Effect of Barium incorporation into Biomaterials: History
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Subjects: Materials Science, Biomaterials
Contributor:
Dagnija Loca

In the present manuscript, a brief overview on barium, its possible utilization, and the
aftermath of its behavior in organisms has been presented. A number of studies have exhibited
both the unwanted outcome barium displayed and the advantages of barium laden compounds,
tested in in vitro and in vivo settings. The plethora of prospective manipulations covered the area
of hydrogels and calcium phosphates, with an end goal of examining barium’s future in the tissue
engineering. Can barium be used as a substitute for other biologically relevant divalent cations? Will the incorporation of barium ions hamper the execution of the essential processes in the organism? Most importantly, can the benefits outweigh the harm?

  • barium
  • biomaterials
  • hydrogels
  • physiology
  • bone tissue regeneration
  • calcium phosphate
  1. Introduction

Scaffolds used in the bone tissue engineering have been under a continuous scrutiny. Establishing an ideal construct that corresponds to the set goals of biocompatibility, biodegradability, promotion of bone regeneration, while at the same time mimicking the distinctive properties of natural bone, has proven to be strenuous [1]. One of the constituents that have taken the spotlight of being the most promising ones are calcium phosphates (CaPs). The spectra of calcium phosphates encompasses twelve CaPs, with the Ca/P molar ratio ranging from 0.5 to 2.0 [2–4]. Particular relevance goes into the fact that they represent the inorganic part of bone and teeth[2], which is why they are closely mentioned with the process of biomineralization.  “Biomineralization can be described as a phenomenon in which a mineral is integrated as a functional and often structural part of living organisms, often in direct and close contact to a matrix forming protein or carbohydrate structure” [5]. As a part of the bone, apatite is presumably formed from the non-stoichiometric and ion-doped CaPs, originating from amorphous form [2,6–8]. In a detailed in situ investigation, Habraken et al. [8] described the process starting from the generated pre-nucleation complexes, called Posner’s clusters, which essentially are calcium triphosphate ion-association complexes. Subsequent stage covered nucleation of amorphous calcium phosphate (ACP), with a following conversion to octacalcium phosphate (OCP), through a continuous binding of calcium ions (Ca2+). The postulated mechanism ends with the formation of apatite, embodying the calcium triphosphate complex as its fundamental structural unit. Well established crystal structure of CaPs, included within the ternary system Ca(OH)2-H3PO4-H2O, enables the transitions from one form to another (e.g. layer-by-Iayer growth mechanism of HAp through OCP), as well as numerous incorporations [9]. Functionalization of CaPs with miscellaneous ions has proven to be beneficial in diverse stages of bone regeneration processes (Figure 1). Up until now, multiple ions have been used to steer the pathways of complex mechanisms transpiring in the body. These ions range from vanadium (V5+), niobium (Nb5+), boron (B3+), gallium (Ga3+), iron (Fe3+), to calcium (Ca2+), cobalt (Co2+), copper(II) (Cu2+), magnesium (Mg2+), strontium (Sr2+), zinc (Zn2+), lithium (Li+), silver (Ag+), fluoride (F-), bromide (Br-), chloride (Cl-), hydroxyl (OH-), hydrogen phosphate (HPO42−), carbonate (CO32-), phosphate (PO43-) and silicate (Si4-)[10–17]. Cationic substitutions of CaP, e.g. HAp generalized through a formula M10(XO4)6Y2, where M is typically a bivalent cation, can occur with a complete or partial replacement of Ca2+[16]. Depending on an ionic radius and concentration, these substitutions can either stabilize the structure or destabilize the lattice [18,19].

