Introduction
In regenerative medicine, considerable progress has been made in improving patients’ quality of life and life expectancy. The development of biomedical implants has contributed significantly to modern healthcare. Metal and non-metal implants with permanent or temporary biomaterials are common in orthopedics, maxillofacial and cranial surgery, ophthalmology, and neurosurgery. Biomaterials can generally form bacterial adhesions and biofilms regardless of their anatomical location, and biomaterials represent one group of materials that can develop these problems [
1‐
4].
By delivering local drugs directly to tissues, unnecessary antimicrobials can be reduced. In addition to hydrogels and nanoparticles, polymers were also tested for releasing topical antibiotics [
5]. The drug concentration at the implant site must also be stable and effective so that bacteria cannot become resistant. Considering that dental implants are expected to last for many decades, the drug-release coating must be able to recharge/replace itself when needed. An appropriate drug delivery agent is PDLA, even though it only improves drug release temporarily. Minocycline microspheres have been used to treat infections around implants for over 20 years [
6‐
9]. Though it often manifests as a slow, chronic condition, it can develop early after surgery or years afterward. Without treatment, peri-implantitis can cause significant bone loss around the implant, osteomyelitis, abscesses, sinusitis, pneumonia, as well as pathological fractures of the jawbone [
1]. 3D printing, called AM, can fabricate several devices. These technologies have many potential applications, but bioengineering is among the most promising. Research using 3D printing can simulate bones, cartilage, or heart valves closely resembling biological tissues. Using AM technology, geometric cues can be created accurately. Growing demand and application of tissue engineering, antimicrobial/anti-biofouling devices, and regenerative medicine have prompted researchers to look for new manufacturing technologies to solve the tissue and organ supply shortages and immunological requirements of implanted devices. Several fields can benefit from this technology. Artificial hips and knees, heart valves, stents, and even vascular grafts are often made from polymeric materials to improve quality of life and, in some cases, increase life expectancy [
10‐
14]. In oral medicine, drugs are often released locally to treat oral diseases. 3D printing can also design unique drug delivery systems because of its precision and three-dimensional composition. The chlorhexidine coating on mouthguards inhibits bacteria growth in the mouth. A wearable oral delivery device constructed with FDM mouthguards containing preloaded drugs. A 3D-printed mouthguard delivers drugs efficiently in personalized dental therapeutics [
15,
16]. Drug-eluting implants prevent infections associated with dental implants and orthopedic implants. Metallic implants are often coated with polymer or ceramic to embed drugs. A metallic implant surface can also be incorporated with covalent bonds, self-assembled layers, and silver nanoparticles. The polymer-based layers are suspected to cause complications in addition to loosening from the implant site, chemical changes, and corrosion. For this reason, inorganic coatings are being studied as a drug delivery system. Not much attention has been paid to metallic drug-eluting systems. The purpose of this mini-review is to summarize recent advancements in implant drug delivery systems [
6,
17,
18]. Dental implants are sealed with healing abutments, which are permanent permucosal implants. This stage increases the risk of infection and failure. Bacteria can be reduced around biomaterials to enhance healing. As a result of the simple design and structure of healing abutments, temporary local drug delivery devices can easily be modified and used as temporary local drug delivery devices. Bacterial infiltration during implant healing is reduced by preventing infection and poor implant-tissue interfaces due to bacterial leaks [
1,
19‐
22]. Nanotechnology has gained significance in dentistry for its potential to enhance materials’ properties at the nanoscale. Nanomaterials can be tailored to interact with biological systems and provide targeted delivery. Biomaterials in Dental Implants: Biomaterials play a crucial role in the success of dental implants, providing the necessary strength, biocompatibility, and integration with the surrounding tissues. Nano-based drug delivery systems can offer localized and sustained release of therapeutic agents. This can be particularly beneficial in the oral environment, providing controlled release directly at the implant site. Nanoformulations allow for precise control over drug release kinetics, improving the therapeutic efficacy of drugs while minimizing side effects. Nano coatings on implant surfaces can help prevent microbial adhesion and reduce the risk of infections. Nanostructured coatings on implant surfaces may enhance osseointegration by promoting better interaction with surrounding bone tissues. Biomaterials can be engineered to deliver anti-inflammatory drugs to mitigate inflammation associated with the implantation process. Ensuring the biocompatibility and long-term safety of nano and biomaterials in the oral environment is a key challenge. Moving from experimental studies to practical clinical applications requires addressing regulatory and translational hurdles. Highlight recent studies showcasing specific nanoparticle formulations that have demonstrated success in drug delivery for dental implants. Discuss any ongoing or recently completed clinical trials investigating the application of nano and biomaterials in drug delivery for dental implants. The integration of nano and biomaterials in drug delivery for dental implants holds great promise for improving the success and longevity of dental implant procedures. Ongoing research continues to explore new materials, formulations, and delivery strategies to address challenges and pave the way for clinical implementation [
1,
2,
23‐
29]. In this review article, the current applications of nano and biomaterials are discussed in drug delivery of dental implants.
