CBSET Inc.

Lexington, MA, United States

CBSET Inc.

Lexington, MA, United States
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Sakakura K.,CVPath Institute Inc. | Ladich E.,CVPath Institute Inc. | Edelman E.R.,CBSET Inc. | Markham P.,CBSET Inc. | And 5 more authors.
JACC: Cardiovascular Interventions | Year: 2014

Transcatheter ablation of renal autonomic nerves is a viable option for the treatment of resistant arterial hypertension; however, structured pre-clinical evaluation with standardization of analytical procedures remains a clear gap in this field. Here we discuss the topics relevant to the pre-clinical model for the evaluation of renal denervation (RDN) devices and report methodologies and criteria toward standardization of the safety and efficacy assessment, including histopathological evaluations of the renal artery, periarterial nerves, and associated periadventitial tissues. The pre-clinical swine renal artery model can be used effectively to assess both the safety and efficacy of RDN technologies. Assessment of the efficacy of RDN modalities primarily focuses on the determination of the depth of penetration of treatment-related injury (e.g., necrosis) of the periarterial tissues and its relationship (i.e., location and distance) and the effect on the associated renal nerves and the correlation thereof with proxy biomarkers including renal norepinephrine concentrations and nerve-specific immunohistochemical stains (e.g., tyrosine hydroxylase). The safety evaluation of RDN technologies involves assessing for adverse effects on tissues local to the site of treatment (i.e., on the arterial wall) as well as tissues at a distance (e.g., soft tissue, veins, arterial branches, skeletal muscle, adrenal gland, ureters). Increasing experience will help to create a standardized means of examining all arterial beds subject to ablative energy and in doing so enable us to proceed to optimize the development and assessment of these emerging technologies. © 2014 American College of Cardiology Foundation Published by Elsevier Inc.


Seifert P.,Applied Sciences, Inc. | Regan K.,CBSET Inc | Zani B.,Applied Sciences, Inc. | Wong G.,CBSET Inc | Stanley J.,CBSET Inc
Journal of Histotechnology | Year: 2013

For pathological investigation, vascular tissues implanted with biomaterials or medical devices require microscopic histology and scanning electron microscopy (SEM) assessment to evaluate biocompatibility with the vascular luminal surface. However, these valuable specimens are often susceptible to SEM and histology tissue preparation artifacts. Correlative variable pressure-scanning electron microscopy (VP- SEM) and histology methods were developed and evaluated, using current SEM technology, allowing direct imaging of hydrated samples without lengthy tissue processing, labor, equipment, and their sequela artifacts. Unstained and silver-stained, fixed swine carotid arteries were assessed using a cooling stage and an environmental secondary electron detector. After VP-SEM imaging, arteries were processed for histology evaluation. Assessment of luminal endothelial surface SEM images and tissue histology of the underlying mural wall was made to determine if low vacuum, cryo-freezing, electron beam exposure, and/or staining affected tissue morphology. Conventional SEM requires lengthy tissue processing with dedicated equipment for solvent dehydration, critical point drying, and metallic sputter coating in order to image under high vacuum for secondary electron imaging. This process causes notable artifacts when samples are later processed for microscopic histology. In contrast, silver staining of swine carotid arteries, followed by aldehyde fixation, facilitated VP-SEM imaging and histology preparation with results that were comparable to conventional SEM and had acceptable tissue morphology. VP-SEM with a cooling stage and an environmental secondary electron detector allows efficient SEM imaging and correlative histological assessment of vascular tissue samples. This correlative method may be further developed and implemented for research applications with biomaterial and medical device implanted tissues. © National Society for Histotechnology 2013.


Cohen-Mazor M.,Vessix Vascular | Mathur P.,Vessix Vascular | Stanley J.R.L.,CBSET Inc. | Mendelsohn F.O.,Center for Interventional Hypertension Therapies | And 5 more authors.
Journal of Hypertension | Year: 2014

