness ranking score, xerostomia inventory and other types of xerostomia questionnaires66–68. The use of these methods in clinical studies, to compare the efficacy of
saliva substitutes, often resulted in natural sialagogues or even placebo’s to perform as good as saliva substitutes69–71. It is striking that patients that received placebo’s would like to continue using it, because
of perceived beneficial effects. This phenomenon shows that perception should not be the parameter to rely on for qualification of saliva substitutes for their function. Patient surveys should be used as a final step in development of saliva substitutes since acceptance of the end user is of major importance. Other comparison methods for functionality of saliva substitutes are measuring salivary flow rate after submission for the purpose that the saliva substitute would have a beneficial effect on flow rate70,72.
Surprisingly, no relevant qualitative assessments seem to exist to test the lubrication properties of saliva substitutes. Lubrication, one of the main function of saliva, does not seem to play a role in the current saliva substitute manufacturing, clinical prescription or patient choice, possibly because of the lack of a good testing system.
The aim of the study
The general aim of this thesis was to develop and test a new method for quantifying oral lubrication on biological relevant tissues ex vivo. This method was used to compare the lubricating properties of whole
saliva and glandular saliva from healthy persons, and patients with xerostomia due to Sjögren’s syndrome or head and neck radiotherapy. Furthermore, the lubricating properties of a variety of saliva substitutes were measured with this method in order to determine their potential in relieving dry mouth symptoms. Finally, it was studied whether salivary lubrication can be improved for healthy persons and Sjögren’s syndrome patients with the use of recombinant supercharged polypeptides.
1. Aguirre, A., Mendoza, B., Levine, M. J., Hatton, M. N. & Douglas, W. H. In vitro characterization of human salivary lubrication. Arch. Oral Biol. 34, 675–677 (1989).
2. Reeh, E. S. et al. Hard tissue lubrication by salivary fluids. Clin. Mater. 6, 151–161 (1990).
3. Bongaerts, J. H. H., Rossetti, D. & Stokes, J. R. The lubricating properties of human whole saliva. Tribol. Lett. 27, 277–287 (2007).
4. Ekström, J., Khosravani, N., Castagnola, M. & Messana, I. Saliva and the control of its secretion. in Dysphagia. Medical Radiology (ed. Ekberg, O.) 21–57 (Springer, 2017).
5. Pedersen, A. M., Bardow, A., Beier Jensen, S. & Nauntofte, B. Saliva and gastrointestinal functions of taste, mastication, swallowing and digestion. Oral Dis. 8, 117–129 (2002).
6. Vissink, A., Wolff, A. & Veerman, E. C. I. Saliva collectors. in Salivary diagnostics (ed. Wong, D. T.) 37–59 (Wiley-Blackwell, 2008).
7. Villa, A. et al. World workshop on oral medicine VI: a systematic review of medication-induced salivary gland dysfunction: prevalence, diagnosis, and treatment. Clin. Oral Investig. 19, 1563–1580 (2015).
8. Thie, N. M. R., Kato, T., Bader, G., Montplaisir, J. Y. & Lavigne, G. J. The significance of saliva during sleep and the relevance of oromotor movements. Sleep Med. Rev. 6, 213–227 (2002).
9. Korsrud, F. R. & Brandtzaeg, P. Characterization of epithelial elements in human major salivary glands by functional markers: Localization of amylase, lactoferrin, lysozyme, secretory component, and secretory immunoglobulins by paired immunofluorescence staining. J. Histochem. Cytochem. 30, 657–666 (1982).
10. Turner, R. J. & Sugiya, H. Understanding salivary fluid and protein secretion. Oral Dis. 8, 3–11 (2002).
11. Humphrey, S. P. & Williamson, R. T. A review of saliva: normal composition, flow, and function. J. Prosthet. Dent. 85, 162–169 (2001).
12. De Almeida, P. D. V. et al. Saliva composition and functions: a comprehensive review. J. Contemp. Dent. Pract. 9, 72– 80 (2008).
13. Carpenter, G. H. The secretion, components, and properties of saliva. Annu. Rev. Food Sci. Technol. 4, 267–276 (2013). 14. Garrett, J. R., Suleiman, A. M., Anderson, L. C. & Proctor, G. B. Secretory responses in granular ducts and acini of submandibular glands in vivo to parasympathetic or sympathetic nerve stimulation in rats. Cell Tissue Res. 264, 117– 126 (1991).
