The Development of an ex vivo Flow System to Assess Acute Arterial Drug Retention of Cardiovascular Intravascular Devices

Purpose: The goal of this study was to develop an ex vivo system capable of rapidly evaluating arterial drug levels in living, isolated porcine carotid arteries.Methods: A vascular bioreactor system was developed that housed a native porcine carotid artery under physiological flow conditions. The ex vivo bioreactor system was designed to quantify the acute drug transfer of catheter-based drug delivery devices into explanted carotid arteries. To evaluate our ex vivo system, a paclitaxel-coated balloon and a perfusion catheter device delivering liquid paclitaxel were utilized. At 1-h post-drug delivery, arteries were removed, and paclitaxel drug levels measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Parallel experiments were performed in a pig model to validate ex vivo measurements.Results: LC-MS/MS analysis demonstrated arterial paclitaxel levels of the drug-coated balloon-treated arteries to be 48.49 ± 24.09 ng/mg and the perfusion catheter-treated arteries to be 25.42 ± 9.74 ng/mg at 1 h in the ex vivo system. Similar results were measured in vivo, as arterial paclitaxel concentrations were measured at 59.23 ± 41.27 ng/mg for the drug-coated balloon-treated arteries and 23.43 ± 20.23 ng/mg for the perfusion catheter-treated arteries. Overall, no significant differences were observed between paclitaxel measurements of arteries treated ex vivo vs. in vivo.Conclusion: This system represents the first validated ex vivo pulsatile system to determine pharmacokinetics in a native blood vessel. This work provides proof-of-concept of a quick, inexpensive, preclinical tool to study acute drug tissue concentration kinetics of drug-releasing interventional vascular devices.

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Polymer-Based Smart Drug Delivery Systems for Skin Application and Demonstration of Stimuli-Responsiveness

Polymers ◽

10.3390/polym13081285 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1285

Author(s):

Louise Van Gheluwe ◽

Igor Chourpa ◽

Coline Gaigne ◽

Emilie Munnier

Keyword(s):

Drug Delivery ◽

Drug Delivery Systems ◽

Ex Vivo ◽

Delivery Systems ◽

Stimuli Responsive ◽

Stimuli Responsive Polymers ◽

Smart Drug ◽

Smart Drug Delivery

Progress in recent years in the field of stimuli-responsive polymers, whose properties change depending on the intensity of a signal, permitted an increase in smart drug delivery systems (SDDS). SDDS have attracted the attention of the scientific community because they can help meet two current challenges of the pharmaceutical industry: targeted drug delivery and personalized medicine. Controlled release of the active ingredient can be achieved through various stimuli, among which are temperature, pH, redox potential or even enzymes. SDDS, hitherto explored mainly in oncology, are now developed in the fields of dermatology and cosmetics. They are mostly hydrogels or nanosystems, and the most-used stimuli are pH and temperature. This review offers an overview of polymer-based SDDS developed to trigger the release of active ingredients intended to treat skin conditions or pathologies. The methods used to attest to stimuli-responsiveness in vitro, ex vivo and in vivo are discussed.

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Development of Piperine-Loaded Solid Self-Nanoemulsifying Drug Delivery System: Optimization, In-Vitro, Ex-Vivo, and In-Vivo Evaluation

Nanomaterials ◽

10.3390/nano11112920 ◽

2021 ◽

Vol 11 (11) ◽

pp. 2920

Author(s):

Ameeduzzafar Zafar ◽

Syed Sarim Imam ◽

Nabil K. Alruwaili ◽

Omar Awad Alsaidan ◽

Mohammed H. Elkomy ◽

...

