Name: microsurgical skills of establishing permanent jugular vein cannulation in rats for serial blood sampling of orally administered drug
Uploaded: 2021-12-14T13:00:00
Description: Watch this Scientific Journal Video about Microsurgical Skills of Establishing Permanent Jugular Vein Cannulation in Rats for Serial Blood Sampling of Orally Administered Drug at JoVE.com

This work is supported by National Natural Science Foundation of China (No. 82003692) to R.X. Zhang; Top Academic Scholarship at Northwestern Polytechnical University to R. Miao.

The procedures described below were performed as part of a protocol approved by the Institutional Animal Care and Use Committee of Northwestern Polytechnical University (No. 202101117).
1. Preoperative preparation (the day before the surgery)
NOTE: Required solutions: normal saline (0.9% w/v sodium chloride), heparinized saline (1% w/v heparin sodium), catheter lock solution, non-steroidal anti-inflammatory drug (NSAID), such as meloxicam solution (2 ...

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Mastering the technique of vessel cannulation requires significant practice and learning the lesson from each operation. Christakis et al. using cumulative sum (CUSUM) analysis, found that a researcher needs to practice 200 rats over a period of one year before being ready for the PK evaluation of drug candidates20. Yet, the operating time required for the vein cannulation can be significantly reduced by the number of rats performed13,20. ...

