Innovations in Dental Implants Integration: Optimizing dental implants performance utilizing stem cells and coatings

Abstract

The last two decades, between 2000 and 2024, significant steps were achieved regarding the interaction between various stem cells and titanium implant surfaces to improve dental implant integration. This literature review focuses on the potential effects of (i) bone marrow mesenchymal stem cells (BMSCs), (ii) periodontal ligament stem cells (PDLSCs), and (iii) dental follicle stem cells (DFSCs) in promoting osseointegration and tissue regeneration. Studies have shown that combining these stem cells with Ti implants enhances bone formation, accelerates implant osseointegration, and improves long‐term implant stability. Additionally, animal models and bioreactors have been employed to evaluate the effects of stem cells on dental implant performance, with some studies showing promising results, although certain models have also yielded inconsistent outcomes. The interaction between stem cells and surface‐modified Ti implants has emerged as a key area of research, with results indicating improved healing times and reduced failure rates. This article provides an overview of these findings, highlighting the role of stem cells in not only replacing lost teeth but also actively regenerating the surrounding biological structures for a more integrated and natural outcome.

1. INTRODUCTION

It is estimated that around 10–15 million dental implants are placed globally every year. ¹ In the European Union alone, approximately 2 million dental implants are placed annually to improve patients' chewing ability, overall well‐being, and prevent bone atrophy at edentulous sites. The dental implant industry has been growing due to factors such as an aging population, increased oral health awareness, and a desire for cosmetic dental procedures. Dental implants come in various types and are typically made from biocompatible materials like titanium (Ti) or Ti alloys or zirconia ceramic. Researchers have made significant progress in enhancing implant osseointegration through the functionalization of implant surfaces, including roughened or nanostructured surfaces. Various studies have investigated the structural and functional bond between living bone and metallic implants. ² , ³ Osseointegration has been described as an affinity between bone and Ti, while others have interpreted it as an immunologic response to the metal surface. ⁴ Although osseointegration is crucial to the success of dental implant procedures, there are challenges or complications related to this process, such as implant fixture movement, infectious diseases, peri‐implantitis, conditions leading to bone resorption, and general tissue damage. ⁵

The literature indicates that the development of a cementum–periodontal ligament (PDL) structure surrounding dental implants can offer further defense against oral bacteria at the implant–bone junction. ⁶ Cementum attains a specialized architecture and function and is involved in the formation of tooth root and periodontal tissue. PDL embedded in the cementum structure serves as an absorbent element functioning to relieve occlusal loads and is rich in mesenchymal stem cells that can be differentiated to induce periodontal tissue regeneration. Cementum formation is essential in tissue engineering approaches aiming at the regeneration of periodontal tissues on the surface of dental implants. ⁷ , ⁸ Nevertheless, the design of bioengineered dental implants that mimic the intricacy of natural dental roots is a significant challenge that necessitates attention to various factors. For example, the biomechanical properties of the regenerated tissues need to match those of natural tissues to ensure proper function and longevity, while the regeneration of PDL and cementum must take place timely to ensure the stability and functionality of the implant during the healing period. ⁹ , ¹⁰ , ¹¹ The healing response can sometimes lead to fibrosis or connective tissue formation without proper structure and fiber orientation, leading to functional tissue regeneration. It is worth noticing that partial and insufficient regeneration of PDL and/or cementum, poor vascularization, poorly organized PDL‐like tissue formation, and other shortcomings have been reported in literature from various preclinical studies using different types of cells and biomaterials. ⁵ , ⁶ In addition, variations in patient anatomy, health status, and healing capacity can affect the success of PDL and cementum regeneration. ¹² Addressing these factors requires interdisciplinary collaboration among material scientists, biologists, engineers, and clinicians to create bioengineered dental implants that can effectively mimic the natural structure and function of dental roots. In the coming years, the development of innovative and intriguing strategies for “next‐generation implantology” will be necessary to create dental implants that meet the most demanding requirements. These requirements include optimal clinical effectiveness, minimal trauma for the patient, faster rehabilitation, one‐stage surgery, and excellent biological integration. The goal is to produce Next‐generation dental implants (NGIs) that meet all these needs.

In tissue engineering, cell systems play a crucial role as they are the fundamental building blocks for regenerating damaged or diseased tissues. These primary cell lines, often harvested from the patient, or stem cells, are cultured in the lab and combined with biomaterials to create scaffolds that mimic the natural tissue environment. The goal is to stimulate the cells to grow, proliferate, and differentiate into the desired tissue type. This approach is especially important in periodontal tissue regeneration, where the aim is to restore the complex structures that support teeth, including the gingiva, bone, and periodontal ligament. By providing the right cellular and structural cues, tissue engineering techniques can promote the regeneration of these tissues, improving oral health and function.

In recent years, “cell sheet engineering” (CSE) has emerged as a promising tissue engineering method for cell transplantation. CSE allows for the acquisition of cells in a sheet format without damaging the extracellular matrix (ECM). Various techniques such as enzyme‐free cell detachment and nanomaterial‐based technologies have been utilized to produce these cell sheets. ¹³ The retention of ECM and cell‐cell junctions in these sheets provides a distinct advantage for tissue regeneration. ¹⁴ In the field of regenerative dentistry, researchers have been exploring the potential of combining CSE with nanotechnologies to regenerate dental and oral tissues, including teeth, alveolar bone, and surrounding soft tissues. ¹⁵ Additionally, CSE has been combined with biologically derived matrices, such as Platelet‐rich Plasma (PRP), a 3D bio‐matrix rich in growth factors and cytokines that stimulate bone formation and soft tissue healing. This combination has shown promising results in increasing peri‐implant bone volume and improving overall implant survival rates. ¹⁶ , ¹⁷ However, the use of biomaterials like bioactive glasses and calcium phosphates in conjunction with cell sheets to enhance bone regeneration has produced mixed results. As such, further research is needed to address challenges like comprehensive preparation, safety, and cell quantity and quality.

