Rapid Design of Bioinspired Alloys - From Modelling to Manufacture

在过去的十年里，英国有超过250万人植入了金属装置来代替他们体内的骨关节。据预测，在未来50年里，我们活到100岁的几率将翻一番，因此这些骨植入物需要持续更长时间。令人担忧的是，目前的数据表明，植入后的失败率每年都在迅速增加。我们目前制造骨植入物的金属并不是专门为体内使用而开发的。相反，这些材料最初是为航空应用而设计的。除了比骨头硬得多之外，这些金属合金还可能含有引起不良生物反应的有毒元素。这项研究的目的是设计新一代的生物激发合金，促进有利的细胞反应，同时展示与身体一致的机械性能。为了设计理想的生物医学合金，有许多特性需要平衡，例如生物相容性（即无毒）、机械性能和耐磨性。通过当前的试错方法同时优化许多参数可能需要数年甚至数十年。为了显著加快这一过程，一种被称为设计合金（ABD）的计算建模方法将被用来发现一系列与骨骼机械性能相匹配的钛成分。通过寻找具有特定微观结构的合金，ABD将首次用于鉴定具有生物功能的成分，如预防感染。由于ABD是一种基于理论的方法，因此验证模型预测将是重要的。这将通过使用一种独特的基于激光的系统将所有合金元素熔化在一起来完成。为了保持这些新金属在临床应用方面的快速进展，将开发一种新的高通量测试作为筛选工具，以识别有希望引起哺乳动物和细菌细胞反应的成分。根据这些结果，将选择无毒和抗菌的组合物。高分辨率显微镜随后将用于了解合金元素，微观结构和生物行为之间的关系。在这些新合金制成的骨植入物被植入病人体内之前，加深我们对身体如何反应的理解将是至关重要的。重要的是，各种细胞类型参与骨再生的行为将被考虑，包括骨形成成骨细胞和骨髓中发现的干细胞。这些细胞生长的速度和它们在新型合金表面形成新骨的能力将与目前使用的金属进行基准测试。由于已知离子可能会从体内的合金中浸出并对周围组织造成损害，因此也将对此进行仔细研究。在骨植入物中，从解剖学上完美贴合的个性化设备中获得的患者和经济利益正在迅速增长。因此，将探索由最有前途的生物启发合金制成的3D打印定制植入物的可能性。将首次研究使用基于金属激光的3D打印机在本地定制合金成分的能力。通过系统地改变激光加工参数和表征所得成分，将开发出一种优化原位合金形成的通用方案。这将为骨植入物定制开辟一个全新的维度，使得在单个植入物的选定区域定制机械性能或生物功能成为可能。支持这项研究的是一个经验丰富的临床和工业顾问委员会，他们将支持这些新型生物激发合金的翻译。这将确保研究成果可以转化为经批准的医疗设备，从而改善患者的生活，降低医疗成本，促进英国经济增长。

In the past decade, over 2.5 million people in the UK had a metal device implanted to replace a skeletal joint in their body. With our chances of living to 100 years old predicted to double in the next 50 years, these bone implants will need to last substantially longer. Alarmingly, current data demonstrates that failure rates rapidly increase each subsequent year after implantation. The metals we currently make bone implants from were not specifically developed for use within the body. Instead, these materials were originally designed for aerospace applications. In addition to being much stiffer than bone, these metal alloys may also contain toxic elements that cause adverse biological reactions. The aim of this fellowship is to design a new generation of bioinspired alloys that promote advantageous cellular responses while exhibiting mechanical properties that are aligned with the body. In order to design the ideal biomedical alloy, there are a number of properties that need to be balanced, for example biocompatibility (i.e. non-toxic), mechanical performance, and wear resistance. Optimising lots of parameters simultaneously via current trial-and-error approaches may take years or even decades. To significantly speed up this process, a computational modelling approach, called Alloys-By-Design (ABD), will be used to discover a range of titanium compositions that match the mechanical properties of bone. For the first time, by searching for alloys with specific microstructures, ABD will be employed to identify compositions with promising biological functionality, such as infection prevention. Since ABD is a theory-based approach, it will be important to validate the model predictions. This will be done by using a unique laser-based system to melt together all the alloying elements. To maintain rapid progress towards using these new metals clinically, a novel high throughput test will be developed as a screening tool to identify compositions that provoke promising mammalian and bacterial cell responses. From these results, non-toxic and antimicrobial compositions will be selected. High resolution microscopy will subsequently be used to understand the relationships between alloying elements, microstructure and biological behaviour. Before bone implants made of these new alloys may be implanted into patients, it will be critical to deepen our understanding of how the body may respond. Importantly, the behaviour of various cell types involved in bone regeneration will be considered, including bone forming osteoblasts and stem cells found in bone marrow. The rate at which these cells grow and their ability to form new bone on the surface of the novel alloys will be benchmarked against currently used metals. Since it is known that ions may leach from alloys within the body and cause damage to surrounding tissue, this will also be carefully studied. The patient and economic benefits gained from personalised devices that anatomically fit perfectly is rapidly growing in bone implants. As such, the possibility to 3D print bespoke implants made from the most promising bioinspired alloy will be explored. For the first time, the ability to locally tailor alloy composition in-situ using a metal laser-based 3D printer will be investigated. By systematically changing the laser processing parameters and characterising the resultant composition, a universal protocol to optimise in-situ alloy formation will be developed. This will open up an entirely new dimension of bone implant customisation, making it possible to tailor mechanical performance or biological functionality in selected areas of a single implant. Underpinning this fellowship is an experienced clinical and industrial advisory board that will support translation of these novel bioinspired alloys. This will ensure that the research may be transformed into approved medical devices that improve patient lives, reduce healthcare costs, and grow the UK economy.