90-Day Mortality Prediction in Elective Visceral Surgery Using Machine Learning
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Our paper, "90-Day Mortality Prediction in Elective Visceral Surgery Using Machine Learning: A Retrospective Multicenter Development, Validation, and Comparison Study" has been published online ahead of print in the International Journal of Surgery.
Authors are C. Riepe, R. van de Water, A. Winter, B. Pfitzner, L. Faraj, R. Ahlborn, M. Schulze, D. Zuluaga, C. Schineis, K. Beyer, J. Pratschke, B. Arnrich, I.M. Sauer, and M.M. Maurer

Machine Learning (ML) is increasingly being adopted in biomedical research, however, its potential for outcome prediction in visceral surgery remains uncertain. This study compares the potential of ML methods for preoperative 90-day mortality (90DM) prediction of an aggregated multi-organ approach to conventional scoring systems and individual organ models.

This retrospective cohort study enrolled patients undergoing major elective visceral surgery between 2014 and 2022 across two tertiary centers. Multiple ML models for preoperative 90DM prediction were trained, externally validated and benchmarked against the American Society of Anesthesiologists (ASA) score and revised Charlson Comorbidity Index (rCCI). Areas under the receiver operating characteristic (AUROC) and precision recall curves (AUPRC) including standard deviations were calculated. Additionally, individual models for esophageal, gastric, intestinal, liver, and pancreatic surgery were developed and compared to an aggregated approach. A total of 7,711 cases encompassing 78 features were included. Overall 90DM was 4% (n = 309). An XBoost classifier demonstrated the best performance and high robustness following external validation (AUROC: 0.86 [0.01]; AUPRC: 0.2 [0.04]). All models outperformed the ASA score (AUROC: 0.72; AUPRC: 0.08) and rCCI (AUROC: 0.81; AUPRC: 0.11). rCCI, patient age and C-reactive protein emerged as most decisive model weights. Models for gastric (AUROC: 0.88 [0.13]; AUPRC: 0.24 [0.26]) and intestinal surgery (AUROC: 0.87 [0.05]; AUPRC: 0.17 [0.09]) revealed the highest organ-specific performances, while pancreatic surgery yielded the lowest results (AUROC: 0.66 [0.08]; AUPRC: 0.22 [0.12]). A combined multi-organ approach (AUROC: 0.84 [0.04]; AUPRC: 0.21 [0.06]) demonstrated superiority over the weighted average across all organ-specific models (AUROC: 0.82 [0.07]; AUPRC: 0.2 [0.13]).

ML offers robust preoperative risk stratification for 90DM in elective visceral surgery. Leveraging training across multi-organ cohorts may improve accuracy and robustness compared to organ-specific models. Prospective studies are needed to confirm the potential of ML in surgical outcome prediction.
Michael Tummings | Human Insights
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Michael TummingsArtist in Residence @ Experimental Surgery – has released his latest book, Human Insights.

In this powerful work, Tummings turns his lens toward the operating theatre, capturing intimate moments of surgical intervention. His photographs explore the human body not as an object of clinical analysis, but as a site of vulnerability, resilience, and transformation. As noted by Jörg Christian Tonn, Tummings' work "reveals the mysteries of the body," offering entirely new perspectives on physical existence and the role of modern medicine.

With the consent of both patients and surgical teams of several university hospitals, Tummings was granted rare access to document procedures involving organ implants and artificial prostheses. The resulting imagery bridges the worlds of art and science, bringing us face-to-face with the beauty of the human body—beyond the rational and dissecting eye.

Human Insights invites viewers to reconsider how we see ourselves and our bodies, especially in moments of repair and healing.
Sparse camera volumetric video applications
The paper "Sparse camera volumetric video applications. A comparison of visual fidelity, user experience, and adaptability" is available open access in Frontiers in Signal Processing.
Authors are Christopher Remde, Igor M. Sauer, and Moritz Queisner.

Volumetric video production in commercial studios is predominantly produced using a multi-view stereo process that relies on a high two-digit number of cameras to capture a scene. Due to the hardware requirements and associated processing costs, this workflow is resource-intensive and expensive, making it unattainable for creators and researchers with smaller budgets. Low-cost volumetric video systems using RGBD cameras offer an affordable alternative. As these small, mobile systems are a relatively new technology, the available software applications vary in terms of workflow and image quality. In this paper we provide an overview of the technical capabilities of sparse camera volumetric video capture applications and assess their visual fidelity and workflow.

We selected volumetric video applications that are publicly available, support capture with multiple Microsoft Azure Kinect cameras and run on consumer-grade computer hardware. We compared the features, usability, and workflow of each application and benchmarked them in five different scenarios. Based on the benchmark footage, we analyzed spatial calibration accuracy, artifact occurrence and conducted a subjective perception study with 19 participants from a game design study program to assess the visual fidelity of the captures.

We evaluated three applications, Depthkit Studio, LiveScan3D and VolumetricCapture. We found Depthkit Studio to provide the best experience for novel users, while LiveScan3D and VolumetricCapture require advanced technical knowledge to be operated. The footage captured by Depthkit Studio showed the least amount of artifacts by a larger margin, followed by LiveScan3D and VolumetricCapture. These findings were confirmed by the participants who preferred Depthkit Studio over LiveScan3D and VolumetricCapture. Based on the results, we recommend Depthkit Studio for the highest fidelity captures. LiveScan3D produces footage of only acceptable fidelity but is the only candidate that is available as open-source software. We therefore recommend it as a platform for research and experimentation. Due to the lower fidelity and high setup complexity, we recommend VolumetricCapture only for specific use-cases where its ability to handle a high number of sensors in a large capture volume is required.
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Gender-based variations in surgical management of colorectal liver metastases
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BMC Cancer published the paper "Gender-based variations in surgical management of colorectal liver metastases: comprehensive analysis". Authors are Pia F. Koch, Kristina Ludwig, Karl H. Hillebrandt, Hannes Freitag, Moritz Blank, Sebastian Knitter, Dominik P. Modest, Felix Krenzien, Georg Lurje, Wenzel Schöning, Johann Pratschke, Igor M. Sauer, Simon Moosburner, and Nathanael Raschzok.

