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Hydroxyapatite (HA) is widely used in bone tissue engineering for its bioactivity and biocompatibility, and a growing number of researchers are exploring ways to improve the physical properties and biological functions of hydroxyapatite. Up to now, HA has been used as inorganic building blocks for tissue engineering or as nanofillers to blend with polymers, furthermore, various methods such as ion doping or surface modification have been also reported to prepare functionalized HA. In this review, we try to give a brief and comprehensive introduction about HA-based materials, including ion-doped HA, HA/polymer composites and surface modified HA and their applications in bone tissue engineering. In addition, the prospective of HA is also discussed. This review may be helpful for researchers to get a general understanding about the development of hydroxyapatite based materials.
- Introduction Bone defects resulting from tumors, trauma or abnormal development frequently require surgical intervention requiring bone grafts. Autografts present important osteogenic characteristics that represent the “gold standard” [ 1 ]. However, this method has been associated with various drawbacks, such as donor site morbidity in the way of infection, pain, and hematoma formation. The limited supply of autograft tissue and the potential risks with allografts have inspired surgeons and engineers to explore new methods to repair bone defects. Among all the reported methods, tissue engineering [ 2 ], which is a comprehensive application of multidisciplinary methods to improve or replace biological tissues, has provided a new choice for the treatment of bone defects. There are several factors that have critical effects in the process of tissue
engineering; the tissue engineering scaffolds are the primary factor in bone tissue engineering [ 3 ]. Furthermore, the ideal materials used for bone tissue engineering should have good bone conductivity and inductivity properties [ 4 , 5 ]. Hydroxyapatite (Ca 10 (PO 4 ) 6 (OH) 2 , HA), as one of the main components of natural bone, can increase the concentration of local Ca2+, which can activate the proliferation of osteoblasts and promote the growth and differentiation of mesenchymal stem cells (MSC) [ 6 ]. Due to its non-immunogenic properties, biocompatibility, bioactivity and good bone conductivity, HA has been widely used in bone repair [ 7 , 8 , 9 , 10 ]. Up to now, various types of HA-based materials such as pure HA, ion-doped HA, and HA/polymer composites, have been designed and investigated, however, some disadvantages of hydroxyapatite, such as brittleness and easy aggregation still exist [ 11 ]; therefore, there is still a long way to go to prepare satisfying HA-based materials. In recent years, many reviews on hydroxyapatite have been published, and most of them focus on the application and preparation of HA [ 12 , 13 , 14 , 15 ]. Both physicians and materials scientists have paid much attention to the investigation and application of HA-based materials. In our opinion, it is a simple and effective method for new researchers to quickly get a whole understanding about HA by reading review works. Thus, in this review, we try to give a brief and comprehensive summary about HA- based materials, which includes ion-doped hydroxyapatite, hydroxyapatite polymer composites and surface modified hydroxyapatite; meanwhile, their applications in bone tissue engineering will also be introduced. Furthermore,
The content of HA will affect the mechanical properties of HA/PLA composites; furthermore, the HA/PLA composites have been prepared into various bone repair medical devices, such as the miniscrew and microplate. Y. Shikinami’s group used PLA composites with 30 wt% HA content for the miniscrew and 40 wt% HA for the microplate, respectively. It was found that although the mechanical property of the composite device was slightly lower than that of natural cortical bone, its strength was much higher than that of pure PLA, and it had excellent fatigue resistance. It can maintain 70% of the initial strength even after alternating bending 60 times, without any damage, while the metal device fully broke off 8 times [ 94 ]. There were also many other types of HA/PLA composites, for example, to mimic the nano-fribrous structure of natural extracellular matrix, nano-fibrous HA/PLA porous scaffold was fabricated by thermally induced phase separation (TIPS) method; the compressive modulus of pure PLA scaffold was only 0.2 MPa, while that of HA/PLA composite scaffold at 20:80 (weight ratio) was as high as 0.63 MPa, which was about three times that of pure PLA [ 95 ]. HA/PLA showed good biocompatibility in cell adhesion and proliferation towards MC3T3-E1 osteoblast precursor cells, MG-63 osteosarcoma cell and L929 fibroblast cells, and the expression of bone specific marker (osteocalcin) was increased [ 96 , 97 , 98 ]. Cell survival and adhesion can be regulated by protein preadsorption on the substrates [ 99 ]. The protein adsorption of HA/PLA composite scaffolds was studied by incubating the scaffolds in FBS/PBS solution. The addition of HA increased the adsorption capacity of protein. Compared with the PLA scaffold, HA/PLA 50:50 and HA/PLA 70:30 composite
scaffolds absorbed 2.4 and 3.2 times serum protein, respectively [ 100 ]. HA/PLA composites can improve osteogenic response in vitro and osteogenesis in vivo [ 101 , 102 , 103 ]. In pure PLA scaffolds, osteoblasts mainly adhered to the outer surface of the polymer. In contrast, osteoblasts were embedded into HA/PLA scaffolds and distributed evenly, and when cultured in vitro for 6 weeks, the expression of bone specific markers (coding bone sialoprotein and osteocalcin) was more abundant in HA/PLA [ 104 ]. The ALP of the HA/PLA composite fiber was significantly higher than that of the pure PLA fiber after 7 days culture [ 101 ]. Based on these in vitro results, HA/PLA nanocomposite fibers are believed to promote the adhesion and growth of osteoblasts and stimulate them to play the functional activities of bone related cells. HA/PLA composite has been widely investigated. However, the biodegradable acid product of PLA may have a negative effect; while HA can effectively neutralize the acidic products, creating a microenvironment conducive to wound healing and bone formation, some in vivo results have demonstrated that HA/PLA scaffolds had good osteogenic capability showing their potential as bone graft substitutes in reconstructive surgery [ 105 ]. In order to fulfil improving the functions of HA/PLA scaffolds, other materials such as collagen or growth factors may be blended with HA/PLA; for example, PLA/HA/collagen scaffold loaded with recombinant human bone morphogenetic protein 2 (rh-BMP 2) was implanted into the defect site of rabbit radius. After 12 weeks, the scaffold was completely fused with the defect area, showing the replacement of new bone (trabecular)
significantly higher than that in the PLGA nanofiber group. After 21 days of culture, the amount of ALP and calcium deposition in the HA/PLGA group was 1.5 and 2. times higher than that in the PLGA group, respectively [ 112 ]. Petrica and colleagues produced HA/PLGA composites and found that 30% HA added into the polymer would maximize the material osteoconductivity [ 114 ]. In the animal experiment of mandibular defect, HA/PLGA scaffold showed a small amount of trabecular bone formed by osteoblasts at 6 weeks, and transformed into mature bone tissue at the end of 12 weeks, but it took 48 weeks for the PLGA control scaffold to form mature bone tissue to fill the defect [ 115 ]. The mechanism may be related to the addition of hydroxyapatite, which is more favorable to the deposition of calcium and phosphorus ions, and the fact that HA can reduce the degradation rate of PLGA and control the pH value during degradation.
