Biomaterials Enhancing Bone Regeneration around Dental Implants: A Comprehensive Review

As there is an increase in the need and demand for dental implants, the search continues for assuring and granting successful replacements that replicate the natural tooth in terms of strength and stability. A stable and successful dental implant means that it is well osseointegrated and free from any inflammatory process. Autologous bone grafts are the rational method used to overcome defects in the alveolar bone where implants are placed; however, they are not favorably used due to many complications. Therefore, an approach is being taken to use biomaterials to modify and coat the implant surface to ensure osteoconductivity, which grants proper osteointegration. This review focused on recent materials used as coatings for implant surfaces to enhance the properties of dental implants. The review resources were highly dependent on the PubMed database and included all the original studies that dealt with biomaterials and their effect on dental implants over the last five years.

Introduction

The healing of bone tissue is a complicated, dynamic, and prolonged biological process that includes phases of inflammation, repair, and remodeling. Every phase is crucial for the effective repair of bone tissue. Nevertheless, the majority of biomaterials have restricted functionality, concentrating either on mechanical support or on specialized biological processes in bone regeneration [1]–[3]. Thus, biomaterials that can dynamically respond to and regulate biological processes, customized for individual requirements, provide significant promise for progress and clinical use in regenerative medicine [4].

Dental implants are presently considered the most effective and dependable method for replacing missing teeth, constructed predominantly from titanium or other biocompatible materials, inserted into the alveolar bone, where they achieve stability by establishing a secured fixation within the bone tissue which is known as osseontegration [5]–[7], but specific short ve long term complications may be considered, such as peri-implant inflammation, supporting bone loss, or failure of osteointegration, which is a complex biological process involves different cell types and tissues and extend from six to twelve months, it relies significantly on bone growth occurring directly on the implant surface after its insertion into the jawbone [8]–[10]. It encompasses direct osteogenesis and indirect osteogenesis, a concept where osteoblasts are deposited on the compromised pre-existing bone surface post implantation, at which bone growth arises from the bone surface. In contrast, direct osteogenesis occurs concurrently when bone growth is initiated from the implant surface by osteoblasts attracted there [11]. As both forms of osteogenesis progress, the stability of the implant is enhanced by a phenomenon known as secondary stability [12]. Thus, the modification of an implant’s surface may substantially enhance its osseoconductivity, thereby promoting bone formation. Clinical outcomes are influenced by numerous factors and procedures, but are predominantly contingent upon the quality and quantity of the alveolar bone [13], since implant stability and survivability has been defied by the shortage of the hosting alveolar bone in respect to height, width, and well-maintained bony walls [14]. Autologous bone grafting has been the conventional method for reconstructing alveolar bony abnormalities owing to its osseoinductive, osteoconductive, and osteogenic characteristics. Nonetheless, the elevated resorption rate of autologous bone transplants, potentially reaching 60%, may compromise clinical outcomes. Furthermore, it may be linked to donor site complications [15], [16]. Recently, Guided bone regeneration (GBR) has experienced significant growth [17]. Polycaprolactone (PCL)-based scaffolds are an example of GBR that exhibits biocompatibility, bioresorbability, and manipulability. Nevertheless, they display deficiencies in rigidity, stability, and osteoconductive properties, which can be boosted by β-tricalcium phosphate (TCP). On the other hand, Mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP) have been confirmed to facilitate osteoblast differentiation and vascularization, thus enhancing bone formation [18].

Materials and Methods

The data collected for this review were selected from the PubMed database for the time range from 2020 to 2025, using keywords indexed in MESH (dental implant, Osseointegration, biomaterials). Inclusion criteria included English-written articles, in vivo and in vitro original studies, while the exclusion criteria comprised any study written in a non-English language and review articles. A total of 544 articles appeared in the search. After applying inclusion and exclusion criteria to filter the search results, a total of 12 manuscripts were selected.

