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Christopher K. Breuer - One of the best experts on this subject based on the ideXlab platform.

  • the evaluation of a tissue engineered cardiac patch seeded with hips derived cardiac progenitor cells in a rat left ventricular model
    PLOS ONE, 2020
    Co-Authors: Yuichi Matsuzaki, Christopher K. Breuer, James W Reinhardt, Shinka Miyamoto, Jacob C Zbinden, Tadahisa Sugiura, Hideki Miyachi, Chang Yuchun, Toshiharu Shinoka
    Abstract:

    Background Ventricular septal perforation and left ventricular aneurysm are examples of potentially fatal complications of myocardial infarction. While various artificial materials are used in the repair of these issues, the possibility of associated infection and calcification is non-negligible. Cell-seeded biodegradable tissue-engineered patches may be a potential solution. This study evaluated the feasibility of a new left ventricular patch rat model to study Neotissue Formation in biodegradable cardiac patches. Methods Human induced pluripotent stem cell-derived cardiac progenitor cells (hiPS-CPCs) were cultured onto biodegradable patches composed of polyglycolic acid and a 50:50 poly (l-lactide-co-e-caprolactone) copolymer for one week. After culturing, patches were implanted into left ventricular walls of male athymic rats. Unseeded controls were also used (n = 10/group). Heart conditions were followed by echocardiography and patches were subsequently explanted at 1, 2, 6, and 9 months post-implantation for histological evaluation. Result Throughout the study, no patches ruptured demonstrating the ability to withstand the high pressure left ventricular system. One month after transplantation, the seeded patch did not stain positive for human nuclei. However, many new blood vessels formed within patches with significantly greater vessels in the seeded group at the 6 month time point. Echocardiography showed no significant difference in left ventricular contraction rate between the two groups. Calcification was found inside patches after 6 months, but there was no significant difference between groups. Conclusion We have developed a surgical method to implant a bioabsorbable scaffold into the left ventricular environment of rats with a high survival rate. Seeded hiPS-CPCs did not differentiate into cardiomyocytes, but the greater number of new blood vessels in seeded patches suggests the presence of cell seeding early in the remodeling process might provide a prolonged effect on Neotissue Formation. This experiment will contribute to the development of a treatment model for left ventricular failure using iPS cells in the future.

  • deconstructing tissue engineered trachea assessing the role of synthetic scaffolds segmental replacement and cell seeding on graft performance
    Acta Biomaterialia, 2020
    Co-Authors: Sayali Dharmadhikari, Jed Johnson, Matthew Wiet, Lumei Liu, Kimberly M Shontz, Audrey White, Andrew Goins, Himani Akula, Susan D Reynolds, Christopher K. Breuer
    Abstract:

    The ideal construct for tracheal replacement remains elusive in the management of long segment airway defects. Tissue engineered tracheal grafts (TETG) have been limited by the development of graft stenosis or collapse, infection, or lack of an epithelial lining. We applied a mouse model of orthotopic airway surgery to assess the impact of three critical barriers encountered in clinical applications: the scaffold, the extent of intervention, and the impact of cell seeding and characterized their impact on graft performance. First, synthetic tracheal scaffolds electrospun from polyethylene terephthalate / polyurethane (PET/PU) were orthotopically implanted in anterior tracheal defects of C57BL/6 mice. Scaffolds demonstrated complete coverage with ciliated respiratory epithelium by 2 weeks. Epithelial migration was accompanied by macrophage infiltration which persisted at long term (>6 weeks) time points. We then assessed the impact of segmental tracheal implantation using syngeneic trachea as a surrogate for the ideal tracheal replacement. Graft recovery involved local upregulation of epithelial progenitor populations and there was no evidence of graft stenosis or necrosis. Implantation of electrospun synthetic tracheal scaffold for segmental replacement resulted in respiratory distress and required euthanasia at an early time point. There was limited epithelial coverage of the scaffold with and without seeded bone marrow-derived mononuclear cells (BM-MNCs). We conclude that synthetic scaffolds support re-epithelialization in orthotopic patch implantation, syngeneic graft integration occurs with focal repair mechanisms, however epithelialization in segmental synthetic scaffolds is limited and is not influenced by cell seeding. STATEMENT OF SIGNIFICANCE: The life-threatening nature of long-segment tracheal defects has led to clinical use of tissue engineered tracheal grafts in the last decade for cases of compassionate use. However, the ideal tracheal reconstruction using tissue-engineered tracheal grafts (TETG) has not been clarified. We addressed the core challenges in tissue engineered tracheal replacement (re-epithelialization and graft patency) by defining the role of cell seeding with autologous bone marrow-derived mononuclear cells, the mechanism of respiratory epithelialization and proliferation, and the role of the inflammatory immune response in regeneration. This research will facilitate comprehensive understanding of cellular regeneration and Neotissue Formation on TETG, which will permit targeted therapies for accelerating re-epithelialization and attenuating stenosis in tissue engineered airway replacement.

