Optimized osteogenesis of biological hydroxyapatite-based bone grafting materials by ion doping and osteoimmunomodulation

Abstract

BACKGROUND:

Biological hydroxyapatite (BHA)-based bone grafting materials have been widely used for bone regeneration in implant surgery. Much effort has been made in the improvement of their osteogenic property as it remains unsatisfactory for clinical use. Osteoimmunomodulation plays a significant role in bone regeneration, which is highly related to active inorganic ions. Therefore, attempts have been made to obtain osteoimmunomodulatory BHA-based bone grafting materials with optimized osteogenic property by ion doping.

OBJECTIVE:

To summarize and discuss the active inorganic ions doped into BHA and their effects on BHA-based bone grafting materials.

METHOD:

A literature search was performed in databases including Google Scholar, Web of Science and PubMed, with the elementary keywords of “ion doped” and “biological hydroxyapatite”, as well as several supplementary keywords. All document types were included in this search. The searching period and language were not limited and kept updated to 2022.

RESULTS:

A total of 32 articles were finally included, of which 32 discussed the physiochemical properties of BHA-based biomaterials, while 12 investigated their biological features in vitro, and only three examined their biological performance in vivo. Various ions were doped into BHA, including fluoride, zinc, magnesium and lithium. Such ions improved the biological performance of BHA-based biomaterials, which was attributed to their osteoimmunomodulatory effect.

CONCLUSION:

The doping of active inorganic ions is a reliable strategy to endow BHA-based biomaterials with osteoimmunomodulatory property and promote bone regeneration. Further studies are still in need to explore more ions and their effects in the crosstalk between the skeletal and immune systems.

Keywords

Ion doping bone regeneration osteoimmunomodulation biological hydroxyapatite bone grafting materials

1. Introduction

Bone defect caused by trauma, disease, surgery, and congenital malformations remains a major health problem worldwide [1]. Currently, the common approaches for the rehabilitation of bone defect depend on the use of either autologous bone or bone substitutes, such as allogenic and xenogeneic bone grafts as well as synthetic materials [1–3]. In implant surgery, biological hydroxyapatite (BHA) has been the most widely used xenogeneic grafting material for bone regeneration for years. However, its osteogenic property remains unsatisfactory and further improvement is of utmost importance. Recently, osteoimmunomodulation has become an attractive new strategy for developing advanced bone grafting materials. It emphasizes that biomaterials should be endowed with immunomodulatory capacity to modulate the local immune environment so as to favor the osteogenesis and osseointegration of implants [4]. It is also found that active inorganic ions are highly involved in osteoimmunomodulation. Therefore, as a safe, effective and cost-saving approach, the doping of various kinds of inorganic ions into BHA has been tried, with the attempt of enhancing its osteogenic property.

For a comprehensive understanding of the research status of ion doped BHA, literature searches have been done in databases including Google Scholar, Web of Science and PubMed, with the elementary keywords of “ion doped” and “biogenic hydroxyapatite”, and several supplementary keywords, including “ion doping”, “ion incorporated”, “ionic incorporation” and “biological apatite”, “biological hydroxyapatite”, “bovine bone” and “porcine bone”. All document types were included in the searches, and the searching period and language were not limited. A total of 1346 articles were found, out of which 121 related articles were filtered further based on their titles and abstracts. Finally, 32 articles focusing on ion-doped biological hydroxyapatite as xenogeneic bone grafting materials (or biomaterials in medication) were included, in which different aspects of BHA were investigated (32 for physiochemical properties, 12 for biological features in vitro and three for biological performance in vivo) (Table 1).

Table 1
Research progress of ion-doped biological hydroxyapatite

Origins Year Authors Materials Ion doping Properties

Type Ions Compounds Physiochemical In vitro In vivo

Bovine 2007 Oktar et al. HA scaffold Multiple Ti, Li Ti₂O, Li₂O Mechanical — —

Bovine 2007 Oktar et al. HA Multiple Si, Mg, Al, Zr SiO₂, MgO, Al₂O₃, ZrO₂ Mechanical — —

Bovine 2008 Gunduz et al. HA Single Zn ZnO Mechanical — —

Bovine 2012 Gunduz et al. HA Multiple B, Si, Ti, F B₂O₃, SiO₂ , P₂O₅, CaF₂ Mechanical — —

Bovine 2013 Duta et al. HA thin films Multiple Li, Al, Mg, Si Li₂O, CaO, Al₂O₃, MgO Mechanical — —

Bovine 2014 Gunduz et al. HA Single Ce CeO₂ Mechanical — —

Bovine 2015 Karamian et al. HA Multiple F, Zr CaF₂ , ZrSiO₄ Mechanical — —

Bovine 2016 Mihailescu et al. HA coatings Single Mg MgF₂, MgO Mechanical HEp-2 cells, antimicrobial —

Bovine 2017 Yetmez et al. HA Multiple Al, Si Mullite (Al₂O₃, SiO₂) Mechanical — —

Bovine 2018 Popescu et al. HA coatings Single Li Li₂CO₃, Li₃PO₄ Mechanical hMSC cells —

Bovine 2019 Chioibasu et al. HA thin films — — — Mechanical SaOs-2 cells —

Bovine 2020 Duta et al. HA coatings on implants — Li Li₂CO₃, Li₃PO₄ Mechanical — —

Bovine 2021 Sengor et al. HA Multiple Mg, F MgF₂ Mechanical — —

Bovine 2021 Sin et al. HA Single Zn ZnO Mechanical Antimicrobial —

Origins	Year	Authors	Materials	Ion doping	Properties
Bovine	2007	Oktar et al.	HA scaffold	Multiple	Ti, Li	Ti₂O, Li₂O	Mechanical	—	—
Bovine	2007	Oktar et al.	HA	Multiple	Si, Mg, Al, Zr	SiO₂, MgO, Al₂O₃, ZrO₂	Mechanical	—	—
Bovine	2008	Gunduz et al.	HA	Single	Zn	ZnO	Mechanical	—	—
Bovine	2012	Gunduz et al.	HA	Multiple	B, Si, Ti, F	B₂O₃, SiO₂ , P₂O₅, CaF₂	Mechanical	—	—
Bovine	2013	Duta et al.	HA thin films	Multiple	Li, Al, Mg, Si	Li₂O, CaO, Al₂O₃, MgO	Mechanical	—	—
Bovine	2014	Gunduz et al.	HA	Single	Ce	CeO₂	Mechanical	—	—
Bovine	2015	Karamian et al.	HA	Multiple	F, Zr	CaF₂ , ZrSiO₄	Mechanical	—	—
Bovine	2016	Mihailescu et al.	HA coatings	Single	Mg	MgF₂, MgO	Mechanical	HEp-2 cells, antimicrobial	—
Bovine	2017	Yetmez et al.	HA	Multiple	Al, Si	Mullite (Al₂O₃, SiO₂)	Mechanical	—	—
Bovine	2018	Popescu et al.	HA coatings	Single	Li	Li₂CO₃, Li₃PO₄	Mechanical	hMSC cells	—
Bovine	2019	Chioibasu et al.	HA thin films	—	—	—	Mechanical	SaOs-2 cells	—
Bovine	2020	Duta et al.	HA coatings on implants	—	Li	Li₂CO₃, Li₃PO₄	Mechanical	—	—
Bovine	2021	Sengor et al.	HA	Multiple	Mg, F	MgF₂	Mechanical	—	—
Bovine	2021	Sin et al.	HA	Single	Zn	ZnO	Mechanical	Antimicrobial	—

