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Surface modifications and coatings to improve osseointegration and antimicrobial activity on titanium surfaces: A statistical review over the last decade
⁎Corresponding author: Amit Biswas. amitb79@gmail.com
∗∗Corresponding author: Konduru Ashok Kumar Raju. kingashok143@gmail.com
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Received: ,
Accepted: ,
This article was originally published by Reed Elsevier India Pvt. Ltd. and was migrated to Scientific Scholar after the change of Publisher.
Abstract
Abstract
Titanium (Ti) is commonly employed therapeutically in many medical sectors associated with bone healing because of its superior mechanical properties and capacity to osseointegrate in the host bone tissue. The titanium surfaces may now be functionalized to offer additional and potentially valuable features. This review article discusses many titanium implant surface modifications, emphasizing their biological significance and the challenges that each one mainly addresses. Before reviewing the genuine reason for titanium surface modification in implanted devices, we briefly explore the process of osseointegration, enhancement of antibacterial properties, biocompatibility, and the historical significance of titanium as an implantable material, and the significant challenges involved. The various physical and chemical alterations that could take place on Ti surfaces are next examined. The rest of our talk will focus on creating inorganic and organic coatings for implanted Ti devices. Finally, we present a synopsis of the surface modification strategies currently being evaluated in clinical settings.
This systematic review aims to evaluate research on titanium implants with significant surface modifications, coatings, and antibacterial capabilities.
Following the PRISMA paradigm, we searched for three electronic databases (Web of Science, PubMed Central, and Google Scholar) using the keywords "titanium implants," "titanium surface modification," and "titanium osseointegration," and "titanium antibacterial activity."
We identified 1,39,336 articles overall that were published between 2012 and 2021, and we then focused on 8917 articles that concentrated on a particular topic. Clear inclusion and exclusion criteria were used in a rigorous screening procedure. Articles that didn't meet certain requirements (were irrelevant, used incorrect techniques, had unsuitable data values, or were only brief letters or communications) were eliminated. Finally, 120 research publications in total are taken into account for this extensive systematic review.
The report summarises current information on titanium implants with significant surface modifications, antibacterial activity, and coatings. It also gives some strong recommendations for future study topics.
Abstract
Highlights
•Article explores titanium implant surface modifications, emphasizing biological significance and associated challenges.•Systematic review examines titanium implants with advanced surface coatings, antibacterial properties.•Data were collected from Web of Science, PubMed Central, and Google Scholar using various keywords.•Titanium implants with advanced surface coatings, focusing on osseointegration and antibacterial properties are reported.•Search keywords: “titanium implants,” “surface modification,” “osseointegration,” and “antibacterial activity.”
Keywords
Titanium implants
Surface modification
Osseointegration
Antibacterial activity
Tissue engineering
1 Introduction
1.1 Titanium as an implantable material for bone: a historical perspective
Researchers in the fields of materials science and implantology have been working for many years to enhance the design of tools used in clinical body part replacement. Due to its unique characteristics and the potential to address functional healing utilizing stiff biocompatible implants and surgical procedures, bone is one of primary target tissues in this systematic review.
Nowadays, Titanium is the best choice of material for many orthopaedic and dental implant applications. One standard measure for effective orthopaedic implants, that have a mechanical property similar to natural bone tissue. Titanium is an appropriate material for the intended usage in this respect since its modulus and hardness characteristics are similar to those of cortical bone tissue. Titanium was first employed in the manufacture of implants in the late 1930s after exceeding stainless steel and cobalt alloys in terms of behaviour.1 Titanium and its alloys, mostly those containing aluminium or vanadium, were first utilised in operations in the 1950's after a decade of usage in dentistry. Ti has a long history of usage in hip and other joint replacement procedures (such as shoulder, elbow, or knee) or spinal fixation devices,3,4 as well as dental applications in implants, crowns, bridges, or other prosthesis.2 Titanium is also used in cardiovascular stents. In these treatments, commercially pure Ti (C.p. Ti) and very low interstitial Ti-6Al-4V are most commonly used for implant production.1 Several experimental and clinical investigations have recently proved Ti-based materials' enhanced biocompatibility and corrosion resistance, two qualities required for an implanted metal device. Ti and other metallic materials give the mechanical resilience and strength required to recreate bone structure properly. Titanium implants function exceptionally well in terms of loadbearing support due to their better mechanical properties (high strength, low weight, fatigue strength and corrosion resistant).4 Furthermore, several mechanical properties of titanium implants, such as stiffness, have a considerable impact on the phenotypic determination of bone cells.5
1.2 Immune response to titanium implants and osseointegration
Decades of experimental research in titanium implantation have shown several areas that still require improvement, despite its amazing effectiveness as a bone tissue implantable material. Osseointegration, which has been identified as a crucial component for implant success, can be characterised as a direct structural and functional link between organised, living bone and the surface of a load-bearing implant.6 For the purposes of determining whether a dental implant is effective, traditional methods considered fibro-osseous integration as a viable method.7 For the purposes of this model, the implant is surrounded by a fibrous collagen tissue that prevents contact with the bone tissue as it heals. Even though they first appeared to be promising, long-term dental implants depending on this strategy usually failed. Infections occurred at implanted region, mechanical loosening of joints, and bone resorption are a few more reasons of implant failure in addition to the development of fibrous tissue. Given this, it is evident that the success or failure of a bone implant depends on the cellular and molecular relation between the implant material and the surrounding tissues. Following an accident or other diseases, implant therapy may throw the balance of bone homeostasis out of whack. Ti implants, while being historically thought of as an inert substance, may cause a soft foreign body reaction since they are formed of nonbiological components, which might ultimately result in implant failure. After the first blood contact with an implant surface, the immune system is activated. Macrophage polarization is influenced by various surface-related features, such as roughness and microstructure. Titanium devices may therefore be identified as foreign objects and encircled by the granulation tissues. In that case, a subsequent immune system response is required to start tissue remodelling for implant integration and prevent persistent inflammation and fibrosis.1,8 If not, the Ti implant might fail, which is mostly attributed to the growth of robust and long-lasting fibrotic tissue that blocks bone cell colonisation and separates the implant from host tissue.
1.3 Titanium surfaces and specialised modifications to enhance implant performance
Materials that are considered inert include titanium and its alloys. Although historically seen as desirable, inert titanium is scarcely capable of fighting infections or actively controlling particular bone cell processes, qualities that are required for bone healing implants. As a result, research efforts have been focused on enhancing titanium surfaces in order to improve at least one of these two difficulties. As a consequence, there are now a variety of titanium surface modifications and coating methods available that may directly encourage bone development or reduce the risk of infection.4 The majority of Ti coatings employ a biological method to recreate the structure and functions of bone tissue. As a consequence, organic and inorganic-related solutions have become used for Ti coating applications. Bone tissue, for example, is composed of both organic (collagenous matrix) and inorganic (calcium phosphate nanocrystals) components.4 Coating materials have also been thoroughly examined in combination with molecules that directly alter osteogenic differentiation processes, such as particular extracellular matrix (ECM) proteins and growth factors (GFs), in order to increase bone formation and improve implant osseointegration.9 Similar to this, antibiotics and bactericides have been added into implant coatings with the goal of minimising and preventing infections linked to implantation operations. We have outlined numerous distinct methods for Ti surface treatments and coatings in this research. We first explain various organic and inorganic coatings before moving on to alterations made to titanium surfaces. With particular attention paid to the biological environment and the potential inclusion of biomolecule carriers, each technique is described, its intended uses are explained, and its advantages and disadvantages are underlined. Finally, we introduce and talk about some of the methods that have been tried out in clinical settings. The previous two decades' worth of pertinent scientific research in the domains described above has been attempted to be covered in this article.
Using research publications that were largely published within the previous ten years, we highlight the most recent advancements in the surface modification of titanium and titanium alloy implants in this review (Fig. 1). Four main categories—mechanical, physical, chemical, and biological—are used to group together the numerous surface alteration techniques. Some modification techniques included elements from other category subcategories and were categorized based on their main idea. We acknowledge the many influential evaluations that have been recently published on the subject of surface modification, enhancement of osseointegration and antibacterial activities for biomaterial implants.10,11 Other reviews have concentrated on certain features of surface modification in Ti and Ti alloys for promoting bone formation, such as the surface corrosion characteristics, biological similarity to bone, and antibacterial activity.12,13 Our study offers a thorough overview of the most recent developments in surface modification techniques for titanium and titanium alloy implants to enhance their osseointegration, encompassing several processes of modification and a sizable sample of the most current investigations. Titanium has the most favorable strength-to-weight ratio among all metals, making it very advantageous in many applications. Additionally, titanium exhibits exceptional resistance to chemical degradation, further enhancing its desirability in several contexts. Titanium has exceptional qualities that make it very suitable for a wide range of applications.
2 Methods
We selected our papers in line with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) standards in order to publish systematic reviews and meta-analyses.14
2.1 Protocol
The PICO framework was used to perform the search strategy based on the hypothesis that "Titanium implant surface alterations will increase the osseointegration and antibacterial activity properties?" A set of keywords is constructed to optimise the published data articles in order to respond to this question.
2.2 Method for scientific data optimization
In April 2022, a search for relevant scientific literature was conducted in the electronic databases Web of Science, PubMed Central, and Google Scholar. The following keywords were used: "titanium implants," "titanium surface modification," "titanium osseointegration," and "titanium antibacterial activity."