Figure 1. Effect different ions display in bone regeneration processes. Obtained from the reference [13]

 

Furthermore, ions have not only been used to ameliorate the structure, morphology and the effect CaPs have, but they have been used also as crosslinking agents for the hydrogels [20]. Hydrogels represent three dimensional hydrophilic polymer network with high affinity toward the water. Depending on their crosslinking approach (chemical or physical), properties like reduced dissolution, or distinctive mechanical and biochemical properties, with various functions (e.g. incorporation of 0.61 wt% of Zn2+ in HAp resulted in the extension of their lag time increasing its antibacterial potential) can materialize [24]. One of the physical approaches of hydrogel crosslinking is with ionic/electrostatic interactions (more information in section 3.1) [21]. Even though large spectra of studies have examined the influence of bivalent cations such as Mg2+[22], Sr2+ [23]and Zn2+[24], there is a scarcity of information regarding the effect of one more alkaline earth metal – barium (Ba2+). Barium’s participation in bone repair and regeneration has placed it in the forefront of recent interest. In nature, barium does not occur in its free ionic form, but as a number of natural salt compounds e.g., barite (BaSO4) or barium chloride (BaCl2) [25]. Barium compounds that are relatively soluble in water are acetate, nitrate, and halides (except fluoride), while compounds with carbonate, chromate, fluoride, oxalate, phosphate, and sulphate are fairly insoluble in water (Table 1) [26]. Bearing the benefits of the ion incorporation in mind, a question arises – why has not the influence of barium on CaPs and their composites been examined more in depth?

  1. Barium comprising biomaterials and their biological performance

Despite the fact that barium, as a divalent cation, has a vast potential to be utilized in combination with biologically relevant biomaterials, the mechanism of apposition or the outcome of possible effects is insufficiently researched. Detailed review of literature has pointed out that when Ba2+ was combined with pertinent polymers (e.g. alginate or hyaluronic acid), it elucidated promising results. Considerably smaller number of studies has underlined the ramifications of the Ba2+ – CaP fusion. Nevertheless, positive data regarding mechanical properties and biocompatibility has been presented.

3.1. Barium loaded hydrogels

Hydrogels are hydrophilic, polymer-based systems that absorb and preserve large amounts of water [54,55]. When making hydrogels, certain sort of a crosslink is formed, whether through chemical crosslinking (covalent or ionic bonds) or physical crosslinking (ionic forces or electrostatic forces). In addition, van der Waals forces and hydrogen bonds can also operate as crosslinks [56].

One of the ways physically crosslinked hydrogels can be synthesized is through the interplay of various ions at mild conditions (room temperature and physiological pH). A hydrogel with stronger properties will be achieved by using metallic ions due to the coordination stemming from Lewis acid–base interactions [54,55]. Commonly, the most explored hydrogels, crosslinked with metal ions, are the ones with coordination tethered by metal cations [57]. For that purpose, such cations as Fe3+, Ca2+, Sr2+ and Zn2+ are widely used. Barium ions have the ability to form salts with particularly low solubility in aqueous media. On this accord, several studies [58–63] have examined the effect of barium crosslinking on the overall properties of different polymers. As a divalent cation, Ba2+ usually forms ionic crosslinks, which transpire as a prerequisite of achieving electrical neutrality in the material [58]. Barium has the capability to establish two crosslinking mechanisms within the materials, already mentioned ionic crosslinks, and physical crosslinks[58]. Ionic are independent of temperature, while physically crosslinked materials are supposed to be temperature – dependent. Further distinction between these two mechanisms is that physically crosslinked materials are formed owing to ion–dipole associations of the BaSO4 groups, producing ionic aggregation i.e., ion-clusters. Ion-clusters secure versatile crosslinks constructed by nano-phase separation of ion-rich domains (1–5nm). In order to prove which crosslinking transpired, structural analysis is required.

