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Tobias Winkler - One of the best experts on this subject based on the ideXlab platform.

  • Unraveling local tissue changes within severely injured skeletal muscles in response to MSC-based intervention using MALDI Imaging mass spectrometry
    Scientific Reports, 2018
    Co-Authors: Oliver Klein, Tobias Winkler, Georg N. Duda, Kristin Strohschein, Grit Nebrich, Michael Fuchs, Herbert Thiele, Patrick Giavalisco, Jan Hendrik Kobarg, Dennis Trede
    Abstract:

    Pre-clinical and clinical studies are now beginning to demonstrate the high potential of cell therapies in enhancing muscle regeneration. We previously demonstrated functional benefit after the transplantation of autologous bone marrow mesenchymal stromal cells (MSC-TX) into a severe muscle Crush Trauma model. Despite our increasing understanding of the molecular and cellular mechanisms underlying MSC’s regenerative function, little is known about the local molecular alterations and their spatial distribution within the tissue after MSC-TX. Here, we used MALDI imaging mass spectrometry (MALDI-IMS) in combination with multivariate statistical strategies to uncover previously unknown peptide alterations within severely injured skeletal muscles. Our analysis revealed that very early molecular alterations in response to MSC-TX occur largely in the region adjacent to the Trauma and only to a small extent in the actual Trauma region. Using “bottom up” mass spectrometry, we subsequently identified the proteins corresponding to the differentially expressed peptide intensity distributions in the specific muscle regions and used immunohistochemistry to validate our results. These findings extend our current understanding about the early molecular processes of muscle healing and highlights the critical role of Trauma adjacent tissue during the early therapeutic response upon treatment with MSC.

  • Improvement of Contraction Force in Injured Skeletal Muscle after Autologous Mesenchymal Stroma Cell Transplantation Is Accompanied by Slow to Fast Fiber Type Shift
    Transfusion Medicine and Hemotherapy, 2013
    Co-Authors: Philipp Von Roth, Tobias Winkler, Carsten Perka, Piotr Radojewski, Kristina Rechenbach, Georg N. Duda
    Abstract:

    SummaryBackground: Skeletal muscle Trauma leads to severe functional deficits, which cannot be addressed by current treatment options. Previous investigation could show the efficacy of a local transplantation (TX) of mesenchymal stroma cells (MSCs) for the therapy of muscle injury. Underlying mechanisms remain to be elucidated. The aim of the present work was to characterize the fiber composition changes following MSC-TX after open Crush injury. Methods: 20 male SD rats received an open Crush Trauma of the left soleus muscle. 2.5 × 106 autologous MSCs were transplanted into the Crushed soleus muscle of 10 animals 7 days after Trauma (group 1, n = 10). Control animals received an injection of saline solution (group 2, n = 10). Histologic analysis of fibrosis, fiber type composition, and muscle force measurements were performed 28 days after Trauma. Results: MSC-TX improved muscle force significantly (fast-twitch, treated: 0.76 (0.51-1.15), untreated: 0.45 (0.32-0.73); p = 0.01). Tetanic stimulation resulted in a significant increase of force development (treated: 0.63 (0.4-1.21), untreated: 0.34 (0.16-0.48); p = 0.04). Histological analyses showed no differences in the amount of fibrotic tissue (treated vs. untreated, p = 0.42). A shift towards fastMHC-positive fibers was observed following MSC-TX (treated vs. untreated; p = 0.01 (mm2) or 0.007 (%)). Conclusion: This study demonstrated an effect of locally administered MSCs in the treatment of skeletal muscle injuries on a structural level. For the first time a fiber type shift towards fastMHC following MSC-TX after Crush injury could be demonstrated and related to MSC-TX. These results might open the discussion of an alternative mode of action of MSCs in tissue regeneration.

  • Intra-Arterial MSC Transplantation Restores Functional Capacity After Skeletal Muscle Trauma.
    The Open Orthopaedics Journal, 2012
    Co-Authors: Philipp Von Roth, Carsten Perka, Georg N. Duda, Kristin Strohschein, Piotr Radojewski, Bernd Preininger, Eric Röhner, Tobias Winkler
    Abstract:

    Introduction: Skeletal muscle Trauma leads to severe functional deficits, which cannot be addressed by current treatment options. Our group could show the efficacy of local transplantation of mesenchymal stroma cells (MSCs) for the treatment of injured muscles. While local application of MSCs has proven to be effective, we hypothesized that a selective intra-arterial transplantation would lead to a better distribution of the cells and so improved physiological recovery of muscle function. Materials and Methodology: 18 female Sprague Dawley rats received an open Crush Trauma of the left soleus muscle. Autologous MSC were transduced using dsCOP-GFP and 2.5 x 10 6 cells were transplanted into the femoral artery of 9 animals one week after Trauma. Control animals (n=9) received a saline injection. Cell tracking, analysis of tissue fibrosis and muscle force measurements were performed after 3 weeks. Results: Systemic MSC-therapy improved the muscle force significantly compared to control (fast twitch: 82.4%, tetany: 61.6%, p = 0.02). The histological analysis showed no differences in the quantity of fibrotic tissue. Histological examination revealed no cells in the Traumatized muscle tissue 21 days after transplantation. Conclusions: The present study demonstrated an effect of systemically administered MSCs in the treatment of skeletal muscle injuries. For possible future therapeutic approaches a systemic application of MSCs seems to present an alternative to a local administration. Such systemic treatment would be preferable since it allows functional improvement and possible cellular concentration at injury sites that are not easily accessible.

