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.

Preliminary In Vivo Experimental Validation of SMA Based Bowel Extender for Short Bowel Syndrome

2009 ◽  
Author(s):  
Brent Utter ◽  
Diann Brei ◽  
Jonathan Luntz ◽  
Daniel Teitelbaum ◽  
Manabu Okawada ◽  
...  
Keyword(s):  
Wireless Communication ◽  
Short Bowel Syndrome ◽  
Medical Condition ◽  
Ex Vivo ◽  
Tensile Loading ◽  
Battery Life ◽  
Small Bowel Length ◽  
Short Bowel ◽  
Surgical Implantation

Short Bowel Syndrome is a serious medical condition caused by insufficient small bowel length resulting in significantly high rates of morbidity and mortality. The limited success of current therapies has prompted the investigation of a new treatment approach based on mechanotransduction — the process through which mechanical tensile loading on the bowel induces longitudinal growth. To enable clinically relevant mechanotransduction growth studies in large animals, such as pigs, a fully implantable and instrumented bowel extender device based on a Shape Memory Alloy (SMA) ratchet was developed and validated in benchtop and ex vivo tests. These devices, however, must also be validated against the unique in vivo environment which presents challenges such as sealing, battery life, surgical implantation, signal attenuation from tissue, and isolating the measurement of tensile loading on the bowel wall. This paper extends the earlier development work to in vivo validation experiments within live pigs. A brief summary of the bowel extender architecture and operation is provided along with earlier ex vivo results that established device limits for in vivo testing. The wireless communication rate was updated to extend battery life and new surgical implantation procedures and lengthening schemes were developed. Two bowel extenders were tested in in vivo experiments ranging from 2.5 to 4.5 days with data collected to validate the wireless communication, SMA ratcheting and load/displacement measurements, confirming that the bowel extender successfully operates in vivo. More importantly, the bowel extenders successfully induced significant growth, which is promising for future studies comparing different lengthening schemes for optimal growth and the development of a clinical device for treating short bowel syndrome in humans.

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.

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.

An Innovative Ex Vivo Vascular Bioreactor as Comprehensive Tool to Study the Behavior of Native Blood Vessels Under Physiologically Relevant Conditions

2019 ◽  
Vol 2 (4) ◽  
Author(s):  
Noemi Vanerio ◽  
Marco Stijnen ◽  
Bas A. J. M. de Mol ◽  
Linda M. Kock
Keyword(s):  
Shear Stress ◽  
Blood Vessels ◽  
Ultrasound Imaging ◽  
Ex Vivo ◽  
Biological Response ◽  
Vessel Diameter ◽  
Tissue Growth ◽  
In Vivo Models

Abstract Ex vivo systems represent important models to study vascular biology and to test medical devices, combining the advantages of in vitro and in vivo models such as controllability of parameters and the presence of biological response, respectively. The aim of this study was to develop a comprehensive ex vivo vascular bioreactor to long-term culture and study the behavior of native blood vessels under physiologically relevant conditions. The system was designed to allow for physiological mechanical loading in terms of pulsatile hemodynamics, shear stress, and longitudinal prestretch and ultrasound imaging for vessel diameter and morphology evaluation. In this first experience, porcine carotid arteries (n = 4) from slaughterhouse animals were cultured in the platform for 10 days at physiological temperature, CO2 and humidity using medium with blood-mimicking viscosity, components, and stability of composition. As expected, a significant increase in vessel diameter was observed during culture. Flow rate was adjusted according to diameter values to reproduce and maintain physiological shear stress, while pressure was kept physiological. Ultrasound imaging showed that the morphology and structure of cultured arteries were comparable to in vivo. Histological analyses showed preserved endothelium and extracellular matrix and neointimal tissue growth over 10 days of culture. In conclusion, we have developed a comprehensive pulsatile system in which a native blood vessel can be cultured under physiological conditions. The present model represents a significant step toward ex vivo testing of vascular therapies, devices, drug interaction, and as basis for further model developments.

