Design principles for animal models

The design of biomedical research is often considered in the design of animal models, because many experiments that clarify the mechanisms of disease and efficacy may not or should not be performed on patients. Often rely on replicating animal models, but must be carefully designed, following the following principles when designing.

First, similarity

A human disease model is replicated in animals. The purpose is to find out the relevant laws that can be generalized (extrapolated) applied to patients. Extrapolation takes risks because animals and people are not a creature. For example, drugs that are ineffective on animals are not equivalent to clinical ineffectiveness, and vice versa. Therefore, an important principle in the design of animal disease models is that the replicated model should be as close as possible to the human disease. It is of course best to be able to find the same spontaneous disease in animals as human diseases. For example, the primary hypertension found by Japanese people is an ideal model for studying human essential hypertension. Spontaneous coronary atherosclerosis is an ideal model for studying coronary heart disease in humans; spontaneous rheumatoid arthritis joints Inflammation is very similar to human juvenile rheumatoid arthritis and is an ideal model, and so on. The animal spontaneous disease model, which is exactly the same as humans, is rare, and often needs to be copied manually. In order to be as similar as possible to human diseases, we must first pay attention to the choice of animals. For example, chicks are best suited for hyperlipidemia because its plasma triglycerides, cholesterol, and free fatty acids levels are very similar to humans, and the lipid composition of low-density and very low-density lipoproteins is similar to humans. Secondly, in order to make the model as similar as possible to human beings, we must constantly improve the methods in practice. For example, ligation of rabbit appendix blood vessels, although it may cause perforation of appendix necrosis and lead to peritonitis, but this is not the same as human perforation appendicitis with perforation and peritoneum. If the rabbit is ligated to the base of the appendix and retain the original blood supply, the resulting appendix Perforation and peritonitis are similar to human conditions and are therefore an ideal method. If the animal type is not similar to the clinical situation, an effective treatment regimen in the animal may not be used clinically, and vice versa. For example, endotoxin shock (intravenous injection of bacteria and its toxins in animals) is not exactly the same as clinically septic shock, so endotoxic shock in animals Effective therapy has long been unusable by clinicians. Nowadays, some people have injected bacteria into the gallbladder of the gallbladder artery and bile duct to replicate the model of human septic shock. It is considered that the animal has both infection and endotoxin poisoning, which is similar to clinical septic shock. In order to determine whether the copied model is similar to a person, a series of checks are required. For example, some people have checked the animal pressure, pulse rate, venous pressure, respiratory rate, arterial blood pH, arterial oxygen partial pressure and carbon dioxide partial pressure, venous blood lactate concentration and blood volume, and found a shock model caused by a quantitative bloodletting method. It is very similar to clinical hemorrhagic shock, so it is considered that the model replicated by some methods is an ideal model. In the same way, according to the theory of traditional Chinese medicine, the mice are fed with rhubarb to make them appear similar to human "spleen deficiency syndrome". If they are cured by Sijunzi soup according to the theory of traditional Chinese medicine, then there is reason to regard it as the animal of human "spleen deficiency syndrome". model.

Second, repeatability

Ideal animal models should be repeatable and even standardized. For example, a one-time quantitative bloodletting method can cause hemorrhagic shock and 100% death, which is consistent with repeatability and standardization requirements. Another example is the use of a dog for myocardial infarction model, because its coronary circulation is similar to humans, and it is most suitable for thoracotomy in exposed animals in experimental animals, but the consequences of dog ligation of coronary arteries are too different. The ligation of the same part of the same artery in the dog is very inconsistent, unpredictable, and cannot be standardized. Conversely, the consequences of ligating the coronary artery in squirrels, hamsters, and guinea pigs are more consistent, predictable, and therefore standard. In order to enhance the reproducibility of animal model replication, it must be in animal species, strain, age, sex, weight, health, feeding management; experimental and environmental conditions, season, circadian rhythm, stress, room temperature, humidity, air pressure, disinfection Bacteria; experimental method steps; drug manufacturer, batch number, purity specification, dosage form, dosage, route, method; anesthesia, sedation, analgesia, etc.; instrument type, sensitivity, accuracy; experimenter skill Consistently, because consistency is reproducible.

Third, feasibility

The replicated animal model should strive to reflect human diseases, which can specifically or can reflect a certain disease or a certain function, metabolism, structural changes, and should have the main symptoms and signs of the disease, after testing or X-ray photos, electrocardiogram, pathological sections, etc. confirmed. If some animals with corresponding lesions are spontaneously present, they should not be used. It is not suitable for patients who are prone to cause diseases that are confused with replication diseases. For example, lead poisoning can be modeled by rats, but it has disadvantages because it is prone to endemic pneumonia and progressive kidney disease in the animal. The latter is easily confused with nephropathy caused by lead poisoning. It is not easy to determine whether the kidney disease is caused by lead poisoning or it. Caused by its own disease. It is easier to determine with Mongolian gerbils, because only lead poisoning will cause it to appear renal lesions.

Fourth, applicability and controllability

Animal models for medical experimental research should be considered in the future clinical application and easy to control the development of their diseases in order to facilitate the research. For example, estrogen can terminate early pregnancy in rats and mice, but it cannot terminate a person's pregnancy. Therefore, the use of estrogen to replicate rat and mouse models of termination of early pregnancy is not applicable, as it is often found that when drugs and estrogen-active drugs are screened in rats and mice, it may be An effective contraceptive, but once it is used, it is not successful. Therefore, if it is known that a compound has estrogenic activity, it is meaningless to observe the effect of terminating pregnancy in this rat or mouse. Another example is that large mice are used as experimental peritonitis because they are highly resistant to Gram-negative bacteria and are not prone to peritonitis. Some animals are particularly sensitive to certain pathogenic factors and are highly prone to death and are not suitable. If the dog's intraperitoneal injection of fecal filtrate causes peritonitis to die quickly (80% within 24 hours of death), it is too late to do experimental treatment observation, and the fecal dose and bacterial strain are not well controlled, so the experimental results cannot be accurately repeated.

5. Easy and economical

When replicating animal models, the methods used should be as easy to implement and economical as possible. Primates are the closest to humans, and the replicated disease models are similar, but rare and expensive, even if the macaques are not available, let alone orangutans and gibbons. Fortunately, many small animals such as large mice, hamsters, guinea pigs, etc. can also replicate a very similar human disease model. They are easy to be genetically defined, the microorganisms in the body can be controlled, the model is significant and stable, age, sex, weight, etc. can be arbitrarily chosen, and the price is easy to obtain, easy to raise and manage, so it can be used as much as possible. Try not to use primates unless you have to, or have, special studies (such as dysentery, poliomyelitis, etc.). In addition to the consideration of the principles of mobility and economy in animal selection, this principle should also be noted in the methods of model replication and the observation of indicators.