Intracranial MEMS based temozolomide delivery in a 9L rat gliosarcoma model

Primary malignant brain tumors (BT) are the most common and aggressive malignant brain tumor. Treatment of BTs is a daunting task with median survival just at 21 months. Methods of localized delivery have achieved success in treating BT by circumventing the blood brain barrier and achieving high concentrations of therapeutic within the tumor. The capabilities of localized delivery can be enhanced by utilizing mirco-electro-mechanical systems (MEMS) technology to deliver drugs with precise temporal control over release kinetics. An intracranial MEMS based device was developed to deliver the clinically utilized chemotherapeutic temozolomide (TMZ) in a rodent glioma model. The device is a liquid crystalline polymer reservoir, capped by a MEMS microchip. The microchip contains three nitride membranes that can be independently ruptured at any point during or after implantation. The kinetics of TMZ release were validated and quantified in?vitro. The safety of implanting the device intracranially was confirmed with preliminary in?vivo studies. The impact of TMZ release kinetics was investigated by conducting in?vivo studies that compared the effects of drug release rates and timing on animal survival. TMZ delivered from the device was effective at prolonging animal survival in a 9L rodent glioma model. Immunohistological analysis confirmed that TMZ was released in a viable, cytotoxic form. The results from the in?vivo efficacy studies indicate that early, rapid delivery of TMZ from the device results in the most prolonged animal survival. The ability to actively control the rate and timing of drug(s) release holds tremendous potential for the treatment of BTs and related diseases.     

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.     

A scalable controlled-release device for transscleral drug delivery to the retina

A transscleral drug-delivery device, designed for the administration of protein-type drugs, that consists of a drug reservoir covered with a controlled-release membrane was manufactured and tested. The controlled-release membrane is made of photopolymerized polyethylene glycol dimethacrylate (PEGDM) that contains interconnected collagen microparticles (COLs), which are the routes for drug permeation. The results showed that the release of 40-kDa FITC-dextran (FD40) was dependent on the COL concentration, which indicated that FD40 travelled through the membrane-embedded COLs. Additionally, the sustained-release drug formulations, FD40-loaded COLs and FD40-loaded COLs pelletized with PEGDM, fine-tuned the release of FD40. Capsules filled with COLs that contained recombinant human brain-derived neurotrophic factor (rhBDNF) released bioactive rhBDNF in a manner dependent on the membrane COL concentration, as was found for FD40 release. When capsules were sutured onto sclerae of rabbit eyes, FD40 was found to spread to the retinal pigment epithelium. Implantation of the device was easy, and it did not damage the eye tissues. In conclusion, our capsule is easily modified to accommodate different release rates for protein-type drugs by altering the membrane COL composition and/or drug formulation and can be implanted and removed with minor surgery. The device thus has great potential as a conduit for continuous, controlled drug release.     

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.     

一种亚低温实验装置的研制

目的研制一种亚低温治疗新生动物缺氧缺血性脑损伤(hypoxic-ischemic brain damage,HIBD)的实验装置,对传统选择性头部亚低温的降温方式进行改良。方法根据牛顿冷却定律,利用热对流和热传导的方式,使用冷空气对实验动物进行选择性头部亚低温,由温控器进行脑内温度的监控。选择HIBD动物,监测脑内初始温度(35℃)降至不同温度的时间和相应的头皮温度,并进行统计分析。结果动物头罩内冷气温度可在2~26℃范围内准确调控,脑内温度从35℃降至28℃所需的平均时间小于40 min,脑内温度与头皮温度呈良好的直线正相关关系(r=0934,P005)。结论通过冷空气对实验动物进行选择性头部亚低温是一种有效、简便的方法。     

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。     

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.     

A novel polymeric chlorhexidine delivery device for the treatment of periodontal disease

An implantable, anti-microbial delivery device for the treatment of periodontal disease has been developed. In this polymer-based delivery system, the encapsulation efficiency, release characteristics, and bioactivity of anti-microbial agent were controlled by the complexation of the drug with cyclodextrins of differing lipophilicity. Microparticles of poly(dl-lactic-co-glycolic acid) (PLGA) containing chlorhexidine (Chx) free base, chlorhexidine digluconate (Chx-Dg) and their association or inclusion complex with methylated-beta-cyclodextrin (MBCD) and hydroxypropyl-beta-cyclodextrin (HPBCD) were prepared by single emulsion, solvent evaporation technique. It was observed that encapsulation efficiency and release of the chlorhexidine derivatives from the microparticles was a function of the lipophilicity of the cyclodextrin. Complexation of the poorly water soluble Chx with the more hydrophilic HPBCD resulted in 62% higher encapsulation efficiency and longer duration of sustained release over a 2-week period than complexation with the more lipophilic MBCD. In contrast, the complexation of the more water-soluble derivative of chlorhexidine, Chx-Dg, with the more lipophilic MBCD improved encapsulation efficiency by 12% and prolonged its release in comparison to both the free Chx-Dg and its complex with HPBCD. Furthermore, it was observed that the initial burst effect could be diminished by complexation with CD. Preliminary studies have shown that the chlorhexidine released from PLGA chips is biologically active against bacterial population that is relevant in periodontitis (P. gingivalis and B. forsythus) and a healthy inhibition zone is maintained in agar plate assay over a period of at least a 1-week. The PLGA/CD delivery system described in this paper may prove useful for the localized delivery of chlorhexidine salts and other anti-microbial agents in the treatment of periodontal disease where prolonged-controlled delivery is desired.     