15. Proctor, G. B. & Carpenter, G. H. Salivary secretion: Mechanism and neural regulation. Saliva Secret. Funct. 24, 14– 29 (2014).
16. Bennick, A., Kells, D. & Madapallimattam, G. Interaction of calcium ions and salivary acidic proline-rich proteins with hydroxyapatite. Biochem. J. 213, 11–20 (1983).
17. Douglas, W. H. et al. Statherin: A major boundary lubricant of human saliva. Biochem. Biophys. Res. Commun. 180, 91– 97 (1991).
18. Gibbons, R. J. Role of adhesion in microbial colonization of host tissues: A contribution of oral microbiology. J. Dent. Res. 75, 866–870 (1996).
19. Carlén, A., Bratt, P., Stenudd, C., Olsson, J. & Strömberg, N. Agglutinin and acidic proline-rich protein receptor patterns may modulate bacterial adherence and colonization on tooth surfaces. J. Dent. Res. 77, 81–90 (1998). 20. Johansson, I., Bratt, P., Hay, D. I., Schluckebier, S. & Strömberg, N. Adhesion of Candida albicans, but not Candida
krusei, to salivary statherin and mimicking host molecules. Oral Microbiol. Immunol. 15, 112–118 (2000).
21. Shi, L., Ardehali, R., Caldwell, K. D. & Valint, P. Mucin coating on polymeric material surfaces to suppress bacterial adhesion. Colloids Surfaces B Biointerfaces 17, 229–239 (2000).
22. Van Nieuw Amerongen, A., Bolscher, J. G. M. & Veerman, E. C. I. Salivary proteins: protective and diagnostic value in cariology? Caries Res. 38, 247–253 (2004).
23. Fragoso, M. A., Torbati, A., Fregien, N. & Conner, G. E. Molecular heterogeneity and alternative splicing of human lactoperoxidase. Arch. Biochem. Biophys. 482, 52–57 (2009).
24. Hannig, M. & Balz, M. Influence of pellicle on enamel erosion. Caries Res. 33, 372–379 (1999).
25. Joiner, A. et al. The protective nature of pellicle towards toothpaste abrasion on enamel and dentine. J. Dent. 36, 360– 368 (2008).
26. Hahn Berg, I. C., Lindh, L. & Arnebrant, T. Intraoral lubrication of PRP-1, statherin and mucin as studied by AFM. Biofouling 20, 65–70 (2004).
27. Lindh, L., Aroonsang, W., Sotres, J. & Arnebrant, T. Salivary pellicles. in Saliva: Secretion and Functions (eds. Ligtenberg, A. J. M. & Veerman, E. C. I.) 24, 30–39 (Monogr. Oral Sci. Karger, 2014).
145468 Vinke BNW.indd 17
28. Ash, A., Wilde, P., Bradshaw, D. J., King, S. P. & Pratten, J. R. Structural modifications of the salivary conditioning film upon exposure to sodium bicarbonate: Implications for lubrication and mouthfeel. Soft Matter 12, 2794–2801 (2016).
29. Yakubov, G. E., McColl, J., Bongaerts, J. H. H. & Ramsden, J. J. Viscous boundary lubrication of hydrophobic surfaces by mucin. Langmuir 25, 2313–2321 (2009).
30. Crouzier, T. et al. Modulating mucin hydration and lubrication by deglycosylation and polyethylene glycol binding. Adv. Mater. Interfaces 2, 1–7 (2015).
31. Käsdorf, B. T. et al. Mucin-inspired lubrication on hydrophobic surfaces. Biomacromolecules 18, 2454–2462 (2017). 32. Nielsen, P. A. et al. Identification of a major human high molecular weight salivary mucin (MG1) as tracheobronchial
mucin MUC5B. Glycobiology 7, 413–419 (1997).
33. Callaghan Rose, M. & Voynow, J. A. Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiol. Rev. 86, 245–278 (2006).
34. Wu, A. M., Csako, G. & Herp, A. Structure, biosynthesis, and function of salivary mucins. Mol. Cell. Biochem. 137, 39–55 (1994).
