Implantable Delivery System Research Articles

Plain radiography in patients treated with intrathecal drug delivery using an implantable pump device

ObjectivesIntrathecal drug administration using an implanted pump system is well established in intractable spasticity and pain. However, despite continuous advancements in manufacturing technology, adverse events related to the pump and catheter still occur. Most of them, such as migration, damage, disconnection and occlusion, are related to the spinal catheter. The aim of this overview is to update radiologists on how plain radiography of the implanted delivery system for intrathecal drug administration should be interpreted and to increase awareness for the need of urgent and timely multidisciplinary troubleshooting.MethodsPlain radiographic images of patients treated with intrathecal drug administration using an implantable drug delivery system were analysed in a multidisciplinary setting at our (university) referral centre for complications in intrathecal drug administration.ResultsExamples of catheter-related adverse events are described and a proposal is made for stepwise interpretation of standard plain radiographic images.ConclusionsPlain radiological images are the mainstay for the diagnosis of catheter-related adverse events in intrathecal drug delivery. Radiologists play an important role in an early diagnosis. An awareness of abnormal radiological findings seems important to avoid a life-threatening withdrawal syndrome.Teaching points• Untimely cessation of intrathecal drug delivery can lead to a life-threatening withdrawal syndrome.• Initially mild symptoms can lead to an exacerbation of a withdrawal syndrome.• Most intrathecal catheter-related problems are visible on plain radiography.• Common causes of catheter problems are migration, lacerations, occlusion and disconnection.• Knowledge on implanted intrathecal catheters is crucial for interpretation of plain radiography.

Glucose-sensitive, injectable and biodegradable composite hydrogels for efficient loading and physiological self-regulated delivery of insulin

Long-term and daily subcutaneous injections of insulin for the treatment of insulin-dependent diabetic patients often lead to poor patient compliance and undesired complications. Phenylboronic acid (PBA)-based polymeric hydrogels have been widely considered as one of the most promising insulin delivery system to replace the frequent insulin injections. However, their applications are limited by clinically irrelevant glucose-responsive range, slow response rate, low tissue-adhesiveness and poor biodegradability, undesirable leakage at normoglycemic state. Herein, we report a novel implantable insulin hydrogel for glucose-regulated delivery of insulin based on a unique particle-hydrogel hybrid platform featuring fast glucose responsiveness at physiological pH, shear-thinning behavior for injection, tissue-adhesive function for long-lasting adherence, and full biodegradability for safe use. The system was thoroughly characterized both in vitro and in vivo and was demonstrated to hold these unique functions. Using streptozotocin-induced diabetic mice as a model, it was shown that a single subcutaneous injection of the insulin-loaded particle-hydrogel formulation led to quasi-steady-state blood glucose levels within the normal range for about two weeks. In addition, the preparation of the formulation only involved simple mixing and self-assembling processes, and thus it had great scalability and reproducibility for practical use. The highly feasible preparation, excellent performance, inherent biocompatibility and biodegradability make this novel composite hydrogel promising platform for diabetes therapy.Phenylboronic acid (PBA)-based polymeric hydrogels have been widely considered as one of the most promising insulin delivery system to replace the frequent insulin injections. However, these hydrogels, mostly based on a variety of PBA-containing acrylamide monomers, are still far from clinical reality. Building upon a unique particle-hydrogel hybrid platform, herein we report a novel implantable insulin storage and delivery system with multifunctionalities including fast glucose-sensitiveness at physiological pH, shear-thinning behavior for injection, tissue-adhesive function for long-lasting adherence, biodegradable materials for safe use and well-controlled insulin release. These unique functions were demonstrated through research both in vitro and in vivo. In addition, the preparation of the formulation was simple, and thus it had great scalability and reproducibility for practical use.

Minor defects of the luminal integrity in arterial introducer eSheaths after transcatheter aortic valve implantation.

