Surface modification – A step forward to overcome the current challenges in orthopedic industry and to obtain an improved osseointegration and antimicrobial properties

Materials Chemistry and Physics 243 (2020) 122579

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Surface modification – A step forward to overcome the current challenges in orthopedic industry and to obtain an improved osseointegration and antimicrobial properties Denisa Alexandra Florea, Delia Albuleț, Alexandru Mihai Grumezescu *, Ecaterina Andronescu Department of Science and Engineering of Oxide Materials and Nanomaterials, Faculty of Applied Chemistry and Materials Science, University Politehnica of Bucharest, 060042, Bucharest, Romania

H I G H L I G H T S

� In order to provide a proper fixation and to avoid implant collapse, surface modification is one of the most promising approaches in this direction. � One of the most promising approach in the orthopedic field to offer a better implant stability, a great fixation and to avoid implant failure due to infections. � The surface of an implant is the main boundary with the surrounding tissue, therefore by bringing new physical, chemical or biological elements onto the surface with the aim of modifying and improving the basic characteristic of an implant can offer enhanced functionality, biocompatibility and antibacterial properties. A R T I C L E I N F O

A B S T R A C T

Keywords: Osseointegration Surface modification Orthopedic implants Antimicrobial coatings Dental implants

The bone tissue is the most dynamic structure in the human body, being capable of self-regeneration after an injury, an accident or even when is affected by a disease. However, its potential to fully regenerate is constrained by some limitations and the need of a medical device becomes vital. Many biomaterials have been used to develop such products and now they are successfully used by physicians. Thus, most of them present some shortcomings which might eventually lead to device malfunction or even failure. In the orthopedic field, implants for long term use should be able to provide a successful restauration of the affected joint. Even if Titanium (Ti), together with stainless steel or Cobalt Chrome-based alloys are materials of a choice in implants industry, they are still subjected to some limitations when inserted in the host such as: wear debris, corrosion, bacterial attachment, improper interactions with the biological environment etc., most of them leading to second surgical interventions and ultimately to implant failure. In order to provide a proper fixation and to avoid implant collapse, surface modification is one of the most promising approaches in this direction.

1. Hard tissue – the basics The bone tissue, also mentioned as hard tissue, can be considered the most dynamic component of the human body due to its ability to act as a self-regenerator throughout the life [1]. Moreover, it is characterized by multifunctionality having a key role in exhibiting four major functions: mechanical support, mineral equilibrium, organ protection and hema­ topoiesis. Additionally, the intense attention given to this tissue in the recent years leaded to the theory that it performs an essential endocrine function. Although it is very studied by researchers worldwide its he­ matopoietic tendency is not yet recognized even if spongy (also called trabecular) bone proved to be a notable source of red blood cells (RBC)

[2,3]. The achievement of these functional aspects is possible only due to bone organization. It is organized in structures which vary in dimensions from nanometers to millimeters leading to a hierarchical union that provides high-level stiffness. This is also fully responsible for its me­ chanical performance offering two of the most important characteristics of a human being: movement and support. From a nanometric point of view, two major phases are materializing the composite material known as bone tissue: organic and mineral phases. Therefore, by having as main components cross-linked collagen-I organized as a matrix which is mineralized with nanocrystals of carbonated apatite, three main char­ acteristics are developed: ductility, stiffness and resilience. When it

* Corresponding author. E-mail addresses: [email protected], [email protected] (A.M. Grumezescu). https://doi.org/10.1016/j.matchemphys.2019.122579 Received 13 August 2019; Received in revised form 17 December 2019; Accepted 23 December 2019 Available online 27 December 2019 0254-0584/© 2019 Published by Elsevier B.V.

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Materials Chemistry and Physics 243 (2020) 122579

comes to the microstructural point of view, the tissue can be classified as denser (compact/cortical bone) and porous (spongy bone); the location and degree of porosity/density is correlated with the functional or bio­ logical need. Consequently, the properties of compact and spongy bone are different, spongy bone being capable to store more energy than compact bone thanks to the high degree of porosity (between 30% and 90%) and rich content of fundamental fluids (blood, marrow etc.) while compact bone is offering rigidity and strength (Fig. 1) [4]. When it comes to cellular particularities, the complexity of the cells involved in bone remodeling are the reason for which the bone tissue is a dynamic structure subjected to change, development and regeneration throughout the entire life. These processes are based on a resorptionformation balance. Essentially, there are two main types of cells involved in this biological mechanism: osteoclasts – having a principal role in resorption and osteoblasts – main bone forming cellular struc­ tures. The balance between resorption and formation is maintained by specific biomolecules such as hormones and ligands which direct, inhibit and control the activity of each type of cell, the activity of osteoclasts and osteoblasts being synchronized in a healthy human being (Fig. 2) [5]. The bone tissue is subjected to a variety of movements daily and, depending on the applied load, it is exposed to multiple types of me­ chanical solicitations. When the load applied to a bone surpasses its strength, bone fracture occurs [3].

