C H A P T E R
22
Basic Experimental Methods
Richard B. Huneke
Drexel University College of Medicine, Philadelphia, PA, USA
O U T L I N E
Introduction 621
Handling and Restraint 621
Sampling Techniques 622
Blood Sampling 622
Cerebrospinal Fluid Collection 622
Milk Collection 623
Semen Collection 623
Urine 623
Bile, Gastric Juice, and Feces 623
Compound Administration 624
INTRODUCTION
Extensive use of the guinea pig in a variety of experi-
mental procedures ranging from inhalation studies to
hearing research has given rise to common biomethod-
ology and the introduction of specialized experimental
techniques. All surgical techniques described in this
chapter should be performed using aseptic technique,
and with the administration of appropriate anesthesia
and analgesia.
HANDLING AND RESTRAINT
The handling and restraint of guinea pigs has been
previously discussed (Donnelly and Brown, 2004; Terril
The Laboratory Rabbit, Guinea Pig, Hamster, and Other Rodents 
DOI: 10.1016/B978-0-12-380920-9.00022-5 621
Specialized Research Techniques 624
Endotracheal Intubation 624
Electrophysiology 625
Cardiovascular Studies 625
Reproductive Studies 626
Hearing Studies 628
Respiratory Studies 629
Musculoskeletal Studies 630
Endocrine Studies 630
Skin Studies 631
References 632
and Clemons, 1998). Guinea pigs are easily handled
and are docile animals; and they should be approached
slowly as they are easily startled and will stampede
when being caught. Guinea pigs can squeal and strug-
gle if not handled gently. Most simple procedures can
be performed on guinea pigs under manual restraint
and chemical restraint is rarely required. When hold-
ing the guinea pig, use both hands to grasp it around
the chest with one hand placed beneath the thorax and
abdomen to provide support while holding (Figure
22.1). Use care not to squeeze too firmly or for too long.
For a large guinea pig or pregnant sow, the rear quar-
ters should be supported with one hand while being
held to prevent injury. The animal can be held firmly
against the body or with the head held in the crook
of the elbow for minor procedures. Another restraint
© 2012 Elsevier Inc.
622 22.  Basic Experimental Methods
FIGURE 22.1  Manual restraint of the guinea pig with one hand
grasping the chest and the other hand supporting the rear legs.
technique involves holding up the anterior portion of
the animal while its rear legs remain on the surface sup-
porting the animal, or by holding the chest and forelegs
in one hand and the pelvis and hind legs in the other
hand. With repeated handling, guinea pigs become
accustomed to being held and struggle less.
SAMPLING TECHNIQUES
Blood Sampling
Obtaining blood samples from guinea pigs is diffi-
cult. The site for percutaneous blood sampling should be
chosen based on the size of the guinea pig, the volume
of blood needed, and the expertise of the person per-
forming the phlebotomy. The volume of blood collected
depends upon the size of the guinea pig and the time
interval between collections. As a general rule, 10% of
the circulating blood volume can be collected every 3–4
weeks. For daily sampling, no more than 1% of blood
volume should be collected without adverse effects to
III. GUINEA PIGS
FIGURE 22.2  Blood collection from the ear vein. The needle is
used to nick the vessel for collection of small amounts of blood.
the animal. The average blood volume of the guinea pig
is 75 ml/kg, therefore 7.5 ml/kg body weight could be
removed every 3–4 weeks (Terril and Clemons, 1998).
Methods employed to obtain small-volume samples
of blood include cutting the nail bed (Hochman and
Blanchard, 1983), puncture of the lateral saphenous vein
(Hem et al., 1998), the digital veins (Keino et al., 2002),
ear vein (Bullock, 1983) (Figure 22.2), the lateral meta-
tarsal vein (Dolence and Jones, 1975), and puncture of
the orbital sinus (Sorg and Buckner, 1964). The size of
the needle tip or lancet used for nicking the blood ves-
sel should be the smallest possible to enable rapid blood
flow. Pressure should be applied after collection to stop
the bleeding. For collection of larger volumes of blood,
cardiac puncture has been used; however, this tech-
nique is always traumatic, must be performed under
anesthesia, and is potentially fatal. Indwelling cannula
placement in the femoral vein or external jugular vein
requires surgical cutdown (Shrader and Everson, 1968),
while cannulation of the lateral saphenous vein can be
performed percutaneously (Nau and Schunck, 1993).
Venipuncture of the cranial vena cava (Reuter, 1987),
femoral vein or artery (Palumbo et al., 1975), and medial
saphenous vein (Figure 22.3) (Carraway and Gray, 1989)
has yielded up to 3 ml per sample. The gauge of needle
used for venipuncture should be slightly smaller than
the size of the vessel. Stone et al. (1961) reported that
carbon dioxide anesthesia increased the yields of blood
and serum particularly when exanguinating the animal.
Cerebrospinal Fluid Collection
Up to 300 µl of cerebrospinal fluid (CSF) may be
collected by tapping the cisterna magna through the
atlanto-occipital space in anesthetized guinea pigs
 Sampling Techniques
FIGURE 22.3  Venipuncture of the saphenous vein. This location
can also be used for intravenous injections.
using 23-gauge hypodermic needles (Reiber and
Schunck, 1983; Suckling and Reiber, 1984). CSF samples
(100 μl) were obtained two times per week from anes-
thetized guinea pigs by inserting a cannula attached to
a 1 ml syringe between the spinous process of the first
and second cervical vertebrae (Fassbender et al., 2001).
By restraining the head of anesthetized animals using a
stereotaxic instrument with ear bars, the tip of the punc-
ture needle can be maintained stably within the cisterna
magna for 6–12 hours. This method allows for repeated
collections with a total volume as large as 1 ml of CSF
(Liu and Guo, 1991). Chronic CSF collection techniques
involve surgically fixing a guide cannula secured to
a silicone rubber disc to the atlanto-occipital mem-
brane, allowing for daily CSF samples to be collected
from conscious, unrestrained guinea pigs (Jones and
Robinson, 1981).
