Microfluidics for Advanced Drug Delivery Systems.

Considerable efforts have been devoted towards developing effective drug delivery methods. Microfluidic systems, with their capability for precise handling and transport of small liquid quantities, have emerged as a promising platform for designing advanced drug delivery systems. Thus, microfluidic systems have been increasingly used for fabrication of drug carriers or direct drug delivery to a targeted tissue. In this review, the recent advances in these areas are critically reviewed and the shortcomings and opportunities are discussed. In addition, we highlight the efforts towards developing smart drug delivery platforms with integrated sensing and drug delivery components

Implantable Microsystem Technologies For Nanoliter-Resolution Inner Ear Drug Delivery

Advances in protective and restorative biotherapies have created new opportunities to use site-directed, programmable drug delivery systems to treat auditory and vestibular disorders. Successful therapy development that leverages the transgenic, knock-in, and knock-out variants of mouse models of human disease requires advanced microsystems specifically designed to function with nanoliter precision and with system volumes suitable for implantation. The present work demonstrates a novel biocompatible, implantable, and scalable microsystem consisted of a thermal phase-change peristaltic micropump with wireless control and a refillable reservoir. The micropump is fabricated around a catheter microtubing (250 μm OD, 125 μm ID) that provided a biocompatible leak-free flow path while avoiding complicated microfluidic interconnects. Direct-write micro-scale printing technology was used to build the mechanical components of the pump around the microtubing directly on the back of a printed circuit board assembly. In vitro characterization results indicated nanoliter resolution control over the desired flow rates of 10–100 nL/min by changing the actuation frequency, with negligible deviations in presence of up to 10× greater than physiological backpressures and ±3°C ambient temperature variation. A biocompatibility study was performed to evaluate material suitability for chronic subcutaneous implantation and clinical translational development. A stand-alone, refillable, in-plane, scalable, and fully implantable microreservoir platform was designed and fabricated to be integrated with the micropump. The microreservoir consists two main components: a cavity for storing the drug and a septum for refilling. The cavity membrane is fabricated with thin Parylene-C layers, using a polyethylene glycol (PEG) sacrificial layer. The septum thickness is minimized by pre-compression down to 1 mm. The results of in vitro characterization indicated negligible restoring force for the optimized cavity membrane and thousands of punctures through the septum without leakage. The micropump and microreservoir were integrated into microsystems which were implanted in mice. The microtubing was implanted into the round window membrane niche for infusion of a known ototoxic compound (sodium salicylate) at 50 nL/min for 20 min. Real-time shifts in distortion product otoacoustic emission thresholds and amplitudes were measured during the infusion. The results match with syringe pump gold standard. For the first time a miniature and yet scalable microsystem for inner ear drug delivery was developed, enabling drug discovery opportunities and translation to human

Recent advances in micro-electro-mechanical devices for controlled drug release applications

In recent years, controlled release of drugs has posed numerous challenges with the aim of optimizing parameters such as the release of the suitable quantity of drugs in the right site at the right time with the least invasiveness and the greatest possible automation. Some of the factors that challenge conventional drug release include long-term treatments, narrow therapeutic windows, complex dosing schedules, combined therapies, individual dosing regimens, and labile active substance administration. In this sense, the emergence of micro-devices that combine mechanical and electrical components, so called micro-electro-mechanical systems (MEMS) can offer solutions to these drawbacks. These devices can be fabricated using biocompatible materials, with great uniformity and reproducibility, similar to integrated circuits. They can be aseptically manufactured and hermetically sealed, while having mobile components that enable physical or analytical functions together with electrical components. In this review we present recent advances in the generation of MEMS drug delivery devices, in which various micro and nanometric structures such as contacts, connections, channels, reservoirs, pumps, valves, needles, and/or membranes can be included in their design and manufacture. Implantable single and multiple reservoir-based and transdermal-based MEMS devices are discussed in terms of fundamental mechanisms, fabrication, performance, and drug release applications.Fil: Villarruel Mendoza, Luis A.. Comisión Nacional de Energía Atómica. Gerencia de Área de Investigación y Aplicaciones no Nucleares. Gerencia de Desarrollo Tecnológico y Proyectos Especiales. Departamento de Micro y Nanotecnología; ArgentinaFil: Scilletta, Natalia Antonela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica. Gerencia de Área de Investigación y Aplicaciones no Nucleares. Gerencia de Desarrollo Tecnológico y Proyectos Especiales. Departamento de Micro y Nanotecnología; ArgentinaFil: Bellino, Martin Gonzalo. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Ciudad Universitaria. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia - Nodo Constituyentes | Comision Nacional de Energia Atomica. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia - Nodo Constituyentes.; ArgentinaFil: Desimone, Martín Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; ArgentinaFil: Catalano, Paolo Nicolás. Comisión Nacional de Energía Atómica. Gerencia de Área de Investigación y Aplicaciones no Nucleares. Gerencia de Desarrollo Tecnológico y Proyectos Especiales. Departamento de Micro y Nanotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentin

Advanced medical micro-robotics for early diagnosis and therapeutic interventions

Recent technological advances in micro-robotics have demonstrated their immense potential for biomedical applications. Emerging micro-robots have versatile sensing systems, flexible locomotion and dexterous manipulation capabilities that can significantly contribute to the healthcare system. Despite the appreciated and tangible benefits of medical micro-robotics, many challenges still remain. Here, we review the major challenges, current trends and significant achievements for developing versatile and intelligent micro-robotics with a focus on applications in early diagnosis and therapeutic interventions. We also consider some recent emerging micro-robotic technologies that employ synthetic biology to support a new generation of living micro-robots. We expect to inspire future development of micro-robots toward clinical translation by identifying the roadblocks that need to be overcome

Design of a Customized multipurpose nano-enabled implantable system for in-vivo theranostics

The first part of this paper reviews the current development and key issues on implantable multi-sensor devices for in vivo theranostics. Afterwards, the authors propose an innovative biomedical multisensory system for in vivo biomarker monitoring that could be suitable for customized theranostics applications. At this point, findings suggest that cross-cutting Key Enabling Technologies (KETs) could improve the overall performance of the system given that the convergence of technologies in nanotechnology, biotechnology, micro&nanoelectronics and advanced materials permit the development of new medical devices of small dimensions, using biocompatible materials, and embedding reliable and targeted biosensors, high speed data communication, and even energy autonomy. Therefore, this article deals with new research and market challenges of implantable sensor devices, from the point of view of the pervasive system, and time-to-market. The remote clinical monitoring approach introduced in this paper could be based on an array of biosensors to extract information from the patient. A key contribution of the authors is that the general architecture introduced in this paper would require minor modifications for the final customized bio-implantable medical device

The Development Of Mems-Based Implantable Oxygen Sensing Systems

Oxygen-based cues are direct assessments for a wide range of in vivo biological effects, ranging from mitochondrial disease to tissue engineering/regenerative medicine. Existing electrochemical oxygen sensors are permanent systems applicable to short-term intraoperative use; devices are extracted before wound closure. Development of biocompatible oxygen sensors for long-term, post-surgery monitoring are therefore, desirable for clinical trials where objective oxygen measures are lacking. A biodegradable oxygen sensor that can break down into non-toxic components after a targeted lifespan, reducing the risk of chronic inflammatory response frequently observed with permanent devices, is another promising approach to advance the postoperative monitoring of oxygen tension and provide an additional means to monitor a number of diseases and injuries that are transient in nature, such as bone fracture, traumatic brain injury and wound healing. In this dissertation, we improved the current oxygen sensing technology to the point that it could be used for long-term applications, and further developed a biodegradable oxygen sensor along with a transient energy source to support the design of completely biodegradable oxygen sensing systems. Specifically, a biocompatible oxygen sensor, integrated with a customized circuit and an off-the-shelf battery were designed, built and tested. Oxygen levels in mouse gluteus muscle and zebrafish trunk muscle were both investigated to examine the sensor’s ability to monitor dynamic oxygen tension in vivo. In addition, a biodegradable battery featuring long shelf life and stable performance in the presence of changing body conditions was designed, fabricated and examined in vitro. Finally, a completely biodegradable oxygen sensor featuring a Mg-Mo galvanic pair was demonstrated. This approach measures physiological oxygen tension in a transient, harmless manner in the body, while simultaneously acting as a potential energy source for additional devices. Additionally, such sensors may have application in transient monitoring of the environment, such as environmental spills and algal tides

