In vivo cancellous bone remodeling on a strontium-containing hydroxyapatite (sr-HA) bioactive cement

The purpose of this study was to investigate the in vivo bone response to the strontium-containing hydroxyapatite (Sr-HA) bioactive bone cement injected into the cancellous bone. Sr-HA cement was injected into the iliac crest of rabbits for 1, 3, and 6 months. Active bone formation and remodeling were observed after 1 month. Newly formed bone was observed to grow onto the bone cement after 3 months. Thick osteoid layer with osteoblasts formed along the bone and guided over the bone cement surface reflected the stimulating effect of Sr-HA. From scanning electron microscopy (SEM) and energy-dispersive X-ray (EDX) analysis, high calcium and phosphorus levels were detected at the interface with a thick layer of 70 microm in width, and fusion of Sr-HA with the bone was observed. Blood vessels were found developing in remodeling sites. The affinity of bone on Sr-HA cement was increased from 73.55 +/- 3.50% after 3 months up to 85.15 +/- 2.74% after 6 months (p < 0.01). In contrast to Sr-HA cement, poly(methyl methacrylate) (PMMA) bone cement was neither osteoconductive nor bioresorbable. Results show that the Sr-HA cement is biocompatible and osteoconductive, which is suitable for use in treating osteoporotic vertebral fractures.     

Development of a strontium-containing hydroxyapatite bone cement

A new route was developed to synthesis a new type of strontium-containing hydroxyapatite (Sr-HAP) bone cement with precursors of tetracalcium phosphate (TTCP), strontium hydrogen phosphate (DSPA), dicalcium phosphate (DCPA), phosphate acid and water. The processing parameters and fundamental properties including pH value, setting time, compressive strength of final hardened body and the cytotoxicity for serial extracts of each cements were investigated. The result shows that the final product of the cement after setting for 24h is nonstoichiometic Sr-containing hydroxyapatite (Ca(10-m-x)Sr(x) square(m)(HPO4)y(PO4)6-y(OH)2-2m square2m, 0相似文献   

Surface treatment of injectable strontium-containing bioactive bone cement for vertebroplasty

A novel injectable bioactive bone-bonding cement (SrHAC) composed of strontium-containing hydroxyapatite (Sr-HA) as the inorganic filler and bisphenol A diglycidylether dimethacrylate (Bis-GMA) as the organic matrix for vertebroplasty was developed previously. In this study, the Sr-HA powders were surface treated with methyl methacrylate (MMA) to improve the interface integration of the two phases. After surface treatment, the compression strength and Young's modulus, which were tested after immersion in distilled water at 37 degrees C for 24 h according to ISO 5833, were increased by 68.65 % (p <.001) and 31.02% (p <.001), respectively. The bending strength and bending stiffness of the bioactive bone cement were significantly improved by 54.44% (p <.001) and 83.90% (p <.001). In addition, the handling property of the cement was also enhanced. In vitro biomechanical testing showed that the stiffness of the fractured spine recovered to 82.5% (p <.01) of the intact condition after cementation with surface-treated SrHAC. The failure load of the spine cemented with original and MMA-treated SrHAC improved by 14.25% (p <.05) and 46.91% (p <.05) in comparison with the fractured spines. Results from this study revealed that the MMA-treated SrHAC has a better mechanical effect for orthopedic applications.     

梯度掺锶羟基磷灰石骨水泥的体外细胞生物学性能

背景：锶掺入羟基磷灰石骨水泥后可以改善材料的结晶性和相容性,但产生的细胞毒性以及对细胞表面黏附、增殖和表达的影响还需要深入研究。 目的：观察梯度掺锶羟基磷灰石骨水泥的体外细胞生物学性能。 方法：制备4组羟基磷灰石骨水泥试样,分别编为0%,1%,5%和10%掺锶羟基磷灰石骨水泥,每组取6个平行试样紫外线照射灭菌3 h备用。浸提递质为含体积分数10%胎牛血清的DMEM培养液。按照掺锶羟基磷灰石骨水泥粉末质量∶浸提液=1 g∶10 mL比例配制。选用L-929成纤维细胞和幼兔成骨细胞,对成骨细胞进行鉴定。扫描电镜观察幼兔成骨细胞在梯度掺锶羟基磷灰石骨水泥表面的黏附和增殖情况,细胞的表达情况采用碱性磷酸酶活性检测法检测。 结果与结论：①不同掺锶量羟基磷灰石骨水泥的细胞毒性评级均为0或1级,各试样的细胞毒性与其掺锶量、作用时间、浸提液浓度有一定关联性。②适量锶元素的加入可以促进成骨细胞的黏附、增殖及表达,改善材料的溶解动力学,提高其生物降解性,更加符合临床要求。但目前尚缺乏有关的远期实验结果。     

