Micro-manufacturing of tissue patterned organ-chips for accelerated deployment of new medicines (Patterned OrganChips)

我们的愿景是开发使能的器官芯片技术，以加快从药物发现到部署支持治疗创新的时间。这将通过专门为在微流控器官芯片的复杂环境中使用而开发的3D生物打印和微制造技术实现。我们的愿景和方法得到了与主要生物制药、器官芯片技术提供商和英国监管机构的合作伙伴关系的支持，以及通过玛丽女王预测体外模型中心与50多家公司和其他利益相关者的广泛社区参与。由于不充分的临床前测试方法和对活体动物试验的依赖，新疗法的开发管道正在失败。这对环境和可持续性产生了重大影响，浪费了能源和资源，以及相关的时间和金钱。据估计，进入临床试验的药物有90%以上最终失败，每一次治疗失败浪费10-15年，超过10亿GB。此外，据估计，仅在英国，药物不良反应每年就导致1万人死亡。除非我们解决这一挑战，否则该行业将无法兑现令人兴奋的新疗法的承诺。器官芯片是一种包含活细胞的生物工程系统，在该系统中，活器官的关键物理、化学和生物方面在实验室中被重现，以概括体内的行为。这项技术通过提供对测试新疗法和预测临床放大性能至关重要的分析平台，有可能解决药物开发流水线中的损耗问题。在美国，2022年的FDA现代化法案规定，器官芯片现在可以用于评估药物的安全性和有效性，作为动物试验的替代方案。然而，迫切需要微制造技术来重建基本的组织/器官异质性。这一研究方案将开发创新的微制造方法，在器官芯片内形成空间图案组织，生产复制复杂的组织内和组织间异质性、梯度和界面的模型。在基于光的图案化、浮力/扩散制造和3D生物打印等新兴技术的基础上，我们将对基质利基环境、细胞种群以及机械和生化分化线索进行空间图案化，以创建组织图案化。我们的新方法将克服复杂的技术挑战，包括可访问性、可扩展性、大小限制、微流体边界条件、3D空间控制、原位交联、生物兼容性和无菌。因此，我们将提供一个经过验证的、行业就绪的方法工具箱，这些方法将促进更准确地表示它们在体内的同源物的模型，增加临床前测试的预测能力。这反过来将刺激更有效、更负担得起和更可持续的治疗渠道，加快从工作台到床边更安全和更有效的药物输送。作为这种空间组织图案化技术的示范，我们将提供一套符合合作伙伴需求的肌肉骨骼(MSK)器官芯片模型。通过开发微制造空间组织图案化方法，我们将使工业迫切需要的下一代器官芯片模型能够加速药物革命。因此，这一方案对于提供更有效和可持续的临床前测试渠道，以提供从工作台到床边的更安全和更有效的治疗至关重要。

Our vision is to develop enabling organ-chip technology to accelerate the time from medicines discovery to deployment supporting therapeutic innovation. This will be achieved through 3D bioprinting and micro-manufacturing techniques developed specifically for use within the complex environment of microfluidic organ-chips. Our vision and approach are supported by partnership with major biopharma, Organ-chip technology providers and by the UK regulators as well as wider community engagement with over 50 companies and other stake holders via Queen Mary's Centre for Predictive in vitro Models. The development pipeline for new therapeutics is failing due to inadequate pre-clinical testing methodologies and a reliance on in vivo animal testing. This has a significant environmental and sustainability impact with wasted energy and resources as well as associated time and money. It is estimated that over 90% of drugs entering clinical trials ultimate fail, wasting 10-15 years and over £1billion for each failed therapeutic. Furthermore, adverse drug reactions are estimated to kill 10,000 people a year in the UK alone. Unless we solve this challenge, industry will not be able to deliver on the exciting promise of new therapeutics. An organ-chip is a bioengineered system containing living cells in which key physical, chemical and biological aspects of a living organ are recreated in the laboratory to recapitulate in vivo behaviour. This technology has the potential to address the attrition in the medicine development pipeline by providing the analytical platforms that are essential for testing new therapeutics and predicting scale up performance in the clinic. In the USA, the FDA Modernisation Act in 2022 mandated that organs-chips can now be used to evaluate drug safety and efficacy as an alternative to animal testing. However, micro-manufacturing techniques are urgently needed to recreate the essential tissue/organ heterogeneity. This research programme will develop innovative micro-manufacturing approaches to spatially pattern tissues within organ-chips, producing models that replicate the complex intra- and inter- tissue heterogeneity, gradients and interfaces. Building on emerging technologies of light-based patterning, buoyancy/diffusion fabrication and 3D bioprinting, we will spatially pattern matrix niche environments, cell populations and mechanical and biochemical differentiation cues to create tissue patterning. Our novel approaches will overcome complex technical challenges including accessibility, scalability, size limitations, microfluidic boundary conditions, 3D spatial control, in situ cross linking, biological compatibility and sterility. We will therefore provide a toolbox of validated, industry-ready methodologies which will facilitate models that more accurately represent their in vivo homologues, increasing predictive power for pre-clinical testing. This in turn will stimulate a more efficient, affordable and sustainable therapeutic pipeline with accelerated delivery of safer and more effective medicines from bench to bedside. As demonstrator exemplars of this spatial tissue patterning technology, we will deliver a suite of musculoskeletal (MSK) organ-chip models aligned with partner needs. By developing micro-manufacturing spatial tissue patterning methodologies, we will enable next generation organ-chip models which industry desperately needs to accelerate the medicines revolution. This programme is therefore critical in providing a more efficient and sustainable preclinical testing pipeline to deliver safer and more effective therapies from bench to bedside.