BackgroundMedical devices such as implant delivery systems are commonly used during minimally invasive procedures in the cardiovascular system. These devices often have lubricious polymer coatings to reduce friction between the device and blood vessels but coatings may separate and potentially cause serious injuries to patients.MethodsLubricious coated eSheaths for transcatheter heart valve implantation were assessed for luminal integrity at the proximal, medial and distal part. We assessed the number, depths and area of luminal trails using environmental scanning electron microscope (ESEM), white light interferometry (WLI) and optical profilometry using area scale fractal complexity (asfc) as surface parameters. A total of 15 eSheaths were retrieved and analyzed after successful femoral transcatheter Sapien 3 implantation in patients (23 mm valve– 14F eSheath, 26 mm valve– 14F eSheath and 29 mm valve– 16F eSheath, n = 5 for each group). Unused eSheaths (14F and 16F) served as controls (n = 5 for each group).ResultsESEM revealed significantly greater number of trails after TAVR passage with the 23 mm, 26 mm and 29 mm valves compared to unused control 14F and 16F eSheaths (13.9 ± 3.1, 14.2 ± 2.3, 15.8 ± 1.7 vs. 0.08 ± 0.1 and 1.0 ± 0.5 [n]; p ≤ 0.0001 for all comparisons). Similarly, WLI showed minor, but significantly greater areas of luminal defects after 23 mm, 26 mm and 29 mm valve implantation vs. 14F and 16F unused controls (7.5 ± 0.9, 10.3 ± 1.1, 10.4 ± 1.4 vs. 4.1 ± 0.4 and 2.2 ± 0.4 [μm2], p = 0.0081). Likewise, the 3D-surface-measurement showed comparable results after implantation of the 23 mm, 26 mm and 29 mm valves vs. 14F and 16F unused control eSheaths (79.5 ± 6.3, 105.9 ± 5.3, 98.8 ± 4.8 vs. 5.1 ± 2.8 and 5.6 ± 0.5 [asfc] p = 0.0001).ConclusionMeasurable defects of the luminal layer occur during balloon expandable TAVR using 14F and 16F eSheaths though this is likely clinically insignificant. Further clinical investigations including a prospective assessment of minor peripheral embolization are needed to fully address the impact of this luminal defects.

Biodegradable star-shaped polycyclic ester elastomers: Preparation, degradability, protein release, and biocompatibility in vitro

Effective local delivery methods for sustained and stable release of protein drugs are urgently needed. Biodegradable elastomers based on star-shaped polycyclic esters have received attention for their drug-loading and drug-release kinetics. However, the long degradation periods resulting from their strong lipophilicity greatly hinder their application. In this study, we synthesized new cross-linked elastomers based on methyl-acrylic-star-poly(ϵ-caprolactone- co-d,l-lactide) cyclic ester and methyl-bi-acrylic-poly(ϵ-caprolactone-b-poly(ethylene glycol)-b-ϵ-caprolactone) with different molecular weights; determined their physical, thermal, and morphological characteristics; and studied their in vitro degradation and release of bovine serum albumin and recombinant human interleukin 2. Elastomer hydrophilicity improved with the introduction of methyl-bi-acrylic-poly(ϵ-caprolactone-b-poly(ethylene glycol)-b-ϵ-caprolactone), and a shorter degradation period (~25 weeks) was achieved. Additionally, the degradation rate could be adjusted by varying the composition of methyl-bi-acrylic-poly(ϵ-caprolactone-b-poly(ethylene glycol)-b-ϵ-caprolactone) to directly influence the degree of swelling, cross-linking density, and sol content of the elastomer. The controlled rate of bovine serum albumin and recombinant human interleukin 2 release increased with a larger degree of swelling, higher sol content, and lower cross-link density of the elastomers. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis showed good biocompatibility. These results suggest that these new elastomers are potential candidates for carrier materials in controlled, implantable delivery systems for protein drugs and other biomedical applications.

