ILAR Journal Online, Volume 36(1) 1994: Farm Animals in Biomedical Research

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ILAR Journal V36(1) 1994 [FORMERLY ILAR NEWS]
Farm Animals in Biomedical Research - Part One

Swine in Biomedical Research: Management and Models
M. Michael Swindle, Alison C. Smith, Kathy Laber-Laird, and Laurel Dungan

M. Michael Swindle, D.V.M., is Professor and Chairman, Alison C. Smith, D.V.M., is an Assistant Professor, Kathy Laber-Laird, D.V.M., M.S., is an Assistant Professor, and Laurel Dungan, D.V.M., is a resident at the Department of Comparative Medicine, Medical University of South Carolina, Charleston, South Carolina.

INTRODUCTION

For the last 2 decades, swine have been used with increasing frequency in biomedical research as replacements for dogs and primates, as well as models of human disease based upon their own unique anatomy and physiology (Stanton and Mersmann, 1986; Swindle, 1992; Tumbleson, 1986).

All of the domestic farm breeds and miniature breeds available in the United States are Sus scrofa domestica. Farm breeds have the disadvantage of a rapid growth rate, increasing from an average weight of 1 kg at birth to 100 kg at 4 months of age. Mature breeding stock typically reach weights of greater than 200 kg. Consequently, these animals are best used for non-survival or short-term projects of less than 3 weeks in duration.

Miniature pigs are more commonly used for long-term projects because of their smaller size and growth rate. Depending on the breed, miniature pigs grow from a birth weight of 0.5 kg to 12-45 kg. at 4 months of age. Breeding stock reach weights of 45-100 kg. Commercially available miniature pigs also tend to be more tractable than domestic breeds raised in an agricultural setting. The most commonly used laboratory breeds of miniature pigs are Yucatan miniature, Yucatan Micropig®, Hanford, Sinclair (Hormel), Pitman-Moore, and Goettingen (Panepinto, 1986).

The purpose of this article is to review the use of swine in biomedical research and to provide general information on the husbandry and management of the various breeds in a laboratory setting. If an institution seeks to raise swine in large numbers, it would be well advised to consult an agricultural scientist involved in swine production programs for advice on facility design and management.

BIOMEDICAL MODELS

Swine are commonly used in cardiovascular research because swine and humans share important anatomic and physiologic characteristics. Their hearts are approximately the same size, and coronary blood flow, hemodynamic and myocardial contractility, development of atherosclerosis are analogous (Stanton and Mersmann, 1986). Consequently, swine are used to study congenital heart disease (Gillette et al., 1991; Mitchell et al., 1994; Swindle et al., 1992), myocardial infarction (Bloor et al., 1992), hemodynamics and shock (Hannon, 1992; Hoban et al., 1992), development of interventional radiology devices including balloon catheters and intravascular stents (Gal and Isner, 1992; White et al., 1992), hypertension (Zambraski et al., 1992), cardiopulmonary bypass and anesthesia (Cameron et al., 1992; Weiskopf et al., 1992), heart failure (Hendrick et al., 1990), and atherosclerosis (Lee et al., 1986).

Swine are also used extensively for nutritional studies because their digestive physiology is similar to humans. Because they are omnivores, swine will readily consume a variety of nutritional supplements and test substances (Swindle et al., 1988). They have also been used for many other studies related to nutrition, including total parenteral nutrition, lipid metabolism, diabetes, alcoholism, gastric ulceration, and splanchnic blood flow (Cohen et al., 1992; Laber-Laird et al., 1992; Tumbleson, 1986).

Organ transplantation studies have been performed using the swine heart (Hall et al., 1986), liver (Flye, 1992), kidney (Pennington, 1992), pancreas (Koyama et al., 1986), and intestine (Pritchard et al., 1986). Many of these organ transplantation studies have been related to immunologic aspects of transplants, including the development of transgenic animals that would be immunologically accepted by humans (Sachs, 1992).

