[Show abstract][Hide abstract] ABSTRACT: The treatment of acute liver failure, a condition with high mortality, comprises optimal clinical care, and in severe cases liver transplantation. However, there are limitations in availability of organ donors. Hepatocyte transplantation is a promising alternative to fill the medical need, in particular the bridge-to-transplant, and as source porcine donors are proposed. In this approach, cell encapsulation is proposed to eliminate or reduce immunosuppression. Besides patients with acute liver failure, patients with alcoholic hepatitis who are unresponsive to a short course of corticosteroids are a target for hepatocyte transplantation. In this review we present an overview of the innate immune barriers in hepatocyte xenotransplantation, including the role of complement and natural antibodies; the role of phagocytic cells and ligands like CD47 in the regulation of phagocytic cells; and the role of Natural Killer cells. We present also some illustrations of physiological species incompatibilities in hepatocyte xenotransplantation, such as incompatibilities in the coagulation system. An overview of the methodology for cell microencapsulation is presented, followed by proof-of-concept studies in rodent and nonhuman primate models of fulminant liver failure: these studies document the efficacy of microencapsulated porcine hepatocytes which warrants progress towards clinical application. Lastly, we present an outline of a provisional clinical trial, that upon completion of preclinical work could start within the upcoming 2-3 years.
International Journal of Surgery (London, England) 09/2015; DOI:10.1016/j.ijsu.2015.08.077 · 1.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Spleen gathers numerous functions and plays a critical role in immunity against encapsulated bacteria. Anatomical injuries or physiological spleen dysfunctions can lead to complete (asplenism) or partial (hyposplenism) functional deficits and expose the patient to the risk of fulminant sepsis, as well as to thromboembolic complications. The purpose of this article is to provide the primary care physician with the tools needed to identify functional disorders of the spleen and to prevent their complications. The latest recommendations for antibiotic prophylaxis and immunization are also addressed.
[Show abstract][Hide abstract] ABSTRACT: Two novel types of hydrogel microspheres (MS) are presented. First, one-component microspheres (1-comMS) were produced from sodium alginate (Na-alg) equipped with thiol-functionalized hydroxyl groups. The functionalization pathway included the conversion of Na-alg into tetrabutylammonium alginate, insertion of new carboxyl groups, grafting of α-amine-ω-thiol poly(ethylene glycol), and restoration of the sodium salt. This modification conserves all original carboxyl groups of Na-alg and allows for covalent disulfide bond formation in addition to ionic crosslinking. Second, two-component microspheres (2-comMS) were obtained from a mixture of Na-alg and Na-alg functionalized with cysteamine. This functionalization was achieved by grafting cystamine dihydrochloride on some carboxyl groups followed by the reduction to cysteamine. Using the one-step MS formation process developed for both MS types, very fast ionic gelation with calcium ions conserves the spherical shape of the polymer solution droplets upon extrusion into the gelation bath, while simultaneously occurring slow covalent crosslinking reinforces the hydrogels. The physical properties of both MS types are adjustable by varying the polymer concentration, the degree of grafting, and the mixing ratio. In vitro cell microencapsulation studies confirmed the cytocompatibility of 1-comMS and 2-comMS.
Chemistry of Materials 05/2015; 27(12):150527153338005. DOI:10.1021/acs.chemmater.5b01098 · 8.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Lymph node involvement in pancreatic adenocarcinoma is a key prognostic factor. Therefore, extending the number of lymph node stations excised in pancreatoduodenectomy may be beneficial to patients with pancreatic adenocarcinoma. This systematic review and meta-analysis examines the outcomes of extended versus standard lymphadenectomy in the published literature.MethodsA meta-analysis of randomized controlled trials (RCTs) comparing extended with standard lymphadenectomy in patients undergoing pancreatoduodenectomy for pancreatic adenocarcinoma was performed. Perioperative outcomes were assessed as pooled odds ratios (ORs) and weighted mean differences. Overall survival was analysed for patients with positive and negative lymph nodes. Results were reported according to the PRISMA statement.ResultsFive RCTs were included, accounting for 724 patients. Extended lymphadenectomy was associated with greater operative time [mean difference: 63 min, 95% confidence interval (CI) 29–96; P < 0.001], increased need for blood transfusions (mean difference: 0.20, 95% CI 0.01–0.30; P = 0.030) and greater postoperative morbidity (OR 1.5, 95% CI 1.25–2.00; P = 0.030), as well as with prolonged diarrhoea after circumferential autonomic nerve dissection around major vessels (OR 12.2, 95% CI 5.3–28.5; P < 0.001). Median survival was similar across the groups in the whole cohort, as well as in subgroups of patients with, respectively, positive and negative lymph node patients.Conclusions
Extended lymphadenectomy has a harmful impact on patients undergoing oncological pancreatoduodenectomy compared with standard lymphadenectomy.
