The Miniature Swine as a Model in Experimental and ... · The Miniature Swine as a Model in...

The Miniature Swine as a Model inExperimental and Translational Medicine

Alain Stricker-Krongrad1, Catherine R. Shoemake1,and Guy F. Bouchard1

AbstractThe use of the miniature swine as a nonrodent species in research has continued to expand for over a decade, and they arebecoming routinely used both in experimental pharmacology and as a therapeutic model for human diseases. Miniature swinemodels are regularly used for studies designed to assess efficacy and safety of new therapeutic compounds given through differentroutes of exposure and are used as an alternative model to rodents, canines, or nonhuman primates. Translational preclinical swinestudy data presented here support the current understanding that miniature swine are the animal model of choice for theassessment of drugs targeting endocrine, dermal, and ocular disorders. Because research investigators need to be familiar withsome of the important features of the models developed in the miniature swine in order to place clinical and experimental findingsin their proper perspective, relevant references and data from these models will be presented, compared, and partially illustrated.

Keywordsminiature swine, minipig, animal models, preclinical trials, endocrinology models, dermal models, ophthalmology models

Overview

While human clinical trials work through clearly defined

phases to evaluate the various effects of new therapeutic enti-

ties (new chemical entities [NCEs] or new biological entities

[NBEs]), trials utilizing animal models of disease are less

defined and mainly conducted in support of a therapeutic ratio-

nale. These animal studies are sometimes referred to as proof-

of-concept trials, and their main objective is to be able to

translate pharmacology and efficacy data from nonhuman spe-

cies into humans. Because the selection of the most appropriate

animal model is an important component of this process,

another research objective is to identify animal models that can

improve the prediction of efficacy and safety outcomes and

thus contribute to decreasing the number of human clinical

trials by eliminating early on any chemical or biological drug

entities showing lack of effectiveness or presenting severe

adverse effects.

Human Clinical Trials

The major goals of phases I and III human clinical trials for

NCEs and NBEs are to evaluate their potency and pharmaco-

kinetic, pharmacodynamic, and therapeutic efficacy. Addition-

ally, bioequivalence human clinical trials aim to demonstrate

the similar nature of generic or biosimilar products to chemical

or biological medicinal products, respectively. Although there

are some variations in the definitions of the early phases of

human clinical trials, conducting preclinical trials with animal

models consistently fits into the general approach of human

drug development.

Animal Models

An animal model is defined as any condition found in an ani-

mal that is of value in studying a biological phenomenon; it is a

pathological mechanism of an animal disorder useful in study-

ing human disease. Animal models may be spontaneous—

monogenetic, multigenetic, environmental—or they may be

induced, such as surgically, pharmacologically, or by transgen-

esis. In contrast to human clinical trials, the major objective of

animal models of diseases is to be able to translate their clinical

pharmacology and therapeutic efficacy to humans in order to

identify candidates for clinical trials in drug development

selection or to improve the prediction of study outcomes in

clinical trial modeling.

There are three major components that make a particular

animal model a valuable model for experimental and transla-

tional medicine: drug exposure, modeling of the disease, and

1 Sinclair Research Center, Columbia, Missouri, USA

Corresponding Author:

Catherine R. Shoemake, Sinclair Research Center, LLC, 562 State Road DD,

Auxvasse, MO 65231, USA.

Email: [email protected]

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relevance to human health. The drug exposure component, or

comparative pharmacokinetics, relates to the pharmacokinetics

and metabolism of the drug of interest; for example, determin-

ing whether the animal species is metabolizing the drug in

question in a manner similar to human metabolism of the same

drug and whether the level of exposure is identical and/or

proportionate and can be used to predict human efficacious

or safe starting doses. The disease modeling component, or

pathology parallelism, relates to the ability of modeling the

disease in the species of interest, specifically determining

whether the disease can be experimentally induced. Relevance

to human health, or translational value, relates to the disease

relevance to the human condition, determining whether the

same pathological mechanisms are at play or if it is just the

manifestation of a phenotypic similarity.

For abovementioned reasons, the identification and charac-

terization of animal models of diseases having a high transla-

tional value have become more and more important at a time

when the severe limitations of rodent models, due to their

smaller size and difference in dermal structure and mechanism

of wound healing compared to humans, have been fully recog-

nized. Swine have historically played a role in experimental

medicine but have not always been amenable to be a laboratory

species due to their prohibitively large size and housing

requirements. The development of miniature swine has effec-

tively created a role for swine in laboratories by providing

breeds of a more manageable size; the benefits of this are

shown in Table 1.

The objective of this publication is to expand on the dif-

ferent ways miniature swine serve as translational models,

above and beyond the traditional classical cardiovascular sur-

gical models typically pursued in domestic swine, that are far

more valuable than other laboratory animal species for the

benefit of human clinical trials and ultimately for the promo-

tion of human health.

Endocrinology Models

Miniature swine are becoming increasingly recognized as

models for type 1 diabetes (T1DM) and glucodynamic stud-

ies. The comparability of the pharmacodynamic response of

these diabetic models with that of humans to known marketed

insulin products (both rapid acting and long acting) is the

overarching consideration of how to best utilize these models.

