Rare earth smart nanomaterials for bone tissue engineering and implantology: Advances, challenges, and prospects

Abstract Bone grafts or prosthetic implant designing for clinical application is challenging due to the complexity of integrated physiological processes. The revolutionary advances of nanotechnology in the biomaterial field expedite and endorse the current unresolved complexity in functional bone graft and implant design. Rare earth (RE) materials are emerging biomaterials in tissue engineering due to their unique biocompatibility, fluorescence upconversion, antimicrobial, antioxidants, and anti‐inflammatory properties. Researchers have developed various RE smart nano‐biomaterials for bone tissue engineering and implantology applications in the past two decades. Furthermore, researchers have explored the molecular mechanisms of RE material‐mediated tissue regeneration. Recent advances in biomedical applications of micro or nano‐scale RE materials have provided a foundation for developing novel, cost‐effective bone tissue engineering strategies. This review attempted to provide an overview of RE nanomaterials' technological innovations in bone tissue engineering and implantology and summarized the osteogenic, angiogenic, immunomodulatory, antioxidant, in vivo bone tissue imaging, and antimicrobial properties of various RE nanomaterials, as well as the molecular mechanisms involved in these biological events. Further, we extend to discuss the challenges and prospects of RE smart nano‐biomaterials in the field of bone tissue engineering and implantology.

Generally, photoluminescence obeys Stokes law that means the wavelength of the emitted fluorescence light is more extended than incident light, termed the "downconversion" luminescence. Downconversion luminescence converts higher-energy photons into lower-energy photons. For instance, ultraviolet (UV) radiation excites Eu 3+ , Tb 3+ , and Dy 3 and emits in the visible region. UV excitation of Nd 3+ emits in the near-infrared (NIR) region. Excitation by long-wavelength radiation (i.e., anti-Stokes luminescence) of Er 3+ or Tm 3+ emits shorter-wavelength light. The emitted fluorescence light is in a shorter wavelength and higher energy than the incident light; thereby, it is called anti-Stokes luminescence or "upconversion" luminescence. Therefore, RE materials are gaining their significance in biomedical imaging owing to the reduction of autofluorescence and penetrating properties in the tissues of biological systems. [10][11][12] Various electronic configurations and variable valence states are crucial in enhancing the stability, broadening the absorption range endowed RE ions with flexible redox properties and unique luminous and electromagnetic characteristics. [13][14][15] These properties of RE elements attribute to the design of nanostructured materials either as major components or as dopants paving the way for new tissue engineering applications. The particle size ranging from 1 to 100 nm of nanoparticles and geometry has been reported to play an essential role in cell-material interactions, affecting cellular uptake, and cell functioning. 16 Most cell-nanoparticle interactions have been facilitated at nano biointerface by several factors such as nanoparticle's shape and surface morphology. 16 The shape/geometry of the nanoparticles directly influences their cellular uptake. It has been observed that rod-shaped particles have the highest uptake, followed by spheres, cylinders, and cubes. 17 Similarly, the neodymium nanoparticle's shape influences the cellular activity in terms of altered mitochondrial membrane potential, reactive oxygen species (ROS), and eventually angiogenesis in endothelial cells. 18 The cellular uptake of nanomaterials such as liposomes, 19 iron oxide, 20 polymeric, 21 gold, [22][23][24] and silica nanoparticles 25 is size dependent. The particle size of the polystyrene spheres increased the binding and affected the immune response in human dendritic cells. 26 Similarly, the RE materials like ceria have the highest cellular uptake and reactive oxygen species production in human monocyte cell line U937, 27 size dependence cell viability in Hela and HEK cells, 28 and size dependence biodistribution of ceria was also observed in rat animal model. 28 Further, rare-earth fluorides such as erbium showed good cell imaging features depends on their size. 29 Besides that, many factors, such as surface chemistry and oxidation states of RE metals like ceria, affected the physiological conditions. 30 Few studies reported that RE materials doped mesoporous silica nanoparticle and polymeric nanoparticles possess positively charged that could be facilitated the cell nanomaterial interactions. 21 Moreover, in vivo assay usually demands controlled particle size to use the enhanced permeation and retention effect, high colloidal stability, and low toxicity. 31 RE metal-based nanoparticles are used in different imaging approaches other than luminescent imaging like magnetic resonance imaging (MRI) and computed tomography (CT). 32 RE materials hold a robust therapeutic potential owing to biocompatibility, optical, and physicochemical properties. Lanthanides are widely used in the electronic and painting industry due to their magnetic and adsorption properties. 33,34 The magnetic properties of some lanthanide cations such as Gd 3+ , Ho 3+ , and Dy 3+ make REbased nanoparticles of these cations very useful in MRI because these cations can induce additional contrast between normal and abnormal regions. 35,36 In the biological field, various functions of RE elements have been reported. Recently, researchers have been trying to use the intrinsic optical properties of RE nanomaterials for in vivo imaging to monitor the physiologic processes. [37][38][39] Besides that, in compliance with unique features, these materials are used for in situ bio-labeling of cellular organelles, photodynamic therapy in tumor targeting, sitespecific delivery of therapeutic molecules with a combination of fluorescence and the therapeutic effect as a theranostic tool. [40][41][42][43][44] Due to the high adsorbing affinity, RE has been widely used as a doping material with metal to produce alloy materials for bone and dental prostheses production. 45,46 RE nanoparticles can be incorporated into the connectivity centers or inside the metal-organic frameworks. 35,47 Highly porous and oriented structures allow RE nanoparticles to accommodate many different functional carrier cargoes like drugs, growth factors and make them attractive materials for biomedical applications. 33 The development of RE-based smart nano-biomaterials with osteogenic, angiogenic, and immunomodulatory potential and in vivo imaging has a massive scope in the field of bone tissue engineering and implantology. Significant advancements have been made with RE in bone grafts and prostheses design in the past two decades. Here, we have listed the advances and potential applications of these RE smart nano-biomaterials in bone tissue engineering and implantology.