Colorectal cancer with liver metastasis affects both men and women. However, therapeutic strategies and long-term outcomes could be influenced by patients' sex, due to variations in tumour biology, lifestyle, and dietary habits. By conducting a comprehensive comparative analysis, this study aims to detail differences in tumour characteristics, postoperative complications, recurrence rates, and survival outcomes between sexes.
We performed a Single-centre retrospective analysis between 2010 and 2022 of all patients undergoing liver surgery for colorectal liver metastases (CRLM) at the Department of Surgery, Charité- Universitätsmedizin Berlin. Patients were stratified by sex. Statistical analysis was performed using RV4.2.We analysed 642 patients who underwent hepatic resections for CRLM. Baseline patient characteristics were comparable between sexes: However, significant differences (p < 0.001) were noted in body mass index (BMI), with females exhibiting lower BMIs (median BMI in females: 23.7 kg/m² vs. males: 26.5 kg/m²). Primary tumour locations varied significantly (p = 0.008), with females presenting more sigmoid colon tumours (37%), while males predominantly had rectal tumours (35%). RAS mutation rates were higher in females (54%) than males (34%, p = 0.005). A higher prevalence of bilobar metastases were evident in men (62%, p = 0.011), yet surgical techniques and complications showed comparable distributions. The time for resection was longer in males (median 304 min vs. 290 min in females); however, conversion to open surgery took place more often in females (5.2% vs. 2.3% in males). Postoperative complications and survival rates showed no significant differences by patients' sex.
Distinct sex-related patterns in tumour characteristics and postoperative outcomes in patients with CRLM were observed, emphasizing the need for further investigations to understand and address gender-based disparities for more personalized clinical management in the future.

The paper is available open access here.

Clinical prognosticators and targets in the immune microenvironment of intrahepatic cholangiocarcinoma
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The work on "
Quality assessment by bile composition in normothermic machine perfusion of rat livers
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Our manuscript “Quality assessment by bile composition in normothermic machine perfusion of rat livers” has been accepted for publication in Tissue Engineering Part A.
Authors are Vanessa Muth, Felix Stobl, Julian Michelotto, Jennifer A. Kirwan, Jeremy Marchand, Nathalie N. Roschke, Simon Moosburner, Johann Pratschke, Igor M. Sauer, Nathanael Raschzok, and Joseph MGV Gassner.

Due to the persistent challenge of organ scarcity in liver transplantation, there is an escalating dependence on organs obtained from extended criteria donors (ECD). Normothermic machine perfusion (NMP) can be used for improved preservation and allows quality assessment of ECD grafts. The primary objective of this study was to assess bile composition within the framework of quality analysis and explore the impact of warm ischemia on its composition in a rodent NMP model.

30 livers from male Sprague Dawley rats were divided into five distinct groups. Each group was subjected to 6 hours of NMP using either DMEM or Steen solution as perfusate, with or without a preceding 30-minute warm ischemia period. We further examined the effect of pressure-controlled perfusion on livers experiencing 30 min WIT using Steen as perfusate. We conducted regular measurements of AST, ALT, LDH, and urea levels in the perfusate at three- hour intervals. We collected bile samples at hourly intervals and assessed biliary pH, LDH, and GGT. Bile acids were measured using mass spectrometry every two hours.

Liver injury parameters were significantly higher in our DCD model. Bile production was significantly reduced in livers exposed to warm ischemia, and the bile showed a significantly more alkaline pH. This correlated with the concentration of total bile acids, which was significantly higher in livers with 30 min WIT. Taurocholic acid and its metabolites were most prominent. Secondary bile acids were significantly reduced in the course of perfusion due to the missing enterohepatic circulation. Prolonged warm ischemia-induced liver injury affects parameters we measured in bile within our small animal NMP model. We hypothesize that this phenomenon may be attributed to the cAMP-driven nature of bile secretion, potentially explaining why DCD livers produce less, yet more concentrated, bile.
200pubmed" target="_blank">Clinical prognosticators and targets in the immune microenvironment of intrahepatic cholangiocarcinoma" has been published by Oncoimmunology. Authors are Isis Lozzi, Alexander Arnold, Matthias Barone, Juliette Claire Johnson, Bruno V. Sinn, Johannes Eschrich, Pimrapat Gebert, Ruonan Wang, Mengwen Hu, Linda Feldbrügge, Anja Schirmeier, Anja Reutzel-Selke, Thomas Malinka, Felix Krenzien, Wenzel Schöning, Dominik P. Modest, Johann Pratschke, Igor M. Sauer, and Matthäus Felsenstein.

Intrahepatic cholangiocarcinoma (ICC) is a disease with poor prognosis and limited therapeutic options. We investigated the tumor immune microenvironment (TIME) to identify predictors of disease outcome and to explore targets for therapeutic modulation. Liver tissue samples were collected during 2008-2019 from patients (n = 139) diagnosed with ICC who underwent curative intent surgery without neoadjuvant chemotherapy. Samples from the discovery cohort (n = 86) were immunohistochemically analyzed on tissue microarrays (TMAs) for the expression of CD68, CD3, CD4, CD8, Foxp3, PD-L1, STAT1, and p-STAT1 in tumor core and stroma areas. Results were digitally analyzed using QuPath software and correlated with clinicopathological characteristics. For validation of TIME-related biomarkers, we performed multiplex imaging mass cytometry (IMC) in a validation cohort (n = 53).

