scholarly journals Marker for the pre-clinical development of bone substitute materials

2017 ◽  
Vol 3 (2) ◽  
pp. 711-715
Author(s):  
Michael de Wild ◽  
Simon Zimmermann ◽  
Marcel Obrecht ◽  
Michel Dard
Keyword(s):  
Bone Graft ◽  
Mechanical Stability ◽  
Clinical Performance ◽  
Ex Vivo ◽  
Region Of Interest ◽  
Defect Site ◽  
Novel Approach ◽  
Bone Substitute Materials ◽  
Clinical Experiments

AbstractThin mechanically stable Ti-cages have been developed for the in-vivo application as X-ray and histology markers for the optimized evaluation of pre-clinical performance of bone graft materials. A metallic frame defines the region of interest during histological investigations and supports the identification of the defect site. This standardization of the procedure enhances the quality of pre-clinical experiments. Different models of thin metallic frameworks were designed and produced out of titanium by additive manufacturing (Selective Laser Melting). The productibility, the mechanical stability, the handling and suitability of several frame geometries were tested during surgery in artificial and in ex-vivo bone before a series of cages was preclinically investigated in the female Göttingen minipigs model. With our novel approach, a flexible process was established that can be adapted to the requirements of any specific animal model and bone graft testing.

scholarly journals Development and Evaluation of Alginate Membranes with Curcumin-Loaded Nanoparticles for Potential Wound-Healing Applications

Pharmaceutics ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 389 ◽  
Author(s):  
Mónica C. Guadarrama-Acevedo ◽  
Raisa A. Mendoza-Flores ◽  
María L. Del Prado-Audelo ◽  
Zaida Urbán-Morlán ◽  
David M. Giraldo-Gomez ◽  
...  
Keyword(s):  
Wound Healing ◽  
Wound Dressing ◽  
Clinical Performance ◽  
Ex Vivo ◽  
High Capacity ◽  
Wound Dressings ◽  
In Vivo Studies ◽  
Potential Use

Non-biodegradable materials with a low swelling capacity and which are opaque and occlusive are the main problems associated with the clinical performance of some commercially available wound dressings. In this work, a novel biodegradable wound dressing was developed by means of alginate membrane and polycaprolactone nanoparticles loaded with curcumin for potential use in wound healing. Curcumin was employed as a model drug due to its important properties in wound healing, including antimicrobial, antifungal, and anti-inflammatory effects. To determine the potential use of wound dressing, in vitro, ex vivo, and in vivo studies were carried out. The novel membrane exhibited the diverse functional characteristics required to perform as a substitute for synthetic skin, such as a high capacity for swelling and adherence to the skin, evidence of pores to regulate the loss of transepidermal water, transparency for monitoring the wound, and drug-controlled release by the incorporation of nanoparticles. The incorporation of the nanocarriers aids the drug in permeating into different skin layers, solving the solubility problems of curcumin. The clinical application of this system would cover extensive areas of mixed first- and second-degree wounds, without the need for removal, thus decreasing the patient’s discomfort and the risk of altering the formation of the new epithelium.

“The Balloon Plug Concept” for Tricuspid Valve Repair Ex Vivo Proof of Concept

2015 ◽  
Vol 10 (1) ◽  
pp. 27-32 ◽  
Author(s):  
Pietro Bajona ◽  
Stefano Salizzoni ◽  
Stijn Vandenberghe ◽  
Charles J. Bruce ◽  
Giovanni Speziali ◽  
...  
Keyword(s):  
Tricuspid Regurgitation ◽  
Ex Vivo ◽  
Tricuspid Valve Repair ◽  
Functional Tricuspid Regurgitation ◽  
Novel Approach ◽  
Annular Dilatation ◽  
Transvalvular Gradient ◽  
Antegrade Flow ◽  
The Right

