Application of nanoparticles as surface modifiers of dental implants for revascularization/regeneration of bone

Abstract

Background

Osseointegrated dental implants are widely established as a first-choice treatment for the replacement of missing teeth. Clinical outcomes are however often compromised by short or longer-term biological complications and pathologies. Nanoparticle-coated materials represent a very active research area with the potential to enhance clinical outcomes and reduce complications of implant therapy. This scoping review aimed to summarize current research on various types of nanoparticles (NPs) used as surface modifiers of dental implants and their potential to promote biological and clinical outcomes.

Methods

A systematic electronic search was conducted in SCOPUS, PubMed and Google Scholar aiming to identify in vivo, in situ, or in vitro studies published between 2014 and 2024. Inclusion and exclusion criteria were determined and were described in the methods section.

Results

A total of 169 articles (44 original papers from Scopus and PubMed, and 125 articles from Google Scholar) were identified by the electronic search. Finally, 30 studies fit the inclusion criteria and were further used in this review. The findings from the selected papers suggest that nanoparticle-coated dental implants show promising results in enhancing bone regeneration and promoting angiogenesis around the implant site. These effects are due to the unique physicochemical properties of nanoparticle-coated implants and the controlled release of bioactive molecules from nanoparticle-modified surfaces.

Conclusion

Nanoscale modifications displayed unique properties which could significantly enhance the properties of dental implants and further accelerate revascularization, and osseointegration while facilitating early implant loading. Yet, since many of these findings were based on in-vitro/in-situ systems, further research is required before such technology reaches clinical application.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12903-024-04966-4.

Background

Dental implants are currently regarded as the most efficient and reliable way to replace lost teeth [1]. Fabricated primarily by titanium or other biocompatible materials they are placed into the alveolar bone, where they get anchored through the process of osseointegration [2]. They can consequently support fixed or removable prostheses, and thus provide a stable and long-lasting dental rehabilitation [3]. Dental implants, however, have certain limitations and can present both short and long-term challenges, including peri-implant inflammation, loss of supporting bone, or loss of osseointegration [4]. There is an increasing interest in developing dental implants with specific bioactive features, able to provoke an enhanced biological response, potentially increasing clinical success and reducing complications and failures. A lot of active research is currently conducted within the area of biomaterial science, aiming to create implants with bioactive features which could shorten and improve post-surgical healing and osseointegration [5].

Osseointegration is the biological process that results with the firm anchorage of the implant in the bone tissue. This process greatly depends on bone formation directly onto the implant surface following its placement into the jawbone (contact osteogenesis) [6]. Thus, surface modification of an implant could significantly improve its osseoconductivity and thus enhance bone formation. The clinical outcomes depend on a variety of factors and procedures but also rely heavily on the quality and quantity of the alveolar bone. Although most areas of the alveolar ridge have a relatively fast healing potential, its degradation can be induced by pathological conditions, with the most common being an inflammatory response to a localized biofilm challenge [7]. Marginal bone resorption is also often observed following implant placement, possibly as part of physiological bone remodelling during wound healing [8].

Nanotechnology can be used to modify implant surface characteristics to increase bioactivity, release desirable bioactive agents or prevent the release of undesired or harmful ones such as metal ions [9]. Recent research suggested the use of nanocomposites to enhance titanium-based implants with the ability of a sustained medication release, which could achieve enhanced clinical outcomes such as improvement of osseointegration [10] or sustained antibacterial action [11]. Nanoparticles (NPs) have been used in implant-based therapy to deliver controlled therapies for periodontal, orthodontic, endodontic, and restorative procedures [12].

Osseointegration remains a complex biological process, extending over a period of 6–12 weeks and involving numerous different cell types and tissues of the human body. Thus, different types of NPs could modify the surface of implants, potentially generating biological and chemical interactions with human cells at different stages of the healing process and leading to improved clinical outcomes through a diversity of pathways [13, 14]. When implanted in vivo, a biomaterial causes a cascade of biological reactions, from the initial granulation tissue to neo angiogenesis and vascularization, formation of collagen matrix and finally resulting in mineralisation and early-stage bone deposition [15]. This review aims to provide an overview of current research on surface modification techniques utilising NPs for the improvement of clinical outcomes of titanium dental implants (Fig. 1).

Fig.1.

The sequence of cellular responses that occur after implantation of an implant. Non-infectious and infectious complications are factors that hinder osseointegration. Factors that improve this process are bioactivation and surface modification with nanotechnology. (Created with BioRender.com, License number CF276BX2MD)

Methods

Search strategy and eligibility criteria

To collect the literature for this scoping review, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines were applied [16]. Figure 2 depicts the flow of information via the various phases required in selecting the papers for this review.

Fig. 2.

Flow chart illustrating the article selection

Inclusion and exclusion criteria

Inclusion criteria

All investigations on NPs, surface modification of dental implants, bone vascularization, bone regeneration and the in vivo, in situ, or in vitro connection of osteogenesis and angiogenesis met the inclusion criteria. English-language full-text publications from 2014 − 2024 were included. To search for other research, we used Google Scholar and the primary studies' reference lists.

Exclusion criteria

Investigations were excluded that did not emphasize the impact of nanoparticles on angiogenesis, bone regeneration, dental implants or vascularization coupling. Studies were also excluded that did not address bone remodelling in the presence of NPs. Additional exclusion criteria were (1) master's and doctorate theses, (2) case studies, (3) editorials and (4) letters to the editor.

Information sources and search

Two registered databases, PubMed and Scopus, as well as a freely accessible web search, Google Scholar, were used for this review. The search included the keywords: nanomaterials, dental implants, surface modification, and bone angiogenesis/vascularization. The mesh terms (nanoparticles AND dental implants), (bone angiogenesis OR bone vascularization) and (nanoparticles AND dental implant AND bone angiogenesis OR bone vascularization) were applied. The search phrases used were keywords from the general (all fields) category. The following filters were used on these terms: Full text, academic literature and English language. The published period of the reference papers was limited from 2014 − 2024.