CD68+ cells were the predominant immune cell type in the TIME of ICC. CD4+high T cell density correlated with better overall survival (OS). Prediction modeling together with validation cohort confirmed relevance of CD4+ cells, PD-L1 expression by immune cells in the stroma and N-stage on overall disease outcome. In turn, IMC analyses revealed that silent CD3+CD4+ clusters inversely impacted survival. Among annotated immune cell clusters, PD-L1 was most relevantly expressed by CD4+FoxP3+ cells. A subset of tumors with high density of immune cells ("hot" cluster) correlated with PD-L1 expression and could identify a group of candidates for immune checkpoint inhibition (ICI). Ultimately, higher levels of STAT1 expression were associated with higher lymphocyte infiltration and PD-L1 expression.
These results highlight the importance of CD4+ T cells in immune response against ICC. Secondly, a subset of tumors with "hot" TIME represents potential candidates for ICI, while stimulation of STAT1 pathway could be a potential target to turn "cold" into "hot" TIME in ICC.
Cytokine-armed vaccinia virus promotes cytotoxicity towards pancreatic carcinoma cells
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The manuscript "Cytokine-armed vaccinia virus promotes cytotoxicity towards pancreatic carcinoma cells via activation of human intermediary CD56dimCD16dim natural killer cells" by Ruonan Wang, Mengwen Hu, Isis Lozzi, Cao Z.J. Jin, Dou Ma, Katrin Splith, Jörg Mengwasser, Vincent Wolf, Linda Feldbrügge, Peter Tang, Lea Timmermann, Karl H. Hillebrandt, Marieluise Kirchner, Philipp Mertins, Georg Hilfenhaus, Christopher Neumann, Thomas Kammertoens, Johann Pratschke, Thomas Malinka, Igor Sauer, Elfriede Nössner, Zhongsheng Guo and Matthäus Felsenstein is available open access in the International Journal of Cancer.
 
Pancreatic ductal adenocarcinoma (PDAC) remains a particularly aggressive disease with few effective treatments. The PDAC tumor immune microenvironment (TIME) is known to be immune suppressive. Oncolytic viruses can increase tumor immunogenicity via immunogenic cell death(ICD). We focused on tumor-selective (vvDD) and cytokine-armed Western-Reserve vaccinia viruses (vvDD-IL2, vvDD-IL15) and infected carcinoma cell lines as well as patient-derived primary PDAC cells. In co-culture experiments, we investigated the cytotoxic response and the activation of human natural killer cells (NK). Infection and virus replication were assessed by measuring virus encoded YFP. We then analyzed intracellular signaling processes and oncolysis via in-depth proteomic analysis, immunoblotting and TUNEL assay. Following the co-culture of mock or virus infected carcinoma cell lines with allogenic PBMCs or NK cell lines, CD56+ NK cells were analyzed with respect to their activation, cytotoxicity and effector function. Both, dose- and time-dependent release of danger signals following infection was assayed. Viruses effectively entered PDAC cells and emitted YFP signals. Infection resulted in concomitant oncolysis. The proteome showed reprogramming of normally active core signaling pathways in PDAC occurred(e.g. MAPK-ERK signaling). Danger-associated molecular patterns were released upon infection and stimulated co-cultured NK cells for enhanced effector cytotoxicity. NK cell subtyping revealed enhanced numbers and activation of a rare CD56dimCD16dim population. Tumor cell killing was primarily triggered via Fas ligands rather than granule release, resulting in marked apoptosis. Cytokine-armed vaccinia viruses induced NK cell activation and enhanced cytotoxicity towards human PDAC cells in vitro. The cytokine-armed virus targets the carcinoma cells with great potential to modulate the TIME in PDAC.
Induced pluripotent stem cell (iPSC) line (EXSURGi001-A) from a patient homozygous for the p.Ala165Thr mutation in the MTARC1 gene
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The paper "Induced pluripotent stem cell (iPSC) line (EXSURGi001-A) from a patient homozygous for the p.Ala165Thr mutation in the MTARC1 gene" in Stem Cell Research is available open access. Authors are Peter Tang, Eriselda Keshi, Silvana Wilken, Louise Wutsdorff, Julienne Mougnekabol, Johann Pratschke, Igor M. Sauer and Nils Haep.

Metabolic dysfunction-associated fatty liver disease (MAFLD), the leading cause of end-stage liver disease in developed countries, is expected to increase over the next decade. Characterized by hepatic steatosis, MAFLD is commonly studied in animal models.
Here, we generated a human induced pluripotent stem cell (iPSC) line from a patient homozygous of the protective MTARC1 gene variant rs2642438:A.
This line displays a normal karyotype and typical pluripotent stem cell morphology and can differentiate into all three germ layers in vitro.
Extracellular NAD+ Response to Post-Hepatectomy Liver Failure: Bridging Preclinical and Clinical Findings
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Our manuscript entitled "Extracellular NAD+ Response to Post-Hepatectomy Liver Failure: Bridging Preclinical and Clinical Findings" has been accepted for publication in Communications Biology. Authors are Can Kamali, Philipp Brunnbauer, Kaan Kamali, Al-Hussein Saqr, Alexander Arnold, Gulcin Harman Kamali, Julia Babigian, Eriselda Keshi, Raphael Mohr, Matthäus Felsenstein, Simon Moosburner, Karl Hillebrandt, Jasmin Bartels, Igor Sauer, Frank Tacke, Moritz Schmelzle, Johann Pratschke, and Felix Krenzien.