The pharmacodynamic response to various marketed insulin

products in miniature swine should approximate those in

humans in order for the model to be both valuable and pre-

dictive; apparent differences must be recognized ahead of use.

Monitoring of morning fasted blood glucose (FBG) levels in

diabetic miniature swine is a necessary element for clinical

management and to assess the consistency (through FBG

range assessment) for overnight-fasted animals across the

pool of available diabetic models.

Induction of Diabetes

Alloxan, or 2,4,5,6-pyrimidinetetrone, is used to induce both

T1DM and type 2 diabetes mellitus (T2DM). Alloxan’s mole-

cular shape is similar to glucose, allowing it to be transported

into the cytosol of pancreatic beta cells by the glucose trans-

porter 2 located in the plasma membrane. Once in the cytosol,

alloxan selectively inhibits glucose-induced insulin secretion

with a thiol group that binds to the enzyme glucokinase in the

beta cells; alloxan additionally induces redox cycling and gen-

erates reactive oxygen species that subsequently induces

destruction of the pancreatic beta cells (Rohilla and Ali 2012).

Once induced, multiple types of insulin are used to maintain

normoglycemia in the T1DM swine. Although intermediate-

acting Humulin1 N (Eli Lilly, Indianapolis, IN) is used most

commonly, long-acting Lantus1 (Sanofi, Bridgewater, NJ) and

rapid-acting Humalog1 (Eli Lilly) are also used.

Biomarkers of Diabetes

At our present facility, glucose measurements are performed on

whole blood with AlphaTRAK1 2 handheld glucometers or on

plasma or serum using a Beckman Coulter AU480 clinical

chemistry analyzer which uses hexokinase as the reaction

enzyme. Circulating insulin and C-peptide levels are measured

using a porcine-specific ELISA (Mercodia, Uppsala, Sweden).

Typical circulating insulin and C-peptide levels in normal and

diabetic Yucatan miniature swine are presented in Table 2. In

stabilized diabetic Yucatan miniature swine that were induced

through alloxan-induced destruction of pancreatic beta cells,

the blood glucose levels increased 7-fold, from a mean of

58.7 mg/dl in normal miniature swine to a mean of 429 mg/

dl in diabetic miniature swine, compared to normal miniature

swine that were fasted overnight for approximately 18 hr fol-

lowed by feeding.

Table 1. Miniature Swine versus Domestic Swine Use inPharmacology and Toxicology.

Miniature swine Domestic swine

Size at sexualmaturity

Smaller, 13–42 kg,reaches sexualmaturity at 4–5months

Larger, >100 kg, reachessexual maturity at 5–6months

Growth rateduring studies

Slow, requires lesscandidate drug

Fast, requires morecandidate drug

Ease of handling Good Poor, unless very youngControlled

genotypeWell characterized:

inbred or closedherds, outbred togreatest extent

Inbred or crossbredbreeds

Microbiologicallydefined?

Yes or no depending onbreed

Yes or no depending onsource

Limitations Chronic studies are noproblem

Studies beyond 28 days’duration or 3 monthsof age is notrecommended due tosize (expect >100 kgat 4 months of age)

2 Toxicologic Pathology



Insulin Pharmacodynamics Experimental Design

In order to compare the pharmacodynamic responses, rapid-

acting and long-acting insulin products were tested in T1DM

for effect onset, peak, and duration times as reflected by

changes in FBG, and these data were compared with the

reported human parameters. In the miniature swine, typical

insulin pharmacokinetic and pharmacodynamic studies

designed to collect this information consisted of two different

study durations—short term and long term. In short-term stud-

ies, animals are generally fasted, and insulin is withheld for

approximately 18 hr prior to dosing to allow any systemic

maintenance insulin to be eliminated and the blood glucose

levels to stabilize. Animals are fed before or at the time of

dosing. Blood glucose level is measured using whole blood

samples with a handheld glucometer to screen for hypoglyce-

mia, and the remainder of each sample is placed in an appro-

priate blood collection tube to be processed for plasma or

serum collection. In long-term studies, the animals are fed and

given their regular maintenance insulin approximately 12 hr

before dosing for the study and are not generally fed at the

time of dosing. The remainder of the study is similar to a day-

long study; the animals are fed and administered regular main-

tenance insulin immediately upon completion of the last time

point of glucose testing for the study.

Type 1 Diabetes

Pharmacodynamic effects from various insulin products with

known properties of onset, peak, and duration times in humans

were studied in the alloxan-induced type 1 diabetic Yucatan

miniature swine, for comparative purposes. For this study, the

well-known prototypical marketed insulin products Huma-

log1, Apidra1, and Lantus1 were administered subcuta-

neously at mealtime to separate groups of animals, then the

blood glucose profiles were recorded over the next 8 hr using

handheld glucometers for rapid-acting insulin (Humalog1,

Apidra1) or over 24 hr for long-acting insulin (Lantus1).

