Middle Cerebral Artery Occlusion Allowing Reperfusion via Common Carotid Artery Repair in Mice

Trotman‐Lucas, Melissa; Kelly, Michael; Janus, Justyna; Gibson, Claire

doi:10.3791/58191

“…113 The group utilised Longa's 42 transient iMCAO method in rats, with both filament insertion and MSC injection via a transected ECA, with the CCA temporarily tied for the duration of iMCAO. 113 CCA repair, reported previously to be successful in rats, 114,115 alongside our recent method development in mice, 101,105 would negate the requirement to transect the ECA, therefore, removing the negative welfare outcomes reported following ECA transection. 102,103,114 Although many IA stem cell delivery experimental models utilise rats, there are examples of these studies conducted in mice.…”

Section: Scientific Applications Of Refinementsmentioning

confidence: 96%

“…50 The alternative iMCAO method we established improves mouse well-being and removes reliance on the CoW for collateral flow during reperfusion, importantly reducing lesion volume variability. 100,101,105 As lesion volume is often the primary outcome measure for neuroprotective in vivo stroke research, large variations within this data can result in low statistical power if sample sizes are not accordingly adjusted to account for this variability. 93 Typically, preclinical stroke studies have low statistical power, a statement supported recently by a meta-analysis revealing that on average, studies show 59% power to detect a 30% inter-group difference.…”

Section: Refining the In Vivo Model Of Imcaomentioning

confidence: 99%

A review of experimental models of focal cerebral ischemia focusing on the middle cerebral artery occlusion model

Trotman‐Lucas

¹

,

Gibson

²

2021

Self Cite

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Cerebral ischemic stroke is a leading cause of death and disability, but current pharmacological therapies are limited in their utility and effectiveness. In vitro and in vivo models of ischemic stroke have been developed which allow us to further elucidate the pathophysiological mechanisms of injury and investigate potential drug targets. In vitro models permit mechanistic investigation of the biochemical and molecular mechanisms of injury but are reductionist and do not mimic the complexity of clinical stroke. In vivo models of ischemic stroke directly replicate the reduction in blood flow and the resulting impact on nervous tissue. The most frequently used in vivo model of ischemic stroke is the intraluminal suture middle cerebral artery occlusion (iMCAO) model, which has been fundamental in revealing various aspects of stroke pathology. However, the iMCAO model produces lesion volumes with large standard deviations even though rigid surgical and data collection protocols are followed. There is a need to refine the MCAO model to reduce variability in the standard outcome measure of lesion volume. The typical approach to produce vessel occlusion is to induce an obstruction at the origin of the middle cerebral artery and reperfusion is reliant on the Circle of Willis (CoW). However, in rodents the CoW is anatomically highly variable which could account for variations in lesion volume. Thus, we developed a refined approach whereby reliance on the CoW for reperfusion was removed. This approach improved reperfusion to the ischemic hemisphere, reduced variability in lesion volume by 30%, and reduced group sizes required to determine an effective treatment response by almost 40%. This refinement involves a methodological adaptation of the original surgical approach which we have shared with the scientific community via publication of a visualised methods article and providing hands-on training to other experimental stroke researchers.

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“…109 The group utilised Longa's 42 transient iMCAO method in rats, with both filament insertion and MSC injection via a transected ECA, with the CCA temporarily tied for the duration of iMCAO. 109 CCA repair, reported previously to be successful in rats, 110,111 alongside our recent method development in mice, 101,105 would negate the requirement to transect the ECA, therefore, removing the negative welfare outcomes reported following ECA transection. 102,103,110 Although many IA stem cell delivery experimental models utilise rats, there are examples of these studies conducted in mice.…”

Section: Scientific Applications Of Refinementsmentioning

confidence: 96%

“…The alternative iMCAO method we established improves mouse well-being and removes reliance on the CoW for collateral flow during reperfusion, importantly reducing lesion volume variability. 100 , 101 , 105 As lesion volume is often the primary outcome measure for neuroprotective in vivo stroke research, large variations within this data can result in low statistical power if sample sizes are not accordingly adjusted to account for this variability. 93 Typically, preclinical stroke studies have low statistical power, a statement supported recently by a meta-analysis revealing that on average, studies show 59% power to detect a 30% inter-group difference.…”