  • Immediate and delayed transplantation of mesenchymal stem cells improve muscle force after skeletal muscle injury in rats
    Journal of Tissue Engineering and Regenerative Medicine, 2012
    Co-Authors: Tobias Winkler, Philipp Von Roth, Georg N. Duda, Piotr Radojewski, Alexander Urbanski, Sebastian Hahn, Bernd Preininger, Carsten Perka
    Abstract:

    Mesenchymal stem cell (MSC) therapy is a promising approach for regaining muscle function after Trauma. Prior to clinical application, the ideal time of transplantation has to be determined. We investigated the effects of immediate and delayed transplantation. Sprague-Dawley rats received a Crush Trauma to the left soleus muscle. Treatment groups were transplanted locally with 2 × 10(6) autologous MSCs, either immediately or 7 days after Trauma. Saline was used as sham therapy. Contraction force tests and histological analyses were performed 4 weeks after injury. GFP-labelled MSCs were followed after transplantation. The Traumatized soleus muscles of the sham group displayed a reduction of twitch forces to 36 ± 17% and of tetanic forces to 29 ± 11% of the non-injured right control side, respectively. Delayed MSC transplantation resulted in a significant improvement of contraction maxima in both stimulation modes (twitch, p = 0.011; tetany, p = 0.014). Immediate transplantation showed a significant increase in twitch forces to 59 ± 17% (p = 0.043). There was no significant difference in contraction forces between muscles treated by immediate and delayed cell transplantation. We were able to identify MSCs in the interstitium of the injured muscles up to 4 weeks after transplantation. Despite the fundamental differences of the local environment, which MSCs encounter after transplantation, similar results could be obtained with respect to functional muscle regeneration. We believe that transplanted MSCs residing in the interstitial compartment evolve their regenerative capabilities through paracrine pathways. Our data suggest a large time window of the therapeutical measures.

  • Mesenchymal Stem Cell Therapy Following Muscle Trauma Leads to Improved Muscular Regeneration in Both Male and Female Rats
    Gender Medicine, 2012
    Co-Authors: Philipp Von Roth, Carsten Perka, Georg N. Duda, Piotr Radojewski, Bernd Preininger, Tobias Winkler
    Abstract:

    Abstract Background Mesenchymal stem cell (MSC) therapy has the potential to enhance muscular regeneration. In previous publications, our group was able to show a dose-response relationship in female animals between the amount of transplanted cells and muscle force. The impact of sex on the regeneration of musculoskeletal injuries following MSC transplantation remains unclear. Objective We investigated histologic and biomechanical regeneration parameters in rats after autologous transplantation of MSCs. Our hypothesis was that female rats have greater muscle regeneration potential than male rats after autologous MSC transplantation. Methods Thirty-six Sprague-Dawley rats received an open Crush Trauma of the left soleus muscle. One week after Trauma, 2.5 × 106 autologous MSCs, harvested from tibial biopsies, were transplanted locally (female, n = 9; male, n = 9). Control animals received saline solution (female, n = 9; male, n = 9). Histologic analysis and biomechanical evaluation by in vivo muscle force measurement were performed 3 weeks after transplantation. Results MSC therapy improved the force of the injured soleus in male rats significantly (twitch: treated, 0.76 [0.51–1.15]; twitch: untreated, 0.45 [0.32–0.73] [P = 0.01]; tetany: treated, 0.63 [0.4–1.21], tetany: untreated, 0.34 [0.16–0.48] [P = 0.04]). Force measurements in females also revealed significant improvements (twitch: treated, 0.71 [0.38–0.96]; twitch: untreated, 0.36 [0.18–0.63] [P = 0.005]; tetany: treated, 0.53 [0.21–0.68]; tetany: untreated, 0.27 [0.11–0.47] [P = 0.01]). The intersexual comparison of fast twitch and tetanic contraction forces revealed no significance (twitch, P = 0.55; tetany, P = 0.19). The histologic analysis showed no differences in the amount of fibrotic tissue (male, P = 0.9; female, P = 0.14) and the size of muscle area (male, P = 0.2; female, P = 0.56) following treatment. Male animals showed higher values for muscle area (P = 0.011) and less fibrosis (P = 0.028), independent of treatment. Conclusion The outcome of skeletal muscle regeneration after injury can be improved in animals of both sexes with MSC transplantation.

Georg N. Duda - One of the best experts on this subject based on the ideXlab platform.

  • Unraveling local tissue changes within severely injured skeletal muscles in response to MSC-based intervention using MALDI Imaging mass spectrometry
    Scientific Reports, 2018
    Co-Authors: Oliver Klein, Tobias Winkler, Georg N. Duda, Kristin Strohschein, Grit Nebrich, Michael Fuchs, Herbert Thiele, Patrick Giavalisco, Jan Hendrik Kobarg, Dennis Trede
    Abstract:

    Pre-clinical and clinical studies are now beginning to demonstrate the high potential of cell therapies in enhancing muscle regeneration. We previously demonstrated functional benefit after the transplantation of autologous bone marrow mesenchymal stromal cells (MSC-TX) into a severe muscle Crush Trauma model. Despite our increasing understanding of the molecular and cellular mechanisms underlying MSC’s regenerative function, little is known about the local molecular alterations and their spatial distribution within the tissue after MSC-TX. Here, we used MALDI imaging mass spectrometry (MALDI-IMS) in combination with multivariate statistical strategies to uncover previously unknown peptide alterations within severely injured skeletal muscles. Our analysis revealed that very early molecular alterations in response to MSC-TX occur largely in the region adjacent to the Trauma and only to a small extent in the actual Trauma region. Using “bottom up” mass spectrometry, we subsequently identified the proteins corresponding to the differentially expressed peptide intensity distributions in the specific muscle regions and used immunohistochemistry to validate our results. These findings extend our current understanding about the early molecular processes of muscle healing and highlights the critical role of Trauma adjacent tissue during the early therapeutic response upon treatment with MSC.