To tackle the challenges associated with the integration of dental implants and bone, customized periodontal structures have been developed to restore lost or damaged periodontal tissues. Though the adoption of PDL sheets has yielded positive outcomes, there is still uncertainty related to the performance of this biological construct, despite the successful establishment of a cementum‐PDL structure on the implant surface. Although Ti alloys are widely used in dental implantology due to their reliability, there is a need to further understand the varying cell behaviors on differently functionalized Ti surfaces. Currently, there is no strong evidence to support the effectiveness of PDL sheets in inducing PDL and cementum development on Ti implants. ⁶ , ⁸ Additionally, it is unknown whether different Ti surface treatments can affect the regenerative potential of PDL‐sheet technology. ¹⁸

This review compiles significant findings from literature involving preclinical in vivo studies, investigating the effects of employing different stem cell types on the surface of Ti implants with or without coatings, toward better osseointegration and the possibility of the development of a cementum –PDL structure surrounding dental implants. A comprehensive grasp of stem cells and their functionalities is crucial for accomplishing this objective.

2. METHODS

We conducted a descriptive literature review in order to obtain a more comprehensive view into the role of various stem cells combined with dental implants in the periodontal tissue regeneration. Articles were identified through combinations of controlled vocabulary and free‐text terms relevant to the topic as described below for each part. Additionally, the reference lists of selected articles were manually screened to identify further relevant studies.

In the first part (Part A) of this review, we included studies that addressed critical aspects of the type of cells that may affect the regeneration capacity around dental implants. The PubMed, Google Scholar, and Scopus databases were searched for articles from 2014 to 2024 using keywords such as: Stem cells; Bone Marrow Mesenchymal Stem Cells; Periodontal Ligament Stem Cells; Dental Follicle Stem Cells (DFSCs); Ti implants; osseointegration; dental implant integration; tissue regeneration; in vivo; clinical; pre‐clinical; animals; humans; and various combinations of them. The applied inclusion criteria were only clinical and pre‐clinical in vivo studies in the English language that used stem cells in combination with dental implants, while conference abstracts and non‐experimental publications, such as reviews, letters to the editor, and opinion articles were excluded. Additionally, references from the selected articles were hand‐searched for relevant in vivo studies that were included as appropriate.

In the second part (Part B), we collected articles written in the English language that provide insights related to different advancements in dental Ti implant surface coatings for enhancing osseointegration, antibacterial/antimicrobial properties, and smart drug delivery. The PubMed, Google Scholar, and Scopus databases were searched for articles without a time limit using keywords such as: dental implant coatings; titanium coatings; hydroxyapatite coatings; ceramic coatings; biomimetic coatings; organic coatings; polymer coatings; antimicrobial coatings; bioactive coatings; hybrid coatings; drug delivery; and different combinations of them. No strict inclusion and exclusion criteria were applied apart from the English language, which was a prerequisite.

3. PART A: STEM CELLS AND TI IMPLANTS

In the time period spanning from 2000 to 2024, numerous research studies have been conducted to investigate the potential effects of bone marrow mesenchymal stem cells (BMSCs), periodontal ligament stem cells (PDLSCs), and dental follicle stem cells (DFSCs) with Ti implant surfaces and their combined interaction for optimized integration of dental implants (Figure 1). Table 1 summarizes in part A the key aspects of recent studies, including the cell sources, transplantation methods, animal models, surface treatment techniques, and main outcomes.

FIGURE 1.

Illustration of the interaction of cells with dental implants in vivo.

TABLE 1.

Summary of the key aspects of the up‐to‐date studies, including the source of the cells, the method of cell transplantation, the animal models used in experiments, surface treatment techniques, and the main outcomes.

Cell source	Cell transplantation	Experimental animal	Surface treatment	Results	References
PDLSCs isolated from extracted human PDL cells	Direct cell culture on implant in bioreactor	Rabbit	*Mini implants were used **	Histologically verified PDL around the dental implants. CBCT: the implant was well‐positioned within the bone and exhibited no signs of migration.	19
BMSCs from rabbit tibia and femur and isolated (PDLSCs) from the lower right incisor	Cell sheet	Rabbit	Pure Ti and zirconium oxide (zirconia) were coated with β‐TCP using a long‐pulse Nd:YAG laser (1064 nm)	When PDLSCs are used alone or co‐cultured with BMSCs, have the ability to create natural periodontal tissue.	20
BMSC‐isolated from rat bone marrow	ECM cell sheets	Rat	Sandblasted, large‐grit, acid‐etched Ti	The ECM sheets derived from BMSCs showed a positive effect on osseointegration both in vivo and in vitro	21
PDL derived cells which contain multipotential stem cells isolated from human periodontal ligament	Cell sheet	Rat	Ti treated with acid etching, blasting, and CaP coating	Cementum and PDL resembling tissue detected on the surface of Ti after undergoing three surface treatments	8
BMSCs collected from rats	Cell sheet	Rat model of osteoporosis	–	Enhanced bone integration Increased volume of surrounding bone	22
Immortalized human periodontal cells	Cell sheets	Mouse	HA coated Ti	Bioimplant: Facilitated fibrous connective tissue growth, Specialized network of blood vessels‐formation of new bone tissue in the affected area	23
Adult derived PDL tissue	–	Rat	HA coated Ti then coated with platinum	PDL: transversely oriented collagen fibers.	24
Dental follicle stem cells from impacted molars and canines	Direct cell culture on implant	(human subjects)	Different bioactive coatings, TiHA and with (TiSiO2), and porous Ti6Al7Nb implants as control (TiCtrl)	Osteogenic differentiation of DF stem cells	25
Εmbryonic dental follicle tissue	–	Murine	HA‐coated dental implant	Regeneration of PDL, cementum and bone defects. Responsiveness to noxious stimuli achieved.	26
PDL stem cells derived from rat periodontal ligament	Matrigel as scaffold	Rat	Sandblasting, Large‐grit acid‐ etching	Arranged PDL tissue around PDL cell seeded implants	27
PDL cells	Direct cell culture on implant in bioreactor	Dogs	–	Regeneration of deficient alveolar bone, development of a lamina dura and implant migration in an intact bone structure.	28
Bone marrow‐derived mesenchymal stem cells from goat.	Porous hollow root‐form poly (DL‐Lactide‐co‐Glycolide) scaffold	Goats	–	Newly formed bone and PDL‐like tissue formation. Differentiation into cementum, bone and periodontal ligament.	29
Maintenance of the original PDL tissue of mongrel dogs	–	Mongrel dogs	TPS, sandblasted and acid attacked (SLA) Ti	Periodontal ligament, alveolar bone, and root cementum formation between the implant and dentin chamber.	30
PDL cells obtained from teeth of 3 dogs	Direct cell culture on implant	Dogs	–	A cementum‐like tissue layer with embedded collagen fibers was successfully formed on some implant surfaces.	31

Abbreviations: ALP, alkaline phosphatase; BMSCs, bone marrow mesenchymal stem cells; CAP, calcium phosphate; ECM, extracellular matrix; HA, hydroxyapatite; PDL, periodontal ligament; PDLSCs, periodontal ligament stem cells; Ti, titanium; TPS, Ti plasma spraying; β‐TCP, beta‐tricalcium phosphate.