In 2017, it was reported that only in the United States of America 6 million people were suffering from bone fractures [6]. Worldwide, the total number of patients (over 50 years) who are exposed to this risk was estimated at 158 million. Moreover, according to the available data the number will increase by 50% in 2040 [7]. Apart from accidents and trauma, which are mostly unpredictable, there are various metabolic bone disorders which are linked to changes in bone’s mineral component homeostasis and might lead to fracture and, additionally, to unproper healing [8,9]. One of the most common bone-related diseases is osteoporosis which usually affect patients over 40-years old and is characterized by reduced mineralization, bone loss and fragility and often lead to a massive damage in bone structure. The damaged structure implies a substantial decrease in bone strength conducting to fractures. As discussed before, in a healthy human being, a balance between bone resorption and bone forming is assured by mul­ tiple factors and when this equilibrium is disturbed, a dysfunctional bone remodeling process occurs leading to a lower bone density. This imbalance is influenced by various factors from day-to-day activities such as: smoking, alcohol consumption, menopause, genetic history, low protein intake, sedentarism etc. However, from a clinical point of view, this disorder is classified by physicians as a ‘silent disease’ due to the absence of pain until fracture [10]. Despite the fact that osteoporosis is a popular subject for clinicians, bioengineers, researchers etc., its treat­ ment still represents a major challenge due to increased cost and

Fig. 1. Bone Anatomy. A schematic drawing of the most profound anatomical features of bone, providing a cross section through cortical and cancellous bone while indicating the sites where the respective cells can be found. Reprinted from an open access source (Scheinpflug, J.; Pfeiffenberger, M.; Damerau, A.; Schwarz, F.; Textor, M.; Lang, A.; Schulze, F. Journey into Bone Models: A Review. Genes 2018, 9, 247.). 2

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Fig. 2. Schematic representation of bone remodeling showing bone lining cells (quiescent osteoblast) at first stage of acti­ vation; osteoclast (resportion); the resorp­ tive lucanae where mononuclear cells differentiate into macrophage (reversal) and deposits of osteoid (formation) and osteo­ cytes (maturation). Reprinted from an open access source (Lowe, B.; Ottensmeyer, M.P.; Xu, C.; He, Y.; Ye, Q.; Troulis, M.J. The Regenerative Applicability of Bioactive Glass and Beta-Tricalcium Phosphate in Bone Tis­ sue Engineering: A Transformation Perspec­ tive. J. Funct. Biomater. 2019, 10, 16.).

2. The interactions between orthopedic devices and physiological environment

complex pathology. Usually, bisphosphonates-based drugs are recom­ mended by orthopedic surgeons as a long-term treatment and metallic implants are preferred for bone fractures. However, recent studies sug­ gested that some of the available medication might provoke severe adverse reactions and some of them were withdraw from the market. It is a complex discussion based on this subject which needs massive attention in order to develop a suitable alternative to the conventional treatments that should prevent the appearance of second bone fractures and to increase bone density [11,12]. Thus, besides osteoporosis, there are many other bone-related diseases which may lead to severe pain, bone loss and fractures such as: Paget’s disease (characterized by a chaotic activity of osteoclasts), Rickets (inadequate chondroid miner­ alization), Nasu-Hakola disease (NHD), Osteogenesis Imperfecta etc. [8, 13–15]. An interesting therapy for bone regeneration was described by Brazilian researchers regarding photobiomodulation (PMBT). This therapy uses a low-level laser that modulates the activity of growth factors, which increase the synthesis of bone matrix and participate to the development of epithelial cells, collagen, fibroblasts and prolifera­ tion of blood vessels. Lately, several studies have demonstrated that PBMT has beneficial effects on bone restauration being a photo­ biostimulatory therapy [97]. A study made on a combination between the biophosphonate Zoledronate (ZOL) and Raloxifene (RAL) showed improved mechanical and material properties of bone compared to the monotherapies, increasing the quantity and quality of the new bone formation. ZOL treats several bone disorders through its capability to diminish the fracture risk by increasing the bone mass, however it has a disadvantage regarding bone quality. This can be avoided according to the study by combining it with RAL, which improves the quality of tis­ sues and mechanical properties by fastening to collagen and increasing tissue hydration. The researchers stated that combination treatments have the potential to develop bone health and avoid skeletal fragility at microscopic and macroscopic levels [98]. Over the last years, modern therapies and devices made of porous calcium phosphate-collagen composite microspheres, aptamer-conjugated hydroxyapatite (Apt-HA), hybrid hydrogels with nanosilver-incorporated halloysite nanotubes and gelatin methacrylate, 3D printed biomaterials with self-assembly micro-nano surface, scaffolds with magnetic micro-environment, chitosan sponge coated with TiO2 nanoparticles, mesoporous silica coated magnetic nanoparticles or demineralized bone powder showed improved results in the promotion of bone regeneration and angiogenesis [99–105].

