Name: a retrograde implantation approach for peritoneal dialysis catheter placement in mice
Uploaded: 2022-07-20T13:00:00
Description: Watch this Scientific Journal Video about A Retrograde Implantation Approach for Peritoneal Dialysis Catheter Placement in Mice at JoVE.com

This work was supported by NIH 1R01HL132325 and R21 DK119740-01 (VCC) and AHA Cardio-oncology SFRN CAT-HD Center grant 857078 (VCC and SL).

For this study, eight female C57BL/6J mice, 8-12 weeks in age, and an average weight of 20 g were used. The mice were housed under standard conditions and were fed with chow and water ad libitum. This study was performed with the approval of the Institutional Animal Care and Use Committee (IACUC), Boston University Medical Center (AN-1549). The procedures described here were performed under sterile conditions.
1. Anesthetize the mouse in an Isoflurane chamber, and inject the ana...

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I., Sequeira, A., Narayan, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Going+home:+Access+for+home+modalities.">Going home: Access for home modalities.</a> Advances in Chronic Kidney Disease. 27 (3), 253-262 (2020).</li><li>van de Luijtgaarden, M. W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Trends+in+dialysis+modality+choice+and+related+patient+survival+in+the+ERA-EDTA+Registry+over+a+20-year+period.">Trends in dialysis modality choice and related patient survival in the ERA-EDTA Registry over a 20-year period.</a> Nephrology Dialysis Transplantation. 31 (1), 120-128 (2016).</li><li>Schaefer, F., Warady, B. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Peritoneal+dialysis+in+children+with+end-stage+renal+disease.">Peritoneal dialysis in children with end-stage renal disease.</a> Nature Reviews. Nephrology. 7 (11), 659-668 (2011).</li><li>Gonzalez-Mateo, G. T., Pascual-Anton, L., Sandoval, P., Aguilera Peralta, A., Lopez-Cabrera, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Surgical+techniques+for+catheter+placement+and+5/6+nephrectomy+in+murine+Models+of+Peritoneal+Dialysis.">Surgical techniques for catheter placement and 5/6 nephrectomy in murine Models of Peritoneal Dialysis.</a> Journal of Visualized Experiments: JoVE. (137), e56746 (2018).</li><li>Chow, K. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Straight+versus+coiled+peritoneal+dialysis+catheters:+A+randomized+controlled+trial.">Straight versus coiled peritoneal dialysis catheters: A randomized controlled trial.</a> American Journal of Kidney Diseases. 75 (1), 39-44 (2020).</li><li>LaPlant, M. B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Peritoneal+dialysis+catheter+placement,+outcomes+and+complications.">Peritoneal dialysis catheter placement, outcomes and complications.</a> Pediatric Surgery International. 34 (11), 1239-1244 (2018).</li><li>Al-Hwiesh, A. K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+modified+peritoneal+dialysis+catheter+with+a+new+technique:+Farewell+to+catheter+migration.">A modified peritoneal dialysis catheter with a new technique: Farewell to catheter migration.</a> Saudi Journal of Kidney Diseases and Transplantation. 27 (2), 281-289 (2016).</li><li>Crabtree, J. H., Chow, K. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Peritoneal+dialysis+catheter+insertion.">Peritoneal dialysis catheter insertion.</a> Seminars Nephrology. 37 (1), 17-29 (2017).</li><li>Flessner, M. F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Peritoneal+changes+after+exposure+to+sterile+solutions+by+catheter.">Peritoneal changes after exposure to sterile solutions by catheter.</a> Journal of the American Society of Nephrology. 18 (8), 2294-2302 (2007).</li><li>Kowalewska, P. M., Margetts, P. J., Fox-Robichaud, A. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Peritoneal+dialysis+catheter+increases+leukocyte+recruitment+in+the+mouse+parietal+peritoneum+microcirculation+and+causes+Fibrosis.">Peritoneal dialysis catheter increases leukocyte recruitment in the mouse parietal peritoneum microcirculation and causes Fibrosis.</a> Peritonial Dialysis International: Journal of the International Society for Peritonial Dialysis. 36 (1), 7-15 (2016).</li><li>Kowalewska, P. M., Patrick, A. 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V., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Tryptophan+metabolites+suppress+Wnt+pathway+and+promote+adverse+limb+events+in+CKD+patients.">Tryptophan metabolites suppress Wnt pathway and promote adverse limb events in CKD patients.</a> The Journal of Clinical Investigation. 132 (1), (2021).</li><li>Belghasem, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Metabolites+in+a+mouse+cancer+model+enhance+venous+thrombogenicity+through+the+aryl+hydrocarbon+receptor-tissue+factor+axis.">Metabolites in a mouse cancer model enhance venous thrombogenicity through the aryl hydrocarbon receptor-tissue factor axis.</a> Blood. 134 (26), 2399-2413 (2019).</li><li>Krediet, R. T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+peritoneal+membrane+in+chronic+peritoneal+dialysis.">The peritoneal membrane in chronic peritoneal dialysis.</a> Kidney International. 55 (1), 341-356 (1999).</li><li>Gonzalez-Mateo, G. T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Chronic+exposure+of+mouse+peritoneum+to+peritoneal+dialysis+fluid:+structural+and+functional+alterations+of+the+peritoneal+membrane.">Chronic exposure of mouse peritoneum to peritoneal dialysis fluid: structural and functional alterations of the peritoneal membrane.</a> Peritonial Dialysis International: Journal of the International Society for Peritonial Dialysis. 29 (2), 227-230 (2009).</li><li>Sukul, N., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Patient-reported+advantages+and+disadvantages+of+peritoneal+dialysis:+results+from+the+PDOPPS.">Patient-reported advantages and disadvantages of peritoneal dialysis: results from the PDOPPS.</a> BMC Nephrology. 20 (1), 116 (2019).</li><li>Lu, Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+method+for+islet+transplantation+to+the+omentum+in+mouse.">A method for islet transplantation to the omentum in mouse.</a> Journal of Visualized Experiments: JoVE. (143), e57160 (2019).</li><li>Gotloib, L., Wajsbrot, V., Shostak, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+short+review+of+experimental+peritoneal+sclerosis:+from+mice+to+men.">A short review of experimental peritoneal sclerosis: from mice to men.</a> The International Journal of Artificial Organs. 28 (2), 97-104 (2005).</li><li>Tateda, K., Matsumoto, T., Miyazaki, S., Yamaguchi, K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Lipopolysaccharide-induced+lethality+and+cytokine+production+in+aged+mice.">Lipopolysaccharide-induced lethality and cytokine production in aged mice.</a> Infection and Immunity. 64 (3), 769-774 (1996).</li><li>Vila Cuenca, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Differences+in+peritoneal+response+after+exposure+to+low-GDP+bicarbonate/lactate-buffered+dialysis+solution+compared+to+conventional+dialysis+solution+in+a+uremic+mouse+model.">Differences in peritoneal response after exposure to low-GDP bicarbonate/lactate-buffered dialysis solution compared to conventional dialysis solution in a uremic mouse model.</a> International Urology and Nephrology. 50 (6), 1151-1161 (2018).</li><li>Penar, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Selected+indices+of+peritoneal+fibrosis+in+patients+undergoing+peritoneal+dialysis.">Selected indices of peritoneal fibrosis in patients undergoing peritoneal dialysis.</a> Postepy Higieny Medycyny Doswiadczalnej (Online). 63, 200-204 (2009).</li><li>Yung, S., Chan, T. 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Three murine models of PD are described. This includes a blind puncture of the peritoneal surface, an open-permanent system, and a closed system10. The blind puncture of the peritoneal surface involves direct peritoneal access similar to intraperitoneal injections but does not allow drainage of dialysate. Being a blinded procedure, this method can injure the abdominal visceral organs. The open-permanent system model keeps the dialysis catheter and instillation port outside the body. However, this ...

