Bioactive coatings for biomedical engineering application: A review of mechanical integrity, biocompatibility, and future smart technologies

Abstract

Bioactive coatings have attracted considerable attention in the context of orthopedic and dental implantology, where establishing a stable and biologically active interface between the implant surface and surrounding hard tissue remains a central challenge. The present review examines the principal coating categories inorganic, organic, and hybrid with particular attention to their roles in promoting osseointegration, supporting bone regeneration, and reducing implant-associated infection in musculoskeletal and craniofacial applications. This review offers an in-depth examination of bioactive coatings, categorizing them into three main classes: inorganic, organic, and hybrid. It delves into their preparation techniques, characterization methods, and evaluation processes, detailing how these coatings are engineered and tested for optimal performance. Beyond the technical aspects, the review highlights several critical issues in the field, such as achieving long-term stability, preserving biofunctionality under physiological conditions, and enabling cost-effective scalability for broad application. Addressing these challenges could lead to significant progress, ranging from enhanced implant performance to reduced complications and improved patient outcomes. By overcoming existing limitations and integrating emerging technologies, bioactive coatings are well-positioned to play an important role in the future of medical device innovation and regenerative medicine, paving the way for more effective and personalized therapeutic solutions.

1. Introduction

In recent years, bioactive coatings have emerged as a critical component in biomedical and biotechnological applications. These coatings have the potential to enhance the performance and biological response of implantable devices and materials, providing an interface between host tissues or cells and the implanted material. This interface promotes cell adhesion, proliferation, and differentiation, ultimately leading to improved healing and integration of the implant.^1–5 Bioactive coatings can be broadly classified into three categories based on their composition: inorganic, organic, and hybrid coatings. Inorganic coatings, such as hydroxyapatite (HA) and calcium phosphate (CaP), are widely used in orthopedic and dental implants owing to their excellent biocompatibility and capacity to promote bone apposition. Organic coatings, including extracellular matrix proteins and hydrogels, have been explored to enhance soft-tissue attachment and reduce early inflammatory responses at the implant-tissue interface.^6–8 Hybrid coatings, which draw on the complementary properties of both inorganic and organic constituents, have demonstrated particular promise in orthopedic and dental contexts where both mechanical integrity and biological activity are required.^9–13

Further investigation and innovation in bioactive coatings offer considerable promise for advancing patient care in biomedical engineering. Enhancing the performance of implantable devices and materials can lead to fewer post-implant complications, faster healing processes, and overall improved clinical outcomes. Nevertheless, several critical aspects must still be carefully examined to ensure successful development and clinical translation. In particular, the long-term stability and biocompatibility of bioactive coatings require more extensive evaluation, and the risks related to coating degradation or functional failure require clearer understanding. Moreover, the application of bioactive coatings to load-bearing orthopedic implants and osseointegrated dental fixtures introduces demanding technical requirements, including resistance to cyclic mechanical loading, long-term chemical stability in physiological fluids, and the capacity to support cell attachment and differentiation over extended periods.^9,14–16

Despite the clear benefits of bioactive coatings, certain limitations remain that must be addressed for reliable clinical use. Long-term durability and sustained bio-functionality are especially important to ensure implant success and patient safety.^14,17–20 Cost is another key factor, as both development and large-scale implementation of these coatings can be cost-prohibitive. The main objective of this review is to present a comprehensive and interdisciplinary overview of the current progress and future prospects of bioactive coatings in biomedical engineering. By classifying these coatings into inorganic, organic, and hybrid categories, the article highlights their distinct characteristics, fabrication methods, and specific roles in improving implant integration and performance.^21–23 In addition, the review critically examines these challenges, including degradation concerns and scalability constraints, while outlining innovative approaches to address them. Ultimately, this work aims to support researchers, clinicians, and industry stakeholders by promoting the development of next-generation bioactive coatings capable of transforming medical implants and enhancing patient care worldwide.^24–28

While several comprehensive reviews have addressed bioactive coatings for orthopedic and dental implants, the majority, including the notable work by Mosas et al., ¹⁴ have focused primarily on material classification, fabrication methods, and general biocompatibility assessments. These contributions have provided valuable foundational knowledge; however, they do not systematically address two critical translational dimensions that are essential for bridging the gap between laboratory research and clinical practice. First, existing reviews typically present in vitro, preclinical in vivo, and clinical data without explicit hierarchical differentiation, which can obscure the evidentiary strength of reported performance claims and hinder researchers’ ability to assess which technologies are truly ready for clinical translation. Second, the regulatory landscape governing bioactive coating approval, including international standards for coating characterization, testing protocols, and quality control, remains conspicuously underexplored in the current literature, despite being a primary barrier to commercialization. The novelty of this review lies in its integrated and comparative treatment of bioactive coatings specifically within orthopedic and dental implantology. Rather than focusing on a single coating type or fabrication method, a unified perspective is offered that spans inorganic, organic, and hybrid systems, with careful attention to their respective mechanical, chemical, and biological performance characteristics. Particular emphasis is placed on long-term stability, osseointegration outcomes, and the translational feasibility of emerging coating strategies, considerations that are essential for advancing implant performance in clinical practice.^29,30

It should be clarified that this work was structured as a narrative review rather than a systematic one; the aim was to bring together a broad, cross-disciplinary picture of where the field currently stands on bioactive coatings for orthopedic and dental implants. No formal systematic protocol was followed. Instead, relevant literature was identified through targeted searches across Scopus, PubMed, Web of Science, and Google Scholar, with the last search update performed in mid-2025. As a result, the reference list spans several decades of work, ranging from foundational studies from the late 1990s up through the most recent papers from 2024 and 2025, though emphasis was placed mainly on publications from the past five years. Search terms included combinations such as bioactive coatings, orthopedic implants, dental implants, hydroxyapatite, magnesium-based alloys, osseointegration, biocompatibility, corrosion resistance, surface modification, and smart coatings, among others. A study was included if it was judged to add something meaningful to the discussion around coating classification, fabrication methods, mechanical performance, biological response, or clinical translation, since these are the core themes around which the review was built. A number of older or foundational papers were retained as well, mainly for historical grounding or methodological context.

2. Types and classification of bioactive coatings

Implant failure can arise from a combination of biological and material-related factors, including inflammation, infection, and fibrous encapsulation due to insufficient bone integration. Mechanical and physicochemical challenges, such as low fracture toughness, fatigue strength, modulus mismatch between the implant and bone (leading to stress shielding), and the generation of particulate debris and ions from corrosion or wear, also contribute significantly, as illustrated in Figure 1.^9,31–33 To address these challenges, bioactive coatings are applied as thin layers of material on the surface of medical devices to enhance biocompatibility and/or impart specific biological functions. These coatings can interact with the surrounding biological environment to promote tissue integration, prevent infection, or deliver therapeutic agents, among other applications.

Figure 1.

Schematic representation of the key causes of implant failure and the mitigating role of new materials and bioactive coatings in improving implant longevity. ⁹

Bioactive coatings can be classified into a unified taxonomy based on coating composition and primary mechanism of action. This framework organizes coatings into four distinct, non-overlapping categories: inorganic/bioceramic coatings, organic/polymeric and protein-based coatings, metallic and metallic-oxide coatings, and composite/hybrid coatings.

2.1. Inorganic/bioceramic coatings

Inorganic coatings, primarily composed of ceramics and bioactive glasses, are widely employed in orthopedic and dental implants due to their excellent biocompatibility and ability to promote direct bone bonding. Hydroxyapatite and other calcium phosphates are the most commonly used materials in this category, as their chemical composition closely resembles the mineral phase of natural bone. These coatings facilitate osseointegration by enabling direct physicochemical bonding with surrounding bone tissue, thereby improving implant stability and long-term fixation. Bioactive glasses, such as 45S5 Bioglass, represent another important subclass, which form a biologically active hydroxycarbonate apatite layer upon exposure to physiological fluids, further enhancing bone regeneration. In addition to orthopedic applications, inorganic coatings are also applied to cardiovascular implants to reduce thrombogenicity. Common fabrication techniques include plasma spraying, electrochemical deposition, and sol-gel processing.^14,34,35

2.2. Organic/polymeric and protein-based coatings

Organic coatings comprise a diverse range of natural and synthetic materials, including polymers, hydrogels, and bioactive proteins. Synthetic biodegradable polymers such as polycaprolactone (PCL), poly (lactic-co-glycolic acid) (PLGA), and polyethylene glycol (PEG) are frequently used to improve biocompatibility, reduce local inflammation, and provide controlled release of therapeutic agents.^36,37 Natural polymers, including chitosan and alginate, offer additional advantages such as inherent antibacterial activity and favorable cell-adhesion properties. Protein-based coatings, incorporating extracellular matrix (ECM) components such as collagen, fibronectin, and laminin, represent a specialized subclass within this organic category. These coatings mimic the native cellular microenvironment, actively promoting cell adhesion, proliferation, and tissue regeneration. In cardiovascular applications, organic coatings are designed to encourage endothelial cell coverage while preventing thrombosis. Fabrication techniques for organic coatings include dip coating, electrospinning, and layer-by-layer assembly.^38–40 The versatility of organic coatings allows them to be tailored for drug-eluting applications, where embedded pharmaceuticals are released locally to modulate the healing response or prevent infection.

