Wojciech Popowski
Damian Koseski
Dominika Domanowska1
Magdalena Zalewska
Magdalena Popowska- 1Department of Oral Surgery, Medical University of Warsaw, Warsaw, Poland
- 2Department of Bacterial Physiology, Institute of Microbiology, Faculty of Biology, University of Warsaw, Warsaw, Poland
The advancement of tissue engineering and the development of novel biomaterials have opened new possibilities for the effective treatment of patients with edentulism and other dental deficiencies, as well as for the prosthetic reconstruction and functional rehabilitation of the stomatognathic system. Bone substitute materials are now widely used in orthopedics, reconstructive surgery, and dentistry to support the regeneration of bone tissue lost due to trauma, inflammation, or tooth extraction. However, surgical procedures within the oral cavity inherently carry a risk of postoperative infection, which can impair healing and compromise treatment outcomes. Unlike natural bone regeneration, bone healing following grafting functions as a repair process that may involve partial resorption of the graft material. Such bone deficiencies can hinder prosthetic reconstruction, making the use of bone substitute materials essential for guided bone regeneration. Bone substitutes can be classified as autogenous, allogenic, xenogenic, or alloplastic, each exhibiting distinct osteoinductive and osteoconductive properties. This review discusses the biological and clinical characteristics of these material groups, with particular attention to their susceptibility to colonization by bacterial strains commonly found in the human oral cavity. It also highlights the risks associated with bacterial biofilm formation and examines its implications for the oral microbiome under dysbiotic conditions.
1 Introduction
Bone substitute materials, as well as guided bone regeneration (GBR) techniques, are particularly useful in many surgical specialties where bone tissue regeneration is required during treatment. They are widely applied in orthopedics, reconstructive surgery (e.g., maxillofacial surgery), and in dentistry, especially in oral surgery and periodontology. The range of applications of bone substitute materials in oral and periodontal surgery is constantly expanding. In these cases, bone regeneration is achieved using materials with osteoconductive and osteoinductive properties (Kozakiewicz and Wach, 2020).
Bone substitute materials were initially based on natural or synthetic hydroxyapatite, but today tricalcium phosphate and its composites with hydroxyapatite are commonly used. These materials are typically highly porous to enhance osteoconductivity, support vascularization, and facilitate cellular infiltration. Their primary application is the reconstruction of the alveolar ridge, aiming to restore bone at defect sites. Ideally, grafts should promote the regeneration of vital bone rather than act as inert fillers, gradually resorbing and being replaced by newly formed bone tissue (Uchida et al., 1984; Shimazaki and Mooney, 1985; Verheij et al., 2009). In addition to osteoconductivity, the regenerative potential of these materials depends on their osteoinductive properties, which recruit and differentiate progenitor cells into osteoblasts, accelerating bone formation. Surface characteristics—including micro- and nano-scale topography, chemical composition, and wettability—further influence cell adhesion, proliferation, and integration with host tissue. Thus, optimal bone substitutes combine porosity, osteoconductive and osteoinductive properties, and favorable surface features to achieve predictable and functional bone regeneration (Kozakiewicz and Wach, 2020). Beyond osteogenic potential, material porosity plays a pivotal role in clinical outcomes. High porosity facilitates vascularization, cell migration, and microbial colonization, but may also increase susceptibility to infection in the oral environment. For example, rough and porous xenogeneic surfaces can harbor periopathogens such as Porphyromonas gingivalis and Fusobacterium nucleatum, while synthetic materials with smoother surfaces may be less prone to bacterial colonization. This microbiological dimension is increasingly relevant, as colonization of graft materials can jeopardize regenerative outcomes (Abushahba et al., 2021; Choi et al., 2023). Postoperative infections associated with bacterial colonization of bone substitute materials constitute a major clinical concern in oral surgery. When pathogens such as Staphylococcus aureus, P. gingivalis, or F. nucleatum adhere to graft surfaces, they initiate biofilm formation that severely compromises bone regeneration and graft integration. The resulting infection can lead to graft resorption, delayed healing, and even implant failure. Given the constant exposure of oral surgical sites to saliva and microbial biofilms, the development of bone substitute materials with intrinsic antibacterial or bioactive properties has become an essential goal in regenerative dentistry. Antibacterial biomaterials not only inhibit microbial adhesion and growth but also modulate the local immune response and promote osteogenesis. Therefore, comparing the susceptibility of various bone substitute materials to microbial colonization is a key step toward identifying strategies for infection-resistant bone regeneration (Nisyrios et al., 2020; Tu et al., 2023; Yu et al., 2024). Finally, resorption rates vary considerably between materials and strongly influence long-term stability. Autografts and β-tricalcium phosphate (β-TCP) are resorbed relatively quickly, often within months, whereas xenogeneic bovine bone mineral and hydroxyapatite may persist for years. Clinicians must balance this property with treatment goals—rapid resorption may be ideal for defect filling and natural remodeling, while slow resorption helps maintain ridge dimensions for implant placement (Artzi et al., 2004; Hirata et al., 2006; Riachi et al., 2012).
It is critical to recognize that physiological bone healing does not replicate embryonic bone development. Rather, it represents a reparative process with inherent limitations (Mardas et al., 2023). Natural bone remodeling—including resorption—follows tooth extraction and is compounded by mechanical loading from prosthetic reconstructions. These processes result in volumetric loss and morphological alterations of the alveolar ridge in both the maxilla and mandible (Khalifa et al., 2016; Hu et al., 2021). The ensuing bone atrophy disrupts skeletal equilibrium and alters occlusal force distribution, thereby perpetuating resorption. Alveolar ridge deficiency following tooth loss presents a significant therapeutic challenge, often precluding functional and esthetic prosthetic rehabilitation (Hansson and Halldin, 2012; Mardas et al., 2023).
Advances in tissue engineering, and consequently the increasing variety of commercially available biomaterials, have opened new avenues for the effective treatment of patients with tooth deficiencies, enabling subsequent prosthetic rehabilitation and restoration of the stomatognathic system. This review aims to compare groups of bone substitute materials with respect to their susceptibility to colonization by various bacterial strains residing in the human oral cavity, as well as the associated risk of biofilm formation and its implications for the oral microbiome under dysbiotic conditions.
2 Bone substitute material in dentistry and periodontology
The application of bone substitute materials today allows for predictable reconstruction of resulting bone deficits. Clinical evidence supporting their use in restoration of alveolar defects, enhancing stability and enabling implant placement was described by (Kim and Kim 2024). The scope of surgical procedures utilizing osteoconductive and osteoinductive bone substitutes is extensive, ranging from post-extraction alveolar ridge augmentation to complex periodontal surgeries, horizontal and vertical alveolar ridge reconstructions, and sinus floor elevation interventions (Elboraey et al., 2025). Rebuilding lost bone tissue is especially critical when implant-prosthetic therapy is planned, as sufficient bone volume is a prerequisite for dental implant placement and subsequent permanent prosthetic restoration (Zhao et al., 2021). The regenerative process of bone comprises multiple contributing factors, of which bone substitute materials are a critical component. Direct influencers of bone healing include initiating and supporting cells—including differentiated, committed, and undifferentiated cells—growth and differentiation factors, and scaffolding materials that serve as carriers for nascent bone (Ansari, 2019).
Bone substitute materials placed into a bone defect—following the creation of the surgical field—initiate the healing process, which comprises four phases: hemostasis, inflammation, proliferation, and maturation. During the hemostatic phase, platelets and clotting factors trigger coagulation and halting bleeding. The inflammatory phase begins approximately 5–6 h post-injury, during which damaged tissues are cleared; inflammatory cells secrete cytokines and growth factors that support the proliferation of fibroblasts and endothelial cells (Cho et al., 2021; Toma et al., 2021; Rodriguez et al., 2024). In the proliferative phase, occurring 2–3 days after injury, contraction of granulation tissue may commence—known as wound contraction—driven by myofibroblasts derived from fibroblasts. Concurrently, increased collagen production supports scarring and leads to contractures during the maturation phase (Fernández-Guarino et al., 2023; Rodriguez et al., 2024).
Bone substitute materials have become indispensable in oral and maxillofacial surgery, periodontology, and implantology, where predictable regeneration of bone tissue is required. These materials differ substantially in their origin, composition, structural properties, and biological behavior, which determines their clinical indications (Table 1).
Table 1. Bone substitute materials summary.
Autogenous bone grafts (block graft, bone milli, bone scraper, suction device, piezo surgery) remain the gold standard due to their inherent osteogenic, osteoinductive, and osteoconductive properties (Miron, 2024). Harvested from intraoral (mandibular ramus, symphysis) or extraoral donor sites, they contain living osteogenic cells and natural growth factors. However, their clinical use is limited by donor site morbidity, limited availability, and unpredictable resorption rates. Autogenous bone grafts require the creation of an additional surgical site at the donor location, which consequently increases morbidity, the risk of infection, hemorrhage, and potential damage to peripheral nerves (Dantas et al., 2024). Despite these limitations, autografts provide the highest regenerative potential and are frequently used in ridge augmentation and reconstructive maxillofacial procedures (Nkenke and Neukam, 2014; Moraschini et al., 2015). Bone is formed through the processes of osteogenesis, osteoinduction, and osteoconduction. Osteogenesis refers to the direct formation of bone by osteoblasts. Osteoinduction is the ability to stimulate the transformation of mesenchymal cells into osteoblasts, thereby promoting bone growth. Osteoconduction is the process by which new bone is able to adhere and grow along the surface of pre-existing bone (Hoexter, 2002).