Data extraction

The selection of papers from the three databases was completed as follows: (1) duplicate papers were removed manually after selecting the papers from the database search; (2) following reading the paper's abstract, the selection was based on the inclusion and exclusion criteria; (3) finally, the full-text paper was read. The included studies were mainly divided into two main groups: (1) in vitro/ in vivo tissue or cellular response of implants with various kinds of nanocomposite surfaces and (2) controlled release of biological molecules from nano scaffolds of dental implants and their effects.

Results

A total of 169 articles (44 original papers from Scopus and PubMed, and 125 articles from Google Scholar) were found in the database searches using the determined keywords. According to the inclusion and exclusion criteria, 2 duplicate articles were eliminated, and 27 non-English language and review papers were removed. Moreover, 110 papers were unrelated to NPs and dental implants. Finally, 30 papers were used to conduct this review. The information flow via the several stages in the process of choosing the studies for this review is illustrated in Fig. 2. Among the included studies, 19 articles described the in vitro/ in vivo tissue or cellular response of implants with various kinds of nanocomposite surfaces as shown in Table 1 and the controlled release of biological molecules from nano scaffolds of dental implants and their effects was described in 11 articles (Table 2).

Table 1.

Different types of nanocomposites and how they react to implants with nanostructured surfaces

No	Authors	Nanocomposite	Methods	Tissue or Cellular Response (in vitro)	Tissue or Cellular Response (in vivo)
1	Shi, et al.(2023) [17]	3D nano ink-printed graft	Ultrasmall calcium phosphate oligomer and bone morphogenetic protein-2 (BMP-2) have been incorporated in a nano ink based on gelatin methacryloyl	- Remarkable potential for osteogenesis and angiogenesis - The signalling, TGA10/PI3K/AKT was activated	- Rapid revascularization - Causes well-structured full thickness bone
2	Cheng, et al.(2020) [18]	Chitosan, Poly (L-lactic acid) nanoparticle	Dental implants were modified with recombinant human bone morphogenetic protein-2-loaded poly (L-lactic acid) inner layer and osteoprotegerin conjugated chitosan outer layer NPs	- Attracts and stimulates BMSCs to differentiate into osteoblasts - Prevents osteoclast differentiation	No information is available
3	Chauhan, et al. [19]	Titanium nanotubes	Simvastatin was introduced into titanium nanotubes that were fabricated on the surface of a screw-shaped dental implant using the ultrasonication dip technique	- Accelerates osseointegration - A high amount of simvastatin was loaded in nanotubes that enhanced osseointegration	- Faster osseointegration and a robust interface on the surface of the implant loaded with simvastatin
4	Romero Gavilán, et al.(2017) [20]	silica sol–gel hybrid biomaterial	A titanium implant was sandblasted, acid-etched, then coated with a silica hybrid sol–gel coating (35M35G30T)	- Increases mRNA of IL-6, alkaline phosphatase (ALP) and osteogenic markers	- Promotes osseointegration, increases the inflammatory response
5	Li, et al.(2023) [21]	Calcium peroxide (CaO2) NPs,	Titanium surface was coated with CaO2@ZIF-67-HA-ADH by mixing zeolite imidazolate framework-67 (ZIF-67), calcium peroxide (CaO2) nanoparticles, and the chemical coupling hyaluronic acid − adipic acid dihydrazide (HA-ADH)	- Promotes pro-osteoblast adhesion, proliferation and differentiation - Promotes human umbilical vein endothelial cell migration and angiogenesis	- Exhibits strong antimicrobial activity
6	Heo, et al.(2016) [22]	Gold NPs	Ti surface was silanized by chemically treating 3-Mercaptopropyl trimethoxy silane and immobilized on their surfaces with the GNP layer (Ti–GNP)	- Enhances expression of COL1, Runx2, OCN, and BSP, osteogenic differentiation markers	- Influences osseous interface formation - GNPs have non-toxic effect
7	Xing, et al. (2020) [23]	siRNA-Cathepsin K (CTSK)-decorated gold NPs	Titanium implants were coated with siRNA-CTSK decorated gold nanoparticles (AuNPs) using layer-by-layer (LbL)	- siRNA-CTSK is released and internalized by preosteoclast cells, macrophages - Increases vascular-related PDGF as well as VEGF gene expression and promotes vascular cell proliferation	- Development of new bone surrounding the titanium implants
8	Beltrán-Partida, et al. (2017) [24]	Titanium dioxide nanotubes	A cost-effective and antibacterial, super oxidized water was used to coat Ti6Al4V alloy with anodized TiO2 nanotubes (NTs) that had been synthesized and disinfected	- Improves the surface roughness and hydrophilicity of the material - Improves VEGFR2 expression and angiogenic factor activation	No information is available
9	Zhu, et.al (2015) [25]	Silver nanoparticles	Immobilization of silver nanoparticles on the surface of titanium that has been sandblasted and acid-etched and optimised the atomic-scale heating impact of silver plasma immersion ion implantation	- Excellent antibacterial action and compatibility with mammalian cells - Mimics the extracellular matrix structure, which offers a favourable surface for biological activities	No information is available
10	Zhong, et al. (2016) [26]	Chitosan and hyaluronic acid-based silver nanoparticles	Chitosan and hyaluronic acid are used to modify the titanium implant surfaces by layer-by-layer self-assembly of silver nanoparticles	- Eliminates planktonic and adhering microorganisms - Inhibits bacterial invasion until the mucosa heals - By controlling the silver release rate and concentration, the toxicity of silver nanoparticles is reduced	No information is available
11	Martinez, et al. (2014) [27]	Silver NPs containing sodalime glass	Homogeneously dispersed silver NPs incorporated in a glassy matrix and coated on implants attached to abutments	No information is available	- Reduces the peri-implantitic bone loss - A more consistent bone resorption crater and less pronounced asymmetry
12	Astasov-Frauenhoffer, et al. (2019) [28]	Anodized titanium disc doped with copper	Anodization with spark assistance in a combined deposition-anodization process to coat titanium discs with copper	- Decreases P. gingivalis bacteria's ability to survive on surfaces - Creates a "safe zone" for better implant recovery and lowers the viable bacterial level	No information is available
13	Lin, et al. (2021) [29]	Chitosan with zinc oxide (ZnO) NPs	Chitosan and chitosan-coated with zinc oxide NPs applied to alkali-treated porous titanium oxide	- Chitosan/ZnO coating inhibits E. coli growth and bacterial adhesion and resists E. coli biofilm formation - After 14 days of immersion, the chitosan/ZnO shows increased bioactivity because to the release of Zn2+ ions	No information is available
14	Wang, et al. (2021) [30]	zinc oxide (ZnO) NPs coated with chitosan (Cs) nanocrystal hydroxyapatite nanoparticles	Polydopamine (PDA), ZnO NPs, and (Cs) nanocrystal hydroxyapatite (HA) are incorporated into a hierarchically hybrid biocoating on titanium implants by oxidative self-polymerization, nanoparticle deposition, solvent casting, and evaporation	- It prevents growth of Escherichia coli and Staphylococcus aureus - Enhances osteogenic differentiation and cytocompatibility	No information is available
15	Yao et al. (2022) [31]	strontium titanate (SrTiO3) and silver double-layered Sr/Ag nanoparticle	SrTiO3 and Sr/Ag nanoparticle coating on Ti implants surface fabricated by hot alkali treatment and magnetron sputtering	- Induces osteoblastic differentiation - Controlled release of Ag caused an antimicrobial efficiency that reduced inflammation surrounding the implants - Promotes pre-osteoblast cell proliferation to improve osteogenesis	- Forms new bone tissue around the implant - promotes osteointegration around the implant - Enhances strength of the bond between the surrounding bone and the implant
16	Takanche, et al. (2018) [32]	Chitosan-gold nanoparticles (GNP)	Chitosan was stabilized in GNPs by simple graft-on technique and Plasmid DNA/c-myb was conjugated with chitosan-gold nanoparticles	- promotes osteogenesis and inhibits osteoclastogenesis	New bone formation and the osseointegration of dental implant - upregulation of bone morphogenic proteins (BMP-2, BMP-7, OPG and ALP) and down regulation of RANKL
17	Hamad, et al. (2018) [33]	nano-zirconia suspension	Titanium implants were coated with nano-zirconia suspension by electrophoretic deposition	No information is available	Enhances and promotes osseointegration after 4 and 12 weeks of healing in New Zealand adult rabbits
18	Qiao, et al. (2015) [34]	Silver Nanoparticles (Ag NPs)	Ag NPs was embedded on the surface of titanium dental implants by using Ag-PIII technique	No information is available	- In Labrador dogs, promotes bone apposition around endosseous dental implants - Ag NPs in the Ag-PIII-treated surface exhibits good biocompatibility for both soft and hard tissue
19	Covarrubias, et al. (2016) [35]	Nanoporous silica and bioactive glass nanoparticles	Titanium dental implant surface was fabricated with nanoporous silica coating loaded with bioactive glass nanoparticles	- Enhances in vitro bone-like apatite formation and stimulates osteogenic differentiation of hBMSCs in absence of osteogenic supplements	- In Sprague Dawley adult rats promotes formation of bone tissue in close contact with the implant surface

