Complementary and synergistic effects on osteogenic and angiogenic properties of copper-incorporated silicocarnotite bioceramic: In vitro and in vivo studies.

Promoting bone regeneration to treat bone defects is a challenging problem in orthopedics, and developing novel biomaterials with both osteogenic and angiogenic activities is sought as a feasible solution. Here, copper-silicocarnotite [Cu-Ca5(PO4)2SiO4, Cu-CPS] was designed and fabricated. In this study, the Cu-CPS ceramics demonstrated better mechanical, osteogenic, and angiogenic properties in vitro and in vivo than pure CPS one. Particularly, CPS with 1.0 wt% CuO (1.0Cu-CPS) exhibited the best performance. Additionally, hydroxyapatite with 1.0 wt% CuO (1.0Cu-HA) was used to explore the respective effects of copper and silicon (Si). According to the in vitro results, it indicated that Cu enhanced the osteogenic activity of CPS ceramics although Si played a dominate role in the osteogenic process. Moreover, Cu could promote an early stage of angiogenesis, and the complementary effect of Si and Cu was found in the late phase. Furthermore, the in vivo results illustrated that the synergistic effect of Cu and Si improved bone and vessel regeneration during the degradation of Cu-CPS scaffolds (P < 0.05). Therefore, Cu-CPS ceramics could improve osteogenesis and angiogenesis through the simultaneous effects of Cu and Si, thus, offering a promising treatment option in orthopedic application for bone tissue regeneration.

High-Dose TGF-ß1 Impairs Mesenchymal Stem Cell-Mediated Bone Regeneration via Bmp2 Inhibition.

Transforming growth factor-ß1 (TGF-ß1) is a key factor in bone reconstruction. However, its pathophysiological role in non-union and bone repair remains unclear. Here we demonstrated that TGF-ß1 was highly expressed in both C57BL/6 mice where new bone formation was impaired after autologous bone marrow mesenchymal stem cell (BMMSC) implantation in non-union patients. High doses of TGF-ß1 inhibited BMMSC osteogenesis and attenuated bone regeneration in vivo. Furthermore, different TGF-ß1 levels exhibited opposite effects on osteogenic differentiation and bone healing. Mechanistically, low TGF-ß1 doses activated smad3, promoted their binding to bone morphogenetic protein 2 (Bmp2) promoter, and upregulated Bmp2 expression in BMMSCs. By contrast, Bmp2 transcription was inhibited by changing smad3 binding sites on its promoter at high TGF-ß1 levels. In addition, high TGF-ß1 doses increased tomoregulin-1 (Tmeff1) levels, resulting in the repression of Bmp2 and bone formation in mice. Treatment with the TGF-ß1 inhibitor SB431542 significantly rescued BMMSC osteogenesis and accelerated bone regeneration. Our study suggests that high-dose TGF-ß1 dampens BMMSC-mediated bone regeneration by activating canonical TGF-ß/smad3 signaling and inhibiting Bmp2 via direct and indirect mechanisms. These data collectively show a previously unrecognized mechanism of TGF-ß1 in bone repair, and TGF-ß1 is an effective therapeutic target for treating bone regeneration disability. © 2019 American Society for Bone and Mineral Research.

Serum copper levels are associated with bone mineral density and total fracture.

BACKGROUND: Both copper deficiency and overexposure have been associated with adverse health effects. Evidence linking copper to bone mineral density (BMD) and total fracture, however, is limited. METHODS: This nationally representative cross-sectional study enrolled participants from the National Health and Nutrition Examination Survey (2011-2014) in the United States. Using unadjusted and multivariate adjusted logistic regression analyses and a two-piecewise linear regression model with a smoothing function, we evaluated the associations between serum copper levels, bone mineral density and total fracture in 722 participants. RESULTS: The study sample (n = 722, mean age: 56.47 ± 11.55 y) represented a population of which 47.2% were men; 43.91% were non-Hispanic white, 18.84% non-Hispanic black and 13.71% Mexican American; 25.9% had total fracture. In the multivariate logistic regression analysis, individuals in the lowest category (<98.5 µg/dL) of serum copper concentration had 0.049 g/cm2 lower total femur BMD and 0.045 g/cm2 lower femoral neck BMD than those in the second concentration category (98.5-114 µg/dL). Individuals in the highest category (≥134 µg/dL) of serum copper concentration had an approximately 4-fold increase in the risk of total fracture than those in the second concentration category. There were no significant associations between per 10 µg/dL increases in serum copper levels and total fracture in multivariate logistic regression analysis after multivariate adjustment (all p > 0.05). However, a differential association between serum copper levels and total fractures between men and women was observed (odds ratio = 1.81, 95% confidence interval 1.08-3.03, p = 0.026 for men and odds ratio = 1.07, 95% confidence interval 0.86-1.32, p = 0.552 for women). CONCLUSION: Moderate serum copper levels are critically important for bone health. Lower serum copper levels are significantly associated with decreased BMD in the total femur and femoral neck. Higher serum copper levels are significantly associated with increased total fracture, especially in men. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: The impact of serum copper concentrations on bone mineral density and total fracture can provide insights into clinical application of copper-containing supplements and biomaterials.