Interfacial behaviour of strontium-containing hydroxyapatite cement with cancellous and cortical bone

The bone-bonding behaviors of various biomaterials have been extensively investigated. However, the precise mechanisms of bone bonding have not yet been clarified, and the differences in interfacial behaviors of biomaterial bonding with cancellous bone and cortical bone have not yet been understood. In this study, strontium-containing hydroxyapatite (Sr-HA) cement, in which 10% calcium ions were substituted by strontium, was performed in a rabbit hip replacement model. Six months later, the morphology and chemical composition of interfaces between Sr-HA cement with cancellous bone and cortical bone were evaluated by field emission scanning electron microscopy (FESEM) and time-of-flight secondary ion mass spectrometry (ToF-SIMS). Remarkable differences between these two interfaces were suggested both in morphology and chemical compositions. An apatite layer was found between Sr-HA cement and cancellous bone with a thickness of about 70 microm. However, only a very thin interface (about 1 microm) was formed with cortical bone. As for the cancellous bone/cement interface, high ions intensity of Ca, P, Sr, Na, and O were confirmed by FESEM-EDX and ToF-SIMS. Differences in morphology and chemical component between these two interfaces provided convincing evidences for the proposed dissolution-precipitation coupling mechanism in the formation of biological apatite.     

Effect of weight-bearing on bone-bonding behavior of strontium-containing hydroxyapatite bone cement

The purpose of this study was to investigate and compare the chemical composition and nanomechanical properties at the bone-cement interface under non-weight-bearing and weight-bearing conditions, in order to understand the effect of weight-bearing on the bone-bonding behavior of strontium-containing hydroxyapatite (Sr-HA) cement. In one group, Sr-HA cement was injected into rabbit ilium (under non-weight-bearing conditions). Unilateral hip replacement was performed with Sr-HA cement (under weight-bearing conditions) in the other group. Six months later, scanning electron microscopy (SEM) with energy-dispersive X-ray (EDX) analysis and nanoindentation tests were conducted on the interfaces between cancellous bone and the Sr-HA cement. The nanoindentation results revealed two different transitional behaviors under different conditions. nder weight-bearing conditions, both the Young modulus and hardness at the interface were considerably higher than those at either the Sr-HA cement or cancellous bone. On the contrary, under non-weight-bearing conditions, both the Young modulus and hardness values at the interface were lower than those at the cancellous bone, but were higher than the Sr-HA cement. In addition, EDX results showed that the calcium and phosphorus contents at the interface under weight-bearing conditions were considerably higher than those under non-weight-bearing conditions. The differences in chemical composition and nanomechanical properties at the cement-bone interface under two different conditions indicate that weight-bearing produces significant effects on the bone-bonding behavior of the Sr-HA cement.     

Three-dimensional printing of strontium-containing mesoporous bioactive glass scaffolds for bone regeneration

In this study, we fabricated strontium-containing mesoporous bioactive glass (Sr-MBG) scaffolds with controlled architecture and enhanced mechanical strength using a three-dimensional (3-D) printing technique. The study showed that Sr-MBG scaffolds had uniform interconnected macropores and high porosity, and their compressive strength was ∼170 times that of polyurethane foam templated MBG scaffolds. The physicochemical and biological properties of Sr-MBG scaffolds were evaluated by ion dissolution, apatite-forming ability and proliferation, alkaline phosphatase activity, osteogenic expression and extracelluar matrix mineralization of osteoblast-like cells MC3T3-E1. The results showed that Sr-MBG scaffolds exhibited a slower ion dissolution rate and more significant potential to stabilize the pH environment with increasing Sr substitution. Importantly, Sr-MBG scaffolds possessed good apatite-forming ability, and stimulated osteoblast cells’ proliferation and differentiation. Using dexamethasone as a model drug, Sr-MBG scaffolds also showed a sustained drug delivery property for use in local drug delivery therapy, due to their mesoporous structure. Therefore, the 3-D printed Sr-MBG scaffolds combined the advantages of Sr-MBG such as good bone-forming bioactivity, controlled ion release and drug delivery and enhanced mechanical strength, and had potential application in bone regeneration.     