A lot of progress has been made in the last decades to develop suit­ able products which fit patient needs when it comes to fractures. However, the challenges still exist in treating those produced as a result of a bone disorder, trauma or accidents and they are related to fracture fixation and stability [16,17]. First of all, in order to acquire such a product, it is very important to understand from the very beginning how it interacts with the human body. Even if most of the biomaterials used for such products are biocompatible and typically not immunogenic, the implantation process produces a perturbation in the homeostatic mechanisms of every human being. Therefore, the immune system exhibits a response known as foreign body reaction at the site of implantation. The inflammatory cells are invading the area of the newly implanted device, being followed by the regeneration of the ‘injured’ tissue. In some cases, the inflammatory reaction is maintained until the implant is isolated from the adjacent tissues by a capsule of fibrous connective tissue [18]. 2.1. Osseointegration One of the most promising approaches to avoid the encapsulation within soft tissue is to create a bioactive interface between implant and the native bone. This phenomenon is known as ‘osseointegration’ and in occurs in three main stages: the primary response of the host after implant insertion, followed by osteogenesis and remodeling processes [19]. The first phase starts when the implant is inserted within the native tissue, being considered by the human body a trauma which triggers the inflammation process after 1–3 days post implantation. After this step, the vascularization occurs inside the gap in the native bone and lasts about 1 week. At this point, gene expression takes place, which means that DNA is converted to a functional signal in the form of specific molecules or proteins with the aim of generating a biological response. Therefore, particular non-collagenous molecules (such as osteonectin, osteocalcin or osteopontin) will influence the differentiation pathway of mesenchymal stem cells into osteoblasts which will form the newly bone extracellular matrix (ECM). The gene expression of osteoblasts is also influenced by mechanical fluctuations appeared at the peri-implant interface and it is a fundamental factor that controls in a positive manner the osteoblasts behavior and will provide an increase level of 3

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newly formed mature bone. However, the changes produced by the implantation of a foreign device in the host activates the expression of osteoclastic genes as well, with the purpose of resorbing the altered bone matrices [20–22]. When the implant or prosthesis comes in contact with the native tissue, there is a high probability to generate the appearance of poly­ meric, ceramic or metallic particles at implant site, action which might induce the appearance of mature osteoclasts. The aim of this response is to neutralize the effect of wear particles, but it stimulates bone resorp­ tion. Therefore, as a consequence the balance between resorption and bone forming is affected and there is a chance to trigger osteoblasts apoptosis, osseointegration becoming deficient [21]. Improper osseointegration might be possible due to other factors as well: osteogenic cells exhibit minimal activity, device micromotion or reduced angiogenesis of peri-implant site [20]. Nowadays, osseointe­ gration is a concept which can be investigated from many perspectives including anatomically, clinically or histologically. It is clear by now that the host response to a biomaterial is correlated with specific factors, most of them depending on surface features. In research, one of the current goals is to understand and exploit the surface structure and function and to create surfaces that can influence in a progressive manner the host response to implants or other orthopedic devices [18].

Ultra-high-molecular-weight polyethylene was introduced in medical industry and it is still chosen by clinicians in present. However, this change resulted in debris generation that affected the mechanical properties as well. Even if improvements have been made in the last decades, the impact of wear debris appearance and foreign body re­ actions are still under investigation. However, in contrast, temporary implants are used only for a specific time period with the aim of sup­ porting bone healing and usually include screws, plates, wires or pins [24]. 3.1. Metallic implants – the main choice in clinical practice Metals are a well-known class of materials used in biomedical engi­ neering for a comprehensive range of implantable devices in various fields including cardiology (artificial heart, coronary stents etc.) and orthopedy (temporary and permanent implants, including dental). They play an important role in orthopedic industry due to the unsurpassed combination of stiffness, toughness and strength which is provided. However, they present a low corrosion resistance, especially when compared to ceramics. Therefore, their adaptability in the human body, which is a highly corrosive environment, needs to be improved because, under these conditions, the consequences are serious and might lead to mechanical failure of the implant. Moreover, their corrosion can lead eventually to the release of unwanted ions and particles which may trigger adverse reactions and will require a second surgical intervention (Table 1) [25]. The effect of such products has been considerably investigated and it was concluded that the wear particles generated by corrosion might stimulate the metabolic pathways of many cellular types including (but not limited to) osteoclasts, osteoblasts, lympho­ cytes, macrophages or fibroblasts. Metal ions can stimulate the pro­ duction of pro-inflammatory mediators by osteoblasts as well and it might contribute to the general inflammatory reaction in peri-implant osteolysis [29].

3. Biomaterials for clinically used orthopedic implants Nowadays, depending on patient’s need, the components of the or­ thopedic implants might be manufactured from metals (including al­ loys), polymers or ceramics. Usually, metallic materials are used in loadbearing joint replacements in order to fix fractures, while polymers possess the remarkable ability to reduce friction and ceramics are used as bioactive coatings on metallic implants or as articulating components especially due to their outstanding wear resistance and bioactivity. However, there are two major classes of implants: temporary (plates, screws, pins, wires) which are supposed to be chosen for short-term applications and permanent (total joint replacements) being an option in cases when it should perform its function throughout the life span of the user. In order to accomplish these requirements several character­ istics must be taken into consideration such as: biocompatibility, its osseointegration potential, mechanical needs, wear resistance and corrosion resistance (Fig. 3) [23]. Permanent orthopedic implants are clinically used for many years. For instance, in case of hip arthritis, a disease associated with severe pain and immobility, the first permanent solution was developed in 1961 by Sir John Charnley by using for total hip replacement Poly­ tetrafluorethylene (PTFE or Teflon) together with an acrylic cement and a metallic implant. Later on, it was discovered that soft tissue masses were formed and both implant and surgery were a failure. In 1962, a step forward has been made thanks to the use of High-molecular-weight polyethylene as an alternative acetabular bearing surface, but the implant durability has been improved only with 5 years. Around 1970