  • Improvement of Contraction Force in Injured Skeletal Muscle after Autologous Mesenchymal Stroma Cell Transplantation Is Accompanied by Slow to Fast Fiber Type Shift
    Transfusion Medicine and Hemotherapy, 2013
    Co-Authors: Philipp Von Roth, Tobias Winkler, Carsten Perka, Piotr Radojewski, Kristina Rechenbach, Georg N. Duda
    Abstract:

    SummaryBackground: Skeletal muscle Trauma leads to severe functional deficits, which cannot be addressed by current treatment options. Previous investigation could show the efficacy of a local transplantation (TX) of mesenchymal stroma cells (MSCs) for the therapy of muscle injury. Underlying mechanisms remain to be elucidated. The aim of the present work was to characterize the fiber composition changes following MSC-TX after open Crush injury. Methods: 20 male SD rats received an open Crush Trauma of the left soleus muscle. 2.5 × 106 autologous MSCs were transplanted into the Crushed soleus muscle of 10 animals 7 days after Trauma (group 1, n = 10). Control animals received an injection of saline solution (group 2, n = 10). Histologic analysis of fibrosis, fiber type composition, and muscle force measurements were performed 28 days after Trauma. Results: MSC-TX improved muscle force significantly (fast-twitch, treated: 0.76 (0.51-1.15), untreated: 0.45 (0.32-0.73); p = 0.01). Tetanic stimulation resulted in a significant increase of force development (treated: 0.63 (0.4-1.21), untreated: 0.34 (0.16-0.48); p = 0.04). Histological analyses showed no differences in the amount of fibrotic tissue (treated vs. untreated, p = 0.42). A shift towards fastMHC-positive fibers was observed following MSC-TX (treated vs. untreated; p = 0.01 (mm2) or 0.007 (%)). Conclusion: This study demonstrated an effect of locally administered MSCs in the treatment of skeletal muscle injuries on a structural level. For the first time a fiber type shift towards fastMHC following MSC-TX after Crush injury could be demonstrated and related to MSC-TX. These results might open the discussion of an alternative mode of action of MSCs in tissue regeneration.

  • Intra-Arterial MSC Transplantation Restores Functional Capacity After Skeletal Muscle Trauma.
    The Open Orthopaedics Journal, 2012
    Co-Authors: Philipp Von Roth, Carsten Perka, Georg N. Duda, Kristin Strohschein, Piotr Radojewski, Bernd Preininger, Eric Röhner, Tobias Winkler
    Abstract:

    Introduction: Skeletal muscle Trauma leads to severe functional deficits, which cannot be addressed by current treatment options. Our group could show the efficacy of local transplantation of mesenchymal stroma cells (MSCs) for the treatment of injured muscles. While local application of MSCs has proven to be effective, we hypothesized that a selective intra-arterial transplantation would lead to a better distribution of the cells and so improved physiological recovery of muscle function. Materials and Methodology: 18 female Sprague Dawley rats received an open Crush Trauma of the left soleus muscle. Autologous MSC were transduced using dsCOP-GFP and 2.5 x 10 6 cells were transplanted into the femoral artery of 9 animals one week after Trauma. Control animals (n=9) received a saline injection. Cell tracking, analysis of tissue fibrosis and muscle force measurements were performed after 3 weeks. Results: Systemic MSC-therapy improved the muscle force significantly compared to control (fast twitch: 82.4%, tetany: 61.6%, p = 0.02). The histological analysis showed no differences in the quantity of fibrotic tissue. Histological examination revealed no cells in the Traumatized muscle tissue 21 days after transplantation. Conclusions: The present study demonstrated an effect of systemically administered MSCs in the treatment of skeletal muscle injuries. For possible future therapeutic approaches a systemic application of MSCs seems to present an alternative to a local administration. Such systemic treatment would be preferable since it allows functional improvement and possible cellular concentration at injury sites that are not easily accessible.

  • Immediate and delayed transplantation of mesenchymal stem cells improve muscle force after skeletal muscle injury in rats
    Journal of Tissue Engineering and Regenerative Medicine, 2012
    Co-Authors: Tobias Winkler, Philipp Von Roth, Georg N. Duda, Piotr Radojewski, Alexander Urbanski, Sebastian Hahn, Bernd Preininger, Carsten Perka
    Abstract:

    Mesenchymal stem cell (MSC) therapy is a promising approach for regaining muscle function after Trauma. Prior to clinical application, the ideal time of transplantation has to be determined. We investigated the effects of immediate and delayed transplantation. Sprague-Dawley rats received a Crush Trauma to the left soleus muscle. Treatment groups were transplanted locally with 2 × 10(6) autologous MSCs, either immediately or 7 days after Trauma. Saline was used as sham therapy. Contraction force tests and histological analyses were performed 4 weeks after injury. GFP-labelled MSCs were followed after transplantation. The Traumatized soleus muscles of the sham group displayed a reduction of twitch forces to 36 ± 17% and of tetanic forces to 29 ± 11% of the non-injured right control side, respectively. Delayed MSC transplantation resulted in a significant improvement of contraction maxima in both stimulation modes (twitch, p = 0.011; tetany, p = 0.014). Immediate transplantation showed a significant increase in twitch forces to 59 ± 17% (p = 0.043). There was no significant difference in contraction forces between muscles treated by immediate and delayed cell transplantation. We were able to identify MSCs in the interstitium of the injured muscles up to 4 weeks after transplantation. Despite the fundamental differences of the local environment, which MSCs encounter after transplantation, similar results could be obtained with respect to functional muscle regeneration. We believe that transplanted MSCs residing in the interstitial compartment evolve their regenerative capabilities through paracrine pathways. Our data suggest a large time window of the therapeutical measures.

