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1. Exceeding the Limits of Static Cold Storage in Limb Transplantation Using Subnormothermic Machine Perfusion

   https://doi.org/10.1055/a-1886-5697  

   Goutard, Marion ; de Vries, Reinier J. ; Tawa, Pierre ; Pendexter, Casie A. ; Rosales, Ivy A. ; Tessier, Shannon N. ; Burlage, Laura C. ; Lantieri, Laurent ; Randolph, Mark A. ; Lellouch, Alexandre G. ; et al ( May 2023 , Journal of Reconstructive Microsurgery)

   Background For 50 years, static cold storage (SCS) has been the gold standard for solid organ preservation in transplantation. Although logistically convenient, this preservation method presents important constraints in terms of duration and cold ischemia-induced lesions. We aimed to develop a machine perfusion (MP) protocol for recovery of vascularized composite allografts (VCA) after static cold preservation and determine its effects in a rat limb transplantation model.

   Methods Partial hindlimbs were procured from Lewis rats and subjected to SCS in Histidine-Tryptophan-Ketoglutarate solution for 0, 12, 18, 24, and 48 hours. They were then either transplanted (Txp), subjected to subnormothermic machine perfusion (SNMP) for 3 hours with a modified Steen solution, or to SNMP + Txp. Perfusion parameters were assessed for blood gas and electrolytes measurement, and flow rate and arterial pressures were monitored continuously. Histology was assessed at the end of perfusion. For select SCS durations, graft survival and clinical outcomes after transplantation were compared between groups at 21 days.

   Results Transplantation of limbs preserved for 0, 12, 18, and 24-hour SCS resulted in similar survival rates at postoperative day 21. Grafts cold-stored for 48 hours presented delayed graft failure (p = 0.0032). SNMP of limbs after 12-hour SCS recovered the vascular resistance, potassium, and lactate levels to values similar to limbs that were not subjected to SCS. However, 18-hour SCS grafts developed significant edema during SNMP recovery. Transplantation of grafts that had undergone a mixed preservation method (12-hour SCS + SNMP + Txp) resulted in better clinical outcomes based on skin clinical scores at day 21 post-transplantation when compared to the SCS + Txp group (p = 0.01613).

   Conclusion To date, VCA MP is still limited to animal models and no protocols are yet developed for graft recovery. Our study suggests that ex vivo SNMP could help increase the preservation duration and limit cold ischemia-induced injury in VCA transplantation.

    

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2. Modeling acute and chronic vascular responses to a major arterial occlusion

   https://doi.org/10.1111/micc.12738  

   Zhao, Erin ; Barber, Jared ; Sen, Chandan K. ; Arciero, Julia ( November 2021 , Microcirculation)

   To incorporate chronic vascular adaptations into a mathematical model of the rat hindlimb to simulate flow restoration following total occlusion of the femoral artery.

   A vascular wall mechanics model is used to simulate acute and chronic vascular adaptations in the collateral arteries and collateral‐dependent arterioles of the rat hindlimb. On an acute timeframe, the vascular tone of collateral arteries and distal arterioles is determined by responses to pressure, shear stress, and metabolic demand. On a chronic timeframe, sustained dilation of arteries and arterioles induces outward vessel remodeling represented by increased passive vessel diameter (arteriogenesis), and low venous oxygen saturation levels induce the growth of new capillaries represented by increased capillary number (angiogenesis).

   The model predicts that flow compensation to an occlusion is enhanced primarily by arteriogenesis of the collateral arteries on a chronic time frame. Blood flow autoregulation is predicted to be disrupted and to occur for higher pressure values following femoral arterial occlusion.

   Structural adaptation of the vasculature allows for increased blood flow to the collateral‐dependent region after occlusion. Although flow is still below pre‐occlusion levels, model predictions indicate that interventions which enhance collateral arteriogenesis would have the greatest potential for restoring flow.

