Resin Infiltration in Pediatric Dentistry Notes

Citation

The article is titled "Resin Infiltration of Non-Cavitated Enamel Lesions in Paediatric Dentistry: A Narrative Review" by Dziaruddin, N., and Zakaria, A.S.I., published in Children in 2022.
DOI: https://doi.org/10.3390/children9121893
License: Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Abstract

Resin infiltration (RI) is a minimal intervention dentistry strategy for addressing dental caries in children.
The technique uses low-viscosity resin to infiltrate non-cavitated carious lesions and enamel porosities, conserving tooth structure.
The review explores the development, clinical applications, shortcomings, and innovations related to RI.
High-level evidence supports RI for arresting non-cavitated proximal caries lesions in primary and permanent teeth.
Efficacy in managing anterior white spot lesions is unclear.
Limitations include limited penetration depth, lack of radiopacity, and questionable long-term color and material stability.
RI is an important micro-invasive technique for non-cavitated and anterior white-spot enamel lesions in children and adolescents.
Keywords: resin infiltration; paediatric dentistry; minimal intervention dentistry; dental caries; dental developmental anomalies

Introduction

Managing dental caries in children is ongoing, with over 600 million children affected worldwide [1].
Modern caries management emphasizes early detection and preventive therapy (minimal intervention dentistry - MID).
Advancement of the lesion should be managed by adopting the minimally invasive operative approach [4].
Resin infiltrant (RI), marketed as Icon® (DMG, Hamburg, Germany), benefits from the discovery of acid etching and Bis-GMA resin monomer.
RI is an important tool supporting MID in managing non-cavitated carious lesions.
RI infiltrates caries lesions with low-viscosity resin to arrest progression without removing tooth structure.
This concept is desirable in pediatric dentistry, as drilling may not be well-tolerated by young and anxious children [7].
The review explores the usage of RI technique in Paediatric Dentistry, dividing the paper into three sections: the past, present and future.

The Past: Development of RI

The Resin Monomer

The idea of infiltrating early caries lesions has existed for more than five decades.
Researchers since the 1970s have conducted many in vitro and in vivo studies to find the right material that is able to infiltrate the early enamel lesion effectively [8–13].
In 1975, Davila et al. [8] investigated adhesives to seal early enamel lesions, proposing that the demineralized surface would act as a locus for infiltration, sealing the lesion entrance and spaces.
Acid conditioning pre-treatment resulted in deeper penetration depth [8].
Robinson et al. [9] used experimental resorcinol-formaldehyde resin to occlude pores of early enamel lesions, occluding up to 90% of pores and reducing demineralization.
The resin was discontinued due to potential cytotoxic hazard towards vital dentine and pulp tissue [9, 10].
Authors suggested infiltrating resin should meet certain standards: low viscosity, hydrophilic, anti-bacterial, non-toxic, aesthetically acceptable and able to polymerize into a solid state [10].
Earlier studies used unfilled resin in the form of dental adhesives and sealants as the infiltrating agent.
In vitro studies on an artificial caries model shows some potential, where all of the studies reported a reduction in caries progression as compared to the control [11–13].
Robinson et al. [11] observed that 60% of the pores were occluded following the infiltration process
Clinical evaluations using sealants and adhesives among children were carried out [14, 15].
Martignon et al. [15] reported a reduced but relatively high lesion progression (43.5%) over 18 months, while Gomez et al. [14] found no significant difference between infiltrated and control lesions in their 24-month clinical study.
Findings might be due to disintegration of the material over time or inadequate sealing of the lesion [14]. Sealants and adhesives showed superficial penetration into natural enamel lesions [16].
Meyer-Lueckel and Paris [17, 18] developed a new material that does not disintegrate easily, has a good sealing ability and is able to penetrate deep into the base of the porous enamel lesion.
The penetration ability of the material into a porous structure is best explained by the Washburn equation [19].
Based on the equation, the porous solid (enamel structure) was regarded as a structure consisting of a collection of open capillaries, which can be penetrated by liquids driven by the capillary forces.
A material with a high penetration coefficient (PC) can penetrate deeper and faster into the porous structure [20] and, upon hardening, can directly occlude and seals the porosity [17].
Meyer-Lueckel and Paris [17] showed that materials with PC of more than 100 cm/s might be more suitable as ‘infiltrants’ for the treatment of early enamel lesions as compared to fissure sealants and adhesives.
Resin materials with high triethylene glycol dimethacrylate (TEGDMA) concentrations tended to show better inhibition of lesion progression [17].
This is probably due to the better penetration capabilities of TEGDMA-based resins [17].
Their experimental resins using a mixture of TEDGMA, 2-hydroxyethyl methacrylate (HEMA), and ethanol showed the highest PC value, attributed to their low contact angle and low viscosity of these components.
However, the mixture consisting of HEMA and ethanol showed inadequate hardening and was thus deemed unsuitable for infiltration of porous enamel.
The mixture of resin monomer TEDGMA and ethanol, on the other hand, showed high PC value and sufficient hardening [18], suggesting that these two components would be the benchmark for the future development of RI.
Further studies on the development of RI were based on the different formulations of TEDGMA and ethanol.
Paris et al. [18] found that 99% of TEDGMA-containing resin gave a PC value of 204 cm/s, while the addition of TEDGMA and ethanol as solvents gave a PC value of 391 cm/s.
The addition of solvent has been shown to increase the penetration coefficient and, consequently, the penetration depths, but inhomogeneities and uncured areas within the resin layer may occur, which can lead to incomplete polymerisation.
The authors suggest that the addition of ethanol to increase penetration abilities should be carefully balanced with the potentially impaired properties of the cured material.
They concluded that low-viscosity RIs, based mainly on TEGDMA, had relatively high PC and were capable of inhibiting the progression of both artificial [21] and natural enamel caries lesions [22].
The high PC values also allow the material penetrates deep into the lesion body in a low-demineralising environment [23, 24], and a 3 min application is sufficient to completely occlude the pores of the early enamel lesion [25].