Milk Collection
Milk can be collected from guinea pigs by hand milk-
ing or by a mechanical milking apparatus. A miniature
milking machine using a mechanical vacuum pump
has been described for collecting between 1.0–9.0 ml
from a lactating sow in one milking (Gupta et al., 1970;
Nelson et al., 1951). To eliminate the need for a mechani-
cal pump system, decreasing noise and allowing for col-
lection in animal holding rooms, the operator can serve
as the vacuum source using a mouth piece (Anderson,
1990; McKenzie and Anderson, 1979), however the
practice of mouth pipetting is discouraged. For satisfac-
tory milking, the level of vacuum should be about 10
inches of mercury and the vacuum pulsations at about
25 per minute (Nelson et al., 1951). It is also possible to
III. GUINEA PIGS
623
aspirate mammary gland ducts with a 30-gauge needle,
if required for experimental procedures (Nonnecke and
Targowksi, 1984).
Semen Collection
Semen can be collected by singly housing adult male
guinea pigs in open-bottom cages and observing service
pans for spontaneous ejaculate. One study showed the
average number of spontaneous ejaculates ranged from
1–5 over a 14-day period (Shepherd and Martan, 1983).
Guinea pig semen can be collected by electroejaculation
using an electrode in the lumbar area and an anal elec-
trode. The mean ejaculate volume using this technique
was 0.5 ml (Freund, 1958). This technique was detailed
further in a report of the characteristics of guinea pig
semen (Freund, 1969).
Urine
Urine collection can be performed using a number of
techniques (Terril and Clemons, 1998). The urinary blad-
der is palpated in the caudal abdominal area and when
gentle pressure is applied, a stream of urine should be
produced. Care should be taken to not apply too much
pressure and rupture the bladder. Cystocentesis may
be used to collect uncontaminated urine using a needle
inserted into the urinary bladder through the abdomi-
nal wall. Cystocentesis should be performed following
a surgical preparation of the caudal abdomen. If bacte-
rial contamination of the urine is acceptable, urine may
be collected from the cage floor or in the pan beneath a
suspended cage or using a metabolism cage which can
separate urine from feces. A surgical method of complete
and continuous urine collection from conscious unre-
strained animals via an exteriorized catheter and tether
has been described (Mandavilli et al., 1991).
Bile, Gastric Juice, and Feces
The portal vein can be cannulated for blood collection
or compound administration by advancing a catheter
from a mesenteric tributary vein. Bile can be collected
from a catheter inserted in the gall bladder to avoid the
difficulty of cannulating the friable bile duct. Both can-
nulae can be exteriorized via stab incisions in the flank
for intermittent sampling (Talbot and Hynd, 1985).
Gastric juice can be collected from conscious restrained
guinea pigs. The animals are fasted and housed on wire-
bottom cages to prevent consumption of bedding and
feces. The guinea pigs are restrained in a vertical position
with a gauze loop around the upper incisors maintaining
its head in extreme dorsoflexion. A 5- or 6-F infant feed-
ing tube is inserted down the throat, being careful not to
624 22.  Basic Experimental Methods

deviate to either side of the buccal cavity. The tube is slid

directly down the esophagus, and gastric juice is with-
drawn, using a 5-ml syringe attached to the feeding tube.
Once the desired volume of juice is collected, the tube is
pinched off as it is withdrawn from the esophagus, to pre-
vent backflow of gastric juice (Shomer et al., 1999).
Feces can be easily collected from the floor of the
guinea pig’s cage. Bauer et al. (2008) measured fecal
steroids using enzyme immunoassays to eliminate the
profound effect of restraint and the blood sampling
procedure on serum cortisol levels. This non-invasive
method was validated for the assessment of fecal cor-
tisol, progesterone, and estrogen metabolites, however,
fecal and plasma testosterone levels did not correlate
significantly.
FIGURE 22.4  Technique for subcutaneous injection in the guinea
pig. Creating a skin fold aids insertion of the needle under the skin.
COMPOUND ADMINISTRATION

Liquids or solids, particularly materials which

create problems of contamination such as radioisotopes
or microorganisms, may be administered in a gelatin
capsule with a small version of a large animal balling
gun (Nelson and Hoar, 1969) or through an administra-
tion tube inserted into the stomach via the oropharynx
(De Brant and Remon, 1991). A simple mouth gag may
be used to enable intragastric intubation of the guinea
pig by one person without the use of sedation or anes-
thesia (Smith et al., 1993). Administering compounds
by adding them to the drinking water does not provide
precise dosing, and due to the guinea pig’s aversion to
novel tastes, is usually not effective. Solutions or suspen-
sions may be introduced into the bronchopulmonary cir-
culation by occluding the esophagus with a special probe
and allowing normal respiratory movements to aspirate
liquids placed in the animal’s oral pharynx (Vlad et al., FIGURE 22.5  Technique for intramuscular injection into the
1970). The most common procedure for the introduction gluteal muscles of the guinea pig. The volume of injection should
of materials in various forms is by injection, either subcu- be limited to 0.3 ml in adults and care should be taken to avoid the
sciatic nerve.
taneous (Figure 22.4), intramuscular (Figure 22.5), intra-
peritoneal, intrathoracic, intracardiac, or intravenous.
Intravenous injections have been administered to guinea Everson, 1968). Implantable osmotic pumps can be used
pigs by way of the dorsal metatarsal vein (Nobunaga for continuous administration of compounds into the
et al., 1966), lateral metatarsal vein (Dolence and Jones, subcutaneous, peritoneal, or vascular spaces.
1975; Grice, 1964), dorsolateral vein of the penis (Grice,
1964; Karlson, 1959), superficial veins of the ventral
abdominal wall (Johnson, 1950), the marginal ear veins
SPECIALIZED RESEARCH TECHNIQUES
(Grice, 1964; Karlson and Feldman, 1953; Markham and
Kent, 1951), sublingual vein (Waynforth and Parkin,
1969), medial saphenous vein (Hochman and Blanchard,
Endotracheal Intubation
1983), or the cranial vena cava (Reuter, 1987). Choice of Endotracheal intubation of the guinea pig is diffi-
injection site will depend on the size of the guinea pig, cult due to the narrow oral cavity and the anatomy of
amount of compound administered, and the experience the larynx and upper airway. A modified commercially
and preference of the handler. An indwelling cannula available laryngoscope blade (Kujime and Natelson,
was used in guinea pigs for both repeated injections and 1981; Turner et al., 1992) or pediatric blade using a
blood sampling (Nau and Schunck, 1993; Shrader and catheter can be used for direct laryngeal intubation

III. GUINEA PIGS

 Specialized Research Techniques
(Blouin and Cormier, 1987; Tremblay et al., 1990).