| BONE CELL BIOLOGY
Bone is a metabolically growing vital organ that gives the body structural (mechanical stability) and functional properties. The bone progenitor cells carry out different functions such as bone formation, resorption, repair, and mineral homeostasis. The bone progenitor cells originate from two cell lineages, mesenchymal and hematopoietic. 48 Osteoblasts and osteocytes are differentiated from the mesenchymal stem cells (MSCs). Bone marrow mononuclear hematopoietic cells differentiate into osteoclasts. [49][50][51] Osteoclasts resorb old and defected bone matrix, and osteoblasts deposit new bone matrix in that place.
Osteogenic cell-secreted osteopontin induces early angiogenesis in developing bone. 82,83 The immune cells, including monocytes, neutrophils, dendritic cells, and B and T lymphocytes, play a vital role in osteoimmunomodulation. Biomaterial-mediated M1 and M2 polarization of macrophages regulate different stages of bone defect healing. 84,85 The key molecules responsible for the signaling between osteoclasts and osteoblasts are regulated by immune cells. [86][87][88] The immune cell-secreted tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β enhance osteoclast differentiation and bone resorption via receptor activator for nuclear factor-κB ligand (RANKL) secretion. 89 These pro-inflammatory cytokines inhibit osteoblast differentiation. 89 Whereas anti-inflammatory cytokines, including IL-4 and IL-10, increase bone formation by inducing osteoblast function and inhibiting osteoclastogenesis. 90 Chen et al. have summarized the biomaterial-immune cell interaction and its effect on bone defect healing and osseointegration. 84,85 Their review suggested the development of novel biomaterials with osteoimmunomodulatory properties for orthopedic and dental applications. Reports from literature had shown the immunomodulatory potential of RE materials, 91,92 which is thoroughly discussed in Section 5.1.2 of this review.
Neuronal cells also significantly contribute to maintaining skeletal homeostasis. The bone marrow consists of the sympathetic nervous system (SNS) and parasympathetic nervous system (PNS). SNS closely associates with the blood vessels through the nutrient foramen and innervating different regions; some nerves reach bone marrow and connect with transcortical vessels in the bone. 93 Further, neuron regulates various hematopoietic cell functions via neurotransmitters' binding to beta-adrenergic receptors. 94 The PNS may innervate the distal femoral metaphysis and uses acetylcholine as the primary neurotransmitter, which binds to muscarinic or nicotinic receptors. 95 Apart from the direct regulation of hematopoietic cells, PNS regulates bone remodeling. [96][97][98][99] Implant-derived magnesium has been reported to promote bone healing via local neuronal production of calcitonin gene-related polypeptide-α (CGRP). 100 RE element Gd-doped magnesium scaffold has been reported to enhance bone defect healing via neuronal CGRP-mediated effect on osteogenesis and angiogenesis. 101 These findings further strengthen the scope of RE-based biomaterials in orthopedics and implantology.