In vivo therapeutic efficacy of TNFα silencing by folate-PEG-chitosan-DEAE/siRNA nanoparticles in arthritic mice.

BACKGROUND: Tumor necrosis factor-alpha (TNFα), a pro-inflammatory cytokine, has been shown to play a role in the pathophysiology of rheumatoid arthritis. Silencing TNFα expression with small interfering RNA (siRNA) is a promising approach to treatment of the condition. METHODS: Towards this end, our team has developed a modified chitosan (CH) nanocarrier, deploying folic acid, diethylethylamine (DEAE) and polyethylene glycol (PEG) (folate-PEG-CH-DEAE15). The gene carrier protects siRNA against nuclease destruction, its ligands facilitate siRNA uptake via cell surface receptors, and it provides improved solubility at neutral pH with transport of its load into target cells. In the present study, nanoparticles were prepared with siRNA-TNFα, DEAE, and folic acid-CH derivative. Nanoparticle size and zeta potential were verified by dynamic light scattering. Their TNFα-knockdown effects were tested in a murine collagen antibody-induced arthritis model. TNFα expression was examined along with measurements of various cartilage and bone turnover markers by performing histology and microcomputed tomography analysis. RESULTS: We demonstrated that folate-PEG-CH-DEAE15/siRNA nanoparticles did not alter cell viability, and significantly decreased inflammation, as demonstrated by improved clinical scores and lower TNFα protein concentrations in target tissues. This siRNA nanocarrier also decreased articular cartilage destruction and bone loss. CONCLUSION: The results indicate that folate-PEG-CH-DEAE15 nanoparticles are a safe and effective platform for nonviral gene delivery of siRNA, and their potential clinical applications warrant further investigation.

Andrographolide prevents human breast cancer-induced osteoclastic bone loss via attenuated RANKL signaling.

Bone metastasis is a common and serious complication in advanced cancers such as breast cancer, prostate cancer, and multiple myeloma. Agents that prevent bone loss could be used to develop an alternative therapy for bone metastasis. RANKL, a member of the tumor necrosis factor superfamily, has been shown to play a significant role in cancer-associated bone loss. In this study, we examined the efficacy of the natural compound andrographolide (AP), a diterpenoid lactone isolated from the traditional Chinese and Indian medicinal plant Andrographis paniculata, in reducing breast cancer-induced osteolysis. AP prevented human breast cancer-induced bone loss by suppressing RANKL-mediated and human breast cancer cell-induced osteoclast differentiation. Molecular analysis revealed that AP prevented osteoclast function by inhibiting RANKL-induced NF-κB and ERK signaling pathway in lower dose (20 µM), as well as inducing apoptosis at higher dose (40 µM). Thus, AP is a potent inhibitor of breast cancer-induced bone metastasis.

Mesoporous bioactive glass as a drug delivery system: fabrication, bactericidal properties and biocompatibility.

Implant-associated infection remains a difficult medical problem in orthopaedic surgery. Here, we report on the fabrication of gentamicin-loaded mesoporous bioactive glass (Gent-MBG) for use as a controlled antibiotic delivery system to achieve the sustained release of antibiotics in the local sites of bone defects. The high surface area and mesoporous structure of MBG enable higher drug loading efficiency (79-83 %) than non-mesoporous biological glass (NBG) (18-19 %). Gent-MBG exhibits sustained drug release for more than 6 days, and this controlled release of gentamicin significantly inhibits bacterial adhesion and prevents biofilm formation by S. aureus (ATCC25923) and S. epidermidis (ATCC35984). Biocompatibility tests with human bone marrow stromal cells (hBMSCs) indicate that MBG has better biocompatibility than NBG. Therefore, Gent-MBG can be used as a controlled drug delivery system to prevent and/or treat orthopedic peri-implant infections.