Frequency-controlled wireless passive microfluidic devices

Microfluidics is a promising technology that is increasingly attracting the attention of researchers due to its high efficiency and low-cost features. Micropumps, micromixers, and microvalves have been widely applied in various biomedical applications due to their compact size and precise dosage controllability. Nevertheless, despite the vast amount of research reported in this research area, the ability to implement these devices in portable and implantable applications is still limited. To date, such devices are constricted to the use of wires, or on-board power supplies, such as batteries. This thesis presents novel techniques that allow wireless control of passive microfluidic devices using an external radiofrequency magnetic field utilizing thermopneumatic principle. Three microfluidic devices are designed and developed to perform within the range of implantable drug-delivery devices. To demonstrate the wireless control of microfluidic devices, a wireless implantable thermopneumatic micropump is presented. Thermopneumatic pumping with a maximum flow rate of 2.86 μL/min is realized using a planar wirelessly-controlled passive inductor-capacitor heater. Then, this principle was extended in order to demonstrate the selective wireless control of multiple passive heaters. A passive wirelessly-controlled thermopneumatic zigzag micromixer is developed as a mean of a multiple drug delivery device. A maximum mixing efficiency of 96.1% is achieved by selectively activating two passive wireless planar inductor-capacitor heaters that have different resonant frequency values. To eliminate the heat associated with aforementioned wireless devices, a wireless piezoelectric normally-closed microvalve for drug delivery applications is developed. A piezoelectric diaphragm is operated wirelessly using the wireless power that is transferred from an external magnetic field. Valving is achieved with a percentage error as low as 3.11% in a 3 days long-term functionality test. The developed devices present a promising implementation of the reported wireless actuation principles in various portable and implantable biomedical applications, such as drug delivery, analytical assays, and cell lysis devices

Beyond Tissue replacement: The Emerging role of smart implants in healthcare

Smart implants are increasingly used to treat various diseases, track patient status, and restore tissue and organ function. These devices support internal organs, actively stimulate nerves, and monitor essential functions. With continuous monitoring or stimulation, patient observation quality and subsequent treatment can be improved. Additionally, using biodegradable and entirely excreted implant materials eliminates the need for surgical removal, providing a patient-friendly solution. In this review, we classify smart implants and discuss the latest prototypes, materials, and technologies employed in their creation. Our focus lies in exploring medical devices beyond replacing an organ or tissue and incorporating new functionality through sensors and electronic circuits. We also examine the advantages, opportunities, and challenges of creating implantable devices that preserve all critical functions. By presenting an in-depth overview of the current state-of-the-art smart implants, we shed light on persistent issues and limitations while discussing potential avenues for future advancements in materials used for these devices

Skin-Integrated wearable systems and implantable biosensors: a comprehensive review

Biosensors devices have attracted the attention of many researchers across the world. They have the capability to solve a large number of analytical problems and challenges. They are future ubiquitous devices for disease diagnosis, monitoring, treatment and health management. This review presents an overview of the biosensors field, highlighting the current research and development of bio-integrated and implanted biosensors. These devices are micro- and nano-fabricated, according to numerous techniques that are adapted in order to offer a suitable mechanical match of the biosensor to the surrounding tissue, and therefore decrease the body’s biological response. For this, most of the skin-integrated and implanted biosensors use a polymer layer as a versatile and flexible structural support, combined with a functional/active material, to generate, transmit and process the obtained signal. A few challenging issues of implantable biosensor devices, as well as strategies to overcome them, are also discussed in this review, including biological response, power supply, and data communication.This research was funded by FCT- FUNDAÇÃO PARA A CIÊNCIA E TECNOLOGIA, grant numbers: PTDC/EMD-EMD/31590/2017 and PTDC/BTM-ORG/28168/2017

Application of Micro-Electro-Mechanical Systems as Neural Interface

Micro-Electro-Mechanical Systems (MEMS) technology comprises of developing miniaturized mechanical and electro-mechanical elements such that the physical dimensions of these devices vary from micron to few millimeters in size.In various human disease disorders, the neural or body regulatory tissues are incapable of conveying commands directly to the target organ and unable to receive appropriate information from receptor mechanism to decide the future course of action. The MEMS based devices are playing important assistive role by becoming crucial interface in treating such disorders. These devices are increasingly being deployed inside the body at sub tissue levels to fulfill information receipt or command transmission gap, thereby enabling the governing tissue opportunity and environment to work effectively, leading to improvement in the neural signal recording and quality of life of the concerned individual. The aim of this paper is to review the present and future of MEMS based devices widely being employed as neural interface in penetrating probes, nerve regeneration, neuron culture and drug delivery devices depending on type of treatment provided to specific neural disorders. Further, they have been recently employed in developing advanced neuro-computer, nerve stimulators, wheel chair control based on head and hand movements and in medical robotics. Due to their stability, biocompatibility, usage and wider acceptability these MEMS based neural interface devices are providing future hope for their deployment in conquering various neurological disorders