Batteryless implantable device with built-in mechanical clock for automated and precisely timed drug administration.

Adherence to medication plays a crucial role in the effective management of chronic diseases. However, patients often miss their scheduled drug administrations, resulting in suboptimal disease control. Therefore, we propose an implantable device enabled with automated and precisely timed drug administration. Our device incorporates a built-in mechanical clock movement to utilize a clockwork mechanism, i.e., a periodic turn of the hour axis, enabling automatic drug infusion at precise 12-h intervals. The actuation principle relies on the sophisticated design of the device, where the rotational movement of the hour axis is converted into potential mechanical energy and is abruptly released at the exact moment for drug administration. The clock movement can be charged either automatically by mechanical agitations or manually by winding the crown, while the device remains implanted, thereby enabling the device to be used permanently without the need for batteries. When tested using metoprolol, an antihypertensive drug, in a spontaneously hypertensive animal model, the implanted device can deliver drug automatically at precise 12-h intervals without the need for further attention, leading to similarly effective blood pressure control and ultimately, prevention of ventricular hypertrophy as compared with scheduled drug administrations. These findings suggest that our device is a promising alternative to conventional methods for complex drug administration.

Neutrophil extracellular traps promote ΔNp63+ basal cell hyperplasia in chronic rhinosinusitis.

BACKGROUND: Neutrophil extracellular traps (NETs) are observed in chronic rhinosinusitis (CRS), although their role remains unclear. OBJECTIVES: This study aimed to investigate the influence of NETs on the CRS epithelium. METHODS: Forty-five sinonasal biopsy specimens were immunofluorescence-stained to identify NETs and p63+ basal stem cells. Investigators treated human nasal epithelial cells with NETs and studied them with immunofluorescence staining, Western blotting, and quantitative real-time PCR. NET inhibitors were administered to a murine neutrophilic nasal polyp model. RESULTS: NETs existed in tissues in patients with CRS with nasal polyps, especially in noneosinophilic nasal polyp tissues. p63+ basal cell expression had a positive correlation with the release of NETs. NETs induced the expansion of Ki-67+p63+ cells. We found that ΔNp63, an isoform of p63, was mainly expressed in the nasal epithelium and controlled by NETs. Treatment with deoxyribonuclease (DNase) I or Sivelestat (NET inhibitors) prevented the overexpression of ΔNp63+ epithelial stem cells and reduced polyp formation. CONCLUSIONS: These results reveal that NETs are implicated in CRS pathogenesis via basal cell hyperplasia. This study suggests a novel possibility of treating CRS by targeting NETs.

Evaluation of Paste-Type Micronized Acellular Dermal Matrix for Soft Tissue Augmentation: Volumetric and Histological Assessment in a Mouse Model.

BACKGROUND: A biological injectable material, paste-type micronized acellular dermal matrix (ADM), has been proven effective in wound healing by filling defects through tissue replacement. This study aimed to compare the efficacy of paste-type micronized ADM on soft tissue augmentation with that of the conventional fillers in animal experiments. METHODS: Two distinct paste-type micronized ADMs, which were mixed with distilled water (mADM) and gelatin (mADM+GEL), respectively, were compared with conventional fillers, hyaluronic acid (HA) and polymethyl methacrylate (COL+PMMA). Thus, four different types of fillers were each injected into the dorsum of nude mice to compare the volume retention and biocompatibility. During the 8-week experimental period, ultrasound and computed tomography (CT) images were obtained for volumetric analysis. Histological evaluation was performed using hematoxylin and eosin and CD 31 staining. RESULTS: According to the CT images at week 8, the mADM and mADM+GEL showed a higher volume persistence rate of 113.54% and 51.12%, compared with 85.09% and 17.65% for HA and COL+PMMA, respectively. The 2-week interval ultrasound images revealed that the mADM showed a volume increase in width rather than in height, and an increase in height for HA did not vary much. Histological analysis showed marked fibrous invasion and neovascularization with the mADM and mADM+GEL compared to that of the conventional fillers. CONCLUSIONS: Paste-type micronized ADM showed soft tissue augmentation with similar effectiveness to that of conventional fillers. Therefore, paste-type micronized ADM has potential as an alternative material for a soft tissue filler in tissue replacement. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Implantable multireservoir device with stimulus-responsive membrane for on-demand and pulsatile delivery of growth hormone.