An erratum was issued for:&#160;<a href="https://www.jove.com/t/63689">A Retrograde Implantation Approach for Peritoneal Dialysis Catheter Placement in Mice</a>. The Authors section was updated from:
Saran Lotfollahzadeh1 
Mengwei Zhang1 
Marc Arthur Napoleon1 
Wenqing Yin1 
Josephine Orrick1 
Nagla Elzind1 
Austin Morrissey1 
Isaac E. Sellinger1 
Lauren D. Stern1 
Mostafa Belghasem2 
Jean M. Francis1 
Vipul C. Chitalia1,3,4 
1Renal Section, Department of Medicine, Boston University School of Medicine 
2Department of Biomedical Science, Kaiser Permanente Bernard J. Tyson School of Medicine 
3Veterans Affairs Boston Healthcare System 
4Institute of Medical Engineering and Sciences, Massachusetts Institute of Technology
to:
Saran Lotfollahzadeh1 
Mengwei Zhang1 
Marc Arthur Napoleon1 
Wenqing Yin1 
Josephine Orrick1 
Nagla Elzind1 
Austin Morrissey1 
Isaac E. Sellinger1 
Lauren D. Stern1 
Mostafa Belghasem2 
Jean M. Francis1 
Vipul C. Chitalia1,3,4 
1Renal Section, Department of Medicine, Boston University Aram V. Chobanian &#38; Edward Avedisian School of Medicine 
2Department of Biomedical Science, Kaiser Permanente Bernard J. Tyson School of Medicine 
3Veterans Affairs Boston Healthcare System 
4Institute of Medical Engineering and Sciences, Massachusetts Institute of Technology

An erratum was issued for:&#160;<a href="https://www.jove.com/t/63689">A Retrograde Implantation Approach for Peritoneal Dialysis Catheter Placement in Mice</a>. The Authors section was updated.