3.1. Periodontal ligament stem cells (PDLSCs)

Stem cells originating from the periodontal ligament stem cells (PDLSCs) have the potential to develop into bone cells. ³² The periodontal ligament is a specialized tissue situated between the cementum and the alveolar bone, containing mesenchymal progenitor cells from the dental follicle that can become cementoblasts and alveolar bone cells. Additionally, this connective tissue provides support to the tooth and maintains tissue balance. PDLSCs exhibit bone cell‐like characteristics, including calcium absorption, high alkaline phosphatase (ALP) activity, presence of osteocalcin, and the ability to form new bone. Isolated PDLSCs resemble fibroblasts and demonstrate clonogenic properties. ³³ Under specific culture conditions, PDLSCs can also differentiate into other cell types, such as fat cells (adipogenic), cartilage cells (chondrogenic), heart muscle cells (cardiomyogenic), nerve cells (neurogenic), and even liver cells (hepatogenic) when exposed to specific bioactive molecules during culture. ³⁴ Starting in 2000, Choi et al. ³¹ conducted a pivotal experiment to investigate the potential for forming new PDL attachment on Ti implants. The study utilized cultured periodontal ligament cells, which were harvested from the teeth of three dogs. These PDL cells were subsequently cultured in vitro and applied to the surfaces of Ti implants. Following a healing period of 3 months, histological analysis was performed to assess the integration of the cultured cells with the implant surfaces. The examination revealed the presence of cementum‐like tissue on certain areas of the implant surface, with collagen fibers demonstrating perpendicular insertion into this newly formed tissue, indicating partial PDL regeneration. These findings suggest the possibility of inducing PDL attachment on Ti implants, which has significant implications for improving implant integration in clinical settings.

In a related study, ³⁰ the formation of PDL tissue on Ti (implants was examined using implants that underwent specific surface modifications to enhance their bioactivity. The Ti implants were treated using three distinct surface techniques: Ti plasma spraying (TPS), sandblasting, and sandblasting followed by acid‐etching (SLA). These surface treatments aimed to improve the adhesion, proliferation, and differentiation of PDL cells on the implant surface. The study evaluated the impact of each surface modification on PDL tissue growth, providing critical insights into how surface characteristics can influence periodontal integration and optimize the functional performance of Ti implants. After 4 months of healing, histological analysis was performed on jaw sections, revealing newly formed PDL, alveolar bone, and root cementum filling the space between the implant and the chamber wall. The same set of experiments was performed in a bioreactor system ²⁸ in PDL cells using Ti pins as a substrate. After implanting the cultured cells in a canine model, assessments of probing depth and motility showed that the implants had integrated successfully, with mechanical characteristics similar to natural teeth. Radiographic examinations also revealed that previously deficient alveolar bone had regenerated, and a lamina dura had formed. Organized PDL tissues surrounding the Ti implant surfaces in PDL‐cell‐seeded implants had also been established ²⁷ when dental progenitor cells from rat periodontal ligament were employed.

Other related study ²⁴ exhibited a new method in which Ti implants were first coated with hydroxyapatite (HA) and then coated with platinum. Adult‐derived periodontal tissue was combined with bone tissue to act as a substitute for cementum. The results showed that the structure of the PDL fibers consisted of transverse collagen fibers and the implant responded to orthodontic forces in a similar way to natural teeth. A year after Lee et al. used an HA‐coated Ti screw encased in PDL cell sheets to be implanted in a mouse model. ²³ After 8 weeks of healing, it facilitated the formation of fibrous connective tissue, established a localized blood vessel network, and promoted the integration of new bone growth into the alveolar bone socket. In another study, ⁸ PDL cell sheets combined with a Ti surface that had been treated with acid etching, sandblasting, and a calcium phosphate coating showed that after implantation and healing in a rat model, the formation of tissue resembling both cementum and PDL on some areas of the Ti surface was achieved. However, the smooth areas of the Ti surface that had been treated with PDL‐derived cell sheets showed osseointegration in almost all areas. In a recent study, ¹⁹ isolated human PDL cells were cultured in a bioreactor in order to attach them to Ti mini dental implants and placed afterwards in rabbit tibia. After obtaining histological sections from the sacrificed rabbits and examining them under a light microscope, the results showed the clear presence of PDL surrounding the dental implants. Cone Beam Computed Tomography (CBCT) examination confirmed that the implants were securely situated within the bone and did not show any signs of migration.

3.2. Bone marrow mesenchymal stem cells (BMSCs)

BMSCs are mature stem cells that originate from the mesoderm. ³⁵ They feature the ability to self‐renew and differentiate into various cell types. When cultured and expanded under specific conditions, they can transform into bone, cartilage, myocardial cells, and epithelial cells. As the precursor of the osteogenic cell lineage, BMSCs are essential for maintaining bone health. Literature indicates that mechanical stimuli play a crucial role in regulating BMSC function, with mechanical loading, such as compression, tension forces, substrate stiffness (SS), fluid shear stress (FSS), hydrostatic pressure (HP), and vibration, promoting osteogenic differentiation, while mechanical unloading inhibits this process and encourages adipogenic or chondrogenic differentiation. ³⁶ There are many studies employing BMSCs for the regeneration of periodontal tissues. However, there is limited evidence that BMSCs alone can result in the complete regeneration of the periodontal apparatus around dental implants. In 2009, Marei et al. ²⁹ investigated a structure made of a porous and hollow material called poly(DL‐Lactide‐co‐Glycolide) to surround a Ti fixture. Then, stem cells derived from the bone marrow of goats were added to the structure and implanted in goats after canine teeth extraction. Within just 1 month, new bone and tissue similar to the periodontal ligament were observed. This demonstrates the remarkable capability of these undifferentiated stem cells to develop into cementum, bone, and periodontal ligament.

