Year : 2016 | Volume
: 1 | Issue : 4 | Page : 138--144
Recent advancements in magnesium implants for orthopedic application and associated infections
Jaslin P James
Biocon Research Limited, Bangalore; Sahrdaya College of Engineering and Technology, India
Jaslin P James
Biocon Research Limited, Bangalore; Sahrdaya College of Engineering and Technology
In recent years extensive research on magnesium and its alloys as potential biodegradable implant materials have been carried out by various research groups around the world. Biodegradable magnesium alloys are more suitable for load-bearing implant applications than their polymeric counterparts because of their superior mechanical strength. Moreover, since their elastic properties resemble those of natural bone, they are considered ideal for hard tissue implants employed in fracture stabilization so that stress shielding is avoided and bone regeneration is enhanced. Also studies have shown that Mg alloy exhibit good biocompatibility with no systemic inflammatory reaction or affection of the cellular blood composition. One of the main advantages of biodegradable implants is the elimination of follow-up surgery to remove the implant after the tissue has healed sufﬁciently. Consequently, extensive studies have been carried out to develop Mg-based alloys with superior mechanical and corrosion performance. This review focuses on the following topics: (i) the design criteria of biodegradable materials; (ii) in vitro performances of currently developed magnesium alloys; (iii) improving properties of Mg based orthopedic implants using surface improvement techniques and other alloying methods; as well as (iv) implant infections and current methods.
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James JP. Recent advancements in magnesium implants for orthopedic application and associated infections.Clin Trials Orthop Disord 2016;1:138-144
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James JP. Recent advancements in magnesium implants for orthopedic application and associated infections. Clin Trials Orthop Disord [serial online] 2016 [cited 2021 Jan 28 ];1:138-144
Available from: https://www.clinicalto.com/text.asp?2016/1/4/138/194813
Over the last 4 decades, innovations in the field of biomaterials and medical technology have had a sustainable impact on the development of biopolymers, metals and ceramics utilized in medical devices and implants. This progress was primarily driven by the demands for enhanced mechanical performance of permanent and non-permanent implants as well as medical devices and artiﬁcial organs and issues of biocompatibility. In the 21 st century, the biomaterials community aims to develop advanced medical devices and implants to meet those requirements, as well as to facilitate the treatment of older as well as younger patients. The major advances in the last 10 years in the cellular and molecular knowledge provided the scientiﬁc foundation for the development of third-generation biomaterials. These discoveries signiﬁcantly affected the way of design and use of biomaterials. At the same time both clinical demands and patient expectations remained to grow. The development of cutting edge treatment strategies that alleviate or at least delay the need of implants represents the main challenge for the biomaterials community in the 21 st century. Hence, the present decade has seen the emergence of the fourth generation biomaterials, the so-called biomimetic or smart materials.
Biodegradable implants, acting as "smart" implants, have attracted increasing interest in the past few years. The main driving force for the development of biodegradable implants is their degradation properties in the physiological environment. The main advantage by this class of material is that the clinical function of permanent implants can be achieved and, the devices may disappear completely once it becomes no longer useful. One of the main advantages of biodegradable implants is the elimination of follow-up surgery to remove the implant after the tissue has healed sufﬁciently (Staiger et al., 2006; FarθI et al., 2010). Consequently, there is a reduction in lifelong problems caused by permanent implants, including long-term endothelial dysfunction, permanent physical irritation and chronic inﬂammatory local reactions (Moravej and Mantovani, 2011). Although polymers are dominant in the current medical market, Mg-based (Zhang et al., 2010, 2012), Fe-based (Peuster et al., 2001; Feng et al., 2012) and Zn-based alloys (Vojtμch et al., 2011; Bowen et al., 2013) have been proposed as better biodegradable materials for load-bearing applications due to their superior combination of strength and ductility over polymers.
