Plasma Surface Modification of Biomedical Implants and Devices: Emphasis on Orthopedic, Dental, and Cardiovascular Applications

Abstract

Plasma surface modification has emerged as a powerful, versatile tool for tailoring the surface properties of biomedical devices and implants without altering the material characteristics in the bulk. This comprehensive review critically examines the current state-of-the-art in plasma-based surface engineering techniques, with a focus on enhancing biocompatibility, bio-functionality, and long-term performance of medical implants. The article systematically explores various plasma processes and their roles in modifying surface chemistry, topography, energy, and wettability. These alterations directly influence protein adsorption, cell adhesion, antibacterial activity, and corrosion resistance, all of which are crucial for successful clinical integration. Special emphasis is placed on the plasma treatment of metallic (e.g., titanium, stainless steel), polymeric (e.g., polytetrafluoroethylene, polyetheretherketone), and composite substrates commonly used in dental, orthopedic, and cardiovascular applications. This review also highlights synergistic strategies, such as plasma-assisted grafting of bioactive molecules and nanostructuring, that enable multifunctional surfaces capable of promoting osseointegration, mitigating inflammation, and preventing biofilm formation. Emerging trends such as atmospheric cold plasmas and the integration of plasma technology with additive manufacturing are outlined as promising future directions. By synthesizing insights from surface science, materials engineering, and biomedical research, this review provides a foundational framework to guide future innovations in plasma-treated biomaterials. It aims to inform both academic researchers and medical device developers seeking to optimize implant–tissue interactions and achieve improved clinical outcomes.

1. Introduction

The development of biomedical devices and implants represents one of the most significant advancements in the convergence of science, medicine, and engineering. Since the mid-20th century, the field has evolved from simple mechanical support to complex, multifunctional systems capable of interacting dynamically with biological tissues [1,2]. This evolution has not only reshaped clinical practice but also significantly improved patients’ quality of life. Early biomedical implants primarily addressed structural deficiencies by restoring function to damaged or diseased tissues. Their success highlighted the enormous potential of implantable devices, setting the stage for decades of innovation.

In the early years, the field was dominated by metallic implants such as titanium (Ti), stainless steel (SS), and cobalt–chromium (Co-Cr) alloys, chosen for their exceptional strength, corrosion resistance, and relative biocompatibility [3,4]. Early applications centered on orthopedic screws and plates, dental implants, and cardiovascular stents [5]. While effective, these early implants were largely inert, designed with an emphasis on mechanical stability and load-bearing capacity rather than active biological performance [6]. Their primary function was to support, replace, or repair damaged structures, with minimal consideration for cellular integration or long-term physiological compatibility [7,8]. As clinical experiences accumulated, however, it became clear that mechanical success alone was insufficient to guarantee long-term outcomes (see Figure 1).

Figure 1. Milestones in the history of biomaterials: transitioning from replacement to regeneration (reproduced from Todros, S. et al., Biomaterials and their biomedical applications: from replacement to regeneration. Processes, 2021. 9(11): p. 1949, under the terms of the Creative Commons Attribution (CC BY 4.0) License) [9].

A major turning point occurred with the recognition that the biological environment does not passively accept foreign materials [10]. Instead, interactions between cells, proteins, and implanted surfaces often determine the device’s ultimate success or failure. Complications such as inflammation, fibrous encapsulation, bacterial infection, and implant rejection underscored the need for implants that could go beyond structural roles and actively harmonize with host tissues [11]. This realization fueled the transition from inert to bioactive implants, marking a paradigm shift in biomedical device design. Modern implants are now required not only to provide strength and durability but also to encourage tissue regeneration, resist microbial colonization, reduce inflammatory responses, and maintain functional stability over extended periods in vivo [12]. This growing complexity has coincided with broader clinical needs, driven by aging populations, the prevalence of chronic conditions, and the demand for personalized medicine. Fields such as orthopedics, cardiovascular therapy, neurology, ophthalmology, and tissue engineering now rely heavily on advanced implantable devices [13,14]. For example, orthopedic implants are expected to support high mechanical loads while simultaneously promoting osseointegration. Cardiovascular stents must prevent restenosis while minimizing thrombosis risks. Neural implants require both biocompatibility and functional electrical conductivity to restore or modulate neurological activity [15]. Each of these applications places unique demands on implant design, underscoring the necessity for materials and surface properties tailored to specific clinical functions.

Recent advances in material science and fabrication technologies have made it possible to address these requirements more effectively. Nanotechnology, surface engineering, and additive manufacturing have enabled the creation of patient-specific implants with unprecedented precision and functionality [16,17]. Beyond metals, polymers and ceramics have emerged as key materials in biomedical device development, valued for their tunability, degradability, and versatility. For instance, bioresorbable polymers are increasingly used in tissue scaffolds and cardiovascular applications, while ceramics such as hydroxyapatite (HA) play vital roles in bone regeneration [18,19,20]. Yet despite these advances, challenges remain. Long-term biocompatibility, immune acceptance, and prevention of infection continue to present significant hurdles [21,22].

To overcome these issues, both bulk material modification and surface engineering strategies have been employed. Bulk modifications can alter the intrinsic properties of an implant, such as mechanical strength or degradation rate. However, surface modifications offer a more efficient pathway by directly tailoring the interface where biological interactions occur, without compromising the mechanical integrity of the underlying material [23,24]. Most biomaterials do not have the perfect surface properties and desirable functions; surface modification plays an important role in tailoring the surface of biomaterials to allow better adaptation to the physiological surroundings and deliver the required clinical performance. Techniques such as plasma treatment, chemical functionalization, coating deposition, and nanopatterning have been explored to improve cellular responses, enhance protein adsorption, or resist bacterial adhesion [25]. Among these, plasma-based surface modification has gained significant attention due to its versatility, environmental friendliness, and ability to introduce a wide range of functional groups under controlled conditions [26,27].

In this context, biomedical devices and implants are no longer viewed as passive placeholders but as active bio-interfaces engineered to integrate seamlessly with the human body [28]. Their development is essential not only for restoring lost function but also for enabling new therapeutic approaches, including regenerative medicine and tissue engineering. A widely recognized framework in tissue engineering is the ‘diamond concept,’ which emphasizes four interdependent elements necessary for effective tissue regeneration: osteogenic cells, scaffolds, bioactive signals, and a suitable mechanical and vascular environment. Recent advancements have extended this concept to incorporate vascularization and host factors, highlighting the importance of integrating biomaterials with angiogenic cues and immune modulation to achieve robust and clinically relevant tissue repair [29,30]. As research continues, the focus is shifting toward multifunctional implants that can simultaneously address mechanical, biological, and chemical demands [31,32]. This ongoing evolution highlights the critical importance of comprehensive reviews that examine both materials and modification strategies, particularly surface engineering approaches such as plasma treatment. A deeper understanding of these methodologies is crucial to guide future research, improve clinical performance, and ultimately enhance patient outcomes.

By synthesizing advances in plasma physics, materials science, and biomedical engineering, this review not only highlights the current state of the art but also explores emerging frontiers in the field. The objective is to provide a holistic understanding of how plasma surface modification can be leveraged to meet the multifaceted challenges of biomedical implant development, specifically in dental, bone, and cardiovascular implants. In doing so, this review aspires to contribute to the design of safer, more effective, and longer-lasting medical devices that improve patient care and clinical outcomes globally.

2. Material Surface Modification

2.1. Need/Requirements of Surface Modification

Despite these innovations, significant challenges remain in the development and clinical deployment of biomedical devices and implants [33,34]. Key challenges include immune rejection, foreign body responses, poor osseointegration, implant-associated infections, and device failure due to degradation or mechanical fatigue [35,36]. These complications often stem from inadequate interactions between the implant surface and the host biological environment. While the bulk material of an implant governs its mechanical and structural performance, it is the surface that interacts directly with biological tissues [37]. Proteins, cells, and microbes encounter the implant surface within seconds to minutes of implantation [38]. Therefore, optimizing surface characteristics is essential for improving biological performance, reducing complications, and extending implant longevity [39,40].