Results and Discussion

Plant Extracts Promoting Osseointegration

Dipterocarpus Tuberculatus

Dipterocarpus Tuberculatus is a plant whose components are widely utilized in traditional medicine; specifically, its leaf gum serves as an anti-venom, while its roots exhibit anti-inflammatory and anti-dysenteric properties. The therapeutic effects and underlying mechanisms of D. tuberculatus are related to their roles in anti-inflammatory response, anti-photoaging, and the promotion of osseointegration [19]. Jung et al. evaluated the hydrophilic properties and the quality of bone growth in Dipterocarpus tuberculatus (MED-coated titanium implants), which utilize a natural plant extract. A MED-coated titanium plate and fixture were evaluated alongside untreated and ozonated titanium. The MED-coated titanium retained its hydrophilicity for 20 days, and it’s known that hydrophilicity creates a conductive environment suitable for bone formation, whereas the ozone-treated titanium rapidly became hydrophobic. Computed tomography and histological studies demonstrated improved bone regeneration associated with the MED coating. Ozonated titanium showed markedly elevated levels for the receptor involved in bone cell adhesion. This occurs by activating focused cell adhesion via the MCL2/FAK/Akt signaling pathway and enhancing the gene expression of bone cell adhesion receptors. MED may serve as an effective coating agent for titanium implantation via MED-mediated cell signaling pathways [20].

Manuka Oil

Manuka essential oil, extracted from the tea tree, sourced from the East Cape region of New Zealand, contains substantial amounts of β-triketones leptospermone chemotype, which is recognized for its exceptional antibacterial properties, including notable oral pathogens, even at low oil levels [21]. In the post implantation period, metallic implants (mesh) for directed bone regeneration may elicit foreign body reactions in adjacent tissues, as well as infections and inflammatory responses induced by microorganisms present in the oral cavity, so Kim et al., investigated the effect of the biocompatible manuka oil on Ti surface in an attempt to minimize the the surgical failure caused by microbial infection and stimulate stable bone regeneration. The anodized TiO2 nanotubular layer significantly improved surface hydrophilicity, bioactivity, and rapid bone regeneration. A concentration of manuka oil between 0.02% and less than 1% can exhibit a synergistic effect on antibacterial activity and demonstrate high biocompatibility. A 0.5% manuka oil coating on the TiO2 nanotube layer is anticipated to inhibit connective tissue stenosis and inflammation due to microbial infection, while simultaneously promoting stable and quick bone regeneration. Manuka oil has shown inhibitory efficacy against all strains, with superior impact against Gram-positive bacteria compared to Gram-negative bacteria [21].

Nanomaterials Promoting Bone Regeneration

Nanotechnology can affect the surface features of implants to enhance bioactivity, facilitate the release of beneficial bioactive molecules, and inhibit undesirable or dangerous substances, such as metal ions [22]. Recent research indicated the application of nanocomposites to augment titanium-based implants with prolonged drug release capabilities, potentially leading to improved clinical outcomes, including increased osseointegration [23], or antibacterial properties. Furthermore, they have been utilized in implant-based therapy to administer controlled treatments for periodontal, orthodontic, endodontic, and restorative procedures [24].

Carbon Nanohorn

Anodization was employed as a surface treatment to enhance osteogenesis around titanium, which is used as the implant material due to its mechanical and biological characteristics. A study found that carbon nanohorn (CNH), a nanometer-sized carbon substance, promotes bone growth. The former study anticipated the use of electrophoresis to achieve anodized titanium surface with carbon nanohorn coating (CNH/AnTi). In vitro results showed, CNH/AnTi exhibited a greater attraction and consequently a greater proliferation of osteoblastic cells compared to AnTi, while in vivo results, 7- and 28-day post implantation of CNH/AnTi or AnTi into the rat femur, showed improved bone growth on the surface of CNH/AnTi compared to AnTi. The region of freshly produced bone tissue immediately adhering to CNH/AnTi was substantially greater than that associated with AnTi, indicating that “contact osteogenesis” was expedited on CNH/AnTi during the initial post implantation phase, which leads to the conclusion that CNH/AnTi would be of great benefit, particularly during the initial phases of bone repair post-surgery [25].