Kramer et al. (1998) utilized a specially constructed
restraint device which assisted in the positioning of the
guinea pig for intubation using an endotracheal tube
with an outside diameter of 2 mm.
Blouin and Cormier (1987) described a technique
for endotracheal intubation without the assistance
of another person. The anesthetized guinea pig was
placed in a supine position on a surgery board with the
upper jaw attached to the surface of the board by an
elastic band over the incisor teeth. By proper position-
ing, the operator could look directly into the opening
of the trachea. A small laryngoscope with a modified
Wisconsin pediatric blade #0 was used. The blade was
narrowed laterally by filing both sides near its extrem-
ity, permitting the blade to advance deeper into the
laryngeal region without causing trauma while still
retaining the tongue and soft palate up and out of the
visual path. A cotton tip applicator was used to clean
secretions as required. A tracheal cannula was made
from an intravenous catheter (14 gauge, 60 mm). The
catheter stylet was filed down to remove the sharpened
point. Under direct vision, the sterile catheter, with the
modified stylet, was advanced into the epiglottis which
was lifted with the tip of the catheter. The catheter was
then lifted slightly and pushed gently forward into
the curved trachea. The laryngoscope and stylet were
withdrawn. Formation of water vapor on a clean mir-
ror, with each breath of the animal, confirmed that the
endotracheal tube was in place.
Electrophysiology
The guinea pig is preferred by many investiga-
tors for study of pre- and neonatal cardiac or corti-
cal activities under various maternal conditions. The
technique of Flexner et al. (1950) for determining fetal
EEG involved delivery by cesarian section into a bath
of warm Ringer’s solution while maintaining an intact
umbilical circulation. Following craniotomy, electrodes
were placed on the cerebral cortex. This procedure was
modified by pushing hook electrodes directly through
the fetal skull where they would rest on or perhaps
1–2 mm into the fetal cortex (Bergstrom et al., 1961). The
technique was further modified in order to prevent loss
of amniotic fluid and avoid the trauma of hysterotomy
by compressing the fetal vertex against the uterine wall
and then pushing the needle electrodes through the
myometrium, scalp, and skull to reach the cerebral cor-
tex. A third electrode was sutured to the myometrium
over the fetal thorax to record the fetal ECG (Rosen and
McLaughlin, 1966a, 1966b; Singer et al., 1973). A chronic
model was developed to measure long-term uterine
activity for up to 4 weeks in pregnant guinea pigs using
a uterine EMG array, intrauterine and intra-abdominal
III. GUINEA PIGS
625
balloon catheters and vascular catheters (Schellenberg
et al., 1995).
Electrical activity has been recorded from the brain
in adult guinea pigs by implanting electrodes on the
surface of the skull, the epidural tissue, or by stereo-
taxically implanting bipolar electrodes into specific
regions of the brain. These techniques have been used
for repeated EEG recording for studying central control
of heart rate (Pedemonte et al., 2003), sleep–wake cycles
(Kato et al., 2007), treatments for epilepsy (Dorandeu
et al., 2005), and auditory and visual evoked potentials
in response to noise and light (Goksoy et al., 2005) in
the guinea pig.
EMG activity was measured to determine muscu-
lophysiologic activity. The cutaneous trunci muscle
reflex, initiated by brief tactile or electrical stimulation
of the skin was shown to be useful as a measure of spi-
nal tract function following spinal cord injury (Blight
et al., 1990). Apomorphine-induced jaw movement
in ketamine-anesthetized guinea pigs was shown to
be similar to lapping jaw movements observed dur-
ing drinking in awake animals by recording electrical
activity of the left anterior digastric and the genioglos-
sus muscles (Gerstner and Goldberg, 1991). To study
how work load on a treadmill affects the overall mus-
cle activity and assists in training induced muscle bio-
chemical alterations, EMG fine wire electrodes were
chronically implanted in fast-twitch and slow-twitch
hind limb muscles (Gardiner et al., 1982). The bladder
cooling reflex in response to infusions of cold saline and
its effect on external urethral sphincter activity in both
the anesthetized and awake guinea pig was studied
using electromyographic recordings (Jiang et al., 2008).
Avan et al. (1992) studied the protective role of the mid-
dle ear muscle in response to loud sounds and active
self-vocalization using implanted EMG electrodes.
Cardiovascular Studies
The early drug development process has put great
emphasis on the potential of the effect of the com-
pound on QT interval prolongation and other cardiac
abnormalities. QT and RR intervals were measured in
6-week and 23-month female conscious guinea pigs to
study age-related characteristics on cardiac repolariza-
tion (Shiotani et al., 2008). The electrical activity of the
hearts of newborn guinea pigs was validated using two
different lead systems (Schwartze and Thoss, 1981).
Cardiovascular parameters were measured in guinea
pigs anesthetized with urethane (1.5 g/kg, i.p.). A poly-
ethylene catheter was inserted into the carotid artery
and attached to a pressure transducer. A Millar microtip
catheter pressure transducer was inserted in to the con-
tralateral carotid artery and advanced to the left ven-
tricle, allowing contractile properties to be measured,
626 22.  Basic Experimental Methods
and ECG was recorded by inserting needle electrodes
according to standard limb leads. These animals were
found to be good models for the hemodynamic effects
of repeated intravenous administrations of compounds
for safety pharmacology studies, allowing for the mea-
surement of heart rate, blood pressure, left ventricular
pressure and ECG (Hauser et al., 2005).
Telemetry has been used to collect cardiovascular
measurements from conscious freely moving guinea
pigs. Using sterile technique, an abdominal incision
was made and a blood pressure sensor was placed in
the descending aorta below the renal arteries, point-
ing upstream. Bipolar electrodes were implanted in
the right thoracic ventral serratus muscle and external
oblique abdominal muscle to measure ECG. The telem-
etry transmitter was implanted in the peritoneal cavity
and sutured to the abdominal wall. ECG intervals and
arterial blood pressure were monitored in these animals
for up to 8 months (Hess et al., 2007; Stemkens-Sevens
et al., 2009). Implantation of the telemetry system was
also accomplished without opening the abdominal
cavity. Telemetry transducers were implanted subcu-
taneously into the back of the neck with the leads for
detecting the lead II ECG fixed on the right shoulder
and left lower thorax, and a blood pressure catheter
introduced into the carotid artery. This subcutaneous
approach allowed for longitudinal measurement of car-
diac parameters for over 28 days (Provan et al., 2005). It
has been difficult to instrument small rodents for multi-
lead ECG recording to fully assess cardiac risks of new
pharmaceutical agents. By comparing cardiac electrical
activity to the magnetic field generated by cardiac acti-
vation currents measured by contactless magnetocar-
diography, Brisinda et al. (2007), showed that multisite
recordings could be used for surface cardiac mapping
and replace the need for surgical implantation of tele-
metric devices for long-term longitudinal studies.
