Animal models of external traumatic wound infections

Figures & data

Figure 1 Surgical site infections (SSIs) are classified as superficial incisional SSI, deep incisional SSI and organ/space SSIs.26

Figure 2 (A) Wound morphology at day 4 post-infection of a representative mouse wound. (B) A Gram-stained section of a mouse skin abrasion specimen showing the biofilms formed by Gram-positive MRSA near the skin surface. Dark blue area: biofilms of MRSA. The mouse skin abrasion specimen was harvested at day 3 post-infection.

Figure 3 Full-thickness burn was created by applying two pre-heated brass blocks (92–95°C) to the opposing sides of an elevated skin fold on the back of a shaved mouse. Square: burned area. Bacteria were applied to surface of burn as a suspension in PBS.

Figure 4 Schematic depiction of laceration wound.

Figure 5 A complex wound involving injury to muscle, fascia, periosteum and bone.126

Table 1 Representative animal models of surgical site infections (SSIs)

Animal species	Microorganism and inoculum	Foreign body	Methods used to produce wounds and infections	End point	Refs
Female CF-1 mouse	S. aureus; P. aeruginosa 10^3 or 10^5 CFU	Segment of cotton thread (Suture)	A longitudinal midline incision, 2.3 ± 0.2 cm in length and extending down to the panniculus carnosus was made on the back. Each wound was infected by the insertion of a contaminated suture through the skin.	No deaths occurred in mice infected with S. aureus, infection persisted for 1 to 2 weeks; a few deaths were recorded in mice infected with P. aeruginosa.	10
Female CF-1 mouse	S. aureus >1 × 10^5 CFU	Catheter segment	A 1 cm incision was made in the lateral abdominal wall. Infection was produced by I.P. challenge in the lateral abdominal wall opposite to the operation wound with S. aureus suspension.	A challenge dose >1 × 10^5 CFU gave nearly 100% infection rates, while an inoculum >5 × 10^8 CFU resulted in mortality. The infection persisted as an intra-abdominal abscess surrounding the catheter for at least 30 days.	15
Male albino Webster-derived CD-1 mouse	B. fragilis (10^5–10^8 CFU); E. coli (10^5–10^8 CFU)	A 6.35 mm filter paper disc	Mice were made neutropenic by the I.P. challenge of cyclophosphamide. The skin of the ventral abdomen was incised in the midline. The infection was induced by the implantation of a carrageenan-saturated disc along with microorganism in the underlying subcutaneous tissue.	In some cases the organisms spread from the local site, and the infections progressed to lethality, especially in neutropenic mice treated with cyclophosphamide.	16
Male or female CF-1 mouse	S. aureus 2 × 10^3 CFU	Dextran or gelatin beads	S. aureus mixed with dextran or gelatin beads were injected subcutaneously into mice.	The abscesses that developed with microcarriers attained a diameter of up to 1.5 cm and persisted for several days.	17
Guinea pig	S. aureus 160 CFU	Dextran microbeads	Inoculating suspensions of S. aureus and dextran microbeads into intramuscular sites on the dorsum of guinea pigs.	As inocula rose from 0.625 to 160 organisms, 0–100% of lesions yielded staphylococcal growth on subculture.	9
Female Sprague-Dawley rat	S. aureus 8 × 10^5 CFU	32 gauge stainless steel (suture)	A 1 cm longitudinal incision was made in the lateral aspect of the thigh. A 2 × 2 cm pocket was formed in the quadriceps muscle down to the femur. S. aureus was pipetted into the pocket.	High mortality was observed in the animals with six of nine rats dying.	19
Female Sprague-Dawley rat	S. aureus 5 × 10^7 CFU	Sterile sand (100 mg)	A standard incision measuring 4 cm in length and 5 mm lateral and parallel to the vertebral column was carried through the skin. The incision was then continued to a depth of approximately 1 cm into the underlying paraspinous muscles. Sterile sand was introduced into each wound and the wound was inoculated with 100 µL of MRSA suspension.	Clinical evidence of wound infection was observed in 8 of 13 (62%) animals.	23

