A polymeric device for controlled transscleral multi-drug delivery to the posterior segment of the eye

The design of drug delivery systems that can deliver multiple drugs to the posterior segment of the eye is a challenging task in retinal disease treatments. We report a polymeric device for multi-drug transscleral delivery at independently controlled release rates. The device comprises a microfabricated reservoir, controlled-release cover and three different fluorescent formulations, which were made of photopolymeized tri(ethyleneglycol)dimethacrylate (TEGDM) and poly(ethyleneglycol)dimethacrylate (PEGDM). The release rate of each fluorescent is controlled by varying the PEGDM/TEGDM ratio in its formulation and the cover. The release kinetics appeared to be related to the swelling ratio of the PEGDM/TEGDM polymers. When the devices were implanted onto rat sclerae, fluorescence was observable in the ocular tissues during 4 weeks’ implantation and distributed locally around the implantation site. Our polymeric system, which can administer multiple compounds with distinct kinetics, provides prolonged action and less invasive transscleral administration, and is expected to provide new tools for the treatment of posterior eye diseases with new therapeutic modalities.     

A device for the spatio-regional delivery of a photocurable drug formulation

We devised a new transtissue drug-delivery system, based on a multiple-needle-arrayed injector that has 36 long and short needles on the needle head, to administer the drug into local points of the target tissue at a well-controlled depth and pitch. A preliminary in vitro study, focusing the time-dependent depth profiling of protein injected in agarose gel as a model tissue using confocal laser scanning microscope, was conducted to evaluate the performance of the multiple-needle-arrayed injector coupled with photoreactive gelatin (styrenated gelatin: St-gelatin) as the sustained-release vehicle. Rhodamine-conjugated albumin, which was mixed with the St-gelatin buffer solution, was the model drug of the in vitro study, and the mixture was injected into agarose gel using the multiple-needle-arrayed injector by single injection, followed by visible-light irradiation to photocure the gelatin solution. Time-dependent distribution from the injected material into the surrounding agarose gel was observed using a confocal laser scanning microscope up to seven days. Injection of the drug material and concomitant withdrawal of the syringe (termed multirod method) enabled the long- and short-rod-like injections into the agarose gel at the same locations of the injected sites. The model drug gradually diffused throughout the agarose gel. In an in vivo study, the comparison of the efficacy of the angiogenic protein (bFGF: 10 microg for each) with placebo was performed using the non-ischemic hind limb model of rabbits. Four weeks after injection, a significant increase in the number of angiogenic capillaries was observed in the mixed St-gelatin/bFGF group compared with that of placebo. The multiple-needle-arrayed injector coupled with a sustained-release vehicle may be an effective drug delivery system for realizing the spatio-regional distribution of angiogenic protein.     

An implantable MEMS drug delivery device for rapid delivery in ambulatory emergency care

We introduce the first implantable drug delivery system based on MEMS (Micro-Electro-Mechanical-Systems) technology specifically designed as a platform for treatment in ambulatory emergency care. The device is named IRD³ (implantable rapid drug delivery device) and allows rapid delivery of drugs. Vasopressin was used as a model drug for in vitro tests as it is a commonly used drug for cardiac resuscitation. Experimental results reveal that the IRD³ provides an effective method for rapid delivery without significant drug degradation. Several medical uses and delivery modalities for IRD³ are proposed. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. N. M. Elman and H. L. Ho Duc contributed equally to this work.     

Intracranial microcapsule drug delivery device for the treatment of an experimental gliosarcoma model

Controlled-release drug delivery systems are capable of treating debilitating diseases, including cancer. Brain cancer, in particular glioblastoma multiforme (GBM), is an extremely invasive cancer with a dismal prognosis. The use of drugs capable of crossing the blood-brain barrier has shown modest prolongation in patient survival, but not without unsatisfactory systemic, dose-limiting toxicity. Among the reasons for this improvement include a better understanding of the challenges of delivery of effective agents directly to the brain tumor site. The combination of carmustine delivered by biodegradable polyanhydride wafers (Gliadel(?)), with the systemic alkylating agent, temozolomide, allows much higher effective doses of the drug while minimizing the systemic toxicity. We have previously shown that locally delivering these two drugs leads to further improvement in survival in experimental models. We postulated that microcapsule devices capable of releasing temozolomide would increase the therapeutic capability of this approach. A biocompatible drug delivery microcapsule device for the intracranial delivery of temozolomide is described. Drug release profiles from these microcapsules can be modulated based on the physical chemistry of the drug and the dimensions of the release orifices in these devices. The drug released from the microcapsules in these experiments was the clinically utilized chemotherapeutic agent, temozolomide. In vitro studies were performed in order to test the function, reliability, and drug release kinetics of the devices. The efficacy of the temozolomide-filled microcapsules was tested in an intracranial experimental rodent gliosarcoma model. Immunohistochemical analysis of tissue for evidence of DNA strand breaks via terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was performed. The experimental release curves showed mass flow rates of 36?μg/h for single-orifice devices and an 88?μg/h mass flow rate for multiple-orifice devices loaded with temozolomide. In vivo efficacy results showed that localized intracranial delivery of temozolomide from microcapsule devices was capable of prolonging animal survival and may offer a novel form of treatment for brain tumors.     