Biomaterials in drug delivery of dental implant
Dental and oral diseases demonstrated the potential of biocompatible materials and systems. Any organ, tissue, or body function can be improved or replaced by a biomaterial that conducts electrically from a system that directly contacts biological tissues. Dental research studies hyaluronic acid, gelatin, collagen, and chitosan due to their capabilities as native tissues [
30‐
32]. Maxillofacial surgery and dentistry use CP in different ways. Several bone graft and dental implant methods have failed because of external infectious diseases and microbial biofilms. Infectious procedure percentages can be reduced, and situations can be improved when antibiotics and CP are combined. For antibiotic delivery, CP and doped vehicles with appropriate mechanical and physicochemical properties are needed [
33]. As a result of pyrophosphate hydrolysis in physiological environments, calcium pyrophosphate, metaphosphate, and orthophosphates are formed. The CP matrix may also contain antibiotics distributed in controlled release as prevention or treatment [
4,
34,
35]. Thus, most drug-eluted ceramic nanoscaffolds are multifunctional, such as delivering drugs, encouraging cell growth, and directing tissue regeneration. There is no doubt that ceramic scaffolds provide superior mechanical support than polymeric scaffolds. The surface area, grain size, and calcium-to-phosphorus ratio of calcium phosphate nanoparticles can further be tailored to control drug-release kinetics. Self-templating molecules have been used to fabricate well-controlled hollow silica nanospheres. Silica nanospheres with hollow cores can accumulate eight times more drugs than their solid counterparts, according to studies. These hollow silica nanospheres also allowed for time-delayed multiple-stage releases [
28,
36].
Research has demonstrated the significant roles played by various growth factors, including BMPs, PDGF, IGFs, and VEGF in craniofacial growth [
37]. Smad-dependent signaling and MAPK signaling are activated during skeletal development and bone formation. Wound healing, bone repair, and remodeling are all affected by fibroblast growth factor signaling during trauma or infection [
38]. Skeletal growth and maintenance are supported by IGFs, similar to IGFs. Also, VEGF influences proliferating, vascularizing, and ossifying of the maxillary and palatine mesenchyme as well as calvarial ossification. These growth factors may be beneficial in enhancing healing in patients with severe craniofacial anomalies due to an imbalance in these factors [
39]. To elicit specific biological responses in humans, growth factors require high doses and multiple injections because of their short half-life in circulation, limited diffusion, rapid degradation, and cleavage [
40]. ECM molecules safeguard and stabilize growth factors in vivo. To achieve localized and sustained release of growth factors, an appropriate carrier system must be selected [
41]. Many materials have been designed to entrap growth factors within or on substrates, including sponges, nanofibrous membranes, micro/nanoparticles, and hydrogels [
42]. BMP-2 and VEGF delivered simultaneously in rats almost completely repaired size defects [
43,
44]. Different methods of immobilization can be used to control growth factor release [
45]. Preclinical and clinical studies of these delivery systems remain limited despite extensive in vitro studies. rhBMP-based products are commercially available. Using rhBMP-2 embedded in an absorbable collagen sponge, sinus lifts and localized alveolar ridge augmentations can be achieved [
46,
47]. Several carrier-based grafts are approved for clinical use, including OP-1 Putty, a collagen graft infused with rhBMP-7 [
48]. Growth factor-containing materials not only maintain controlled release kinetics of growth factors but also provide a porous osteoconductive framework for bone ingrowth. Combining or sequentially delivering multiple growth factors can also accelerate bone regeneration. Despite the challenges associated with determining the right concentrations of growth factor combinations, customizing release profiles, controlling gradients, and timing, various delivery vehicles have proven effective in stimulating bone healing and angiogenesis [
49‐
51]. For instance, combinations of PDGF/IGF-I in methylcellulose gels have shown increased defect filling in periodontal lesions during phase I/II human clinical trials [
52,
