We are grateful for the financial support from the Natural Science Foundation of Shaanxi Province (grant number 2021SF-118) and the National Natural Science Foundation of China (grant numbers 81973409, 82204631).

The animals were purchased from Xi&#39;an Jiaotong University. All animal experiment procedures were approved by the Institutional Animal Ethical Committee of Xi&#39;an Jiaotong University (approval number: SCXK [Shaanxi] 2021-103). The mice were kept for one week with 5 mice per cage. They were allowed free access to food and water. The animals were maintained at room temperature (RT; 24 &#176;C &#177; 1 &#176;C) and light/dark cycle (12 h/12 h) before the study was performed.
1. Buffer and equipment preparation
<ol>
	<li>C. albicans cell culture
	<ol>
		<li>Inoculate a monoclonal colony of C. albicans (SC5314) from a yeast extract peptone dextrose (YPD) plate medium with an inoculating loop into 5 mL of YPD liquid medium (YPD + 50 &#181;g/mL carbenicillin).</li>
		<li>Shake C. albicans cells subsequently at a speed of 220 rpm at 30 &#176;C overnight.</li>
		<li>Centrifuge the suspension at 400 x g for 5 min at RT. Resuspend the C. albicans cells in normal saline and dilute the concentration of cells&#160;to 1 x 106 cells/mL via visually adjusting the turbidity to be the same as a 0.5 McFarland.</li>
	</ol>
	</li>
	<li>Preparation of normal saline
	<ol>
		<li>Weigh 0.9 g of sodium chloride and dissolve in 100 mL of deionized water to prepare 0.9% normal saline.</li>
	</ol>
	</li>
	<li>Surgical instruments preparation
	<ol>
		<li>Autoclave (121 &#176;C, 30 min) the surgical instruments (scissors, forceps, hemostatic forceps, needle holders, suture needles) and titanium-nickel alloy wire (about 0.5 mm in diameter) before use.</li>
	</ol>
	</li>
</ol>
2. Mouse PJI model establishment
<ol>
	<li>Randomly divide 30 C57BL/6 mice (male, 15-20 g) into 3 groups (10 mice/group), namely, control group, blank implant group (titanium-nickel wire implantation without C. albicans infection), and PJI group (titanium-nickel wire implantation with C. albicans infection).</li>
	<li>Anesthetize the mice with 1-4% isoflurane inhalation before removing the hair on the left hindlimb and disinfecting it with iodine. The loss of the righting reflex and no response to the toe stimulation confirms the depth of anesthesia. While&#160;anesthetizing, apply ophthalmic ointment on both eyes to prevent corneal dryness and to replenish heat during surgery and recovery.</li>
	<li>For the mice in the control group, do not provide any treatment. Provide them free access to water and food.</li>
	<li>For the mice in the blank implant group and PJI group, make a 5 mm longitudinal incision on the knee of each left hindlimb with a #10 blade or a sterile razor to expose joints.</li>
	<li>Make a hole of 5 mm in length in the femoral intramedullary canal by inserting a sterile syringe (26 G) needle.</li>
	<li>Insert a smooth nickel-titanium alloy wire (0.5 mm in diameter, 5 mm in length) into the hole before being cut with scissors (Figure 1).</li>
	<li>For the mice in the blank implant group, add 2 &#181;L of YPD medium along the nickel-titanium alloy wire drop by drop before closing the wound layer by layer using a nylon suture (0.15 mm diameter).</li>
	<li>For the mice in the PJI group, inoculate 2 &#181;L of C. albicans cells&#160;(1 &#215; 106 cells/mL) into the joint space of mice along the nickel-titanium alloy wire drop by drop before closing the wound layer by layer using a nylon suture.</li>
	<li>House the mice with free access to water and food for 14 days. Administer meloxicam by subcutaneous injection (4 mg/kg) every 24 h for up to 3 days.</li>
	<li>After 14 days, anesthetize the mice with 3% isoflurane before euthanizing the mice by cervical dislocation.</li>
</ol>
3. PJI model evaluation
<ol>
	<li>Evaluation of infections in major organs
	<ol>
		<li>Collect the kidneys, liver, and spleen from the mice after euthanizing.</li>
		<li>Add 500 &#181;L of sterile normal saline in each organ and grind the tissues on a homogenizer at&#160;4 &#176;C.</li>
		<li>Add 100 &#181;L of the homogenate prepared in step 3.1.2 to a YPD plate before spreading it evenly with a bent rod.</li>
		<li>Place the YPD plates inverted into a 37 &#176;C incubator for 48 h.</li>
		<li>Observe and count the number of colonies visually.</li>
	</ol>
	</li>
	<li>Observation of C. albicans and biofilms on the implants
	<ol>
		<li>Carefully cut the skin over the joint of the mice with scissors before collecting the implant with tweezers.</li>
		<li>Keep the implants immersed in a 2.5% glutaraldehyde solution for fixation at 4 &#176;C for 48 h.</li>
		<li>Rinse the implants with sterile PBS three times before immersing them in 1% osmium acid solution for 3 h.</li>
		<li>Rinse the implants with sterile PBS three times before immersing them in 50%, 70%, 80%, 90%, and 100% ethanol solutions for 15 min for dehydration.</li>
		<li>Keep the implants immersed in tert-butanol for 30 min three times before freeze-drying the implants.</li>
		<li>Fix the implant samples to the sample stage, sputter coat the implant with gold (10 nm coating), and observe it under a scanning electronic microscope (SEM) under a high vacuum and 1.5 kV.</li>
	</ol>
	</li>
	<li>Pathological analysis of the femur tissues
	<ol>
		<li>Collect the femoral tissues with scissors after euthanizing the mice.</li>
		<li>Immerse the femur tissues in 4% paraformaldehyde solution for fixation at 4 &#176;C for 48 h.</li>
		<li>Place the femur tissues in 10% formalin for 1 week.</li>
		<li>Dehydrate the femur tissues by immersing them in 50%, 70%, 80%, 90%, and 100% ethanol solutions for 15 min, respectively.</li>
		<li>Embed the dehydrated femur tissues in paraffin before sectioning the tissues into 4 &#181;m samples using a microtome.</li>
		<li>Stain the femur sections with hematoxylin and eosin by following a standard protocol before pathological analysis21.</li>
	</ol>
	</li>
</ol>