Table 2 Representative animal models of skin abrasion wound infection

Animal species	Microorganism & inoculum	Methods used to produce wound and infections	Wound area	End point	Refs
Female BALB/c mouse	S. aureus 1 × 10^8 CFU	Mice were pre-treated with cyclophosphamide. Skin abrasion wounds were made on the dorsal surfaces of mice using needles by creating 6 × 6 crossed scratch lines within a defined 1 × 1 cm area. Bacterial suspension was inoculated over the crossed scratches with a pipette tip.	1 × 1 cm	A stable infection, persisted for over 10 days, was developed in the mouse wounds as characterized by bioluminescence imaging.	27
Female C57 Black mouse	S. aureus 4 × 10^7 CFU	Twenty-five square millimeter square-shaped wounds were created in the skin of the back by scarification using a needle, run ten times parallel in one direction and another ten times perpendicular to the original tracks. Bacterial suspension was topically placed on each wound.	25 mm^2	This method resulted in a reproducible MRSA wound colonization model, which persisted for up to 5 days post inoculation.	28
Male CF-1 mouse	S. aureus, S. epidermidis, S. saprophyticus, Micrococcus luteus. 10^5 CFU	Mice were pre-treated with cyclophosphamide. One drop (0.02 mL) of the prepared culture suspension of S. aureus or S. epidermidis was applied to the shaved skin, which was scraped with a scalpel.	10 mm^2	89% of the mice (96 of 108) developed large abscesses (15 mm diameter).	29
Female BALB/c mouse	S. aureus 10^7 CFU	An area of ca. 2 cm^2 on the mouse back was tape stripped. Bacterial infection was initiated by topically placing on the skin a 5 µL S. aureus suspension.	2 cm^2	The number of CFU recoverable from the wound 4 hours after bacterial application was 7.03 ± 0.37 log10.	31
B7-1 or B7-2 Tg mice	C. albicans 10^7 CFU	The exposed skin was gently abraded with fine-grade, sterile sandpaper. C. albicans blast conidia were pipetted onto the surface of the wound.	2 × 2 cm	Infection remained localized to the stratum corneum of the epidermis, rarely invaded the viable epidermis, and never invaded the dermis. The infection persisted over 5 to 7 days in the mice.	34
Sprague-Dawley rat	P. aeruginosa 10^8 CFU	Partial thickness skin corresponding to 20% TBSA was removed from the rats by an electro-dermatome. Rats were inoculated on the wound surface with P. aeruginosa suspension.	20% TBSA	All animals died within 4 days, with histological evidence of invasion and widespread visceral seeding.	35
Male or female New Zealand white rabbit	S. aureus 1 × 10^6 to 1.2 × 10^9 CFU	An electric dermatome set to a thickness of 0.0015 inches created a superficial abrasion (roughly 2.0 × 2.0 cm) on the shaved dorsum. Wounds were inoculated with 50 µL of encapsulated S. aureus suspension.	2 × 2 cm	On the abraded skin sites the bacteria flourished for all time periods at 6, 12, 24 and 48 h post-infection.	36

Table 3 Representative animal models of burn wound and infections

Animal species	Microorganism & inoculum	Methods used to produce wounds and infections	Area of burn	Burning time	End point	Refs
Rat	Not infected	Boiling water.	30% TBSA	3 or 10 s		37
Male Sprague Dawley rat	P. aeruginosa 10^5 CFU	Boiling water. Burns were topically inoculated with P. aeruginosa broth.	20% TBSA	10 s	Without treatment, 19 of 20 rats died.	49
Female CF1 mouse	P. aeruginosa 100 CFU	Ethanol bath. The infections were initiated by an immediate subcutaneous injection of bacterial suspension in the burned area.	30% TBSA	10 s	The animals appeared moribund 20 h after infection.	59
Female C57BL/6J mouse	P. aeruginosa 1 × 10^7 CFU	A full thickness flame burn was achieved using a Bunsen burner applied to the exposed skin. P. aeruginosa suspension was applied topically to the burn wound on day 5 after burn injury.	35% TBSA	10 s	Long-term survival of the infected mice was 25%.	67
Male CD1 mouse	P. aeruginosa 10 to 10^6 CFU	Applying two pre-heated brass blocks (92–95°C) to the opposing sides of an elevated skin folder on the backs of shaved mice. After the infliction of burns, the eschars were immediately injected intradermally with P. aeruginosa suspension.	%5 TBSA	5 s	Survival at 10 d was 60% with infected burns. P. aeruginosa (consistently 10^8 CFU/gtissue) were recovered from the unburned muscle by 24 hours for all the different inocula of bacteria.	68
Guinea pig	S. aureus 10^8 CFU	A copper plate heated to 150°C was placed on the shaved back. Burns were infected 15 min after the burning by the smearing of S. aureus suspension onto the burned surfaces.	1 cm × 1 cm	10 s	Twenty four hours after infection, the bacterial count in the untreated burns reached 2 × 10^9 CFU/g-eschar.	74
Yorkshire pig	Not infected	Burns were made by placing a heated aluminum bar on the dorsum of the animal. The aluminum bar was heated to 200°C with a gas burner.	<15% TBSA	30 s		81
Male Wistar rat	Not infected	Absorbent lint cloth that had been immersed in boiling water (100°C) was placed over the dorsum.	2.5 × 2.5 cm	5 or 12 s		85
Male Wistar rat	Not infected	Based on skin contact with a glass chamber through which water circulates at a predetermined temperature (35–60°C).	7 cm^2	1 min–7 days		86