2.3 Guidelines for inclusion and exclusion
Inclusion standards.(a)Research papers written in English.(b)Implant studies using titanium and its alloys.(c)Research with full-text publications.(d)Articles with open access.
Exclusion standards.(a)Research utilizing irrelated titanium implants.(b)Unrelated articles, materials, improper technique, incorrect data values, and brief letters or communications.(c)Systematic and conversational reviews.(d)Case studies.(e)Studies that didn't fit the predetermined inclusion criteria, were irrelevant, duplicated, or all of the above.
2.4 Data collection and evaluation
The titles and abstracts of the selected publications were obtained and recorded into an Excel spreadsheet. Articles that made no mention of the research question were removed. The data is then evaluated and displayed using GraphPad Prism 8. The flowchart is prepared by considering various stages of data collection and extraction (Fig. 2). The main four stages of the flowchart are considered, they are search engine optimization, screening, eligibility, and included.
3 Trends over the last 10 years in publications and research (2012–2021)
Surface modification and antibacterial activity have become essential research areas because of rapid advancements in implantation, doping, manufacturing processes, modelling, and membrane application. In reality, it was impossible to determine the actual quantity of papers published, incredibly different databases generated different outcomes. Several statistical review articles for various topics and domains have recently appeared in the literature.15,16 Tober examined four standard search engines, including PubMed, ScienceDirect, Scopus, and Google Scholar, to discover which is best for performing laser medical literature searches based on recall, accuracy, and importance.
In this study, researchers used the Web of Science database to collect data on research statistics from a range of publications. The search contained only scientific publications and reviews that were directly related to the keywords "titanium implants," "titanium surface modification," "titanium osseointegration," and "titanium antibacterial activity." Any article or review that contains material, such as "titanium," but does not belong in the relevant field has been eliminated using further data processing. For example, while the word titanium was appropriately used in the paper, it was determined that the primary focus was on physical and mechanical characterizations. In order to limit the data to publications that are pertinent to surface modification and antibacterial activity, such articles have now been eliminated. Fig. 3 demonstrates the overall research trend for the yearly publication of scholarly publications throughout the last decade examined in the three platforms of Web of Science, PubMed Central, and Google Scholar.
It should be noted that, while Web of Science, PubMed, and Google Scholar are all scientific literature databases, Web of Science has the bulk of articles available with a subscription. The bulk of publications on biomedical literature from MEDLINE and life science journals may be found in PubMed Central. However, a large number of publications in all study fields will be available in Google Scholar. As a result, the variance in the number of published articles based on each database is presented.
The classification of implant surface modifications into six generations is shown in Fig. 4i. Etching was an essential part of the first generation of machined surface enhancement techniques via mechanical processes. Despite the many advancements in surface modification techniques, etching continues to be extensively used in commercial systems, either as an independent final surface modification or in conjunction with other methods. According to the data shown in Fig. 4(ii), the plasma spray coating technique is followed by etching as the second method, as indicated by published reports, with a utilization rate of over 15 %. Furthermore, other alternative techniques, such as sandblasting and sandblasting combined with acid etching (SLA) are also utilised in the surface modification procedures.
3.1 The effect of surface properties on the in vivo osteogenic process
In vivo investigations involving direct contact between bone tissue and the implant surface are extremely important in order to fully understand the boosting effect of numerous innovative titanium implant surface changes on osteointegration. The majority of the trials used in this evaluation used millimeter-scale, commercially pure titanium implants in a variety of forms. Independent researchers used several surface modification methods to create novel titanium implant surface topographies for enhanced osteointegration. Numerous anatomical areas of various experimental animal models housed the implants. At the starting and long stages of bone formation, the biological effects of newly developed titanium implant surfaces were contrasted with those of conventional smooth or rough surfaces. The bone-to-implant contact represents the quantity of fresh or existing bone associated with the implant surface, and other important histomorphometry metrics were utilised to assess the degree of osseointegration. The surface characteristics will play an important role in the osseointegration of biomedical implants. The widely used surface modification technique is the development of multifunctional TiO2 nanotubular surfaces on titanium implants. The physical characterizations of the multifunctional TiO2 nanotubular surfaces are shown in Fig. 5 with proper permissions from the published research article.17
Scanning electron microscopy (SEM) was used to analyze the morphological properties of thin films consisting of TiO2 nanotube arrays. These films were fabricated on titanium substrates using anodic oxidation at three different voltages: 10 V, 20 V, and 25 V. The oxidation process operated for a duration of 2 h. Subsequently, the films were subjected to annealing at a temperature of 450 °C for a period of 2 h. The nanotubes exhibited external diameters of 50 nm at 10 V, 70 nm at 20 V, and 100 nm at 25 V. The Atomic Force Microscopy (AFM) analysis revealed a positive correlation between the surface roughness of TiO2 nanotubes, as quantified by the average roughness of the profile (Ra), and their diameter. The surface roughness of sandblasting with large grit and acid-etching (SLA) was found to be decreased compared to TiO2 nanotubes with sizes of 70 and 100 nm, as shown in Fig. 5B. The X-ray diffraction (XRD) patterns of the nanotube films revealed the presence of solely titanium (Ti) peaks in the unannealed anodized nanotubes. These Ti peaks were found to be similar to those seen in selective laser melting (SLA) and polished titanium (Ti) surfaces. Nevertheless, the process of annealing at a temperature of 450 °C for a duration of 2 h resulted in the emergence of anatase TiO2 peaks. This observation indicates that the TiO2 nanotube layers underwent a transformation from an amorphous state to an anatase crystalline structure. The hydrophilicity of TiO2 nanotubes was shown to be enhanced with increasing diameters, as evidenced by a reduction in contact angle and an increase in surface energy. The contact angles of simulation body fluid (SBF) were found to be lower compared to those of double distilled water (ddH2O). Additionally, all TiO2 nanotubes exhibited higher hydrophilicity when compared to the surfaces of SLA and smooth Ti (refer to Fig. 5D).17Table 1 summarises the collected study publications, surface modifications, and results.
| S.No | Author [Ref. No.] | Substrate | Coating composition | Surface Modification Technique | Biocompatibility | Conclusions |
| 1 | Mariscal Munoz et al., 201518 | Commercially pure Ti (grade 4) discs | Rough TiO2 (Ra = 10.57 μm) | Grit-grinding,Pulsed laser ablation | When osteoblasts were cultivated on L surfaces, the number of metabolically active cells was marginally reduced by day 7 (P < 0.05). | By using the Yb: YAG laser on titanium surfaces, a hybrid nano-to-microscale surface able to promote osteoblast development and activity is created. |
| 2 | Peng Chen et al., 201719 | Commercially pure Ti | Mirror-polished TiO2 (Sa = 32 nm) | Mirror-polishing femtosecond (fs) laser irradiation | fsTi increased MC3T3-E1 cell osteogenic growth and calcification | Surface modification with femtosecond laser irradiation did not significantly alter the surface chemistry or molecular properties of the Ti substrate. |
| 3 | Yulia Zhukova et al., 201720 | Commercially pure Ti | Ordered and disordered nano tubular nanostructured titania (Ra >20 nm). | Electrochemical oxidation,Physical vapor deposition. | Examined MC3T3-E1 cell osteogenic differentiation driven by nano topography. | Preosteoblasts have distinct morphologies, adhesion, and migratory patterns when exposed to ordered and disordered nano topography. |
| 4 | M Moussa et al., 201721 | Ti Cp-IV | TiO2 surface with a TiNxOy coating. | Sandblasting,Magnetron sputtering | On days 2, 7, 14, and 21 of each trial, RNA was extracted and resazurin assays were performed. | When compared to the micro rough standard SLA, TiNxOy coatings promote osteoblast attachment and spreading. |
| 5 | Xiaojing He et al., 201622 | Commercially pure Ti | TiO2 containing Sr/Ag 0.40 | Micro-arc oxidation using magnetron sputtering. | The qualitative outcomes of cell proliferation on specimens after 1, 4, and 7 days of incubation. | Antibacterial activity, greater cytocompatibility, increased osteoblast spreading, and differentiation were all observed in Sr/Ag-doped TiO2 coatings. |
| 6 | Yong-Su Kwon et al., 201823 | Commercially pure Ti | TiO2 microstructure (Ra = 1.2 μm) | Grit-blasting,Hydrothermal treatment. | Using a cell counting kit, cell attachment (at 4 h) and proliferation (at 24hrs and 72 h) were evaluated. | Early cellular activities and development into osteoblasts were improved by the hydrophilic phosphate ion surface. |