  • the role of myeloid cell derived pdgf b in Neotissue Formation in a tissue engineered vascular graft
    Regenerative Medicine, 2017
    Co-Authors: Ekene Onwuka, Christopher K. Breuer, Cameron A Best, Andrew J Sawyer, Eric Heuer, Malik Sams, Matthew Wiet, Hong Zheng, Themis R Kyriakides
    Abstract:

    Aim: Inflammatory myeloid lineage cells mediate Neotissue Formation in tissue-engineered vascular grafts, but the molecular mechanism is not completely understood. We examined the role of vasculogenic PDGF-B in tissue-engineered vascular graft Neotissue development. Materials & methods: Myeloid cell-specific PDGF-B knockout mice (PDGF-KO) were generated using bone marrow transplantation, and scaffolds were implanted as inferior vena cava interposition grafts in either PDGF-KO or wild-type mice. Results: After 2 weeks, grafts from PDGF-KO mice had more remaining scaffold polymer and less intimal Neotissue development. Increased macrophage apoptosis, decreased smooth muscle cell proliferation and decreased collagen content was also observed. Conclusion: Myeloid cell-derived PDGF contributes to vascular Neotissue Formation by regulating macrophage apoptosis, smooth muscle cell proliferation and extracellular matrix deposition.

  • novel bioresorbable vascular graft with sponge type scaffold as a small diameter arterial graft
    The Annals of Thoracic Surgery, 2016
    Co-Authors: Tadahisa Sugiura, Christopher K. Breuer, Tai Yi, Shuhei Tara, Hidetaka Nakayama, Hirotsugu Kurobe, Toshiharu Shinoka
    Abstract:

    Background Current commercialized small-diameter arterial grafts have not shown clinical effectiveness due to their poor patency rates. The present study evaluated the feasibility of an arterial bioresorbable vascular graft, which has a porous sponge-type scaffold, as a small-diameter arterial conduit. Methods The grafts were constructed by a 50:50 poly (1-lactic-co-e-caprolactone) copolymer (PLCL) scaffold reinforced by a poly (1-lactic acid) (PLA) nanofiber. The pore size of the PLCL scaffold was adjusted to a small size (12.8 ± 1.85 μm) or a large size (28.5 ± 5.25 μm). We compared the difference in cellular infiltration, followed by tissue remodeling, between the groups. The grafts were implanted in 8- to 10-week-old female mice (n = 15 in each group) as infrarenal aortic interposition conduits. Animals were monitored for 8 weeks and euthanized to evaluate Neotissue Formation. Results No aneurysmal change or graft rupture was observed in either group. Histologic assessment demonstrated favorable cell infiltration into scaffolds, neointimal Formation with endothelialization, smooth muscle cell proliferation, and elastin deposition in both groups. No significant difference was observed between the groups. Immunohistochemical characterization with anti-F4/80 antibody demonstrated that macrophage infiltration into the grafts occurred in both groups. Staining for M1 and M2, which are the two major macrophage phenotypes, showed no significant difference between groups. Conclusions Our novel bioresorbable vascular grafts showed well-organized neointimal Formation in the high-pressure arterial circulation environment. The large-pore scaffold did not improve cellular infiltration and Neotissue Formation compared with the small-pore scaffold.

