Development and characterization of a Yucatan miniature biomedical pig permanent middle cerebral artery occlusion stroke model

Abstract

BackgroundEfforts to develop stroke treatments have met with limited success despite an intense need to produce novel treatments. The failed translation of many of these therapies in clinical trials has lead to a close examination of the therapeutic development process. One of the major factors believed to be limiting effective screening of these treatments is the absence of an animal model more predictive of human responses to treatments. The pig may potentially fill this gap with a gyrencephalic brain that is larger in size with a more similar gray-white matter composition to humans than traditional stroke animal models. In this study we develop and characterize a novel pig middle cerebral artery occlusion (MCAO) ischemic stroke model.MethodsEleven male pigs underwent MCAO surgery with the first 4 landrace pigs utilized to optimize stroke procedure and 7 additional Yucatan stroked pigs studied over a 90 day period. MRI analysis was done at 24 hrs and 90 days and included T2w, T2w FLAIR, T1w FLAIR and DWI sequences and associated ADC maps. Pigs were sacrificed at 90 days and underwent gross and microscopic histological evaluation. Significance in quantitative changes was determined by two-way analysis of variance and post-hoc Tukey’s Pair-Wise comparisons.ResultsMRI analysis of animals that underwent MCAO surgery at 24 hrs had hyperintense regions in T2w and DWI images with corresponding ADC maps having hypointense regions indicating cytotoxic edema consistent with an ischemic stroke. At 90 days, region of interest analysis of T1 FLAIR and ADC maps had an average lesion size of 59.17 cc, a loss of 8% brain matter. Histological examination of pig brains showed atrophy and loss of tissue, consistent with MRI, as well as glial scar formation and macrophage infiltration.ConclusionsThe MCAO procedure led to significant and consistent strokes with high survivability. These results suggest that the pig model is potentially a robust system for the study of stroke pathophysiology and potential diagnostics and therapeutics.

Loss of Female Sex Hormones Exacerbates Cerebrovascular and Cognitive Dysfunction in Aortic Banded Miniswine Through a Neuropeptide Y–Ca 2+ ‐Activated Potassium Channel–Nitric Oxide Mediated Mechanism

“…Thus, we recognize a limitation of the model is an inability to study HFpEF in a context of natural aging, along with a gradual loss of sex hormones. However, the strength of this swine model lies in its translational relevance to human hemodynamic and cardiovascular function, in addition to similarities inherent to the brain (ie, pig brains are gyrencephalic and contain >60% white matter) . Overall, the strengths of the swine model from both a translational hemodynamic and a cognitive perspective outweigh its weakness as a true model of senescence.…”

Induced Pluripotent Stem-Cell-Derived Neural Cell Types in Treatment of Stroke

“…However, the cost, specialized facilities, regulatory burden, and ethical issues associated with primate models make alternative large-animal models such as sheep and pigs more attractive in some respects. The pig stroke model offers a significant advantage over rodent models as pigs have much larger gyrencephalic brains with gray-white matter composition more similar to humans [108,109]. Utilization of animal models with similar white matter composition is of significant importance as white matter injuries uniquely contribute to clinical deficits in stroke patients and it will be important to determine if iNSC treatment will be able to appropriately differentiate and integrate in both gray-and white-matter compartments [110,111].…”

“…As outlined by the STAIR [103] and STEPS II [104] meetings, it is vital that successful rodent therapies be confirmed in other animal models of stroke prior to advancing to human clinical trials. Several large-animal models of ischemic stroke have been developed and iNSC transplantation studies in these species are eagerly awaited [105][106][107]. Due to similarities between humans and primates, the primate model would seem to be a natural fit for studies of iNSC treatments.…”

A Bama Minipig Model of Laryngopharyngeal Reflux and the Change of Laryngopharyngeal Mucosal Ultrastructure

“…The miniature pig has been widely accepted as the experimental animal. [22][23][24][25] With its body size being only one-fourth to one-third of an ordinary pig, 26 it is easy to be operated and thus suitable to establish a LPR model. Although the pathological mechanisms of LPR and GERD are similar, LPR model was rarely reported, compared to GERD model.…”