Involvement of matrix metalloproteinases in the growth plate response to physiological mechanical load

2010 ◽  
Vol 108 (1) ◽  
pp. 172-180 ◽  
Author(s):  
Adi Reich ◽  
Stav Simsa Maziel ◽  
Ziv Ashkenazi ◽  
Efrat Monsonego Ornan
Keyword(s):  
Growth Plate ◽  
Mechanical Loading ◽  
Mechanical Load ◽  
Tissue Growth ◽  
Matrix Assembly ◽  
Growth Plates ◽  
Load Release ◽  
Catch Up

Enzymes from the matrix metalloproteinase (MMP) family play a crucial role in growth-plate vascularization and ossification via proteolytic cleavage and remodeling of the extracellular matrix. Their regulation in the growth plate is crucial for normal matrix assembly. Endochondral ossification, which takes place at the growth plates, is influenced by mechanical loading. Using an in vivo avian model for mechanical loading, we have found increased blood penetration into the growth plates of loaded chicks. The purpose of this work was to study the involvement of MMP-2, -3, -9, -13, and -16 in the growth plate's response to loading and in the catch-up growth resulting from load release. We found that mechanical loading, as well as release from load, upregulated MMP-2, -9, and -13 expressions. In contrast, MMP-3, associated with cartilage injuries, and its associated protein connective tissue growth factor (CTGF), were downregulated by the load. However, after release from load, MMP-3 was upregulated and CTGF levels were elevated and caught up with the control. MMP-3 and CTGF were also downregulated after 60 min of mechanical stretching in vitro. These results demonstrate the central role of MMPs in the growth plate's response to mechanical loading, as well as in the catch-up growth followed load release.

scholarly journals Tissue engineering for compensating short bowel syndrome

2018 ◽  
Vol 20 (2) ◽  
pp. 259-264
Author(s):  
A V Kosulin ◽  
L N Beldiman ◽  
S V Kromsky ◽  
A A Kokorina ◽  
E V Mikhailova ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Small Intestine ◽  
Short Bowel Syndrome ◽  
Mechanical Stability ◽  
Clinical Problem ◽  
Cell Types ◽  
Short Bowel ◽  
Wide Range

Short bowel syndrome is an important clinical problem characterized by a high incidence of serious complications, deaths and socioeconomic consequences. Parenteral nutrition provides only a temporary solution without reducing the risk of complications. This applies equally to surgical treatment, in particular to small intestine transplantation and related concomitant interventions, which only facilitate the adaptation of the intestine to new conditions. Potential approaches have been analyzed in the treatment of the syndrome of the small intestine, which can be offered by dynamically developing tissue engineering. Various types of carriers and cell types that are used in experiments for obtaining tissue engineering designs of the intestine are discussed. A wide range of variants of such constructions is analyzed that can lead to obtaining an organ prosthesis with a cellular organization and mechanical stability similar to those of the native small intestine, which will ensure the necessary biocompatibility. It is established that one of the optimal carriers for today are extracellular matrices obtained by decellularization of the native small intestine. This process allows to preserve the microarchitecture of the small intestine, which greatly facilitates the process of filling the matrix with cells both in vitro and in vivo. It has also been established that mesenchymal stromal multipotent cells and organoid units obtained from the tissue of the native small intestine are particularly prominent among the most promising participants in the cellular ensemble.

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.

scholarly journals Adult zebrafish intestine resection: a novel model of short bowel syndrome, adaptation, and intestinal stem cell regeneration

2015 ◽  
Vol 309 (3) ◽  
pp. G135-G145 ◽  
Author(s):  
K. A. Schall ◽  
K. A. Holoyda ◽  
C. N. Grant ◽  
D. E. Levin ◽  
E. R. Torres ◽  
...  
Keyword(s):  
Stem Cell ◽  
Short Bowel Syndrome ◽  
Intestinal Adaptation ◽  
Intestinal Stem Cell ◽  
Brdu Incorporation ◽  
In Vivo Model ◽  
In Vivo Models ◽  
Short Bowel ◽  
Intestinal Length

Loss of significant intestinal length from congenital anomaly or disease may lead to short bowel syndrome (SBS); intestinal failure may be partially offset by a gain in epithelial surface area, termed adaptation. Current in vivo models of SBS are costly and technically challenging. Operative times and survival rates have slowed extension to transgenic models. We created a new reproducible in vivo model of SBS in zebrafish, a tractable vertebrate model, to facilitate investigation of the mechanisms of intestinal adaptation. Proximal intestinal diversion at segment 1 (S1, equivalent to jejunum) was performed in adult male zebrafish. SBS fish emptied distal intestinal contents via stoma as in the human disease. After 2 wk, S1 was dilated compared with controls and villus ridges had increased complexity, contributing to greater villus epithelial perimeter. The number of intervillus pockets, the intestinal stem cell zone of the zebrafish increased and contained a higher number of bromodeoxyuridine (BrdU)-labeled cells after 2 wk of SBS. Egf receptor and a subset of its ligands, also drivers of adaptation, were upregulated in SBS fish. Igf has been reported as a driver of intestinal adaptation in other animal models, and SBS fish exposed to a pharmacological inhibitor of the Igf receptor failed to demonstrate signs of intestinal adaptation, such as increased inner epithelial perimeter and BrdU incorporation. We describe a technically feasible model of human SBS in the zebrafish, a faster and less expensive tool to investigate intestinal stem cell plasticity as well as the mechanisms that drive intestinal adaptation.

