Hydrothermal conversion of porous Ca carbonate biominerals into antibiotic and antiosteoporotic Ca phosphate bone implant materials containing Mg, Sr, Zn and Ag ions

每年进行数以百万计的骨移植手术，以修复因创伤或肿瘤切除而造成的骨缺损。人工合成的磷酸钙基(CAP)材料(主要是陶瓷)通常被用作骨移植的替代品。它们与骨的化学相似确保了生物相容性，而大孔隙率使帽材料能够通过天然骨组织嵌入到毛孔中而牢固地整合到骨中。由于合成材料的力学性能一般不如天然骨，因此通常希望逐渐吸收合成的帽状植入物，同时用天然骨替代。在人体内，热力学上最稳定的CaP矿物相--羟基磷灰石--几乎是不可吸收的。因此，许多CAP植入物表现为双相磷酸钙(BCP)，由羟基磷灰石和更易溶的磷酸三钙(类似于矿物白锁石)组成。在镁离子存在下，白锁石比羟基磷灰石更容易形成。在合成植入物的降解过程中，加入到白锁石中的镁离子被释放出来，并刺激天然骨的形成。类似地，已知锶和锌离子可以刺激骨形成并延缓骨吸收。因此，这些离子在治疗骨质疏松相关的骨丢失和骨折方面起着重要的作用。银离子的抗菌作用可能被用来避免手术移植过程中的伤口感染。本项目旨在通过一步水热工艺开发新型抗菌和抗骨质疏松BCP骨植入材料，避免高温烧结。大孔碳酸钙生物矿物质(珊瑚骨骼和海胆脊椎)将被BCP假象取代，同时保留自然孔隙度。提出了一种适合于在热液矿物置换过程中将多种功能离子(镁、锶、锌、银)同时掺入BCP支架中的方法。生成的材料将被详细分析其掺杂浓度和分布。此外，还将分析BCP材料在模拟体液中降解时释放的离子浓度。这些浓度将通过修改生产参数调整材料的离子含量来优化以刺激骨形成(根据公布的值)。银改性材料的抗菌性能将通过细菌培养实验(抑制细菌生长和生物膜形成)进行研究和优化。本研究有望为制备基于BCP的多功能骨替代材料提供一种有效的新方法，有望成为传统帽状骨移植替代品的有价值的替代品。

Millions of bone graft procedures are performed annually to repair bone defects caused by trauma or tumor resection. Synthetic calcium phosphate-based (CaP) materials (mostly ceramics) are commonly used as bone graft substitutes. Their chemical similarity to bone guarantees biocompatibility while macroporosity enables firm integration of CaP materials into the bone by ingrowth of natural bone tissue into the pores. Since the mechanical performance of the synthetic materials is generally inferior to natural bone, gradual resorption of synthetic CaP implants and simultaneous replacement by natural bone is often desirable. In the human body, the thermodynamically most stable mineral phase of CaP, hydroxyapatite, is almost non-resorbable. Therefore, many CaP implants represent biphasic calcium phosphates (BCP) as a composite of hydroxyapatite and the more soluble tricalcium phosphate (similar to the mineral whitlockite). In the presence of Mg ions the formation of whitlockite is favoured over hydroxyapatite. Mg ions incorporated into whitlockite are released during degradation of the synthetic implant and stimulate the formation of natural bone. Similarly, Sr and Zn ions are known to stimulate bone formation and retard bone resorption. Hence, these ions play an important role in the treatment of bone loss and fracture related to osteoporosis. The antibacterial effect of Ag ions can potentially be employed to avoid wound infection during surgical graft procedures.This project aims at the development of novel antimicrobial and antiosteoporotic BCP bone implant materials via a single-step hydrothermal process, avoiding high-temperature sintering. Macroporous calcium carbonate biominerals (coral skeletons and sea urchin spines) will be replaced pseudomorphically by BCP while the natural porosity is preserved. A method suitable for simultaneously incorporating a number of functional ions (Mg, Sr, Zn and Ag) into the BCP scaffolds during the hydrothermal mineral replacement process will be developed. Resulting materials will be analyzed in detail for their dopant concentration and distribution. Additionally, ion concentrations released by the BCP materials upon degradation in simulated body fluid will be analyzed. These concentrations will be optimized for stimulating bone formation (according to published values) by adjusting the ion contents of the materials through modification of the production parameters. Antibacterial properties of the Ag-modified materials will be investigated by bacterial culture experiments (inhibition of bacterial growth and biofilm formation) and optimized as well. This research project is expected to provide an effective new method of producing BCP-based multifunctional bone replacement materials that may represent valuable alternatives to conventional CaP bone grafts substitutes.