Onset, peak, and duration were determined by reviewing the

collective group profile figures. Blood glucose profile data in

the diabetic Yucatan generally compared well with the pub-

lished human glucodynamic data for time to onset of effect and

peak effect for the rapid-acting insulins tested (Table 3). These

data suggest the Yucatan diabetic model, under these condi-

tions, has similar pharmacodynamic responses to humans for

onset and peak effects but not necessarily for duration for the

rapid-acting insulin. In humans, the long-acting insulin showed

similar onset and duration, but it showed a peak effect in min-

iature swine, but no peak was normally reported at all in

humans. These differences in pharmacodynamic response

could be due to the duration of fasting, the high doses of insulin

administered to the miniature swine, the use of a small number

of animals in these trials, or a partial biological difference in

the glucodynamic profiles of the various insulins between min-

iature swine and humans.

Type 2 Diabetes and Metabolic Syndrome

Miniature swine are also an ideal model for T2DM, which has a

multifactorial genetic cause in humans, because they are

genetically close to humans, susceptible to both spontaneous

and diet-induced obesity, have a dyslipidemia profile similar to

that of humans and can exhibit all aspects of metabolic syn-

drome. Type 2 diabetic miniature swine require no extra main-

tenance and are used for intravenous glucose and meal

tolerance testing, incretin studies, and also metabolic studies.

Dyslipidemia may be induced in many breeds of miniature

swine by feeding a high-fat atherogenic diet as illustrated in

Yucatan miniature swine in Table 4. The Yucatan miniature

swine have been considered a superior breed for atherosclerosis

studies (M. M. Swindle 1992). The Ossabaw pig is also sensi-

tive to diet-induced dyslipidemia (Lee et al. 2009). Sinclair

miniature swine, with a origin similar to the Gottingen and

Ossabaw miniature swine, readily develop dyslipidemia as

well. Adult castrated male Sinclair miniature swine maintained

on a high-fat diet for 3 months demonstrate an increase in

fasting triglyceride levels and a moderate increase in fasting

blood glucose, when low-dose alloxan is administered to par-

tially ablate the population of pancreatic beta cells (Table 5).

Type 2 diabetic miniature swine can be maintained at either

obese or normal body condition and thus provide many options

for studying the various facets of metabolic syndrome from

insufficient insulin secretion to reduced insulin sensitivity.

Dermal Models

Swine have been used extensively in dermal research because

of the comparability of their integument to that of humans.

During the past half century, they have been used in preclinical

dermal toxicology, dermal pharmacokinetics, dermal photo-

toxicity, dermal wound healing studies, and a broad array of

Table 2. Circulating Levels of Insulin and C-peptide in Type 1Diabetes Mellitus (T1DM) Yucatan Miniature Swine.

Insulin(pmol/L)

C-peptide(pmol/L)

Fasting glucose(mg/dl)

Normal Yucatan 50–100 60–130 50–70T1DM diabetic Yucatan — — 300–500

Note. — represents below the detection limit.

Table 3. Comparison of Diabetic Human and Diabetic YucatanMiniature Swine Response to Insulin.

Species Insulin OnsetPeak effect(hr)

Duration(hr)

Human Lispro (Humalog) <15 min 0.5–1.5 hr 3–5 hrMiniature swine <15 min 0.5–2 hr >8 hrHuman Glulisine (Apidra) <15 min 0.5–1.5 hr 3–5 hrMiniature swine <15 min 1.5–3 hr >8 hrHuman Glargine (Lantus) 1 hr Peakless 20–26 hrMiniature swine 1.5 hr 8 hr 24 hr

Stricker-Krongrad et al. 3



other biomedical research applications (Brown, Stricker-

Krongrad, and Bouchard 2013; Gad, Stricker-Krongrad, and

Skaanild 2015). Reviews of the use of swine in such studies

have been previously published (Fujii et al. 1997; Gad,

Stricker-Krongrad, and Skaanild 2015; Monteiro-Riviere and

Riviere 1996; M. M. Swindle 2007). In the field of toxicology,

swine skin has been used for acute and repeat-dose dermal

toxicology, dermal absorption, allergic contact dermatitis,

phototoxicity, and photosensitization studies. Models have

been created both in vivo and in vitro with skin membranes

and grafts. Both miniature and domestic breeds have been used

for these types of studies; however, miniature breeds such as

Sinclair, Yucatan, Hanford, and Gottingen may be more advan-

tageous due to their smaller size at sexual maturity. Using these

miniature breeds allows investigators to conduct experiments

in mature (rather than pediatric) animals with a consistent size

and health status. Each breed may be utilized in some aspect of

dermal toxicology (Brown, Stricker-Krongrad, and Bouchard

2013; Gad, Stricker-Krongrad, and Skaanild 2015; Svendsen

2006; M. M. Swindle et al. 2012). The value of miniature swine

dermal models for preclinical safety is confirmed by Ganderup

(2012) who reviewed miniature swine safety and efficacy data

on 43 marketed drugs with previously reported adverse

responses. Approximately 50% of the reviewed drugs had a

dermal indication, and 27 drugs had both human and miniature

swine data to enable a comparison. Overall, the predictive

value of miniature swine safety and efficacy studies to human

outcomes of all reviewed drugs were 89% and 100%, respec-

tively. Select models of the expanding landscape of dermal

studies and applications discussed below include transdermal

absorption, skin stripping, evaluating topical reactions, and

various aspects of wound healing.

