Osteoarthritic cartilage regeneration using a combination of tough biomaterials and nanotechnology-enabled gene therapy.

骨关节炎是一种肌肉骨骼疾病，软骨--保护关节处骨骼末端的橡胶状衬垫--由于磨损而受损，导致虚弱的疼痛。在英国，大约三分之一的45岁以上的人(875万)积极寻求骨关节炎的治疗，到65岁时，80%的人口患有骨关节炎。研究表明，在成人生活中，人类的软骨没有经历过明显的更替。其主要原因是缺乏对关节的血液供应：没有营养物质，软骨细胞(存在于关节中的细胞)不能生长或制造更多的软骨。因此，随着我们年龄的增长，更多的软骨会受到不可逆转的破坏，最终导致骨与骨的摩擦。生物材料是再生软骨的理想策略，因为它们可以为软骨细胞的增殖提供支架，同时充当修复细胞的药物仓库。然而，也存在一些挑战。首先，研究表明，当关节受到骨性关节炎的影响时，软骨会发生变化，其力学性能需要恢复到关节炎前的水平，软骨细胞才能长出新的健康软骨。此外，与骨质疏松症相关的变化也会导致药物疗效下降。这是一项艰巨的挑战，需要生物材料支架模拟软骨的自然机械特性，才能使人体的自然愈合过程有效地工作，并提高任何治疗干预的效果。这也意味着我们现在可以扩展生物材料的潜力，使其超越单纯的软骨替代，发展到实际的软骨再生。理想情况下，理想的生物材料也必须是可注射的，以实现微创的输送程序，而不是开放手术。同样重要的是，生物材料支架必须装载治疗炎症的药物。最近的研究指出，基因疗法是修复软骨细胞中缺陷基因的一种很有前途的方法，这些缺陷基因会引发炎症反应，从而破坏软骨。然而，在软骨细胞内传递基因是非常具有挑战性的，并阻碍了这些疗法的发展。我的团队首次开发了纳米颗粒，可以在软骨细胞内传递基因，克服了目前基因疗法在骨性关节炎治疗中的局限性。这个项目的总体目标是将一种模拟软骨的生物材料与纳米颗粒启用的基因疗法相结合，以促进骨性关节炎的同步治疗和新的软骨产生。个人目标是：1.软骨置换：开发模拟软骨受压的生物材料，并且是可注射的和生物相容的。软骨再生：研究生物材料对软骨生成的影响。骨关节炎的治疗：将再生生物材料与基因治疗相结合，在治疗关节炎的同时促进软骨再生。本研究的主要应用在于开发治疗骨关节炎和软骨再生的新疗法。这种技术的好处将产生巨大的经济和社会影响。慢性疼痛导致患者行动不便，这对身体(肥胖症增加60%，心血管疾病增加3倍)和精神(社会孤立和丧失独立性)都有影响。最近的一份报告估计，在未来十年，骨关节炎将花费NHS超过1000亿GB，主要是由于缺乏有效的治疗方法。开放式办公室的长期问题对经济产生了额外的影响，损失了3600万个工作日，经济生产损失超过32亿GB，用于社会服务的支出超过2亿GB。OA是残疾生活津贴(DLA)最常见的情况，令人震惊的统计数据显示，每200人中只有1人领取重返工作岗位的福利。从这些数字中可以清楚地看出，这项研究是有影响力的，也是及时的。

Osteoarthritis is a musculoskeletal condition where cartilage - the rubber-like padding that protects the ends of bones at the joints - becomes damaged due to wear and tear, causing debilitating pain. Around 1 in 3 people in the UK over 45 years of age (8.75 million) have actively sought treatment for osteoarthritis, and 80% of the population suffers it by age 65. Studies have shown that human cartilage experiences no significant replacement in adult life. The main reason for this is a lack of blood supply to the joints: without nutrients, chondrocytes (cells present in the joints) cannot grow or make more cartilage. Hence, as we age, more cartilage gets irreversibly damaged, eventually leading to bone rubbing against bone.Biomaterials present an ideal strategy to regenerate cartilage, as they can offer a scaffolding for chondrocytes to proliferate, while acting as a depot for medicine to heal cells. However, some challenges exist. First, studies have showed that cartilage changes when the joint is affected by OA, and that its mechanical properties need to be returned to pre-arthritic levels before chondrocytes can grow new healthy cartilage. Moreover, OA-associated changes also lead to decreased efficacy of drugs. This is a difficult challenge, which requires the biomaterial scaffold to mimic the natural mechanical properties of cartilage for the body's natural healing process to work effectively, as well as enhance the efficacy of any therapeutic interventions. This also means that we can now expand the potential of biomaterials to advance beyond mere cartilage replacement to actual cartilage regeneration. Ideally, an optimal biomaterial must also be injectable to allow a minimally invasive delivery procedure, as opposed to open surgery. It is also important that the biomaterial scaffold must be loaded with drugs to treat inflammation. Recent studies have pointed at gene therapy as a promising approach to restore defective genes in chondrocytes that trigger an inflammatory response and consequent destruction of cartilage. However, the delivery of genes inside chondrocytes is very challenging and hampers the development of these therapies. My group has developed nanoparticles that can, for the first time, deliver genes inside chondrocytes, overcoming the current limitations of gene therapy in OA treatment.The overall aim of this project is to combine a cartilage-mimicking biomaterial with nanoparticle-enabled gene therapy to promote simultaneous OA treatment and new cartilage production. The individual objectives are:1. Cartilage Replacement: Develop biomaterials that mimic the compression forces of cartilage and are injectable and biocompatible.2. Cartilage Regeneration: Study the effects of biomaterials on cartilage production.3. Osteoarthritis treatment: Combine a regenerative biomaterial with gene therapy to simultaneously treat inflammation and promote cartilage regeneration in OA.The main application of this research lies on the development of new therapies for OA and cartilage regeneration. The benefits of such a technology will have a tremendous economic and social impact. Chronic pain leads to reduced mobility in patients, which has an impact both physically (60% increase in obesity, 3-fold increase of cardiovascular disease) and mentally (social isolation and loss of independence). A recent report estimated that OA will cost the NHS over £100 billion over the next decade, mostly due to the lack of efficient therapies. The chronic aspect of OA has an added impact on the economy, with 36 million workdays lost with a loss of economic production of over £3.2 billion and over £200 million spent on social services. OA is the most common condition for Disability Living Allowance (DLA), with the staggering statistic of only 1 in 200 people on benefits returning to work. It becomes clear from these numbers that this research is impactful and timely.