Nano Boron Nitride

Boron effect on osteoblasts’ proliferation and differentiation has been highly noted in previous studies. Özmeriç et al. experimented with Boron nitride as a coating for fifty-four dental titanium implants with two distinct thicknesses, which were bilaterally implanted into the tibias of twelve New Zealand rabbits. After four weeks, Bone-implant contact (BIC) and the ratios of new bone area to total area (BATA) were measured, and the removal torque (RT) test was performed. No inflammatory response was observed around any implant. The augmented new bone formation around nano-BN-coated titanium implants indicates the advantageous osseoinductive characteristics of the BN coating. BN-coated implants exhibited similar biomechanical and histomorphometric outcomes to conventional titanium implants throughout a 4-week evaluation period [26].

Nanostructured Hydroxyapatite

A novel nanostructured hydroxyapatite surface modification was implanted in the iliac crest of ten sheep to assess the implant surface topography and the biomechanical, histomorphometric, and histological bone responses. Thirty implants were administered utilizing three distinct surface modifications (ten implants for each group): implants featuring a nano-sized crystalline hydroxyapatite coating, implants with a hydrophilic sandblasted and acid-etched titanium surface, and the TiUnite group, which included implants characterized by a highly crystalline and phosphate-enriched anodized titanium-oxide surface. The three implant designs with enhanced surfaces demonstrated equivalent osseointegration throughout the initial phases of low-density bone healing in the ovine model (Table I) [27].

Table I. Summary of the Materials and Their Effect on Bone

Material	Effect
Dipterocarpus tuberculatus	Osteocinductivity.
Manuka oil	Antibacterial effect.
Carbon nanohorn	Osteoblast proliferation.
Nano Boron nitride
Nanostructured hydroxyapatite	1. Increased cell adhesion, so increased osteoconductivity.
	2. Increase cell proliferation, viability, and spreading.
	3. Increased type I and osteopontin expression.
45S5 and S53P4 bioactive glasses (BAGs)	Antibacterial properties.
Bioactive Glass 45S5 and zinc oxide (ZnO) powder	Antibacterial effect.
Tantalum	- Exhibited the largest surface potential, superior hydrophilicity, and maximum protein adsorption.
	- Markedly enhanced the adhesion, proliferation, and osteogenic differentiation of BMSCs.
Whey protein	Inhibitor of infection.
Simvastatin	- Increasing osteoblasts formation.
	- Inhibiting osteoclast formation.
Allylamine	- Enhanced MG-63 cell growth.
	- Elevated alkaline phosphatase activity.
	- Overexpression of OCN, OPG, and COL-I.

Bioactive Materials Promoting Bone Regeneration

Bioactive Glasses (BAGs)

Peri-implantitis (PI), which is commonly known as the predominant cause of implant failure, 1% to 47% incidence rate, can be defined as a plaque-induced inflammatory condition resulting from the formation of a complex biofilm of bacteria on the surface of implant [28]. Bioactive glasses 45S5 and S53P4 (BAGs), a category of biomaterials effectively utilized in air particle abrasion techniques, have extensive antibacterial and antibiofilm properties against various Gram-positive and Gram-negative oral bacteria [29], which is mostly attributed to elevated pH levels and local osmolarity induced by the dissolution of Na, Si, and Ca2+ ions. The original 45S5 BAG has been altered to incorporate zinc oxide (ZnO) powder [30], from this compound, Zn2+ ions will be liberated, infiltrating the cell membrane of the bacteria, leading to the production of deleterious reactive oxygen species (ROS) and thus inducing mortality of the bacteria. A study was performed on the maxillary first molar region of 30 rats, which were randomized into five distinct groups, one group received implants with a biofilm of Fusobacterium nucleatum and Porphyromonas gingivalis (IB), implants with biofilm subjected to inert glass air-abrasion (inert) were placed in the second group, sterile implants (S) were placed in the third group; while implants with biofilm subjected to 45S5 Bioactive glass air-abrasion (45S5) were implanted in the fourth group; and lastly implants with biofilm subjected to 45S5 Bioactive glass supplemented with ZnO positioned in the fifth group. Following an 8-week healing period, air-abrasion of contaminated moderately rough implant surfaces with either 45S5 or ZnO-containing bioactive glasses showed better osseointegration and bone defect regeneration (Table I) [31].