Correspondingly ²² applied BMSC sheets onto Ti implants, which were subsequently surgically implanted. After 8 weeks, samples underwent thorough examination via micro‐CT reconstruction and histomorphometric evaluation. The results demonstrated a notable enhancement in bone volume within the treated group, along with the development of fresh bone and an accelerated rate of bone‐implant contact encircling the BMSC‐implant constructs. BMSC‐derived ECM sheets promoting osseointegration in vitro and in vivo had also been proven when ECM sheet‐implant complexes were created by combining ECM sheets from rat BMSCs with sandblasted, large‐grit, acid‐etched implants. ²¹ The authors observed more uniform and stable attachment of ECM sheet wrapping the surface of the implants, as shown in Figure 2. In summary, BMSCs are considered highly suitable for dental tissue regeneration studies due to their high osteogenic potential, mechanical sensitivity, and ability to contribute to the regeneration of bone and PDL‐like tissues essential— elements for stable and long‐lasting dental implants, either in classic osseointegration approaches or in PDL regeneration directly onto titanium surface. ²⁰

FIGURE 2.

Characteristics of ECM sheet–implant complexes obtained using SEM. Representative SEM images of (a–c) SLA implants, (d–f) BMSC sheet–implant complexes, and (g–i) ECM sheet–implant complexes. Scale bar = 1 mm (a, d and g), 20 μm (b, e and h), 2 μm (c, f and i). (j) Energy spectrum analysis results. ²¹

3.3. Dental follicle stem cells

The dental follicle (DF) is an ectomesenchyme‐derived connective tissue sac enveloping the developing tooth and thought to be crucial in tooth development and eruption. ³⁷ There is consensus that DF progenitor cells have the capacity to generate the periodontium, indicating the presence of stem cells within the DF that can give rise to cementum, periodontal ligament (PDL), and alveolar bone. The dental follicle (DF) typically disappears once tooth eruption is complete. However, it is often present in impacted teeth, such as the third molar. Many individuals require extraction of impacted third molars to alleviate inflammation or as part of orthodontic treatment, and these tissues are usually discarded as medical waste. Therefore, the concept of harvesting DFSCs from impacted teeth is a viable option. DFSCs are a type of stem cell involved in the development of periodontal tissues. ³⁸ Numerous preclinical studies have shown that DFSCs can regenerate periodontal tissues. ³⁹ Their effect in periodontal tissue formation around dental implants was evaluated in one study. A dental implant coated with HA and surrounded by embryonic dental follicle tissue was implanted into a murine tooth‐loss model in the lower first molar region. The bio‐hybrid implant effectively restored physiological functions, including bone remodeling and repairing severe bone defects. In addition, it responded to noxious stimuli by regenerating periodontal tissues like the periodontal ligament and cementum. ²⁶ In another study, cells were isolated from harvested dental follicle (DF) tissue obtained from impacted canine/molars and differentiated into bone cells with or without the presence of BMP–2 and TGFβ1. ²⁵ These cells were then cultured directly onto Ti implants with different bioactive coatings such as hydroxyapatite (TiHA) and silica titanate (TiSiO₂), and porous Ti6Al7Nb implants as control (TiCtrl). Findings suggest that even in the absence of exogenous osteogenic factors, (TiHA) implants, and to a lesser extent, (TiCtr)l and (TiSiO₂) implants, can induce and sustain osteogenic differentiation of DF stem cells. This indicates that DF stem cells have a natural tendency for osteogenic differentiation.

3.4. Combination of different types of cells for periodontal tissue regeneration

A crosstalk between different cells contributes to tooth root development and the regeneration of periodontal tissues. ⁴⁰ Thus, the development of periodontal tissues such as cementum, bone, and PDL around dental implants may require the spatiotemporal involvement of different cell types and the understanding of the underlying mechanisms.

Lastly, Safi et al. ²⁰ proposed that the combination of BMSCs from the tibia and femur of rabbits, as well as isolated stem cells from the periodontal ligament (PDLSCs), forms cell sheets. Pure Ti and zirconium oxide (zirconia) were coated with beta‐tricalcium phosphate (β‐TCP) using a long‐pulse Nd: YAG laser (1,064 nm) and implanted along with BMSCs, PDLSCs, and a combination of both. Results indicated that co‐culturing BMSCs with PDLSCs, as well as using PDLSCs alone, resulted in the formation of PDL tissue that showed positive periostin expression.

In order to obtain a more comprehensive view into the role of different types of cells in periodontal tissues regeneration, here we summarize the key aspects of up‐to‐date studies regarding the source of the cells, the method of cell transplantation, the animal models used in experiments, surface treatment techniques, and the main outcomes.

The combination of dental implant coatings with stem cells holds great promise in regenerative dental implantology. As described above, in vivo studies have shown that by using stem cells and cell sheet engineering on dental implants, bio‐hybrid dental implants can be developed with enhanced functionality. Although many of these procedures are not directly applicable in human therapies and are still far away from clinical translation, they highlight the significant potential of tissue engineering in advancing dental implantology.

4. PART B: ADVANCEMENTS IN TI IMPLANT SURFACE COATINGS: ENHANCING OSSEOINTEGRATION, ANTIBACTERIAL PROPERTIES, AND SMART DRUG DELIVERY

The characteristics of the surface that stem cells are grown on have a significant impact on their capacity to adhere, proliferate, and express their different functionalities. Ti (Ti) implants' high biocompatibility, corrosion resistance, and longevity have made them indispensable in regenerative medicine. However, Ti implants are bio‐inert by nature, which restricts their capacity to integrate with surrounding tissues and increases the risk of infection and lengthy healing durations, despite these benefits. The limitations of bare Ti surfaces have been addressed by recent research efforts that concentrate on improving Ti surfaces through coatings that enhance cell adhesion, encourage osseointegration, and offer antibacterial protection. ⁵ , ⁴¹

Different types of coating have been applied on Ti dental implants. These include different materials such as bioactive minerals, synthetic or natural polymers, as well as biomolecules such as peptides or growth factors.