Erratum: A Retrograde Implantation Approach for Peritoneal Dialysis Catheter Placement in Mice

End-stage renal disease burden 
Chronic kidney disease (CKD) is a worldwide health problem1. Current estimates suggest that more than 850 million people worldwide have kidney disease. The prevalence of kidney disease almost doubles the number of people with diabetes (422 million) and is more than 20 times the prevalence of cancer (42 million) or HIV/AIDS (36.7 million) patients worldwide2. Approximately one in seven Americans have CKD, and two in 1,000 Americans have ESKD requiring a kidney transplant or dialysis support3. Considering the escalating burden of ESKD worldwide, optimizing dialysis technology is crucial3.
Peritoneal dialysis 
PD is a significantly underutilized modality for the treatment of ESKD in the United States. According to the United States Renal Data System (USRDS), the percentage of prevalent PD patients was only 11% in 20204,5. PD confers several advantages over in-center hemodialysis (HD), including a better quality of life, fewer clinic visits, and a decrease in Medicare expenditures6,7. Additionally, PD is a home-based therapy and is associated with a much lower risk of severe infections such as bacteremia and endocarditis that are often related to hemodialysis catheters. Furthermore, PD can be initiated rapidly with an urgent start protocol, decreasing the need for dialysis initiation with indwelling vascular catheters8. PD is considered the preferred method of dialysis in the pediatric ESKD population9.
Peritoneal impairment induced by peritoneal dialysis 
PD entails introducing PD fluid (dialysate) into the peritoneum, which results in inflammation and remodeling of the peritoneal membrane over time. Peritoneal inflammation triggers fibrosis, culminating in the potential loss of ultrafiltration capabilities of the membrane over time. Preservation of the peritoneal membrane is a significant challenge in PD, and further research is critically important to ensure that best clinical practices are available to practitioners. There are well-established murine models to help further the understanding of pathophysiological mechanisms of peritoneal infection and inflammation, solute, water transport kinetics, and membrane failure; still, technical issues with the catheter often limit these models10.
Analyzing the peritoneal membrane changes 
In ESKD patients, dialysate is traditionally introduced in the peritoneal cavity through a Tenkhoff catheter with a deep and superficial cuff. The patients can potentially experience catheter-related complications, including catheter migration, infusion pain, and poor drainage of the dialysate11,12,13. Two major types of peritoneal catheters have been introduced for humans, coiled or straight, to minimize these complications12. Several modifications, including an extra cuff to the conventional two-cuffed catheters, have been added to the original catheters to prolong PD catheter survival11. The insertion technique varies according to several factors by preventing catheter migration to be added after survival, including the availability of the resources and the level of expertise14.
In contrast, the murine models of peritoneal dialysis have fundamental differences in techniques and purpose compared to human peritoneal catheters. For example, peritoneal catheters in murine models are used primarily to study membrane alterations and are less intended for bidirectional drainage functions. The current technique suffers from potential port dislodgement and catheter migration due to the handling of the animals. In the conventional murine models, the access ports were not fixed to the skin. This aspect created an unstable access port, which in awake animals might get dislodged, resulting in catheter migration. Given the importance of murine models in peritoneal membrane research, it is imperative to create effective surgical techniques to generate reliable models. Therefore,&#160;we set out to optimize the conventional model of PD catheter placement. It is important to note that the catheter itself causes histopathologic alterations in the peritoneal membrane, and, thus, any conclusions regarding the effect of PD solutions in animal studies must be interpreted in the context of the PD catheter as a foreign body15,16,17.
Peritoneal membrane histopathology 
PD failure is mainly related to fibrosis and excess angiogenesis resulting in the loss of an osmolar concentration gradient. In addition, the peritoneal membrane filtration capacity might be affected by peritonitis. In addition, infectious peritonitis is a well-established cause for change in the dialysis modality from peritoneal dialysis to hemodialysis.18.

