Synergising mechanical and osteogenic properties for personalized bone tissue engineering via co-3D printing with fibre reinforced composite and blood

理想的生物材料支架应具有与皮质骨匹配的力学性能和成骨性能，以促进新骨再生。目前还不存在具有这两种特性的支架。目前由生物玻璃、生物陶瓷和颗粒增强复合材料制成的支架仅在松质骨范围内实现了力学性能。皮质骨比松质骨强一个数量级。金属，如钛，被广泛应用于骨科手术，在那里寻求高机械性能。然而，它们比骨头要硬得多。钛的杨氏模量大约是皮质骨的10倍。这种机械性能的不匹配屏蔽了周围骨骼的生理压力，这会削弱它们，使它们随着时间的推移容易骨折。因此，迫切需要匹配人类皮质骨力学性能的支架材料。骨形态发生蛋白2 （bone morphogenic protein 2, BMP2）等强效成骨生物分子现已广泛应用于各种骨科手术，如治疗骨不愈合骨折。然而，临床使用的超生理剂量引起了各种并发症，如不受控制的过度骨生长和癌症。与BMP2超生理剂量相关的不良反应已导致FDA对脊柱融合装置（在钛笼中装载的inffuse -BMP2胶原蛋白）发出警告，并随后对类似产品产生排斥反应。这促使研究人员研究其他促进成骨的方法。人类已经进化到可以在小范围内完全治愈骨折。这个过程是由再生血肿/血块（RHC）触发和调节的，RHC包含丰富的内源性因子和细胞群，这些因子和细胞群对干细胞/祖细胞募集、免疫调节、成骨分化和最终的骨愈合至关重要。然而，在骨科手术中骨折复位、内固定和清创过程中，RHC经常被干扰或移除，导致骨再生不良。使用患者自己的血液重建骨折中的RHC可能会克服目前骨折治疗的主要限制，并实现个性化再生植入物，与干细胞治疗或骨髓穿刺相比，成本低，易于部署，对患者风险低。该项目的目的是生产3D打印连续纤维增强复合材料支架结合工程人血凝胶，以获得具有与皮质骨相匹配的力学性能的成骨支架。具体目标是：1。开发3D打印工艺制造连续纤维增强复合材料支架。用可调的结构参数测试打印支架的力学性能。设计具有可调机械性能的血液凝胶。纤维增强复合材料与血凝胶共印骨髓干细胞在血液复合支架中的体外成骨分化试验。

An ideal biomaterial scaffold for healing load-bearing large bone defects should have cortical bone matching mechanical properties and osteogenic properties for promoting new bone regeneration. Scaffolds possessing these two traits currently do not exist. Current scaffolds made of bioglasses, bioceramics and particle reinforced composites have only achieved mechanical properties in the cancellous bone range. Cortical bone is an order of magnitude stronger than cancellous bone. Metals, such as titanium, are widely used in orthopaedic surgeries where high mechanical properties are sought. However, they are much stiffer than bone. The Young's modulus of titanium is approximately 10 times of cortical bone. This mismatch in mechanical properties shields the physiological stresses from the surrounding bone, which weakens them and makes them prone to fracture over time. Therefore, scaffolds matching human cortical bone mechanical properties are urgently needed.Potent osteogenic biomolecules such as bone morphogenic protein 2 (BMP2) are now widely used in various orthopaedic surgeries such as treating non-union fractures. However, the supraphysiological dosage used in clinic has caused various complications such as uncontrolled excessive bone growth and cancer. The adverse effects associated with supraphysiological dosage of BMP2 has led to a FDA warning to a spinal fusion device (Infuse-BMP2 loaded collagen in a titanium cage) and subsequent rejection of similar products. This has prompted researchers to investigate other means to enhance osteogenesis. Human beings have evolved to fully heal bone fractures at small scales. This process is triggered and regulated by the Regenerative Hematoma/Clot (RHC), which comprises a rich source of endogenous factors and cell populations that are critical for stem/progenitor cell recruitment, immunomodulation, osteogenic differentiation, and ultimate bone healing. However, the RHC is often disturbed or removed during fracture reduction, internal fixation, and debridement in orthopaedic surgeries, leading to poor bone regeneration. Rebuilding the RHC in bone fractures using the patient's own blood could potentially overcome major current limitations in fracture treatment and enable personalized regenerative implants that are low in cost, easily deployable, and low risk to patients compared to stem cell therapies or bone marrow aspiration.The aim of this project is to produce 3D printed continuous fibre reinforced composite scaffolds combined with engineered human blood gels to obtain osteogenic scaffolds with mechanical properties matching cortical bone.The specific objectives are:1. Develop a 3D printing process to fabricate continuous fibre reinforced composite scaffolds. Test the mechanical properties of the printed scaffolds with tuneable architectural parameters.2. Engineer blood gels with tuneable mechanical properties. Co-printing of fibre reinforced composite and blood gel.3. Test in vitro osteogenic differentiation of bone marrow stem cells in blood-composite scaffolds.