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

一种理想的用于修复承重大骨缺损的生物材料支架应具有与骨皮质相匹配的力学性能和促进新骨再生的成骨性能。具有这两个特征的支架目前还不存在。目前由骨水泥、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机械性能。皮质骨比松质骨强一个数量级。金属，例如钛，广泛用于需要高机械性能的整形外科手术中。然而，它们比骨头硬得多。钛的杨氏模量约为皮质骨的10倍。这种机械性能的不匹配屏蔽了周围骨骼的生理应力，这削弱了它们，并使它们随着时间的推移而易于骨折。骨形态发生蛋白2（Bone Morphogenic Protein 2，BMP2）是一种新型的骨形成生物分子，目前已广泛应用于骨不连等骨科手术中。然而，临床上使用的超生理剂量已引起各种并发症，如不受控制的过度骨生长和癌症。与BMP 2的超生理剂量相关的不良反应导致FDA对脊柱融合器械（钛笼中的输注-BMP 2负载胶原蛋白）发出警告，随后拒绝类似产品。这促使研究人员研究其他方法来增强骨生成。人类已经进化到可以在小范围内完全治愈骨折。这一过程由再生性血肿/凝块（RHC）触发和调节，再生性血肿/凝块包含丰富的内源性因子和细胞群，这些因子和细胞群对于干细胞/祖细胞募集、免疫调节、成骨分化和最终骨愈合至关重要。然而，在骨科手术的骨折复位、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中的主要局限性，并实现个性化的再生植入物，其成本低，易于部署，与干细胞疗法或骨髓抽吸相比，对患者的风险较低。该项目的目的是生产3D打印的连续纤维增强复合材料支架，结合工程化的人类血液凝胶，与皮质骨力学性能相匹配的成骨支架材料。开发一种3D打印工艺来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的共打印.骨髓干细胞在血液复合支架材料中体外成骨分化的实验研究。

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.