2.2. Methods of Surface Modification

Material selection plays a critical role in implant design. Metals, polymers, ceramics, and composites each offer distinct advantages and limitations [41,42,43,44]. However, changing the base material to address surface-related issues is not always feasible. Bulk modifications may compromise the mechanical properties, increase costs, or introduce new biocompatibility concerns [45]. In contrast, surface modification offers a targeted approach, allowing control over surface chemistry, topography, wettability, and energy without affecting the core mechanical properties of the material [40]. This strategy enables the retention of desirable structural characteristics while enhancing biological responses. As a result, surface engineering has become a cornerstone in the design of next-generation biomedical implants [46,47].

A variety of surface modification techniques have been developed to address the diverse requirements of biomedical applications (see Figure 2). These include physical methods such as sandblasting and laser texturing, chemical treatments such as acid etching and silanization, and biological functionalization through the immobilization of peptides, proteins, or growth factors [48,49,50]. More advanced approaches involve self-assembled monolayers, layer-by-layer deposition, ion implantation, and sol–gel coatings [51,52,53]. Each technique offers unique advantages and is selected based on the desired surface functionality, substrate compatibility, and application-specific requirements. However, many of these methods suffer from limitations such as complexity, lack of uniformity, potential cytotoxicity, and challenges in scalability [23]. In recent years, plasma-based surface modification has gained prominence as a highly effective, clean, and versatile alternative that addresses many of these limitations.

Figure 2. Different material modification methodologies for biomedical devices and implants. (PECVD: Plasma-Enhanced Chemical Vapor Deposition, DBD: Dielectric Barrier Discharge, PAC: Plasma-Activated Coating, RGD: Arginine–Glycine–Aspartic acid, BMP: Bone Morphogenetic Protein, PIII/D: Plasma Immersion Ion Implantation and Deposition, NO: Nitric Oxide).

3. Plasma Surface Modification

Plasma surface modification provides precise control over surface characteristics through ionized gas environments and is recognized as a powerful approach in materials engineering. Plasma, often described as the fourth state of matter [54], arises when high-energy input drives ionization, bond dissociation, and bond formation, producing a mixture of atoms, ions, electrons, free radicals, and metastable species [55]. The term “plasma” was first coined by Irving Langmuir in 1928, as noted by Braithwaite [56] and later defined by Chen [57] as a quasi-neutral gas of charged and neutral particles exhibiting collective behavior, plasma has since become central to surface engineering strategies. When directed onto materials, its reactive species can induce nanoscale chemical and physical modifications such as tuning surface energy, introducing functional groups, removing contaminants, and creating controlled roughness, while preserving bulk integrity [58,59,60,61]. These alterations directly affect protein adsorption, cell adhesion, and antimicrobial activity, which are critical for biomedical applications [62,63]. Plasma processes are broadly divided into low-pressure and atmospheric-pressure systems [27], with the former offering high uniformity and precise control suited for medical and research applications, and the latter, including Dielectric Barrier Discharge (DBD) and plasma jets, enabling open-air operation advantageous for heat-sensitive substrates and in situ treatments [64,65]. Commercial plasma systems vary in configuration, power source, and operating pressure, allowing selection based on substrate type and application. Representative examples of commonly used plasma surface modification equipment are summarized in Table S1. More advanced techniques, such as Plasma Immersion Ion Implantation (PIII), incorporate ions into surfaces to enhance wear and corrosion resistance as well as bioactivity, while plasma polymerization facilitates the deposition of ultrathin coatings that support bioactive molecule immobilization or drug-release functionalities [63,66,67].

The advantages of plasma surface modification are multifold [27]. It is a dry, solvent-free approach that minimizes reliance on hazardous chemicals, thereby supporting environmentally sustainable practices [68]. Because plasma treatments are generally carried out at low temperatures, they help maintain the structural integrity of heat-sensitive polymers and composites. The technique is highly versatile, compatible with diverse materials, and adaptable to complex geometries with large surface area-to-volume ratios [69]. Moreover, plasma processes are scalable for industrial applications and can achieve effective modification in a short duration. These attributes of efficiency, adaptability, and environmental safety make plasma treatments especially valuable in biomedical applications, where both precision and biocompatibility are essential [70].

Compared with other surface modification methods such as chemical etching, sol–gel deposition, and laser texturing, plasma-based processes offer unique advantages in versatility, cleanliness, and environmental control [13]. Plasma treatments can functionalize metallic, ceramic, and polymeric substrates at low temperatures without altering bulk properties, while allowing precise tuning of surface chemistry and topography. In contrast, chemical etching and sol–gel coatings often require wet chemistry steps, generate chemical waste, and may suffer from poor adhesion or residual contamination. Laser texturing provides excellent spatial precision but can induce thermal damage or stress in temperature-sensitive materials [71]. In addition to these methods, high-energy beam techniques such as ion implantation, electron beam irradiation, and laser ablation have also been explored for biomedical surface modification. These approaches enable precise nanoscale tailoring, enhanced wear and corrosion resistance, and incorporation of bioactive species into the near-surface region; however, they generally demand high vacuum systems, complex control, and significant energy input, which can increase cost and risk of thermal degradation, particularly for polymers and composites. By contrast, plasma modification achieves comparable or complementary effects under milder, more environmentally sustainable conditions, while maintaining excellent control over surface chemistry and topography. Despite challenges related to vacuum requirements and large-scale uniformity, plasma methods provide an optimal balance of tunability, reproducibility, and biocompatibility, making them especially suitable for modern biomedical and clinical applications [72].

A key advantage of plasma technology lies in its ability to act synergistically with other surface modification strategies. Plasma–substrate interactions encompass processes such as physical sputtering, chemical functionalization, crosslinking, etching, and thin-film deposition, which together make the method highly adaptable for virtually all categories of biomaterials (see Figure 3). Surfaces modified by plasma display enhanced adhesion, providing an excellent platform for subsequent functionalization. For instance, plasma activation enables the covalent attachment of peptides, proteins, or polymers to implant surfaces, thereby improving their bioactivity. Similarly, plasma-induced nanostructuring can be integrated with antibacterial coatings to create multifunctional interfaces that promote tissue integration while preventing microbial colonization. This versatility establishes plasma surface modification as a core technology for engineering smart and responsive biomedical devices.

Figure 3. Schematic representation of the various interactions between plasma and a substrate surface (reproduced from Pillai, R.R. et al., Plasma Surface Engineering of Natural and Sustainable Polymeric Derivatives and Their Potential Applications. Polymers, 2023. 15(2): p. 400, under the terms of the Creative Commons Attribution (CC BY 4.0) License) [27].

Various plasma sources are employed for surface modification of biomedical implants and devices, each offering distinct operational characteristics and advantages. The selection of a plasma source depends on factors such as the desired type and extent of modification, substrate material, and intended biomedical application. Plasma systems differ in excitation mechanisms, operating pressure, power input, and temperature profile, all of which influence plasma chemistry and the resulting surface properties. Commonly used sources include radio-frequency (RF) plasma, DBD plasma, microwave plasma, and cold atmospheric plasma (CAP). RF plasma provides uniform surface activation and precise control over parameters but requires vacuum operation, which limits scalability and increases system cost. DBD plasma operates at atmospheric pressure and is suitable for large-area treatment, though it may produce non-uniform discharges and localized heating. Microwave plasma generates high plasma density and efficient energy transfer but has a complex reactor design and limited adaptability to irregular geometries. CAP enables low-temperature modification of heat-sensitive materials; however, its shallow penetration depth and discharge instability can pose challenges. The key operational characteristics and parameters of these plasma systems are summarized in Table 1.

Table 1. Different plasma sources and their respective operating conditions/parameters.

Plasma Source	Typical Operating Pressure	Plasma Temperature (K)	Electron Temperature (eV)	Plasma Density (cm−3)	Discharge Voltage/Current
RF Plasma	10−2–10−1 Torr	300–1000	1–5	108–1012	100–500 V/10–500 mA	Widely used for uniform surface activation and cleaning of metals and polymers.
DBD Plasma	Atmospheric Pressure	300–1000	1–3	109–1011	1–20 kV/<10 mA	Operates at atmospheric pressure, suitable for large-area and in situ treatments.
Microwave Plasma	10−3–10−1 Torr	400–1500	2–10	1010–1013	1–2 kV/100–500 mA	Provides high plasma density and energy efficiency, used for dense coatings.
CAP	1 atm	300–350	1–2	109–1011	1–20 kV/few mA	Enables non-thermal surface modification and sterilization of temperature-sensitive materials.