Allogeneic grafts (Free Frozen Bone, Freeze-dried Bone Allograft, Demineralized freeze-dried Bone allograft, Deproteinized bone graft), derived from human donors and processed as freeze-dried or demineralized bone matrix, retain osteoconductive and partially osteoinductive capacity but lack viable osteogenic cells. However, allogeneic grafts carry the risk of disease transmission, toxicity related to sterilization processes, variable host immune responses, and limited availability (Lu et al., 2016). They are rich in type I collagen, which constitutes the organic component of bone, providing a matrix that supports cell attachment and proliferation (Rico-Llanos et al., 2021). However, they do not produce inorganic calcium nor provide the mineral scaffold required for full bone regeneration. Unlike autogenous bone, allogeneic grafts do not exhibit osteogenesis; their regenerative potential is mediated solely through osteoinduction and osteoconduction. The porosity and structural integrity of allografts depend on processing techniques, which also influence resorption kinetics. These materials are commonly applied in socket preservation, ridge augmentation, and sinus floor elevation, offering a safe and readily available alternative when autografts are limited or contraindicated (Hoexter, 2002).
Xenogeneic grafts (material derived from corals, animal bone, calcifying algae, or wood), most commonly bovine-derived deproteinized bone mineral, act as osteoconductive scaffolds with a highly porous architecture that closely mimics human bone. Their resorption rate is generally slow, which helps maintain space and volume but may interfere with complete replacement by vital bone. These properties make xenografts particularly useful in sinus floor elevation, ridge preservation, and periodontal regeneration. Studies confirm their long-term dimensional stability, though limited osteoinductive capacity remains a drawback (Hoexter, 2002; Miron, 2024).
Alloplastic materials (calcium phosphates, glass ceramics, polymers, metals), including synthetic hydroxyapatite, β-tricalcium phosphate (β-TCP), biphasic calcium phosphates, and bioactive glasses, represent a broad category of bone substitutes. It is an osteoconductive material composed of very small, unbound calcium crystals, which collectively provide an extremely large surface area (Hoexter, 2002). Hydroxyapatite is highly osteoconductive and structurally stable, but resorbs slowly. In contrast, β-TCP resorbs more rapidly, being replaced by newly formed bone, although excessive resorption may compromise volume maintenance. Biphasic mixtures aim to combine the stability of hydroxyapatite with the remodeling capacity of β-TCP. Their micro- and macroporosity enhance vascular infiltration and cell colonization, a critical factor for osteoconductivity. Bioactive glass, by releasing silica and calcium ions, stimulates osteoblastic activity and angiogenesis, adding an osteostimulative dimension to its osteoconductive nature. These materials are extensively used in ridge augmentation, socket preservation, and periodontal defects (Zhao et al., 2021). Examples of commercially available bone substitute materials in oral surgery are presented in Table 2.
Table 2. Examples of commercially available bone substitute materials in oral surgery.
From a regulatory perspective, the use of bone substitute materials in dental surgery and implantology is subject to strict classification within the European Union. In accordance with Regulation (EU) 2017/745 on medical devices (MDR), these materials are considered Class III implantable medical devices, representing the highest risk category. Consequently, their market approval requires a full conformity assessment conducted under the supervision of a Notified Body. The required documentation encompasses detailed technical files, biocompatibility assessments, physicochemical and material testing, functional performance evaluations, and a clinical evaluation report (CER). Only upon successful evaluation by the Notified Body is a CE certificate issued, after which the device is formally registered in the European medical device database (EUDAMED). This regulatory framework emphasizes the critical importance of both safety and efficacy in the clinical application of bone substitute materials.
3 Microbial interactions with bone graft materials
3.1 Microbiome composition
The oral cavity is a complex ecosystem composed of multiple distinct niches, including the tongue, palate, buccal mucosa, and teeth, each providing a unique environment that shapes resident microbial populations (Morrison et al., 2023). Among the body's microbial communities, the oral microbiome exhibits the second-highest diversity after the gut, encompassing bacteria, archaea, viruses, fungi, and protozoa (Santamaría et al., 2011; Benn et al., 2018). Bacteria dominate these communities and have been most extensively characterized, colonizing both saliva and oral surfaces such as mucosa, teeth, and tongue (Morrison et al., 2023). At the phylum level, a healthy oral bacterial community is largely composed of Actinobacteria, Fusobacteria, Proteobacteria, Firmicutes, and Bacteroidetes, which together account for nearly all oral bacteria (approximately 96%), with Fusobacteria and Bacteroidetes being the most abundant (Verma et al., 2018; Nearing et al., 2020; Baker et al., 2024). On the genus level, oral microbial communities exhibit remarkable stability, with 11 genera—including Streptococcus, Prevotella, Veillonella, Lactobacillus, Actinomyces, and Neisseria—present in over 99% of individuals and representing roughly 78% of total abundance (Morrison et al., 2023). Fungi represent another significant component of the oral ecosystem. More than 100 species have been detected in healthy mouths, with Candida spp. being the most prevalent and contributing to the early stages of biofilm formation (Ghannoum et al., 2010; Janus et al., 2017).
However, considerable interindividual variation exists at the species and strain levels, highlighting the personalized nature of the oral microbiome (Nearing et al., 2020). Also, several host- and environment-related variables appear to influence additionally the oral microbiome. Hormonal status is one important factor: cyclical hormonal changes during the menstrual cycle have been associated with shifts in the abundance of the following genera: Campylobacter, Haemophilus, Oribacterium, and Prevotella (Li X. et al., 2022). Similarly, pregnancy induces distinct microbial alterations, including increased levels of Neisseria spp., Porphyromonas spp., and Treponema spp., whereas non-pregnant women typically exhibit higher abundances of Streptococcus spp. and Veillonella spp. (Saadaoui et al., 2021). The dysbiosis in oral microbiota is linked to the development of a range of systemic conditions—malignancies such as head and neck, pancreatic, and colorectal cancers, and in chronic inflammatory and immune-mediated disorders including rheumatoid arthritis, systemic lupus erythematosus, hypertension, and Alzheimer's disease (Li Y. et al., 2022; Łasica et al., 2024). Diet represents another key modifier of the oral ecosystem: diets rich in fiber and unsaturated fatty acids (medium-chain, monounsaturated from fish, and polyunsaturated) are associated with greater microbial diversity, whereas frequent consumption of refined carbohydrates and sugars fosters the expansion of certain bacterial groups. The intake of carbonated beverages has been positively correlated with the prevalence of Bacteroidetes, Gammaproteobacteria, Fusobacterium, and Veillonella (Hansen et al., 2018; Chumponsuk et al., 2021). Environmental factors additionally alter the shape of the oral microbiome—smoking consistently favors the enrichment of anaerobic taxa (Mason et al., 2015), oral hygiene habits substantially influence microbial diversity and community structure (Wade, 2021), or geographic location and climate drives species- and strain-level differences (Mason et al., 2015; Li X. et al., 2022).
In diseases of the oral cavity, including periodontitis and dental caries, a marked shift in the microbial community structure—a state of dysbiosis—has been observed. For instance, the most well-recognized periodontal pathogens comprising the so-called “red complex,” which emerges during the later stages of dental biofilm development, are P. gingivalis, Treponema denticola, and Tannerella forsythia. Researchers have noted that this “red complex” is consistently identified as part of the climax community within biofilms at sites exhibiting progressive periodontitis. Similarly, in dental caries, other noteworthy bacterial taxa detected in substantial abundance within dental plaque of adults with active lesions include Streptococcus spp., Actinomyces spp., Propionibacterium spp., and Veillonella spp. (Holt and Ebersole, 2005; He et al., 2015; Łasica et al., 2024).
Alterations in dentition, including tooth extraction or other surgical interventions within the oral cavity, also exert a considerable impact on the composition and stability of the oral microbiome. Such procedures may disrupt the ecological balance of microbial communities, creating conditions that favor the overgrowth of pathogenic bacteria. In a study investigating the impact of mandibular third molar extraction on the periodontal microbiota and clinical parameters of adjacent teeth, it was found that the microbial community was predominantly composed (90% of sequences) of Firmicutes, Proteobacteria, Fusobacteriota, Bacteroidota, and Actinobacteriota. Pathogenic bacteria that showed a significant increase compared to the preoperative period included Prevotella spp., Campylobacter spp., Porphyromonas spp., Pseudomonas spp., and Campylobacter gracilis (Zhang et al., 2024).
In the context of bone grafting and oral surgical procedures, several bacterial taxa are particularly associated with postoperative complications. Opportunistic pathogens such as S. aureus, P. aeruginosa, E. faecalis, P. gingivalis, and F. nucleatum have been isolated from infected graft sites and peri-implant lesions. These organisms possess virulence factors enabling biofilm formation, resistance to host immunity, and production of tissue-degrading enzymes (Table 3).
Table 3. Clinically relevant bacteria associated with bone graft and implant-related infections.
3.2 Bacteria-related implications in oral surgery
Bone substitute materials application clinical success depends not only on osteoconductive and osteoinductive properties but also on their interaction with the complex oral microbiome. The physicochemical characteristics of grafts, including surface roughness and porosity, influence the extent and specificity of microbial adhesion. Colonization of these materials by oral bacteria represents the first step toward biofilm formation, a process that may compromise regenerative outcomes. Understanding the host–material–microbiome triad is essential. Immunological responses to biomaterials, microbial colonization, and biofilm formation represent a dynamic and interconnected continuum that ultimately influences clinical outcomes in implant-based treatments. Optimally designed biomaterials should modulate immune response, resist microbial adhesion, and prevent biofilm maturation to ensure successful bone regeneration and long-term prosthetic function.
Bone substitute materials enabling predictable alveolar bone reconstruction and implant-supported rehabilitation. However, synthetic and allogeneic materials may induce host immune responses as foreign bodies, potentially affecting regeneration outcomes, beginning with protein adsorption, macrophage recruitment, and potential fusion into foreign-body giant cells—events that can compromise integration and healing (Anderson et al., 2008; Moraschini et al., 2020; Albrektsson et al., 2023; ten Brink et al., 2024). Persistent inflammation resulting from this immune response may lead to fibrous encapsulation, thereby reducing the functional stability of the graft or implant (Anderson et al., 2008). The issue of trauma is also not negligible with respect to infections originating at the site of injury. This is associated with the production of pro- and anti-inflammatory mediators, largely by immune effector cells (e.g., neutrophils), which participate in the restoration of homeostasis through the early physiological inflammatory response. Such a response is beneficial in the process of wound healing. However, the occurrence of secondary wound infections following trauma is of particular concern, as these may ultimately progress to sepsis or multiple organ failure (Binkowska et al., 2015). In the context of the oral cavity, the pH of healthy gingival tissues is approximately 6.9, increasing to around 7.2–7.4 under pathological conditions. This shift in pH can modulate gene expression in subgingival bacteria, thereby favoring the proliferation of pathogenic anaerobes such as Porphyromonas gingivalis, which thrives optimally at a pH of approximately 7.5 (Santacroce et al., 2023). The transmucosal design of dental implants introduces a chronic route for microbial invasion, exposing peri-implant tissues to infection and increasing susceptibility to peri-implantitis, which affects up to 25% of implants over time (Reis et al., 2025).
