RESTORE: engineeRing an Enhanced vesicle SysTem for coOrdinated fRacture rEpair

骨折和下背痛等骨骼损伤在老年人中非常常见，并且在全球范围内造成越来越大的医疗和社会经济负担，仅150，000多例与骨质疏松症相关的骨折每年就给英国经济造成超过17亿英镑的损失。到2040年，这一数字预计将翻一番，给全球医疗系统带来巨大压力，并严重影响生活质量。目前，标准的临床方法是将骨组织从同一患者的一个部位移植到另一个部位（自体移植物），从另一个患者（同种异体移植物）或合成骨移植替代品（BGS）。这些方法是次优的，减少了患者的流动性，并增加了感染的风险。在BGS的情况下，所形成的骨通常不如患者自身的组织，增加了继发性骨折和进一步住院的可能性。现代组织工程（TE）方法试图将患者自身的干细胞与设计用于模拟自然物理骨环境的3D支架结合起来。这些干细胞被认为在移植到患者体内时会转化为骨细胞，直接形成新的骨组织。然而，尽管最初的积极结果，没有常规的临床应用存在。这是因为不可能制造足够的干细胞来将实验室中观察到的阳性结果转化为真实的临床环境，这些细胞需要直接从患者中分离或从冷冻储备中扩增。这使得在医院环境中细胞的衍生和扩增在逻辑上是不切实际的，并且使得该过程与临床医生的要求不相容。此外，最近的证据表明，直接干细胞再生的传统观点是不准确的，许多干细胞移植在组织损伤部位并不直接有助于骨修复。相反，这些细胞通过分泌称为细胞外囊泡（EV）的纳米颗粒来实现其积极的治疗效果。这些囊泡比细胞小约1000倍，含有多种生物因子，可促进早期骨形成。与干细胞不同，通过将细胞用作生物工厂，可以在规定的条件下制造大量电动汽车。与细胞不同，这些囊泡相对容易大量分离，其治疗效果能够在长期储存和应用之前进行验证和质量检查。也许最重要的是，与干细胞不同，EV的含量在患者中施用时不会改变，从而增加了所得疗法的安全性。因此，电动汽车的应用可以捕捉细胞方法的优势，同时提供更高水平的标准化，可扩展性和质量控制。该项目将设计一个先进的再生平台，用于局部协调输送治疗电动汽车，以恢复骨功能。该平台将利用电动汽车的特性来驱动对健康骨形成至关重要的关键再生反应，例如招募局部祖细胞和形成天然矿物质模板以驱动新组织形成。这是我们如何处理骨折修复和TE的一个范式转变，提供了一种无细胞但生物等效的方法，以可控和可再生的方式捕获天然骨发育的先天复杂性。即刻结果将评价该平台技术在非承重场景（例如，腿部骨折抬高）中的潜力。而进一步的物理加固（例如使用钛笼）将允许在承重情况下（例如脊柱手术）的更广泛应用。从长远来看，预计这种方法将提供一种适应性强的平台技术，可以重新配置用于更广泛的肌肉骨骼应用。

Skeletal injuries such as bone fractures and lower back pain are extremely common amongst the elderly and present a growing worldwide medical and socioeconomic burden, with over 150,000 osteoporosis-related fractures alone costing more than £1.7 billion per annum to the UK economy. This number is expected to double by 2040, putting a tremendous strain on healthcare systems worldwide and severely impacting quality of life. At present, standard clinical approaches apply bone tissue grafted from one site to another in the same patient (autograft), from another patient (allograft) or synthetic bone graft substitutes (BGS). These approaches are suboptimal, reducing patient mobility and introducing an increased risk of infection. In the case of BGS, the resulting bone formed is often inferior to the patient's own tissue, increasing the likelihood of secondary fracture and further hospitalisation.Modern tissue engineering (TE) approaches have sought to combine a patient's own stem cells with 3D scaffolds designed to mimic the natural physical bone environment. These stem cells are thought to transform into bone cells when grafted in the patient, directly forming new bone tissue. However, despite initial positive results, no routine clinical applications exist. This is because it has not been possible to manufacture enough stem cells to translate the positive results observed in the laboratory into a real world clinical setting, with these cells either needing to be isolated directly from the patient or expanded from a frozen stock. This makes the derivation and expansion of cells in a hospital environment logistically impractical and renders the process incompatible with the requirements of the clinician. Furthermore, recent evidence has shown that the traditionally held view of direct stem cell regeneration is inaccurate, with many stem cells grafted at the site of tissue damage not directly contributing to bone repair. Rather, these cells achieve their positive therapeutic effects through the secretion of nanoparticles called extracellular vesicles (EVs). These vesicles are approximately 1000 times smaller than a cell and contain a wide variety of biological factors that drive early bone formation. Unlike stem cells, large numbers of EVs can be manufactured under defined conditions by using the cell as a biological factory. Unlike cells, these vesicles are relatively simple to isolate in large quantities, with their therapeutic effects able to be validated and quality checked prior to long-term storage and application. Perhaps most importantly, unlike stem cells, the content of EVs will not change when administered in a patient, increasing the safety profile of the resulting therapy. As such, the application of EVs could capture the advantages of a cellular approach, while offering enhanced levels of standardisation, scalability and quality control.This project will engineer an advanced regenerative platform for the local coordinated delivery of therapeutic EVs to RESTORE bone function. The platform will exploit the properties of EVs to drive key regenerative responses critical for healthy bone formation, such as the recruitment of local progenitor cells and formation of a natural mineral template to drive new tissue formation. This is a paradigm shift in how we approach fracture repair and TE, delivering a cell-free, yet biologically equivalent approach that captures the innate complexity of natural bone development in a controlled and reproducible manner. Immediate outcomes will evaluate the potential of this platform technology in non-weight bearing scenarios (e.g. elevated leg fractures). While further physical reinforcement (e.g. using a titanium cage) will permit broader application in instances of weight bearing, such as spinal surgeries. In the longer-term, it is anticipated that this approach will provide an adaptable platform technology that can be reconfigured for wider musculoskeletal applications.