| NANOMATERIALS AND CELLS INVOLVED IN BONE REGENERATION
The unprecedented pathological or congenital malfunctions affect bone metabolism by aberrant or restricted actions of the aforementioned bone cells. Thereby understanding the pathophysiology of these cells cues the novel therapeutic targets for bone-related diseases. Many therapeutic strategies have been developed like small molecules, recombinant proteins, peptides, and plant-based phytochemicals to eliminate bone therapy-related complications. Recently, the role of nanoparticles has significantly compromised the need for bone therapeutics. The organic and inorganic components of the bone matrix directly facilitate bone regeneration and maintain bone homeostasis. RE nanomaterials can be designed in combination with organic and inorganic components of the bone matrix to improve bone regeneration. Various metal ions, including RE, had been reported to modulate the osteocyte, osteoblast, and osteoclast activity. Gold nanoparticles incorporated gelatin hydrogels promote proliferation and differentiation of human adipose-derived stem cells toward osteoblast cells in a dose-dependent manner. 102 Another study indicated that the gold nanoparticles suppress osteoclast formation in a dose-dependent manner and increase bone density that can be useful in preventing and treating osteoporosis. 103 The gold nanoparticle-labeled MSCs improve contrast for imaging, and gold nanoparticles preserve the migratory capacity of MSCs. 104 The gold nanoparticle-functionalized mesoporous silica nanoparticles synergistically increase the immunomodulatory effects and direct osteogenic stimulation by increasing the osteogenic differentiation capability of MC3T3-E1 cells and accelerate new bone formation in a critical-sized cranial defect site in rats. 105 The therapeutic potential of Ag-Au-HA compositions would be excellent for bone regeneration and fracture healing. 106 Surface modification of bone grafts with silver nanoparticles, samarium, and TiO 2 prevents the risk of contamination and infection in alveolar bone and dental implant surgery. 107,108 The iron oxide nanoparticles coated with dextrin and chitosan increase osteoblast proliferation and differentiation. 109,110 The inorganic nanoparticles like calcium phosphate nanoparticles increase the osteogenic differentiation of rat bone marrow stromal cells, [111][112][113] and magnesium-containing biocomposites facilitate femur fracture repair. 100,[114][115][116][117][118][119][120][121] In this pipeline, the RE nanoparticles have tremendous potential for bone graft development since it has versatile bio applications, including an antioxidant to antimicrobial effect. [122][123][124] Furthermore, RE metals can be doped in the abovementioned nanoparticles to redevelop the smart nano-biomaterials with improved antimicrobial, immunomodulatory potential of ceria, 125,126 the osteoangiogenic effect of europium, [127][128][129] contrast imaging potential of Gd, 130,131 and laser irradiation property of neodymium. 132,133 This review exemplifies the role of various RE nanomaterials for the therapeutic modulation of these important bone cells.

| BONE DEFECT HEALING
Critical size or large bone defects need medical interventions to restore. 134 with endothelial cells and osteoblasts, then progresses to hard callus formation, also known as primary bone formation; this stage represents the most active period of osteogenesis. 143 Following these processes, the bone remodeling phase begins with coordinated osteoblast and osteoclast activities. Reabsorption of callus tissues by osteoclast is followed by lamellar bone formation. The ROS-producing ability of RE nanoparticles such as ceria activates the RANKL pathway to induce osteoclastogenesis. 78,79 Moreover, angiogenesis is a critical factor for bone remodeling because it provides the appropriate conditions for osteoblast and osteoclast activities. [143][144][145] The RE materials such as europium has the potent role of angiogenic activity via ROS production. 127,128

| APPLICATION OF RE SMART NANO-BIOMATERIALS IN BONE TISSUE ENGINEERING
Bio-implants are orchestrated specialized materials that render the ability to replace or restore the specific functions of the damaged organs or tissues. 146,147 One of the recently identified such materials belongs to RE metal groups. The different RE nanomaterial synthesis methods and their physicochemical properties are listed in Table 1.
In addition, RE nanomaterials have a lot of biological applications.
Reports from literature had report antioxidants potential of ceria, 125,126 osteo-angiogenic effects of europium, 127-129 laser irradiation property of neodymium, 132,133 and contrast imaging potential of Gd. 130,131 Various biological applications, especially concerning bone tissue engineering application of RE materials, are summarized in Table 2. The outcomes of bone fracture healing strategies are still not satisfactory due to the lack of osteoinduction, osteoconduction, immunomodulation, and osteointegration ability of biomaterials. The use of emerging RE nanomaterials has the potential to address these challenges. In the past two decades, significant advancements have been made using RE materials in bone implants and prostheses design.
This review attempts to comprehensively exemplify the potential usage of RE elements in bone graft and implant development. We profoundly discuss the challenges in using RE nanomaterials in bone regenerative medicine, particularly in the osteogenic process.