Abstract 1320: Local and sustained delivery of tamoxifen for the prevention of ER+ breast cancer using a nanochannel delivery platform

Abstract A high incidence (∼75%) of primary breast cancers are estrogen receptor positive (ER+), and a large fraction of these patients can pursue chemopreventive therapies. However, due to adverse side effects, only 5% to 20% of the women at high risk who could benefit from chemotherapeutics enroll in preventive treatment. There is a clear need for alternative preventive strategies that minimize side effects and improve enrollment and compliance. Selective estrogen receptor modulators, such as tamoxifen (TMX), have been shown to reduce ER+ breast cancer incidence by up to 50% among high-risk women. Importantly, along with raloxifene, it is one of only two FDA-approved drugs for breast cancer prevention. TMX has been in use for over 40 years and has a proven record in pre- and post-menopausal women. However, the drug is marred by side effects, the most common being symptoms of menopause. Further, women treated systemically and chronically with TMX were found to have an increased incidence of endometrial carcinoma. Although rare, this side effect, along with other serious adverse effects (such as blood clots, strokes, and cataracts), has resulted in a debate concerning TMX use in cancer prevention. As the key for breast cancer chemoprevention relies upon long-term delivery of drugs while circumventing side effects, we have developed a novel local delivery strategy for the constant and sustained administration of TMX. We maintain a long-term, local release of TMX in mammary tissues by utilizing a novel implantable nanochannel Delivery System (nDS). The nDS consists of a bioinert, implantable, and mechanically robust silicon membrane which houses an exact number of densely packed slit-nanochannels as small as 2.5 nm with tight tolerances on size, geometry, and surface properties. Providing steady levels of TMX at the mammary gland target through nDS delivery maximizes the therapeutic index while limiting the unwanted secondary effects, which will ultimately improve patient compliance. In this work we chemically induced tumorigenesis in Sprague-Dawley rats by N-methyl-N-nitrosourea (NMU) injection to promote development of estrogen-dependent tumors. We performed ovariectomies seven days after NMU injection to mimic post-menopausal biology. nDS implants loaded with either TMX or PEG400 (negative control) were inserted under the left abdominal mammary gland to determine effects of nDS-TMX on tumor growth and biomarkers. Utilizing LC/MS we were able to determine the amount of TMX released from the nDS. Rats were examined for palpable tumors to assess breast tumor incidence, latency to onset, and multiplicity. Our results show that the nDS implant enables the effective delivery of TMX in this breast tumor model. Further, this technology has the potential to rapidly provide long-term breast cancer protection with significant improvement in the quality of life of patients at high risk, thereby saving thousands of lives every year. Citation Format: Carly S. Filgueira, Eugenia Nicolov, Andrea Ballerini, R. Lyle Hood, Priya Jain, Giacomo Bruno, Alessandro Grattoni. Local and sustained delivery of tamoxifen for the prevention of ER+ breast cancer using a nanochannel delivery platform. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1320.

Assessment of alkoxylphenacyl-based polycarbonates as a potential platform for controlled delivery of a model anti-glaucoma drug

Treatment strategies for glaucoma will benefit from injectable and/or implantable delivery systems that can achieve sustained delivery of neuroprotective agents (to the posterior segment) and/or intraocular pressure lowering drugs (to the anterior segment). In this regard, we have evaluated the suitability of a new polymer (alkoxylphenacyl-based polycarbonates copolymer with polycaprolactone; AP-PCL 20% w/w) as a platform for ocular drug delivery. Brimonidine tartrate (BRT) was applied as a model anti-glaucoma drug. The polymer was applied to develop injectable (nanoparticles) and implantable (microfilms) delivery systems. Nanoparticles fabricated from AP-PCL were stable and have an average size less than 200nm. The AP-PCL microfilms prepared by compression molding showed a gradual hydrolytic in-vitro degradation monitored by water uptake, weight loss, microscopy, DSC and FT-IR measurements. AP-PCL microfilms achieve sustained delivery of BRT for up to 90days. Biocompatibility of AP-PCL-based delivery systems was demonstrated from studies in human trabecular meshwork cell line as well as after intravitreal injections in rats. The overall trend demonstrated that AP-PCL delivery systems may be considered as suitable candidates for prolonged drug delivery in chronic ocular disorders such as glaucoma.

Coronary and peripheral interventions: an update.