  • tissue engineered small diameter arterial vascular grafts from cell free nanofiber pcl chitosan scaffolds in a sheep model
    PLOS ONE, 2016
    Co-Authors: Takuma Fukunishi, Toshiharu Shinoka, Tai Yi, Cameron A Best, Toshihiro Shoji, Tadahisa Sugiura, Brooks V Udelsman, Devan Ohst, Huaitao Zhang, Christopher K. Breuer
    Abstract:

    Tissue engineered vascular grafts (TEVGs) have the potential to overcome the issues faced by existing small diameter prosthetic grafts by providing a biodegradable scaffold where the patient’s own cells can engraft and form functional Neotissue. However, applying classical approaches to create arterial TEVGs using slow degrading materials with supraphysiological mechanical properties, typically results in limited host cell infiltration, poor remodeling, stenosis, and calcification. The purpose of this study is to evaluate the feasibility of novel small diameter arterial TEVGs created using fast degrading material. A 1.0mm and 5.0mm diameter TEVGs were fabricated with electrospun polycaprolactone (PCL) and chitosan (CS) blend nanofibers. The 1.0mm TEVGs were implanted in mice (n = 3) as an unseeded infrarenal abdominal aorta interposition conduit., The 5.0mm TEVGs were implanted in sheep (n = 6) as an unseeded carotid artery (CA) interposition conduit. Mice were followed with ultrasound and sacrificed at 6 months. All 1.0mm TEVGs remained patent without evidence of thrombosis or aneurysm Formation. Based on small animal outcomes, sheep were followed with ultrasound and sacrificed at 6 months for histological and mechanical analysis. There was no aneurysm Formation or calcification in the TEVGs. 4 out of 6 grafts (67%) were patent. After 6 months in vivo, 9.1 ± 5.4% remained of the original scaffold. Histological analysis of patent grafts demonstrated deposition of extracellular matrix constituents including elastin and collagen production, as well as endothelialization and organized contractile smooth muscle cells, similar to that of native CA. The mechanical properties of TEVGs were comparable to native CA. There was a significant positive correlation between TEVG wall thickness and CD68+ macrophage infiltration into the scaffold (R2 = 0.95, p = 0.001). The fast degradation of CS in our novel TEVG promoted excellent cellular infiltration and Neotissue Formation without calcification or aneurysm. Modulating host macrophage infiltration into the scaffold is a key to reducing excessive Neotissue Formation and stenosis.

Toshiharu Shinoka - One of the best experts on this subject based on the ideXlab platform.

  • the evaluation of a tissue engineered cardiac patch seeded with hips derived cardiac progenitor cells in a rat left ventricular model
    PLOS ONE, 2020
    Co-Authors: Yuichi Matsuzaki, Christopher K. Breuer, James W Reinhardt, Shinka Miyamoto, Jacob C Zbinden, Tadahisa Sugiura, Hideki Miyachi, Chang Yuchun, Toshiharu Shinoka
    Abstract:

    Background Ventricular septal perforation and left ventricular aneurysm are examples of potentially fatal complications of myocardial infarction. While various artificial materials are used in the repair of these issues, the possibility of associated infection and calcification is non-negligible. Cell-seeded biodegradable tissue-engineered patches may be a potential solution. This study evaluated the feasibility of a new left ventricular patch rat model to study Neotissue Formation in biodegradable cardiac patches. Methods Human induced pluripotent stem cell-derived cardiac progenitor cells (hiPS-CPCs) were cultured onto biodegradable patches composed of polyglycolic acid and a 50:50 poly (l-lactide-co-e-caprolactone) copolymer for one week. After culturing, patches were implanted into left ventricular walls of male athymic rats. Unseeded controls were also used (n = 10/group). Heart conditions were followed by echocardiography and patches were subsequently explanted at 1, 2, 6, and 9 months post-implantation for histological evaluation. Result Throughout the study, no patches ruptured demonstrating the ability to withstand the high pressure left ventricular system. One month after transplantation, the seeded patch did not stain positive for human nuclei. However, many new blood vessels formed within patches with significantly greater vessels in the seeded group at the 6 month time point. Echocardiography showed no significant difference in left ventricular contraction rate between the two groups. Calcification was found inside patches after 6 months, but there was no significant difference between groups. Conclusion We have developed a surgical method to implant a bioabsorbable scaffold into the left ventricular environment of rats with a high survival rate. Seeded hiPS-CPCs did not differentiate into cardiomyocytes, but the greater number of new blood vessels in seeded patches suggests the presence of cell seeding early in the remodeling process might provide a prolonged effect on Neotissue Formation. This experiment will contribute to the development of a treatment model for left ventricular failure using iPS cells in the future.