[Show abstract][Hide abstract] ABSTRACT: Robotic technology commenced to be adopted for the field of general surgery in the 1990s. Since then, the da Vinci surgical system (Intuitive Surgical Inc, Sunnyvale, CA, USA) has remained by far the most commonly used system in this domain. The da Vinci surgical system is a master-slave machine that offers three-dimensional vision, articulated instruments with seven degrees of freedom, and additional software features such as motion scaling and tremor filtration. The specific design allows hand-eye alignment with intuitive control of the minimally invasive instruments. As such, robotic surgery appears technologically superior when compared with laparoscopy by overcoming some of the technical limitations that are imposed on the surgeon by the conventional approach.
This article reviews the current literature and the perspective of robotic general surgery.
While robotics has been applied to a wide range of general surgery procedures, its precise role in this field remains a subject of further research. Until now, only limited clinical evidence that could establish the use of robotics as the gold standard for procedures of general surgery has been created. While surgical robotics is still in its infancy with multiple novel systems currently under development and clinical trials in progress, the opportunities for this technology appear endless, and robotics should have a lasting impact to the field of general surgery.
Langenbeck s Archives of Surgery 02/2015; 400(3). DOI:10.1007/s00423-015-1278-y · 2.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In vivo, bone marrow-derived multipotent mesenchymal stromal cells (MSC) have been identified at sites of tumors, suggesting that specific signals mobilize and activate MSC to migrate into areas surrounding tumors. The signals and migratory mechanisms that guide MSC are not well understood. Here, we investigated migration of human MSC induced by conditioned medium of Huh-7 hepatoma cells (Huh-7 CM). Using a transwell migration system, we showed that human MSC migration was increased in the presence of Huh-7 CM. Using a human cytokine antibody array, we detected increased levels of MIP-1δ and MIP-3α in Huh-7 CM. Recombinant chemokines MIP-1δ and MIP-3α induced MSC migration in 3 out of 5 MSC donors. Anti-MIP-1δ and anti-MIP-3α antibodies added to Huh-7 CM decreased MSC migration, further suggesting that MIP-1δ and MIP-3α were implicated in the Huh-7 CM-induced MSC migration. By real-time PCR, we observed an absence of chemokine receptors CCR2 and CXCR2 and low expression of CCR1, CCR5 and CCR6 in MSC. Expression of these chemokine receptors were not regulated by Huh-7 CM. Furthermore, matrix metalloproteinase 1 (MMP-1) expression was strongly increased in MSC after incubation with Huh-7 CM, suggesting that MSC migration depends on MMP-1 activity. The signaling pathway MAPK/ERK was activated by Huh-7 CM but its inhibition by PD98059 did not impair Huh-7 CM-induced MSC migration. Further, long-term incubation of MSC with MIP-1δ increased α-smooth muscle actin expression, suggesting its implication in the Huh-7 CM-induced evolvement of MSC into myofibroblast. In conclusion, we reported that two inflammatory cytokines, MIP-1δ and MIP-3α are able to increase MSC migration in vitro. These cytokines might be responsible for migration and evolvement of MSC into myofibroblasts in the stromal reaction around tumors.
Stem Cells and Development 01/2015; 24(10). DOI:10.1089/scd.2014.0176 · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background & aims:
Mesenchymal stem cell (MSC) transplantation was shown to be effective for the treatment of liver fibrosis, but the mechanisms of action are not yet fully understood. We transplanted encapsulated human MSCs in two mouse models of liver fibrosis to determine the mechanisms behind the protective effect.
Human bone marrow-derived MSCs were microencapsulated in novel alginate-polyethylene glycol microspheres. In vitro, we analyzed the effect of MSC-conditioned medium on the activation of hepatic stellate cells and the viability, proliferation, cytokine secretion, and differentiation capacity of encapsulated MSCs. The level of fibrosis induced by bile duct ligation (BDL) or carbon tetrachloride (CCl4) was assessed after intraperitoneal transplantation of encapsulated MSCs, encapsulated human fibroblasts, and empty microspheres.
MSC-conditioned medium inhibited hepatic stellate cell activation and release of MSC secreted anti-apoptotic (IL-6, IGFBP-2) and anti-inflammatory (IL-1Ra) cytokines. Viability, proliferation, and cytokine secretion of microencapsulated MSCs were similar to those of non-encapsulated MSCs. Within the microspheres, MSCs maintained their capacity to differentiate into adipocytes, chondrocytes, and osteocytes. 23% (5/22) of the MSC clones were able to produce anti-inflammatory IL-1Ra in vitro. Microencapsulated MSCs significantly delayed the development of BDL- and CCl4-induced liver fibrosis. Fibroblasts had an intermediate effect against CCl4-induced fibrosis. Mice transplanted with encapsulated MSCs showed lower mRNA levels of collagen type I, whereas levels of matrix metalloproteinase 9 were significantly higher. Human IL-1Ra was detected in the serum of 36% (4/11) of the mice transplanted with microencapsulated MSCs.