4.1. Organic coatings for dental implants

There has been a lot of interest in polymeric coatings on Ti dental implants due to their potential to increase osseointegration, decrease bacterial colonization, and improve biocompatibility. A variety of biocompatible polymers, including polycaprolactone (PCL), ⁴² polylactic acid (PLA), and polyethylene glycol (PLGA), can be used to create these coatings. ⁴³ These polymers can provide an environment that is conducive to cell adhesion and growth. For example, cpTi and Ti–6Al–4V discs coated with PLGA and PLGA/collagen nanofibers can promote cell attachment, proliferation, and osteogenic differentiation of human mesenchymal stem cells (hMSCs) over 21 days. ⁴³ These polymeric matrices may be made even more effective by adding bioactive substances, such as growth factors or antimicrobial agents, which provide a prolonged release of therapeutic drugs and lower the risk of infections linked to implants. ⁴⁴ Polysaccharide antibacterial coatings on smooth and laser micro‐patterned titanium surfaces as reservoirs for antibacterial agents were developed and loaded with triclosan. ⁴⁵ Hyaluronic acid/chitosan multilayers were successfully formed after acid hydrolysis of the Ti‐6Al‐4V alloy that were able to release ∼25% of the loaded drug in PBS within the first 10 h. Furthermore, polymeric coatings can be engineered to attain particular surface characteristics, such as roughness or hydrophilicity, which are essential for improving the interaction between the implant and the surrounding tissues. Methods including electrospinning, dip‐coating, and layer‐by‐layer assembly are frequently used to provide consistent, regulated polymeric coatings on Ti surfaces. ⁴⁶ Different natural or synthetic polymers have been used in combination with inorganic additives as possible candidates to improve the properties of dental implants. Osteogenic nanofibers composed of a composite blend of polycaprolactone, gelatin, dexamethasone, β‐glycerophosphate, ascorbic acid, and hydroxyapatite were prepared through electrospinning for coating titanium screw type implants and were implanted in rabbit tibia. Through μ‐CT scanning and histomorphometric analysis, the authors reported a significant increase in osteogenesis in the peri‐implant zone and higher osseointegration compared to un‐coated controls. ⁴⁷ Polycaprolactone and polycaprolactone/fluoride‐substituted hydroxyapatite (PCL/FHA) nanocomposite coatings with varying FHA compositions (10, 20, and 30 wt.%) were used to coat alkali‐treated Ti6Al4V substrates using an in‐situ sol‐gel method to enhance corrosion resistance and in vitro bioactivity. The increase in the FHA content resulted in an increase in hydrophilicity due to the presence of hydroxyl groups and surface roughness that further promoted the adhesion strength. ⁴⁸ In another study, ⁴⁹ a Ti‐25Zr biometallic alloy was coated with an electrospun composite of PCL and chitosan reinforced with nanosized CaTiO₃ and BaTiO₃ fillers and presented not only antibacterial properties but also increased ALP activity when cultured with a preosteoblastic cell line. The nanofibrous structure of the coating presented high surface area and porosity and a hydrophilic surface that promoted cell proliferation and ALP activity.

Silver nanoparticles (AgNPs) were incorporated into CS‐heparin multilayers via layer‐by‐layer (LbL) self‐assembly on alkali‐heat treated Ti substrates. ⁵⁰ A sustained Ag⁺ release for 28 days was observed, while the coatings promoted human gingival fibroblast adhesion and proliferation. The combination of Ag and chitosan significantly reduced bacterial adhesion and biofilm formation, demonstrating the LbL technique as a promising approach for antimicrobial implant coatings. Overall, creating polymeric coatings is a viable way to enhance Ti dental implants' lifetime and functionality in clinical settings, although clinical evidence is still lacking.

Some polymers are used with antibiotics to transfer antibacterial action, ⁵¹ , ⁵² while others are based on chitosan, nitrogen‐containing polyethylene, and quarterly ammonic chemicals. Antibiotics may accumulate in tissues other than the target, and while loading them onto polymers results in the intended antibacterial action, they do not provide sustained release. ⁵³ A dual‐layered drug carrier was developed using rhBMP‐2‐loaded PLGA microparticles and vancomycin‐loaded photo‐crosslinked chitosan (CS) hydrogel to enhance the antibacterial and osteogenic properties of dental implants. Vancomycin reduced Staphylococcus aureus by up to 88%, while BMP‐2 stimulated bone regeneration. The carrier released vancomycin rapidly for 2 days and rhBMP‐2 for 12 days. Although mild inflammation was observed, the system improved osteointegration, making it a promising dental implant coating. ⁵⁴ The majority of natural polymers degrade quickly and lack mechanical strength when compared to synthetic polymers, which might cause unequal medication particle leaching. ⁵⁵ , ⁵⁶ For this reason, these polymers are frequently combined with inorganic systems, such as metal oxides, hydroxyapatite (HA), and so on, to provide effective antibacterial activity. By connecting a quaternary amine unit to the polymeric chain, for example, bactericidal functionalization may be carried out, which can transform the polymer into a carrier of antibiotics with a biocidal effect. Ciprofloxacin was injected into chitosan microspheres and nano HA coatings on Ti surfaces using encapsulation and diffusion processes. Both the ciprofloxacin levels and the presence of nano HA were observed to affect the coatings' antibacterial efficacy against S. aureus. ⁵⁷ , ⁵⁸ The inherent antibacterial and pro‐osteoblastic properties of chitosan coatings on Ti dental implants are drawing interest because they improve the implants' biocompatibility and performance. By facilitating electrostatic interactions between the positively charged chitosan surface and the negatively charged bacterial and osteoblastic cells, these coatings promote cell proliferation while preventing bacterial development. Furthermore, because of its selective dissolubility, chitosan is a potential material for enhancing the functionality and durability of dental implants by enabling the controlled release of integrated therapeutic medicines. ⁵⁵ , ⁵⁹ Dental implant antifouling coatings, especially polyethylene glycol‐like (PEG‐like) coatings, are intended to improve tissue integration and lessen bacterial adherence. Through plasma polymerization, these coatings are put to Ti surfaces, improving their hydrophilicity and adding reactive groups that encourage cell attachment while lowering the risk of infection. The antifouling coatings seek to improve the lifetime and performance of dental implants by efficiently warding off microorganisms or eliminating them upon contact. ⁶⁰