Download the Issue @ a Glance podcast Subscribe to the EHJ Podcast ![Graphic][1] When Andreas Gruntzig started his journey to become the founder of catheter-based cardiovascular interventions, he started—and this is often forgotten—in the peripheral circulation, at first in the iliac and later in the femoral arteries, with his home-made balloon. Only later did he dare to access the coronary circulation.1 The first Current Opinion article of this issue ‘ Drug-coated balloon treatment for lower extremity vascular disease intervention: an international positioning document ’ authored by Thomas Zeller from the HerzZentrum Bad Krozingen in Germany2 reminds us that not only coronary, but also peripheral interventions have made remarkable progress ever since. In particular, drug-coated balloons provide a novel method to deliver antiproliferative drugs such as paclitaxel locally into the arterial wall without the need for a chronically implanted delivery system. Following early positive pilot studies, two large pivotal trials confirmed the superiority of drug-coated balloons over plain old balloon angioplasty in the treatment of femoro-popliteal lesions. Even long lesions and in-stent restenosis showed promising mid-term technical and clinical results in small single-centre randomized studies. Unfortunately, these results have not been reproduced for below-the-knee applications. As a result, guidelines have not yet provided recommendations regarding the use of drug-coated balloons in peripheral interventions due to the lack of robust evidence. In the coronary circulation, potent antithrombotic therapies are commonly used to reduce the risk of recurrent ischaemic events and death, particularly in patients with acute coronary syndromes.3 Of note, such interventions inevitably lead to an increase in bleeding which in turn is associated with a prolonged length of stay, greater resource consumption, and eventually with a higher morbidity and mortality.4,5 Consequently, inclusion of bleeding as a safety endpoint in randomized controlled trials is essential in the … [1]: /embed/inline-graphic-1.gif

Adaptive continuous‐time model predictive controller for implantable insulin delivery system in Type I diabetic patient

SummaryThis paper presents a physiological model of glucose–insulin (GI) interaction and design of a Continuous‐time Model Predictive Controller (CMPC) to regulate the blood glucose (BG) level in Type I diabetes mellitus (TIDM) patients. For the designing of the CMPC, a nonlinear physiological model of TIDM patient is linearized as a ninth‐order state‐space model with an implanted insulin delivery device. A novel control approach based on Continuous‐time Model Predictive technique is proposed for the BG regulation with rejection of periodic or random meal and exercise disturbances in the process. To justify its efficacy a comparative analysis with Linear Quadratic Gaussian (LQG) control, and recently published control techniques like Proportional‐Integral‐Derivative (PID), Linear Quadratic Regulator with Loop Transfer Recovery (LQR/LTR) and H‐infinity has been established. The efficiency of the controller with respect to accuracy and robustness has been verified via simulation. The proposed controller performances are assessed in terms of ability to track a normoglycaemic set point of 81 mg/dl (4.5 mmol/l) in the presence of Gaussian and stochastic noise. Copyright © 2016 John Wiley & Sons, Ltd.

An alternative approach to controlled release of oxprenolol from the implantable delivery system based on biodegradable copolymer and genistein

ABSTRACTThis paper describes the development of covalent star-shaped poly(L-lactide/ϵ-caprolactone) random copolymer-oxprenolol (OXP) conjugates as a potential approach to controlling drug release from implantable delivery systems. We prepared synthesized materials containing 14–17 mol% OXP, which were conjugated via an ester bond. The conjugates, which were composed of biodegradable copolyester chains, natural genistein as a central core and drug, were characterized by hydrogen nuclear magnetic resonance (1H-NMR), Fourier transform infrared spectroscopy (FTIR) and viscosity methods. We evaluated the cyto- and genotoxicity of the synthesized copolymeric matrices, followed by the conjugates, with bacterial luminescence, protozoan and Salmonella typhimurium TA1535 assays. Furthermore, we performed in vitro mammalian assays of the obtained products with V79 cells. We found that the in vitro release of OXP from the obtained star-shaped conjugates was dependent on the structure of the synthesized biodegradable matrices.

