Manufacturing Nanostructured Contact Lenses for Drug Delivery

本研究项目的目的是开发微粒软性隐形眼镜作为一种新的眼科给药载体，以减少药物损失，消除全身副作用，提高药物疗效和依从性。纳米颗粒以几种纳米制造工艺分散在水凝胶中，以改善水凝胶的机械、电学、光学和传输性能。在这个项目中，PI计划开发一种新的制备纳米粒子的方法，探索粒子在水凝胶中的包埋机理和微观结构的演变，以及当粒子添加到聚合介质中时，粒子包埋对凝胶物理和传输性能的影响。在这里，该项目将专注于控制水凝胶的药物释放性能的具体应用，以开发用于输送眼科药物的延长配戴式隐形眼镜。这项研究的三个具体目标是：(I)开发载药的高交联性纳米颗粒，并了解纳米颗粒中的颗粒形成和药物传输的机理；(Ii)在高交联性纳米颗粒的存在下聚合硅胶水凝胶，以制造负载药物的高交联性纳米颗粒的隐形眼镜；(Iii)表征颗粒加载的隐形眼镜，以了解凝胶的微观结构、药物传输以及与使用这些材料制作隐形眼镜相关的所有其他性能。这项研究将结合建模和实验来探索纳米颗粒和镜片制备的基本原理，同时专注于开发用于药物输送的隐形眼镜的最终目标。目前，大约90%的眼科药物配方是作为眼药水使用的。虽然滴眼剂方便且被患者接受，但这些药物的生物利用度低(5%)，全身摄取产生副作用，依从性低。当每天需要多次滴眼液时，依从性可能低于50%，甚至更小，即使有治疗方法，这也会导致眼部疾病的恶化。由于药物在泪膜中的滞留时间增加，通过隐形眼镜给药时，眼科药物的生物利用度增加到约50%。生物利用度的提高(50%)导致较低的副作用，并可能导致更高的依从性，因为使用隐形眼镜连续给药约2周。在初步结果中，开发了一种新的方法，可以在不使用任何表面活性剂的情况下制备超小(~4 nm)粒子，释放药物超过15天。这种不使用表面活性剂制造纳米粒子的新方法可以扩展到工业标准，它可能在纳米制造的几个领域有用，特别是当添加表面活性剂不受欢迎或过于昂贵的时候。这一概念也已通过制造透明颗粒凝胶得到验证，该凝胶中装载了含有青光眼药物噻吗洛尔的新型纳米颗粒。研究还证实，含有高度交联微粒的隐形眼镜可以在2-3周内以治疗率递送噻吗洛尔。如果成功，装载微粒的隐形眼镜将导致眼科药物递送的范式转变，因为它将消除目前递送系统中的几个缺陷，包括非常低的生物利用度(5%)、潜在的副作用和低依从性。装载纳米颗粒的镜片将具有更高的生物利用度(50%)，从而产生更低的副作用，并可能导致更高的顺应性。这项研究本质上是多学科的，因为该项目结合了新材料、运输、生物医学工程和建模方面的专业知识。此外，这项研究可能会导致眼科药物输送领域的范式转变，从而导致重大的社会影响，特别是在青光眼治疗领域，全球约有6680万人受到影响，导致670万人双眼失明。

The objective of this research project is to develop particle-laden soft contact lenses as a new vehicle for ophthalmic drug delivery in order to reduce drug loss, eliminate systemic side effects, and improve drug efficacy and compliance. Nanoparticles are dispersed in hydrogels in several nanomanufacturing processes for improving mechanical, electrical, optical, and transport properties of hydrogels. In this project, the PIs plan to develop a new approach for preparing nanoparticles, explore the mechanisms of particle entrapment in hydrogels and evolution of microstructure, and the effect of the particle entrapment on physical and transport properties of the gels, when the particles are added to the polymerizing medium. Here, the project will focus on the specific application of controlling the drug release properties of the hydrogels to develop extended wear contact lenses for delivering ophthalmic drugs. The three specific aims of the research are: (i) Develop drug loaded highly crosslinked nanoparticles and understand the mechanism of particle formation and drug transport in the nanoparticles; (ii) Polymerize silicone-hydrogels in presence of the highly crosslinked nanoparticles to fabricate contact lenses loaded with drug encapsulated highly crosslinked nanoparticles; (iii) Characterize the particle loaded contact lenses to understand microstructure, drug transport, and all other properties of the gels relevant to the use of these materials for contact lenses. The research will combine both modeling and experiments to explore fundamentals of nanoparticle and lens preparation while focusing on the eventual goal of developing contact lenses for drug delivery. Currently, approximately 90 percent of all ophthalmic drug formulations are applied as eye-drops. While eye-drops are convenient and well accepted by patients, these suffer from low bioavailability (5 percent), side-effects due to systemic uptake, and low compliance. The compliance could be lower than 50 percent and further smaller when multiple eye drops are required each day, which contributes to worsening of the ophthalmic disease even when treatments are available. The bioavailability increases to about 50 percent when ophthalmic drugs are delivered through contact lenses because of the increase in the residence time of the drugs in the tear film. The increased bioavailability (50 percent) results in lower side effects, and will likely lead to higher compliance because of the continuous drug delivery for about 2-weeks with a contact lens. In preliminary results a novel approach has been developed of making ultrasmall (~4 nm) particles without utilizing any surfactant that release drugs for over 15 days. This novel approach of making nanoparticles without using surfactants is scalable to industrial standards, and it could be useful in several areas of nanomanufacturing, particularly when addition of surfactant is undesirable or too expensive. This concept has also been proven by fabricating transparent particle-laden gels loaded with novel nanoparticles containing a glaucoma drug timolol. It has also been established that contact lenses containing the highly crosslinked particles can deliver timolol at therapeutic rates for 2-3 weeks.If successful, the particle-loaded lenses will lead to a paradigm shift in ophthalmic drug delivery as it will eliminate several deficiencies in current delivery systems including very low bioavailability (5 percent), potential side-effects, and low compliance. The nanoparticle-loaded lenses will have higher bioavailability (50 percent), resulting in lower side effects, and will likely lead to higher compliance. This research is inherently multidisciplinary as the project combines expertise in new materials, transport, biomedical engineering, and modeling. Also, this research will likely leads to paradigm shifts in the area of ophthalmic drug delivery, and thus lead to a significant societal impact particularly in the area of glaucoma therapy which affects about 66.8 million people in the world, leaving 6.7 million with bilateral blindness.