3D printing multifunctional devices without internal interfaces for cartilage repair

我们的目标是创造第一个可用于增材制造（基于vat的立体光刻）的“墨水”，以生产具有刚度和成分梯度的复杂结构，而无需任何连接或内部接口。虽然这项技术将有广泛的应用，但我们将首先使用它来满足骨科手术中尚未满足的临床需求：可以愈合受损软骨的设备。目前，很少有，如果有的话，存在的材料，具有真正的连续组成或刚度梯度。当然没有一个具有良好的机械性能。溶胶-凝胶杂化材料是由有机和无机组分紧密混合的共同网络组装而成的，但在纳米尺度以上，它们表现为单一材料，与复合材料区别开来。重要的是，我们已经在初步研究中表明，我们可以将溶胶-凝胶材料作为粘性液体分层，就在它们凝胶之前，因此形成没有内部连接或界面的单一材料。我们有3D打印它们，但只是网格结构。在这里，我们将首次开发新的混合油墨，可用于在缸基立体光刻（SLA）中制造复杂的孔隙结构。由于运动损伤、创伤或与年龄相关的磨损导致关节软骨损伤的可能性随着活跃人口的年龄增长而增加。目前修复膝关节软骨小缺损的最佳方法是微骨折，即在骨下打小孔，释放骨髓，用脆弱的纤维软骨填充缺损。软骨只能维持2-5年，否则必须重复手术。最终，需要进行全关节置换，这是一项涉及移除大量组织的大手术，只能持续15-25年。需要替代医疗设备，例如使用具有专门设计的化学和结构的先进材料。如果成功的话，我们就可以应用这项技术来帮助对抗关节炎，随着年龄的增长，这种疾病会影响每个人。我们目前的3D打印混合材料显示出再生软骨的巨大潜力，因为它激发干细胞产生关节软骨样基质，而不是功能较差的纤维软骨。重要的是，它的机械性能可以与软骨相匹配，并将机械信号传递给在其中生长的细胞，这对产生高质量的软骨至关重要。然而，我们之前的3D打印技术只能生产原木桩结构。设备的架构需要更加复杂。由于软骨很薄，大多数缺陷会深入到下面的骨骼中，所以我们设计了一种设备，我们假设它可以在适当的位置再生骨骼和软骨。进入骨头的部分对于确保植入物在愈合过程中保持原位也很重要。本研究的新颖性包括：植入体的结构设计；用于制造它的材料（可用于SLA的新型溶胶-凝胶混合材料）以及溶胶-凝胶混合材料将首次在复杂架构中进行3D打印（使用SLA）的事实。接下来的细胞研究表明，适当的刺激提供给干细胞，使其沿着所需的路径（骨或软骨），并确保潜在的血管化骨长入，临床前研究将进行。我们的项目合作伙伴将协助技术转移：赢创和Makevale将生产聚合物原材料，史密斯和侄子将评估市场潜力，确定翻译里程碑，并在他们的关节炎羊模型中测试我们优化的设备。该提案将在10-20年的时间框架内使医疗器械公司、患者、整形外科医生和卫生服务（例如NHS）受益。由于目前有三分之一的工作人员年龄超过50岁，卫生服务部门必须能够获得技术，使患者能够迅速重返工作岗位，并减少翻修手术的数量。

We aim to create the first "inks" that can be used in additive manufacturing (vat based stereolithography) to produce complex architectures with stiffness and compositions gradients without any joins or internal interfaces. While this technology will have a wide range of applications, we will first use it to fulfil an unmet clinical need in orthopaedic surgery: devices that can heal damaged cartilage. Currently, there are very few, if any, materials that exist that have a true continuous composition or stiffness gradients. There are certainly none that have good mechanical properties. Sol-gel hybrid materials are assembled of intimately mixed co-networks of organic and inorganic components, but above the nanoscale they appear as single materials, distinguishing them from composite materials. Importantly, we have shown in our pilot studies that we can layer sol-gel materials as viscous liquids, just before they gel, so forming single materials with no internal joins or interfaces. We have 3D printed them, but only as grid-like architectures. Here, we will develop new hybrid inks that can be used to make complex pore architectures in vat based stereolithography (SLA), for the first time.Damage to articular cartilage due to sports injuries, trauma or age-related wear are increasingly likely as an active population ages. Current best practice for regeneration of small defects in knee cartialge is microfracture, which involves making small holes into the underlying bone to liberate the marrow, which fills the defect with weak fibrous cartilage. The cartilage only lasts 2-5 years before the procedure must be repeated. Eventually, total joint replacements are needed, which are major operations that involve removing a lot of tissue, and only last 15-25 years. Alternative medical devices are needed, e.g. using advanced materials with specifically designed chemistry and architecture. If successful, we can then apply the technology to help combat arthritis, something that effects everyone as they age. Our current 3D printed hybrid material shows great potential for regenerating cartilage because it provokes stem cells to produce articular cartilage-like matrix, rather than functionally inferior fibrocartilage. Importantly its mechanical properties can match that of the cartilage and transfer mechanical cues to the cells growing within it, which is critical for generation of high-quality cartilage. However, our previous 3D printing technique could only produce log-pile structures. The architecture of the device needs to be more complex. As cartilage is thin, most defects penetrate deep into the underlying bone, so we have designed a device that we hypothesise can regenerate the bone and the cartilage in appropriate locations. The part that goes into the bone will also be important for ensuring the implant stays in place during healing. Novelty of the research includes: the architectural design of the implant; the materials used to make it (new sol-gel hybrids that can be used in SLA) and the fact that sol-gel hybrids will be 3D printed in complex architectures (using SLA) for the first time. Following cell studies to show appropriate stimulus is provided to stem cells to send them down the required route (bone or cartilage), and ensuring potential for vascularized bone ingrowth, preclinical studies will be carried out. Our project partners will assist in technology transfer: Evonik and Makevale will produce the polymeric raw materials and Smith and Nephew will assess market potential, identify translation milestones and test our optimised device in their arthritis sheep model.This proposal will benefit medical device companies, patients, orthopaedic surgeons, and health services (e.g. the NHS) in a 10-20 year timeframe. As a third of workers are now over 50, it is critical that health services have access to technology that can allow patients to return to work quickly and reduce numbers of revision surgery.