Table A

Origins	Year	Authors	Materials	Ion doping			Properties
				Type	Ions	Compounds	Physiochemical	In vitro	In vivo
Porcine	2012	Liu et al.	HA	Single	F	NaF	Chemical, mechanical	—	—
Porcine	2015	Li et al.	HA	Single	F	NaF	Mechanical	MG63 cells, osteogenesis	—
Porcine	2017	Qiao et al.	HA	Single	F	NaF	Mechanical	MG63 cells, attachment, protein adsorption	—
Porcine	2018	Liu et al.	HA	Single	F	NaF	Mechanical	rBMSC cells, osteogenesis	SD rats
Porcine	2018	Qiao et al.	HA	Single	F	NaF	Mechanical	rBMSC cells, osteogenesis, Wnt/β-catenin signaling pathway	SD rats, micro-CT
Porcine	2019	Wu et al.	HA	Single	F	NaF	Mechanical	rBMSC, Raw 264.7 and HUVEC cells, osteogenesis, angiogenesis, osteoimmunomodulation	SD rats, micro-CT, H&E staining
Porcine	2020	Lin et al.	HA	Single	Co	CoCl₂	Mechanical	—
Teeth	2013	Kim et al.	Tooth-derived bone grafting material	—	—	—	—	-	(Clinical case report)
Fish, grouper, frogs, pigeons, rats	2015	Liu et al.	Apatite	Single	F	NaF	Chemical, mechanical	—	—

Table B

Origins	Year	Authors	Materials	Ion doping			Properties
				Type	Ions	Compounds	Physiochemical	In vitro	In vivo
Turkey femur bone	2019	Esmaeilkhanian et al.	HA	—	—	—	Temperature-dependent mechanical, chemical	—	—
Food industry bio-wastes	2020	Bee et al.	HA	—	—	—	Mechanical	—	—
Sea urchin spines	2020	Gómez Vázquez et al.	HA	—	—	—	Mechanical	—	—
Equine	2021	Lee et al.	HA scaffold	—	—	—	Mechanical	NIH-3T3 cells, osteogenesis	—
Pigeon	2021	Sharifianjazi et al.	HA	—	—	—	Mechanical	UMR-106 cells, ALP activity	—
Crocodile eggshell	2021	Auniq et al.	HA	Single	F	NaF	Mechanical	—	—
Eggshell, cuttlefish bones, mussel shells	2021	Cestari et al.	HA	—	—	—	Mechanical	—	—
Eggshell	2021	Mardziah et al.	HA	Single	Zn	Zn(NO₃)₂	Mechanical	—	—
Cockle shell	2021	Citradewi et al.	HA	Single	Ag	Silver nanoparticle	Mechanical	Antimicrobial	—
Total							32	12	3

2. BHA

BHA is a carbonated, non-stoichiometric Ca-deficient hydroxyapatite, which is different from synthetic hydroxyapatite (HA) in composition, stoichiometry, crystal size, morphology, crystallinity degree, degradation rate, and overall biological performance [5–7]. It is usually extracted from biological sources or wastes [8–15] (Table 2).

Table 2
Origins of biological hydroxyapatite

Categories Origins

Mammalian bones and teeth Bovine, porcine, camel, horse and turkey bones

Marine or aquatic sources Sea urchin spine, fish bone and scale

Shell Cockle, clam, eggshell and seashell

Mineral Limestone

Others Plants and algae

Categories	Origins
Mammalian bones and teeth	Bovine, porcine, camel, horse and turkey bones
Marine or aquatic sources	Sea urchin spine, fish bone and scale
Shell	Cockle, clam, eggshell and seashell
Mineral	Limestone
Others	Plants and algae

Yet, as a xenogeneic bone graft, the clinical performance of BHA is not satisfactory due to the lack of osteoinductivity [16,17]. Therefore, many attempts have been made to incorporate bioactive factors into BHA to make it osteoinductive [18–24]. Since 1991, initial histological evidence and further proof in vivo have indicated that, optimizing the physicochemical properties of biomaterials could endow them with osteoinductive ability rather than delivering proteins or cells [25–27]. Represented by trace elements and ion doping, the delivery of inorganic factors could not only optimize the properties of target materials, but also show lower cost and easier storage, compared with the incorporation of organic factors such as drugs, fibrins, cytokines, growth factors, etc. [17,28–30]. The existence of these incorporated ions may affect the crystallization, mechanical properties, degradation, and biological activity of BHA, and consequently affect its physiological function in vivo, such as the development of teeth and bone, whereas their absence could lead to bone loss or fragility [5]. Such naturally incorporated ions in BAH indicate the feasibility of foreign ion doping due to the tolerance of its crystal lattice. In BHA, OH⁻ can be easily replaced by a small amount of F⁻ and CO₃ ²⁻, while Ca²⁺ can be replaced by Sr²⁺, Mg²⁺ and Zn²⁺ [31–33]. The domino effect imposed on the finest levels of BHA structure by doping with foreign ions is to illustrate the potential of this approach to affect a number of microstructural parameters and, thus, properties exhibited by the material [34–39].

3. Osteoimmunomodulation

According to osteoimmunomodulation, bone regeneration is a complex dynamic remodeling process which depends on both the biological behavior of osteoblastic lineage and the coordination and regulation of immune and cardiovascular systems. As the representative immune cell in bone regeneration, macrophage has been found to be involved in the regulation of bone homeostasis. Its biological functions are heavily influenced by inorganic ions through some molecular signaling pathways, including but not limited to the toll-like receptors (TLRs), the mitogen-activated protein kinase (MAPK), the Wnt and the transient receptor potential cation channel member 7 (TRPM7), as well as the downstream signaling pathways intranuclear like nuclear factor-kappa B (NF-κB) (Fig. 1).

Fig. 1.

Potential molecular mechanism of osteoimmunomodulation caused by ion incorporation. Immune cells, especially macrophages, play a key role in bone homeostasis. Bioactive ions are closely related to both the bone remodeling process and the immune system. There are several bioactive ions related molecular signaling pathways that tightly link the bone regeneration process with the immune system.

In mammals, TLRs family are expressed on antigen presenting cells such as dendritic cells and macrophages, serving as key pattern recognition receptors (PRR) with central roles to sense diverse pathogen-associated molecular patterns (PAMPs) [40]. TLRs normally react to foreign implants and further stimulate the expression of inflammatory cytokine genes. However, some specific bioactive ions such as Zn²⁺ and Mg²⁺ could inhibit the expression of TLRs signaling pathway instead [41,42].

Consisting of famous ERK, JNK and p38 kinase families, MAPK cascades play a crucial role in the transduction of extracellular signals to cellular responses, the reaction to oxidation stress and inflammation stimulation [43]. By regulating the secretion of inflammatory factors, bioactive ions like Mg²⁺ could indirectly affect MAPK signaling pathway to further control the proliferation, differentiation and apoptosis of osteo lineage [44].