35. Davies, H. S. et al. Secondary structure and glycosylation of mucus glycoproteins by Raman spectroscopies. Anal. Chem. 88, 11609–11615 (2016).
36. Bolscher, J., Veerman, E., van Nieuw Amerongen, A., Tulp, A. & Verwoerd, D. Distinct populations of high-Mr mucins secreted by different human salivary glands discriminated by density-gradient electrophoresis. Biochem. J. 309, 801–806 (1995).
37. Yang, X. et al. Immobilization of pseudorabies virus in porcine tracheal respiratory mucus revealed by single particle tracking. PLoS One 7, 1–9 (2012).
38. Castro, I. et al. Oral dryness in Sjögren’s syndrome patients. Not just a question of water. Autoimmun. Rev. 12, 567– 574 (2013).
39. Jahn, S. & Klein, J. Hydration lubrication: the macromolecular domain. Macromolecules 48, 5059–5075 (2015). 40. Ma, L., Gaisinskaya-Kipnis, A., Kampf, N. & Klein, J. Origins of hydration lubrication. Nat. Commun. 6, (2015). 41. Aliko, A. et al. World workshop on oral medicine VI: Clinical implications of medication-induced salivary gland
dysfunction. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 120, 185–206 (2015).
42. Wolff, A. et al. A guide to medications inducing salivary gland dysfunction, xerostomia, and subjective sialorrhea: a systematic review sponsored by the world workshop on oral medicine VI. Drugs R&D 17, 1–28 (2017).
43. Pow, E. H. N. et al. Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for early-stage nasopharyngeal carcinoma: Initial report on a randomized controlled clinical trial. Int. J. Radiat. Oncol. Biol. Phys. 66, 981–991 (2006).
44. Vissink, A. et al. Clinical management of salivary gland hypofunction and xerostomia in head-and-neck cancer patients: successes and barriers. Int. J. Radiat. Oncol. Biol. Phys. 78, 983–91 (2010).
45. Al-Hashimi, I. Xerostomia secondary to Sjögren’s syndrome in the elderly. Drugs Aging 22, 887–899 (2005). 46. Bayetto, K. & Logan, R. Sjögren’s syndrome: a review of aetiology, pathogenesis, diagnosis and management. Aust.
Dent. J. 55, 39–47 (2010).
47. López-Pintor, R. M. et al. Xerostomia, hyposalivation, and salivary flow in diabetes patients. J. Diabetes Res. 2016, (2016).
48. Porter, S. R., Scully, C. & Hegarty, A. M. An update of the etiology and management of xerostomia. Oral Surgery, Oral Med. Oral Pathol. Oral Radiol. Endodontology 97, 28–46 (2004).
49. Nederfors, T. Xerostomia and hyposalivation. Adv. Dent. Res. 14, 48–56 (2000).
50. Wolff, M. & Kleinberg, I. Oral mucosal wetness in hypo- and normosalivators. Arch. Oral Biol. 43, 455–462 (1998). 51. Morzel, M. Siying, T. Brignot, H. & Lherminier, J. Immunocytological detection of salivary mucins (MUC5B) on the
mucosal pellicle lining human epithelial buccal cells. Microsc. Res. Tech. 77, 453-457 (2014).
52. Alliende, C. et al. Reduced sulfation of muc5b is linked to xerostomia in patients with Sjögren syndrome. Ann. Reum. Dis. 67, 1480–1487 (2008).
53. Dijkema, T. et al. MUC5B levels in submandibular gland saliva of patients treated with radiotherapy for head-and-neck cancer: a pilot study. Radiat. Oncol. 7, (2012).
54. Castro, I. et al. Decreased salivary sulphotransferase activity correlated with inflammation and autoimmunity parameters in Sjögren’s syndrome patients. Rheumatology 51, 482–490 (2012).
55. Chaudhury, N. M. A., Shirlaw, P., Pramanik, R., Carpenter, G. H. & Proctor, G. B. Changes in saliva rheological properties and mucin glycosylation in dry mouth. J. Dent. Res. 94, 1660–1667 (2015).
