Engineering Nitric Oxide Delivery Platforms for Wound Healing Applications

在全球范围内，有一些公共卫生问题比抗菌素耐药性（AMR）更重要。AMR不承认边界;因此，这场斗争必须是一场协调的多学科努力。在这个“后抗生素时代”，迫切需要不依赖传统抗生素来对抗感染的新技术。目前，尚无强有力的临床证据表明含抗菌剂的敷料在预防或治疗慢性伤口方面比不含药敷料更有效。对先进敷料的系统性审查不断显示缺乏具有临床相关终点的高质量研究。事实上，伤口敷料每年约占英格兰初级保健处方成本的1.2亿英镑，仅银基抗菌敷料就花费了2500多万英镑。支持这些敷料有效性的临床证据很少，需要临床医生输入成本和患者影响，以实现慢性伤口管理和愈合的最终目标。该项目的目标是战略性地开发制造先进伤口敷料的技术，试图对抗感染（而不会导致AMR），同时鼓励皮肤组织再生。慢性伤口的成功治疗取决于识别和治疗阻碍愈合过程的因素。最近人们认识到，在慢性伤口中发现的细菌存在于称为生物膜的社区中，这有助于感染和延迟愈合。因此，标准的伤口管理变得更加复杂，新的解决方案需要针对生物膜。一氧化氮（NO）是一种有效的治疗慢性伤口愈合，因为它已被证明是一种有效的抗生物膜剂，它在主动伤口再生中起着关键作用。NO的作用模式与传统抗生素不同，因此不会导致AMR。该项目的目的是开发一个平台，通过拴系含有笼状NO储库的化合物从模型敷料中释放NO，所述笼状NO储库能够以受控和持续的方式释放NO，以利用其双重作用。这是通过4个步骤实现的。首先，通过环保制造工艺设计和开发功能化模型敷料表面。其次，这些官能化表面将被改性以在表面的外部上具有氮基团。该氮基团将允许附接笼状NO储存器。第三，笼状NO储存器将在剂量和释放方面进行优化。最后，这些表面将被测试杀死细菌的功效，同时保持对人体细胞无毒。提出的这种创新的NO递送平台解决了对有效伤口愈合技术的需求，该技术具有扩展这种特殊分子在伤口护理中的临床适用性的特性。通过开发这项技术，有一个真实的机会，可以成为针对这一流行病的解决方案的一部分，同时参与科学上优秀的工业相关研究。

There are a few public health issues of greater importance globally than antimicrobial resistance (AMR). AMR does not recognise borders; thereby necessitating the fight to be a coordinated multidisciplinary effort. In this 'post-antibiotic era' the urgency for new technologies that do not rely on traditional antibiotics to combat infection is in essential. Currently there is no robust clinical evidence showing that dressings containing antimicrobials are more effective than unmedicated dressings for the prevention or treatment of chronic wounds. Systemic reviews of advanced dressings constantly show the lack of high-quality studies with clinically relevant endpoints. Indeed, wound dressings account for about £120 million of prescribing costs in primary care in England each year, with more than £25 million being spent on silver based antimicrobial dressings alone. The clinical evidence supporting the efficacy of these dressings is sparse and is in need of clinician input into cost and patient implication for the ultimate goal of management and healing of chronic wounds. The goal of this project is to strategically develop the technology to fabricate advanced wound dressings by trying to fight infection (without contributing to AMR) and simultaneously encouraging skin tissue regeneration. Successful treatment of a chronic wounds depends on identifying and treating factors that impede the healing process. It has recently been recognised that bacteria that are found in chronic wounds reside in communities called biofilms which contribute to infection and delayed healing. Therefore, standard wound management becomes more complex and new solutions need to be biofilm-targeted. Nitric Oxide (NO) is an effective therapeutic for chronic wound healing as it has been proven as a potent anti-biofilm agent and it plays a key role in active wound regeneration. The mode of action of NO is different to conventional antibiotics and as such will not contribute to AMR. The aim of this project is to develop a platform to release NO from model dressings by tethering compounds containing caged NO reservoirs which are able to release NO in a controlled and sustained manner in order to exploit its dual role. This is achieved in 4 steps. Firstly, the design and development of functionalised model dressing surfaces by environmentally friendly manufacturing processes is performed. Secondly, these functionalised surfaces will be modified to have a nitrogen group on the exterior of the surface. This nitrogen group will allow for attachment of the caged NO reservoirs. Thirdly, the caged NO reservoirs will be optimised in terms of dose and release. Finally, these surfaces will be tested for efficacy of killing bacteria while remaining non-toxic to human cells. This innovative NO delivery platform proposed addresses the demand for effective wound healing technologies that has the properties to expand the clinical applicability of this exceptional molecule in wound care. By developing this technology there is a real opportunity to be part of the solution targeting this epidemic while simultaneously participating in scientifically excellent, industrially relevant research.