Wnt proteins constitute a large family of cysteine-rich secreted glycoproteins, which could activate at least three different signaling pathways: the canonical pathway, the planar cell polarity pathway, and the Wnt/Ca²⁺ pathway [45]. Bioactive ions such as F⁻ and Mg²⁺ are related to the expression of canonical Wnt/β-catenin signaling, which can affect the entire osteoblastic lineage to control the bone remodeling process further [46,47].

TRPM7 is one of the non-selective cation TRP channels, which mainly controls the influx of Ca²⁺ and Mg²⁺. Located in the surface of macrophages and bone mesenchymal cells, TRPM7 senses mechanical stimulation and mediates cations influx to regulate inflammation reaction and bone regeneration consequently [48,49].

NF-κB is a transcription factor found in all nucleated cell types. It is a vital component of the molecular processes such as the development and activation of immune cells, inflammatory responses, and osteoclast differentiation. It was reported that F⁻ and Mg²⁺ could affect the expression of NF-κB signaling pathway both in macrophage and bone lineage, to regulate inflammation and bone remodeling, respectively. [49,50]. Currently, NF-κB signaling pathway is the most evident intranuclear signaling pathway in osteoimmunomodulation.

Based upon the literature, for every single ion, its effect on the osteoimmunomodulation of macrophages may involve more than one signaling pathway mentioned above, either fully or partially. Besides, some parts of signaling pathways remain unclear. Therefore, more work is needed to clarify the underlying mechanism of active ion-doping caused osteoimmunomodulation.

4. Ions doped into BHA

4.1. Fluoride

Fluoride (F) is one of the vital trace nutrient elements for human health. Through thermal treatment with hydrofluoric acid, F⁻ was doped into BHA from bovine bone, resulting in several crystal structural changes including increased crystallinity and decreased crystal size [51]. F⁻ could substitute CO₃ ²⁻ in the HA crystal lattice to make it more resistant to acid [52]. Further investigation has proven that, the doping of F⁻ may not only promote the crystallization of BHA (Fig. 2, [53]), but also enhance its osteogenic capacity in vitro and in vivo in a concentration-dependent manner [46,50,53–57].

Fig. 2.

The change of hydroxyapatite crystal structure by fluoride incorporation. SEM images: (a, b) FPHA (test group, F⁻: 1.0 mol/L, immersion period: 24 h, heat treatment); (c, d) PHA (heat treatment); (e, f) PHA (blank control) under 500× and 20,000× magnifications. Reproduced from ref. [53] with permission from The Japanese Society for Dental Materials and Devices, copyright 2012.

In previous studies, fluoride doped porcine bone (F-PHA) was prepared successfully by immersing PHA in sodium fluoride solution (NaF) with gradient concentrations and subsequent thermal treatment [50,53]. It was found that structural and functional changes of PHA were caused by the doping of F⁻. Specifically, the spheroid-like crystals of PHA were changed into rod-like after F⁻ doping, resulting in F⁻ concentration-dependent increased compressive strength, as well as decreased porosity and solubility [56]. In addition, it has also been found that F⁻ could enhance the synthesis of bone-associated glycoproteins in bone mesenchymal stem cells (BMSCs), thereby promoting cell adhesion, protein adsorption and ALP activity, leading to the increase of mineral deposition in vitro [46,57].

Also, such effects were dose-dependent with F⁻ [50 ]. In the low concentration (0.24–24 μM) of F⁻, in vivo vascularized bone formation can be achieved via finetuning the F⁻ concentration, while the peak osteogenic effect was found at 2.4–24 μM [50]. On the basis of previous finding, animal experiments in SD rats and beagle dogs have been carried out to investigate the performance of F-PHA in bone augmentation [58]. 12 weeks later, the F-PHA groups showed a significantly higher alveolar ridge width than the PHA group on the macroscopic level [58]. Histologically, it was observed that F-PHA particles were surrounded by newly formed bone, where the proportion of non-mineralized tissue was significantly lower than that in the PHA group [58].

Further investigation revealed the molecular mechanism of F-PHA in osteoimmunomodulation. On the one hand, osteogenic activities of F-PHA may be associated with the activation of canonical Wnt/β-catenin signaling pathway, as well as the inhibition of receptor activator of nuclear factor-κB ligand/osteoprotegerin (RANKL/OPG) signaling pathway [46]. Moreover, F⁻ was found to elicit a significant osteoimmunomodulatory effect in the modulation of inflammatory cytokines, and the expression of osteogenic factors such as BMP2, OSM, spermine and spermidine, as well as angiogenic factors including VEGF and IGF-1 during the early response [50], leading to more new bone formation in vivo [46] (Fig. 3).

Fig. 3.

Fluoride incorporation leading to new bone formation in vivo. (a) The 5 mm diameter calvarial defects in rats grafted with pBAp (left) and F-pBAp (right). (b) Representative SEM image showing the grafted xenograft granules (scale bar = 300 μm). (c) Representative reconstructed micro-CT images (scale bar = 1 mm) showing bone growth (blue) around the grafted materials (white), as well as the H&E staining histology showing the ingrowth of bone tissues (low magnification: scale bar = 100 μm; high magnification: scale bar = 1 mm; G: grafted materials; NB: new bone). (d) Young’s moduli of newly formed bone round grafted pBAp or F-pBAp at week 12 (significant difference between groups was indicated as ^∗ P < 0.05). (e) Quantification of the bone volume (BV)/total volume (TV) of the calvarial defect area grafted with pBAp or F-pBAp at week six and week 12 (significant difference between groups was indicated as ^∗ P < 0.05). (f) Representative Goldner’s trichrome staining of the grafted areas at week six and week 12 showing the growth of new bone around the grafted materials (scale bar = 100 μm). (g) Representative TRAP staining showing osteoclastogenesis around the grafted pBAp and F-pBAp (scale bar = 100 μm). (h) Representative Goldner’s trichrome staining of the undecalcified tissue confirming the direct contact between the new bone and the grafted materials (scale bar = 100 μm). (i) Fluorescent IHC images showing the activation of β-catenin around the grafted materials (scale bar =200 μm). Reproduced from ref. [46] with permission from the Royal Society of Chemistry, copyright 2018.

On the other hand, F⁻ participated in immune response and inflammation regulation in a dose-dependent manner. In detail, the low concentration of F⁻ promoted the polarization of macrophages to the M2 phenotype by increasing the expression of IκB-𝛼 (NF-κB inhibitor 𝛼) to inhibit nuclear factor kappa light chain enhancer of NF-κB signaling pathway [50]. This was demonstrated by the increased expression of cellular surface markers including arginase and CD11c, as well as the decreased expression of CCR7 and iNOS [50]. Whereas, the high concentration of F⁻ over 24 μM showed evident cytotoxicity, inducing the secretion of inflammation factors including IL-1β, TNF-𝛼, M-CSF, and stimulating RANKL/OPG signaling pathway to inhibit bone regeneration (Fig. 4) [50].

Fig. 4.

Effects of fluoride on bone regeneration and underlying mechanism. In BMSCs, F⁻ in the range of 0.24–2.4 μM could regulate the formation of vascularized bone in vivo [50]. The peak osteogenic effect of F⁻ was found at 2.4–24 μM, which may be associated with the activation of the canonical Wnt/rmβ-catenin signaling pathway, and the inhibition of RANKL/OPG signaling pathway [46]. During the early response, F⁻ increased the expression of osteogenic factors and angiogenic factors [50]. In macrophages, a low concentration of F⁻ promoted the polarization of macrophages to the M2 phenotype by stimulating NF-κB signaling pathway [50]. High concentrations of F⁻ over 24 μM started to show cytotoxicity, induced the secretion of inflammation factors, and stimulated RANKL/OPG signaling pathway to inhibit bone regeneration [50].

