scholarly journals Parameters of biliary hydrodynamic injection during endoscopic retrograde cholangio-pancreatography in pigs for applications in gene delivery

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0249931
Author(s):  
Yuting Huang ◽  
Robert L. Kruse ◽  
Hui Ding ◽  
Mohamad I. Itani ◽  
Jonathan Morrison ◽  
...  
Keyword(s):  
Gene Delivery ◽  
Vital Signs ◽  
Biliary Tree ◽  
Large Animal ◽  
Endoscopic Retrograde ◽  
Flow Rates ◽  
Hydrodynamic Injection ◽  
Large Animal Models ◽  
Injection Parameters ◽  
Tree Injury

The biliary system is routinely accessed for clinical purposes via endoscopic retrograde cholangiopancreatography (ERCP). We previously pioneered ERCP-mediated hydrodynamic injection in large animal models as an innovative gene delivery approach for monogenic liver diseases. However, the procedure poses potential safety concerns related mainly to liver or biliary tree injury. Here, we sought to further define biliary hydrodynamic injection parameters that are well-tolerated in a human-sized animal model. ERCP was performed in pigs, and hydrodynamic injection carried out using a novel protocol to reduce duct wall stress. Each pig was subjected to multiple repeated injections to expedite testing and judge tolerability. Different injection parameters (volume, flow rate) and injection port diameters were tested. Vital signs were monitored throughout the procedure, and liver enzyme panels were collected pre- and post-procedure. Pigs tolerated repeated biliary hydrodynamic injections with only occasional, mild, isolated elevation in aspartate aminotransferase (AST), which returned to normal levels within one day post-injection. All other liver tests remained unchanged. No upper limit of volume tolerance was reached, which suggests the biliary tree can readily transmit fluid into the vascular space. Flow rates up to 10 mL/sec were also tolerated with minimal disturbance to vital signs and no anatomic rupture of bile ducts. Measured intrabiliary pressure was up to 150 mmHg, and fluid-filled vesicles were induced in liver histology at high flow rates, mimicking the changes in histology observed in mouse liver after hydrodynamic tail vein injection. Overall, our investigations in a human-sized pig liver using standard clinical equipment suggest that ERCP-guided hydrodynamic injection will be safely tolerated in patients. Future investigations will interrogate if higher flow rates and pressure mediate higher DNA delivery efficiencies.

Minimally Invasive Injection to the Phrenic Nerve in a Porcine Hemidiaphragmatic Paralysis Model: A Pilot Study

Neurosurgery ◽  
2019 ◽  
Vol 87 (4) ◽  
pp. 847-853 ◽  
Author(s):  
Pavlos Texakalidis ◽  
Muhibullah S Tora ◽  
Skyler Canute ◽  
Nathan Hardcastle ◽  
Kelly Poth ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Phrenic Nerve ◽  
Vital Signs ◽  
Swine Model ◽  
Large Animal ◽  
Diaphragmatic Dysfunction ◽  
Thoracoscopic Approach ◽  
Large Animal Models ◽  
Cord Injury ◽  
Motor Neuron Loss

Abstract BACKGROUND Neurodegenerative diseases and spinal cord injury can affect respiratory function often through motor neuron loss innervating the diaphragm. To reinnervate this muscle, new motor neurons could be transplanted into the phrenic nerve (PN), allowing them to extend axons to the diaphragm. These neurons could then be driven by an optogenetics approach to regulate breathing. This type of approach has already been demonstrated in the peripheral nerves of mice. However, there is no established thoracoscopic approach to PN injection. Also, there is currently a lack of preclinical large animal models of diaphragmatic dysfunction in order to evaluate the efficacy of potential treatments. OBJECTIVE To evaluate the feasibility of thoracoscopic drug delivery into the PN and to assess the viability of hemidiaphragmatic paralysis in a porcine model. METHODS Two Landrace farm pigs underwent a novel procedure for thoracoscopic PN injections, including 1 nonsurvival and 1 survival surgery. Nonsurvival surgery involved bilateral PN injections and ligation. Survival surgery included a right PN injection and transection proximal to the injection site to induce hemidiaphragmatic paralysis. RESULTS PN injections were successfully performed in both procedures. The animal that underwent survival surgery recovered postoperatively with an established right hemidiaphragmatic paralysis. Over the 5-d postoperative period, the animal displayed stable vital signs and oxygenation saturation on room air with voluntary breathing. CONCLUSION Thoracoscopic targeting of the porcine PN is a feasible approach to administer therapeutic agents. A swine model of hemidiaphragmatic paralysis induced by unilateral PN ligation or transection may be potentially used to study diaphragmatic reinnervation following delivery of therapeutics.