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。     

脊柱三维运动测试实验装置的研制

目的研制一套模拟人体脊柱在体运动的离体加载装置,进行脊柱生物力学实验研究。方法利用轴承原理,在加载盘上设计安装旋转锁定装置,加载时旋转于所需测试位置后用螺栓锁定状态,再通过万能材料试验机提供自动加载动力源,在脊柱标本上施加前屈/后伸、左/右侧弯和左/右轴向旋转6个方向的纯力矩,模拟脊柱的在体运动,并用三维扫描仪对脊柱标本加载前后位置进行扫描测量。利用该加载装置对6具1岁龄猪颈椎(C2-C6)在6种加载状态下进行运动范围测量,并对该加载装置进行精度验证和误差分析。结果建立了一套人体脊柱三维运动实验装置,6具猪颈椎标本经加载测量得到6个方向的中性区和活动范围数据,总测量误差值小于3.5%。结论该装置巧妙的设计较好地模拟了脊柱在体运动,可实现人体脊柱的快速加载,费用低、方法简单实用,能大大提高实验的效率,在脊柱的离体加载方面具有较大的推广应用价值。     

Characterization of an alginate-based drug delivery system for neurological applications

This paper presents a drug delivery system based on alginate gels. The biocompatibility, the flexibility in size and shape, and the ability to entrap biomolecules make alginate-based systems ideal for in vivo drug delivery. Specifically, by considering the target application of neural regeneration and neuroprotection, the issue of biocompatibility as well as morphologic compatibility (e.g. shape and size of an implant) have to be addressed. The authors describe various types of alginate gels; fibers of cylindrical shape resulted the best choice in terms of simplicity of realization, insertion and release effectiveness, as shown by preliminary in vivo assays. Consequently, fibers release is tested in vitro and theoretically modelled, in order to obtain mathematical correlations between the release kinetics and key parameters affecting the realization procedure.     

A dual-targeting near-infrared biomimetic drug delivery system for HBV treatment

Hepatitis B virus (HBV) infection is a serious global public health threat. It remains elusive to achieve a functional HBV cure with currently available antivirals. Herein, a photo-responsive delivery vehicle composed of Nd³⁺-sensitized core–shell upconversion nanoparticle (UCNP), mesoporous silica nanoparticle (MSN), antisense oligonucleotides (ASOs), and capsid-binding inhibitor C39 was established, which was named UMAC according to the initials of its components. Subsequently, the as-synthesized delivery vehicle was encapsulated by β- D -galactopyranoside (Gal) modified red blood cell (RBC) membrane vesicles, which enabled precise targeting of the liver cells (UMAC-M-Gal). Both in vitro and in vivo experiments demonstrated that this biomimetic system could successfully achieve controlled drug release under light conditions at 808 nm, leading to effective suppression of HBV replication in this dual-targeted therapeutic approach. Together, these results substantiate the system has huge prospects for application to achieve functional HBV cure, and provides a promising novel strategy for drug delivery.     

SiRNA-phospholipid conjugates for gene and drug delivery in cancer treatment

Due to low charge density and stiff backbone structure, small interfering RNA (siRNA) has inherently poor binding ability to cationic polymers and lipid carriers, which results in low siRNA loading efficiency and limits siRNA success in clinical application. Here, siRNA-phospholipids conjugates are developed, which integrate the characteristics of the two phospholipids to self-assemble via hydrophilic siRNA and hydrophobic phospholipid tails to overcome the siRNA's stiff backbone structures and enhance the siRNA loading efficiency. In this study, the thiol-modified sense and antisense siRNA are chemically conjugated with phospholipids to form sense and antisense siRNA-phospholipid, and then these sense or antisense siRNA-phospholipids with equal amounts are annealed to generate siRNA-phospholipids. The siRNA-phospholipids can serve dual functions as agents that can silence gene expression and as a component of nanoparticles to embed hydrophobic anticancer drugs to cure tumor. siRNA-phospholipids together with cationic lipids and DSPE-PEG2000 fuse around PLGA to form siRNA-phospholipids enveloped nanoparticles (siRNA-PCNPs), which can deliver siRNAs and hydrophobic anticancer drugs into tumor. In animal models, intravenously injected siRNA-PCNPs embedded DOX (siPlk1-PCNPs/DOX) is highly effective in inhibiting tumor growth. The results indicate that the siRNA-PCNPs can be potentially applied as a safe and efficient gene and anticancer drug delivery carrier.     

