Hickman Catheter Use for Long-Term Vascular Access in a Preclinical Swine Model

Central venous catheters (CVCs) are invaluable devices in large animal research as they facilitate a wide range of medical applications, including blood ...

Johns Hopkins University School of Medicine

Macaques are an excellent model for many human diseases, including reproductive diseases such as endometriosis. A long-recognized need for early biomarkers of endometriosis has not yet resulted in consensus. While biomarker studies have examined many bodily fluids and targets, cervicovaginal secretions have been relatively under-investigated. Extracellular vesicles (EVs, including exosomes and microvesicles) are found in every biofluid examined, carry cargo including proteins and RNA, and may participate in intercellular signaling. Little is known about EVs in the cervicovaginal compartment, including the effects of reproductive tract disease on quantity and quality of EVs.

Potential role of cervicovaginal extracellular particles in diagnosis of endometriosis.

Chronic diarrhea poses a significant threat to the health of NHP research colonies, and its primary etiology remains unclear. In macaques, the clinical presentation of intractable diarrhea and weight loss that are accompanied by inflammatory infiltrates within the gastrointestinal tract closely resembles inflammatory bowel disease of humans, dogs, and cats, in which low serum and tissue cobalamin (vitamin B12) levels are due to intestinal malabsorption. We therefore hypothesized that macaques with chronic idiopathic diarrhea (CID) have lower serum cobalamin concentrations than do healthy macaques. Here we measured serum cobalamin concentrations in both rhesus and pigtailed macaques with CID and compared them with those of healthy controls. Serum cobalamin levels were 2.5-fold lower in pigtailed macaques with CID than control animals but did not differ between rhesus macaques with CID and their controls. This finding supports the use of serum cobalamin concentration as an adjunct diagnostic tool in pigtailed macaques that present with clinical symptoms of chronic gastrointestinal disease. This use of serum vitamin B12 levels has implications for the future use of parenteral cobalamin supplementation to improve clinical outcomes in this species.

Serum Cobalamin (Vitamin B12) Concentrations in Rhesus Macaques (Macaca mulatta) and Pigtailed Macaques (Macaca nemestrina) with Chronic Idiopathic Diarrhea.

Gastrointestinal (GI) hemorrhage accompanies several common diseases of rhesus macaques (Macaca mulatta). Guaiac fecal occult blood testing (gFOBT) is a non-invasive means to detect such bleeding in several species; however, there are currently no data indicating reliability of this test to detect GI hemorrhage in macaques.

Evaluation of the guaiac fecal occult blood test for detection of gastrointestinal bleeding in the rhesus macaque (Macaca mulatta).

To develop and validate a deep learning-based approach to the fully-automated analysis of macaque corneal sub-basal nerves using in vivo confocal microscopy (IVCM).

Deep learning-based analysis of macaque corneal sub-basal nerve fibers in confocal microscopy images.

To characterize corneal subbasal nerve plexus features of normal and simian immunodeficiency virus (SIV)-infected macaques by combining in vivo corneal confocal microscopy (IVCM) with automated assessments using deep learning-based methods customized for macaques.

Combining In Vivo Corneal Confocal Microscopy With Deep Learning-Based Analysis Reveals Sensory Nerve Fiber Loss in Acute Simian Immunodeficiency Virus Infection.

Food avoidance secondary to disease or stress can lead to weight loss and rapid deterioration of clinical condition in the common marmoset (Callithrix jacchus). Currently, there are no data supporting the use of any pharmaceuticals as an appetite stimulant in this species; however, benzodiazepines are frequently used for this purpose in other species.

The use of midazolam as an appetite stimulant and anxiolytic in the common marmoset (Callithrix jacchus).

Tapered low-volume, low-pressure (LVLP) cuffs have been introduced to improve sealing and reduce injury from tracheostomy and endotracheal intubation compared to traditional cylindrical high-volume, low-pressure (HVLP) cuffs. The objective of this study is to develop a swine model of tracheostomy injury and to compare live tissue response following LVLP and HVLP tracheostomy placement.

Impact of Low-Volume, Low-Pressure Tracheostomy Cuffs on Acute Mucosal Injury in Swine.

Spinal cord injury (SCI) is a devastating disease with limited effective treatment options. Animal paradigms are vital for understanding the pathogenesis of SCI and testing potential therapeutics. The porcine model of SCI is increasingly favored because of its greater similarity to humans. However, its adoption is limited by the complexities of care and range of testing parameters. Researchers need to consider swine selection, injury method, post-operative care, rehabilitation, behavioral outcomes, and histology metrics. Therefore, we systematically reviewed full-text English-language articles to evaluate study characteristics used in developing a porcine model and summarize the interventions that have been tested using this paradigm. A total of 63 studies were included, with 33 examining SCI pathogenesis and 30 testing interventions. Studies had an average sample size of 15 pigs with an average weight of 26 kg, and most used female swine with injury to the thoracic cord. Injury was most commonly induced by weight drop with compression. The porcine model is amenable to testing various interventions, including mean arterial pressure augmentation ( = 7), electrical stimulation ( = 6), stem cell therapy ( = 5), hypothermia ( = 2), biomaterials ( = 2), gene therapy ( = 2), steroids ( = 1), and nanoparticles ( = 1). It is also notable for its clinical translatability and is emerging as a valuable pre-clinical study tool. This systematic review can serve as a guideline for researchers implementing and testing the porcine SCI model.