| 7 | Shuang Li et al., 201824 | Stoichiometric pure HA and CHA powders | Micro-nano hybrid CHAp | Dip coating,Carbonated hydroxyapatite (CHAp). | CHA coatings demonstrated good biocompatibility with no discernible toxicity. | Surfaces treated with CHAp, particularly the hybrid (micron-nano) surface, improved cellular adhesion, proliferation, and differentiation. |
| 8 | Hirotsugu Umeda et al., 201725 | Ti discs | TiO2 coated with apatite | Blast coating with flame spraying. | On day five, the ALP activity increased. | The blast-coated surface elevated cellular ALP, which facilitated osteogenic differentiation and cell adhesion. |
| 9 | Zhang H et al., 201726 | Ti discs grade 2 | UV-treated TiO2 nano structure | Alkali and UV light therapy. | On TNS, cell growth and ALP activity were both enhanced. | On UV-treated surfaces, cellular adhesion, proliferation, differentiation, and protein adsorption were all improved. |
| 10 | Zhang Wenjie et al., 201627 | commercial TC4 titanium alloy | MAO-treated TiO2 layered with Strontium | Micro arc oxidation (MAO) | The healing time of 6 weeks is indeed. | The MAO-Strontium coating stimulated bone growth and osseointegration more quickly than the other experimental substrate groups. |
| 11 | B. Giuliano Maino et al., 201728 | Ti6Al4V | TiO2 micro structured rough surface | Sandblasting and acid-etching (SLA) | There were no complications with the healing of the wound, and no infections or animal deaths were noted. | The SLA surface demonstrated much more removal torque than the control. However, the BIC was similar for both groups. |
| 12 | Coelho PG et al., 201629 | Ti6Al4V | Micro-nano surface with dual acid etching | Nanotexture blasting,Acid etching | A short healing period of 9 days is indeed. | In comparison to the acid-etched surface, the nano-structured surface provided better bone attachment and strength. |
| 13 | Trisi P et al., 201630 | Ti | TiO2 Laser micro textured | Pulsed laser surface texturing | An 8-week healing period is required. | When compared to the machined surface, the laser-treated surface had higher mechanical strength and BIC. |
| 14 | Algabri Shaoki et al., 201631 | Commercial grade IV pure titanium powders. | Rough and uneven 3D surface production | Anodic oxidation, Selective laser melting (SLM). | The titanium surface created by SLM increased biocompatibility and cell adhesion. Healing time is 9 weeks. | There was no statistically significant difference between the groups after anodic oxidation, but the removal torque values (RTVs) of SLM were greater than those of machining but lower than those of surface (bone volume, BIC). |
| 15 | Insan Jang et al., 201732 | Ti | TiO2 nanotube with rhBMP-2, and Ibuprofen. | Anodic oxidation,Dip coating | The recommended recovery time frame is eight weeks. | Ibuprofen-loaded TiO2 had a higher BIC than rhBMP2, which had a higher BIC than unloaded TiO2, and machined TiO2 had the lowest BIC. |
| 16 | Furqan A. Shah et al., 201633 | C. p. Ti, grade 4) | TiO2 hybrid (micro-nano) roughened surface with Sa = 3.35 μm. | Selective laser ablation | 8 weeks of healing time needed | When compared to machined surfaces, laser-treated surfaces demonstrated improved biomechanical stability. |
| 17 | David J Cohen et al., 201734 | Ti–6Al–4V | Hybrid (micro–nano) roughened TiO2 surface with Ravg. = 2.47 μm. | Acid etching,Grit-blasting,Laser sintering | The healing time of 10 weeks is indeed. | In comparison to the solid surface, the rough surface allowed for better bone ingrowth. |
| 18 | Vivianne Chappuis et al., 201835 | C.p.Ti grade 4 | Hydrophilic ufgTi (ultra-fine-grained nano-patterned) surface with grain size 300 nm. | SLActive surface treatment. | Short healing improvement was reported in Weeks 4 and 8. | In terms of mechanical properties, ufgTi excelled. High degrees of osteointegration were maintained by the hydrophilic surface even in damaged bone. |
| 19 | E. Velasco Ortega et al., 201936 | Ti–6Al–4V | Oxidized TiO2 micro-nano rough surface (Ra = 1.37 μm) | Sandblasting,Acid etching,Oxidation | The 12-week recovery time is appropriate. | The roughness of the SLA surface was higher than that of oxidized surface. However, both groups have comparable BIC. |
| 20 | Hong-zhi Zhou et al., 201737 | Ti | Microarc oxidized TiO2 surface | Microarc oxidization (MAO) and Machining (MA) | The healing time of 4 weeks is indeed. | In comparison to modified SLA surface, the MAO surface was significantly more superhydrophilic and demonstrated somewhat more bone growth. |
| 21 | Pelegrine AA et al., 201938 | C.pTi grade 4 | TiO2 nanotubular surface | Anodization,Double acid etching | Short healing improvement was reported in Weeks 2 and 6. | The nano-tubular surface demonstrated enhanced wettability, periimplant bone growth, and osseointegration. |
| 22 | Keng-Liang Ou et al., 201639 | ASTM grade IV titanium | TiO2 micro-nano rough surface (Ra = 1.0 μm) | Grit-blastingAcid etching,Electrochemical oxidation | The healing duration for the three substrates is 2, 4, and 6 weeks, respectively. | In comparison to the control surfaces, the nano-rough structured surface demonstrated the highest biocompatibility with blood and increased osseointegration. |
| 23 | Niloufar Khosravi et al., 201840 | Ti | TiO2 Nano-tubular surface | Grit-blastingAcid etching,Electrochemical oxidation | The peri implant healing region was monitored from day 3–42 after implantation. | In comparison to the machined surface, the nano-tubular surface displayed higher blood vessel density, BV/TV, and BIC. |
| 24 | E. Calciolari et al., 201741 | Ti | SLActive rough hydrophilic TiO2 surface | SLActive is an added chemical process.SLA: large-grit sandblasting and double-acid etching. | Early healing points taken into account on day 4, 7, and 14. | At the early stages of healing, the hydrophilic-SLA group had a decreased inflammatory response and greater osteogenic activity. |
| 25 | S. Alexandre Gehrke et al., 201642 | Ti | CaMg incorporated Micro structured surface (Ra = 0.89 μm) | Grit blasting | Healing at week 4, 6 after implantation. | Bone mineralization and BIC were both improved after Ca-Mg deposition, which boosted osseointegration. |
| 26 | Yan-pin Fan et al., 201643 | Cp Ti | Strontium-oxide layer with a nanostructured structure on a micro-rough SLA surface (Ra = 2.35 μm). | Hydrothermal treatment for SLA metallic-oxide inclusion | Time units, week 3, 6, for healing. | Strontium inclusion enhanced the early bone growth and increased osseointegration, as evidenced by increased BIC and removal torque. |
| 27 | S.C. Sartoretto et al., 201644 | Ti6Al4V | Sodium incorporated rough hydrophilic TiO2 surface (Sa = 0.99 μm) | Acid etching,Sandblasting,Alkali treatment | Bone area (BA) and BIC measurements were taken on 30 μm of thin samples at day 7, 14, 21, and 28 of post implantation. | Compared to the untreated-SLA, the hydrophilic stimulated SLA surface shown better BIC and bone area on day 14. |
| 28 | Yonggang Dang et al., 201645 | C.p. Ti | Grit-blasted TiO2 Titania nanotubes loaded with strontium | Electrochemical anodization,Grit-blasting | After implant installation, the healing points are reported at week 4 and 12. | Among the examined groups, Titania nanotube loaded with strontium had the greatest BIC. |
| 29 | David H. Kwon et al., 201746 | C.p. Ti | TiO2 anodic surface with acid treatment | Blasting,Anodic oxidation, immersion | Healing time period after week 3 | In comparison to the control, the addition of Zoledronic acid considerably increased implant durability, bone development, and osseointegration. |
| 30 | H T Sirin et al., 201547 | C.p. Ti | Titanium nano structured surface with HAp deposition | Anodization,HAp deposition | Healing time period after week 10 | Compared to control, osseointegration was enhanced by anodization and HA deposition. NanoTi + HAp surface and NanoTi surface displayed similar effects. |
| 31 | Ajay Sharma et al., 201648 | C.p. Ti | Hydrophilic, nano rough surface incorporated with Ca, P, O2. | Anodization | Healing time period after week 4 | Anodization improves early osteointegration. |
| 32 | Zhou-Shan Tao et al., 201649 | C.p. Ti | Strontium (Sr) with HAp coated TiO2 surface | Electrochemical deposition | Healing time period after week 12 | Strontium was added to the HAp layer to enhance bone formation at BIC. The Strontium + HAp coated surface with a 20 % composition had the best mechanical and osseointegration capabilities. |
| 33 | M J. Coathup et al., 201750 | Ti-6Al-4V | Grit blasted (Ra = 6 μm),HAp-coated (Ra = 2 μm),Laser-textured surfaces | Grit blasting,Machining,Plasma spray coating,Laser texturing surface | Healing time period after week 6 | In comparison to the machined surface, all modified implant surfaces showed greater BIC. But the HAp-coated surface's BIC excelled the laser-textured and blasted surfaces. |
| 34 | Jun-Beom Lee et al., 201951 | C.p. Ti | SLA surface with UV treatment | Sandblasting,Acid etching,UV treatment | The substrates began to heal on day 10, and 28, post-implantation. | BIC and osseointegration enhanced after UV therapy. |
| 35 | Wonhee Park et al., 201552 | C.p. Ti | Hydrophilic micro-rough TiO2 microfiber (87 % porosity) | Acid etching and UV treatment | The substrates began to heal on week 2, and 4, post implantation. | Bone development and implant attachment strength are enhanced in UV-treated implants. |
| 36 | Mistry et al., 201653 | Ti-6Al-4V | Ti surface coated with HAp (Ra = 90 μm),Ti surface coated with bioglass (Ra = 30 μm) | Micro plasma spray coating | Healing time period after 1 year | In the maxillary area, the bioactive glass-coated surface demonstrated improved osteo-integration. A similar impact was seen in the three groups' mandibular area. |
| 37 | Zi Li Wang et al., 201754 | C.p. Ti | CaTiO3 coating having pore size 1–4 nm,HAp coating having pore size 100–200 μm) | Chemical (NaOH and CaCl2) treatment and plasma spray coatings | Time period after weeks 2, 4, 8, and 12. | In comparison to the untreated machined surface, the CaTiO3 and Hydroxy apatite coated surface had equivalent BIC and mechanical strength. |
| 38 | Yingmin Su et al., 201755 | Ti-6Al-4V | Nanorough surface with Ca + ions (Ra = 20.58 nm),Nanorough surface with Na + ions (Ra = 21.46 nm) | Chemical treatment (NaOH and CaCl2) | Time period after weeks 1, 4, and 8. | In comparison to the machined surface, BIC was higher in Na+ and Ca + integrated nanorough implants. Ca + inclusion resulted in better new bone formation as compared to the other groups. |
