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1. Sub-Zero Non-Freezing of Vascularized Composite Allografts Preservation in Rodents

   https://doi.org/10.21203/rs.3.rs-3750450/v1  

   Filz von Reiterdank, Irina; Tawa, Pierre; Berkane, Yanis; de Clermont-Tonnerre, Eloi; Dinicu, Antonia; Pendexter, Casie; Goutard, Marion; Lellouch, Alexandre G; Mink van der Molen, Aebele B; Coert, JH; et al (December 2023, Research Square)

   Abstract Ischemia is a major limiting factor in Vascularized Composite Allotransplantation (VCA) as irreversible muscular injury can occur after as early as 4-6 hours of static cold storage (SCS). Organ preservation technologies have led to the development of storage protocols extending rat liver ex vivo preservation up to 4 days. Development of such a protocol for VCAs has the added challenge of inherent ice nucleating factors of the graft, therefore this study focused on developing a robust protocol for VCA supercooling. Rodent partial hindlimbs underwent subnormothermic machine perfusion (SNMP) with several loading solutions, followed by cryoprotective agent (CPA) cocktail developed for VCAs. Storage occurred in suspended animation for 24h and VCAs were recovered using SNMP with modified Steen. This study shows a robust VCA supercooling preservation protocol in a rodent model. Further optimization is expected to allow for its application in a transplantation model, which would be a breakthrough in the field of VCA preservation.*Irina Filz von Reiterdank & Pierre Tawa Contributed equally. 

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2. VCA supercooling in a swine partial hindlimb model

   https://doi.org/10.1038/s41598-024-63041-8  

   Berkane, Yanis; Filz_von_Reiterdank, Irina; Tawa, Pierre; Charlès, Laura; Goutard, Marion; Dinicu, Antonia_T; Toner, Mehmet; Bertheuil, Nicolas; Mink_van_der_Molen, Aebele_B; Coert, J_Henk; et al (June 2024, Scientific Reports)

   Abstract Vascularized composite allotransplantations are complex procedures with substantial functional impact on patients. Extended preservation of VCAs is of major importance in advancing this field. It would result in improved donor-recipient matching as well as the potential for ex vivo manipulation with gene and cell therapies. Moreover, it would make logistically feasible immune tolerance induction protocols through mixed chimerism. Supercooling techniques have shown promising results in multi-day liver preservation. It consists of reaching sub-zero temperatures while preventing ice formation within the graft by using various cryoprotective agents. By drastically decreasing the cell metabolism and need for oxygen and nutrients, supercooling allows extended preservation and recovery with lower ischemia–reperfusion injuries. This study is the first to demonstrate the supercooling of a large animal model of VCA. Porcine hindlimbs underwent 48 h of preservation at − 5 °C followed by recovery and normothermic machine perfusion assessment, with no issues in ice formation and favorable levels of injury markers. Our findings provide valuable preliminary results, suggesting a promising future for extended VCA preservation. 

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3. 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)

   Abstract 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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4. Supercooling: a promising technique for prolonged preservation in solid organ transplantation, and early perspectives in vascularized composite allografts

   https://doi.org/10.3389/frtra.2023.1269706  

   Berkane, Yanis; Hayau, Justine; Filz_von_Reiterdank, Irina; Kharga, Anil; Charlès, Laura; Mink_van_der_Molen, Abele B; Coert, J Henk; Bertheuil, Nicolas; Randolph, Mark A; Cetrulo, Curtis L; et al (October 2023, Frontiers in Transplantation)

   Ex vivopreservation of transplanted organs is undergoing spectacular advances. Machine perfusion is now used in common practice for abdominal and thoracic organ transportation and preservation, and early results are in favor of substantially improved outcomes. It is based on decreasing ischemia-reperfusion phenomena by providing physiological or sub-physiological conditions until transplantation. Alternatively, supercooling techniques involving static preservation at negative temperatures while avoiding ice formation have shown encouraging results in solid organs. Here, the rationale is to decrease the organ's metabolism and need for oxygen and nutrients, allowing for extended preservation durations. The aim of this work is to review all advances of supercooling in transplantation, browsing the literature for each organ. A specific objective was also to study the initial evidence, the prospects, and potential applications of supercooling preservation in Vascularized Composite Allotransplantation (VCA). This complex entity needs a substantial effort to improve long-term outcomes, marked by chronic rejection. Improving preservation techniques is critical to ensure the favorable evolution of VCAs, and supercooling techniques could greatly participate in these advances. 

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5. A Measurement-Derived Functional Model for the Interaction Between Congestion Control and QoE in Video Conferencing

   He, Jia; Ammar, Mostafa; Zegura, Ellen (March 2023, Springer)

   Video Conferencing Applications (VCAs) that support remote work and education have increased in use over the last two years, contributing to Internet bandwidth usage. VCA clients transmit video and audio to each other in peer-to-peer mode or through a bridge known as a Selective Forwarding Unit (SFU). Popular VCAs implement congestion control in the application layer over UDP and accomplish rate adjustment through video rate control, ultimately affecting end user Quality of Experience(QoE). Researchers have reported on the throughput and video metric performance of specific VCAs using structuredexperiments. Yet prior work rarely examines the interaction between congestion control mechanisms and rate adjustment techniques that produces the observed throughput and QoE metrics. Understanding this interaction at a functional level paves the way to explain observed performance, to pinpoint commonalities and key functional differences across VCAs, and to contemplate opportunities for innovation. To that end, we first design and conduct detailed measurements of three VCAs(WebRTC/Jitsi, Zoom, Blue Jeans) to develop understanding of their congestion and video rate control mechanisms. We then use the measurement results to derive our functional models for the VCA client and SFU. Our models reveal the complexity of these systems and demonstrate how, despite some uniformity in function deployment, there is significant variability among the VCAs in the implementation of these functions. 

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