Comparative Anatomy and Function

Dermal anatomic and physiologic similarities between minia-

ture swine and humans include a sparse hair coat, a relatively

thick epidermis, epidermal turnover kinetics, lipid composi-

tion, lipid biophysical properties, and arrangement of dermal

collagen and elastic fibers. The differences are the interfolli-

cular muscle, the distribution and function of apocrine versus

eccrine sweat glands, thickness of the stratum corneum (SC),

the basement membrane epitopes, and cytochrome P-450 bio-

transformation isoenzymes (Svendsen 2006; M. M. Swindle

et al. 2012).

Transdermal Absorption

In general, the miniature swine is accepted as an appropriate

model for topical agent testing, and skin penetrance is second

only to macaques in its similarity to humans for both lipophilic

and hydrophilic drugs. There are other factors that make the

miniature swine ultimately superior to macaques as an animal

model, including the adhered dermal structure, much less hairy

surface area compared to macaques, and their ease of handling.

Human permeability is higher than pigs for most compounds

tested (Panchagnula, Stemmer, and Ritschel 1997), but minia-

ture swine are still a recognized predictive model for human

drug candidate dermatopharmacology studies (Simon and Mai-

bach 2000).

Skin Stripping for Dermal Penetration

Tape stripping is a simple and effective method for removing

the SC (Figure 1) and is commonly employed during in vivo

studies investigating the percutaneous penetration and disposi-

tion of topically applied candidate drugs as well as in investi-

gations of drugs intended to restore damaged epithelial barriers

(Escobar-Chavez et al. 2008). One study was performed with

the objective to assess the remaining thickness of the SC fol-

lowing 0, 10, 20, 30, 40, and 50 repetitions of tape stripping of

skin on 3 young adult male Yucatan miniature swine weighing

33–36 kg each. Following the clipping of the pelage over the

Table 5. Circulating Levels of Triglycerides and Glucose in Type 2Diabetes Mellitus (T2DM) Sinclair Miniature Swine.

Triglycerides (mg/dl) Fasting glucose (mg/dl)

Normal Sinclair 50 50–70T2DM diabetic Sinclair 150 120–160

Table 4. Mean Lipid Profiles of Yucatan Miniature Swine in Responseto Being Fed a High-fat Diet.

Dietduration

Cholesterol(mg/dl)

Triglycerides(mg/dl)

Low-densitylipoprotein

(mg/dl)

High-densitylipoprotein

(mg/dl)

Prefeeding 117 50 39 52.1Day 30 329 73 147 66.7Day 60 520 42 208 80.7

Note. N ¼ 15. Age at prefeeding ¼ 1 month.

Figure 1. Hematoxylin and eosin staining of normal Yucatan minia-ture swine skin. Arrows point to the stratum corneum, the layerremoved with tape stripping.




dorsal lumbar and thoracic areas, six 5 cm � 5 cm sites were

demarcated, and the skin was stripped using 1.8-mm clear

acrylic adhesive tape applied with uniform, firm pressure. The

analysis of results by light microscopy showed an inverse pat-

tern of SC thickness to the number of tape stripping repetitions.

After 20 strippings, the number of remaining SC layers was

reduced from 11–15 to 2–6, and 50 passes were required to

remove nearly all the SC in each animal. No immediately

detectable underlying changes were observed in the epidermis

or dermis. These data demonstrate that miniature swine skin

can be stripped of SC in a linear fashion based upon repetition

of the technique and suggest that this is an acceptable model in

miniature swine.

Clinical Evaluation of Topical Reactions

Draize scoring, developed by John Draize (1951), provides a

method of grossly assessing the degree of inflammation based

on quantifying the values that are at risk of interpretation bias

or being considered insignificant. Originally developed for use

in rabbits, it has been modified for use in both swine and

humans and thus is often referred to as the modified Draize

score. In dermal studies, erythema and edema need quantified

analysis. Erythema and edema are each graded on a scale

ranging from 0 to 4, with a maximum total possible score

of 8 for irritation encompassing both erythema and edema. For

edema, this ranges from 0¼ ‘‘no edema’’ to 4¼ ‘‘severe edema

raised >1 mm and extending beyond the area of exposure’’; and

for erythema, this ranges from ‘‘no erythema’’ to ‘‘severe

erythema or slight eschar formation.’’ Slight, well defined, and

moderate to severe are graded as 1, 2, and 3, respectively.

Dermal Inflammation

Urticaria is dermal edema that results from vascular dilation

and leakage of fluid into the skin in response to molecules

released from mast cells. Human studies assessing efficacy of

topical and oral therapies for the treatment of urticarial reac-

tions frequently involve inducing wheal and flare reactions

with intradermal injections of histamine (Clough, Boutsiouki,

and Church 2001; Cole, Clough, and Church 2001; Reddy and

Singh 1976). To develop a comparable and reproducible der-

mal urticaria model in miniature swine, Hanford miniature

swine, ages 3–18 months, were pricked on their backs with a

skin test device (Lincoln Diagnostics Inc, Decatur, IN) that was

loaded with a vehicle or varying concentrations of histamine.

