Progress of research on the surface functionalization of tantalum and porous tantalum in bone tissue engineering

Tantalum and porous tantalum are ideal materials for making orthopedic implants due to their stable chemical properties and excellent biocompatibility. However, their utilization is still affected by loosening, infection, and peripheral inflammatory reactions, which sometimes ultimately lead to implant removal. An ideal bone implant should have exceptional biological activity, which can improve the surrounding biological microenvironment to enhance bone repair. Recent advances in surface functionalization have produced various strategies for developing compatibility between either of the two materials and their respective microenvironments. This review provides a systematic overview of state-of-the-art strategies for conferring biological functions to tantalum and porous tantalum implants. Furthermore, the review describes methods for preparing active surfaces and different bioactive substances that are used, summarizing their functions. Finally, this review discusses current challenges in the development of optimal bone implant materials.


Introduction
Bone is one of the most complex organizational structures in the human body.Under normal physiological conditions, bone can regenerate and heal spontaneously.Small bone defects can gradually self-heal through the formation of new bone [1].However, large bone defects caused by fractures, tumor removal, joint replacement, and congenital defects exceed the body's ability to heal itself [2].Therefore, bone grafts are needed to repair bone defects and promote bone regeneration [3].Common grafting techniques encompass autografts, allografts, xenografts, and synthetic bone grafts [4].However, their widespread use in clinical applications is limited due to infections, secondary trauma, donor inadequacies, and rejections.Bone tissue engineering (BTE), a technique that combines bone biology and engineering, has been developed to overcome these limitations [5].BTE is an emerging interdisciplinary field that is largely inspired by the repair or replacement of damaged native bone tissue [6].BTE can provide an innovative strategy for repairing large bone defects and creating excellent biomimetic substitutes for bones.
Bone regeneration and remodeling are incredibly complex and dynamic processes that require the coordination of multiple biomolecules and the microenvironment to achieve appropriate healing results [7].Substitutes employed in bone repair need to have biological characteristics similar to those of natural tissues, with the ability to mimic or facilitate the repair processes outlined above to attain the desired bone healing status [8].At present, metals such as titanium and cobalt-chromium alloys and stainless steel are mainly used as transplant materials.However clinical studies have shown that these materials do not achieve early and long-term stability at the metal-bone interface.In this context, tantalum and porous tantalum are new options that offer excellent mechanical properties, corrosion resistance, biocompatibility, and outstanding antimicrobial capabilities.
Tantalum was first used in medicine in 1940 [9].Later, as knowledge about tantalum increased, its application was expanded to various clinical fields, such as dental implants, artificial joints, and artificial spines [10][11][12][13][14]. Studies have shown that cells can maintain normal growth morphology and continue to survive on the surface of tantalum metal [15,16].Moreover, when tantalum is used to manufacture some biomaterials, the addition of tantalum coatings or tantalum particles can improve the biological activity of the biomaterials and promote bone growth [17,18].With the present development of additive manufacturing technology, the production techniques of tantalum have gradually matured [19].As porous forms of tantalum, porous tantalum has been proven to have satisfactory bone integration ability and osteoconductivity, allowing osteoblast proliferation and differentiation and promoting the growth of bones, tendons, and ligaments.Furthermore, porous tantalum has an elastic modulus close to that of human natural cancellous and cortical bones, which is conducive to minimizing the stress-shielding effect and preventing implant loosening and detachment [12,20].Therefore, using tantalum and porous tantalum as bone repair materials has become an effective strategy in clinical practice.
An ideal bone implant not only requires a material that has excellent characteristics but also requires proper integration with the recipient site postimplantation.Although tantalum and porous tantalum have satisfactory properties, they have certain shortcomings that prevent them from achieving ideal results in practical clinical applications.In light of this situation, a number of approaches have been proposed to enhance the surface bioactivity of implants with the aim of achieving fast and early bone growth as well as stable osseointegration.
This review systematically examines the basic properties of tantalum and porous tantalum, explores their applications in BTE, and provides a summary of various surface functionalization strategies associated with the two materials.