Table 2.

Controlled release of biological molecules from nano scaffolds of dental implants and their effects

No	Authors	Nanomaterial	Coating methods	Results	Effects
1	Sun, et al. (2018) [36]	PLGA-coated titanium oxide nanotube	Sustained release of bone growth factor developed via coating the surface of a titanium implant with PLGA film and arrays of anodized TiO2 nanotubes	- rhBMP-2 release is efficiently sustained by PLGA film TiO2 nanotube growth factor delivery method - Promotes proliferation and differentiation of MC3T3-E1 osteoblasts	- This structure might serve as a reservoir for anti-inflammatory and antibacterial drugs
2	Wang, et al. (2017) [37]	Silica-gentamycin (SG) NPs	Antibiotic nano delivery self-decomposable silica-based system NPs	- A high concentration of gentamycin is provided by rapid release throughout the first 8 h - Gentamycin is kept at a therapeutic concentration via slow release of the drug in subsequent doses	- Provides a novel antimicrobial coating to cure bacterial infections
3	Tang, et al. (2022) [38]	Mg-doped calcium phosphate NPs (CaPNPs)	The surface of the porous implant coated with Layer-by-layer (LBL) self-deposition of CaPNPs-grafted arginine-glycine-aspartate cell adhesion sequence (RGD) and transcribed activator (MCPRT)/CKIP-1 siRNA complex and polylysine (PLL)	- Silences CKIP-1, an inhibitor of bone formation - Facilitates proliferation, adhesion, and osteogenic differentiation of MG63 cells - PLL/MCPRT-siRNA/Ti implants create new bone development and bone contact areas in and around their pores	Increases the initial stability of implants and accelerates osseointegration
4	Eawsakul, et al. (2021) [39]	Nanocoating BMP-2 on titanium layer by layer	Dental implant modified by layer-by-layer nanocoating of BMP-2	- Enhances MC3T3-E1 cells growth with sustained release of BMP-2 - Promotes bone cell growth and stimulates calcium deposition - Stimulates platelet activation	- Calcium deposition and bone cell development are stimulated by prolonged BMP-2 release - increases bone formation by stimulating platelet activation
5	Diniz, et al. (2016) [40]	Silver lactate (SL)-based RGD-coupled alginate hydrogel	SL-containing RGD-coupled alginate hydrogel scaffold optimized for stem cell transport with antibacterial characteristics	- SL exhibits antimicrobial properties against Aggregatibacter actinomycetemcomitans (Aa) - (GMSCs) encapsulated in SL containing alginate hydrogel develops into osteogenic tissue	- GMSCs entrapped in an alginate hydrogel modified with RGD and containing SL - Exhibits promising antibacterial characteristics for bone tissue engineering against Aa bacteria
6	Dong, et al. (2017) [41]	Titania nanotube arrays anchored with silver NPs (AgNPs)	Peri-implant infection was treated utilizing low pH-triggered silver nanoparticles grafted onto the titanium implant surface	- Improves the release of AgNPs from the TNT-AL-AgNPs implant - Increases the antibacterial activity against both gram-positive and gram-negative bacteria - Increases the proliferation and development of osteoblasts	- For the management of peri-implant infections, the low pH-triggered AgNPs releases from TNT-AL-AgNPs may serve as an antimicrobial-releasing implant model
7	Godoy-Gallardo, et al. (2016) [42]	Silver (Ag) electrodeposition and 3 Triethoxysily propyl succinic anhydride, TESPSA silanization	Dental implant treated with Ag and (TESPSA) silane would promote osseointegration and reduce bone resorption induced by ligature-dependent peri-implantitis	- Compared to untreated controls, implants show reduced peri-implant bone resorption following ligature-induced peri-implantitis	- Dental implants have had successful antibacterial surface treatments using silver electrodeposition or TESPSA silane immobilization
8	Liu, et al. (2017) [43]	Gold nanoparticles and PLGA sheet	Titanium implants were immersed in to the PLGA solution containing AntagomiRNAs loaded gold nanoparticles	- Release of encapsulated AuNP-antagomiR204 from the PLGA sheet were taken up by adherent BMSCs - Release of AuNP-antagomiR204 from PLGA sheet promoted osseointegration in in vivo animal model	- Improvement of osseointegration in the context of T2DM for dental implantation by gradual deliver the miRNA inhibitor from AuNP-antagomiR204 embedded PLGA sheet
9	Gunputh, et al. (2019) [44]	Zinc oxide and hydroxyapatite nanoparticles	surface of TiO2 nanotubes was coated with an antimicrobial layer of nano zinc oxide particles	- The coating appeared stable in SBF over 24 h - Slow release of Zn from the zinc oxide and hydroxyapatite nanoparticles was effective in killing around 60% of S. aureus attached to the coating	TiO2 nanotubes decorated with Zinc oxide and hydroxyapatite nanoparticles show promising potential biocompatibility with human bone
10	Lee, et al. (2017) [45]	Chitosan gold nanoparticles	Titanium surface of implant was coated with PPARγ cDNA conjugated Chitosan gold nanoparticles	- induced bone formation and mineralization in Diabetes mellitus induced rats - Strongly activated mitochondrial biogenesis and cell viability via p-AMK and Wnt/β-catenin signaling - PPARγ gene delivery on regional dental implants contributed to osseointegration,	Regional PPARγ expression improves osseointegration and implant durability in diabetes patients, making it a potential therapeutic gene for dental implants
11	Wen, et al. (2023) [46]	Zinc oxide nanoparticles (ZnO)	Surface of implant was modified by ZnO nanoparticle-loaded mesoporous TiO2 coatings via the evaporation-induced self-assembly method and one-step spin coating	- long-term steady-state release of Zn2 + improved adhesion, proliferation, and osteogenic activity of bone mesenchymal stem cells (BMSC) - Possess a higher capability for enhancing bone regeneration, antibiosis, and osseointegration in vivo	Accelerated osseointegration and inhibition of bacterial infection; potential for peri-implantitis of dental implants