The oral mucosa is colonized by microorganisms, which predisposes surgical sites to infection. This colonization is particularly critical during the healing of newly created operative wounds. Oral wounds cannot be completely immobilized due to the functional demands of the surrounding tissues, and contact with avascular structures limits metabolic exchange during the healing process. Two types of wound healing can be distinguished: primary healing (per primam intentionem), in which tissue regenerates to restore the original structural and functional properties, and secondary healing (per secundam intentionem), where tissue is replaced by fibrous scar tissue, and true regeneration does not occur. Contemporary oral surgery prioritizes primary healing to achieve optimal clinical outcomes (Dragovic et al., 2020). Surgical procedures in the oral cavity carry a significant risk of postoperative infections, which can delay the healing process. Suture materials, commonly used in procedures such as bone regeneration, are recognized as foreign bodies and increase infection risk by serving as surfaces for microbial adhesion. Approximately two-thirds of postoperative infections arise at the incision site, with the presence of sutures further elevating this risk. Microbial colonization of suture materials is a critical factor that negatively influences tissue response to these foreign bodies (Dragovic et al., 2020).
When placed in the oral cavity, bone substitute materials are exposed to the oral microbiome, a highly diverse environment where material characteristics such as surface roughness and porosity largely determine bacterial adhesion. Once microbes adhere, they enter the classic biofilm cycle—adhesion, proliferation, matrix production, and maturation. Bacterial biofilm formation on biomaterials has been widely described by (Li et al. 2023). These biofilms are well-known for their resistance to host defenses and antimicrobial treatments, often leading to graft failure.
3.3 Bacterial biofilm formation
Bone substitute materials used in dental implantology are inherently exposed to the oral environment, where their surface properties (composition, roughness, porosity) critically influence microbial interactions. Early bacterial adhesion onto such materials is the first step in biofilm formation, followed by proliferation, matrix production, and eventual maturation—each phase intensifying microbial resilience. A key recent study demonstrated that five representative pathogens (Escherichia coli, S. aureus, Streptococcus mutans, Enterococcus faecalis, and Pseudomonas aeruginosa) adhere similarly to xenogeneic, allogeneic, and synthetic block bone grafts, indicating that material origin alone does not prevent colonization under in vitro conditions (Nisyrios et al., 2020). In this same study, scanning electron microscopy revealed bacterial clusters not only on planar surfaces but also deep within topographic niches, which are features of porous bone substitutes that shelter bacteria from shear forces and host defenses (Nisyrios et al., 2020). These porous scaffolds facilitate vascularization and host cell infiltration, but paradoxically also foster complex microenvironments ideal for bacterial retention. As biofilm develops, bacteria produce extracellular polymeric substances (EPS) that trap nutrients and enable communication, resulting in enhanced protection against antimicrobials. The detailed description on bacterial biofilm formation on implantable devices was extensively reviewed by (Khatoon et al. 2018). The summary of biofilm-colonizing bacteria is presented in Table 4.
Table 4. Summary of bone substitution materials and colonizers.
Furthermore, systematic reviews indicate that bone substitute materials—even when sterilized—can harbor organic and inorganic impurities, such as donor cellular remnants or heavy metal residues, which may further modulate bacterial colonization and immune response (Struzik et al., 2024). These contaminants can provide additional surfaces or niches that favor microbial persistence. Clinical studies of peri-implant disease show that disrupted host–microbe balance near implant surfaces leads to increased presence of periopathogens such as P. gingivalis, T. forsythia, and T. denticola in biofilms, especially when the implant is exposed to saliva or micro-leakage at the interface (Dhir, 2013; Zhao et al., 2021). These bacteria are known to produce virulence factors that provoke inflammatory responses and stimulate osteoclastogenesis, accelerating alveolar bone loss. The colonization of bone substitute materials and dental implants by oral microorganisms follows a well-defined ecological succession that mirrors classical biofilm development on natural tooth surfaces. Immediately upon implantation or surgical exposure, the biomaterial surface is coated with a conditioning film of salivary proteins and host molecules, which provides binding sites for bacterial adhesion. This initial pellicle is rapidly colonized by early colonizers, predominantly Gram-positive facultative aerobes such as Streptococcus oralis and Actinomyces naeslundii (Siddiqui et al., 2022). These organisms attach within hours, exploiting surface roughness and porosity of grafts and implants, and they establish the first microbial clusters that serve as a foundation for subsequent biofilm maturation.
As the biofilm matures over the next several days, moderate colonizers integrate into the developing community. Genera such as Veillonella and Fusobacterium are characteristic at this stage, taking advantage of metabolic by-products of the early colonizers and establishing metabolic cooperation (Dieckow et al., 2024). Importantly, F. nucleatum acts as a bridging species, facilitating co-aggregation between early and late colonizers. These interactions gradually lower the redox potential of the biofilm environment, generating anaerobic niches particularly within the porous scaffold of xenogeneic or alloplastic bone substitutes. The final stage of succession involves the establishment of late colonizers, typically obligate anaerobes with pathogenic potential. Species such as P. gingivalis, Prevotella intermedia, and T. denticola appear after 1–2 weeks of biofilm development, when anaerobic microenvironments are sufficiently stabilized (Dutra et al., 2025). These organisms are strongly implicated in peri-implantitis and graft-related infections, as their virulence factors drive persistent inflammation, osteoclast activation, and progressive alveolar bone loss. Their colonization is therefore not only a marker of biofilm maturity but also a critical determinant of adverse clinical outcomes.
The physicochemical properties of the material play an important modulatory role throughout this process. High surface roughness and interconnected porosity, which are desirable for osteoconduction and vascular ingrowth, also provide protected niches that promote early bacterial adhesion and persistence (Choi et al., 2023). Scanning electron microscopy studies have demonstrated that both smooth and porous regions of bone graft materials harbor dense bacterial clusters, with porosity favoring deep biofilm penetration (Nisyrios et al., 2020). This duality presents a challenge: while porosity supports bone regeneration, it also predisposes to microbial colonization and biofilm maturation.
Surface roughness modifies initial bacterial adhesion: rough titanium or graft surfaces show higher colony forming units in early adhesion assays compared to smoother materials. Surface energy, wettability, and microtopography (micropores, crevices) correlate strongly with bacterial load in vitro (Dhir, 2013; Kligman et al., 2021; Zhao et al., 2021). Implant surfaces with micropits, grooves, or porous matrices therefore represent higher risk zones for biofilm initiation if not properly managed. As the biofilm matures, it develops gradients of oxygen tension and nutrient availability; facultative anaerobes near surface transition to anaerobic bacteria deeper inside, mirroring peri-implantitis biofilm structure observed clinically (Dhir, 2013; Zhao et al., 2021). These anaerobes produce enzymes and toxins that degrade extracellular matrix and bone tissue, while also evading immune detection.
The intimate placement of bone grafts in direct contact with host tissue means that biofilm can interfere with graft integration, decreasing bone-to-material contact and promoting micro-motion, which further impedes healing. The presence of bacterial biofilms on grafts often is linked to delayed healing, graft failure, or need for graft removal documented in both animal and human models (Nisyrios et al., 2020; Zhao et al., 2021). Understanding the sequential process—from adhesion to biofilm maturation—on graft materials is thus essential for advancing long-term outcomes in implant-prosthetic dentistry.
4 Biofilm formation preventive approaches
The human oral cavity is densely colonized by microorganisms, creating a significant risk of contamination during dental and maxillofacial surgical procedures. Early postoperative infection control is critical, as disruption of initial colonizers can prevent or delay the establishment of pathogenic late colonizers. Contamination of grafts with oral bacteria, particularly S. aureus, which is frequently implicated in bone infections, may lead to surgical site infection and impaired healing.
Optimal protection against infection is generally achieved through appropriate antibiotic prophylaxis. Preoperative administration of 2 g amoxicillin 1 h prior to implant placement or procedures involving bone substitute materials has been recommended and is considered effective in reducing postoperative infection risk (Milic et al., 2021; Remschmidt et al., 2023). However, oral antibiotics can sometimes be ineffective, and local applications may present an unfavorable balance between dosing efficacy and potential toxicity, with the additional concern of promoting antibiotic resistance (Kolmas et al., 2014; Abe et al., 2022; Senthil and Çakir, 2024; Łasica et al., 2024). Evidence on the benefits of adjunctive antibiotic therapy in bone regeneration is mixed; some studies report no significant advantage over prophylactic “one-shot” administration (Lyons et al., 2008).
Surgical protocols that minimize graft exposure and ensure optimal soft tissue closure further limit microbial colonization. Preoperative oral decontamination using antiseptic mouth rinses—chlorhexidine (0.12–1%), cetrimide (1%), or povidone-iodine (1%)—significantly reduces bacterial load and decreases postoperative infection risk (Kosutic et al., 2009; Johnson et al., 2015). During sinus floor elevation procedures, autogenous bone particles collected during access preparation (e.g., using bone filters) are susceptible to contamination. Strict aspiration protocols, irrigation with saline or antiseptic solutions, and consideration of prophylactic antibiotics reduce bacterial exposure, including pathogens such as Aggregatibacter actinomycetemcomitans and P. gingivalis (Manor et al., 2015; Purcz et al., 2015).