Treprostinil Administered to Treat Pulmonary Arterial Hypertension Using a Fully Implantable Programmable Intravascular Delivery System: Results of the DelIVery for PAH Trial

The use of systemic prostanoids in severe pulmonary arterial hypertension (PAH) is often limited by patient/physician dissatisfaction with the delivery methods. Complications associated with external pump-delivered continuous therapy include IV catheter-related bloodstream infections and subcutaneous infusion site pain. We therefore investigated a fully implantable intravascular delivery system for treprostinil infusion. A multicenter, prospective, single-arm, clinical trial (DelIVery for Pulmonary Arterial Hypertension) was conducted by using an implantable intravascular delivery system. The implanted pumps were refilled percutaneously at least every 12weeks. The primary end point was the rate of catheter-related complications using the new model 10642 catheter compared with a predefined objective performance criterion of 2.5 per 1,000 patient-days based on the literature. Patients (n= 60) with severe PAH (World Health Organization group 1) receiving a stable dose of IV treprostinil for at least 4weeks received an implant device and were followed up for 12.1 ± 4.4months. Six catheter-related complications occurred, corresponding to a complication rate of 0.27 per 1,000 patient-days. The 97.5%upper one-sided confidence bound of 0.59 was less than the predefined criterion of 2.5 per 1,000 patient-days (P< .0001). Plasma treprostinil levels at 1week postimplantation were highly correlated with baseline levels (r= 0.91; P< .0001). The delivery system management time as reported bythe patients was 2.5 ± 1.7 hours per week preimplantation, and this time decreased to 0.6± 0.8 hour per week at 6months' postimplantation (P< .0001). All patients rated overall satisfaction with the implantable system as good, very good, or excellent at 6 weeks and 6months. There were no catheter-related bloodstream infections or catheter occlusions. The implantable intravascular delivery system delivered treprostinil to patients with PAH with a low rate of catheter-related complications and a high rate of patient satisfaction. ClinicalTrials.gov; No.: NCT01321073; URL: www.clinicaltrials.gov.

A Review on Long Acting PLGA Based in Situ Forming Microparticles Formulation for a Novel Drug Delivery System

Pharmaceutical research has recently been focusing on new inject able drug delivery systems which provide long therapeutic effects, minimum initial burst effect, reduced side effects, and involving simplified production stages and facilitate application process. In situ forming micro particle (ISM) systems, one of the latest approaches in this field, offer a new encapsulation technique and meet the objectives state above. Factors such as the carrier use to form the multiparticles, amount and type of drug and the vehicle type can be taken as the main performance criteria for these systems. Ongoing studies have shown that this new multiparticulate drug delivery system is suitable for achieving new implant delivery system with low risk of dose-dumping, capable of being modulated to exhibit varying release patterns, reproducible, easily applicable and well-tolerable. A novel in situ method for the preparation of inject able biodegradable poly(lactide-co-glycolide) (PLGA) micro particle for the controlled delivery of drug using DMSO as solvent. A stable dispersion of PLGA microglobules (‘premicroparticles’ or ‘embryonic micro particles’) in a vehicle mixture usually biocompatible oils on injection comes in contact with water from aqueous buffer or physiological fluid, thereby hardening the microglobules into solid matrix type micro particles entrapping the drug (in situ forming micro particles). The myotoxicity was assessed by measuring the cumulative release of creatine kinase (CK) to evaluate the muscle damage caused by this formulation. CK release will be significant lower decreased with a lower polymer phase: oil phase ratio. The vivo studies confirmed the in vitro data and showed good muscle compatibility of the ISM-system.

Risk of intracranial hypertension with intrauterine levonorgestrel.

Risk of intracranial hypertension with intrauterine levonorgestrel.

Docetaxel/2-Hydroxypropyl β -Cyclodextrin Inclusion Complex Increases Docetaxel Solubility and Release from a Nanochannel Drug Delivery System.

Breast cancer remains the second leading cause of cancer deaths for women in the U.S. The need for new and alternative strategies to treat this cancer is imperative. Here we show the optimization of our nanochannel delivery system (nDS) for constant and sustained delivery of docetaxel (DTX) for thetreatment of triple negative breast cancer. DTX is a highly hydrophobic drug, making it difficult to reach the therapeutic levels when released in aqueous solutions from our implantable delivery system. To overcome this challenge and test the release of DTX from nDS, we prepared DTX/2-hydroxypropyl β-cyclodextrin (DTX/HPCD) inclusion complexes in different molar ratios. The 1:10 DTX/HPCD complex achieved 5 times higher solubility than the 1:2 complex and 3 times higher in vitrorelease of DTX than with free DTX. When released in SCID/Beige mice from nanochannel system, the DTX/HPCD complex showed reduced tumor growth, comparable to the standard bolus injections of DTX, indicating that the structural stability and biological activity of DTX were retained in the complex, after its diffusion through the nanochannel system.

