Development of a System for Application of Dynamic Mechanical Compression on Intervertebral Discs in Organ Culture and Investigation of Load Magnitude Effects

2007 ◽  
Author(s):  
Casey L. Korecki ◽  
Jeffrey J. MacLean ◽  
James C. Iatridis
Keyword(s):  
Organ Culture ◽  
Intervertebral Discs ◽  
Small Sample ◽  
In Vivo Studies ◽  
Large Animal Model ◽  
Large Animal ◽  
In Vivo Models ◽  
Compression Loading ◽  
Dynamic Mechanical

In vivo studies on the intervertebral disc (IVD) indicate that the magnitude, frequency, and duration of applied compression loading results in alterations in mRNA expression, composition, and annulus fibrosus structure [1]. In vivo models typically use small animal models or small sample sizes that make it difficult to evaluate multiple dependent variables on the same tissue. In this study, it was considered a priority to utilize a large animal model to investigate the effects of magnitude of compression loading on interacting dependent variable measurements of disc cell viability, biosynthesis, composition, structure, and biomechanics. A bovine IVD organ culture system was used because it provides control over mechanical and chemical boundary conditions while maintaining viable cells and normal cell-matrix interactions. To date, there are no studies investigating the response of the IVD in organ culture to dynamic mechanical loading.

scholarly journals Reversal of renal dysfunction by targeted administration of VEGF into the stenotic kidney: a novel potential therapeutic approach

2012 ◽  
Vol 302 (10) ◽  
pp. F1342-F1350 ◽  
Author(s):  
Alejandro R. Chade ◽  
Silvia Kelsen
Keyword(s):  
Renal Dysfunction ◽  
Renal Injury ◽  
Renal Scarring ◽  
In Vivo Studies ◽  
Large Animal Model ◽  
Therapeutic Effects ◽  
Large Animal ◽  
Targeted Intervention ◽  
High Level

Renal microvascular (MV) damage and loss contribute to the progression of renal injury in renovascular disease (RVD). Whether a targeted intervention in renal microcirculation could reverse renal damage is unknown. We hypothesized that intrarenal vascular endothelial growth factor (VEGF) therapy will reverse renal dysfunction and decrease renal injury in experimental RVD. Unilateral renal artery stenosis (RAS) was induced in 14 pigs, as a surrogate of chronic RVD. Six weeks later, renal blood flow (RBF) and glomerular filtration rate (GFR) were quantified in vivo in the stenotic kidney using multidetector computed tomography (CT). Then, intrarenal rhVEGF-165 or vehicle was randomly administered into the stenotic kidneys ( n = 7/group), they were observed for 4 additional wk, in vivo studies were repeated, and then renal MV density was quantified by 3D micro-CT, and expression of angiogenic factors and fibrosis was determined. RBF and GFR, MV density, and renal expression of VEGF and downstream mediators such as p-ERK 1/2, Akt, and eNOS were significantly reduced after 6 and at 10 wk of untreated RAS compared with normal controls. Remarkably, administration of VEGF at 6 wk normalized RBF (from 393.6 ± 50.3 to 607.0 ± 45.33 ml/min, P < 0.05 vs. RAS) and GFR (from 43.4 ± 3.4 to 66.6 ± 10.3 ml/min, P < 0.05 vs. RAS) at 10 wk, accompanied by increased angiogenic signaling, augmented renal MV density, and attenuated renal scarring. This study shows promising therapeutic effects of a targeted renal intervention, using an established clinically relevant large-animal model of chronic RAS. It also implies that disruption of renal MV integrity and function plays a pivotal role in the progression of renal injury in the stenotic kidney. Furthermore, it shows a high level of plasticity of renal microvessels to a single-dose VEGF-targeted intervention after established renal injury, supporting promising renoprotective effects of a novel potential therapeutic intervention to treat chronic RVD.