| 39 | S. Galli et al., 201756 | C.p. Ti - gr.4 | TiO2 with Mg-ion coated surface | Electro spinning,Physical vapor deposition | Best healing outcome at day 1, 2, and 7. | At the bone implant interface, the Mg ion's immediate release encouraged fast bone growth and the activation of osteogenic pathways. |
| 40 | V.Offermanns et al., 201657 | C.p. Ti - gr.4 | Strontium nanostructured coating surface | Magnetron sputtering | Best healing outcome at week 6, and 12. | Sr-release substantially boosted new bone formation and BIC at 6 weeks. |
| 41 | Marcio V. Cardoso et al., 201758 | C.p. Ti - gr.4 | Phosphorylated pullulan (10 %) + 1 μg BMP2 | Dip coating | Healing outcome at week 4, and 12. | Higher BIC and peri implant bone growth at an early phase of bone healing were supported by titanium implant surfaces functionalized with inorganic and organic polymers containing 10 wt% phosphate. |
| 42 | Kewen Li et al., 201859 | Ti-6Al-4V | Nanostructured graphene surface coating | Chemical vapor deposition (CVD) | Healing outcome at week 4, 12, and 24. | In comparison to the untreated surface, graphene nanocoating improved osteogenesis and osteointegration. |
| 43 | Ting Ma et al., 201760 | C.p. Ti - gr.4 | SLA dopamine with Zoledronic acid treatment | Sandblasting,Dip coating | The time period for healing is 8 weeks after implantation. | Dopamine and Zoledronic acid coating increased osteointegration over time, as seen by higher BIC and removal torque. |
| 44 | Aranka Ilea et al., 201961 | C.p. Ti - gr.4 | Nano HAp with silicon inclusion coated surfaces | Selective laser melting (SLM) | The time period for healing is month 2, 4, and 6 after implantation. | When compared to uncoated scaffolds, nano-HAp-Si coated scaffolds demonstrated superior osteointegration. |
The above table summarises several common methods for modifying implant surfaces18–61. Fig. 6 demonstrates an overview of the cellular response at the bone-implant interface utilizing osteogenic differentiation. During the first stages of the biological response, the implant's surface morphology, topology, and surface properties play crucial roles that ultimately determine the implant's level of osteointegration.18,19 Physical properties and chemical compositions are the primary factors that determine the biological improvements of metallic implants.22,27 It is already known that topography describes the surface's biomechanical and structural features. In general, average surface roughness has been categorized into as follows: smooth (Ra = 0.5 μm), machined/minimal (Ra = 0.5–1 μm), moderate (Ra = 1–2 μm), and rough (Ra>2 μm).30,33,39
Surface modifications that enhance hydrophilicity and roughness are beneficial to the osteogenic differentiation of cells and implant osteointegration.40,41 Both macroscopic and microscopic roughness helps the mechanical attachment of the implant to bone.42,44 Cell adhesion is also promoted by hydrophilic surfaces. By increasing the surface area available for cell adhesion, bone-implant contact, and implant stability, roughening improves biomechanical integrity after the ingrowth of a new bone matrix at the bone-implant interface.52,53 Surface roughness may be modified to enhance its chemistry and stimulate osteogenic activation. Coating with various molecules may change the surface's roughness and structure, and structural changes to the surface impact the physicochemical properties.33,35,54
The first step in the process of bone implant surface development is the establishment of an adequate rough morphology.33 The procedures listed in Table 1 are some of the most common ones used to roughen the surfaces of implants. Both chemical and physical modification techniques, including as grinding and laser texturing, are used in the production of the essential implant surface roughness. When it comes to changing the chemical surface composition, the use of acid etching and other chemical modification techniques is far more likely to be successful than the use of physical methods. As an example, it has been shown that hydrogen adsorption and the creation of stable titanium hydride on the surface of titanium may occur as a consequence of acid etching of titanium with HCl and H2SO4.35,38
The formation of a TiO2 passivation layer on physically roughened titanium surfaces is a fascinating mechanism. It has been proposed that nano-patterning, together with appropriate macro- and micro-features of an implant, plays a crucial role in the biological response.41,47 There is evidence that laser texturing is replacing the more common practice of sandblasting and acid etching (SLA) on implants in clinical situations because the resulting nano-topography is more visually attractive. When it comes to the surface structuring of metal implants, laser texturing is one of the most cutting-edge and promising technologies since it enables the development of a desired, controllable, and repeatable surface geometry over several dimensions.51,53 There are no extra chemicals added to the surface during production that may be detrimental. More so, laser texturing randomly produces metal nanodroplets on the implant surface, leading to a nano-roughened topography with foamed, and rounded nano-features.54,55
Fig. 7A shows the results of a scanning electron microscopy (SEM) study, which revealed the complex shape and organization of the adhering cells, including the existence of pseudopodia. However, the number and structure of these cells were evaluated using confocal microscopy with FITC-Phalloidin labeling. As can be seen in Fig. 7C, the Cell-counting kit-8 (CCK8) was used to evaluate the adherence of hASCs. Human adipose-derived stem cells (hASCs) extended lamellipodia on all three types of titanium dioxide (TiO2) nanotube surfaces after 2 h of incubation. In addition, the nanotube surfaces were shown to have a greater number of adhering cells compared to smooth titanium surfaces, sandblasted with big grit, and acid-etched (SLA). Cells revealed a round shape with short pseudopodia on the SLA surface, but a round morphology without pseudopodia and the fewest adherent cells on the smooth Ti surface. After 4 h of growth, it was clear that the length of the pseudopodia, which resembled a net, had increased for all three groups of TiO2 nanotubes. More cells were found to be firmly attached to the nanotube groups' surfaces compared to those of SLA and smooth titanium. The SLA pseudopodia extended, but at a shorter length than the nanotube clusters. The cells showed a round shape with no evidence of pseudopodia when cultivated on a smooth titanium surface. After 24 h, the cells on the nanotube surface had taken on a more polygonal shape, while those on the SLA and smooth titanium surfaces had taken on a spindle form. CCK8 assays showed that at 2, 4, and 24 h post-development, human adipose-derived stem cells (hASCs) adhered better to TiO2 nanotube surfaces than they did to sandblasted and acid-etched (SLA) surfaces (p 0.05). When compared to the other groups, the cell count in the group with 70 nm nanotubes was statistically substantially higher (p 0.05).17
Further ion and molecule functionalization of a titanium implant surface may be undertaken for the following reasons: (a) removing proteins that may promote unwanted cell attachment and the development of fibrotic tissue or bacterial adhesion; (b) promoting the adhesion of desired cell types, such as osteogenic progenitor cells and osteoblasts; and (c) regulating immune cell responses that control inflammation during the healing process. Functionality is imparted to the material by including or bonding inorganic ions or molecules (such as magnesium (Mg), calcium (Ca), and strontium (Sr)) and organic molecules (such as amines) to match the needs of the application (e.g., peptides, proteins and drugs). Research on HAp has been going on for a long back, and it is often chosen as a possible coating material. Its deposition may encourage BIC and bone development, and it is currently being used in therapeutic situations. That is being put to use now. Plasma spraying, electrochemical/micro-arc/anodic oxidation, immersion, acid etching, and laser ablation are only some of the methods that may be used to deposit coating molecules (Table 1). Surface molecules may be created automatically but unpredictably (a process known as indirect coatings, such as anodic oxidation or immersion), or they can be deposited directly on the surface in a regulated density using a different method (e.g., plasma spraying, laser ablation).
3.2 Metal surfaces with multifunctional bioactive and antibacterial properties
Many approaches have been considered in the literature to create titanium surfaces both bioactive and antibacterial. The next sections explain recent discoveries that are consistent with this classificational explanation. Organic antibacterial agents (mostly antibiotics) were not considered with inorganic antibacterial agents. Metallic nanoparticles, metallic ions, and oxides are like silver, copper, zinc, and cerium, have been studied as inorganic antibacterial agents. Inorganic antibacterial medications frequently have a wide range of bioactivity, allowing for the treatment of poly-microbial infections as well as the inhibition of infection by unidentified bacteria, as well as the development of limited resistance. In this sense, one of the most important problems with the use of antibiotics nowadays is the issue of resistant bacterial strains. On the other hand, the key disadvantages are their relatively recent application, which suggests challenges in certification and regulatory considerations as well as in locating the ideal therapeutic window, with efficient antibacterial activity without cytotoxic consequences. Surfaces with nanoscale characteristics, surface modifications without the addition of a foreign substance, and thick coatings (those greater than 1 μm thick) were all taken into consideration separately from thin coatings (those less than 1 μm thick).