    

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3. Morphological and kinematic specializations of walking frogs

   https://doi.org/10.1002/jez.2182  

   Reynaga, Crystal M. ; Astley, Henry C. ; Azizi, Emanuel ( May 2018 , Journal of Experimental Zoology Part A: Ecological and Integrative Physiology)

   The anuran body plan is defined by morphological features associated with saltatory locomotion, but these specializations may have functional consequences for other modes of locomotion. Several frog species use a quadrupedal walking gait as their primary mode of locomotion, characterized by limbs that move in diagonal pairs. Here, we examine how walking species may deviate from the ancestral body plan and how the kinematics of a quadrupedal gait are modified to accommodate the anuran body plan. We use a comparative analysis of limb lengths to test the hypothesis that quadrupedal anurans shift away from the standard anuran condition defined by short forelimbs and long hindlimbs. We also use three‐dimensional high‐speed videography in four anuran species (Kassina senegalensis,Melanophryniscus stelzneri,Phrynomantis bifasciatus, andPhyllomedusa hypochondrialis) to characterize footfall patterns and body posture during quadrupedal locomotion, measuring the angle and timing of joint excursions in the fore‐ and hindlimb during walking to compare kinematics between limbs of disparate lengths. Our results show frogs specialized for walking tend to have less disparity in the lengths of their fore‐ and hindlimbs compared with other anurans. We find quadrupedal walking species use a vertically retracted hindlimb posture to accommodate their relatively longer hindlimbs and minimize body pitch angle during a stride. Overall, this novel quadrupedal gait can be accommodated by changes in limb posture during locomotion and changes in the relative limb lengths of walking specialists.

    

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4. Assessing the hemodynamic contribution of capillaries, arterioles, and collateral arteries to vascular adaptations in arterial insufficiency

   https://doi.org/10.1111/micc.12591  

   Arciero, Julia ; Lembcke, Lauren ; Burch, Myson ; Franko, Elizabeth ; Unthank, Joseph ( October 2019 , Microcirculation)

   There is currently a lack of clarity regarding which vascular segments contribute most significantly to flow compensation following a major arterial occlusion. This study uses hemodynamic principles and computational modeling to demonstrate the relative contributions of capillaries, arterioles, and collateral arteries at rest or exercise following an abrupt, total, and sustained femoral arterial occlusion.

   The vascular network of the simulated rat hindlimb is based on robust measurements of blood flow and pressure in healthy rats from exercise and training studies. The sensitivity of calf blood flow to acute or chronic vascular adaptations in distinct vessel segments is assessed.

   The model demonstrates that decreasing the distal microcirculation resistance has almost no effect on flow compensation, while decreasing collateral arterial resistance is necessary to restore resting calf flow following occlusion. Full restoration of non‐occluded flow is predicted under resting conditions given all chronic adaptations, but only 75% of non‐occluded flow is restored under exercise conditions.

   This computational method establishes the hemodynamic significance of acute and chronic adaptations in the microvasculature and collateral arteries under rest and exercise conditions. Regardless of the metabolic level being simulated, this study consistently shows the dominating significance of collateral vessels following an occlusion.

    

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5. Modeling acute blood flow responses to a major arterial occlusion

   https://doi.org/10.1111/micc.12610  

   Zhao, Erin ; Barber, Jared ; Burch, Myson ; Unthank, Joseph ; Arciero, Julia ( March 2020 , Microcirculation)

   The development of earlier and less invasive treatments for peripheral arterial disease requires a more complete understanding of vascular responses following a major arterial occlusion. A mechanistic model of the vasculature of the rat hindlimb is developed to predict acute (immediate) changes in vessel diameters and smooth muscle tone following femoral arterial occlusion.

   Vascular responses of collateral arteries and distal arterioles to changes in pressure, shear stress, and metabolism are assessed before and after occlusion. The effects of exercise are also simulated and compared with venous flow measurements from WKY rats.

   The model identifies collateral arteries as the primary contributors to flow compensation following occlusion. Increasing the number of capillaries has minimal effect on blood flow while increasing the number of collateral arteries significantly increases flow, since the primary site of resistance shifts upstream to the collateral arteries following occlusion. Despite significant collateral dilation, calf flow remains below pre‐occlusion levels and the deficit becomes more severe with increased activity.

   Although unable to compensate fully for an occlusion, the model demonstrates the importance of the shear response in collateral arteries and the metabolic response in the distal microcirculation in acute adaptations to a major arterial occlusion.

    

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