4.2. Zinc

The content of zinc (Zn) normally ranges between 0.012 and 0.025 wt.% in human bone, which is relatively higher than that in whole fat-free adult tissues and plasma [59]. Zn plays a crucial part in a variety of physiological functions, markedly being a co-factor in hundreds of enzymes involved in bone functions and metabolism [35,60].

It was previously reported that among the tested materials, BHA derived from bovine bone doped with 5% ZnO (Zn-BHA) showed the best mechanical properties [59,61,62]. The microstructure of 5% Zn-BHA comprised well-developed ZnO-like crystals dispersed on the surface and pores of the BHA matrix, which enhanced the microhardness of BHA [59]. It should be emphasized that ZnO did not increase the compressive strength of BHA but the hardness only [59]. Besides, the incorporation of ZnO seemed to narrow the sintering temperature range of BHA up to 1200 °C, when Zn-BHA exhibited the best densification behavior [59]. Once the sintering temperature further increased, Zn-BHA became vulnerable, and decomposition occurred.

Based on such structural optimization, Zn-BHA showed concentration-dependent bioactivity, antibacterial, anti-inflammatory and osteogenic abilities [63,64]. In addition, HA doped with less than 1% of Zn showed effective antibacterial properties, while the maximum inhibitory effect of 2% Zn on Gram-positive and Gram-negative bacteria was (50 ± 5)% and (77 ± 5)%, respectively [65,66]. The cytocompatibility of Zn²⁺ was often described as a non-toxic level [67]. In some situations, however, the toxicity was observed with Zn-HA and different Zn-based compounds as well, which was probably due to the mechanical damage caused by a sedimentation of Zn-HA particles over cell membranes [68,69]. Indeed, it was reported that Zn-HA which formed the largest particles with irregular shapes and hard edges, would induce the highest lethality due to the mechanical damage to cell membranes [68].

Moreover, it was found that Zn²⁺ could promote osteoblast proliferation and osteocalcin production, accelerate bone matrix maturation, and inhibit osteoclast activity [62]. The deficiency of Zn²⁺ in vivo could alter the number and function of neutrophil granulocytes, monocytes, natural killer-, T-, and B-cells [70]. The potential mechanism might be closely related to the effect of Zn²⁺ on osteoimmunomodulation, as Zn²⁺ homeostasis was tightly controlled by a transporter family called Zn signaling [70–72]. Besides, Zn²⁺ could increase the release of anti-inflammatory IL-10, and reduce the expression of TNF-𝛼 and IL-1β, which may be due to the regulation of TLR-4 signaling pathway [41,73,74] (Fig. 5), although the detailed molecular mechanism needs to be clarified further.

Fig. 5.

Effect of zinc on bone regeneration. Zn²⁺ homeostasis was tightly controlled by Zn signaling [70–72]. Zn²⁺ could increase the release of active β-catenin and reduce the expression of TNF-𝛼 and IL-1β, which may be due to the regulation of TLR-4 pathway [41,73,74].

4.3. Magnesium

Magnesium (Mg) is the fourth most abundant cation in the human body, and its deficiency can lead to bone loss. Thus, the doping of Mg seems to be a potential approach to improve the biological properties of bone grafting materials [47,75].

When BHA was doped with MgO, SiO₂, Al₂O₃, ZrO₂ and Y₂O₃, respectively, the crystal lattice of BHA had a higher capability to accommodate Mg²⁺ than other cations attributed to the difference in cation size [78]. Mg-BHA was the only one following the general trend of better sintering performance at higher temperature, and the best one with sintering performance and density [78]. It is worth noting that when sintered at 650–1000 °C, Mg doping might induce a partial decomposition of HA into tricalcium phosphate (TCP), forming Mg-HA/TCP compound [79]. It contained a distinctly different microstructure from single phase Mg-HA, including mixed needle-like and plate-like crystalline particles, with improved specific surface areas over the range of 91.0–104.3 m²/g [79].

It is known that Mg shows a high degree of biocompatibility with living cells, and plays an important role in bone health by stimulating osteoblast proliferation in the early stages of osteogenesis [79]. It has been demonstrated that Mg could enhance BMSCs adhesion and further stimulate osteoblast proliferation [80,81]. Mg was found to promote new bone formation on dental implants, control the initial degradation rate and guide bone regeneration [82]. Mg²⁺ doped biological hydroxyapatite (Mg-BHA) has a similar composition, morphology, and crystallinity to that of biological apatite, without cytotoxic effects at low doping concentrations of Mg²⁺. In contrast, a higher concentration of Mg²⁺ at 5 mM may impair osteoblast activity and contribute to bone diseases [76,77]. A previous study modified BHA thin film with MgF₂ or MgO by pulsed laser deposition technique, which could reinforce HA hexagonal-type phase (P63/m (176) space group) and increase the spheroidal crystal particulates over the thin film to enrich the surface morphology [83]. This Mg-BHA thin film could not only promote cell adhesion and further improve the osseointegration properties of implants, but also show good performances in cell proliferation, osteogenic and antibacterial activities [83].

The underlying mechanism of Mg²⁺ in bone regeneration and immune modulation seems closely related to the stimulation of BMSCs and macrophages both. In BMSCs, it was reported that Mg²⁺ induced the accumulation of active β-catenin, and further up-regulated the expression of Wnt/β-catenin signaling pathway to stimulate the osteogenic differentiation [84,85].

For macrophages, it was found that Mg²⁺ suppressed the production of TNF-𝛼, IL-6 and other inflammatory cytokines by inhibiting TLR signaling pathway, which ulteriorly promoted the polarization of macrophages to the M2 phenotype [42,86]. In addition, Mg²⁺ promoted the expression of IL-10, BMP-2, transforming growth factor β1 (TGF-β1) and other osteogenic related factors [86]. TGF-β, which played a significant role in osteoimmunomodulation, could further inhibit the inflammation progress in bone tissue and enhance the recruitment and mobilization of BMSCs [87,88]. Most recently, it was reported that Mg²⁺ may act in a previously unknown biphasic mode in bone repair [49]. In the early stage of inflammation, Mg²⁺ contributed to an upregulated expression of TRPM7 in macrophage, which caused Mg²⁺ influx and consequently led to the cleavage and nuclear accumulation of TRPM7-cleaved kinase fragments (M7CKs) [49]. Then, M7CKs triggered the phosphorylation of histone 3 at serine 10 (H3S10) in nucleus, stimulated the promoters of inflammatory cytokines and therefore resulted in the primary formation of pro-osteogenic immune microenvironment [49]. In the later remodeling phase, the continuous Mg²⁺ exposure upregulated NF-κB signaling pathway, which may increase osteoclastic-like cells and inhibit bone regeneration [49] (Fig. 6). Hence, Mg²⁺ seems to be a crucial regulator worthy for further exploration, as it locates at the central intersection of complex cell signaling pathway network for bone regeneration and immune regulation.