A method for inducing prolonged (30 s or more)
cardiac tachyarrhythmias was developed after rapidly
pacing the heart prior to a single 200-V transthoracic
stimulus, establishing a small animal model for evalu-
ating short-term pharmacologic effects of electrical
therapies (Malkin et al., 1998). Ventricular arrhythmias
were also induced in halothane-anesthetized guinea
pigs receiving a continuous infusion of adrenaline (epi-
nephrine) (12.5 µg/kg/min). Arrhythmogenicity was
significantly increased with vagotomy and higher con-
centrations of halothane (Noda and Hashimoto, 2004).
A reproducible technique for creating congestive
heart failure by aortic banding was detailed by Ling
and Bold (1976). Briefly, guinea pigs were anesthetized
and ventilated with a small animal respirator. An inci-
sion was made in the skin and a thoracotomy was per-
formed in the left third intracostal space. The lung was
pushed dorsally to expose the left ventricle and atrium
III. GUINEA PIGS
and the pericardium was opened. Blunt dissection
separated the tissue connecting the ascending aorta and
the pulmonary trunk. An aortic constrictor (clip bored
with a 1.99-mm diameter drill bit) was placed around
the ascending aorta, the muscles and skin were closed,
and the animal was allowed to recover. This technique
resulted in a 74% survival rate, and animals eutha-
nized at 10 days post-surgery showed marked passive
congestion of liver, spleen, kidney, and lung, as well
as severe centrilobular fatty change of the liver. This
technique was used by Kingsbury et al. (1999) to study
chronic left ventricular outflow obstruction. After an
average of 149 days of banding, there was marked evi-
dence of cardiac hypertrophy (72% increase in heart to
body weight ratio compared to sham operated controls)
and heart failure.
Aortic outflow was measured using a 2.5-mm elec-
tromagnetic flow probe placed on the ascending aorta
following a midline thoracotomy. Aortic flow was also
measured using thermodilution cardiac output deter-
mined by bolus injection of 0.4 ml of physiologic saline
solution (25°C) into the right atrium. The temperature
change was registered by a thermistor probe in the
superficial saphenous artery and cardiac output was cal-
culated with a dedicated thermodilution cardiac output
computer. After comparing the thermodilution method
to the instantaneous aortic flow, it was determined to be
a useful, reliable, and less invasive means of determin-
ing cardiac output in the guinea pig (Hart et al., 1987).
Watanabe et al. (2008) showed that the lower lip of
the guinea pig contains parasympathetic fibers origi-
nating from the otic parasympathetic ganglion which
evoke decreases in lower lip blood flow and systemic
arterial blood pressure when electrically stimulated by
a bipolar silver electrode.
Reproductive Studies
Guinea pigs have not typically been used for repro-
ductive toxicology studies. Compared to other rodents,
the estrous cycle is approximately 18 days long, the
vagina is closed by a membrane making evaluation of
vaginal cytology difficult to impossible during much
of the cycle, and the 64-day gestation period is rela-
tively long. Other disadvantages compared to the tra-
ditional rodent species are the variability in pregnancy
rates, small and variable litter size, relative maturity at
birth, and difficulty in repeat dosing of pregnant females
(Rocca and Wehner, 2009).
To determine the time of conception for fertility
studies and for obtaining cohorts of pregnant females
for developmental studies, guinea pigs were mated
on the females’ post-partum estrus. Pregnant females
were co-housed with males starting approximately
4 weeks prior to expected parturition to decrease female
 Specialized Research Techniques
mortality rates associated with pairing during later ges-
tation (Rocca and Wehner, 2009).
Several techniques have been used to determine the
timing of the estrous cycle for timed pregnancy and
for early determination of pregnancy. Vaginal smears
were taken when the vagina was perforate to time the
estrous cycle, with the first day of the cycle taken as the
day preceding the post-ovulatory influx of leukocytes
when cornification was at a maximum (Poyser, 1987).
Electrical impedance of the vaginal mucous membrane
was measured in the guinea pig using a probe con-
structed from two silver ring electrodes set 3 mm apart
and firmly attached to a plastic rod, diameter 4–5 mm.
The probe was introduced into the vagina and electrical
impedance was measured by a transistor indicator with
a 1-kHz oscillator (Bartos, 1977). A cyclic increase was
found during the proestrus phase, more than at other
times of the cycle. The disappearance of this cyclic affect
indicated early pregnancy (Bartos and Sedlacek, 1977).
For early pregnancy studies, the presence or absence of
implantation sites in the uterus could be observed at 8
days of pregnancy (Wisel et al., 1994).
Prenatal growth has been studied in guinea pigs.
Several methods have been used to influence fetal
growth (Jones et al., 1990). Guinea pigs at gestational
days 41–42 were injected four times daily over 4 days
with 10 ml of 50% glucose intraperitoneally resulting in
increased fetal weight. The withholding of food from
guinea pigs at days 43–44 of pregnancy for 48 hours
led to a sharp fall in maternal and fetal plasma insulin
and thyroid hormone concentration, and elevations in
plasma glucagon and cortisol, and also depressed fetal
weight by about 10%. A unilateral ligation of the uter-
ine artery at day 30 of gestation caused growth restric-
tion of  50% in fetuses adjacent to the arterial tie when
measured 10–15 days after the ligation. This effect of
growth was particularly apparent in the visceral tis-
sues and liver, whereas the brain was relatively spared.
A modification of the uterine artery ligation technique
performed between days 30–35 of gestation, resulted
in a similar reduction in fetal growth, but a higher
fetal survival rate. Instead of ligating the main uter-
ine artery which supplies the blood to one horn of the
uterus, approximately half (typically two of four) of
the branches leading from the uterine artery directly to
one placenta were ablated using a diathermy unit. The
treated fetuses showed a 70% reduction in mean body
weight at term and had a 245% increase from normal
mean values for the brain/liver weight ratios show-
ing the “brain sparing effect” from the redistribution
of blood flow to maintain development of the brain
(Turner and Trudinger, 2009). The uterine artery liga-
tion method was used to study uterine and placental
blood flow by injecting 15-µm microspheres labeled
with 46Sc and counting radioactivity in dissected tissues
III. GUINEA PIGS
627
(Jones and Parer, 1983). Jansson (1991) showed that
three consecutive radiolabeled-microsphere injections
at 10-minute intervals in guinea pigs at 47–52 days ges-
tation had minimal effect on regional blood flows and
central hemodynamics in anesthetized and awake ani-
mals, and allowed for multiple measurements of pla-
cental blood flows.