Liver fibrosis progressing to cirrhosis is a major risk factor for liver cancer, impacting surgical treatment and survival. Our study investigates extracellular Nicotinamide adenine dinucleotide (eNAD+) in liver fibrosis, analyzing patients undergoing surgery and exploring NAD+'s therapeutic potential in a mouse model of extended liver resection and in vitro using 3D hepatocyte spheroids.

eNAD+ correlated with aspartate transaminase (AST) and bilirubin after liver resection (AST: r = 0.2828, p = 0.0087; Bilirubin: r = 0.2584, p = 0.0176). Post-hepatectomy liver failure (PHLF) was associated with higher eNAD+ peaks (n = 10; p = 0.0063). Postoperative eNAD+ levels decreased significantly (p < 0.05), but in advanced liver fibrosis or cirrhosis, this decline diminished or increased. NAD+ biosynthesis enzymes, NAMPT and NMNAT3, were significantly upregulated in higher fibrosis stages (p < 0.0001). NAD+ administration in 3D hepatocyte spheroids rescued hepatocytes from TNFα-induced cell death and improved viability (p < 0.0001). In mice, NAD+ treatment significantly improved survival (p = 0.0155) and liver regeneration (p = 0.0186) after extended liver resection.

eNAD+ is upregulated in PHLF, and NAD+ biosynthesis enzymes show higher expression in liver fibrosis. eNAD+ administration improved survival and hepatocyte viability, offering a potential target for future therapies.

Viscoelastic properties of colorectal liver metastases reflect the tumour cell viability
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Our paper on "Viscoelastic properties of colorectal liver metastases reflect the tumour cell viability" has been accepted for publication in Journal of Translational Medicine.

Colorectal cancer is one of the third most common cancers in the world and up to 50% of the patients develop liver metastases (CRLM) within five years. To improve and personalize therapeutic strategies, new diagnostic tools are urgently needed. An improvement could be achieved by considering biomechanical tumour properties with the implementation of magnetic resonance elastography (MRE). Our main hypothesis is that ex vivo MRE combined with histological evaluation of CRLM could provide the knowledge for using tissue mechanical properties as a diagnostic marker for cell viability in tumours.

We examined 34 CRLM samples from patients who had undergone liver resection at the Charité – Universitätsmedizin Berlin, Department of Surgery. The samples were investigated with an ex vivo MRE.  We employed a frequency range from 500 Hz to 5300 Hz, with increments of 400 Hz. For histological analysis, the samples were stained with H&E for categorization by a board-certified pathologist based on their grade of regression. The radiological response was evaluated using the RECIST-criteria.

Five samples showed major response to chemotherapy, 6 samples partial response, and 23 samples showed no response. Analysis of shear wave speed c significant correlation for frequencies including 2100 Hz and above depending on the grade of regression, indicating that low cell viability in CRLM is associated with higher tumour stiffness. Analysis of frequency-independent values of the SP-model showed a more elastic-solid behaviour at low cell viability. Our results suggest that MRE can be used to characterize the biomechanical properties associated with cell viability in CRLM, showing a higher stiffness and elastic-solid behaviour with high regression. In the future, MRE could help to improve the diagnostic tools to create an individual, tailored therapy plan for patients with CRLM.

Authors are Lisa-Marie Skrip, Simon Moosburner, Peter Tang, Jing Guo, Steffen Görner, Heiko Tzschätzsch, Clarissa Hosse, Uli Fehrenbach, Alexander Arnold, Dominik Modest, Felix Krenzien, Wenzel Schöning, Thomas Malinka, Johann Pratschke, Björn Papke, Josef A. Käs, Ingolf Sack, Igor M. Sauer, and Karl H. Hillebrandt,
Distinctive protein expression in elderly livers in a Sprague-Dawley rat model of normothermic ex vivo liver machine perfusion
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Our manuscript “Distinctive protein expression in elderly livers in a Sprague-Dawley rat model of normothermic ex vivo liver machine perfusion” has been published in the latest issue of the European Journal of Medical Research,
Authors are Maximilian Zimmer, Karl H. Hillebrandt, Nora M. Roschke, Steffen Lippert, Oliver Klein, Grit Nebrich, Joseph M.G.V. Gassner, Felix Strobl, Johann Pratschke, Felix Krenzien, Igor M. Sauer, Nathanael Raschzok, and Simon Moosburner.

Liver grafts are frequently declined due to high donor age or age mismatch with the recipient. To improve the outcome of marginal grafts, we aimed to characterize the performance of elderly vs. young liver grafts in a standardized rat model of normothermic ex vivo liver machine perfusion (NMP).

Livers from Sprague-Dawley rats aged 3 or 12 months were procured and perfused for 6 h using a rat NMP system or collected as a reference group (n = 6/group). Tissue, bile, and perfusate samples were used for biochemical, and proteomic analyses.

All livers cleared lactate during perfusion and continued to produce bile after 6 h of perfusion (614 mg/h). Peak urea levels in 12-month-old animals were higher than in younger animals. Arterial and portal venous pressure, bile production and pH did not differ between groups. Proteomic analysis identified a total of 1477 proteins with oxidoreductase and catalytic activity dominating the gene ontology analysis. Proteins such as aldehyde dehydrogenase 1A1 and 2-Hydroxyacid oxidase 2 were significantly more present in livers of older age.

Young and elderly liver grafts exhibited similar viability during NMP, though proteomic analyses indicated that older grafts are less resilient to oxidative stress. Our study is limited by the elderly animal age, which corresponds to mature but not elderly human age typically seen in marginal human livers. Nevertheless, reducing oxidative stress could be a promising therapeutic target in the future.
Thrombogenicity assessment of perfusable tissue engineered constructs: a systematic review
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Our systematic review on "Thrombogenicity assessment of perfusable tissue engineered constructs" has been accepted for publication in Tissue Engineering, Part B, and is available online ahead of print.

Vascular surgery faces a critical demand for novel vascular grafts that are biocompatible and thromboresistant. This urgency particularly applies to bypass operations involving small caliber vessels. In the realm of tissue engineering, the development of fully vascularized organs holds great promise as a solution to organ shortage for transplantation. To achieve this, it is imperative to (re-)construct a biocompatible and non-thrombogenic vascular network within these organs. In this systematic review, we identify, classify and discuss basic principles and methods used to perform in vitro/ex vivo dynamic thrombogenicity testing of perfusable tissue engineered organs and tissues. We conducted a pre-registered systematic review of studies published in the last 23 years according to PRISMA-P Guidelines, comprising a systematic data extraction, in-depth analysis and risk of bias assessment of 116 included studies. We identified shaking (n=28), flow loop (n=17), ex vivo (arterio-venous shunt, n=33) and dynamic in vitro models (n=38) as main approaches for thrombogenicity assessment. This comprehensive review unveils a prevalent lack of standardization and serves as a valuable guide in the design of standardized experimental setups.