In recent years, significant progress has been achieved in the development of novel ways to texturing and bio-functionalizing implants. Because of the complexity of the responses from cells and tissues, measuring the potential for novel surface modifications to be implemented requires a thorough study. Fig. 8a demonstrates a representation of osseointegration for commercially pure titanium (CpTi), TiO2 nanotubes (TNT), and polarized TNT (TNT-Ps) in a rat distal femur model after 5 weeks of in vivo study. The research findings were obtained from the published article with proper permission from the concerned publishing house.62 The appropriate positioning of the implant was seen in the harvested samples after a period of 5 weeks of implantation, as determined by the analysis of CT scans (Fig. 8b). In tensile testing, it has been shown that the shear modulus of polarised-TNT (123.26 ± 2 MPa) is much higher compared to that of TNT (83.28 MPa) and CpTi (39.21 ± 7 MPa). The results of this study suggest that there is a strong initial connection between the implant and the host tissue. The occurrence of bone fractures seen during the tensile test provided further validation of the findings obtained from TNT-P (polarised-TNT), hence suggesting a stronger link between the implant and surrounding tissue. The use of scanning electron microscopy (SEM) in the analysis of stained samples has facilitated a deeper understanding of the process of implant-bone bonding. Fig. 8c displays scanning electron microscope (SEM) images of all samples exhibiting interfacial bonding. The presence of gaps in control CpTi samples results in poor bonding. The analysis of TNT-P samples reveals evidence of initial osseointegration, which may be attributed to an improved contact between cells and the implant at the interface with the bone. The authors conducted a histological examination of the interface between the implant and bone, with a focus on investigating the biocompatibility of TNT-P implants and the potential impact of surface charge on the process of new bone formation. Fig. 8d,e displays histological micrographs depicting the interaction between bone tissue and CpTi, TNT, and TNT-P materials. The zone displaying an orange-red color corresponds to the process of osteoid growth, while the area exhibiting a greenish-blue color indicates the presence of mineralized bone. Additionally, the bluish-black specks seen inside the sample are a result of Masson Goldner's Trichrome staining, specifically highlighting the nuclei. The qualitative histology microscopy examinations conducted on osteoid formation reveal the absence of any cytotoxicity concerns related to TNT-P.62Table 2 gives an overview of the academic research works addressing on invitro bioactivity. Table 3 also concentrates on the same research areas but in the identified articles the authors have not performed the bioactivity test and the rest of all characterizations were performed and evaluated.
| S.No | Author [Ref. No.] | Substrate | Coating composition | Surface Modification Technique | Bioactivity | Antibacterial activity | Bio-compatibility | Conclusions |
| 1 | S. Ferraris et al., 201463 | Commercially pure Ti | Ag | oxidation and silver doping | Apatite formation in SBF <14 days | Antibacterial activity on S. aureus (>1 mm halo for disk diffusion) | There is no cytotoxicity at 2.6 % of silver content | In vitro bioactivity and substantial antibacterial activity against S. aureus are displayed by the treated surfaces. |
| 2 | Archana Rajendran et al., 201464 | Titanium | Ag | Dip coating | Apatite formation in SBF <1 days | Antibacterial activity on S. aureus, Visible halo (at >0.64 % silver) in disk diffusion | There is no cytotoxicity till 2.3 % silver on MG63 osteosarcoma cells | Around 99 percent bacterial killing efficacy was demonstrated for 6–8 ppm Ag incorporation in heat-treated Ag-incorporated titanium samples. |
| 3 | Vinod Prabu et al., 201565 | Ti-6Al-4V | Ag | Dip coating | Apatite formation in SBF <7 days | Antibacterial activity on S. aureus | There is no cytotoxicity till 0.6 % silver, cytotoxicity for 1.3 % silver | The silver-titanate layer emitted Ag+ ions into the environment and showed antibacterial action against Staphylococcus aureus. |
| 4 | Sanja Erakovic et al., 201466 | C. p. Ti | Silver-doped hydroxy apatite lignin | Electrophoretic Deposition | After 7 days in SBF, HAp deposited over the surface | Active vs S aureus after 24hrs. | Peripheral blood mononuclear cells for biocompatible | An effective lignin concentration of 1 wt percent made for a fantastic lead material for potential biological applications in the future. |
| 5 | Yong Huang et al., 201767 | C. p. Ti | TiO2 incorporated with Ag and Sr codoped HAp surface (25 μm thick) | Anodic oxidation,Electrodeposition | After 5 days in SBF, HAp deposited over the surface | Active vs S. aureus (complete Inhibition halo after 24 h) | Biocompatible for BMSCs | The silver-doped HA coatings have a constant and efficient ability to eliminate S. aureus germs. |
| 6 | Xue Liu et al., 201668 | Ti-6Al-4V | Silver nanoparticles doped hydroxyapatite | Laser surface treatment and painting with PVA binder | After 5 days in SBF, HAp deposited over the surface | Active vs S. aureus (based on silver content) | up to 2 % of silver mice bone cells is biocompatible | Applications such as labeling, optoelectronic devices, and ratio metric sensors may benefit from the usage of multicolor emission materials. |
| 7 | Yong Huang et al., 201569 | Commercially pure Ti | Copper doped Hydroxyapatite | Electroplating | After 10 days in SBF, HAp deposited over the surface | Active vs E. coli. (Halo inhibition) | MC3T3 - Mouse osteoblast cells | Compared to the HAp coating, the CuHAp film demonstrated greater corrosion resistance in SBF. |
| 8 | F.Ordikhani et al., 201470 | Titanium | Chitosan + Bioglass | Electrophoretic deposition (EPD) | After 28 days in SBF, HAp deposited over the surface | Vancomycin added at a concentration greater than 0.5 g/l completely eradicates S. aureus. | In vitro cell tests revealed that vancomycin had almost no negative effects on biological responses, but bioactive glass improved cell survival, adhesion, and proliferation in MG-63 osteoblast-like cells. | |
| 9 | Sigrid Seuss et al., 201471 | Ti-6Al-4V | Chitosan and bioglass | Electrophoretic deposition (EPD) | After 21 days in SBF, HAp deposited over the surface | Active vs E. coli bacterial adhesion | By using AC-EPD, it is feasible to create chitosan-BG coatings that are strong, bioactive, and antibacterial with the potential to be used in bone tissue engineering and orthopaedics. | |
| 10 | Takashi Kizuki et al., 201472 | Titanium | Ag | Dip coating | Apatite formation in SBF <1 day | Antibacterial activity on S. aureus | The titanium materials had excellent antibacterial activity and could produce an apatite surface layer in SBF in addition to slowly releasing silver ions. | |
| 11 | S. Kalaivani et al., 201473 | C. p. Ti | Copper doped CaSiO3 | Electrophoretic Deposition | After 3 days soaked in SBF, complete coverage with hydroxy apatite layer | Active vs E coli., and S. aureus | The EPD approach has produced a homogeneous coating of CaSiO3 and Cu2+ replacements in CaSiO3, and until a heat treatment temperature of 800 °C, no change in the phase behaviour has been observed. | |
| 12 | Dilek Teker et al., 201474 | Commercially pure Ti | Silver doped HAp, CaTiO3, TiO2 multi-layered surface (910–14 μm thickness) | Micro Arc Oxidation | After 1–7 days soaked in SBF, HAp layer deposited over the surface | Active vs E coli, S.aureus (99 % viability reduction) | The multi-layer coating improved the antibacterial effectiveness against E. coli and S. aureus and expedited the bio-mimetic precipitation of apatite in simulated bodily fluid. | |
| 13 | Faiz Muhaffel et al., 201675 | Ti-6Al-4V | Silver doped HAp in TiO2 multi-layer surface (11–19 μm thick) | Micro Arc Oxidation (MAO) | After 72hrs soaked in SBF, HAp layer deposited over the surface | Active vs S aureus: (99 % viability reduction); against E. coli is 13 mm. inhibition halo | AgNO3 addition to the base electrolyte improved the hydroxy apatite layer's crystallinity, predominated rutile phase in TiO2 layer, and encouraged the precipitation of silver nanoparticles on hydroxy apatite layer. | |
| 14 | V. Kotharu et al., 201276 | Commercially pure Ti | TiO2 loaded with silver + HAp | Plasma electrolytic process | After 10 days soaked in SBF, HAp will cover completely | Active vs E. coli. (Halo inhibition) | Compared to the uncoated Cp Ti implant material, the AgHAp/TiO2 coating significantly improves corrosion resistance and adds capacitive properties. |
| S.No | Author [Ref. No.] | Substrate | Coating composition | Surface Modification Technique | Antibacterial activity | Bio-compatibility | Conclusions |
| 1 | Julianna K. Bronk et al., 201477 | Titanium | Bacterial collagen | Grafting surface | Active vsS. aureus, and S. epidermidis, | MG63 primary osteoblasts | A streptococcal collagen-mimetic protein with alpha-2 integrin binding can operate as a biointerface with osteoconductive characteristics while preventing bacterial adhesion. |