Sinus lift procedures are a well-established technique, performed for over 30 years with a low complication rate. In a retrospective analysis of 202 procedures in 127 patients, the most common intraoperative complication was Schneiderian membrane perforation (25.7%), which did not correlate with postoperative complications. Observed postoperative complications included wound infection, abscess formation, or dehiscence requiring drainage (9 cases) (Moreno Vazquez et al., 2014). Potential complications may also involve acute or chronic maxillary sinusitis, which can be resistant to pharmacological treatment (Chirilǎ et al., 2016; Jiam et al., 2017). Similarly, infection at graft sites in socket preservation procedures may lead to failure to maintain the alveolus, requiring additional ridge augmentation before implant placement (Mazzucchi et al., 2020).
In reconstructive surgery, perioperative infections around biomaterials remain a major challenge (Kolmas et al., 2014; Senthil and Çakir, 2024). Infections in the alveolar processes of the maxilla or mandible can result in graft or material loss, procedural failure, and preclusion of subsequent implant-prosthetic rehabilitation. Antimicrobial strategies include the use of autologous platelet-rich fibrin (A-PRF), which provides growth factors for bone regeneration and immune cells with antimicrobial and anti-inflammatory properties (Caruana et al., 2019; Popowski et al., 2025). Additionally, surface modifications of implants and bone substitute materials—such as smoother finishes, bioactive coatings, controlled porosity, and antimicrobial release—can limit bacterial adhesion and biofilm formation, promoting successful regeneration over infection-driven failure.
Various bone substitute materials have been studied for their antimicrobial properties and regenerative potential. Freeze-dried bone allograft (FDBA) is successfully used in the treatment of juvenile periodontitis defects, often combined with local and systemic tetracycline therapy (Mabry et al., 1985). In sinus lift procedures, the addition of metronidazole to FDBA improved graft homogeneity and bone density, whereas control groups without metronidazole showed heterogeneous bone formation and air bubbles in graft structures on early CT scans, possibly indicating anaerobic contamination (Choukroun et al., 2008). Similarly, incorporation of doxycycline (4%) or clindamycin into demineralized freeze-dried bone allograft (DFDBA) has been shown to reduce bacterial counts (e.g., P. gingivalis) in periodontal pockets, though statistical significance compared to controls is variable (Lyons et al., 2008; Deepak et al., 2020). Autolyzed, antigen-free allogenic bone (AAA) demonstrated improved intrabony defect regeneration compared to controls, with low detection of P. gingivalis and no A. actinomycetemcomitans after 3 years (Flemmig et al., 1998). A summary of available data on the antibacterial properties of bone substitute materials is presented in Table 5.
Table 5. Antibacterial properties of bone substitute materials.
Innovative materials combining demineralized bone matrix (DBM), calcium sulfate, and nanomaterials such as curcumin and silver nanoparticles (CU-NP and AgNP, respectively) have shown excellent antibacterial activity against A. naeslundii and S. oralis while maintaining favorable mechanical properties, highlighting their potential in maxillary bone regeneration (Senthil and Çakir, 2024). BioOss has demonstrated utility in peri-implantitis treatment and regenerative therapy for advanced periodontitis, though further long-term studies are needed (Esposito et al., 2012; Kaldas et al., 2020). Hydroxyapatites doped with silver, copper, strontium, or selenium, as well as bioactive glass with zinc, copper, or strontium, exhibit antimicrobial activity against Gram-positive and Gram-negative oral pathogens, maintain osteoblast biocompatibility, and support bone regeneration (Chen et al., 2007; Gong et al., 2018; Li Y. et al., 2022; Lv et al., 2022; Naruphontjirakul et al., 2023). Studies emphasize that the antimicrobial efficacy depends on ion concentration, with higher levels required for certain pathogens (e.g., 1% Ag for S. aureus), and that combinations of ions can balance cytotoxicity and enhance biological activity (Kolmas et al., 2014; Maqbool et al., 2021; Zheng et al., 2021; Anand et al., 2022; Li Y. et al., 2022; Weiss et al., 2023).
Cements and composites, such as silver-substituted tricalcium phosphate (Ag-TCP), zinc-substituted β-tricalcium phosphate, and multifunctional bioactive glasses, show promising antimicrobial activity against clinically relevant pathogens (E. coli, S. aureus, Enterococcus faecium, P. aeruginosa), with good biocompatibility and regenerative potential (Zamani et al., 2019; Honda et al., 2020; Fadeeva et al., 2021; Naruphontjirakul et al., 2023). These materials may reduce reliance on systemic antibiotics, contributing to safer and more effective bone regeneration and implant therapy. Nevertheless, in vivo studies are needed to evaluate bone quality, clinical outcomes, and the frequency of inflammatory complications.
In conclusion, contamination of grafts with saliva and oral bacteria is a key factor in postoperative infections, with S. aureus being the most common pathogen in bone infections. Alloplastic materials enhanced with metal ions (e.g., silver, copper) show significant antibacterial activity in vitro against oral bacteria and demonstrate superior resistance to infection compared to unmodified materials. Recent years have witnessed significant advances in the design of next-generation antibacterial bone substitute materials. These include nano-engineered composites, ion-doped ceramics, and bioactive polymer–ceramic hybrids that combine osteoconductive scaffolds with sustained antimicrobial release. Materials such as silver- and strontium-doped hydroxyapatite, copper- and zinc-enriched bioglasses, and chitosan-based calcium phosphate scaffolds have demonstrated dual activity—promoting osteogenesis while suppressing microbial biofilm formation (Fadeeva et al., 2021; Li et al., 2023; Naruphontjirakul et al., 2023). Table 6 summarizes representative studies highlighting emerging biomaterials with documented antibacterial and osteogenic properties. While antibiotic prophylaxis can reduce inflammatory complications and support bone regeneration, evidence does not consistently show additional benefit from extended antibiotic regimens, with “one-shot” prophylaxis often sufficient (Lyons et al., 2008; Milic et al., 2021; Remschmidt et al., 2023). Further research is necessary to optimize biomaterial composition, antimicrobial strategies, and clinical protocols for safe and effective bone regeneration in oral surgery.
Table 6. Summary of innovative antibacterial bone substitute materials.
5 Structure–property–function relationships in antibacterial biomaterials
The antibacterial efficacy of bone substitute materials is closely linked to their physicochemical attributes. Surface roughness, porosity, charge distribution, and ion release profiles govern bacterial adhesion and biofilm formation. For instance, increased nanoscale roughness enhances osteoblast attachment but simultaneously provides niches for microbial retention. Therefore, achieving a balance between osteoconductivity and antibacterial protection requires fine-tuning of surface topography and surface energy. Moreover, ion-doped materials (Ag+, Cu2+, Zn2+) prevent the adhesion of bacteria and the development of biofilms by release antimicrobial factors, that disrupt bacterial cell walls and inhibit quorum sensing while stimulating osteogenic differentiation through signaling pathways such as Wnt/β-catenin and BMP2. Composite materials incorporating polymers like chitosan or gelatin provide additional bacteriostatic barriers and control ion release kinetics. Understanding these structure–property–function interrelations will guide the rational design of future biomaterials with integrated antibacterial and regenerative functionalities (Yoda et al., 2014; Fosca et al., 2023; He et al., 2023; Wang et al., 2023; Kang et al., 2025; Kubiak-Mihkelsoo et al., 2025).
6 Conclusions and recommendation
Bone substitute materials play a pivotal role in oral and maxillofacial surgery, providing predictable outcomes in the reconstruction of alveolar bone defects and facilitating implant-supported rehabilitation. Microbial colonization and subsequent biofilm formation on graft surfaces constitute major determinants of clinical outcome, as they may delay healing, compromise integration, and predispose to graft failure. The susceptibility of a material to bacterial adhesion is largely determined by its physicochemical characteristics, including porosity, surface roughness, and wettability. Recent developments in biomaterial science, particularly the incorporation of antimicrobial agents such as silver, copper, zinc, and bioactive nanoparticles, offer promising strategies to mitigate microbial colonization while preserving osteogenic potential. Nonetheless, the majority of supporting evidence remains limited to in vitro studies, underscoring the need for robust in vivo and clinical investigations.
Based on available data it is recommended:
i. Autogenous bone should be utilized whenever feasible; when alternative substitutes are indicated, the choice of material must consider not only osteogenic potential but also susceptibility to microbial colonization.
ii. Rigorous perioperative infection control protocols—including preoperative antiseptic rinses, appropriate single-dose antibiotic prophylaxis, and meticulous surgical closure—should be considered standard practice to minimize postoperative complications.
iii. Surgical techniques should aim to avoid graft exposure and ensure tension-free wound closure to limit microbial infiltration.
iv. Further development of biomaterials incorporating antimicrobial ions, nanoparticles, and bioactive coatings is strongly encouraged, with emphasis on optimizing antibacterial efficacy while ensuring cytocompatibility and long-term stability.
v. Surface modifications that balance porosity for osteoconduction with reduced microbial adhesion should be prioritized in the design of future grafting materials.
vi. Longitudinal, randomized clinical trials are required to validate the antibacterial efficacy and regenerative potential of modified bone substitutes under clinical conditions.
vii. Standardized methodologies for assessing antibacterial properties of grafting materials should be established to allow reliable interstudy comparisons.
viii. Future investigations should focus on the host–material–microbiome interface to elucidate the immunological and microbiological mechanisms underlying graft integration and long-term clinical success.