The signs of estrus, including lordosis, in response
to manual touch of the back of the guinea pig, and the
opening of the vaginal orifice have been described
(Young et al., 1937). The effects on spontaneous ovula-
tion associated with the unilateral or bilateral sectioning
of the superior ovarian nerves (SON) were analyzed in
guinea pigs at different time intervals of the estrous cycle
with day 1 defined as the day when the animal presents
complete loss of the vaginal membrane. Sectioning of
the right, left or both SONs on day 5 (early luteal phase)
resulted in a significant increase in the number of fresh
corpora lutea, however, ovulation rates were not affected
when unilateral or bilateral sectioning was performed
during the late luteal phase (day 12) suggesting that the
SON modulates ovulation and the degree of modulation
varies along the estrous cycle (Luna et al., 2003). Lordosis
has been used to study the noradrenergic system and
its effects on this behavior (Thornton et al., 1988) and to
investigate a non-luteal source of progesterone secretion
in guinea pigs (Feder and Goy, 1985).
Surgical sterilization of guinea pigs has been
described by Jenkins (2000). Ovariohysterectomy of
guinea pigs is performed aseptically through a midline
abdominal incision using care when entering the abdo-
men to avoid the large thin-walled cecum and bladder.
The uterus is located and followed to the oviduct and
infundibulum. The blood vessels to the ovary are iden-
tified and ligated, taking care not to leave a portion of
the oviduct. The uterus and uterine vessels are ligated
just cranial to the cervix. The mesometrium of hystrico-
morph rodents can contain an abundance of fat, so care
must be taken when locating and ligating the ovar-
ian and uterine vessels. Abdominal closure is routine.
To perform an ovarectomy, the ovaries are accessed
through individual incisions in the skin caudal to the
kidney continued into the retroperitoneal space. Light
pressure placed on the abdomen causes the ovary and
oviduct to enter the incision. The ovary is exteriorized,
ligated with suture at its base, and resected. The ligated
vascular pedicle is returned to the abdomen and the
dorsal abdominal wall and skin are closed.
Orchiectomy of the male guinea pig is done asepti-
cally by making a 1-cm incision through the skin and
vaginal tunic ventrally on both sides of the scrotum. The
testis is removed from the tunic and retracted caudally
to expose a section of the vas deferens and the vascu-
lar structures of the spermatic cord, which are ligated.
The duct and vessels are transected distally to the
628 22.  Basic Experimental Methods
ligature and the stump is returned to the inguinal canal.
Because of the large inguinal opening, the inguinal canal
is closed by suturing the tunic and the skin is closed
(Jenkins, 2000).
Hearing Studies
Preyer described for the first time in 1881 a pinna
reflex in guinea pigs in response to sound, reporting
the reflex movements to tones from 1000–41 000 cycles
per second (Horton, 1933; Preyer, 1890). Using tone-
shock conditioning to specific tones, it was shown that
guinea pigs could respond to specific tones rather than
just noise (Upton, 1929) and that the auditory sensitivity
ranged between 64 and 8192 cycles per second, similar
to the perception of sound by humans (Horton, 1933).
Early studies using recording electrodes in the cochlea
showed that tonal interference has its locus in the hair
cells of the organ of Corti (Wever and Lawrence, 1941),
described the threshold of auditory action potentials
for low tones in the guinea pig (Davis et al., 1950),
and developed techniques for recording single-fiber
responses from the cochlear nerve of guinea pigs from
acoustical stimulation (Tasaki, 1954).
Asarch et al. (1975) presented an excellent descrip-
tion of the anatomy of the guinea pig ear and detailed
two surgical approaches to the guinea pig temporal
bone and to the inner ear. The superior approach, made
by an incision at the superior anterior attachment of
the auricle and removing the lateral wall of the epitym-
panic space, exposed the round window, epitympa-
num, lateral canal, and external auditory canal, leaving
the tympanic membrane intact. The inferior approach
through the neck exposes the cochlea, Eustachian canal,
horizontal and posterior semicircular canals, tympanic
membrane, and ossicles. A description of the surgical
approach to the endolymphatic sac and the cochlear
aqueduct surgical closure of the endolymphatic sac
and duct is described for creation of a model of endo-
lymphatic hydrops in the guinea pig (Andrews and
Bohmer, 1989). Efferent cochlear innervation, through
the olivo-cochlear bundle, has been postulated to exert
a protective mechanism on the inner ear. A technique
for vestibular neurectomy of both ipsi- and contralat-
eral cochlear efferent fibers in the guinea pig involving
a suboccipital route to the posteriomedial aspect of the
temporal bone allowed for minimal removal and retrac-
tion of cerebellar tissue (Barbara et al., 1999).
The guinea pig has been used to study the progres-
sion and treatment of deafness by employing amino-
glycoside antibiotics to eliminate hair-cell function in
the organ of Corti. Bilateral destruction of the organ of
Corti was produced by administering 14 subcutane-
ous injections of 450 mg/kg of amikacin with one daily
injection 5 days a week (Cazals et al., 1983). A single
III. GUINEA PIGS
subcutaneous dose of kanamycin (400 mg/kg) followed
in 2 hours by an intravenous injection of the potent
diuretic, ethacrynic acid (40 mg/kg), caused the perma-
nent loss of hearing and death of cochlear hair cells in
guinea pigs for both acute and chronic studies (Nourski
et al., 2004; West et al., 1973). Deafness was also
induced by administering the loop diuretic, furosemide
(100 mg/kg) intravenously, followed by kanamycin (400
or 500 mg/kg) subcutaneously. Loop diuretics increase
the concentration of the aminoglycoside in the scala
media causing the loss of the mitochondrial membrane
which results in apoptosis of the hair cells (Hildebrand
et al., 2005). Conlon and Smith (1998) showed that the
co-administration of gentamycin (100 mg/kg/day for
30  days) and iron (2 mg/kg/day or 6 mg/kg/day for
30 days) resulted in a more rapid and profound eleva-
tion in compound action potential thresholds compared
with animals receiving gentamycin alone. When neomy-
cin is administered systemically at levels high enough to
induce ototoxcity, nephrotoxicity also results. To avoid
the systemic results and to allow for a contralateral con-
trol ear, neomycin was applied by surgical intracochlear
infusion. Using a post-auricular approach and expos-
ing the temporal bone in anesthetized guinea pigs, two
holes were drilled into the bullae. A 26-gauge needle
was used to dispense approximately 0.1 ml of 100 mg
neomycin/ml normal saline solution into one of the
holes while the second served as a vent, then the inci-
sion was closed. This technique produced significant
loss of spiral ganglion cells along the cochlear spiral
(Zappia and Altschuler, 1989). Dodson et al. (1994) used
this method of cochlear perfusion of neomycin in guinea
pigs at ages 1 week and 6 weeks to study the effects of
postnatally acquired sensorineural deafness on the mat-
uration of the auditory pathway. The mechanisms for
noise-, chemical-, and drug-induced ototoxicity in devel-
oping guinea pigs and other mammals are reviewed by
Henley and Rybak (1995).