| 2 | M G Gallardo et al., 201478 | Titanium | Coating with human lactoferrin derived peptide (hLf1-11) | Silanization/absorption for the surface grafting | S. sanguis and L.salivarius for biofilm reduction | Biocompatible for the fibroblasts (human foreskin) | Coating Ti materials with hLf1-11 is a realistic and helpful method for reducing bacterial infection while improving the long-term effectiveness and durability of the dental implants. |
| 3 | Tingting Wang et al., 201779 | Titanium | TiO2 nanotubes with PLGA coating | Anodic oxidation | MC3T3-E1 cell adhesion is improved | The regulated synthesis, properties, and ibuprofen release patterns of TNTs/PLGA are described in this paper. | |
| 4 | Zhenming Wang et al., 201580 | Titanium | BSA nanoparticles with chitosan + alginate | Selective laser sintering, NaOH treatment | S.epidermidis adhesion reduction (Approx. 90 %) | Excellent adhesion, proliferation, ALP for BMSC | The nano-structured coating enables the long term release of Van and BMP 2. |
| 5 | Wang, Zhenming et al., 201681 | Titanium | BSA nanoparticles with chitosan + alginate | Selective laser sintering, Polydopamine coating | Excellent adhesion, proliferation, ALP for BMSC (rabbits). | Biomimetic ECM coatings including RGD and BMP might be used to a number of biomedical devices to increase bioactivity and biocompatibility. | |
| 6 | I.V.Sukhorukova et al., 201582 | Ti-grade. IV | TiCaPCON film,TiC0.5Ca3(PO4)2 | Selective Laser Sintering (SLS) | Active vs S. aureus,S. epidermidis | The bactericidal effect was not significant, and it frequently manifested as a change in either the optical densities of bacterial suspensions or the morphology of bacterial colonies. | |
| 7 | M.Diefenbeck et al., 201683 | Ti-6Al-4V | TiO2 layer surface | Plasma chemical oxidation (PCO) | In-vivo active model (rat osteomyelitis) | Gentamicin-SDS and gentamicin-tannic acid coatings of titanium alloy implants have a good preventive effect against implant-related osteomyelitis. The coatings not only inhibit or limit bacterial development, but also prevent bacterial contamination. | |
| 8 | Deyan Li et al., 201784 | Ti-6Al-4V | Hydroxyapatite (HAp) coating | Cold spraying | Active vs E.coli (killing almost 99 %) | A long-lasting antibacterial activity and good biocompatibility were confirmed in the GS-containing HA coating. | |
| 9 | Sophie C. Cox et al., 201685 | Ti-6Al-4V | Calcium orthophosphates (CaPO4) cement | Selective Laser Melting (SLM) | Active vs S. aureus,S. epidermidis | It was shown that employing antibiotic cement inside the implant models, rather than a blank cement cylinder, regulated the release properly. | |
| 10 | A. Kazek-Kęsik et al., 201686 | Ti-15Mo | TiO2 coated with PLGA surface | Dip coating and Plasma electrolytic oxidation | Up to 4 h there is no adhesion of S. aureus | Biocompatible up to 7 days for MG63 | The surface modification increased the substrate's ability to withstand corrosion while the polymer coating degraded evenly. |
| 11 | Jiabei Zhou et al., 201287 | Titanium | Chitosan/CaPO4e | Electrochemical coating | Component ratio and surface topography will effects on drug release behaviour. | It might imply that a high porosity surface would promote drug loading and that having the proper chitosan composition proportion would also be helpful. | |
| 12 | Dong Zheng et al., 201388 | Titanium | Coated with Carboxymethyl chitosan (CMCS) | Surface grafting | Active vs S. epidermidis (Approx. 85 % of reduction) | Biocompatible for the primary osteoblasts | The utilization of DA and PDA anchors to attach bioactive capabilities such as CMCS and BMP2 to biomaterials has great promise for future therapeutic applications. |
| 13 | Mariam Taha et al., 201489 | Titanium | Hydroxy apatite + cyclodextrin | Dip coating,Plasma spray,Thermal treatments | Active vs E.coli,S.aureus | Drug/CDs cavities, drug/COOH, and other modes of drug-polyBTCA/MeCD coating interaction have all been studied in order to improve drug adsorption on implant surfaces. | |
| 14 | Ketul C. Popat et al., 201290 | Titanium | TiO2 nanotubular surface | Anodic oxidation | Reduction of S. epidermidis adhesion after 4hr | 65 % more osteoblast adhesion compared to flat Ti, | Gentamicin-loaded nanotubes are excellent at reducing bacterial adherence. |
| 15 | Moom Sinn Aw et al., 201391 | Titanium | TiO2 nanotubular surface | Electrochemical anodization | It is shown that titanium nanotube-titanium drug-drug carrier releasing implants have the ability to initiate the release of drug carriers by ultrasound. | ||
| 16 | Karan Gulati et al., 201592 | Titanium | TiO2 nanotubular surface | Anodic oxidation in three steps | Preparation of unbound titania nanocapsules for use as drug delivery nanocarriers in a variety of targeted and localised drug delivery applications. | ||
| 17 | Chaoming Xie et al., 201693 | Titanium | Hydroxy apatite nanoparticles with polydopamine | Selective laser sintering | Excellent adhesion, proliferation, ALP for BMSC (rats). | In vitro BMSC growth experiments and in vivo Sprague Dawley rat implantation revealed that the multilayer nanofilms showed strong osteoinductivity. | |
| 18 | Lu Han et al., 201494 | Titanium | Chitosan coated surface | Sodium hydroxide treatment, and Silanization | ALP activity increased and calcium deposition for in vivo BMSC (rabbits). | The current coating process is a practical and efficient way for immobilising biomolecules on surfaces. | |
| 19 | Chaoming Xie et al., 201595 | Titanium | Polypyrene with hydroxy apatite and silver nanoparticles | Pulsed electro-chemical synthesis | More than 90 % of bactericidal for E.coli and S.Epidermidis | Excellent ALP activity for the BMSC. | Three type of coatings were shown via electrodeposition on titanium surfaces: pure PPy, HA-PPy, and HA-Ag-PPy coatings. |
| 20 | Chao-Ming Xie et al., 201496 | Titanium | Hydroxy apatite added with chitosan and silver NPs | Electro-chemical deposition | More than 90 % of bactericidal for E.coli and S.Epidermidis | Excellent adhesion, proliferation, ALP for BMSC. | A simple and efficient way of incorporating growth factors and antibacterial compounds into CaP coatings. |
| 21 | Chaoming Xie et al., 201797 | Titanium | Incorporated of polydopamine or polypyrene microcapsules | Electro-chemical deposition | Excellent adhesion, proliferation, ALP for BMSC (rats). | Electrical treatment and on-demand medication administration are possible uses for PDA-PPy-MCs. | |
| 22 | Supriya Kheur et al., 201798 | Commercially pure Titanium | Silver films | Magnetron sputtering | Active vs, S. mutans, S. aureus at 24 h | 20 % viability reduction of human gingival fibroblast at 72hr | The antibacterial effectiveness and cytocompatibility of human gingival fibroblasts were proven by nanoscale silver coatings on titanium surfaces. |
| 23 | Doo-Hoon Song et al., 201299 | Commercially pure Titanium | TiO2 + silver NPs | Magnetron sputtering | Active vs S. aureus. specific reduction after 3hr and total destruction colonies at 24hr. | 10 % viability reduction for L-929 fibroblasts | In this work, titanium oxide coatings with magnetron sputtered Ag nanoparticles provide an effective antibacterial layer with long-lasting biocompatibility. |
| 24 | Nathan A. Trujillo et al., 2012100 | Commercially pure Titanium | Silver doped with hydroxy apatite | Magnetron sputtering | Active vs S. epidermidis at 8–48 h. The coating delamination after 24 h. | The deposition procedure successfully regulated the concentration and topographical regularity of silver inside the hydroxyapatite coating. | |
| 25 | Maria A. Surmeneva et al., 2017101 | Commercially pure Titanium | Multilayer coating of silver nanoparticles/calcium phosphate | electrophoretic deposition, RF magnetron sputtering | Turbidity test for Active vs E. coli. | Mitochondrial activity reduction for MG63 cells in 1–3 days. | Degradation without delamination was primarily caused by the multilayered coating's homogeneous disintegration. |
| 26 | Jiaxing Wang et al., 2017102 | Ti-6Al-4V | Zinc oxide | Magnetron sputtering | In vitro and in vivo comparison of active vs. S. aureus, S. epidermidis, E. coli, and P. aeruginosa (mouse) | There was no cytotoxic impact on rat bone MSCs. | ZnO-modified surfaces shown a strong capacity to combat bacterial adhesion biofilms. |
| 27 | Heng-Li Huang et al., 2013103 | Commercially pure Titanium | Zirconium dioxide | Magnetron sputtering | Active vs S. aureus; enhanced activity by doping with Ag or Cu. | There will be many advantages by incorporating silver and copper into ZrO2 to form a ZrO2Ag and ZrO2Cu, in medical devices. | |
| 28 | D. Wojcieszak et al., 2017104 | Ti-6Al-4V | Silver, Gold, Copper dopped titanium | Magnetron sputtering | at 24 h, Active vs E. coli, S. aureus, C. albicans | The effect of copper, silver, and gold additions on the microstructure, corrosion resistance, hardness, wettability, and antibacterial activity of Ti-based films was discussed. | |
| 29 | Yin-Yu Chang et al., 2014105 | Commercially pure Titanium | Tantalam oxide (Ta2O5) crystalline/amorphous surface | Magnetron sputtering | Improved bioactivity for amorphous coating | Excellent at crystalline coating towards skin fibroblasts | Ta2O5 coatings may be produced in either amorphous or crystalline forms using pulsed magnetron sputtering and quick thermal annealing (RTA). |
| 30 | C.Gasquères et al., 2012106 | Ti-6Al-4V | Silver dopped titanium dioxide | Anodic spark deposition (ASD) | Gentamicin resistant at 12hrs. | On titanium medical grade alloy, a TiO2 surface coating with silver particles was effectively deposited. | |
