Electronic MEMS for triggered delivery

Implantable electronic devices such as pacemakers and neural implants are often used for electrical stimulation. The usage of microfabrication techniques to produce microelectromechanical systems (MEMS) has allowed engineers to address a wider range of clinical indications. A new direction in the area of MEMS technology is the goal of achieving pulsatile drug delivery. The digital capabilities of MEMS may allow greater temporal control over drug release compared to traditional polymer-based systems, while the batch-processing techniques used in the microelectronics industry can lead to greater device uniformity and reproducibility than is currently available to the pharmaceutical industry. A repertoire of structures, including microreservoirs, micropumps, valves, and sensors, is being developed that will provide a strong foundation for the design of integrated, responsive MEMS for drug delivery.     

Integrated microsystems for controlled drug delivery

Efficient drug delivery and administration are needed to realize the full potential of molecular therapeutics. Integrated microsystems that incorporate extremely fast sensory and actuation capabilities can fulfill this need for efficient drug delivery tools. Photolithographic technologies borrowed from the semiconductor industry enable mass production of such microsystems. Rapid prototyping allows for the quick development of customized devices that would accommodate for diverse therapeutic requirements. This paper reviews the capabilities of existing microfabrication and their applications in controlled drug delivery microsystems. The next generation of drug delivery systems--fully integrated and self-regulating--would not only improve drug administration, but also revolutionize the health-care industry.     

Hard and soft micromachining for BioMEMS: review of techniques and examples of applications in microfluidics and drug delivery

Recent development in microfabrication (micromachining, microelectromechanical systems, MEMS) permits the integration of hard and soft structures, and enables the design of controllable microfluidic systems, which may be applied to drug delivery. In this paper, we present a tutorial review of both classical "hard" and more recent "soft" micromachining techniques. We then provide examples where these techniques are combined to produce hydrogel-based microfluidic control systems. The most complex of these systems utilizes a very small hydrogel based on phenylboronic acid to control the flow of an insulin solution in response to changes in glucose concentration.     

Microfabrication technologies for oral drug delivery

Micro-/nanoscale technologies such as lithographic techniques and microfluidics offer promising avenues to revolutionalize the fields of tissue engineering, drug discovery, diagnostics and personalized medicine. Microfabrication techniques are being explored for drug delivery applications due to their ability to combine several features such as precise shape and size into a single drug delivery vehicle. They also offer to create unique asymmetrical features incorporated into single or multiple reservoir systems maximizing contact area with the intestinal lining. Combined with intelligent materials, such microfabricated platforms can be designed to be bioadhesive and stimuli-responsive. Apart from drug delivery devices, microfabrication technologies offer exciting opportunities to create biomimetic gastrointestinal tract models incorporating physiological cell types, flow patterns and brush-border like structures. Here we review the recent developments in this field with a focus on the applications of microfabrication in the development of oral drug delivery devices and biomimetic gastrointestinal tract models that can be used to evaluate the drug delivery efficacy.     

BioMEMS in drug delivery

The drive to design micro-scale medical devices which can be reliably and uniformly mass produced has prompted many researchers to adapt processing technologies from the semiconductor industry. By operating at a much smaller length scale, the resulting biologically-oriented microelectromechanical systems (BioMEMS) provide many opportunities for improved drug delivery: Low-dose vaccinations and painless transdermal drug delivery are possible through precisely engineered microneedles which pierce the skin's barrier layer without reaching the nerves. Low-power, low-volume BioMEMS pumps and reservoirs can be implanted where conventional pumping systems cannot. Drug formulations with geometrically complex, extremely uniform micro- and nano-particles are formed through micromolding or with microfluidic devices. This review describes these BioMEMS technologies and discusses their current state of implementation. As these technologies continue to develop and capitalize on their simpler integration with other MEMS-based systems such as computer controls and telemetry, BioMEMS' impact on the field of drug delivery will continue to increase.     