53]. In recent years, approaches have been developed that incorporate biomimicry of bone and the surrounding soft tissues of the peri-implant surrounding the implant. Several extracellular matrix proteins, peptides, and growth factors have been used to modify dental implant surfaces. Using these biofunctional coatings, osseointegration and peri-implant soft tissue integration can be enhanced and maintained, reducing the risks of biofilm-induced peri-implant inflammation. Bioabsorbable polymeric coatings on titanium surfaces can release osteoconductive or antibacterial molecules over time. Wet and submerged simulated body fluids with calcium and phosphorus have coated titanium surfaces with HA [
54‐
56]. Calcium-phosphorus coatings, including HA, are essentially osteoconductive to bone. Calcium/phosphorus ratios, crystallinities, and coating thickness are all factors that affect the biodegradation properties of these materials. HA is commonly coated on Ti implant surfaces using plasma spraying (a conventional atmospheric plasma-spraying method). A spray’s chemical and physical properties are affected by the spray’s parameters, such as its flame combination and spraying flow rate [
23,
29]. After five years, there has been an assessment of approximately 95% clinical success with HA-coated implants. The success rate of implants has now dropped significantly to under 80% after 10 years. HA coating layer problems may have caused such a low success rate. Clinical evaluations of cylindrical implants were conducted, however. Clinical trials are nevertheless needed to evaluate calcium–phosphorus coatings in greater detail [
13,
29,
57]. Implants restore oral function and aesthetics by replacing missing teeth. Materials like titanium and its alloys are often used in these implants. There has been a revolution in tooth replacement thanks to dental implants, which are very successful. Osseointegration occurs when an implant fuses with surrounding bones due to mechanical properties. To improve long-term effectiveness and aesthetic outcomes, new implant designs, surface modifications, and implant-abutment connections are being investigated [
24,
58‐
60]. Porous HA can be manufactured through ceramic slip foaming, replicated reticulated foam scaffolds, destruction of sacrificial porogens like polymer beads, or hydrothermal conversion of calcium-based coral or bone. Drug delivery systems can be developed with spherical porous HA granules. Water and sodium chloride were adjusted to adjust the structure of spherical granules with various pore and channel structures. The release of anti-inflammatory or antibacterial drugs from HA at implantation sites was studied in a previous study. Several drugs have been found to enhance bone formation at the implant site so that HA can be loaded with these agents. It is being investigated whether the complex microchannel structures of HA granules can be used to control the release rate of drugs [
28,
58,
61,
62].
On the surface of the coating, osteoblasts attach directly to the surface of the HA coating, demonstrating its biocompatibility with hard tissue. It has been reported that metal implants coated with HA enhance bone apposition and prevent metal-ion release into the bone. However, there are a few critical issues with the HA coating layer. There are several reasons for the failure of Ti dental implants. HA particles that have delaminated or worn out impede the healing process of the bone and cause inflammation around the implant. An implant in a load-bearing area is prone to breaking because of the thick coating layer. Coating calcium-phosphorus with different coating techniques has been successfully achieved and investigated recently. Other calcium-phosphorus coatings, however, do not offer the same long-term clinical benefits as plasma-sprayed HA [
29,
63‐
65]. The similarity between HA and natural bone mineral makes it an ideal bone graft and implant material. Implants in orthopedic and dental applications undergo osteointegration to integrate with the surrounding bone. It promotes bone cell attachment and growth for reconstructive procedures, joint replacements, and dental implants. HA is used in tissue engineering as a scaffold material for tissue regeneration. Porous structures allow cells to infiltrate, travel nutrients, and develop new tissue. The HA scaffold provides mechanical support and guides tissue growth by mimicking the natural extracellular matrix. These implants repair cartilage, regenerate bone and manufacture tissues. Integrating HA with 3D printing and additive manufacturing has led to a new era of personalized implants [
24,
63,
66,
67].