The irritation and wheal and flare responses of the dermis were

visually evaluated with Draize scoring, as described above, and

wheal size measurement. The reactions of the skin were

assessed at 10, 20 or 25, and 45 min after test formulation

application. Histamine dose-dependently induced skin irrita-

tion at both 10 and 20 min after treatment, and responses began

diminishing at 20 min after treatment (Table 6). The most

prominent erythema and edema responses were observed at

10 min after treatment, which slightly diminished 20 min after

treatment. Histamine also caused skin wheals that ranged

between 4 and 7 mm in diameter. After establishment of urti-

carial responses, the miniature swine were pricked on their

backs again with 25 or 50 mg/ml histamine, and the test sites

were then topically treated with placebo, hydrocortisone

cream, or antihistamine cream after 15 min in order to deter-

mine whether the histamine-induced wheals would then

respond to commonly available over-the-counter products.

Both hydrocortisone and antihistamine reproducibly inhibited

urticaria that was induced by 25 mg/ml histamine, and both had

an even more robust effect on the more intensive urticaria

induced by 50 mg/ml histamine (Figures 2 and 3). Noting that

the human studies evaluated the preventive effects of therapeu-

tic agents by treating before implementing histamine-induced

wheal and flare (Clough, Boutsiouki, and Church 2001; Cole,

Clough, and Church 2001; Reddy and Singh 1976), it is

expected that the response to treatment in the present model

is reduced compared to what it would be if the same preventive

process was studied. Therefore, this urticaria model can cur-

rently be used for the testing topical treatments for dermal

irritation and inflammation; it also has the potential to expand

and be further developed as a model.

Psoriasis is a long-lasting autoimmune disease character-

ized by patches of abnormal skin. These skin patches are

typically red, itchy, and scaly. They may vary in severity from

small and localized to diffuse. In the miniature swine, daily

intradermal challenge with chemokine (interleukin [IL]-23)

induces a psoriasis-like skin phenotype, with erythema, epi-

dermal hyperplasia, hyperkeratosis, parakeratosis, spongiosis,

and dermal leukocyte infiltration. Eight 3 cm � 3 cm sections

are delimited within the dorsal scapular to dorsal lumbar

region on each animal, 4 sections on each lateral side. Each

animal receives daily intradermal administration of IL-28

within each section for 7 consecutive days. Each section is

scored for plaque characteristics such as erythema, scaling,

and induration using a modified psoriasis area and severity

index introduced by Fredriksson and Pettersson (1978). Skin

histology can be performed to assess epidermal thickness,

parakeratosis, and marker of angiogenesis and proliferation

Table 6. Effects of Different Concentrations of Histamine on Dermal Irritation in a Hanford Miniature Pig Measured with Draize Scoring andWheal and Flare.

Treatments Control (50% glycerin) Histamine (3 mg/ml) Histamine (10 mg/ml) Histamine (25 mg/ml)

Time points (min) 10 20 10 20 10 20 10 20Draize score (maximum score: 8) 1 + 0 1 + 1 3 + 0 2 + 1 5 + 1 3 + 1 5 + 0 4 + 0Wheal size (mm) 2 + 1 3 + 1 4 + 0 5 + 0 5 + 1 6 + 1 6 + 1 7 + 1

Note. N ¼ 16. Results are expressed as mean + standard deviation.




by immunohistochemistry (e.g., CD31 and Ki67, respec-

tively). This model can subsequently be utilized to evaluate

the response to treatment using products that are being

developed.

Wound Healing

For many decades, swine have been a standard model for

wound healing. Rabbit and rodent models are used in wound

healing mainly due to lower expense and can be used for

screening tests; however, they have significant differences

from humans including a dense pelage and a thin epidermis

and dermis, and they heal predominately through wound con-

traction. Since pigs have fixed skin, their gross healing char-

acteristics including having similar elastic properties quantify

them as being similar to humans. Swine and humans have a

comparable dermal–epidermal ratio of 10–13:1, and the actual

skin thickness varies between regions of the body (Sullivan

et al. 2001). Reepithelization is an important component of

wound healing in swine as in humans. Farm pigs may have

exaggerated wound healing because of their rapid growth char-

acteristics; miniature swine have been used for chronic wound

healing models because they more accurately simulate adult

human healing rates (Chvapil and Chvapil 1992).

Excisional and Incisional Wound Healing

Partial thickness cutaneous wounds in swine undergo signifi-

cant reepithelization as a primary component of the healing

process. Partial thickness wounds are created with a derma-

tome that can be set at varying depths. The size of the lesions

created varies between studies, but generally they are square

lesions within the range of 3.0 cm on each side (M. M. Swindle

2007; Bolton, Pines, and Rovee 1988; Chvapil 1992; Mertz,

Figure 2. Observation of urticaria resolution 10 and 25 min after treatment with placebo, hydrocortisone, or antihistamine, beginning 15 minafter pricking with 25 mg/ml histamine. Arrows point to areas of urticaria. Responses 45 min after treatment are not shown; urticaria was almostcompletely resolved in both hydrocortisone and antihistamine treatment groups.