2.3. Metallic and metallic-oxide coatings

Metallic coatings, composed of biocompatible metals and their oxides, serve primarily to enhance corrosion resistance, improve mechanical properties, and impart specific biological functionalities. Titanium and its alloys are widely used due to their excellent corrosion resistance and ability to form a stable TiO₂ oxide layer that promotes tissue integration. ⁴¹ Tantalum coatings have also gained attention for their superior osteoconductivity and high fracture toughness. Beyond structural reinforcement, certain metallic coatings are engineered for antibacterial purposes. Silver and copper oxide coatings, for instance, release metal ions that disrupt bacterial cell membranes and inhibit biofilm formation, thereby reducing the risk of peri-implant infection. ³⁶ These coatings are typically applied via physical vapor deposition (PVD), magnetron sputtering, or anodic oxidation. By combining mechanical durability with bioactive functionality, metallic coatings offer a robust solution for load-bearing implant applications.

2.4. Composite/hybrid coatings

Composite or hybrid coatings combine two or more of the above material classes to achieve synergistic multifunctionality that cannot be attained by any single component alone. For example, polymer-ceramic composites integrate the osseointegration capacity of HA or CaP with the drug-delivery capability and mechanical flexibility of biodegradable polymers. Similarly, hybrid organic-inorganic coatings, often fabricated via sol-gel or layer-by-layer deposition, can be designed to simultaneously promote bone bonding, release therapeutic agents, and modulate inflammatory responses. The composition, architecture, and surface topography of composite coatings can be precisely engineered to tailor their biological and mechanical performance. For instance, incorporating bioactive glass nanoparticles into a chitosan matrix enhances both mineralization and antibacterial activity, while the addition of metallic nanoparticles (e.g., silver) further broadens the antimicrobial spectrum.^36,41 This category represents the frontier of bioactive coating design, offering customizable platforms that address the multifactorial challenges of implant failure.

2.5. Coating-tissue interactions and selection criteria

The biological performance of bioactive coatings is governed by a complex interplay of multiple physicochemical and biological factors, including chemical composition, surface topography, wettability, surface charge, and the ability to release therapeutic agents in a controlled manner. Each coating category interacts with the surrounding biological environment through distinct mechanisms that ultimately determine its clinical efficacy.^36,38 Inorganic/bioceramic coatings promote bone growth primarily through direct physicochemical bonding with mineralized bone tissue, a process facilitated by the formation of a carbonated apatite layer on the coating surface upon exposure to physiological fluids. This bone-bonding capacity makes them particularly suitable for load-bearing orthopedic and dental applications where stable long-term fixation is paramount. In contrast, organic/polymeric and protein-based coatings exert their effects through biochemical signaling and physical mimicry of the native ECM. By presenting bioactive ligands and appropriate mechanical cues, these coatings stimulate specific cellular responses, including adhesion, proliferation, and differentiation, while simultaneously reducing local tissue irritation and modulating inflammatory cascades.

Metallic and metallic-oxide coatings facilitate tissue integration through a combination of surface oxide chemistry and topographical features that promote protein adsorption and osteoblast attachment. Additionally, the controlled release of antibacterial metal ions from certain metallic coatings provides a dual function of structural support and infection prophylaxis. Composite/hybrid coatings, by integrating multiple material classes, can orchestrate synergistic tissue responses, such as concurrent osseointegration, angiogenesis, and antibacterial protection, thereby addressing the multifactorial nature of implant failure.^36–40,42 Understanding these differential interaction mechanisms is essential for the rational design and clinical selection of bioactive coatings. The choice of a particular coating system must be guided by the specific biological and mechanical requirements of the intended application, taking into consideration factors such as implant location, loading conditions, patient health status, and the desired biological outcomes. By systematically correlating coating properties with their biological performance, researchers and clinicians can develop tailored coating strategies that optimize implant integration, minimize complications, and ultimately improve patient outcomes.^38,40,43

2.6. Challenges and future perspectives

Although bioactive coatings offer great potential for advancing biomedical applications, their future development and clinical adoption still encounter several critical issues. A key concern is achieving long-term stability and durability within complex physiological environments. These coatings must tolerate mechanical loads, biochemical interactions, and gradual degradation while preserving their biological function. For example, ceramic coatings such as hydroxyapatite are highly effective for osseointegration but can be brittle, making them susceptible to cracking or delamination under stress. Polymer-based coatings, despite their excellent biocompatibility, may gradually degrade and release by-products that can provoke inflammatory reactions. Hybrid coatings, which aim to combine the advantages of both inorganic and organic materials, often suffer from fabrication compatibility problems, rendering large-scale production technically complex and cost-prohibitive.^44,45

Another important issue relates to scalability and cost efficiency. Deposition methods such as plasma spraying or sol-gel processing, while effective, are often expensive and rely on specialized equipment, limiting their widespread implementation. Furthermore, designing coatings with multiple functions, such as antimicrobial activity, controlled drug delivery, or improved mechanical performance, requires precise engineering and extensive testing to comply with safety and regulatory requirements. The response of host tissues to bioactive coatings can also differ widely depending on patient-specific factors such as age, underlying health conditions, and immune status. This variability highlights the growing need for more personalized coating designs, which further complicates the development process.^44,45 Progress in this field will depend on close collaboration between materials scientists, engineers, and clinicians to develop solutions that successfully balance performance, reliability, and affordability in medical device coatings. Future research directions should focus on advanced fabrication techniques, predictive computational modeling of coating-tissue interactions, and the development of smart, stimuli-responsive coatings that can adapt to changing physiological conditions, thereby realizing the full translational potential of bioactive surface engineering.^46–48

3. Fabrication techniques and comparative analysis

3.1. Techniques for applying bioactive coatings

Various methods exist for applying bioactive coatings to implantable devices and materials (Figure 2). The choice of method depends on the properties of the coating and the substrate material, as well as the intended clinical application of the device.

Figure 2.

Relative preparation methods of different types of coatings with kind permission from. ³⁸

Some common methods include physical vapor deposition (PVD), electrospinning, sol-gel coating, dip coating, spray coating, plasma spraying, and layer-by-layer assembly.^49–51 Each method has its advantages and drawbacks, and the selection depends on the specific coating and substrate properties and the desired application. By understanding the principles of each method and its interaction with both the coating material and the substrate, researchers can develop tailored coatings to improve patient outcomes.

3.2. Comparative analysis of application methods for bioactive coatings

Applying bioactive coatings to implantable medical devices involves a range of techniques, each offering unique advantages and facing specific challenges. These methods play an important role in enhancing the functional and structural characteristics of coatings, ensuring optimal performance and biocompatibility tailored to medical applications. Below, we explore the most common methods, their benefits, and limitations, as detailed in various studies.^1,50–52

3.2.1. Physical vapor deposition (PVD)

Physical vapor deposition is a leading technique for producing high-quality and uniform coatings with excellent adhesion to substrates. It provides precise control over coating thickness and composition, making it particularly suitable for applications requiring precise material properties. However, its high equipment costs, limited scalability, and challenges in coating complex geometries remain significant barriers to broader use.^1,50

3.2.2. Electrospinning

Electrospinning is renowned for its ability to produce porous coatings with fine control over thickness and composition, which is particularly advantageous for incorporating therapeutic agents into the coating matrix. Its compatibility with diverse substrates further broadens its biomedical applications. Nonetheless, electrospun coatings may suffer from poor adhesion on certain substrates, limited scalability, and difficulty in uniformly coating intricate geometries, which limits their applicability in some contexts.^38,52

3.2.3. Sol-gel coating

The sol-gel coating method is valued for its ability to produce highly uniform coatings with exceptional purity and homogeneity. It offers precise control over coating thickness and composition, along with compatibility across a range of substrates. However, the method is constrained by challenges such as limited scalability, relatively low achievable coating thickness, and difficulty in applying coatings to complex geometries, which restricts its use in certain applications.^39,50

3.2.4. Dip coating

Dip coating stands out for its simplicity and cost-effectiveness, offering a straightforward approach to creating uniform coatings with adjustable thickness. This method is compatible with a variety of substrates and offers a dependable and accessible option for many applications. However, its inability to adequately coat complex geometries, challenges with scalability, and susceptibility to issues such as cracking or peeling can limit its effectiveness.^38,52

3.2.5. Spray coating

Spray coating offers distinct advantages in its ability to coat complex geometries at high deposition rates. It provides control over coating thickness and composition, making it versatile for a range of substrate types. Despite these benefits, achieving uniform coatings can be difficult, and issues such as overspray, material waste, and limited incorporation of therapeutic agents present challenges to its broader adoption.^38,52

3.2.6. Plasma spraying

Plasma spraying is a preferred method for applications requiring thick coatings and compatibility with various substrates. It offers high deposition rates and is particularly effective for coating complex geometries. However, its drawbacks include limited control over coating composition and thickness, poor adhesion to some substrates, and challenges in achieving uniform coatings, which can impede its use in specific medical device applications.^39,52

3.2.7. Layer-by-layer assembly

Layer-by-layer assembly is an advanced technique for creating highly uniform coatings with precise control over thickness and composition. Its compatibility with diverse materials and substrates makes it highly adaptable for various biomedical applications. Nevertheless, the method is constrained by limited scalability, difficulty in coating complex geometries, and challenges in creating thicker coatings or embedding therapeutic agents effectively.^50,52

In summary, each coating technique offers unique opportunities and constraints, underscoring the importance of selecting a method based on the specific requirements of the substrate and the intended application. By understanding these nuances, researchers and engineers can optimize the performance of medical devices, leveraging the strengths of these techniques to advance biocompatibility and functionality, ultimately improving patient outcomes.