Repeated acquisition of blood samples from small laboratory animals, such as rodents, guinea pigs, and rabbits, is an important aspect for pharmaceutical lead optimization and also for reducing the number of animals used in research1,2. The pipeline for developing new diagnostic tools and drug formulation (e.g., vaccine) requires access to different volumes of blood in order to evaluate their robustness and performance in vivo, such as pharmacokinetics (PK), toxicity, and sensitivity3,4,5.
The laboratory approach to blood sample collection is broadly classified into two types, surgical and nonsurgical6. The nonsurgical approach is relatively easy to grasp for the researcher, which includes common techniques, such as cardiac puncture, orbital sinus puncture, and bleeding of the saphenous and tail vein. Multiple blood sampling is possible by some non-surgical methods, but the sample volume is small and can cause physical wound and psychological stress to the animals1. On the other hand, the surgical approach is a favorite alternative to repeated venipuncture, and it involves placement of a temporary or permanent cannula in the blood vessels of animals7,8,9. The large blood volume could be repeatedly withdrawn through the cannula in conscious rats while avoiding the stress and pain due to the handling technique, restrain, and anesthesia7,8,10,11. However, the cannula implantation requires an experienced researcher with adequate training in order to successfully collect the blood.
Blood collection through jugular vein cannulation (JVC) in rats is the most widely used method to study the drug PK6,10,12,13. Yet, establishment of the JVC rat model needs careful practice of microsurgical skills and knowledge of postsurgical care and maintenance. Especially, after the surgery, the rat requires administration of analgesics and sufficient recovery time to reach stable physiological condition for further experiments13,14,15. Although the body weight gain (i.e., &#62;10 g) is a valid and commonly applied indicator for the rat&#39;s recovery, it is not uncommon that the rats have unexpected death postoperatively due to dehydration, infection, and inflammation, which could be subtle to notice at the early onset14,15. In addition, catheter obstruction in the JVC model remains to be an issue during the blood collection.
The present protocol has demonstrated in detail the microsurgical procedures for JVC in an anesthetized rat with specific focus on the identification, isolation, and cannulation of the jugular vein. The importance of physiological and hematological monitoring of the rats during the recovery phase is highlighted. Finally, serial blood samples were collected through the venous catheter to study the PK of the orally administered natural phenol ellagic acid with poor bioavailability (i.e., low systemic concentration) to verify the JVC rat model.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>0.5 mL test tube containing EDTA anticoagulant</td>
			<td>Xinkang</td>
			<td>N/A</td>
			<td>collecting blood samples for hematology test</td>
		</tr>
		<tr>
			<td>0.5*20 mm 1.0-mL syringe</td>
			<td>KLMEDICAL</td>
			<td>N/A</td>
			<td>washing or replacing the fluid with saline</td>
		</tr>
		<tr>
			<td>0.6*28.5 mm 5.0-mL syringe</td>
			<td>HD</td>
			<td>N/A</td>
			<td>Subcutaneous injection</td>
		</tr>
		<tr>
			<td>1.0-mL Blunt tipped syringe (22G)</td>
			<td>skillsmodel</td>
			<td>S4-PKT22G</td>
			<td>Inject the saline and collect blood samples through catheter</td>
		</tr>
		<tr>
			<td>1.5 mL sterile microcentrifuge tube</td>
			<td>Axygen</td>
			<td>MCT-150-C-S</td>
			<td>Store sterile catheter lock solution heparinized saline and meloxicam solution</td>
		</tr>
		<tr>
			<td>1.5&#160;mL microcentrifuge tubes</td>
			<td>Biosharp</td>
			<td>BS-15-M</td>
			<td>blood collection</td>
		</tr>
		<tr>
			<td>1/2&#160; circle cutting 5*12 mm suture needle</td>
			<td>skillsmodel</td>
			<td>S4-FHZ</td>
			<td>Thread the muscle layer to fix the catheter</td>
		</tr>
		<tr>
			<td>3/8 circle cutting 7*17 mm suture needle</td>
			<td>skillsmodel</td>
			<td>S5-FHZ</td>
			<td>Suture the incision of rat cortex</td>
		</tr>
		<tr>
			<td>6-0 sterile non-absorbable silk suture thread</td>
			<td>JUNSHENG</td>
			<td>N/A</td>
			<td>ligature</td>
		</tr>
		<tr>
			<td>75% medical alcohol</td>
			<td>HONGSONG</td>
			<td>N/A</td>
			<td>Disinfection</td>
		</tr>
		<tr>
			<td>Adhensive tape</td>
			<td>LIUTAI</td>
			<td>N/A</td>
			<td>positioning the rat</td>
		</tr>
		<tr>
			<td>Autoclave sterilization tape</td>
			<td>Biosharp</td>
			<td>BS-QT-028</td>
			<td>Mark sterilized items</td>
		</tr>
		<tr>
			<td>Automated blood cell counter</td>
			<td>Sysmex</td>
			<td>XN-550</td>
			<td>Hematology test</td>
		</tr>
		<tr>
			<td>Castroviejo micro scissors</td>
			<td>skillsmodel</td>
			<td>WA1010</td>
			<td>Cut the opening in the blood vessel</td>
		</tr>
		<tr>
			<td>Centrifuge</td>
			<td>Thermo Fisher Scientific</td>
			<td>75002402</td>
			<td>Plasma preparation</td>
		</tr>
		<tr>
			<td>Clean cushion</td>
			<td>Qingjie</td>
			<td>N/A</td>
			<td>Prepare the operation area</td>
		</tr>
		<tr>
			<td>Cotton balls</td>
			<td>HC</td>
			<td>N/A</td>
			<td>Wound disinfection and sterilization</td>
		</tr>
		<tr>
			<td>Cotton swabs</td>
			<td>BEITAGOGO</td>
			<td>N/A</td>
			<td>Disinfection</td>
		</tr>
		<tr>
			<td>Curved hemostat</td>
			<td>skillsmodel</td>
			<td>N/A</td>
			<td>ligature</td>
		</tr>
		<tr>
			<td>DN50 Stainless-steel rat restrainer</td>
			<td>skillsmodel</td>
			<td>S4-RGDQ1</td>
			<td>Restrict the movement of rats for easy operation</td>
		</tr>
		<tr>
			<td>Ellagic acid</td>
			<td>Aladdin</td>
			<td>E102710-25g</td>
			<td>natural phenol for oral administration</td>
		</tr>
		<tr>
			<td>Half-curved forceps</td>
			<td>skillsmodel</td>
			<td>53072</td>
			<td>Lift the muscle layer and tissue, isolate the jugular vein and tie the suture</td>
		</tr>
		<tr>
			<td>Heating pad</td>
			<td>Warm mate</td>
			<td>N/A</td>
			<td>preventing heat loss of animal</td>
		</tr>
		<tr>
			<td>Heparin sodium</td>
			<td>Solarbio</td>
			<td>H8060</td>
			<td>anticoagulant</td>
		</tr>
		<tr>
			<td>Iodophor</td>
			<td>Xidebao</td>
			<td>N/A</td>
			<td>Clean the wound</td>
		</tr>
		<tr>
			<td>Iris scissors</td>
			<td>skillsmodel</td>
			<td>54002</td>
			<td>Bluent separation the muscle layer</td>
		</tr>
		<tr>
			<td>Isoflurane</td>
			<td>RWD</td>
			<td>R510-22-16</td>
			<td>anaesthesia</td>
		</tr>
		<tr>
			<td>LED lamp</td>
			<td>EMPERORFEEL</td>
			<td>N/A</td>
			<td>sugery</td>
		</tr>
		<tr>
			<td>Liquid chromatography-mass spectroscopy</td>
			<td>Thermo Fisher Scientific</td>
			<td>VQF01-20001/ TSQ02-10002</td>
			<td>detection of drug concentration in plasma</td>
		</tr>
		<tr>
			<td>Meloxicam</td>
			<td>Hongqiang</td>
			<td>N/A</td>
			<td>Analgesic</td>
		</tr>
		<tr>
			<td>Normal saline</td>
			<td>KL</td>
			<td>N/A</td>
			<td>Prepara the solution and protect blood vessels from drying out</td>
		</tr>
		<tr>
			<td>Pet razor</td>
			<td>Codos</td>
			<td>3180</td>
			<td>Shaving the fur</td>
		</tr>
		<tr>
			<td>Phosphate-buffered saline</td>
			<td>ZHHC</td>
			<td>PW012</td>
			<td>Preparation of Ellagic acid solution</td>
		</tr>
		<tr>
			<td>PU catheter</td>
			<td>skillsmodel</td>
			<td>RJVC-PU</td>
			<td>Jugular vein cannulation</td>
		</tr>
		<tr>
			<td>Small animal operation anesthesia console</td>
			<td>RWD</td>
			<td>68620</td>
			<td>Operation workstation</td>
		</tr>
		<tr>
			<td>Spray bottle</td>
			<td>Other</td>
			<td>N/A</td>
			<td>aseptic workstation</td>
		</tr>
		<tr>
			<td>Stainless steel plug (22G)</td>
			<td>skillsmodel</td>
			<td>S4-PKD22G</td>
			<td>Plug the catheter to ensure its sealing</td>
		</tr>
		<tr>
			<td>Stainless steel trochar</td>
			<td>skillsmodel</td>
			<td>S$-PKDGZ</td>
			<td>Guide the catheter exteriorization</td>
		</tr>
		<tr>
			<td>Sterile lock solution</td>
			<td>skillsmodel</td>
			<td>SK-FB</td>
			<td>lock the catheter to ensure its sterility</td>
		</tr>
		<tr>
			<td>Straight feeding needle</td>
			<td>skillsmodel</td>
			<td>N/A</td>
			<td>Oral gavage</td>
		</tr>
		<tr>
			<td>Surgical pouch</td>
			<td>BKMAM</td>
			<td>N/A</td>
			<td>container for sterilization of surgical instruments</td>
		</tr>
		<tr>
			<td>Surgical scissors</td>
			<td>skillsmodel</td>
			<td>J21070</td>
			<td>Cut incision on rat skin</td>
		</tr>
		<tr>
			<td>Vessel dilator balanced forceps</td>
			<td>skillsmodel</td>
			<td>WA3020</td>
			<td>Expand the blood vessel and guide the cannula to slide in</td>
		</tr>
		<tr>
			<td>ZS-MV Small animal anesthesia machine</td>
			<td>ZSLab</td>
			<td>1057003</td>
			<td>inducing and maintaining anaesthesia</td>
		</tr>
	</tbody>
</table>

