Generating durable and resilient repair of cartilage defects using tissue-specific adult stem cells - a systematic, therapeutic approach

骨关节炎是世界上导致身体残疾的最大原因，然而，目前还没有临床上有效的治疗方法来恢复受影响关节的正常、无痛运动。骨性关节炎的病变始于弥漫在整个关节的孤立的小软骨缺陷，如果这些缺陷能够被修复，就有很好的机会恢复功能并防止进一步的疾病。在过去的二十年里，组织工程师一直在使用一种反复试验的方法来修复软骨缺损，使用越来越多和巧妙的支架和细胞，而很少考虑关节软骨的正常生长机制。这一方法的总而言之是，这一研究领域自大约25年前开始以来并没有取得重大进展。将细胞移植到关节中的方法存在固有的弱点，无法改进。英国国家临床卓越研究所的指南指出，目前的移植方法不能为患者提供长期的临床效果，也不是短期受益的经济有效的解决方案。我们的做法将打破现状，因为它解决了迄今阻碍进展的主要问题并提供了具体的解决办法。进展的主要绊脚石是缺乏合适的细胞来恢复关节的正常软骨。干细胞是修复受损关节的关键成分，在关节软骨中发现成体干细胞及其形成新的永久软骨的能力是一个重要的进步。使用干细胞时的一个问题是，它们产生的组织是未成熟的--未成熟的软骨没有成年软骨的相同特性，因此容易失败。最近的一项重大成就是了解了将未成熟的软骨转化为具有成人特性的软骨需要哪些因素。关键的问题是，我们能否使用干细胞制造新的软骨，然后将其转化为像成人软骨一样坚硬和耐用，从而提供一个功能齐全的植入物，以恢复受损关节的无痛运动？我们的解决方案是使用3D生物打印结合软骨干细胞来制造新的软骨。生物打印使我们能够精确、快速和可重复地制造复杂的结构，最大限度地发挥干细胞的生长潜力，生产更大、更厚的植入物。然后，我们将对工程组织进行改造，使其具有成人软骨的功能，然后将其植入患者体内进行临床前测试。这种方法很简单，并且模拟了在体内发生的相同的生物过程，以高度加速和受控的方式产生持久和有弹性的关节软骨。它还提供了一条明确的途径，系统地将软骨生物学和生物制造方面的最新进展转化为患者的利益。考虑到挑战的范围，我们已经调整了我们的方法，使其成为自动化和可扩展的，提供了治疗数千人而不是少数人的真正潜力。为实现这一目标而组建的团队是多学科的、高度专注的、在解决方案的每个特定方面都具有领先地位的专家。

Osteoarthritis is the single largest cause of physical disability in the world, and yet, there are no clinically effective treatments to restore normal, pain-free movement of affected joints. Osteoarthritic lesions begin as small isolated cartilage defects that spread across the joint, if these defects can be repaired, an excellent opportunity exists to restore function and prevent further disease. For the past two decades tissue engineers have used a trial and error approach to repair cartilage defects, using an increasing and ingenious variety of scaffolds and cells with little regard to the normal growth mechanisms of articular cartilage. The sum of this approach is that this field of research has not moved significantly forward since its inception some 25 years ago. The method of transplanting cells into joints has inherent weaknesses that cannot be improved. The National Institute of Clinical Excellence UK guidelines state current transplantation methods do not provide long-term clinical effectiveness for patients nor are they cost-effective solution for short-term benefit. Our approach will break the status quo as it addresses and provides concrete solutions to the major problems that have thus far hindered progress. The major stumbling block to progress has been the lack of suitable cells to restore normal cartilage in joints. Stem cells are critical components in any solution to repair damaged joints, and the discovery of adult stem cells in articular cartilage and their ability to make new permanent cartilage has been an important advance. A problem when using stem cells is that the tissue they produce is immature - immature cartilage does not have the same properties as adult cartilage and is consequently prone to failure. A major recent achievement has been to understand what factors are required to convert immature cartilage into one that has adult properties. The critical question is, can we make new cartilage using stem cells, then transform it so that it is as stiff and durable as adult cartilage to provide a fully functional implant to restore pain-free movement in damaged joints? Our solution is to use 3D bio-printing in combination with cartilage stem cells to make new cartilage. Bioprinting allows us to make complex structures precisely, quickly and reproducibly, maximising the growth potential of stem cells to produce larger and thicker implants. We will then transform the engineered tissue so that it functions like adult cartilage before implanting it into the patient for preclinical testing. This approach is simple and emulates the same biological processes that occur in the body to produce durable and resilient articular cartilage in a highly accelerated and controlled manner. It also provides a clear pathway to systematically translate recent advances in cartilage biology and biofabrication into patient benefits. Given the scope of the challenge we have tailored our approach to be automated and scalable, offering the real potential to treat thousands rather than the few. The team assembled to accomplish this goal is multidisciplinary, highly focused and leading experts in each particular aspect of the solution.