Basic characteristics and related applications of tantalum and porous tantalum 2.1. Basic characteristics
Tantalum was first discovered in 1802 and purified by Werner about one hundred years later [21].At room temperature, tantalum is a relatively stable metal with a hardness of 6-6.5 on the Mohs hardness scale [22].Its melting point is extremely high, reaching 3017 • C, second only to carbon, tungsten, rhenium, and osmium [23].In addition, tantalum has excellent thermal and electrical conductivity and has been used in some industrial fields that require heat-resistant materials and high-strength components [24].From a chemical perspective, when tantalum is exposed to air, it easily forms a stable Ta 2 O 5 oxide layer on its surface.This oxide layer has excellent characteristics.Firstly, it has superior corrosion resistance and can withstand exposure to most strong acids and alkalis, allowing tantalum to remain stable in body fluid environments [25].Secondly, it can prevent the leaching of metal ions and reduce the occurrence of local inflammatory reactions [26].Thirdly, it improves the hydrophobic properties and electrostatic effects of the tantalum metal surface, making the tantalum metal surface conducive to cell adhesion [27][28][29].Fourthly, due to the presence of the oxide layer, tantalum has low susceptibility to bacterial adhesion and proliferation on its surface [30].
In practical clinical applications, mechanical wear or fluid erosion may cause ion detachment and accumulation from the material surface, resulting in some toxic effects.Therefore, Wang et al, tested the effects of different concentrations of tantalum nanoparticles (Ta-NPs) on mouse osteoblasts [31].The findings indicate that low concentrations of Ta-NPs have the effect of promoting the proliferation of osteoblasts, and as the concentration of Ta-NPs increases, the effect weakens.However, as long as the concentration is below 200 g ml −1 , the survival rate of osteoblasts remains at a stable level.Other experiments have also proven these results [26,[32][33][34][35].In addition, Zhu et al, tested the particle release rate of tantalum-coated implants, and the results showed that after soaking in phosphate-buffered saline for 28 d, the concentration of tantalum was still less than 2 µg l −1 [36].
Porous tantalum was first developed and manufactured by Kaplan et al.Afterward, as the understanding about porous tantalum deepened, its manufacturing process also improved.Current research shows that the desirable pore size of porous tantalum bioactivity is 400-600 µm, with 75%-80% porosity, which is similar to the structure of human cancellous bone [37].Not only does porous tantalum have high strength, corrosion resistance, excellent hydrophilicity, and the favorable biocompatibility of tantalum-it also exhibits superior osseointegration ability due to its loose and porous structure [12].Compared with tantalum, porous tantalum has the following key advantages: the elastic modulus is close to that of normal human bone, which is conducive to reducing the stress-shielding effect and preventing bone resorption [12].Having a high porosity is beneficial for cell adhesion and proliferation, matrix secretion, nutrient exchange, influx of bone-inducing proteins, and vascular formation, facilitating bone ingrowth and osseointegration [12,38].The porous structure of porous tantalum has a high coefficient of friction, which increases the stability of porous tantalum implants [39].Porous tantalum has excellent wear resistance, which improves the success rate of surgery and the lifespan of porous tantalum implants.In order to test the biological properties of porous tantalum, scholars mixed bone marrow mesenchymal stem cells (BMSCs), MG63 osteoblasts, and dental pulp stem cells with porous tantalum and found that porous tantalum did not have adverse effects.Rather, porous tantalum promoted cell growth, proliferation, adhesion, and osteogenic differentiation [16,40,41].
Therefore, considering these properties, porous tantalum can be regarded as a metal bone graft material with considerable potential.
Based on the excellent properties of tantalum and porous tantalum, a series of studies have been carried out on their use as a graft.It has been found that although tantalum and porous tantalum have excellent biological properties, in clinical practice, it is difficult to use them to exert effects that match the recipient tissue structure, which often results in a series of complications.These complications include graft loosening, peripheral inflammatory reactions, and infections, which are closely related to the biological inertness of metal grafts and their surrounding environment [42,43].Therefore, in order to solve this problem, people choose to functionalize the surface of tantalum and porous tantalum by uniformly attaching a series of natural or artificial bioactive components to the metal surface through different methods and releasing these components in a controlled manner, thus achieving the functionalization of the metal materials.

Related applications
In recent years, tantalum and porous tantalum implants have garnered growing interest and have been increasingly used in various clinical procedures, including knee and hip replacements, dental implants, foot and ankle surgeries, as well as the treatment of femoral head necrosis and spinal fusions.These uses are associated with specific results.Table 1 Currently, clinical treatment of joint dysfunction due to various causes mainly comprises joint replacement, with the most representative techniques in the approach being total knee arthroplasty (TKA) and total hip arthroplasty (THA) [44,51,71].Postoperative revisions are increasing with the gradual increase in the application of the techniques in the clinic [51].Among these, bone defects are the primary challenge for healthcare professionals involved in postoperative revisions.In response to this problem, tantalum-based substitutes have been utilized to fill and repair defective areas.In several studies, tantalum-based substitutes were used to provide structural support for bone defects, demonstrating favorable repair results in follow-ups [45][46][47][48][49]52].Moreover, when they are used to address more severe defects, tantalum-based substitutes also show great potential for application [44,50,[53][54][55][56].
Osteonecrosis of the femoral head (ONFH) is a common orthopedic disease associated with a high disability rate that requires timely intervention and treatment [72].Following implantations and during follow-ups, tantalum-based implants have been demonstrated some therapeutic effect on ONFH, preserving the femoral head before ONFH progresses to its final stage [57][58][59].In addition, due to their inherent good mechanical strength as well as suitable modulus of elasticity, porous tantalum implants have been used in several interbody fusions (LIF), exhibiting efficacy comparable to that of autologous bone grafts [60][61][62].
In previous studies, titanium alloys were reported to be the most commonly used metal grafts in dentistry.To analyze the efficacy of tantalumbased implants, Bencharit et al compared the results of dental implantation of porous tantalum and titanium, finding that the porous tantalum implant group exhibited more significant restorative results compared to those observed in the titanium implant group [63].Additionally, Huang et al found that the group with composite titanium-tantalum implants showed greater cytocompatibility and superior bone repair potential compared to the group with pure titanium implants [64].
Tantalum-based implants are also employed in specific foot and ankle surgeries and for treating fractures caused by various factors [65][66][67][68][69][70].Although most tantalum-based implants have produced relatively satisfactory results, there are currently no specific targeted studies on their long-term clinical safety and effectiveness.Consequently, future research should focus on addressing this gap.