Section: Refining the In Vivo Model Of Imcaomentioning

confidence: 99%

“… 113 We have engaged proactively with the stroke community to deliver hands-on training to numerous labs in the UK, Germany and USA involving over 20 researchers. To extend the reach into the community we published a visualised method of our refined approach 105 which has been viewed over 8000 times since publication in early 2019 and over 2000 times in the last six months. Subsequent work published by ourselves and others brings attention to this refined approach and we continue to offer it as our standard training model to incoming members of our group and in other research groups who contact us for training advice.…”

Section: Dissemination and Uptake Of The Refined In Vivo Model Of Imcaomentioning

confidence: 99%

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A review of experimental models of focal cerebral ischemia focusing on the middle cerebral artery occlusion model

Trotman‐Lucas

¹

,

Gibson

²

2021

Self Cite

View full text Add to dashboard Cite

Cerebral ischemic stroke is a leading cause of death and disability, but current pharmacological therapies are limited in their utility and effectiveness. In vitro and in vivo models of ischemic stroke have been developed which allow us to further elucidate the pathophysiological mechanisms of injury and investigate potential drug targets. In vitro models permit mechanistic investigation of the biochemical and molecular mechanisms of injury but are reductionist and do not mimic the complexity of clinical stroke. In vivo models of ischemic stroke directly replicate the reduction in blood flow and the resulting impact on nervous tissue. The most frequently used in vivo model of ischemic stroke is the intraluminal suture middle cerebral artery occlusion (iMCAO) model, which has been fundamental in revealing various aspects of stroke pathology. However, the iMCAO model produces lesion volumes with large standard deviations even though rigid surgical and data collection protocols are followed. There is a need to refine the MCAO model to reduce variability in the standard outcome measure of lesion volume. The typical approach to produce vessel occlusion is to induce an obstruction at the origin of the middle cerebral artery and reperfusion is reliant on the Circle of Willis (CoW). However, in rodents the CoW is anatomically highly variable which could account for variations in lesion volume. Thus, we developed a refined approach whereby reliance on the CoW for reperfusion was removed. This approach improved reperfusion to the ischemic hemisphere, reduced variability in lesion volume by 30%, and reduced group sizes required to determine an effective treatment response by almost 40%. This refinement involves a methodological adaptation of the original surgical approach which we have shared with the scientific community via publication of a visualised methods article and providing hands-on training to other experimental stroke researchers.

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Near‐Infrared Fluorophores for Thrombosis Diagnosis and Therapy

Sun

¹

,

Hettie

²

,

Zhu

³

2021

Advanced Therapeutics

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Thrombosis is an adverse physiological event wherein the resulting thrombus and thrombus‐induced diseases collectively result in high morbidity and mortality rates. Currently, nano‐medicines that incorporate fluorophores emitting in the near‐infrared‐I (NIR‐I, 700–900 nm) spectral region have been adopted to afford thrombosis theranostics. However, several unsolved problems such as limited penetration depth and image quality severely impede further applications of such nano‐medicine systems. Fortunately, the ability to incorporate fluorophores emitting in the NIR‐II (1000–1700 nm) window into nano‐medicine systems can unambiguously identify biological processes with high signal‐to‐noise, deep tissue penetration depth, and high image resolution. Considering the inherently favorable properties of NIR‐II fluorophores, it is believed that they have enormous potential to quickly become incorporated into nano‐medicine systems for thrombosis theranostics. In this review, i) the development of NIR fluorescence as an imaging modality and fluorescent agents is discussed; ii) the recent development of NIR‐I fluorophore‐based nano‐medicine systems for thrombosis theranostics is comprehensively summarized; iii) the state‐of‐the‐art NIR‐II fluorophores that are designed for the specific purpose of affording thrombotic diagnosis is highlighted; iv) possible forward avenues for the use of NIR‐II fluorophores toward thrombosis diagnosis and therapy are speculated; and v) the potential for their clinical translation is discussed.

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Middle Cerebral Artery Occlusion Allowing Reperfusion via Common Carotid Artery Repair in Mice

Cited by 12 publications

References 19 publications

A review of experimental models of focal cerebral ischemia focusing on the middle cerebral artery occlusion model

A review of experimental models of focal cerebral ischemia focusing on the middle cerebral artery occlusion model

A review of experimental models of focal cerebral ischemia focusing on the middle cerebral artery occlusion model

Near‐Infrared Fluorophores for Thrombosis Diagnosis and Therapy

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