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

我们现在的寿命比过去长得多。但这样做的一个不幸后果是，随着我们步入晚年，我们生病或受伤的可能性急剧增加。老年人面临的一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导致疼痛，导致骨折，并导致每年数万人行动不便和痛苦，花费纳税人数千万英镑。因此，迫切需要新的治疗方法来使骨骼更好地愈合。通常，从受伤或患病的人身上取出的健康部位的骨块可能被用来促进受伤部位的骨愈合(称为“自体移植”)，或者也可以使用最近去世的人的骨(“同种异体移植”)。但这些方法有几个缺点--例如，组织有限，愈合不良，甚至有可能传播危及生命的疾病。我们需要其他方法来帮助治愈许多受骨骼疾病和损伤影响的人。克服这些问题的一个潜在方法是在实验室从头开始制造新组织，使用人造材料和一种细胞来源--如干细胞--作为建筑材料。或者，可以设计和开发人造材料，以鼓励身体比单独治疗更好地自我愈合。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丢失的组织。在这项研究计划中，我们试图制造一种新型的智能组织支架，这种支架将促进骨骼愈合。为此，我们计划设计可以植入人体的支架和材料，其中包含数百万微小的中空药物或化学物质，称为纳米颗粒。这种纳米粒子的直径小于一根头发的宽度，我们相信我们可以将它们改造成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“壳”的化学成分，以便它们以不同的速率释放药物货物。这一点非常重要，因为组织修复涉及一系列以非常不同的速度发生的重要步骤--例如，早期不正确的化学物质释放可能会阻止或减缓愈合，而后期的化学物质释放可能对促进愈合非常重要。这就是为什么设计能够以不同的速率释放不同化合物的支架是至关重要的。此外，某些化学物质可能对鼓励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发挥正确的作用。为了确保正确的化学物质被传递到正确的细胞，我们还计划设计在其表面具有标记的颗粒，以针对特定类型的细胞--例如骨骼细胞。然后，我们计划将这些化学物质释放包拴在不同类型的生物兼容材料上。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效率，以及看看支架在促进骨骼愈合方面的作用有多好。为此，我们将用染料标记纳米颗粒的含量，并测量各种不同细胞(例如骨细胞或血管细胞)对它们的释放和摄取。最后，我们将使用令人兴奋的X射线计算机断层扫描技术，将支架植入实验性啮齿动物的模拟骨骼损伤中，以测试它们是否提高了骨骼愈合的速度和程度。最终，我们想要做这些实验，以便我们能够开发新的治疗方法来预防骨骼疾病，改善人类的骨骼愈合。这个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.