3.3. Effective factors for choosing a bioactive coating method

Choosing the optimal method for applying bioactive coatings to implantable devices and materials is a multifaceted decision that demands careful evaluation of several key factors. These factors include the properties of both the substrate material and the coating material, the specific requirements of the intended application, practical manufacturing considerations, and the stringent regulatory standards governing medical devices. The substrate material, whether metallic, polymeric, or ceramic, significantly influences the choice of coating method. Metals, commonly used for orthopedic or cardiovascular implants, typically demand coatings with robust adhesion and corrosion resistance. Polymers, used in applications such as drug delivery systems, require compatibility with more delicate coating techniques that do not compromise the substrate’s structural integrity. Ceramics, valued for their biocompatibility and mechanical stability, often benefit from coatings that enhance their biological functionality without altering their intrinsic properties. The characteristics of the desired coating, such as its thickness, porosity, and composition, also play a pivotal role. For instance, thinner coatings with high uniformity may necessitate techniques like PVD, while thicker, porous coatings for applications such as orthopedic implants might require plasma spraying or electrospinning. The coating’s porosity can influence its biological performance, such as promoting cell adhesion or enabling controlled drug release, making it a critical parameter in the design of effective bioactive coatings.

Application-specific requirements further refine the choice of coating method. Devices exposed to mechanical stresses, such as joint implants, require coatings that can endure mechanical stress without undergoing degradation. Similarly, stents used in cardiovascular interventions may necessitate coatings that support endothelialization while resisting restenosis. Matching the coating method to the mechanical and biological demands of the device is essential for its success in clinical settings. Practical manufacturing considerations, including scalability, cost-effectiveness, and process reproducibility, are equally important. Advanced deposition techniques like PVD or plasma spraying, while delivering high-quality results, often come with substantial equipment costs and limited scalability. Conversely, simpler methods such as dip coating or spray coating may offer greater economic feasibility for large-scale production but may compromise precision or uniformity. Regulatory requirements present another layer of complexity in the decision-making process. Medical devices must adhere to stringent safety and efficacy standards, with coatings often undergoing rigorous testing to demonstrate biocompatibility, stability, and performance. The selected coating method must not only meet these criteria but also ensure compliance with stringent international standards and guidelines, which can influence the choice of both materials and processes.

By meticulously evaluating these diverse factors-material and coating properties, application-specific needs, manufacturing constraints, and regulatory compliance-researchers and manufacturers can make informed decisions. This systematic approach ensures the selection of the most suitable bioactive coating method, ultimately enhancing the performance, safety, and reliability of medical devices.^37,49,51

4. Key properties of bioactive coatings

4.1. General properties of bioactive coatings

Enhancing the properties of bioactive coatings is important for improving their performance in applications such as orthopedic and dental implants, as well as drug delivery systems. Several methods can be used to enhance these properties:

• 1. Biocompatibility: Bioactive coatings can be made more biocompatible by incorporating bioactive agents or surface-modifying agents. For example, graphene oxide (GO) can interact with cells and growth factors, promoting cell adhesion, growth, and differentiation. Bioactive peptides can also be used to modify the coating surface, leading to enhanced bone formation. ⁵³

• 2. Corrosion behavior: The corrosion behavior of bioactive coatings can be improved by optimizing their composition and structure, as Figure 3. Adding metal ions, such as nano zinc ions, to calcium phosphate coatings can enhance corrosion resistance and biocompatibility. ⁵⁴ These improvements were not simply reported in the literature but were confirmed experimentally in our own laboratory, where potentiodynamic corrosion testing and in-vitro antibacterial assays on nitrided NiTi substrates provided direct evidence for the enhanced corrosion resistance and biocompatibility of the coating. ⁵⁴

• 3. Mechanical properties: The mechanical properties of bioactive coatings can be enhanced by incorporating reinforcing agents or optimizing the fabrication process. For example, a composite coating of hydroxyapatite and graphene oxide on titanium substrates can improve hardness and elastic modulus. Laser cladding can also be used to prepare bioactive glass coatings on titanium substrates, resulting in improved mechanical properties and bioactivity.^55,56

• 4. Multifunctionality: Some studies aim to enhance multiple properties of bioactive coatings simultaneously, in addition to the aforementioned approaches. For example, in a study by Askarnia et al., ⁵⁷ a composite coating consisting of hydroxyapatite, graphene oxide, and chitosan was prepared on magnesium substrates, resulting in improved biocompatibility, corrosion resistance, and mechanical properties. The authors attributed the multifunctional properties of the coating to the synergistic effect of the individual components.

Figure 3.

(a) Potentiodynamic plots of the nickel–titanium (NiTi) alloy after immersion for 24 h, and of hydroxyapatite (HA)-coated, nitrided NiTi, nano-hydroxyapatite (NHA)-coated, and ciprofloxacin-loaded nano-hydroxyapatite (NHACip)-coated samples after immersion for 120 h in simulated body fluid (SBF); (b) Equivalent electrical circuits of hierarchical coatings used for investigating corrosion behavior, with kind permission from. ⁵⁴

The studies mentioned discuss various strategies to enhance the properties of bioactive coatings, including incorporating bioactive agents, surface-modifying agents, and reinforcing agents, as well as optimizing the coating fabrication process. The choice of strategies and materials depends on the specific application and requirements. Improving the properties of bioactive coatings is important for enhancing their performance in orthopedic and dental implants, as well as in drug delivery systems. Biocompatibility can be increased through the use of bioactive agents or surface-modifying agents such as graphene oxide (GO) and bioactive peptides. Corrosion behavior can be improved by adjusting the composition and structure of the coatings for example, by adding nano-zinc ions to calcium phosphate coatings. ⁵⁸ Reinforcing agents and optimization of the fabrication process can enhance the mechanical properties of the coatings. One example is the use of a composite coating made of hydroxyapatite and graphene oxide to improve hardness and elastic modulus. Additionally, laser cladding can be employed to prepare bioactive glass coatings, resulting in improved mechanical properties and bioactivity.

4.2. Biocompatibility

Bioactive coatings can improve the biocompatibility of implantable devices by promoting cell adhesion, proliferation, and differentiation, thereby enhancing the integration of the implant with surrounding tissue and helping to prevent infection. However, the biocompatibility of these coatings depends on several factors, including the coating material, the application method, and the specific requirements of the application (see Figure 4). By understanding these factors, researchers can develop coatings that optimize the performance of implantable devices and improve patient outcomes.

Figure 4.

A schematic of parameters affecting the biocompatibility of materials, with kind permission from. ⁵⁹

Bioactive coatings promote biocompatibility with biological tissue by enhancing cell adhesion and signaling, releasing therapeutic agents, and preventing bacterial growth. This leads to improved tissue response, faster healing processes, and effective infection prevention.^59–61 Tissue response is enhanced by providing a surface that mimics the extracellular matrix, promoting cell adhesion and signaling for better tissue growth and integration with the implant. The healing process is improved by releasing therapeutic agents-such as growth factors or antimicrobial compounds-that promote tissue regeneration and prevent infection. Infection prevention is achieved by reducing bacterial adhesion and growth on the implant’s surface, either through the release of antimicrobial agents or by modifying the surface properties.^62,63

Examples of bioactive coatings include hydroxyapatite coatings, which mimic bone tissue; antibiotic-releasing coatings for preventing infection; and silver-containing coatings that inhibit bacterial growth. For instance, a coating may contain silver nanoparticles that are released over time. These nanoparticles can interact with the bacterial cell wall, disrupting its structure and function and leading to cell death.^54,64,65 By understanding the mechanisms of biocompatibility, researchers can design and optimize bioactive coatings for specific applications, thereby improving the performance and safety of implantable devices.

4.2.1. The relation between biocompatibility and corrosion behavior of bioactive coatings

The biocompatibility and corrosion behavior of bioactive coatings are closely interconnected. The formation of a dense and uniform coating structure enhances both the corrosion resistance and biocompatibility of the coating. Such a structure reduces the corrosion rate, limits the release of toxic ions, and creates a more favorable environment for cell attachment and growth. Corrosion behavior influences biocompatibility by affecting ion release and the local cellular environment, while biocompatibility can, in turn, impact corrosion behavior by influencing the corrosion rate and the long-term stability of the coating. Therefore, it is essential to consider both properties when designing and optimizing bioactive coatings for specific applications.^66–70

4.2.2. Mechanisms of biocompatibility in bioactive coatings

The biocompatibility of bioactive coatings with biological tissues hinges on their ability to promote cellular interactions, deliver therapeutic agents, and inhibit bacterial colonization. These mechanisms collectively enhance tissue integration, accelerate healing, and prevent infections, ultimately improving patient outcomes. The following section provides an overview of these mechanisms and examines how specific bioactive coatings achieve these effects.^60,61,64,71

4.2.2.1. Enhancing tissue response

One of the primary functions of bioactive coatings is to facilitate a favorable tissue response by mimicking the extracellular matrix (ECM) of the surrounding biological environment. This biomimicry promotes cellular adhesion, proliferation, and signaling, creating an interface conducive to tissue integration. For example, bioactive coatings can be engineered to incorporate specific proteins or peptides, such as RGD (arginine-glycine-aspartate) sequences, which are recognized by cell surface receptors. These biofunctional molecules facilitate integrin-mediated adhesion, triggering downstream signaling pathways that stimulate cell growth and differentiation. This process supports the natural and seamless integration of the implant with the host tissue, reducing the likelihood of inflammation or rejection. The result is improved implant stability and long-term functionality.