Asymmetric Loading Promotes Early Signs of Intervertebral Disc Degeneration in Large Animal Organ Culture

2009 ◽  
Author(s):  
Casey L. Korecki ◽  
Benjamin A. Walter ◽  
Karolyn E. Godburn ◽  
James C. Iatridis
Keyword(s):  
Animal Models ◽  
Intervertebral Disc ◽  
Organ Culture ◽  
Biological Response ◽  
In Vivo Studies ◽  
Large Animal ◽  
Large Animal Models ◽  
Bending Loads ◽  
Ivd Degeneration

Intervertebral disc (IVD) degeneration is a complex pathology, involving alterations in mechanical and biological function. Mechanical injury to IVDs may contribute to the development of IVD degeneration, and can arise following excessive loading or repeated exposure to loading levels which are not instantaneously damaging. Lateral bending and flexion produced the highest maximum shear strains in human IVDs and are considered the motions that place the IVD at greatest risk of injury (1). The biological response of the IVD to combined bending and compression has been examined in vivo in rat and mouse tail bending models demonstrating structural disruption, apoptosis and remodeling (2,4). However, there are practical limitations to current in vivo studies, as it can be difficult to apply repeated bending loads to the disc in vivo, and few large animal models exist capable of tracking the early biological, structural and compositional changes from asymmetrical loading. IVD organ culture allows control over mechanical boundary conditions and investigation of cellular responses to loading while the IVD remains largely intact, and allows the use of large animal models which more closely mimic the nutritional and compositional nature of human IVDs.

scholarly journals A patient-like swine model of gastrointestinal fibrotic strictures for advancing therapeutics

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ling Li ◽  
Mohamad I. Itani ◽  
Kevan J. Salimian ◽  
Yue Li ◽  
Olaya Brewer Gutierrez ◽  
...  
Keyword(s):  
Argon Plasma Coagulation ◽  
Argon Plasma ◽  
Large Animal Model ◽  
Swine Model ◽  
Large Animal ◽  
High Grade ◽  
Gi Tract ◽  
Endoscopic Techniques ◽  
Approved Drugs

AbstractGastrointestinal (GI) strictures are difficult to treat in a variety of disease processes. Currently, there are no Food and Drug Administration (FDA) approved drugs for fibrosis in the GI tract. One of the limitations to developing anti-fibrotic drugs has been the lack of a reproducible, relatively inexpensive, large animal model of fibrosis-driven luminal stricture. This study aimed to evaluate the feasibility of creating a model of luminal GI tract strictures. Argon plasma coagulation (APC) was applied circumferentially in porcine esophagi in vivo. Follow-up endoscopy (EGD) was performed at day 14 after the APC procedure. We noted high grade, benign esophageal strictures (n = 8). All 8 strictures resembled luminal GI fibrotic strictures in humans. These strictures were characterized, and then successfully dilated. A repeat EGD was performed at day 28 after the APC procedure and found evidence of recurrent, high grade, fibrotic, strictures at all 8 locations in all pigs. Pigs were sacrificed and gross and histologic analyses performed. Histologic examination showed extensive fibrosis, with significant collagen deposition in the lamina propria and submucosa, as well as extensive inflammatory infiltrates within the strictures. In conclusion, we report a porcine model of luminal GI fibrotic stricture that has the potential to assist with developing novel anti-fibrotic therapies as well as endoscopic techniques to address recurring fibrotic strictures in humans.

scholarly journals The pathophysiologic role of the protein kinase Cδ pathway in the intervertebral discs of rabbits and mice: In vitro, ex vivo, and in vivo studies

2012 ◽  
Vol 64 (6) ◽  
pp. 1950-1959 ◽  
Author(s):  
Michael B. Ellman ◽  
Jae-Sung Kim ◽  
Howard S. An ◽  
Jeffrey S. Kroin ◽  
Xin Li ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Ex Vivo ◽  
Intervertebral Discs ◽  
In Vivo Studies ◽  
Protein Kinase Cδ

scholarly journals Niobium Carbide Loaded by Macrophage for Targeted Phototherapy Ablation of Breast Cancer

2020 ◽  
Author(s):  
Chiara Da Pieve ◽  
Gabriela Kramer Marek ◽  
Jolanta Saczko ◽  
Anant Shah ◽  
Florian Raes
Keyword(s):  
Animal Study ◽  
Human Body ◽  
Targeted Delivery ◽  
Near Infrared ◽  
Niobium Carbide ◽  
Reactive Oxygen Species Generation ◽  
Large Animal Model ◽  
Large Animal ◽  
Photodynamic Effect