Implantable devices for on-demand and pulsatile drug delivery have attracted considerable attention; however, many devices in clinical use are embedded with the electronic units and battery inside, hence making them large and heavy for implantation. Therefore, we propose an implantable device with multiple drug reservoirs capped with a stimulus-responsive membrane (SRM) for on-demand and pulsatile drug delivery. The SRM is made of thermosensitive POSS(MEO2MA-co-OEGMA) and photothermal nanoparticles of reduced graphene oxide (rGO), and each of the drug reservoirs is filled with the same amount of human growth hormone (hGH). Therefore, with noninvasive near-infrared (NIR) irradiation from the outside skin, the rGO nanoparticles generate heat to rupture the SRM in the implanted device, which can open a single selected drug reservoir to release hGH. Therefore, the device herein is shown to release hGH reproducibly only at the times of NIR irradiation without drug leakage during no irradiation. When implanted in rats with growth hormone deficiency and irradiated with an NIR light from the outside skin, the device exhibits profiles of hGH and IGF1 plasma concentrations, as well as body weight change, similar to those in animals treated with conventional s.c. hGH injections.

Cabozantinib-Loaded PLGA Nanoparticles: A Potential Adjuvant Strategy for Surgically Resected High-Risk Non-Metastatic Renal Cell Carcinoma.

Patients with high-risk non-metastatic renal cell carcinoma (RCC) are at risk of metastatic relapse following nephrectomy. Cabozantinib (CZ), a potent multitarget tyrosine kinase inhibitor, interferes with angiogenesis and immunosuppression associated with surgery-induced metastasis. Here, we explored the therapeutic potential of CZ-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (CZ-PLGA-NPs) as an adjuvant strategy for targeting post-nephrectomy metastasis. A clinically relevant subline recapitulating post-nephrectomy lung metastasis of high-risk human RCC, namely Renca-SRLu5-Luc, was established through in vivo serial selection of luciferase-expressing murine RCC Renca-Luc cells. CZ was encapsulated into PLGA-NPs via the conventional single emulsion technique. The multifaceted preclinical antimetastatic efficacy of CZ-PLGA-NPs was assessed in Renca-SRLu5-Luc cells. CZ-PLGA-NPs with a smooth surface displayed desirable physicochemical properties, good CZ encapsulation efficiency, as well as controlled and sustained CZ release. CZ-PLGA-NPs exhibited remarkable dose-dependent toxicity against Renca-SRLu5-Luc cells by inducing G2/M cell cycle arrest and apoptosis. CZ-PLGA-NPs attenuated in vitro colony formation, migration, and invasion by abrogating AKT and ERK1/2 activation. An intravenous injection of CZ-PLGA-NPs markedly reduced lung metastatic burden and prolonged lifespan with favorable safety in the Renca-SRLu5-Luc experimental lung metastasis model. The novel CZ-PLGA-NPs system with multifaceted antimetastatic effects and alleviating off-target toxicity potential is a promising adjunctive agent for patients with surgically resected high-risk RCC.

Amino-Functionalized Mesoporous Silica Particles for Ocular Delivery of Brimonidine.

To treat glaucoma, conventional eye drops are often prescribed. However, the eye drops have limited effectiveness as a result of low drug bioavailability due to their rapid clearance from the preocular space. To resolve this, we proposed amino-functionalized mesoporous silica (AMS) particles as delivery carriers of the glaucoma drug, brimonidine. Because of the presence of mesopores, brimonidine (BMD) could be encapsulated in the AMS with a loading amount of 41.73 µg/mg (i.e., drug loading capacity of about 4.17%) to give the BMD-AMS, which could release the drug in a sustained manner over 8 h. BMD-AMS was also shown to be mucoadhesive due to the presence of both hydroxyl and amino groups in the surface, allowing for formation of hydrogen bonds and an ionic complex with the mucin, respectively. Therefore, when topically administered to rabbit eyes in vivo, BMD-AMS could reside in the preocular space for up to 12 h because of its adherence to the mucous layer. To assess in vivo efficacy, we examined the variance in intraocular pressure (IOP) and brimonidine concentration in the aqueous humor (AH) after applying BMD-AMS to the eye, which was compared with that induced by Alphagan P, the marketed brimonidine eye drops. For BMD-AMS, the duration in the decrease in IOP and the area under the drug concentration in the AH-time curve (AUC) were 12 h and 2.68 µg·h/mL, respectively, which were about twice as large as those obtained with Alphagan P; this finding indicated enhanced ocular bioavailability of brimonidine with BMD-AMS.