Tantalum

Tantalum (Ta) is a rare metal that is considered one of the best biomaterials in implant dentistry due to its superior corrosion resistance and exceptional biocompatibility, with reduced bacterial adhesion, exhibiting adaptability as an implant material. Vacuum plasma spraying under chosen ideal parameters was utilized to create micro-nano porous structured implant coating, which in turn was compared with titanium-coated (Ti/Ti) and sandblasted implants (Ti) in terms of numerous characteristics. A study investigated tantalum implant coating and the osseointegration process on the mandibular canine using micro-CT, histological sections, and energy dispersive X-ray spectroscopy. The results showed that the tantalum coating exhibited the largest surface potential, superior hydrophilicity, and maximum protein adsorption compared to other coatings. Moreover, enhanced cellular adhesion, proliferation, and osteogenic differentiation of bone morphogenic stem cells. In vivo, results demonstrated favorable osseointegration, characterized by enhanced bone mineral density and the production of new bone surrounding the implants, without the release of tantalum particles. Collectively, tantalum-coated titanium dental implants could represent a novel category of dental implants [32].

Natural Proteins Promoting Bone Regeneration

Natural biopolymer pectin, peptide amphiphiles, and enzyme-mimicking fullerene moieties are utilized to create an extracellular matrix-like environment around the implant surfaces, which markedly improves cellular adhesion, facilitates mineral deposition, osteoconductivity, and increases the expression of osteoblast-specific genes. In addition to the antibacterial qualities of the biopolymer-artificial enzyme composite against Escherichia coli and Bacillus subtilis, which can mitigate the infection risk [33].

Whey protein, a natural protein constituent and one of the main proteins in cow’s milk, is believed to affect the activity of viruses, germs, and bacteria, making it an inhibitor of infection. A study was conducted using a natural protein mixed with Moringa oleifera, which was used as a coating for approximately twelve implants placed on the right and left femurs of six rabbits. In comparison, the other twelve implants were left untreated. The histological and immunohistological evaluation of the slides after two weeks regarding the treated implants exhibited a higher number of bone forming cells, and at 6 weeks, more mature bone was distinguished at the implant bone interface coated with the mixture [34].

Drugs Promoting Bone Regeneration

Simvastatin is a drug used for cholesterol lowering, which has bone promoting characteristics [35]. A randomized controlled trial examined the impact of alveolar ridge splitting and simvastatin-loaded xenograft on guided bone regeneration and simultaneous implantation. Twenty-two patients were randomly allocated into two groups of eleven patients each. Participants in Group I underwent alveolar ridge splitting (ARS) with guided bone regeneration (GBR), and a bone graft composed of simvastatin (SMV) gel and a barrier membrane, concurrently with implantation. Group II underwent the identical treatment procedure, excluding SMV gel. Clinical and radiological changes were evaluated at baseline, 6 months, and 9 months post-surgery. Alveolar ridge splitting combined with GBR-augmented SMV enhances clinical and radiographic outcomes associated with dental implants compared to GBR alone. Enhancing guided bone regeneration (GBR) with socket preservation using a membrane (SMV) in alveolar ridge splitting may improve implant osseointegration and promote alterations in peri-implant tissues [36].

