49 research outputs found

    The Development Of Mems-Based Implantable Oxygen Sensing Systems

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    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

    Mechanical characterization and in vivo operation of an implantable drug delivery MEMS device

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    Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Materials Science and Engineering, 2005.Includes bibliographical references.The goal of this thesis was to advance an implantable drug delivery MEMS (MicroElectroMechanical Systems) device developed in our laboratory. This device was designed to locally deliver multiple substances in complex release profiles in order to maximize the effectiveness of drug therapies. It consists of an array of microreservoirs etched into a silicon substrate. Different types and dosages of drugs can be contained in these reservoirs capped by thin gold membranes. The drug release is achieved by the application of a small anodic potential on the gold membrane in a chloride containing medium (such as the body fluid). The gold membrane will corrode and disintegrate so that the drug contained within the reservoir is free to diffuse into the surrounding medium. Previous researchers have demonstrated in vitro and in vivo release of tracer molecules as well as a radiolabled chemotherapeutic agent (carmustine, or BCNU) from the device. However, systematic characterization of the mechanical and electrochemical behavior of gold membranes on the drug delivery device was necessary in order to achieve more reliable device performance and to demonstrate efficacy of BCNU delivered from the MEMS device against an experimental tumor model. A bulge test apparatus was constructed to characterize the mechanical properties of gold membranes. Uniform pressure was applied from underneath the gold membrane and the membrane deflection was measured using optical interferometry. Analyzing the deflection and pressure data allowed extraction of the elastic modulus and residual stress of the gold membrane.(cont.) Gold membranes with in-plane sizes ranging from 20 to 200pim showed lower modulus (126-168 GPa) than bulk (111) single crystal gold (189 GPa). But their yield strength (317-351 MPa) was higher than the bulk value. An in situ experimental setup was constructed to observe the electrochemical disintegration process of the gold membranes. Real time images recorded from a CCD camera showed non-uniform corrosion occurring first around the membrane edges. Bulge tests on the corroded membranes indicated a gradual loss of mechanical integrity of the gold membranes due to corrosion. The gold membrane disintegration probably occurred by a combination of membrane thinning through active dissolution and accumulation of plastic deformation due to the transient formation of a passive film on top of the gold membrane in each voltammetry cycle. Dense gold membranes with reproducible opening behavior are critical to the success of large scale in vivo studies and future commercial applications. Defects in the gold membranes led to premature leakage of BCNU, a small molecule drug. Wafers with sputtered gold membranes patterned by wet etching had a higher device yield and membrane quality than wafers with evaporated gold membranes patterned by lift off. The mechanical and electrochemical studies provided guidance to improve the operation reliability and reproducibility of the drug delivery device. In vivo release of BCNU from the drug delivery device was demonstrated in a rat flank model. Acute temporal release kinetics of 14C labeled BCNU in vivo was evaluated by analysis of the plasma 14C concentration using the accelerator mass spectrometry (AMS) technique.(cont.)The in vivo 14C labeled BCNU release profile from the activated devices was similar to that of the in vitro and subcutaneously injected controls. The time to reach a steady-state plasma 14C concentration was on the order of one hour. Efficacy of BCNU delivered from the drug delivery device was demonstrated in a 9L rat flank tumor model. Co-formulation of PEG with BCNU led to complete and rapid release of payload in vivo. The retarding effect of BCNU on the tumor growth was dose dependent in the range of 0.67 - 2 mg. BCNU delivered from activated devices seemed to be as effective as equipotent injections of BCNU against the tumor growth. This tumor effect study provided preliminary efficacy validation of the drug delivery device as well as important dosage information for further efficacy evaluation of the BCNU/IL-2 combination therapy.by Yawen Li.Ph.D