| Cerium
Cerium is the most abundant RE element, approximately 50-60 ppm found on the earth's surface. Cerium exhibits unique redox behavior due to its electron configuration, filling the 4f orbital in the ground state and standard oxidation numbers of +3 or + 4. Oxide forms of cerium include cerium oxide or ceria (CeO 2 ), and dicerium trioxide or sesquioxide (Ce 2 O 3) has been broadly utilized for various applications, such as electrolytes in fuel and solar cells, detection systems, surface polishing, and catalysis. The redox equilibrium between two oxidation states results in the ROS and reactive nitrogen species (RNS) regulation. At the nanoscale level, the reactivity of CeO 2 is more effective as the high surface-to-volume ratio results in elevated surface oxygen vacancies, which is responsible for the enhanced biological activities such as antimicrobial, antioxidants, and angiogenic responses. 91 The applications of CeO 2, especially in bone formation, are discussed in the following sections.

| Redox modulator
Redox signaling is essential for physiological and pathological conditions. Under physiological conditions, there will be a balance between oxidants and antioxidants, which maintains the redox state at the threshold level. The redox states altered beyond the tolerable threshold level lead to apoptosis. Oxidative stress caused by generating abundant ROS in the living system is obnoxious. The body itself has a defense mechanism to modulate such redox states, whereas, in some pathological conditions like bone fracture microenvironment, the levels of ROS are abundantly high and affect bone reconstruction.
Excessive ROS production can induce osteoclastogenesis and suppresses the osteoblastic differentiation process. Therefore, it is essential to balance the equilibrium by using antioxidants to modulate the redox states. Nanoceria acts as an antioxidant therapeutic. The different sizes ( been analyzed by intravenous injection in rats. 28 The nanoceria was detected in blood, brain, liver, and spleen. The liver and spleen contain a large percentage of the injected dose, with no significant clearance over 720 h and very little nanoceria entered brain parenchyma.  234 The schematic representation of the preparation of the alginate/glass beads with ceria is given in Figure 1I. Akt. 200 Similarly, the water-soluble oligochitosan-coated CeO 2 nanoparticle-loaded injectable hydrogel shows biocompatibility and radical-scavenging effect. 155 Furthermore, it downregulates the expression of angiogenic proteins and pro-inflammatory cytokines in AMD cellular models like human retinal pigment epithelium-19 and umbilical endothelium cell lines. 155 It also has been documented that nanoceria alleviates the endometrial lesions induced in the mice model by decreasing oxidative stress and inhibiting angiogenesis. Moreover, nanoceria was also observed to protect endometriosisrelated adverse effects on the oocytes, which is critical for a successful pregnancy. 248 The genotoxicity studies in liver cells revealed that the high dose (1000 mg/kg body weight) of ceria nanoparticles induces DNA damage in peripheral blood leukocytes, micronucleus formation in blood cells, and total cytogenetic changes in the bone marrow. Ceria nanoparticles exhibit higher tissue distribution and greater clearance in large fractions through urine and feces than CeO 2 bulk, whereas the maximum amount of micro-sized CeO 2 excretes in feces. 249 Nanoceria significantly inhibits the production of ROS in A2780 ovarian cancer cells. Nanoceria treatment also inhibits VEGF165-induced proliferation, capillary tube formation, activation of VEGFR2 and MMP2 in HUVECs.
Thus, nanoceria can be used as an anti-angiogenic therapeutic agent during cancer treatment. 250 This pro-angiogenic and anti-angiogenic potential of ceria-based nanoparticles might be related to the dose of ceria content in the nanoparticles, the cell type, and disease condition.
Optimizing the proper dose of cerium in the ceria nanoparticles is crucial for pro-angiogenic effect-mediated bone defect healing. glycogen, ATP content, and type I fiber ratio, resulting in higher muscle endurance. 260 The cerium/zirconia/alumina composite enhances the osteogenic response in vitro and in vivo. 207 Nano CeO 2 -containing calcium sulfate hemihydrate composite with 5% w/w shows a higher bone regenerative potential. 208 Freeze-dried CeO 2 nanoparticles-modified bioglass scaffolds rapidly promote the F I G U R E 2 Legend on next page.
proliferation and osteogenic differentiation of human BMSCs. The enhanced osteoinductivity of ceria-bioglass scaffolds is mainly related to the activated ERK pathway. Rat cranial defect model revealed that ceria-bioglass scaffolds accelerate collagen deposition, osteoclast formation, and bone regeneration compared to bioglass scaffolds. 76 Nanocrystalline CeO 2 promotes dentinogenesis in the damaged teeth root. 209 All aforementioned osteogenic properties of cerium-doped innovative nanomaterials indicate the potential applications of cerium in bone tissue engineering and implantology.