4.2.2.2. Accelerating the healing process

Bioactive coatings also play a pivotal role in the healing process by acting as reservoirs for therapeutic agents, including growth factors, anti-inflammatory compounds, or antimicrobial agents. These coatings enable the controlled release of these agents at the implantation site, providing a localized therapeutic effect. Growth factors such as bone morphogenetic proteins (BMPs) or vascular endothelial growth factors (VEGFs) can be incorporated into bioactive coatings to stimulate tissue regeneration. By releasing these agents in a time-dependent manner, the coating provides sustained support for cell proliferation and matrix remodeling, thereby accelerating wound healing and tissue repair. In addition, bioactive coatings can deliver antimicrobial agents, helping to prevent infections during the critical postoperative period. This localized delivery reduces the need for systemic treatments, minimizing potential side effects while maximizing efficacy at the target site.

4.2.2.3. Preventing infection

Another critical aspect of biocompatibility is the ability of bioactive coatings to prevent bacterial adhesion and growth, which are major concerns for implantable devices. Bacteria can form biofilms on implant surfaces, leading to persistent infections that are challenging to treat. Bioactive coatings address this issue through various strategies. Some are embedded with antimicrobial agents, such as antibiotics or metal nanoparticles-that are released over time to inhibit bacterial colonization. Others are engineered with specific surface properties, such as hydrophobicity or nanoscale roughness, that deter bacterial adhesion. These coatings not only provide immediate protection but also help maintain a sterile environment around the implant for extended periods.

In summary, bioactive coatings rely on a range of mechanisms to improve biocompatibility, facilitating smooth interactions with biological tissues and enhancing the overall performance of medical implants. These approaches include encouraging cell attachment, supporting tissue regeneration, enabling the controlled release of therapeutic agents, and preventing bacterial growth. By addressing key challenges in medical device applications, such strategies contribute to better implant performance and improved patient outcomes. The examples below illustrate how these mechanisms play a role in increasing the effectiveness and reliability of implantable devices.

4.2.2.4. Hydroxyapatite coatings

Hydroxyapatite coatings are widely used to enhance the biocompatibility of orthopedic and dental implants. HA closely resembles the mineral composition of natural bone, facilitating the formation of a bone-like layer around the implant. This biomimetic property promotes osseointegration, ensuring long-term stability and reducing the risk of implant failure. Advanced hydroxyapatite coatings may also be functionalized with peptides or growth factors to further enhance cell adhesion and signaling. This tailored approach not only improves the immediate tissue response but also supports long-term integration and healing.^60,72,73

4.2.2.5. Antibiotic-releasing coatings

Coatings designed to release antibiotics address the dual challenge of enhancing biocompatibility while preventing infections. These coatings provide localized antibiotic delivery, targeting bacteria at the implantation site without exposing the entire body to systemic antibiotics. This approach reduces the risk of systemic toxicity and helps mitigate antibiotic resistance. The release profile of antibiotics can be finely tuned, allowing for sustained protection over weeks or even months. This prolonged effect is particularly valuable for preventing infections during the critical period of tissue integration.^61,74

4.2.2.6. Silver-containing coatings

Silver-containing coatings represent another effective strategy for preventing infections. Silver nanoparticles, known for their broad-spectrum antimicrobial properties, are embedded within the coating matrix. These nanoparticles interact with bacterial cell walls, disrupting their structure and metabolic processes and ultimately leading to cell death. The gradual release of silver ions ensures long-lasting antimicrobial activity without compromising the biocompatibility of the implant. Additionally, the nanoscale features of these coatings can deter bacterial adhesion, further enhancing their effectiveness. ⁶⁴

4.2.2.7. Advancing biocompatibility through innovation

Understanding the mechanisms of biocompatibility enables researchers to design bioactive coatings tailored to specific applications. Whether promoting cell adhesion, delivering therapeutic agents, or preventing infections, these coatings address critical challenges associated with implantable devices. Continued advancements in materials science, nanotechnology, and bioengineering hold promise for the development of next-generation coatings that combine enhanced functionality, safety, and efficacy. By leveraging these innovations, bioactive coatings are poised to revolutionize the performance and safety of medical implants, ultimately improving outcomes for patients worldwide.^61,64

4.2.3. Distinguishing in vitro, in vivo, and clinical evidence of biocompatibility

Much of the reported biocompatibility of bioactive coatings still rests on in vitro assays cell viability tests, MTT assays, and short-term proliferation studies conducted on osteoblast or fibroblast lines. These platforms are convenient and reproducible, yet they cannot capture the complexity of a living organism: there is no blood flow, no immune surveillance, and no mechanical loading comparable to what an implant experiences inside the body. In vivo studies close some of this gap by exposing coatings to systemic factors such as vascularization, inflammatory cascades, and the foreign-body response, which often reveal outcomes that in vitro data alone would not predict.^75,76 For instance, a coating showing excellent cell attachment on a culture plate may still trigger a fibrous capsule or delayed bone apposition once implanted in an animal model. This discrepancy is not a flaw in either method but a reminder that the two operate at fundamentally different levels of biological complexity, and conclusions drawn from one should not be extrapolated uncritically to the other.

Clinical evidence, where it exists, adds a further layer that neither in vitro nor animal data can fully substitute. Human physiology, patient comorbidities, mechanical demand, and years-long follow-up periods introduce variables that laboratory and preclinical models simply cannot reproduce. Unfortunately, long-term clinical outcome data for many bioactive coatings, particularly newer nanostructured or hybrid formulations remain scarce, largely because regulatory pathways and follow-up registries have not kept pace with material innovation.^77,78 As a result, most claims of “biocompatibility” in the current literature are supported at the in vitro or, at best, short-term in vivo stage, while clinical validation lags considerably behind. Going forward, biocompatibility should be reported with explicit reference to its evidentiary level, in vitro, preclinical in vivo, or clinical rather than treated as a single, undifferentiated property, since conflating these stages risks overstating the maturity of a given coating technology.

4.3. Porosity of bioactive coatings

4.3.1. Influence of porosity on the implant’s mechanical and biological properties

The porosity of a coating on an implant can significantly affect its mechanical and biological properties (see Figure 5). A highly porous coating can make the implant less stiff and more prone to deformation, whereas a less porous coating can increase rigidity. Porosity also influences the fatigue strength of the implant, with more porous coatings being more likely to fail under cyclic loading.^79–81 From a biological perspective, a highly porous coating can improve tissue integration and regeneration but may also increase the risk of infection. Conversely, a less porous coating can reduce the risk of infection but may limit tissue integration and regeneration. The optimal porosity depends on several factors, including the type of implant, its anatomical location, and intended use. Various coating techniques, such as plasma spraying, can be employed to control the porosity of the coating. Overall, the porosity of the coating plays a critical role in determining the overall performance of the implant and can be tailored to meet the requirements of specific applications.^82,83

Figure 5.

Scanning electron microscopy (SEM) micrographs of scaffolds composed of polycaprolactone (PCL), polylactic acid (PLA), and gelatin nanofibers (GNF) incorporated with taurine (Tau): (a) PCL/PLA/GNF; (b) PCL/PLA/GNF/Tau 0.1%; (c) PCL/PLA/GNF/Tau 1%; and (d) PCL/PLA/GNF/Tau 10%, with kind permission from. ⁷⁹

4.3.2. Effect of the dense coating on tissue regeneration

Dense coatings, typically crafted from ceramics or metals, serve as a foundation for engineering implantable devices with enhanced regenerative capabilities. By modifying the surface chemistry, topography, or by incorporating bioactive molecules into these coatings, their potential to stimulate tissue regeneration and improve device integration is significantly elevated. Each of these approaches plays a distinct yet interrelated role in enhancing cellular and tissue responses, ultimately contributing to better patient outcomes. Surface chemistry is pivotal in determining cellular responses such as adhesion, proliferation, and differentiation. Chemical modifications can influence wettability, surface charge, and the availability of functional groups, thereby enhancing protein adsorption and subsequent cellular attachment. For example, the incorporation of bioactive ions such as calcium and phosphorus mimics the mineral composition of bone, promoting osteoconduction and supporting bone tissue growth. Additionally, functionalization with amino or carboxyl groups can enhance interactions with specific proteins in the extracellular matrix (ECM), creating a favorable environment for cell signaling and tissue regeneration. Advanced techniques such as plasma spraying, ion implantation, or chemical vapor deposition allow for precise control over these chemical alterations.^84–86

The micro- and nanoscale physical features of dense coatings also significantly influence their interaction with cells. By engineering the surface topography, coatings can provide mechanical cues that guide cell adhesion, migration, and orientation. Structures such as ridges, grooves, and nanopores mimic the natural ECM, enabling better integration with surrounding tissues. For instance, nanoscale roughness on titanium implants has been shown to enhance osteoblast adhesion and proliferation, thereby accelerating osseointegration. Techniques like laser surface texturing, electrochemical etching, and nanoimprinting offer precise control over topographical modifications, ensuring optimal cellular responses tailored to specific applications.^87–89

Embedding bioactive molecules within dense coatings further elevates their regenerative potential by actively modulating biological processes at the implant site. Growth factors such as BMP-2 or VEGF can be immobilized or encapsulated within the coating to stimulate cell differentiation and promote vascularization, respectively. Similarly, coatings that release antimicrobial agents-such as silver nanoparticles or antibiotic compounds-help reduce the risk of infection. Advanced fabrication methods, including sol-gel encapsulation, layer-by-layer assembly, and electrophoretic deposition, ensure that bioactive molecules remain stable and are released in a controlled manner, thereby maintaining their therapeutic efficacy over time.