Fig. 6.

Effects of magnesium on bone regeneration and immune modulation. In BMSCs, Mg²⁺ induced the accumulation of active β-catenin and further upregulated the expression of Wnt/β-catenin signaling pathway [84,85]. For macrophages, Mg²⁺ suppressed the production of inflammatory cytokines by inhibiting TLR signaling pathway [42,86]. In addition, Mg²⁺ promoted the expression of osteogenic related factors [86]. In the early stage of inflammation, Mg²⁺ upregulated the expression of TRPM7, which led to Mg²⁺ influx [49]. Then, M7CKs triggered the phosphorylation of H3S10 in the nucleus, which stimulated the promoters of inflammatory cytokines [49]. In the later remodeling phase, continuous Mg²⁺ exposure upregulated NF-κB signaling pathway, which may increase the proliferation of osteoclastic-like cells and inhibit bone regeneration [49].

4.4. Lithium

Lithium (Li) is present in human body in trace amounts as an essential element [89]. Li⁺ is smaller than Mg²⁺ and Zn²⁺, so that it can easily pass through biological membranes to reach target sites [90], indicating its medical potential as an active ion. It has been proven to be a reliable pharmaceutical ingredient with few side effects [91].

It was reported that doping Li₂CO₃ could increase the porosity of BHA [91,92]. Besides, Li-substituted BHA thin films with PLD using Li₂CO₃ and Li₃PO₄ as dopants showed obvious surfaces with a rough and irregular morphology, consisting in general of spheroidal particles, which improved the angiogenesis capability and osteo-conductivity of BHA [92]. Additionally, Li-BHA films elicited improved wettability due to proper porosity and roughness, which could further induce rapid bone regeneration compared with BHA coatings [92]. This was supported by an in vivo evaluation on the osteogenic performance of Li-BHA coatings, where more new osseous structures were detected. It was believed that the incorporation of Li might create a delivery vehicle for bioactive agents to promote, even accelerate osseointegration in close relation with an improved anchorage of bone metallic implants [5]. However, for Li⁺, there is still a lack of detailed molecular mechanism, especially in promoting bone regeneration and osteointegration.

4.5. Others

The physiochemical and biological features of some other ion-incorporated BHA have also been investigated. Both positive and negative effects have been observed.

BHA incorporated with Na₄P₂O₇ (NP) was synthesized in 1999. With the increase of NP content, BHA gradually transformed into different crystalline phases composed of TCP/HA, TCP/HA/NP or TCP/NP, forming natural porous biomaterials with better bioactivity than pure BHA [93]. Besides, it was reported that BHA doped with CeO₂ showed reinforced microhardness and compression strength [62]. Other reports demonstrated that the osteogenic activity of Ce was related to TGF-β and BMP-2/Smad signaling pathways [94,95]. Additionally, the expression level of ERK signaling pathway was also correlated to Ce in a time-dependent manner [96]. Moreover, the incorporation of titanium (Ti) caused the cracking of BHA crystals and enhanced porosity [91]. Recently, BHA thin films doped with Ti₆Al₄V were synthesized by selective laser melting technology, demonstrating better biomineralization capacity and lower degradability than the control [97]. The incorporation of boron (B) into BHA led to improved compressive strength [61], whereas the doping of SiO₂ resulted in a structural degradation of BHA [78].

In contrast, it was reported that Al₂O₃ doping showed no physiochemical enhancement on BHA, which was probably due to the large gap between the optimal sintering temperature of Al₂O₃ and BHA [78,98]. The doping of ZrO₂ into BHA showed a microstructure similar to Al₂O₃ doping, indicating poor improvement of the mechanical characteristics of BHA [78].

5. Conclusions

In the hope of improving the osteogenic property of BHA-based bone grafting materials, a new concept, namely osteoimmunomodulation has drawn much attention and been followed. Among several approaches, the doping of active inorganic ions into BHA has been demonstrated to be a reliable, reproducible and cost-saving strategy. Also, enhanced osteogenesis has been observed for such ion doped BHA in vitro and in vivo. Although some molecular signaling pathways have been confirmed in the process of ion-doping induced osteoimmunomodulation in macrophages, further studies are still needed as multiple signaling pathways seem involved for each single ion simultaneously. Moreover, it is also of great necessity to explore the effects of multiple ionic co-doping into BHA and the potential mechanism. Additionally, it is of more crucial significance to carry out more translational researches of ion-doped BHA, so as to truly promote the development and application of bone grafting materials.

Footnotes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (NSFC 81970975, 81901055).

Conflict of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.

References

Shi

Zhou

Fan

and Wei

, Hydroxyapatite based materials for bone tissue engineering: A brief and comprehensive introduction, Crystals 11(2) (2021), 149.

Balogh

Z.J.

Reumann

M.K.

Gruen

R.L.

Mayer Kuckuk

Schuetz

M.A.

Harris

I.A.

, Advances and future directions for management of trauma patients with musculoskeletal injuries, Lancet 380(9847) (2012), 1109–1119.

Wen

C.Y.

Qin

Lee

K.M.

and Chan

KM.

, The use of brushite calcium phosphate cement for enhancement of bone-tendon integration in an anterior cruciate ligament reconstruction rabbit model, J Biomed Mater Res Part B Appl Biomater 89B(2) (2009), 466–474.

Chen

Klein

Murray

R.Z.

Crawford

Chang

, Osteoimmunomodulation for the development of advanced bone biomaterials, Mater Today 19(6) (2016), 304–321.

Duta

Neamtu

Melinte

R.P.

Zureigat

O.A.

Popescu-Pelin

Chioibasu

, In vivo assessment of bone enhancement in the case of 3D-printed implants functionalized with lithium-doped biological-derived hydroxyapatite coatings: A preliminary study on rabbits, Coatings 10(10) (2020), 992.

Mondal

Hoang

Manivasagan

Moorthy

M.S.

Kim

H.H.

Vy Phan

T.T.

, Comparative characterization of biogenic and chemical synthesized hydroxyapatite biomaterials for potential biomedical application, Mate Chem Phys 228 (2019), 344–356.

Liu

Chen

Pan

and Darvell

B.W.

, The effect of excess phosphate on the solubility of hydroxyapatite, Ceram Int 40(2) (2014), 2751–2761.

Bee

S.L.

and Hamid

Z.A.A.

, Hydroxyapatite derived from food industry bio-wastes: Syntheses, properties and its potential multifunctional applications, Ceram Int 46(11) (2020), 17149–17175.

Esmaeilkhanian

Sharifianjazi

Abouchenari

Rouhani

Parvin

and Irani

, Synthesis and characterization of natural nano-hydroxyapatite derived from turkey femur-bone waste, Appl Biochem Biotechnol 189(3) (2019), 919–932.

10.

Gómez Vázquez

N.S.

Luque Morales

P.A.

Gomez Gutierrez

C.M.

Nava Olivas

O.D.J.

Villarreal Sánchez

R.C.

Vilchis Nestor

A.R.

, Hydroxyapatite biosynthesis obtained from sea urchin spines (strongylocentrotus purpuratus): Effect of synthesis temperature, Processes 8(4) (2020), 486.

11.

Kim

Y.K.

Lee

I.W.

Kim

K.W.