  • Mesenchymal Stem Cell Therapy Following Muscle Trauma Leads to Improved Muscular Regeneration in Both Male and Female Rats
    Gender Medicine, 2012
    Co-Authors: Philipp Von Roth, Carsten Perka, Georg N. Duda, Piotr Radojewski, Bernd Preininger, Tobias Winkler
    Abstract:

    Abstract Background Mesenchymal stem cell (MSC) therapy has the potential to enhance muscular regeneration. In previous publications, our group was able to show a dose-response relationship in female animals between the amount of transplanted cells and muscle force. The impact of sex on the regeneration of musculoskeletal injuries following MSC transplantation remains unclear. Objective We investigated histologic and biomechanical regeneration parameters in rats after autologous transplantation of MSCs. Our hypothesis was that female rats have greater muscle regeneration potential than male rats after autologous MSC transplantation. Methods Thirty-six Sprague-Dawley rats received an open Crush Trauma of the left soleus muscle. One week after Trauma, 2.5 × 106 autologous MSCs, harvested from tibial biopsies, were transplanted locally (female, n = 9; male, n = 9). Control animals received saline solution (female, n = 9; male, n = 9). Histologic analysis and biomechanical evaluation by in vivo muscle force measurement were performed 3 weeks after transplantation. Results MSC therapy improved the force of the injured soleus in male rats significantly (twitch: treated, 0.76 [0.51–1.15]; twitch: untreated, 0.45 [0.32–0.73] [P = 0.01]; tetany: treated, 0.63 [0.4–1.21], tetany: untreated, 0.34 [0.16–0.48] [P = 0.04]). Force measurements in females also revealed significant improvements (twitch: treated, 0.71 [0.38–0.96]; twitch: untreated, 0.36 [0.18–0.63] [P = 0.005]; tetany: treated, 0.53 [0.21–0.68]; tetany: untreated, 0.27 [0.11–0.47] [P = 0.01]). The intersexual comparison of fast twitch and tetanic contraction forces revealed no significance (twitch, P = 0.55; tetany, P = 0.19). The histologic analysis showed no differences in the amount of fibrotic tissue (male, P = 0.9; female, P = 0.14) and the size of muscle area (male, P = 0.2; female, P = 0.56) following treatment. Male animals showed higher values for muscle area (P = 0.011) and less fibrosis (P = 0.028), independent of treatment. Conclusion The outcome of skeletal muscle regeneration after injury can be improved in animals of both sexes with MSC transplantation.

Johannes Karl Maria Fakler - One of the best experts on this subject based on the ideXlab platform.

  • Technical limitations of REBOA in a patient with exsanguinating pelvic Crush Trauma: a case report
    Patient Safety in Surgery, 2019
    Co-Authors: Orkun Özkurtul, Holger Staab, Georg Osterhoff, Benjamin Ondruschka, Andreas Höch, Christoph Josten, Johannes Karl Maria Fakler
    Abstract:

    Background Resuscitative endovascular balloon occlusion of the aorta (REBOA) is an effective adjunct in hemodynamic unstable patients with uncontrolled and non-compressible torso hemorrhage promoting temporary stability during injury repair. The aim of our study was to analyze real life usability of REBOA based on a case report and to review the literature with respect to its possibilities and limitations. Case presentation We present the case of a 17-years old female patient who sustained a severe roll-over Trauma and pelvic Crush injury as a bicyclist by a truck. Upon arrival of the first responders, the patient was awake, alert, and following commands. Subsequent to lifting the truck, the patient became hypotensive and required cardiopulmonary resuscitation, application of a pelvic binder, and endotracheal intubation at the accident scene. She was then admitted by ambulance to our Trauma center under ongoing resuscitative measures. After primary survey, it was decided to perform a REBOA with surgical approach to the left femoral artery. Initial insertion of the catheter was successful but could not be advanced beyond the inguinal region. Hence, the patient was transferred to the operating room (OR) but died despite maximum therapy. In the OR and later autopsy, we found a long-distance ruptured and dehiscent external iliac artery with massive bleeding into the pelvis in the context of a bilateral vertical shear fractured pelvic bone. Conclusion REBOA can be a useful adjunct but there is a major limitation with potential vascular injury after pelvic Trauma. In these situations, cross-clamping the proximal aorta or pre-peritoneal pelvic packing as “traditional” approaches of hemorrhage control during resuscitation may be the most considerable methods for temporary stabilization in severely injured Trauma patients. More clinical and cadaveric studies are needed to further understand indications and limitations of REBOA after severe pelvic Trauma.

  • technical limitations of reboa in a patient with exsanguinating pelvic Crush Trauma a case report
    Patient Safety in Surgery, 2019
    Co-Authors: Orkun Özkurtul, Holger Staab, Georg Osterhoff, Benjamin Ondruschka, Andreas Höch, Christoph Josten, Johannes Karl Maria Fakler
    Abstract:

    Resuscitative endovascular balloon occlusion of the aorta (REBOA) is an effective adjunct in hemodynamic unstable patients with uncontrolled and non-compressible torso hemorrhage promoting temporary stability during injury repair. The aim of our study was to analyze real life usability of REBOA based on a case report and to review the literature with respect to its possibilities and limitations. We present the case of a 17-years old female patient who sustained a severe roll-over Trauma and pelvic Crush injury as a bicyclist by a truck. Upon arrival of the first responders, the patient was awake, alert, and following commands. Subsequent to lifting the truck, the patient became hypotensive and required cardiopulmonary resuscitation, application of a pelvic binder, and endotracheal intubation at the accident scene. She was then admitted by ambulance to our Trauma center under ongoing resuscitative measures. After primary survey, it was decided to perform a REBOA with surgical approach to the left femoral artery. Initial insertion of the catheter was successful but could not be advanced beyond the inguinal region. Hence, the patient was transferred to the operating room (OR) but died despite maximum therapy. In the OR and later autopsy, we found a long-distance ruptured and dehiscent external iliac artery with massive bleeding into the pelvis in the context of a bilateral vertical shear fractured pelvic bone. REBOA can be a useful adjunct but there is a major limitation with potential vascular injury after pelvic Trauma. In these situations, cross-clamping the proximal aorta or pre-peritoneal pelvic packing as “traditional” approaches of hemorrhage control during resuscitation may be the most considerable methods for temporary stabilization in severely injured Trauma patients. More clinical and cadaveric studies are needed to further understand indications and limitations of REBOA after severe pelvic Trauma.

Philipp Von Roth - One of the best experts on this subject based on the ideXlab platform.

  • Improvement of Contraction Force in Injured Skeletal Muscle after Autologous Mesenchymal Stroma Cell Transplantation Is Accompanied by Slow to Fast Fiber Type Shift
    Transfusion Medicine and Hemotherapy, 2013
    Co-Authors: Philipp Von Roth, Tobias Winkler, Carsten Perka, Piotr Radojewski, Kristina Rechenbach, Georg N. Duda
    Abstract:

    SummaryBackground: Skeletal muscle Trauma leads to severe functional deficits, which cannot be addressed by current treatment options. Previous investigation could show the efficacy of a local transplantation (TX) of mesenchymal stroma cells (MSCs) for the therapy of muscle injury. Underlying mechanisms remain to be elucidated. The aim of the present work was to characterize the fiber composition changes following MSC-TX after open Crush injury. Methods: 20 male SD rats received an open Crush Trauma of the left soleus muscle. 2.5 × 106 autologous MSCs were transplanted into the Crushed soleus muscle of 10 animals 7 days after Trauma (group 1, n = 10). Control animals received an injection of saline solution (group 2, n = 10). Histologic analysis of fibrosis, fiber type composition, and muscle force measurements were performed 28 days after Trauma. Results: MSC-TX improved muscle force significantly (fast-twitch, treated: 0.76 (0.51-1.15), untreated: 0.45 (0.32-0.73); p = 0.01). Tetanic stimulation resulted in a significant increase of force development (treated: 0.63 (0.4-1.21), untreated: 0.34 (0.16-0.48); p = 0.04). Histological analyses showed no differences in the amount of fibrotic tissue (treated vs. untreated, p = 0.42). A shift towards fastMHC-positive fibers was observed following MSC-TX (treated vs. untreated; p = 0.01 (mm2) or 0.007 (%)). Conclusion: This study demonstrated an effect of locally administered MSCs in the treatment of skeletal muscle injuries on a structural level. For the first time a fiber type shift towards fastMHC following MSC-TX after Crush injury could be demonstrated and related to MSC-TX. These results might open the discussion of an alternative mode of action of MSCs in tissue regeneration.

  • Intra-Arterial MSC Transplantation Restores Functional Capacity After Skeletal Muscle Trauma.
    The Open Orthopaedics Journal, 2012
    Co-Authors: Philipp Von Roth, Carsten Perka, Georg N. Duda, Kristin Strohschein, Piotr Radojewski, Bernd Preininger, Eric Röhner, Tobias Winkler
    Abstract:

    Introduction: Skeletal muscle Trauma leads to severe functional deficits, which cannot be addressed by current treatment options. Our group could show the efficacy of local transplantation of mesenchymal stroma cells (MSCs) for the treatment of injured muscles. While local application of MSCs has proven to be effective, we hypothesized that a selective intra-arterial transplantation would lead to a better distribution of the cells and so improved physiological recovery of muscle function. Materials and Methodology: 18 female Sprague Dawley rats received an open Crush Trauma of the left soleus muscle. Autologous MSC were transduced using dsCOP-GFP and 2.5 x 10 6 cells were transplanted into the femoral artery of 9 animals one week after Trauma. Control animals (n=9) received a saline injection. Cell tracking, analysis of tissue fibrosis and muscle force measurements were performed after 3 weeks. Results: Systemic MSC-therapy improved the muscle force significantly compared to control (fast twitch: 82.4%, tetany: 61.6%, p = 0.02). The histological analysis showed no differences in the quantity of fibrotic tissue. Histological examination revealed no cells in the Traumatized muscle tissue 21 days after transplantation. Conclusions: The present study demonstrated an effect of systemically administered MSCs in the treatment of skeletal muscle injuries. For possible future therapeutic approaches a systemic application of MSCs seems to present an alternative to a local administration. Such systemic treatment would be preferable since it allows functional improvement and possible cellular concentration at injury sites that are not easily accessible.

  • Immediate and delayed transplantation of mesenchymal stem cells improve muscle force after skeletal muscle injury in rats
    Journal of Tissue Engineering and Regenerative Medicine, 2012
    Co-Authors: Tobias Winkler, Philipp Von Roth, Georg N. Duda, Piotr Radojewski, Alexander Urbanski, Sebastian Hahn, Bernd Preininger, Carsten Perka
    Abstract:

    Mesenchymal stem cell (MSC) therapy is a promising approach for regaining muscle function after Trauma. Prior to clinical application, the ideal time of transplantation has to be determined. We investigated the effects of immediate and delayed transplantation. Sprague-Dawley rats received a Crush Trauma to the left soleus muscle. Treatment groups were transplanted locally with 2 × 10(6) autologous MSCs, either immediately or 7 days after Trauma. Saline was used as sham therapy. Contraction force tests and histological analyses were performed 4 weeks after injury. GFP-labelled MSCs were followed after transplantation. The Traumatized soleus muscles of the sham group displayed a reduction of twitch forces to 36 ± 17% and of tetanic forces to 29 ± 11% of the non-injured right control side, respectively. Delayed MSC transplantation resulted in a significant improvement of contraction maxima in both stimulation modes (twitch, p = 0.011; tetany, p = 0.014). Immediate transplantation showed a significant increase in twitch forces to 59 ± 17% (p = 0.043). There was no significant difference in contraction forces between muscles treated by immediate and delayed cell transplantation. We were able to identify MSCs in the interstitium of the injured muscles up to 4 weeks after transplantation. Despite the fundamental differences of the local environment, which MSCs encounter after transplantation, similar results could be obtained with respect to functional muscle regeneration. We believe that transplanted MSCs residing in the interstitial compartment evolve their regenerative capabilities through paracrine pathways. Our data suggest a large time window of the therapeutical measures.

  • Mesenchymal Stem Cell Therapy Following Muscle Trauma Leads to Improved Muscular Regeneration in Both Male and Female Rats
    Gender Medicine, 2012
    Co-Authors: Philipp Von Roth, Carsten Perka, Georg N. Duda, Piotr Radojewski, Bernd Preininger, Tobias Winkler
    Abstract:

    Abstract Background Mesenchymal stem cell (MSC) therapy has the potential to enhance muscular regeneration. In previous publications, our group was able to show a dose-response relationship in female animals between the amount of transplanted cells and muscle force. The impact of sex on the regeneration of musculoskeletal injuries following MSC transplantation remains unclear. Objective We investigated histologic and biomechanical regeneration parameters in rats after autologous transplantation of MSCs. Our hypothesis was that female rats have greater muscle regeneration potential than male rats after autologous MSC transplantation. Methods Thirty-six Sprague-Dawley rats received an open Crush Trauma of the left soleus muscle. One week after Trauma, 2.5 × 106 autologous MSCs, harvested from tibial biopsies, were transplanted locally (female, n = 9; male, n = 9). Control animals received saline solution (female, n = 9; male, n = 9). Histologic analysis and biomechanical evaluation by in vivo muscle force measurement were performed 3 weeks after transplantation. Results MSC therapy improved the force of the injured soleus in male rats significantly (twitch: treated, 0.76 [0.51–1.15]; twitch: untreated, 0.45 [0.32–0.73] [P = 0.01]; tetany: treated, 0.63 [0.4–1.21], tetany: untreated, 0.34 [0.16–0.48] [P = 0.04]). Force measurements in females also revealed significant improvements (twitch: treated, 0.71 [0.38–0.96]; twitch: untreated, 0.36 [0.18–0.63] [P = 0.005]; tetany: treated, 0.53 [0.21–0.68]; tetany: untreated, 0.27 [0.11–0.47] [P = 0.01]). The intersexual comparison of fast twitch and tetanic contraction forces revealed no significance (twitch, P = 0.55; tetany, P = 0.19). The histologic analysis showed no differences in the amount of fibrotic tissue (male, P = 0.9; female, P = 0.14) and the size of muscle area (male, P = 0.2; female, P = 0.56) following treatment. Male animals showed higher values for muscle area (P = 0.011) and less fibrosis (P = 0.028), independent of treatment. Conclusion The outcome of skeletal muscle regeneration after injury can be improved in animals of both sexes with MSC transplantation.

  • SYSTEMIC MESENCHYMAL STEM CELL TRANSPLANTATION FOR THE TREATMENT OF SKELETAL MUSCLE Trauma
    2011
    Co-Authors: Philipp Von Roth, Georg Matziolis, Carsten Perka, Georg N. Duda, Piotr Radojewski, Tobias Winkler
    Abstract:

    Objectives: Skeletal muscle Trauma leads to severe functional deficits. Present therapeutic treatments are unsatisfying and insufficient postTraumatic regeneration is a problem in Trauma and orthopaedic surgery. Mesenchymal stem cell (MSC) therapy is a promising tool in the regeneration of muscle function after severe Trauma. Our group showed increased contraction forces compared to a non-treated control group 3 weeks after MSC transplantation (TX) into a skeletal muscle Trauma. In addition we demonstrated a dose-response relationship of the amount of MSC and force enhancement. We furthermore investigated the fate of the transplanted MSC labelled with very small iron oxide particles using 7 Tesla-MRI. Histological analysis revealed fusion events between existing myofibers but only to a low amount. The increase of muscle force can not be explained by these events only. Before further steps are taken the impact of paracrine effects and the homing to the site of Trauma of the MSC has to be evaluated. Experimental studies about the functional regeneration of Traumatized skeletal muscule after systemic MSC-TX do not exist. Methods: 36 female SD-rats received open Crush Trauma of the left soleus muscle. One week after Trauma 2.5 x 106 autologous MSC, harvested from tibial biopsies, were transplanted intraarterially (i.a., femoral arte-ria, group 1) or intravenously (i.v., tail vein, group 2) (n=18). Control animals received saline (i.a.: group 3; i.v.: group 4) (n=18). Histological analysis and biomechanical evaluation by in vivo muscle force measurement was performed 3 weeks after TX. Results: Twitch stimulation of the healthy right soleus muscles resulted in a contraction force of 0.52±0.14 N. Forces of tetanic contraction in the uninjured muscles reached 0.98±0.27 N. The i.a. MSC-TX improved the muscle force of the injured soleus significantly compared to control (twitch: 82,4%, p=0.02, tetany: 61.6%, p=0.02). Contraction forces of muscles treated i.v. (MSC vs. saline) showed no significant difference. The histological analysis showed no differences in the amount of fibrotic tissue. Conclusions: The presented study demonstrates the effect of systemic MSC-TX in the treatment of severe skeletal muscle injuries. Interestingly, the functional regeneration could only be increased by i.a. application. The entrapment of MSC in the lungs and the dilution effect in the circulation, when injecting the MSC i.v. could be the reason. For possible future therapeutic approaches a systemic application is considered to be favourable compared to local injections due to the better distribution of the cells in the target muscle.