Authors are Luna M. Haderer, Yijun Zhou, Peter Tang, Assal Daneshgar, Brigitta Globke, Felix Krenzien, Anja Reutzel-Selke, Marie Weinhart, Johann Pratschke, Igor M. Sauer, Karl H. Hillebrandt, and Eriselda Keshi.
Quality assessment by bile composition in normothermic machine perfusion of rat livers
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Our manuscript “Quality assessment by bile composition in normothermic machine perfusion of rat livers” has been accepted for publication in Tissue Engineering Part A.
Authors are Vanessa Muth, Felix Stobl, Julian Michelotto, Jennifer A. Kirwan, Jeremy Marchand, Nathalie N. Roschke, Simon Moosburner, Johann Pratschke, Igor M. Sauer, Nathanael Raschzok, and Joseph MGV Gassner.

Due to the persistent challenge of organ scarcity in liver transplantation, there is an escalating dependence on organs obtained from extended criteria donors (ECD). Normothermic machine perfusion (NMP) can be used for improved preservation and allows quality assessment of ECD grafts. The primary objective of this study was to assess bile composition within the framework of quality analysis and explore the impact of warm ischemia on its composition in a rodent NMP model.

30 livers from male Sprague Dawley rats were divided into five distinct groups. Each group was subjected to 6 hours of NMP using either DMEM or Steen solution as perfusate, with or without a preceding 30-minute warm ischemia period. We further examined the effect of pressure-controlled perfusion on livers experiencing 30 min WIT using Steen as perfusate. We conducted regular measurements of AST, ALT, LDH, and urea levels in the perfusate at three- hour intervals. We collected bile samples at hourly intervals and assessed biliary pH, LDH, and GGT. Bile acids were measured using mass spectrometry every two hours.

Liver injury parameters were significantly higher in our DCD model. Bile production was significantly reduced in livers exposed to warm ischemia, and the bile showed a significantly more alkaline pH. This correlated with the concentration of total bile acids, which was significantly higher in livers with 30 min WIT. Taurocholic acid and its metabolites were most prominent. Secondary bile acids were significantly reduced in the course of perfusion due to the missing enterohepatic circulation. Prolonged warm ischemia-induced liver injury affects parameters we measured in bile within our small animal NMP model. We hypothesize that this phenomenon may be attributed to the cAMP-driven nature of bile secretion, potentially explaining why DCD livers produce less, yet more concentrated, bile.
A new bicornuate model of rat uterus transplantation
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Our work on a “A new bicornuate model of rat uterus transplantation” has been accepted for publication in Acta Obstetricia et Gynecologica Scandinavica.

Uterus transplantation has revolutionized reproductive medicine for women with absolute uterine factor infertility, resulting in more than 40 reported successful live births worldwide to date. Small animal models are pivotal to refine this surgical and immunological challenging procedure aiming to enhance safety for both the mother and the child.
We established a syngeneic bicornuate uterus transplantation model in young female Lewis rats. All surgical procedures were conducted by an experienced and skilled microsurgeon who organized the learning process into multiple structured steps. Animals underwent meticulous preoperative preparation and postoperative care. Transplant success was monitored by sequential biopsies, monitoring graft viability and documenting histological changes long-term. Bicornuate uterus transplantation were successfully established achieving an over 70% graft survival rate with the passage of time. The bicornuate model demonstrated safety and feasibility, yielding outcomes comparable to the unicornuate model in terms of ischemia times and complications. Longitudinal biopsies were well-tolerated, enabling comprehensive monitoring throughout the study. Our novel bicornuate rat uterus transplantation model provides a distinctive opportunity for sequential biopsies at various intervals after transplantation and therefore comprehensive monitoring of graft health, viability, and identification of potential signs of rejection. Furthermore, this model allows for different interventions in each horn for comparative studies without interobserver differences contrary to the established unicornuate model. By closely replicating the clinical setting, this model stands as a valuable tool for ongoing research in the field of uterus transplantation, promoting further innovation and deeper insights into the intricacies of the uterus transplant procedure.

Authors are Dietrich Polenz, Igor Maximilian Sauer, Friederike Martin, Anja Reutzel-Selke, Muhammad Imtiaz Ashraf , Anja Schirmeier , Steffen Lippert, Kirsten Führer, Johann Pratschke, Stefan Günther Tullius, and Simon Moosburner.
Depletion of donor dendritic cells ameliorates immunogenicity of both skin and hind limb transplants
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Our manuscript "Depletion of donor dendritic cells ameliorates immunogenicity of both skin and hind limb transplants" has been accepted for publication in Frontiers in Immunology, section Alloimmunity and Transplantation. Authors are Muhammad Imtiaz Ashraf, Joerg Mengwasser, Anja Reutzel-Selke, Dietrich Polenz, Kirsten Führer, Steffen Lippert, Peter Tang, Edward Michaelis, Rusan Catar, Johann Pratschke, Christian Witzel, Igor M. Sauer, Stefan G. Tullius, and Barbara Kern.