Table 4 Representative animal models of laceration wound infections

Animal species	Microorganism & inoculum	Methods used to produce wounds and infections	End point	Refs
Guinea pig	S. aureus 10^7 CFU	Two 3 cm incisions were made parallel and equidistant from the vertebral column, through the subcutaneous tissue down to the fascia. Bacterial inoculum was delivered to the selected wound using an ultra-micro blowout pipette.	Purulent exudates were observed in over 60% of contaminated wounds, and bacterial positive cultures were found in 100% of the contaminated wounds.	88
Guinea pig	S. pyogenes (7.8 × 10^7 CFU) S. aureus (9 × 10^7 CFU)	Four dorsal lacerations with 3 cm length were made parallel to the spine and to deep fascia. Bacterial inoculum was placed in each laceration by using a pipette system.	Four days after infection, the bacterial counts were over 10^7 CFU/g-tissue for both bacterial species.	94
Male lab rat	S. aureus 0.4 to 1.6 × 10^7 CFU	Two 3 cm full-thickness lacerations were made on each animal, with one on either side of the thoracolumbar spine. The wounds were inoculated with bacterial suspension.	No non-treated control wounds were used in the study. No long-term follow up was carried out.	96
Guinea pig	Mixed bacterial inoculum containing 1.6 to 2.4 × 10^8 CFU of S. aureus, B. fragilis and P. multocida.	Wounds were created on the dorsum of animals by making four paravertebral lacerations, 2 cm long, and 2 cm apart, extending to deep fascia. Wound edges were clamped with hemostat for 5 sec to create crushed, devitalized tissue. Bacterial inoculum was instilled into each laceration using a sterile pipette system.	At 6 d after bacterial inoculation, 33% animals had either erythema, induration or purulence and the bacterial counts >10^5 CFU/g-tissue.	97
Albino rat	Mixed culture of S. aureus, P. mirabilis, P. aeruginosa and K. pneumoniae 3 × 10^7 CFU	Two parallel vertical incisions through skin were made in the masseter muscle, 1.5 cm long, 3 mm apart, and extending to lateral surface of mandibular ramus. Pliers were inserted into two parallel incisions to the depth of the wound and squeezed firmly causing necrosis of the tissue. Each wound was then contaminated with 0.03 mL of moist soil which contained equal concentrations of the four bacterial species used.	No results of non-treated control wounds were reported by the authors. For wounds lavaged with tap water, at 6 d after contamination, positive bacterial cultures were found in all wounds, and 13 of 20 wounds were observed purulent.	98
Male Wistar albino rat	S. aureus S. pyogenes 2 × 10^7 CFU	Two paravertebral linear incisions (2 cm long, 4 cm apart) reaching the deep fascial layer were made. 1.5 cm of segments of the wound edges were crushed with hemostats for 5 sec. Bacterial Aliquots of 0.2 mL were dripped into each wound and left for resorption without spilling from the wound edges.	Infections were developed in 71.4% animals. Six days after bacterial inoculation, the bacterial counts > 10^4 CFU/g-tissue.	99

Table 5 Representative animal models of excisional wound infections

Animal species	Microorganism & inoculum	Methods used to produce infections	Wound area	End point	Refs
Male BALB/c mouse	E. coli 5 × 10^6 CFU	Four full-thickness excisional wounds were made in a line along the dorsal surface. Wounds measured 8 × 12.5 mm^2. The bottom of the wound was panniculus carnosus. A bacterial suspension (50 µL) was inoculated into each wound using a yellow tip.	8 × 12.5 mm	Infected wounds in living mice showed only a slight loss of bacterial luminescence over a period of 4 h. The next day, control infected wounds in living mice had lost, on an average, 90% of the original luminescence signal.	100
Female mutant diabetic mouse	S. aureus 1 × 10^5 CFU	Two round, full-thickness wounds were prepared on the back of each mouse using a punch biopsy instrument (3 mm diameter). Each wound was covered with a sterilized transparent dressing and inoculated with 10^5 CFU MRSA or MSSA in 30 µL of PBS.	3 mm diameter	Wounding and infection caused by MRSA on the back of the diabetic mice significantly induced increased CFU on wounds compared to those of the MRSA-infected normal mice.	105
Male Wistar rat	Not infected	A full thickness of the excision wound of circular area 400 mm2 and 2 mm depth was created.	4 cm^2		108
Female domestic pig	Not infected	Excisional dermal wounds (n = 10; two sets of 5) were created on the back of each pig. Full-thickness sections of skin (1 × 1 in.) were removed during the wounding process.	1 × 1 in n = 10		113
Female Yorkshire pig (diabetic and non-diabetic)	S. aureus 2 × 10^8 CFU	Fourteen full thickness excisional wounds (1.5 × 1.5 × 0.5 cm) were created using a blade. 1 mL of the bacterial suspension was injected into each chamber.	1.5 × 1.5 cm	Diabetic wounds showed a sustained significant infection compared to non-diabetic wounds over the whole time course of the experiment.	114
New Zealand White rabbit with both sexes	Not infected	Two matching, full-thickness, square, cutaneous wounds approximately 2 cm × 2 cm were then created on the right and left dorsal hindquarters.	2 × 2 cm		116