Revascularization and angiogenesis for bone bioengineering in implantation

Physiological bone repair and tissue regeneration depend on angiogenesis and revascularization [47]. Tissue necrosis of the flap during reconstruction may affect bone-related tissues, resulting in infection, resorption, malunion, and deformity [48]. The formation of new vessels from pre-existing vascular networks depends on the migration and proliferation of differentiated endothelial cells [49]. During the initial phase, an increase in endothelial cell-derived growth factors, such as vascular endothelial growth factor A (VEGF-A) and fibroblast growth factors (FGFs), promotes vessel destabilization and induces vessel sprouting and endothelial cell proliferation [50]. Enzymes such as matrix metalloproteinases enhance the biological availability of growth factors encapsulated in the extracellular matrix (ECM) and promote the remodelling of the ECM [51]. The resolution phase begins after developing the new vessels and establishing perfusion. During this phase, there is a decrease in VEGF levels and an increase in platelet-derived factors, angiopoietins, and transforming growth factor-β1 (TGFβ1) [48]. More vascularization and blood perfusion may happen in inappropriate fracture healing because of a higher inflammatory response and enhanced angiogenic cytokine release [52].

The function and differentiation of osteoclasts and osteoblasts appear to be regulated by subsets of macrophages, the M1 and M2 subsets [53]. The M1 phenotype of macrophages secrete pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, which impede osteogenesis and promote osteoclastogenesis [54]. In contrast, osteogenic cytokines BMP2 and VEGF are secreted by the anti-inflammatory M2 phenotype, which can decrease inflammation and promote bone repair [55]. Therefore, focusing on macrophages, particularly on the M2 subset has been considered an effective strategy to improve bone regeneration. Nanomaterials including gold, TiO2, and cerium oxide (CeO2) have been demonstrated to be efficient macrophage polarisation agents [56–58]. Organic/inorganic hybrid materials have garnered significant interest in the production of pharmaceuticals and medical devices due to their unique physicochemical features (e.g.; dental implants, vascular stents, scaffolds for tissue engineering, and drug delivery carriers, etc.) [59].

Nanotechnology and dental implants

Nanotechnology is an interdisciplinary and multidisciplinary science that contributes innovations for solving health-related problems [60]. In dentistry, nanotechnology has improved the mechanical, physical, and biological qualities of materials, as well as introduced novel diagnostic modalities and nanoparticle loading systems [61]. Applications of nanotechnology in oral biology primarily focus on improving implant osseointegration and osseous tissue regeneration [62]. Nanostructured implants can enhance bone regeneration and promote the process of osseointegration supporting effective implantation [63].

Surface modification of titanium-based implants

Titanium is recognised as a biocompatible substance that facilitates osseointegration, but some research suggests that titanium particles are released due to tribocorrosion [64] or possibly the presence of peri-implantitis may contribute to an adverse immune response and exacerbate tissue destruction and other undesirable tissue outcomes [65]. Berryman et al. evaluated the effect of titanium particles in peri-implant tissues of peri-implantitis patients and concluded that these particles have the potential to trigger immune responses. 90% of tissue samples close to peri-implantitis lesions contained titanium particles. They also found that the titanium particle-affected areas had higher levels of RANKL, IL-33, and TGF-α which are associated with inflammation and tissue disintegration [66].