Polymeric micelle-templated synthesis of hydroxyapatite hollow nanoparticles for a drug delivery system

Hydroxyapatite (HA) hollow nanoparticles (HNPs) have great potential in nanoscaled delivery devices due to their small size, excellent biocompatibility and expected high capacity. However, the preparation of HA HNPs for their application in a drug delivery system has rarely been reported because HA has a complicated crystal structure and it is difficult to obtain stable HA HNPs with hollows that are only nanoscaled in size. In the present study, HA HNPs were successfully produced through a novel polymeric micelle-templating method. The micelles were structured with completely insoluble Pluronic P123 molecules at cloud point as the core and Tween-60 molecules as the shell by the hydrophobic interaction of the alkyl chains with the insoluble P123 core. The morphology of the HA HNPs could be transformed from nanospheres to nanotubes by adding citric acid as a cosurfactant. The prepared HA HNPs had a much higher drug payload than traditional nanoparticles, using vancomycin as the model drug. Most importantly, the HA nanotubes were coupled with a layer of citrate molecules on the HA surfaces, which could further improve the drug load efficiency and could form an excellent pH-controlled open/closed gate for drug release with the addition of cationic polyelectrolytes.     

Strontium-containing hydroxyapatite bioactive bone cement in revision hip arthroplasty

Clinical outcome of cemented implants to revision total hip replacement (THR) is not as satisfactory as primary THR, due to the loss of bone stock and normal trabecular pattern. This study evaluated a bioactive bone cement, strontium-containing hydroxyapatite (Sr-HA) bone cement, in a goat revision hip hemi-arthroplasty model, and compared outcomes with polymethylmethacrylate (PMMA) bone cement. Nine months after operation, significantly higher bonding strength was found in the Sr-HA group (3.36+/-1.84 MPa) than in the PMMA bone cement group (1.23+/-0.73 MPa). After detached from the femoral component, the surface of PMMA bone cement mantle was shown relatively smooth, whereas the surface of the Sr-HA bioactive bone cement mantle was uneven, by SEM observation. EDX analysis detected little calcium and no phosphorus on the surface of PMMA bone cement mantle, while high content of calcium (14.03%) and phosphorus (10.37%) was found on the surface of the Sr-HA bone cement mantle. Even higher content of calcium (17.37%) and phosphorus (10.84%) were detected in the concave area. Intimate contact between Sr-HA bioactive bone cement and bone was demonstrated by histological and SEM observation. New bone bonded to the surface of Sr-HA cement and grew along its surface. However, fibrous tissue was observed between PMMA bone cement and bone. The results showed good bioactivity of Sr-HA bioactive bone cement in this revision hip replacement model using goats. This in vivo study also suggested that Sr-HA bioactive bone cement was superior to PMMA bone cement in terms of bone-bonding strength. Use of bioactive bone cement may be a possible solution overcoming problems associated with the use of PMMA bone cement in revision hip replacement.     

Gentamicin-loaded bone cement with clindamycin or fusidic acid added: biofilm formation and antibiotic release