The most effective strategies often combine chemical, topographical, and molecular modifications to create multifunctional coatings tailored to specific clinical scenarios. For instance, a dental implant coating might integrate nanoscale roughness to improve mechanical stability, chemical groups to enhance protein binding, and slow-releasing antimicrobial agents to prevent infection. Similarly, orthopedic implants benefit from coatings that combine osteoconductive ceramics with growth factor-loaded reservoirs, promoting robust bone regeneration and integration. By applying these combined approaches, dense coatings can effectively support tissue engineering goals, leading to enhanced functionality and improved biocompatibility of medical implants.^80,82,90 Ongoing research and continued advances in surface modification methods remain important for further refining these coatings, ensuring they perform reliably and meet the stringent requirements of a wide range of clinical applications.

4.4. Mechanical properties of bioactive coatings

Bioactive coatings are an important component of medical implants, as they play a pivotal role in achieving seamless integration with biological tissues while maintaining the functionality and durability of the device. These coatings are engineered not only to promote biocompatibility but also to provide mechanical strength and resilience, ensuring long-term performance under the demanding conditions of the human body. Their mechanical properties-such as hardness, toughness, adhesion strength, elastic modulus, wear resistance, and fatigue resistance are critical in addressing challenges like mechanical loading, wear, corrosion, and cyclic stress. To achieve optimal outcomes, these properties must be carefully tailored to complement the substrate material, ensuring mechanical compatibility and stability.

Research by Meghwal et al. ⁹¹ highlights the multiscale mechanical performance of high-entropy alloy coatings, demonstrating promising corrosion behavior and mechanical integrity, which are important for load-bearing applications. This study underscores the importance of selecting materials that exhibit both mechanical robustness and biocompatibility when designing implants. Similarly, Lin et al. ⁹² explored hybrid ZnO/chitosan antimicrobial coatings for titanium implants, reporting enhanced mechanical and bioactive properties. The combination of these materials not only improves mechanical strength but also addresses the critical issue of bacterial infections, which can significantly compromise implant success. Ballarre et al. ⁹³ presented a versatile coating system based on silica, gentamicin, and chitosan, which improved the early-stage performance of titanium implants. The incorporation of gentamicin not only offers antibacterial properties but also contributes to the mechanical stability of the coating, ultimately enhancing overall implant performance.

The limitations of bioactive glasses have been widely reported in the literature. Studies by Mosas et al. ¹⁴ and Sha et al. ⁹⁴ point out that these materials tend to be brittle and exhibit low mechanical strength, which restricts their direct use in load-bearing situations. To address this, the authors suggest using bioactive glasses as coatings rather than as bulk materials. In this way, the mechanical strength of the underlying metal alloys can be utilized, resulting in a composite system that combines structural support with biological functionality. Such an approach plays an important role in designing implants that can tolerate the complex and repetitive forces present in the human body. The following section outlines the most important mechanical properties associated with bioactive coatings.

4.4.1. Hardness

Hardness is a cornerstone of bioactive coating performance, particularly in implants subjected to abrasive and compressive forces, such as joint replacements and dental implants. Hard coatings resist wear and maintain surface integrity, which is essential for reducing the release of wear particles that could trigger inflammation or osteolysis. Ceramics like hydroxyapatite and zirconia are widely used for their high hardness, helping them withstand significant wear in load-bearing applications. However, excessive hardness can introduce brittleness, increasing the likelihood of cracks and coating failure under mechanical stress. Conversely, toughness ensures that coatings can absorb energy and resist crack propagation, providing resilience under both dynamic and static loads. Composite coatings, which blend the hardness of ceramics with the ductility of metals such as titanium, have emerged as a promising solution to balance hardness and toughness, making implants more durable in demanding environments.^95–99

4.4.2. Adhesion strength

The bond strength between the bioactive coating and its substrate is critical to the reliability of implantable devices. Adhesion strength must be sufficient to prevent delamination, particularly under high mechanical loads or during prolonged use. Poor adhesion can lead to exposure of the substrate, increasing the risk of implant failure and adverse biological responses, such as inflammation or infection. Adhesion strength depends on factors such as substrate surface preparation, coating deposition technique, and the chemical interactions between the coating and substrate. Methods like plasma spraying, PVD, and electrochemical deposition are widely employed to achieve robust adhesion. Surface modifications such as grit blasting, laser etching, or applying an intermediate bonding layer further enhance adhesion. For instance, titanium substrates are often roughened to improve the bonding of hydroxyapatite coatings, creating a mechanically interlocked interface that enhances the implant’s longevity and stability. ¹⁰⁰

4.4.3. Elastic modulus and stress compatibility

The elastic modulus of a bioactive coating is a measure of its stiffness and its ability to deform elastically under stress. To ensure mechanical compatibility, the modulus of the coating should be tailored to align with that of the surrounding biological tissues and the implant substrate. A mismatch in elastic modulus can lead to stress shielding, where the implant bears the majority of the mechanical load, reducing stress on adjacent bone and potentially causing bone resorption and implant loosening. Hydroxyapatite, with an elastic modulus of approximately 70-100 GPa, provides better compatibility with bone (10-30 GPa) compared to metallic substrates like titanium alloys, which have a modulus of 100-120 GPa. Coatings with a gradient structure or hybrid composition are being developed to bridge these differences, ensuring better load distribution and minimizing stress concentrations at the coating-substrate interface.^101,102

4.4.4. Wear and fatigue resistance

Wear resistance is vital for implants in high-friction environments, such as joint replacements. The durability of bioactive coatings depends on their ability to withstand repeated mechanical contact without degradation. Ceramic coatings like HA and bioactive glasses are renowned for their wear resistance, but their inherent brittleness may lead to failure under certain conditions. To address this, composite and functionally graded coatings-which combine the superior wear resistance of ceramics with the flexibility of metals-are gaining traction. Fatigue resistance, defined as a coating’s ability to endure cyclic mechanical loading, is equally critical for implants in dynamic environments. Microstructural features such as grain size, porosity, and phase composition significantly influence fatigue performance. Dense coatings with minimal defects are more resistant to fatigue-induced cracks, thereby extending the implant’s lifespan.^103–105

In summary, the mechanical properties of bioactive coatings-hardness, toughness, adhesion strength, elastic modulus, and wear and fatigue resistance-must be intricately designed to meet the unique demands of medical implants. Advances in materials engineering, including the development of composite coatings and surface modification techniques, are providing innovative solutions to optimize these properties. ¹⁰⁶ As a result, bioactive coatings continue to improve implant performance, ensuring better integration, durability, and patient outcomes in diverse biomedical applications. Interfacial adhesion still stands out as perhaps the single most decisive factor shaping the clinical fate of a bioactive coating, given that even a mechanically robust layer can fail catastrophically once the bond to the underlying substrate is compromised. During deposition, residual stresses tend to build up at the coating-substrate interface, particularly in plasma-sprayed or PVD-derived ceramic layers, largely as a result of mismatches in thermal expansion and elastic modulus, leaving behind latent sites where cracks can initiate. It has been shown that graded interlayers incorporating titanium-hydroxyapatite compositional transitions can reduce interfacial shear stress by more than 30%, substantially delaying the onset of delamination under simulated physiological loading.^107–109 Such graded architectures work by distributing mechanical strain across a broader interfacial zone rather than letting it concentrate at a single discontinuous boundary, which directly tackles one of the most persistent causes of early implant failure: coating detachment under repeated mechanical insult. For this reason, adhesion optimization is no longer viewed as a secondary finishing step but rather as a primary design parameter, one that needs to be built into the coating architecture from the very earliest stages.