Table 6 Representative animal models of open fracture infections

Animal species	Microorganism & inoculum	Methods used to produce infections	End point	Refs
Male New Zealand White rabbit	S. aureus 10^7 CFU	The medial side of the tibia was exposed and a reproducible fracture of the mid-part of the tibial shaft was created. Bacterial suspension was injected into the site of the fracture through a previously placed needle.	Thirty-four rabbits (out of 62) were diagnosed as being infected. At the time of death, thirty-three of them had a positive culture for S. aureus.	118
Canine	S. aureus 10^6 CFU	Canine right tibiae were fractured with a penetrating, captive-bolt device. S. aureus suspension was given to the canines via the medullary canal proximal and distal to the fracture.	In the presence of S. aureus, VE GF mRNA expression on day 7 decreased from initial day 0 levels.	123
Male Sprague-Dawley rat	S. aureus 1.8 × 10^3 CFU to 9.2 × 10^3 CFU	A 1 cm longitudinal trough was created in the tibia medullary cavity by using a high-speed drill. S. aureus was introduced into the exposed medullary cavity at the rearmost section of the lumen by using a micro-syringe.	The minimal inoculum of S. aureus that reproducibly infected 50% and 95% of tibiae after 24 h was 1.8 × 10^3 CFU and 9.2 × 10^3 CFU, respectively.	124
SuKolk-cross female sheep	S. aureus 3 × 10^8 CFU	The mid-shaft of the tibia was exposed through a 2 cm longitudinal incision over the subcutaneous border. A chevron osteotomy was created using a Gigli saw. S. aureus was introduced into the osteotomy on a piece of sterile bovine type I collagen.	The wounds showed early signs of infection, with soft tissue swelling at the fracture site by the end of the first week.	125
Goat	S. aureus 10^3 CFU	A chevron osteotomy was created with a power saw. S. aureus suspensions were placed at the fracture site on a 5 × 5 mm piece of absorbable gelatin sponge.	There were significantly fewer and less severe infections in fractures fixed with external fixation than in those fixed with an intramedullary nail with or without reaming.	127
Male Sprague Dawley rat	S. aureus 10^2 CFU	Fracture device with a blunted blade placed at the mid-shaft of the femur. A weight of 0.94 kg was dropped from 15.3 cm. S. aureus inoculum was placed directly into the wound after both ends of the fracture were exposed.	A reproducible rate of infection of 90–100% was displayed using this model.	128
Male Sprague Dawley rat	S. aureus 10^5 CFU	A 6 mm mid-diaphyseal full-thickness defect was created with a small reciprocating saw blade. The defects in all animals were implanted with 30 mg of type I bovine collagen and wetted with S. aureus suspension.	Purulence and pin loosening were observed in 4 of the 10 wounds. Bacteria in the bone increased significantly between the 2 and 6 h time points. There was a further increase between the 6 and 24 h time points.	132
Syrian hamsters	S. aureus (10^4 CFU), P. mirabilis (10^6 CFU)	An osteotomy was made with an osteotomy blade on an air saw. Bacterial suspension was injected into the muscle over the femur.	Animals killed at 1 week had many organisms in the muscle at the site of the osteotomy. The animals killed at 2 weeks rarely had organisms in the tissue but only in the bone.	133
New Zealand white rabbits	S. aureus 10^8 CFU	Using a 2.5 mm drill, a hole was placed through both cortices of the femur. The hole was then tapped with a 3.5 mm tap. Half of the rabbits received a 3.5 mm stainless screw, and for the other half the hole was left empty. The wound was inoculated with S. aureus suspension.	In the study group received screws, 30 out of 49 rabbits (61.2%) became infected, while in the control group without screw, 19 out of 53 (35.8%) became infected.	134

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