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			<td>&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160; Isoflurane, USP</td>
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			<td>&#160;&#160;&#160;&#160;&#160;&#160; Lipopolysaccharide from E.coli</td>
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			<td>Vicryl Suture</td>
			<td>AD-Surgical</td>
			<td>#L-G330R24</td>
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a retrograde implantation approach for peritoneal dialysis catheter placement in mice

Murine models are employed to probe various aspects of peritoneal dialysis (PD), such as peritoneal inflammation and fibrosis. These events drive peritoneal membrane failure in humans, which remains an area of intense investigation due to its profound clinical implications in managing patients with end-stage kidney disease (ESKD). Despite the clinical importance of PD and its related complications, current experimental murine models suffer from key technical challenges that compromise the models&#39; performance. These include PD catheter migration and kinking and usually warrant earlier catheter removal. These limitations also drive the need for a greater number of animals to complete a study. Addressing these drawbacks, this study introduces technical improvements and surgical nuances to prevent commonly observed PD catheter complications in a murine model. Moreover, this modified model is validated by inducing peritoneal inflammation and fibrosis using lipopolysaccharide injections. In essence, this paper describes an improved method to create an experimental model of PD.

All the implanted catheters were functional till the end of the study, and catheter dislodgement or kinking did not complicate any of the implanted catheters. The current, modified technique was further validated with a peritonitis-induced model using LPS. The control mice received 200 &#181;L of daily normal saline injections, while the experimental mice were injected with 200 &#181;L of LPS, as discussed in protocol step 11, for a total of 7 days following catheter implantation.
The peritone...

Watch this Scientific Journal Video about A Retrograde Implantation Approach for Peritoneal Dialysis Catheter Placement in Mice at JoVE.com

A Retrograde Implantation Approach for Peritoneal Dialysis Catheter Placement in Mice

This article describes modifications of a procedure to implant a peritoneal dialysis catheter in a murine model to avoid major technical issues observed with the conventional techniques.

Murine models are employed to probe various aspects of peritoneal dialysis (PD), such as peritoneal inflammation and fibrosis. These events drive ...

The previous protocols for mouse models of peritoneal dialysis suffer from limitations precluding their long-term use. These limitations, such as catheter coiling and dislodgement, are addressed in this study. This technique prevents PD catheter malfunction for mechanical reasons, allowing their use for a longer time to study pathologies, such as peritoneal fibrosis.This technique will provide a better mouse model to probe molecular pathogenesis and novel therapeutics of peritoneal fibrosis. A key limitation of PD in humans. PD is the mainstay of renal replacement therapy in pediatric patients with ESKD.This optimized model will provide a better test bed to investigate all the issues with PD in humans. Generation of an animal model has a learning curve. This step-by-step video will assist an individual in implementing this technique to generate a durable model for peritoneal dialysis successfully.To begin place the fully anesthetized eight to 12 weeks old C57 black/6J mouse in a left lateral position. After shaving the mouse as specified in the manuscript, disinfect the surgical area by exposing the right flank of the mouse to the heating blanket. Then place the sterile surgical drape over the mouse.Assign the access port pocket one centimeter above the mouse tail. Hold the installation segment with the non-dominant index and thumb finger over the assigned area near the tail. Place the catheter above the skin, and estimate the place for the catheter's tube insertion within the abdominal cavity.Then mark the assigned place for tube insertion, respecting the minimal bending of the tube near the anterior midline. Punch a side hole over the frame of the reservoir section with the mouse ear tagger. Make a horizontal one centimeter wide skin incision one centimeter above the tail.Then bluntly dissect the subcutaneous plane from the underlying muscular layer to make a pouch for the catheter placement to ensure the installation port freely resides in the ideal port pocket. Past the 3-0 suture from the customized side hole. Fix the access port to the muscular bed by tightening the passed suture, keeping the tubing course cephalad.Make a one centimeter incision over the formally marked area near the midline. Place a loose purse string suture with 4-0 round absorbable suture around the incised abdominal wall muscle. Make a one centimeter incision over the muscular layer close to the right midline and pass the proximal felt of the catheter inside the incision.Pass the catheter tube through the prepared tract. Tighten the prepared purse string suture around the tube, while keeping the second felt outside the purse string over the muscular layer, and close the skin with 3-0 absorbable sutures. Ensure that the placed catheter is functional.Check the function with a one milliliter syringe attached to the specific Huber needle for the port. Inject normal saline into the installation port. After confirming a smooth flow with a zero tolerance for resistance, close the skin incisions around the port reservoir with 3-0 absorbable sutures.Enter the port with the Huber needle and inject 100 microliters of normal saline into the port to confirm the patent course. Then inject 200 microliters of lipopolysaccharide, followed by 100 microliters of saline for tube irrigation and ensure that there is no resistance. After seven days of LPS injections and two weeks of catheter implantation, plan for the peritoneal biopsy.After confirming successful anesthesia, make a midline skin incision from bladder to sub xiphoid. Then perfuse the subfascial plane with cold PBS. Make sure the plane is completely dissected without disturbing the integrity of the peritoneum.Analysis of the hematoxylin and eosin stained sections showed a substantial increase in the extracellular matrix, or ECM, in the subperitoneal space. The average ECM in the sub peritoneal space of the control mice was half of that in the LPS exposed mice. The Masson's Trichrome staining detects fibrosis, measured as intensity density normalized to the surface area.Altered vascularity and widening of the subperitoneal space were analyzed using endothelial cell marker CD31, and measured as integrated density in randomly selected high-power field images. Compared to the control, LPS-induced mice showed a threefold increase in subperitoneal fibrosis, approximately eight to ninefold increase in the vascularity, and a twofold increase in the subperitoneal space, marked as SP, were observed. Place the catheter above the skin and mark the point for the catheter insertion, while avoiding the bending of the tube.The insertion should be near the interior midline. Providing the more durable murine PD catheter placement method will allow the researchers to design and execute longer term experiments to probe and target peritoneal membrane failure.