  • novel bioresorbable vascular graft with sponge type scaffold as a small diameter arterial graft
    The Annals of Thoracic Surgery, 2016
    Co-Authors: Tadahisa Sugiura, Christopher K. Breuer, Tai Yi, Shuhei Tara, Hidetaka Nakayama, Hirotsugu Kurobe, Toshiharu Shinoka
    Abstract:

    Background Current commercialized small-diameter arterial grafts have not shown clinical effectiveness due to their poor patency rates. The present study evaluated the feasibility of an arterial bioresorbable vascular graft, which has a porous sponge-type scaffold, as a small-diameter arterial conduit. Methods The grafts were constructed by a 50:50 poly (1-lactic-co-e-caprolactone) copolymer (PLCL) scaffold reinforced by a poly (1-lactic acid) (PLA) nanofiber. The pore size of the PLCL scaffold was adjusted to a small size (12.8 ± 1.85 μm) or a large size (28.5 ± 5.25 μm). We compared the difference in cellular infiltration, followed by tissue remodeling, between the groups. The grafts were implanted in 8- to 10-week-old female mice (n = 15 in each group) as infrarenal aortic interposition conduits. Animals were monitored for 8 weeks and euthanized to evaluate Neotissue Formation. Results No aneurysmal change or graft rupture was observed in either group. Histologic assessment demonstrated favorable cell infiltration into scaffolds, neointimal Formation with endothelialization, smooth muscle cell proliferation, and elastin deposition in both groups. No significant difference was observed between the groups. Immunohistochemical characterization with anti-F4/80 antibody demonstrated that macrophage infiltration into the grafts occurred in both groups. Staining for M1 and M2, which are the two major macrophage phenotypes, showed no significant difference between groups. Conclusions Our novel bioresorbable vascular grafts showed well-organized neointimal Formation in the high-pressure arterial circulation environment. The large-pore scaffold did not improve cellular infiltration and Neotissue Formation compared with the small-pore scaffold.

  • tissue engineered small diameter arterial vascular grafts from cell free nanofiber pcl chitosan scaffolds in a sheep model
    PLOS ONE, 2016
    Co-Authors: Takuma Fukunishi, Toshiharu Shinoka, Tai Yi, Cameron A Best, Toshihiro Shoji, Tadahisa Sugiura, Brooks V Udelsman, Devan Ohst, Huaitao Zhang, Christopher K. Breuer
    Abstract:

    Tissue engineered vascular grafts (TEVGs) have the potential to overcome the issues faced by existing small diameter prosthetic grafts by providing a biodegradable scaffold where the patient’s own cells can engraft and form functional Neotissue. However, applying classical approaches to create arterial TEVGs using slow degrading materials with supraphysiological mechanical properties, typically results in limited host cell infiltration, poor remodeling, stenosis, and calcification. The purpose of this study is to evaluate the feasibility of novel small diameter arterial TEVGs created using fast degrading material. A 1.0mm and 5.0mm diameter TEVGs were fabricated with electrospun polycaprolactone (PCL) and chitosan (CS) blend nanofibers. The 1.0mm TEVGs were implanted in mice (n = 3) as an unseeded infrarenal abdominal aorta interposition conduit., The 5.0mm TEVGs were implanted in sheep (n = 6) as an unseeded carotid artery (CA) interposition conduit. Mice were followed with ultrasound and sacrificed at 6 months. All 1.0mm TEVGs remained patent without evidence of thrombosis or aneurysm Formation. Based on small animal outcomes, sheep were followed with ultrasound and sacrificed at 6 months for histological and mechanical analysis. There was no aneurysm Formation or calcification in the TEVGs. 4 out of 6 grafts (67%) were patent. After 6 months in vivo, 9.1 ± 5.4% remained of the original scaffold. Histological analysis of patent grafts demonstrated deposition of extracellular matrix constituents including elastin and collagen production, as well as endothelialization and organized contractile smooth muscle cells, similar to that of native CA. The mechanical properties of TEVGs were comparable to native CA. There was a significant positive correlation between TEVG wall thickness and CD68+ macrophage infiltration into the scaffold (R2 = 0.95, p = 0.001). The fast degradation of CS in our novel TEVG promoted excellent cellular infiltration and Neotissue Formation without calcification or aneurysm. Modulating host macrophage infiltration into the scaffold is a key to reducing excessive Neotissue Formation and stenosis.

