Severe injuries to peripheral nerves are challenging to repair. Standard-of-care treatment for nerve gaps >2 to 3 centimeters is autografting; however, autografting can result in neuroma formation, loss of sensory function at the donor site, and increased operative time. To address the need for a synthetic nerve conduit to treat large nerve gaps, we investigated a biodegradable poly(caprolactone) (PCL) conduit with embedded double-walled polymeric microspheres encapsulating glial cell line–derived neurotrophic factor (GDNF) capable of providing a sustained release of GDNF for >50 days in a 5-centimeter nerve defect in a rhesus macaque model. The GDNF-eluting conduit (PCL/GDNF) was compared to a median nerve autograft and a PCL conduit containing empty microspheres (PCL/Empty). Functional testing demonstrated similar functional recovery between the PCL/GDNF-treated group (75.64 ± 10.28%) and the autograft-treated group (77.49 ± 19.28%); both groups were statistically improved compared to PCL/Empty-treated group (44.95 ± 26.94%). Nerve conduction velocity 1 year after surgery was increased in the PCL/GDNF-treated macaques (31.41 ± 15.34 meters/second) compared to autograft (25.45 ± 3.96 meters/second) and PCL/Empty (12.60 ± 3.89 meters/second) treatment. Histological analyses included assessment of Schwann cell presence, myelination of axons, nerve fiber density, and g-ratio. PCL/GDNF group exhibited a statistically greater average area occupied by individual Schwann cells at the distal nerve (11.60 ± 33.01 μm2) compared to autograft (4.62 ± 3.99 μm2) and PCL/Empty (4.52 ± 5.16 μm2) treatment groups. This study demonstrates the efficacious bridging of a long peripheral nerve gap in a nonhuman primate model using an acellular, biodegradable nerve conduit.

The macrolide rapamycin and its analogues (rapalogs) constitute the first generation of mammalian target of rapamycin (mTOR) inhibitors. Since the introduction of rapamycin as an immunosuppressant, there has been extensive progress in understanding its complex mechanisms of action. New insights into the function of mTOR in different immune cell types, vascular endothelial cells and neoplastic cells have opened new opportunities and challenges regarding mTOR as a pharmacological target. Currently, the two known mTOR complexes, mTOR complex (mTORC) 1 and mTORC2, are the subject of intense investigation, and the introduction of second‐generation dual mTORC kinase inhibitors (TORKinibs) and gene knockout mice is helping to uncover the distinct roles of these complexes in different cell types. While the pharmacological profiling of rapalogs is advanced, much less is known about the properties of TORKinibs. A potential benefit of mTOR inhibition in transplantation is improved protection against transplant‐associated viral infections compared with standard calcineurin inhibitor‐based immunosuppression. Preclinical and clinical data also underscore the potentially favourable antitumour effects of mTOR inhibitors in regard to transplant‐associated malignancies and as a novel treatment option for various other cancers. Many aspects of the mechanisms of action of mTOR inhibitors and their clinical implications remain unknown. In this brief review we discuss new findings and perspectives of mTOR inhibitors in transplantation.

Delivery of ASCs in poloxamer addresses multiple facets of the complexity of nerve/muscle unit regeneration, representing a promising avenue for further study. Muscle Nerve 58: 251-260, 2018.

Taken together, our results point to the potential for repetitive AD-MSC administration in improving outcomes after VCA. Future studies are warranted into optimization of the dosing and frequency of AD-MSC therapy, either alone or used in, combination with other cell therapies (such as hematopoietic stem cells or bone marrow-derived MSC or dendritic cells) for optimization of appropriate conditioning or maintenance regimens.

BackgroundVascularized composite allotransplantation opens new possibilities in reconstructive transplantation such as hand or face transplants. Lifelong immunosuppression and its side-effects are the main drawbacks of this procedure. Mesenchymal stem cells (MSCs) have clinically useful immunomodulatory effects and may be able to reduce the burden of chronic immunosuppression. Herein, we assess and compare characteristics and immunomodulatory capacities of bone marrow- and adipose tissue-derived MSCs isolated from the same human individual across defined human leukocyte antigen (HLA) barriers.Materials and methodsSamples of omental (o.) adipose tissue, subcutaneous (s.c.) adipose tissue, and bone marrow aspirate from 10 human organ donors were retrieved and MSCs isolated. Cells were characterized by flow cytometry and differentiated in three lineages: adipogenic, osteogenic, and chondrogenic. In mixed lymphocyte reactions, the ability of adipose-derived mesenchymal stem cells (ASCs) and bone marrow-derived mesenchymal stem cells (BMSCs) to suppress the immune response was assessed and compared within individual donors. HLA mismatched or mitogen stimulations were analyzed in co-culture with different MSC concentrations. Supernatants were analyzed for cytokine contents.ResultsAll cell types, s.c.ASC, o.ASC, and BMSC demonstrated individual differentiation potential and cell surface markers. Immunomodulating effects were dependent on dose and cell passage. Proliferation of responder cells was most effectively suppressed by s.c.ASCs and combination with BMSC resulted in highly efficient immunomodulation. Immunomodulation was not cell contact-dependent and cells demonstrated a specific cytokine secretion.ConclusionWhen human ASCs and BMSCs are isolated from the same individual, both show effective immunomodulation across defined HLA barriers in vitro. We demonstrate a synergistic effect when cells from the same biologic system were combined. This cell contact-independent function underlines the potential of clinical systemic application of MSCs.