    Packaging for a drug delivery microelectromechanical system

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    Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Materials Science and Engineering, 2005.Includes bibliographical references (p. 52-55).Local drug delivery is a fast expanding field, and has been a center of attention for researchers in medicine in the last decade. Its advantages over systemic drug delivery are clear in cancer therapy, with localized tumors. A silicon microelectromechanical drug delivery device was fabricated for the purpose of delivering chemotherapeutic agents such-as carmustine, a potent brain cancer drug, directly to the site of the tumor. Limitations in the delivery capacity of the device led to the design of a new package. This package is made from thermally bonded Pyrex® 7740 frames that are anodically bonded to the drug delivery chip. It increases the capacity of the chip, is smaller than the previous package and possesses true hermeticity, because of the bonding processes involved. This work describes the fabrication steps of the new package and a problem with the thermal bonding of Pyrex® frames preventing the achievement of a package true to the original design. A temporary solution was devised and the completed package was tested with regards to its intended goals. It managed to increase the load capacity of the chip by a, factor of 10, with potential for more, while decreasing the overall size of the package. Short-term hermeticity was achieved for this package by using a UV-cured epoxy to bond some pieces, which was not in the original design. Future work will focus on finding a permanent solution to the aforementioned problem, and directions for it were suggested.by Hong Linh Ho Duc.S.M

    Implantable Nanofluidic Membrane and Smart Electronic System for Drug Release Control

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    L'abstract è presente nell'allegato / the abstract is in the attachmen

    Biocompatibility of an implantable ophthalmic drug delivery device

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    Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2007.Includes bibliographical references (p. 90-94).Diseases of the posterior eye present clinicians with a treatment challenge mainly due to the region's inaccessible location. Several drugs, including those available for the treatment of exudative age-related macular degeneration, are currently delivered by periodic injection into the eyeball. To avoid the risks and complications associated with this method, several implantable, timed release devices have been investigated to deliver these drugs directly to affected areas. Draper Laboratory and Massachusetts Eye and Ear Infirmary have proposed an implantable, fully programmable, mechanical device for long-term drug delivery to the eye wall. To investigate the biocompatibility of this solution, test devices containing gears or a ball bearing were designed to mimic elements of its moving parts, geometry and materials. Cell culture studies identified a polytetrafluoroethylene filter with 100m pores as a promising addition to seal devices from interaction with fibroblasts. Test devices with or without this membrane were implanted on the rabbit eye for 2 or 10 week periods. They were evaluated mechanically after implant, and surrounding tissues were inspected histologically. Gross observation revealed a significant amount of tissue formation around the devices, especially in the conjunctiva.(cont.) Devices had to be cut away from the eye surface, and there was a significant amount of tissue inside the gear devices. Notably less tissue surrounded and invaded the ball bearing devices. Histological evaluation identified the invading tissue as fibrotic at both time points, though significantly more was seen at longer implant times. Eye wall tissue was typically unharmed during implant, though an additional layer of fibrosis between the eye and the device was common. Mechanical testing of long-term gear devices after implant revealed a 1000 fold increase in torque required to turn the elements, but long-term ball bearing devices were significantly less affected (100 fold increase). Torque also increased in devices with membrane covers, due to similar fibrosis. However, in these implants, tissue was forced to enter through only the 0.002in. openings around the base of the devices. Biocompatibility for this device may best be achieved by minimizing the amount of relative micro motion allowed between the device and the eye and by sealing all openings with a porous polytetrafluoroethylene filter.by Sarah J. Cohen.S.M

    Noninvasive quantification of drug delivery from an implantable MEMS device

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    Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, February 2005.Includes bibliographical references.(cont.) sensors in vivo in real time and corroborated by scintillation of urine samples. The goal of monitoring drug delivery from an implant in vivo, in real time and without disturbing the tissue environment, was accomplished. The results described in this thesis suggest a number of future studies including feedback-controlled delivery of drugs and real-time monitoring and analysis of the effect of the immune response to foreign bodies on drug and analyte transport.The goal of this thesis was to develop a method for quantifying the rate of release of drugs from an implanted MEMS (micro electro mechanical systems) drug delivery device without disrupting the surrounding tissue. Most current methods for evaluating tissue response to implants and drug release are invasive and destructive. A method for measuring drug transport from implants in vivo, non-invasively and in real time, would have the potential to yield new information about the body's response to implants and the impact of the tissue response on drug and analyte transport. An impedance based sensor was designed to monitor the release of drug from the drug delivery MEMS device reservoirs. The sensor measures the change in conductivity of the contents of the reservoir as the drug dissolves, which is related to the drug release rate. A four element equivalent circuit was developed to describe the impedance spectrum of the reservoirs based on the physical components of the system. The solution resistance and double layer capacitance elements are functions of the amount of drug that has dissolved and were used to measure the drug release rate in real time. The sensors were tested by monitoring drug release in vitro in saline. Independent measurements of the radioactive tracer released from the well were in complete quantitative agreement with the release rates measured by the electrochemical sensors. A finite element transport model of the system also gave predicted release times in agreement with the sensor and radioactivity measurements of release times in stirred saline. MEMS devices with impedance sensors were implanted subcutaneously in rats and activated after 3-11 days post-implantation. Release of radiolabeled mannitol was monitored by theby Audrey M. Johnson.Ph.D