The formation of staphylococcal biofilms on experimental bone cements, loaded with 0.5 or 1.0 g of active gentamicin and an additional equivalent amount of gentamicin, clindamycin, or fusidic acid was investigated. The biofilms were formed in a modified Robbins device over a 3-day time span and the influence of the additional antibiotics was quantified by expressing the number of colony forming units relative to the corresponding bone cement containing only gentamicin. Combinations of gentamicin with either fusidic acid or clindamycin reduced growth of clinical isolates of both gentamicin-sensitive Staphylococcus aureus and gentamicin-resistant coagulase-negative staphylococci to approximately 28%. To determine whether adding a second antibiotic has influence on the gentamicin release, cement blocks were placed in phosphate buffer and aliquots were taken at designated sampling intervals. The influence of the additional antibiotics was quantified by expressing the percentage released of the total amount of antibiotic incorporated in the different bone cements. After 3 days, all bone cements had released similar percentages of gentamicin, whereas more clindamycin and fusidic acid were released after doubling their concentration in the bone cements. In conclusion, bone cements loaded with combinations of gentamicin and clindamycin or fusidic acid are more effective in preventing biofilm formation than bone cements with gentamicin as a single drug. In addition, the presence of clindamycin or fusidic acid in gentamicin-loaded bone cement has no influence on the total gentamicin release.     

靶向给药体系在骨转移瘤中的研究进展

骨骼是除肝脏和肺脏外恶性肿瘤最常见的转移部位.骨转移(bone metastasis)被认为是临床严重的并发症之一.有文献显示超过70％的各类癌症晚期患者会发生骨转移,骨转移会诱发骨痛、病理性骨折、脊髓压迫和高钙血症等,因其导致的死亡率和致残率分别为20％和45％.在保证治疗原发肿瘤的基础上,怎样最大限度的治疗骨转移瘤和诱发最小的副作用是目前医学界研究的热点.靶向给药体系(targeted drug delivery system)包括双磷酸盐类、四环素类、单克隆抗体、聚乙烯亚胺等,它能有效的抑制骨转移,旨在为治疗骨转移提供更有效的策略.     

Hydroxyapatite/poly(epsilon-caprolactone) composite coatings on hydroxyapatite porous bone scaffold for drug delivery

Hydroxyapatite (HA) porous scaffold was coated with HA and polycaprolactone (PCL) composites, and antibiotic drug tetracycline hydrochloride was entrapped within the coating layer. The HA scaffold obtained by a polymeric reticulate method, possessed high porosity ( approximately 87%) and controlled pore size (150-200 microm). Such a well-developed porous structure facilitated usage in a drug delivery system due to its high surface area and blood circulation efficiency. The PCL polymer, as a coating component, was used to improve the brittleness and low strength of the HA scaffold, as well to effectively entrap the drug. To improve the osteoconductivity and bioactivity of the coating layer, HA powder was hybridized with PCL solution to make the HA-PCL composite coating. With alteration in the coating concentration and HA/PCL ratio, the morphology, mechanical properties, and biodegradation behavior were investigated. Increasing the concentration rendered the stems thicker and some pores to be clogged; as well increasing the HA/PCL ratio made the coating surface be rough due to the large amount of HA particles. However, for all concentrations and compositions, uniform coatings were formed, i.e., with the HA particles being dispersed homogeneously in the PCL sheet. With the composite coating, the mechanical properties, such as compressive strength and elastic modulus were improved by several orders of magnitude. These improvements were more significant with thicker coatings, while little difference was observed with the HA/PCL ratio. The in vitro biodegradation of the composite coatings in the phosphate buffered saline solution increased linearly with incubation time and the rate differed with the coating concentration and the HA/PCL ratio; the higher concentration and HA amount caused the increased biodegradation. At short period (<2 h), about 20-30% drug was released especially due to free drug at the coating surface. However, the release rate was sustained for prolonged periods and was highly dependent on the degree of coating dissolution, suggesting the possibility of a controlled drug release in the porous scaffold with HA+PCL coating.     

Doxorubicin-loaded amphiphilic polypeptide-based nanoparticles as an efficient drug delivery system for cancer therapy