| 31 | L.Cianferotti et al., 2013107 | C. p. Ti | Silver deposited β-Ca3(PO4)2 with chitosan (50 μm thick) | Electrophoretic Deposition | Active vs E coli., S.aureus | MG63 up to 1.3%mol silver biocompatible | Treatment with strontium ranelate over time has been found to reduce the risk of fracture. |
| 32 | Xiangyu Zhang et al., 2016108 | C. p. Ti | Zinc doped TiO2 surface (10 mm thick) | Micro Arc Oxidation (MAO) | Active vs E. coli, S. aureus (90 % viability reduction) | Excellent antibacterial capabilities are displayed by the Zn-incorporated TiO2 layer. | |
| 33 | Xiangyu Zhang et al., 2017109 | Commercially pure Ti | Copper nanoparticles dopped TiO2 surface (5–10 mm thickness) | Micro Arc Oxydation (MAO) | Active vs S. aureus (based on copper content) | Preosteoblasts up to 0.3 g/l copper; endothelial cells up to 3 g/l copper. | Because of the combined actions of release-killing and contact-killing, the Cu NPs coatings display high antibacterial activity. |
| 34 | Zhaojun Jia et al., 2015110 | C. p. Ti | Titanium dioxide loaded with silver nanoparticles | MAO, dip coating of dopamine, and silver nitrate reduction | Bacterial killing into nanotubes; Active vs S.aureus | MG63 and in vivo biocompatible tests | research on the creation of new antibacterial strategies as well as the problem of how mammal cells relate to surfaces coated with Ag nanoparticles. |
| 35 | Ruoyun Wang et al., 2017111 | Ti-6Al-4V | Zinc-doped TiO2 surface (13 μm thick) | Magnetron sputtering of Zr, electrolyte with Zinc in MAO. | Complete bacterial killing for Zr doped; less for undoped. | MC3T3-E1 cell adhesion is improved | Because of the prolonged release of Zn2+, the Zn-ZrO2/TiO2 micro rough coatings have strong antibacterial ability against S. aureus. |
| 36 | Masoud Roknian et al., 2017112 | C. p. Ti | TiO2 with Zinc oxide nanoparticles | Plasma electrolytic oxidation | Based on ZnO content; bacterial are killing | The impact of adding ZnO NPs to the phosphate electrolyte, micro-structural analysis, antimicrobial effect, and corrosion behaviour were all evaluated. | |
| 37 | H. Hu et al., 2012113 | Commercially pure Ti | Titanium dioxide added with Ca, P, Zn | Plasma electrolytic oxidation (PEO) | Based on zinc content bacterial are killing | Rat bone marrow stromal cells; Zinc ions shows positive action | On titanium, nano rough and nanostructured zinc-incorporated TiO2 coatings have outstanding antibacterial properties and can encourage bMSC differentiation into osteogenic cells. |
| 38 | Ozkan Gokcekaya et al., 2017114 | Titanium | Silver doped HAp | Using electrostatic spray coating method | Active vs E coli (100 % viability reduction of planktonic cells) | Human osteoblasts biocompatibility | Electrostatic spraying was used to effectively produce rough coatings of Ag-incorporated HA on Ti and SS substrates. |
| 39 | M.Chozhanathmisra et al., 2016115 | Ti-6Al-4V | Al2Si2O5(OH)4 Zn and Sr2+/Sm2+ doped HAp | Electro deposition | Active vs E. coli, S. aureus (Halo inhibition) | MG63 and in vivo biocompatible tests | Ti6Al4V will have greater bioactivity and increased corrosion resistance owing to a Zn-HNT/M-HA bilayer coating. |
| 40 | M.C.Misra et al., 2017116 | Ti-6Al-4V | Al2Si2O5(OH)4 Ce doped hydroxyapatite | Electro deposition | Active vs E. coli, S. aureus (Halo inhibition) | The developed HNT-Ce-HA coating on titanium alloy by electrodeposition can serve effectively as a biomaterial for orthopaedic applications. | |
| 41 | M.F.Gad El-Rab et al., 2012117 | C. p. Ti | Titanium dioxide with calcium phosphate | Anodic oxidation (TiO2); electrodeposition (CaP) | Active vs S aureus | This study looks at the corrosion resistance, morphological, and antibacterial characteristics of cp-Ti, anodized, and CaP anodized Titanium samples. | |
| 42 | Xuefei Zhang et al., 2017118 | Commercially pure Ti | Silver nanoparticles doped hydroxy apatite | Electrochemical crystallization, and reduction of silver ions, thermal treatment for 8hrs at 170 °C. | Active vs E coli. (after 8 h, planktonic cells inhibit completely) | The presence of silver nanoparticles on the surface resulted in coatings that effectively control E. coli growth during the two-stage cathodic electrolytic synthesis of Ag-HA. | |
| 43 | Zhen Geng et al. 2015119 | Commercially pure Ti | Silver or strontium doped Sr | Hydrothermal method; Dopamine assisted immobilization of HAp | Active vs E. coli, S. aureus (Halo inhibition) | MG63 and in vivo biocompatible tests Cytotoxicity reduced by addition of strontium | UVHap-assisted immobilization preserves the phase purity and crystallinity of hydroxy apatite and is appropriate for surface changes of bone scaffolds utilised in non-bearing locations. |
| 44 | Yung-Chin Yang et al., 2017120 | Ti-6Al-4V | HAp with zinc nanoparticles | Flame spray | Active vs E. coli, S. aureus (Halo inhibition) | Excellent at crystalline coating towards skin fibroblasts | In the qualitative and quantitative antibacterial tests, show significant inhibition zone. |
3.3 Discussion and summary
Titanium implants also succeeded when their surfaces were functionalized or coated with certain compounds to increase their bioactive properties. Functionalization may also be accomplished by photo functionalization using UV light just before implantation. Surface roughness was increased, and super hydrophilic features were generated following UV treatment, both of which promoted beneficial physicochemical changes and improves bone repair.62–66 There was significantly more implant anchoring and bone development at the 4-week point for UV-treated microfiber implants compared to the non-UV-treated control group after implantation of these implants into rat femur bone.83 Compared to human jawbones, the biocompatibility of HAp and bioactive glass-coated implants was much higher than that of machined implants. Based on these findings, an increase in the hydrophilicity of the surface has a good impact on surface energy. This encourages osteoblasts' cell adhesion and proliferation, which are essential for bone formation or regeneration.65–76
Metal ions such as calcium, magnesium, sodium, and strontium are just a few examples that have been shown to work in biomedical applications to promote bone development. Titanium's passive oxide was changed into a bioactive oxide (CaTiO3) which interact more with living things by the addition of calcium ions (Ca2+) to the titanium surface.85,87,94 By treating titanium with NaOH and CaCl2, nano-bioactive CaTiO3 coated screws were created and noted positive effects on osteointegration and biocompatibility. The results with uncoated implants at 12 weeks were comparable to those with HAp-coated implants. As compared to Na+ incorporation, the implantation of a nano-rough Ti alloy at weeks 4 and 8 improved both osteoconductive and overall bone development. The divalent Ca2+ integrates more deeply into the layer of the nano-rough structure, allowing for a steady release over time. This improves bioactivity and boosts the development of trabecular bone. Similarly, calcium, and magnesium supports osteogenic differentiation and angiogenesis, both of which are essential in the process of bone repair. Surface bioactivity and osteointegration have been enhanced as a result of Mg2+ integration into Ti surfaces. It's interesting to note that after being implanted into the tibia and femur of osteoporotic rats for 7 days, Mg released from mesoporous titanium films considerably enhanced bone growth.115 Moreover, it is possible to demonstrate a positive osteogenic effect of Mg2+ doped surfaces in contrast to uncoated ones by showing a threefold enhanced synthesis of BMP6, a critical growth factor involved in bone formation. Since it inhibits the generation of osteoclasts and stimulates the activity of osteoblasts, Sr is another important bioactive metal for promoting bone formation. It has been shown that incorporating Sr2+ onto Ti surfaces improves osteointegration, particularly due to the continuous release seen. In an osteoporotic rat tibia model, nanostructured Ti implants functionalized with different levels of Sr2+ facilitated bone healing. After six and twelve weeks of implantation, these materials stimulated much greater bone development and osteointegration than the uncoated surface.117–119
In addition to bioactive metallic ion coating, both organic and inorganic biopolymers have been explored for potential surface functionalization applications. For instance, the use of polyphosphoric acid and phosphorylated pullulan resulted in better early peri-implant bone healing and osteointegration in a pig bone defect model (a polysaccharide).34,81,35,80 In addition, applying a coating of graphene, which is a two-dimensional modification of carbon with an unique nano-topography and a distinctively hard and rough structure, to a nanostructured titanium surface improved osteointegration in a model of the implantation of a rabbit femur.41–45 Yet, not all functional improvements result in observable advantages for users. In spite of the fact that plasma polymerization pectin nanocoating appeared like a promising method, it did not substantially increase osteointegration in comparison to the surface that served as the control.