Keyword(s):

Drug Delivery ◽

Drug Delivery System ◽

Delivery System ◽

Oral Delivery ◽

Ex Vivo ◽

In Vitro Release ◽

System Optimization ◽

Globule Size

Hypertension is a cardiovascular disease that needs long-term medication. Oral delivery is the most common route for the administration of drugs. The present research is to develop piperine self-nanoemulsifying drug delivery system (PE-SNEDDS) using glyceryl monolinoleate (GML), poloxamer 188, and transcutol HP as oil, surfactant, and co-surfactant, respectively. The formulation was optimized by three-factor, three-level Box-Behnken design. PE-SNEDDs were characterized for globule size, emulsification time, stability, in-vitro release, and ex-vivo intestinal permeation study. The optimized PE-SNEDDS (OF3) showed the globule size of 70.34 ± 3.27 nm, percentage transmittance of 99.02 ± 2.02%, and emulsification time of 53 ± 2 s Finally, the formulation OF3 was transformed into solid PE-SNEDDS (S-PE-SNEDDS) using avicel PH-101 as adsorbent. The reconstituted SOF3 showed a globule size of 73.56 ± 3.54 nm, PDI of 0.35 ± 0.03, and zeta potential of −28.12 ± 2.54 mV. SEM image exhibited the PE-SNEDDS completely adsorbed on avicel. Thermal analysis showed the drug was solubilized in oil, surfactant, and co-surfactant. S-PE-SNEDDS formulation showed a more significant (p < 0.05) release (97.87 ± 4.89% in 1 h) than pure PE (27.87 ± 2.65% in 1 h). It also exhibited better antimicrobial activity against S. aureus and P. aeruginosa and antioxidant activity as compared to PE dispersion. The in vivo activity in rats exhibited better (p < 0.05) antihypertensive activity as well as 4.92-fold higher relative bioavailability than pure PE dispersion. Finally, from the results it can be concluded that S-PE-SNEDDS might be a better approach for the oral delivery to improve the absorption and therapeutic activity.

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BioMEMS Technologies for Regenerative Medicine

MRS Proceedings ◽

10.1557/proc-1139-gg02-01 ◽

2008 ◽

Vol 1139 ◽

Cited By ~ 3

Author(s):

Jeffrey T. Borenstein

Keyword(s):

Drug Delivery ◽

Regenerative Medicine ◽

Drug Delivery Systems ◽

Ex Vivo ◽

Delivery Systems ◽

Organ Shortage ◽

Engineered Tissues ◽

Drug Concentrations

AbstractThe emergence of BioMEMS fabrication technologies such as soft lithography, micromolding and assembly of 3D structures, and biodegradable microfluidics, are already making significant contributions to the field of regenerative medicine. Over the past decade, BioMEMS have evolved from early silicon laboratory devices to polymer-based structures and even biodegradable constructs suitable for a range of ex vivo and in vivo applications. These systems are still in the early stages of development, but the long-term potential of the technology promises to enable breakthroughs in health care challenges ranging from the systemic toxicity of drugs to the organ shortage. Ex vivo systems for organ assist applications are emerging for the liver, kidney and lung, and the precision and scalability of BioMEMS fabrication techniques offer the promise of dramatic improvements in device performance and patient outcomes.Ultimately, the greatest benefit from BioMEMS technologies will be realized in applications for implantable devices and systems. Principal advantages include the extreme levels of achievable miniaturization, integration of multiple functions such as delivery, sensing and closed loop control, and the ability of precision microscale and nanoscale features to reproduce the cellular microenvironment to sustain long-term functionality of engineered tissues. Drug delivery systems based on BioMEMS technologies are enabling local, programmable control over drug concentrations and pharmacokinetics for a broad spectrum of conditions and target organs. BioMEMS fabrication methods are also being applied to the development of engineered tissues for applications such as wound healing, microvascular networks and bioartificial organs. Here we review recent progress in BioMEMS-based drug delivery systems, engineered tissue constructs and organ assist devices for a range of ex vivo and in vivo applications in regenerative medicine.

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Sequential deconstruction of composite drug transport in metastatic breast cancer

Science Advances ◽

10.1126/sciadv.aba4498 ◽

2020 ◽

Vol 6 (26) ◽

pp. eaba4498 ◽

Cited By ~ 3

Author(s):

Shreya Goel ◽

Guodong Zhang ◽

Prashant Dogra ◽

Sara Nizzero ◽

Vittorio Cristini ◽

...