TiO
2 nanotubes with HA-enhanced bone tissue integration. TiO
2 nanotubes were modified with carbon nanotubes, polymers, and proteins. Matrix-assisted pulsed laser evaporation (MAPLE) can deposit polymeric materials and heat-sensitive biomolecules. Osteogenic cells can be stimulated by coating HA or titanium with bioabsorbable molecules. Recent approaches include using peptides and peptidomimetics as titanium surface additives. Biomolecules have been used to enhance bone healing because of their chemical and functional versatility. Adsorption, entrapment, and covalent binding are the three main methods of immobilizing molecules. Collagen in the extracellular matrix of titanium dental implants enhances osseointegration and soft tissue growth, thus improving the seal between the implant and the gum. Cells can also be attached to the extracellular matrix by coating titanium with osteopontin and bone sialoprotein. Though large extracellular matrix proteins are low in chemical stability and quickly resorbable in biological fluids, they may still be helpful [
54,
68]. Recently, HA carriers have attracted considerable attention as drug delivery systems. Several biomedical applications can benefit from these systems, including controlled and targeted drug release [
24].
In most cases, HA coatings allow metallic implants to become more biocompatible and osseointegrated, reducing the risk of implant failure and improving their stability over the long term. It often mimics natural bone minerals using HA and other bioactive coatings. These coatings can stimulate bone formation and healing around implants. Dental implants have been found to integrate better with bioactive coatings, particularly in compromised clinical settings. Researchers seek to develop multifunctional coatings, optimize coating techniques, and research novel coating materials. Electrochemical deposition, plasma spraying, and biomimetic mineralization are used to optimize the composition and adhesion of HA coatings. Implants used in orthopedics, dentistry, and other biomedical fields are improving in durability and performance due to advancements in coating methodologies. In terms of biocompatibility and safety, HA is one of the most advantageous drug carriers. The body tolerates it well since it is a natural component of bone. Low cytotoxicity, minimal inflammatory response, and good biocompatibility have been demonstrated for HA-based drug delivery systems. In biomedical applications, particularly in regenerative medicine, this makes them ideal [
24,
69,
70]. Biological and mechanical implant properties are enhanced through approaches such as implant coatings in implant dentistry. Biocompatibility, antibacterial properties, and bioactivity can be enhanced with different coatings applied to zirconia surfaces. As a result of their bioactivity, bioactive coatings on zirconia can induce the formation of hydroxyapatite in biological environments, which is necessary for promoting bone growth [
71].
The successful integration of a biomaterial into the host tissue and the resulting clinical outcomes are primarily influenced by the host’s immune response to the foreign biomaterial. These interactions between biomaterials and the immune system are intricate, and gaining a comprehensive understanding of them could enhance their regenerative capabilities [
72]. Upon the implantation of any biomaterial, there is an immediate triggering of inflammatory reactions to safeguard the adjacent tissues. The biomaterial’s surface becomes coated with an initial layer of proteins as host plasma proteins adhere to it [
73]. Fibrinogen, in particular, plays a role in attracting inflammatory cells to the implant surface, facilitating platelet adhesion, and promoting the formation of chemoattractant-rich clots for further cellular growth [
74,
75]. It seems that a controlled immune response is beneficial for biocompatible biomaterials to effectively fulfill their intended functions. The nature of these immune reactions is, in part, shaped by immune cells such as mast cells, macrophages, and lymphocytes. Mast cells, for instance, release fibrosis-inducing molecules and pro-fibrogenic cytokines, which hinder tissue regeneration and promote fibrosis rather than healing [
76]. M1 macrophages exhibit classical activation, whereas M2 macrophages promote wound healing [
77,
78]. A prolonged presence of M1 macrophages negatively impacts bone regeneration, despite their importance in the initial stages of bone repair. Consequently, the bone regeneration process needs to transition from proinflammatory M1 to anti-inflammatory M2 activities [
79]. Bone regeneration and healing are dependent on this shift between M1 and M2 phenotypes, rather than being driven by a single specific phenotype [
80]. Bone replacement biomaterials, including CP biomaterials like DCP bioceramics, have provided significant benefits to orthopedic and dental patients worldwide, overcoming the limitations of natural bone grafts [
81]. To achieve regenerative outcomes comparable to natural bone grafts, the performance of these biomaterials must be further enhanced. Strategies for modulating, rather than suppressing, the immune response have been explored to promote better integration and regeneration performance with implanted bone biomaterials. To achieve this, smart biomaterials have been designed to activate the desired immune response, facilitating tissue/material integration and remodeling [
82]. The adhesion of immune cells and the secretion of cytokines may be directly influenced by ECM proteins. When tissue damage occurs, signaling molecules are released, activating the repair immune response by stimulating the TLR of resident immune cells [
83].