3.1.1. The use of metals in total hip arthroplasty As mentioned above, total hip arthroplasty (THA) is a very common surgery for orthopedic physicians due to the highest rate of patients affected by osteoporosis, osteoarthritis or other trauma/accidents. Essentially, a basic implant is composed of a stem (femoral component), a femoral head, a liner and the acetabular cup. The femoral head is added on the top of the stem and is positioned into the liner. The acetabular cup comes in contact with the liner, both of them having a protecting role – the cup protects the native bone tissue, while the liner provides protection from wear damage [23]. The lifetime of a hip implant is correlated to certain aspects including the daily activities of the patient and the materials used for its manufacturing. In order to increase the lifespan of hip implants there are several aspects which need to be considered including: long term sta­ bility, minimum wear debris, early fixation etc. [12]. There are several combinations of materials clinically used in THA: Metal-on-Metal

Fig. 3. Orthopedic implants – types and characteristics to be considered when designing an orthopedic implant. 4

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crown/bridge/denture) and the dental prosthesis (sits onto the abut­ ment) and they can be fixed by using a dental cement or by screws. Their availability on the market is wide, being accessible in various sizes or shapes and commercialized by multiple brands. Due to its suitable Young Modulus, high strength, advantageous corrosion resistance, su­ perior biocompatibility, titanium (together with its alloys) is one of the most exploited material for the fabrication of dental implants. Commercially Pure Titanium – IV Grade (CpTi) is usually used with restoration purposes and in endosseous dental implants, being classified as a ‘gold standard’ in metallic implants in both orthopedic and dental areas. However, it has been reported that its surface is not osteo­ conductive nor osteoinductive, therefore the osteogenesis is hardly encouraged [36–39]. Another popular Ti-based alloy is Ti–6Al–4V which is used for crown, brackets and implantable components due to its remarkable mechanical properties and endurance to corrosion due to the appearance of a TiO2 protective layer on its surface when in contact with physiological environment. Thus, the loads performed in the oral cavity during chewing may lead to the destruction of this layer and can provoke leakage of metallic particles or ions into the proximate tissues [40]. Co–Cr alloys are also known as metallic materials with good corro­ sion resistance and high stiffness, but they are difficult to process by technicians especially due to their high hardness. Usually, they are processed by the casting method but is time consuming and porosityrelated concerns may appear when certain parameters are not obeyed. However, the popularity of 3D printing in the industry showed prom­ ising improvements in terms of handling. As mentioned in the above sections, CoCrMo is one of the most used CoCr-based alloys in the in­ dustry due to its outstanding wear resistance, biocompatibility and corrosion resistance. Despite the variety of dental alloys, there are some shortcomings which limit their utility in day to day practice including (but not limited to) stress corrosion cracking, areas that are subjected to stress concentration, fatigue, manufacturing technique, cost etc. [41–43].

Table 1 The effects of most common metal ions which may appear due to excessive corrosion. Type of metal ions

Possible effect

Reference

Cobalt – Co

- it has been used in orthopedic industry for more than 40 years, but it might induce anemia when present in a higher amount in the host - can generate the inhibition of Iron (Fe) absorption into blood - osteoblasts exposed to Co ions are subjected to a reduction is proliferation (which is dose dependent); this is applicable as well for Cr ions exposure - ulcers - CNS (central nervous system) disturbances - accumulation of Cr ions in tissues, can generate metallosis and genotoxicity in body cells - urinary disfunctions - may induce allergic contact dermatitis - present a toxic effect on cells producing serious damage in cultures at high concentrations (HC) - tendency for carcinogenicity in HC - at a concentration higher than 10 ppm showed toxicity after 24h of exposure - can influence the production of RANKL ligand which is an osteoclastic generator - it was reported that for dental implants it might present negative effects in bone remodeling - might be a factor in the appearance of Alzheimer’s disease - epileptic effects - may induce cytotoxicity for fibroblasts - toxic in HC - can provoke cardiac failure, coma, diarrhea, inhibition of sulphate oxidase’s activity - in HC can interfere in the metabolic activity of Ca (Calcium) and P (phosphorus)

[26,28, 29]

Chromium – Cr

Nikel – Ni

Titanium – Ti

Aluminium - Al Vanadium - V Molybdenum Mo

[26,29]

[26,27]

[29,30]

[26] [31] [26]

(MoM), Ceramic-on-Metal (CoM), Metal-on-polymer (MoP) or Ceramic-on-Ceramic (CoC). MoM prostheses have reached their maximum popularity in the first decade of the 21st century, but by the end of the first decade complications related to wear debris appeared [32–34]. However, metals such as titanium, stainless steel and CoCr (Cobalt Chromium) alloys (including CoCrMo - (Cobalt–Chro­ mium–Molybdenum) are still used in the orthopedic area but the need of improved products is tremendous [23].