4. Plasma Surface Modification in Biomedical Applications

Biomedical implants and devices must satisfy stringent surface criteria to ensure successful integration and long-term functionality within the human body. The ideal surface promotes biocompatibility, supports cell adhesion and proliferation, resists bacterial colonization, and maintains mechanical and chemical stability under physiological conditions. For instance, orthopedic implants such as titanium alloys require surfaces that facilitate osteoblast attachment and bone bonding through appropriate roughness and hydrophilicity. Dental implants benefit from micro- and nano-textured surfaces that enhance osseointegration while minimizing bacterial adhesion. Cardiovascular devices, including stents and vascular grafts, demand smooth, hemocompatible surfaces that reduce thrombosis and support endothelialization. Polymeric implants, such as catheters or scaffolds, require surfaces optimized for protein adsorption and minimal immune response. These requirements vary with implant location and function but consistently depend on surface chemistry, energy, topography, and wettability parameters that plasma modification can precisely tailor to achieve the desired biological and mechanical performance.

Over the last decades, numerous advances have employed plasma-engineered surfaces for biomedical implants and devices. Plasma treatments enable fine control over surface chemistry, topography, and energy, resulting in improved cell adhesion, proliferation, and differentiation. Material properties such as wear resistance and corrosion resistance can also be enhanced without compromising bulk integrity, highlighting plasma’s versatility in developing next-generation, multifunctional biomedical implants.

Plasma-modified surfaces are evaluated primarily through physicochemical and biological characteristics that determine their performance in vivo. Key properties include surface chemistry (functional groups, elemental composition), surface energy and wettability, topography and roughness at micro- and nanoscale, and mechanical integrity (hardness, adhesion, wear resistance). These parameters directly influence protein adsorption, cell attachment and proliferation, hemocompatibility, and antibacterial activity. Coating thickness, uniformity, and stability under physiological conditions are additional critical factors. Plasma treatments offer precise tuning of these properties while preserving the bulk material, enabling implants and devices to meet stringent clinical and functional requirements.

The mechanism of plasma surface modification varies with the application and substrate type. In general, plasma interacts with surfaces through physical and chemical processes driven by energetic ions, electrons, radicals, and UV photons. These species remove contaminants, break surface bonds, and introduce functional groups such as hydroxyl, carbonyl, or carboxyl moieties, enhancing surface energy and wettability. In orthopedic applications, plasma promotes protein adsorption and cell attachment by increasing roughness and introducing bioactive functional groups. For dental implants, plasma cleaning and activation improve coating adhesion and reduce bacterial colonization on titanium and zirconia surfaces. In cardiovascular devices, low-temperature plasma modifies polymeric materials to enhance hemocompatibility and reduce platelet adhesion without altering bulk properties. Plasma serves as a versatile, non-equilibrium tool for precise control of surface chemistry and topography, improving biological performance across diverse biomedical systems.

4.1. Dental Implant Applications

Dental implants are a cornerstone of restorative dentistry, offering reliable replacement of missing teeth with excellent functional and esthetic outcomes [73]. Their long-term clinical success relies on effective osseointegration and soft tissue integration, both of which are strongly influenced by the physicochemical and topographical characteristics of the implant surface. Titanium and its alloys remain the materials of choice due to their mechanical strength and biocompatibility; however, their unmodified surfaces often exhibit limited bioactivity. Plasma treatment acts mechanistically by generating energetic species (ions, radicals, electrons, UV photons) that remove surface contaminants, etch the titanium or polymer surface, and introduce functional groups such as hydroxyl and oxygen species. These modifications increase hydrophilicity, enhance protein adsorption (e.g., fibronectin, laminin), and improve osteoblast attachment at the implant–tissue interface [74,75]. These modifications not only optimize early biological responses but also reduce healing periods, improve implant stability, and lower the likelihood of long-term complications (see Figure 4).

Figure 4. Bio-functionalization of dental implants with surface modification.

In the context of multifunctional surface compatibility, plasma-assisted strategies have been widely investigated. At the bone–implant interface, plasma-deposited thin calcium phosphate coatings have been shown to support osteogenesis while maintaining structural integrity. Yoshinari et al. [76] demonstrated that controlled infrared heating could prevent cracking and enable immobilization of bioactive molecules, including bisphosphonates and simvastatin, with the latter enhancing BMP-2 expression to accelerate bone regeneration. Expanding on this, Yoshinari et al. [77] further reported that simvastatin acid immobilization on titanium-based surfaces is strongly influenced by plasma treatments. Using quartz crystal microbalance–dissipation analysis, they showed that the highest adsorption of simvastatin acid occurred on O₂-plasma-treated hexamethyldisiloxane (HMDSO) coatings, where hydrophilicity and surface functionalization with –OH and O₂ groups enhanced drug immobilization. These findings highlight the potential of plasma-polymerized organic films combined with O₂ activation to improve bioactive molecule loading on dental implants, thereby promoting osteogenesis. Similarly, Balamurugan et al. [78] applied radio-frequency magnetron sputtering to deposit calcium phosphate, zinc chloride, and silver nitrate layers on Ti-6Al-4V surfaces, demonstrating both antibacterial activity against Staphylococcus aureus and Staphylococcus epidermidis and maintenance of coating uniformity. Plasma polymerization of HMDSO followed by O₂ plasma activation further enabled stable drug immobilization, highlighting the dual functionality of plasma treatments for bone regeneration and infection control.

Soft tissue integration is equally critical to prevent peri-implantitis. Yoshinari et al. [76] emphasized that multi-grooved surface topographies combined with immobilized adhesive proteins, such as fibronectin and laminin-5, promoted epithelial attachment. Complementary findings by Yoshinari et al. [79] using QCM-D analysis showed that fibronectin adsorption on plasma-modified titanium surfaces depends strongly on surface chemistry. While hydrophobic HMDSO coatings and short O₂ plasma treatments (10 min) both supported high levels of fibronectin adsorption, prolonged O₂ plasma treatment reduced protein adsorption. These results suggest that both hydrophobic interactions and ionic bonding via –OH or O₂ functional groups can mediate fibronectin attachment, underscoring the importance of controlled plasma processing in promoting stable soft tissue integration. Similarly, Marín-Pareja et al. [80] showed that collagen grafting on plasma-treated or acid-etched titanium enhanced fibroblast adhesion, proliferation, and extracellular matrix remodeling, with covalent immobilization providing higher stability than physisorption. These approaches illustrate how plasma-based modifications can simultaneously address osteogenic, soft tissue, and antimicrobial requirements of dental implants.

Successful bone defect repair relies heavily on osseointegration. Mechanical adequacy and surface wettability are additional factors influencing osseointegration. Silva et al. [81] demonstrated that controlled plasma oxidation could increase titanium oxide layer roughness and stability while improving wettability, which correlates with faster bone integration. Alves et al. [82] further refined this approach for dental implants by employing hollow cathode discharge plasma nitriding at moderate temperatures (400–500 °C), achieving enhanced surface roughness and wettability without geometric distortion. Non-thermal plasma treatments have also been shown to support osseointegration under clinically relevant conditions; Nevins et al. [83] reported increased bone-to-implant contact and reduced bone loss in a canine model, while Duske et al. [84] demonstrated that argon–oxygen plasma decreased titanium contact angles, promoting osteoblastic cell spreading regardless of surface topology. Titanium remains the benchmark material in craniofacial surgery, but increasing attention is being given to polymeric biomaterials as possible substitutes. Their major drawback, however, lies in their bioinert nature, which often restricts effective interaction and integration with surrounding tissues. Extending plasma strategies to polymeric biomaterials, Al Maruf et al. [85] reported that PIII improved osseointegration of polyetheretherketone (PEEK) and polyether ketone (PEK) implants in a sheep model, achieving outcomes comparable to 3D-printed titanium.