Different methods of surface functionalization
Due to the excellent properties of tantalum and porous tantalum, a series of studies have been carried out on their use in grafting.The studies found that although tantalum and porous tantalum have excellent biological properties, they often fail to produce results that match the recipient tissue structure in clinical practice, leading to a series of complications.These complications include the loosening of grafts, peripheral inflammatory reactions, and infections, which are likely to be caused by the biological inertness of metal grafts and their surrounding environment.Therefore, to solve this problem, the surfaces of tantalum and porous tantalum are sometimes functionalized by uniformly attaching a series of natural or artificial bioactive components to the metal surface using different methods and releasing these components in a controlled manner.Currently, various design methods for the surface functionalization of tantalum and porous tantalum have been developed, including sol-gel, micro-arc oxidation (MAO), laser melting, and magnetron sputtering.The following sections provide a detailed description of these methods.

Sol-gel method
The sol-gel method is a wet chemistry-based synthetic technique, which is widely used in various fields of material engineering [73,74].The typical sol-gel process is mainly composed of two different stages, namely sol and gel.In the sol stage, various small molecules are converted into colloidal solutions.In the gel stage, a series of catalysts are added

Titanium-tantalum composites
Enhanced bone healing compared to pure titanium [64] Foot and ankle surgery

Porous tantalum
Good bone growth occurs after ankle surgery [65,66] Other fractures

Tantalum screws with multiple holes
Reduced postoperative complications of femoral neck fractures and promoted bone healing [67] Porous tantalum Favors fracture healing, appears well integrated with host bone [68][69][70] to promote condensation reactions, thus forming a rigid and highly interconnected three-dimensional network gel [74][75][76].In these two stages, the synthesis of materials can be regulated by adjusting the pH of the solution, temperature, and concentration of reactants in the reaction [77].In addition to being adjustable, the sol-gel method offers some unique advantages over other traditional methods, such as its simple steps, flexible experimental methods, low cost, and its ability to significantly enhance the coating adhesion on metal biomaterial substrates [77,78].Therefore, researchers have used the sol-gel method to modify metal materials.Balamurugan et al and Wang et al produced hydroxyapatite (HA) coatings and functionalized titanium alloys using the sol-gel method, which significantly improved the biochemical properties of titanium alloys as metal implants [79,80].In addition, through in vivo and in vitro experiments, Zhang et al confirmed that porous titanium scaffolds coated using the sol gel method have better osteogenic properties [81].As for tantalum, Yu et al prepared a layered porous bioglass film on the surface of tantalum using the sol-gel method and equipped it with BMP-2, resulting in improved osseointegration when co-cultured with MC3T3-E1 cells [82].Therefore, with the advancement of BTE, the sol-gel method holds great potential for improving the biological functionality of bone implants.

MAO
MAO technology, also known as plasma electrolytic oxidation (PEO) and microplasma oxidation (MPO) [83,84] can be described as a variant of anodic oxidation.The main process that occurs under MAO is anodic polarization in a metal and its alloy, which happens outside the dielectric electrical breakdown voltage, thus forming a layer of oxide coating on the surface of the metal body [85][86][87][88].This coating has excellent characteristics, such as reducing the stiffness and elastic modulus of the metal, endowing the metal with some corrosion and fatigue resistance, considerable thickness, high porosity, and a high concentration of electrolyte components [89][90][91].These features can be controlled by adjusting the voltage, current density, and component addition during processing [92], figure 1. Krza˛kała et al reported on the application of this technique in the formation of bioactive surfaces on titanium and its alloys [84].However, there is relatively scant literature on the application of tantalum and its alloys.In recent years, as research on tantalum and its alloys has X Li et al intensified, it has been discovered that tantalum has excellent corrosion resistance and suitable biocompatibility, making it a metal with promising potential for bone reconstruction applications.However, bare tantalum does not bond directly with bone when implanted-it requires some special bio-activation processes.It is in this context that scholars have begun to study the surface functionalization of tantalum and its alloys using MAO technology [93].Using MAO and alkaline pretreatment, Gao et al prepared tantalum with considerable bioactivity, successfully employing it to repair cranial defects in rabbits [94].
For example, Fialho et al characterized MAO-treated tantalum through a bioactivity analysis and showed that the oxide coating formed after the treatment of the tantalum surface by the MAO technique could greatly enhance apatite induction capacity, which increased with the applied voltage [92].In addition, compared to pure tantalum, MAO-treated tantalum has been shown to have superior hydrophilicity and antimicrobial properties, offering better application potential [95].