Once deafness is established, therapeutic treatment
success can be studied by recording action potentials in
the auditory nerve. These potentials can be simulated
by both bipolar and monopolar electrical stimulation
(Miller et al., 1998) or 4-millisecond tone pips at vary-
ing frequencies (Conlon and Smith, 1998). Anatomical
changes to the hair cells can be assessed by histologi-
cal examination of the tissue following fixation with
paraformaldehyde (Zappia and Altschuler, 1989). The
use of intravital confocal laser scanning microscopy
allows the visualization of individual cells inside intact
tissue with preserved blood and nerve supply and for
the investigation of structural changes caused by toxic-
ity or trauma. A ventral surgical approach to expose the
middle ear cavity allowed optical access to the cochlea.
Fluorescent vital dyes (calcein AM and RH 795) were
administered directly to the cochlea and stained the
 Specialized Research Techniques
cytoplasm and cell membranes of sensory inner and
outer hair cells. After exposing the tympanic membrane
to 130 dB of sound pressure for 10 minutes, there was
a distinct reorganization of the cytoarchitecture and a
change in the shape of the visible outer hair cells (Tomo
et al., 2007).
The low regenerative capacity of the hair cells of the
mammalian inner ear is a major obstacle for functional
recovery following sensorineural hearing loss. Mouse
embryonic stem cells labeled with green fluorescent pro-
tein were transplanted to the aminoglycoside-damaged
organ of Corti of guinea pigs. These cells were injected
into the scala media cavity of the inner ear. Nine weeks
after the xenotransplant, the cells were shown to local-
ize close to the damaged organ of Corti structure in the
scala media, however, there was no evidence of inte-
gration (Hildebrand et al., 2005). An adenoviral vector
expressing the bacterial lacZ reporter gene was injected
in the endolymphatic sac of guinea pigs. A large number
of transduced cells were found in the endolymphatic
sac and duct, the vestibular end organ, the cochlea, and
the stapes 4 days after the injection. Gene transfer could
be used to substitute specific defective genes for treating
hereditary deafness or allow for long-term overexpres-
sion of protective tropic factors to protect inner ear cells
from death due to ototoxicity (Yamasoba et al., 1999).
In order to determine the best technique for delivery of
cells or gene therapy to the inner ear cells, Backhouse
et al. (2008) assessed three surgical procedures for cell
delivery into the cochlea; a cochleostomy into the scala
tympani; direct access to Rosenthal’s canal via localized
fracture of the osseous spiral lamina; and direct access
to the auditory nerve via a translabyrinthine surgical
approach. Using microspheres to simulate placement,
delivery, and dispersion of cells, they found that the
technique giving direct access to Rosenthal’s canal to
offer the most promising approach.
Another approach to improve hearing in patients
with residual acoustical hearing is the use of cochlear
implants. The guinea pig ear can be utilized to test
new implant devices or develop techniques for surgical
implantation. To install the implant, a dorsolateral, poste-
rior auricular approach is used to gain access to the bulla
and the cochlea. A cochleostomy is made with a 0.7-mm
diameter drill over the basal turn at a low speed. The
implant electrode is inserted with atraumatic technique
to the first point of resistance and the cochleostomy is
plugged with fascia to prevent perilymph leakage. The
extra-cochlear portion of the electrode is secured to mus-
cle with sutures to prevent extrusion (Chang et al., 2009).
Preservation of hearing in the implanted ear is a goal
of cochlear implant surgery. Utilizing an application of
dexamethasone to the round window at the time of the
implant protected the residual hearing of guinea pigs
with cochlear implants (Chang et al., 2009).
III. GUINEA PIGS
629
Respiratory Studies
Guinea pigs are one of the oldest models of allergic
airway response in asthma, with studies conducted for
over 100 years (Auer and Lewis, 1910; Gay et al., 1909;
Zosky and Sly, 2007). Smith and Broadley (2007) deter-
mined an optimal sensitization protocol for creating a
guinea pig with an early asthmatic response followed
by a late-phase bronchoconstrictor response, airway
hyperresponsiveness to inhaled histamine and metha-
choline and inflammatory cell infiltration in the airways,
hallmarks of human asthma. The guinea pigs were sen-
sitized by intraperitoneal injection of ovalbumin (OA,
100 µg per animal) and aluminum hydroxide (100 mg)
in 1 ml of normal saline, in divided doses bilaterally,
with a booster injection of the same solution on day 5.
After 14–21 days from the first injection, the animals
were placed in a stainless steel chamber and exposed to
a nebulized solution of OA (10 µg in saline) for 1 hour
with animals showing bronchoconstriction at the time
of exposure. For collection of pulmonary inflammatory
cell infiltrates, bronchoalveolar lavage can be performed
after euthanasia by inserting an intravenous catheter
into the trachea, instilling saline into the lung, and col-
lecting the fluid (Mukaiyama et al., 2004; Smith and
Broadley, 2007).
Normal average values for tidal volume (1.68 ml),
respiratory rate (84/minute), minute volume (139 ml),
resistance (0.73 cmH2O/ml/second), and compliance
(0.20 ml/cmH2O) were reported by Amdur and Mead
(1958) following their development of techniques for
measurement of intrapleural pressure and ventilatory
activity. Intrapleural pressures were measured by a fluid-
filled tube inserted into the chest cavity and connected
to pressure recorders, while ventilatory measurements
were determined by a body plethysmography. The tech-
nique of plethysmography improved with the use of
computer systems to extract the data and by recording
from animals without surgical preparation (Alarie et al.,
1970; Douglas et al., 1972).