Beyond bone integration, corrosion resistance and cellular adhesion are crucial for long-term stability. Huang et al. [86] found that TiN-coated and ion-nitrided Ti substrates exhibited superior corrosion resistance and enhanced osteoblast adhesion compared to untreated titanium. Plasma-sprayed HA and Al₂O₃-TiO₂ (AT) coatings further improved surface roughness, microhardness, and corrosion resistance, with bilayer AT/HA coatings demonstrating optimal in vitro bone osteo-induction [87]. Functional hydroxyl groups introduced via plasma treatments have been correlated with enhanced bone-to-implant contact and polygonal osteoblast morphology, highlighting the importance of surface chemistry in bone fixation [88].

Plasma-based strategies have also been explored to mitigate peri-implant infections while maintaining soft tissue compatibility. Yoshinari et al. [89] investigated the initial adherence of Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans on titanium modified with dry processes, including ion implantation, oxidation, ion plating, and ion beam mixing. They observed that bacterial adhesion increased on calcium-implanted surfaces but was significantly reduced on alumina-coated surfaces, suggesting that appropriate surface engineering can suppress oral pathogen colonization. Similarly, Bunz et al. [90] demonstrated that zirconia abutments coated with HA or metal additives impaired fibroblast adhesion, emphasizing the need for balancing antimicrobial coatings with cellular compatibility. In contrast, Paiwand et al. [91] showed that titanium implants modified via plasma electrolytic oxidation and loaded with silver or zinc ions achieved a 99–99.999% reduction in bacterial viability, suggesting a promising route for advanced antibacterial implants. Similarly, Chuang et al. [92] fabricated dual-functional titanium surfaces combining HMDSZ films, oxygen plasma-induced hydrophilic groups, and BMP2/CHX hydrogel grafts to simultaneously enhance bone integration and inhibit bacterial colonization. Logesh et al. [93] extended this concept with plasma electrolytic oxidation to incorporate HA, multi-walled carbon nanotubes, and silver nanoparticles, achieving improved mechanical, corrosion-resistant, and antibacterial properties.

Inspired by natural tooth attachment, Fischer et al. [94] developed a basement membrane-derived cell adhesion peptide nanocoating that selectively promotes keratinocyte attachment and hemidesmosome formation, potentially providing a durable soft tissue seal for percutaneous devices. Non-thermal nitrogen plasma treatment has also been shown to improve hydrophilicity, introduce nitrogen functional groups, and promote osteogenic activity on titanium implants, mitigating surface aging effects (see Figure 5) [95]. Moreover, strontium-doped HA coatings prepared via RF plasma spray improved protein release kinetics, accelerated osteoid formation, and enhanced bone mineralization compared to pure HA coatings [96]. Finally, Ti-Al₂O₃-HA composites fabricated through spark plasma sintering demonstrated enhanced mechanical strength, corrosion resistance, and cytocompatibility, emphasizing the synergistic benefits of compositional and plasma-based surface modifications [97].

Figure 5. SEM analysis of the (a,d) Ti, (b,e) plasma, and (c,f) N₂ plasma discs. Scanning probe micrographs of the (g) Ti, (h) plasma, and (i) N2 plasma surfaces. (j) Contact angles of the Ti, plasma, and N₂ plasma discs. * p < 0.05 compared with Ti. (adapted from Yan, S. et al., Osseointegration Properties of Titanium Implants Treated by Nonthermal Atmospheric-Pressure Nitrogen Plasma. International Journal of Molecular Sciences, 2022. 23(23): p. 15420, under the terms of the Creative Commons Attribution (CC BY 4.0) License) [95].

Expanding plasma strategies beyond titanium, Yoshinari et al. [98] demonstrated that O₂ plasma treatment of PMMA denture bases significantly increased adsorption of the antimicrobial peptide histatin 5. This modification enhanced hydrophilicity, introduced carboxyl and oxygen functional groups, and resulted in more than sixfold higher peptide adsorption compared to untreated PMMA. Importantly, histatin 5-adsorbed PMMA surfaces showed markedly reduced Candida albicans colonization, highlighting the potential of plasma-activated polymeric substrates to mitigate denture-associated infections.

Across plasma-modified biomaterial surfaces, protein adsorption and subsequent cell behavior are primarily governed by the interplay between surface chemistry, wettability, and nanoscale topography. Plasma activation introduces functional groups such as –OH, –COOH, and –NH₂, which increase surface energy and improve the adsorption and conformation of bioactive proteins. According to the Vroman effect, mobile serum proteins initially adsorb and are later replaced by higher-affinity species, forming a dynamic, biologically active interface. On moderately hydrophilic surfaces, proteins retain native-like conformations that expose cell-binding motifs, promoting integrin-mediated adhesion and signaling. In contrast, highly hydrophobic or excessively hydrophilic surfaces can either denature proteins or inhibit stable adsorption. Surface roughness and elastic modulus further tune these effects, with nanoscale features facilitating focal adhesion formation and controlled cell spreading. This unified mechanism explains the enhanced bioactivity observed in plasma-treated surfaces across dental, orthopedic, and cardiovascular applications, linking hydrophilicity, chemistry, and topography to functional biological outcomes. Table 2 summarizes previously reported works on the application of plasma surface modification in dental implant research.

Table 2. Reported works on the application of plasma surface modification for dental implant applications.

Sl. No.	Purpose of Study	Plasma	Reference
1	Surface compatibility	HMDSO	[76]
2	Stimulate bone formation	O2 plasma treatment	[77]
3	Peri-implant infection	RF sputtering	[78]
4	Fibronectin adsorption	O2 plasma treatment	[79]
5	Biological sealing	O2 plasma treatment	[80]
6	Biocompatibility and mechanical adequacy	Oxidation	[81]
7	Osseointegration	Plasma nitriding	[82]
8	Osseointegration	Air plasma	[83]
9	Spreading of osteoblastic cells	Ar plasma	[84]
10	Osseointegration	Plasma ion immersion implantation	[85]
11	Corrosion resistance and cell adhesion	Cathodic arc plasma	[86]
12	Corrosion resistance, microhardness, surface roughness	Plasma spray coating	[87]
13	Cell adhesion	RF plasma	[88]
14	Oral pathogen colonization	Ion implantation	[89]
15	Antibacterial coatings	Plasma spraying	[90]
16	Antibacterial potential	Plasma electrolytic oxidation	[91]
17	Inhibit bacterial infection	Plasma chemical vapor deposition	[92]
18	Mechanical properties, corrosion resistance, and antibacterial efficacy	Plasma electrolytic oxidation	[93]
19	Antimicrobial resistance	Ar plasma	[94]
20	Aging of the material	Atmospheric-pressure N2 plasma	[95]
21	Osteogenic properties, protein release kinetics, dissolution behavior	Plasma-sprayed HA coatings	[96]
22	Properties of Ti-Al2O3-HA composite	Spark plasma sintering	[97]
23	Adsorption of antimicrobial peptide histatin-5	O2 plasma treatment	[98]
24	Osseointegration	O2 plasma treatment	[99]
25	Improved cell adhesion and mineralization responses	O2 PIII	[100]
26	Biocompatibility and mechanical properties	Non-thermal plasma	[101]
27	Peri-implant bone density	CAP preconditioning	[102]
28	Osseointegration	Vacuum plasma treatment	[103]
29	Faster early-stage osseointegration	Ar-O2 plasma	[104]
30	Improved implant stability measures	Vacuum plasma treatment	[105]

4.2. Bone Implant Applications

Plasma surface modification enhances bone implant performance by tailoring surface chemistry, roughness, and bioactivity. Mechanistically, plasma-assisted techniques such as plasma spraying, plasma electrolytic oxidation, and low-temperature plasma deposition generate surfaces with controlled porosity, roughness, and chemical functionality. HA and related calcium phosphate coatings remain a central focus for enhancing the bioactivity of metallic implants due to their osteoconductive properties and strong affinity with natural bones. Plasma spraying and other plasma-assisted deposition techniques have been widely applied to fabricate these coatings. Zhou et al. [106] demonstrated that fluoridated HA/calcium silicate composite coatings deposited via suspension plasma spraying can optimize both bonding strength and dissolution rate, with a 3:7 HA to calcium silicate ratio providing the highest mechanical and bioactive performance. Ke et al. [107] developed gradient HA coatings using LENS^TM followed by plasma spray deposition, incorporating MgO and Ag₂O to enhance antibacterial properties while improving adhesive bond strength through an interfacial layer. Rezaei et al. [108] applied HA/HA-Mg double-layer coatings on SS, achieving suitable porosity for bone ingrowth and reducing release of toxic substrate elements. Zheng et al. [109] enhanced HA coating adhesion by forming HA/Ti composite coatings via atmospheric plasma spraying, while laser treatment of plasma-sprayed HA coatings increased crystallinity and induced multi-layered porosity conducive to osseointegration [110].