To evaluate the safety and effectiveness of different bipolar radiofrequency system algorithms in interrupting the renal sympathetic nerves and reducing renal norepinephrine in a healthy porcine model. METHODS:: A porcine model (N = 46) was used to investigate renal norepinephrine levels and changes to renal artery tissues and nerves following percutaneous renal denervation with radiofrequency bipolar electrodes mounted on a balloon catheter. Parameters of the radiofrequency system (i.e. electrode length and energy delivery algorithm), and the effects of single and longitudinal treatments along the artery were studied with a 7-day model in which swine received unilateral radiofrequency treatments. Additional sets of animals were used to examine norepinephrine and histological changes 28 days following bilateral percutaneous radiofrequency treatment or surgical denervation; untreated swine were used for comparison of renal norepinephrine levels. RESULTS:: Seven days postprocedure, norepinephrine concentrations decreased proportionally to electrode length, with 81, 60 and 38% reductions (vs. contralateral control) using 16, 4 and 2-mm electrodes, respectively. Applying a temperature-control algorithm with the 4-mm electrodes increased efficacy, with a mean 89.5% norepinephrine reduction following a 30-s treatment at 68°C. Applying this treatment along the entire artery length affected more nerves vs. a single treatment, resulting in superior norepinephrine reduction 28 days following bilateral treatment. CONCLUSION:: Percutaneous renal artery application of bipolar radiofrequency energy demonstrated safety and resulted in a significant renal norepinephrine content reduction and renal nerve injury compared with untreated controls in porcine models.


Kolachalama V.B.,Harvard-MIT Division of Health Sciences and Technology | Kolachalama V.B.,Charles Stark Draper Laboratory | Pacetti S.D.,Abbott Laboratories | Franses J.W.,Harvard-MIT Division of Health Sciences and Technology | And 10 more authors.
Circulation | Year: 2013

BACKGROUND - Drug-coated balloons are increasingly used for peripheral vascular disease, and, yet, mechanisms of tissue uptake and retention remain poorly characterized. Most systems to date have used paclitaxel, touting its propensity to associate with various excipients that can optimize its transfer and retention. We examined zotarolimus pharmacokinetics. METHODS AND RESULTS - Animal studies, bench-top experiments, and computational modeling were integrated to quantify arterial distribution after zotarolimus-coated balloon use. Drug diffusivity and binding parameters for use in computational modeling were estimated from the kinetics of zotarolimus uptake into excised porcine femoral artery specimens immersed in radiolabeled drug solutions. Like paclitaxel, zotarolimus exhibited high partitioning into the arterial wall. Exposure of intimal tissue to drug revealed differential distribution patterns, with zotarolimus concentration decreasing with transmural depth as opposed to the multiple peaks displayed by paclitaxel. Drug release kinetics was measured by inflating zotarolimus-coated balloons in whole blood. In vivo drug uptake in swine arteries increased with inflation time but not with balloon size. Simulations coupling transmural diffusion and reversible binding to tissue proteins predicted arterial distribution that correlated with in vivo uptake. Diffusion governed drug distribution soon after balloon expansion, but binding determined drug retention. CONCLUSIONS - A large bolus of zotarolimus releases during balloon inflation, some of which pervades the tissue, and a fraction of the remaining drug adheres to the tissue-lumen interface. As a result, the duration of delivery modulates tissue uptake where diffusion and reversible binding to tissue proteins determine drug transport and retention, respectively. © 2013 American Heart Association, Inc.


Shammas N.W.,Midwest Cardiovascular Research Foundation | Aasen N.,Boston Scientific Inc. | Bailey L.,CBSET Inc | Budrewicz J.,CBSET Inc | And 2 more authors.
Journal of Endovascular Therapy | Year: 2015

Purpose: To determine the number of runs with blades up (BU) using the JetStream Navitus to achieving optimal debulking in a porcine model of femoropopliteal artery in-stent restenosis (ISR). Methods: In this porcine model, 8 limbs were implanted with overlapping nitinol self-expanding stents. ISR was treated initially with 2 blades-down (BD) runs followed by 4 BU runs (BU1 to BU4). Quantitative vascular angiography (QVA) was performed at baseline, after 2 BD runs, and after each BU run. Plaque surface area and percent stenosis within the treated stented segment were measured. Intravascular ultrasound (IVUS) was used to measure minimum lumen area (MLA) and determine IVUS-derived plaque surface area. Results: QVA showed that plaque surface area was significantly reduced between baseline (83.9%±14.8%) and 2 BD (67.7%±17.0%, p=0.005) and BU1 (55.4%±9.0%, p=0.005) runs, and between BU1 and BU2 runs (50.7%±9.7%, p<0.05). Percent stenosis behaved similarly with no further reduction after BU2. There were no further reductions in plaque surface area or percent stenosis with BU 3 and 4 runs (p=0.10). Similarly, IVUS (24 lesions) confirmed optimal results with BU2 runs and no additional gain in MLA or reduction in plaque surface area with BU3 and 4. IVUS confirmed no orbital cutting with JetStream Navitus. There were no stent strut discontinuities on high-resolution radiographs following atherectomy. Conclusion: JetStream Navitus achieved optimal tissue debulking after 2 BD and 2 BU runs with no further statistical gain in debulking after the BU2 run. Operators treating ISR with JetStream Navitus may be advised to limit their debulking to 2 BD and 2 BU runs to achieve optimal debulking. © The Author(s) 2015.