Magnesium and the risk of cardiovascular events: a meta-analysis of prospective cohort studies.

BACKGROUND: Prospective studies that have examined the association between dietary magnesium intake and serum magnesium concentrations and the risk of cardiovascular disease (CVD) events have reported conflicting findings. We undertook a meta-analysis to evaluate the association between dietary magnesium intake and serum magnesium concentrations and the risk of total CVD events. METHODOLOGY/PRINCIPAL FINDINGS: We performed systematic searches on MEDLINE, EMBASE, and OVID up to February 1, 2012 without limits. Categorical, linear, and nonlinear, dose-response, heterogeneity, publication bias, subgroup, and meta-regression analysis were performed. The analysis included 532,979 participants from 19 studies (11 studies on dietary magnesium intake, 6 studies on serum magnesium concentrations, and 2 studies on both) with 19,926 CVD events. The pooled relative risks of total CVD events for the highest vs. lowest category of dietary magnesium intake and serum magnesium concentrations were 0.85 (95% confidence interval 0.78 to 0.92) and 0.77 (0.66 to 0.87), respectively. In linear dose-response analysis, only serum magnesium concentrations ranging from 1.44 to 1.8 mEq/L were significantly associated with total CVD events risk (0.91, 0.85 to 0.97) per 0.1 mEq/L (P(nonlinearity)= 0.465). However, significant inverse associations emerged in nonlinear models for dietary magnesium intake (P(nonlinearity)= 0.024). The greatest risk reduction occurred when intake increased from 150 to 400 mg/d. There was no evidence of publication bias. CONCLUSIONS/SIGNIFICANCE: There is a statistically significant nonlinear inverse association between dietary magnesium intake and total CVD events risk. Serum magnesium concentrations are linearly and inversely associated with the risk of total CVD events.

Effects of Baduanjin () exercise on knee osteoarthritis: a one-year study.

OBJECTIVES: Knee osteoarthritis (OA) is a major cause of pain and functional limitation. Short-term Baduanjin () exercise had been testified to be beneficial to the disease. This study conducted an initial assessment of the one-year Baduanjin exercise on knee OA. METHODS: The recruited patients practiced Baduanjin at the community recreational center. Sessions were held for 30 min five times a week for one year. Knee pain, stiffness, physical disability, general health, knee extensors and flexors strength, and aerobic ability were measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Medical Outcomes Study Short Form-36 (SF-36), the 6-Minute Walk Test (6-MWT), and the Isokinetic Strength of the Knee Extensors and Flexors (ISKEF). Body mass index (BMI) was also calculated before and after the study period for comparison. RESULTS: Twenty-eight patients signed the informed consent. Six patients withdrew from the trial. Twenty-two patients (29 knees) completed the one-year study. After one-year Baduanjin exercise, WOMAC pain (132.0±69.6 vs. 56.2±67.6, P=0.000), stiffness (64.7±54.8 vs. 22.3±34.6, P=0.000), and physical function subscales (386.1±275.8 vs. 182.0±235.7, P=0.003); SF-36 body pain (45.7±20.0 vs. 57.4±17.9, P=0.005), general health (50.5±20.0 vs. 62.1±16.1, P=0.004), role emotional (64.4±26.1 vs. 73.5±21.3, P=0.047), and health transition (3.3±1.0 vs. 2.6±1.0, P=0.008); BMI (25.0±2.9 vs. 24.4±2.9, P=0.032); 6-MWT (565.7±94.6 vs. 610.5±66.7, P=0.036); and ISKEF Peak Torque (the Knee Extensors: 60.5±25.5 vs. 76.8±31, P=0.000; the Knee Flexors: 29.3±15.9 vs. 37.1±15.8, P=0.001) were significantly improved. No adverse effects resulted from the exercise. CONCLUSIONS: It suggested that the long-term Baduanjin could be a feasible and safe exercise option for knee OA.

Hydrodynamic delivery of chitosan-folate-DNA nanoparticles in rats with adjuvant-induced arthritis.