Carsten Perka - One of the best experts on this subject based on the ideXlab platform.

  • Improvement of Contraction Force in Injured Skeletal Muscle after Autologous Mesenchymal Stroma Cell Transplantation Is Accompanied by Slow to Fast Fiber Type Shift
    Transfusion Medicine and Hemotherapy, 2013
    Co-Authors: Philipp Von Roth, Tobias Winkler, Carsten Perka, Piotr Radojewski, Kristina Rechenbach, Georg N. Duda
    Abstract:

    SummaryBackground: Skeletal muscle Trauma leads to severe functional deficits, which cannot be addressed by current treatment options. Previous investigation could show the efficacy of a local transplantation (TX) of mesenchymal stroma cells (MSCs) for the therapy of muscle injury. Underlying mechanisms remain to be elucidated. The aim of the present work was to characterize the fiber composition changes following MSC-TX after open Crush injury. Methods: 20 male SD rats received an open Crush Trauma of the left soleus muscle. 2.5 × 106 autologous MSCs were transplanted into the Crushed soleus muscle of 10 animals 7 days after Trauma (group 1, n = 10). Control animals received an injection of saline solution (group 2, n = 10). Histologic analysis of fibrosis, fiber type composition, and muscle force measurements were performed 28 days after Trauma. Results: MSC-TX improved muscle force significantly (fast-twitch, treated: 0.76 (0.51-1.15), untreated: 0.45 (0.32-0.73); p = 0.01). Tetanic stimulation resulted in a significant increase of force development (treated: 0.63 (0.4-1.21), untreated: 0.34 (0.16-0.48); p = 0.04). Histological analyses showed no differences in the amount of fibrotic tissue (treated vs. untreated, p = 0.42). A shift towards fastMHC-positive fibers was observed following MSC-TX (treated vs. untreated; p = 0.01 (mm2) or 0.007 (%)). Conclusion: This study demonstrated an effect of locally administered MSCs in the treatment of skeletal muscle injuries on a structural level. For the first time a fiber type shift towards fastMHC following MSC-TX after Crush injury could be demonstrated and related to MSC-TX. These results might open the discussion of an alternative mode of action of MSCs in tissue regeneration.

  • Intra-Arterial MSC Transplantation Restores Functional Capacity After Skeletal Muscle Trauma.
    The Open Orthopaedics Journal, 2012
    Co-Authors: Philipp Von Roth, Carsten Perka, Georg N. Duda, Kristin Strohschein, Piotr Radojewski, Bernd Preininger, Eric Röhner, Tobias Winkler
    Abstract:

    Introduction: Skeletal muscle Trauma leads to severe functional deficits, which cannot be addressed by current treatment options. Our group could show the efficacy of local transplantation of mesenchymal stroma cells (MSCs) for the treatment of injured muscles. While local application of MSCs has proven to be effective, we hypothesized that a selective intra-arterial transplantation would lead to a better distribution of the cells and so improved physiological recovery of muscle function. Materials and Methodology: 18 female Sprague Dawley rats received an open Crush Trauma of the left soleus muscle. Autologous MSC were transduced using dsCOP-GFP and 2.5 x 10 6 cells were transplanted into the femoral artery of 9 animals one week after Trauma. Control animals (n=9) received a saline injection. Cell tracking, analysis of tissue fibrosis and muscle force measurements were performed after 3 weeks. Results: Systemic MSC-therapy improved the muscle force significantly compared to control (fast twitch: 82.4%, tetany: 61.6%, p = 0.02). The histological analysis showed no differences in the quantity of fibrotic tissue. Histological examination revealed no cells in the Traumatized muscle tissue 21 days after transplantation. Conclusions: The present study demonstrated an effect of systemically administered MSCs in the treatment of skeletal muscle injuries. For possible future therapeutic approaches a systemic application of MSCs seems to present an alternative to a local administration. Such systemic treatment would be preferable since it allows functional improvement and possible cellular concentration at injury sites that are not easily accessible.

  • Immediate and delayed transplantation of mesenchymal stem cells improve muscle force after skeletal muscle injury in rats
    Journal of Tissue Engineering and Regenerative Medicine, 2012
    Co-Authors: Tobias Winkler, Philipp Von Roth, Georg N. Duda, Piotr Radojewski, Alexander Urbanski, Sebastian Hahn, Bernd Preininger, Carsten Perka
    Abstract:

    Mesenchymal stem cell (MSC) therapy is a promising approach for regaining muscle function after Trauma. Prior to clinical application, the ideal time of transplantation has to be determined. We investigated the effects of immediate and delayed transplantation. Sprague-Dawley rats received a Crush Trauma to the left soleus muscle. Treatment groups were transplanted locally with 2 × 10(6) autologous MSCs, either immediately or 7 days after Trauma. Saline was used as sham therapy. Contraction force tests and histological analyses were performed 4 weeks after injury. GFP-labelled MSCs were followed after transplantation. The Traumatized soleus muscles of the sham group displayed a reduction of twitch forces to 36 ± 17% and of tetanic forces to 29 ± 11% of the non-injured right control side, respectively. Delayed MSC transplantation resulted in a significant improvement of contraction maxima in both stimulation modes (twitch, p = 0.011; tetany, p = 0.014). Immediate transplantation showed a significant increase in twitch forces to 59 ± 17% (p = 0.043). There was no significant difference in contraction forces between muscles treated by immediate and delayed cell transplantation. We were able to identify MSCs in the interstitium of the injured muscles up to 4 weeks after transplantation. Despite the fundamental differences of the local environment, which MSCs encounter after transplantation, similar results could be obtained with respect to functional muscle regeneration. We believe that transplanted MSCs residing in the interstitial compartment evolve their regenerative capabilities through paracrine pathways. Our data suggest a large time window of the therapeutical measures.