Author contributions
WP: Conceptualization, Methodology, Writing – review & editing. DK: Formal analysis, Investigation, Writing – original draft. DD: Investigation, Writing – original draft. MZ: Formal analysis, Investigation, Writing – original draft. MP: Conceptualization, Investigation, Methodology, Writing – original draft, Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
Generative AI statement
The author(s) declare that no Gen AI was used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Abe, F. C., Kodaira, K., Motta, C. de C. B., Barberato-Filho, S., Silva, M. T., Guimarães, C. C., et al. (2022). Antimicrobial resistance of microorganisms present in periodontal diseases: a systematic review and meta-analysis. Front. Microbiol. 13:961986. doi: 10.3389/fmicb.2022.961986
Abushahba, F., Gürsoy, M., Hupa, L., and Närhi, T. O. (2021). Effect of bioactive glass air-abrasion on Fusobacterium nucleatum and Porphyromonas gingivalis biofilm formed on moderately rough titanium surface. Eur. J. Oral Sci. 129:e12783. doi: 10.1111/eos.12783
Albrektsson, T., Tengvall, P., Amengual, L., Coli, P., Kotsakis, G. A., and Cochran, D. (2023). Osteoimmune regulation underlies oral implant osseointegration and its perturbation. Front. Immunol. 13:1056914. doi: 10.3389/fimmu.2022.1056914
Álvarez, S., Leiva-Sabadini, C., Schuh, C. M. A. P., and Aguayo, S. (2022). Bacterial adhesion to collagens: implications for biofilm formation and disease progression in the oral cavity. Crit. Rev. Microbiol. 48, 83–95. doi: 10.1080/1040841X.2021.1944054
Amid, R., Kheiri, A., Kheiri, L., Kadkhodazadeh, M., and Ekhlasmandkermani, M. (2021). Structural and chemical features of xenograft bone substitutes: a systematic review of in vitro studies. Biotechnol. Appl. Biochem. 68, 1432–1452. doi: 10.1002/bab.2065
Anand, A., Sengupta, S., Kanková, H., Švančárková, A., Beltrán, A. M., Galusek, D., et al. (2022). Influence of copper-strontium co-doping on bioactivity, cytotoxicity and antibacterial activity of mesoporous bioactive glass. Gels 8:743. doi: 10.3390/gels8110743
Anderson, J. M., Rodriguez, A., and Chang, D. T. (2008). Foreign body reaction to biomaterials. Semin. Immunol. 20, 86–100. doi: 10.1016/j.smim.2007.11.004
Ansari, M. (2019). Bone tissue regeneration: biology, strategies and interface studies. Prog. Biomater. 8, 223–237. doi: 10.1007/s40204-019-00125-z
Arcos, D., and Vallet-Regí, M. (2020). Substituted hydroxyapatite coatings of bone implants. J. Mater. Chem. B 8, 1781–1800. doi: 10.1039/C9TB02710F
Artzi, Z., Weinreb, M., Givol, N., Rohrer, M. D., Nemcovsky, C. E., Prasad, H. S., et al. (2004). Biomaterial resorption rate and healing site morphology of inorganic bovine bone and beta-tricalcium phosphate in the canine: a 24-month longitudinal histologic study and morphometric analysis. Int. J. Oral Maxillofac. Implants 19, 357–368.
Baker, J. L., Mark Welch, J. L., Kauffman, K. M., McLean, J. S., and He, X. (2024). The oral microbiome: diversity, biogeography and human health. Nat. Rev. Microbiol. 22, 89–104. doi: 10.1038/s41579-023-00963-6
Benn, A., Heng, N., Broadbent, J. M., and Thomson, W. M. (2018). Studying the human oral microbiome: challenges and the evolution of solutions. Aust. Dent. J. 63, 14–24. doi: 10.1111/adj.12565
Binkowska, A. M., Michalak, G., and Słotwiński, R. (2015). Current views on the mechanisms of immune responses to trauma and infection. Cent. Eur. J. Immunol. 40, 206–216. doi: 10.5114/ceji.2015.52835
Bunyaratavej, P., and Wang, H. L. (2001). Collagen membranes: a review. J. Periodontol. 72, 215–229. doi: 10.1902/jop.2001.72.2.215
Canullo, L., Rossetti, P. H. O., and Penarrocha, D. (2015). Identification of Enterococcus faecalis and Pseudomonas aeruginosa on and in implants in individuals with peri-implant disease: a cross-sectional study. Int. J. Oral Maxillofac. Implants 30, 583–587. doi: 10.11607/jomi.3946
Caruana, A., Savina, D., Macedo, J. P., and Soares, S. C. (2019). From platelet-rich plasma to advanced platelet-rich fibrin: biological achievements and clinical advances in modern surgery. Eur. J. Dent. 13, 280–286. doi: 10.1055/s-0039-1696585
Chen, W., Oh, S., Ong, A. P., Oh, N., Liu, Y., Courtney, H. S., et al. (2007). Antibacterial and osteogenic properties of silver-containing hydroxyapatite coatings produced using a sol gel process. J. Biomed. Mater. Res. A 82, 899–906. doi: 10.1002/jbm.a.31197
Chen, Y., Shi, T., Li, Y., Huang, L., and Yin, D. (2022). Fusobacterium nucleatum: the opportunistic pathogen of periodontal and peri-implant diseases. Front. Microbiol. 13:860149. doi: 10.3389/fmicb.2022.860149
Chirilǎ, L., Rotaru, C., Filipov, I., and Sǎndulescu, M. (2016). Management of acute maxillary sinusitis after sinus bone grafting procedures with simultaneous dental implants placement - a retrospective study. BMC Infect. Dis. 16(Suppl. 1):94. doi: 10.1186/s12879-016-1398-1
Cho, Y.-D., Kim, K.-H., Lee, Y.-M., Ku, Y., and Seol, Y.-J. (2021). Periodontal wound healing and tissue regeneration: a narrative review. Pharmaceuticals 14:456. doi: 10.3390/ph14050456
Choi, S., Jo, Y.-H., Luke Yeo, I.-S., Yoon, H.-I., Lee, J.-H., and Han, J.-S. (2023). The effect of surface material, roughness and wettability on the adhesion and proliferation of Streptococcus gordonii, Fusobacterium nucleatum and Porphyromonas gingivalis. J. Dental Sci. 18, 517–525. doi: 10.1016/j.jds.2022.09.010
Choukroun, J., Simonpieri, A., Del Corso, M., Mazor, Z., Sammartino, G., and Dohan Ehrenfest, D. M. (2008). Controlling systematic perioperative anaerobic contamination during sinus-lift procedures by using metronidazole: an innovative approach. Implant Dent. 17, 257–270. doi: 10.1097/ID.0b013e318181349a
Chumponsuk, T., Gruneck, L., Gentekaki, E., Jitprasertwong, P., Kullawong, N., Nakayama, J., et al. (2021). The salivary microbiota of Thai adults with metabolic disorders and association with diet. Arch. Oral Biol. 122:105036. doi: 10.1016/j.archoralbio.2020.105036
Dantas, L. R., Ortis, G. B., Suss, P. H., and Tuon, F. F. (2024). Advances in regenerative and reconstructive medicine in the prevention and treatment of bone infections. Biology 13:605. doi: 10.3390/biology13080605
Deepak, V., Josephin, J. J., Babu, P. R., Guntakandla, V. R., Gooty, J. R., Malgikar, S., et al. (2020). Evaluation of efficacy of injectable-guided tissue regeneration with and without clindamycin on the colonization of Porphyromonas gingivalis by real-time polymerase chain reaction. J. Contemp. Dent. Pract. 21, 36–40. doi: 10.5005/jp-journals-10024-2742
Dhir, S. (2013). Biofilm and dental implant: the microbial link. J. Indian Soc. Periodontol. 17, 5–11. doi: 10.4103/0972-124X.107466
Dieckow, S., Szafrański, S. P., Grischke, J., Qu, T., Doll-Nikutta, K., Steglich, M., et al. (2024). Structure and composition of early biofilms formed on dental implants are complex, diverse, subject-specific and dynamic. NPJ Biofilms Microbiomes 10:155. doi: 10.1038/s41522-024-00624-3
Dragovic, M., Pejovic, M., Stepic, J., Colic, S., Dozic, B., Dragovic, S., et al. (2020). Comparison of four different suture materials in respect to oral wound healing, microbial colonization, tissue reaction and clinical features-randomized clinical study. Clin. Oral Investig. 24, 1527–1541. doi: 10.1007/s00784-019-03034-4
Dutra, T. P., Robitaille, N., Altabtbaei, K., Dabdoub, S. M., and Kumar, P. S. (2025). Community dynamics during de novo colonization of the nascent peri-implant sulcus. Int. J. Oral Sci. 17:37. doi: 10.1038/s41368-025-00367-7
Elboraey, M. O., Alqutaibi, A. Y., Aboalrejal, A. N., Borzangy, S., Zafar, M. S., Al-Gabri, R., et al. (2025). Regenerative approaches in alveolar bone augmentation for dental implant placement: techniques, biomaterials, and clinical decision-making: a comprehensive review. J. Dent. 154:105612. doi: 10.1016/j.jdent.2025.105612
El-Ghannam, A. (2005). Bone reconstruction: from bioceramics to tissue engineering. Expert Rev. Med. Devices 2, 87–101. doi: 10.1586/17434440.2.1.87
Esposito, M., Grusovin, M. G., and Worthington, H. V. (2012). Treatment of peri-implantitis: what interventions are effective? A Cochrane systematic review. Eur. J. Oral Implantol. 5(Suppl), S21–41.
