A Portable Electrohydrodynamic Device for in-situ Production of Multi-Layered Drug-Loaded Meshes

提出的研究描述了一种新的工程方法，用于伤口和烧伤治疗的控释药物的定点递送，该方法基于一种创新的便携式设备，该设备允许原位生成纳米/微纤维网。这些纤维可以在核-壳结构中包含多层活性药物成分（api）（可能多达至少四层），允许从蛋白质到低分子量抗生素的药物区隔，包括创新的治疗性低聚糖。具有分区结构的纳米和微纤维目前在药物输送领域引起了极大的兴趣，因为它们具有高表面积、高流体渗透性、将不相容的药物随时分离到物理上不同的环境、通过掺入控释聚合物来调节药物释放速度的能力以及宏观网状结构的物理灵活性和多功能性。此外，鉴于最近对联合疗法的重视，使用同轴和多轴电流体动力（EHD）技术产生分区系统的可能性非常有吸引力。这种应用的一个例子是伤口和烧伤的治疗，在这种情况下，网状物形状的灵活性可以整齐地填充病变，网状物的高流体渗透性促进组织再生，治疗剂的可调释放和网状物的生物降解都是完全可行的属性，这将使药物负载纳米纤维方法非常有利。另一种尚未在实践中实现的可能性是在创伤点原位生成微/纳米纤维。如果这是可能的，那么将节省宝贵的治疗时间，因为设计用于止血，预防感染，减轻疼痛或促进愈合的药物可以以一种可应用于广泛病变结构和区域的形式快速施用。事实上，便携式系统也可用于冲突情况，用于在家中治疗糖尿病溃疡等行动不便的患者，或用于难民营等医疗上无法到达的地区，而使用生物可降解聚合物基将使网状物在一段时间内被简单地吸收，而不会损害与敷料去除相关的病变。此外，在紧急情况下，当患者可能因静脉通路不良而失去知觉（例如海洛因过量）或甚至可能发生癫痫发作（例如癫痫持续状态），口服/静脉给药变得不切实际时，在需要点产生高渗透性微纤维网的能力能够实现替代鼻腔途径，以实现持续和受控的药物释放。因此，总的来说，一个简单和廉价的复杂药物负载纤维网管理的“现场”系统将为各种情况的患者带来巨大的好处，并将代表工程主导的治疗发展的重大突破。然而，很明显，这样一个系统会带来一系列深刻的工程挑战。尽管纤维生产技术最近取得了进步，但生产具有分隔系统的纤维需要体积庞大，价格昂贵（20万英镑），台式高压电源和注射器泵，这些都局限于实验室或工厂环境。开发一种便携式、手持式、更便宜（< 2000英镑）的微型EHD设备，可以产生多层治疗材料，这可能会彻底改变微/纳米纤维的实际适用性。我们相信，基于我们迄今为止的工作，这样的方法现在是可能的，这里概述的项目侧重于与我们的原型设备开发和药物结合挑战相关的工程问题，将为该方法在广泛的治疗应用中使用奠定基础。

The proposed research describes a novel engineering approach to point-of-need delivery of controlled release medications for wound and burn treatment, based on an innovative portable device which allows in situ generation of nano-/micro fibrous meshes. These fibres can contain multiple layers of active pharmaceutical ingredients (APIs) in a core-shell configuration (potentially up to at least four layers), allowing compartmentalisation of agents ranging from proteins to low molecular weight antibiotics and including innovative therapeutic oligosaccharides. Nano- and microfibres with compartmentalised structures are currently attracting a great deal of interest within the drug delivery arena due to the advantages of high surface area, high fluid permeation, ready separation of incompatible drugs into physically distinct environments, the ability to tune drug release rates via incorporation into controlled release polymers and the physical flexibility and versatility of the macroscopic mesh structure. Furthermore, given recent emphasis on combination therapies, the possibility of generating compartmentalised systems using, for example, coaxial and multi-axial electrohydrodynamic (EHD) technology is highly attractive. One example of such an application is the treatment of wounds and burns, whereby the flexibility of shape of the meshes to neatly fill the lesion, the high fluid permeation of the mesh facilitating tissue regrowth, the tunable release of therapeutic agents and the biodegradation of the mesh are all perfectly feasible attributes that would render a drug-loaded nanofibre approach highly advantageous. A further possibility, not yet realised in practice, is the generation of micro/nanofibres in situ at the point of trauma. Were this to be possible, then valuable time to treatment would be saved as agents designed to stop bleeding, prevent infection, reduce pain or promote healing could be administered quickly in a form which could be applied to a wide range of lesion architectures and areas. Indeed, a portable system could also be used in conflict situations, for patients with mobility difficulties being treated at home for conditions such as diabetic ulcer or for otherwise medically inaccessible regions such as refugee camps, while the use of biodegradable polymer bases would allow the mesh to simply be resorbed over a period of time without damage to the lesion associated with dressing removal. Moreover, the capability to generate highly permeable microfibrous meshes at point-of-need enables an alternative nasal route for sustained and controlled drug release when oral/intravenous drug delivery is rendered impractical during emergencies where the patient may be unconscious with poor vein access (e.g. heroin overdose) or may even be having a seizure (e.g. status epilepticus). Overall, therefore, a 'field' system for simple and inexpensive administration of complex drug-loaded fibre meshes would have huge patient benefit for a wide range of conditions and would represent a significant breakthrough in engineering-led therapeutic development. Clearly, however, such a system would present a series of profound engineering challenges. Despite recent advances in fibre production technology, the generation of fibres with compartmentalised systems requires bulky, expensive (>£20k), bench-top high voltage supply and syringe pumps that are confined to a laboratory or factory environment. Developing a portable, hand-held, cheaper (<£2k), miniature EHD device that can generate multilayered therapeutic materials could revolutionise the practical applicability of micro/nanofibres. We believe, based on our work to date, that such an approach is now possible and the project outlined here, which focuses on the engineering issues associated with the development of our prototype device and the challenges of drug incorporation, would lay the foundation for the use of this approach in a wide range of therapeutic applications.