  • Mesenchymal Stem Cell Therapy Following Muscle Trauma Leads to Improved Muscular Regeneration in Both Male and Female Rats
    Gender Medicine, 2012
    Co-Authors: Philipp Von Roth, Carsten Perka, Georg N. Duda, Piotr Radojewski, Bernd Preininger, Tobias Winkler
    Abstract:

    Abstract Background Mesenchymal stem cell (MSC) therapy has the potential to enhance muscular regeneration. In previous publications, our group was able to show a dose-response relationship in female animals between the amount of transplanted cells and muscle force. The impact of sex on the regeneration of musculoskeletal injuries following MSC transplantation remains unclear. Objective We investigated histologic and biomechanical regeneration parameters in rats after autologous transplantation of MSCs. Our hypothesis was that female rats have greater muscle regeneration potential than male rats after autologous MSC transplantation. Methods Thirty-six Sprague-Dawley rats received an open Crush Trauma of the left soleus muscle. One week after Trauma, 2.5 × 106 autologous MSCs, harvested from tibial biopsies, were transplanted locally (female, n = 9; male, n = 9). Control animals received saline solution (female, n = 9; male, n = 9). Histologic analysis and biomechanical evaluation by in vivo muscle force measurement were performed 3 weeks after transplantation. Results MSC therapy improved the force of the injured soleus in male rats significantly (twitch: treated, 0.76 [0.51–1.15]; twitch: untreated, 0.45 [0.32–0.73] [P = 0.01]; tetany: treated, 0.63 [0.4–1.21], tetany: untreated, 0.34 [0.16–0.48] [P = 0.04]). Force measurements in females also revealed significant improvements (twitch: treated, 0.71 [0.38–0.96]; twitch: untreated, 0.36 [0.18–0.63] [P = 0.005]; tetany: treated, 0.53 [0.21–0.68]; tetany: untreated, 0.27 [0.11–0.47] [P = 0.01]). The intersexual comparison of fast twitch and tetanic contraction forces revealed no significance (twitch, P = 0.55; tetany, P = 0.19). The histologic analysis showed no differences in the amount of fibrotic tissue (male, P = 0.9; female, P = 0.14) and the size of muscle area (male, P = 0.2; female, P = 0.56) following treatment. Male animals showed higher values for muscle area (P = 0.011) and less fibrosis (P = 0.028), independent of treatment. Conclusion The outcome of skeletal muscle regeneration after injury can be improved in animals of both sexes with MSC transplantation.

  • SYSTEMIC MESENCHYMAL STEM CELL TRANSPLANTATION FOR THE TREATMENT OF SKELETAL MUSCLE Trauma
    2011
    Co-Authors: Philipp Von Roth, Georg Matziolis, Carsten Perka, Georg N. Duda, Piotr Radojewski, Tobias Winkler
    Abstract:

    Objectives: Skeletal muscle Trauma leads to severe functional deficits. Present therapeutic treatments are unsatisfying and insufficient postTraumatic regeneration is a problem in Trauma and orthopaedic surgery. Mesenchymal stem cell (MSC) therapy is a promising tool in the regeneration of muscle function after severe Trauma. Our group showed increased contraction forces compared to a non-treated control group 3 weeks after MSC transplantation (TX) into a skeletal muscle Trauma. In addition we demonstrated a dose-response relationship of the amount of MSC and force enhancement. We furthermore investigated the fate of the transplanted MSC labelled with very small iron oxide particles using 7 Tesla-MRI. Histological analysis revealed fusion events between existing myofibers but only to a low amount. The increase of muscle force can not be explained by these events only. Before further steps are taken the impact of paracrine effects and the homing to the site of Trauma of the MSC has to be evaluated. Experimental studies about the functional regeneration of Traumatized skeletal muscule after systemic MSC-TX do not exist. Methods: 36 female SD-rats received open Crush Trauma of the left soleus muscle. One week after Trauma 2.5 x 106 autologous MSC, harvested from tibial biopsies, were transplanted intraarterially (i.a., femoral arte-ria, group 1) or intravenously (i.v., tail vein, group 2) (n=18). Control animals received saline (i.a.: group 3; i.v.: group 4) (n=18). Histological analysis and biomechanical evaluation by in vivo muscle force measurement was performed 3 weeks after TX. Results: Twitch stimulation of the healthy right soleus muscles resulted in a contraction force of 0.52±0.14 N. Forces of tetanic contraction in the uninjured muscles reached 0.98±0.27 N. The i.a. MSC-TX improved the muscle force of the injured soleus significantly compared to control (twitch: 82,4%, p=0.02, tetany: 61.6%, p=0.02). Contraction forces of muscles treated i.v. (MSC vs. saline) showed no significant difference. The histological analysis showed no differences in the amount of fibrotic tissue. Conclusions: The presented study demonstrates the effect of systemic MSC-TX in the treatment of severe skeletal muscle injuries. Interestingly, the functional regeneration could only be increased by i.a. application. The entrapment of MSC in the lungs and the dilution effect in the circulation, when injecting the MSC i.v. could be the reason. For possible future therapeutic approaches a systemic application is considered to be favourable compared to local injections due to the better distribution of the cells in the target muscle.