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Normothermic machine perfusion (NMP) provides clinicians an opportunity to assess marginal livers before transplantation. However, objective criteria and point‐of‐care (POC) biomarkers to predict risk and guide decision making are lacking. In this investigation, we characterized trends in POC biomarkers during NMP and compared primate donation after circulatory death (DCD) livers with short and prolonged warm ischemic injury. Following asystole, livers were subjected to either 5 minutes (DCD‐5min, n = 4) or 45 minutes (DCD‐45min, n = 4) of warm ischemia time. Livers were flushed with heparinized UW solution, and preserved in cold storage before NMP. During flow‐controlled NMP, circulating perfusate and tissue biopsies were collected at 0, 2, 4, 6, and 8 hours for analysis. DCD‐45min livers had greater terminal portal vein pressure (8.5 vs. 13.3 mm Hg, P = 0.027) and terminal portal vein resistance (16.3 vs. 32.4 Wood units, P = 0.005). During perfusion, DCD‐45min livers had equivalent terminal lactate clearance (93% vs. 96%, P = 0.344), greater terminal alanine aminotransferase (163 vs. 883 U/L, P = 0.002), and greater terminal perfusate gamma glutamyltransferase (GGT) (5.0 vs. 31.7 U/L, P = 0.002). DCD‐45min livers had higher circulating levels of flavin mononucleotide (FMN) at hours 2 and 4 of perfusion (136 vs. 250 ng/mL, P = 0.029; and 158 vs. 293 ng/mL, P = 0.003; respectively). DCD‐5min livers produced more bile and demonstrated progressive decline in bile lactate dehydrogenase, whereas DCD‐45min livers did not. On blinded histologic evaluation, DCD‐45min livers demonstrated greater injury and necrosis at late stages of perfusion, indicative of nonviability. Conclusion: Objective criteria are needed to define graft viability during NMP. Perfusate lactate clearance does not discriminate between viable and nonviable livers during NMP. Perfusate GGT and FMN may represent POC biomarkers predictive of liver injury during NMP. We characterized trends in point‐of‐care biomarkers during normothermic machine liver perfusion using non‐human primate DCD livers with short versus prolonged warm ischemic injury. Perfusate gamma‐glutamyl transferase and flavin mononucleotide may represent novel point‐of‐care biomarkers predictive of liver injury during NMP.

Subnormothermic machine perfusion (SNMP) of liver grafts is currently less clinically developed than normothermic and hypothermic approaches, but may have logistical advantages. At intermediate temperatures, the oxygen demand of the graft is low enough to be satisfied with an acellular perfusate, obviating the need for oxygen carrying molecules. This intermediate metabolic rate, however, is sufficient to support the production of bile, which is emerging as an important indicator of graft injury and viability. In this study, we hypothesized that the biliary compartment would be more sensitive than perfusate in detecting graft injury during SNMP. To test this hypothesis in a rat model, we performed liver transplants with DCD and control liver grafts after 1 h of acellular room temperature machine perfusion (acRTMP) or static cold storage (SCS). Point of care liver function tests were measured in biliary and perfusate samples after 1 h of machine perfusion. Following transplantation, rats were sacrificed at 24 h for assessment of post-transplant graft function and histology. All point-of-care liver function tests were significantly more concentrated in the biliary compartment than the perfusate compartment during acRTMP. DCD liver grafts could be distinguished from control liver grafts by significantly higher markers of hepatocyte injury (AST, ALT) in the biliary compartment, but not in the perfusate compartment. Classical markers of cholangiocyte injury, such as gammy-glut amyl transferase (GGT), amylase (AML), and alkaline phosphatase were detectable in the biliary compartment, but not in the perfusate compartment. In comparison to SCS, graft preservation by acRTMP produced a significant survival benefit in DCD liver transplantation (75 vs. 0%, < 0.0030). Together, these findings demonstrate that during acRTMP, the biliary compartment may be a more sensitive indicator of graft injury than the perfusate compartment. Moreover, acRTMP provides superior graft preservation to SCS in rat DCD liver transplantation.

Functional neuromuscular stimulation (FNS) is used to improve the lives of people living with spinal cord injuries. In motor system neuroprostheses, FNS consists of multiple channels of electrical stimulation on peripheral nerves to produce controlled muscle contractions and generate useful movements of paralyzed limbs. Current FNS systems that enable standing require high levels of constant stimulation. In human studies, high levels of constant stimulation cause early onset fatigue. To accommodate the needs of prolonged standing, more sophisticated advanced stimulation paradigms (ASPs) activate altering combinations of several muscles that have the same desired function. Each muscle is activated at less than full strength and the intensity of muscle activation varies over time. The objective of an ASP is to balance the shifting activation of muscle combinations such that the resulting total output is constant. Examples of ASPs include carousel, interleaved, and sum-of phase-shifted sinusoids (SOPS). Preliminary data from two human subjects shows the SOPS paradigm provides an increase in time to fatigue compared to constant stimulation (13.8 vs. 2.3 minutes and 9.5 vs. 4.2 minutes for subjects 1 and 2, respectively). Proper balance of the ASP parameters currently requires time-consuming manual tuning. We are developing an automated tuning method in felines. Three cats were implanted bilaterally with 16-channel C-FINE electrodes on the sciatic nerve. A JR3 moment transducer measures the ankle moment produced from stimulation of individual and multiple channels. Automated computational algorithms developed in this study should optimize performance of ASPs to delay the onset of fatigue in human subjects.