Application of Micro- and Nano-Electromechanical Devices to Drug Delivery

Micro- and nano-electromechanical systems (MEMS and NEMS)-based drug delivery devices have become commercially-feasible due to converging technologies and regulatory accommodation. The FDA Office of Combination Products coordinates review of innovative medical therapies that join elements from multiple established categories: drugs, devices, and biologics. Combination products constructed using MEMS or NEMS technology offer revolutionary opportunities to address unmet medical needs related to dosing. These products have the potential to completely control drug release, meeting requirements for on-demand pulsatile or adjustable continuous administration for extended periods. MEMS or NEMS technologies, materials science, data management, and biological science have all significantly developed in recent years, providing a multidisciplinary foundation for developing integrated therapeutic systems. If small-scale biosensor and drug reservoir units are combined and implanted, a wireless integrated system can regulate drug release, receive sensor feedback, and transmit updates. For example, an “artificial pancreas” implementation of an integrated therapeutic system would improve diabetes management. The tools of microfabrication technology, information science, and systems biology are being combined to design increasingly sophisticated drug delivery systems that promise to significantly improve medical care.     

Design of diffusion‐controlled drug delivery devices for controlled release of Paclitaxel

Controlled drug delivery devices were predicted in a reverse engineering framework for the controlled release of Paclitaxel, an anti‐cancer drug, widely used in the treatment of solid tumors. Using quantitative structure–property relationship models for mutual diffusion coefficients of the drug in biocompatible and biodegradable polymers and partition coefficients of the drug between polymers and blood, a framework was developed to predict optimal drug delivery devices for desired dosage regimens. The validation of the predicted mutual diffusion and partition coefficients using experimental data was reported in previous studies. Optimal design parameters along with selection of most appropriate polymers suitable for different dosage regimens, selected based on current clinical practice, were predicted for maximum bioavailability of the drug while maintaining the released drug concentration in blood within the therapeutic range. Reservoir and monolithic type of diffusion‐controlled drug delivery devices of different shapes and sizes were predicted with different initial drug loadings and bioavailability for different dosage regimens. The effects of the released Paclitaxel from these devices on the tumor growth were also modeled using a previously reported mathematical pharmacokinetic–pharmacodynamic model. The proposed approach can easily be used to design other diffusion‐controlled drug delivery devices.     

Microfabricated nanochannel implantable drug delivery devices: trends, limitations and possibilities

This is a review of the application of microfabrication technologies, borrowed from the semiconductor industry, to drug delivery implants incorporating structures in the nanometer dimension. In the futuristic ideal, these systems would involve the implantation of precisely microfabricated drug delivery systems with nanopores, nanochannels and/or nanoreservoirs fabricated from silicon, coupled with electronic sensing and actuator systems, for the precise, timed and/or targeted delivery of drugs. After more than a decade in conceptualisation and experimentation, four systems that have commercial potential are discussed: i) implantable microchips with on-demand microdosage for one or more therapeutic agents under internal control or external control using a wireless link; ii) nanopore pumps, implantable titanium pumps, consisting of a drug reservoir with a nanopore-release membrane, capable of delivering potent small or macromolecules at constant serum levels for sustained periods of time; iii) nanocages, microfabricated nanopore immunoisolation chambers for cellular implants, capable of natural feedback-controlled delivery of proteins and peptides; and iv) nanobuckets, micromachined silicon porous particles with drug-loading capacity and targeting ligands for localised delivery. Each of the systems, along with future trends in microfabrication manufacturing, limitations and possibilities, are discussed.     

Implantable microchip: the futuristic controlled drug delivery system

There is no doubt that controlled and pulsatile drug delivery system is an important challenge in medicine over the conventional drug delivery system in case of therapeutic efficacy. However, the conventional drug delivery systems often offer a limited by their inability to drug delivery which consists of systemic toxicity, narrow therapeutic window, complex dosing schedule for long term treatment etc. Therefore, there has been a search for the drug delivery system that exhibit broad enhancing activity for more drugs with less complication. More recently, some elegant study has noted that, a new type of micro-electrochemical system or MEMS-based drug delivery systems called microchip has been improved to overcome the problems related to conventional drug delivery. Moreover, micro-fabrication technology has enabled to develop the implantable controlled released microchip devices with improved drug administration and patient compliance. In this article, we have presented an overview of the investigations on the feasibility and application of microchip as an advanced drug delivery system. Commercial manufacturing materials and methods, related other research works and current advancement of the microchips for controlled drug delivery have also been summarized.     