Etching

Resin infiltration into porous enamel lesion is driven by capillary forces, influenced by pore volume and capillary radius.
The presence of the highly mineralised surface layer with low pore volume might prevent the penetration of the infiltrating resin into the subsurface porosities underneath it [26].
Elimination of the surface layer to expose the porous subsurface lesion is desirable to aid the penetration of the resin. To achieve this, pre-treatment conditioning of the surface layer is needed prior to the infiltration process [16].
Etching the enamel with 30–40% phosphoric acid allows the low- viscosity resins to ‘penetrate’ the microporosities, forming resin tags and micromechanical interlocking between the resins and the enamel [28].
Grey and Shellis [29] successfully etched the artificial enamel caries with 36% phos- phoric acid, which improved the penetration of the resin into the subsurface enamel lesion.
However, Meyer-Lueckel et al. [30] found out that the penetration depth of the resin into the enamel porosities between the artificial and natural caries lesion was different.
They postulated that the mineral content of the surface layer in natural caries lesions might be higher and more inhomogeneous due to the continuous cycles of de- and remineralisation in the oral cavity.
They later concluded that complete erosion of the surface layer is necessary to expose the subsurface lesion prior to infiltration with low-viscosity resins.
Meyer-Lueckel, Paris and their team [30, 31] have demonstrated that in comparison to 37% phosphoric acid and 5% hydrochloric acid, the use of 15% hydrochloric acid gel for 90–120 s was effective in not only eroding the surface layer but led to nearly complete removal of the structure.
Elimination of the surface layer also can be performed mechanically, by using a diamond bur or polishing strip [32].
However, optimum surface erosion seems the best option in allowing the penetration of the low-viscosity resin into the subsurface enamel lesion effectively.

Ethanol

The use of ethanol as a solvent is believed to reduce the viscosity of the penetrating resin, as well as remove the remaining residual water that might be present at the bottom of the body lesion.
Meyer-Lueckel et al. [16] found that the addition of ethanol enhanced the penetration ability of dental adhesives.
The addition of 10% and 20% of ethanol had shown to increase the PC as well as the penetration depth [17, 18].
However, there is concern regarding the addition of the evaporating solvent that might possibly cause inhomogeneities and incomplete polymerised areas within the resin itself [18].
Paris et al. [33] conducted an in vitro study on extracted primary molars using experimental resins with and without the addition of ethanol.
Although the PC value of ethanol-containing resin is higher, both the solvent-free and ethanol- containing resins managed to infiltrate the lesion completely.
Hence, the authors suggest that concerning the potential effect of ethanol on the polymerisation of the RI, a solvent-free infiltrant is preferable [33].
In order to facilitate the removal of residual water and protein within the body lesion, the commercially available RI add-ons another step: pre-treatment of the enamel surface with ethanol following the acid etching procedure.