Beyond static adhesion, what really determines whether early mechanical success translates into lasting clinical performance is how a bioactive coating holds up under cyclic physiological loading over time. Orthopedic and dental implants routinely undergo millions of loading cycles each year, and even microscopic flaws can grow into macroscopic cracks through fatigue-driven mechanisms if the coating lacks sufficient fracture toughness. Hybrid polymer-ceramic composite coatings have emerged as a particularly effective way to counter this, since the ductile polymeric phase is able to absorb and redistribute strain energy that would otherwise drive brittle crack propagation through a purely ceramic matrix. Incorporating a polycaprolactone interlayer within a bioactive glass coating was found to extend fatigue life by nearly threefold compared with monolithic ceramic controls under cyclic compressive testing.^107,108 Wear resistance benefits in a similar way within these hybrid systems, as the composite structure limits third-body abrasive damage caused by micro-debris at the implant–tissue interface. Taken together, these observations suggest that fatigue and wear resistance are attributes that need to be engineered jointly rather than treated as separate, unrelated coating properties.

Finally, the long-term chemical and structural stability of bioactive coatings within the body’s aggressive, electrolyte-rich environment remains an unresolved challenge, and one that has a direct bearing on implant survivorship over years of service. Hydrolytic degradation, localized pitting corrosion, and the gradual dissolution of calcium-phosphate phases can slowly weaken the coating–substrate bond long after initial osseointegration has already occurred, sometimes only becoming clinically apparent several years down the line. Self-healing coating strategies are emerging as a promising response to this problem: microencapsulated corrosion inhibitors or reactive sol-gel matrices can be triggered upon micro-crack formation, offering a route toward autonomous repair without the need for surgical intervention. Self-healing silane-based coatings applied to titanium substrates were shown to retain more than 85% of their original adhesion strength after twelve months of simulated body fluid immersion, considerably outperforming conventional static coatings.^109–113 Systems of this kind mark a meaningful shift away from passive protective layers and toward interfaces that respond dynamically to damage as it occurs. As the field continues to mature, combining self-healing functionality with the adhesion- and fatigue-optimized architectures discussed above will likely shape the next generation of clinically durable bioactive coatings.

4.5. Potential risks of bioactive coatings

The degradation or failure of bioactive coatings on medical devices can pose significant risks to patient health. Some of the potential risks associated with such degradation or failure are outlined below:

4.5.1. Inflammation and infection

The degradation or failure of bioactive coatings can lead to the release of toxic or inflammatory substances, which may cause local inflammation or infection. This can result in implant failure, tissue damage, and systemic infections. For example, in a study by Tian et al., ¹¹⁴ the degradation of a magnesium alloy implant coating led to a local inflammatory response and an increased risk of infection. Their results demonstrated that, given the extremely complex biological environment in the human body, composite coatings may be promising due to their combined properties. However, as the number of interfaces in composite coatings increases, the adhesion strength not only between the coating and substrate but also at the interfaces of different layers must be carefully considered. A lack of adhesion strength at any interface poses a potential risk of coating delamination.

4.5.2. Implant loosening or migration

The degradation or failure of bioactive coatings can lead to implant loosening or migration, which may cause pain, discomfort, and reduced mobility. This can also result in implant failure and the need for revision surgery. In a study by Kenney et al., ¹¹⁵ the failure of a bioactive coating on a hip implant resulted in implant loosening and necessitated revision surgery.

4.5.3. Corrosion of the implant

The degradation or failure of bioactive coatings can lead to corrosion of the underlying implant, which may cause the release of metal ions or particles into the body. This can result in adverse local or systemic reactions, such as metal allergy, hypersensitivity, or toxicity. For example, in a study by Saberi et al., ¹¹⁶ the corrosion of a magnesium alloy implant coating led to the release of magnesium ions, resulting in local tissue inflammation and systemic toxicity.

4.5.4. Delayed healing

The degradation or failure of bioactive coatings can lead to delayed healing or impaired tissue integration, which may result in implant failure or a reduced implant lifespan. In a study by Kligman et al., ¹¹⁷ the failure of a bioactive coating on a dental implant resulted in delayed osseointegration and reduced implant stability. The risks associated with the degradation or failure of bioactive coatings highlight the importance of proper design, rigorous testing, and ongoing monitoring of these coatings to ensure patient safety and the effectiveness of medical devices. By addressing these risks, researchers and manufacturers can improve the quality and safety of bioactive coatings and enhance the overall success of medical implants.

5. Evaluation methods for bioactive coatings

5.1. Methods of evaluating bioactive coatings

Evaluating the biocompatibility and corrosion behavior of bioactive coatings is essential for assessing their performance and safety in biomedical applications. A variety of methods are available to evaluate these properties.

For biocompatibility evaluation^118–120:

• o Cell Viability Assays: These assays measure the viability and proliferation of cells cultured on the coating using various quantitative methods.

• o Cell Attachment and Spreading Assays: These techniques assess the attachment and spreading behavior of cells on the coating surface, typically using microscopy.

• o Immunohistochemistry Assays: These methods evaluate the expression of specific proteins and cellular markers in response to the coating.

• o Cytotoxicity Assays: These tests determine the potential toxic effects of the coating on cells.

• o In Vitro Cell Culture Models: Advanced models, such as 3D or co-culture systems, are used to better mimic the in vivo environment and assess biocompatibility under more physiologically relevant conditions.

• o In Vivo Animal Models: These studies evaluate the tissue response to the coating in a living organism, providing critical data on biocompatibility and integration.

For corrosion behavior evaluation:

• o Electrochemical Impedance Spectroscopy (EIS): This technique measures the electrical impedance of the coating to evaluate its corrosion behavior and protective properties.

• o Potentiodynamic Polarization: This method measures current density as a function of potential to assess the corrosion behavior and corrosion rate of the coating.

• o Electrochemical Noise Analysis: This technique measures fluctuations in corrosion potential and current to evaluate the corrosion behavior and rate.

• o X-ray Photoelectron Spectroscopy (XPS): This surface-sensitive technique analyzes the elemental composition and chemical states to evaluate corrosion behavior and coating degradation.

• o Atomic Force Microscopy (AFM): This method visualizes surface topography and roughness at the nanoscale to assess corrosion-related changes and degradation.

• o Scanning Electron Microscopy (SEM) and Energy-Dispersive X-ray Spectroscopy (EDS): These techniques are used to visualize surface morphology and analyze elemental composition, providing insight into corrosion behavior and coating degradation.

The choice of evaluation methods for bioactive coatings depends on the specific requirements of the intended application and the characteristics of the coating itself. Employing a combination of these techniques provides a comprehensive assessment of both biocompatibility and corrosion resistance. This integrated approach supports the development of improved coatings with enhanced performance and safety for medical devices.^121,122

5.2. In-vivo test

5.2.1. In-vivo animal models

In vivo animal models are commonly used to study the biocompatibility and corrosion behavior of bioactive coatings. These models help researchers understand how the coating interacts with surrounding tissues and affects the body as a whole. The most frequently used animal models in this research include rats, rabbits, and pigs. Rats are widely used in orthopedic and dental implant studies because their bone structure and physiology share similarities with those of humans. Rabbits, due to their larger size and specific anatomical sites, are often employed in cardiovascular and orthopedic implant research. Pigs are also commonly used in orthopedic and dental implant studies, as their bone structure and physiology closely resemble those of humans. ¹²³

It is essential to use these animal models ethically and in accordance with relevant regulations and guidelines. Researchers should carefully select the most appropriate model based on their specific research question and interpret the results with caution, as biological responses may differ between animals and humans. Additionally, alternative methods such as in vitro and ex vivo models can provide valuable insights into biocompatibility and corrosion behavior while offering more ethical and cost-effective approaches.

5.2.2. Ethical considerations

The use of animal models for testing bioactive coatings raises important ethical concerns. To address these concerns, researchers should follow the 3Rs principle, which promotes minimizing animal use, reducing their suffering, and using alternative methods whenever possible. Animal welfare must be prioritized throughout the research process, including appropriate housing and care. Compliance with regulations and guidelines, such as the Animal Welfare Act and oversight by Institutional Animal Care and Use Committees (IACUC), is essential to ensure humane treatment. Ethical considerations are important for the welfare of animals, and researchers should prioritize alternatives to animal testing while complying with regulations to minimize harm.^124,125

5.2.3. Ensuring relevance of in vivo tests

To ensure that animal testing results are relevant to humans in biomedical research, researchers must consider several factors. First, they need to select animal models that closely resemble human physiology, genetics, and disease states-for example, using rats and mice due to their physiological similarities to humans. Second, they must standardize experimental protocols to ensure consistent and reproducible results, controlling variables such as age, sex, and environmental conditions. Finally, researchers should validate animal models by comparing the responses of animal and human cells, tissues, or organs to the same stimuli when possible. By following these steps, researchers can enhance the accuracy and reliability of their findings and improve the translation of their results to human applications, thereby ensuring the validity and relevance of biomedical research.^126,127

5.3. In vitro testing

In vitro tests are commonly used to assess the biocompatibility and corrosion behavior of bioactive coatings. These tests are cost-effective and allow for controlled experimental conditions. Some commonly used in vitro tests include^104,105:

• o Cell Viability Assays: These measure the viability of cells exposed to the coating and provide insights into cytotoxicity and biocompatibility.

• o Cell Adhesion Assays: These assess the ability of cells to adhere to the coating, offering insights into surface properties and biocompatibility.