Various plethysmograph chambers and exposure
chambers have been designed by research laborato-
ries to measure airway conductance in guinea pigs for
studying asthma and other respiratory diseases. Several
plethysmography units were designed with two cham-
bers, one encasing the head/neck cavity and the other
containing the thoracic/abdominal cavity with a rubber
neck divider ensuring a tight seal around each cham-
ber. These systems are useful in exposing the guinea
pig to the aerosol, while measuring respiratory-related
changes in pressure within the chamber containing the
body (Ball et al., 1991; Danko and Chapman, 1988).
A single-chamber plethysmograph chamber was
designed which allowed for repeated and long-term
evaluation of pulmonary performance since the animal
630 22.  Basic Experimental Methods
was not restrained by a neck divider used as a seal
between the two-chamber units (Wong and Alarie,
1982). Chong et al. (1998) compared the measurement
of histamine-induced bronchoconstriction using a dou-
ble-chamber plethysmograph to that using a single-
chamber body box plethysmograph with a central inlet
for aerosol administration. They found that the single-
chambered plethysmograph correlated well with the
double-chambered unit in measuring pulmonary resis-
tance, and the single chamber eliminated stress from
restraint, the potential for non-physiological airway
resistance due to the neck collar, and allowed for long-
term studies since the animal was unrestrained and
able to eat and drink during the study.
To test the pulmonary or toxic effect of various
compounds on the lungs, several systems have been
designed for aerosol exposure of substances to guinea
pigs, both while restrained by a neck collar (Snyder
et al., 1988), unrestrained (Lewis et al., 2007), or while
unrestrained in permanent housing units allowing for
exposure of up to 60 guinea pigs at one time (Brown
and Moss, 1981).
Chambers have been developed for hyperbaric expo-
sure (Ederstrom et al., 1971; Giblin et al., 1995; Rose
et al., 1970; Shoshani et al., 1998). In one long-term
study, adult guinea pigs were exposed to 2.5 atmo-
spheres absolute (22.3 psig) for 2–2.5 hours three times
per week on alternate days for up to 50 weeks with no
apparent ill effects and a steady gain in body weight
(Giblin et al., 1995). To study the effects of hypoxia,
guinea pigs have been exposed to inspired gas contain-
ing 100% down to 8% O2 balanced with N2. Yilmaz et
al. (2005) exposed 4-month-old, awake, spontaneously
breathing guinea pigs raised at sea level, intermediate
altitude (1250 meters), and high altitude (3800 meters),
to 100%, 21%, and 12% inspired O2.
The effect of hypoxia was studied in the developing
fetal guinea pig brain by inducing maternal hypoxia in
dams at 50 and 60 days gestation. Dams were placed
in a chamber with a probe to monitor oxygen tension
and exposed to 7% O2 for 40 minutes. There was a 50%
reduction in Na, K, and ATPase activity in brains of
the 60-day (near-term) fetuses compared to the 50-day
preterm fetuses, indicating a high degree of susceptibil-
ity of the near-term brain cell membrane functions to
maternal hypoxia (Mishra and Delivoria-Papadopoulos,
1988).
Musculoskeletal Studies
Spontaneous joint degeneration and osteoarthritis
occur in the knee of the Dunkin-Hartley guinea pig and
appear to provide an excellent model for the human dis-
ease. Changes in the cartilage and responses to therapy
can be studied histologically and by scanning-electron
III. GUINEA PIGS
microscopy, but is limited to observing the cartilage
at single time points. A cohort of 30 animals between
2 and 9 months were imaged using a 2.35-T Oxford
Instrument 31-cm bore magnet. High-quality 2-D MR
images of the knee of anesthetized guinea pigs were
generated in about 30 min showing the articular car-
tilage, subchondral bone, trabecular bone, triangular
menisci, and other facets of joint anatomy in fine detail
and allowed for serial studies demonstrating the pro-
gression of arthritis (Watson et al., 1997). The imag-
ing technique was improved using three-dimensional
Varian 4.7-T MRI system, and anesthetized animals
were imaged for less than 2 hours. High-resolution,
high signal-to-noise 3-D images of the animals seri-
ally generated at 3, 6 , 9 and 12 months of age, showed
changes in cartilage integrity, and bone and meniscus
changes which correlated to macroscopic and histologi-
cal changes in the animals at 12 months (Tessier et al.,
2003). Using the change in medial tibial plateau cartilage
volume as a MRI biomarker of osteoarthritis, 3-D MR
images of 9-month-old guinea pigs treated with doxy-
cycline (0.6 or 3.0 mg/kg/day) or vehicle for 66 days
were acquired 7 days pre- and 66 days post dosing. The
medial tibial plateau cartilage loss for vehicle treated
was 20.5%, while animals treated with 0.6 mg/kg/day
doxycycline lost 8.6%, and those treated with 3.0 mg/
kg/day lost 10%, demonstrating the value of data col-
lected by serial MRI (Bowyer et al., 2009).
Endocrine Studies
A technique for bilateral adrenalectomy of guinea
pigs in two stages was presented by Hoar (1966). The
presentation includes a review of the literature, photo-
graphs of the operation, a list of equipment, and com-
ments on anesthetic techniques and post-operative
care. Hopcroft (1966) used a transverse abdominal inci-
sion to remove both adrenals in a single-stage opera-
tion. This approach allowed better exposure of both
adrenals and, with the intestines limited within a plas-
tic bag containing normal saline, it also allowed more
space in which to maneuver within the abdominal
cavity.
Surgical thyroidectomy in guinea pigs is a relatively
simple procedure but care must be taken to avoid
injury to the recurrent laryngeal nerves. Young et al.
(1952) and Peterson et al. (1952) were among the first
to describe a thyroidectomy technique while Fabre and
Marescaux (1966, 1969) and Fabre et al. (1970) noted
and measured the rapid recovery of thyroid activ-
ity due to the development of small areas of remain-
ing thyroid tissue. Kromka and Hoar (1975) drew from
these published reports and added some procedural
refinements in their presentations of an improved
technique.