In the study conducted by Gasa et al., barium was used on acidic polymer electrolyte membranes (PEM), based on sulfonated poly(ether ketone ketone) (SPEKK), so as to reduce the sorption of aqueous media and consequentially improve their mechanical properties and stability [58]. The crosslinking between sulphonate groups occurred by the exchange of barium ions with the protons in SPEKK membranes. Increase of the exchanged barium resulted in the decrease of equilibrium water sorption (17wt%). However, when the Ba2+ exchange was above 64%, the fluid uptake was practically independent of temperature and methanol activity in water-ethanol solutions. Nonetheless, if the percentage of exchanged cation was lower, the temperature dependence was visible (<45 ̊C weak dependence, >45 ̊C sharp upturn in the water sorption). The reason for this behavior is most likely the glass-to-rubbery state transition of the water-swollen SPEKK. Moreover, thermal stability was considerably improved in dry conditions. As it was mentioned before, size of the barium ions is substantial in comparison to others, hence they exhibit less mobility than the mobile protons that were interchanged. When combined with the partially deprotonated hyaluronic acid, barium (similar to other bivalent cations) results in the formation of chelate-like complexes, followed by an increasing degree of cross-linking within or between polymer chains [59]. The viscosity of the hyaluronate solution was substantially lowered with an increase of cation concentration, while the conformation was radically changed.

Conversely, the highest number of papers was associated with crosslinking of barium and alginate [60,62,64–68]. 

The “egg box model” is commonly used to describe the formation of alginate gels. The divalent ions interacted jointly with G blocks to form ionic bridges between adjoining chains [62,71].

Due to this specific binding and the size of the ion itself, barium crosslinked gel manifested lower swelling degree, thus, it was more stable in aqueous media [62]. In a study by Bajpai et al.[66,72], alginate formed beads were placed in a buffer medium with pH 7.4. Barium ions bounded to the carboxylic (COO-) groups, starting the process of exchange with sodium ions situated in the swelling medium. After the maximum swelling of the beads was achieved, barium ions in the egg-box junctions started to diffuse out and the beads began slowly disintegrating in a longer period of time owing to the ion size [66]. 

The paucity of information regarding the association of barium and different types of polymers, and their effect on biological performance can be credited to only several papers, dating back to 1990s [74–76]. However, even with promising results several of these groups obtained, no detailed work on further barium use was performed.

3.2. Synthesis of calcium phosphates containing barium

As a divalent cation, barium extends the possibility of being incorporated within different calcium phosphates. There have been few studies concerning the preparation of barium–calcium apatites [77–81]. Bigi et al., have tried to form barium–calcium hydroxyapatite (BaCaHAp) by a solid state reaction at 1200°C and by a precipitation method at 100°C [82]. The products obtained by the solid state reaction, at high temperatures, covered the array of barium concentrations from 0 to 100 atom%. By using that method, lattice dimensions and the FT-IR absorption frequencies displayed linear increase, following the increase of atom% of Ba2+. Only small quantities of Ba2+ were incorporated in HAp by precipitation from the aqueous system. Liu et al., synthesized calcium phosphate cement (CPC) powder with a mixture of α-tricalcium phosphate (α-TCP) and dicalcium phosphate dihydrate (DCPD) at the mass ratio of 9:1, with the addition of 20wt% starch and 20wt% BaSO4 [80]. Their aim was to look into the effects of BaSO4 on injectability and radiopacity, as well as the mechanical and biocompatibility properties of the CPC system. The compressive strength of the construct increased to over 50 MPa, with the injectability index higher than 90% (50 N at a constant injection speed of approximately 10 mm/min). In addition, the recorded radiopacity was high, while the setting times and biodegradation behaviour was satisfying. Moreover, in vitro tests on hemolysis, endotoxins and apoptosis, as well as subcutaneous implantation in vivo, demonstrated that the barium laden cement was nontoxic and biocompatible. In an another example of doping α-TCP with Ba2+ [83], stoichiometric amounts of ammonium dihydrogen phosphate (NH4H2PO4) and barium carbonate (BaCO3) were used with an end product of Ba-substituted α-TCP, (Ca1-xBax)3(PO4)2 (x = 0.05, 0.10, and 0.15). The results showed that the unit-cell volumes of the product were larger than that of undoped product (undoped a=12.87271 Å, b=27.28034 Å, c=15.21275 Å; doped a=13.0965 Å, b=27.9046 Å, c=15.4021 Å), which would suggest that the reactivity of barium doped α-TCP is higher. Yasukawa and his team synthesized carbonated BaCaHAp solid solution, with different Ba/(Ba + Ca) (XBa) atomic ratios (0-1), using the wet precipitation method, at 100oC [79]. Their results showed that no pure BaCaHAp was able to form, due to the irreversible adsorption amount of carbon dioxide (CO2). However, it should be noted that the information on substitution efficiency of barium was not mentioned in the study. Yoder et al., synthesized carbonated barium hydroxylapatite (CBaApOH) and carbonated barium chlorapatite (CBaApCl) by aqueous synthesis. The end goal was to define the mechanism of carbonate substitution at 60 or 90 °C, as before it was only preformed at solid state, high-temperature synthesis [78]. Their main conclusions were that the synthesis parameters had to be closely monitored to avoid the precipitation of simple salts (BaCO3, Ba3(PO4)2 and BaApCl), mainly because of their close molar solubilities. CBaApCl and CBaApOH demonstrated solubilities that are marginally higher than the solubilities of their noncarbonated analogs, at low carbonate concentrations.