Establishing a Mouse Model for Candida albicans Biofilm-Related PJI

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L., Wilson, D., Hube, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Candida+albicans+pathogenicity+mechanisms.">Candida albicans pathogenicity mechanisms.</a> Virulence. 4 (2), 119-128 (2013).</li><li>Fan, 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=Candida+albicans+biofilms:+antifungal+resistance,+immune+evasion,+and+emerging+therapeutic+strategies.">Candida albicans biofilms: antifungal resistance, immune evasion, and emerging therapeutic strategies.</a> International Journal of Antimicrobial Agents. 60 (5-6), 106673 (2022).</li><li>Tong, Y., Tang, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Candida+albicans+infection+and+intestinal+immunity.">Candida albicans infection and intestinal immunity.</a> Microbiological Research. 198, 27-35 (2017).</li><li>Kanaguchi, 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=Effects+of+salivary+protein+flow+and+indigenous+microorganisms+on+initial+colonization+of+Candida+albicans+in+an+in+vivo+model.">Effects of salivary protein flow and indigenous microorganisms on initial colonization of Candida albicans in an in vivo model.</a> Bmc Oral Health. 12, 36 (2012).</li><li>Gulati, M., Nobile, C. 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D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Candida+albicans+biofilms+and+human+disease.">Candida albicans biofilms and human disease.</a> Annual Review of Microbiology. 69, 71-92 (2015).</li><li>Mack, D., 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=Biofilm+formation+in+medical+device-related+infection.">Biofilm formation in medical device-related infection.</a> The International Journal of Artificial Organs. 29 (4), 343-359 (2006).</li><li>Miller, R., 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=Periprosthetic+joint+infection:+A+review+of+antibiotic+treatment.">Periprosthetic joint infection: A review of antibiotic treatment.</a> JBJS Reviews. 8 (7), e1900224 (2020).</li><li>Brown, T. S., 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=Periprosthetic+joint+infection+with+fungal+pathogens.">Periprosthetic joint infection with fungal pathogens.</a> The Journal of Arthroplasty. 33 (8), 2605-2612 (2018).</li><li>Kojic, E. M., Darouiche, R. O. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Candida+infections+of+medical+devices.">Candida infections of medical devices.</a> Clinical Microbiology Reviews. 17 (2), 255-267 (2004).</li><li>Schoof, 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=Fungal+periprosthetic+joint+infection+of+the+hip:+a+systematic+review.">Fungal periprosthetic joint infection of the hip: a systematic review.</a> Orthopedic Reviews (Pavia). 7 (1), 5748 (2015).</li><li>Izakovicova, P., Borens, O., Trampuz, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Periprosthetic+joint+infection:+current+concepts+and+outlook.">Periprosthetic joint infection: current concepts and outlook.</a> EFORT Open Reviews. 4 (7), 482-494 (2019).</li><li>Tande, A. J., Patel, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Prosthetic+joint+infection.">Prosthetic joint infection.</a> Clinical Microbiology Reviews. 27 (2), 302-345 (2014).</li><li>Stocks, G., Janssen, H. F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Infection+in+patients+after+implantation+of+an+orthopedic+device.">Infection in patients after implantation of an orthopedic device.</a> ASAIO Journal. 46 (6), S41-S46 (2000).</li><li>Shahi, A., Tan, T. L., Chen, A. F., Maltenfort, M. 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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The infection caused by the contamination of surgical instruments or the surgical environment during surgery is the major reason for most implant infections24,25,26,27. Therefore, a mouse C. albicans biofilm-related PJI model was constructed in this study. Compared to the traditional PJI model in which sterile stainless-steel particles suspended in saline were used as the implant, a ni...