Present: Clinical Usage and Limitations of the Current RI

Arresting Non-Cavitated Early Enamel Lesion

The ultimate aim of developing RI is to delay the restorative procedure on a non- cavitated early enamel lesion.
Placement of restoration will irreversibly remove the sound tooth structure surrounding the lesion and initiates the so-called ‘restorative cycles’ [34].
The use of fluoride varnish and casein phosphopeptide-amorphous calcium phosphate (CPP-ACP), coupled with good oral hygiene practise has been the mainstream in managing the non-cavitated early enamel lesion previously [35, 36].
RI, on the other hand, infiltrates the early enamel lesion using the low-viscosity resin monomer.
The concept of this technique is based on the understanding of the structure and demineralisation process of the early enamel lesion itself.
Following the demineralisation of enamel under an acidic challenge, minerals are dissolved out of the enamel, creating porosities within the enamel structure.
These porosities act as a diffusion pathway for the dissolved minerals and acids. Infiltrating the early enamel lesion will occlude the pores and seals the lesion inside instead of at the surface.
This will block the diffusion pathway of the organic acids, thus arresting the caries progression and inhibiting future demineralisation [17]. Further, infiltration also improves the mechanical strength of the porous enamel [24], resisting future demineralisation.
The clinical success of infiltrating early enamel lesions is evident in the literature, both for primary and permanent teeth.
Infiltrating the non-cavitated early enamel lesion on the proximal surface has been the subject of many clinical trials.
Ekstrand et al. [40], Page et al. [41] and Ammari et al. [42] reported a significant reduction in caries progression of the lesions on primary molars after infiltration with resin as compared to fluoride therapy.
The therapeutic effects of RI over the fluoride varnish application were 21% higher over a two-year study period [41].
Urquhart et al. [43] reported that a combination of both RI and the application of 5% fluoride varnish on proximal early enamel lesions were five times more likely to cause caries arrest as compared to no treatment.
Similar success was also reported in clinical trials on proximal lesions of permanent teeth, favouring the use of RI over fluoride therapy in managing non-cavitated proximal enamel lesions [44–46].
The performance of RI on the occlusal surface of teeth also has been investigated.
Bakshandeh and Ekstrand [47] conducted a split-mouth study on the efficacy of RI in seal- ing the occlusal early enamel lesion of the primary molar tooth.
Barakat and El-Soud [48] conducted another split-mouth study on children comparing the effectiveness of RI and compomer as a pit and fissure sealant material and concluded that infiltration of the occlusal surface with resin provides a better retention rate as compared to compomer but harbours more bacteria due to the fluoride-releasing ability of the latter material.
The usage of RI in non-cavitated occlusal and proximal early enamel lesions is en- dorsed by the American Dental Association [49] in their evidence-based clinical practice guideline published in 2018.
The guideline recommends the use of RI alone or in a combination of 5% fluoride varnish in arresting and reversing the non-cavitated lesion on the proximal surface, whereas for the lesion on the occlusal surface, a combination of RI and 5% fluoride varnish can be considered as an alternative to the conventional treatment of using fluoride varnish or fissure sealant.
They believed that the relatively high cost of RI, as compared to sealants, might be the deterrent factor for its widespread use in community-based dentistry.
Two recently published systematic [50] and umbrella [51] reviews on the caries inhibition ability of RI on early enamel lesions showed that the relative risk for caries progression for the caries-infiltrated lesion is significantly reduced.
Infiltrating the caries lesion is more effective for both primary and permanent teeth as compared to no treatment or other non-invasive preventive measures such as fluoride varnish, fissure sealant and oral hygiene instruction [50, 51].
The comparison of RI efficacy and caries lesion progression on primary and permanent teeth favours the successors, mainly attributed to the structural difference of enamel between the primary and permanent teeth.
Lesion progression is quicker in primary teeth due to the fact that the enamel structure is less mineralised, more porous and thinner [50] as compared to permanent teeth.

