Smart materials for targeted stem cell fate and function in skeletal repair

我们现在比过去活得长多了。但不幸的是，随着我们进入晚年，我们生病或受伤的机会急剧增加。老年人面临的一个大问题是与骨骼和关节相关的疾病和损伤。像骨质疏松症和关节炎这样的疾病会引起疼痛，导致骨折，导致成千上万的人无法移动和痛苦，每年花费纳税人数千万英镑。因此，迫切需要新的治疗方法，使骨骼更好地愈合。通常，从受伤或患病的人的健康部位取出的骨块的移植可以用于促进受伤部位的骨愈合（称为“自体移植物”），或者可以使用来自最近死亡的人的骨（“同种异体移植物”）。但这些方法有几个弱点-例如，有限的组织，愈合不良，甚至可能传播危及生命的疾病。我们需要替代方法来帮助治愈许多受骨骼疾病和损伤影响的人。克服这些问题的一种潜在方法是在实验室中通过使用人造材料和细胞来源（如干细胞）作为建筑材料从头开始制造新组织。或者，可以设计和开发人造材料，以鼓励身体比单独更好地自我修复。这种材料有时被称为“生物活性”或“智能”材料，因为它们中的化学信息可以指导体内已经存在的细胞和组织再生缺失的组织。在这项研究计划中，我们想尝试制造一种新型的智能组织支架，以促进骨骼愈合。为了做到这一点，我们计划设计可以植入体内的支架和材料，其中包含数百万个微小的中空药物或化学品储存库，称为纳米颗粒。这种纳米颗粒的直径小于一根人类头发的宽度，我们相信我们可以设计它们，使其具有促进组织再生所必需的许多品质。例如，我们计划改变它们“外壳”的化学成分，使它们以不同的速度释放毒品。这是非常重要的，因为组织愈合涉及一系列以非常不同的速率发生的重要步骤-例如，在早期阶段不正确地释放化学物质可能会停止或减缓愈合，而在后期阶段释放化学物质可能对促进愈合非常重要。这就是为什么设计以不同速率释放不同化合物的支架至关重要。此外，某些化学物质可能对促进一种类型的细胞促进愈合很重要，但可能会阻止其他类型的细胞完成正确的工作。为了确保正确的化学物质被传递到正确的细胞，我们还计划设计表面有标记的颗粒，这些标记将它们靶向特定类型的细胞-例如骨细胞。然后，我们计划将这些化学释放包拴在不同类型的生物相容性材料上。接下来，我们将测试我们的"智能"支架在正确的时间将化学物质输送到正确的细胞方面的有效性，以及观察支架在促进骨愈合方面的功能。为此，我们将用染料标记纳米颗粒的内容物，并测量它们的释放和各种不同细胞的吸收，例如骨细胞或血管细胞。最后，我们将在实验啮齿动物的模拟骨损伤中植入支架，以测试它们是否能提高骨骼愈合的速度和程度，使用令人兴奋的X射线计算机断层扫描技术。最终，我们希望通过这些实验来开发新的治疗方法，以预防骨骼疾病并改善人类的骨骼愈合。该项目汇集了一个由工程师和生物学家组成的跨学科团队，试图实现这一目标。

We are now living much longer than we used to. But an unfortunate consequence of this is that as we reach later life the chances that we can become ill or injured increase dramatically. One big problem that elderly people face is illness and injury associated with the bones and joints. Diseases like osteoporosis and arthritis cause pain, cause bone fractures and lead to immobility and distress to tens of thousands of people each year, costing the taxpayer tens of millions of pounds. So new treatments that enable the skeleton to heal better are urgently required. Often a transplant of pieces of bone taken from a healthy site on an injured or diseased person might be used to promote bone healing at an injury site (called an 'autograft'), or alternatively bone from a person who has recently died might be used (an 'allograft'). But these approaches have several weaknesses - for instance, limited tissue, poor healing or even the potential of the transmission of life-threatening diseases. We need alternative approaches to help cure the many people affected by bone disease and injury.A potential way of overcoming these problems is to make new tissue from scratch in the lab by using artificial materials and a source of cells - such as stem cells - as building materials. Alternatively, artificial materials could be designed and developed to encourage the body to heal itself better than it would do alone. Such materials are sometimes called 'bioactive' or 'smart' materials because the chemical information in them can direct cells and tissue already present in the body to regenerate the missing tissue. In this research proposal we want to try to make a new kind of smart tissue scaffold that will improve bone healing.To do this, we plan to design scaffolds and materials which can be implanted in the body and which contain millions of tiny hollow reservoirs of drugs or chemicals, called nanoparticles. Such nanoparticles have diameters of less than the width of a single human hair and we believe we can engineer them to have many qualities necessary for promoting the regeneration of tissue. For example, we plan to change the chemical composition of their 'shell' so that they release their drug cargo at different rates. This is very important, because tissue healing involves a series of important steps occurring at very different rates - the incorrect release of a chemical at an early stage, for instance, may stop or slow healing, whereas its release at a later stage may be very important in promoting healing. This is why it is vitally important to design scaffolds that release different compounds at different rates. Also, certain chemicals may be important for encouraging one type of cell to promote healing, but may stop other types cells from doing their correct jobs. To ensure the right chemicals are delivered to the right cells, we also plan to design particles that have markers on their surface that target them to a particular sort of cell - a bone cell for instance. We then plan to tether these chemical release packets to different types of biocompatible materials.We will next test how effective our 'smart' scaffolds are in delivering chemicals to the correct cells at the correct times, as well as seeing how well the scaffolds function in promoting bone healing. To do this, we will tag the contents of nanoparticles with a dye and measure their release and uptake by a variety of different cells, for example bone cells or blood vessel cells. Finally we will implant scaffolds in simulated bone injuries in experimental rodents to test if they improve how fast and how well bones heal, using exciting techniques in x-ray computed tomography.Ultimately, we want to do these experiments so that we can develop new treatments to prevent bone disease and improve bone healing in people. This project brings together an interdisciplinary team of engineers and biologists to try and achieve this goal.