| Europium
Europium is the least dense, the softest, and the most volatile member of the lanthanide series. The europium element was discovered in 1901 by French chemist Eugène-Anatole Demarçay and was named for Europe. Europium occurs in minute amounts in many RE minerals such as monazite and bastnasite. The primary use of europium is in optical displays, TV screens, and fluorescent lamps. Europium is also used in scintillators for X-ray tomography and as a source of blue color in light-emitting diodes. 261 The bio labeling property of europium ions has been used to synthesize the cyclen-based europium (III) complex as a lanthanide luminescent contrast agent for bone structure analysis by incorporating the iminodiacetate functionalities as selective Ca(II) binding motifs. This contrast agent selectively visualizes the damaged bone structure (microcracks). 211 The gold nanoparticles conjugated with the europium luminescent probe and the peptide (pHLIP•EuL•Au) target the platelets in low pH 6.5 and translocate the pHLIP across the membrane. 212 H 2 O 2, a redox signaling molecule generated by europium hydroxide nanoparticles, activates the endothelial nitric oxide synthase that promotes nitric oxide production in a PI3K (phosphoinositide 3-kinase)/ Akt-dependent manner, eventually triggering angiogenesis. 213 The molecular mechanisms underlying the europium hydroxide nanorods (EHNs) induced angiogenesis are given in Figure 2IV. It has been further evidenced that microwave-assisted synthesized europium (III) hydroxide nanorods exert pro-angiogenic properties through ROS generation and activation of the MAPK pathway. 129 On the other hand, Gd 2 O 3 :Eu 3+ nanotubes generate excessive ROS injury to the mitochondria and DNA in BMSCs, and the release of cathepsin B by lysosomal rupture triggered cell death necrosis. 262 The nanotubes of

| Gadolinium
Gd occurs in many minerals and other RE materials, but it is obtained primarily from bastnasite. It was discovered by a Finnish chemist Johan Gadolin. 263 Gd is known for its high potential in MRI. Nevertheless, its imaging, a radiation-free alternative to the 99mTc-HDP bone scan (BS) to detect metastasis of cancer bone. 130 Since Gd-based contrast agents (GBCAs) are used for MRI enhancers in the bone; it has some adverse effects on the body. For instance, Gd concentration in bone is significantly higher in exposed subjects than in control subjects. Gd can be retained in bone up to 5 years after one GBCA administration. 271 The Gd-exposed tibia shows a higher Gd concentration compared to the control group. 272 Based on the reports mentioned above from the literature, Gd can be used not only for the bone regeneration application but also to visualize the damaged bone and newly formed bone in vivo.