PubMed | CBSET Inc.
Type: Journal Article | Journal: EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology | Year: 2016

We sought to evaluate the incidence of embolic material in porcine brains following vascular interventions using hydrophilic-coated sheaths.A new self-expanding stent and delivery system (SDS) was deployed through a hydrophilic-coated (Flexor Ansel; Cook Medical, Bloomington, IN, USA) guiding sheath into the iliac and/or carotid arteries of 23 anaesthetised Yucatan mini swine. The animals were euthanised at three, 30, 90 and 180 days and their brains were removed for histological analysis. In an additional single control animal, the guiding sheath was advanced but no SDS was deployed. Advancement of the coated guiding sheath with or without the SDS was associated with frequent foreign material in the arterioles of the brain. The embolic material was amorphous, non-refractile, non-crystalline, non-birefringent and typically lightly basophilic with a slightly stippled appearance on haematoxylin and eosin (H&E) stain. Material was observed at all time points involving 54% of all study animals (i.e., test and control) and in vitro after incubation in 0.9% saline.The hydrophilic coating on a clinically used guiding sheath readily avulses and embolises to the brain during deployment in a porcine model. Further documentation of this effect and monitoring in clinical scenarios are warranted.


PubMed | Midwest Cardiovascular Research Foundation, Boston Scientific Inc. and CBSET Inc
Type: Journal Article | Journal: Journal of endovascular therapy : an official journal of the International Society of Endovascular Specialists | Year: 2015

To determine the number of runs with blades up (BU) using the JetStream Navitus to achieving optimal debulking in a porcine model of femoropopliteal artery in-stent restenosis (ISR).In this porcine model, 8 limbs were implanted with overlapping nitinol self-expanding stents. ISR was treated initially with 2 blades-down (BD) runs followed by 4 BU runs (BU1 to BU4). Quantitative vascular angiography (QVA) was performed at baseline, after 2 BD runs, and after each BU run. Plaque surface area and percent stenosis within the treated stented segment were measured. Intravascular ultrasound (IVUS) was used to measure minimum lumen area (MLA) and determine IVUS-derived plaque surface area.QVA showed that plaque surface area was significantly reduced between baseline (83.9%14.8%) and 2 BD (67.7%17.0%, p=0.005) and BU1 (55.4%9.0%, p=0.005) runs, and between BU1 and BU2 runs (50.7%9.7%, p<0.05). Percent stenosis behaved similarly with no further reduction after BU2. There were no further reductions in plaque surface area or percent stenosis with BU 3 and 4 runs (p=0.10). Similarly, IVUS (24 lesions) confirmed optimal results with BU2 runs and no additional gain in MLA or reduction in plaque surface area with BU3 and 4. IVUS confirmed no orbital cutting with JetStream Navitus. There were no stent strut discontinuities on high-resolution radiographs following atherectomy.JetStream Navitus achieved optimal tissue debulking after 2 BD and 2 BU runs with no further statistical gain in debulking after the BU2 run. Operators treating ISR with JetStream Navitus may be advised to limit their debulking to 2 BD and 2 BU runs to achieve optimal debulking.