  1. Biological influence of barium

Several studies have reported that barium laden materials provide a favourable environment for the cells and array of divergent functions [68]. The actual data collected on the overall biological influence of barium, incorporated in various calcium phosphates and hydrogels, is still scarce. 

Three independent studies have also underlined the role of barium incorporation as an ameliorating component for drug delivery systems [61,72,87]. 

  1. Barium toxicity

Even with a high potential of being a good substitute for commonly used metallic ions, barium has certain downsides. Knowing the current data available, and the fact that barium is known to be toxic, approach to using barium as a crosslinking agent is still used with precaution [26,44,50]. Causes for individuals sensitivity to barium toxicity, as well as its role on epigenetic factors, are correlated with specific geographic/geological areas, and the distributed information are quite limited [25]. In order to avoid these ramifications, extensive studies with different approaches are needed. For example, studies on leakage of alginate gels, crosslinked with Ba2+ ions, have shown that when using low concentrations and vigorous rinsing of barium beads, there is no leakage of the ion, hence no repercussions [64,88].

  1. Future directions and conclusions

Albeit being one of the metallic ions, with all the characteristics ascribed to them (ionic radii, solubility, oxidation number etc.), barium has not gone the comprehensive and diverse research. Most of the findings and knowhow on barium have their origin in the second half of the 20th century, with scarce follow up in the recent years.

In the previous sections, we presented a brief outlook on barium itself, its integration within hydrogels and its potential to be merged with biologically relevant calcium phosphates (Figure 6). Biological influence and toxicity assessment has put barium in the shadow of the other important ions such as calcium, strontium and zinc. Several sources have underlined the negative side of barium in the organism – potential toxicity, blocking of potassium channels, lowering of cell viability etc. However, the positive results should not be merely side-lined. Crosslinking of barium and polymers resulted in stronger matrix, lower swelling degree, tighter formation and higher water resistance. As for the biological ramifications, islets embedded in microcapsules containing barium were able to reverse diabetes for almost a year. Furthermore, the cell lines CCL-13 and L929 grew rapidly and reached confluence after three days on barium crosslinked matrix. Once barium was combined with calcium phosphates, such as HAp and α-TCP, obtained cements exhibited nontoxicity and biocompatibility, with faster setting time. Moreover, in a separate study using akermanite as a starting point, the increase of Ba2+ ratio increased the ability to form apatite.

Figure 6. Brief overview of effects recorded in presence of barium ions in in vitro and in vivo setting. Figure created in BioRender.com

Bearing all the information in mind, it must be emphasized that the toxic effects were for oral or intravenous administration of barium containing matrices. Consequently, the limited research on local barium influence on cells or antimicrobial properties should be further explored, as the shown potential and possibly much lower administrated dose rate are one of the important factors. Added deduction that stemmed from the thorough literature search is that the studies performed on barium incorporation, effects and influence, are outdated. A fresh outlook on the overall behaviour of barium and barium loaded compounds is of vital importance. Use of the state-of-the-art equipment and newly established methodologies will yield new discoveries and help to clarify the potential benefits that barium has to offer in the field of bone tissue regeneration and possibly propel barium in the forefront of science.

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This entry is adapted from the peer-reviewed paper 10.3390/ma14195772

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