Hebda, and Eaglstein 1986; Ordman and Gillman 1966; Kerri-

gan et al. 1986; Sullivan et al. 2001; Wang et al. 2001; Singer

and McClain 2003; Middelkoop et al. 2004). Full-thickness

excisional wounds are created to the depth of the fascia using

either scalpel incisions or biopsy punches. These deep wounds

have wound contraction and granulation as the initial predomi-

nate healing processes. Excision wounds at this depth made

with a scalpel are generally of 3 to 5 cm size on each side.

Circular lesions of 1-2 cm diameter may be created with biopsy

punches. These wounds tend to heal by development of scar

tissue. The depth of the wounds varies from 0.8 to 1.5 cm

depending upon location on the body. The most common area

is bilaterally on the flank. Wounds of this size usually have a

volume of 10 to 15 ml. Total number of full-thickness

wounds are generally limited to 8 per animal. Wounds of this

size would be expected to achieve 40% reduction with gran-

ulation in 7 to 8 days (M. M. Swindle 2007; Chvapil 1992;

Middelkoop et al. 2004). Incisional wounds are made using a

scalpel and are also studied for testing new closure devices or

suture materials. The depth and location may vary depending

upon the goals of the study. Incisional wound healing is

quicker than the other types of wounds, and each animal

should be used as its own control.

Geometric Determinants of Wound Healing

To investigate the relationships between wound geometry and

wound healing rates, wounds of varying size and shape were

created in adult Yucatan miniature swine. The primary out-

comes of interest were time to complete healing (defined as

full epithelialization), healing rate (defined as absolute change

in area from baseline over time), and linear healing rate

(defined as change in wound ‘‘radius’’ over time). Although

larger wounds took longer time to heal than the smaller ones,

Figure 3. Observation of urticaria resolution 10 and 25 min after treatment with placebo, hydrocortisone, or antihistamine, beginning 15 minafter pricking with 50 mg/ml histamine. Arrows point to areas of urticaria. Responses 45 min after treatment are not shown; urticaria was almostcompletely resolved in both hydrocortisone and antihistamine treatment groups.




there was no appreciable difference in healing rate associated

with the wound shape, as shown in Table 7. For example, the

average healing time for 20 cm wounds was 56, 56, and 49 days

for circles, squares, and triangles, respectively. Mean healing

rates were 2.1, 2.6, and 3.3 cm2 per week for 10, 20, and 30 cm2

wounds, respectively. Results for the outcome of absolute

wound healing rates were calculated using planimetry data.

There was a strong correlation between healing rate and initial

wound area. It was determined that linear healing rates were

largely unaffected by either initial wound area or wound shape.

Ischemic Wound Healing

Swine have long been utilized as models to study the effects

of treatments on skin flaps and grafts due to their physiologic

similarities to humans, as discussed above (M. M. Swindle

2007). Kerrigan et al. (1986) published a detailed summary of

the various types of flaps and grafts studied in plastic surgery.

Skin flaps are generally made on the dorsal flank, the but-

tocks, or the limbs, and they are generally full-thickness flaps.

Tissue ischemia of wounds in diabetics is a consequence of

developing vascular complications, which limit the supply of

blood and blood-borne products to the wound site and

severely impairs the wound healing process. In order to

establish a model of chronic ischemic wound healing in dia-

betic miniature swine, the wound healing process was inves-

tigated in bipedicle ischemic flaps in chemically induced

diabetic miniature swine. Bipedicle flaps (5 cm � 15 cm)

were created, a silicone film was placed underneath some of

the bipedicle flaps to create ischemic conditions, then 0.8-cm

diameter center punches were created and scored during heal-

ing for erythema, edema, granulation, and epithelialization

(Table 8). Erythema and edema were more prominent in

ischemic skin wounds. Additionally, granulation and epithe-

lialization were delayed in ischemic skin wounds, with the

delay in epithelialization being the most noticeable difference

between the two wound types.

Ophthalmology Models

As with the endocrine and dermal models, the use of miniature

swine for ophthalmology models is varied and expanding. The

anatomic similarities to human eyes, along with comparable

physiologic processes, enable miniature swine to be good can-

didates for surgical procedures and reliable for model develop-

ment and subsequent testing of potential therapeutic agents

(Kyhn et al. 2008; Rosolen, Rigaudiere, and Le Gargasson

2003; Sachs et al. 2005).

Table 7. Geometric Determinant of Wound Healing Time and Rate of Linear Healing in the Miniature Swine.