Other studies have involved wound healing and plastic and reconstructive surgery (Kerrigan et al., 1986), fetal surgery (Randall, 1986), and pharmacology and toxicology (Kurihara-Bergstrom et al., 1986; Feletou and Teisseire, 1992). Reproductive physiology and endocrine functions have also been studied (Tumbleson, 1986).

Swine are used extensively in surgical training classes for health care practitioners. Initially they were used to train medical students and residents in surgical skills ( and Bobbie, 1983) but are now used extensively to train graduate physicians, nurses, and technical staff' in endoscopic and stapling surgical techniques, laser surgery, and microsurgery.

When comparing studies using swine, the differences in physiology, genotype, and phenotype and in maturity at a given body weight need to be considered, not only among breeds, but among breeds from different producers. It is best to use the same breed and age, however, this is not always possible. In order to make hemodynamic comparisons, values should be indexed to body weight in kilograms or body surface area. Because of varying growth rates among breeds, animals may differ in age and maturity at the same weight. This factor should also be considered when comparing data (Smith et al., 1990; Smith et al., in press). Genotype matching has become increasingly important in achieving reproducibility among animals.

Anesthesia, analgesia, and surgical care are important subjects and have received much attention in the literature. Reviews on these important subjects are available (Riebold and Thurmon, 1986; Smith et al., in press; Swindle et al., 1988).

HUSBANDRY

Guidelines for housing laboratory swine have been published in the Guide for the Care and Use of Laboratory Animals (Guide) (NRC, 1985) and in the Guide for the Care and Use of Agricultural Animals in Agricultural Research and Teaching (Ag Guide) (Consortium for Developing a Guide, 1988), which require that swine be housed in facilities comparable to a well-managed farm. Also, the proceedings of a Scientists Center for Animal Welfare conference provide recommendations for husbandry and handling of swine (Mench et al., 1992). Although agricultural animals, including swine, are now covered by the Animal Welfare Act and consequently are regulated by the U.S. Department of Agriculture, no written standards are available to date. While the guidelines listed above do not take miniature pigs into consideration, a comparison of husbandry practices for miniature pigs with those of domestic farm breeds has recently been published (Fisher, 1993).

The recommendations in both the Guide and the Ag Guide for housing and grouping swine are confusing and contradictory and neither takes miniature pigs into consideration. The Guide has more stringent requirements for floor space than the Ag Guide and should be used as the standard for biomedical institutions. The Guide requires 6 to 60 square feet per pig (0.56-5.57 sq m/pig) depending upon the body weight and the number of animals housed within the same enclosure. It does not distinguish between a sow with a litter and groupings of more mature animals. The Ag Guide recommends 35 sq ft (3.15 sq m) for a sow with a litter. In our experience, miniature pigs with litters actually require less space than could be calculated from the standards in either document. A variance of this type should be reviewed by the institution's IACUC.

Ambient temperature requirements for swine are not listed in the Guide, but the Ag Guide recommends a temperature range of 50°-77°F (10°-25°C) for adult animals and temperature ranges of 590-90^°(15°-32°C) for less mature animals with the higher values being required for neonates. Based on our experience with miniature swine, temperatures should be between 75°-80°F (24°-26°C). Heat lamps or other heat sources should be placed in the comer of the cage to provide extra warmth for neonates, which typically require temperatures of 85°-90°F (30°-32°C). Care must be taken to ensure that temperature measurements are made at the level of the animals because of the differential between the floor and wall thermostats (Fisher, 1993). Care should also be taken to ensure that animals are kept dry while the pens are being cleaned, as wet animals frequently become chilled. Animals housed in agricultural situations can withstand a wide range of temperatures if shelter is available.

Humidity and air changes are not detailed by existing guidelines. We use rooms with 10-15 air changes per hour with 100 percent fresh outside air and a relative humidity of 40-70 percent, which is consistent with general American Association for Accreditation of Laboratory Animal Care (AAALAC) facility standards. If lighting is provided by artificial means with light timers, the lighted cycle should be 12-16 hours especially if breeding is performed (Consortium for Developing a Guide, 1988; Fisher, 1993).

