Innovative dental biomaterials have been developed in order to stimulate higher biocompatibility and faster healing times using responsive surfaces for regenerative procedures. However, saliva is one of the fluids to interact with these biomaterials in the first instance. Studies have revealed significant negative effects on the biomaterials' properties, biocompatibility and bacterial colonisation after saliva contact. Nevertheless, the current literature is unclear about the profound effects of saliva on regenerative procedures. The scientific community urges further detailed studies associating innovative biomaterials/saliva/microbiology/immunology in order to clarify clinical outcomes. This paper discusses and provides information about the challenges of research using human saliva, the lack of standardisation in protocols applying saliva, and tentative applications of saliva proteins associated with innovative dental biomaterials.
This paper brings up the lack of evidence in saliva research associated with innovative biomaterials for application in oral surgeries.
Invites a discussion about the challenges and possible solutions to research applying human saliva.
Suggests some future directions for saliva research in fundamental, preclinical and clinical studies.
Background: saliva versus innovative biomaterials versus oral ecosystem
The oral fluid named 'saliva' is recognised for possessing several beneficial properties in the oral ecosystem, nutrition, digestion and systemic human health.1 Characteristics such as lubrication, digestion, protection and re-mineralisation are of paramount importance for a stable systemic life. Saliva is an oral fluid found in the majority of people, excluding only people possessing extremely rare systemic diseases that compromise the production of saliva, demanding the use of artificial saliva.
From the clinical perspective, saliva is uninterruptedly exhibited in oral surgical procedures applying biomaterials and it is constantly interacting with oral tissues/oral fluids.1,2 Dental clinicians usually employ several techniques to prevent the direct interaction of saliva with dental procedures; however, the capacity of this oral fluid to spread quickly on the oral tissues in addition to the huge number of minor/major salivary glands present in the human mouth/gingiva suggest a persistent interaction with biomaterials applied in surgeries.1,2
The complexity to develop oral biomaterials promoting high biocompatibility and significant antibacterial properties has induced researchers and companies to manufacture biomaterials with responsive surfaces, stimulating faster interactions with beneficial cells.3,4 Dental implants possessing hydrophilic surfaces for rapid cell adhesion or antibacterial surfaces to prevent infection, membranes for bone regeneration with biodegradable properties and bone substitutes structured with different porosities are examples of these complexities aiming for better healing conditions in surgical procedures.3,4,5
Discussion and 'open question'
The application of these innovative biomaterials in conjunction with oral procedures may result in saliva contact before the completion of the surgical procedure. Previous studies from our group have shown that saliva may negatively influence the physical-chemical properties of hydrophilic dental implants,4 plus reduced biocompatibility of osteogenic cells related to hard/soft tissues regeneration.4,6 Other studies have shown that saliva-contaminated biomaterials have demonstrated to stimulate bacterial colonisation.7,8 An in vivo study applying dental implants and biomaterials for bone augmentation procedures where local saliva contamination (peri-implantitis contamination) was induced demonstrated an intense reduction in the osseointegration status and bone regeneration quality.9
This arrangement of findings suggests a significant negative role of the early/late saliva interaction with innovative biomaterials for oral regenerative procedures causing limited biocompatibility and increased bacterial colonisation (Fig. 1).
On the other hand, advanced studies have promoted the concept of applying isolated saliva proteins on surfaces in order to functionalise biomaterials and stimulate biocompatibility. Sun and co-authors revealed the application of isolated Histatin-1 (saliva protein) on titanium surfaces and into collagen membranes demonstrating an induced spreading of bone-related cells over the surfaces and promotion of higher taxes of newly formed bone in vivo, respectively.11,12 Interestingly, some saliva proteins have been reported as direct antimicrobial/antibacterial molecules due to their isolated action, such as adrenomedullin, statherin, histatins, lysozyme (antibacterial) and α-Defensins, β-Defensins, lactoferricin, lactoperoxidase, myeloperoxidase (antimicrobial).13,14 These investigations reveal that specific proteins present in the saliva composition may be promoters of immune/innate defences and might be applied for beneficial defensive outcomes in oral surgical procedures or to functionalise biomaterials.
The challenges regarding saliva research are broad due to the diverse spectrum of saliva compositions and different proteomic mapping/quantification in each person. Moreover, patients' nutrition, age and systemic/local diseases play huge roles in the saliva composition.15 Additionally, the protocols and techniques applied for human saliva collection, storage and application methods in preclinical and clinical biomaterials research are highly distinct.1 Therefore, most of the research demonstrated in the current literature cannot be totally intercorrelated, opening a clear need for investigations into this topic (Table 1).
Concluding remarks and future perspectives
Current studies have suggested avoiding saliva interaction in early and late stages in order to prevent infections or loss of biomaterials' properties, inducing that saliva contamination is considered harmful for oral regenerative procedures associated with biomaterials. However, this information is not completely 'scientifically clear' in the literature based on a large number of complex studies, resulting in the requirement for further advanced basic and clinical studies.