Organic Material Promoting Bone Regeneration

Allylamine as a coating for zirconia dental implant surfaces was tested to investigate the amount of osseointegration. A study investigated the improvement of zirconia dental implant characteristics by glow discharge plasma at various energy levels (25, 50, 75, 100, and 200 W). In vitro evaluations included scanning electron microscopy, wettability analysis, and energy-dispersive X-ray spectroscopy, among others, while in vivo studies involved the implantation of zirconia dental implants into rabbit femurs, followed by assessments of stability, micro-CT imaging, and histomorphometric analysis. The findings indicated that grafting GDP allylamine at 25 and 50 W boosted the surface characteristics of zirconia significantly by enhancing MG-63 cell growth and elevated alkaline phosphatase activity; additionally, overexpression of OCN, OPG, and COL-I has been observed in the gene expression study; however, only 25 W allylamine grafting, under optimal energy conditions, facilitated in vivo osseointegration and new bone development while averting bone level loss around the dental implant. This indicates a promising approach for augmenting the bioactivity of Zr dental implant surfaces [37].

Implant and Diabetes

Diabetes is considered a serious issue in the process of osseointegration around dental implants; therefore, multiple studies have documented the advantageous effect of exendin-4 on the process of osteointegration in diabetic clinical cases undergoing implantation. Shi et al. developed exendin-4-loaded microspheres utilizing poly (lactic-co-glycolic acid) (PLGA) and chitosan to provide a suitable sustained-release system targeting the former purpose, and experimented it on a type 2 diabetes mellitus (T2DM) rat paradigm. Histological and radiological assessment were performed after four weeks. The results revealed that Exendin-4-loaded microspheres may augment the proliferation and osteogenic differentiation of diabetic bone marrow stem cells. In vivo tests showed that exendin-4-loaded microspheres markedly enhanced osseointegration and bone growth surrounding implants in T2DM rats, without influencing blood glucose levels. Consequently, the localized administration of exendin-4-encapsulated chitosan-PLGA microspheres may represent a promising therapeutic approach to enhance the effectiveness of dental implants in persons with type 2 diabetes mellitus. Following seven days of osteogenic induction, the alkaline phosphatase (ALP) secretion in diabetic bone marrow-derived stem cells (BMSCs) was inferior to that of normal BMSCs, but the ALP secretion in the exendin-4 group exceeded that of the type 2 diabetes mellitus (T2DM) group. After 21 days, the calcium nodule formation in diabetic BMSCs was markedly inferior to that in normal BMSCs, whereas the pharmacological intervention considerably enhanced the deposition of mineralized nodules [38].

Conclusion

Dental implants are considered nowadays the trend in dental substitutes. Still, the milestone for their success is highly dependent on the osseointegration process, which requires many surface modifications and material coatings to be implemented.

As hydrophilicity creates a good osteoconductive environment, Dipterocarpus tuberculatus helps maintain a hydrophilic environment for a longer period, which is also one of the effects of Tantalum that additionally stimulates adhesion, proliferation, and osteogenic differentiation of bone morphogenic stem cells. Considering that most failed implant cases refer to infection and inflammation, manuka oil, Boron nitride, and 45S5, S53P4 bioactive glasses (BAGs) used as a coating on the Ti surface act as antimicrobial and anti-inflammatory agents, thereby decreasing the tendency for implant failure.

Nanomaterials, on the other hand, enhance the release of certain drugs, which leads to a prolonged effect. Implants coated with carbon nanohorns result in improved bone implant interaction, leading to better stability. It also increases the proliferation of osteoblast cells, especially in the early period post implantation.

Zirconia dental implant properties may be enhanced by allylamine, specifically at the lowest energy level, which may improve osseointegration. In contrast, at a higher energy level, it may increase the expression of alkaline phosphatase.

In diabetic cases, exendin-4-loaded microspheres may boost bone marrow stem cells proliferation and differentiation, thereby improving osteointegration around dental implants.

Conflict of Interest

The authors declare that there is no conflict of interest.