    The Development of an in Vivo Spinal Fusion Monitor Using Microelectromechanical (Mems) Technology to Create Implantable Microsensors

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    Surgical fusion of the spine is a conventional approach, and often last alternative, to the correction of a degenerative painful spinal segment. The procedure involves the surgical removal of the intervertebral disc at the problematic site, and the placement of a bone graft that is commonly harvested from the patients iliac crest and placed within the discectomized space. The surrounding bone is expected to incorporate and remodel into the bone graft to eventually provide an immobilized site. Spinal instrumentation often accompanies the bone graft to provide further immobility to the targeted site, thus augmenting the fusion process. However, the status of a fusion and the incorporation of bone across a destabilized spinal segment are often difficult for the surgeon to assess. Radiographic methods provide static views of the fusion site that possess excessive limitations. The radiographic image cannot provide the surgeon with information regarding fusion integrity when the patient is mobile and the spine is exposed to multiple motions. Fortunately, technological advances utilizing microelectromechanical system technology (MEMS) have provided insight into the development of miniature devices that exhibit high resolution, electronic accuracy, miniature sizing, and have the capacity to monitor long-term, real-time in vivo pressures and forces for a variety of situations. However, numerous challenges exist with the utilization of MEMS devices for in vivo applications.This work investigated the feasibility of utilizing implantable microsensors to monitor the pressure and force patterns of bone incorporation and healing of a spine fusion in vivo. The knowledge obtained from this series of feasibility tests using commercially available transducers to monitor pressures and forces, will be applied towards the development of miniature sensors that utilize MEMS technology to monitor real-time, long-term spine fusion in living subjects. The packaging, radiographic, and sterilization characteristics of MEMS sensors were eva

    The Development of an in Vivo Spinal Fusion Monitor Using Microelectromechanical (Mems) Technology to Create Implantable Microsensors

    Get PDF
    Surgical fusion of the spine is a conventional approach, and often last alternative, to the correction of a degenerative painful spinal segment. The procedure involves the surgical removal of the intervertebral disc at the problematic site, and the placement of a bone graft that is commonly harvested from the patients iliac crest and placed within the discectomized space. The surrounding bone is expected to incorporate and remodel into the bone graft to eventually provide an immobilized site. Spinal instrumentation often accompanies the bone graft to provide further immobility to the targeted site, thus augmenting the fusion process. However, the status of a fusion and the incorporation of bone across a destabilized spinal segment are often difficult for the surgeon to assess. Radiographic methods provide static views of the fusion site that possess excessive limitations. The radiographic image cannot provide the surgeon with information regarding fusion integrity when the patient is mobile and the spine is exposed to multiple motions. Fortunately, technological advances utilizing microelectromechanical system technology (MEMS) have provided insight into the development of miniature devices that exhibit high resolution, electronic accuracy, miniature sizing, and have the capacity to monitor long-term, real-time in vivo pressures and forces for a variety of situations. However, numerous challenges exist with the utilization of MEMS devices for in vivo applications.This work investigated the feasibility of utilizing implantable microsensors to monitor the pressure and force patterns of bone incorporation and healing of a spine fusion in vivo. The knowledge obtained from this series of feasibility tests using commercially available transducers to monitor pressures and forces, will be applied towards the development of miniature sensors that utilize MEMS technology to monitor real-time, long-term spine fusion in living subjects. The packaging, radiographic, and sterilization characteristics of MEMS sensors were eva

    The design of polymeric microneedles for the delivery of sensors for real-time physiological monitoring