High-temperature plasma spraying often leads to dehydroxylation and phase transformations. Heimann et al. [111] developed a model explaining the formation of chemically and mechanically inhomogeneous porous calcium phosphate coatings on titanium substrates and highlighted the role of titania bond coats in duplex HA–titania systems. Pillai et al. [112] fabricated βTCP and HA/βTCP composite coatings via plasma spraying, showing that thermal treatment at 800 °C allows reconversion of αTCP to βTCP, enabling coatings with tunable dissolution properties. Xue et al. [113] compared HA coatings with 56% and 98% crystallinity, demonstrating that high-crystallinity coatings exhibited lower dissolution, higher shear strength, and stable in vivo integration.

Ion substitution and doping further enhance bioactivity and osteointegration. Candidato et al. [114] developed Zn-doped HA coatings via solution precursor plasma spraying; high Zn content (>10 mol%) inhibited HA formation but promoted calcium zinc phosphate without altering lattice structure. Li et al. [115] demonstrated that 10% Sr-substituted HA (SrHA) coatings on Ti implants significantly improved bone-to-implant contact, bone volume, and push-out strength in ovariectomized rats compared to HA coatings. Cao et al. [116] synthesized Mg- and Sr-co-substituted HA coatings with improved bonding strength and cellular proliferation, while Vu et al. [117] incorporated ZnO, SiO₂, and Ag₂O into HA coatings to accelerate bone mineralization and provide antibacterial effects. Ke et al. [118] reported that MgO- and SiO₂-doped HA coatings enhanced bone–implant interface shear modulus compared to bare Ti and pure HA. U et al. [119] showed that alkaline post-treatment of plasma electrolytic oxidation (PEO)-coated magnesium substrates sealed surface pores, optimized roughness, and enhanced osteoblast adhesion, while Aydin et al. [120] confirmed biocompatibility and osteoimmune modulation on PEO-treated WE43 magnesium alloys.

Hacking et al. [121] employed physical vapor deposition to mask surface chemistry without altering topography, demonstrating durable, homogeneous titanium layers on HA coatings (see Figure 6). Larsson et al. [122] reported that HA-coated abutments for bone conduction hearing implants improved soft tissue integration compared to conventional titanium, with reduced pocket depth and epidermal downgrowth. Finke et al. [123] introduced amino-functional plasma polymer coatings to promote focal adhesion and cytoskeletal development, while Seo et al. [124] enhanced osteoblastic differentiation by immobilizing RGD peptides on plasma-treated Ti surfaces.

Figure 6. SEM images of cell culture disks with (a) polished Ti, (b) polished Ti + PVD Ti mask, (c) grit-blasted Ti, (d) grit-blasted Ti + PVD Ti mask, (e) HA-coated, and (f) HA-coated + PVD Ti mask surface. SEM, ×1000 (adapted with permission from Hacking, S.A., et al., A physical vapor deposition method for controlled evaluation of biological response to biomaterial chemistry and topography. Journal of Biomedical Materials Research Part A, 2007. 82A(1): p. 179–187) [121].

Khang et al. [125] quantified the contribution of nanometer (<100 nm) and sub-micron (>100 nm) surface features on titanium for endothelial and osteoblast adhesion. Sub-micron features increased surface energy by 27% and promoted endothelial adhesion density by 200%, while nanometer features increased surface energy by 10% and endothelial adhesion by 50%. Aligned surface patterns selectively enhanced adhesion of endothelial and bone cells by 400% and 50%, respectively, indicating that sub-micron to nanometer topography significantly improves cytocompatibility.

Singh et al. [126] investigated plasma spray deposition of biomimetic HA/TiO₂ coatings on low-elastic β-phase Ti-35Nb-7Ta-5Zr alloy. Using L-9 orthogonal array experiments, the effect of powder ratio, gas flow, and feed rate on hardness and adhesion strength was analyzed. Optimal surface hardness occurred with 50:50 HA/TiO₂, high gas flow, and low feed rate, while maximum adhesion was achieved at 70:30 HA/TiO₂, low gas flow, and high feed rate. Morphology showed splats, globules, and craters, highlighting the importance of process optimization.

Surface modification of titanium and its alloys plays a critical role in implant performance. Glow-discharge nitriding combined with oxidation improves wear resistance, corrosion resistance, and bioactivity [127]. Plasma-assisted treatments can reduce nickel release from NiTi shape memory alloys, mitigating cytotoxicity while maintaining shape memory properties [128,129]. Chrzanowski et al. [130] demonstrated that smooth, plasma-modified NiTi surfaces provided optimal biocompatibility by minimizing nickel release and supporting cell differentiation, outperforming alkali-treated or thermally oxidized surfaces. Liu et al. [131] reported that low-temperature plasma alloying of Co-Cr alloys with nitrogen or nitrogen–carbon mixtures enhances hardness, wear, and corrosion resistance without compromising biocompatibility. Maleki-Ghaleh et al. [132] coated Ti-6Al-4V with sol–gel tricalcium magnesium silicate using plasma spraying, improving corrosion resistance and osteoblast/mesenchymal stem cell proliferation. Duplex surface engineering combining plasma nitriding and Ti/TiN multilayers on SS316L femoral heads significantly enhanced cyclic fatigue, nanohardness, and wear resistance compared to SS316L with multilayer Ti/TiN coating and bare SS [133].

Plasma electrolytic oxidation has been widely employed to incorporate bioactive elements. Zakaria et al. [134] developed fluoridated HA coatings on Ti6Al4V via PEO, producing irregular micropores, TiO₂, HA, tricalcium phosphate, and fluorapatite phases that improved antibacterial properties while maintaining bioactivity. Cao et al. [116] demonstrated that co-substituted HA coatings improve mechanical performance and cell proliferation.

PEEK is increasingly used as a metal substitute due to its favorable bulk mechanical properties, but its low surface energy can inhibit cell adhesion. Plasma and ozone treatments combined with grafting of poly(sodium styrene sulfonate) significantly enhanced surface bioactivity and biomineralization without compromising mechanical integrity [135]. Plasma-sprayed titanium coatings on PEEK further improve trabecular bone apposition and extraction resistance [136].

Beyond HA, transition metal-substituted calcium hexa-orthophosphates with NaSiCON (Na superionic conductor) structures are being investigated to enhance ionic conductivity and degradation resistance for electrical bone growth stimulation [137]. Plasma-modified diamond-like carbon (DLC) coatings have been shown to improve hydrophilicity, reduce stress, and enhance osteogenic potential [138]. Collectively, these approaches highlight the versatility of plasma-assisted surface modifications to optimize mechanical, chemical, and biological performance across a range of implant materials. A summary of reported studies on plasma surface modification for bone implant applications is presented in Table 3.

Table 3. Reported works on the application of plasma surface modification for bone implant applications.