An amphiphilic anionic copolymer, methoxy poly(ethylene glycol)-b-poly(l-glutamic acid-co-l-phenylalanine) (mPEG-b-P(Glu-co-Phe)), with three functionalized domains, was synthesized and used as a nanovehicle for cationic anticancer drug doxorubicin hydrochloride (DOX·HCl) delivery via electrostatic interactions for cancer treatment. The three domains displayed distinct functions: PEG block chain for prolonged circulation; poly(phenylalanine) domain for stabilizing the nanoparticle construct through hydrophobic/aromatic interactions; and the poly(glutamic acid) domain for providing electrostatic interactions with the cationic drug to be loaded. The copolymer could self-assemble into micellar-type nanoparticles, and DOX was successfully loaded into the interior of nanoparticles by simple mixing of DOX·HCl and the copolymer in the aqueous phase. DOX-loaded mPEG-b-P(Glu-co-Phe) nanoparticles (DOX-NP) had a superior drug-loading content (DLC) (21.7%), a high loading efficiency (almost 98%) and a pH-triggered release of DOX. The size of DOX-NP was ～140 nm, as determined by dynamic light scattering measurements and transmission electron microscopy. In vitro assays showed that DOX-NP exhibited higher cell proliferation inhibition and higher cell uptake in A549 cell lines compared with free DOX·HCl. Maximum tolerated dose (MTD) studies showed that DOX-NP demonstrated an excellent safety profile with a significantly higher MTD (15 mg DOX kg^?1) than that of free DOX·HCl (5 mg DOX kg^?1). The in vivo studies on the subcutaneous non-small cell lung cancer (A549) xenograft nude mice model confirmed that DOX-NP showed significant antitumor activity and reduced side effects, and then enhanced tumor accumulation as a result of the prolonged circulation in blood and the enhanced permeation and retention effect, compared with free DOX, indicating its great potential for cancer therapy.     

Light-sensitive intelligent drug delivery systems of coumarin-modified mesoporous bioactive glass

Functionalized mesoporous bioactive glasses (MBG) with photoactive coumarin demonstrates photo-responsive dimerization resulting in reversible gate operation. Coumarin-modified MBG was used as a drug delivery carrier to investigate drug storage/release characteristics using phenanthrene as a model drug. Irradiation with UV light (>310 nm) induced photo-dimerization of the coumarin-modified MBG, which led to the pores’ closing with cyclobutane dimers and trapping of the guest phenanthrene in the mesopores. However, irradiating the dimerized-coumarin-modified MBG with shorter wavelength UV light (～250 nm) regenerates the coumarin monomer derivative by the photo-cleavage of cyclobutane dimers, such that trapped guest molecules are released from the mesopores. The structural, morphological, textural and optical properties are well characterized by X-ray diffraction, transmission electron microscopy, N² adsorption/desorption, and UV–visible spectroscopy. The results reveal that the MBG exhibits the typical ordered characteristics of the hexagonal mesostructure. The system demonstrates great potential in light-sensitive intelligent drug delivery systems and disease therapy fields.     

载药人工骨给药系统治疗骨髓炎的研究与进展

背景：传统口服抗生素治疗因趋化能力弱、剂量难以控制及全身副反应等作用削弱其广泛的应用。载药人工骨长效、定点、可控地释放药物,弥补了系统抗生素治疗的缺陷。 目的：通过新型局部给药系统材料,制备及药物释放动力学等方面综合和对比分析,指导以后载药人工骨的研发和选择应用。 方法：应用PubMed和Sciencedirect数据库检索2001-01/2011-11关于局部给药系统对骨髓炎及骨缺损治疗相关方面的文献,英文检索词为“drug delivery system, osteomyelitis, bone defect, bone substitute”。排除无关及重复性研究,同一领域则选择权威杂志近期发表文献,保留25篇进一步归纳总结。 结果与结论：骨的重建与修复需要满足3个条件,即要满足骨诱导、骨传导和骨生成,此外合适的骨组织生长环境也必不可少。根据材料特点将人工骨分为生物陶瓷材料,生物材料,高分子材料,复合材料。也可根据材料的吸收性分为可生物降解型和非生物降解型。载药人工骨局部给药系统靶位点释放药物,具有提供骨良好修复环境与骨诱导的特点。载药骨的药物释放量需对载药浓度选择,局部药物释放时间,感染类型确定药物种类的选择,人工骨材料选择,药物与人工骨是否发生化学反应,对骨材料性质的影响等方面进行比较和控制。     

骨内植入式药物缓释系统载体材料研究现状及进展

植入式药物缓释系统在治疗骨科感染、肿瘤等方面具有良好的作用。随着组织工程学的进展,研制了不同的材料作为骨内植入式药物缓释系统的载体,拟对骨内植入式药物缓释系统载体材料研究现况及进展进行综述。     