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    Ce mémoire de maîtrise porte sur le développement d’un système d’administration de microaiguilles pour livrer des sondes et des capteurs fluorescents dans le contexte du diagnostic et de la surveillance des soins de santé. Bien que parfois négligés en faveur des soins de santé axés sur le traitement, le diagnostic précoce de la maladie et la surveillance préventive des paramètres biologiques peuvent considérablement améliorer les résultats des soins de santé et joueront probablement un rôle plus important dans les années à venir. Cependant, il reste des obstacles importants à cette approche, à savoir le caractère relativement invasif et perturbateur des analyses biologiques. La nécessité de se rendre dans une clinique et de subir un prélèvement de sang (ou de liquide biologique) invasif présente des inconvénients importants par rapport aux traitements classiques, qui consistent souvent de médicaments pouvant être pris à domicile sans douleur. Une solution à ces problèmes réside dans la mise au point de systèmes minimalement invasifs de diagnostic et de suivi médical, idéalement ceux qui peuvent être utilisés à domicile sans nécessiter de personnel qualifié. À cet égard, les microaiguilles sont une technologie au potentiel énorme, car leur petite taille les rend peu invasives et pratiquement indolores, et leur nature simple à usage unique permet potentiellement une administration à domicile par le patient. Particulièrement prometteuses pour les applications de diagnostic et de surveillance sont les microaiguilles en polymère soluble; fabriquées à partir de polymères synthétiques ou biologiques injectables, ces microaiguilles sont solubilisées après la perforation de la peau, libérant ainsi les composés qu’elles contiennent. Bien que prévu initialement pour la livraison d'agents thérapeutiques, en utilisant ces microaiguilles pour livrer des molécules fluorescentes spécifiquement conçues, il est possible de créer un tatouage médical de diagnostic affichant un signal fluorescent précis. En associant cette technologie à un détecteur de fluorescence portable, la surveillance en temps réel d’un large éventail de paramètres biologiques pourrait devenir accessible en dehors du contexte clinique. Afin de fournir un contexte pour le développement de cette technologie, cette mémoire commence par une revue des principes et des avancées majeures récentes dans le domaine des applications diagnostiques des microaiguilles (Chapitre 1). Par la suite, un tatouage par microaiguille est présenté sous la forme d'un capteur de ROS délivré sur la peau, avec des implications diagnostiques pour le vieillissement et la carcinogenèse de la peau liés aux UV, ainsi que pour des affections inflammatoires telles que le psoriasis, comme validation de concept (Chapitre 2). En outre, un autre tatouage par microaiguille est introduit, consistant d’un capteur spécialement adapté ciblant le système lymphatique, permettant la quantification en temps réel du drainage lymphatique, avec des implications pour la détection précoce de plusieurs affections, notamment le lymphœdème (Chapitre 3).This Master’s thesis concerns the development of a microneedle (MN) delivery system for fluorescent dyes and sensors in the context of diagnostics and healthcare monitoring. While sometimes overlooked in favor of treatment-focused healthcare, early disease diagnosis and preventative monitoring of biological parameters can meaningfully improve healthcare outcomes and will likely play a greater role in coming years. However, significant obstacles to this approach remain, namely the relatively invasive and disruptive nature of biological analyses. The need to travel to a clinic and undergo invasive blood (or biological fluid) sampling presents significant inconveniences relative to common treatments, often consisting of medications that can be taken painlessly at home. A solution to these problems lies in the development of minimally invasive systems for diagnostics and healthcare monitoring, ideally ones which can be used at home without the need for trained personnel. In this regard, MNs are a technology with tremendous potential, as their small size renders them minimally invasive and virtually painless, and their simple, single-use nature potentially allows for at-home administration by the patient. Showing particular promise for diagnostic and monitoring applications are dissolving polymeric MNs; made from injectable synthetic or biological polymers, these MNs are solubilized after breaching the skin, releasing any compound contained within. Though initially envisioned for the delivery of therapeutic agents, by using these MNs to deliver specifically designed fluorescent molecules, it is possible to create a diagnostic medical tattoo displaying a precise fluorescent signal. By pairing this technology with a portable fluorescence detector, real-time monitoring of a wide range of biological parameters could become accessible outside of a clinical setting. To provide context for the development of this technology, this thesis begins with a review of the principles and major recent advances in the field of diagnostic applications of MNs (Chapter 1). Subsequently, a proof-of-concept MN tattoo is introduced in the form of a ROS-sensor delivered to the skin, with diagnostic implications for UV-related skin aging and carcinogenesis, as well as inflammatory conditions such as psoriasis (Chapter 2). Further, another MN tattoo is introduced, consisting of a specifically tailored sensor targeting the lymphatic system, allowing the real-time quantification of lymphatic drainage, with implications in the early detection of several conditions, including lymphedema (Chapter 3)
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