Application of Materials as Medical Devices with Localized Drug Delivery Capabilities for Enhanced Wound Repair.

The plentiful assortment of natural and synthetic materials can be leveraged to accommodate diverse wound types, as well as different stages of the healing process. An ideal material is envisioned to promote tissue repair with minimal inconvenience for patients. Traditional materials employed in the clinical setting often invoke secondary complications, such as infection, pain, foreign body reaction, and chronic inflammation. This review surveys the repertoire of surgical sutures, wound dressings, surgical glues, orthopedic fixation devices and bone fillers with drug eluting capabilities. It highlights the various techniques developed to effectively incorporate drugs into the selected material or blend of materials for both soft and hard tissue repair. The mechanical and chemical attributes of the resultant materials are also discussed, along with their biological outcomes in vitro and/or in vivo. Perspectives and challenges regarding future research endeavors are also delineated for next-generation wound repair materials.

Adapter-based Safety Injection System for Prevention of Wrong Route and Wrong Patient Medication Errors.

Wrong-route or -patient medication errors due to human mistakes have been considered difficult to resolve in clinical settings. In this study, we suggest a safety injection system that can help to prevent an injection when a mismatch exists between the drug and route or patient. For this, we prepared two distinct adapters with key and keyhole patterns specifically assigned to a pair of drug and route or patient. When connected to a syringe tip and its counterpart, a catheter injection-port, respectively, the adapters allowed for a seamless connection only with their matching patterns. In this study, each of the adapters possessed a specific key and keyhole pattern at one end and the other end was shaped to be a universal fit for syringe tips or catheter injection-ports in clinical use. With the scheme proposed herein, we could generate 27,000 patterns, depending on the location and shape of the key tooth in the adapters. With a rapid prototyping technique, multiple distinct pairs of adapters could be prepared in a relatively short period of time and thus, we envision that a specific adapter pair can be produced on-site after patient hospitalization, much like patient identification barcodes.

Multi-physics simulations for investigating the effect of electrode conditions on transscleral ocular iontophoresis for particulate drug delivery into ocular tissues.

Purpose: Transscleral ocular iontophoresis has been proposed to deliver charged particulate drugs to ocular tissues effectively by transmitting a weak electrical current through the sclera. The electric fields formed are influenced by the electrode conditions, thus affecting the amount of particulate drugs delivered to the ocular tissues via iontophoresis. Computational simulation is widely used to simulate drug concentrations in the eye; therefore, reflecting the characteristics of the drugs in living tissues to the simulations is important for a more precise estimation of drug concentration. In this study, we investigated the effect of electrode conditions (location and size) on the efficacy of transscleral iontophoresis. Methods: We first determined the simulation parameters based on the comparison of the amount of drug in the sclera in the simulation and in vivo experimental results. The injection of the negatively charged nanoparticles into the cul-de-sac of the lower eyelid was simulated. The active electrode (cathode) was attached to the skin immediately above the injection site, while the return electrode (anode) was placed over the eyebrow. The drug concentration distribution in the eye, based on either the location or size of each electrode, was evaluated using the finite element method with the estimated simulation parameters. Results: Our results indicate that drug permeability varies depending on the location and the size of the electrodes. Conclusion: Our findings demonstrate that the determination of optimal electrode conditions is necessary to enhance the effectiveness of transscleral iontophoresis. Supplementary Information: The online version contains supplementary material available at 10.1007/s13534-024-00359-2.

Fe-Porphyrin Cross-Linked Hydrogel for Reactive Oxygen Species Scavenging and Oxygen Generation in Diabetic Wounds.

Healing chronic diabetic wounds is challenging because of excessive reactive oxygen species (ROS) and hypoxia in the wound microenvironment. To address this issue, we propose a hydrogel wound dressing composed of polyethylene glycol (PEG) cross-linked with a biomimetic catalase, Fe-containing porphyrin (FeP) (i.e., FeP hydrogel). The immobilized FeP can serve as a catalyst for both ROS scavenging and O2 generation. The properties of the hydrogels were optimized by varying the composition ratios of the two constituent materials based on their mechanical properties and catalytic activity. Our in vitro cell experiments revealed that the FeP-80 hydrogel enhanced the proliferation and migration of keratinocytes and dermal fibroblasts and promoted the expression of angiogenic growth factors in keratinocytes. When tested with an in vivo diabetic chronic wound model, the FeP-80 hydrogel promoted wound healing by facilitating re-epithelialization, promoting angiogenesis, and suppressing inflammation, compared with other control groups.