Aesthetic Improvement of the Anterior White-Spot Lesion (WSL)

The ability of RI to infiltrate the non-cavitated early enamel lesion offers a new pathway and treatment modality in managing enamel WSL on the anterior teeth.
The presence of the WSL is a result of enamel structure porosities, either due to enamel decalcification following the caries process or developmental disturbance during enamel formation.
Poor aesthetic appearance [53], low self-esteem and negative psychosocial impact [54] have been reported in relation to the presence of WSL on anterior teeth among children.
Post-orthodontic decalcification is commonly associated with the presence of WSL on anterior teeth [55], where it increases the prevalence of WSL by three-fold as compared to those who were not wearing the appliance [56].
Fluorosis and molar-incisor hypomineralisation (MIH) are the two most common developmental anomalies associated with WSL formation.
Reversal of the decalcification process (in the case of post-orthodontic decalcification) and improvement of the aesthetic value have been the aim of managing WSL on anterior teeth. Improvement in the child’s oral health and quality of life has been reported following the treatment of WSL [69].
Infiltrating the WSL with resin allows the low-viscosity resin to penetrate the intercrys- talline spaces of the hypomineralised and porous enamel. This resulted in an improvement in the refractive index value of the porous enamel (1.52), close to the value of normal enamel [78].
This has dramatically and instantly improved the appearance of the anterior teeth with WSL. High patient satisfaction has been reported following the infiltration of WSL [79, 80].
Further, infiltration improves the surface microhardness [81] and shear bond strength while reducing the surface roughness of the infiltrated WSL [82].
Several systematic reviews concluded that there is inconclusive evidence to strongly support the use of RI in managing WSL on anterior teeth.
This is merely due to insufficient high-quality clinical trials rather than the clinical inefficiency of the technique itself.
Positive camouflaging effects were reported on the WSL of anterior teeth treated with RI.
Wang et al. [86] reported a favourable aesthetic outcome of RI over fluoride varnish among their orthodontic patients.
Knosel et al. [87], in their clinical study on post-orthodontic WSL, stated that the lesion showed significant aesthetic improvement and blended well with the normal enamel, even after a 24-months follow-up.
Meta-analysis performed by Borouni and colleagues [85] showed a significantly higher optical improvement following infiltration as compared to the regular application of fluoride varnish.
Two studies have been conducted by Gu et al. [71] and later Shan et al. [72] comparing the effects of RI and microabrasion in treating post-orthodontic WSL.
They concluded that both techniques improve the aesthetic outcome of the WSL, but better and longer aesthetic outcomes were observed among the lesions treated with RI.
Clinical trials conducted by Gugnani et al. [74] reported an effective masking ability of RI on teeth with mild to moderate fluorosis, while Schoppmeier et al. [88] concluded that RI with increased etching and infiltration time gave significantly better aesthetic outcomes in comparison to bleaching.
Gencer and Kirzioglu [89], in another study, concluded that treatment with RI on anterior teeth with fluorosis gave the highest colour changes as compared to fluoride varnish, CPP-ACP and microabrasion.
A recently conducted systematic review also favours RI over microabrasion and bleach- ing in the management of fluorosis [90].
Earlier studies by Kim et al. [93] found that the MIH teeth treated with RI showed significant colour changes after one week of treatment.
RI showed some potential and can be effective in reversing the white opacities, provided that the surface layer has been removed sufficiently.
Elbaz and Mahfous [95] and Bhandari et al. [96] both investigated the effect of RI in mild MIH-affected incisors and reported the efficacy of the RI technique in masking the opacities and improving the aesthetic appearance of the incisors.
Hasmun et al. [69] used a combination of microabrasion and RI in managing MIH-affected incisors in 23 children and observed a significant reduction in brightness and surface areas affected by the opacities.
The European Association of Paediatric Dentistry (EAPD) [68] suggested that RI can be considered as one of the treatment options in managing MIH-affected incisors, either alone or in combination with other treatments including microabrasion, external bleaching and direct composite restoration, depending on the severity and depth of the lesion.

