Characterizing the Ex-Vivo Mechanical Properties and Corresponding In-Vivo Impact of Synthetic Urogynecological Meshes

2011 ◽  
Author(s):  
Andrew J. Feola ◽  
Pamela Moalli ◽  
Suzan Stein ◽  
Zegbeh Jallah ◽  
Jon Shepherd ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Abdominal Wall Hernia ◽  
The United States ◽  
Pelvic Organ ◽  
Synthetic Mesh ◽  
Scientific Data ◽  
Societal Costs ◽  
Large Numbers

Pelvic organ prolapse and urinary incontinence are common conditions in women that significantly diminish quality of life. With roughly 225,000–280,000 women requiring surgery each year in the United States alone, societal costs are over a billion dollars annually (1). While repair with synthetic mesh products have become the surgical treatment of choice, these meshes require very little premarket testing because they are based on previously approved abdominal wall hernia products (510K devices). Thus, there is little scientific data on the efficacy of meshes for gynecological surgery. Moreover, with the recent FDA warning citing large numbers of unreported complications in patients, there is growing concern about the use of gynaecological mesh, especially for transvaginal placement (2). Thus, there is a need to examine the ex-vivo properties of these meshes and relate them to their in-vivo function and outcomes for gynecological applications.

Repurposing N,N-Dimethylacetamide (DMA), a Pharmaceutical Excipient, as a Prototype Novel Anti-inflammatory Agent for the Prevention and/or Treatment of Preterm Birth

2018 ◽  
Vol 24 (9) ◽  
pp. 989-992 ◽  
Author(s):  
Samir Gorasiya ◽  
Juliet Mushi ◽  
Ryan Pekson ◽  
Sabesan Yoganathan ◽  
Sandra E. Reznik
Keyword(s):  
Preterm Birth ◽  
Ex Vivo ◽  
The United States ◽  
Occurrence Rate ◽  
Pharmaceutical Excipient ◽  
Ongoing Work ◽  
Exciting Line ◽  
Pregnant Mice

Background: Preterm birth (PTB), or birth that occurs before 37 weeks of gestation, accounts for the majority of perinatal morbidity and mortality. As of 2016, PTB has an occurrence rate of 9.6% in the United States and accounts for up to 18 percent of births worldwide. Inflammation has been identified as the most common cause of PTB, but effective pharmacotherapy has yet to be developed to prevent inflammation driven PTB. Our group has discovered that N,N-dimethylacetamide (DMA), a readily available solvent commonly used as a pharmaceutical excipient, rescues lipopolysaccharide (LPS)-induced timed pregnant mice from PTB. Methods: We have used in vivo, ex vivo and in vitro approaches to investigate this compound further. Results: Interestingly, we found that DMA suppresses cytokine secretion by inhibiting nuclear factor-kappa B (NF-κB). In ongoing work in this exciting line of investigation, we are currently investigating structural analogs of DMA, some of them novel, to optimize this approach focused on the inflammation associated with PTB. Conclusion: Successful development of pharmacotherapy for the prevention of PTB rests upon the pursuit of multiple strategies to solve this important clinical challenge.

Animal Models and Alternatives in the Quality Control of Vaccines: Are In Vitro Methods or In Vivo Methods the Scientific Equivalent of the Emperor's New Clothes?

1995 ◽  
Vol 23 (1) ◽  
pp. 61-73
Author(s):  
Coenraad Hendriksen ◽  
Johan van der Gun
Keyword(s):  
Quality Control ◽  
Test Methods ◽  
In Vitro Test ◽  
Large Numbers ◽  
Alternative Approach ◽  
Inactivated Vaccines ◽  
Vitro Test

In the quality control of vaccine batches, the potency testing of inactivated vaccines is one of the areas requiring very large numbers of animals, which usually suffer significant distress as a result of the experimental procedures employed. This article deals with the potency testing of diphtheria and tetanus toxoids, two vaccines which are used extensively throughout the world. The relevance of the potency test prescribed by the European Pharmacopoeia monographs is questioned. The validity of the potency test as a model for the human response, the ability of the test to be standardised, and the relevance of the test in relation to the quality of the product are discussed. It is concluded that the potency test has only limited predictive value for the antitoxin responses to be expected in recipients of these toxoids. An alternative approach for estimating the potency of toxoid batches is discussed, in which a distinction is made between estimation of the immunogenic potency of the first few batches obtained from a seed lot and monitoring the consistency of the quality of subsequent batches. The use of animals is limited to the first few batches. Monitoring the consistency of the quality of subsequent batches is based on in vitro test methods. Factors which hamper the introduction and acceptance of the alternative approach are considered. Finally, proposals are made for replacement, reduction and/or refinement (the Three Rs) in the use of animals in the routine potency testing of toxoids.