  • beyond burst pressure initial evaluation of the natural history of the biaxial mechanical properties of tissue engineered vascular grafts in the venous circulation using a murine model
    Tissue Engineering Part A, 2014
    Co-Authors: Yuji Naito, Toshiharu Shinoka, Yong Ung Lee, Jay D Humphrey, Spencer N Church, Daniel Solomon, Christopher K. Breuer
    Abstract:

    We previously developed and validated a murine model for investigating Neotissue Formation in tissue-engineered vascular grafts (TEVGs). Herein, we present the first longitudinal assessment of both the microstructural composition and the mechanical properties of a TEVG through the process of neovessel Formation (total scaffold degradation). We show that when (poly)glycolic acid-based biodegradable scaffolds were used as inferior vena cava interposition grafts in mice, the evolving neovessel developed biaxial properties that approached those of the native vein within 24 weeks of implantation. Further, we found that these changes in biaxial properties related temporally to extracellular matrix production and remodeling, including deposition of collagen (types I and III), elastic fibers (elastin and fibrillin-1), and glycosaminoglycans in addition to changes in matrix metalloproteinase (MMP)-2 and -9 activity. Improving our understanding of the mechanobiological principles underlying vascular Neotissue Formation in TEVGs holds great promise for improving the design of TEVGs and enabling us to continue the translation of this technology from the bench to the clinic.

  • vascular tissue engineering towards the next generation vascular grafts
    Advanced Drug Delivery Reviews, 2011
    Co-Authors: Yuji Naito, Narutoshi Hibino, Toshiharu Shinoka, Daniel R Duncan, Spencer N Church, Daniel Solomon, Muriel A Cleary, Animesh Rathore, Corey W Fein, Christopher K. Breuer
    Abstract:

    The application of tissue engineering technology to cardiovascular surgery holds great promise for improving outcomes in patients with cardiovascular diseases. Currently used synthetic vascular grafts have several limitations including thrombogenicity, increased risk of infection, and lack of growth potential. We have completed the first clinical trial evaluating the feasibility of using tissue engineered vascular grafts (TEVG) created by seeding autologous bone marrow-derived mononuclear cells (BM-MNC) onto biodegradable tubular scaffolds. Despite an excellent safety profile, data from the clinical trial suggest that the primary graft related complication of the TEVG is stenosis, affecting approximately 16% of grafts within the first seven years after implantation. Continued investigation into the cellular and molecular mechanisms underlying vascular Neotissue Formation will improve our basic understanding and provide insights that will enable the rationale design of second generation TEVG.

Tadahisa Sugiura - One of the best experts on this subject based on the ideXlab platform.

  • the evaluation of a tissue engineered cardiac patch seeded with hips derived cardiac progenitor cells in a rat left ventricular model
    PLOS ONE, 2020
    Co-Authors: Yuichi Matsuzaki, Christopher K. Breuer, James W Reinhardt, Shinka Miyamoto, Jacob C Zbinden, Tadahisa Sugiura, Hideki Miyachi, Chang Yuchun, Toshiharu Shinoka
    Abstract:

    Background Ventricular septal perforation and left ventricular aneurysm are examples of potentially fatal complications of myocardial infarction. While various artificial materials are used in the repair of these issues, the possibility of associated infection and calcification is non-negligible. Cell-seeded biodegradable tissue-engineered patches may be a potential solution. This study evaluated the feasibility of a new left ventricular patch rat model to study Neotissue Formation in biodegradable cardiac patches. Methods Human induced pluripotent stem cell-derived cardiac progenitor cells (hiPS-CPCs) were cultured onto biodegradable patches composed of polyglycolic acid and a 50:50 poly (l-lactide-co-e-caprolactone) copolymer for one week. After culturing, patches were implanted into left ventricular walls of male athymic rats. Unseeded controls were also used (n = 10/group). Heart conditions were followed by echocardiography and patches were subsequently explanted at 1, 2, 6, and 9 months post-implantation for histological evaluation. Result Throughout the study, no patches ruptured demonstrating the ability to withstand the high pressure left ventricular system. One month after transplantation, the seeded patch did not stain positive for human nuclei. However, many new blood vessels formed within patches with significantly greater vessels in the seeded group at the 6 month time point. Echocardiography showed no significant difference in left ventricular contraction rate between the two groups. Calcification was found inside patches after 6 months, but there was no significant difference between groups. Conclusion We have developed a surgical method to implant a bioabsorbable scaffold into the left ventricular environment of rats with a high survival rate. Seeded hiPS-CPCs did not differentiate into cardiomyocytes, but the greater number of new blood vessels in seeded patches suggests the presence of cell seeding early in the remodeling process might provide a prolonged effect on Neotissue Formation. This experiment will contribute to the development of a treatment model for left ventricular failure using iPS cells in the future.

  • Intravascular Ultrasound Characterization of a Tissue-Engineered Vascular Graft in an Ovine Model
    Journal of Cardiovascular Translational Research, 2017
    Co-Authors: Victoria K. Pepper, Shinka Miyamoto, Cameron A Best, Tadahisa Sugiura, Hideki Miyachi, Elizabeth S. Clark, Ekene A. Onwuka, Eric D. Heuer, Lilamarie E. Moko, Darren P. Berman
    Abstract:

    Patients who undergo implantation of a tissue-engineered vascular graft (TEVG) for congenital cardiac anomalies are monitored with echocardiography, followed by magnetic resonance imaging or angiography when indicated. While these methods provide data regarding the lumen, minimal inFormation regarding Neotissue Formation is obtained. Intravascular ultrasound (IVUS) has previously been used in a variety of conditions to evaluate the vessel wall. The purpose of this study was to evaluate the utility of IVUS for evaluation of TEVGs in our ovine model. Eight sheep underwent implantation of TEVGs either unseeded or seeded with bone marrow-derived mononuclear cells. Angiography, IVUS, and histology were directly compared. Endothelium, tunica media, and graft were identifiable on IVUS and histology at multiple time points. There was strong agreement between IVUS and angiography for evaluation of luminal diameter. IVUS offers a valuable tool to evaluate the changes within TEVGs, and clinical translation of this application is warranted.

  • novel bioresorbable vascular graft with sponge type scaffold as a small diameter arterial graft
    The Annals of Thoracic Surgery, 2016
    Co-Authors: Tadahisa Sugiura, Christopher K. Breuer, Tai Yi, Shuhei Tara, Hidetaka Nakayama, Hirotsugu Kurobe, Toshiharu Shinoka
    Abstract:

    Background Current commercialized small-diameter arterial grafts have not shown clinical effectiveness due to their poor patency rates. The present study evaluated the feasibility of an arterial bioresorbable vascular graft, which has a porous sponge-type scaffold, as a small-diameter arterial conduit. Methods The grafts were constructed by a 50:50 poly (1-lactic-co-e-caprolactone) copolymer (PLCL) scaffold reinforced by a poly (1-lactic acid) (PLA) nanofiber. The pore size of the PLCL scaffold was adjusted to a small size (12.8 ± 1.85 μm) or a large size (28.5 ± 5.25 μm). We compared the difference in cellular infiltration, followed by tissue remodeling, between the groups. The grafts were implanted in 8- to 10-week-old female mice (n = 15 in each group) as infrarenal aortic interposition conduits. Animals were monitored for 8 weeks and euthanized to evaluate Neotissue Formation. Results No aneurysmal change or graft rupture was observed in either group. Histologic assessment demonstrated favorable cell infiltration into scaffolds, neointimal Formation with endothelialization, smooth muscle cell proliferation, and elastin deposition in both groups. No significant difference was observed between the groups. Immunohistochemical characterization with anti-F4/80 antibody demonstrated that macrophage infiltration into the grafts occurred in both groups. Staining for M1 and M2, which are the two major macrophage phenotypes, showed no significant difference between groups. Conclusions Our novel bioresorbable vascular grafts showed well-organized neointimal Formation in the high-pressure arterial circulation environment. The large-pore scaffold did not improve cellular infiltration and Neotissue Formation compared with the small-pore scaffold.