Swine are best housed in pens made of chain link or panels with vertical slats or bars. If solid floors are used, they should be deeply bedded with wood shavings to prevent the animals from slipping. The wood shavings also provide environmental enrichment as they are a substance in which the pigs can root. Extra care must be taken when using wood shavings with animals that are being fasted before surgery, as they will eat the bedding. Raised slotted flooring or slatted floors are also acceptable as long as a type with small openings is used to prevent hoof injury (Figure 1). If animals are housed on raised floors, a regular program of hoof trimming will have to be provided for long-term animals (those held for more than 3 months). Dog cages provide good short-term housing for special purposes such as post-operative care, however, either raised floors or non-skid pads need to be placed in the cages.

Facilities that maintain breeding swine need to provide for farrowing and weaning. Domestic farm breeds, but not miniature breeds, require a farrowing crate or pen to prevent them from crushing the piglets. If the piglets are allowed access to heat lamps and bedding for warmth, it is our experience that farrowing crams or even separation panels are unnecessary. Piglets will start to consume feed at approximately 3 weeks, and the starter ration should be provided in an area of the pen not accessible by the sow. Domestic farm breeds have an average gestation period of 114 days, while some of the miniature breeds farrow at shorter times (for example, the Yucatan pig has a gestation period of 111 days). Weaning for both domestic and miniature breeds occurs at 3 to 6 weeks.

Swine are social animals and should be provided with the opportunity to interact with other members of their species and with humans. If housing by compatible groups is not possible because of protocol restrictions or cage size, then animals should be able to see each other and preferably touch noses through the walls of the pens. Incompatible animals will fight and dominant animals may severely injure others in the pen especially at feeding time. If animals are housed without bedding, then toys such as basketballs or large balls made of impervious materials can be provided to satisfy the rooting behavior. Swine can be trained and made docile by positive interactions with humans such as rubbing or scratching the head and back. Animals may also be trained with food rewards of vegetables or fruit. Stressful housing situations in combination with other factors, including diet and environmental fluctuations, may result in gastric ulceration (Panepinto, 1986; Swindle et al., 1988).

In biomedical research institutions, standard formulations of commercial agricultural feed should be avoided. Commercial farm rations are designed to provide rapid growth and contain antibiotics and other growth promoters unless special formulations are requested. Several commercial manufacturers now provide diets for miniature pigs which are higher in fiber and provide for less rapid growth without compromising nutritional requirements. Starter, maintenance, and lactation diets are available and a calculated amount may be fed either once or twice a day. Pigs will readily consume medications mixed in normal rations or camouflaged with either canned dog food or chocolate syrup. Pigs will form a dunging pattern and will usually defecate opposite from where their food is provided depending upon the cage configuration. More information on nutrient requirements for swine can be found in NRC (1988).

Water is best provided by an automated watering system as water deprivation can easily occur because pigs will refuse to drink from soiled water containers and quickly overturn floor pans and water bowls. Care must be taken not to deprive them of water for long periods of time, even preoperatively, because they are susceptible to "salt poisoning.'' This condition results in clinical neurologic deficits secondary to water deprivation or over-administration of sodium salts in as little as 12 hours (Fisher, 1993).

HANDLING

Restraint methods, commonly used in agricultural settings such as "snout snaring" or other aggressive physical types of restraints should be discouraged in biomedical research institutions because of the stress they induce. Swine may be humanely restrained in commercially available restraint slings (Figure 2) or institutions may construct their own (Panepinto, 1986). Swine may be herded into the comer of a pen using a handheld plywood or plastic panel when restraint is necessary in the pen. If restrained manually, they should be held in the same manner as dogs and not held upside down by the rear legs. Physical examinations, rectal temperature checks, and injections may be performed while a pig is distracted by food.

Short-term chemical restraint agents and anesthetics may be used if the procedure requires them. Techniques and agents are reviewed elsewhere (Riebold and Thurmon, 1986; Smith et al., in press; Swindle et al., 1988).