3.2. Ceramics and polymers – current state of art in orthopedic industry 3.2.1. MoC and MoP Hip implants evolution in orthopedic market As mentioned before, when it comes to MoM and MoP hip implants, various concerns have been reported over the time. CoC alternatives have been developed in order to overcome some of them, including metal debris generation or wear-induced osteolysis, in case of ultrahigh molecular weight polyethylene (UHMWP) usage. A specific parameter which must be considered in CoC hip implants is lubrication, which is a key factor in terms of performance. An inadequate lubrication may cause several complications such as squeaking and increased friction. Since 1990, more than 3 million implants with components made of 1st gen­ eration alumina were inserted in patients with hip-related problems. Alumina was a material of a choice in this regard due to its low friction, admirable wettability and high wear resistance, but even if its properties made it suitable for this type of applications, unexpected high fracture rates were registered due to its intrinsic brittleness. This malfunction leaded to the development of 2nd and 3rd generation of alumina bear­ ings. The purity of the 3rd generation was higher than 98% and it had in its structure a minor amount of MgO (magnesium oxide) so as to prevent the grain growth in the sintering stage. Although this generation enhanced the properties of its predecessors, its use has been limited due to reliability causes. Later, yttria-stabilized zirconia was proposed as an option thanks to its higher toughness and strength when compared to brittle alumina and it was implanted in around 600K patients in the US and EU. Though, it has also encountered a massive failure because of premature LTD (low temperature degradation) or phase transformations in vivo. Consequently, in 2000 ceramic-composite hip implants have been developed and are still used nowadays, alumina-zirconia combi­ nations being the most popular in the field as a result of their decreased fracture and wear rates [45–47].

3.1.2. Metallic implants in stomatology In the last decades, a massive evolution has been made in dentistry field for the delivery of durable and successful products which possess suitable biological and mechanical features when compared to con­ ventional treatments. An ideal dental implant should be produced from materials that own a series of specific characteristics such as: nontoxicologic to both patient and operator, the structural and functional properties of the chosen material should withstand the aggressive oral environment, therefore it should possess a high fracture resistance, a suitable modulus of elasticity and thermal conduction. In the same time, it must reach the esthetic conditions of shape and color, it has to encourage an appropriate oral hygiene and inhibit the plaque accumu­ lation. Moreover, the total cost of the product must be realistic for both dental technician and dentist. The materials used should be easily inserted and/or removed in the oral cavity in order to assure a proper maintenance and the possibility of intervention in case of adverse re­ actions [35]. Basically, a dental implant operates as an anchor for a crown or for replacement teeth and is used as a treatment option in case of dental diseases, injury, tooth decay, accidents or other unpredictable problems. All the dental implants acts as real teeth and are composed of three components: the fixture (which becomes bonded to the jawbone after insertion, behaves as an artificial root), the abutment (support for the 5

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3.2.2. Ceramics and polymers in total knee replacement A total hip replacement procedure is a very complex and painful surgery performed on patients with the aim of replacing an arthritic or broken knee joint with an artificial prosthesis. Basically, a knee joint prosthesis substitutes the end of the femur and tibia with two compo­ nents and a plastic insert between them. Every knee prosthesis is exposed to a cycling loading during a normal walking cycle which usually cause fatigue failure and wear. In metal-on-polyethylene pros­ theses, the polyethylene bearing on the tibial side is subjected to high load through sliding and rolling movements. Yet, in case of metal inserts the situation is not better, because wear debris might lead to metal particles accumulation in the surrounding healthy tissues. An important aspect regarding total knee replacement is the recovery period after hospital discharge which involves an active life with constant exercise in order to assure a successful range of motions for the joint. However, chronic pain may be developed in patients with total hip replacement and numerous reports attested that severe pain appeared even in the hospitalization period on both rest and movement. It is well known by now that wear debris is the main challenge for metallic knee implants together with incorrect sizing, ineffective design of the main compo­ nents, the appearance of infections or hypersensitivity. However, at the moment, titanium, CoCr and their alloys are materials of a choice for this type of prosthesis. Since 1972, efforts have been made in order to introduce ceramics in the components of knee prosthesis. The combi­ nation between polyethylene insert and ceramic tibial and femoral components was a failure especially in cases where cementless fixation was chosen. The following progress suggested that an improvement in implant longevity might be assured by using only one ceramic compo­ nent (the femoral one), but it was an unsuccessful attempt due to high cost and difficult manufacturing process and poor fixation. In 1997 a giant producer in the industry designed a femoral component made from alumina and zircona which was identically (from a geometrical point of view) to those composed of CoCrMo alloy and showed promising results in terms of polyethylene wear, being approved for clinical use [48–52].