Ezati, M., Safavipour, H., Houshmand, B., and Faghihi, S. (2018). Development of a PCL/gelatin/chitosan/β-TCP electrospun composite for guided bone regeneration. Prog. Biomater. 7, 225–237. doi: 10.1007/s40204-018-0098-x
Fadeeva, I. V., Goldberg, M. A., Preobrazhensky, I. I., Mamin, G. V., Davidova, G. A., Agafonova, N. V., et al. (2021). Improved cytocompatibility and antibacterial properties of zinc-substituted brushite bone cement based on β-tricalcium phosphate. J. Mater. Sci. Mater. Med. 32:99. doi: 10.1007/s10856-021-06575-x
Fernández-Guarino, M., Hernández-Bule, M. L., and Bacci, S. (2023). Cellular and Molecular Processes in Wound Healing. Biomedicines 11:2526. doi: 10.3390/biomedicines11092526
Flanagan, D. (2017). Enterococcus faecalis and dental implants. J. Oral Implantol. 43, 8–11. doi: 10.1563/aaid-joi-D-16-00069
Flemmig, T. F., Ehmke, B., Bolz, K., Kübler, N. R., Karch, H., Reuther, J. F., et al. (1998). Long-term maintenance of alveolar bone gain after implantation of autolyzed, antigen-extracted, allogenic bone in periodontal intraosseous defects. J. Periodontol. 69, 47–53. doi: 10.1902/jop.1998.69.1.47
Fosca, M., Streza, A., Antoniac, I. V., Vadalà, G., and Rau, J. V. (2023). Ion-doped calcium phosphate-based coatings with antibacterial properties. J. Funct. Biomater. 14:250. doi: 10.3390/jfb14050250
Garbo, C., Locs, J., D'Este, M., Demazeau, G., Mocanu, A., Roman, C., et al. (2020). Advanced Mg, Zn, Sr, Si multi-substituted hydroxyapatites for bone regeneration. Int. J. Nanomedicine 15, 1037–1058. doi: 10.2147/IJN.S226630
Ghannoum, M. A., Jurevic, R. J., Mukherjee, P. K., Cui, F., Sikaroodi, M., Naqvi, A., et al. (2010). Characterization of the oral fungal microbiome (mycobiome) in healthy individuals. PLoS Pathog. 6:e1000713. doi: 10.1371/journal.ppat.1000713
Gong, J., Yang, L., He, Q., and Jiao, T. (2018). In vitro evaluation of the biological compatibility and antibacterial activity of a bone substitute material consisting of silver-doped hydroxyapatite and Bio-Oss®. J. Biomed. Mater. Res. Part B Appl. Biomater. 106, 410–420. doi: 10.1002/jbm.b.33843
Hansen, T. H., Kern, T., Bak, E. G., Kashani, A., Allin, K. H., Nielsen, T., et al. (2018). Impact of a vegan diet on the human salivary microbiota. Sci. Rep. 8:5847. doi: 10.1038/s41598-018-24207-3
Hansson, S., and Halldin, A. (2012). Alveolar ridge resorption after tooth extraction: a consequence of a fundamental principle of bone physiology. J. Dent. Biomech. 3:1758736012456543. doi: 10.1177/1758736012456543
Hassan, I., Al-Tamimi, J., Ebaid, H., Habila, M. A., Alhazza, I. M., and Rady, A. M. (2023). Silver nanoparticles decorated with curcumin enhance the efficacy of metformin in diabetic rats via suppression of hepatotoxicity. Toxics 11:867. doi: 10.3390/toxics11100867
He, J., Li, Y., Cao, Y., Xue, J., and Zhou, X. (2015). The oral microbiome diversity and its relation to human diseases. Folia Microbiol. 60, 69–80. doi: 10.1007/s12223-014-0342-2
He, Z., Jiao, C., Wu, J., Gu, J., Liang, H., Shen, L., et al. (2023). Zn-doped chitosan/alginate multilayer coatings on porous hydroxyapatite scaffold with osteogenic and antibacterial properties. Int. J. Bioprint. 9:668. doi: 10.18063/ijb.v9i2.668
Hirata, M., Murata, H., Takeshita, H., Sakabe, T., Tsuji, Y., and Kubo, T. (2006). Use of purified beta-tricalcium phosphate for filling defects after curettage of benign bone tumours. Int. Orthop. 30, 510–513. doi: 10.1007/s00264-006-0156-1
Hoexter, D. L. (2002). Bone regeneration graft materials. J. Oral Implantol. 28, 290–294. doi: 10.1563/1548-1336(2002)028<0290:BRGM>2.3.CO;2
Holt, S. C., and Ebersole, J. L. (2005). Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia: the “red complex”, a prototype polybacterial pathogenic consortium in periodontitis. Periodontology 2000 38, 72–122. doi: 10.1111/j.1600-0757.2005.00113.x
Honda, M., Kawanobe, Y., Nagata, K., Ishii, K., Matsumoto, M., and Aizawa, M. (2020). Bactericidal and bioresorbable calcium phosphate cements fabricated by silver-containing tricalcium phosphate microspheres. Int. J. Mol. Sci. 21:3745. doi: 10.3390/ijms21113745
Hong, W. Q., Lee, W.-H., Musa, S. H., Kamaruzaman, N. A., and Loo, C.-Y. (2025). Evaluation of hydrogel loading with curcumin and silver nanoparticles: biocompatibilities and anti-biofilm activities. Biometals 38, 663–682. doi: 10.1007/s10534-025-00670-0
Hu, K.-F., Lin, Y.-C., Huang, Y.-T., and Chou, Y.-H. (2021). A retrospective cohort study of how alveolar ridge preservation affects the need of alveolar ridge augmentation at posterior tooth implant sites. Clin. Oral Invest. 25, 4643–4649. doi: 10.1007/s00784-021-03778-y
Janjua, O. S., Qureshi, S. M., Shaikh, M. S., Alnazzawi, A., Rodriguez-Lozano, F. J., Pecci-Lloret, M. P., et al. (2022). Autogenous tooth bone grafts for repair and regeneration of maxillofacial defects: a narrative review. Int. J. Environ. Res. Public Health 19:3690. doi: 10.3390/ijerph19063690
Janus, M. M., Crielaard, W., Volgenant, C. M. C., van der Veen, M. H., Brandt, B. W., and Krom, B. P. (2017). Candida albicans alters the bacterial microbiome of early in vitro oral biofilms. J. Oral Microbiol. 9:1270613. doi: 10.1080/20002297.2016.1270613
Jiam, N. T.-L., Goldberg, A. N., Murr, A. H., and Pletcher, S. D. (2017). Surgical treatment of chronic rhinosinusitis after sinus lift. Am. J. Rhinol. Allergy 31, 271–275. doi: 10.2500/ajra.2017.31.4451
Johnson, N. R., Kazoullis, A., Bobinskas, A. M., Jones, L., Hutmacher, D. W., and Lynham, A. (2015). Bacterial comparison of preoperative rinsing and swabbing for oral surgery using 0.2% chlorhexidine. J. Investig. Clin. Dent. 6, 193–196. doi: 10.1111/jicd.12099
Kaldas, M., Barghorn, A., and Schmidlin, P. R. (2020). Actinomycosis as a rare local manifestation of severe periodontitis. Case Rep. Dent. 2020:5961452. doi: 10.1155/2020/5961452
Kang, Q., Wang, W., Wu, S., and Hu, G. (2025). B-doped nano-hydroxyapatite facilitates proliferation and differentiation of osteoblasts. J. Orthop. Surg. Res. 20:62. doi: 10.1186/s13018-024-05414-3
Kargozar, S., Mozafari, M., Ghodrat, S., Fiume, E., and Baino, F. (2021). Copper-containing bioactive glasses and glass-ceramics: from tissue regeneration to cancer therapeutic strategies. Mater. Sci. Eng. C 121:111741. doi: 10.1016/j.msec.2020.111741
Kermani, F., Nazarnezhad, S., Mollaei, Z., Mollazadeh, S., Ebrahimzadeh-Bideskan, A., Askari, V. R., et al. (2023). Zinc- and Copper-doped mesoporous borate bioactive glasses: promising additives for potential use in skin wound healing applications. Int. J. Mol. Sci. 24:1304. doi: 10.3390/ijms24021304
Ketonis, C., Barr, S., Adams, C. S., Hickok, N. J., and Parvizi, J. (2010). Bacterial colonization of bone allografts: establishment and effects of antibiotics. Clin. Orthopaedics Related Res. 468:2113. doi: 10.1007/s11999-010-1322-8
Khalifa, A. K., Wada, M., Ikebe, K., and Maeda, Y. (2016). To what extent residual alveolar ridge can be preserved by implant? A systematic review. Int. J. Implant Dentistry 2:22. doi: 10.1186/s40729-016-0057-z
Khanijou, M., Zhang, R., Boonsiriseth, K., Srisatjaluk, R. L., Suphangul, S., Pairuchvej, V., et al. (2021). Physicochemical and osteogenic properties of chairside processed tooth derived bone substitute and bone graft materials. Dent. Mater. J. 40, 173–183. doi: 10.4012/dmj.2019-341
Khatoon, Z., McTiernan, C. D., Suuronen, E. J., Mah, T.-F., and Alarcon, E. I. (2018). Bacterial biofilm formation on implantable devices and approaches to its treatment and prevention. Heliyon 4. doi: 10.1016/j.heliyon.2018.e01067