Laser cladding technology
Laser cladding technology refers to the addition of a layer of 1-2 mm coating material on the surface of an implant, and then using a high-energy laser to melt the coating and the surface of the implant matrix, forming an alloy layer with different ion structures on the surface of the implant matrix.This alloy layer not only significantly improves the surface performance of the implant but also endows the implant with superior biological properties by introducing specific ions into the alloy layer [96].Liu et al deposited hydroxyapatite bioceramic coatings with varying amounts of lanthanum oxide (La2O3) on the surface of titanium alloys using laser fusion cladding.They found that the appropriate amount of La2O3 could increase the mineralization rate of bone apatite and improve the bioactivity of coatings [97].Zhang et al prepared a microgradient porous tantalum scaffold containing unique nanostructures on its surface through laser melting and electroacid oxidation.They conducted animal implantation experiments, revealing that the early bone union of the experimental group was significantly improved compared to that of the control group.This demonstrated that the porous tantalum scaffolds fabricated using the technique hold considerable potential for clinical applications [98].

Functionalized tantalum and porous tantalum with different substances
At present, substances such as growth factors (GFs), collagen, peptides, different types of drugs, and some inorganic components that can endow tantalum and porous tantalum with specific biological functions are mainly used to achieve desired application outcomes.Table 2.

GFs
GFs not only play an important role in cell survival, proliferation, differentiation, and migration but also have various roles in different stages of bone repair figure 2 [124,125].Accordingly, scholars have attempted to functionalize the surface of tantalum and porous tantalum using GFs to increase the surface biological activity of tantalum and porous tantalum.Currently, the most studied GFs are bone morphogenetic proteins (BMPs), transforming GF (TGF), and vascular endothelial GF (VEGF).These GFs hold great potential in bone healing and regulating the behavior of osteoblasts [126,127].BMPs are naturally secreted proteins that play an important role in the development of the entire skeletal system [128,129].They mainly regulate the osteogenic process in vivo by stimulating the expression of related osteogenic transcription factors [ 130,131].In addition, BMPs regulate the growth and development of organisms by interacting with signaling pathways such as TGF-β, notch, and fibroblast GF (FGF) [132,133].Currently, the main BMPs used for processing tantalum and porous tantalum are BMP-2 and BMP-7.BMP-2 is a rather important GF that promotes osteoblast differentiation and induces bone formation [134].Yu et al first prepared a layered porous bioglass film on the surface of tantalum using the sol-gel method and then loaded BMP-2 onto the film through immersion and exfoliation methods, thus improving the growth status of osteoblasts and the expression of alkaline phosphatase (ALP) [82].In addition, Kreulen et al chose to implant a porous tantalum scaffold containing BMP-2 into the tibial talar joint of the human ankle and observed satisfactory osseointegration at the implant-bone interface 4-6 weeks postoperatively [102].BMP-7, also known as osteoprotegerin-1 (OP-1), plays an important role in bone development, bone defect repair, and cartilage differentiation [135][136][137].Zhang et al prepared a porous tantalum/chondrocyte/BMP-7 composite using a secondary precipitation method and observed its culture.The results showed that porous tantalum treated with BMP-7 was conducive to the growth of chondrocytes [103].Furthermore, Wang et al prepared BMP-7/porous tantalum composite materials by immersing porous tantalum rods in BMP-7 solution.In a rabbit model of femoral condylar cartilage defect repair, the porous tantalum group containing BMP-7 formed more cartilage and bone tissue than the pure porous tantalum group, and the volume fraction of new bone, the number of bone trabeculae, and maximum release force of bone were higher than in the control group [104].
In addition to BMP, TGF-β of the TGF family plays an important role in the skeletal microenvironment [138].TGF-β mainly maintains the homeostasis of the bone microenvironment through physical and biological stimuli [139].TGF-β regulates the differentiation and function of osteoblasts and osteoclasts-from lineage recruitment to terminal differentiation-to balance bone formation and absorption [139].Moreover, TGF-β regulates the formation of extracellular matrix (ECM) proteins and proteases, such as ALP, osteocalcin, osteoprotegerin, and collagen in bone, thus exerting a regulatory effect on bone [140].Considering the unique role of TGFβ in the skeletal microenvironment, researchers are increasingly exploring the treatment of tantalum and porous tantalum with TGF-β.Co-culturing with TGF-β1 has been found to increase the ability of the porous tantalum/MG63 osteoblast-like cell complex to secrete ECM [105].In animal tests, Zhang et al first compounded TGF-β1 with porous tantalum particles and then implanted the material into Beagle dogs.They found that the rate of new bone and neovascularization in the experimental group was significantly increased, indicating that TGF-β1 compounded porous tantalum biomaterial has high osteogenic activity, which can accelerate early bioconjugation of porous tantalum with surrounding bone tissue and shorten healing time [106].
Given the unique advantages of GFs, scholars have attempted to functionalize tantalum and porous tantalum by combining multiple GFs in addition to using a single GF.Zhou et al prepared tantalum scaffolds loaded with VEGF, TGF, and calcium phosphatepolyacyl lactate (CaP-PLA) coating, and confirmed through in vivo animal experiments that the scaffolds can provide GFs, physical support, and structural guidance for new bone growth and facilitate guidance of subchondral bone regeneration and are a promising material for bone grafting [107] figure 3(A).