Objective Functional tricuspid regurgitation (TR) is recognized as a significant cause of morbidity and mortality in cardiothoracic surgery. We hypothesized that a variably expandable, transvalvular balloon mounted on a catheter could be percutaneously inserted and fixed to the right ventricle apex. This novel approach could provide a minimally invasive way to eliminate clinically relevant TR caused by annular dilatation. This study was performed to test the ex vivo hemodynamic effects and the feasibility of the “balloon plug concept.” Methods Twenty harvested calf tricuspid valves were placed in a mechanical simulator. Tricuspid regurgitation was created by annular stretching and displacement of the papillary muscles so as to create central TR. A flexible catheter with a 4-cm–long, soft, fusiform balloon was positioned across the valve so that the balloon was suspended centrally across the valve annular plane. After activating the mechanical ventricle, data were collected with balloon inflation volumes of saline from 5 to 20 mL. Transvalvular pressure gradients and leaflet mechanics were evaluated with incremental inflation. Results In all cases, 5-mL inflation did not significantly reduce TR and 20-mL inflation caused obstruction to antegrade flow (mean transvalvular gradient > 4 mm Hg). Inflation between 10 and 15 mL caused significant reduction in TR with acceptable transvalvular gradients (<3 mm Hg). Conclusions The balloon plug concept showed promising ex vivo hemodynamic results. In vivo investigations are warranted to evaluate percutaneous techniques, thrombogenicity, and effects of repeated balloon-leaflet contact on valve integrity.

scholarly journals Rational cotargeting of HDAC6 and BET proteins yields synergistic antimyeloma activity

2019 ◽  
Vol 3 (8) ◽  
pp. 1318-1329 ◽  
Author(s):  
Jennifer S. Carew ◽  
Claudia M. Espitia ◽  
Weiguo Zhao ◽  
Valeria Visconte ◽  
Faiz Anwer ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Family Members ◽  
Apoptosis Induction ◽  
Histone Deacetylase 6 ◽  
Novel Approach ◽  
Bet Inhibitors ◽  
Hdac6 Inhibitor ◽  
Bet Protein

Abstract Inhibition of bromodomain and extra terminal (BET) protein family members, including BRD4, decreases the expression of c-MYC and other key oncogenic factors and also significantly induces histone deacetylase 6 (HDAC6) expression. On the basis of the role of HDAC6 in malignant pathogenesis, we hypothesized that rational cotargeting of HDAC6 and BET family proteins may represent a novel approach that yields synergistic antimyeloma activity. We used genetic and pharmacologic approaches to selectively impair HDAC6 and BET function and evaluated the consequential impact on myeloma pathogenesis. These studies identified HDAC6 upregulation as an efficacy reducing mechanism for BET inhibitors because antagonizing HDAC6 activity synergistically enhanced the activity of JQ1 in a panel of multiple myeloma (MM) cell lines and primary CD138+ cells obtained from patients with MM. The synergy of this therapeutic combination was linked to significant reductions in c-MYC expression and increases in apoptosis induction. Administration of the clinical HDAC6 inhibitor ricolinostat was very well tolerated and significantly augmented the in vivo antimyeloma activity of JQ1. Ex vivo pharmacodynamic analyses demonstrated that the combination of JQ1 and ricolinostat led to significantly lower MM cell proliferation and increased apoptosis and diminished expression of c-MYC and BCL-2. These data demonstrate that cotargeting of HDAC6 and BET family members is a novel and clinically actionable approach to augment the efficacy of both classes of agents that warrants further investigation.

scholarly journals Drug discovery for psychiatric disorders using high-content single-cell screening of signaling network responses ex vivo

2019 ◽  
Vol 5 (5) ◽  
pp. eaau9093 ◽  
Author(s):  
Santiago G. Lago ◽  
Jakub Tomasik ◽  
Geertje F. van Rees ◽  
Hannah Steeb ◽  
David A. Cox ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Single Cell ◽  
Drug Targets ◽  
Ex Vivo ◽  
Signaling Network ◽  
Antipsychotic Treatment ◽  
Channel Blockers ◽  
Functional Responses ◽  
Novel Approach