Murata

Akazawa

, Tooth-derived bone graft material, J Korean Assoc Oral Maxillofac Surg 39(3) (2013), 103–111.

12.

Lee

M.C.

Seonwoo

Jang

K.J.

Pandey

Lim

Park

, Development of novel gene carrier using modified nano hydroxyapatite derived from equine bone for osteogenic differentiation of dental pulp stem cells, Bioact Mater 6(9) (2021), 2742–2751.

13.

Sharifianjazi

Esmaeilkhanian

Moradi

Pakseresht

Asl

M.S.

Karimi Maleh

, Biocompatibility and mechanical properties of pigeon bone waste extracted natural nano-hydroxyapatite for bone tissue engineering, Mater Sci Eng B 264 (2021), 114950.

14.

Cestari

Agostinacchio

Galotta

Chemello

Motta

and Sglavo

V.M.

, Nano-hydroxyapatite derived from biogenic and bioinspired calcium carbonates: Synthesis and in vitro bioactivity, Nanomaterials 11(2) (2021), 264.

15.

Citradewi

P.W.

Hidayat

Purwiandono

Fatimah

and Sagadevan

, Clitorea ternatea-mediated silver nanoparticle-doped hydroxyapatite derived from cockle shell as antibacterial material, Chem Phys Lett 769 (2021), 138412.

16.

Zapanta LeGeros

, Apatites in biological systems, Prog Cryst Growth Charact Mater 4(1) (1981), 1–45.

17.

Chen

Zheng

Chang

and Xiao

, Nutrient element-based bioceramic coatings on titanium alloy stimulating osteogenesis by inducing beneficial osteoimmmunomodulation, J Mater Chem B 2(36) (2014), 6030–6043.

18.

Ramesh

Ratnayake

J.T.B.

Moratti

S.C.

and Dias

G.J.

, Effect of chitosan infiltration on hydroxyapatite scaffolds derived from New Zealand bovine cancellous bones for bone regeneration, Int J Biol Macromol 160 (2020), 1009–1020.

19.

Rodrigues

C.V.

Serricella

Linhares

A.B.

Guerdes

R.M.

Borojevic

Rossi

M.A.

, Characterization of a bovine collagen-hydroxyapatite composite scaffold for bone tissue engineering, Biomater 24(27) (2003), 4987–4997.

20.

Krishnamurithy

Murali

M.R.

Hamdi

Abbas

A.A.

Raghavendran

H.B.

and Kamarul

, Characterization of bovine-derived porous hydroxyapatite scaffold and its potential to support osteogenic differentiation of human bone marrow derived mesenchymal stem cells, Ceram Int 40(1, Part A) (2014), 771–777.

21.

Budiatin

A.S.

Gani

M.A.

Samirah

Ardianto

Raharjanti

A.M.

Septiani

, Bovine hydroxyapatite-based bone scaffold with gentamicin accelerates vascularization and remodeling of bone defect, Int J Biomater 2021 (2021), 5560891.

22.

Feng

and Cui

, Fibroin/collagen hybrid hydrogels with crosslinking method: Preparation, properties, and cytocompatibility, J Biomed Mater Res A 84A(1) (2008), 198–207.

23.

Liu

Wang

X.M.

Chen

Cui

F.Z.

Liu

H.Y.

Mao

, Injectable bone cement based on mineralized collagen, J Biomed Mate Res B 94B(1) (2010), 72–79.

24.

Wang

X.L.

Xie

X.H.

Zhang

Chen

S.H.

Yao

, Exogenous phytoestrogenic molecule icaritin incorporated into a porous scaffold for enhancing bone defect repair, J Orthop Res 31(1) (2013), 164–172.

25.

Ripamonti

, Bone induction in nonhuman primates: An experimental study on the baboon, Clin Ortho Relat Res 269 (1991), 284–294.

26.

Zhang

Zhou

Zhang

Chen

and Wu

, A study of porous block HA ceramics and its osteogenesis, in: Bioceramics and the Human Body, Elsevier, Amsterdam, 1991, pp. 408–415.

27.

Yuan

de Bruijn

J.D.

de Groot

and Zhang

, Tissue responses of calcium phosphate cement: A study in dogs, Biomater 21(12) (2000), 1283–1290.

28.

Bessa Goncalves

Silva

A.M.

Bras

J.P.

Helmholz

Luthringer-Feyerabend

B.J.C

Willumeit-Romer

, Fibrinogen and magnesium combination biomaterials modulate macrophage phenotype, NF-kB signaling and crosstalk with mesenchymal stem/stromal cells, Acta Biomater 114 (2020), 471–484.

29.

Chu

S.J.

Salama

M.A.

Salama

Garber

D.A.

Saito

Sarnachiaro

G.O.

, The dual-zone therapeutic concept of managing immediate implant placement and provisional restoration in anterior extraction sockets, Compend Contin Educ Dent 33(7) (2012), 524–532, 34.

30.

Sin

J.C.

Quek

Lam

S.M.

Zeng

Lin

, Punica granatum mediated green synthesis of cauliflower-like ZnO and decorated with bovine bone-derived hydroxyapatite for expeditious visible light photocatalytic antibacterial, antibiofilm and antioxidant activities, J Environ Chem Eng 9(4) (2021), 105736.

31.

Kuang

G.M.

Yau

W.P.

Yeung

K.W.K.

Pan

Lam

W.M.

, Strontium exerts dual effects on calcium phosphate cement: Accelerating the degradation and enhancing the osteoconductivity both in vitro and in vivo , J Biomed Mate Res A 103(5) (2015), 1613–1621.

32.

Arcos

and Vallet Regí

, Substituted hydroxyapatite coatings of bone implants, J Mater Chem B 8(9) (2020), 1781–1800.

33.

Liu

Matinlinna

J.P.

Chen

Ning

Pan

, Effect of thermal treatment on carbonated hydroxyapatite: Morphology, composition, crystal characteristics and solubility, Ceram Int 41(5, Part A) (2015), 6149–6157.

34.

Uskoković

, Ion-doped hydroxyapatite: An impasse or the road to follow? Ceram Int 46(8) (2020), 11443–11465.

35.

Tite

Popa

A.C.

Balescu

L.M.

Bogdan

I.M.

Pasuk

Ferreira

J.M.F.

, Cationic substitutions in hydroxyapatite: Current status of the derived biofunctional effects and their in vitro interrogation methods, Mater 11(11) (2018), 2081.

36.

Akram

Ahmed

Shakir

Ibrahim

W.A.W.

and Hussain

, Extracting hydroxyapatite and its precursors from natural resources, J Mater Sci 49(4) (2013), 1461–1475.

37.

Zhang

Zhai

Lin

Pan

and Chang

, Synthesis, in vitro hydroxyapatite forming ability, and cytocompatibility of strontium silicate powders, J Biomed Mater Res B 93B(1) (2010), 252–257.

38.

Lin

W.C.

Tang

C.M.

C.C.

and Chuang

C.C.

, Evaluating the feasibility of applying cobalt-hydroxyapatite ingots as radiotherapy markers, Mater Today Commun 24 (2020), 101162.

39.

Mansour

Abu Nada

Elhadad

A.A.

Mezour

M.A.

Ersheidat

Al Subaie

, Biomimetic trace metals improve bone regenerative properties of calcium phosphate bioceramics, J Biomed Mater Res A 109(5) (2021), 666–681.