material [58]. 4. Novel direction in orthopedic research Considering all the above-mentioned aspects it can be concluded that, even if suitable properties are possessed by various biomaterials, patients are still exposed to possible complications including infections, implant wear, failure or displacement. Therefore, research is focused on strategies that might prevent these issues and in the same time to be cost effective. Such strategies include, but are not limited to: surface modi­ fication, biofunctionalization, reinforcing techniques etc. The aim of all these efforts is to assure two major fundamental requirements – first, a fast osseointegration and second, long-term stability and functionality [59, 60,66]. 4.1. Surface modification One of the most important property that should be possessed by an orthopedic implant is to induce osseointegration as soon as they are implanted in the host. Consequently, the stimulation of osseointegration is one of the most studied subjects in this field. The surface properties of a biomaterial (wettability, surface morphology or topography) are crucial when it encounters the biological environment. For example, surface morphology and topography present the ability to direct the differentiation pathways of stem cells or to influence the proliferation and migration of the desired cellular phenotype, while hydrophilicity strongly attracts cell adhesion [60,61,66]. In order to enhance osseointegration several surface modification practices have been developed over the years considering the factors which influence in a positive manner the long-term stability of an implant and offer an antimicrobial behavior as well (Fig. 4). Several studies showed that certain patterns in topography increase the me­ chanical link to the nearby tissues due to a higher surface area which leads to an improved stability [60,62,63,66,78]. The mature biofilm formation is a well-known problem in the biomedical area, and it can be generated under multiple conditions including the implantation of a newly device within the host. Biofilm appearance is influenced by bacterial adhesion which takes place in two steps: initial interaction between proteins and implant surface and the molecules binding process on the surface. Once biofilm is developed, its eradication is quite difficult despite all the antibiotic-based treatments prescribed after the initial intervention and repeated surgical post­ operative interventions. The biofilm resistance to antibiotics is one of the main issues regarding implant-related infections and, at the moment, there is no treatment available which might guarantee efficiency when it comes to biofilm prevention and eradication. Moreover, infections appeared due to biofilm formation are one of the main causes of hip and knee prosthesis failure. Statistically, 2 million patients were diagnosed with nosocomial in­ fections because of implants in the United States. In Europe, the costs estimated for the treatment of implant-associated infections is very high, for instance, in the United Kingdom, 7–11 million British pounds are spent each year in this regard. World Health Organization (WHO) re­ ported that 60% of the patients with nosocomial infections were re­ ported after implantation of a medical device and they are suffering from severe pain as a consequence. Multiple studies pointed out that most of the infections in dental and orthopedics fields are related to Staphylococcus aureus (34%) and Staphylococcus epidemidis (32%) bacteria. As a consequence, a long-term success depends on the anti­ bacterial properties of the implantable devices which are not able to actively resist to bacterial colonization and adhesion in the actual configuration for approved clinical use. Surface modification serves as an effective alternative to conventional materials exploited in order to create an antimicrobial character with the aim of decreasing the infec­ tion occurrence [64,65,66,74,75,79]. Considering all these aspects, surface treatments can be classified in

3.2.3. Dental implants Recently, dental implants have gained a lot of attention, the litera­ ture on this topic evolving very fast over the last decades [53]. Ceramic implants appeared around 40 years ago and were composed of single and poly crystal alumina, but implant facture was observed due to toughness and low bend strength. Implant fracture is a discouraging problem for both patients and dentists because it leads to implant loss, therefore the use of alumina implants was avoided. Nowadays, another challenge is represented by the esthetic appearance of implant which must match the artificial prosthesis with the native tooth, and it must be able to fulfil all the requirements in terms of shape, size, translucency, surface and color. Additionally, implant malposition is a considerable drawback of dental implants due to the increased risks of biomechanical difficulties. Inadequate positioning of the implant lead to compromised tissue support for long-term success of the implant. Esthetic features such as contours and profile might be affected as well by implant malposition. Ceramic-based restorations with no metals in their composition allow an improved light transmission, therefore the opac­ ity/translucent properties became one important selection criteria for material. Nowadays, there is a range of ceramic-based systems available that possess many physical and mechanical properties. These systems are promising if they present higher translucency because they can provide additional light transmission and a reduction in terms of reflection [54–57]. When it comes to dental ceramics available today in the industry, we can mention two major categories: silica and non-silica-based ceramics. The first ones, are the older than the second category, being introduced around 1900 as porcelain jacket crowns. Thus, polycrystalline zirconia is one of the non-silica-based ceramic clinically chosen in the present for crowns due to its suitable esthetic parameters, high toughness and strength. Moreover, it has been commercially used for the first time as a CAD/CAM manufactured 6

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Fig. 4. Surface treatments used in order to achieve enriched osseointegration and implant stability.

two categories: coatings addition (e.g. calcium phosphate-based coat­ ings) and surface modification (chemical, physical, biological treat­ ments). The addition of coatings refers to the spread of a substance onto a substrate, therefore creating an additional layer that offers extra beneficial properties to the substrate, while surface modification by chemical, physical or biological treatments involves a significant change in the structure of the bulk materials (e.g. addition of functional groups) [63].