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Research

JoVE Journal

Medicine

Implantation of a Carotid Cuff for Triggering Shear-stress Induced Atherosclerosis in Mice

It is widely accepted that alterations in vascular shear stress trigger the expression of inflammatory genes in endothelial cells and thereby induce atherosclerosis (reviewed in 1 and 2). The role of shear stress has been extensively studied in vitro investigating the influence of flow dynamics on cultured endothelial cells 1,3,4 and in vivo in larger animals and humans 1,5,6,7,8. However, highly reproducible small animal models allowing systematic investigation of the influence of shear stress on plaque development are rare. Recently, Nam et al. 9 introduced a mouse model in which the ligation of branches of the carotid artery creates a region of low and oscillatory flow. Although this model causes endothelial dysfunction and rapid formation of atherosclerotic lesions in hyperlipidemic mice, it cannot be excluded that the observed inflammatory response is, at least in part, a consequence of endothelial and/or vessel damage due to ligation.
In order to avoid such limitations, a shear stress modifying cuff has been developed based upon calculated fluid dynamics, whose cone shaped inner lumen was selected to create defined regions of low, high and oscillatory shear stress within the common carotid artery 10. By applying this model in Apolipoprotein E (ApoE) knockout mice fed a high cholesterol western type diet, vascular lesions develop upstream and downstream from the cuff. Their phenotype is correlated with the regional flow dynamics 11 as confirmed by in vivo Magnetic Resonance Imaging (MRI) 12: Low and laminar shear stress upstream of the cuff causes the formation of extensive plaques of a more vulnerable phenotype, whereas oscillatory shear stress downstream of the cuff induces stable atherosclerotic lesions 11. In those regions of high shear stress and high laminar flow within the cuff, typically no atherosclerotic plaques are observed.
 
In conclusion, the shear stress-modifying cuff procedure is a reliable surgical approach to produce phenotypically different atherosclerotic lesions in ApoE-deficient mice.

The constricting cuff presented in this article is designed to induce atherosclerosis in the murine common carotid artery. Due to the conical shape of its inner lumen the implanted cuff generates well-defined regions of low, high and oscillatory shear stress triggering the development of atherosclerotic lesions of different inflammatory phenotypes.

It is widely accepted that alterations in vascular shear stress trigger the expression of inflammatory genes in endothelial cells and thereby induce ...

Carotid Artery Infusions for Pharmacokinetic and Pharmacodynamic Analysis of Taxanes in Mice

When proposing the use of a drug, drug combination, or drug delivery into a novel system, one must assess the pharmacokinetics of the drug in the study model. As the use of mouse models are often a vital step in preclinical drug discovery and drug development1-8, it is necessary to design a system to introduce drugs into mice in a uniform, reproducible manner. Ideally, the system should permit the collection of blood samples at regular intervals over a set time course. The ability to measure drug concentrations by mass-spectrometry, has allowed investigators to follow the changes in plasma drug levels over time in individual mice1, 9, 10. In this study, paclitaxel was introduced into transgenic mice as a continuous arterial infusion over three hours, while blood samples were simultaneously taken by retro-orbital bleeds at set time points. Carotid artery infusions are a potential alternative to jugular vein infusions, when factors such as mammary tumors or other obstructions make jugular infusions impractical. Using this technique, paclitaxel concentrations in plasma and tissue achieved similar levels as compared to jugular infusion. In this tutorial, we will demonstrate how to successfully catheterize the carotid artery by preparing an optimized catheter for the individual mouse model, then show how to insert and secure the catheter into the mouse carotid artery, thread the end of the catheter out through the back of the mouse&#8217;s neck, and hook the mouse to a pump to deliver a controlled rate of drug influx. Multiple low volume retro-orbital bleeds allow for analysis of plasma drug concentrations over time.