scholarly journals Between biology and medicine: perspectives on the use of dendritic cells in anticancer therapy

2017 ◽  
Vol 71 (0) ◽  
pp. 0-0
Author(s):  
Agnieszka Szczygieł ◽  
Elżbieta Pajtasz-Piasecka
Keyword(s):  
Dendritic Cells ◽  
Ex Vivo ◽  
Anticancer Therapy ◽  
Point Of View ◽  
Proper Function ◽  
Innate And Adaptive Immunity ◽  
Factors Affecting ◽  
Antigen Presenting

Dendritic cells (DCs), as a link between innate and adaptive immunity, play a pivotal role in maintaining homeostasis of the immune system. The DC population is characterized by heterogeneity; it consists of many subpopulations which, despite their phenotypic and localization differences, play an essential function – they are professional antigen presenting cells. Due to their role, DCs can be utilized in a new cancer treatment strategy. Their main purpose is to generate an anticancer response leading to the elimination of cancer cells. The tumor microenvironment, abundant in immunosuppressive factors (e.g. IL-10, TGF-β, Arg1, IDO), impairs the proper function of DCs. For this reason, various strategies are necessary for ex vivo preparation of DC-based vaccines and for the support of in vivo DCs to fight against tumors. DC-based vaccines are combined with other forms of immunotherapy (e.g. blockade of immune checkpoint molecules, e.g. PD-1 or CTLA-4) or conventional types of therapies (e.g. chemotherapy). Despite the enormous progress that has been made in anticancer therapy in the past two decades, there are still many unresolved issues regarding the effectiveness of the DCs usage. In this paper we described, in both a mouse and a human subject, a series of DC subpopulations, differentiating in normal conditions or under the influence of cancer microenvironment. We listed factors affecting the quality of the in vivo and ex vivo generations of antitumoral responses, significant from a therapeutic point of view. Moreover, the most important strategies for the use of DCs in anticancer therapies, as well as further developments on this field, have been discussed.

scholarly journals Development and Optimization of a Fluorescent Imaging System to Detect Amyloid-β Proteins: Phantom Study

2018 ◽  
Vol 9 ◽  
pp. 117959721878108 ◽  
Author(s):  
David Tes ◽  
Karl Kratkiewicz ◽  
Ahmed Aber ◽  
Luke Horton ◽  
Mohsin Zafar ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Imaging System ◽  
Ex Vivo ◽  
Amyloid Β ◽  
The United States ◽  
Fluorescent Imaging ◽  
Fluorescent Properties ◽  
In Vivo Experiments ◽  
The Brain

Alzheimer disease is the most common form of dementia, affecting more than 5 million people in the United States. During the progression of Alzheimer disease, a particular protein begins to accumulate in the brain and also in extensions of the brain, ie, the retina. This protein, amyloid-β (Aβ), exhibits fluorescent properties. The purpose of this research article is to explore the implications of designing a fluorescent imaging system able to detect Aβ proteins in the retina. We designed and implemented a fluorescent imaging system with a range of applications that can be reconfigured on a fluorophore to fluorophore basis and tested its feasibility and capabilities using Cy5 and CRANAD-2 imaging probes. The results indicate a promising potential for the imaging system to be used to study the Aβ biomarker. A performance evaluation involving ex vivo and in vivo experiments is planned for future study.

Contract Clinical Research: A Rapidly Changing Marketplace

1996 ◽  
Vol 9 (6) ◽  
pp. 406-415
Author(s):  
Daniel Krichbaum ◽  
Alan Rosenthal
Keyword(s):  
Clinical Research ◽  
The United States ◽  
Considerable Change ◽  
Business Strategies ◽  
Quality Data ◽  
Scientific Integrity ◽  
Research Activities ◽  
Large Numbers ◽  
Research Organizations

Drug development in the United States has undergone considerable change over the past decade. The outsourcing of clinical research activities to Contract Research Organizations (CROs) continues to escalate in an attempt to speed drugs to market faster. The increasing use of business strategies at the investigational site level has fostered the emergence of specialty networks and Site Management Organizations (SMOs). SMOs offer pharmaceutical and biotechnology sponsors the ability to work with a tightly managed network of experienced professional multispecialty research centers that can enroll large numbers of patients and provide high quality data. While these organizations have fundamentally changed the way drugs are developed, they have also contributed to an acceleration of the process and an improvement in the scientific integrity and quality of the data.