ABSTRACTAltough nanomaterial-mediated phototherapy has been extensively studied, the major antitumor success is limited to treating subcutaneous tumor on nude, lacking of clinically-relevant big animal study. Therefore, it is urgent to make further investigation on the typical big model, which is more closely related to the human body. In this work, niobium carbide (NbC) was selected as photoactive substance in virtue of its outstanding near infrared (NIR) absorption properties and resultantly NIR-triggered hyperthemia and reactive oxygen species generation for the synergetic photothermal and photodynamic effect. Moreover, macrophage was used as bio-carrier for the targeted delivery of NbC and the phagocytosis of macrophages was proved to be able to retain the photothermal/photodynamic effect of NbC. Resultantly, macrophage loaded NbC could realize complete removal of solid tumor on both of nude mice and big animal of rabbits. Meanwhile, two-dimensional ultrasound, shave wave elastography (SWE) and contrast-enhanced ultrasound (CEUS) have been applied for monitoring the physiological evolutions of in vivo tumor post treatment, which clearly disclosed the photoablation process of tumor and provided a new way for the surveillance of tumor on the big animal study. Hence, large animal model study in this work presented higher clinical significance than the previous studies.SignificanceFindings show that niobium carbide carried by macrophages can be used for targeted phototherapy. At the same time, we applied the rabbit tumor model which is closer to the human body microenvironment.

scholarly journals Intracoronary Delivery of Porcine Cardiac Progenitor Cells Overexpressing IGF-1 and HGF in a Pig Model of Sub-Acute Myocardial Infarction

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2571
Author(s):  
Cristina Prat-Vidal ◽  
Verónica Crisóstomo ◽  
Isabel Moscoso ◽  
Claudia Báez-Díaz ◽  
Virginia Blanco-Blázquez ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Growth Factor ◽  
Progenitor Cells ◽  
Large Animal Model ◽  
Cardiac Progenitor Cells ◽  
Large Animal ◽  
Insulin Growth Factor ◽  
Decellularized Extracellular Matrix ◽  
Preclinical Animal Models

Human cardiac progenitor cells (hCPC) are considered a good candidate in cell therapy for ischemic heart disease, demonstrating capacity to improve functional recovery after myocardial infarction (MI), both in small and large preclinical animal models. However, improvements are required in terms of cell engraftment and efficacy. Based on previously published reports, insulin-growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) have demonstrated substantial cardioprotective, repair and regeneration activities, so they are good candidates to be evaluated in large animal model of MI. We have validated porcine cardiac progenitor cells (pCPC) and lentiviral vectors to overexpress IGF-1 (co-expressing eGFP) and HGF (co-expressing mCherry). pCPC were transduced and IGF1-eGFPpos and HGF-mCherrypos populations were purified by cell sorting and further expanded. Overexpression of IGF-1 has a limited impact on pCPC expression profile, whereas results indicated that pCPC-HGF-mCherry cultures could be counter selecting high expresser cells. In addition, pCPC-IGF1-eGFP showed a higher cardiogenic response, evaluated in co-cultures with decellularized extracellular matrix, compared with native pCPC or pCPC-HGF-mCherry. In vivo intracoronary co-administration of pCPC-IGF1-eGFP and pCPC-HFG-mCherry (1:1; 40 × 106/animal), one week after the induction of an MI model in swine, revealed no significant improvement in cardiac function.

scholarly journals Anti-Inflammatory Potential of Daturaolone from Datura innoxia Mill.: In Silico, In Vitro and In Vivo Studies

2021 ◽  
Vol 14 (12) ◽  
pp. 1248
Author(s):  
Muhammad Waleed Baig ◽  
Humaira Fatima ◽  
Nosheen Akhtar ◽  
Hidayat Hussain ◽  
Mohammad K. Okla ◽  
...  
Keyword(s):  
In Silico ◽  
Therapeutic Potential ◽  
In Vivo Studies ◽  
Metabolic Reaction ◽  
Datura Innoxia ◽  
In Vivo Models ◽  
Immobility Time ◽  
Anti Inflammatory