Nanomaterials as dental implant surface modifiers

Excellent osteogenic and angiogenic effects were observed in an in vitro investigation using a hierarchical 3D graft nano-ink comprising ultrasmall calcium phosphate oligomers and bone morphogenetic protein [17]. In vivo fast revascularization was observed and the biomimetic graft resulted in well-structured full-thickness bone around the implant [17]. Cheng et al. [18] fabricated pH-sensitive double-layered NPs consisting of an inner layer of recombinant human bone morphogenetic protein-2-loaded poly (L-lactic acid) and an outer layer of osteoprotegerin conjugated chitosan. They found that the double-layered NPs attracted bone marrow-derived mesenchymal stem cells (BMSCs) that differentiated into osteoblasts and prevented osteoclast formation. Thus, pH-sensitive double-layered NPs, which inhibit bone resorption and promote bone formation, are appropriate for dental implant surfaces [18]. Chauhan et al. [19] conducted in vitro and in vivo assays of dental implants with surface-modified nanotubes loaded with simvastatin. They found increased osteogenic activity, and faster osseointegration with a robust interface on the modified implant surface at four weeks of healing. Thus, the potential use of the nanoparticle-assembled coating technique in dental implants for bone regeneration shows great prospects.

A gelatin methacryloyl-based nano-ink system with incorporated ultrasmall calcium phosphate oligomer and bone morphogenetic protein-2 (BMP-2) was created by Shi et al. [17] Using a high-resolution projection-based 3D printing method, a biomimetic hierarchical structure was added to the scaffold. This nano-ink demonstrated marked osteogenic and angiogenic effects in vitro and could be printed at high resolution to construct grafts that resembled bone structure. The regeneration process is facilitated via the integrin alpha-10/phosphatidylinositol 3 kinase/protein kinase B (ITGA10/PI3K/AKT) signalling pathway. The graft accelerated in vivo revascularization and bone formation and demonstrated outstanding osteogenic and angiogenic effects in vitro [17]. Based on the included studies, the various types of nanoparticles that are used as surface modifiers for the modification of dental implants are (I) inorganic-based nanomaterials (silica and calcium peroxide) and (II) metal-based nanomaterials (gold, titanium, silver, copper, zinc and strontium). These different materials are mentioned below.

Inorganic-based nanomaterials

Silica-based nanoparticles

Gavilan et al. demonstrated that silica sol–gel hybrid biomaterial-coated implants increased osteoblast activity [20]. In vitro studies indicated that the bioactive potential of sol–gel-coated implants was higher than that of untreated ones. A nearly fourfold increase was noted in the mRNA expression of alkaline phosphatase (ALP), a biomarker for osteoblast differentiation. They also found a twofold increase in the mRNA expression of IL-6, a regulator of pre-osteoblast differentiation and initiator of apoptosis in mature osteoblasts. Finally, silica activated RANKL and osteoprotegerin mRNA expression, thereby modulating bone resorption [20].

Calcium peroxide nanoparticles

Li et al. created a CaO₂@ZIF-67-HA-ADH coating by combining CaO₂ NPs, a zeolite imidazolate framework-67 (ZIF-67), and the chemical coupling agent hyaluronic acid − adipic acid dihydrazide (HA-ADH) [21]. The pH-responsive CaO₂@ZIF-67-HA-ADH coating demonstrated superior osteogenic, angiogenic, and antibacterial properties. The coating effectively enhanced implant osseointegration and prevented bacterial infection [21]. In animal implantation experiments, the CaO₂@ZIF67-HA-ADH coating exhibited strong antimicrobial activity three days after implantation and excellent osseointegration four weeks after implantation [21].

Metal-based nanoparticles

Gold nanoparticles

Heo et al. created osseointegrated titanium implants by surface-functionalizing them using gold nanoparticles (GNPs). Cell assays revealed that an implant immobilised with the GNPs layer promoted osteogenic differentiation of human adipose-derived stem cells. This resulted in a significant rise in osteogenic differentiation-specific markers, such as COL1, Runx2, OCN, and BSP. In vivo results further showed that the osseous interface formation was significantly increased by the implant immobilised with the GNP layer. To form an osseous contact and maintain the development of nascent bone, dental implants immobilised with the GNP layer were found to be beneficial in both in vitro and in vivo studies [22].

New hierarchical nanostructures have been created by Xing et al. [23] for titanium implant surface coating in clinical applications. Using biocompatible natural building blocks, GNPs decorated with siRNA-CTSK (Cathepsin K) were constructed layer by layer on titanium implants to produce a super-structured multilayer of functionalized NPs. In vivo studies showed that the nanostructured coating significantly improved osseointegration by enhancing angiogenesis integrated with the regenerated bone [23].

Titanium oxide nanotubes

TiNTs fabricated using anodic oxidation with a specific PLGA layer were created by Sun et al. [36]. In this study, increased implant osseointegration was found due to increased osteoblast viability. Moreover, this layer served as a drug reservoir for antibacterial and anti-inflammatory agents [36]. After a dip-coating process, a coating solution consisting of PLGA and rhBMP-2 was well-distributed on the surface of TiNTs because of its hydrophilic property. A growth factor delivery method utilising PLGA and TiO2 nanotubes efficiently maintained the release of rhBMP-2 and stimulated MC3T3-E1 cell growth and differentiation [36]. In line with these findings, Beltran-Partida et al. reported that enhancement of a material's surface roughness and hydrophilicity stimulated in vitro endothelial function, causing increased angiogenic factor expression [24]. Hence, TiNTs are considered an appealing design for medical device applications. Furthermore, this type of surface can be used in conjunction with other signalling growth factors and cytokines that might further promote osseointegration [24].

Silver-based nanoparticles

Zhu et al. immobilized the surface of titanium that has been acid-etched, large-grit, and sandblasted (SLA) with silver NPs by optimizing the atomic-scale heating effect of immersion ion implantation in silver plasma [25]. As shown by Zhu and co-workers, silver NPs have good antibacterial activity and biocompatibility with mammalian cells and mimic the structure of the natural extracellular matrix. Zhong et al. [26] developed a unique initial layer on titanium surfaces using phase-transited lysozyme, on which multilayer coatings incorporated silver NPs via a layer-by-layer self-assembly process utilizing hyaluronic acid and chitosan.