Mg-based alloys as biodegradable implants have remarkable advantages over Fe-based and Zn-based ones. Therefore, the study of Fe-based and Zn-based alloys as biodegradable implants is limited to only a few groups worldwide (Peuster et al., 2001; Bowen et al., 2013). Although iron, magnesium and zinc are all essential nutritional elements for a healthy body, the recommended daily intake for adults of magnesium (240-420 mg/d) is up to 52.5 times more than that of iron (8-18 mg/d) and zinc (8-11 mg/d) (Trumbo et al., 2002). Pure zinc implants may be a concern for patients because a daily intake of 100-300 mg can induce health problems and a higher dosage can be even more harmful. The elastic modulus of magnesium (41-45 GPa) is closer to that of natural bone (3-20 GPa) than that of iron ($211.4 GPa) or zinc ($90 GPa) (Staiger et al., 2006; Bowen et al., 2013). The mismatch of elastic moduli can lead to the implant carrying a greater portion of the load and cause stress shielding of the bone (Chen et al., 2014). This biomedical incompatibility can result in critical clinical issues, such as damage to the healing process, early implant loosening, skeletal thickening and chronic inﬂammation (Kraus et al., 2012). Both pure iron and pure magnesium have been reported to possess excellent biocompatibility in the human body and show no signs of local or systemic toxicity (Staiger et al., 2006). However, researchers have recently concluded that iron is a poor choice for biodegradable stents because the corrosion products from the iron accumulate over 9 months and are retained in the arterial wall of the living rat model as voluminous ﬂakes which threaten the wall's integrity (Holzapfel et al., 2013). Moreover, magnesium implants have been proven to stimulate the formation of new bone when they are implanted as bone ﬁxtures (Witte et al., 2006).
The investigation of magnesium alloys as cardiovascular and orthopedic implants is not a new concept (Witte, 2010). The ﬁrst clinical application was reported in 1878 by the physician Huse (1878), who successfully used magnesium wire ligatures to stop bleeding vessels. However, early clinical investigators (Andrews, 1917; Seelig, 1924) soon found that magnesium was too brittle, had limited mechanical properties and degraded too quickly. As a result, the application of magnesium and its alloys as medical implants had nearly stopped. With the technological advances in developing high-purity magnesium with high mechanical and corrosion performance, renewed interest in bio applications of Mg-based alloys began with studies by Heublein et al. (2000, 2003), who took advantage of the degradation characteristic of magnesium alloys to develop cardiovascular stents. Clinical trials have shown no symptoms of allergic or toxic reactions to magnesium stents. Magnesium stents can achieve an immediate angiographic result similar to the other permanent metallic stents, and can degrade completely and safely after 4 months (Di Mario et al., 2004; Zartner et al., 2005). Recently, the ﬁrst commercially available Mg-based orthopedic product has emerged. Despite the remarkable progress that has been made on the development of Mg-based alloys as biodegradable implants over the last 15 years, a number of fundamental challenges are still unsolved. The extensive range of applications of Mg-based alloys is still inhibited mainly by their high degradation rates and consequent loss in mechanical integrity at pH levels between 7.4 and 7.6 and in the high chloride environments of physiological systems (Kannan and Raman, 2008). Moreover, the rapid formation of hydrogen gas bubbles, usually within the ﬁrst week after surgery, could be a negative effect of Mg-based implants (Poinern et al., 2012).
The Design Criteria of the Biodegradable Materials
Biodegradable materials are designed to provide temporary support during the healing process of a diseased tissue and to progressively degrade thereafter (Hermawan, 2012). This concept requires the materials to provide desired mechanical properties for the intended use and suitable corrosion resistance for progressive degradation. It also requires the materials to possess acceptable biocompatibility and bioactivity within the human body, as new generation biomaterials (Narayan, 2010). Obviously, the speciﬁc design and selection criteria of biodegradable materials depend on the intended applications. Screws, pins, needles and other load-bearing orthopedic applications are implanted in the bone to maintain mechanical integrity over 12-18 weeks while the bone tissue heals (Staiger et al., 2006). Thus dedicated Mg-based alloys should combine both high strength and a low modulus close to that of bone to avoid ''stress shielding''. Erinc et al. (2009) proposed speciﬁc mechanical and corrosion requirements for biomaterials purposed for bone ﬁxtures: the corrosion rate needs to be less than 0.5 mm per year in simulated body ﬂuid at 37°C, the strength higher than 200 MPa and the elongation greater than 10%. Coronary stents, which are another exciting medical application for Mg-based alloys, are implanted to open blood vessels and must function in dynamic blood ﬂow. The ideal biodegradable stent should possess sufﬁcient mechanical properties, appropriate degradation rate, excellent hemocompatibility and biocompatibility, and drug delivery capacity. The stents are expected to degrade at a very slow rate for the ﬁrst 6-12 months to maintain optimal mechanical integrity during arterial vessel remodeling. Afterwards, the degradation should progress at a sufﬁcient rate without causing an intolerable accumulation of degradation products around the implantation site. Ultimately, stents should completely degrade within 12-24 months after implantation (Hermawa et al., 2010).