scholarly journals BNO 1095, a Standardized Dry Extract from the Fruits of Vitex agnus-castus, Impairs Angiogenesis-related Endothelial Cell Functions In Vitro

Planta Medica ◽  
2021 ◽  
Author(s):  
Iris Bischoff-Kont ◽  
Laura Brabenec ◽  
Rebecca Ingelfinger ◽  
Bernhard Nausch ◽  
Robert Fürst
Keyword(s):  
Endothelial Cell ◽  
Ex Vivo ◽  
Collagen Gel ◽  
Tissue Growth ◽  
Endothelial Cell Proliferation ◽  
Dry Extract ◽  
Cell Functions ◽  
Agnus Castus

AbstractBNO 1095, a standardized dry extract from the fruits of Vitex agnus-castus, represents an approved herbal medicinal product for the treatment of premenstrual syndrome. Angiogenesis, the formation of new blood vessels from pre-existing capillaries, plays a major role in physiological situations, such as wound healing or tissue growth in female reproductive organs, but it is also of great importance in pathophysiological conditions such as chronic inflammatory diseases or cancer. Angiogenesis is a highly regulated multi-step process consisting of distinct key events that can be influenced pharmacologically. Few studies suggested anti-angiogenic actions of V. agnus-castus fruit extracts in in vivo and ex vivo models. Here, we provide for the first time profound in vitro data on BNO 1095-derived anti-angiogenic effects focusing on distinct angiogenesis-related endothelial cell functions that are inevitable for the process of new blood vessel formation. We found that V. agnus-castus extract significantly attenuated undirected and chemotactic migration of primary human endothelial cells. Moreover, the extract efficiently inhibited endothelial cell proliferation and reduced the formation of tube-like structures on Matrigel. Of note, the treatment of endothelial cell spheroids almost blocked endothelial sprouting in a 3D collagen gel. Our data present new and detailed insights into the anti-angiogenic actions of BNO 1095 and, therefore, suggest a novel scope of potential therapeutic applications of the extract for which these anti-angiogenic properties are required.

scholarly journals Murine intrarectal instillation of purified recombinant C. difficile toxins enables mechanistic studies of pathogenesis

2020 ◽  
Author(s):  
Nicholas O. Markham ◽  
Sarah C. Bloch ◽  
John A. Shupe ◽  
Erin N. Laubacher ◽  
M. Kay Washington ◽  
...  
Keyword(s):  
Ex Vivo ◽  
The United States ◽  
Immunofluorescent Staining ◽  
Inflammatory Infiltration ◽  
Toxin B ◽  
Tissue Sections ◽  
Clostridioides Difficile ◽  
Hematoxylin And Eosin ◽  
Negative Controls

AbstractClostridioides difficile is linked to nearly 225,000 antibiotic-associated diarrheal infections and almost 13,000 deaths per year in the United States. Pathogenic strains of C. difficile produce toxin A (TcdA) and toxin B (TcdB), which can directly kill cells and induce an inflammatory response in the colonic mucosa. Hirota, et al. first introduced the intrarectal instillation model of intoxication using TcdA and TcdB purified from VPI 10463 and 630 C. difficile strains. Here, we expand this technique by instilling purified, recombinant TcdA and TcdB, which allows for the interrogation of how specifically mutated toxins affect tissue. Mouse colons were processed and stained with hematoxylin and eosin (H&E) for blinded evaluation and scoring by a board-certified gastrointestinal pathologist. The amount of TcdA or TcdB needed to produce damage was lower than previously reported in vivo and ex vivo. Furthermore, TcdB mutants lacking either endosomal pore-formation or glucosyltransferase activity resemble sham negative controls. Immunofluorescent staining revealed how TcdB initially damages colonic tissue by altering the epithelial architecture closest to the lumen. Tissue sections were also immunostained for markers of acute inflammatory infiltration. These staining patterns were compared with slides from a human C. difficile infection (CDI). The intrarectal instillation mouse model with purified recombinant TcdA and/or TcdB provides the flexibility needed to better understand structure/function relationships across different stages of CDI pathogenesis.

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