Silver NPs are cytotoxic, but toxicity can be minimized by controlling the delivery rate and final concentration. A sustained release of silver over 14 days prevents bacteria from entering the mucosa until it heals [26]. Using a peri-implantitis experiment model, Martinez et al. found that implants coated with soda lime glass containing silver NPs limited bone loss caused by peri-implantitis [27].

Copper-based nanoparticles

Titanium functionalized with copper dramatically lowers the number of attached viable bacteria [67]. Astasov-Frauenhoffer and colleagues [28] revealed that copper can also be deposited in P gingivalis at low concentrations as nanosized deposits, which lead to periimplantitis and dental implant failure. This finding may be used in the treatment of implant-related local infections followed by bone regeneration [28].

Zinc and zinc oxide-based nanoparticles

Lin et al. confirmed that titanium coated with chitosan and zinc oxide (ZnO) could be a good material that was compatible with osteoblast-like MG-63 cells and inhibited the formation of E. Coli biofilms [29]. Dental implants coated with ZnO NPs lower the risk of implant failure, and enhance osteointegration, by promoting bone formation and suppressing infection at the implant site [30, 68]. These implants can be used for orthopaedic and dental implant applications as demonstrated by Wang and coworkers [30]. They coated implants using polydopmanine, ZnO NPs and chitosan /nanocrystal hydroxyapatite [30]. This coating could be promising for orthopaedic and dental implant applications.

Strontium-based nanoparticles

Yao et al. [31] developed a strontium titanate (SrTiO₃) and silver double-layered Sr/Ag nanoparticle coating on a Ti surface and confirmed that it significantly enhanced MC3T3-E1 cell adhesion, proliferation and osteogenic differentiation. In vitro investigations revealed that the Sr/Ag double-layered coating possesses exceptional biological features, including suppressing infection, enhancing cytocompatibility, and promoting osteogenic differentiation. Furthermore, in vivo data showed that the SrTiO₃ coating significantly promoted osteointegration around the implant and enhanced bond strength between implant and surrounding bone [31].

Controlled release of biomolecules from nano scaffolds

Efficiently sustaining rhBMP-2 release in addition to stimulating MC3T3-E1 osteoblast growth and differentiation was achieved by Sun et al. They fabricated TiO₂ nanotube arrays with a PLGA layer by anodic oxidation. Their experimental data proved that this structure might also be used as a reservoir because it was shown to enhance osteoblast viability, adhesion, and bone formation, which improved implant osseointegration [36].

Wang et al. investigated the release of gentamycin from silica-gentamycin NPs that were incorporated into a gelatine matrix and cross-linked on microarc-oxidized titanium. When the gelatine decomposed, a rapid release in the first 8 h delivered a high concentration of gentamycin, and a subsequent slow release retained the concentration of gentamycin at a therapeutic level. The NPs were liberated as the gelatine on the titanium coating gradually degraded. Their design provided a new antibiotic coating for treating bacterial infections with a low antibiotic dose and a prolonged duration of action [37].

A porous structure combined with local CKIP-1 siRNA delivery represents a promising technique for achieving faster and stronger osseointegration of dental implants. Tang et al. [38] created a bioactive porous dental implant using metal injection moulding. Layer-by-layer self-deposition was used to coat the surface of the porous implants with Mg-doped calcium phosphate NPs (CaPNPs)-grafted arginine-glycine-aspartate cell adhesion sequence (RGD) and transcribed activator (TAT) (MCPRT)/CKIP-1 siRNA complex and polylysine. The in vitro results showed that the MCPRT-siRNA coating enhanced MG63 cell adhesion and proliferation, as well as protein expression (ALP and OC) and bone formation-related gene expression (OPN, OC, and COL-1). The in vivo findings indicated that the porous structure of the implant surface coupled with Mg-doped CaPNPs that caused the local gradual release of MCPRT-siRNA accelerated new bone formation at an early stage. These implants have an excellent effect on promoting bone growth and achieving an increased bone contact area, which could result in early implant stability and a shortened treatment period of dental implantation in patients with osteoporosis [38].

Eawsakul et al. modified the implant surface to stimulate osteoblast cell adhesion. They immobilized BMP-2 on titanium modified by a layer-by-layer nanocoating of BMP-2 on dental implants and then sprayed with poly(lactide-co-glycolide). The coating generated sustained release of BMP-2 within a therapeutic window and increased bone cell development, stimulation of calcium deposition and platelet activation to promote bone formation [39].

Diniz et al. [40] demonstrated the efficacy of silver lactate (SL)-containing RGD-coupled alginate hydrogel scaffold as a promising antibacterial stem cell delivery vehicle. This scaffold inhibited Aggregatibacter actinomycetemcomitans proliferation and dramatically reduced the bacterial burden on the surface of titanium discs. Silver ions were successfully released from the SL-loaded alginate microspheres for up to 2 weeks. A high level of mineral matrix deposition and elevated expression of genes linked to osteogenesis confirmed the osteogenic differentiation of gingival mesenchymal stem cells (GMSCs) and human bone marrow mesenchymal stem cells (hBMMSCs) enclosed in the SL-loaded alginate microspheres.

Dong et al. grafted silver NPs in titanium nanotube arrays on the implant surface via a low pH-sensitive acetal linker to control the release of antimicrobial drugs from the implant surface. These surface-modified implants released high doses of silver NPs at pH 5.5, thereby improving osteoblast differentiation and proliferation in vitro [41].

Godoy-Gallardo et al. used antibacterial coatings (silver electrodeposition and 3- (triethoxysilyl) propyl succinic anhydride silane) on dental implants to minimise bone resorption caused by ligature-induced peri-implantitis and to improve osseointegration. Their radiographic results indicated that peri-implant bone resorption following ligature-induced periimplantitis was decreased [42].

Discussion

The utilization of nanomaterials and stem cells in tissue regeneration is an emerging area with tremendous potential for treating maxillofacial bone issues [63]. As indicated in Tables 1 and 2, surface modifications of dental implants with NPs have been studied to enhance their biocompatibility and antimicrobial activity. Implant surfaces have been modified with nanoscale biological scaffolds to improve osseointegration, increase hydrophilicity, encapsulate osteoprogenitor cells, or release bioactive molecules (growth factors, cytokines, etc.) [69].

