Biomaterials (Mf/Zn/F-BCPs) for osteoporosis therapy

项目摘要(摘要) 骨质疏松症是一种无声的、衰弱的骨骼疾病，当(破骨细胞)骨吸收的速度 远大于(由成骨细胞形成的)骨形成的速率，导致骨丢失、骨质退化。 质量差，导致骨骼强度和骨脆性降低，容易骨折。当前 FDA批准的药物被证明可以防止进一步的骨丢失，但还没有证明可以恢复骨骼 已经死于这种疾病了。此外，这些药物中有许多有严重的副作用(例如，乳房 雌激素治疗引起的癌症、颌骨骨坏死和双膦酸类药物的延迟愈合 毒品)。本研究的总体目标是开发新型创新化合物MZF-CAP和MZ- CAP/FF(MZ-CAP和黄烷/黄酮类化合物的组合，FF)，这将是安全、负担得起和有效的 用于预防和逆转骨丢失。 初步数据显示，MZF-CAP制剂作为补充剂或注射使用 预防矿物质缺乏或雌激素缺乏(卵巢切除)引起的大鼠骨丢失。对于 继续研究，具体目标是：(1)制备(A)MZF-帽(含低氟)和(B)MZ- CAP/FF(不含氟化物与黄烷素/黄酮类化合物组合，FF，已知可抑制与 骨吸收)，并表征其性质(组成、离子释放、溶解)和体外 来自骨形成(成骨细胞)或骨吸收(破骨细胞)细胞的反应；(2)评估 精选MZF-CAP和MZ-CAP/FF制剂作为补充剂对(A)预防和(B) 与钙相比，卵巢切除或矿物质缺乏引起的骨丢失的恢复或逆转 +维生素D补充剂；(3)评价MZF-CAP和MZ-CAP/FF预防骨丢失的效果 在更大的动物模型(绵羊)中；以及(4)确定MZF-CAPS和MZ-CAP/FF对 以下水平：(A)分子(基因表达)和细胞(骨细胞密度)；(B)生物力学 (C)微观结构(皮质骨和松质骨厚度、松质骨 (D)生物化学(基质/矿物比率、骨矿化程度)‘和 生物矿物(骨矿物质组成、结晶度和溶解性能)。分析方法将 包括：X射线衍射、傅里叶变换红外光谱、热重分析、扫描电子显微镜、显微分析。 计算机断层扫描。 意义：拟议研究的结果可能会导致开发安全和负担得起的 预防和逆转骨质疏松症和其他骨质疏松症引起的骨丢失的治疗 虚病。这些结果将极大地影响公众健康，缓解巨大的社会压力。 与骨质疏松症相关的经济负担。

Project Summary (Abstract) Osteoporosis, a silent debilitating bone disease, results when the rate of bone resorption (by osteoclasts) is much greater than the rate of bone formation (by osteoblasts) causing bone loss, deterioration of bone quality, leading to decreased bone strength and bone fragility and susceptibility to bone fracture. Current FDA-approved drugs are shown to prevent further bone loss but have not been shown to restore bone already lost to the disease. Furthermore, many of these drugs have serious side effects (e.g., breast cancer from estrogen therapy, osteonecrosis of the jaw and delayed healing from bisphosphonate-based drugs). The over-all objective of the study is to develop novel innovative compounds, MZF-CaP and MZ- CaP/FF (a combination of MZ-CaP and flavan/flavonoids, FF), that will be safe, affordable and effective for prevention and reversal of bone loss. Preliminary data showed that MZF-CaP formulations administered as a supplement or by injection prevented bone loss induced by mineral deficiency or estrogen deficiency (ovariectomy) in rats. For the continuing study, the specific aims are to: (1) prepare (a) MZF-CaP (with low fluoride) and (b) MZ- CaP/FF (without fluoride combined with flavan/flavonoids, FF, known to inhibit cytokines associated with bone resorption) and characterize their properties (composition, ion release, dissolution) and the in vitro response elicited from bone-forming (osteoblasts) or bone-resorbing (osteoclasts) cells; (2) evaluate the effect of selected MZF-CaP and MZ-CaP/FF preparations as supplement on the (a) prevention and (b) restoration or reversal of bone loss induced by ovariectomy or mineral deficiency, compared with calcium + vitamin D supplement; (3) evaluate the effect of MZF-CaP and MZ-CaP/FF on prevention of bone loss in a larger animal model (sheep); and (4) determine the effects of MZF-CaPs and MZ-CaP/FF on the following levels: (a) molecular (gene expression) and cellular (osteocyte density); (b) biomechanical (bone strength, bone density); (c) microstructural (cortical and trabecular bone thickness, trabecular bone porosities, anisotropy); (d) biochemical (matrix/mineral ratio, degree of bone mineralization)' and biomineral (bone mineral composition, crystallinity and dissolution properties). Analytical methods will include: x-ray diffraction, FT-IR spectroscopy, thermogravimetry, scanning electron microscopy, micro- computed tomography. Significance: Results from the proposed studies could lead to the development of safe and affordable therapy that will target both prevention and reversal of bone loss due to osteoporosis and other bone- deficient diseases. These results will greatly impact public health and alleviate the tremendous socio- economic burden associated with osteoporosis.