口服渗透泵药物传递系统

渗透泵递药系统由于其可靠性和可以长时间在预定的时间内按零级速率释放药物的性能,是最有效的药物控释系统。此类递药系统基于渗透压控制有效成分的释放。在很大程度上,这些系统中的药物传递释放不受胃肠道生理因素影响。本文简要讨论了口服渗透泵片剂的基本成分,关键的处方因素和不同类型的渗透泵控释系统。     

聚乳酸乙醇酸在微球控释制剂中的研究进展

聚乳酸乙醇酸(PLGA)是生物可降解的聚合物,已取得了美国FDA的批准,用于组织工程支架和药物载体。由于其具有良好的生物相容性和生物可降解性,近20年来成为小分子药物、蛋白质和其他大分子(DNA、RNA或多肽类)化合物的缓释控释制剂研究的热点。对于PLGA微球制剂的研究主要集中在疫苗类、激素类、抗生素类、抗肿瘤类、神经营养物质类等药物控释制剂。主要介绍近5年来这些药物微球的研究情况,为进一步开发利用PLGA作为药物载体提供参考。     

Drug delivery across length scales

Abstract

Over the last century, there has been a dramatic change in the nature of therapeutic, biologically active molecules available to treat disease. Therapies have evolved from extracted natural products towards rationally designed biomolecules, including small molecules, engineered proteins and nucleic acids. The use of potent drugs which target specific organs, cells or biochemical pathways, necessitates new tools which can enable controlled delivery and dosing of these therapeutics to their biological targets. Here, we review the miniaturisation of drug delivery systems from the macro to nano-scale, focussing on controlled dosing and controlled targeting as two key parameters in drug delivery device design. We describe how the miniaturisation of these devices enables the move from repeated, systemic dosing, to on-demand, targeted delivery of therapeutic drugs and highlight areas of focus for the future.     

胶原微球作为药物载体的研究进展

近年来,微粒给药系统的发展为大分子药物靶向及缓控释给药提供更多的方法,但对药物载体的要求也越来越高。胶原因其良好的生物相容性、生物可降解性及极低的免疫原性成为药物载体材料研究的新热点。本文对胶原作为药物载体的研究进展进行了综述,包括胶原微球、胶原包衣微球及胶原复合材料微球的研究。     

Engineering design and molecular dynamics of mucoadhesive drug delivery systems as targeting agents

The goal of this critical review is to provide a critical analysis of the chain dynamics responsible for the action of micro- and nanoparticles of mucoadhesive biomaterials. The objective of using bioadhesive controlled drug delivery devices is to prolong their residence at a specific site of delivery, thus enhancing the drug absorption process. These mucoadhesive devices can protect the drug during the absorption process in addition to protecting it on its route to the delivery site. The major emphasis of recent research on mucoadhesive biomaterials has been on the use of adhesion promoters, which would enhance the adhesion between synthetic polymers and mucus. The use of adhesion promoters such as linear or tethered polymer chains is a natural result of the diffusional characteristics of adhesion. Mucoadhesion depends largely on the structure of the synthetic polymer gels used in controlled release applications.     

Recent advances in asymmetric membrane capsule based osmotic pump: a patent overview

Conventional drug delivery systems have little control over their drug release and almost no control over the effective concentration at the target site. This kind of dosing pattern may result in constantly changing, unpredictable plasma concentrations. Drugs can be delivered in a controlled pattern over a long period of time by the process of osmosis. Osmotic devices are the most promising strategy based systems for controlled drug delivery. They are the most reliable controlled drug delivery systems and could be employed as oral drug delivery systems. The present review is concerned with the study of drug release through asymmetric membrane capsule systems. When these systems are exposed to water, low levels of water soluble additive are leached from polymeric material i.e. the semipermeable membrane and the drug releases in a controlled manner over an extended period of time. Drug delivery from this system is not influenced by the different physiological factors within the gut lumen and the release characteristics can be predicted easily from the known properties of the drug and the dosage form. This patent review is useful in the knowledge of asymmetric membrane capsule osmotic pump for its application.     