Sl. No.	Purpose of Study	Plasma Treatment	Reference
1	Improve the bonding strength	Suspension Plasma Spraying	[106]
2	Adhesive bond strength	Plasma spray deposition	[107]
3	Biocompatible coatings	Plasma spray	[108]
4	Enhance bond strength	Plasma spray	[109]
5	Increased crystallinity	Plasma spray	[110]
6	Bio-functionality	Plasma spray	[111]
7	Coatings with tunable dissolution	Plasma spray	[112]
8	Bonding strength	Plasma spray	[113]
9	Functionalization	Plasma spray	[114]
10	Improve the biological functions	Plasma spray	[116]
11	Enhance osseointegration	Plasma spray	[117]
12	Adhesive bond strength	Plasma spray	[118]
13	Biodegradability	Plasma electrolytic oxidation	[119]
14	Osteogenic and immunomodulatory potential	Plasma electrolytic oxidation	[120]
15	Biological response evaluation	Plasma spray	[121]
16	Soft tissue integration	Plasma spray	[122]
17	Rapid cellular acceptance	Plasma polymer functionalization	[123]
18	Tissue integration	Plasma polymerization	[124]
19	Biomimetic coating	Plasma spray deposition	[126]
20	Biocompatibility and tissue healing	Glow discharge	[127]
21	Bioactivity characteristics	Low-temperature plasma	[128]
22	Improve corrosion resistance and biocompatibility	Low-temperature plasma treatment	[129]
23	Biocompatibility	Plasma sputtering	[130]
24	Improve hardness, wear, corrosion properties	Plasma surface alloying	[131]
25	Corrosion resistance	Plasma spray	[132]
26	Cyclic fatigue resistance	Plasma nitriding	[133]
27	Improve the bio-functionality	Plasma electrolytic oxidation	[134]
28	Biomineralization	Plasma surface activation	[135]
29	Improve osseointegration	Plasma spray	[136]
30	Biocompatible coatings	Plasma spray	[137]
31	Biocompatibility	Nitrogen and Ar plasma	[138]
32	Improved cell adhesion	Non-thermal atmospheric-pressure plasma	[139]
33	Improved osseointegration	Ar/O2 plasma treatment	[140]
34	Mechanical stability	Plasma spraying	[141]
35	Bone healing, reduced bacterial colonization	Plasma spray	[142]
36	Improved bone implant fixation, mechanical stability	Plasma spray (HA/TiO2)	[143]
37	Osseointegration	Plasma spray	[144]
38	Improved cell affinity	N2/RF plasma on PEEK	[145]

4.3. Cardiovascular Implant Applications

Cardiovascular implants, such as stents and other intravascular devices, are commonly employed to restore or maintain blood flow in patients with cardiovascular conditions. Even with improvements in stent design and materials, their long-term effectiveness is often limited by issues such as insufficient endothelialization, thrombosis, restenosis, and corrosion. Consequently, surface modification has become essential to enhance hemocompatibility, biological performance, and mechanical durability without compromising the device’s structural integrity [146]. To achieve this, plasma treatments are used on metallic and polymeric stent surfaces, where energetic ions and radicals etch, functionalize, and restructure the surface. These processes generate hydrophilic functional groups, create nanoscale surface roughness, and deposit bioactive coatings, collectively improving hemocompatibility and supporting endothelial cell adhesion.

Polymeric and metallic materials are widely used in cardiovascular implants due to their unique physicochemical properties, mechanical performance, and biocompatibility. The biocompatibility of polymeric materials is critical, as it governs bacterial adhesion, hemocompatibility, and interactions with host cells. Surface modification strategies have been developed to enhance these properties while retaining the bulk characteristics of the material. Pavithra et al. [147] summarized the mechanisms of biofilm formation and highlighted factors influencing bacterial adhesion and hemocompatibility. Physical, chemical, and biological surface modification techniques have been shown to improve polymer–cell interactions, enabling the design of cost-effective, biocompatible polymers suitable for in vivo applications.

For metallic stents, alloys such as MP35N (Co-Ni-Cr-Mo), NiTi, and 316L SS are commonly employed. Loya et al. [148] demonstrated that controlled RF plasma processing of MP35N stent wires can generate high-aspect-ratio dendritic nanopillars, promoting surface texture that may enhance endothelialization. Similarly, Samaroo et al. [149] and follow-up studies by Lu et al. [150] revealed that patterned Ti surfaces at the nanometer scale can significantly improve endothelial cell adhesion and alignment, mimicking natural endothelium morphology. Such nanostructured or patterned surfaces can potentially enhance stent efficacy by promoting faster re-endothelialization, which is critical to preventing thrombosis.

Nitinol, valued for its shape memory and superelastic properties, also benefits from plasma-based surface modifications. Wang et al. [151] reported that low-temperature plasma coating of NiTi stents increases surface hydrophilicity and improves anticoagulation properties, while Song et al. [152] demonstrated that plasma polymerization of 1,2-diaminocyclohexane followed by α-lipoic acid grafting yields mechanically stable and blood-compatible stent surfaces capable of inhibiting neointimal hyperplasia. Beyond polymer coatings, Yin et al. [153] developed covalent attachment strategies to immobilize tropoelastin on SS stents, supporting endothelial growth while modulating smooth muscle infiltration. Plasma-assisted techniques can also deposit inorganic coatings, such as Ti-O films, to enhance chemical and mechanical durability under the combined conditions of deformation and corrosion [154].

316L SS stents have been further modified to improve hemocompatibility through plasma polymerization. Yang et al. [155] fabricated pulsed-plasma polymeric allylamine films that immobilize heparin, resulting in reduced platelet adhesion, enhanced endothelial cell proliferation, and suppression of thrombus formation in vivo. Fluorocarbon coatings, applied via plasma polymerization, have been studied by Lewis et al. [156], demonstrating that thin films (~36 nm) can withstand the plastic deformation of stent expansion while maintaining chemical inertness and thromboresistance. Similarly, Shen et al. [157] showed that plasma nanocoating on micropatterned nitinol surfaces enhances endothelialization, with micropores outperforming microgrooves in promoting cell adhesion.

Arterial diseases that restrict blood flow pose a major clinical challenge due to the risk of heart attack, stroke, and organ failure. Lahann et al. [158] addressed the thrombogenicity of metallic stents by coating them with an ultrathin polymer layer via chemical vapor deposition polymerization of 2-chloroparacyclophan. The poly(2-chloroparaxylylene) layer was further modified using sulfur dioxide plasma to introduce hydrophilic functional groups. This dual treatment improved hemocompatibility significantly, reducing platelet adhesion from 85% on bare metal to 20% on the treated surface, demonstrating the potential of plasma-assisted polymer coatings to mitigate thrombus formation.

Advanced stent designs increasingly combine structural, surface, and drug delivery strategies. Su et al. [159] developed a bioresorbable poly(L-lactic acid) stent with expandable multiple-lobe geometry, showing reduced platelet adhesion after surface plasma treatment. Enomoto et al. [160] demonstrated that patterned DLC coatings on polymer-based drug reservoirs can control initial burst release, potentially mitigating late thrombosis. Hong et al. [161] showed that abciximab-coated stents effectively inhibit neointimal hyperplasia in coronary arteries, reducing restenosis and late lumen loss.

NiTi shape memory alloys also require careful surface engineering to control nickel release and enhance blood compatibility. Chlanda et al. [162] demonstrated that low-temperature plasma oxidation followed by deposition of amorphous carbon (a-C:N:H) or TiO₂ layers produces homogeneous, nanocrystalline surfaces with improved adhesion, wettability, and antithrombogenic properties. Similarly, Chen et al. [163] deposited SiC:H organic-like films on Ti50Ni50 alloys to improve corrosion resistance and hydrophobicity, which can be further functionalized with polymer grafts to enhance endothelial compatibility. For a concise comparison of reported works related to cardiovascular implant applications, see Table 4.

Table 4. Reported works on the application of plasma surface modification for cardiovascular implant applications.