50 kDa chitosan was conjugated with folate, a specific tissue-targeting ligand. Nanoparticles such as chitosan-DNA and folate-chitosan-DNA were prepared by coacervation process. The hydrodynamic intravenous injection of nanoparticles was performed in the right posterior paw in normal and arthritic rats. Our results demonstrated that the fluorescence intensity of DsRed detected was 5 to 12 times more in the right soleus muscle and in the right gastro muscle than other tissue sections. ß-galactosidase gene expression with X-gal substrate and folate-chitosan-plasmid nanoparticles showed best coloration in the soleus muscle. Treated arthritic animals also showed a significant decrease in paw swelling and IL-1ß and PGE2 concentration in serum compared to untreated rats. This study demonstrated that a nonviral gene therapeutic approach using hydrodynamic delivery could help transfect more efficiently folate-chitosan-DNA nanoparticles in vitro/in vivo and could decrease inflammation in arthritic rats.

[Research advance of treatment of peripheral nerve injury with neuromuscular electric stimulation].

OBJECTIVE: To review researches of treatment of peripheral nerve injury with neuromuscular electrical stimulation (NMES) regarding mechanism, parameters, and clinical application at home and abroad. METHODS: The latest original literature concerning treatment of peripheral nerve injury with NMES was extensively reviewed. RESULTS: NMES should be used under individual parameters and proper mode of stimulation at early stage of injury. It could promote nerve regeneration and prevent muscle atrophy. CONCLUSION: NMES plays an important role in clinical application of treating peripheral nerve injury, and implantable stimulation will be the future.

In vitro and in vivo evaluation of akermanite bioceramics for bone regeneration.

This study investigated the effects of a calcium magnesium silicate bioceramic (akermanite) for bone regeneration in vitro and in vivo, with beta-tricalcium phosphate (beta-TCP) as a control. In vitro, the human bone marrow-derived mesenchymal stromal cells (hBMSCs) were cultured in an osteogenic medium supplemented with a certain concentration of two bioceramics' extracts for 20 days. An MTT assay showed that akermanite extract promoted proliferation of hBMSC significantly more than did beta-TCP extract. The results of alkaline phosphatase (ALP) activity test and the expression of osteogenic marker genes such as ALP, osteopontin (OPN), osteocalcin (OCN) and bone sialoprotein (BSP) demonstrated that the osteogenic differentiation of hBMSC was enhanced more by akermanite extract than by beta-TCP extract. In vivo, a histomorphology analysis and histomorphometry of the two porous bioceramics implants in rabbit femur defect models indicated that both in early- and late-stage implantations, akermanite promoted more osteogenesis and biodegradation than did beta-TCP; and in late-stage implantations, the rate of new bone formation was faster in akermanite than in beta-TCP. These results suggest that akermanite might be a potential and attractive bioceramic for tissue engineering.

Effects of naringin on the proliferation and osteogenic differentiation of human bone mesenchymal stem cell.

Rhizoma drynariae is used commonly in the treatment of osteoporosis and bone nonunion in traditional Chinese medicine. Modern pharmacological research indicates that naringin is the main effective component of rhizoma drynariae, which can induce the expression of the osteogenic marker in the osteoblast cell line. However, no former study has described its effect on bone mesenchymal stem cells (BMSCs). In our experiment, we co-cultured human BMSCs with different concentrations of naringin solution, then the osteogenic differentiation markers and proliferation ability were analyzed. The results indicated that a certain concentration (1-100 microg/ml) of the naringin solution may enhance the proliferation and osteogenic differentiation of human BMSCs. Also, our research explains excellently the anti-osteoporotic and bone nonunion treatment mechanism of rhizoma drynariae, thus contributing to the exploration of osteogenic differentiation agents from Chinese herbs.

Proliferation and osteoblastic differentiation of human bone marrow stromal cells on hydroxyapatite/bacterial cellulose nanocomposite scaffolds.

