Naaz Thotathil, John J Amante, Micah Wingell, Grace W Hutter, Ultan Fallon, Yiling Fan, Keegan Mendez, Ellen T Roche, Cathal J Kearney
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引用次数: 0
Abstract
Introduction: Given the precise temporal coordination of natural biological processes, administering therapeutic agents at specific times can be used to enhance efficacy in a range of applications. To achieve such controlled drug delivery, various stimulus-responsive techniques (e.g., ultrasound, temperature changes, and electromagnetic radiation) have been developed. However, many of these current methods exhibit limitations, such as premature leakage prior to stimulus activation or delayed and prolonged responsiveness to stimuli. Our research introduces a soft robotic pressure-actuated drug delivery pump aimed at improving therapeutic efficacy through precisely-timed drug administration.
Methods: This device utilizes silicone - a low-modulus material - for both the therapeutic reservoir and the actuation chamber to create a biocompatible and conformable interface, facilitating controlled drug release and offering the potential to be adapted as an implantable drug delivery system. Two ports in the actuation chamber allow the therapeutic reservoir to be refilled. We actuated the pressure reservoir of the device in the range of 28.5 - 59.8 mmHg and tested: the pressure-dependent release from the device; repeated release; baseline release, and the ability to deliver a wide-range of therapeutics.
Results: Importantly, the system demonstrated a reliable On/Off mechanism - confirmed by actuating to ∼80% of opening pressure over 5 days - which addresses a key limitation in many existing technologies. In vitro, the device was used to deliver a range of therapeutics and had non-significant differences versus manual delivery of therapeutics in relevant assays: antibiotics (doxycycline; reduced E. coli viability by 49.6% vs. 49.8%); adeno-associated virus (AAV; transduced 73.5% vs. 76.2% of cells); dexamethasone (2D fibroblast scratch wound closure 50.9% vs. 51.0%); and successful delivery of viable cells (viability of 83% vs. 100%). We additionally developed a finite element model to model the pressure/volume release trend, and demonstrated the effect of membrane stiffness on release.
Discussion: Our results demonstrate that the device can consistently administer therapeutics and molecules of various sizes and functions while maintaining their bioactivity, showcasing its potential for repeated, precisely-timed therapeutic delivery.
导言：鉴于自然生物过程的精确时间协调，在特定时间施用治疗剂可用于增强一系列应用的疗效。为了实现这种受控的药物递送，各种刺激响应技术（例如，超声波，温度变化和电磁辐射）已经开发出来。然而，目前的许多方法都存在局限性，例如在刺激激活之前过早泄漏或对刺激的反应延迟和延长。我们的研究介绍了一种软机器人压力驱动给药泵，旨在通过精确定时给药来提高治疗效果。方法：该装置利用硅胶-一种低模量材料-用于治疗储存库和驱动室，以创建生物相容性和一致性界面，促进药物释放控制，并提供适应作为植入式药物输送系统的潜力。在驱动室的两个端口允许治疗储存库被重新填充。我们在28.5 - 59.8 mmHg范围内驱动装置的压力储层，并测试了装置的压力依赖性释放；重复发布;基线释放，以及提供广泛治疗的能力。结果：重要的是，该系统展示了可靠的开/关机制，通过在5天内驱动到80%的开启压力来证实，这解决了许多现有技术的一个关键限制。在体外，该装置用于递送一系列治疗药物，在相关检测中与人工递送治疗药物无显著差异：抗生素（强力霉素；大肠杆菌活力降低49.6%对49.8%）；腺相关病毒（AAV）： 73.5%对76.2%的细胞转导；地塞米松（2D成纤维细胞划伤愈合50.9% vs 51.0%）；成功递送活细胞（存活率83% vs 100%）。我们还建立了一个有限元模型来模拟压力/体积释放趋势，并证明了膜刚度对释放的影响。讨论：我们的研究结果表明，该设备可以在保持其生物活性的同时，持续地管理各种大小和功能的治疗药物和分子，展示了其重复，精确定时治疗递送的潜力。
期刊介绍：
The translation of new discoveries in medicine to clinical routine has never been easy. During the second half of the last century, thanks to the progress in chemistry, biochemistry and pharmacology, we have seen the development and the application of a large number of drugs and devices aimed at the treatment of symptoms, blocking unwanted pathways and, in the case of infectious diseases, fighting the micro-organisms responsible. However, we are facing, today, a dramatic change in the therapeutic approach to pathologies and diseases. Indeed, the challenge of the present and the next decade is to fully restore the physiological status of the diseased organism and to completely regenerate tissue and organs when they are so seriously affected that treatments cannot be limited to the repression of symptoms or to the repair of damage. This is being made possible thanks to the major developments made in basic cell and molecular biology, including stem cell science, growth factor delivery, gene isolation and transfection, the advances in bioengineering and nanotechnology, including development of new biomaterials, biofabrication technologies and use of bioreactors, and the big improvements in diagnostic tools and imaging of cells, tissues and organs.
In today`s world, an enhancement of communication between multidisciplinary experts, together with the promotion of joint projects and close collaborations among scientists, engineers, industry people, regulatory agencies and physicians are absolute requirements for the success of any attempt to develop and clinically apply a new biological therapy or an innovative device involving the collective use of biomaterials, cells and/or bioactive molecules. “Frontiers in Bioengineering and Biotechnology” aspires to be a forum for all people involved in the process by bridging the gap too often existing between a discovery in the basic sciences and its clinical application.
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