Kim, D. W., Lee, D., Ryu, J., Kook, M.-S., Park, H.-J., and Jung, S. (2025). Evaluation of hydroxyapatite-β-tricalcium phosphate collagen composites for socket preservation in a canine model. J. Funct. Biomater. 16:286. doi: 10.3390/jfb16080286
Kim, S., and Kim, S.-G. (2024). Advancements in alveolar bone grafting and ridge preservation: a narrative review on materials, techniques, and clinical outcomes. Maxillofac Plast Reconstr. Surg. 46:14. doi: 10.1186/s40902-024-00425-w
Kligman, S., Ren, Z., Chung, C.-H., Perillo, M. A., Chang, Y.-C., Koo, H., et al. (2021). The impact of dental implant surface modifications on osseointegration and biofilm formation. J. Clin. Med. 10:1641. doi: 10.3390/jcm10081641
Kolmas, J., Groszyk, E., and Kwiatkowska-Różycka, D. (2014). Substituted hydroxyapatites with antibacterial properties. Biomed. Res. Int. 2014:178123. doi: 10.1155/2014/178123
Kosutic, D., Uglesic, V., Perkovic, D., Persic, Z., Solman, L., Lupi-Ferandin, S., et al. (2009). Preoperative antiseptics in clean/contaminated maxillofacial and oral surgery: prospective randomized study. Int. J. Oral Maxillofac. Surg. 38, 160–165. doi: 10.1016/j.ijom.2008.11.023
Kozakiewicz, M., and Wach, T. (2020). New oral surgery materials for bone reconstruction—a comparison of five bone substitute materials for dentoalveolar augmentation. Materials 13:2935. doi: 10.3390/ma13132935
Kubiak-Mihkelsoo, Z., Kostrzebska, A., Błaszczyszyn, A., Pitułaj, A., Dominiak, M., Gedrange, T., et al. (2025). Ionic doping of hydroxyapatite for bone regeneration: advances in structure and properties over two decades—a narrative review. Appl. Sci. 15:1108. doi: 10.3390/app15031108
Kulkarni Aranya, A., Pushalkar, S., Zhao, M., LeGeros, R. Z., Zhang, Y., and Saxena, D. (2017). Antibacterial and bioactive coatings on titanium implant surfaces. J. Biomed. Mater. Res. A 105, 2218–2227. doi: 10.1002/jbm.a.36081
Łasica, A., Golec, P., Laskus, A., Zalewska, M., Gedaj, M., and Popowska, M. (2024). Periodontitis: etiology, conventional treatments, and emerging bacteriophage and predatory bacteria therapies. Front. Microbiol. 15:1469414. doi: 10.3389/fmicb.2024.1469414
Li, K., Cao, H., Huang, H., Tang, S., Wang, H., Yang, Q., et al. (2025). Advances in copper-containing biomaterials for managing bone-related diseases. Regen. Biomater. 12:rbaf014. doi: 10.1093/rb/rbaf014
Li, P., Yin, R., Cheng, J., and Lin, J. (2023). Bacterial biofilm formation on biomaterials and approaches to its treatment and prevention. Int. J. Mol. Sci. 24:11680. doi: 10.3390/ijms241411680
Li, X., Liu, Y., Yang, X., Li, C., and Song, Z. (2022). The oral microbiota: community composition, influencing factors, pathogenesis, and interventions. Front. Microbiol. 13:895537. doi: 10.3389/fmicb.2022.895537
Li, Y., Wang, W., Han, J., Li, Z., Wang, Q., Lin, X., et al. (2022). Synthesis of silver- and strontium-substituted hydroxyapatite with combined osteogenic and antibacterial activities. Biol. Trace Elem. Res. 200, 931–942. doi: 10.1007/s12011-021-02697-z
Liao, Y., Li, H., Shu, R., Chen, H., Zhao, L., Song, Z., et al. (2020). Mesoporous hydroxyapatite/chitosan loaded with recombinant-human amelogenin could enhance antibacterial effect and promote periodontal regeneration. Front. Cell. Infect. Microbiol. 10:180. doi: 10.3389/fcimb.2020.00180
Lu, H., Liu, Y., Guo, J., Wu, H., Wang, J., and Wu, G. (2016). Biomaterials with antibacterial and osteoinductive properties to repair infected bone defects. Int. J. Mol. Sci. 17:334. doi: 10.3390/ijms17030334
Lv, Y., Chen, Y., Zheng, Y., Li, Q., Lei, T., and Yin, P. (2022). Evaluation of the antibacterial properties and in-vitro cell compatibilities of doped copper oxide/hydroxyapatite composites. Colloids Surf. B Biointerfaces 209:112194. doi: 10.1016/j.colsurfb.2021.112194
Lyons, L. C., Weltman, R. L., Moretti, A. J., and Trejo, P. M. (2008). Regeneration of degree ii furcation defects with a 4% doxycycline hyclate bioabsorbable barrier. J. Periodontol. 79, 72–79. doi: 10.1902/jop.2008.070161
Mabry, T. W., Yukna, R. A., and Sepe, W. W. (1985). Freeze-dried bone allografts combined with tetracycline in the treatment of juvenile periodontitis. J. Periodontol. 56, 74–81. doi: 10.1902/jop.1985.56.2.74
Manor, Y., Alkasem, A., Mardinger, O., Chaushu, G., and Greenstein, R. B.-N. (2015). Levels of bacterial contamination in fresh extraction sites after a saline rinse. Int. J. Oral Maxillofac. Implants 30, 1362–1368. doi: 10.11607/jomi.3980
Maqbool, M., Nawaz, Q., Atiq Ur Rehman, M., Cresswell, M., Jackson, P., Hurle, K., et al. (2021). Synthesis, characterization, antibacterial properties, and in vitro studies of selenium and strontium co-substituted hydroxyapatite. Int. J. Mol. Sci. 22:4246. doi: 10.3390/ijms22084246
Mardas, N., Macbeth, N., Donos, N., Jung, R. E., and Zuercher, A. N. (2023). Is alveolar ridge preservation an overtreatment? Periodontology 2000 93, 289–308. doi: 10.1111/prd.12508
Mason, M. R., Preshaw, P. M., Nagaraja, H. N., Dabdoub, S. M., Rahman, A., and Kumar, P. S. (2015). The subgingival microbiome of clinically healthy current and never smokers. ISME J. 9, 268–272. doi: 10.1038/ismej.2014.114
Mazzucchi, G., Lollobrigida, M., Laurito, D., Di Nardo, D., Berlutti, F., Passariello, C., et al. (2020). Microbiological and FE-SEM assessment of d-PTFE membrane exposed to oral environment after alveolar socket preservation managed with granular nc-HA. J. Contemp. Dent. Pract. 21, 404–409. doi: 10.5005/jp-journals-10024-2805
Milic, T., Raidoo, P., and Gebauer, D. (2021). Antibiotic prophylaxis in oral and maxillofacial surgery: a systematic review. Br. J. Oral Maxillofac. Surg. 59, 633–642. doi: 10.1016/j.bjoms.2020.09.020
Miron, R. J. (2024). Optimized bone grafting. Periodontology 2000 94, 143–160. doi: 10.1111/prd.12517
Moraschini, V., de Almeida, D. C. F., Calasans-Maia, M. D., Kischinhevsky, I. C. C., Louro, R. S., and Granjeiro, J. M. (2020). Immunological response of allogeneic bone grafting: a systematic review of prospective studies. J. Oral Pathol. Med. 49, 395–403. doi: 10.1111/jop.12998
Moraschini, V., Poubel, L. A., da, C., Ferreira, V. F., and Barboza, E. dos S. P. (2015). Evaluation of survival and success rates of dental implants reported in longitudinal studies with a follow-up period of at least 10 years: a systematic review. Int. J. Oral Maxillofac. Surg. 44, 377–388. doi: 10.1016/j.ijom.2014.10.023
Moreno Vazquez, J. C., Gonzalez de Rivera, A. S., Gil, H. S., and Mifsut, R. S. (2014). Complication rate in 200 consecutive sinus lift procedures: guidelines for prevention and treatment. J. Oral Maxillofac. Surg. 72, 892–901. doi: 10.1016/j.joms.2013.11.023
Morrison, A. G., Sarkar, S., Umar, S., Lee, S. T. M., and Thomas, S. M. (2023). The contribution of the human oral microbiome to oral disease: a review. Microorganisms 11:318. doi: 10.3390/microorganisms11020318
Naruphontjirakul, P., Kanchanadumkerng, P., and Ruenraroengsak, P. (2023). Multifunctional Zn and Ag co-doped bioactive glass nanoparticles for bone therapeutic and regeneration. Sci. Rep. 13:6775. doi: 10.1038/s41598-023-34042-w
Nearing, J. T., DeClercq, V., Van Limbergen, J., and Langille, M. G. I. (2020). Assessing the variation within the oral microbiome of healthy adults. mSphere 5, e00451–e00420. doi: 10.1128/mSphere.00451-20
Nisyrios, T., Karygianni, L., Fretwurst, T., Nelson, K., Hellwig, E., Schmelzeisen, R., et al. (2020). High potential of bacterial adhesion on block bone graft materials. Materials 13:2102. doi: 10.3390/ma13092102
Nkenke, E., and Neukam, F. W. (2014). Autogenous bone harvesting and grafting in advanced jaw resorption: morbidity, resorption and implant survival. Eur. J. Oral Implantol. 7(Suppl. 2), S203–217.