Recently Polyetheretherketone was characterized as a promising new biomaterial for coating Ti‐6Al‐4V implants as a composite with inorganic silicon nitride (SiNx). Using spin coating and physical vapor deposition, hierarchical PEEK/SiNx coatings mimicking mineralized tissues were fabricated. The resulting coatings exhibit Young's modulus of 45–65 GPa, similar to cortical bone and enamel, and show enhanced wear, corrosion resistance, and apatite formation ability. ⁶¹

4.2. Bioactive mineral coatings on dental implants

Different types of bioactive coatings have been developed for dental implants through hydrothermal deposition, electrophoretic deposition, enameling, sol‐gel, or plasma spraying. Of these, the sol‐gel method has attracted interest due to its ability to produce biocompatible hybrid materials, especially those containing phosphorus in combination with zirconium or Ti. Materials like TiO₂ and SiO₂ have been found to be biocompatible; hence, they are applied in drug delivery systems even to orthopedic prostheses.

The sol‐gel process, based on hydrolysis and polycondensation of organometallic compounds, allows the addition of bioactive substances, increasing functionality. Current research is directed towards enhancing material‐tissue interactions through novel approaches, such as surface functionalization. This approach enables the incorporation of bioactive components into the material, enhancing biocompatibility and bioactivity. Hydroxyapatite (HA), a naturally occurring phosphorus‐containing material, is widely studied for its biocompatibility and application in coatings. ⁶²

Research has shown that hybrid materials obtained by the sol‐gel method can exhibit very good prospects for medical applications. Numerous studies reported some promising medical perspectives of the use for hybrids synthesized by the sol‐gel method ⁶³ , ⁶⁴ , ⁶⁵ , ⁶⁶ , ⁶⁷ and potential applications for orthopedic or dental implant coatings. ⁵² , ⁶⁸ Hybrid silica‐chitosan coatings on Grade‐4 titanium implants were synthesized via the sol‐gel process and characterized using ²⁹Si‐NMR and ¹³C‐NMR to confirm network formation and covalent bonding. Hydrolytic degradation studies showed effective silicon release, supporting bone formation. Varying chitosan and TEOS levels modulated Si release, while in vitro tests confirmed the biocompatibility of the coatings and their antibacterial properties. ⁶⁹

HA (Ca₁₀(PO₄)6(OH)₂) and nano HA, as well as tricalcium phosphate (TCP) are among the most widely employed coating materials for Ti surface modification because they are naturally occurring components of bone and teeth. By promoting osteoblast activity and bone deposition surrounding the implant, HA‐coated implants have been demonstrated to dramatically improve bone formation and implant durability. In contrast to uncoated Ti surfaces, HA‐coated Ti implants showed increased bone‐to‐implant contact, particularly in load‐bearing applications, which promotes faster and stronger osseointegration. However, up to now, there are no established manufacturing standards for the deposition of HA on dental implant surfaces. ⁷⁰ Numerous HA‐coated implant failures have been documented in the past, ⁷¹ although it appears that these failures may be caused by inadequate and non‐uniform coatings, coating separation from the HA implants, and HA coating resorption. ⁷² HA pillars/nanorods on the surfaces of Ti‐6Al‐4V were developed as a strategy to enhance the osseointegration of dental implants. The nano‐structured HA‐coated Ti‐6Al‐4V dental implants showed improved hardness and tribological properties that may enhance cell attachment and differentiation. ⁷³ In a systematic review evaluating TCP and HA coatings on dental implants including in vivo studies, it could not be proved that either type of coating had a statistically significant beneficial effect on bone‐to‐implant contact (BIC) after up to 84 days of implantation, compared to control Ti implants. ⁷⁴ Bioglass is another extensively studied coating because of its capacity to create a chemical bond with bone tissue. Moreover, bioactive glass coatings have the potential to emit advantageous ions that encourage cell division and proliferation. ⁷⁵ , ⁷⁶ , ⁷⁷ , ⁷⁸ Bioactive glass‐coated implants exhibited noticeably greater cell proliferation, fostering an environment that is conducive to bone repair and implant durability. ⁷⁹ However, problems associated with coating structure, coefficient of thermal expansion, mechanical performance, manufacturing process, etc. have limited their use. Although evidence shows comparable osseointegration with HA coated dental implants, ⁸⁰ there are not many clinical studies that confirm their long‐term efficacy. ⁸¹

Bioactive coatings have also been used to deliver drugs in situ. Pyo et al. ⁸² immersed titanium implants in a phosphate buffered saline solution to create a biomimetic CaP coating that was further used for the immobilization of zoledronate. Although they did not observe any statistically significant difference in BIC values compared to control implants without the drug, they observed a positive effect on the bone volume around the drug‐loaded implants. In another study, ⁸³ alendronate release from HA‐coated titanium implants in loading concentrations of 0.02, 0.06, 0.18 mg/cm² enhanced bone apposition and peri‐implant bone, with the intermediate dose showing the greatest effect, especially compared to pure, non‐HA coated implants.

4.3. Other coatings

Recent advancements also include coatings incorporating rare earth metals such as samarium and cerium, as well as other metals and ions like calcium, strontium, and gallium. ⁵³ It has been shown that ceramics containing strontium improve bactericidal activity and encourage bone formation and regeneration. ⁸⁴ A Ti dioxide microporous covering doped with strontium and zinc increased osteoblast adhesion while preventing S. aureus growth. ⁸⁵ Bone integration, biocompatibility, and antibacterial activity were all markedly improved by dual doping Ti nanotubes with strontium and samarium. ⁸⁶ The utilization of coatings with metal ions such as copper and silver ⁸⁷ , ⁸⁸ on dental implants has emerged as an innovative technique, enhancing crucial aspects for successful oral rehabilitation. These coatings play a pivotal role in promoting antimicrobial properties, angiogenesis, osteogenesis, and osseointegration. Among the elements garnering considerable attention for these coatings is Cerium. ⁸⁹ Ce‐coated implants have demonstrated exceptional biocompatibility, contributing to the reduction of bacterial infections, facilitating blood vessel formation, and stimulating bone regeneration. A schematic illustration of the implant surface modified by nano‐CeO₂ (rod‐CeO₂, cube‐CeO₂, and octa‐CeO₂) for antibacterial and anti‐inflammatory properties is presented in Figure 3.