Keyword(s):

Drug Delivery ◽

Drug Transport ◽

Ex Vivo ◽

Metastatic Breast ◽

Lesion Size ◽

Whole Body ◽

High Temporal Resolution ◽

Breast Cancers ◽

Advanced Therapies

It is challenging to design effective drug delivery systems (DDS) that target metastatic breast cancers (MBC) because of lack of competent imaging and image analysis protocols that suitably capture the interactions between DDS and metastatic lesions. Here, we integrate high temporal resolution of in vivo whole-body PET-CT, ex vivo whole-organ optical imaging, high spatial resolution of confocal microscopy, and mathematical modeling, to systematically deconstruct the trafficking of injectable nanoparticle generators encapsulated with polymeric doxorubicin (iNPG-pDox) in pulmonary MBC. iNPG-pDox accumulated substantially in metastatic lungs, compared to healthy lungs. Intratumoral distribution and retention of iNPG-pDox varied with lesion size, possibly induced by locally remodeled microenvironment. We further used multiscale imaging and mathematical simulations to provide improved drug delivery strategies for MBC. Our work presents a multidisciplinary translational toolbox to evaluate transport and interactions of DDS within metastases. This knowledge can be recursively applied to rationally design advanced therapies for metastatic cancers.

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Abundance of Four Sulfur Mustard-DNA Adducts ex Vivo and in Vivo Revealed by Simultaneous Quantification in Stable Isotope Dilution–Ultrahigh Performance Liquid Chromatography–Tandem Mass Spectrometry

Chemical Research in Toxicology ◽

10.1021/tx4003403 ◽

2014 ◽

Vol 27 (4) ◽

pp. 490-500 ◽

Cited By ~ 29

Author(s):

Lijun Yue ◽

Yuxia Wei ◽

Jia Chen ◽

Huiqin Shi ◽

Qin Liu ◽

...

Keyword(s):

Dna Adducts ◽

Sulfur Mustard ◽

Ex Vivo ◽

Tandem Mass ◽

Stable Isotope Dilution ◽

Simultaneous Quantification ◽

Chromatography Tandem Mass Spectrometry ◽

Liquid Chromatography Tandem Mass ◽

Ultrahigh Performance Liquid Chromatography

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Apolipoprotein E Receptor 2′ Mediates Pathogenic Effects of Dimeric β2glycoprotein I and of Anti- β2glycoprotein I Antibodies in Vivo

Blood ◽

10.1182/blood.v112.11.408.408 ◽

2008 ◽

Vol 112 (11) ◽

pp. 408-408

Author(s):

Zurina Romay-Penabad ◽

Rolf T Urbanus ◽

Elizabeth Pappalardo ◽

Yong Hwang ◽

Ronald H.W.M. Derksen ◽

...

Keyword(s):