HEALTH CARE

The best method to ensure having healthy research animals is to procure them from a reliable source, which has been evaluated by the institutional veterinarian. The health status of domestic farm breeds is variable depending upon the endemic diseases in the region of the country and the quality of the management and health care program of the farmer. Purchasing pigs at auctions is almost certain to introduce porcine diseases to the research facility. Specific-pathogen free (SPF) status is a specific term in swine management ensuring that the source of animals is free of many infectious and parasitic diseases with a notable exception being mycoplasmosis. While non-SPF sources may still be healthy and suitable for research, the animals should be evaluated by a veterinarian. Regardless of the source of the animals, our experience is that a 3-day stabilization period following shipment is recommended for animals undergoing survival surgical procedures. Depending on the source of the animal, quarantine and conditioning programs may be necessary for animals on long-term projects. If research animals are being maintained for long-term projects, it may be necessary to establish a vaccination program. Potential pathogens to vaccinate for include Bordetella, Pasteurella, erysipelas, Hemophilus, Clostridium, parvovirus, leptospira, Escherichia coli, transmissible gastroenteritis, and rotavirus. Veterinary advice should be sought on which organisms are of particular importance to the research facility. A program to control internal and external parasites should also be established based on a physical examination and an evaluation of fecal samples.

If a facility is raising neonates, a program of care should include clipping the needle teeth and injecting iron dextran to protect against physiologic anemia, which occurs in newborn pigs.

Health programs for miniature swine are the same as for domestic farm breeds, and in-depth discussions of health management programs are available in veterinary textbooks (Leman et al., 1992).

SUMMARY

Swine, both miniature and domestic farm breeds, will continue to be used in research and teaching in the foreseeable future. Biomedical models have been well described (Stanton and Mersmann, 1986; Swindle, 1992; Tumbleson, 1986) and overviews of methods of anesthesia, analgesia, and handling appropriate for research institutions are available (Riebold and Thurmon, 1986; Smith et al., in press; Swindle et al., 1988). The differences between miniature pigs and domestic farm breeds, as well as the differences among breeds within the same category, must be taken into account when designing scientific protocols and management plans.

This manuscript is meant to provide general guidelines for multi-species research institutions that may only occasionally use swine. Readers are advised to consult the in-depth references provided for specific details.

REFERENCES

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Cameron, D. E., K. H. Tam, W. Cheng, and M. Braxton. 1992. Studies in the physiology of cardiopulmonary bypass using a swine model. Pp. 185-196 in Swine as Models of Biomedical Research, M. M. Swindle, ed. Ames, Iowa: Iowa State University Press.

Cohen, I. T., S. O. Nelson, and M. P. Hirsh. 1992. The role of the Hanford minipig as an animal model in pediatric surgery and neonatal intensive care. Pp. 57-63 in Swine as Models in Biomedical Research, M. M. Swindle, ed. Ames, Iowa: Iowa State University Press.

Consortium for Developing a Guide for the Care and Use of Agricultural Animals in Agricultural Research and Teaching. 1988. Guide for the Care and Use of Agricultural Animals in Agricultural Research and Teaching. Champaign, Illinois: Association Headquarters (Available at a cost of $5.00 each from Association Headquarters, 309 West Clark Street, Champaign, IL 61820. Tel: 1-217-356-3182).

Feletou, M., and B. Teisseire. 1992. Vascular pharmacology of the micropig: Importance of the endothelium. Pp. 74-95 in Swine as Models in Biomedical Research, M. M. Swindle, ed. Ames, Iowa: Iowa State University Press.

Fisher, T. F. 1993. Miniature swine in biomedical research: Applications and husbandry considerations. Lab Animal 22(5):47-50.

Flye, M.W. 1992. Orthotopic liver transplantation in outbred and partially inbred swine. Pp. 44-56 in Swine as Models in Biomedical Research, M. M. Swindle, ed. Ames, Iowa: Iowa State University Press.

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FIGURE 1 Pig housed in a chain length run on raised flooring. Note the use of automatic watering and the presence of a Teflon ball for environmental enrichment.

FIGURE 2 Yucatan miniature pig humanely restrained in a Panepinto sling.