56. Chaudhury, N. M. A., Proctor, G. B., Karlsson, N. G., Carpenter, G. H. & Flowers, S. A. Reduced mucin-7 (muc7) sialylation and altered saliva rheology in Sjögren’s syndrome associated oral dryness. Mol. Cell. Proteomics 15, 1048– 1059 (2016).
57. Jellema, A. P., Slotman, B. J., Doornaert, P., Leemans, C. R. & Langendijk, J. A. Impact of radiation-induced xerostomia on quality of life after primary radiotherapy among patients with head and neck cancer. Int. J. Radiat. Oncol. Biol. Phys. 69, 751–760 (2007).
58. López-Jornet, P. & Camacho-Alonso, F. Quality of life in patients with Sjögren’s syndrome and sicca complex. J. Oral Rehabil. 35, 875–881 (2008).
59. Fernández-Martínez, G., Zamora-Legoff, V. & Hernández Molina, G. Oral health-related quality of life in primary Sjögren’s syndrome. Reum. Clin 14, 124–126 (2018).
60. Miyamoto, S. T., Valim, V. & Fisher, B. A. Health-related quality of life and costs in Sjögren’s syndrome. Rheumatology (2019).
61. Plemons, J. M., Al-Hashimi, I., Marek, C. L. & American Dental Association Council on Scientific Affairs. Managing xerostomia and salivary gland hypofunction: executive summary of a report from the American Dental Association Counsil on Scientific Affairs. J. Am. Dent. Assoc. 145, 867–873 (2014).
62. Hatton, M. N., Levine, M. J., Margarone, J. E. & Aguirre, A. Lubrication and viscosity features of human saliva and commercially available saliva substitutes. J. Oral Maxillofac. Surg. 45, 496–499 (1987).
63. Hahnel, S., Behr, M., Handel, G. & Bürgers, R. Saliva substitutes for the treatment of radiation-induced xerostomia: a review. Support. Care Cancer 17, 1331–1343 (2009).
64. Furness, S., Worthington, H. V, Bryan, G., Birchenough, S. & McMillan, R. Interventions for the management of dry mouth: topical therapies. Cochrane database Syst. Rev. (2011). doi:10.1002/14651858.CD009603.pub2
65. Carpenter, G. Artificial salivas: why are they not more useful? in Dry Mouth (ed. Carpenter, G.) 165–173 (Springer Berlin Heidelberg, 2015).
66. Davies, A. N. A comparison of artificial saliva and chewing gum in the management of xerostomia in patients with advanced cancer. Palliat. Med. 14, 197–203 (2000).
67. Shahdad, S. A., Taylor, C., Barclay, S. C., Steen, I. N. & Preshaw, P. M. A double-blind, crossover study of Biotène Oralbalance and BioXtra systems as salivary substitutes in patients with post-radiotherapy xerostomia. Eur. J. Cancer Care (Engl). 14, 319–326 (2005).
68. Mouly, S. J. et al. Management of xerostomia in older patients: a randomised controlled trial evaluating the efficacy of a new oral lubricant solution. Drugs Aging 24, 957–965 (2007).
69. Van der Reijden, W. A., Van der Kwaak, H., Vissink, A., Veerman, E. C. & Van Nieuw Amerongen, A. Treatment of xerostomia with polymer-based saliva substitutes in patients with Sjögren’s syndrome. Arthritis Rheum. 39, 57–63 (1996).
70. Sweeney, M. P., Bagg, J., Baxter, W. P. & Aitchison, T. C. Clinical trial of a mucin-containing oral spray for treatment of xerostomia in hospice patients. Palliat. Med. 11, 225–232 (1997).
71. Gil-Montoya, J. A., Guardia-López, I. & González-Moles, M. A. Evaluation of the clinical efficacy of a mouthwash and oral gel containing the antimicrobial proteins lactoperoxidase, lysozyme and lactoferrin in elderly patients with dry mouth - a pilot study. Gerodontology 25, 3–9 (2008).
72. Femiano, F. et al. A comparison of salivary substitutes versus a natural sialogogue (citric acid) in patients complaining of dry mouth as an adverse drug reaction: a clinical, randomized controlled study. Oral Surgery, Oral Med. Oral Pathol. Oral Radiol. Endodontology 112, e15–e20 (2011).
145468 Vinke BNW.indd 19