Acute cellular rejection remains a significant obstacle affecting successful outcomes of organ transplantation including vascularized composite tissue allografts (VCA). Donor antigen presenting cells (APC), particularly dendritic cells (DC), orchestrate early alloimmune responses by activating recipient effector T cells. Employing a targeted approach, we investigated the impact of donor-derived conventional DC (cDC) and APC on the immunogenicity of skin and skin-containing VCA grafts, using mouse models of skin and hind limb transplantation.
By post-transplantation day 6, skin grafts demonstrated severe rejections, characterized by predominance of recipient CD4 T cells. In contrast, hind limb grafts showed moderate rejection, primarily infiltrated by CD8 T cells. While donor depletion of cDC and APC reduced frequencies, maturation, and activation of DC in all analysed tissues of skin transplant recipients, reduction in DC activities was only observed in the spleen of hind limb recipients. Donor cDC and APC depletion did not impact all lymphocyte compartments but significantly affected CD8 T cells and activated CD4 T in lymph nodes of skin recipients. Moreover, both donor APC and cDC depletion attenuated the Th17 immune response, evident by significantly reduced Th17 (CD4+IL-17+) cells in the spleen of skin recipients and reduced levels of IL-17E and lymphotoxin-α in the serum samples of both skin and hind limb recipients. In conclusion, our findings underscore the highly immunogenic nature of skin component in VCA. The depletion of donor APC and cDC mitigates the immunogenicity of skin grafts while exerting minimal impact on VCA.
Surgical planning in virtual reality: a systematic review
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We just published a review on surgical planning in VR in the Journal of Medical Imaging. In the systematic review we look into how virtual reality (VR) is transforming surgical planning. With VR physicians can assess patient-specific image data in 3D, enhancing surgical decision-making and spatial localization of pathologies. We found that benefits of VR become more evident. However, its application in surgical planning remains experimental, with a need for refined study designs, improved technical reporting, and enhanced VR software usability for effective clinical implementation. Authors of "Surgical planning in virtual reality: a systematic review" are Prof. Dr. Moritz Queisner and Karl Eisenträger.

Virtual reality (VR) technology has emerged as a promising tool for physicians, offering the ability to assess anatomical data in 3D with visuospatial interaction qualities. This systematic review aims to provide an up-to-date overview of the latest research on VR in the field of surgical planning.
A comprehensive literature search was conducted based on the preferred reporting items for systematic reviews and meta-analyses covering the period from April 1, 2021 to May 10, 2023. The review summarizes the current state of research in this field, identifying key findings, technologies, study designs, methods, and potential directions for future research. Results show that the application of VR for surgical planning is still in an experimental stage but is gradually advancing toward clinical use. The diverse study designs, methodologies, and varying reporting hinder a comprehensive analysis. Some findings lack statistical evidence and rely on subjective assumptions. To strengthen evaluation, future research should focus on refining study designs, improving technical reporting, defining visual and technical proficiency requirements, and enhancing VR software usability and design. Addressing these areas could pave the way for an effective implementation of VR in clinical settings.
Optimizing environmental enrichment for Sprague Dawley rats: Exemplary insights into the liver proteome
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Considering the expected increase in the elderly population and the growing emphasis on aging-related biomedical research, the demand for aged laboratory animals has surged, challenging established husbandry practices. Our objective was to establish a cost-effective method for environmental enrichment, utilizing the liver as a representative organ to assess metabolic changes in response to differing enrichment levels.
We conducted a six-month study involving 24 male Sprague Dawley rats who were randomly assigned to four environmental enrichment groups. Two groups were housed in standard cages, while the others were placed in modified rabbit cages. Half of the groups received weekly playtime in an enriched rat housing unit. We evaluated hormone levels, playtime behavior, and subjective handling experience. Additionally, liver tissue proteomic analysis was performed.
Initial corticosterone levels and those after 3 and 6 months showed no significant differences. Yet, testosterone levels were lower in the control group by the end of the study (p=0.007). In the liver tissue, we detected 1,871 distinct proteins, with 77% of them being consistent across all groups. In gene ontology analysis, no specific pathways were overexpressed. In semiquantitative analysis, we observed differences in proteins associated in lipid metabolism such as Apolipoprotein A-I and Acyl-CoA 6-desaturase, which were lower in the control group (p= 0.024 and p=0.009). Enriched environments reduced rat distress, large cages eased handling, and conflicts between rats lessened with bi-weekly interactions.

The manuscript "Optimizing environmental enrichment for Sprague Dawley rats: Exemplary insights into the liver proteome" has been accepted for publication in PLOS ONE.
Authors are Nathalie N. Roschke, Karl H. Hillebrandt, Dietrich Polenz, Oliver Klein, Joseph MGV Gassner, Johann Pratschke, Felix Krenzien, Igor M. Sauer, Nathanael Raschzok, and Simon Moosburner.
Proteomic analysis of decellularized mice liver and kidney extracellular matrices
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Based on the collaboration between the Department of General, Visceral, and Transplant Surgery, University Hospital Münster, and Experimental Surgery, Department of Surgery, Charité – Universitätsmedizin Berlin our work on the "Proteomic analysis of decellularized mice liver and kidney extracellular matrices" has been accepted for publication in Journal of Biological Engineering.

In this study, we employed a bottom-up proteomic approach to elucidate the intricate network of proteins in the decellularized extracellular matrices of murine liver and kidney tissues. This approach involved the use of a novel, perfusion-based decellularization protocol to generate acellular whole organ scaffolds. Proteomic analysis of decellularized mice liver and kidney ECM scaffolds revealed tissue-specific differences in matrisome composition, while we found a predominantly stable composition of the core matrisome, consisting of collagens, glycoproteins, and proteoglycans. Liver matrisome analysis revealed unique proteins such as collagen type VI alpha-6, fibrillin-2 or biglycan. In the kidney, specific ECM-regulators such as cathepsin z were detected. The identification of distinct proteomic signatures provides insights into how different matrisome compositions might influence the biological properties of distinct tissues. This experimental workflow will help to further elucidate the proteomic landscape of decellularized extracellular matrix scaffolds of mice in order to decipher complex cell-matrix interactions and their contribution to a tissue-specific microenvironment.