MSC-derived soluble molecules are responsible for an anti-fibrotic effect in experimental liver fibrosis.
Journal of Hepatology 10/2014; 62(3). DOI:10.1016/j.jhep.2014.10.030 · 11.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Advanced surgical procedures have traditionally been a domain of open surgery. However, minimally invasive approaches are evolving with the development of robotic technology which appears capable to overcome technical limitations of conventional laparoscopy. While traditionally perceived as impossible indications for minimally invasive surgery, reports on robotic organ transplantations have surfaced with promising results.
[Show abstract][Hide abstract] ABSTRACT: Regenerative medicine aims to replace a body function or specific cell loss. It includes therapies at the forefront of modem medicine, issuing from translational biomedical research. Transplantation of organs and cells has revolutionized the management of patients for whom medical treatment is a failure. Unfortunately, organ shortage is limiting treatment possibility. As an example, among the 15,000 patients with type I diabetes in Switzerland, only approximately 30 can receive a pancreas or an islet transplant per year. Second example, 500 patients die each year in Switzerland from alcoholic cirrhosis because no treatment is available. Transplantation of islet cells, hepatocytes, mesenchymal stem cells or dopaminergic neurons represents hope fora therapy available for large populations of patients.
[Show abstract][Hide abstract] ABSTRACT: Bone marrow was recently proposed as an alternative and potentially immune-privileged site for pancreatic islet transplantation. The aim of the present study was to assess the survival and rejection mechanisms of free and encapsulated xenogeneic islets transplanted into the medullary cavity of the femur, or under the kidney capsule of streptozotocin-induced diabetic C57BL/6 mice. The median survival of free rat islets transplanted into the bone marrow or under the kidney capsule was 9 and 14 days, respectively, whereas that of free human islets was shorter, 7 days (bone marrow) and 10 days (kidney capsule). Infiltrating CD8+ T cells and redistributed CD4+ T cells, and macrophages were detected around the transplanted islets in bone sections. Recipient mouse splenocytes proliferated in response to donor rat stimulator cells. One month after transplantation under both kidney capsule or into bone marrow, encapsulated rat islets had induced a similar degree of fibrotic reaction and still contained insulin positive cells. In conclusion, we successfully established a small animal model for xenogeneic islet transplantation into the bone marrow. The rejection of xenogeneic islets was associated with local and systemic T cell responses and macrophage recruitment. Although there was no evidence for immune-privilege, the bone marrow may represent a feasible site for encapsulated xenogeneic islet transplantation.
PLoS ONE 03/2014; 9(3):e91268. DOI:10.1371/journal.pone.0091268 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Magnetic resonance imaging (MRI) gadolinium-perfusion was applied in simulated Donation after Cardiac Death (DCD) in porcine kidneys to measure intrarenal perfusion. Adenosine triphosphate (ATP) resynthesis during oxygenated hypothermic perfusion was compared to evaluate the "ex vivo organ viability". Adenine nucleotide (AN) was measured by P nuclear magnetic resonance (NMR) spectroscopy. Whereas this latter technique requires sophisticated hardware, gadolinium-perfusion can be realized using any standard proton-MRI scanner. The aim of this work was to establish a correlation between the two methods.
Twenty-two porcine kidneys presenting up to 90 min warm ischemia were perfused with oxygenation at 4°C using our magnetic resonance-compatible machine. During the perfusion, P NMR spectroscopy and gadolinium-perfusion sequences were performed. Measures obtained from the gadolinium-perfusion were the speed of elimination of the cortical gadolinium and the presence or absence of a corticomedullar shunt. For ATP resynthesis analysis, P chemical shift imaging was acquired and analyzed. All the kidneys have been submitted to histologic examination.
ATP resynthesis was observed in all organs presenting a cortical gadolinium elimination slope of (-) 23° or greater. In organs with lower gadolinium elimination, no AN or only precursors were detected. This study reveals a link between the two methods and demonstrates ex vivo viability in 93% of the analyzed kidneys. Benefits and side effects of both methods are discussed.
Oxygenated hypothermic perfusion enables the evaluation of kidneys in DCD simulated situation; gadolinium-perfusion can be introduced into any center equipped with a proton-MRI scanner allowing results superposable with ATP measurement.