Aripiprazole-montmorillonite: a new organic-inorganic nanohybrid material for biomedical applications.

Poor aqueous solubility and the unpleasant taste of aripiprazole (APZ) have been recurring problems, owing to its low bioavailability and low patient tolerance, respectively. Herein, we prepared a nanohybrid system that was based on a bentonite clay material, montmorillonite (MMT), which could both mask the taste and enhance the solubility of APZ (i.e., APZ-MMT). To further improve the efficacy of this taste masking and drug solubility, APZ-MMT was also coated with a cationic polymer, polyvinylacetal diethylamino acetate (AEA). In vitro dissolution tests at neutral pH showed that the amount of drug that was released from the AEA-coated APZ-MMT was greatly suppressed (<1%) for the first 3 min, thus suggesting that AEA-coated APZ-MMT has strong potential for the taste masking of APZ. Notably, in simulated gastric juice at pH 1.2, the total percentage of APZ that was released within the first 2 h increased up to 95% for AEA-coated APZ-MMT. Furthermore, this in vitro release profile was also similar to that of Abilify®, a commercially available medication. In vivo experiments by using Sprague-Dawley rats were also performed to compare the pharmacokinetics of AEA-coated APZ-MMT and Abilify®. AEA-coated APZ-MMT exhibited about 20% higher systemic exposure of APZ and its metabolite, dehydro-APZ, compared with Abilify®. Therefore, a new MMT-based nanovehicle, which is coated with a cationic polymer, can act as a promising delivery system for both taste masking and for enhancing the bioavailability of APZ.

Evaluation of poly(lactic-co-glycolic acid) plate and screw system for bone fixation.

In this study, we investigated the efficacy and safety of the recently developed modifiable bioabsorbable plates and screws, which are made of PLGA [poly(lactic-co-glycolic acids)]. An in vitro extract test and a mammalian erythrocyte micronucleus test revealed that neither cytotoxicity nor genotoxicity was observed with the plates and screws tested in this study. An in vivo mandible fracture model in rabbit was introduced to evaluate the in vivo efficacy and of the PLGA-based plates and screws. At 4, 6, 8, and 10 weeks after implantation, tissue specimens were taken from the implanted sites of the rabbits and a histologic analysis was performed for each of the specimens. After 4 weeks, the plate was covered by connective tissues and severe chronic active inflammation in soft tissue was observed. After 6 weeks, the inflammation decreased and some of the specimens exhibited new bone formation around the periosteum. After 8 and 10 weeks, new bone formation was observed with all samples, where almost no severe inflammation was involved, implying the healing of the fracture. Given these, it can be suggested that the biodegradable plate and screw system that we evaluated in this study is effective for treatment of mandible fracture, one of the regions under a high load-bearing condition. The adjustment process and the long-term follow-up study are in progress for clinical application of the plate and screw system introduced in this study.

Metal-organic framework for biomimetic nitric oxide generation and anticancer drug delivery.

The potential therapeutic implications of nitric oxide (NO) have drawn a great deal of interest for reversing multidrug resistance (MDR) in cancer; however, previous strategies utilized unstable or toxic NO donors often oxidized by the excessive addition of reactive oxygen species, leading to unexpected side effects. Therefore, this study proposed a metal-organic framework (MOF), Porous coordination network (PCN)-223-Fe, to be loaded with a biocompatible NO donor, L-arginine (L-arg; i.e., PCN-223-Fe/L-arg). This specific MOF possesses a ligand of Fe-porphyrin, a biomimetic catalyst. Thus, with PCN-223-Fe/L-arg, L-arg was released in a sustained manner, which generated NO by a catalytic reaction between L-arg and Fe-porphyrin in PCN-223-Fe. Through this biomimetic process, PCN-223-Fe/L-arg could generate sufficient NO to reverse MDR at the expense of hydrogen peroxide already present and highly expressed in cancer environments. For treatment of MDR cancer, this study also proposed PCN-223-Fe loaded with an anticancer drug, irinotecan (CPT-11; i.e., PCN-223-Fe/CPT-11), to be formulated together with PCN-223-Fe/L-arg. Owing to the synergistic effect of reversed MDR by NO generation and sustained release of CPT-11, this combined formulation exhibited a higher anticancer effect on MDR cancer cells (MCF-7/ADR). When intratumorally injected in vivo, coadministration of PCN-223-Fe/L-arg and PCN-223-Fe/CPT-11 greatly suppressed tumor growth in nude mice bearing MDR tumors.

