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

骨关节炎软骨再生结合使用坚韧的生物材料和纳米技术支持的基因疗法。

• 批准号: EP/W021234/1
• 负责人: Nuria Oliva-Jorge
• 金额: $ 54.27万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FW021234%2F1
• 关键词: Osteoarthritic; cartilage; regeneration; using; combination

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.

骨关节炎是一种肌肉骨骼疾病，软骨——保护关节骨骼末端的橡胶状填充物——由于磨损而受损，导致虚弱的疼痛。在英国，45岁以上的人中约有三分之一（875万人）积极寻求骨关节炎治疗，80%的人在65岁之前患有骨关节炎。研究表明，人的软骨在成年后没有明显的替换。造成这种情况的主要原因是关节的血液供应不足：没有营养，软骨细胞（存在于关节中的细胞）就不能生长或产生更多的软骨。因此，随着年龄的增长，越来越多的软骨受到不可逆转的损伤，最终导致骨头相互摩擦。生物材料可以为软骨细胞增殖提供支架，同时也可以作为治疗细胞的药物仓库，是软骨再生的理想策略。然而，也存在一些挑战。首先，研究表明，关节受到OA影响时，软骨会发生变化，在软骨细胞生长出新的健康软骨之前，软骨的力学性能需要恢复到关节炎前的水平。此外，oa相关的改变也会导致药物疗效下降。这是一项艰巨的挑战，它要求生物材料支架模仿软骨的自然力学特性，以使人体的自然愈合过程有效地工作，并提高任何治疗干预措施的功效。这也意味着我们现在可以扩大生物材料的潜力，从单纯的软骨替代发展到真正的软骨再生。理想情况下，一种最佳的生物材料也必须是可注射的，以允许微创分娩过程，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，基因治疗是一种很有前途的方法，可以恢复软骨细胞中引发炎症反应和随之软骨破坏的缺陷基因。然而，在软骨细胞内传递基因是非常具有挑战性的，阻碍了这些治疗的发展。我的团队已经开发出纳米颗粒，首次可以在软骨细胞内传递基因，克服了目前OA治疗中基因治疗的局限性。该项目的总体目标是将软骨模拟生物材料与纳米颗粒基因治疗相结合，以促进OA治疗和新软骨生成的同时进行。个人目标是：1；软骨置换：开发模拟软骨压缩力、可注射且具有生物相容性的生物材料。软骨再生：研究生物材料对软骨生成的影响。骨性关节炎治疗：将再生生物材料与基因治疗相结合，在治疗骨性关节炎炎症的同时促进软骨再生。本研究的主要应用在于开发OA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能力降低，这对身体（肥胖增加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，由于缺乏有效的治疗方法，OA将在未来十年花费NHS超过1000亿英镑。OA的慢性方面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32亿英镑，社会服务支出超过2亿英镑。OA是领取伤残生活津贴（DLA）的最常见病症，令人震惊的统计数据显示，每200名领取津贴的人中只有1人重返工作岗位。从这些数字中可以清楚地看出，这项研究是有影响力和及时的。