Candida albicans (C. albicans) commensally reside in many parts of the human body1, which is also the most common opportunistic pathogen that causes life-threatening invasive fungal infections, especially in immunocompromised patients2,3. C. albicans can transform between yeast and mycelium states as a polymorphic fungus. The mycelium state exhibits higher virulence, stronger adhesion, and invasion of cells and tissues4,5. Besides, C. albicans can form biofilms on the surfaces of biomedical materials such as dentures, catheters, and stents1,6,7. The dense three-dimensional structure of biofilms restricts the infiltration of antifungal drugs, expresses drug-resistant genes, and down-regulates the metabolism of fungal cells to resist immune system clearance6,7. Therefore, biofilms-related infections&#160;are quite challenging in clinics8.
Staphylococcus aureus, coagulase-negative staphylococcus, and enterobacter are the main pathogens causing PJI9. Although the incidence of fungal PJI is relatively low (about 1%)10, the treatment cost of fungal PJI is higher11, the treatment cycle is longer11, and the treatment success rate is lower10 than bacterial PJI. In recent years, the incidence of fungal PJI has been increasing year-by-year10. Candida PJI accounts for 77%-84% of fungal PJI10,12, and C. albicans is the most common in Candida (54%). Therefore, fungal PJI needs to be studied.
Currently, PJI is treated via revision surgery by (1) removing the infected implant, (2) debridement, (3) antimicrobial treatment, and (4) reimplantation. After thorough debridement, an antibiotic containing bone cement is placed, and the patient is treated with antibiotics systemically for more than 6 weeks to effectively control the infection before a new implant is placed13. However, this method cannot fully eliminate pathogens in tissues, and recurrent infections treated with long-term antimicrobial therapy are highly likely to develop in drug-resistant strains14,15,16.
Establishing animal models of PJI is important for the research and development of new drugs or therapeutics for PJI. In the development of PJI, large dead spaces are formed around the prosthesis, leading to the formation of hematomas, which further block the blood supply of the surrounding tissues and impair the effect of antibiotics11,15. Due to the difficulty in mimicking the surrounding environment of the prosthesis, traditional animal models cannot accurately simulate the actual situation of PJI17,18.
In this paper, a C. albicans biofilm-associated PJI model in mice was constructed by using a clinically widely used titanium-nickel wire to simulate joint implants19,20. This PJI model exhibits the advantages of easy operation, high successful rate, high repeatability, and high clinical correlation. It is expected to be an important model for studying the prevention and treatment of C. albicans biofilm-related PJI.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>0.5 Mactutrius turbidibris</td>
			<td>Shanghai Lujing Technology Co., Ltd</td>
			<td>5106063</td>
			<td></td>
		</tr>
		<tr>
			<td>4 &#176;C refrigerator</td>
			<td>Electrolux (China) Electric Co., Ltd</td>
			<td>ESE6539TA</td>
			<td></td>
		</tr>
		<tr>
			<td>Agar</td>
			<td>Beijing Aoboxing Bio-tech Co., Ltd</td>
			<td>01-023</td>
			<td></td>
		</tr>
		<tr>
			<td>Analytical balances</td>
			<td>Shimadzu</td>
			<td>ATX124</td>
			<td></td>
		</tr>
		<tr>
			<td>Autoclaves Sterilizer</td>
			<td>SANYO</td>
			<td>MLS-3750</td>
			<td></td>
		</tr>
		<tr>
			<td>Carbenicillin</td>
			<td>Amresco</td>
			<td>C0885</td>
			<td></td>
		</tr>
		<tr>
			<td>Eclipse Ci Nikon upright optical microscope&#160;</td>
			<td>Nikon</td>
			<td>Eclipse Ts2-FL</td>
			<td></td>
		</tr>
		<tr>
			<td>Glucose</td>
			<td>Macklin&#160;</td>
			<td>D823520</td>
			<td></td>
		</tr>
		<tr>
			<td>Inoculation ring</td>
			<td>Thermo Scientific</td>
			<td>251586</td>
			<td></td>
		</tr>
		<tr>
			<td>Isoflurane</td>
			<td>RWD</td>
			<td>20210103</td>
			<td></td>
		</tr>
		<tr>
			<td>NaCl</td>
			<td>Xi&#39;an Jingxi Shuanghe Pharmaceutical Co., Ltd</td>
			<td>20180108</td>
			<td></td>
		</tr>
		<tr>
			<td>Paraformaldehyde</td>
			<td>Beyotime Biotechnology</td>
			<td>P0099</td>
			<td></td>
		</tr>
		<tr>
			<td>Peptone</td>
			<td>Beijing Aoboxing Bio-tech Co., Ltd</td>
			<td>01-001</td>
			<td></td>
		</tr>
		<tr>
			<td>RWD R550 multi-channel small animal anesthesia machine&#160;</td>
			<td>RWD</td>
			<td>R550</td>
			<td></td>
		</tr>
		<tr>
			<td>SEM</td>
			<td>Hitachi</td>
			<td>TM-1000</td>
			<td></td>
		</tr>
		<tr>
			<td>Temperature incubator</td>
			<td>Shanghai Zhichu Instrument Co., Ltd</td>
			<td>ZQTY-50N</td>
			<td></td>
		</tr>
		<tr>
			<td>Ultrapure water water generator</td>
			<td>Heal Force</td>
			<td>NW20VF</td>
			<td></td>
		</tr>
		<tr>
			<td>Ultrasound machine</td>
			<td>Do-Chrom</td>
			<td>DS10260D</td>
			<td></td>
		</tr>
		<tr>
			<td>Yeast extract</td>
			<td>Thermo Scientific&#160;Oxoid</td>
			<td>LP0021B</td>
			<td></td>
		</tr>
	</tbody>
</table>

