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

每年进行数百万次骨移植手术，以修复由创伤或肿瘤切除引起的骨缺损。合成磷酸钙基（CaP）材料（主要是陶瓷）通常用作骨移植替代品。它们与骨的化学相似性保证了生物相容性，而大孔隙率通过天然骨组织向内生长到孔隙中使CaP材料牢固地整合到骨中。由于合成材料的机械性能通常劣于天然骨，因此合成CaP植入物的逐渐再吸收和同时被天然骨替代通常是期望的。在人体中，CaP的化学上最稳定的矿物相羟基磷灰石几乎是不可吸收的。因此，许多CaP植入物代表双相磷酸钙（BCP）作为羟基磷灰石和更可溶的磷酸三钙（类似于矿物白磷钙石）的复合物。在镁离子存在下，白磷钙石的形成优于羟基磷灰石。结合到白磷钙石中的镁离子在合成植入物降解期间释放并刺激天然骨的形成。类似地，已知Sr和Zn离子刺激骨形成并延缓骨吸收。因此，这些离子在治疗与骨质疏松症相关的骨丢失和骨折中起着重要作用。银离子的抗菌作用可以潜在地用于避免外科移植手术中的伤口感染。本项目旨在通过一步水热工艺开发新型抗菌和抗肿瘤的BCP骨植入材料，避免高温烧结。大孔碳酸钙生物矿物（珊瑚骨骼和海胆刺）将被BCP假晶取代，同时保留天然孔隙度。将开发一种适合于在热液矿物置换过程中同时将许多功能离子（Mg、Sr、Zn和Ag）并入BCP支架中的方法。将详细分析所得材料的掺杂剂浓度和分布。此外，将分析BCP材料在模拟体液中降解后释放的离子浓度。通过修改生产参数调整材料的离子含量，优化这些浓度以刺激骨形成（根据已公布的值）。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，并进行优化。该研究项目有望提供一种生产基于BCP的多功能骨替代材料的有效新方法，该材料可能是传统CaP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.