• o Cell Proliferation Assays: These evaluate the ability of cells to multiply on the material or coating.

• o Hemocompatibility Assays: These assess compatibility with blood components by measuring platelet adhesion, activation, clotting time, and hemolysis.

• o ELISA Assays: These detect specific proteins or antibodies in a sample, providing indicators of biocompatibility or immune response.

• o Microbial Adhesion Tests: These evaluate bacterial adhesion to the material to assess susceptibility to colonization or infection.

• o Immune Response Assays: These measure immune cell activation, cytokine production, and other markers of immune response to assess the immunogenicity of the coating.

• o Electrochemical Tests: These evaluate corrosion behavior using methods such as potentiodynamic polarization, electrochemical impedance spectroscopy (EIS), or electrochemical noise (EN) analysis to understand corrosion resistance and degradation.

It is important to note that in vitro tests represent a simplified version of the complex interactions occurring in the human body and may not fully reflect how a coating behaves in real-life physiological conditions. Therefore, the results of in vitro tests should be interpreted with caution and, whenever possible, verified through in vivo studies.

6. Biomedical applications of bioactive coatings

6.1. Functional benefits and application-specific uses of bioactive coatings

Bioactive coatings are used on medical devices to enhance their compatibility with the body and improve overall performance.^128,129 As illustrated in Figure 6, the aging population is increasing, leading to a growing number of elderly individuals requiring tissue replacement with biomaterials. Consequently, the development of bioactive coatings for medical applications has become increasingly important. These coatings can promote tissue integration, reduce the risk of infection, and enhance the overall performance of medical devices.

Figure 6.

Population changes in elderly individuals by country, highlighting the increasing demand for bioactive coatings on implants to address age-related healthcare challenges. ¹²⁹

Bioactive coatings have emerged as a major advancement in the design and performance of medical devices, offering effective solutions to long-standing challenges such as biocompatibility, infection prevention, and extended device lifespan. By actively interacting with biological systems, enabling targeted delivery of therapeutic agents, and improving mechanical performance, these coatings have become a key element in contemporary medical device engineering. Several of their key applications and associated benefits are outlined below.

6.1.1. Tissue integration

Bioactive coatings significantly improve the integration of medical devices with surrounding biological tissues. This interaction is particularly critical for orthopedic and dental implants, where osseointegration-a direct structural and functional connection between living bone and the implant surface-is paramount. Coatings such as hydroxyapatite and bioactive glasses facilitate this process by mimicking the mineral composition of natural bone, thereby reducing the risk of implant loosening or failure and ensuring long-term stability.

6.1.2. Infection control

One of the foremost risks associated with implanted medical devices is infection, often caused by bacterial colonization and biofilm formation. Antimicrobial bioactive coatings provide a proactive defense mechanism by locally releasing antimicrobial agents such as silver ions, antibiotics, or antimicrobial peptides. This localized action minimizes systemic side effects and reduces dependence on systemic antibiotics, which can contribute to antibiotic resistance.

6.1.3. Drug delivery optimization

The integration of bioactive coatings with drug delivery systems has transformed the efficacy and specificity of therapeutic interventions. These coatings can be engineered to release drugs at a controlled rate, targeting specific tissues or cellular environments. For instance, coatings that respond to environmental triggers such as pH changes or temperature shifts can release therapeutic agents precisely when needed, enhancing treatment efficacy while minimizing systemic toxicity.

6.1.4. Enhanced mechanical durability

In applications where mechanical stress is a concern, such as in joint replacements or cardiovascular stents-bioactive coatings improve wear resistance and mechanical integrity. By reducing friction and wear at the device-tissue interface, these coatings not only extend the functional lifespan of implants but also reduce the need for revision surgeries. Advanced techniques, such as ion implantation and nanostructured surface engineering, have further enhanced their durability.

6.1.5. Inflammation reduction

Bioactive coatings can also help mitigate the inflammatory responses often triggered by foreign materials in the body. Coatings designed to mimic the extracellular matrix or incorporate anti-inflammatory agents can attenuate immune reactions, ensuring patient comfort and reducing complications such as fibrosis or chronic inflammation.

In summary, bioactive coatings have brought a major shift to the medical device landscape by introducing more functional and responsive implant surfaces. Rather than serving solely as a protective layer, these coatings actively engage with the body, supporting vital biological responses such as bone integration in orthopedic implants and tissue repair in cardiovascular stents. By integrating capabilities like localized drug release, infection control, and inflammation reduction, they greatly improve both device performance and biocompatibility. Designing such coatings demands precision and adaptability, as they must align with the specific requirements of diverse tissues and physiological conditions. Some notable specialized applications include^130,131:

6.1.5.1. Orthopedic implants

Orthopedic devices, such as hip and knee replacements, benefit significantly from bioactive coatings like hydroxyapatite, which enhance osseointegration. Recent advancements include the incorporation of growth factors such as BMP-2 (bone morphogenetic protein-2) to stimulate bone regeneration and the development of multilayered coatings for sustained therapeutic release. Optimizing coating thickness and composition remains a key strategy for balancing mechanical and biological performance.

6.1.5.2. Cardiovascular stents

Bioactive coatings on cardiovascular stents are designed to address restenosis-a narrowing of blood vessels following implantation. Drug-eluting stents release anti-proliferative agents, such as sirolimus or paclitaxel, which inhibit smooth muscle cell proliferation. Additionally, coatings that promote endothelialization accelerate the formation of a protective endothelial layer, reducing the risk of thrombosis and enhancing device biocompatibility.

6.1.5.3. Dental implants

Dental implants leverage bioactive coatings to improve stability and integration with alveolar bone. Coatings that release antimicrobial agents, such as chlorhexidine or silver nanoparticles, help prevent peri-implant infections, while growth factor-embedded coatings promote faster healing and osseointegration. Innovations in bioresorbable coatings are also emerging to simplify long-term implant maintenance.

6.1.5.4. Drug delivery systems

In drug delivery applications, bioactive coatings offer unparalleled precision and specificity. Functionalized coatings incorporating targeting ligands-such as antibodies or peptides-ensure selective binding to target cells or tissues. Coatings that respond to physiological cues, such as pH-sensitive polymers for tumor targeting, provide dynamic control over drug release profiles, improving therapeutic outcomes in oncology and chronic disease management.

Achieving long-term stability while preserving bioactivity remains a central challenge in the advancement of bioactive coatings. These coatings are continually exposed to the body’s complex physiological environment, where fluctuating pH levels, enzymatic activity, and mechanical stresses can compromise their adhesion, structure, and functionality. To perform effectively over extended periods, coatings must withstand these dynamic conditions without succumbing to degradation or delamination. Current deposition techniques, such as plasma spraying, electrochemical deposition, and layer-by-layer assembly, often involve intricate processes that come with significant costs. Scaling these methods for widespread production while maintaining consistency and quality presents a formidable challenge. Exploring more accessible and economical solutions, such as additive manufacturing, could play a pivotal role in bridging this gap, offering a pathway to cost-effective, high-quality bioactive coatings. As clinical demands on orthopedic and dental implants continue to evolve, coating systems are increasingly expected to combine multiple functions, antimicrobial protection, controlled local drug release, and mechanical resilience within a single, manufacturable architecture. Meeting these requirements calls for close collaboration between materials scientists, biomedical engineers, and clinicians. Stimuli-responsive and biomimetic coating strategies, informed by advances in nanotechnology, offer a promising direction for developing surfaces that adapt to the dynamic physiological environment of bone and oral tissue, with the ultimate aim of improving long-term implant survival and patient outcomes.^132–134

6.2. Smart and multifunctional bioactive coatings

A defining feature of next-generation bioactive coatings lies in their capacity to sense and respond autonomously to localized physiological cues rather than passively awaiting degradation-driven release. pH-responsive architectures, for instance, exploit the acidic microenvironment generated during early-stage bacterial colonization, typically dropping below pH 6.0 around an infected implant surface to trigger antimicrobial agent release only when needed, thereby limiting the systemic and local toxicity associated with constant elution. ¹³⁵ Thermo-responsive polymeric layers built from poly (N-isopropylacrylamide) derivatives undergo a reversible conformational collapse near physiological transition temperatures, allowing drug payloads to remain sequestered until a mild, clinically inducible thermal stimulus initiates release with millimeter-scale spatial precision. Enzyme-triggered systems extend this logic further by embedding cleavable peptide linkers that respond selectively to matrix metalloproteinases upregulated during peri-implant inflammation, effectively coupling therapeutic release to the biological signature of tissue distress itself. Taken together, these mechanisms shift the coating from a static reservoir toward a feedback-driven therapeutic interface, one whose behavior is dictated by the immediate biochemical state of the surrounding tissue rather than a predetermined elution profile.