implanted in vivo within a canine model. However, an extensive range of biological molecules can be added on the surface of an implant in order to promote osteoinduction including, but not limited to, large proteins, glycosaminoglycans (GAG) and growth factors. Large proteins or GAG such as collagen or chondroitin sulphate deliver a biomimetic layer on the implant surface which improves osseointegration once implanted. When it comes to growth factors, they have the capacity to modulate the response and differentiation pathway of stem cells, to decrease inflammation at the implantation site, to induce angiogenesis and to act as a chemical attractant for osteoprogenitors, all of these properties making them suitable candidates for surface coatings. The biofunctionalization of a surface can be done by using small peptides as well. They are derived from protein molecules and can be used to in­ crease adhesion of osteoblasts and, consequently, to enhance osseoin­ tegration. One of their main advantage is their size which allows a higher concentration to be integrated in the coating when compared to whole proteins [67]. In 2018, another approach has been considered by Shim et al., who synthetized a coating made of biphasic calcium phosphate nanoparticles functionalized with heparin-alendronate molecules with immobilized bone morphogenetic protein – 2 which influenced the differentiation pathway of human adipose derived stem cells (h-ADSC), fact pointed out by the expression of four main osteogenic genes – RUNX2, osteocalcin, osteopontin and ALP. Additionally, when implanted in rat models with calvarial defect a faster bone regeneration was observed [73]. Lately, a positive response was reported for Ti-surfaces with increase roughness and biofunctionalized with fibrinogen as well. It was established that osteoblasts attachment and proliferation rates are superior for coated substrates then for uncoated Ti, the osteoblast specific gene upregula­ tion was considerably improved, and in addition, no potential risk of bacteria colonization was remarked [74]. It is well-known that bisphosphonates have the ability to subject osteoclasts under apoptosis, phenomenon which can be exploited in terms of implant fixation and accelerate bone formation. Therefore, bisphosphonates have been used in coatings with the aim of increasing osteogenesis at the implantation site. Several studies have been made to determine the consequences over the surrounding healthy bone under different circumstances including their usage as drugs for different dis­ orders [75–78]. The use of bisphosphonate as a compound of coatings has proved to be efficient in terms of bone-implant interactions and increase in the amount of adjacent bone tissue [67,79].

4.1.1. Types of coatings for improved osseointegration When it comes to coating addition, calcium phosphate-based coat­ ings have gained attention of researchers in the last decades being investigated for both orthopedic and dental implants. As mentioned above, the inorganic phase of bone represents a major percentage of its overall structure, therefore the use of inorganic compounds as coatings for classic implants was evaluated. Starting from this point, hydroxy­ apatite (HA) (Ca10(PO4)6OH2), a ceramic from CaP family, is widely used in different forms in stomatology and medicine these days and it was chosen as a main material for various types of coatings as well. Numerous studies over the time pointed out that HA-based coatings might improve osseointegration of metallic implants. Recently, Ciobanu et al., suggested that cerium-doped HA/collagen coatings, were cerium was doped within HA matrix under biomimetic conditions, could induce a faster osseointegration of pure titanium implants [67–69]. In dentistry, the HA layer deposited on implants showed multiple advantages such as: enhanced osseointegration, faster healing, beneficial for load stress distribution, improved linkage with bone, higher biocompatibility etc. During the remodeling stage Ca and P ions are released into the peri-implant area from the newly added coating, phenomenon which lead to the saturation of body fluids allowing the formation of biological apatite (a considerable source of osteoblastic cells). This theory was also sustained when in vivo tests were performed on a Ti–6Al–4V dental implant coated with HA-nanorods. Micro-computed tomography (Micro-CT) revealed that new bone was formed around the coated implant [70,71]. 4.1.2. Substrate biofunctionalization Recently, HA-based coatings have been used as a carrier for bio­ molecules, growth factors and even DNA. For instance, HA coatings supplemented with BMP-7 (bone morphogenetic protein – 7) showed promising results in terms of bone ingrowth, applied on a prosthesis 7

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Many other techniques, biomolecules and materials have been used and developed over the last decades which presented suitable responses after in vivo and in vitro testing and sustain the idea that surface modification might lead to an improvement in terms of osseointegration [72,80–85]. However, even if superior osteointegrative properties can be obtained, there are still some limitation to overcome regarding the bacterial colonization and implant failure due to infections. For instance, in case of simple CaP coatings, the bacterial attachment might happen straightforward, especially due to high roughness and the need of an antimicrobial stimulate is mandatory [86].

chemical composition of the surface, which might affect the posttreatment biocompatibility of the device or material. Blasting can also obtain nanorough surfaces that have a higher resistance to corrosion and support upregulation of osteoblast-specific genes [107,108]. 4.1.5. Laser ablation Laser ablation represents a method of applying short pulses from a powerful laser to obtain micro- and nanostructures. The advantage is that there is a decreased risk of contamination and the mechanical properties remain the same, while being able to work on complex im­ plants from the geometrically point of view. Recent studies were made on titanium surfaces that changed their roughness and achieved an increased osseointegration and new bone formation and an important antibacterial level through the hydrophobicity of the surface [107]. Laser techniques lately get a special attention from experts and engi­ neers being a great and adaptable tool to enhance the response of the biological structures to titanium implants. The core benefit implicates the ability of adjusting the chemical composition and the surface texture by generating pits, pillars, grooves, ripples, columns [109].