Collagen
Collagen is an important organic component that constitutes the ECM and bone structure [141].
There are many types of collagen, with type I being the most common and accounting for 80%-90% of the total body collagen.Type I collagen has a number of excellent biological characteristics and is a biomaterial with considerable application potential [141][142][143].In recent years, continuous research on collagen and tantalum has found that introducing collagen into porous tantalum can improve the corresponding function of the material and promote its integration with surrounding bone tissue.A study has found that by coating tantalum with type I collagen and culturing osteoblasts on its surface, osteoblasts can maintain favorable viability, indicating that the treated tantalum has good biocompatibility [108].Regarding specific functionalization, Liu et al first co-cultured porous tantalum and Bio-Gide collagen membranes (CM) with BMSCs in vitro, and then implanted them into a rabbit model with femoral head cartilage defects.After a period of time, they observed high-quality new cartilage near the bone defect area, demonstrating the application potential of this composite material [109].In order to obtain robust results from large-scale animal experiments, Wei et al manufactured different composite materials using BMSCs, porous tantalum, and chondrocyte/CM and implanted them into randomly assigned goat models of large osteochondral defects for cultivation.The cultivation results indicate that the composite material has favorable bone repair effects, and the combination of three-dimensional CM enables the material to maintain the phenotype of chondrocytes and significantly promote the expression of chondrogenic genes [110] figure 3(B).These results provide new ideas for the surface functionalization of porous tantalum and a new treatment strategy for treating large bone defects in load-bearing areas.

Peptides
Peptides are short chains with less than 50 amino acids connected by peptide bonds, encompassing a wide variety of types and mostly exhibiting favorable biological activity [144].Among them, RGD peptide (Arg-Gly-Asp) has been extensively studied.It represents a cell adhesion motif found in many ECMs and has rich and diverse structures [145,146].These structures are highly involved in important physiological activities of cells, such as cell proliferation, adhesion, apoptosis, and differentiation [146].Therefore, the RGD peptide family is considered an excellent substance for use in tissue engineering, and, considering the excellent properties of tantalum and porous tantalum, researchers have begun exploring the use of RGD peptides for surface functionalization of tantalum or porous tantalum.
McNichols et al first used anodic oxidation technology to fabricate nano-adhesive tantalum surfaces, and then covalently modified the tantalum surface using cyclic RGDfK peptides.The results showed that the combination of nano-adhesive surfaces and cyclic RGDfK peptides produced a structurally superior endothelial coating on a surface, resulting in high cell density and superior connection and diffusion, which is beneficial for bone repair after implantation [111].In order to obtain conclusive results, Wang et al implanted a porous tantalum scaffold coated with the cyclic RGDfK peptide into a rabbit model of segmental bone defects in the radius.The findings revealed that compared with untreated porous tantalum scaffolds, the treated porous tantalum scaffold had increased bone formation at the interface and in the pores and better biomechanical properties [112].In addition, Gan et al treated porous tantalum with different concentrations of the RGD peptide and then co-cultured it with MG63 osteoblasts.After a period of time, they observed that the adhesion rate of osteoblasts and the expression of related osteogenic genes in the porous tantalum treated with RGD peptide were significantly higher than those in the control group.The best results were obtained with 5 g l −1 RGD peptide, indicating that porous tantalum treated with RGD peptide was conducive to promoting bone formation and had excellent application potential [113].Mas-Moruno et al used physical adsorption as well as in silico covalent binding methods to modify tantalum with RGD peptide and characterize it.In addition, cell adhesion studies using human osteoblast-like cells were used to evaluate the biological properties resulting from RGD peptide modification, and it was concluded that tantalum modified with RGD peptide had superior biological properties and was favorable for osteoblast adhesion and spreading [114].

Drugs
In response to infections and low bone levels in clinical practice, researchers have attempted to functionalize tantalum and porous tantalum with different drugs to reduce the occurrence of diseases.
By combining the chemical grafting of triethoxysilane (APTES) and the electrostatic assembly of carboxymethyl chitosan (CCS) and Vancomycin (Van), Liu et al fabricated a porous tantalum scaffold containing Van.They proved through experiments that the scaffold can kill initial adhesion bacteria, control infection, and improve the immune microenvironment [115] figure 3(C).In addition, creating a composite coating containing polyhydroxyalkanoates (PHAs) on the tantalum surface provided a certain antibacterial effect on tantalum and protected the tantalum implant from attack by gram-positive and negative bacteria [116].Besides conventional antibiotics, specific anti-tuberculosis drugs have become a new option.Fialho et al first used two anti-tuberculosis drugs Isoniazid (INH) and Rifampicin (RIF) to form a relatively stable physical cross-link with Gellan Gum (GG) hydrogel.They then treated the porous tantalum surface with dopamine (PDA) to increase adhesion and created a drug-carrying composite hydrogel film on the porous tantalum surface and confirmed through experiments that the treated porous tantalum stent has certain antibacterial properties but it has virtually no effect on bone formation around the scaffold [117].
As for certain drugs related to osteogenesis, Garbuz et al conducted a study using different experimental groups to evaluate the impact of a composite coating consisting of calcium phosphate (CaP) and alendronate on porous tantalum on new bone formation.The final results showed that adding this composite coating enhances the biological fixation of implants and promotes the healing of bone defects, thereby playing a beneficial role in promoting bone formation [118].