This knowledge 'gap' generates wide opportunities for future research that may clarify these questions involving dental procedures/saliva/microbiology/biomaterials. Based on our experience, innovative biomaterials have demonstrated intense interaction with saliva due to their surface sensitivity, changing important characteristics related to biocompatibility. Additionally, the applied protocols for saliva collection, storage and application should be as similar as possile to the clinical reality, trying to explore the saliva properties directly after collection.
Modern techniques and molecular data, such as proteomics, genomics, meta-transcriptomics and meta-metabolomics, are the perspectives to understand the deep influence of saliva on the beneficial cells and bacteria, thus, subsequently, the outcomes in the clinical environment, revealing if there are positive pathways to apply saliva proteins in oral regenerative procedures or if the saliva interaction must be completely avoided in all the clinical procedures. Lastly, promising functionalised biomaterials using isolated saliva proteins might be developed in the near future, exploring the beneficial effects of specific proteins to improve clinical outcomes.
Kunrath M F, Dahlin C. The Impact of Early Saliva Interaction on Dental Implants and Biomaterials for Oral Regeneration: An Overview. Int J Mol Sci 2022; 23: 2024.
Fischer N G, Aparicio C. The salivary pellicle on dental biomaterials. Colloids Surf B Biointerfaces 2021; 200: 111570.
Liang Y, Luan X, Liu X. Recent advances in periodontal regeneration: A biomaterial perspective. Bioact Mater 2020; 5: 297-308.
Kunrath M F, Correia A, Teixeira E R, Hubler R, Dahlin C. Superhydrophilic Nanotextured Surfaces for Dental Implants: Influence of Early Saliva Contamination and Wet Storage. Nanomaterials (Basel) 2022; 12: 2603.
Henkel J, Woodruff M A, Epari D R et al. Bone Regeneration Based on Tissue Engineering Conceptions - A 21st Century Perspective. Bone Res 2013; 1: 216-248.
Hirota M, Ikeda T, Sugita Y, Ishijima M, Hirota S, Ogawa T. Impaired osteoblastic behaviour and function on saliva-contaminated titanium and its restoration by UV treatment. Mater Sci Eng C Mater Biol Appl 2019; 100: 165-177.
Dorkhan M, Svensäter G, Davies J R. Salivary pellicles on titanium and their effect on metabolic activity in Streptococcus oralis. BMC Oral Health 2013; 13: 32.
Turri A, Čirgić E, Shah F A et al. Early plaque formation on PTFE membranes with expanded or dense surface structures applied in the oral cavity of human volunteers. Clin Exp Dent Res 2021; 7: 137-146.
Jinno Y, Johansson K, Toia M et al. Impact of salivary contamination during placement of implants with simultaneous bony augmentation in iliac bone in sheep. Br J Oral Maxillofac Surg 2019; 57: 1131-1136.
Schweikl H, Hiller K-A, Carl U et al. Salivary protein adsorption and Streptococccus gordonii adhesion to dental material surfaces. Dent Mater 2013; 29: 1080-1089.
Sun W, Ma D, Bolscher J G M et al. Human Salivary Histatin-1 Promotes Osteogenic Cell Spreading on Both Bio-Inert Substrates and Titanium SLA Surfaces. Front Bioeng Biotechnol 2020; 8: 584410.
Sun P, Shi A, Shen C, Liu Y, Wu G, Feng J. Human salivary histatin-1 (Hst1) promotes bone morphogenetic protein 2 (BMP2)-induced osteogenesis and angiogenesis. FEBS Open Bio 2020; 10: 1503-1515.
Fábián T K, Hermann P, Beck A, Fejérdy P, Fábián G. Salivary defence proteins: their network and role in innate and acquired oral immunity. Int J Mol Sci 2012; 13:4295-4320.
Marsh P D, Do T, Beighton D, Devine D A. Influence of saliva on the oral microbiota. Periodontol 2000 2016; 70: 80-92.
Belstrøm D, Fiehn N-E, Nielsen C H et al. Differences in bacterial saliva profile between periodontitis patients and a control cohort. J Clin Periodontol 2014; 41: 104-112.
Marcel F. Kunrath thanks Osteology Foundation (Lucerne, Switzerland) for the support during the Research Scholarship in Sweden and the fruitful discussions with the team of SalivaTec laboratory in Viseu, Portugal.
This study was supported by the Osteology Research Scholarship (Osteology Foundation, Lucerne, Switzerland) to Marcel F. Kunrath, and the Area of Advance Materials of Chalmers and GU Biomaterials within the Strategic Research Area Initiative launched by the Swedish Government.
The authors declare no conflicts of interest.
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Kunrath, M., Dahlin, C. Does saliva contamination interfere or stimulate regenerative processes applying current biomaterials on oral surgical sites?. Br Dent J 234, 305–307 (2023). https://doi.org/10.1038/s41415-023-5573-7