An aerosol deposition method was used to evaluate the osteogenic potential of zirconia coated with HA for improved osseointegration by Cho et al. (2015). A thin layer of HA on zirconia showed shallow, regular craters as analyzed by SEM and XRD. By measuring the thickness and uniformity of the HA films by SEM, a significant improvement in the wettability of the surface coated with HA was demonstrated. Based on confocal laser scan microscopy, the attachment of MC3T3-E1 preosteoblasts to titanium and zirconia surfaces did not differ significantly; however, cells attached to the zirconia with HA showed a lower proliferation rate than cells attached to the uncoated zirconia. However, the osteogenic response to HA-coated zirconia was shown to be remarkable. The findings indicate that HA coatings promote osteogenesis and improve surface modification [
84].
HA coatings with 4-Hexylresorcinol components were tested in vitro and in vivo by Kim et al. (2011). HA and 4-HR were successfully deposited onto titanium surfaces using an aerosol deposition technique, confirmed by x-ray diffraction and Fourier transform infrared. HA + 4-HR coatings were more adhesion-efficient than HA alone. Osteocalcin expression was significantly increased with the HA + 4-HR coating compared to the HA-only coating. Following eight weeks, 4 h-coated dental implants were removed faster than HA-only implants. A significant increase in bone formation and bone-to-implant contact values was observed in the HA + 4-HR group 8 weeks after surgery. Implants coated with HA + 4-HR were more durable than those coated with HA alone. It can be considered an option in tooth extraction cases or poor bone quality [
85].
Lee et al. (2014) studied the growth of peri-implant bone using collagen, hydroxyapatite (HA), and collagen plus HA (CH) implants in combination with uncoated, hydroxyapatite (HA), and collagen plus HA implants. Coating of HA on titanium was observed in a characteristic phase. Diffraction patterns were maintained after collagen and BMP-2 coating, but collagen and BMP-2 were not. It was confirmed that collagen exists by infrared absorption. Bone formation around the implant and bone-in-crack were significantly enhanced by CH surfaces over UC surfaces. BMP-2 added to implant surfaces was less effective than CH coatings. CH group was significantly more likely to form new bone and have a higher BIC. There was no significant difference between the other groups [
86]. Comparing different types of silica-coated micropatterned zirconia surfaces for fibroblast adherence and antibacterial effects, Laranjeira et al. (2014) According to the study results, zirconia coated with silica lowers bacterial adhesion based on surface morphology. Additionally, microstructured bioactive coatings can improve the adhesion of soft tissues, fibrin network formation, and cell growth. By reducing biofilm adherence and improving protein adsorption, they reduce biofilm formation and increase soft tissue adherence [
87]. Y-TZP and HA were mixed in various ratios by Pardun et al. (2015) to produce coatings. In the experiments, osteoblast adhesion and proliferation were stimulated by dissolving HA. The bioactivity of calcium phosphate increased when immersed in simulated body fluid, but its mechanical and chemical stability decreased. Based on the author’s research, coatings with more outstanding tetragonal zirconia content have excellent interfacial bonding, mechanical strength, and bioactivity potential [
26].