40.

Kawai

and Akira

, TLR signaling, Semin Immunol 19(1) (2007), 24–32.

41.

Grandjean Laquerriere

Laquerriere

Jallot

Nedelec

J.M.

Guenounou

Laurent-Maquin

, Influence of the zinc concentration of sol-gel derived zinc substituted hydroxyapatite on cytokine production by human monocytes in vitro , Biomater 27(17) (2006), 3195–3200.

42.

Sugimoto

Romani

A.M.

Valentin-Torres

A.M.

Luciano

A.A.

Ramirez Kitchen

C.M.

Funderburg

, Magnesium decreases inflammatory cytokine production: A novel innate immunomodulatory mechanism, J Immunol 188(12) (2012), 6338–6346.

43.

Zhang

and Liu

H.T.

, MAPK signal pathways in the regulation of cell proliferation in mammalian cells, Cell Res 12(1) (2002), 9–18.

44.

Zou

Z.G.

Rios

F.J.

Montezano

A.C.

and Touyz

R.M.

, TRPM7, magnesium, and signaling, Int J Mol Sci 20(8) (2019), 1877.

45.

Baron

and Kneissel

, WNT signaling in bone homeostasis and disease: From human mutations to treatments, Nat Med 19(2) (2013), 179–192.

46.

Qiao

Liu

Luo

Huang

Liu

, Contribution of the in situ release of endogenous cations from xenograft bone driven by fluoride incorporation toward enhanced bone regeneration, Biomater Sci 6(11) (2018), 2951–2964.

47.

Wang

Tang

Zhang

Wang

Lai

, Surface modification of magnesium alloys developed for bioabsorbable orthopedic implants: A general review, J Biomed Mater Res B 100B(6) (2012), 1691–1701.

48.

Xiao

Yang

H.Q.

Gan

Y.H.

Duan

D.H.

L.H.

Guo

, Brief reports: TRPM7 senses mechanical stimulation inducing osteogenesis in human bone marrow mesenchymal stem cells, Stem Cells 33(2) (2015), 615–621.

49.

Qiao

Wong

K.H.M.

Shen

Wang

, TRPM7 kinase-mediated immunomodulation in macrophage plays a central role in magnesium ion-induced bone regeneration, Nat Commun 12(1) (2021), 2885.

50.

Xia

Mai

Feng

Wang

and Liu

, Sodium fluoride under dose range of 2.4–24 μM, a promising osteoimmunomodulatory agent for vascularized bone formation, ACS Biomater Sci Eng 5(2) (2019), 817–830.

51.

Murugan

Sampath Kumar

T.S.

and Panduranga Rao

, Fluorinated bovine hydroxyapatite: Preparation and characterization, Mater Lett 57(2) (2002), 429–433.

52.

LeGeros

R.Z.

and Tung

M.S.

, Chemical stability of carbonate- and fluoride-containing apatites, Caries Res 17(5) (1983), 419–429.

53.

Liu

Chen

and Chen

, Preparation and characterization of fluorinated porcine hydroxyapatite, Dent Mater J 31(5) (2012), 742–750.

54.

Huang

Mai

Zhang

Qiao

, Effects of fluoridation of porcine hydroxyapatite on osteoblastic activity of human MG63 cells, Sci Technol Adv Mater 16(3) (2015), 035006.

55.

Liu

Pan

Chen

and Matinlinna

J.P.

, Insight into bone-derived biological apatite: Ultrastructure and effect of thermal treatment, Biomed Res Int 2015 (2015), 601025.

56.

Qiao

Liu

Zhang

and Chen

, Changes in physicochemical and biological properties of porcine bone derived hydroxyapatite induced by the incorporation of fluoride, Sci Technol Adv Mater 18(1) (2017), 110–121.

57.

Liu

Qiao

Huang

Chen

Fang

, Fluorination enhances the osteogenic capacity of porcine hydroxyapatite, Tissue Eng Part A 24(15-16) (2018), 1207–1217.

58.

Liu

Huang

Chen

Huang

Liu

, Effects of fluorinated porcine hydroxyapatite on lateral ridge augmentation: An experimental study in the canine mandible, Am J Transl Res 12(6) (2020), 2473–2487.

59.

Gunduz

Erkan

E.M.

Daglilar

Salman

Agathopoulos

and Oktar

F.N.

, Composites of bovine hydroxyapatite (BHA) and ZnO, J Mater Sci 43(8) (2008), 2536–2540.

60.

Mardziah

C.M.

Ramesh

Tan

C.Y.

Chandran

Sidhu

Krishnasamy

, Zinc-substituted hydroxyapatite produced from calcium precursor derived from eggshells, Ceram Int 47(23) (2021), 33010–33019.

61.

Gunduz

Ahmad

Salman

Inan

A.T.

Ekren

Agathopoulos

, Sintering effect on boron based bioglass doped composites of bovine hydroxyapatite, Adv Mater Res 445 (2012), 982–987.

62.

Gunduz

Gode

Ahmad

Gokce

Yetmez

Kalkandelen

, Preparation and evaluation of cerium oxide-bovine hydroxyapatite composites for biomedical engineering applications, J Mech Behav Biomed Mater 35 (2014), 70–76.

63.

Toledano

Osorio

Vallecillo-Rivas

Osorio

Lynch

C.D.

Aguilera

F.S.

, Zn-doping of silicate and hydroxyapatite-based cements: Dentin mechanobiology and bioactivity, J Mech Behav Biomed Mater 114 (2021), 104232.

64.

Guo

Xia

Zheng

Zhu

Liu

and Zhou

, A pure zinc membrane with degradability and osteogenesis promotion for guided bone regeneration: In vitro and in vivo studies, Acta Biomater 106 (2020), 396–409.

65.

de Lima

C.O.

de Oliveira

A.L.M.

Chantelle

Silva Filho

E.C.

Jaber

and Fonseca

M.G.

, Zn-doped mesoporous hydroxyapatites and their antimicrobial properties, Colloids Surf B Biointerfaces 198 (2021), 111471.

66.

Predoi

Iconaru

Predoi

Buton

and Motelica-Heino

, Zinc doped hydroxyapatite thin films prepared by sol-gel spin coating procedure, Coatings 9(3) (2019), 156.

67.

Ito

Kawamura

Otsuka

Ikeuchi

Ohgushi

Ishikawa

, Zinc-releasing calcium phosphate for stimulating bone formation, Mate Sci Eng C 22(1) (2002), 21–25.

68.

Popa

C.L.

Deniaud

Michaud-Soret

Guégan

Motelica-Heino

and Predoi

, Structural and biological assessment of zinc doped hydroxyapatite nanoparticles, J Nanomater 2016 (2016), 1062878, 1–10.

69.

Predoi

Iconaru

S.L.

Deniaud

Chevallet

Michaud-Soret

Buton

, Textural, structural and biological evaluation of hydroxyapatite doped with zinc at low concentrations, Materials (Basel) 10(3) (2017), 229.

70.

Haase

and Rink

, Zinc signals and immune function, BioFactors 40(1) (2014), 27–40.

71.

Fukada

Hojyo

and Furuichi

, Zinc signal: A new player in osteobiology, J Bone Miner Metab 31(2) (2013), 129–135.

72.