Surface modification is a key component in determining tissue reactivity to titanium dental implants, affecting clinical osseointegration outcomes [70]. Enhancing osseointegration via surface functionalization of implants has been investigated through several strategies, including release of biological substances, encapsulation of osteoprogenitor cells, and making implants more hydrophilic [71]. Implementation of more efficient implant surfaces that could promote osseointegration and the enduring success of dental implants has been introduced [72]. Nowadays, much research has been conducted to develop new strategies for inhibiting the release of titanium particles and possible potential pathogenic effects [73]. Research has suggested surface modification using NPs loaded with bioactive molecules to improve implants' corrosion resistance and indirectly control the release of titanium particles [74].

As outlined in Figs. 3 and 4, NPs are frequently employed to include bioactive compounds, such as different proteins (e.g. bone extracellular matrix proteins), microbial polymers, growth factors, flavonoids, hormones, and steroids in prospective drug delivery systems. Nanoparticle assembly into hierarchical structures is now being utilised as a versatile platform for generating functional supraparticles and nanostructured films [23]. This greatly improves interaction between the biological surroundings and the material interface [75].

Fig. 3.

The biological effect of surface functionalized dental implants with various nanoparticle modifiers. (Created with BioRender.com, License number MD278BW2BI)

Fig. 4.

Schematic illustration of localized release of bioactive molecules from dental implants which are functionalized with bioactive molecules loaded nanoparticles as carriers/ modifiers. (Created with BioRender.com, License number GH278CA6AE)

Among inorganic nanomaterials, silica NPs offer various attractive properties. including tuneable particle size and shape, simplicity of large-scale manufacturing, and high biocompatibility and stability [76]. In dentistry, silica-based NPs are used as dental fillers, tooth polishing agents, and for treating hypersensitivity. Titanium implants were coated with protein-based silica nanoparticles to enhance their osteogenic and bioactivity effect [20, 77]. An advantage of using silica is its positive effect on bone metabolism [37].

Calcium peroxide (CaO₂) NPs coated implants have potential applications in dental and orthopaedic implants because they enhance the hypoxic environmental conditions of the surrounding tissue [78]. CaO₂ is pH-responsive and reacts with water to produce Ca(OH)₂ and O₂ in a neutral environment, thus providing oxygen and Ca²⁺ for bone tissue healing as well as a microenvironment that is alkaline to promote osteoblast differentiation and proliferation [79, 80].

Gold NPs (GNPs) have interesting properties for utilisation in dentistry because they are characterized by biocompatibility and antibacterial as well as antifungal effects [81]. In the tissue engineering field, GNPs are appealing materials for use as osteogenic agents to accomplish bone tissue regeneration. Numerous studies discovered that after cellular uptake, GNPs had a beneficial influence on the osteogenic differentiation of osteoprogenitor cells [22, 82, 83].

TiNTs have a high potential for their use in dental implants since they exhibit a highly fine nanostructure and large surface area [84], which promote osteoblast activity and osseointegration. Recent studies demonstrated that TiNTs significantly facilitated mesenchymal stem cell adhesion and differentiation [85]. Titanium implants coated with TiNTs minimise oxidative stress and stimulate osteogenesis in bone remodelling [86].

Silver NPs surface modifications for dental implants are recommended because they enhance osteogenesis, soft-tissue integration, and antibacterial effects [87]. Silver is electrostatically attracted to the bacterial cell wall, which disrupts the bacterium's structure. Therefore, several Ag NP-modified films have been created for disinfection of dental implants [25].

An essential component for human health is copper. This metal preserves bone volume by accelerating bone regeneration. Copper-based NPs, because of their antibacterial, osteogenic, and angiogenic effects, have been used to improve titanium dental implants' bioactivity and antibacterial properties [88]. Copper-incorporated scaffolds were found to stimulate bone repair [89].

Zinc (Zn) and zinc oxide (ZnO) NPs are utilized to modify dental implants because they have osteogenic and antimicrobial effects (see Table 1). ZnO NPs have antibacterial activity against nearly all bacteria and are biosafe materials [90]. Furthermore, Zn deficit reduces bone formation because it is necessary for enzyme systems that influence cell proliferation and differentiation [29].

Strontium (Sr) has excellent osteogenic potential and is thus frequently used in dental and orthopaedic implants [91]. Sr has a similar structure to calcium that promotes expression, nuclear localization, and transcriptional activity of β-catenin by activating the CaSR/PI3K/Akt signalling pathway and inhibiting the production of GSK3 [92]. Furthermore, through upregulating Wnt5a expression, Sr stimulates Runx2, ALP, OCN, and COL-I expression [93]. Incorporating bioactive ions like strontium, magnesium, or copper into bone analogues assists in regenerating vascularized bone to some extent [94].

By using various surface modification methods, several osteogenic-promoting material-loaded nanocomposites were coated onto titanium surfaces, which were subsequently released to regulate responses at the interface between implants and host tissues (Fig. 3). The materials that are loaded can promote osteoblast growth and enhance osseointegration of the implant.

Titanium implants cannot always integrate with the surrounding bone tissue because of insufficient surface bonding and the formation of new bone [95]. One serious surgical complication that is challenging to treat is peri-implant bone loss. Much research has concentrated on creating a sustained bone growth factor delivery method employing nanoparticle scaffolds to solve this problem [36]. Incorporating NPs into implant materials can achieve improved bone regeneration by regulating localised drug release.

Nanocomposites provide a diverse design framework for implant materials, with controlled bioactive chemical release patterns according to specific therapeutic needs [96].

Conclusions

Nanoengineering has been used to improve the bioactive and antibacterial properties of dental implants, aiming to promote desirable biological processes such as angiogenesis and osseointegration, thus improving short and long-term treatment outcomes. Numerous investigations have demonstrated that NPs enhance medication transport across cell membranes, enabling intracellular drug delivery to stimulate bone regeneration. These nanomaterials demonstrated a precise and efficient immobilisation of several bioactive molecules and growth factors. Titanium implants coated with NPs show lower oxidative stress and can enhance angiogenesis and osseointegration. By inducing bone cell proliferation and differentiation at the implant site, nanocomposites may be engineered to release osteoinductive chemicals under controlled conditions and to promote bone formation.