This method was developed with the goal of delivering a steady drug solution via the carotid artery, to assess the pharmacokinetics of novel drugs in mouse models.

When proposing the use of a drug, drug combination, or drug delivery into a novel system, one must assess the pharmacokinetics of the drug in the study ...

The Supraclavicular Fossa Ultrasound View for Central Venous Catheter Placement and Catheter Change Over Guidewire

The supraclavicular fossa ultrasound view can be useful for central venous catheter (CVC) placement. Venipuncture of the internal jugular veins (IJV) or subclavian veins is performed with a micro-convex ultrasound probe, using a neonatal abdominal preset with a probe frequency of 10 Mhz at a depth of 10-12 cm. Following insertion of the guidewire into the vein, the probe is shifted to the right supraclavicular fossa to obtain a view of the superior vena cava (SVC), right pulmonary artery and ascending aorta. Under real-time ultrasound view, the guidewire and its J-tip is visualized and pushed forward to the lower SVC. Insertion depth is read from guidewire marks using central venous catheter. CVC is then inserted following skin and venous dilation. The supraclavicular fossa view is most suitable for right IJV CVC insertion. If other insertion sites are chosen the right supraclavicular fossa should be within the sterile field. Scanning of the IJVs, brachiocephalic veins and SVC can reveal significant thrombosis before venipuncture. Misplaced CVCs can be corrected with a change over guidewire technique under real-time ultrasound guidance. In conjunction with a diagnostic lung ultrasound scan, this technique has a potential to replace chest radiograph for confirmation of CVC tip position and exclusion of pneumothorax. Moreover, this view is of advantage in patients with a non-p-wave cardiac rhythm were an intra-cardiac electrocardiography (ECG) is not feasible for CVC tip position confirmation. Limitations of the method are lack of availability of a micro-convex probe and the need for training.

The overall goal is to enable clinicians to insert a central venous catheter under real-time ultrasound guidance via the right supraclavicular fossa view of the lower part of the superior vena cava. This view is useful for different catheter insertion sites, thrombosis detection before insertion and ultrasound guided correction of misplaced catheters.

The supraclavicular fossa ultrasound view can be useful for central venous catheter (CVC) placement. Venipuncture of the internal jugular veins (IJV) or ...

Non-fluoroscopic Catheter Tracking for Fluoroscopy Reduction in Interventional Electrophysiology

A technological platform (MediGuide) has been recently introduced for non-fluoroscopic catheter tracking. In several studies, we have demonstrated that the application of this non-fluoroscopic catheter visualization system (NFCV) reduces fluoroscopy time and dose by 90-95% in a variety of electrophysiology (EP) procedures. This can be of relevance not only to the patients, but also to the nurses and physicians working in the EP lab. Furthermore, in a subset of indications such as supraventricular tachycardias, NFCV enables a fully non-fluoroscopic procedure and allows the lab staff to work without wearing lead aprons. With this protocol, we demonstrate that even complex procedures such as ablations of atrial fibrillation, that are typically associated with fluoroscopy times of &#62;30 min in conventional settings, can safely be performed with a reduction of &#62;90% in fluoroscopy exposure by the additional use of NFCV.

Radiation exposure is an underestimated risk in complex ablation procedures. Here, we describe a protocol to significantly decrease fluoroscopy time and dosage for both the patient and the lab staff by using a novel non-fluoroscopic catheter visualization system.

A technological platform (MediGuide) has been recently introduced for non-fluoroscopic catheter tracking. In several studies, we have demonstrated that ...

