A Strain Rate-Dependent Constitutive Model for Göttingen Minipig Cerebral Arteries

Pearson, Noah; Boiczyk, Gregory M; Kote, Vivek Bhaskar; Sundaramurthy, Aravind; Subramaniam, Dhananjay Radhakrishnan; Rubio, Jose E.; Unnikrishnan, Ginu; Reifman, Jaques; Monson, Kenneth L.

doi:10.1115/1.4053796

Cited by 4 publications

(2 citation statements)

References 26 publications

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“…In a recent experimental study on cerebral bridging veins (Sánchez-Molina et al, 2021), it was not possible to determine the relaxation time constant to any reasonable level of accuracy. In post-mortem middle cerebral arteries from minipigs, the time constant was estimated to be 0.0402 s (Pearson et al, 2022), although no uncertainty estimate is given for this value. This is however very close to the values estimated by Valdez-Jasso et al ( 2011) of approximately 0.05 s in the aorta and carotid artery.…”

Section: Vessel Wall Dynamicsmentioning

confidence: 99%

Dynamic cerebral autoregulation is governed by two time constants: Arterial transit time and feedback time constant

Payne

2024

The Journal of Physiology

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Dynamic cerebral autoregulation (dCA) is the mechanism that describes how the brain maintains cerebral blood flow approximately constant in response to short‐term changes in arterial blood pressure. This is known to be impaired in many different pathological conditions, including ischaemic and haemorrhagic stroke, dementia and traumatic brain injury. Many different approaches have thus been used both to analyse and to quantify this mechanism in a range of healthy and diseased subjects, including data‐driven models (in both the time and the frequency domain) and biophysical models. However, despite the substantial body of work on both biophysical models and data‐driven models of dCA, there remains little work that links the two together. One of the reasons for this is proposed to be the discrepancies between the time constants that govern dCA in models and in experimental data. In this study, the processes that govern dCA are examined and it is proposed that the application of biophysical models remains limited due to a lack of understanding about the physical processes that are being modelled, partly due to the specific model formulation that has been most widely used (the equivalent electrical circuit). Based on the analysis presented here, it is proposed that the two most important time constants are arterial transit time and feedback time constant. It is therefore time to revisit equivalent electrical circuit models of dCA and to develop a more physiologically realistic alternative, one that can more easily be related to experimental data. imageKey points Dynamic cerebral autoregulation is governed by two time constants. The first time constant is the arterial transit time, rather than the traditional ‘RC’ time constant widely used in previous models. This arterial transit time is approximately 1 s in the brain. The second time constant is the feedback time constant, which is less accurately known, although it is somewhat larger than the arterial transit time. The equivalent electrical circuit model of dynamic cerebral autoregulation should be replaced with a more physiologically representative model.

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Section: Vessel Wall Dynamicsmentioning

confidence: 99%

Dynamic cerebral autoregulation is governed by two time constants: Arterial transit time and feedback time constant

Payne

2024

The Journal of Physiology

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“…The Göttingen Minipig is the commonly used pig strain by the pharmaceutical industry, as they are genetically coherent and well-characterized, and by using the same strain, pharmaceutical companies can rely on historical control data when interpreting findings in drug safety studies ( 9 ). Minipigs have already been used as animal models for several clinical indications such as cardiovascular ( 10 ), dental conditions ( 11 ), diabetes ( 12 ), heart disease ( 13 ), skin conditions ( 14 , 15 ), and acute and chronic intestinal inflammation ( 2 , 16 ). Furthermore, the neonatal Göttingen Minipig shares a striking number of developmental similarities with human neonates ( 17 – 21 ).…”

Section: Introductionmentioning

confidence: 99%

Development of a neonatal Göttingen Minipig model for dose precision in perinatal asphyxia: technical opportunities, challenges, and potential further steps

Stroe,

Van Bockstal,

Valenzuela

et al. 2023

Front. Pediatr.

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Animal models provide useful information on mechanisms in human disease conditions, but also on exploring (patho)physiological factors affecting pharmacokinetics, safety, and efficacy of drugs in development. Also, in pediatric patients, nonclinical data can be critical for better understanding the disease conditions and developing new drug therapies in this age category. For perinatal asphyxia (PA), a condition defined by oxygen deprivation in the perinatal period and possibly resulting in hypoxic ischemic encephalopathy (HIE) or even death, therapeutic hypothermia (TH) together with symptomatic drug therapy, is the standard approach to reduce death and permanent brain damage in these patients. The impact of the systemic hypoxia during PA and/or TH on drug disposition is largely unknown and an animal model can provide useful information on these covariates that cannot be assessed separately in patients. The conventional pig is proven to be a good translational model for PA, but pharmaceutical companies do not use it to develop new drug therapies. As the Göttingen Minipig is the commonly used pig strain in nonclinical drug development, the aim of this project was to develop this animal model for dose precision in PA. This experiment consisted of the instrumentation of 24 healthy male Göttingen Minipigs, within 24 h of partus, weighing approximately 600 g, to allow the mechanical ventilation and the multiple vascular catheters inserted for maintenance infusion, drug administration and blood sampling. After premedication and induction of anesthesia, an experimental protocol of hypoxia was performed, by decreasing the inspiratory oxygen fraction (FiO2) at 15%, using nitrogen gas. Blood gas analysis was used as an essential tool to evaluate oxygenation and to determine the duration of the systemic hypoxic insult to approximately 1 h. The human clinical situation was mimicked for the first 24 h after birth in case of PA, by administering four compounds (midazolam, phenobarbital, topiramate and fentanyl), frequently used in a neonatal intensive care unit (NICU). This project aimed to develop the first neonatal Göttingen Minipig model for dose precision in PA, allowing to separately study the effect of systemic hypoxia versus TH on drug disposition. Furthermore, this study showed that several techniques that were thought to be challenging or even impossible in these very small animals, such as endotracheal intubation and catheterization of several veins, are feasible by trained personnel. This is relevant information for laboratories using the neonatal Göttingen Minipig for other disease conditions or drug safety testing.

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Strain-induced collagen denaturation is rate dependent in failure of cerebral arteries

et al. 2023

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A Strain Rate-Dependent Constitutive Model for Göttingen Minipig Cerebral Arteries

Cited by 4 publications

References 26 publications

Dynamic cerebral autoregulation is governed by two time constants: Arterial transit time and feedback time constant

Dynamic cerebral autoregulation is governed by two time constants: Arterial transit time and feedback time constant

Development of a neonatal Göttingen Minipig model for dose precision in perinatal asphyxia: technical opportunities, challenges, and potential further steps

Strain-induced collagen denaturation is rate dependent in failure of cerebral arteries

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