 Specialized Research Techniques
Skin Studies
Historically, the most commonly used safety tests
to detect either skin or systemic immune-based hyper-
sensitivity reactions are those using guinea pigs
(Landsteiner and Chase, 1939; Ramsdell, 1928; Weaver
et al., 2003). Protocols of predictive contact allergy tests
can generally be divided into three main phases: the
induction phase, which stimulates the first contact with
the chemical and during which antigen is presented to
lymphocytes in the skin, the rest period without treat-
ment during which sensitized cells are proliferating in
the lymph nodes, and the challenge or provocation phase
during which skin reactions are elicited after new expo-
sure to the chemical (Maurer et al., 1994). A number of
protocols have been described identifying chemicals that
possess the ability to cause significant skin sensitization,
but ultimately only the guinea pig maximization test of
Magnusson and Kligman (1969) and the closed patch
test of Buehler (1965) continue to be accepted by regula-
tory authorities in Europe and the USA (Basketter and
Kimber, 2007; Consumer Product Safety Commission,
2009; Organisation for Economic Co-operation and
Development, 1981, 1992). The maximization test is the
most frequently used test in Europe while the Buehler
test is most common in the USA (Maurer et al., 1994).
Several reviews have questioned the ability of these tests
to predict human systemic hypersensitivity (Weaver
et al., 2003) and to identify skin sensitization hazards
(Basketter and Kimber, 2007; Kimber et al., 2001). More
recently, the local lymph node assay (LLNA) using mice
has been described to evaluate skin sensitization poten-
tial to chemicals and has been accepted by validation
authorities in the United States and Europe (Gerberick
et al., 2007). While the maximization test and the
Buehler test continue to be used, the LLNA is now
the recommended method for new assessments of rela-
tive potency, and/or for the investigation of the influence
of vehicle or formulation on skin sensitization potency
(Basketter et al., 2008; Kimber et al., 2001). The meth-
ods for the Magnusson and Buehler tests are described
below.
For the Magnusson maximization test (Magnusson
and Kligman, 1969), albino outbred guinea pigs weigh-
ing 300–500 grams are used, avoiding older animals
since they are less sensitive. Groups of 10–25 animals
are used per test compound. The fur from the dorsal
neck is shaved and three intradermal injections of 0.1 ml
each are made with the chemical, the chemical incor-
porated in Freund’s complete adjuvant, and adjuvant
alone. These injections are repeated on the other side of
the neck. One week after the injections, the same area
is clipped. The test agent in petrolatum is spread over
a 2 cm by 4 cm patch of filter paper and placed on the
guinea pig’s neck area and secured with overlapping
III. GUINEA PIGS
631
adhesive tape and then secured by an elastic adhesive
bandage wound around the torso of the animal. The
dressing is left in place for 48 hours. The animals are
challenged 2 weeks after the topical application with
another patch test, this time the patch is secured and
remains in place for 24 hours. The challenge is read
24 hours after removing the patch to allow for any irri-
tation from the securing tape to subside, and again at
48 hours to detect any weak, slowly developing reac-
tions. Uncertain tests can be repeated within 3–4 days.
The reactions are scored on a 4-point scale, 0  no reac-
tion, 1    scattered mild redness, 2    moderate and
diffuse redness, 3    intense redness and swelling. The
important parameter in maximization testing however
is the frequency of sensitization not intensity.
The Buehler closed-patch sensitization test (Buehler,
1965; Buehler et al., 1985) used young 250-gram albino
outbred either-sex guinea pigs. Prior to testing, the
primary irritation threshold of the test agent is deter-
mined in a pilot study, and the concentration producing
minimal amounts of erythemia is used to sensitize. An
absorbent pad (patch) approximately 4–6 cm2 is wet-
ted with 0.5 ml of the test solution and is applied to the
shaved back or flank of a guinea pig and secured with a
coverlet. The animal is then placed in a restrainer with
adjustments made to ensure the animal is restrained
but not immobilized. Patches are left on the restrained
animal for 6 hours. The compound is applied in the
same area weekly for 3 weeks. Two weeks after the
last compound application, the animals are challenged
with the highest non-irritating concentration of the
same test material applied by the patch for 6 hours on
a shaved naïve site. At 24 and 48 hours after application
of the challenge patch, the sites are graded for degree
of erythema and are assigned numbers of 0 through
3, similar to the scoring described for the Magnusson
maximization test. Animals with inconclusive results
can be retested within a couple of weeks of the primary
challenge.
Guinea pigs have also been used to study skin
wound healing and for testing a variety of agents to
treat or promote wound repair (Carrel and Hartmann,
1916; Spain and Loeb, 1916). Typically partial- or full-
thickness wounds are created by excising approximately
2  2 cm skin segments from the dorsum of the anesthe-
tized animal. Biopsy punches can also be used to create
the skin lesions (Bernstein et al., 1994). Wounds can be
closed by primary intention with simple interrupted
sutures (Silverstein and Landsman, 1999) or covered and
allowed to heal by contraction (Davidson et al., 1992;
Lindenbaum et al., 1995). Burns to the skin have also
been studied in the guinea pig. Partial-thickness skin
burns can be inflicted by immersing the ventral part of
the anesthetized animal in 100°C water for 3 seconds
(Nanney, 1982; Sakurai et al., 1997) or bathing small
632 22.  Basic Experimental Methods
areas of the guinea pig’s shaved back in 75°C water for
10 seconds (Tan et al., 2002). A reproducible method to
create deep partial-thickness burns utilizes a cylindri-
cal aluminum template (3.76 cm diameter) heated in a
water bath for 2 hours prior to the injury at a constant
temperature of 75°C. The heated templates are applied
to the skin surface in the mid back area on either side for
5 seconds using minimal pressure creating burn wounds
(Kaufman et al., 1990).
A wound model for studying ischemic skin ulcers
utilized guinea pigs. A 5-cm trans-scapular incision was
made in the anesthetized guinea pigs. Using blunt dis-
section, a subcutaneous path is opened wide enough to
accommodate the rubber tip of the plunger of a 10-ml
syringe. The stopper is inserted through the tunnel to
a site over the vertebral column and 2 cm posterior to
the scapula. The insert and skin overlying it are tightly
encircled with a rubber band tourniquet, preventing
blood flow to a 5-cm2 circle of skin over the insert. After
24 hours, the rubber band tourniquet is released and
the insert is removed. These ulcers resemble human
ischemic ulcers in their progression from edema and
blister development through black eschar formation
(Constantine and Bolton, 1986).
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