Fe-containing metal-organic framework with D-penicillamine for cancer-specific hydrogen peroxide generation and enhanced chemodynamic therapy.

Chemodynamic therapy (CDT) is based on the production of cytotoxic reactive oxygen species, such as hydroxyl radicals (•OH). Thus, CDT can be advantageous when it is cancer-specific, in terms of efficacy and safety. Therefore, we propose NH2-MIL-101(Fe), a Fe-containing metal-organic framework (MOF), as a carrier of Cu (copper)-chelating agent, d-penicillamine (d-pen; i.e., the NH2-MIL-101(Fe)/d-pen), as well as a catalyst with Fe-metal clusters for Fenton reaction. NH2-MIL-101(Fe)/d-pen in the form of nanoparticles was efficiently taken into cancer cells and released d-pen in a sustained manner. The released d-pen chelated Cu that is highly expressed in cancer environments and this produces extra H2O2, which is then decomposed by Fe in NH2-MIL-101(Fe) to generate •OH. Therefore, the cytotoxicity of NH2-MIL-101(Fe)/d-pen was observed in cancer cells, not in normal cells. We also suggest a formulation of NH2-MIL-101(Fe)/d-pen combined with NH2-MIL-101(Fe) loaded with the chemotherapeutic drug, irinotecan (CPT-11; NH2-MIL-101(Fe)/CPT-11). When intratumorally injected into tumor-bearing mice in vivo, this combined formulation exhibited the most prominent anticancer effects among all tested formulations, owing to the synergistic effect of CDT and chemotherapy.

Implantable device actuated by manual button clicks for noninvasive self-drug administration.

Self-injectable therapy has several advantages in the treatment of metabolic disorders. However, frequent injections with needles impair patient compliance and medication adherence. Therefore, we develop a fully implantable device capable of on-demand administration of self-injection drugs via noninvasive manual button clicks on the outer skin. The device is designed to infuse the drug only at the moment of click actuation, which allows for an accurate and reproducible drug infusion, and also prevents unwanted drug leakage. Using a mechanical means of drug infusion, this implantable device does not contain any electronic compartments or batteries, making it compact, and semi-permanent. When tested in animals, the device can achieve subcutaneous injection-like pharmacokinetic and pharmacodynamic effects for self-injection drugs such as exenatide, insulin, and glucagon.

Microneedles coated with composites of phenylboronic acid-containing polymer and carbon nanotubes for glucose measurements in interstitial fluids.

A microneedle (MN) sensor coated with a sensing composite material was proposed for measuring glucose concentrations in interstitial fluid (ISF). The sensing composite material was prepared by blending a polymer containing glucose-responsive phenylboronic acid (PBA) moieties (i.e., polystyrene-block-poly(acrylic acid-co-acrylamidophenylboronic acid)) with conductive carbon nanotubes (CNTs). The polymer exhibited reversible swelling behavior in response to glucose concentrations, which influenced the distribution of the embedded CNTs, resulting in sensitive variations in electrical percolation, even when coated onto a confined surface of the MN in the sensor. We varied the ratio of PBA moieties and the loading amount of CNTs in the sensing composite material of the MN sensor and tested them in vitro using an ISF-mimicking gel with physiological glucose concentrations to determine the optimal sensitivity conditions. When tested in animal models with varying blood glucose concentrations, the MN sensor coated with the selected sensing material exhibited a strong correlation between the measured electrical currents and blood glucose concentrations, showing accuracy comparable to that of a glucometer in clinical use.

Implantable device with magnetically rotating disk for needle-free administrations of emergency drug.