Implantable drug delivery device using frequency-controlled wireless hydrogel microvalves

This paper reports a micromachined drug delivery device that is wirelessly operated using radiofrequency magnetic fields for implant applications. The controlled release from the drug reservoir of the device is achieved with the microvalves of poly(N-isopropylacrylamide) thermoresponsive hydrogel that are actuated with a wireless resonant heater, which is activated only when the field frequency is tuned to the resonant frequency of the heater circuit. The device is constructed by bonding a 1-mm-thick polyimide component with the reservoir cavity to the heater circuit that uses a planar coil with the size of 5–10 mm fabricated on polyimide film, making all the outer surfaces to be polyimide. The release holes created in a reservoir wall are opened/closed by the hydrogel microvalves that are formed inside the reservoir by in-situ photolithography that uses the reservoir wall as a photomask, providing the hydrogel structures self-aligned to the release holes. The wireless heaters exhibit fast and strong response to the field frequency, with a temperature increase of up to 20°C for the heater that has the 34-MHz resonant frequency, achieving 38-% shrinkage of swelled hydrogel when the heater is excited at its resonance. An active frequency range of ~2 MHz is observed for the hydrogel actuation. Detailed characteristics in the fabrication and actuation of the hydrogel microvalves as well as experimental demonstrations of frequency-controlled temporal release are reported.     

缓释管组成结构对药物缓释速率的影响因素研究

为探究药物本身及缓释管组成结构等因素对药物缓释速率的影响,以孕酮、睾酮和雌二醇作为缓释试验药物,对硅胶缓释管的封堵方式、管长、管壁厚度以及所填充药物的方式等因素对药物缓释速率的影响进行了检测。实验结果表明,药物的结构对其本身的缓释速率具有决定性作用。硅胶缓释管的封堵方式、管长、管壁厚度及所填充药物的方式都对药物的缓释速率具有显著的调节作用,且调节作用的大小与药物本身缓释性能的大小成正比。另外,我们新研制的玻璃-硅胶缓释管释放面积小,药物储存能力大,特别适用于释放速率较快的药物在体内的长期缓释。     

A polymeric controlled drug delivery device for peptides based on a surface desorption/diffusion mechanism

Further investigations of the mechanisms underlying continuous peptide delivery from a newly developed Accurel polypropylene/collodion device are described. This module was prepared by lumen-loading an aqueous peptide solution into a piece of microporous Accurel polypropylene tubing which was subsequently end-sealed and encapsulated by a collodion membrane. By using vasopressin (VP) as a 'model' peptide, various aspects of the known semi-reversible protein/polymer surface interaction are shown to be present for VP and polypropylene i.e. prominent adsorption on the large surface area, which follows a bimodal adsorption isotherm, but with very limited desorption, and which can be enhanced by exchange with other proteins. Based on these findings as well as the observed steady state levels of VP on 24 h immersions in a small fixed volume, the previously proposed mechanism of pseudo-zero-order release could be evaluated further: the adsorbed peptide molecules function as a stock of near-constant activity, since desorption is rather limited, and as long as rapid exchange of bound peptide by external proteins can be prevented by a sufficiently thick (greater than 60 micron) collodion membrane, a slow long-term diffusion process will take place. Under 'infinite sink' conditions, the devices gave linear cumulative release curves for weeks. The present module is a novelty among the known membrane-controlled drug-delivery reservoir systems, since it has been loaded by an unsaturated drug solution and because the encapsulating membrane is not the sole release-rate-controlling factor.     

基于粉雾剂的宫颈给药装置结构设计

目的为了克服传统宫颈给药方式存在的剂型缺陷,本文设计了一种基于粉雾剂的宫颈给药装置,并通过结构设计使该装置能够满足一般粉雾剂药物的给药作用,将粉雾剂药物送达人体病变位置。方法通过模拟现有吸入粉雾剂的装置结构,设计此宫颈给药装置,使粉雾剂均匀喷洒在人体宫颈内,以便于人体宫颈黏膜吸收粉雾剂药物。应用流体力学计算此装置所要求提供的压强参数,同时通过ANSYS软件定性分析该装置在规定参数下的可行性。结果装置在气流速度60L/min、出口压力1MPa状态下可以使粉雾剂达到很好的湍流状态,利于粉雾剂的分散。结论该装置能够满足一般粉雾剂的给药要求,对粉雾剂的分散效果明显。     