FIGURE 3.

Illustration of implant surface modified by nano‐CeO₂ for antibacterial and anti‐inflammatory properties. ⁸⁹

New Ti‐graphene combinations for use in dental implants have become possible since graphene's debut in the dentistry field. The biomechanical behavior of bioactive materials in dental implants has been examined. ⁹⁰ Finite element analysis, which offers a reliable and accurate assessment in both clinical and in vitro analysis, was used to investigate the effects of implant thread design and three distinct bioactive materials—Ti alloy, graphene, and reduced graphene oxide (rGO)—on stress, strain, and deformation in the implant system. The results showed that Ti implants covered with graphene oxide performed better mechanically than Ti implants coated with graphene. Additionally, it was shown that making the Ti implant functional will lessen the strain on the implant system, lowering the risk of implant breakage. ⁹¹ Graphene coatings have the potential to significantly enhance osteogenic differentiation of BMSCs in vitro by modulating the FAK/P38 signaling pathway. ⁹² Additionally, they may promote the osteointegration of dental implants in vivo. However, further research, particularly involving human subjects, is required to confirm these potential applications. Similarly, there is evidence that carbon‐based coatings can modulate cellular responses, such as promoting osteoblast activity and minimizing inflammatory reactions while providing corrosion resistance. These coatings are stable and have the capacity to support osseointegration by promoting the attachment, growth, and differentiation of bone cells, properties that showcase their potential applications for improving the performance of dental implants. ⁹³ In another study, Jang et al. demonstrated both in vitro and in vivo that rGO‐coated Ti–6Al–4V scaffolds with irregular micropores are capable of enhancing osseointegration and bone regeneration. The rGO‐pTi scaffolds promoted osteogenic activity in vitro and improved bone formation in vivo. These results suggest their strong potential as advanced biomaterials for bone tissue engineering applications. ⁹⁴ However, pre‐clinical and clinical studies, particularly long‐term evaluations in humans, are still needed to fully establish their efficacy and safety in real‐world applications.

4.4. Peptide, growth factor, and extracellular matrix coatings on dental implants

Peptides have attracted a lot of interest as coatings for dental implants due to their bioactivity, ability to promote cell adhesion and differentiation, ease of functionalization, and potential to decrease the risks of peri‐implant inflammation induced by oral bacteria. ⁹⁵ Without the cost and complexity of complete protein coatings, these short amino acid chains offer a targeted way to enhance implant integration by replicating specific ECM protein domains. ⁹⁶ Bioactive peptides as of Arg–Gly–Asp sequence have been associated with higher BIC values compared to control in in vivo studies, similarly to ECM protein coatings, such as collagen type I–III, chondroitin sulfate, and hyaluronic acid. ⁹⁷ An in vivo study in mice showed that recombinant‐mouse‐OPN (rOPN) coated on dental implants enhanced direct osteogenesis during osseointegration, which was achieved in reduced time. ⁹⁸

Recombinant human bone morphogenetic protein (rhBMP–2), vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF‐2), and transforming growth factor b1 (TGF‐b1) are the most used growth factors in dental implantology. However, in a systematic review evaluating the effect of biological implant coatings on bone formation around peri‐implant bone tissue, low performance was recorded in most of the studies that used BMP‐2 as coating. The reason for this observation was attributed to incomplete or low immobilization of the growth factors. ⁹⁹ Guang et al. ¹⁰⁰ investigated the effect of coating acid‐etched (SLA) titanium implants with recombinant rat VEGF added in simulated body fluid (SBF) after implantation in rat knees. They performed immunohistochemistry to detect CD31and osteocalcin (OCN) expression after 1, 2, and 4 weeks. At weeks 2 and 4, the VEGF‐coated groups had a higher proportion of CD31‐positive and OCN‐positive cells compared to the control groups. The impact of coating dental implants with carboxyethylphosphonic acid and fibroblast growth factor 2 (FGF–2) on osseointegration was evaluated after implantation in the tibia of minipigs. ¹⁰¹ Implants were placed with either standard surface treatment (control) or FGF‐22 biofunctionalized surface treatment. After 4 weeks, the test group showed significantly better BIC values, though no significant differences were found in new bone formation or bone density. The results suggest that FGF‐2 biofunctionalization enhances bone mineralization at the cortical level, potentially reducing the osseointegration period. Platelet‐rich plasma (PRP) and platelet‐rich fibrin (PRF) have been used to coat the dental implants in an effort to optimize stability and osseointegration. PRP is an autologous platelet concentrate rich in growth factors, while PRF is an autologous, second‐generation platelet concentrate with a fibrin matrix containing platelets, leukocytes, cytokines, and stem cells. ¹⁰² It releases growth factors like PDGF, VEGF, TGF‐β, and IGF, which aid in soft and hard tissue healing. Both have been used as an aid to primary or secondary stability and bone regeneration around dental implants, although without a profound positive effect. In order to promote effective PRF coating of dental implants, a recent study evaluated different surface treatments, sandblasting and acid etching, plasma spraying and UV light treatment, and concluded that sandblasting and acid etching were superior in terms of PRF attachment compared to UV light and plasma spraying. ¹⁰³ In a double‐blinded, randomized split‐mouth trial, the researchers evaluated the impact of a liquid platelet‐rich fibrin (PRF)‐coated implant surface on osseointegration and rehabilitation time. ¹⁰⁴ Fifteen patients received 30 implants, divided into control and liquid PRF groups, with 1‐year follow‐up. While no significant differences were found between the groups for clinical parameters like torque, implant stability, reestablishment of masticatory function, or marginal bone loss, the liquid PRF group showed slightly better results in initial and final implant stability and a slightly shorter rehabilitation period. The study concluded that liquid PRF coating did not significantly affect the analyzed parameters. In another study, dental implants coated with rhBMP‐2 showed significantly better stability than those with PRF or no coating at 6 and 12 weeks after insertion. ¹⁰⁵ The authors concluded that RhBMP–2 enhanced implant stability more effectively than PRF or the control group. Different clinical studies have shown an increase in secondary stability after coating dental implants with PRF, while others have shown a non‐significant difference. ¹⁰⁶ , ¹⁰⁷