Authors are Anna-Maria Diedrich, Assal Daneshgar, Peter Tang, Oliver Klein, Annika Mohr, Olachi A. Onwuegbuchulam, Sabine von Rueden, Kerstin Menck, Annalen Bleckmann, Mazen A. Juratli, Felix Becker, Igor M. Sauer, Karl H. Hillebrandt, Andreas Pascher, and Benjamin Struecker.
miRNA as potential biomarkers after liver transplantation: A systematic review
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The publication "miRNA as potential biomarkers after liver transplantation: A systematic review" is now available online in Transplantation Reviews. Authors are Pia F. Koch, Kristina Ludwig, Felix Krenzien, Karl H. Hillebrandt, Wenzel Schöning, Johann Pratschke, Nathanael Raschzok, Igor M. Sauer, and Simon Moosburner.

Early and accurate diagnosis of acute cellular rejection (ACR) and graft complications after liver transplantation is crucial for timely intervention and improved patient outcomes, but their diagnosis rely currently on invasive biopsy sampling, thus prompting the search for non-invasive Biomarkers. MicroRNA (miRNA) have emerged as promising biomarkers in various pathological conditions, and their potential utility in diagnosing acute cellular rejection after liver transplantation has gained significant interest.

This systematic review analyzes studies exploring miRNA as biomarkers for ACR and graft dysfunction in liver transplantation (PROSPERO ID CRD42023465278). The Cochrane Collaboration tool for assessing risk of bias was employed. Population data, identified miRNA and their dynamic regulation, as well as event prediction were compared. Data extraction and quality assessment were performed independently by two reviewers.

The results highlight the potential of miRNA as specific, non-invasive biomarkers for ACR and graft dysfunction following liver transplantation. However, further research is needed to validate these findings and establish standardized diagnostic panels to incorporate them into clinical practice and explore miRNA-based therapies in the future.
AI-based intra- and postoperative measurement from stereoimages
The publication "Redefining the Laparoscopic Spatial Sense: AI-based Intra- and Postoperative Measurement from Stereoimages“ has been accepted for the 38th AAAI Conference on Artificial Intelligence and is available via https://doi.org/10.48550/arXiv.2311.09744. The publication is the result of a fruitful collaboration between Karlsruhe Institute of Technology (KIT), Fraunhofer FIT, University of Bayreuth, and Charité – Universitätsmedizin Berlin. Authors are Leopold Müller, Patrick Hemmer, Moritz Queisner, Igor Sauer, Simeon Allmendinger, Johannes Jakubik, Michael Vössing, and Niklas Kühl.

A significant challenge in image-guided surgery is the accurate measurement task of relevant structures such as vessel segments, resection margins, or bowel lengths. While this task is an essential component of many surgeries, it involves substantial human effort and is prone to inaccuracies. In this paper, we develop a novel human-AI-based method for laparoscopic measurements utilizing stereo vision that has been guided by practicing surgeons. Based on a holistic qualitative requirements analysis, this work proposes a comprehensive measurement method, which comprises state-of-the-art machine learning architectures, such as RAFT-Stereo and YOLOv8. The developed method is assessed in various realistic experimental evaluation environments. Our results outline the potential of our method achieving high accuracies in distance measurements with errors below 1 mm. Furthermore, on-surface measurements demonstrate robustness when applied in challenging environments with textureless regions. Overall, by addressing the inherent challenges of image-guided surgery, we lay the foundation for a more robust and accurate solution for intra- and postoperative measurements, enabling more precise, safe, and efficient surgical procedures.

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Rise of tissue- and species-specific 3D bioprinting based on decellularized extracellular matrix-derived bioinks and bioresins
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The publication "Rise of tissue- and species-specific 3D bioprinting based on decellularized extracellular matrix-derived bioinks and bioresins" is now available online in Biomaterials and Biosystems. Authors are Laura Elomaa, Ahed Almalla, Eriselda Keshi, Karl H. Hillebrandt, Igor M. Sauer, and Marie Weinhart.

Thanks to its natural complexity and functionality, decellularized extracellular matrix (dECM) serves as an excellent foundation for creating highly cell-compatible bioinks and bioresins. This enables the bioprinted cells to thrive in an environment that closely mimics their native ECM composition and offers customizable biomechanical properties. To formulate dECM bioinks and bioresins, one must first pulverize and/or solubilize the dECM into non-crosslinked fragments, which can then be chemically modified as needed. In bioprinting, the solubilized dECM-derived material is typically deposited and/or crosslinked in a layer-by-layer fashion to build 3D hydrogel structures. Since the introduction of the first liver-derived dECM-based bioinks, a wide variety of decellularized tissue have been employed in bioprinting, including kidney, heart, cartilage, and adipose tissue among others. This review aims to summarize the critical steps involved in tissue-derived dECM bioprinting, starting from the decellularization of the ECM to the standardized formulation of bioinks and bioresins, ultimately leading to the reproducible bioprinting of tissue constructs.
Moderate LMWH anticoagulation improves success rate of hind limb allotransplantation in mice
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The publication "Moderate LMWH Anticoagulation Improves Success Rate of Hind Limb Allotransplantation in Mice" is now available online in Plastic & Reconstructive Surgery-Global Open. Authors are B. Kern, M.-I. Ashraf, A. Reutzel-Selke, J. Mengwasser, D. Polenz, E. Michaels, J. Pratschke, S.G. Tullius, Ch. Witzel, and I.M. Sauer.

The mouse hind limb model represents a powerful research tool in vascularized composite tissue allotransplantation, but its applicability is limited due to poor graft survival (62%–83%). Vascular thrombosis and massive hemorrhage are the major causes for these drop-outs. We hypothesize that because of better anticoagulation effect and lower risk of thrombocytopenia, application of low molecular weight heparin (LMWH) will minimize vascular complications and enhance graft and animal survival.