There is a paucity of efficacious new compounds to treat neuropsychiatric disorders. We present a novel approach to neuropsychiatric drug discovery based on high-content characterization of druggable signaling network responses at the single-cell level in patient-derived lymphocytes ex vivo. Primary T lymphocytes showed functional responses encompassing neuropsychiatric medications and central nervous system ligands at established (e.g., GSK-3β) and emerging (e.g., CrkL) drug targets. Clinical application of the platform to schizophrenia patients over the course of antipsychotic treatment revealed therapeutic targets within the phospholipase Cγ1–calcium signaling pathway. Compound library screening against the target phenotype identified subsets of L-type calcium channel blockers and corticosteroids as novel therapeutically relevant drug classes with corresponding activity in neuronal cells. The screening results were validated by predicting in vivo efficacy in an independent schizophrenia cohort. The approach has the potential to discern new drug targets and accelerate drug discovery and personalized medicine for neuropsychiatric conditions.

Abstract 381: Ex vivo Heart Function Analysis in Adult Zebrafish

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Alexey V Dvornikov ◽  
Hong Zhang ◽  
Xiaolei Xu
Keyword(s):  
Ex Vivo ◽  
Function Analysis ◽  
Heart Function ◽  
Heart Diseases ◽  
Genetic Modifiers ◽  
Adult Zebrafish ◽  
Inherited Cardiomyopathy ◽  
Novel Approach ◽  
Vertebrate Model

Zebrafish ( Danio rerio ) is an efficient vertebrate model of human cardiomyopathy which is amenable to the medium throughput screening approaches opening opportunities to search new genetic modifiers via mutagenesis screening and assessing compound-based therapies at larger scale. The advent of genome editing technology enables the generation of a panel of genetic models of cardiomyopathy with mutations in leading cardiomyopathy genes. However, one of the major bottlenecks for adult zebrafish as a cardiomyopathy model is the lack of appropriate cardiac functional assays. Due to small heart size, in vivo methods such as those based on echocardiography, are limited by their insufficient resolution. Here, we report the development of an ex vivo approach aimed to facilitate phenotyping in adult zebrafish. We show that our method is able to quantify parameters of pump function of the heart, including end-diastolic/systolic length/volumes, ejection and shortening fractions, and velocities of contraction/relaxation. We defined the basic parameters of these indices using different wild-type strains, age, and sex, and then demonstrated that our method can be useful in definition of progression of pathogenesis of both acquired (doxorubicin-injected) and inherited cardiomyopathy models. We conclude that our novel approach shall facilitate cardiac phenotyping in adult zebrafish models of heart diseases.

TTP889, a Novel Orally Active Partial Inhibitor of FIXa Inhibits Clotting in Two A/V Shunt Models without Prolonging Bleeding Times.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1886-1886 ◽  
Author(s):  
Robert Rothlein ◽  
Jane M. Shen ◽  
Najih Naser ◽  
Devi R. Gohimukkula ◽  
Thomas B. Caligan ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Anticoagulant Activity ◽  
Clot Formation ◽  
Once Daily ◽  
Post Surgery ◽  
Novel Approach ◽  
Clotting Cascade ◽  
Orally Active ◽  
Coagulation Pathway

Abstract Based on previous studies showing the efficacy of FactorIXa (FIXa) blockade using an active site-blocked form of this coagulation enzyme, we speculated that partial inhibition of the intrinsic coagulation pathway would offer a novel approach to attenuate intravascular clot formation without promoting untoward bleeding. Here we describe the anticoagulant activity of TTP889, a small molecule partial inhibitor of FIXa activity. TTP889 is orally absorbed with a PK profile that is conducive to once daily dosing. It is selective for FIXa in that it shows little to no activity against several other proteases in the clotting cascade including FXa, FXIa, FXIIa or FVIIa in a unique clotting assay. In vivo, TTP889 inhibited fibrin deposition in a rat arteriovenous (A/V) shunt model. In this model, vehicle treated rats had 104mg ± 43 of fibrin deposited on a silk thread after a 15 minute shunt while TTP889 treated rats had significantly less fibrin deposited (39mg ± 18 p=<0.001). Furthermore, TTP889 inhibited clotting in a porcine A/V shunt model where pressure across a hemodialysis filter that was shunting the carotid artery to the jugular vein was used as an indirect marker of clot formation. In this model, TTP889 at 0.3mg/kg performed as well as 150U/kg of heparin over the 90-minute shunt. Of additional importance, TTP889 has no effect on bleeding times as measured by APTT or ACT assays ex-vivo or by bleeding time and volume from incisions in the skin or spleen in vivo. Together, these data support that TTP889 is a selective partial inhibitor of FIXa activity that offers a novel approach to attenuate clot formation associated with intravascular clotting without promoting untoward bleeding. TTP 889 is currently in Phase II and is being evaluated for the prevention of DVT in hip fracture patients with treatment starting one week post surgery and continued for 3 weeks.