Controlled Delivery of Levothyroxine Using Porous Silicon as a Drug Nanocontainer

Porous silicon (pSi) materials are regarded as promising drug delivery vehicles due to their biocompatibility, in vivo degradation, and resorption. We examine pSi films as a platform for the controlled delivery of levothyroxine, as a means to overcome problems with consistent dosage of this drug by oral administration. Oxidized pSi films were modified with 3-(aminopropyl)triethoxysilane (APTES), creating a surface chemistry that increased levothyroxine drug loading capacity by 50 % and sustained drug release under physiological conditions for 14 days. Release kinetics from APTES-functionalized films initially followed a zero-order release profile, which is highly desirable for drug delivery. The loading and release profiles of levothyroxine suggest that the film size required to deliver a therapeutic dose is feasible for further consideration as an implantable delivery system.

Novel Approaches to the Management of Advanced Peripheral Artery Disease: Perspectives on Drug-Coated Balloons, Drug-Eluting Stents, and Bioresorbable Scaffolds.

Introducing anti-restenotic drug-based treatment modalities in femoropopliteal interventions is the potential revolutionizing reperfusion treatment of peripheral artery disease. Durability of recanalization procedures using drug-coated balloons (DCB) and drug-eluting stents (DES) yields in excellent mid-term and long-term technical and clinical outcomes and may be cost saving on the long term as compared to traditional treatment modalities such as plain old balloon angioplasty (POBA) and bare metal nitinol stent implantation. Drug-eluting bioresorbable scaffolds are another drug-based promising treatment option but are still investigational. In particular, DCB provide a novel method to locally deliver paclitaxel into the arterial wall without the need of a chronically implanted delivery system or even if those devices will be indicated, they can be delivered focally. Following the first positive pilot studies, two large pivotal trials have confirmed superiority of DCB over plain old balloon angioplasty (POBA) in the treatment of TASC II A and B femoropopliteal lesions. Even for more complex femoropopliteal lesions such as long lesions and instent restenosis, single center studies and small randomized studies have shown promising mid-term technical and clinical results. For DES, follow-up data for the only commercially available device are now presented up to 5years with excellent clinical outcome regarding freedom from target lesion revascularization and improvement of walking capacity. This review article summarizes the current knowledge and perspectives of drug-based endovascular treatment modalities in femoropopliteal interventions and discusses still unresolved needs.

Microglia Determine Brain Region-Specific Neurotoxic Responses to Chemically Functionalized Carbon Nanotubes.

Surface tunability and their ability to translocate plasma membranes make chemically functionalized carbon nanotubes (f-CNTs) promising intracellular delivery systems for therapeutic or diagnostic purposes in the central nervous system (CNS). The present study aimed to determine the biological impact of different types of multiwalled CNTs (MWNTs) on primary neuronal and glial cell populations isolated from fetal rat frontal cortex (FCO) and striatum (ST). Neurons from both brain regions were generally not affected by exposure to MWNTs as determined by a modified LDH assay. In contrast, the viability of mixed glia was reduced in ST-derived mixed glial cultures, but not in FCO-derived ones. Cytotoxicity was independent of MWNT type or dose, suggesting an inherent sensitivity to CNTs. Characterization of the cell populations in mixed glial cultures prior to nanotube exposure showed higher number of CD11b/c positive cells in the ST-derived mixed glial cultures. After exposure to MWNTs, CNT were uptaken more effectively by CD11b/c positive cells (microglia), compared to GFAP positive cells (astrocytes). When exposed to conditioned media from microglia enriched cultures exposed to MWNTs, ST-derived glial cultures secreted more NO than FCO-derived cells. These results suggested that the more significant cytotoxic response obtained from ST-derived mixed glia cultures was related to the higher number of microglial cells in this brain region. Our findings emphasize the role that resident macrophages of the CNS play in response to nanomaterials and the need to thoroughly investigate the brain region-specific effects toward designing implantable devices or delivery systems to the CNS.

The nanochannel delivery system for constant testosterone replacement therapy.