Hydrogel probe for iontophoresis drug delivery to the eye

The aim of this study was to evaluate the use of a solid hydrogel loaded with a drug solution as a probe for ejecting drugs to the eye upon application of low current iontophoresis. Hydroxyethyl methacrylate (HEMA), cross-linked with ethylene glycol dimethacrylate (EGDMA), and cross-linked arabinogalactan or dextran were prepared to form solid hydrogels. The hydrogels were examined for their mechanical suitability, absorption of drug solution and in vitro release properties when applying an iontophoretic current through the drug-loaded hydrogel into a solid-agar surface. Transconjunctival and transscleral iontophoresis of gentamicin sulfate was studied in healthy rabbits using drug-loaded disposable HEMA hydrogel disc probes. Gentamicin concentrations in different eye segments were assayed using a fluorescence polarization immunoassay. Preliminary corneal toxicity was examined in rabbits using a current intensity of 2.5 and 5.1 mA/cm2 for 60 and 120 s. The most appropriate hydrogel is composed of HEMA, 2% EGDMA and 75% water. lontophoresis onto agar gel was found indicative for the evaluation of iontophoretic activity of a hydrogel. Transscleral iontophoretic treatment resulted in high concentrations of drugs in the posterior segments of the eye. Application of iontophoresis onto the rabbit eye caused a reversible swelling of the cornea which lasted a few hours after application. Low current iontophoresis using drug-loaded hydrogel has a potential clinical value in obtaining high drug concentration at posterior segments of the eye.     

Development and characterization of a scalable microperforated device capable of long-term zero order drug release

A drug delivery system that consists of microperforated polyimide microtubes was developed and characterized. Two groups of polyimide tubes were used. One set consisted of microtubes (I.D. = 125 μm) with 32.9 ± 1.7 μm size holes. The second set consisted of larger tubes (I.D. = 1000 μm) with 362–542 μm holes. The number of holes was varied between 1 and 3. The small tubes were loaded with crystal violet (CV) and ethinyl estradiol (EE) and the drug release studies were performed in 0.01 M phosphate buffered saline (PBS) (pH 7.1–7.4) at 37.0 ± 1.0°C for upto 4 weeks. The large tubes were loaded with CV and the drug release was studied in vitro in PBS and also ex vivo in rabbit’s vitreous humor. Linear release rates with R² > 0.9900 were obtained for all groups with CV and EE. Release rates of 7.8 ± 2.5, 16.2 ± 5.5, and 22.5 ± 6.0 ng/day for CV and 30.1 ± 5.8 ng/day for EE were obtained for small tubes. For large tubes, a release rate of 10.8 ± 4.1, 15.8 ± 4.8 and 22.1 ± 6.7 μg/day was observed in vitro in PBS and a release rate of 5.8 ± 1.8 μg/day was observed ex vivo in vitreous humor.     

Direct drug delivery to the brain

The authors of the review discuss the present-day state of and promising approaches to directed delivery of biological agents into the brain. Special attention is drawn to micellar and liposomal transport through the blood-brain barrier (BBB) targeted by immunochemical vectors, such as native or hydrophobized antibodies to specific antigens located at the BBB or in the brain parenchyma.     

Noninvasive drug delivery to the brain

Although brain-targeted delivery of pharmaceuticals can be achieved by direct introduction of the drug into the CNS, the techniques available for accomplishing this are associated with various medical risks which are unacceptably high. Methods for noninvasive delivery of pharmacologically active agents to the brain are discussed with emphasis placed on chemical delivery systems.     

Hydrogel probe for iontophoresis drug delivery to the eye

The aim of this study was to evaluate the use of a solid hydrogel loaded with a drug solution as a probe for ejecting drugs to the eye upon application of low current iontophoresis. Hydroxyethyl methacrylate (HEMA), cross-linked with ethylene glycol dimethacrylate (EGDMA), and cross-linked arabinogalactan or dextran were prepared to form solid hydrogels. The hydrogels were examined for their mechanical suitability, absorption of drug solution and in vitro release properties when applying an iontophoretic current through the drug-loaded hydrogel into a solid-agar surface. Transconjunctival and transscleral iontophoresis of gentamicin sulfate was studied in healthy rabbits using drug-loaded disposable HEMA hydrogel disc probes. Gentamicin concentrations in different eye segments were assayed using a fluorescence polarization immunoassay. Preliminary corneal toxicity was examined in rabbits using a current intensity of 2.5 and 5.1 mA/cm² for 60 and 120 s. The most appropriate hydrogel is composed of HEMA, 2% EGDMA and 75% water. Iontophoresis onto agar gel was found indicative for the evaluation of iontophoretic activity of a hydrogel. Transscleral iontophoretic treatment resulted in high concentrations of drugs in the posterior segments of the eye. Application of iontophoresis onto the rabbit eye caused a reversible swelling of the cornea which lasted a few hours after application. Low current iontophoresis using drug-loaded hydrogel has a potential clinical value in obtaining high drug concentration at posterior segments of the eye.     