CaP-based materials
CaP-based materials are a class of substances with physical and chemical properties that are similar to those of natural human bones.Typical CaP-based materials are CaP and HA, which have superior bone conductivity and can promote bone formation [147].By loading HA coating on the surface of tantalum, Antonio et al, confirmed that it can improve the biocompatibility of tantalum and stimulate new bone formation [119].
In previous experiments, researchers have used different methods, such as the sol-gel method, ion immersion injection method, electrochemical deposition method, plasma spray method, and magnetron sputtering technology, to load CaP-based materials and achieved favorable outcomes [148][149][150][151][152]. In order to test the specific efficacy of CaP-based material modification, a series of different experiments were conducted.Zhou et al used amorphous calcium phosphate (ACP) nanospheres and HA nanorod coatings to modify porous tantalum and conducted in vitro and in vivo experiments.The experimental results showed that these two modifications significantly improved the biocompatibility of tantalum scaffolds and were conducive to achieving osteogenic mineralization [120].Barrere et al prepared a biomimetic CaP coating with a uniform distribution and a thickness of 30 µms by immersing porous tantalum in simulated body fluid (SBF).Afterward, the modified porous tantalum scaffold was implanted into a goat model with femoral backbone defects for cultivation.After cultivation, it was found that the experimental group exhibited a high bone encapsulation rate and a fast bone growth rate [121].

Metal materials
Various types of metal materials are available, but, currently, the main ones used for the functionalization of tantalum are strontium (Sr), silver (Ag), and copper (Cu).
Sr, an element that is naturally present in the human body, promotes angiogenesis and bone formation [153,154].Cheng et al first manufactured a 3D-printed porous tantalum scaffold and then loaded Sr onto the surface of the scaffold with the help of PDA.Through experiments, they demonstrated that after Sr was loaded onto the porous tantalum surface, the early adhesion and expansion of rat BMSCs improved, and a number of osteogenic behaviors were significantly enhanced.In addition, the modified scaffold showed an enhanced ability to promote angiogenesis, and the expression of related genes was significantly increased [38].These results confirm the modification effect of Sr on porous tantalum scaffolds and have certain clinical application potential.
Ag has a broad spectrum of efficient antibacterial properties that can inhibit various bacteria.Moreover, due to the diverse antibacterial mechanisms of Ag, it rarely causes resistance, making it a suitable choice for improving treatment [155,156].Lin et al loaded Ag ions onto the surface of a titanium-tantalum alloy through a glandular oxidation method and then demonstrated through antibacterial experiments that the loading of Ag ions significantly improved the resistance of the alloy to S. aureus [122].
Cu is an effective antibacterial element that can disrupt bacterial cell membranes, DNA, and electron transport chains.It also exhibits low cytotoxicity and high cell compatibility [157][158][159].In addition, Cu can be metabolized and excreted by the human body, thereby avoiding the toxic effects caused by the accumulation of metal ions [160].It is precisely these excellent characteristics that make it a suitable material for the antibacterial modification of tantalum.Wang et al deposited a nanostructured copper coating on the surface of tantalum using magnetron sputtering and then proved through experiments that the treated tantalum has a stable and strong antibacterial effect on S. aureus and E. coli, making it a promising candidate for antibacterial implants [123].

Related functions of surface functionalization
Differential functionalization strategies can lead to different functional improvements in tantalum and porous tantalum, which subsequently affect their biological performance after implantation.At present, our main focus is on bone integration, anti-infection, and angiogenesis.

Promoting bone integration
Bone integration is the most important factor in achieving long-term fixation of metal grafts, and the surface properties and composition of metal grafts play a key role in the process of bone integration [161,162].Although porous tantalum is more conducive to bone growth than tantalum, pure porous tantalum does not completely mimic normal bone tissue in terms of structural composition and mechanical properties.Moreover, the rate of autologous tissue cells growing into porous tantalum implants is relatively slow and cannot meet the needs of early activity.Therefore, there is a necessity for further improvements to the biological characteristics of a graft through surface functionalization in order to achieve early fixation and longterm survival of a graft [161,163].CaP and HA, the main components of human bone, have been used for surface functionalization of tantalum and porous tantalum to achieve improved bone ingrowth and stable osseointegration [119][120][121].In addition, Zhu et al have verified through experiments that the addition of tantalum nanoparticles can improve the bone integration ability of polyether ether ketone (PEEK) [164].Based on this finding, future studies can consider the surface functionalization of tantalum and porous tantalum scaffolds using PEEK to achieve superior bone implantation results.