PubMed | AO Research Institute Davos, CBSET Inc., Massachusetts Institute of Technology, IlluminOss Medical and 2 more.
Type: Journal Article | Journal: Journal of biomedical materials research. Part B, Applied biomaterials | Year: 2016

Percutaneous intramedullary fixation may provide an ideal method for stabilization of bone fractures, while avoiding the need for large tissue dissections. Tibiae in 18 sheep were treated with an intramedullary photodynamic bone stabilization system (PBSS) that comprised a polyethylene terephthalate (Dacron) balloon filled with a monomer, cured with visible light in situ, and then harvested at 30, 90, or 180 days. In additional 40 sheep, a midshaft tibial osteotomy was performed and stabilized with external fixators or external fixators combined with the PBSS and evaluated at 8, 12, and 26 weeks. Healing and biocompatibility were evaluated by radiographic analysis, micro-computed tomography, and histopathology. In nonfractured sheep tibiae, PBSS implants conformably filled the medullary canal, while active cortical bone remodeling and apposition of new periosteal and/or endosteal bone was observed with no significant macroscopic or microscopic observations. Fractured sheep tibiae exhibited increased bone formation inside the osteotomy gap, with no significant difference when fixation was augmented by PBSS implants. Periosteal callus size gradually decreased over time and was similar in both treatment groups. No inhibition of endosteal bone remodeling or vascularization was observed with PBSS implants. Intramedullary application of a light-curable PBSS is a biocompatible, feasible method for fracture fixation.


PubMed | CVPath Institute Inc. and CBSET Inc.
Type: Journal Article | Journal: JACC. Cardiovascular interventions | Year: 2014

Transcatheter ablation of renal autonomic nerves is a viable option for the treatment of resistant arterial hypertension; however, structured pre-clinical evaluation with standardization of analytical procedures remains a clear gap in this field. Here we discuss the topics relevant to the pre-clinical model for the evaluation of renal denervation (RDN) devices and report methodologies and criteria toward standardization of the safety and efficacy assessment, including histopathological evaluations of the renal artery, periarterial nerves, and associated periadventitial tissues. The pre-clinical swine renal artery model can be used effectively to assess both the safety and efficacy of RDN technologies. Assessment of the efficacy of RDN modalities primarily focuses on the determination of the depth of penetration of treatment-related injury (e.g., necrosis) of the periarterial tissues and its relationship (i.e., location and distance) and the effect on the associated renal nerves and the correlation thereof with proxy biomarkers including renal norepinephrine concentrations and nerve-specific immunohistochemical stains (e.g., tyrosine hydroxylase). The safety evaluation of RDN technologies involves assessing for adverse effects on tissues local to the site of treatment (i.e., on the arterial wall) as well as tissues at a distance (e.g., soft tissue, veins, arterial branches, skeletal muscle, adrenal gland, ureters). Increasing experience will help to create a standardized means of examining all arterial beds subject to ablative energy and in doing so enable ustoproceed to optimize the development and assessment of these emerging technologies.


PubMed | University of Washington, CBSET Inc, The Forsyth Institute, Harvard University and 2 more.
Type: Journal Article | Journal: PLoS genetics | Year: 2015

Mutations in sorting nexin 10 (Snx10) have recently been found to account for roughly 4% of all human malignant osteopetrosis, some of them fatal. To study the disease pathogenesis, we investigated the expression of Snx10 and created mouse models in which Snx10 was knocked down globally or knocked out in osteoclasts. Endocytosis is severely defective in Snx10-deficient osteoclasts, as is extracellular acidification, ruffled border formation, and bone resorption. We also discovered that Snx10 is highly expressed in stomach epithelium, with mutations leading to high stomach pH and low calcium solubilization. Global Snx10-deficiency in mice results in a combined phenotype: osteopetrosis (due to osteoclast defect) and rickets (due to high stomach pH and low calcium availability, resulting in impaired bone mineralization). Osteopetrorickets, the paradoxical association of insufficient mineralization in the context of a positive total body calcium balance, is thought to occur due to the inability of the osteoclasts to maintain normal calcium-phosphorus homeostasis. However, osteoclast-specific Snx10 knockout had no effect on calcium balance, and therefore led to severe osteopetrosis without rickets. Moreover, supplementation with calcium gluconate rescued mice from the rachitic phenotype and dramatically extended life span in global Snx10-deficient mice, suggesting that this may be a life-saving component of the clinical approach to Snx10-dependent human osteopetrosis that has previously gone unrecognized. We conclude that tissue-specific effects of Snx10 mutation need to be considered in clinical approaches to this disease entity. Reliance solely on hematopoietic stem cell transplantation can leave hypocalcemia uncorrected with sometimes fatal consequences. These studies established an essential role for Snx10 in bone homeostasis and underscore the importance of gastric acidification in calcium uptake.

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