| Neodymium
Neodymium is a ductile and malleable silvery-white metal. Austrian chemist Carl Auer von Welsbach discovered neodymium in 1885.
Neodymium occurs in the least amount in the rocks of Earth's crust.
The major application of neodymium is in high-strength permanent magnets used in high-performance electric motors and generators, the electronics industry, and the ceramics industry for glazes and color glass in various shades from pink to purple. Neodymium-stabilized yttrium aluminum garnet (YAG) is a component of many modern lasers, and neodymium glasses are used in fiber optics. 273 Neodymium is used in a laser oscillator to irradiate the specimen. Nd:YVO 4 laser oscillator has a threshold average laser power of 160 mW required to drill through a 0.75-mm thick cortical bone with a peak intensity of 1.3 GW/cm 2 . 223 Nd-YAG laser irradiation in the near-infrared ray (NIR) area has been reported to promote bone healing via the expression of ALP, RANKL, and OPG. It indicated that osteoblast-like cells activate genes related to bone metabolism by combining mechanical F I G U R E 4 I. Photoemission spectra of BNPs: (a) survey spectra and high-resolution spectra of (b) Ag 3d (c) Nd 3d. II. Emission spectra of AgÀNd BNPs on excitation with 808 nm reveals mission ability in the NIR (750-1600 nm) region, with strong emission in the region of the second biological window, which is more transparent for deep tissue penetration. III.  Figure 4IV). 280 Rocha et al.
found that neodymium-doped LaF 3 core/shell nanoparticles emerge as relevant sub-tissue optical probes for bioimaging. 281 Further experiments from their team reported that Nd 3+ -doped LaF 3 (Nd 3+ :LaF 3 ) nanoparticles exhibit fluorescence in three main emission channels of Nd 3+ ions like 910, 1050, and 1330 nm, respectively. The optimal fluorescence of Nd 3+ -doped LaF 3 nanoparticles in terms of relative emission intensities, penetration depths, and sub tissue optical dispersion is higher in 4F 3/2 !4I 11/2 (1050 nm in the second biological window) than the 4F 3/2 !4I 9/2 (910 nm, in the first biological window). 282 Nano-sized neodymium oxide (Nd 2 O 3 ) arrests the S-phase of the cell cycle, disrupts mitochondrial membrane potential, and inhibits proteasome activity, leading to autophagy in non-small cell lung cancer NCI-H460 cell. 283 Microwave-assisted polyol-based chitosan-   168 It has been reported that Eu III(OH) 3 and TbIII(OH) 3 promote angiogenesis in the transgenic zebrafish model. (Figure 5I,III,IV) 295  bone regeneration, such as pro-angiogenic, immunomodulatory, antimicrobial, and osteogenic. 18,129,197,280 The various biological processes and signaling molecules involved in RE material-mediated bone defects healing are depicted in Figure 6. The advances in RE nanobiomaterials for bone tissue engineering and implantology are aforementioned in this review. Overall, potential applications of RE materials in bone tissue engineering and implantology are depicted in Furthermore, in the bone fracture microenvironment, the ROS levels are abundantly high and affect bone reconstruction. 300 Excessive ROS production can induce osteoclastogenesis, 57 whereas F I G U R E 7 Potential applications of RE biomaterials in bone tissue engineering and implantology hydrogen peroxide suppresses the osteoblastic differentiation process in primary mouse BMSCs. 301 There is an opposing role of RE materials in producing reactive oxygen species and altering the redox states in the bone defect site. Thereby, it is inevitable to tune or modulate the redox signaling intersecting the current problem. Most of these studies lack the in-depth investigation on local and systemic adverse effects of in vivo applied RE nano-biomaterials in long-term use.
Therefore Effective bone regeneration requires a continuous blood supply.
Coordination between osteogenesis and angiogenesis is crucial for proper bone regeneration. [306][307][308] Osteogenesis, angiogenesis, and osseointegration are essential for the successful restoration of bone mass.
Tuning of such factors by designing with RE nano biomaterials is critical for bone tissue engineering. 46,309 In recent years, great attention has been drawn to coupling angiogenesis and osteogenesis to promote type H ves- In-depth analysis of local and systemic adverse effects of REnanobiomaterials in large animal models close to humans is another prospect that streamlines the clinical application of RE nano-bio materials.
The clinical complication can be minimized by using rare-earth nanomaterials as a co dopant in new scaffold-based mechanics like 3D printing or electrospinning. [313][314][315] Electrospinning is the most practical and widely explored technique for synthetic membranous grafts. Biopolymers like collagen, silk, and synthetic polymers like polyethylene glycol (PEG) and poly(lactic acid) (PLLA) have been designed for tissue regeneration purposes. 316,317 Using the RE-based nanomaterials with these techniques may yield a remarkable outcome in accelerating bone defect healing with structural and mechanical stability. RE materials doped electrospun or 3D-printed scaffolds may aid to warrant the sustained release and site-specific delivery of RE elements based on their physicochemical properties.

DATA AVAILABILITY STATEMENT
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study ORCID Janak Lal Pathak https://orcid.org/0000-0003-2576-443X