Exploration of leads with therapeutic potential in inflammatory disorders is worth pursuing. In line with this, the isolated natural compound daturaolone from Datura innoxia Mill. was evaluated for its anti-inflammatory potential using in silico, in vitro and in vivo models. Daturaolone follows Lipinski’s drug-likeliness rule with a score of 0.33. Absorption, distribution, metabolism, excretion and toxicity prediction show strong plasma protein binding; gastrointestinal absorption (Caco-2 cells permeability = 34.6 nm/s); no blood–brain barrier penetration; CYP1A2, CYP2C19 and CYP3A4 metabolism; a major metabolic reaction, being aliphatic hydroxylation; no hERG inhibition; and non-carcinogenicity. Predicted molecular targets were mainly inflammatory mediators. Molecular docking depicted H-bonding interaction with nuclear factor kappa beta subunit (NF-κB), cyclooxygenase-2, 5-lipoxygenase, phospholipase A2, serotonin transporter, dopamine receptor D1 and 5-hydroxy tryptamine. Its cytotoxicity (IC50) value in normal lymphocytes was >20 µg/mL as compared to cancer cells (Huh7.5; 17.32 ± 1.43 µg/mL). Daturaolone significantly inhibited NF-κB and nitric oxide production with IC50 values of 1.2 ± 0.8 and 4.51 ± 0.92 µg/mL, respectively. It significantly reduced inflammatory paw edema (81.73 ± 3.16%), heat-induced pain (89.47 ± 9.01% antinociception) and stress-induced depression (68 ± 9.22 s immobility time in tail suspension test). This work suggests a possible anti-inflammatory role of daturaolone; however, detailed mechanistic studies are still necessary to corroborate and extrapolate the findings.

A novel in vivo large animal model of lumbar spinal joint degeneration

2018 ◽  
Vol 18 (10) ◽  
pp. 1896-1909 ◽  
Author(s):  
Tian Wang ◽  
Matthew H. Pelletier ◽  
Chris Christou ◽  
Rema Oliver ◽  
Ralph J. Mobbs ◽  
...  
Keyword(s):  
Animal Model ◽  
Large Animal Model ◽  
Large Animal ◽  
Joint Degeneration ◽  
Lumbar Spinal

scholarly journals Autologous transplantation of canine long-term marrow culture cells genetically marked by retroviral vectors

Blood ◽  
1992 ◽  
Vol 79 (2) ◽  
pp. 356-364 ◽  
Author(s):  
RF Carter ◽  
AC Abrams-Ogg ◽  
JE Dick ◽  
SA Kruth ◽  
VE Valli ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Autologous Transplantation ◽  
Large Animal Model ◽  
Multiple Infections ◽  
Large Animal ◽  
Retroviral Infection ◽  
Hematopoietic Stem ◽  
Marrow Cells

Abstract Retroviral infection of bone marrow cells in long-term marrow cultures (LTMCs) offers several theoretical advantages over other methods for gene transfer into hematopoietic stem cells. To investigate the feasibility of this approach in a large animal model system, we subjected LTMCs from nine dogs to multiple infections with retrovirus containing the neomycin phosphotransferase gene (neo) during 21 days of culture. Feeder layers, cocultivation, polycations, and selection were not used. The in vitro gene transfer efficiency was 70% as determined by polymerase chain reaction amplification of neo sequences in colony- forming unit granulocyte-macrophage (CFU-GM) obtained from day-21 LTMCs. Day-21 LTMC cells were infused into autologous recipients with (four dogs) and without (three dogs) marrow-ablative conditioning. At 3 months posttransplant, up to 10% of marrow cells contained the neo gene. This percentage declined to 0.1% to 1% at 10 to 21 months posttransplant. Neo was also detected in individual CFU-GM, burst- forming unit-erythroid (BFU-E), and CFU-Mix progenitors derived from marrow up to 21 months postinfusion and in cultures of peripheral blood- derived T cells up to 19 months postinfusion. There was no difference in the percentage of neo-marked cells present when dogs that received marrow ablative conditioning were compared with dogs receiving no conditioning. Detection of neo-marked marrow cells almost 2 years after autologous transplantation in a large mammalian species shows that retroviral infection of marrow cells in LTMCs is a potentially nontoxic and efficient protocol for gene transfer. Further, our results suggest that marrow conditioning and in vivo selection pressure to retain transplanted cells may not be absolute requirements for the retention of genetically marked cells in vivo.

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