Concentrated growth factor (CGF) is a second‐generation platelet concentrate derived from the patient's own blood, containing osteoinductive growth factors and an osteoconductive fibrin matrix. ¹⁰⁸ It plays a crucial role in bone regeneration and healing ¹⁰⁹ as it contains factors like the PDGF and the EGF, which are known to stimulate the proliferation of mesenchymal and osteogenic cells. CGF‐coated implants were created using a Round Up device, allowing the implants to release growth factors (VEGF, TGF‐β1, and BMP–2) and matrix metalloproteinases (MMP–2 and MMP–9) over time. ¹¹⁰ Surgical outcomes showed that CGF‐permeated implants led to better osseointegration and fewer post‐surgical complications, suggesting CGF's potential to improve implant healing and osseointegration. In a recent publication of a case report, ¹¹¹ crestal bone loss around osseointegrated dental implants was evaluated after implantation of Concentrated Growth Factor (CGF). Compared to the non‐concentrated growth factor group, CGF significantly improved bone density around dental implants. From baseline to 9 months, crestal bone levels showed no significant differences between the groups, though CGF demonstrated better bone mineralization, as verified through cone beam computed tomography. Future developments in platelet derivatives are expected to prioritize improving cost‐efficiency, shortening preparation times, and increasing surgical effectiveness. This emphasis is crucial, as there are still concerns about the complexity and cost of these procedures relative to their clinical benefits.

5. PROGRESS, OBSTACLES, AND LIMITATIONS IN THE USE OF STEM CELLS

PDL cell transplantation is currently considered one of the most reliable regenerative techniques for the repair of damaged or lost periodontal tissues. While the initial results using PDL sheets appear promising, and although a cementum‐PDL structure has been obtained around the implant surface, it is unclear how this biological construct could work in a clinical environment. Moreover, although Ti alloys have gained a strong reliability in dental implantology, there is a need to better characterize the different cell behaviors on differently functionalized Ti surfaces. To date, there is no strong evidence of the effectiveness of the PDL cells or PDL cell sheets in improving the bio‐integration of Ti implants; nonetheless, there is no evidence of whether different Ti surface treatments may affect the regenerative potential of PDL‐sheets technology. The utilization of BMSCs and DFSCs for the regeneration of periodontal ligament around dental implants holds great promise in the field of regenerative dentistry. Extensive research on these stem cells has provided a foundation for understanding their potential to promote the recovery of peri‐implant tissues that have been compromised by conditions such as peri‐implantitis. Recent research suggests that the application of BMSCs and DFSCs to Ti implants can improve bone integration and increase the surrounding bone's volume. This approach also displays a significant inclination towards osteogenic differentiation, leading to favorable impacts on the quality of the bone surrounding the implant. Furthermore, co‐cultivating BMSCs with PDLCs has resulted in the formation of PDL tissue, while some studies that utilized only DFSCs provided positive results on periodontal ligament regeneration.

The potential of stem cell therapies for periodontal tissue regeneration as well as their application on implant surfaces is promising, yet several limitations must be addressed. Access and viability of the cells are critical issues as the process of harvesting these cells from the dental follicle, bone marrow, and periodontal ligament can significantly affect their quality. ¹¹² , ¹¹³ Low viability can compromise treatment effectiveness, highlighting the need for standardized protocols to optimize cell processing. Furthermore, factors such as cell differentiation and the biological effects of aging can influence the regenerative capacity of stem cells. Age‐related changes in the biological environment may alter stem cell behavior, which is particularly relevant given that older populations often require periodontal and implant treatments more frequently. ¹¹⁴ The interaction between stem cells and the implant environment remains not fully understood. Research indicates that the characteristics of implant surfaces, such as roughness and hydrophilicity, can affect how well stem cells integrate, which may lead to higher failure rates if not properly managed. ¹¹⁵ In addition to these biological challenges, regulatory hurdles and ethical considerations surrounding the use of stem cells complicate their application. The high costs associated with stem cell therapies may further limit accessibility for many patients. ¹¹⁶ Although some clinical trials have begun to explore the use of stem cells in periodontal regeneration, ¹¹⁷ there have yet to be any trials focusing specifically on their use with implants.

6. CONCLUDING REMARKS

In summary, utilization of PDL stem cells using BMSCs and DFSCs for regenerating PDL tissue around dental implants displays encouraging outcomes. As stem cell behavior and the regenerative microenvironment are still a matter of thorough research, regenerative aspects in dental implantology hold exciting prospects, especially through the use of bioactive molecules and ECM protein coatings or inorganic materials and surface patterning and functionalization. These offer novel and effective solutions for peri‐implant tissue regeneration and have enormous potential for advancing the field of regenerative medicine. Coatings for dental implants offer promising benefits for improving osseointegration and reducing healing times, but they face limitations such as complex and costly fabrication processes, coating stability, long‐term effectiveness, and biocompatibility. Future advancements could focus on developing more efficient and durable coating materials, incorporating controlled release systems for growth factors or antibiotics for antimicrobial effectiveness, and tailoring coatings to individual patient needs for improved personalized treatment. Long‐term preclinical and clinical studies and regulatory progress will be crucial in addressing these challenges and expanding the use of novel concepts and materials for coatings in dental implantology.

AUTHOR CONTRIBUTIONS

Ioannis Tsamesidis: Conceptualization; methodology; software; validation; investigation; writing—original draft; writing—review and editing; data curation. Athanasios Christodoulou: Writing—review and editing; visualization; writing—original draft; data curation. Evangelia Stalika: writing—review and editing. Georgia K. Pouroutzidou: Writing—original draft; methodology. Eleana Kontonasaki: Conceptualization; methodology; validation; investigation; writing—original draft; writing—review and editing; data curation; supervision.

FUNDING INFORMATION

None.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

Tsamesidis I, Christodoulou A, Stalika E, Pouroutzidou GK, Kontonasaki E. Innovations in Dental Implants Integration: Optimizing dental implants performance utilizing stem cells and coatings. Biotechnol. Prog. 2025;41(6):e70060. doi: 10.1002/btpr.70060

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.