Huang

Yan

and Guan

, Zinc homeostasis in bone: Zinc transporters and bone diseases, Int J Mol Sci 21(4) (2020), 1236.

73.

Bose

Roy

and Bandyopadhyay

, Recent advances in bone tissue engineering scaffolds, Trends Biotechnol 30(10) (2012), 546–554.

74.

Gammoh

N.Z.

and Rink

, Zinc in Infection and Inflammation, Nutrients 9(6) (2017), 624.

75.

Sengor

, Microstructure and mechanical properties of composites of bovine derived hydroxyapatite (BHA) reinforced with MgF₂ , Int J Adv Eng Pure Sci 33(1) (2021), 116–121.

76.

Yuan

Wei

Huang

Zhang

Chen

Zhang

, Injectable PLGA microspheres with tunable magnesium ion release for promoting bone regeneration, Acta Biomater 85 (2019), 294–309.

77.

Leidi

Dellera

Mariotti

and Maier

J.A.M.

, High magnesium inhibits human osteoblast differentiation in vitro , Magnesium Res 24(1) (2011), 1–6.

78.

Oktar

F.N.

Agathopoulos

Ozyegin

L.S.

Gunduz

Demirkol

Bozkurt

, Mechanical properties of bovine hydroxyapatite (BHA) composites doped with SiO₂, MgO, Al₂O₃, and ZrO₂ , J Mater Sci Mater Med 18(11) (2007), 2137–2143.

79.

Stipniece

Salma-Ancane

Borodajenko

Sokolova

Jakovlevs

and Berzina-Cimdina

, Characterization of Mg-substituted hydroxyapatite synthesized by wet chemical method, Ceram Int 40(2) (2014), 3261–3267.

80.

Chang

and Wang

, In vitro bioactivity of akermanite ceramics, J Biomed Mater Res A 76A(1) (2006), 73–80.

81.

and Chang

, Degradation, bioactivity, and cytocompatibility of diopside, akermanite, and bredigite ceramics, J Biomed Mate Res B Appl Biomater 83B(1) (2007), 153–160.

82.

Zhang

H.Y.

Jiang

H.B.

Kim

J.E.

Zhang

Kim

K.M.

and Kwon

J.S.

, Bioresorbable magnesium-reinforced PLA membrane for guided bone/tissue regeneration, J Mech Behav Biomed Mater 112 (2020), 104061.

83.

Mihailescu

Stan

G.E.

Duta

Chifiriuc

M.C.

Bleotu

Sopronyi

, Structural, compositional, mechanical characterization and biological assessment of bovine-derived hydroxyapatite coatings reinforced with MgF₂ or MgO for implants functionalization, Mater Sci Eng C Mater Biol Appl 59 (2016), 863–874.

84.

Hung

C.C.

Chaya

Liu

Verdelis

and Sfeir

, The role of magnesium ions in bone regeneration involves the canonical Wnt signaling pathway, Acta Biomater 98 (2019), 246–255.

85.

Chang

and Wang

, In vitro bioactivity of akermanite ceramics, J Biomed Mater Res A 76A(1) (2006), 73–80.

86.

Wang

Dai

Liu

Wang

, Improved osteogenesis and angiogenesis of magnesium-doped calcium phosphate cement via macrophage immunomodulation, Biomater Sci 4(11) (2016), 1574–1583.

87.

Wan

Zhen

Jiao

Jia

, Injury-activated transforming growth factor β controls mobilization of mesenchymal stem cells for tissue remodeling, Stem Cells 30(11) (2012), 2498–2511.

88.

Zhen

Wen

Jia

Crane

J.L.

Mears

S.C.

, Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis, Nat Med 19(6) (2013), 704–712.

89.

Schrauzer

G.N.

, Lithium: Occurrence, dietary intakes, nutritional essentiality, J Am Coll Nutr 21(1) (2002), 14–21.

90.

Kaygili

Keser

Ates

and Yakuphanoglu

, Synthesis and characterization of lithium calcium phosphate ceramics, Ceram Int 39(7) (2013), 7779–7785.

91.

Oktar

F.N.

Agathopoulos

Goller

Gökçe

Kayali

E.S.

and Salman

, Highly bioactive porous composite scaffolds of bovine hydroxyapatite (BHA-Ti, BHA-TiO₂, BHA-Li₂O), Key Eng Mater (2007), 330–332, 411–444.

92.

Popescu

A.C.

Florian

P.E.

Stan

G.E.

Popescu-Pelin

Zgura

Enculescu

, Physical-chemical characterization and biological assessment of simple and lithium-doped biological-derived hydroxyapatite thin films for a new generation of metallic implants, Appl Surf Sci 439 (2018), 724–735.

93.

Lin

F.-H.

Liao

C.J.

Chen

K.S.

and Sun

J.S.

, Preparation of a biphasic porous bioceramic by heating bovine cancellous bone with Na₄P₂O₇ ⋅ 10H₂O addition, Biomater 20(5) (1999), 475–484.

94.

Xiao

Q.F.

Chen

X.D.

and Guo

Y.-P.

, Cerium-doped whitlockite nanohybrid scaffolds promote new bone regeneration via SMAD signaling pathway, Chem Eng J 359 (2019), 1–12.

95.

Liu

D.D.

Zhang

J.C.

Zhang

Wang

S-X

and Yang

M-S

, TGF-β/BMP signaling pathway is involved in cerium-promoted osteogenic differentiation of mesenchymal stem cells, J Cell Biochem 114(5) (2013), 1105–1114.

96.

Zhu

D.Y.

Yin

J.H.

Zhang

C.Q.

Q.F.

, Incorporation of cerium oxide in hollow mesoporous bioglass scaffolds for enhanced bone regeneration by activating the ERK signaling pathway, Biofabrication 11(2) (2019), 025012.

97.

Chioibasu

Duta

Popescu-Pelin

Popa

Milodin

Iosub

, Animal origin bioactive hydroxyapatite thin films synthesized by RF-Magnetron sputtering on 3D printed cranial implants, Metals 9(12) (2019), 1332.

98.

Yetmez

Erkmen

Z.E.

Kalkandelen

Ficai

and Oktar

F.N.

, Sintering effects of mullite-doping on mechanical properties of bovine hydroxyapatite, Mater Sci Eng C Mater Biol Appl 77 (2017), 470–475.

Optimized osteogenesis of biological hydroxyapatite-based bone grafting materials by ion doping and osteoimmunomodulation

Abstract

BACKGROUND:

OBJECTIVE:

METHOD:

RESULTS:

CONCLUSION:

Keywords

1. Introduction

Table 2 Origins of biological hydroxyapatite Categories Origins Mammalian bones and teeth Bovine, porcine, camel, horse and turkey bones Marine or aquatic sources Sea urchin spine, fish bone and scale Shell Cockle, clam, eggshell and seashell Mineral Limestone Others Plants and algae

4.1. Fluoride

4.5. Others

5. Conclusions

Footnotes

Acknowledgements

Conflict of interest

References

Table 2
Origins of biological hydroxyapatite

Categories Origins

Mammalian bones and teeth Bovine, porcine, camel, horse and turkey bones

Marine or aquatic sources Sea urchin spine, fish bone and scale

Shell Cockle, clam, eggshell and seashell

Mineral Limestone

Others Plants and algae