microsurgical skills of establishing permanent jugular vein cannulation in rats for serial blood sampling of orally administered drug

Blood sampling in small laboratory animals is necessary for pharmaceutical lead optimization but can cause great harm and stress to experimental animals, which could potentially affect results. The jugular vein cannulation (JVC) in rats is a widely used model for repeated blood collection but requires adequate training of surgery skills and animal care. This article details the microsurgical procedures for establishing and maintaining a permanent JVC rat model with specific focus on the placement and sealing of the jugular cannula. The importance of monitoring physiological (e.g., body weight, food, and water intake) and hematological parameters, was highlighted with results presented for 6 days post-surgery during the rat&#39;s recovery. The drug-plasma concentration-time profile of orally administered natural phenol ellagic acid was determined in the JVC rat model.

This protocol has thoroughly demonstrated how to establish a long-term JVC model using microsurgical skills for serial blood collection. Figure 1A shows the essential surgical instruments and materials used to conduct the surgery. The specification of PU catheter with three blue marks is also illustrated, which is helpful for guiding the researcher to place the vein cannula in step 3.3., how to use the marks on the PU catheter to guide the cannulation (Figure 1B...

Watch this Scientific Journal Video about Microsurgical Skills of Establishing Permanent Jugular Vein Cannulation in Rats for Serial Blood Sampling of Orally Administered Drug at JoVE.com

Microsurgical Skills of Establishing Permanent Jugular Vein Cannulation in Rats for Serial Blood Sampling of Orally Administered Drug

Detailed microsurgical techniques are demonstrated to establish a longer-term jugular vein cannulation rat model for sequential blood collection in the same animal. Physiological and hematological parameters have been monitored during the rat's recovery phase. This model has been applied to study pharmacokinetics of orally administered polyphenol without inducing animal stress.

Blood sampling in small laboratory animals is necessary for pharmaceutical lead optimization but can cause great harm and stress to experimental animals, ...

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