a periprosthetic joint candida albicans infection model in mouse

Periprosthetic joint infection (PJI) is one of the common infections caused by Candida albicans (C. albicans), which increasingly concerns surgeons and scientists. Generally, biofilms that can shield C. albicans from antibiotics and immune clearance are formed at the infection site. Surgery involving the removal of the infected implant, debridement, antimicrobial treatment, and reimplantation is the gold standard for the treatment of PJI. Thus, establishing animal PJI models is of great significance for the research and development of new drugs or therapeutics for PJI. In this study, a smooth nickel-titanium alloy wire, a widely used implant in orthopedic clinics, was inserted into the femoral joint of a C57BL/6 mouse before the C. albicans were inoculated into the articular cavity along the wire. After 14 days, mature and thick biofilms were observed on the surface of implants under a scanning electronic microscope (SEM). A significantly reduced bone trabecula was found in the H&amp;E staining of the infected joint specimens. To sum up, a mouse PJI model with the advantages of easy operation, high successful rate, high repeatability, and high clinical correlation was established. This is expected to be an important model for clinical studies of C. albicans biofilm-related PJI prevention.

Author Spotlight: Advancing Research on Candida albicans Biofilm-Associated Prosthetic Joint Infections 

A Periprosthetic Joint Candida albicans Infection Model in Mouse

Transferring the samples onto a plate medium and counting colonies after overnight incubation is commonly used to assess the local pathogen load near the lesion22,23. In our study, the microbial culture of liver, kidney, and spleen samples was negative, indicating that the model in this study only led to local infection instead of systemic infection in the mice23.
The SEM images of the implants are shown in <str...

Watch this Scientific Journal Video about Advancing Research on Candida albicans Biofilm-Associated Prosthetic Joint Infections at JoVE.com

Periprosthetic joint infection (PJI) caused by dangerous pathogens is common in clinical orthopedics. Existing animal models cannot accurately simulate the actual situation of PJI. Here, we established a Candida albicans biofilm-associated PJI mouse model to research and develop new therapeutics for PJI.

Periprosthetic joint infection (PJI) is one of the common infections caused by Candida albicans (C. albicans), which increasingly concerns surgeons and ...

a-periprosthetic-joint-candida-albicans-infection-model-in-mouse

Research

JoVE Journal

Immunology and Infection

524 Views.  Xi’an Jiaotong University. Periprosthetic joint infection (PJI) caused by dangerous pathogens is common in clinical orthopedics. Existing animal models cannot accurately simulate the actual situation of PJI. Here, we established a Candida albicans biofilm-associated PJI mouse model to research and develop new therapeutics for PJI.