Wound shape Wound size (cm2) Average healing time (d) Average healing rate (cm2/week) Average linear healing rate (cm/week)

Circle 10 33 2.1 0.57Square 10 35 2.1 0.46Equilateral triangle 10 33 2.1 0.65Circle 20 56 2.6 0.62Square 20 56 2.6 0.53Equilateral triangle 20 49 2.6 0.57Circle 30 70 3.3 0.65Square 30 54 3.3 0.70Equilateral triangle 30 70 3.3 0.57

Table 8. Scoring of Wounds in Normal and Ischemic Skin in Diabetic Yucatan Miniature Swine.

Erythema/edema Granulation Epithelialization

Days Normal Ischemic Normal Ischemic Normal Ischemic

0 1.0 0.8 4.0 4.0 4.0 4.02 1 1 4.0 4.0 4.0 4.07 1 1.3 0.1 0.8 2.4 3.812 0 1 0.0 0.8 0.4 1.514 0 0.5 0.0 0.0 0.8 1.5Note. n ¼ 6.Score Erythema/edema Granulation/epithelialization0 No erythema *100%1 Very slight erythema (barely perceptible) *75%2 Well-defined erythema *50%3 Moderate to severe erythema *25%4 Severe erythema to slight eschar formation <15%




Comparative Anatomy and Function

The orbit of swine is open at the lateral aspect, as compared to

the closed orbit of humans in which the eye is completely

enclosed by bone. There are 7 extraocular muscles attached

to the orbital wall in deep fossae, while humans have 6. In

addition, humans have an annular ligament, the annulus of

Zinn, surrounding the optic nerve that is absent in swine (M.

M. Swindle 2007; Adams 1988; Curtis, Edwards, and Gonyou

2001). Pigs, unlike humans, have a translucent nictitating

membrane that crosses the eye horizontally from the medial

canthus; this membrane serves as a protective ‘‘third eyelid’’

and contains a nictitans gland for lubrication. The globe dimen-

sions range from 19.6 to 25.0 mm in height, 21.9 to 25.1 mm in

width, and 19.4 to 22.4 mm in depth. The cornea is horizontally

oval in shape. The sclera and iris are usually pigmented. The

retina is very similar to humans (M. M. Swindle 2007; K. E.

Swindle and Ravi 2007; Reilly et al. 2008, Ruiz-Ederra et al.

2005; Shafiee et al. 2008; Kyhn et al. 2008; Iandiev et al. 2006;

Czajka et al. 2004; Sachs et al. 2005; Petters et al. 1997). The

pig does not have a tapetum lucidum, a true macula, or a fovea;

they do have a cone-rich visual streak (Fernandez de Castro

et al. 2014). Pigs have binocular vision and some degree of

color vision.

Uveitis

A miniature swine model of uveitis is induced by an acute

intravitreal injection of 200 ng bacterial lipopolysaccharide in

saline under anesthesia. All miniature swine are examined

with slit-lamp microscopy and indirect or direct ophthalmo-

scopy throughout days 1 to 6 postinjection. Corneal neovas-

cularization, vitreous opacity, and anterior chamber cells and

flare are evaluated, and clinical scoring is performed using

Hogan’s classification (Hogan, Kimura, and Thygeson 1959;

Kimura, Thygeson, and Hogan 1959). Aqueous and vitreous

are collected at necropsy; the presence of leukocytes in the

vitreous is evaluated by a total cell count using a hematocyt-

ometer, and a differential cell count is performed in the aqu-

eous solution under a microscope after staining. In addition,

inflammatory cells in sections of the anterior and posterior

segment structures are quantified by a grading scale. Drug

treatments, such as methotrexate, mercaptopurine, corticos-

teroids, or triamcinolone can be evaluated in this model (Gil-

ger et al. 2013).

Retinal Detachment

The predominant number of porcine ophthalmic models in the

literature involves the retina because of the anatomic and phy-

siologic characteristics described above. Retinal detachment in

humans can develop for a variety of reasons including trauma

and metabolic disorders. The condition can be created surgi-

cally in swine (Iandiev et al. 2006). A lateral canthotomy is

created, and a circumscript vitrectomy is performed in the

region of the detachment. The vitreous is replaced with

physiologic saline. A subretinal injection of saline followed

by 0.25% sodium hyaluronate is administered using thin glass

pipettes. This results in a rhegmatogenous detachment of the

retina in the selected area. Clinical ophthalmic examinations

are performed postoperatively, and the vitreoretinopathy is

graded on a scale of 0 to 5 using the Silicone Study Classifi-

cation System (Machemer et al. 1991). Briefly, grade 1 indi-

cates an inner retinal wrinkling, while grades 3–5 indicate the

number of quadrants with retinal detachment. Using this

model, drug therapies and experimental surgical corrective

treatments can be tested (Boone et al. 1996).

Cataracts

Diabetic miniature swine are routinely screened for clinical

ocular abnormalities including visible ‘‘mature’’ cataracts

(Table 9, Figure 4). Over the course of a 6-month period, the

prevalence was 30% (80 positive animals of 266 animals).