Sl. No.	Purpose of Study	Plasma Treatment	Reference
1	Enhance endotheliazation	Radio-frequency plasma	[148]
2	Vascular endothelial cell adhesion	Plasma-based dry etching	[150]
3	Biocompatibility	Plasma Coating	[151]
4	Biocompatibility	Plasma polymerization	[152]
5	Biocompatibility	Plasma Coating	[153]
6	Plastic deformation and corrosion	Plasma immersion ion implantation	[154]
7	Hemocompatibility	Plasma polymerization	[155]
8	Adhesion properties	Plasma polymerization	[156]
9	Endothelialization	Low-pressure gas glow-discharge plasma	[157]
10	Improvement of hemocompatibility	Sulfur dioxide plasma	[158]
11	Platelet adhesion, inflammation	Pulsed-plasma polymerization	[159]
12	Preventing stent restenosis	Plasma polymerization	[161]
13	Adhesion strength	Glow-discharge low-temperature plasma	[162]
14	Biocompatibility	Asymmetric bipolar DC-pulsed-plasma-assisted CVD	[163]
15	Improved endothelial cell adhesion and migration	Atmospheric-pressure plasma	[164]
16	Improved endothelial cell adhesion and migration	Atmospheric-pressure plasma	[165]

4.4. Other Biomedical Implants and Devices

The success of biomedical implants depends strongly on the interplay between surface properties, host tissue response, and long-term durability. Beyond dental, bone, and cardiovascular implants, plasma modifications improve implant performance across metals, polymers, and ceramics. Mechanistically, plasma interacts with surfaces via energetic ions, radicals, and photons to clean, etch, functionalize, and graft bioactive molecules. This leads to enhanced hemocompatibility, antibacterial activity, corrosion resistance, and cellular adhesion. Titanium and its alloys remain the benchmark materials for load-bearing implants because of their favorable mechanical properties and biocompatibility. Plasma-assisted microwave chemical vapor deposition of SiCNH coatings on Ti-6Al-4V and γ-TiAl alloys enhanced hardness, surface energy, and hydrophobicity, leading to improved cellular adhesion and proliferation [166]. Beyond titanium, alternative metals such as niobium and tantalum have been explored. When subjected to microblasting and reactive ion etching, these metals exhibited cleaner and rougher surfaces with higher surface energy compared with titanium, offering superior electrochemical stability and enhanced bioactivity [167].

Surface modification of SS alloys also benefits from plasma treatments. Plasma nitriding of AISI type 303 austenitic steel produced γN phases that not only increased hardness but also imparted strong antibacterial activity, illustrating a dual improvement in durability and biocompatibility [168]. For cardiovascular devices, Ti-O films deposited onto 316L stainless steel by plasma immersion ion implantation and deposition (PIII&D) demonstrated excellent mechanical durability under deformation and clinically acceptable corrosion resistance, suggesting utility in stent applications [168].

Carbon-based thin films, particularly DLC, have been widely investigated for implants due to their chemical inertness, low friction, and hemocompatibility. Fluorinated DLC (F-DLC) coatings improved blood compatibility, significantly reducing platelet adhesion and thrombus formation in vivo (see Figure 7) [169,170]. Doping DLC films with calcium and phosphorus further reduced platelet adhesion compared with pyrolytic carbon, a standard heart valve material [171]. Plasma-deposited DLC on NiTi alloys not only improved corrosion resistance but also suppressed nickel ion release, addressing the metallosis risk of shape memory alloys [172].

Figure 7. Histology of fibrous capsule of SUS and F-DLC groups. Representative histological images of the fibrous capsules are shown (28 days after implantation). (a) Azan stain; original magnification, ×100. (b) Hematoxylin and eosin stain; original magnification, ×200 (adapted with permission from Hasebe, T. et al., Fluorinated diamond-like carbon as antithrombogenic coating for blood-contacting devices. Journal of Biomedical Materials Research Part A, 2006. 76A(1): p. 86–94) [169].

Polymeric coatings are central in vascular and soft tissue applications. Plasma-treated polyurethane (PU) films exhibited higher wettability and endothelial cell adhesion, enhancing their suitability as vascular device coatings [173]. PU-PEG composites modified to nanoscale roughness promoted endothelial cell adhesion and proliferation even at 10–100 nm feature sizes [174]. Broader applications of plasma-modified microstructured polymers such as SU8 and polydimethylsiloxane (PDMS) demonstrated increased protein binding and improved fibronectin-mediated cell adhesion, beneficial in tissue engineering and microfluidic devices [175].

Other polymers, including poly(hydroxymethylsiloxane), have shown plasma-dependent biological responses. O₂ plasma treatments generated SiO₂-like surfaces with poor adhesion, whereas Ar⁺ beam treatments produced SiCxOy phases that facilitated fibroblast proliferation [176]. Nanoscale gratings fabricated on PMMA and PDMS guided smooth muscle cell alignment while suppressing excessive proliferation, indicating potential for vascular grafts [177]. Plasma modification of polytetrafluoroethylene (PTFE) and PET surfaces, followed by immobilization of collagen, laminin, or heparin, reduced fibrinogen adsorption and platelet adhesion, suggesting improved long-term patency of vascular grafts [178].

HA-based coatings are widely used for orthopedic and dental implants due to their chemical similarity to bone. However, conventional plasma-sprayed HA often suffers from poor adhesion. To address this, HA-Ti composite coatings with superior bonding strength and bioactivity were developed [179], while silica-doped HA coatings improved bioactivity [180]. A low-energy plasma-spraying technique produced phase-pure HA coatings with excellent osseointegration potential [181]. Reinforcement of HA with calcium silicate enhanced mechanical strength and hemocompatibility [182]. Bilayer coatings, such as Al₂O₃-TiO₂ combined with HA, further improved corrosion resistance and bioactivity of Ti-6Al-4V substrates [183].

Magnesium alloys, valued for their biodegradability, have also been treated with plasma-based methods. Plasma electrolytic oxidation generated MgO-rich layers that enhanced corrosion resistance and cytocompatibility while aligning with green chemistry principles [184]. Plasma oxidation has also been applied to 3D-printed Ti implants, increasing surface hardness and improving tribological performance [185].

Incorporating antibacterial functionality into implant surfaces is increasingly important. Silver nanoparticle-modified surfaces provide a robust strategy. Ag-loaded TiO₂ nanotubes produced by plasma oxidation and sputtering showed excellent antibacterial activity without cytotoxicity [186]. Silver-substituted HA/TiO₂ coatings fabricated by plasma electrolytic processing offered enhanced corrosion resistance, bioactivity, and antibacterial behavior [187].

Beyond inorganic or polymeric coatings, plasma modification has also enabled covalent immobilization of bioactive molecules. Using energetic ion-assisted plasma processes, proteins were directly grafted onto implant surfaces, maintaining bioactivity while reducing the risk of immune rejection [188]. Such biofunctionalized coatings represent a step toward implants that not only integrate structurally but also actively regulate biological responses. Details of relevant studies that explored plasma surface modification for other biomedical implants and devices are summarized in Table 5.

Table 5. Reported works on the application of plasma surface modification for other biomedical implants and devices.

Sl. No.	Purpose of Study	Plasma Treatment	Reference
1	Mechanical and surface parameters	Plasma-assisted microwave CVD	[166]
2	Cell and tissue attachment	RF CF4–oxygen plasma	[167]
3	Antibacterial properties	Plasma nitriding	[168]
4	Hemocompatibility	Plasma-enhanced chemical vapor deposition	[169]
5	Thrombogenicity	RF plasma-enhanced chemical vapor deposition	[170]
6	Biocompatibility	Plasma immersion ion implantation	[171]
7	Corrosion resistance	Plasma immersion ion implantation	[172]
8	Blood compatibility	He plasma	[173]
9	Enhanced growth of human endothelial cells	Air plasma	[174]
10	Fibronectin adhesion and cell attachment and growth	Air plasma	[175]
11	Cell sensitivity	O2 plasma	[176]
12	Morphology and motility of smooth muscle cells	O2 plasma	[177]
13	Blood compatibility	Radio-frequency glow discharge	[178]
14	Mechanical properties	Plasma spray	[179]
15	In vivo bioactivity and early bone ingrowth	Plasma spray	[180]
16	Osseointegration and bone growth	Low-energy plasma spraying	[181]
17	Performance for bio-implant applications	Plasma spray	[182]
18	Microhardness and corrosion resistance	Plasma spray	[183]
19	Enhance tissue integration, durability, and corrosion resistance	Plasma electrolytic oxidation	[184]
20	Mechanical and wear properties	Plasma oxidation	[185]
21	Antibacterial Performance and Bioactivity	Plasma electrolyte oxidation	[186]
22	Corrosion-resistant, bioactive and antibacterial	Plasma electrolytic processing	[187]
23	Surface hydrophilicity	Plasma immersion ion implantation	[188]
24	Strength and durability	Plasma polymerization	[189]
25	Cell Affinity	Ar plasma discharge	[190]
26	Fracture toughness or biocompatibility	Inductively Coupled Plasma Etching	[191]
27	Increased healing rate, reduced bacterial load	He plasma	[192]
28	Accelerated wound healing	CAP	[193]
29	Antimicrobial, wound-healing stimulation	CAP	[194]
30	Enhanced biomolecule immobilization, cell spreading and bioactivity	Plasma polymerization	[195]