scholarly journals Pre-Clinical Evaluation of Biological Bone Substitute Materials for Application in Highly Loaded Skeletal Sites

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 883 ◽  
Author(s):  
Sónia de Lacerda Schickert ◽  
Jeroen J.J.P. van den Beucken ◽  
Sander C.G. Leeuwenburgh ◽  
John A. Jansen
Keyword(s):  
Animal Models ◽  
Bone Substitute ◽  
Mechanical Stability ◽  
Ex Vivo ◽  
Bone Defects ◽  
Comprehensive Overview ◽  
Bone Defect Healing ◽  
Bone Substitute Materials ◽  
Substitute Materials ◽  
Highly Loaded

The development of bone substitute materials (BSMs) intended for load-bearing bone defects is highly complicated, as biological and mechanical requirements are often contradictory. In recent years, biological BSMs have been developed which allow for a more efficient integration of the material with the surrounding osseous environment and, hence, a higher mechanical stability of the treated defect. However, while these materials are promising, they are still far from ideal. Consequently, extensive preclinical experimentation is still required. The current review provides a comprehensive overview of biomechanical considerations relevant for the design of biological BSMs. Further, the preclinical evaluation of biological BSMs intended for application in highly loaded skeletal sites is discussed. The selected animal models and implantation site should mimic the pathophysiology and biomechanical loading patterns of human bone as closely as possible. In general, sheep are among the most frequently selected animal models for the evaluation of biomaterials intended for highly loaded skeletal sites. Regarding the anatomical sites, segmental bone defects created in the limbs and spinal column are suggested as the most suitable. Furthermore, the outcome measurements used to assess biological BSMs for regeneration of defects in heavily loaded bone should be relevant and straightforward. The quantitative evaluation of bone defect healing through ex vivo biomechanical tests is a valuable addition to conventional in vivo tests, as it determines the functional efficacy of BSM-induced bone healing. Finally, we conclude that further standardization of preclinical studies is essential for reliable evaluation of biological BSMs in highly loaded skeletal sites.

scholarly journals An event-based paradigm for analyzing fluorescent astrocyte activity uncovers novel single-cell and population-level physiology

2018 ◽  
Author(s):  
Yizhi Wang ◽  
Nicole V. DelRosso ◽  
Trisha Vaidyanathan ◽  
Michael Reitman ◽  
Michelle K. Cahill ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Single Cells ◽  
Region Of Interest ◽  
Population Level ◽  
Analytical Framework ◽  
Model Organisms ◽  
Imaging Data ◽  
Fluorescent Indicators ◽  
Event Based

AbstractRecent work examining astrocytic physiology centers on fluorescence imaging approaches, due to development of sensitive fluorescent indicators and observation of spatiotemporally complex calcium and glutamate activity. However, the field remains hindered in fully characterizing these dynamics, both within single cells and at the population-level, because of the insufficiency of current region-of-interest-based approaches to describe activity that is often spatially unfixed, size-varying, and propagative. Here, we present a paradigm-shifting analytical framework that releases astrocyte biologists from ROI-based tools. Astrocyte Quantitative Analysis (AQuA) software enables users to take an event-based approach to accurately capture and quantify the irregular activity observed in astrocyte imaging datasets. We apply AQuA to a range of ex vivo and in vivo imaging data, and uncover previously undescribed physiological phenomena in each. Since AQuA is data-driven and based on machine learning principles, it can be applied across model organisms, fluorescent indicators, experimental modes, and imaging resolutions and speeds, enabling researchers to elucidate fundamental astrocyte physiology.