OBJECTIVE: The burn victim's inherent state of hyperinflammation frequently camouflages septic events delaying the initiation of targeted intensive care therapy. Accurate biomarkers are urgently needed to support sepsis detection before patients' clinical deterioration. SUMMARY OF BACK-GROUND DATA: Evidence on the usefulness of pancreatic stone protein (PSP) as a powerful diagnostic and prognostic marker in critically ill patients has recently accumulated. METHODS: Analysis of biomarker kinetics (PSP, routine markers) was performed on 90 patients admitted to the Zurich Burn Center between May 2015 and October 2018 with burns 15% total body surface area with regard to infection and sepsis (Sepsis-3) over a 14-day time course. RESULTS: PSP differentiated between sepsis, infection and sterile inflammation from day 3 onward with an area under the curve of up to 0.89 (P < 0.001), therefore, competing with procalcitonin (area under the curve = 0.86, P < 0.001). Compared to routine inflammatory biomarkers, only PSP demonstrated a significant interaction between time and presence of sepsis -signifying a steeper increase in PSP levels in septic patients as opposed to those exhibiting a nonseptic course (interaction P < 0.001). Event-related analysis demonstrated tripled PSP serum levels within 72 hours and doubled levels within 48 hours before a clinically apparent sepsis. CON-CLUSION: PSP is able to differentiate between septic and nonseptic patients during acute burn care. Its steep rise up to 72 hours before clinically overt deterioration has the potential for physicians to timely initiate treatment with reduced mortality and costs.

Vascularized composite allotransplantation (VCA) has emerged as a useful reconstructive option for patients suffering from major tissue defects and functional deficits. While the technical feasibility has been optimized and more than 130 VCAs have been performed during the last two decades, hurdles such as acute and chronic allograft rejection, graft deterioration, and eventual functional impairment need to be addressed. Recently, chronic graft rejection and progressive failure have been linked to vascular alterations observed in the allografts. Graft vasculopathy (GV) may play a pivotal role in long-term graft deterioration. The understanding of the underlying pathophysiological processes and their initial triggers is of utmost importance in the prevention, attenuation, and therapy of GV. While there are reports on the etiology and development of GV in solid organ transplantation, there are limited data with respect to chronic rejection and GV in the realm of VCA. Nevertheless, recent reports from long-term VCA recipients suggest that GV could truly jeopardize allografts in the follow-up evaluation. Chronic rejection and GV include different entities and might have different pathways in distinct organs. Herein, we reviewed the current literature on vascular changes during both acute and chronic allograft rejection, with a focus on their clinical and translational significance for VCA.

Background: Mesenchymal stromal cell (MSC)-based cytotherapies fuel the hope for reduction of chronic systemic immunosuppression in allotransplantation, and our group has previously shown this capability for both swine and human cells. MSCs harvested from distinct anatomical locations may have different behavior and lead to different outcomes in both preclinical research and human trials. To provide an effective reference for cell therapy studies, we compared human and porcine MSCs from omental fat (O-ASC), subcutaneous fat (SC-ASC) and bone marrow (BM-MSC) under rapid culture expansion with endothelial growth medium (EGM). Methods: MSCs isolated from pigs and deceased human organ donors were compared for yield, viability, cell size, population doubling times (PDT), surface marker expression and differentiation potential after rapid expansion with EGM. Immunosuppressant toxicity on MSCs was investigated in vitro for four different standard immunosuppressive drugs. Immunomodulatory function was compared in mixed lymphocyte reaction assays (MLR) with/without immunosuppressive drug influence. Results: Human and porcine omental fat yielded significantly higher cell numbers than subcutaneous fat. Initial PDT was significantly shorter in ASCs than BM-MSCs and similar thereafter. Viability was reduced in BM-MSCs. Porcine MSCs were positive for CD29, CD44, CD90, while human MSCs expressed CD73, CD90 and CD105. All demonstrated confirmed adipogenic differentiation capacity. Cell sizes were comparable between groups and were slightly larger in human cells. Rapamycin revealed slight, mycophenolic acid strong and significant dose-dependent toxicity on viability/proliferation of almost all MSCs at therapeutic concentrations. No relevant toxicity was found for Tacrolimus and Cyclosporin A. Immunomodulatory function was dose-dependent and similar between groups. Immunosuppressants had no significant adverse effect on MSC immunomodulatory function. Schweizer et al. MSCs From Distinct Donor Locations Discussion: MSCs from different harvest locations and donor species differ in terms of isolation yields, viability, PDT, and size. We did not detect relevant differences in immunomodulatory function with or without the presence of immunosuppressants. Human and pig O-ASC, SC-ASC and BM-MSC share similar immunomodulatory function in vitro and warrant confirmation in large animal studies. These findings should be considered in preclinical and clinical MSC applications.