Quantitation of Intra-peritoneal Ovarian Cancer Metastasis

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancy in the United States. Mortality is due to diagnosis of 75% of women with late stage disease, when metastasis is already present. EOC is characterized by diffuse and widely disseminated intra-peritoneal metastasis. Cells shed from the primary tumor anchor in the mesothelium that lines the peritoneal cavity as well as in the omentum, resulting in multi-focal metastasis, often in the presence of peritoneal ascites. Efforts in our laboratory are directed at a more detailed understanding of factors that regulate EOC metastatic success. However, quantifying metastatic tumor burden represents a significant technical challenge due to the large number, small size and broad distribution of lesions throughout the peritoneum. Herein we describe a method for analysis of EOC metastasis using cells labeled with red fluorescent protein (RFP) coupled with in vivo multispectral imaging. Following intra-peritoneal injection of RFP-labelled tumor cells, mice are imaged weekly until time of sacrifice. At this time, the peritoneal cavity is surgically exposed and organs are imaged in situ. Dissected organs are then placed on a labeled transparent template and imaged ex vivo. Removal of tissue auto-fluorescence during image processing using multispectral unmixing enables accurate quantitation of relative tumor burden. This method has utility in a variety of applications including therapeutic studies to evaluate compounds that may inhibit metastasis and thereby improve overall survival.

Ovarian cancer metastasis is characterized by numerous diffuse intra-peritoneal lesions, such that accurate visual quantitation of tumor burden is challenging. Herein we describe a method for in situ and ex vivo quantitation of metastatic tumor burden using red fluorescent protein (RFP)-labeled tumor cells and optical imaging.

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancy in the United States.  Mortality is due to diagnosis of 75% of ...

Surgical Approach for Middle Cerebral Artery Occlusion and Reperfusion Induced Stroke in Mice

Stroke is a leading cause of death worldwide and continues to be one of the major causes of long-term adult disabilities. About 87% of strokes are ischemic in origin and occur in the territory of the middle cerebral artery (MCA). Currently the only Food and Drug Administration (FDA) approved drug for the treatment of this devastating disease is tissue plasminogen activator (tPA). However, tPA has a small therapeutic window for administration (3 - 6 hr), and is only effective in 4% of the patients who actually receive it. Current research focuses on understanding the pathophysiology of stroke in order to find potential therapeutic targets. Thus, reliable models are crucial, and the MCA occlusion (MCAo) model (also termed the intraluminal filament or suture model) is deemed to be the most clinically relevant surgical model of ischemic stroke, and is fairly non-invasive and easily reproducible. Typically the MCAo model is used with rodents, especially with mice due to all the genetic variations available for this species. Here we describe (and present in the video) how to successfully perform the MCAo model (with reperfusion) in mice to generate reliable and reproducible data.

In order to understand the pathophysiology of stroke, it is important to use reliable models. This paper will describe one of the most frequently used stroke models in mice, termed the middle cerebral artery occlusion (MCAo) model (also termed the intraluminal filament or suture model) with reperfusion.

Stroke is a leading cause of death worldwide and continues to be one of the major causes of long-term adult disabilities. About 87% of strokes are ...

Implantation of Combined Telemetric ECG and Blood Pressure Transmitters to Determine Spontaneous Baroreflex Sensitivity in Conscious Mice

Blood pressure (BP) and heart rate (HR) are both controlled by the autonomic nervous system (ANS) and are closely intertwined due to reflex mechanisms. The baroreflex is a key homeostatic mechanism to counteract acute, short-term changes in arterial BP and to maintain BP in a relatively narrow physiological range. BP is sensed by baroreceptors located in the aortic arch and carotid sinus. When BP changes, signals are transmitted to the central nervous system and are then communicated to the parasympathetic and sympathetic branches of the autonomic nervous system to adjust HR. A rise in BP causes a reflex decrease in HR, a drop in BP causes a reflex increase in HR.
Baroreflex sensitivity (BRS) is the quantitative relationship between changes in arterial BP and corresponding changes in HR. Cardiovascular diseases are often associated with impaired baroreflex function. In various studies reduced BRS has been reported in e.g., heart failure, myocardial infarction, or coronary artery disease. 
Determination of BRS requires information from both BP and HR, which can be recorded simultaneously using telemetric devices. The surgical procedure is described beginning with the insertion of the pressure sensor into the left carotid artery and positioning of its tip in the aortic arch to monitor arterial pressure followed by the subcutaneous placement of the transmitter and ECG electrodes. We also describe postoperative intensive care and analgesic management. After a two-week period of post-surgery recovery long-term ECG and BP recordings are performed in conscious and unrestrained mice. Finally, we include examples of high-quality recordings and the analysis of spontaneous baroreceptor sensitivity using the sequence method.

The baroreflex is a heart-rate regulation mechanism by the autonomic nervous system in response to blood-pressure changes. We describe a surgical technique to implant telemetry transmitters for continuous and simultaneous measurement of electrocardiogram and blood pressure in mice. This can determine spontaneous baroreflex sensitivity, an important prognostic marker for cardiovascular disease.