A monolithic polymeric microdevice for pH-responsive drug delivery

A drug-delivery microdevice integrating pH-responsive nano-hydrogel particles functioning as intelligent nano valves is described. The polymeric microdevices are monolithic without requiring peripheral control hardware or additional components for controlling drug-release rates. pH-responsive nanoparticles were synthesized and embedded into a composite membrane. The resulting pH-responsive composite membranes were integrated with PDMS micro reservoirs via a room-temperature transfer bonding technique to form the proof-of-concept microdevices. In vitro release characterization of the microdevices was conducted in which the release rate of Vitamin B₁₂ (VB₁₂) as a model drug increased dramatically when the local pH value was decreased from 7.4 to 4. This device concept can serve as a platform technology for intelligent drug delivery in response to various in vivo environmental signals.     

A new probe for targeting drug delivery system

Recently, TDDS (Targeting drug delivery system) plays an important role in enhancing the bioavailability and targeting of anti-tumor drugs. How to transport drugs quickly and precisely to their target sites of action has not been solved fundamentally. A large number of researches have identified artemisinin and its analogs have the merit of precisely targeting to cancer cell, and low side effects to healthy tissue. Thus, if these compounds could be attached to established anti-tumor drugs with probe, a novel targeting anti-tumor drugs will be put into practice in the future. The novel drugs delivery system will be a powerful weapon against cancer disease for their unique targeting.     

A polyvalent aptamer system for targeted drug delivery

Poor efficacy and off-target systemic toxicity are major problems associated with current chemotherapeutic approaches to treat cancer. We developed a new form of polyvalent therapeutics that is composed of multiple aptamer units synthesized by rolling circle amplification and physically intercalated chemotherapy agents (termed as “Poly-Aptamer-Drug”). Using a leukemia cell-binding aptamer and doxorubicin as a model system, we have successfully constructed Poly-Aptamer-Drug systems and demonstrated that the Poly-Aptamer-Drug is significantly more effective than its monovalent counterpart in targeting and killing leukemia cells due to enhanced binding affinity (∼40 fold greater) and cell internalization via multivalent effects. We anticipate that our Poly-Aptamer-Drug approach will yield new classes of tunable therapeutics that can be utilized to effectively target and treat cancers while minimizing the side effects of chemotherapy.     

Cardiac electrophysiological imaging systems scalable for high-throughput drug testing

Multi-parametric electrophysiological measurements using optical methods have become a highly valued standard in cardiac research. Most published optical mapping systems are expensive and complex. Although some applications demand high-cost components and complex designs, many can be tackled with simpler solutions. Here, we describe (1) a camera-based voltage and calcium imaging system using a single ??economy?? electron-multiplying charge-coupled device camera and demonstrate the possibility of using a consumer camera for imaging calcium transients of the heart, and (2) a photodiode-based voltage and calcium high temporal resolution measurement system using single-element photodiodes and an optical fibre. High-throughput drug testing represents an application where system scalability is particularly attractive. Therefore, we tested our systems on tissue exposed to a well-characterized and clinically relevant calcium channel blocker, nifedipine, which has been used to treat angina and hypertension. As experimental models, we used the Langendorff-perfused whole-heart and thin ventricular tissue slices, a preparation gaining renewed interest by the cardiac research community. Using our simplified systems, we were able to monitor simultaneously the marked changes in the voltage and calcium transients that are responsible for the negative inotropic effect of the compound.     

A review of glycosylated carriers for drug delivery

Carbohydrates not only represent a vast potential as structure building blocks of living cells but also have proved as a promising candidate for drug delivery. Glycosylation of nanocarriers instructs some gratifying characteristic, which leads to the evolution of promising delivery systems. Some path-breaking advantages of glycosylated carriers include the engineered release profile of bioactives when introduced into biological system. Being natural product of living system these carriers also upshots as a multifaceted drug delivery vehicle and reduces the toxicity associated with unmodified drug carrier and therapeutic agent. An additional attribute of these carriers is to alter the pharmacokinetic profile of drugs positively with stabilization of drug carrier. The presence of lectin receptors on different cell surfaces makes the glycosylated carrier appreciable for targeted delivery of drugs to improve their therapeutic index. Active participation of some lectin receptors in immune responses to antigen overlaid the application of glycosylated carriers in delivery of antigen and immunotherapy for treatment of ailments like cancer. These advantages revealed the promising potential of glycosylated carriers in each perspective of drug delivery. Collectively this review presents an overview of different applications of glycosylated carriers, with a focus on their applicability in development of a nanoconstruct with GRAS status.