Instructive acellular tissue engineering (IATE)

目前英国有1000万人受到肌肉骨骼疾病的影响，每年花费国民健康服务47.6亿英镑。令人担忧的是，随着预期寿命的增加和老年人对持续生活质量的需求，这种压力预计只会增加。因此，非常需要再生受损或患病骨骼的新方法。理想情况下，这些技术应该改善患者的治疗效果，同时也具有成本效益。除了从身体的另一部分移植骨之外，这在规模上是有限的，并导致局部发病率，目前的骨再生方法通常依赖于将浓缩剂量的单一蛋白质与结构材料相结合。然而，由于这些方法不能模拟骨的自然形成过程，因此它们可能是次优的，甚至会导致显著的副作用。因此，在过去的十年里，研究人员集中精力开发一种新的策略，组织工程。该领域旨在通过将三个主要组成部分结合在一起来模仿自然再生。组织工程将细胞与指导性生物因子结合，并将它们纳入材料中，以允许它们被递送到预期部位。尽管在组织工程方面取得了许多进展，并且在实验室规模上取得了有希望的结果，但这些技术中很少有达到临床应用。这通常是由于基于细胞的产品不符合与安全性和再现性相关的监管标准，因为细胞在植入时的行为可能难以控制。此外，批准生物疗法的复杂过程极其昂贵，可能需要10年以上的时间。在这个项目中，将开发一种新型的骨再生治疗方法，模仿我们身体自身的发育过程。这种脱细胞方法将导致一种安全的治疗方法，其目的是绕过与当前治疗相关的问题。研究表明，在骨骼的健康发育过程中，纳米级（十亿分之一米）颗粒从骨形成细胞（成骨细胞）中释放出来，这些细胞充当将创建该组织的矿物质成分所需的所有元素聚集在一起的位点。这些颗粒，称为细胞外囊泡，已被证明是重要因子（例如蛋白质）的载体，可以指导和促进骨形成。还发现这些囊泡可能向参与愈合过程的其他细胞发出信号，增强其效果。因此，基于这种囊泡递送的骨再生疗法的发展代表了一个令人兴奋的机会，可以概括我们的身体在健康状态下再生的方式。在这个项目中，我们将研究骨细胞形成这些再生囊泡的过程，并使用一系列技术来挖掘它们所包含的进一步信息。这一新的基础知识将使我们能够开发一种安全的疗法，利用并最大限度地发挥囊泡的自然愈合能力。在该计划中，我们将利用我们的多学科专业知识来设计一种能够可控地释放囊泡沿着其他已知的促进骨再生的非细胞因子的材料。这项工作将提供一种技术，可以局部注射到骨骼疾病或损伤的部位，我们将证明其有效性，以提高矿物形成超过目前的临床黄金标准。与我们的项目合作者一起，我们还将探索使用生物打印过程将这种材料形成3D结构的机会，这将有助于引导骨再生。虽然该计划的主要重点是开发一种能够再生骨的新型脱细胞技术，但我们也将研究软骨细胞衍生的囊泡的能力。编程囊泡来修复软骨的可能性非常有吸引力，因为这种组织的自我修复能力有限，并且经常在肌肉骨骼损伤中受损

There are currently 10 million people in the UK affected by musculoskeletal disorders, which costs the National Health Service £4.76 billion annually. Alarmingly with increasing life expectancy and the demand for sustained quality of life in older years, this pressure is only expected to rise. As such, new approaches to regenerate damaged or diseased bones are greatly needed. Ideally, these technologies should improve patient outcomes while also being cost effective.Outside of grafting bone from another part of the body, which is limited in scale and results in local morbidity, current approaches to regenerate bone typically rely on combining concentrated doses of single proteins with structural materials. However, since these approaches do not mimic the natural formation process of bone they can be sub-optimal and even result in significant side effects. Therefore, in the past decade researchers have focused on developing a new strategy, tissue engineering. This field aims to imitate natural regeneration by bringing together the three major constituents. Tissue engineering combines cells with instructive biological factors and incorporates them into a material to allow them to be delivered to the intended site. Despite many advancements in tissue engineering and promising results at a laboratory scale, very few of these technologies reach clinical use. This is typically due to cell-based products not meeting regulatory standards associated with safety and reproducibility since the behaviour of cells when implanted may be difficult to control. Furthermore, the complex process of approving biological therapies is extremely expensive and may take over 10 years. In this project, a novel bone regeneration treatment will be developed that mimics our body's own development processes. This acellular approach will lead to a safe therapy, which aims to circumnavigate the issues associated with current treatments. Research has shown that during healthy development of bone nanosized (one billionth of a metre) particles are released from bone forming cells (osteoblasts) that act as sites to bring together all of the elements needed to create the mineral component of this tissue. These particles, termed extracellular vesicles, have been shown to be carriers of important factors (for example proteins) that may instruct and encourage bone formation. It has also been found that these vesicles may signal to other cells involved in healing processes enhancing their effect. As such, the development of a bone regeneration therapy based on delivery of such vesicles represents an exciting opportunity to recapitulate the way our bodies regenerate in a healthy state. In this project, we will study the process by which bone cells form these regenerative vesicles and use a range of techniques to unearth further information on what they contain. This new fundamental knowledge will allow us to develop a safe therapy, which exploits and maximises the natural healing capacity of vesicles. During the programme, we will use our multidisciplinary expertise to engineer a material capable of controllably releasing vesicles along with other acellular factors known to encourage bone regeneration. This work will deliver a technology that may be locally injected into a site of bone disease or injury for which we will demonstrate its effectiveness to enhance mineral formation beyond current clinical gold standards. With our project collaborators, we will also explore the opportunity to form this material using a bioprinting process into 3D structures that will help to guide bone regeneration. While the primary focus of this programme is to develop a novel acellular technology capable of regenerating bone, we will also examine the capacity of vesicle derived from cartilage cells. The possibility to programme vesicles to repair cartilage is very attractive since this tissue has limited self-healing capacity and is often compromised in musculoskeletal injuries