In this study, we prepared hydroxyapatite/bacterial cellulose (HAp/BC) nanocomposite scaffolds utilizing the biomimetic technique, and investigated the proliferation and osteoblastic differentiation of stromal cells derived from human bone marrow (hBMSC) on them. Scanning electron microscopy proved that cells could adhere and spread on scaffolds. The hBMSC seeded on the nanocomposites exhibited better adhesion and activity than those seeded upon the pure BC. After 6 days of culture on scaffolds, the cells proliferated faster on the nanocomposites than on the pure BC, as assessed by Alamar Blue assay. Real-time reverse transcription PCR results showed that the alkaline phosphatase (ALP) activity of hBMSC and the expression of osteopontin, osteocalcin, bone sialoprotein, and ALP mRNA were all higher for up to 7 days for hBMSC cultured on the nanocomposites than for those cultured upon the pure BC with and without the presence of osteogenic supplements (L-ascorbic acid, glycerophosphate, and dexamethasone, p<0.05). These results suggest that the attachment, proliferation, and differentiation in cultured hBMSC can be modulated by the HAp/BC nanocomposite scaffold properties. In summary, we have developed a scaffold that displays in vitro biocompatibility, which may have potential use for bone tissue engineering.

Effect of berberine on Staphylococcus epidermidis biofilm formation.

Staphylococcus epidermidis is one of the main causes of medical device-related infections owing to its adhesion and biofilm-forming abilities on biomaterial surfaces. Berberine is an isoquinoline-type alkaloid isolated from Coptidis rhizoma (huang lian in Chinese) and other herbs with many activities against various disorders. Although the inhibitory effects of berberine on planktonic bacteria have been investigated in a few studies, the capacity of berberine to inhibit biofilm formation has not been reported to date. In this study, we observed that berberine is bacteriostatic for S. epidermidis and that sub-minimal inhibitory concentrations of berberine blocked the formation of S.epidermidis biofilm. Using viability assays and berberine uptake testing, berberine at a concentration of 15-30mug/mL was shown to inhibit bacterial metabolism. Data from this study also indicated that modest concentrations of berberine (30-45mug/mL) were sufficient to exhibit an antibacterial effect and to inhibit biofilm formation significantly, as shown by the tissue culture plate (TCP) method, confocal laser scanning microscopy and scanning electron microscopy for both S. epidermidis ATCC 35984 and a clinical isolate strain SE243. Although the mechanisms of bacterial killing and inhibition of biofilm formation are not fully understood, data from this investigation indicated a potential application for berberine as an adjuvant therapeutic agent for the prevention of biofilm-related infections.

Bone-protective effects of nonviral gene therapy with folate-chitosan DNA nanoparticle containing interleukin-1 receptor antagonist gene in rats with adjuvant-induced arthritis.

Interleukin-1 receptor antagonist (IL-1Ra), is a natural blocker of the inflammatory cytokine interleukin-1. Using a rat adjuvant-induced arthritis (AIA) model of rheumatoid arthritis (RA), we examined the protective effects of IL-1Ra in bone metabolism in vivo after folate-mediated nonviral gene delivery. We detected secreted human IL-1Ra protein in serum and cultured primary osteoblasts of rats that were treated with chitosan-IL-1Ra and folate-IL-1Ra-chitosan nanoparticles, respectively. In vivo, IL-1Ra gene delivery significantly reverted alterations in bone turnover observed in arthritic animals by modulating the level of osteocalcin (OC) as well as the activities of alkaline phosphatase and tartrate-resistant acid phosphatase. The protective effects of these nanoparticles were evident from the decrease in the expression levels of interleukine-1beta and prostaglandin E(2) as well as osteoclast number and other histopathological findings. Compared to naked DNA and chitosan-DNA, folate-chitosan-DNA nanoparticles were less cytotoxic and enhanced IL-1Ra protein synthesis in vitro and offered a better protection against inflammation and abnormal bone metabolism in vivo. Nonviral gene therapy with folate-chitosan-DNA nanoparticles containing the IL-1 Ra gene seemed to protect against bone damage and inflammation in rat adjuvant-induced arthritis model.

Baduanjin alleviates the symptoms of knee osteoarthritis.