In Vitro Performances of Currently Developed Magnesium Alloys
The corrosion behaviors of multi elemental Mg-based alloys are difﬁcult to predict. The corrosion reaction of magnesium in aqueous environments is
which produces magnesium hydroxide and hydrogen gas (Witte et al., 2008). Magnesium hydroxide can act as a corrosion protective layer in water but it starts to lose this useful function and convert into highly soluble magnesium chloride when the chloride concentration is above 30 mM (Witte et al., 2008). Hydrogen gas is a major concern for using Mg-based alloys for orthopedic applications because bone vascularizes and transports the excessive hydrogen gas poorly, thus resulting in the formation of potentially harmful gas pockets (Persaud-Sharma and McGoron, 2012). Although recent research has shown that the hydrogen gas can be exchanged rapidly through the skin and/or accumulate in fatty tissue and therefore hydrogen gas adjacent to an implant may not be of major concern, it is better to eliminate it by improving the material itself. An effective strategy is to improve the corrosion resistance of Mg-based alloys, which can signiﬁcantly reduce the amount of hydrogen gas. Although pure magnesium corrodes very fast, the corrosion rate of the newly developed Mg-based alloy can be signiﬁcantly reduced by alloying adjustment, heat treatment, processing and surface modiﬁcation.
Previous investigations have shown that alloys with reduced grain size after extrusion also exhibits a much slower corrosion rate than the same alloys in the as-cast condition; examples include Mg-Nd-Zn-Zr (Zhang et al., 2012), Mg-Ca (Li et al., 2008) and ZK60 (Li et al., 2008) alloys. The improved corrosion resistance is believed to be related to the high grain boundary density and dislocation density and the redistribution of the second phase, but the fundamental principle is not clearly understood. Ralston et al. (2010) reported that a relationship exists between grain size and corrosion rate, and is similar to the classic Hall-Petch relationship.
The alloying elements have a direct inﬂuence on the corrosion resistance of Mg-based alloys. It should be noted that most elements have a critical limit with regard to their improvement of corrosion resistance that falls within their solubility in magnesium: beyond the critical limit, further addition leads to the deterioration of the corrosion resistance (Antunes and de Oliveira, 2012). Surface modiﬁcation can be an effective strategy to improve the corrosion resistance (Arciola et al., 2012; Holzapfel et al., 2013; Ordikhani et al., 2014). However, once the coating has broken down, the problem of excessive corrosion remains (Zhang et al., 2010).
Corrosion fatigue, which is the failure of a material under the simultaneous action of cyclic loads such as tension, compression or bending and corrosive attack, is mainly responsible for the mechanical failures of metallic implants. In general, the corrosion fatigue limits of Mg-based alloys in vivo are smaller than the fatigue limits in air. Fatigue crack initiation is frequently reported to occur at stress concentration sites, manufacturing defects, casting defects, grain boundaries and inclusions of the metallic implants (Persaud-Sharma and McGoron, 2012). The fatigue cracks for the corrosion fatigue initiated from corrosion pits, whereas in air they were generated from micro pores. Although, the results have paved the way for a basic understanding of corrosion fatigue behavior, there is still a need for more in-depth studies of this behavior on biomedical Mg-based alloys.
Cytotoxicity testing serves as a key indicator for quickly screening the biocompatibility of alloys. In theory, no metals have an unlimited intake in the human body. Many alloying elements may cause toxic reactions beyond the tolerance limit (Staiger et al., 2006). The biocompatibility of developed alloys is inﬂuenced by the amount of the released elements, which is related to the corrosion rate of the alloy in the application environment. Magnesium is well known to be biocompatible in the human body, though a magnesium level in serum exceeding 1.05 mM can lead to muscular paralysis, hypotension and respiratory distress. Also, cardiac arrest is known to occur for a severely high serum level of 6-7 mM (Staiger et al., 2006). The determination of allowable limits of released species would likely depend upon the location of the implant and available localized pathways or mechanisms for dealing with corrosion products. For example, it is reasonable to expect that there would be different considerations given to the release of corrosion product from stents exposed directly to blood as compared with orthopedic implants.
Jablonská et al. (2015) evaluated ﬁve commonly alloyed elements in magnesium, namely Zn, Mn, Y, Gd and Nd. Magnesium and calcium are well-known biocompatible elements and have the highest daily allowable dosages. Apart from the different tolerance abilities of cell lines, the reason behind these results could be related to the corrosion rate. Corrosion of Mg-based alloys leads to changes in the pH value and ion concentration, which have a negative effect on cell viability. Some of the present authors have studied the inﬂuence of pure magnesium with different corrosion rates obtained by different extrusion ratios and extrusion temperatures. The results confirm that the corrosion rate has a signiﬁcant inﬂuence on the cell viability, as well as on cell attachment and spreading (Jablonská et al., 2015).