The most recent incidence (past 2.5 months) was 20.4% (38

positive animals with 60 affected eyes from a pool of 186

previously negative animals). Eighteen animals had bilateral

and 20 animals had unilateral cataracts (oculus dexter: 31 and

oculus sinister: 29). Cataract onset ranged from 2 to 19

months postinduction of diabetes with an average onset of

11 months. Cataracts were detected earlier in animals when

euglycemia was intentionally less controlled, which supports

the current predominant theory of glycation-induced cataract

development. Interestingly, swine, unlike humans, are not

capable of glycating their hemoglobin due to the lack of pene-

tration of glucose into the red cells. Miniature swine with

cataracts appear to function acceptably well despite the

assumed visual handicap.

Glaucoma

A model of glaucoma via surgical induction of increased

intraocular pressure (IOP) has been created in Yucatan minia-

ture swine. In this study, animals had bilateral IOP measure-

ments performed prior to surgical intervention to establish a

baseline IOP. IOP measurements were taken with a Tono-pen

Table 9. Prevalence of Cataracts over a 2.5-month Period in DiabeticYucatan Miniature Swine.a

Category Number

Average total number of pigs in diabetic colony duringperiod

186

Number of pigs diagnosed with cataracts 38Bilateral cataracts 18Unilateral cataracts 20Right eye 31Left eye 29Months postinduction range 2–19Average months postinduction 11

aSome animals were intentionally less euglycemic controlled than others.Cataracts were detected earlier in these poorly regulated animals.




VET™ veterinary tonometer. In order to reduce venous drai-

nage from the eyes, episcleral veins were scarified by cauter-

ization in each eye. IOPs were periodically measured for

several weeks postcauterization surgery. Pharmacologic inter-

vention was then begun with a commercially available syn-

thetic prostamide analog with ocular hypotensive activity.

Drops were applied once daily, and IOPs continued to be mea-

sured. After 7 weeks of daily treatment, eye drops were dis-

continued, and IOP measurements were obtained continuously.

All animals presented with significant increases in IOP dur-

ing postsurgical intervention (p � .005) and significant

decreases in IOP with pharmacological therapy (p � .0006).

Pretreatment mean IOP was 19 + 4 mmHg, postsurgery mean

IOP was 24 + 5 mmHg, posttreatment mean IOP was 18 + 4

mmHg, and recovery mean IOP was 20 + 4 mmHg. Therefore,

Yucatan miniature swine could be considered a viable model

for surgically induced glaucoma. Also, it has been shown that

the miniature swine eye is responsive to pharmacological

Figure 4. Gross and histologic comparison of normal (A, top) lens and lens with cataracts (B, bottom) in Yucatan miniature swine. Hematoxylinand eosin stain.




therapy to reduce IOP and as such could be a potential model

for future pharmacological research.

Diabetic Retinopathy

A miniature swine model was also developed and characterized

for long-term effects of diabetes mellitus on retinal function

and structure. Nine animals were used: 3 were nondiabetic, 3

had been diabetic for 5 to 8 months, and 3 had been diabetic for

13 to 17 months. Electroretinograms were performed under

isoflurane anesthesia using a portable, full-field, flash system.

A-wave, b-wave, and oscillatory potential (OP) amplitudes

were evaluated. At maximum scotopic intensity, some animals

had increased a-wave amplitudes when compared with the nor-

mal animals. B-wave amplitudes appeared normal or reduced.

At standard scotopic intensity, OP amplitudes appeared

increased or normal. Animals were euthanized, eyes enu-

cleated, and fixed in 2.5% glutaraldehyde in sodium cacodylate

buffer for transmission electron microscopy. Images of capil-

laries from inner nuclear (INL) and inner plexiform/ganglion

cell (IPL/GCL) layers were obtained from each diabetic and

each normal miniature swine. Basement membrane thickness

was significantly increased (p < .001) in the diabetic miniature

swine, both in the INL and in the IPL/GCL. ERG results varied

across all animals; the strongest correlation was between base-

ment membrane thickness and OP amplitude. It has previously

been found that diabetes is responsible for basement membrane

thickening in miniature swine, making them a useful model for

studying mechanisms and treatments at various stages of dia-

betic retinopathy (Hainsworth et al. 2002).

Translational Research

The identification and characterization of animal models and

diseases having a high translational value have become more

and more important at a time when the limitations of rodent

models have been fully recognized. As has been described, the

miniature swine can play a role beyond its classical use as a

model for surgical studies. The miniature swine is a relevant

model for the evaluation of therapeutics aimed at treating endo-

crine diseases such as T1DM and T2DM, inflammatory dis-

eases, wound healing, dermal diseases other than wound

healing, and multiple ophthalmic diseases. The use of minia-

ture swine in biomedical research is continuing to grow. Excit-

ing new advances in model development and the relevance of

miniature swine in the study of human disease will continue to

increase in prominence in the future.

Authors’ Contribution

Authors contributed to conception or design (AS, CS); data acquisi-

tion, analysis, or interpretation (AS, GB); drafting the manuscript

(AS); and critically revising the manuscript (AS, CS, GB). All authors

gave final approval and agreed to be accountable for all aspects of

work in ensuring that questions relating to the accuracy or integrity of

any part of the work are appropriately investigated and resolved.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to

the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, author-

ship, and/or publication of this article.

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