Porcine Model of Spinal Cord Injury: A Systematic Review.

Extracellular vesicles (EVs) have potential in disease treatment since they can be loaded with therapeutic molecules and engineered for retention by specific tissues. However, questions remain on optimal dosing, administration, and pharmacokinetics. Previous studies have addressed biodistribution and pharmacokinetics in rodents, but little evidence is available for larger animals. Here, we investigated the pharmacokinetics and biodistribution of Expi293F-derived EVs labelled with a highly sensitive nanoluciferase reporter (palmGRET) in a non-human primate model (Macaca nemestrina), comparing intravenous (IV) and intranasal (IN) administration over a 125-fold dose range. We report that EVs administered IV had longer circulation times in plasma than previously reported in mice and were detectable in cerebrospinal fluid (CSF) after 30-60 minutes. EV association with PBMCs, especially B-cells, was observed as early as one minute post-administration. EVs were detected in liver and spleen within one hour of IV administration. However, IN delivery was minimal, suggesting that pretreatment approaches may be needed in large animals. Furthermore, EV circulation times strongly decreased after repeated IV administration, possibly due to immune responses and with clear implications for xenogeneic EV-based therapeutics. We hope that our findings from this baseline study in macaques will help to inform future research and therapeutic development of EVs.

Pharmacokinetics and biodistribution of extracellular vesicles administered intravenously and intranasally to .

Tissue fibrosis results from uncontrolled healing responses leading to excessive mesenchymal cell activation and collagen and other extracellular matrix deposition. In the gastrointestinal tract, fibrosis leads to narrowing of the lumen and stricture formation. A drug treatment to prevent fibrosis and strictures in the gastrointestinal tract would be transformational for patient care. We aimed to develop a stricture treatment with the following characteristics and components: a small molecule with strong antifibrotic effects that is delivered locally at the site of the stricture to ensure correct lesional targeting while protecting the systemic circulation, and that is formulated with sustained-release properties to act throughout the wound healing processes.

Injectable, Drug-Eluting Nanocrystals Prevent Fibrosis and Stricture Formation In Vivo.

The common marmoset (), a New World NHP, has emerged as important animal model in multiple areas of translational biomedical research. The quality of translational research in marmosets depends on early diagnosis, treatment, and prevention of their spontaneous diseases. Here, we characterize an outbreak of infectious cholangiohepatitis that affected 7 adult common marmosets in a single building over a 10-mo period. Marmosets presented for acute onset of lethargy, dull mentation, weight loss, dehydration, hyporexia, and hypothermia. Blood chemistries at presentation revealed markedly elevated hepatic and biliary enzymes, but mild neutrophilia was detected in only 1 of the 7. Affected marmosets were unresponsive to rigorous treatment and died or were euthanized within 48 h of presentation. Gross and histopathologic examinations revealed severe, necrosuppurative cholangiohepatitis and proliferative cholecystitis with bacterial colonies and an absence of gallstones. Perimortem and postmortem cultures revealed single or dual isolates of  and . Other postmortem findings included bile duct hyperplasia, periportal hepatitis, bile peritonitis, ulcerative gastroenteritis, and typhlitis. Environmental contamination of water supply equipment with  spp. was identified as the source of infection, but pathogenesis remains unclear. This type of severe, infectious cholangiohepatitis with proliferative cholecystitis with  spp. had not been reported previously in marmosets, and we identified and here describe several contributing factors in addition to contaminated drinking water.

Jessica Izzi

Department of Molecular and Comparative Pathobiology,
Research Animal Resources,
Department of Molecular and Comparative Pathobiology, Research Animal Resources

Johns Hopkins University School of Medicine

Hickman Catheter Use for Long-Term Vascular Access in a Preclinical Swine Model

Jessica Izzi

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Molecular and Comparative Pathobiology,Research Animal Resources,Department of Molecular and Comparative Pathobiology, Research Animal Resources

Johns Hopkins University School of Medicine

Hickman Catheter Use for Long-Term Vascular Access in a Preclinical Swine Model

Department of Molecular and Comparative Pathobiology,
Research Animal Resources,
Department of Molecular and Comparative Pathobiology, Research Animal Resources