Gene delivery to large animal models using AAV vectors

2015 ◽  
Vol 25 ◽  
pp. S290
Author(s):  
J. Chamberlain ◽  
J. Seto ◽  
J. Ramos ◽  
S. Hauschka ◽  
G. Odom
Keyword(s):  
Animal Models ◽  
Gene Delivery ◽  
Large Animal ◽  
Large Animal Models

Cardiac Gene Delivery in Large Animal Models: Antegrade Techniques

2016 ◽  
pp. 227-235 ◽  
Author(s):  
Shin Watanabe ◽  
Lauren Leonardson ◽  
Roger J. Hajjar ◽  
Kiyotake Ishikawa
Keyword(s):  
Animal Models ◽  
Gene Delivery ◽  
Large Animal ◽  
Large Animal Models ◽  
Cardiac Gene

scholarly journals Targeted Gene Delivery through the Respiratory System: Rationale for Intratracheal Gene Transfer

2019 ◽  
Vol 6 (1) ◽  
pp. 8 ◽  
Author(s):  
Michael Katz ◽  
Anthony Fargnoli ◽  
Sarah Gubara ◽  
Kenneth Fish ◽  
Thomas Weber ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Gene Delivery ◽  
Viral Vectors ◽  
Cell Types ◽  
Normal Lung ◽  
Target Cells ◽  
Specific Cell ◽  
Large Animal ◽  
Large Animal Models ◽  
Dna And Rna

Advances in DNA- and RNA-based technologies have made gene therapy suitable for many lung diseases, especially those that are hereditary. The main objective of gene therapy is to deliver an adequate amount of gene construct to the intended target cell, achieve stable transduction in target cells, and to produce a clinically therapeutic effect. This review focuses on the cellular organization in the normal lung and how gene therapy targets the specific cell types that are affected by pulmonary disorders caused by genetic mutations. Furthermore, it examines the pulmonary barriers that can compromise the absorption and transduction of viral vectors and genetic agents by the lung. Finally, it discusses the advantages and limitations of direct intra-tracheal gene delivery with different viral vectors in small and large animal models and in clinical trials.

scholarly journals Nonviral ultrasound-mediated gene delivery in small and large animal models

2019 ◽  
Vol 14 (4) ◽  
pp. 1015-1026 ◽  
Author(s):  
Maxim Bez ◽  
Josquin Foiret ◽  
Galina Shapiro ◽  
Gadi Pelled ◽  
Katherine W. Ferrara ◽  
...  
Keyword(s):  
Animal Models ◽  
Gene Delivery ◽  
Large Animal ◽  
Large Animal Models

scholarly journals Molecular Mechanisms of Fetal Tendon Regeneration Versus Adult Fibrous Repair

2021 ◽  
Vol 22 (11) ◽  
pp. 5619
Author(s):  
Iris Ribitsch ◽  
Andrea Bileck ◽  
Alexander D. Aldoshin ◽  
Maciej M. Kańduła ◽  
Rupert L. Mayer ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Molecular Mechanisms ◽  
Unmet Need ◽  
Tendon Healing ◽  
Tendon Injury ◽  
Inflammatory Factors ◽  
Large Animal ◽  
Post Injury ◽  
Tendon Regeneration ◽  
Large Animal Models

Tendinopathies are painful, disabling conditions that afflict 25% of the adult human population. Filling an unmet need for realistic large-animal models, we here present an ovine model of tendon injury for the comparative study of adult scarring repair and fetal regeneration. Complete regeneration of the fetal tendon within 28 days is demonstrated, while adult tendon defects remained macroscopically and histologically evident five months post-injury. In addition to a comprehensive histological assessment, proteome analyses of secretomes were performed. Confirming histological data, a specific and pronounced inflammation accompanied by activation of neutrophils in adult tendon defects was observed, corroborated by the significant up-regulation of pro-inflammatory factors, neutrophil attracting chemokines, the release of potentially tissue-damaging antimicrobial and extracellular matrix-degrading enzymes, and a response to oxidative stress. In contrast, secreted proteins of injured fetal tendons included proteins initiating the resolution of inflammation or promoting functional extracellular matrix production. These results demonstrate the power and relevance of our novel ovine fetal tendon regeneration model, which thus promises to accelerate research in the field. First insights from the model already support our molecular understanding of successful fetal tendon healing processes and may guide improved therapeutic strategies.

scholarly journals Endoscopic Fistulotomy – ‘The Suprapapillary Punch’: A Method of Access to the Bile Duct during ERCP

1994 ◽  
Vol 8 (1) ◽  
pp. 33-35
Author(s):  
Noel B Hershfield
Keyword(s):  
Bile Duct ◽  
Common Bile Duct ◽  
Endoscopic Retrograde Cholangiopancreatography ◽  
Biliary Tree ◽  
Usual Method ◽  
Endoscopic Retrograde ◽  
The Common ◽  
A Minor ◽  
Endoscopic Fistulotomy

Endoscopic retrograde cholangiopancreatography (ERCP) is established as the method of choice to investigate the biliary tree when obstruction is suspected. On rare occasions, the papilla cannot be entered because of anatomical or pathological abnormalities. This report describes endoscopic fistulotomy or the suprapapillary punch that has been carried out at the Foothills Hospital in Calgary, Alberta, on 30 of 623 patients referred for ERCP for conditions causing obstruction of the common bile duct or suspected obstruction of the common bile duct. The following communication also describes the method of suprapapillary punch or endoscopic fistulotomy. Results have been excellent with only one complication, a minor attack of pancreatitis after the procedure. In summary, the suprapapillary punch or fistulotomy is a safe and useful method for entering the common bile duct when access by the usual method is impossible.

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