Calcium phosphate is the main inorganic component of bone. Calcium phosphate-based biomaterials have demonstrated great potential in bone tissue engineering due to their superior biocompatibility, pH-responsive degradability, excellent osteoinductivity, and similar components to bone. Calcium phosphate nanomaterials have gained more and more attention for their enhanced bioactivity and better integration with host tissues. Additionally, they can also be easily functionalized with metal ions, bioactive molecules/proteins, as well as therapeutic drugs; thus, calcium phosphate-based biomaterials have been widely used in many other fields, such as drug delivery, cancer therapy, and as nanoprobes in bioimaging.
Nowadays, over two million bone grafts are needed for bone defects 
, which are caused by trauma, infection, and tumors, since the size of the defect is far larger than the self-healing capability of bone tissue. Autologous bone grafts are still considered the gold standard to achieve bone defect repair 
. Allografts also show excellent bioactivity, but the drawbacks are still obvious, including possible disease transmission, immune rejection, second injury, and donor site morbidity 
. Thus, various bone substitutes have been made to solve the limitation of bone repair caused by the autologous bone, such as inorganic implants or organic implants. Usually, inorganic implants used for bone defects tend to be peri-implantitis 
, be non-degradable 
, and lack osteoinductivity 
, which bring about the continuous inhibition of bone regeneration and cause the absence of strong and effective mechanical support from newborn bone. Thus, patients may suffer a lot from default treatment.
Bone tissue engineering is a promising approach for the regeneration and repair of damaged bone tissues. Biomaterial-based approaches have emerged as an alternative to these traditional methods. Biomaterials can provide a scaffold for cell adhesion, proliferation, and differentiation, and they can also release growth factors and other bioactive molecules to promote bone regeneration. Biomaterials used for bone tissue engineering should have properties such as biocompatibility, biodegradability, osteoconductivity, and osteoinductivity. Biomaterials can be classified into the following four categories based on their composition: calcium phosphate-based biomaterials, metallic biomaterials, polymeric biomaterials, and composite biomaterials. Among these, calcium phosphate-based biomaterials have received the most attention due to their excellent biocompatibility, bioactivity, and similarity to the mineral component of bone 
Compared to conventional calcium phosphate-based graft materials, calcium phosphate nanomaterials offer several distinct advantages and show unique properties for bone tissue engineering, including enhanced bioactivity, tailored physical and chemical properties, controlled drug delivery, better integration with host tissue, and ease of fabrication and scalability. Specifically, these biomaterials have a high surface area to volume ratio, which provides more space for cell adhesion and proliferation and also promotes cell differentiation 
, as well as loading more therapeutic ingredients 
. Additionally, the nano-sized particles can enhance the mechanical properties and show a profile of controlled drug release.
Thus, calcium phosphate nanomaterials have attracted more and more attention, and various preparation strategies have been developed to satisfy clinical requirements. The preparation methods include wet chemical precipitation, solvothermal synthesis, the sol-gel method, microwave-assisted method, sonochemical synthesis, the enzyme-assisted method, as well as spray drying and electrospinning. Among these, the precipitation method is the most commonly used method for the preparation of nano-calcium phosphate-based biomaterials, while the other methods also have their advantages, which are further discussed in the following section.
Furthermore, calcium phosphate-based nanomaterials can be tailored by adjusting their size, shape, and surface chemistry. Functionalized calcium phosphates are endowed with osteogenic properties, angiogenic properties, antimicrobial properties, bioimaging capabilities, and so on. Herein, calcium phosphate-based nanomaterials showed great potential in bone regeneration, antitumor therapy, and drug delivery. Thus, the research is intended to give a comprehensive summary of the preparation, multifunctionality, and application of nano calcium phosphate-based biomaterials for bone tissue engineering, and it also addresses the attention of readers and provides inspiration for the design of bioactive materials for bone tissue engineering.