Apolipoprotein E ◽

Laser Scanning ◽

Carotid Arteries ◽

Ex Vivo ◽

Thrombus Formation ◽

Peritoneal Macrophages ◽

Laser Scanning Microscopy ◽

Target Cells ◽

Pathogenic Effects

Abstract Antiphospholipid antibodies (aPL) recognize β2Glycoprotein (β2GPI)-bound to receptor (s) in target cells and trigger a pro-coagulant/pro-inflammatory phenotype [i e.:expression of tissue factor (TF), vascular cell adhesion molecule-1 (VCAM-1)] that lead to thrombosis. The interaction of β2GPI with target cells may involve more than one protein. Investigators have shown that dimeric β2GPI binds to apolipoprotein E receptor 2′ (apoER2′) in platelets, in the absence of anti-β2GPI antibodies, increases their activation and induces enhanced thrombosis and TF activity in mice. However, the role of apoER2′ in vivo in Antiphospholipid Syndrome (APS) is not completely understood. Here, we examined the in vivo effects of dimeric β2GPI and of anti-β2GPI antibodies (IgG-APS) in apoER2′ deficient (−/−) mice and in normal mice pre-treated with recombinant soluble domain 1 of apoER2′ (BD1). In vivo, dynamics of thrombus formation (thrombus sizes), TF activities in carotid artery homogenates and in peritoneal macrophages and ex vivo expression of VCAM-1 in aortas and of TF activity in peritoneal macrophages were examined in the various types of mice after two i.p. injections with 40 μg of recombinant dimeric β2GPI – or with the corresponding monomer control – or with 500 μg IgG-APS (isolated from a patient with APS by protein G Sepharose) or with control IgG (IgG-NHS). Mice injected with IgG-APS had significant titers of anticardiolipin (aCL) and anti-β2GPI antibodies in their sera. In vivo, IgG-APS increased significantly the size of the induced thrombi as well as the TF activities in carotid arteries and in peritoneal macrophages in C57BL/6J (wild type) mice when compared to same type of mice treated with IgG-NHS. Similarly, ex vivo expression of VCAM-1 in mouse aortas and of TF in peritoneal macrophages, detected by two photon excitation laser scanning microscopy were increased in normal mice treated with IgG-APS when compared to control mice. The pre-treatment with 40 μg of BD1 i.p., significantly reduced those effects. Importantly, dimeric β2GPI (in the absence of anti-β2GPI antibodies) or IgGAPS did not increase significantly thrombus size, TF activities in homogenates of carotid arteries or in peritoneal macrophages, or ex vivo expression of VCAM-1 and TF in mice lacking apoER2′. Conclusions: Altogether these data show that dimers of β2GPI mimic pathogenic effects of anti-β2GPI antibodies in mice. Most importantly, apoER2′ is a mediator of those effects in vivo. These findings may provide insights not only for a better understanding of the pathophysiology of APS but may be important in the development of new targeted therapies, by means of interfering with the binding of β2GPI-aPL complexes with their receptor(s) in target cells in vivo.

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Pharmacokinetics of Pullulan–Dexamethasone Conjugates in Retinal Drug Delivery

Pharmaceutics ◽

10.3390/pharmaceutics14010012 ◽

2021 ◽

Vol 14 (1) ◽

pp. 12

Author(s):

Eva Kicková ◽

Amir Sadeghi ◽

Jooseppi Puranen ◽

Shirin Tavakoli ◽

Merve Sen ◽

...

Keyword(s):

Drug Delivery ◽

Drug Delivery Systems ◽

Ex Vivo ◽

Large Fraction ◽

Delivery Systems ◽

Intravitreal Injections ◽

Aqueous Humor Outflow ◽

Charged Nanoparticles ◽

Average Size

The treatment of retinal diseases by intravitreal injections requires frequent administration unless drug delivery systems with long retention and controlled release are used. In this work, we focused on pullulan (≈67 kDa) conjugates of dexamethasone as therapeutic systems for intravitreal administration. The pullulan–dexamethasone conjugates self-assemble into negatively charged nanoparticles (average size 326 ± 29 nm). Intravitreal injections of pullulan and pullulan–dexamethasone were safe in mouse, rat and rabbit eyes. Fluorescently labeled pullulan particles showed prolonged retention in the vitreous and they were almost completely eliminated via aqueous humor outflow. Pullulan conjugates also distributed to the retina via Müller glial cells when tested in ex vivo retina explants and in vivo. Pharmacokinetic simulations showed that pullulan–dexamethasone conjugates may release free and active dexamethasone in the vitreous humor for over 16 days, even though a large fraction of dexamethasone may be eliminated from the eye as bound pullulan–dexamethasone. We conclude that pullulan based drug conjugates are promising intravitreal drug delivery systems as they may reduce injection frequency and deliver drugs into the retinal cells.

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Experimental Carotid Stenosis and Endothelial Injury in the Rabbit: An In Vivo Model to Study Intravascular Platelet Aggregation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648436 ◽

1992 ◽

Vol 67 (03) ◽

pp. 302-305 ◽

Cited By ~ 35

Author(s):

Paolo Golino ◽

Giuseppe Ambrosio ◽

Immacolata Pascucci ◽

Massimo Ragni ◽

Enrico Russolillo ◽

...