Despite its potential still several challenging areas remain to be investigated before such technology is fully mature for clinical adoption. Up till now only a few in vivo studies have assessed the chemical and mechanical properties of the implant, as well as the results of surface modifications, which is critical for understanding and predicting cell responses and therapeutic success. Therefore, long-term in vivo investigations are required to assess whether nanomaterial-modified dental implants can offer the anticipated outcomes. Furthermore, the implant fixture is but one component in a highly complex system, where human tissue, mechanical components and bacteria remain in constant interaction for the long term [97]. The most common conditions that currently threaten the longevity of implant therapy such as mucositis and peri-implantitis, have their origin not at the implant-bone interface, but at the peri-implant mucosa margin, where the biofilm accumulates on the prosthesis [98]. To that end, antibacterial surface modifications of the implant fixture alone might be inadequate to result into clinical improvements, unless combined with similar modifications of the other important components such as the abutment and prosthesis. As implant dentistry is evolving from focus into osseointegration to focus into a homeostatic bioengineered system, research on bioactive coatings should expand from the implant fixture to include all other critical components, such as the abutment and prosthesis. Anabolic bio-coatings and modifications targeting angiogenesis and ossification might be more applicable for the implant fixtures, while antibiofilm and antibacterial modifications might be better suited for the parts of the systems exposed in the biofilm, such as the prosthesis and the abutment.

Due to the challenge of requiring a substantial number of articles across several databases to conduct a systematic review, this scoping review aimed to highlight the knowledge gap in the improvement of revascularization using nanoparticles (NPs). The findings from this review suggest that NPs hold great promise for the development of bioactive dental implant coatings. However, more comprehensive conclusions will require a larger number of studies in the future.

Future perspectives

In the field of nano-engineered dental implants would include:

• A multidisciplinary approach is necessary to improve the biological, physical, and chemical performance of nanoparticle-coated dental implants. An engineering study of the correct selection of biomaterial composition and implant surface/geometry should confirm that they play a major role in obtaining good compatibility, revascularization and last osseointegration after implantation surgery.

• Further investigation is required to fully understand how biological molecules and cells interact with implant surfaces, how various chemical compositions and nanocomposites affect these interactions as well as how these interactions finally translate to improve clinical outcomes in terms of vascularization, and osseointegration.

• Nanotoxicity and possible human health risks of NPs should be carefully assessed both in short and long term.

Abbreviations

AKT

Protein kinase B

ALP

Alkaline Phosphatase

ATP

Adenosine Triphosphate

bFGF

Basic Fibroblast Growth Factor

BAFo

Bone Area Fraction occupancy

BIC

Bone-Implant Contact

BMSCs

Bone Marrow Mesenchymal Stem Cells

BMP-2

Bone Morphogenetic Protein-2

BSP

Bone Sialoprotein

CaO₂

Calcium Peroxide

Ca(OH)₂

Calcium hydroxide

CKIP-1

Silence Casein Kinase-2 Interacting Protein-1

COL 1

Collagen type I

CTSK

Cathepsin K

ECM

Extracellular Matrix

Erk1/2

Extracellular signal-Regulated Kinase 1/2

FGF

Fibroblast Growth Factor

GNPs

Gold nanoparticles

HA-ADH

Hyaluronic Acid − Adipic Acid Dihydrazide

HIF-1α

Hypoxia-inducible factor 1-alpha

IL-1

Interleukin 1

IL-6

Interleukin 6

IL-33

Interleukin 33

ITGA10

Integrin Subunit Alpha 10

MAPK

Mitogen-activated protein kinases

MIM

Metal Injection Moulding

MSCs

Mesenchymal Stem Cells

mRNA

messenger Ribonucleic Acid

O₂

Oxygen

OC

Osteocalcin

OCN

Osteocalcin

OPN

Osteopontin

PDGF

Platelet-Derived Growth Factor

PDA

Polydopamine

PLGA

Poly (Lactic-co-Glycolic Acid)

PI3K

Phosphatidylinositol 3-kinase

PRISMA

Preferred Reporting Items for Systemic Reviews and Meta-Analysis

RANKL

Receptor Activator of Nuclear factor Kappa beta (NFkB) Ligand

rhBMP-2

Recombinant Human Bone Morphogenetic Protein-2

RGD

Arginylglycylaspartic acid

SAE-Ti

Sandblasted Acid-Etched titanium

SG

Silica-Gentamycin

siRNA

Small interfering RNA

SL

Silver Lactate

SLA

Sand-blasted, Large grit, and Acid-etched

Sr

Strontium

TAT

Transcribed Activator

TGF-β1

Transforming Growth Factor β1

TiNTs

Titanium Oxide Nanotubes

TNFα

Tumour Necrosis Factor alpha

VECs

Vascular Endothelial Cells

VEGF

Vascular Endothelial Growth Factor

TZIF-67

Zeolite Imidazolate Framework-67

ZnO NPs

Zinc Oxide nanoparticles

Authors’ contributions

Conceptualization: Z. Soe and CN. Limjeerajarus. Validation: A. Lertpimonchai and N. Limjeerajarus. Writing original draft preparation: Z. Soe, R. Wahyudi. Writing review and editing: Z. Soe and V. Everts. Supervision: CN. Limjeerajarus and N. Limjeerajarus. Critically revised the manuscript: N. Mattheos, V. Everts, Kevin A. Tompkins and Thanaphum Osathanon. Funding acquisition: CN. Limjeerajarus, N. Limjeerajarus and Thanaphum Osathanon . All authors critically revised and approved the final manuscript for publication.

Funding

Dental Faculty Research Fund DRF66001, Faculty of Dentistry, Chulalongkorn University (to C.N.L.), and the NSRF via the Program Management Unit for Human Resources & Institutional Development, Research and Innovation (B16F640118 to N.L. and T.O.) of Bangkok, Thailand.

Availability of data and materials

All data generated or analyzed during this study are included in this published article, further inquiries are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.