2. Applications of Calcium Phosphate-Based Nanomaterials in Bone Tissue Engineering
Calcium phosphate-based nanomaterials show superior biocompatibility, show osteoinductivity, and have high surface area and porosity. Thus, they have been widely used for bone regeneration 
. Additionally, calcium phosphate-based nanomaterials can be doped with special compounds to promote bone repair directly. Susmita et al. designed 3D calcium phosphate scaffolds, resembling the structure of cortical and cancellous bones, to provide a stronger, denser structure to develop compressive strengths of the scaffold and maintain the central interconnected porosity for cell proliferation and vascularization. The scaffold was incorporated with natural compounds from ginger root and garlic powder, which can enhance bone healing when used in vivo, and improved the bioavailability of these medicinal compounds 
. Furthermore, many metal elements also have various influences on the process of bone regeneration, such as silicon, magnesium, cerium, and so on. Based on this theory, Fe and Zn were combined with tricalcium phosphate (TCP) via co-deposition because these two elements can improve new blood vessel formation, which can significantly promote bone regeneration; then, the Fe/Zn-modified TCP powders were turned into a solid, and micropores were formed inside at room temperature. The composites achieved the sustained release of metal (Ca2+
) ions, which can promote the process of bone repair 
. Additionally, because of the low mechanical strength, brittleness, and quick resorption rate, CaP-based scaffolds need to be reinforced with mechanical strength and be improved regarding bioactivity. It is reported that bioceramic powders (hydroxyapatite and β-tricalcium phosphate) have been embedded in mixed solutions of chitosan and silk fibroin to improve both the mechanical properties and the differentiation of mesenchymal stem cells since chitosan and silk fibroin have shown better bioactivity in supporting the growth and differentiation of BMSCs. Additionally, the polymer solution can be used as the bioink of robocasting equipment to print 3D scaffolds with fixed system parameters at room temperature, and this scaffold achieved great performance regarding mechanical properties and biocompatibility 
. Calcium phosphate-based materials can also be used as carriers to load cells or growth factors, which can improve effective therapeutic ingredients in bone defect areas, can keep the sustained release of these factors, and can provide enough room for osteoblasts and new blood vessels 
. Li et al. reported that bone marrow mesenchymal stem cells and platelet-rich plasma combined with a calcium phosphate cement scaffold achieved more newly formed bone areas than normal calcium phosphate cement scaffolds in an in vivo experiment 
Recently, near-infrared-emitting persistent luminescence nanoparticles have been used as an optical probe for bioimaging and biosensing 
. Though they show low absorptivity in deep-tissue imaging, achieving stable in vivo luminescence is still a great challenge 
. Chen et al. developed Eu3+
ion-dual-doped CaP nanoparticles via co-precipitation using block copolymer polylactide-block-monomethoxy as a template. The nanoparticles showed prolonged stability (more than 80 days), improved the T1-weighted MRI signal intensity, and decreased T2-weighted MRI signal intensity, which resulted in darker images for the better observation of changes in local areas in vivo 
. Additionally, to monitor the in vivo performance of calcium phosphate cements, which show a high structural similarity to bone 
, calcium phosphate cements linked with gadolinium (III) by bisphosphonates were developed, and they showed shortened T1 relaxation times of the water in tissues and achieved signal enhancement in a T1-weighted MRI. In this way, the highly accurate evaluation of the implant shape both in MRI and CT for a prolonged time period (about 8 weeks) was achieved 
Calcium phosphate-based nanoparticles are also desirable materials for drug delivery 
. Doxorubicin could activate the immunogenic cell death of tumor cells through an apoptosis pathway, including reactive oxygen species, which could lead to DNA cleavage and mitochondrial dysfunction 
, while the multidrug resistance of cancers may result in poor prognosis 
. To address this issue, a selenium-doped CaP, serving as the doxorubicin carrier, was designed for reversing the multidrug resistance of tumors. Se-doped CaP is pH-sensitive and dox can be released specifically in the tumor sites due to the acid microenvironment. Thus, the uptake of anticancer drugs of tumor cells was raised, and Se ions released could decrease reactive oxygen species of tumor cells and the expression of ATP-binding cassette transporters, which reverse multidrug resistance 
. The surgery of bone tumors causes large bone defects, and calcium phosphate bone pastes have been widely used as bone substitutes in clinics to replace allogenous bone, providing strong and stable support for the defect sites without internal fixation 
, for many years, and the result of anticancer is also well described in the long run 
. Furthermore, there is the theory that calcium ions play a vital role in tumor necrosis by regulating the stability of the intracellular concentration of calcium ions 
, and a high concentration of calcium in the microenvironment of the tumor can encourage tumor calcification 
. Based on this phenomenon, calcium phosphate can combine with some special materials, such as ferritin, which is a promising load for targeted delivery, to protect ferritin from interception to achieve the function of targeted delivery to the tumor effectively, and the shell of calcium phosphate not only counterbalances the acidic microenvironment around tumors but also accelerates the immunomodulation and calcification of cancers 
. CaP nanoparticles can also be coated to camouflage, which may result in intracellular calcium overload and induce apoptosis. For example, TiO2
-coated CaP can elevate the generation of reactive oxygen species, due to the demonstrative property of inorganic sonosensitizers, and can provide calcium ions due to the acidic microenvironment of the tumor