The goal of testosterone replacement is to provide long-term physiological supplementation at sufficient levels to mitigate the symptoms of hypogonadism. The objective of this work is to determine if the implantable nanochannel delivery system (nDS) can present an alternative delivery strategy for the long-term sustained and constant release of testosterone. A formulation of common testosterone esters (F1) was developed to enable nanochannel delivery of the low water soluble hormone. In vivo evaluation of testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels by liquid chromatography/mass spectrometry and a multiplex assay, respectively, in castrated Sprague-Dawley rats implanted with nDS-F1 implants or polymeric pellets was performed over a 6-month period. The percent of testosterone concentrations observed that fell within the normal range of testosterone levels for each animal was calculated and used to compare the study groups. Sustain release of testosterone in vivo for over 6 months. The subcutaneous release of F1 from nDS implants exhibited sustained in vivo release kinetics and attained stable clinically relevant plasma testosterone levels. Plasma LH and FSH levels were significantly diminished in nDS-F1 implant-treated animals, confirming biological activity of the released testosterone. In conclusion, we demonstrate that nDS-F1 implants represents a novel approach for the treatment of male hypogonadism. Further studies will be performed in view of translating the technology to clinical use.

Drug-coated balloon treatment for lower extremity vascular disease intervention: an international positioning document.

The advent of drug-coated balloons (DCBs) provides a novel means to locally deliver paclitaxel into the arterial wall without the need of a chronically implanted delivery system. The widespread use of these devices in the clinical arena is contemporary with the introduction and adoption of paclitaxel eluting stents for peripheral vascular intervention. However, DCB remain highly attractive approach as the long-term consequences of permanent metallic implants in peripheral applications are still unknown. Notably, the clinical value of DCB is supported by robust pre-clinical evidence regarding safety and efficacy. Likewise, the clinical value of DCB in patients has also been demonstrated by multiple randomized clinical trials in the superficial femoral artery (SFA) and proximal popliteal artery territory. However, the widespread clinical adoption of DCB into routine clinical practice remains elusive. The evidence on the value of DCB has been summarized in consensus documents and in clinical practice guidelines. In the coronary field, currently available information has been summarized in two comprehensive Experts' Consensus Documents and the European Society of Cardiology (ESC) guidelines on coronary revascularization.1–3 These documents emphasized that not all DCB are created equal and that a ‘class effect’ cannot be anticipated as the results obtained with different DCB are not uniform. This remains a major challenge since many CE marked devices are currently available yet many of these have not been supported by robust clinical results. In the peripheral territory, the information regarding the clinical use of DCB is scarce. Moreover, no previous consensus document exists describing the clinical applications and indications for the use of this technology …

Drug-coated balloons: how should we incorporate into our practice in treating superficial femoral artery lesions?

Drug-coated balloons (DCBs) provide a novel method to locally deliver paclitaxel into the arterial wall without the need of a chronically implanted delivery system. Following the first positive pilot studies, two large pivotal trials have confirmed superiority of DCBs over plain old balloon angioplasty (POBA) in the treatment of TASC II A and B femoro-popliteal lesions. Even for more complex femoro-popliteal lesions such as long lesions and in-stent restenosis, single-center studies and small randomized studies have shown promising mid-term technical and clinical results. This review article summarizes the current knowledge about DCBs in femoro-popliteal interventions, supplements published guidelines with evidence-based recommendations, and discusses still unresolved needs.

Polymeric Implants for the Delivery of Green Tea Polyphenols

Polymeric implants (millirods) have been tested for local delivery of chemotherapeutic agents in cancer treatment. Modeling of drug release profiles is critical as it may provide theoretical insights on rational implant design. In this study, a biodegradable poly (ε-caprolactone) (PCL) polymeric implant delivery system was tested to deliver green tea polyphenols (GTPs), both in vitro and in vivo. Factors including polymer compositions, supplements, drug loads, and surface area of implants were investigated. Our data showed that GTPs were released from PCL implants continuously for long durations, and drug load was the main determining factor of GTPs release. Furthermore, rates of in vitro release and in vivo release in the rat model followed similar kinetics for up to 16 months. A mathematical model was deduced and discussed. GTP implants have the potential to be used systemically and locally at the tumor site as an alternative strategy.