Blood pressure (BP) and heart rate (HR) are both controlled by the autonomic nervous system (ANS) and are closely intertwined due to reflex mechanisms. ...

Real-Time Dynamic Navigation System for the Precise Quad-Zygomatic Implant Placement in a Patient with a Severely Atrophic Maxilla

Zygomatic implants (ZIs) are an ideal way to address cases of a severely atrophic edentulous maxilla and maxilla defects because they replace extensive bone augmentation and shorten the treatment cycle. However, there are risks associated with the placement of ZIs, such as penetration of the orbital cavity or infra-temporal fossa. Furthermore, the placement of multiple ZIs makes this surgery risky and more difficult to perform. Potential intraoperative complications are extremely dangerous and may cause irreparable losses. Here, we describe a practical, feasible, and reproducible protocol for a real-time surgical navigation system for precisely placing quad-zygomatic implants in the severely atrophic maxilla of patients with residual bone that does not meet the requirements of conventional implants. Hundreds of patients have received ZIs at our department based on this protocol. The clinical outcomes have been satisfactory, the intraoperative and postoperative complications have been low, and the accuracy indicated by infusion of the designed image and postoperative three-dimensional image has been high. This method should be utilized during the entire surgical procedure to ensure ZI placement safety.

Here, we present a protocol to achieve precise quad-zygomatic implant placement in patients with severely atrophic maxilla using a real-time dynamic navigation system.

Zygomatic implants (ZIs) are an ideal way to address cases of a severely atrophic edentulous maxilla and maxilla defects because they replace extensive ...

Dynamic Navigation for Dental Implant Placement

In modern implantology, the application of surgical navigation systems is becoming increasingly important. In addition to static surgical navigation methods, a guide-independent dynamic navigation implant placement procedure is becoming more widespread. The procedure is based on computer-guided dental implant placement utilizing optical control. This work aims to demonstrate the technical steps of a new dynamic computer-aided implant surgery (DCAIS)&#160;system (design, calibration, surgery) and check the accuracy of the results. Based on cone-beam computed tomography (CBCT) scans, the exact positions of implants are determined with dedicated software. The first step of the operation is the calibration of the navigation system, which can be performed in two ways: 1) based on CBCT images taken with a marker or 2) based on CBCT images without markers. Implants are inserted with the aid of real-time navigation according to the preoperative plans. The accuracy of the interventions can be evaluated based on postoperative CBCT images. The preoperative images containing the planned positions of the implants and postoperative CBCT images were compared based on the angulation (degree), platform, and apical deviation (mm) of the implants. To evaluate the data, we calculated the standard deviation (SD), mean, and standard error of the mean (SEM) of deviations within planned and performed implant positions. Differences between the two calibration methods were compared based on this data. Based on the interventions performed so far, the use of DCAIS allows for high-precision implant placement. A calibration system that does not require labeled CBCT recording allows for surgical intervention with similar accuracy as a system that uses labeling. The accuracy of the intervention can be improved by training.

Dynamic computer-aided implant surgery (DCAIS) is a controlled implant surgical placement method performed without a surgical template using optical control. The real-time intraoperative control of movement and position of the surgical device simplifies the procedure and gives more freedom to the surgeon, providing similar precision as static navigation methods.

In modern implantology, the application of surgical navigation systems is becoming increasingly important. In addition to static surgical navigation ...

A Mice Model of Chlorhexidine Gluconate-Induced Peritoneal Damage

Peritoneal fibrosis is an important complication of peritoneal dialysis (PD). To investigate and address this problem, an appropriate animal model of PD is required. The present protocol establishes a chlorhexidine gluconate (CG) induced peritoneal fibrosis model that mimics the condition of a patient with PD. Peritoneal fibrosis was induced by intraperitoneal injection of 0.1% of CG in 15% ethanol for 3 weeks (administered every other day), for a total of nine times in male C57BL/6 mice. Peritoneal functional tests were then performed on day 22. After the mice were sacrificed, the parietal peritoneum of the abdominal wall and the visceral peritoneum of the liver were harvested. They were thicker and more fibrotic when analyzed microscopically after Masson's trichrome staining. The ultrafiltration rate decreased, and glucose mass transport indicated a CG-induced increase in peritoneal permeability. The PD model thus established may have applications in improving PD technology, dialysis efficacy, and prolonging patient survival.

The present protocol establishes a peritoneal dialysis (PD) mouse model of chlorhexidine gluconate (CG)-induced peritoneal fibrosis. The current model is simple and easy to use compared to other PD animal models.

Peritoneal fibrosis is an important complication of peritoneal dialysis (PD). To investigate and address this problem, an appropriate animal model of PD ...