Improving Properties of Mg Based Orthopedic Implants
To make use of magnesium alloys as orthopedic implant is an idea which has developed already in the first half of the 20 th century. Mg is an essential element in life and about half of the 30 g which can be found in the body is stored in bones. The material is load bearing and the mechanical properties tensile yield strength, fracture toughness or Young's modulus is more similar to those of natural bone than polymers, ceramics implant materials or titanium which remains the most common and preferred implant material. However, due to their high degradation rates accompanied by hydrogen release up to now only few implant prototypes are about to come for orthopedic or cardiovascular applications. The major problem still remains as the decrease of the degradation rate to keep the stability of the implant and to reduce the ion release and H 2 production to a value the body can deal with (Poinern et al., 2012).
There are several approaches to tailor the degradation rate. The first method is the use of alloying elements such as rare earth elements (Witte, 2010), Ca, Y, Ag (Li et al., 2008). Accompanied by heat treatments or for example extrusion processes which change the microstructure and thus the mechanical and corrosive properties. If this is still not enough then the surface coatings come into play. The principle idea behind this method is to reduce the immediate corrosion to a level the body can cope with directly after implantation. Over time the coating should also degrade offering the possibility for the underlying Mg material to have access to the surrounding liquid which will then start the degradation process of the metal. In literatures there are several approaches that can be found (Arciola et al., 2012; Glinel et al., 2012; Yang et al., 2013). The most often used coating is based on calcium phosphates (Yang et al., 2009). This is relatively straight forward because a material which is also found in the inorganic matrix of the bone is used as coating. In addition under some particular circumstances it is already a corrosion product of the degrading Mg material. The application of CaP coatings not only changes the surface chemistry and can be influenced by the presence of chloride salts and proteins (Yang et al., 2009). To improve the performance of the CaP coatings also composites with degradable polymers were prepared. Degradable (bio) polymers as such are also a useful approach to increase the resistance of the Mg material against corrosion. They not only hinder the immediate corrosion but also can influence the long-term behavior of the specimens. In addition these layers can be chemically modified to introduce specific properties or can be used as drug delivery systems. A promising alternative to relatively thick polymer coatings can be the covalent binding of proteins to activated Magnesium alloy surfaces (Kannan and Raman, 2008). The most straight forward approach however is to make use of the naturally formed protective layer which is found after some immersion time. The formation of this biomimetic coating was studied in several experiments.
Mg specimens were soaked at optimal conditions of temperature and incubation time, in growth medium under cell culture conditions (Kraus et al., 2012). Apatite, and in particular hydroxyapatite (Ca (PO 4 ) 6 (OH) 2 , HA), has been widely used as the coating of bone implant materials because of its excellent biocompatibility, nontoxicity, bone in stability, bioactivity and ductility. Many surface coating techniques were developed to mitigate corrosion by separating the metal surface from its surroundings or incorporation of corrosion inhibiting chemicals. The chemical immersion method is an originally developed existing technique, which is suitable for preparing apatite coating on substrates of multiple materials and various shapes (Chu, 2013). Thus, the surface modiﬁcation of Mg material via formation of apatite coating on Mg alloy substrate offers great potential as absorbable bone implant materials (Mavrogenis et al., 2009).
Biomaterial science has greatly progressed in the achievement of a safe biocompatibility of implant materials, free from damage to neighboring tissues. However one of the major drawbacks to implanted devices remains the possibility of bacterial adhesion to biomaterials, which causes biomaterial related infection. And indeed, implanted biomaterials are still known to be particularly susceptible to microbial colonization and able of favoring the onset of infections. Therefore, the search for biomaterials those are able to provide the optimal resistance to infection can be based only on the deep understanding of the interactions between bacteria and biomaterials. Orthopedic implant-associated infections are of great important serious complications in orthopedic surgery and a major cause of implant failure. The risk of infection is anyway common to most medical ﬁelds, whenever biomaterials are used to restore organ functions. Greater are the implications for life supporting devices, which, in case of infection, cannot be removed or else their substitution can expose the patient to a higher risk of mortality. Bacterial colonization and biofilm formation are particularly problematic due to the ability of sessile bacteria to withstand host immune responses and are highly resistant to biocides, antibiotics and hydrodynamic shear forces than their planktonic counterparts (Glinel et al., 2012). The biofilm presence and the poor vascularization of the implant bone interface makes infections extremely difficult to treat. Increasing use of orthopedic devices the number of infected implants also increases. Therefore it is very important to reduce these infections via progressing in operating standards, minimizing the possibility of contamination during surgery and through other essential precautions. Physiochemical modifications of implant surfaces, anti-adhesive and antimicrobial coatings and drug-eluting composite coatings are some ways to inhibit the bacterial adhesion (Ordikhani et al., 2014). The most common pathogens causing infection are the Gram-positive Staphylococcus aureus and Staphylococcus epidermidis, found at the site of approximately 90% of all implants. Chitosan-vanomycin composite coatings have been explored as a drug delivery system to prevent bone implant infections (Yang et al., 2013).