刺激反应性释药系统的研究进展

刺激反应性释药系统（SSDDS）是一种新型的药物载体。它能够感知人体病理、生理的变化（pH值、温度）或者体外施加的信号（超声、磁信号）,然后根据信号变化调节自身的理化性质,进而调控释放其所携带的药物。SSDDS可由水凝胶、脂质体及磁性纳米微球等制备而成。与非刺激反应性释药系统相比,它具有反馈调节,可控性更强,靶向治疗作用更显著等优点。将对近年来刺激反应性释药系统的研究进展作一综述。     

Bioreducible heparin-based nanogel drug delivery system

Bioreducible heparin (HEP)-based nanogels were prepared by derivatizing HEP with vinyl group followed by copolymerizing with cystamine bisacrylamide in aqueous medium in the absence of surfactant. The hydrodynamic diameter of the HEP nanogels could be tuned in the range from 80 to 200 nm. Doxorubicin (DOX) was loaded into the HEP nanogels, and high drug loading content (30%) and efficiency (90%) were achieved. In vitro drug release test revealed that this drug delivery system exhibited strongly redox-sensitive drug release behavior that would greatly favor the in vivo drug delivery performance of the nanogels. After injected into tumor-bearing mice through tail vein, the DOX-loaded HEP nanogels showed remarkable accumulation in tumors as demonstrated by in vivo near infared fluorescence imaging and ex vivo DOX concentration measurements. The doxorubicin accumulation at tumor site goes beyond 9% injected dose per gram of tumor through such delivery system, making that DOX-loaded HEP nanogels have significantly superior in vivo antitumor activity.     

A bioactive triphasic ceramic-coated hydroxyapatite promotes proliferation and osteogenic differentiation of human bone marrow stromal cells

Hydroxyapatite (HA) ceramics are widely used as bone graft substitutes because of their biocompatibility and osteoconductivity. However, to enhance the success of therapeutic application, many efforts are undertaken to improve the bioactivity of HA. We have developed a triphasic, silica-containing ceramic-coated hydroxyapatite (HASi) and evaluated its performance as a scaffold for cell-based tissue engineering applications. Human bone marrow stromal cells (hBMSCs) were seeded on both HASi and HA scaffolds and cultured with and without osteogenic supplements for a period of 4 weeks. Cellular responses were determined in vitro in terms of cell adhesion, viability, proliferation, and osteogenic differentiation, where both materials exhibited excellent cytocompatibility. Nevertheless, an enhanced rate of cell proliferation and higher levels of both alkaline phosphatase expression and activity were observed for cells cultured on HASi with osteogenic supplements. These findings indicate that the bioactivity of HA endowed with a silica-containing coating has definitely influenced the cellular activity, projecting HASi as a suitable candidate material for bone regenerative therapy.     

A nanogel of on-site tunable pH-response for efficient anticancer drug delivery

A smart, soft and small nanoparticulate drug carrier that can efficiently transport therapeutics into tumor cells to control the intracellular drug concentration will enable major advancements in cancer therapy. To facilitate a remote modulation of the intracellular pH-regulated drug release, we have designed a new class of pH-responsive chitosan-based nanogels (<200 nm) by the physical interpenetration of chitosan chains into a nonlinear poly(ethylene glycol) (nonlinear PEG) chain network. The resultant PEG-chitosan nanogels not only respond to the changes in environmental pH over the physiologically important range of 5.0–7.4, but – more importantly – also enable us to remotely modulate the pH response by external cooling/heating. The nanogel, as well as the nanogel loaded with a model anticancer drug 5-fluorouracil (5-FU), is capable of varying its surface charge from nearly neutral to positive around tumor extracellular pH (～6.0–6.2) to facilitate cell internalization. Subsequently, the significantly increased acidity in subcellular compartments (～5.0) can trigger 5-FU release from the endocytosed drug carriers. While this nanogel serving as a drug carrier exhibits a reduced toxicity in combined chemo-thermo treatments, it has shown significantly enhanced therapeutic efficacy in combined chemo-cryo treatments of the model B16F10 melanoma cells, indicating its great potential for cancer therapy.