Piaia, L., Silva, S. S., Gomes, J. M., Franco, A., et al. (2021). Chitosan/β-TCP composites scaffolds coated with silk fibroin: a bone tissue engineering approach. Biomed. Mater. 17. doi: 10.1088/1748-605X/ac355a
Popowski, W., Domanowska, D., Koseski, D., Ostrowski, R., Zalewska, M., Małecka-Giełdowska, M., et al. (2025). Analysis of the oral microbiome composition of healthy individuals and the in vitro antibacterial activity of platelet-rich fibrin from these individuals against oral pathogenic bacteria. Front. Microbiol. 16:1691046. doi: 10.3389/fmicb.2025.1691046
Purcz, N. M., Birkenfeld, F., Oetke, M., Will, M., Purcz, L., Gaßling, V., et al. (2015). Increased infection rates of sinus floor elevations after the use of a bone filter. Clin. Oral Investig. 19, 1115–1119. doi: 10.1007/s00784-014-1336-9
Reis, I. N. R. D., Huamán-Mendoza, A. A., Ramadan, D., Honório, H. M., Naenni, N., Romito, G. A., et al. (2025). The prevalence of peri-implant mucositis and peri-implantitis based on the world workshop criteria: a systematic review and meta-analysis. J. Dent. 160:105914. doi: 10.1016/j.jdent.2025.105914
Remschmidt, B., Schwaiger, M., Gaessler, J., Wallner, J., Zemann, W., and Schwaiger, M. (2023). Surgical site infections in orthognathic surgery: prolonged versus single-dose antibiotic prophylaxis. Int. J. Oral Maxillofac. Surg. 52, 219–226. doi: 10.1016/j.ijom.2022.06.002
Riachi, F., Naaman, N., Tabarani, C., Aboelsaad, N., Aboushelib, M. N., Berberi, A., et al. (2012). Influence of material properties on rate of resorption of two bone graft materials after sinus lift using radiographic assessment. Int. J. Dent. 2012:737262. doi: 10.1155/2012/737262
Rico-Llanos, G. A., Borrego-González, S., Moncayo-Donoso, M., Becerra, J., and Visser, R. (2021). Collagen Type I biomaterials as scaffolds for bone tissue engineering. Polymers 13:599. doi: 10.3390/polym13040599
Roca-Millan, E., Jané-Salas, E., Marí-Roig, A., Jiménez-Guerra, Á., Ortiz-García, I., Velasco-Ortega, E., et al. (2022). The application of beta-tricalcium phosphate in implant dentistry: a systematic evaluation of clinical studies. Materials 15:655. doi: 10.3390/ma15020655
Rodriguez, A. B., Alhachache, S., Velasquez, D., and Chan, H.-L. (2024). A systematic review of oral wound healing indices. PLoS ONE 19:e0290050. doi: 10.1371/journal.pone.0290050
Saadaoui, M., Singh, P., and Al Khodor, S. (2021). Oral microbiome and pregnancy: a bidirectional relationship. J. Reprod. Immunol. 145:103293. doi: 10.1016/j.jri.2021.103293
Salvi, G. E., Fürst, M. M., Lang, N. P., and Persson, G. R. (2008). One-year bacterial colonization patterns of Staphylococcus aureus and other bacteria at implants and adjacent teeth. Clin. Oral Implants Res. 19, 242–248. doi: 10.1111/j.1600-0501.2007.01470.x
Santacroce, L., Passarelli, P. C., Azzolino, D., Bottalico, L., Charitos, I. A., Cazzolla, A. P., et al. (2023). Oral microbiota in human health and disease: a perspective. Exp. Biol. Med. 248, 1288–1301. doi: 10.1177/15353702231187645
Santamaría, J., López, L., and Soto, C. (2011). Detection and diversity evaluation of tetracycline resistance genes in grassland-based production systems in Colombia, South America. Front. Microbiol. 2:252. doi: 10.3389/fmicb.2011.00252
Santos, M. S., Silva, J. C., and Carvalho, M. S. (2024). Hierarchical biomaterial scaffolds for periodontal tissue engineering: recent progress and current challenges. Int. J. Mol. Sci. 25:8562. doi: 10.3390/ijms25168562
Senthil, R., and Çakir, S. (2024). Nano apatite growth on demineralized bone matrix capped with curcumin and silver nanoparticles: dental implant mechanical stability and optimal cell growth analysis. J. Oral Biosci. 66, 232–240. doi: 10.1016/j.job.2023.12.004
Sharifianjazi, F., Sharifianjazi, M., Irandoost, M., Tavamaishvili, K., Mohabatkhah, M., and Montazerian, M. (2024). Advances in zinc-containing bioactive glasses: a comprehensive review. J. Funct. Biomater. 15:258. doi: 10.3390/jfb15090258
Sharon, V. M., and Malaiappan, S. (2025). Biocompatibility and periodontal regenerative potential of hydroxyapatite nanoparticles from Portunus Sanguinolentus Shells: a crystallographic, morphological, and molecular gene expression analysis. J. Dent. 157:105762. doi: 10.1016/j.jdent.2025.105762
Shen, Q., Qi, Y., Kong, Y., Bao, H., Wang, Y., Dong, A., et al. (2022). Advances in copper-based biomaterials with antibacterial and osteogenic properties for bone tissue engineering. Front. Bioeng. Biotechnol. 9:795425. doi: 10.3389/fbioe.2021.795425
Shimazaki, K., and Mooney, V. (1985). Comparative study of porous hydroxyapatite and tricalcium phosphate as bone substitute. J. Orthopaedic Res. 3, 301–310. doi: 10.1002/jor.1100030306
Siddiqui, D. A., Fidai, A. B., Natarajan, S. G., and Rodrigues, D. C. (2022). Succession of oral bacterial colonizers on dental implant materials: an in vitro biofilm model. Dent. Mater. 38, 384–396. doi: 10.1016/j.dental.2021.12.021
Struzik, N., Kensy, J., Piszko, P. J., Kiryk, J., Wiśniewska, K., Kiryk, S., et al. (2024). Contamination in bone substitute materials: a systematic review. Appl. Sci. 14:8266. doi: 10.3390/app14188266
Tang, R., Gui, X., Han, R., Gao, C., Zhang, H., Lu, S., et al. (2025). A shape-adaptive hydrogel with dual antibacterial and osteogenic properties for alveolar bone defect repair. J. Mater. Chem. B 13, 1712–1730. doi: 10.1039/D4TB02242D
ten Brink, T., Damanik, F., Rotmans, J. I., and Moroni, L. (2024). Unraveling and harnessing the immune response at the cell–biomaterial interface for tissue engineering purposes. Adv. Healthc. Mater. 13:2301939. doi: 10.1002/adhm.202301939
Toma, A. I., Fuller, J. M., Willett, N. J., and Goudy, S. L. (2021). Oral wound healing models and emerging regenerative therapies. Transl. Res. 236, 17–34. doi: 10.1016/j.trsl.2021.06.003
Tu, Y., Ren, H., He, Y., Ying, J., and Chen, Y. (2023). Interaction between microorganisms and dental material surfaces: general concepts and research progress. J. Oral Microbiol. 15:2196897. doi: 10.1080/20002297.2023.2196897
Tzach-Nahman, R., Mizraji, G., Shapira, L., Nussbaum, G., and Wilensky, A. (2017). Oral infection with Porphyromonas gingivalis induces peri-implantitis in a murine model: evaluation of bone loss and the local inflammatory response. J. Clin. Periodontol. 44, 739–748. doi: 10.1111/jcpe.12735
Uchida, A., Nade, S. M., McCartney, E. R., and Ching, W. (1984). The use of ceramics for bone replacement. A comparative study of three different porous ceramics. J. Bone Joint Surg. Br. 66-B, 269–275. doi: 10.1302/0301-620X.66B2.6323483
Ullah, I., Hussain, Z., Ullah, S., Zahra, Q. U. A., Zhang, Y., Mehmood, S., et al. (2023). An osteogenic, antibacterial, and anti-inflammatory nanocomposite hydrogel platform to accelerate bone reconstruction. J. Mater. Chem. B 11, 5830–5845. doi: 10.1039/D3TB00641G
Verheij, J., Geraets, W., van der Stelt, P., Horner, K., Lindh, C., Nicopoulou-Karayianni, K., et al. (2009). Prediction of osteoporosis with dental radiographs and age. Dentomaxillofac. Radiol. 38, 431–437. doi: 10.1259/dmfr/55502190
Verma, D., Garg, P. K., and Dubey, A. K. (2018). Insights into the human oral microbiome. Arch. Microbiol. 200, 525–540. doi: 10.1007/s00203-018-1505-3
Wade, W. G. (2021). Resilience of the oral microbiome. Periodontology 2000 86, 113–122. doi: 10.1111/prd.12365
Wang, R., Shi, M., Xu, F., Qiu, Y., Zhang, P., Shen, K., et al. (2020). Graphdiyne-modified TiO2 nanofibers with osteoinductive and enhanced photocatalytic antibacterial activities to prevent implant infection. Nat. Commun. 11:4465. doi: 10.1038/s41467-020-18267-1
Wang, X., Huang, S., and Peng, Q. (2023). Metal ion-doped hydroxyapatite-based materials for bone defect restoration. Bioengineering 10:1367. doi: 10.3390/bioengineering10121367
Weiss, K. M., Kucko, S. K., Mokhtari, S., Keenan, T. J., and Wren, A. W. (2023). Investigating the structure, solubility, and antibacterial properties of silver- and copper-doped hydroxyapatite. J. Biomed. Mater. Res. Part B Appl. Biomater. 111, 295–313. doi: 10.1002/jbm.b.35151
Yoda, I., Koseki, H., Tomita, M., Shida, T., Horiuchi, H., Sakoda, H., et al. (2014). Effect of surface roughness of biomaterials on Staphylococcus epidermidis adhesion. BMC Microbiol. 14:234. doi: 10.1186/s12866-014-0234-2
Yu, Y.-M., Lu, Y.-P., Zhang, T., Zheng, Y.-F., Liu, Y.-S., and Xia, D.-D. (2024). Biomaterials science and surface engineering strategies for dental peri-implantitis management. Mil. Med. Res. 11:29. doi: 10.1186/s40779-024-00532-9
Zamani, D., Moztarzadeh, F., and Bizari, D. (2019). Alginate-bioactive glass containing Zn and Mg composite scaffolds for bone tissue engineering. Int. J. Biol. Macromol. 137, 1256–1267. doi: 10.1016/j.ijbiomac.2019.06.182
Zhang, Y., Liu, M., Ma, H., Zhang, X., Li, N., Chen, X., et al. (2024). Effect of impacted mandibular third molar extraction on periodontal microbiota and clinical parameters of adjacent teeth: a randomized clinical trial. J. Craniomaxillofac. Surg. 52, 937–947. doi: 10.1016/j.jcms.2024.06.001
Zhao, R., Yang, R., Cooper, P. R., Khurshid, Z., Shavandi, A., and Ratnayake, J. (2021). Bone grafts and substitutes in dentistry: a review of current trends and developments. Molecules 26:3007. doi: 10.3390/molecules26103007
Zheng, K., Niu, W., Lei, B., and Boccaccini, A. R. (2021). Immunomodulatory bioactive glasses for tissue regeneration. Acta Biomater. 133, 168–186. doi: 10.1016/j.actbio.2021.08.023
Keywords: oral cavity, guided bone regeneration, bone substitute material, oral surgery, colonization, bacterial strains, microbial colonization, bacterial biofilm
Citation: Popowski W, Koseski D, Domanowska D, Zalewska M and Popowska M (2025) Bacterial colonization of bone substitute materials used in oral surgery: mechanisms, clinical implications, and preventive strategies—A narrative review. Front. Microbiol. 16:1715632. doi: 10.3389/fmicb.2025.1715632
Received: 29 September 2025; Accepted: 31 October 2025;
Published: 27 November 2025.
Edited by:
George Grant, Independent Researcher, Aberdeen, United KingdomReviewed by:
Jia Xu, Guangdong Province Stomatological Hospital, ChinaFrancesco Inchingolo, University of Bari Aldo Moro, Italy
Sonia Sarfraz, University of Oulu, Finland
Copyright © 2025 Popowski, Koseski, Domanowska, Zalewska and Popowska. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Wojciech Popowski, d29qY2llY2gucG9wb3dza2lAd3VtLmVkdS5wbA==; Magdalena Popowska, bWEucG9wb3dza2FAdXcuZWR1LnBs