Anti-infection
Post-implantation infections remain a difficult clinical problem, which always leads to the failure of orthopedic implants as well as high expenditure costs.Therefore, there is a necessity of finding a reasonable way to give tantalum and porous tantalum certain antimicrobial properties.Van is an antibiotic with considerable antibacterial power.It plays a major role in the treatment of clinical infections.Therefore, Qian et al chose to encapsulate Van into poly(lactic-coglycolic acid) (PLGA) microspheres and then loaded them into additively-manufactured porous tantalum (AM-Ta) via gelatin methacryloyl hydrogel, thus creating a novel scaffold.Then through antibacterial as well as osteogenesis-related experiments, they proved that the composite scaffold not only has suitable osseointegration ability but also possesses considerable antibacterial properties [165].The composite coating made of Van and CCS has also been proven to be capable of functionalizing 3D-printed porous tantalum, enabling it to quickly kill initial sticky bacteria and resist biofilm formation [115].In addition, Fialho et al studied the magnetron-sputtered coating of antibacterial nanoparticles on tantalumbased surfaces.This coating has certain antibacterial activity and can effectively kill adhering bacteria and surrounding planktonic bacteria, thereby preventing perioperative infections [100].Today, there are various anti-infection strategies for tantalum and porous tantalum, but most of them are limited to in vitro or animal experiments.Further research is needed to evaluate their specific clinical application effects.

Promoting angiogenesis
In the process of bone regeneration, angiogenesis is a major element, mainly because both intramembrane and endochondral ossification occur during the growth of neovascularized tissue [166].Therefore, an ideal scaffold for bone defect repair should have a fibrous porous structure, mimicking the environment of the ECM to facilitate revascularization as well as new bone formation [167].However, the tantalum and porous tantalum scaffolds that are currently used do not have a fibrous porous structure, hindering their ability to promote angiogenesis and limiting their application in bone regeneration.Magnesium (Mg) is a necessary element in the process of bone development-it has effective angiogenesis and osteogenic properties.However, simply combining Mg ions with porous tantalum scaffolds cannot create optimal adhesion distribution.Inspired by the adhesion of mussels, Ma et al utilized the adhesive properties of dopamine to immobilize Mg ions and functionalize 3D-printed porous tantalum scaffolds.Subsequently, they conducted a series of in vitro and in vivo experiments to verify that the treated porous tantalum scaffolds had enhanced surface biological activity and improved angiogenesis and osteogenic effects [168] figure 4. In addition, in previous studies, VEGF has been proven to modify bone-implanted scaffolds to achieve superior angiogenic effects [169].
However, there is currently no research to prove its effect on the functionalization of tantalum and porous tantalum.
This area can be explored as a new topic for future research.

Discussion
At present, the metal materials widely used in clinical practice include titanium alloy, cobalt-chromium alloy, and stainless steel.However, as research progresses, it has been found that the biological activity of titanium is not sufficient to achieve rapid integration X Li et al Figure 5. Schematic of a signaling pathway that may be involved in the osteogenic effects of Ta.Reproduced from [37].CC BY 4.0.
with the recipient's bone.Stainless steel has low strength and corrosion resistance, high stiffness, and weak interaction with host bone after implantation, making it difficult for its surface to adhere and bond with bone tissue.In addition, the high elastic modulus of cobalt-chromium alloy leads to excessive loadbearing after implantation into the host, resulting in the stress-shielding effect, which leads to a loosening and even failure of the implant, thus limiting the use of the alloy as a graft in clinical practice.In this context, tantalum and porous tantalum have gained attention due to their superior mechanical properties, corrosion resistance, and biocompatibility as well as excellent antibacterial properties.
As bone grafting materials, tantalum and porous tantalum have shown excellent properties and have been used in many clinical fields.Studies have explained the potential osteogenic mechanisms of these materials through some classic signaling pathways figure 5.However, there is currently relatively scant in-depth biological research on tantalum and porous tantalum.Thus, there is a necessity for a comprehensive exploration.In addition, although tantalum and porous tantalum have desirable biological characteristics, when used as bone implants for treatment, they do not fully exert effects that match the recipient's tissue structure but instead result in complications.Therefore, enhancing their biological characteristics and increasing their clinical utilization have become important topics of investigation.At present, there are various functionalization strategies for tantalum and porous tantalum, but most strategies are limited to in vitro cell experiments and animal studies and cannot be successfully used in clinical experiments.Furthermore, some bioactive substances face issues of poor stability, easy detachment, and difficulty in controlling a sustained release.Therefore, further studies are needed to find suitable functionalization strategies and successfully apply them in clinical practice.The ideal tantalum and porous tantalum implants of the future should have the following characteristics: low cost, the controllable release of surface-active substances, stable presence in the human body fluid environment, and favorable biological properties.If these goals are achieved, we believe that tantalum and porous tantalum will become widely used in orthopedic implants.

Conclusion
This article systematically describes the physical, chemical, and biological characteristics of tantalum and porous tantalum and provides a detailed summary of various surface functionalization strategies.Currently, in BTE, there are numerous opportunities where bone transplant materials can be utilized in conjunction with surface functionalization techniques.However, various issues must be addressed to expedite the implementation of functionalization techniques in clinical care.First, given the complexity of a bone structure, it is crucial to optimize the porosity of the implanted material and the associated structures.Second, the biological properties required for biomaterial implantation in different pathological microenvironments should be explored.Finally, the release of biomolecules from implanted materials should be both safe and controlled.We believe that as research continues, optimal strategies for combining the techniques will be found to improve clinical applications.