scholarly journals Potential Use of Eggshell as Bone Graft Compared with Bovine for Bone Defect: A Systematic Review Study

2021 ◽  
Vol 9 (F) ◽  
pp. 470-473
Author(s):  
Hanif Andhika Wardhana ◽  
Mujaddid Idulhaq ◽  
Rhyan Darma Saputra ◽  
Rieva Ermawan ◽  
Musa Fasa Roshada
Keyword(s):  
Systematic Review ◽  
Bone Graft ◽  
Bone Regeneration ◽  
Bone Defect ◽  
Clinical Performance ◽  
Bone Grafts ◽  
Bone Tissue Regeneration ◽  
In Vivo Studies ◽  
Bovine Bone

Background : The use of Bone Graft in the management of Bone Defect is a challenge in the world of orthopedics. Recently, eggshell containing hydroxyapatite has become a new hope in the use of an economical and efficient bone graft in the treatment of bone defects. The aim of this systematic review was to explore the available literature on the clinical performance of eggshells as bone grafts in guided bone regeneration. Method : Two databases (PubMed and Cochrane) were searched from January 2010 to September 2020. Clinical trials using eggshells as bone grafts were included in the review. Animal and in vivo studies were excluded from the review. Results : A total of 202 studies were taken, then screened and 15 studies finally included. Clinical and radiological evaluations show complete recovery after the procedure. Comparison with synthetic hydroxyapatite shows similar healing characteristics. Conclusion : Eggshell compared to bovine showed no difference in bone healing. Within the limitations of the included studies, eggshells can be used safely and efficiently in integrated bone regeneration procedures. Keywords: Bone tissue regeneration; eggshell; bovine; bone defect; bone graft  

scholarly journals Mueller Matrix-Based Approach for the Ex Vivo Detection of Riboflavin-Treated Transparent Biotissue

2021 ◽  
Vol 11 (23) ◽  
pp. 11515
Author(s):  
Lennart Jütte ◽  
Gaurav Sharma ◽  
Dierk Fricke ◽  
Maximilian Franke ◽  
Merve Wollweber ◽  
...  
Keyword(s):  
Mechanical Stability ◽  
Ex Vivo ◽  
Measurement Data ◽  
Mueller Matrix ◽  
Cross Linking ◽  
Sample Number ◽  
Non Invasive ◽  
Collagen Cross Linking ◽  
Corneal Collagen

Corneal collagen cross-linking is an established procedure for the treatment of certain eye diseases which is applied to enhance the mechanical stability of such biotissue without deteriorating its functionality. However, being transparent, the optical analysis of the outcome of such treatments is cumbersome and relies on relatively expensive experimental equipment. We aim to apply the Mueller matrix polarimetry for the detection of photo-induced collagen cross-linking in transparent biotissue after treatment with riboflavin and UV irradiation. A simple Mueller matrix polarimetry setup could provide a fast and non-invasive analysis of transparent media to sensitively detect small photo-induced cross-linking effects in biotissue. We demonstrated the current capabilities of the approach on non-planar porcine cornea samples ex vivo. We reported the distinction between untreated and riboflavin-treated samples. The differences observed were correlated with the variation of certain Mueller matrix elements and parameters derived from the decomposition. The measurement data show variation in the cross-linked and non-cross-linked samples, although the effect of the UV treatment on the riboflavin-treated samples was not at the same level of significance yet and needs further investigation. The Mueller matrix measurement represents a promising approach for the detection of the effects of corneal collagen cross-linking. Further studies with a larger sample number are required to validate this approach. In the future, this could enable the reliable and non-invasive detection of photo-induced effects in biotissue and open the possibility for in vivo application, e.g., in eye disease treatment or the detection of scar collagen development.

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