4.5. Batch-to-Batch Variability and Quality Considerations

Across the application of plasma surface modification in biomedical implants and devices, reproducibility and process consistency are critical for clinical translation. Key performance indicators such as functional group density, surface wettability, nanoscale roughness, coating thickness, adhesion strength, and overall process yield are often reported with inherent variability between batches. Low-temperature plasma treatments typically yield a smaller variation in contact angle and minor deviations in surface functionalization, while plasma-sprayed HA coatings may exhibit small differences in porosity or crystallinity depending on powder feed and plasma parameters. Successful implementations rely on controlled process conditions, in situ monitoring, and post-treatment characterization to ensure reproducibility, with acceptance criteria commonly defined by material-specific key performance indicators such as hydrophilicity, coating uniformity, mechanical integrity, and cell response. While many literature reports focus on individual demonstrations, these parameters provide a practical framework for evaluating plasma step robustness and guide industrial adaptation. Table 6 provides an overview of plasma-based surface modification methods and their associated clinical or pre-clinical outcomes in biomedical implants.

Table 6. Summary of plasma-based surface modification techniques and their reported clinical or pre-clinical outcomes in biomedical implants.

Plasma Technique	Substrate/Application	Key Surface Effect	Reported Biological or Clinical Outcome	References
Oxygen plasma treatment	Ti dental implants	Generation of –OH/–COOH groups, enhanced surface energy and wettability	Promoted protein adsorption, faster osseointegration, and shorter healing time in vivo	[99]
Oxygen PIII	Ti dental implants, hMSCs	Increased oxidation, rutile TiO2 phase, enriched –OH groups	Improved cell adhesion, proliferation, and mineralization responses	[100]
Non-thermal atmospheric pressure	Bone Implants	Surface functionalization	Improved cell adhesion, higher in vitro bovine serum albumin (BSA) adsorption, increased bone formation	[139]
Atmospheric-pressure plasma jet treatment	Coronary stents	Enhanced hydrophilicity, increased surface roughness, and functional group incorporation	Improved endothelial cell adhesion and migration, potential for re-endothelialization	[164]
Non-thermal Ar/O2 plasma treatment	Ti implants in rat femoral bone	Increased hydrophilicity and surface activation	1.3× higher bone implant contact and mineral apposition rate, improved osseointegration	[140]
Plasma spraying (HA, TiO2, TiN)	Orthopedic coatings	Formation of porous, bioactive ceramic surfaces	Increased bone implant integration and long-term mechanical stability	[141]
Non-thermal atmospheric plasma	Ti dental and orthopedic implants	Enhanced surface hydrophilicity, decreased carbon contamination	Biocompatibility and mechanical properties	[101]
Plasma spray	Ti alloy and SS implants for bone healing	Cell adhesion and proliferation, and antibacterial	Bone healing, reduced bacterial colonization and infection risks	[142]
Non-thermal gas plasma treatment	Ti Dental Implant	Enhancing osseointegration	Shorter healing times, reduced vertical bone loss	[83]
CAP clinical therapy (He plasma)	Diabetic foot ulcers	Antibacterial action and angiogenic stimulation	Significant wound-size reduction, increased healing rate, reduced bacterial load	[192]
CAP preconditioning (mini-pig)	Sand-blasted/acid-etched Ti dental implants	Surface activation, improved protein binding	Higher BIC and peri-implant bone density in pre-clinical model	[102]
CAP (clinical trial)	Chronic/diabetic foot ulcers (clinical patients)	ROS/RNS, antimicrobial and pro-healing signaling	Accelerated wound healing, reduced bacterial load (randomized trials)	[193]
CAP	Diabetic foot ulcers	Antimicrobial + wound-healing stimulation	Improved wound closure vs. placebo/standard care in RCT	[194]
Plasma polymerization (e.g., HMDSO, acrylic acid)	Polymer/ceramic scaffolds and coatings	Tunable organofunctional thin films, controlled hydrophilicity	Enhanced biomolecule immobilization, improved cell spreading and bioactivity	[195]
Plasma spraying (HA/TiO2)	Orthopedic implant coatings	Porous, bioactive ceramic layers with controlled crystallinity	Improved bone implant fixation, mechanical stability, and long-term integration	[143]
Plasma-sprayed HA-parameter studies	HA coatings (orthopedics)	Changes in porosity, crystallinity, thickness	Process parameters affect dissolution rate and osseointegration potential	[144]
Nitrogen/RF plasma on PEEK	PEEK surfaces (orthopedic/dental substitutions)	Introduction of nitrogen/amine groups, increased surface energy	Improved cell affinity, wettability; modifies crystallinity/self-bonding	[145]
Vacuum Plasma Treatment	Dental Implants	Impurities removal	Improved osseointegration	[103]
Atmospheric-pressure plasma	Coronary stents	Increased hydrophilicity and functional group incorporation	Reduced thrombogenic markers	[165]
Non-thermal Ar/O2 plasma	Ti implants	Surface activation, higher wettability	~1.3× higher bone implant contact and mineral apposition rate in rat model	[196]
PEO	Anodized Ti/orthopedic surfaces	Oxide layer modification	Improved cellular responses in in vitro and in vivo models	[197]

5. Conclusions

Plasma surface modification has emerged as a powerful and adaptable approach for improving the performance of biomedical implants and devices. Through precise tailoring of surface chemistry, morphology, and functionality, plasma-based methods address critical clinical challenges such as enhancing osseointegration, promoting soft tissue integration, providing antimicrobial activity, improving corrosion resistance, and enabling localized drug delivery. These advances are particularly impactful in bone, dental, and cardiovascular implants, where they strengthen biological compatibility and long-term functionality without compromising the intrinsic properties of the substrate. Beyond these applications, plasma modification has also proven effective in polymeric scaffolds, MEMS, and other biomedical platforms, underscoring its versatility across material classes. Looking ahead, combining plasma-based strategies with emerging biomaterials and regenerative technologies is expected to play a pivotal role in shaping the next generation of clinically relevant implant systems.

Despite its versatility and effectiveness, plasma surface modification faces certain limitations. The technique is highly dependent on the type of substrate and the specific biomedical application, with some materials or complex geometries being challenging to modify uniformly. Vacuum-based systems, while precise, are often limited to small-scale or laboratory settings, making large-scale implementation difficult. Atmospheric plasma approaches, though more flexible, can suffer from non-uniform treatment over irregular surfaces and require careful parameter optimization to avoid undesired effects. Additionally, the need for specialized equipment and trained personnel can restrict its routine application in clinical or industrial settings.

While plasma-based surface modification continues to demonstrate strong potential in biomedical device optimization, several translational challenges remain. From a regulatory standpoint, the lack of standardized plasma process parameters, validation protocols, and long-term biocompatibility datasets complicates Food and Drug Administration (FDA) and International Organization for Standardization (ISO) approval pathways. Manufacturers must establish traceable quality systems, define process acceptance criteria, and verify stability of plasma-modified surfaces through accelerated aging and sterilization studies. Cost-effectiveness is another consideration, as scaling plasma systems from laboratory setups to high-throughput industrial lines requires investment in vacuum infrastructure, gas control systems, and in situ monitoring. However, recent advances in atmospheric-pressure plasma and roll-to-roll or chairside plasma systems are reducing these barriers, offering more consistent and scalable options for medical manufacturing. In addition, it is important to note that most reported studies on plasma-based surface modification remain at the pre-clinical stage, with limited clinical investigations available, particularly for dental, orthopedic, and cardiovascular implants. While these pre-clinical results are highly promising, broader and well-controlled clinical studies are needed to confirm safety, reproducibility, and long-term performance under real-world conditions. Expanding the clinical evidence base will be essential to translate these surface modification strategies into routine medical practice. Future work should integrate plasma processing into established manufacturing frameworks, emphasize cost-performance optimization, and align with regulatory expectations to enable reliable clinical translation.