Limited Penetration Depth

One of the drawbacks of RI is the limited penetration depth of the material into the carious lesion.
Despite various systematic reviews describing the efficacy of RI infiltrating the early enamel lesion, the penetration of the low-viscosity resin is limited to the enamel structure and did not perform well in the dentinal lesion.
Peters et al. [45] reported that while the resin managed to infiltrate 100% into the inner enamel lesion (E2), only 64% of the outer dentine lesion (D1) was infiltrated by RI.
Schneider et al. [98] studied the penetration ability of RI on extracted teeth using microcomputed tomography and concluded that the resin was incapable of completely infiltrating the advanced carious lesion, with areas of resin inhomogeneity found within the lesion.
Several in vitro studies on bovine and extracted premolar teeth reported the mean penetration depth of the RI to be less than 70% [99–101].
The penetration depth of RI in primary teeth is better as compared to the permanent teeth [104, 105].
The limited penetration depth of the resin will have some clinical implications.
Liang et al. [103] suggested that the clinician should appropriately select which of the non-cavitated carious lesion is suitable for RI, guided by the depth of the lesion. This is also true for deeper WSL found on incisors teeth diagnosed with MIH.
Due to the variety in the lesion depth of MIH-affected incisors, the masking ability of the RI might differ between cases; thus, case selection is very important to ensure an optimum aesthetic result.

Not Radiopaque

Ideally, a dental material should possess a certain degree of opacity in the radiograph.
However, the RI is radiolucent in the radiograph, showing no clear distinction between the material and the infiltrated enamel and dentinal lesion.
International Standard Organisation (ISO) recommends a dental material should have a radiopacity equivalent to or greater than the radiopacity produced by the thickness of pure aluminium [107].
This will cause problems for the clinician as the penetration depth of the resin would not be visible radiographically.
Further, the potential caries progression of the infiltrated lesion could not be monitored.
Instead, multiple radiographs need to be taken periodically, and comparisons between radiographs need to be made for the sake of monitoring the success or failure of the infiltration technique.
Development of RI with radiopaque properties has been conducted actively by some researchers.

Long-Term Colour and Material Stability

RI has been associated with poor long-term colour stability [109].
The infiltrated teeth are unable to retain the masking effects and are susceptible to staining by the colouring agents present in the diet, as proved by various in vitro studies.
Significant colour changes have been reported following immersion with coffee [110, 111], tea [110], red wine [112, 113] and grape juice [114].
The colour changes were also more apparent in resin-infiltrated teeth as compared to teeth treated with remineralising agents [115].
Surface roughness also has been implicated as the cause of staining, mainly involving resin-based restoration [112].
The rough surface can act as the niche for dental plaque and bacterial adhesion, including stains and colouring from the diet.
Changes in surface integrity increase the tendency of the infiltrated teeth towards water absorption, which leads to sur- face staining and loss of surface gloss [119].
Despite the long-term colour instability, repolishing the surface of infiltrated teeth has improved the brightness of the discoloured surface [112, 120].
Clinicians should wipe off the excess resin from the surface before light-curing to prevent excess material from sticking on the enamel surface, potentially attracting plaque accumu- lation [78].
Bleaching of the infiltrated surface has been suggested to improve discoloura- tion [116, 121].
Clinical studies of resin-infiltrated anterior teeth did not report any significant discolouration or staining effects post-infiltration. Nevertheless, most of the clinical studies were of short-term follow-up.
A true reflection on the colour stability of the resin-infiltrated anterior teeth could not be made.
Clinicians should warn the parents and patient regarding the potential staining effects of the resin-infiltrated teeth and advice them for regular polishing and avoidance of certain foods and beverages that could stain the tooth structure if possible.