Prompt administration of first-aid drugs can save lives during medical emergencies such as anaphylaxis and hypoglycemia. However, this is often performed by needle self-injection, which is not easy for patients under emergency conditions. Therefore, we propose an implantable device capable of on-demand administration of first-aid drugs (i.e., the implantable device with a magnetically rotating disk [iMRD]), such as epinephrine and glucagon, via a noninvasive simple application of the magnet from the outside skin (i.e., the external magnet). The iMRD contained a disk embedded with a magnet, as well as multiple drug reservoirs that were sealed with a membrane, which was designed to rotate at a precise angle only when the external magnet was applied. During this rotation, the membrane on a designated single-drug reservoir was aligned and torn to expose the drug to the outside. When implanted in living animals, the iMRD, actuated by an external magnet, delivers epinephrine and glucagon, similar to conventional subcutaneous needle injections.

Chromophoric cerium oxide nanoparticle-loaded sucking disk-type strip sensor for optical measurement of glucose in tear fluid.

BACKGROUND: Noninvasive monitoring of tear glucose levels can be convenient for patients to manage their diabetes mellitus. However, there are issues with monitoring tear glucose levels, such as the invasiveness of some methods, the miniaturization, inaccuracy, or the high cost of wearable devices. To overcome the issues, we newly designed a sucking disk-type (SD) strip biosensor that can quickly suck tear fluid and contains cerium oxide nanoparticle (CNP) that causes a unique color change according to the glucose level of the tear without complicated electronic components. METHODS: The SD strip biosensor composed of three distinct parts (tip, channel, and reaction chamber) was designed to contain the sensing paper, onto which tear fluid can be collected and delivered. The sensing paper treated with CNP/APTS (aminopropyltriethoxysilane) /GOx (glucose oxidase) was characterized. Then we carried out the reliability of the SD strip biosensor in the diabetic rabbit animals. We quantitatively analyzed the color values of the SD strip biosensor through the colorimetric analysis algorithm. RESULTS: We contacted the inferior palpebral conjunctiva (IPC) of a diabetic rabbit eye using an SD strip biosensor to collect tears without eye irritation and successfully verified the performance and quantitative efficacy of the sensor. An image processing algorithm that can optimize measurement accuracy is developed for accurate color change measurement of SD strip biosensors. The validation tests show a good correlation between glucose concentrations measured in the tear and blood. CONCLUSION: Our findings demonstrate that the CNP-embedded SD strip biosensor and the associated image processing can simply monitor tear glucose to manage diabetes mellitus.

Linear delivery of verapamil via nanofibrous sheet-based system.

PURPOSE: To achieve linear delivery of a highly water-soluble oral drug, verapamil, with a nanofibrous sheet-based system. METHODS: The nanofibrous sheets made of poly (lactic-co-glycolic acid) were used as a diffusion barrier to cap a tablet containing verapamil. For controlled drug delivery, we varied the sheet thickness to 20 µm, 50 µm and 80 µm to give the capped drug tablets, 20CT, 50CT and 80CT, respectively. RESULTS: Drug release was more sustained as the sheet thickness increased. Thus, the periods for almost complete drug release could be extended up to 14 h with the 80 µm-thick sheets. As we assessed the linear least square fits to the in vitro drug release data from the capped tablets, 20CT and 50CT showed a fairly good correlation with linear release. The periods of linear release were 6 h and 8 h for 20CT and 50CT, respectively, both releasing more than 85% drug during this period. CONCLUSION: We conclude that a drug tablet capped with nanofibrous sheets is a promising system for linear delivery of a highly water-soluble oral drug.

Microchip for sustained drug delivery by diffusion through microchannels.

To enable sustained drug delivery, we prepared microchips of simple structure for drug release based on diffusion through microchannels. The microchips were fabricated with poly(methyl methacrylate), embedded with one or more microwells and microchannels of controlled length. The channels were filled with biocompatible polymer, poly(ethylene glycol), to serve as a drug diffusion barrier. The wells served as drug reservoirs and were filled with a fine powder of a model compound, fluorescein. Three different drug delivery microchip designs were prepared, each equipped with a channel of 1, 4, or 8 mm length. Drug release from these devices all exhibited a delay followed by sustained release over time. As the channel length increased from 1 to 8 mm, the onset time and duration of drug release also increased from 0.5 to 7 day and from 11 days to 28, respectively. We also prepared microchips equipped with multiple microwells, each connected to a channel of different length. In this way, a chip with channels of 1, 4, and 8 mm length exhibited a continuous drug release from 0.5 to 35 days. A future study is in progress to develop the microchips made of biodegradable materials. Therefore, we conclude that a microchip embedded with multiple sets of microwells and microchannels of different length can be designed to enable sustained drug release for controlled and prolonged periods of time.