Self-triggered smart biomaterials

聚合物生物材料通常是作为植入的医疗设备的一部分引入人体组织中的合成物质，或用于替代器官或身体功能，在医疗保健中越来越普遍。生物材料的引入带来了微生物感染的风险，这对患者构成了重大风险，并给NHS带来了负担，需要长期、复杂的治疗，而这些治疗往往不成功。随着一些设备的感染率接近100%，迫切需要开发出防止在医疗设备表面形成细菌生物膜的方法。通常情况下，感染涉及细菌最初附着在生物材料表面，然后通过细分和生长形成生物膜来定植。这种生物膜对抗生素治疗具有高度抵抗力，并成为感染在体内进一步传播的蓄水池。这可能导致败血症和死亡。为了有效地解决生物材料中生物膜的发展问题，这个项目在开发智能材料方面有两个关键目标--对光(外部应用)或感染(内部刺激)等刺激做出反应的材料。首先，我们寻求在之前的EPSRC项目和我们实验室的一些进一步的最新结果的基础上，这代表了一种新的方法来杀死任何可能仍然能够附着在聚合物上的细菌。这使用了可见光和光敏剂的组合--一种可以利用光催化产生活性氧的分子，这对杀死细菌非常有效。使用这种化学的一个关键点是，活性物种的范围能够攻击细菌中的广泛靶点，而不是单一的作用模式，这是传统方法的局限性，如抗生素。因此，这种方法绕过了抗菌素耐药性的发展问题，并具有长期的效果，这应该会使它在未来得到临床医生的支持。在这篇文章中，我们将在挤压中使用合成化学、材料科学和工程方法来开发新的方法，将光敏剂结合在细菌的直接附着点-医疗器械表面。我们将使用多层挤出技术在用于制造传统医疗设备的基材上制造薄涂层，如聚氯乙烯。我们将调整这个系统的效率，以最大限度地生产活性氧，并对光诱导过程以及它们如何有效杀灭细菌进行全面的化学和物理表征。其次，在一种关联的方法中，我们将建立在有趣的最近结果的基础上，这些结果表明我们可以使用pH来控制适合于医疗器械应用的聚合物中模型药物物质的裂解速度。尤其是在尿管感染中，在感染开始时会观察到pH值的变化，因此有机会开发能够杀死细菌感染的材料，以响应其自身的发展，从而阻止感染。利用合成化学，我们将为聚合物开发新的‘积木’，这种聚合物可以用来在现有的医疗器械材料上制造一种响应性涂层。这将使我们能够设计出天生能够抵抗细菌附着的聚合物。在实践中，这涉及到合成聚合物来制造我们的新候选材料，然后使用一系列光谱、显微和物理方法来表征它们的表面化学。然后，我们将通过尝试培养通常会引起感染的细菌的生物膜来评估材料抵抗细菌附着的能力。这将使我们能够开发出可以安装在医疗设备上的材料，如气管导管、导尿管或人工晶状体，这将对患者和医疗设备公司产生广泛的影响。

Polymeric biomaterials, which are typically synthetic substances introduced into body tissue as part of an implanted medical device or used to replace an organ or bodily function, are increasingly ubiquitous in healthcare. The introduction of biomaterials brings with it a risk of infection from microorganisms, representing a major risk to patients and burden to the NHS requiring extended, complex treatments, which are often unsuccessful. With infection rates approaching 100% in some devices, there is an urgent unmet need to develop ways to prevent bacterial biofilms forming on the surface of medical devices.Typically, infection involves initial attachment of bacteria to the surface of the biomaterial, followed by colonisation through subdivision and growth into a biofilm. This biofilm is highly resistant to treatment by antibiotics, and acts as a reservoir for further spread of infection in the body. This can lead to sepsis and death. To effectively address the problem of biofilm development in biomaterials, this project has two key aims in the development of smart materials-those which are responsive to a stimulus such as light (applied externally) or the onset of infection (where the stimulus is internal).Firstly, we seek to build on a previous EPSRC project, and some further recent results from our lab, which represents a new way to kill any bacteria which may still be able to attach to the polymer. This uses a combination of visible light and photosensitisers - a class of molecule which can use light to catalytically produce reactive oxygen, which is highly effective at killing bacteria. A key point in using this chemistry is that the range of active species are able to attack a wide range of targets in bacteria, rather than a single mode of action, which is a limitation of traditional approaches, such as antibiotics. As such, the approach gets round the issue of development of antimicrobial resistance, and has a long lived effect, which should allow it to be supported by clinicians in the future.In this strand, we will use synthetic chemistry, materials science and engineering methods in extrusion to develop new ways to incorporate photosensitisers at the direct point of bacterial attachment - the medical device surface. We will use multi-layered extrusion techniques to make thin coatings on substrates used to manufacture traditional medical devices, such as PVC. We will tune the efficiency of this system to maximise production of reactive oxygen, and carry out a full chemical and physical characterisation of the light-induced processes and how effectively they kill bacteria. Secondly, in a linked approach, we will build on interesting recent results which show we can use pH to control rate of cleavage of a model drug substance from a polymer suitable for use in medical device applications. A change in pH is observed at the onset of infection in urinary catheter infections in particular, so there is an opportunity to develop materials which are able to kill a bacterial infection in response to its own development, thereby stopping the infection in its tracks. Using synthetic chemistry, we will develop new 'building blocks' for polymers which can be used to make a responsive coating to a current medical device material. This will allow us to engineer polymers which are inherently able to resist the attachment of bacteria. In practice, this involves polymer synthesis to make our new candidate materials, then characterising their surface chemistry using a range of spectroscopic, microscopic and physical methods. We will then assess the ability of the materials to resist bacterial attachment by trying to grow biofilms of bacteria which typically cause infections.Together this will allow us to develop materials which may be incorporated in or on medical devices such as endotracheal tubes, urinary catheters, or intraocular lenses, which would have wide impact for patients and medical device companies.