Parallel advances in embedded sensing and adaptive surface engineering are pushing bioactive coatings toward genuine implant-level intelligence rather than isolated drug-delivery function. Nanostructured biomimetic surfaces, inspired by periosteal and enamel microarchitectures, are now being engineered to modulate osteoblast adhesion dynamically in response to mechanical loading history, an approach that helps reconcile the competing demands of early osseointegration and long-term bone remodeling. ¹³⁶ Increasingly, conductive polymer composites incorporating graphene or MXene interlayers are being explored as rudimentary biosensing platforms capable of transmitting impedance-based signals correlated with local infection or micromotion, opening a pathway toward wireless, real-time monitoring of implant status without additional surgical hardware.^137–139 Self-healing coating chemistries, built on dynamic covalent or disulfide-exchange networks, complement this sensing capability by allowing micro-damage sustained under cyclic loading to be autonomously repaired, thereby extending functional lifespan without requiring re-intervention. ⁷¹ As these strands converge, orthopedic and dental implants are moving toward surfaces that not only deliver therapy but also continuously report on and adapt to their own mechanical and biological environment.

7. Current challenges, standardization, and future perspectives

7.1. Overview of research in the field of bioactive coatings

Research in the field of bioactive coatings has been ongoing for several years, with the primary goals of developing new coating materials, understanding the biocompatibility and mechanisms of action of existing coatings, and evaluating their performance in various settings. In vitro studies using cell culture models have been widely conducted to assess the biocompatibility and performance of bioactive coatings. These studies have demonstrated that bioactive coatings can enhance cell adhesion, proliferation, and differentiation, as well as promote tissue regeneration. For example, a study on graphene oxide coatings reported improved bone cell adhesion and proliferation, leading to better bone growth and integration with surrounding tissue. In vivo studies involving animal models have also been performed and have shown that bioactive coatings can improve tissue integration, reduce inflammation, and prevent infection. For instance, research on magnesium-based coatings revealed enhanced bone regeneration and improved biocompatibility of titanium implants in a rabbit model. Additionally, clinical studies have been carried out to evaluate the safety and effectiveness of bioactive coatings in humans. These studies have shown that bioactive coatings can enhance the performance and longevity of implantable devices, decrease the likelihood of infection, and improve patient outcomes. For example, a clinical study on hydroxyapatite-coated dental implants demonstrated a significantly higher success rate and improved stability compared to non-coated implants.^140–142

Current and future research in the field of bioactive coatings aims to further enhance their biocompatibility and therapeutic effectiveness. This includes developing new materials, exploring new applications, and improving the design and performance of existing coatings. Examples include the development of coatings that incorporate growth factors or stem cells to promote tissue regeneration, as well as coatings designed for localized drug delivery in diseases such as cancer or osteoporosis. In summary, bioactive coatings have shown significant potential in improving the integration of implantable devices, reducing inflammation, and promoting tissue regeneration. Clinical studies have confirmed their safety and efficacy in humans, contributing to better patient outcomes. Future research will continue to focus on developing new materials and optimizing existing coatings to further enhance their therapeutic effectiveness and biocompatibility.

7.2. Challenges in the field of bioactive coatings

Bioactive coatings have shown promising results in various studies; however, several challenges must still be addressed to further improve their performance. As illustrated in Figures 7 and 8, one of the major obstacles is the lack of standardized testing methods to evaluate their compatibility and effectiveness. This leads to inconsistent results and makes it difficult to compare different coatings. Proposed solutions include the development of standardized testing protocols and the establishment of consistent reporting guidelines.

Figure 7.

The challenge of bioactive coating influences bone growth at the implant site and prevents post-operative complications, such as techniques for their applications, different types of bioactive coatings, and biocompatibility properties, with kind permission from. ¹⁴³

Figure 8.

Multi-functional hierarchical coatings with antibiotics are deposited on the implants with kind permission from. ⁵⁴

Another significant challenge is the lack of appropriate test methods that accurately reflect the complex biological interactions between coatings and living tissue. To address this, researchers are working to develop new testing methods that better simulate the in vivo environment, including the use of advanced imaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) to visualize and understand coating–tissue interactions in greater detail. Characterizing the biological effects of coatings on tissue also presents difficulties. This includes understanding their mechanisms of action, the influence of coating composition and thickness, and their long-term stability.^142,144 Proposed solutions involve the use of advanced analytical techniques and the conduct of long-term in vivo studies to gather more comprehensive data.

Understanding the complex interactions between coatings and tissue is another key challenge, as these coatings can both promote regeneration and, in some cases, induce inflammation or interfere with normal tissue function. Researchers aim to develop coatings that can regulate the immune response and aid tissue regeneration without adversely affecting surrounding healthy tissue. In summary, while bioactive coatings hold great promise for medical applications, their development still requires significant progress. Key challenges include the need for standardized testing methods, the establishment of more physiologically relevant test systems, better characterization of biological effects, and a deeper understanding of the intricate interactions between bioactive coatings and biological tissues. Addressing these challenges will be essential for advancing the field and ensuring the safe and effective use of these coatings in clinical practice.

To address these challenges, proposed solutions include the development of new testing methods, the use of advanced analytical and imaging techniques, and continued research into bioactive coatings and their interactions with biological tissues. Overcoming these obstacles will improve the safety and effectiveness of bioactive coatings and expand their potential for clinical applications.

8. Future perspectives of bioactive coatings

The field of bioactive coatings is rapidly evolving, and several future perspectives hold promise for further advancing this technology. One of the key challenges in the development of bioactive coatings is the need for long-term stability, encompassing both the coating’s physical properties and its biological functionality. The coating must be able to withstand the harsh conditions of the body, including mechanical stresses, pH fluctuations, and exposure to enzymes and other biomolecules. At the same time, its biofunctionality-such as the ability to promote cell adhesion, proliferation, and differentiation-must be maintained over extended periods. Another important consideration is cost-effectiveness. While bioactive coatings have shown great potential in improving the performance of implantable devices, their implementation can be costly. Therefore, there is a need to develop cost-effective fabrication techniques and materials that do not compromise the coating’s properties or efficacy.

In recent years, several innovative approaches have been proposed to address these challenges. For instance, the use of nanotechnology has shown great promise in enhancing both the stability and efficacy of bioactive coatings. Nanoparticles can be incorporated into the coating matrix to improve mechanical strength, reduce degradation rates, and enhance antibacterial properties. Additionally, the use of 3D printing and other additive manufacturing techniques enables the fabrication of complex and customized bioactive coatings with precise control over their composition and structure.

In summary, the continued development of bioactive coatings holds great promise for improving the performance of implantable devices in biomedical and biotechnological applications. Key future directions include addressing the need for long-term stability, maintaining biofunctionality, and improving cost-effectiveness. Approaches such as nanotechnology and 3D printing offer promising pathways to enhance the stability and efficacy of these coatings. With further research and development, more effective and cost-efficient bioactive coatings can be realized, ultimately enabling the design of safer and more reliable medical implants.

9. Conclusion

Bioactive coatings have undeniably transformed the landscape of medical device technology, offering a powerful strategy to bridge the gap between synthetic materials and biological systems. This review has highlighted the multifaceted role of these coatings, demonstrating their critical function in enhancing biocompatibility, providing targeted therapeutic action, and ensuring the long-term mechanical integrity of implants. From promoting osseointegration in orthopedics and dentistry to enabling controlled drug delivery and preventing infections, bioactive coatings have become an important component of modern medicine.

The performance and success of these coatings are governed by a complex interplay of factors, including material selection, surface chemistry and topography, porosity, and mechanical properties such as hardness, adhesion strength, and fatigue resistance. Achieving an optimal balance between these characteristics is essential for ensuring that coatings can withstand the demanding physiological environment while maintaining their biofunctionality over time. As discussed, this requires precise control over fabrication processes, from traditional methods like plasma spraying to advanced techniques such as layer-by-layer assembly and additive manufacturing.

A critical theme emerging from this review is the inherent interconnectedness of a coating’s properties. For instance, porosity simultaneously influences mechanical stability and tissue integration, while corrosion behavior is directly linked to both ion release and the long-term biocompatibility of the device. This complexity necessitates a holistic approach to coating design and evaluation. The risks associated with coating degradation or failure-ranging from inflammation and infection to implant loosening-underscore the vital importance of rigorous, standardized testing protocols. The adoption of consistent methods for both in vitro and in vivo evaluation, as well as the development of advanced characterization techniques, is paramount for ensuring patient safety and enabling meaningful comparison across different studies and coatings.

Looking forward, the field is poised for continued innovation driven by emerging technologies and increasingly complex clinical demands. The integration of nanotechnology, the development of “smart” stimuli-responsive coatings, and the application of 3D printing for patient-specific solutions represent promising avenues for future research. These advancements aim to address persistent challenges, including the need for enhanced long-term stability, improved cost-effectiveness, and the creation of truly multifunctional coatings capable of simultaneously supporting tissue regeneration, fighting infection, and delivering therapeutics.

In conclusion, bioactive coatings represent a cornerstone of contemporary implant engineering. Through continued interdisciplinary collaboration-uniting materials scientists, biologists, engineers, and clinicians-the field can overcome existing hurdles and unlock the full potential of these technologies. By refining our understanding of coating-biology interactions and translating fundamental research into robust clinical solutions, bioactive coatings will continue to play a pivotal role in improving patient outcomes and setting new standards for the safety and efficacy of medical implants.

ORCID iDs

Alireza Souri https://orcid.org/0000-0001-8306-5069

Majid Naseri https://orcid.org/0000-0001-5961-1402

Artem Okulov https://orcid.org/0000-0002-2955-1370