Future: Innovation to Improve the Current RI

RI with Remineralising and Antibacterial Properties

Incorporation of an antibacterial or remineralising agent into the current RI formu- lation will offer huge advantages to the patients.
Incorporation of fillers within the RI may increase in viscosity and stiffness of the material, which will affect the penetration ability of the resin.
It was suggested that the concentration of filler within a resin-based dental material should not exceed 15% of the total weight ratio [124].
Advancement in the field of nanotechnology can formulate a nano-sized filler where the remineralising and antibacterial agent is incorporated into the RI without affecting it's penetrative ability.
Hashemian et al. [125] investigated the penetration ability, mechanical properties and calcium release ability of their experimental RI consisting of 10% polyurethane acrylate oligomer (PUA) and 88% TEDGMA. The resin showed a good penetration coefficient of 133 cm/s, exceeding the minimum threshold of 100 cm/s required for effective penetration of resin into the enamel porosity. The penetration depth was up to 120 µm.
The author added either HAP or BAG as filler into the formulation of their experimental resin where incorporation of both fillers increased the microhardness and modulus of elasticity of the RI, as well as water sorption and solubility of the material.
Prodan et al. [127] reported using the fluoride-releasing glass filler, where incorporation of the filler improves the DC and strength of the material and inhibits demineralisation through the fluoride-releasing effect.
Several investigations on Sfalcin et al. [128], Dai et al. [129] and Obeid et al. [130] showed using Cap as fillers in RI in where it increased the surface hardness and the DC value of the RI, and positive calcium and phosphate ion release were observed under pH-cycling challenge.
Incorporation of antibacterial agents as fillers have improved the mechanical properties and caries arrest ability of the RI [97, 131–136].
Kielbassa et al. [97] investigated the effectiveness and penetration ability of silver-enhanced RI where it’s antibacterial effects was incorporated into the form of nanosilver particles (AgNP).
Cuppini et al. [135] described using the ionic liquid 1-n-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide (BMI.NTf2) encapsulated with methacrylate-based microcapsules as the RI fillers where the addition of the fillers did not alter the handling and mechanical behavior of the material.
Addition of chlorhexidine and iodonium salts improved the DC and microhardness of the experimental resin and inhibited the S. mutans and L. acidophilus biofilm, while the incorporation of the quaternary ammonium-based resin monomer at 2.5% to 10% by weight ratio reduced the S. mutans bacterial count without affecting the surface roughness of the material.
Incorporation of guanidine hydrochloride as filler of RI was also effective in disrupting the growth of S. mutans biofilm without affecting the SFE, DC and contact angle of the material.
Conclusively, the addition of remineralising and antibacterial agents as the nano-sized filler has opened a new prospective in the development of a RI with enhanced anticaries properties.

Self-Etching RI

Developing a self-etching RI, especially in the field of Paediatric Dentistry, would cut down the lengthy procedure, providing better management of the paediatric patient, especially those with short-term attention spans.
Wang et al. [142] have investigated the penetrative ability of their experimental self-etching RI, which consists of the resin monomer TEDGMA and phosphoric acid 2-hydroxyethyl methacrylate ester (PAM). which showed some potential as the penetration depth was found to be similar to the control when no acid etching was performed prior to the infiltration procedure.
75% TEDGMA: 25% PAM as the best ratio to be used as a self-etching RI.

Radiopaque RI

Moeinian [108] investigated the use of strontium hydroxyapatite (SrHA) nanoparticles and strontium bioglass (SrBG) as a filler mixed into the resin monomer TEDGMA. The author found out that the mixture resulted in a below-average radiopacity and increased the viscosity of the RI, thus limiting its potential to infiltrate the carious lesion.
The author later used barium and tin methacrylate monomers as potential radiopaque material. The incorporation of both radiopaque resin monomers produced a homogenous mixture with TEDGMA with low viscosity and contact angle values. Although both mixtures managed to infiltrate the lesion to a certain depth, they were not clearly visible in the digital radiograph.
Efforts in formulating a radiopaque RI were also made by Pedreira et al. [143] and Nowak-Wachol et al. [144] where,the mixture of 45% zirconium oxide particles (by weight) with RI monomer produced radiopacity higher than enamel when viewed using a digital radiograph.

Micro-Filled RI

The current RI is highly effective in arresting the non-cavitated enamel lesion by occluding the pores and blocking the diffusion pathways of the minerals and acids where the performance in arresting deep dentinal carious lesions is poor.
This has led Meyer-Lueckel and Paris [145, 146], together with their innovative research team members, to conduct a series of experimental studies investigating the possibility of incorporating fillers into the RI monomer matrix without jeopardising its penetrative ability. They found that the filler size influenced the penetration ability of the resins, where RI with 42 µm of organic filler displayed an indifferent penetration percentage as the commercial unfilled RI [145].

Conclusions

RI has emerged as one of the important micro-invasive techniques in addressing non-cavitated and white-spot enamel lesions in children and adolescents.
However, some issues of concern have been raised over the radiopacity, colour stability and its usage in deep dentinal lesions.
Improvisation of the current RI is ongoing actively at the moment, aiming to address the clinical issues associated with the material.
Nevertheless, most of the studies are laboratory-based, which might lead to different outcomes clinically. Thus, further research in terms of clinical trials is needed.