A novel self-gripping long-term resorbable mesh providing temporary support for open primary ventral and incisional hernia.

A novel synthetic fully long-term resorbable self-gripping mesh has been recently developed to reinforce soft tissue where weakness exists during ventral hernia repair open procedures. This resorbable mesh is a macroporous, knitted, poly-L-lactide, poly-trimethylene carbonate copolymer monofilament mesh with the ProGrip™ technology, providing grips on one side of the mesh. A new poly-L-lactide, poly-trimethylene copolymer was developed to provide the required features for mechanical support during at least 20 weeks covering the critical healing period, including resistance to fatigue under cyclic loading conditions, as it occurs in patients. The yarns and mesh initial physical and biomechanical properties were characterized. Then, the mesh mechanical strength was evaluated over time. The mechanical properties of the proposed mesh were found to be above the generally recognized threshold value to mechanically support the repair site of a hernia over a 20-week period during in-vitro cyclic loading test. The mesh performance was evaluated in vivo using a published preclinical porcine model of hernia repair at 4-, 12- and 20-weeks post implantation. The burst strength of the hernia repair sites reinforced with the new mesh were higher at 4 & 12 weeks and comparable at 20 weeks to the one of the native abdominal walls. At all time points, the mesh was well tolerated with moderate inflammation and was fast integrated in the abdominal wall at 4 weeks. Particularly, the grips were nicely engulfed in the newly formed connective tissue. They must facilitate the anchoring of the mesh by their extension from the mesh and their mushroom shape. The preclinical data of the self-gripping resorbable mesh suggests that it has all the favorable characteristics for future clinical use during ventral hernia repair open procedures.

Can magnetisation transfer magnetic resonance imaging help for the follow-up of synthetic hernia composite meshes fate? A pilot study.

PURPOSE: This study aims at evaluating the non-invasive Magnetic Resonance Imaging (MRI) technic to visualize a synthetic composite hernia mesh using a rodent model and to document the integration of this device over 4 months. METHODS: Uncoated polyethylene terephthalate mesh and synthetic composite mesh-faced on the visceral side with a chemically engineered layer of copolymer of glycolide, caprolactone, trimethylene carbonate, and lactide to minimize tissue attachment-were placed intraperitoneally in rats, facing the caecum previously scraped to promote petechial bleeding and subsequent adhesions. Meshes fate follow-up was performed 4, 10, and 16-weeks post-implantation using a rodent dedicated high field MRI. Magnetization transfer (MT) images were acquired, associated with pneumoperitonealMRI performed after intraperitoneal injection of 8 mL gas to induce mechanical stress on the abdominal wall. RESULTS: Uncoated meshes were clearly visible using both T2-weighted and MT imaging during the whole study while composite meshes conspicuity was not so evident on T2-weighted MRI and could be improved using MT imaging. Adhesions and collagen infiltration were massive for the uncoated meshes as expected. On the contrary, composite meshes showed very limited adhesion, and, if any, occurring at the edge of the mesh, starting at the fixation points. CONCLUSIONS: Magnetization transfer imaging allows to detect mesh integration and, associated with pneumoperitoneum, was able to probe the effective minimizing effect of the synthetic polymeric barrier on visceral attachments. However, magnetization transfer imaging could not unambiguously allow the visualization of the mesh through the polymeric barrier.

Natural killer cells prevent CD28-mediated Foxp3 transcription in CD4+CD25- T lymphocytes.

OBJECTIVE: CD4(+)CD25(+) regulatory T lymphocytes (Treg) have been initially shown to prevent organ-specific autoimmunity. It is now accepted that Treg homeostasis depends in part on the peripheral conversion of naïve CD4(+)CD25(-) T cells. This conversion implicates acquisition of the Treg-specific markers, forkhead winged helix protein 3 (Foxp3), after CD28 costimulation. Because natural killer cells (NK) are critical for efficient cytotoxic T-cell priming and TH1 polarization, we investigated their role in Foxp3 induction in CD4(+) T lymphocytes. MATERIALS AND METHODS: Human CD4(+)CD25(-) T lymphocytes were activated in vitro by CD28 costimulation in the presence of interleukin-2-activated NK. Three days after initial activation, Foxp3 protein and RNA expression were determined by flow cytometry and reverse transcription polymerase chain reaction. In vivo influence of activated NK on Foxp3 expression was studied in an adoptive transfer model of CD45.2(+) CD4(+)CD25(-) lymphocytes into CD45.1(+) mice. RESULTS: Interleukin-2-activated NK decreased Treg conversion of adoptively transferred murine CD4(+)CD25(-) T cells in vivo. Likewise, human-activated NK, but not resting NK, decreased CD28-driven Foxp3 expression in CD4(+)CD25(-) T lymphocytes, while at the same time increasing proliferation and interferon-gamma (IFN-gamma) production. Neutralization of IFN-gamma partially restored Treg conversion and prevented TH1 polarization after CD28 costimulation. CONCLUSION: The current study suggests that activated NK interfere with CD28-mediated Foxp3 expression in CD4(+)CD25(-) T lymphocytes. Our experiments further underline a molecular interaction between IFN-gamma and Foxp3 downstream of CD28 signaling. Together, these results demonstrate that activated NK play a critical role at the initiation step of immune responses by modulating peripheral Treg differentiation.

Role of STAT3 in CD4+CD25+FOXP3+ regulatory lymphocyte generation: implications in graft-versus-host disease and antitumor immunity.

Immunological tolerance is maintained by specialized subsets of T cells including CD4(+)CD25(+)FOXP3(+) regulatory cells (Treg). Previous studies established that Treg thymic differentiation or peripheral conversion depend on CD28 and Lck signaling. Moreover, foxp3 gene transfer in murine CD4(+)CD25(-) T lymphocytes results in the acquisition of suppressive functions. However, molecular pathways leading to FOXP3 expression remain to be described. In this study, we investigated the molecular events driving FOXP3 expression. We demonstrated that CD28 activation in CD4(+)CD25(-) T lymphocytes leads to STAT3 Tyr(705) phosphorylation in an Lck-dependent manner. STAT3 neutralization during naive peripheral CD4(+)CD25(-) T cell conversion into Treg through costimulation with TCR/CD28 and TGF-beta1, decreased FOXP3 expression, prevented the acquisition of suppressive functions and restored the ability of the converted lymphocytes to produce IL-2 and IFN-gamma. Furthermore, we observed that STAT3 ablation using small interfering RNA strategies inhibited FOXP3 expression and suppressive functions among naturally differentiated CD4(+)CD25(+) T lymphocytes, suggesting a direct role of STAT3 in Treg phenotype and function maintenance. CD4(+)CD25(+) T lymphocytes transduced with specific STAT3 small interfering RNA were devoid of suppressive functions and failed to control the occurrence of acute graft-vs-host disease. Finally, STAT3 inhibition in CD4(+) lymphocytes enhanced the anti-tumor immunity conferred by a lymphocyte adoptive transfer. In summary, our findings determine that STAT3 is critical in the molecular pathway required for FOXP3 expression. STAT3 modulation should be taken into account when assessing how regulatory T cells contribute to inflammatory diseases and tumor immunosurveillance.