Floating drug delivery systems for prolonging gastric residence time: a review

Oral delivery of the drug is the most preferable route of drug delivery due to the ease of administration, patient compliance and flexibility in the formulations. Recent technological advancements have been made in controlled oral drug delivery systems by overcoming physiological difficulties, such as short gastric residence time and highly variable gastric emptying time. Gastroretentive dosage forms have been designed over the past three decades to overcome these difficulties. Several technical approaches are currently utilized in the prolongation of gastric residence time, including highdensity, swelling and expanding, polymeric mucoadhesive, ion-exchange, raft forming, magnetic and floating drug delivery systems (FDDS), as well as other delayed gastric emptying devices. In this review, the current technological developments of FDDS including patented delivery systems and marketed products, and their advantages and future potential for oral controlled drug delivery are discussed.     

Combinatorial design of biomaterials for drug delivery: opportunities and challenges

Background: The rational design of biodegradable polymeric devices for controlled drug delivery and tissue engineering is an important area of research for advancing new therapies for cancer, diabetes and immune-related disorders. In an era of escalating costs for discovery-based research, there is an urgent need to develop new and rapid methods to design drug delivery systems. Objective/methods: By merging this field of study with rapid and high throughput methods of design, optimization and development, researchers have been able to accelerate the discovery and design processes for these devices. Combinatorial research enables the rapid identification of key regions of interest. Conclusion: This review focuses on the opportunities and challenges in the area of combinatorial biomaterials design for drug delivery, as there has been a great deal of significant progress over the past decade to propel this approach for the rational design of biomaterials.     

5-Fluorouracil delivery from a novel three-dimensional micro-device: in vitro and in vivo evaluation

A novel three-dimensional biodegradable micro-device using microelectromechanical systems technology was developed for implantable controlled drug delivery. In order to evaluate the effect of monomer composition and molecular weight of poly(lactic-co-glycolic acid) (PLGA) on the drug release, three 5-Fluorouracil loaded micro-devices, made of 50/50, 27 kDa; 50/50, 40 kDa and 75/25 27 kDa PLGA, were prepared and characterized by in vitro and in vivo methods. The in vitro drug release from three micro-devices followed zero-order kinetics, and PLGA micro-device with the higher molecular weight and lactide/glycolide ratio tended to a longer sustained release period. The in vivo release results agreed with the in vitro results and drug release in vivo was faster than that in vitro for each of micro-devices. And three micro-devices showed different tumor inhibition effect in the tumor bearing mice. In addition, the SEM and weight loss experiments showed that PLGA micro-devices with lower molecular weight and lactide/glycolide ratio had faster degradation. These data provided the information for the optimization of the novel three-dimensional biodegradable micro-device to obtain more suitable systems for controlled release and to meet release requirements of different drugs.     

Some interactions of natural and synthetic anionic polymers with biologically active substances

Anionic polymers are nowadays extensively used in drug form technology, especially in drug delivery and drug targeting. Development of proper drug and macromolecular excipient composition allows controlled drug delivery in the term of the drug concentration in blood or other tissues, and in the term of the action-time. Between anionic polymers most frequently carbopols, eudragits, alginates and pectins are used. Application of anionic polymers in drug form technology is an up to date problem. According to new synthesis methods and new anionic polymers, new drug delivery systems would be researched. Most selective and safe devices should be developed, concerning biodegradation aspects.     

Intelligent drug delivery systems: polymeric micelles and hydrogels

Advanced drug delivery systems try to adjust the site and/or the rate of the release to the physiological conditions of the patient, to the progression of the illness, or to the circadian rhythms. Being different from classical pre-programmed controlled release dosage forms, the new devices aim to provide the drug release profile best for the needs of each patient. Intelligent drug delivery systems are mostly based on stimuli-responsive polymers which sense a change in a specific variable and activate the delivery; this phenomenon being reversible. This review reports on recent advances in the development of open-loop and closed-loop control systems based on stimuli-responsive polymers and their application in the drug delivery field as pulsatile and self-regulated devices. The aim of this review is to describe the most recent advances in the development of intelligent micelles and hydrogels which are sensitive to pH, specific molecules (with a mention to the molecular imprinting), temperature, irradiation or electric field, and the applications of which these mechanisms are intended.