Calcium phosphate-loaded biopolymer composites are among most intensively and increasingly studied research areas, since they can be applied in a wide variety of forms by adjusting their physical–chemical properties to many requirements [1]. The appropriate mixture of biopolymer and bioceramic particles can provide a chemical composition that is similar to native bone and the extracellular matrix, containing inorganic minerals and organic collagenous material [2]. However, weak interfacial bonds have been reported to exist between biopolymers and bioceramic particles, which hinders the perfect formation of bioceramic–biopolymer composite scaffolds for bone repair implementations. In this context, applying certain bonding agents containing two different functional groups can build a so-called molecular bridge between the interface of biopolymer and bioceramic particles that could provide an ideal solution [3]. In this case, one of the functional groups is organophilic in nature and can react with the polymers, while the other type of functional group can attach to the bioceramic surface to create a strong bond. Using these bonding agents, the mechanical properties of composite scaffolds could be improved.

Current general procedure for healing damaged bone structure may involve the use of bone grafts or substitutes [4]. Synthetic bone grafts or substitutes must have appropriate physical structure and mechanical as well as chemical properties. In applications involving high structural loads, It is also important that the bone substitutes can endure the biological conditions without the failure or degradation of implant materials. Fixation of orthopedic implants can lead to structural changes that may cause release of toxic or health-impairing particles or ions [5]. Bioceramics can be produced according to various methods which can generate different phases such as crystalline, polycrystalline, amorphous, or their composites [6]. The biological performance of CaPs is dependent on their physicochemical properties and determines their application potential [7]. Hydroxyapatite (HAp) is regarded as the most thermally and chemically stable phase among the CaPs; therefore, it is an ideal material to produce composites with polymers. Meanwhile, nanostructured CaPs are suitable for drug or gene delivery and carrier systems owing to their large surface areas [8]. It is also known that CaP scaffolds have hierarchical nano- and microstructures, which can provide outstanding assistance in bone healing. The integration of bioceramics into biopolymer matrices is able to mix the strength and osteoconductivity of calcium phosphate-based bioceramics with good mechanical characteristics and controlled bioresorbability of a polymeric matrix. The preparation of composites can be performed either by biopolymer infusion into the porous bioceramic scaffold [9] or by dispersing the ceramic particles into the base polymer solution [10]. In the latter case, the resulting dispersion can be further processed by electrospinning or spin coating onto the implants’ surfaces to produce composite coatings, or the use of specific post-dispersion treatment to obtain the desired scaffold materials ^{[11][12][13][14]}[11,12,13,14]. The main benefits of coating medical devices are the considerable enhancement of their biocompatibility and their long-term stability. In general, bioceramic particles or coatings are able to provide bioactive properties to the polymer matrix. The level of bioactivity can be adjusted by choosing the appropriate weight ratio, particle form and size, and the suitable dispersion of filler agents [15]. It has also been reported that a higher surface-area-to-volume ratio of ceramic particle fillers can cause higher bioactivity [16]. Addition of bioactive particles to bioresorbable polymers can also alter processes of polymer degradation, reportedly due to ion-exchange processes in biological environments ^[17][18][17,18]. This process reportedly imparts a pH-buffering effect at the polymer surface, thus altering the acidic polymer degradation. In similar research, it was observed that biopolymers with embedded HAp/CaP particles degraded consistently owing to water penetration at the interfacial areas [19]. Studies have described how the degradation and resorption mechanisms of composite scaffolds allow the cells to adhere, proliferate, and secrete their extracellular matrix (ECM), whilst the scaffolds gradually degrade, providing new space for bone cells or tissues to grow [20].

2. CaP Containing Biopolymer Composites in Bone Tissue Engineering

CaP fillers can be prepared synthetically, using chemicals to precipitate the different phases of calcium phosphate. It is widely recognized that the precipitation parameters and the post-treatment of the resulting powder determine the final phase structure [21]. In most cases, CaP powder is a mixture of the different phases (monetite, brushite, hydroxyapatite, tricalcium-phosphate, or even amorphous apatites) in various ratios. The different phases show different morphologies that affect their chemical and biological performances. The phase purity can be improved by applying appropriate post-treatments. The quality of calcium precursors used also affects the morphology, and the particle size and shape [22]. Other methods applied for CaP preparation include hydrothermal ^[23][24][25][23,24,25], sol-gel ^[26][27][26,27], electrochemical [28], solid phase powder milling ^[29][30][31][29,30,31], and spray freeze-drying techniques ^[32][33][32,33]. Additionally, because the human bone contains trace elements such as Mg, Zn, Sr, etc., the mineralization of CaP particles with such bioactive ions makes them more biocompatible. Generally, the ionic substitutions can be rendered cationic by replacing the Ca²⁺ with Mg²⁺, Zn²⁺, Sr²⁺, Si⁴⁺ ions, or anionic when the PO₄³⁻ groups are substituted by CO₃²⁻ or fluoride anions. The preparations, thorough characterizations, and properties of these materials have been exhaustively studied and reported in numerous papers and summarized in reviews ^{[34][35][36][37][38][39][40]}[34,35,36,37,38,39,40]. A further purpose of ionic substitution is to achieve antibacterial properties, using silver or other specific additives ^[41][42][41,42]. Furthermore, there is an emerging effort to prepare CaP particles from natural sources, such as fishbone ^[43][44][43,44], oyster shell [45], eggshell ^[46][47][46,47], mussel shell [48], snail shell [49], as well as bovine origins, and marble [50]. Reports on the naturally derived CaP powders indicate that these alternatives are more environmentally friendly, sustainable, and cost-effective compared with synthetic preparations. In addition, waste recycling is an urgent contemporary issue, since waste generation puts a huge burden on the environment. These natural preparation methods also provide good solutions in this context, able to turn unwanted waste into important functional material. Another advantage of using these materials is that trace elements such as Mg, Na, K, and Sr as well as carbonate anions can be found in CaPs prepared from organic source, which is important for bioactivity [51]. In this case, the preferred preparation method has been calcination, which can generate HAp powders with high crystallinity, in a process capable of fast and economic production requiring less chemical consumption [51]. However, it is important to mention their disadvantages, since the CaPs obtained from natural sources may contain contaminants harmful to the human body, which cannot be eliminated by heat treatment. Moreover, the concentrations and ratios of trace elements are strongly dependent on the source material, and living organisms contain different amounts of minerals depending on species, age, and other factors. These factors are hard to control, so the reproducibility of these CaPs is problematic. This fact may impede their applicability in clinical or pharmaceutical use, as these industries demand the strictest standards for biomaterials.