OBJECTIVES: To assess the feasibility and safety of using the health-promoting traditional Chinese exercise, known as Baduanjin, in treating knee osteoarthritis (OA). SUBJECTS: Twenty-eight (28) female patients who met the American College of Rheumatology criteria for osteoarthritis of the knee signed the informed consent and were randomized into the Baduanjin group (n=14) and the control group (n=14). Eleven (11) patients in the Baduanjin group and 10 patients in the control group completed the trial. INTERVENTION: The Baduanjin group patients exercised following taped commands in the community entertainment room during 30-minute classes five times a week for 8 weeks, whereas the control group received no treatment. OUTCOME MEASURES: Indicators that include knee pain, stiffness, physical disability, general health, quadriceps strength, and aerobic ability were measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Medical Outcomes Study Short Form-36 (SF-36), the 6-Minute Walk Test (6-MWT), and the Isokinetic Strength of the Knee Extensors (ISKE). RESULTS: Compared with the control group, the participants in the Baduanjin group had statistically significant improvements in percentage changes of the WOMAC pain subscale (-61.8+/-35.7% versus 44.6+/-102.8%; p=0.006), the WOMAC stiffness subscale (-53.4+/-46.1% versus 135.8+/-386.7%; p=0.029), the WOMAC physical function subscale (-7.4+/-81.9% versus 140.5+/-151.9%; p=0.024), 6-MWT (11.9+/-7.5% versus 1.6+/-13.0%; p=0.036), and Peak Torque of the ISKE (15.1+/-33.7% versus -16.1+/-16.6%; p=0.016). The SF-36's General Health, Social Function, and Mental Health subscales had no significant changes between those in the Baduanjin and control groups. As such, no adverse events from treatment were reported. CONCLUSIONS: This study suggested that the Baduanjin exercise provided a safe and feasible treatment option for patients with knee OA, as well as offered reductions in pain, stiffness, and disability, which helped improve the patients' quadriceps strength and aerobic ability.

In vitro proliferation and differentiation of human mesenchymal stem cells cultured in autologous plasma derived from bone marrow.

Expansion of human mesenchymal stem cells (hMSCs) in medium supplemented with fetal bovine serum (FBS) has a potential risk of transmitting viral and prion diseases and causing immunological rejection. The aim of our present study was to find a substitute for the traditional FBS in culture of hMSCs to facilitate the clinical application of hMSCs. We used autologous plasma derived from bone marrow (APM) as a substitute for FBS and found that, when cultured with APM, the cell surface markers and the proportion of hMSCs in the G(0)/G(1) phase and the S+G(2)/M phase resembled those cultured with FBS. However, there were fewer early apoptotic cells in APM-supplemented medium than in FBS (p < 0.01). APM resulted in much greater thymidine incorporation than FBS (p < 0.001). There were significantly more alkaline phosphatase (ALP)-positive fibroblast colony-forming units (CFU-Fs) covering larger areas in APM than in FBS (p < 0.01). Also, APM induced greater ALP activity, more mineralized nodules, and greater expression of osteogenic genes than did FBS. In addition, when cultured in adipogenic medium, there were fewer oil-red O-positive cells and lower expression of adipogenic gene with APM than with FBS. In conclusion, expansion of hMSCs in APM-supplemented medium instead of traditional FBS is more advantageous. It could promote cell proliferation, enhance osteogenic differentiation, and suppress adipogenic differentiation of hMSCs and is therefore a safer and more effective substitute for FBS in clinical cytotherapy processes.

[Effect of melittin on apoptosis and necrosis of U2 OS cells].

OBJECTIVE: To study the effect of melittin on apoptsis and necrosis of osteosarcoma cell line U2 OS in vitro. METHODS: Osteosarcoma cell line U2 OS was treated with melittin. The growth and proliferation was observed by MTT assay and cell counting, and the necrosis was estimated by Trypan blue staining. The cell apoptsis, Fas and Apo2. 7 expression were detected by cytometer. RESULTS: The data showed that melittin could inhibit the proliferation of U2 OS dose-dependently at 16 and 64 mg/L. Cell apoptsis was detected by cytometer, when the cells were treated by 16 mg/L and 32 mg/L of melittin respectively, and the percentages of Fas and Apo2. 7 positive cells were increased. CONCLUSION: Melittin inhibits the proliferation of osterosarcoma cell line through up-regulating Fas expression and inducing apoptsis.

[Research development of hydroxyapatite-based composites used as hard tissue replacement].

Hydroxyapatite has been considered as the most promising materials for hard tissue replacements, due to its similar chemical composition and crystallographic structure to that of bone mineral. But the brittleness is one of the most serious obstacles for its wider applications as load-bearing implants. Therefore, various HA composites get much attention. In the present paper, HA composites were introduced according to the kind of reinforcement. Although bioactive ceramics, bioactive glass or glass-ceramic, bio-inactive ceramics, polymers and metals all have been used to fabricate HA composites, no one can well satisfy the requirements for hard tissue replacement. The vital problem of the existing HA composites is that the biological properties cannot match with the mechanical properties well.