Figure 1 .
Figure 1.Representative schematic of Ta2O5 coating of MAO.(A) Growth mechanism: (a) initiation of spark discharges after the rapid formation of the oxide layer (b) formation of bubbles and ignition of plasma (c) new oxide formation (d) start of new discharges with the generation of gas bubbles and plasma, leading to the formation of a new oxide coating.(B) Schematic of transport phenomena that take place during the MAO process.(C) Diagram of the formation of Ta2O5 coating through the equation 2Ta 5+ + 5H2O → Ta2O5 + 10 H + .Reproduced from [92].CC BY 4.0.

Figure 2 .
Figure 2. Key growth factors involved in the different phases of bone regeneration.Healing of bone injuries is a complex process that involves a series of catabolic and anabolic processes, resulting in the formation of new intact bone tissue.The regeneration process can be divided into four phases that overlap each other: (A) inflammatory phase, (B) soft callus formation, (C) mineralization and resorption of the soft callus, and (D) bone remodeling.Each phase is regulated by a myriad of cytokines and growth factors secreted by different cell types.Revascularization and angiogenesis occur from the inflammatory phase up to the resorption phase.BMP = bone morphogenetic protein, FGF = fibroblast growth factor, GDF-5 = growth/differentiation factor 5, IGF-1 = insulin-like growth factor 1, M-CSF = macrophage colony-stimulating factor, OPG = osteoprotegerin, PDGF = platelet-derived growth factor, PlGF = placental growth factor, PTH = parathyroid hormone, RANKL = receptor activator of nuclear factor κB ligand, SDF-1 = stromal cell-derived factor 1, TGF-β = transforming growth factor β, TNF-α = tumor necrosis factor α, and VEGF = vascular endothelial growth factor.Reprinted from [124], Copyright (2015), with permission from Elsevier.

Figure 3 .
Figure 3. Schematic of surface functionalization correlation: (A) Preparation of CaP-PLA composite coated porous tantalum scaffolds loaded with VEGF/TGF and a strategy note for bone defect repair applications.Reprinted from [107], Copyright (2014), with permission from Elsevier.(B) Schematic of the repair of large osteochondral defects in goats' femoral head using BMSCs/pTa-chondrocytes/CM biphasic scaffold.Reproduced from [110].CC BY 4.0.(C) Preparation of a Van-carboxymethyl chitosan composite-coated 3D-printed porous tantalum scaffold and an illustration of its osteogenic and antibacterial properties.Reprinted with permission from[115].Copyright (2022) American Chemical Society.

Figure 4 .
Figure 4. Immobilization of magnesium ions with dopamine on a 3D-printed porous tantalum scaffold.(A) Schematic of the process.(B) in vivo osteogenesis after 8 and 12 weeks of stent implantation into the femur, showed improved osteogenesis with Mg-doped scaffolds.(C) Immunofluorescence staining of angiogenesis in vivo after implantation, revealing a dense distribution of immunofluorescence areas in the Ta-PDA-Mg2 group.Reprinted from [168], Copyright (2020), with permission from Elsevier.

Table 1 .
shows the relevant clinical applications of tantalum and porous tantalum.
[101]00] the particles released from the target are deposited on the substrate in the form of a thin film.This technology has several important advantages compared to previous coating technologies; for example, high deposition rate, ready sputtering of any metal, alloy, or compound, and high adhesion of deposited thin film coatings[99,100].However, despite these advantages, magnetron sputtering technology has been used relatively infrequently in the past, mainly because it requires advanced vacuum technology and has relatively high cost limitations.Fialho et al deposited porous Ta 2 O 5 layers containing calcium (Ca) and phosphorus (P) as well as zinc (Zn) nanoparticles on tantalum-based surfaces using DC magnetron sputtering and MAO techniques and experimentally verified that the modified tantalum implants possess superior osteocompatibility and antibacterial activity[100].Zinc oxide is known to have excellent antimicrobial properties, and the addition of appropriate amounts of zinc oxide to implant materials enhances the proliferation and differentiation of osteoblasts.Ding et al deposited a composite coating containing tantalum oxide on the surface of a titanium alloy through magnetron sputtering.They discovered that the composite coating, when doped with zinc oxide, exhibited improved corrosion resistance and antibacterial properties over tantalum oxide coating alone.This study introduced a new approach for depositing composite coatings using magnetron sputtering technology[101].
Magnetron sputtering technology is a highly efficient vacuum coating technique mainly used to deposit metals, alloys, and compounds onto substrate materials.The process of magnetron sputtering involves forming a circular glow plasma outside the cathode surface, and the resulting ions accelerate towards the cathode and bombard its surface, releasing particles from the cathode.

Table 2 .
demonstrates the strategy of functionalizing tantalum and porous tantalum with different substances.