Continuous intravesical lidocaine treatment for interstitial cystitis/bladder pain syndrome: safety and efficacy of a new drug delivery device

Limited treatment options exist for patients who suffer from a painful bladder condition known as interstitial cystitis/bladder pain syndrome (IC/BPS). Whether given systemically (orally) or by short-duration (1 to 2 hours) exposure via intravesical instillation, therapeutic agents have exhibited poor efficacy because their concentrations in the bladder are low. A previous attempt to develop a drug delivery device for use in the bladder was unsuccessful, likely as a result of poor tolerability. A continuous lidocaine-releasing intravesical system (LiRIS) was designed to be retained in the bladder and release therapeutic amounts of the drug into urine over a period of 2 weeks. The device was tested in healthy volunteers and IC/BPS patients and was found to be well tolerated in both subject groups because of its small size and freedom of movement within the bladder. The 16 women with IC/BPS who were enrolled in the study met the National Institute of Diabetes and Digestive and Kidney Diseases criteria for bladder hemorrhages or Hunner's lesions. Subjects received either LiRIS 200 mg or LiRIS 650 mg for 2 weeks. Safety, efficacy, cystoscopic appearance of the bladder, and limited pharmacokinetic data were collected. Both doses were well tolerated, and clinically meaningful reductions were seen in pain, urgency, voiding frequency, and disease questionnaires. Cystoscopic examinations showed improvement on day 14 (day of removal) compared with day 1, including resolution of Hunner's lesions in five of six subjects with baseline lesions. Global response assessment showed an overall responder rate of 64% at day 14 and a sustained overall responder rate of 64% 2 weeks later. Extended follow-up suggests that the reduction in pain was maintained for several months after the device was removed.     

Controlled release of bupivacaine HCl through microchannels of biodegradable drug delivery device

Local and prolonged delivery of local analgesics is much desired for post-operative pain management. For delivery of local analgesics at a constant rate over couple of days, a microfluidic device comprised of a drug reservoir and microchannels for drug release was developed using a biodegradable polymer, 85/15 poly(lactic-co-glycolic acid). Unlike conventional methods relying on material property, this device enables convenient modulation of the release speed of drugs by a simple change of the channel geometry such as the length and cross-sectional area. Bupivacaine was selected as our model local analgesic drug and its diffusional transport through microchannels was studied using the microfluidic devices. However, since the salt form of bupivacaine, bupivacaine hydrochloride, has pH-dependent solubility, its precipitation in microchannels had an adverse impact on the release performance of the microfluidic drug delivery devices. Thus, in this investigation, the diffusional transport and precipitation of bupivacaine hydrochloride in microfluidic channels were studied using in vitro release experiments and optical analysis. Furthermore, a concept of co-delivery of bupivacaine hydrochloride together with acidic additives was demonstrated to achieve a zero-order delivery of bupivacaine hydrochloride without the clogging of microchannels by its precipitation.     

A passive MEMS drug delivery pump for treatment of ocular diseases

An implantable manually-actuated drug delivery device, consisting of a refillable drug reservoir, flexible cannula, check valve, and suture tabs, was investigated as a new approach for delivering pharmaceuticals to treat chronic ocular diseases. Devices are fabricated by molding and bonding three structured layers of polydimethylsiloxane. A 30 gauge non-coring needle was used to refill the reservoir; this size maximized the number of repeated refills while minimizing damage to the reservoir. The check valve cracking pressure was 76 ± 8.5 mmHg (mean ± SE, n = 4); the valve sustained > 2000 mmHg of reverse pressure without leakage. Constant delivery at 1.57 ± 0.2 μL/sec and 0.61 ± 0.2 μL/sec (mean ± SE, n = 4) under 500 mmHg and 250 mmHg of applied pressure, respectively, was obtained in benchtop experiments. The valve closing time constant was 10.2 s for 500 mmHg and 14.2 s for 250 mmHg. Assembled devices were successfully demonstrated in benchtop, ex vivo, and in vivo experiments.