The infecting organisms are either introduced during implantation of prosthesis or derived from a temporary bacteremia. Then, they adhere to biomaterials and grow to form a bioﬁlm. Despite the many possible deﬁnitions, bacterial bioﬁlms can simply be described as a structured consortium of bacteria encased in a self-produced matrix. Depending on bacterial species, strain type and environmental conditions, the bioﬁlm matrix consists of substances of various chemical natures such as exopolysaccharides, proteins, teichoic acids and extracellular DNA (eDNA). Bacterial bioﬁlms are able to resist antibiotics, disinfectants, phagocytosis and other components of the innate and adaptive immune and inﬂammatory defence system of the host (Stewart and Costerton, 2001; Arciola et al., 2005).
The complex mechanisms required to form a functional, mature staphylococcal bioﬁlm are still under investigation. However, based on in vitro experimental models, bioﬁlm formation is classically viewed as a four-step process: 1) initial attachment of bacterial cells; 2) cell aggregation and accumulation in multiple cell layers; 3) bioﬁlm maturation and 4) detachment of cells from the bioﬁlm into a planktonic state to initiate a new cycle of bioﬁlm formation elsewhere (Costerton et al., 2005).
The role of biomaterial science in reducing biofilm-related infections
Infection-resistant materials can be constructed by various approaches. Some of the most experimented methods include: ﬁnishing biomaterial surfaces with repellent coatings, antimicrobials, surfactants, hydroxyapatites, or with some selected biological molecules. Modiﬁcation of the biomaterial surface to give anti-adhesive properties, doping the material with antimicrobial substances and combining anti-adhesive and antimicrobial effects in the same coating are all some of the currently employed techniques (Arciola et al., 2012). Furthermore, in orthopedics another requirement to be reached is the realization of a material able to oppose bioﬁlm formation and, at the same time, to support bone repair. Among recent researches for new biomaterials having intrinsic antibacterial properties, able to hamper the formation of a bioﬁlm, new quaternised chitosan derivatives appear promising (Arciola et al., 2012).
The identiﬁcation of the bioﬁlm components PIA (Polysaccharide Intercellular Adhesin), extracellular DNA and proteins, the possibility to manipulate the agr system (genes (agrA, agrC, agrD, and agrB)) and thus to modulate bioﬁlm expression are the bases for novel antibioﬁlm strategies. Immunological approaches blocking early bacterial adhesion and colonization, applications of enzymes able to interfere with the bioﬁlm synthesis or able to disrupt formed bioﬁlms, exploiting of quorum sensing inhibitors: all may prove to be useful in preventing or treating the infections that compromise the success of medical devices. The use of materials coated with immobilized antibacterial substances, particularly cationic antimicrobial peptides, appears very innovative and promising. Nanotechnologies and nanomaterials in medical research have created new therapeutic horizons and are rapidly growing (Arciola et al., 2012).
The current review shows that signiﬁcant progress has been made over the last 20 years in both the development of Mg-based alloys, the characterization of in vitro and in vivo performances of possible ''smart implants'' and their implant infection possibilities. The design criteria for the next generation implants require the materials to provide appropriate mechanical properties, suitable corrosion, infection resistance and excellent biocompatibility, and to be bioactive in the human body. To achieve these benchmarks, the solution is to develop the next generation of Mg-based alloys with superior performance. Mechanical and corrosive performances strongly depend on the microstructure of the alloys, which result from alloy design, element selection, processing history, heat treatment and amount of impurities. Mg based alloys exhibit the highest strength and ductility, the best corrosion resistance and great biosafety in the form of both stents and screws.
Future works need to focus on the development of more improved properties in Mg-based alloys using various strategies, including alloying, impurity control, processing and coating; and also development of functional Mg-based alloys by alloying with elements that are functional in the human body, such as Ca, Zr, Sn and Sr. It will be more good to reveal the biological degradation at the interface between implants and surrounding tissues; and develop novel porous magnesium scaffolds, magnesium matrix composites and bulk metallic glasses, hybrid materials, like Mg-based alloys coated with polymers or functional ceramics, to meet diverse implant requirements, to perform as a drug delivery system, or to have cell- and tissue-speciﬁc properties.
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