4.1.3. The development of antimicrobial coatings The antimicrobial properties of orthopedic and dental implants have been widely investigated by researchers worldwide and various mate­ rials have been subjected to examination under various conditions [87–91]. Three major approaches can be considered when designing such a coating: antimicrobial agent-release, bacteria repelling/non-adhering coating and contact killing surfaces. Agent-release coatings involves leakage of an antimicrobial substance over a defined timeframe with the aim of destructing adhered bacteria. The advantage of this technique when compared to antibiotics admin­ istration is that the release of the agent is made by diffusion, degradation or hydrolysis which allows the delivery of a high concentration locally without surpassing the toxicity limits. Thus, the reservoirs on the coat­ ings are limited making their action provisional. As an alternative to this type of coatings, contact-killing coatings have been elaborated to over­ come the reservoir limitation issue. These coatings consist of compounds attached to the material surface by covalent bonding and they exhibit their antimicrobial activity by membrane interactions. The bacteria repelling surfaces are created in order to avoid the biofilm formation from the earliest stage by using non-cytotoxic mechanisms. It is based on molecule immobilization onto the surface which can possess anti-adhesion properties (e.g. PEG). Recently, the modification of sur­ face topography proved to be promising in terms of modulation of bacterial adhesion [92]. Numerous studies were conducted regarding the incorporation of different antimicrobial compounds within a coating including Silver, Copper, Magnesium, Selenium, Zinc oxide which proved to be efficient in bacterial inhibition [66,92–95]. However, a coating which might possess antimicrobial properties and can enhance osseointegration in the same time is preferred. Titania (TiO2) nanotube coatings proved to be a useful tool in both achieving a faster osseointegration and inhibiting bacterial attachment and colonization. For instance, in vitro tests sug­ gested that osteoblasts had a proper adhesion on the substrate, while P. aeruginosa viability was reduced [96]. Polydopamine (PDA) repre­ sents a substance, which is able to adhere at various types of substrates having numerous functional groups that support the immobilization of biomolecules and fastening of metal ions. PDA was used for modifying the surface of orthopedic implants to regulate the cell proliferation, differentiation and migration, improving the implant function. Osseointegration and antimicrobial activity is also provided by PDA-based coatings [106].

4.1.6. Acid etching Acid etching is a surface modification method used frequently for titanium or titanium-based alloy surfaces. In order to get micro sized pits that improve the cell adhesion and osseointegration, a strong acid like HCl, HNO3 or H2SO4 is needed to harm the top layer of titanium di­ oxide. This technique was described in literature in the experiment of Klokkevold et al. where titanium screws obtained a modified surface through acid etching, showing improved osseointegration both in vitro and in vivo compared to normal implants. A new concept in this regard is represented by the combination of acid etching and blasting which creates nanotopography surfaces and achieves an impressive implant adaption and connection [110]. 4.1.7. Anodization Anodization is another method used to modify the surface of tita­ nium and titanium-based alloys. Anodic voltage is applied to the ma­ terial surface in an ionic solution to obtain a thick layer of oxide on the top of the material and this ensures a higher corrosion protection to the material. The anodization conditions such as voltage, reaction time or electrolyte concentration influences the morphology and structure of the layer. The study of Ercan et al. described the positive effect which a titania anodized surface has on the osteoblast adhesion and proliferation and a negative effect on bacteria adhesion. Their work also demon­ strated the increased calcium deposition on the surface [107]. 4.1.8. Chemical modification Chemical surface modification can occur through various methods such as chemical vapor deposition (CVD) or sol-gel synthesis. CVD oc­ curs through a chemical reaction if a gaseous reactant gets in contact with a heated surface, producing a modulated coating with high purity of the deposited chemical products and suitable surface topography. The sol-gel method implies the formation of a mineral phase from the polymerization of low molecular precursors, which ends being a colloidal solution (sol) as inorganic host for the organic molecules as guests. The final product is a gel that serves as scaffold for immobilized guest molecules. Another material that improves the surface properties and morphology of metal devices is titanium nitride, which has an impressive chemical stability and is able to resist to high temperatures and corrosion. I has been documented that titanium nitride is biocom­ patible having a high chemical inertness, hardness suitable for exposure to mechanical stress and antimicrobial effect [111–114].

4.1.4. Blasting Blasting is a simple technology, which uses hard abrasive particles against a metallic surface to remove the contamination on the surface. This technique has the ability to roughen the smooth surfaces and smoothen the rough ones. In biomedicine, the particles that are suitable for blasting are ceramics such as, but not limited to titania, hydroxy­ apatite and alumina which create a rough surface improving the strength between bone and orthopedic implants leading to an increased osseointegration. The study of Wennerberg et al. used alumina with particle sizes of 25–75 μm to obtain a surface roughness of 1.1–1.4 μm and it demonstrated that the appliance of 75 μm particles developed better the new bone formation and achieved a higher biointegration. The only disadvantage of this technology is that it might change the

5. Conclusions There is a wide range of medical devices available on the market but most of them still present some downsides which need to be overcome. 8

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One of the most promising approach in the orthopedic field to offer a better implant stability, a great fixation and to avoid implant failure due to infections. This can be reached by the surface modification of an implant. Most of the alternatives elaborated by scientists in the last years showed promising results, but in order to make them clinically avail­ able, investigations should be made further in terms of in vivo testing and clinical trials. Moreover, a coating which can be manufactured at an industrial scale, with a proper design and a feasible cost might lead to a novel generation of orthopedic and dental implants.

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