Keyword(s):

Platelet Aggregation ◽

Coronary Flow ◽

Carotid Arteries ◽

Ex Vivo ◽

Endothelial Injury ◽

In Vivo Model ◽

Canine Coronary Artery ◽

Wall Interaction ◽

Experimental Canine

SummaryPrevious studies have shown that experimental canine coronary artery stenosis associated with endothelial injury results in a typical pattern of coronary flow characterized by gradual decreases in coronary flow to almost zero values followed by restorations of flow to normal values. This pattern of flow, called cyclic flow reductions (CFRs), is the consequence of recurrent platelet aggregation at the site of the stenosis and endothelial injury and subsequent dislodgement of the thrombus. In the present study, platelet activation and aggregation in vivo was induced by placing an external constrictor around carotid arteries with endothelial injury in anesthetized rabbits. Carotid blood flow velocity was measured continuously with a Doppler flow probe positioned proximally to the constrictor. After placement of the constrictor, CFRs developed in 14 of 14 rabbits with a mean frequency of 16.5 ± 2.3 cycles/h. CFRs were observed for 30 min, and the animals were treated with either an i.v. bolus of aspirin (10 mg/kg) or R 68070 (20 mg/kg), a drug with simultaneous TxA2 synthase and TxA2/PGH2 receptor blocking properties. Aspirin completely inhibited CFRs in 4 of 7 rabbits, whereas R 68070 eliminated CFRs in 7 of 7 animals. In the 3 animals that did not respond to aspirin, administration of ketanserin (0.25 mg/ kg i.v.), a selective serotonin S2 receptor antagonist, completely abolished CFRs. Both aspirin and R 68070 resulted in a marked reduction in serum TxB2 formation and in a complete inhibition of ex vivo platelet aggregation in response to arachidonic acid, whereas aggregation in response to U46619, a TxA2 mimetic, was inhibited only in R 68070-treated rabbits. We conclude that 1) CFRs develop in rabbit carotid arteries at sites of experimental stenosis and endothelial injury; 2) this model can be usefully employed to study platelet aggregation and platelet-vessel wall interaction in vivo and to test the efficacy of antiplatelet interventions.

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Development of a Bioreactor to Culture Tissue Engineered Ureters Based on the Application of Tubular OPTIMAIX 3D Scaffolds

Urologia Internationalis ◽

10.1159/000368419 ◽

2015 ◽

Vol 95 (1) ◽

pp. 106-113 ◽

Cited By ~ 4

Author(s):

Volker Seifarth ◽

Matthias Gossmann ◽

Heinz Peter Janke ◽

Joachim O. Grosse ◽

Christoph Becker ◽

...

Keyword(s):

Tissue Engineering ◽

Ex Vivo ◽

Cell Types ◽

Physiological Parameter ◽

Scaffold Material ◽

3T3 Fibroblasts ◽

Ureter Replacement ◽

Bioreactor System ◽

Collagenous Material

Regenerative medicine, tissue engineering and biomedical research give hope to many patients who need bio-implants. Tissue engineering applications have already been developed based on bioreactors. Physiological ureter implants, however, do not still function sufficiently, as they represent tubular hollow structures with very specific cellular structures and alignments consisting of several cell types. The aim of this study was to a develop a new bioreactor system based on seamless, collagenous, tubular OPTIMAIX 3D prototype sponge as scaffold material for ex-vivo culturing of a tissue engineered ureter replacement for future urological applications. Particular emphasis was given to a great extent to mimic the physiological environment similar to the in vivo situation of a ureter. NIH-3T3 fibroblasts, C2C12, Urotsa and primary genitourinary tract cells were applied as co-cultures on the scaffold and the penetration of cells into the collagenous material was followed. By the end of this study, the bioreactor was functioning, physiological parameter as temperature and pH and the newly developed BIOREACTOR system is applicable to tubular scaffold materials with different lengths and diameters. The automatized incubation system worked reliably. The tubular OPTIMAIX 3D sponge was a suitable scaffold material for tissue engineering purposes and co-cultivation procedures.

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