The Impact of Mesh Implantation on Vaginal Smooth Muscle Innervation and Contraction

2013 ◽  
Author(s):  
Zegbeh C. Jallah ◽  
Pamela Moalli ◽  
Andrew Feola ◽  
William Barone ◽  
Stacy Palcsey ◽  
...  
Keyword(s):  
Structural Integrity ◽  
Surgical Repair ◽  
The United States ◽  
Pelvic Organ ◽  
Muscle Innervation ◽  
Vaginal Canal ◽  
The Cost ◽  
Vaginal Smooth Muscle ◽  
The Impact

Pelvic organ prolapse (POP) is a multifactorial disorder characterized by the descent of the pelvic organs into the vaginal canal. This disorder is associated with decreased quality of life, and even depression, yet 50% of women over the age of fifty are living with POP. The cost associated with the repair of POP exceeds one billion dollars annually, in the United States alone. This rather exorbitant figure includes the cost of surgery performed for symptom management, but does not include strategies which address the underlying cause of the disorder for which there are none. Because failure rates of native tissue repairs are as high as 30%, vaginal mesh is increasingly used in the surgical repair of POP. The procedure aims to reinforce the fibromuscular layer of the vagina and the paravaginal attachments, thus providing structural integrity to the weakened native tissues. However, the use of mesh is limited by mesh-related complications including exposure, erosion, pain contraction and infection.

Ex-Vivo Expansion of Multipotent CD133+ Stem Cells with VEGF, FLT3l and SCGF.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4147-4147
Author(s):  
Sonja Loges ◽  
Martin Butzal ◽  
Uta Fischer ◽  
Ursula M. Gehling ◽  
Dieter K. Hossfeld ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Stem Cell ◽  
Culture System ◽  
Ex Vivo ◽  
Ex Vivo Expansion ◽  
Facs Analysis ◽  
Hematopoietic Stem ◽  
Large Numbers

Abstract The rare CD133+ stem cell population contains both hematopoietic and endothelial progenitors. Successful ex-vivo expansion of this multipotent population would therefore be of great benefit in many clinical settings including stem cell transplantation and gene therapy. We developed a cell culture system containing the recombinant human cytokines vascular endothelial growth factor (VEGF), FLT3 ligand (FLT3L) and stem cell growth factor (SCGF) for ex-vivo expansion of purified human CD133+ stem cells obtained from leukapheresis products from patients pre-treated with G-CSF. FACS analysis, colony assays and NOD-SCID transplantation studies were performed to monitor stem cell and endothelial phenotype in-vitro and in-vivo. Cultivation with VEGF, FLT3L and SCGF induced a mean 2200-fold increase of total cell counts in 5 weeks. FACS analysis revealed persistence of 6–15% CD133+ stem cells indicating proliferation and survival of primitive hematopoietic stem cells. 5–6% of the proliferating cells expressed the endothelial markers CD144 (VE-Cadherin) and von-Willebrand factor (vWF). Ex-vivo expanded stem cells could be differentiated into adherent endothelial cells after withdrawal of SCGF and FLT3L allowing generation of large numbers of endothelial cells. Colony-assays showed an increase of hematopoietic and endothelial colonies after 5 weeks of ex-vivo expansion indicating simultaneous proliferation of hematopoietic and endothelial precursors under the established culture conditions (CFU-E 60-fold, CFU-GEMM 48-fold, CFU-GM 59-fold, CFU-G 99-fold, CFU-M 1356-fold and CFU-EC 1843-fold). To assess in-vivo functionality, hematopoietic stem cells expanded ex-vivo for 7, 14, 21 and 32 days were transplanted into sublethally irradiated NOD-SCID mice. For each expansion period, the mean percentage of anti-human CD45 positive bone marrow cells 3 months post-transplantation was 11, 3, 3 and 1%, respectively. Human CD45+ cells for each set of experiments contained a mean of 15, 26, 8 and 32% T-cells (CD3+), 9, 0, 7 and 21% B-cells (CD19+), 24, 2, 2 and 11% monocytes (CD14+), 21, 3, 1 and 12% granulocytes (CD33+) and 19, 37, 44 and 24% stem cells (CD34+) (d7 (n=5), d14 (n=4), d21 (n=7) and d32 (n=6) respectively). Our experiments showed multilineage engraftment of human stem cells expanded for more than 4 weeks ex-vivo. Therefore our culture system provides a tool to generate large numbers of human stem and endothelial cells for clinical purposes.

scholarly journals TAT-μUtrophin mitigates the pathophysiology of dystrophin and utrophin double-knockout mice

2011 ◽  
Vol 111 (1) ◽  
pp. 200-205 ◽  
Author(s):  
Jarrod A. Call ◽  
James M. Ervasti ◽  
Dawn A. Lowe
Keyword(s):  
Knockout Mice ◽  
Skeletal Muscles ◽  
Ex Vivo ◽  
Eccentric Contraction ◽  
Mdx Mice ◽  
Double Knockout ◽  
Replacement Treatment ◽  
Generating Capacity

