3D Printed Calcium Phosphate Scaffolds with Natural Medicinal Compounds for Dental Applications

摘要 修订后的R 01申请旨在使用天然药用化合物（NMCs）增强生物活性 合成骨移植物在合成骨移植物中递送NMCs，如磷酸钙（CaP） 支架是调节骨细胞-材料相互作用以改善体内成骨的关键， 血管生成使用NMCs，我们建议研究骨诱导性，3D打印（3DP）CaP骨移植物 而不使用任何生长因子（GF）或蛋白质，用于整形外科和牙科。然而，在这方面， 临床上仍然需要创新骨诱导合成可再吸收生物材料 血管生成，表现出类似于自体移植物的生物学特性。我们建议使用NMCs，如姜黄素 来自姜黄，来自芦荟的乙酰甘露聚糖，以及维生素D3等必需营养素， 在CaP中骨整合，而不是使用GF。在我们的初步研究中， 显示了由于NMCs的存在而导致的血管生成和增强的骨生成。我们发现 姜黄素可促进3DP CaP支架的成骨和血管生成。根据我们以前的工作，我们 还证实了在CaP中添加掺杂剂如Mg 2+、Si 4+、Zn 2+和Ag+可以改善CaP中的pH值， 机械性能，增强骨生成和血管生成，同时改善抗微生物反应， vivo.结合我们对纳米材料的令人兴奋的初步结果和掺杂剂化学的既定数据，我们 建议展示下一代不含任何GF或蛋白质的合成骨移植物，用于 牙科和骨科，这是本申请的前提。 本研究的目的是验证我们的中心假设，即负载NMC的掺杂CaP多孔3D 打印（3DP）支架将增强体内成骨和血管生成特性。理由是，一旦 我们了解不同NMCs所需的剂量，它们的释放动力学，以及骨细胞- 材料的相互作用调制，关键的知识差距，我们可以设计无GF合成骨移植物 类似于临床应用中的自体移植物。我们的长期目标是证明临床相关患者 匹配的、成骨和血管生成掺杂的CaP或CaP-聚合物支架与NMCs， 在整形外科和牙科中用于修复、替换和增强的自体骨。实现我们 研究目标，我们提出了两个具体目标。目标1的重点是了解NMC的影响 提高多孔CaP陶瓷和陶瓷-聚合物复合支架的体外生物活性。目标二是 专注于使用载有NMC的多孔CaP陶瓷测量体内骨生成和血管生成， 陶瓷-聚合物复合支架。如果成功的话，NMC还可以与其他牙科材料一起使用， 骨科应用。

Abstract This revised R01 application aims to use natural medicinal compounds (NMCs) to enhance bioactivity of synthetic bone grafts. The delivery of NMCs in synthetic bone grafts, such as calcium phosphate (CaP) scaffolds, is critical to modulate bone cell-materials interactions to improve in vivo osteogenesis and angiogenesis. Using NMCs, we propose to investigate osteoinductive, 3D-Printed (3DP) CaP bone grafts without using any growth factors (GF) or proteins towards applications in orthopedics and dentistry. However, there still exists a clinical need to innovate osteoinductive synthetic resorbable biomaterials that will promote angiogenesis, exhibiting biological properties similar to autografts. We propose to use NMCs such as curcumin from turmeric, acemannan from aloe vera, and essential nutrients such as Vitamin D3 to improve osseointegration in CaPs instead of using GFs. In our preliminary studies, we have seen promising results showing angiogenesis and enhanced osteogenesis due to the presence of NMCs. We have found that curcumin can enhance osteogenesis and angiogenesis of 3DP CaP scaffolds. From our previous work, we have also established that addition of dopants such as Mg2+, Si4+, Zn2+ and Ag+ in CaP can improve mechanical properties, enhance osteogenesis and angiogenesis while improving antimicrobial response in vivo. Combining our exciting preliminary results on NMCs and established data on dopant chemistry, we propose to demonstrate next generation of synthetic bone grafts without any GF or proteins for applications in dentistry and orthopedics, which is the premise of this application. The objective of this research is to test our central hypothesis that NMC-loaded doped CaP porous 3D Printed (3DP) scaffolds will enhance osteogenic and angiogenic properties in vivo. The rationale is that once we understand the required dose for different NMCs, their release kinetics, and the mechanism of bone cell- materials interactions modulation, the key knowledge gaps, we can design GF free synthetic bone grafts similar to autografts in clinical applications. Our long-range goal is to demonstrate clinically relevant patient matched, osteogenic and angiogenic doped CaP or CaP– polymer scaffolds with NMCs that will substitute autologous bone for repair, replacement, and augmentation in orthopedics and dentistry. To achieve our research objectives, we propose two Specific Aims. Aim 1 is focused on understanding the influence of NMCs on enhanced bioactivity of porous CaP ceramic, and ceramic-polymer composite scaffolds in vitro. Aim 2 is focused on measuring osteogenesis and angiogenesis in vivo using NMC loaded porous CaP ceramic and ceramic-polymer composite scaffolds. If successful, NMCs can also work with other materials for dental and orthopedic applications.