Fifty allogeneic hind limb transplantations were performed (C57BL/6 to DBA/2 mice) using five different anticoagulation protocols. Bleeding and thromboembolic events were recorded macroscopically by postoperative hemorrhage and livid discoloration of the graft, respectively. Graft perfusion and survival were monitored daily by capillary-refill-time of graft toes within 2–3 seconds. Vascular congestion and tissue necrosis were examined by histological evaluation of hematoxylin-eosin-stained tissue sections.

All transplantations were technically successful. Increase in thromboembolic events and a concomitant decrease in bleeding events were observed with the decreasing concentration of heparin in the perfusion solution. Although treatment of donor and recipient with low dose of LMWH could not reduce thromboembolic events, moderate dose effectively reduced these events. Compared with the poor outcome of graft perfusion with heparin alone, additional treatment of donor and recipient with low dose of LMWH improved graft and animal survival by 18%. Interestingly, animals treated with moderate dose of LMWH demonstrated 100% graft and animal survival.
Treatment of donor and recipient mice with a moderate dose of LMWH prevents vascular complications and improves the outcome of murine hind limb transplants.
Solid fraction determines stiffness and viscosity in decellularized pancreatic tissues
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The article „Solid fraction determines stiffness and viscosity in decellularized pancreatic tissues“ in Biomaterials Advances is now available online.
There is free access to a PDF of the article here until August 20, 2022!

The role of extracellular matrix (ECM) composition and turnover in mechano-signaling and the metamorphic fate of cells seeded into decellularized tissue can be elucidated by recent developments in non-invasive imaging and biotechnological analysis methods. Because these methods allow accurate quantification of the composition and structural integrity of the ECM, they can be critical in establishing standardized decellularization protocols. This study proposes quantification of the solid fraction, the single-component fraction and the viscoelasticity of decellularized pancreatic tissues using compact multifrequency magnetic resonance elastography (MRE) to assess the efficiency and quality of decellularization protocols. MRE of native and decellularized pancreatic tissues showed that viscoelasticity parameters depend according to a power law on the solid fraction of the decellularized matrix. The parameters can thus be used as highly sensitive markers of the mechanical integrity of soft tissues. Compact MRE allows consistent and noninvasive quantification of the viscoelastic properties of decellularized tissue. Such a method is urgently needed for the standardized monitoring of decellularization processes, evaluation of mechanical ECM properties, and quantification of the integrity of solid structural elements remaining in the decellularized tissue matrix.

Authors are Joachim Snellings, Eriselda Keshi, Peter Tang, Assal Daneshgar, Esther C. Willma, Luna Haderer, Oliver Klein, Felix Krenzien, Thomas Malink, Patrick Asbach, Johann Pratschke, Igor M. Sauer, Jürgen Braun, Ingolf Sack, and Karl Hillebrandt.

VolumetricOR | Surgical Innovation
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Our paper "VolumetricOR: A new Approach to Simulate Surgical Interventions in Virtual Reality for Training and Education" is available in the latest issue of Surgical Innovation.

Surgical training is primarily carried out through observation during assistance or on-site classes, by watching videos as well as by different formats of simulation. The simulation of physical presence in the operating theatre in virtual reality might complement these necessary experiences. A prerequisite is a new education concept for virtual classes that communicates the unique workflows and decision-making paths of surgical health professions (i.e. surgeons, anesthesiologists, and surgical assistants) in an authentic and immersive way. For this project, media scientists, designers and surgeons worked together to develop the foundations for new ways of conveying knowledge using virtual reality in surgery.
A technical workflow to record and present volumetric videos of surgical interventions in a photorealistic virtual operating room was developed. Situated in the virtual reality demonstrator called VolumetricOR, users can experience and navigate through surgical workflows as if they are physically present . The concept is compared with traditional video-based formats of digital simulation in surgical training.

VolumetricOR let trainees experience surgical action and workflows a) three-dimensionally, b) from any perspective and c) in real scale. This improves the linking of theoretical expertise and practical application of knowledge and shifts the learning experience from observation to participation.
Discussion: Volumetric training environments allow trainees to acquire procedural knowledge before going to the operating room and could improve the efficiency and quality of the learning and training process for professional staff by communicating techniques and workflows when the possibilities of training on-site are limited.

Authors are Moritz Queisner, Michael Pogorzhelskiy, Christopher Remde, Johann Pratschke, and Igor M. Sauer.
Tissue Engineering for the Diaphragm
"Tissue Engineering for the Diaphragm and its Various Therapeutic Possibilities – A Systematic Review" is available here in Advanced Therapeutics (open access).

Diaphragmatic impairments exhibit high morbidity as well as mortality while current treatment options remain unsatisfactory. Tissue engineering (TE) approaches have explored the generation of an optimal biocompatible scaffold for diaphragmatic repair through tissue decellularization or de novo construction, with or without the addition of cells. The authors conducted a systematic review on the current state of the art in diaphragmatic tissue engineering (DTE) and found 24 articles eligible for final synthesis. The included approaches studied decellularization-based graft generation and de novo bioscaffold construction. Three studies focused on in vitro host-scaffold interaction with synthesized, recellularized grafts and decellularized extracellular matrix scaffolds. Another three studies investigated evaluation tools for decellularization efficacy. Among all studies, recellularization is performed in both decellularization-based and de novo generated scaffolds. De novo constructed biocomposites as well as decellularized and recellularized scaffolds induced pro-regenerative remodeling and recovery of diaphragmatic function in all examined animal models. Potential therapeutic applications comprise substance defects requiring patch repair, such as congenital diaphragmatic hernia, and functional diseases demanding an entire organ transplant, like muscular dystrophies or dysfunction after prolonged artificial respiration.

Autors are Agnes K. Boehm, Karl H. Hillebrandt, Tomasz Dziodzio, Felix Krenzien, Jens Neudecker, Simone Spuler, Johann Pratschke, Igor M. Sauer, and Marco N. Andreas.
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