Previously, we demonstrated functional substitution of dystrophin by TAT-μUtrophin (TAT-μUtr) in dystrophin-deficient mdx mice. Herein, we addressed whether TAT-μUtr could improve the phenotype of dystrophin and utrophin double-knockout ( mdx:utr−/−) mice. Specifically, we quantitatively compared survival and quality of life assessments in mdx:utr−/− mice receiving TAT-μUtr protein administration against placebo-treated mdx:utr−/− mice (PBS). Additionally, skeletal muscles from TAT-μUtr and PBS mice were tested in vivo and ex vivo for strength and susceptibility to eccentric contraction-induced injury. We found the TAT-μUtr treatment extended life span 45% compared with mice administered PBS. This was attributed to significantly increased food consumption (3.1 vs. 1.8 g/24 h) due to improved ability to search for food as daily cage activities were greater in TAT-μUtr mice (e.g., 364 vs. 201 m ambulation/24 h). The extensor digitorum longus muscles of TAT-μUtr-treated double-knockout mice also displayed increased force-generating capacity ex vivo (8.3 vs. 6.4 N/cm2) and decreased susceptibility to injury ex vivo and in vivo. These data indicate that the functional benefits of TAT-μUtr replacement treatment extend to the mdx:utr−/− double-knockout mouse and support its development as a therapy to mitigate muscle weakness in patients with Duchenne muscular dystrophy.

scholarly journals Fluid Structural Analysis of Urine Flow in a Stented Ureter

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
J. Carlos Gómez-Blanco ◽  
F. Javier Martínez-Reina ◽  
Domingo Cruz ◽  
J. Blas Pagador ◽  
Francisco M. Sánchez-Margallo ◽  
...  
Keyword(s):  
Computational Models ◽  
Mechanical Characterization ◽  
Ex Vivo ◽  
Biological Tissues ◽  
Urine Flow ◽  
Computational Environment ◽  
Computational Fluid Dynamics Cfd

Many urologists are currently studying new designs of ureteral stents to improve the quality of their operations and the subsequent recovery of the patient. In order to help during this design process, many computational models have been developed to simulate the behaviour of different biological tissues and provide a realistic computational environment to evaluate the stents. However, due to the high complexity of the involved tissues, they usually introduce simplifications to make these models less computationally demanding. In this study, the interaction between urine flow and a double-J stented ureter with a simplified geometry has been analysed. The Fluid-Structure Interaction (FSI) of urine and the ureteral wall was studied using three models for the solid domain: Mooney-Rivlin, Yeoh, and Ogden. The ureter was assumed to be quasi-incompressible and isotropic. Data obtained in previous studies from ex vivo and in vivo mechanical characterization of different ureters were used to fit the mentioned models. The results show that the interaction between the stented ureter and urine is negligible. Therefore, we can conclude that this type of models does not need to include the FSI and could be solved quite accurately assuming that the ureter is a rigid body and, thus, using the more simple Computational Fluid Dynamics (CFD) approach.

Design of an SMA Actuated Mechanotransductive Implant for Correcting Short Bowel Syndrome

2010 ◽  
Author(s):  
Brent Utter ◽  
Brian Barnes ◽  
Jonathan Luntz ◽  
Diann Brei ◽  
Daniel H. Teitelbaum ◽  
...  
Keyword(s):  
Short Bowel Syndrome ◽  
Mechanical Load ◽  
Medical Condition ◽  
Ex Vivo ◽  
The United States ◽  
Tissue Growth ◽  
Force Model ◽  
Short Bowel ◽  
Unique Shape

Short bowel syndrome is a serious medical condition afflicting an estimated 20,000 to 200,000 people in the United States with mortality rates as high as 40%, despite current treatments. Recent research on mechanotransduction, the process through which mechanical load induces tissue growth, has successfully demonstrated permanent growth of healthy, functional bowel in small animals. Unfortunately, the underlying technological approaches limit further research of growth under different load profiles and extension to safe clinical devices. This paper presents a fully implantable bowel extender which expands via a unique Shape Memory Alloy (SMA) driven ratcheting mechanism, measures the bowel tension and load, and enables studies of mechanotransductive bowel tissue growth where the displacement or load may be controlled wirelessly in real-time. The architecture and operation of the bowel extender is illustrated, focusing on the SMA driven ratcheting mechanism that incrementally expands the device. To help visualize the SMA wire and reset spring design, an alternative graphical method is outlined which transforms the SMA material curves into a Reset View based on predictions of the system forces. An analytical model predicts the ratchet mechanism force with tooth and pawl geometry selected based on packaging, load-bearing, and kinematic constraints. Force limits to maintain tissue health are established from ex vivo and in vivo porcine small bowel loading experiments. The Reset View methodology is applied to design a bowel extender prototype which is used to experimentally validate the ratchet force model. The functionality device is demonstrated, operating against loads much larger than specified, validating the device’s ability to enable new studies of mechanotransductive bowel growth in pigs.

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