Inflammation is a complex, non-linear process central to many of the diseases that affect both developed and emerging nations. A systems-based understanding of inflammation, coupled to translational applications, is therefore necessary for efficient development of drugs and devices, for streamlining analyses at the level of populations, and for the implementation of personalized medicine. We have carried out an iterative and ongoing program of literature analysis, generation of prospective data, data analysis, and computational modeling in various experimental and clinical inflammatory disease settings. These simulations have been used to gain basic insights into the inflammatory response under baseline, gene-knockout, and drug-treated experimental animals for in silico studies associated with the clinical settings of sepsis, trauma, acute liver failure, and wound healing to create patient-specific simulations in polytrauma, traumatic brain injury, and vocal fold inflammation; and to gain insight into host-pathogen interactions in malaria, necrotizing enterocolitis, and sepsis. These simulations have converged with other systems biology approaches (e.g., functional genomics) to aid in the design of new drugs or devices geared towards modulating inflammation. Since they include both circulating and tissue-level inflammatory mediators, these simulations transcend typical cytokine networks by associating inflammatory processes with tissue/organ impacts via tissue damage/dysfunction. This framework has now allowed us to suggest how to modulate acute inflammation in a rational, individually optimized fashion. This plethora of computational and intertwined experimental/engineering approaches is the cornerstone of Translational Systems Biology approaches for inflammatory diseases.</.

METHODS:Following liver transplantation, a 26-year old female suffered from primary non-function of the transplant. The patient was subsequently treated with a modular extracorporeal liver support concept until a suitable organ became available. A bioreactor was charged with human liver cells, obtained from a discarded cadaveric graft (470 g, viability: 60%). The bioreactor was integrated into an extracorporeal circuit with continuous single pass albumin dialysis and continuous veno-venuous hemodiafiltration for detoxification and fluid reduction. RESULTS:Over the total system application time of 79 h, a significant reduction of the plasma levels of total bilirubin (21.1 mg/dl at start, 10.1 mg/dl at end of therapy) and ammonia (100 versus 22.7 micromol/l) was achieved. During treatment the patient's neurological status significantly improved from coma stage IV to I permitting extubation. Recovery of kidney function with a urine output of 1325 ml/24 h compared to 45 ml/24 h prior to system application, was noted. Over the treatment period, an improvement of coagulation status was observed. Adverse events were absent. CONCLUSIONS:This first successful clinical treatment of a patient with liver failure suggests that a modular approach combining both primary human liver cell bioreactor technology and detoxification methods is promising.

Modular extracorporeal liver support (MELS) is an integrative concept for the treatment of hepatic failure with appropriate extracorporeal therapy units tailored to suit the actual clinical needs of each patient. The CellModule is a specific bioreactor charged with primary human liver cells harvested from human donor livers found to be unsuitable for transplantation due to steatosis, cirrhosis, or traumatic injury. The DetoxModule enables albumin dialysis for the removal of albumin-bound toxins, reducing the biochemical burden of the liver cells and replacing the bile excretion of hepatocytes in the bioreactor. A DialysisModule for continuous venovenous hemofiltration can be added to the system if required in hepatorenal syndrome.

Purpose: Approximately one fifth of the explained donor livers cannot be transplanted because of organ impairment (e.g. steatosis, fibrosis, cirrhosis or traumatic injury). We investigated the possibility of regenerating and using cells from discarded organs in a hybrid liver support system. Methods: 31 livers rejected from transplantation, were isolated by a modified enzymatic five-step-isolation method, including the perfusion of the hepatic artery. The purified parenchymal and non-parenchmal liver cells were co-cultured in a four-compartment bioreactor with a three-dimensional network of interwoven capillary membranes and integrated oxygenation. This Cell-Module, combined with plasmaseparation, can be used as one module in the Modular Extracorporeal Liver Support (MELS) system. Results: 31 discarded livers (51% steatosis, 13% arteriosclerosis, 13% cirrhosis, 10% fibrosis, 13% other reasons) with a weight of 1748±576 g (mean±SD) and a donor age of 60±14 yrs were processed. The livers were preserved in UW (60%), HTK (30%) or Celsior (10%) solution. The cold ischemia time amounted 19±8 hrs. A trypan blue test viability of 60±14% was achieved. The liver cells from 20 organs were cultured for 18±10 days in the Cell-Module. The cell isolation of 11 organs failed because of absent separation of steatotic cells (n=5), a cell viability <45% (n=4) or insufficient organ digestion (n=2). These organs were high grade impaired (steatosis, fibrosis, cirrhosis >80%). Four Cell-Modules were successfully used in bridging three patients to orthotopic liver transplantation (OLT). Two patients were suffering from acute liver failure (ALF), one was suffering from acute-on-chronic liver failure. One of the patients with ALF was bridged a second time to re-OLT, after primary graft non-function. The duration of therapy ranged from 7 to 74 hrs. No application had to be suspended due to adverse effects. The beneficial development of several biochemical parameters (e.g. bilirubin, ammonia) was measured.

Purpose of study. In liver failure the insufficient metabolism of endogenous toxins has been shown to be fatal. Most of these toxins are albumin-bound. Since liver assist devices based of albumin adsorption were found to be promising in binding these toxins, we sought to determine the effects of single-pass albumi dialysis in patients suffering from acute liver failure (ALF). Methods. Within the scope of a “Modular Extracorporeal Live Support” (MELS) system the “DetoxModule” was investigated Eight treatments of single-pass albumin dialysis in three patient with ALF were applied. Causes of ALF were valproic acid intoxication combined with acute hepatitis A, primary graft non function, and acute rejection following liver transplantation. All patients received hemodialysis with albumin-saturated dialysat (4.5 L of 4.4% human albumin solution) over a six-hour period We measured the course of serum total bilirubin concentration at a surrogate marker for the detoxification efficiency of single-pass albumin dialysis. Results. No adverse haemodynamic effects were observed during clinical applications. A significant decrease of serum total bilirubin concentration was seen after treatment (median: 20,7 mg/dL ± 13 mg/dL, p <0,01). Considering the unstable clinical status of patients suffering from ALF, the treatment with single pass albumin dialysis was safe, thus allowing further clinical applications. Furthermore, the described detoxification method in an effective and simple procedure, easy to apply in any clinical setting.