[Show abstract][Hide abstract] ABSTRACT: Minimally invasive approaches for cholecystectomy are evolving in a surge for the best possible clinical outcome for the patients. As one of the most recent developments, a robotic set of instrumentation to be used with the da Vinci Si Surgical System has been developed to overcome some of the technical challenges of manual single incision laparoscopy.
From February 2011 to February 2013, all consecutive robotic single site cholecystectomies (RSSC) were prospectively collected in a dedicated database. Demographic, intra- and postoperative data of all patients that underwent RSSC at our institution were analyzed. Data were evaluated for the overall patient cohort as well as after stratification according to patient BMI (body mass index) and surgeon's experience.
During the study period, 82 patients underwent robotic single site cholecystectomy at our institution. The dominating preoperative diagnosis was cholelithiasis. Mean overall operative time was 91 min. Intraoperative complications occurred in 2.4% of cases. One conversion to open surgery due to the intraoperative finding of a gallbladder carcinoma was observed and two patients needed an additional laparoscopic trocar. The rate of postoperative complications was 4.9% with a mean length of stay of 2.4 days. No significant differences were observed when comparing results between robotic novices and robotic experts. Patients with higher BMI trended towards longer surgical console and overall operative time, but resulted in similar rates of conversions and complications when compared to normal weight patients.
Robotic Single-Site cholecystectomy can be performed safely and effectively with low rates of complications and conversions in patients with differing BMI and by surgeons with varying levels of experience.
[Show abstract][Hide abstract] ABSTRACT: The progress of medical therapies, which rely on the transplantation of microencapsulated living cells, depends on the quality of the encapsulating material. Such material has to be biocompatible, and the microencapsulation process must be simple and not harm the cells. Alginate-poly(ethylene glycol) hybrid microspheres (alg-PEG-M) were produced by combining ionotropic gelation of sodium alginate (Na-alg) using calcium ions with covalent crosslinking of vinyl sulfone-terminated multi-arm poly(ethylene glycol) (PEG-VS). In a one-step microsphere formation process, fast ionotropic gelation yields spherical calcium alginate gel beads, which serve as a matrix for simultaneously but slowly occurring covalent cross-linking of the PEG-VS molecules. The feasibility of cell microencapsulation was studied using primary human foreskin fibroblasts (EDX cells) as a model. The use of cell culture media as polymer solvent, gelation bath, and storage medium did not negatively affect the alg-PEG-M properties. Microencapsulated EDX cells maintained their viability and proliferated. This study demonstrates the feasibility of primary cell microencapsulation within the novel microsphere type alg-PEG-M, serves as reference for future therapy development, and confirms the suitability of EDX cells as control model.
[Show abstract][Hide abstract] ABSTRACT: Mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) have been extensively investigated in small animal models to treat both acute and chronic liver injuries. Mechanisms of action are not clearly elucidated but may include their ability to differentiate into hepatocyte-like cells, to reduce inflammation, and to enhance tissue repair at the site of injury. This approach is controversial and evidence in large animals is missing. Side effects of MSC infusion such as the contribution to a fibrotic process have been reported in experimental settings. Nevertheless, MSCs moved quickly from bench to bedside and over 280 clinical trials are registered, of which 28 focus on the treatment of liver diseases. If no severe side-effects were observed so far, long-term benefits remain uncertain. More preclinical data regarding mechanisms of action, long term safety and efficacy are warranted before initiating large scale clinical application. The proposal of this review is to visit the current state of knowledge regarding mechanisms behind the therapeutic effects of MSCs in the treatment of experimental liver diseases, to address questions about efficacy and risk, and to discuss recent clinical advances involving MSC-based therapies.
Stem Cell Research 08/2013; 11(3):1348-1364. DOI:10.1016/j.scr.2013.08.011 · 3.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Two types of hydrogel microspheres have been developed. Fast ionotropic gelation of sodium alginate (Na-alg) in the presence of calcium ions was combined with slow covalent cross-linking of poly(ethylene glycol) (PEG) derivatives. For the first type, the fast obtainable Ca-alg hydrogel served as spherical matrix for the simultaneously occurring covalent cross-linking of multi-arm PEG derivative. A two-component interpenetrating network was formed in one step upon extruding the mixture of the two polymers into the gelation bath. For the second type, heterobifunctional PEG was grafted onto Na-alg prior to gelation. Upon extrusion of the polymer solution into the gelation bath, fast Ca-alg formation ensured the spherical shape and was accompanied by cross-linker-free covalent cross-linking of the PEG side chains. Thus, one-component hydrogel microspheres resulted. We present the physical properties of the hydrogel microspheres and demonstrate the feasibility of cell microencapsulation for both types of polymer networks.