In a study in which SLA-treated titanium implants were implanted into the femur metaphysis of osteoporotic rats, it was discovered that coating the implants with osteoinductive hormone molecules like dopamine, which is involved in osteoblast differentiation and mineralization, and zoledronic acid, which has a favorable effect on new bone formation, significantly improved implant integration after eight weeks of implantation.93,97 Comparing implant surfaces coated with dopamine and/or zoledronic acid to the SLA surface, the superior BIC rich in trabecular microstructure was revealed by significantly larger RTVs.42,43,50 Since dopamine coating decreased the activation of genes involved in osteoclast differentiation, it promoted bone growth. Antimicrobial substances used on titanium implants' surface, such as the bactericidal cationic peptide GL13K, not only decreased microbial activity after 6 weeks but also accelerated the process of osteointegration in a rabbit femur model. In the late phases of bone healing in the rabbit femur, selective laser-structured titanium implants with silicon-substituted nano-HAp on their surfaces encouraged more ordered bone formation. Coating methods using cells have been developed in addition to those using ions, proteins, or chemicals. Cells taken from the patient's body are placed at the bone implant interface. When bone marrow stromal cells (BMSCs) and endothelial progenitor cells (EPCs) were co-cultured on titanium implants, it is observed that the implants showed better osteointegration than machined-smooth surfaces after 8 weeks of implantation in irradiated rat tibia.60,81,94
A surface modification method for improving surface chemistry and topography in favour of pro-osteogenic characteristics is the additional coating of structured titanium implants with bioactive compounds. The next stage of surface functionalization may further imitate the natural bone environment by in vitro priming implant surfaces with live cells found in bone tissue. This strategy will need much research before being used clinically as it involves more ethical and pre-implantation protocols.
By the chapter's end, readers will have a better understanding of why optimizing coating techniques and combinations with structural approaches were so important across all trials examined in the effort to enhance osteointegration. New titanium-based implant surfaces with enhanced micro-to-nano hybrid topographies have been created by combining chemical treatment with various means of modifying the surface topography. In both healthy and damaged bone, bone regeneration may develop at an early age, which might improve osteointegration at the bone-implant interface.
4 Conclusions
The most recent studies on the ability of titanium implants to integrate with bone have revealed potential augmentation procedures that involve improving the surface's porosity, hydrophilicity, and nano-structuring, typically with the help of coatings made of bioactive substances.
The hydrophilic surfaces exhibited better osteoinduction and reduced inflammatory response; when paired with nano-patterning, boosted osteointegration can be accomplished. Long researched as a covering material, HAp, the main inorganic component of bone tissues, is still commonly used. For cementless fixed implants, it has previously been clinically proven that its deposition can improve BIC and bone tissue production. New coating formulations, including calcium titanate or bioactive glass, however, show promise as potential surface-modification options for implants. In order to further biofunctionalized the implant, it is required to create a rough, nano-textured surface and apply multiple procedures in sequential order. Surface loading with cells is an intriguing alternative to covering surfaces with bioactive chemicals. This functionalization has not received much research since it is more difficult to apply in clinical settings because of cell preparation rules and regulations. However, as cell-based treatment and customized medicine advance in many other therapeutic fields, this strategy may eventually attract greater attention.
Improving specific evaluation parameters will be crucial for creating next-generation implants in order to support biological assessment and cross-study comparability. These criteria include the use of primary human cells in addition to cell lines, mRNA and protein analysis of cell responses, prolonged in vitro and in vivo cell monitoring, and accurate histomorphometry of the tissue at the implant interface.
Overall, metal implants for the healing of bones and joints have been quite successful in recent years. To meet therapeutic needs, such as reducing the risk of implant loss and infection, novel surface modification methods employing laser texturing and antibacterial property enhancement using cutting-edge coatings are now available. Understanding how bone cells interact with implants in greater detail will help the designers of implants for various patient populations to fully realize the potential of future technology.
In recent years, surface engineering has advanced to multifunctional characteristics, regulation of host response, biological activity, and antibacterial behavior as the features necessary for physiological osseointegration of titanium implants, preventing the hazards of persistent infection or inflammation. Adapting protein adsorption, encouraging macrophage polarization, surface morphological patterns, biomimetic coatings, medical administration, no modulation, and macrophage death are some methods that may be used to modify the inflammatory response. The development of titanium surfaces with these three demonstrated functionalities bioactivity, anti-inflammatory and antibacterial activity remains undeveloped and requires additional investigation.
Titanium surfaces can be coated with variable-thickness inorganic bioactive films containing a suitable inorganic agent, such as Ag, Cu, or Zn, to elicit an antibacterial action by contact killing, release killing, or with both modes. This will promote osseointegration, osteogenesis, and serve as an antibacterial barrier to inhibit bacterial colonisation. If the implant material of the coating possesses osteoconductive qualities, such as hydroxy apatite, bioactive glasses, or electro-chemically generated oxide layers, osteointegration is considerably improved. However, there are certain issues with this technique. Although the majority of the experimental processing methods used to create these coatings have been well consolidated, some of them, such as plasma spray or sputtering, which are commonly used to deposit thick coatings and sub-micrometric thin coatings, may necessitate a significant investment in equipment. Furthermore, the metallic ions created by coating may have a negative influence on neighbouring cells and tissues; as a result, the coating proportions should be carefully adjusted to achieve an acceptable degree of bacteria destruction while allowing cells to exist. Some ions, in addition to their antibacterial capabilities, can have therapeutic effects, such as increasing angiogenesis (Cu2+, for example), which is necessary for expediting tissue healing and self-repair. Additionally, co-doping with other ions (such as silver and strontium) can reduce Ag's cytotoxicity effect and increase the surface capacity for bone regeneration.
Electrochemical oxidation of nanotubular surfaces is a good approach for generating multifunctional titanium or titanium alloy implants. The TiO2 nanotubes have been shown to be effective for both osseointegration promotion and antibacterial effects via photocatalytic activity and the release of metallic ions integrated into their structure. Interestingly, the TiO2 nanotubular surfaces have the potential to be used in applications other than bone-contact implants due to their superhydrophobic properties, such as cardiovascular applications to limit blood coagulation. Early studies have demonstrated the ability of TiO2 NTs to modify the expression of molecules associated with inflammation in endothelial and smooth muscle cells; upcoming studies will examine whether a similar effect can be seen in bone cells as well, providing researchers with new tools to control the host response to bone implants.
Alternately, by applying surface chemical treatments with acid and alkali solutions to Ti and Ti alloy implants, micro- and/or nano-scale roughness surfaces endowed with functional metal ions, such as Ca, Sr, and Ag, can be created. When treated with NaOH to produce sodium hydrogen titanate, the material demonstrated strong ion exchange capabilities with univalent, divalent, and trivalent ions as well as the ability to incorporate several ions at once. Heat treatment combined with moderate temperature results in the gradual release of these functional ions. The bioactive and antibacterial titanium and titanium alloy implant developed in this manner are advantageous to promote osseointegration and elicit an antimicrobial effect due to the release of metallic ions and the micro- and/or nano-topology that increases cell responsiveness and upregulates gene expression.
Clinical implications
This systematic review sheds light on the potential of titanium implant surface modifications to enhance osseointegration, antibacterial properties, and biocompatibility. With 120 research publications considered, it provides valuable insights into the future of implantable titanium devices. The findings suggest exciting prospects for improving implant materials, potentially leading to better patient outcomes and reduced complications in various medical fields. Future research in this area could yield innovative solutions with significant clinical implications, benefiting bone healing and implant success rates.
Ethical statement for solid state ionics
Hereby, I Dr. Amit Biswas consciously assure that for the manuscript Surface modifications and coatings to improve osseointegration and antimicrobial activity on titanium surfaces: A statistical review over the last decade the following is fulfilled.1)This material is the authors' own original work, which has not been previously published elsewhere.2)The paper is not currently being considered for publication elsewhere.3)The paper reflects the author's own research and analysis in a truthful and complete manner.4)The paper properly credits the meaningful contributions of co-authors and co-researchers.5)The results are appropriately placed in the context of prior and existing research.6)All sources used are properly disclosed (correct citation). Literally copying of text must be indicated as such by using quotation marks and giving proper reference.7)All authors have been personally and actively involved in substantial work leading to the paper, and will take public responsibility for its content.
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I agree with the above statements and declare that this submission follows the policies of Solid State Ionics as outlined in the Guide for Authors and in the Ethical Statement.
Date: 27/11/2024.
Corresponding author's signature: Dr. Amit Biswas.
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This manuscript does not involve any Guardian/Patient data reports to submit consent forms.
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All data generated or analyzed during this review are included in this published article. All figures used in the manuscript are collected from the electronic data source from web of science, Pubmed and Google scholar search engines.
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Credit authors statements
Konduru Ashok Kumar Raju did the histological investigation, contributed to the publication's systemic data collecting, and created the graphs and figures. He wrote the whole review article and was a substantial contributor to the manuscript.
Amit Biswas conducted the histological examination and helped with data processing, editing, and proofreading the entire work. The final manuscript was reviewed and approved by all contributors.
Funding and/or conflicts of interests/competing interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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