  • tissue engineered small diameter arterial vascular grafts from cell free nanofiber pcl chitosan scaffolds in a sheep model
    PLOS ONE, 2016
    Co-Authors: Takuma Fukunishi, Toshiharu Shinoka, Tai Yi, Cameron A Best, Toshihiro Shoji, Tadahisa Sugiura, Brooks V Udelsman, Devan Ohst, Huaitao Zhang, Christopher K. Breuer
    Abstract:

    Tissue engineered vascular grafts (TEVGs) have the potential to overcome the issues faced by existing small diameter prosthetic grafts by providing a biodegradable scaffold where the patient’s own cells can engraft and form functional Neotissue. However, applying classical approaches to create arterial TEVGs using slow degrading materials with supraphysiological mechanical properties, typically results in limited host cell infiltration, poor remodeling, stenosis, and calcification. The purpose of this study is to evaluate the feasibility of novel small diameter arterial TEVGs created using fast degrading material. A 1.0mm and 5.0mm diameter TEVGs were fabricated with electrospun polycaprolactone (PCL) and chitosan (CS) blend nanofibers. The 1.0mm TEVGs were implanted in mice (n = 3) as an unseeded infrarenal abdominal aorta interposition conduit., The 5.0mm TEVGs were implanted in sheep (n = 6) as an unseeded carotid artery (CA) interposition conduit. Mice were followed with ultrasound and sacrificed at 6 months. All 1.0mm TEVGs remained patent without evidence of thrombosis or aneurysm Formation. Based on small animal outcomes, sheep were followed with ultrasound and sacrificed at 6 months for histological and mechanical analysis. There was no aneurysm Formation or calcification in the TEVGs. 4 out of 6 grafts (67%) were patent. After 6 months in vivo, 9.1 ± 5.4% remained of the original scaffold. Histological analysis of patent grafts demonstrated deposition of extracellular matrix constituents including elastin and collagen production, as well as endothelialization and organized contractile smooth muscle cells, similar to that of native CA. The mechanical properties of TEVGs were comparable to native CA. There was a significant positive correlation between TEVG wall thickness and CD68+ macrophage infiltration into the scaffold (R2 = 0.95, p = 0.001). The fast degradation of CS in our novel TEVG promoted excellent cellular infiltration and Neotissue Formation without calcification or aneurysm. Modulating host macrophage infiltration into the scaffold is a key to reducing excessive Neotissue Formation and stenosis.

  • tgf β receptor 1 inhibition prevents stenosis of tissue engineered vascular grafts by reducing host mononuclear phagocyte activation
    The FASEB Journal, 2016
    Co-Authors: Yong Ung Lee, Cameron A Best, Juan De Dios Ruizrosado, Nathan Mahler, Shuhei Tara, Toshihiro Shoji, Tadahisa Sugiura, Avione Y Lee, Frank Robledoavila, Narutoshi Hibino
    Abstract:

    Stenosis is a critical problem in the long-term efficacy of tissue-engineered vascular grafts (TEVGs). We previously showed that host monocyte infiltration and activation within the graft drives stenosis and that TGF-β receptor 1 (TGF-βR1) inhibition can prevent it, but the latter effect was attributed primarily to inhibition of mesenchymal cell expansion. In this study, we assessed the effects of TGF-βR1 inhibition on the host monocytes. Biodegradable TEVGs were implanted as inferior vena cava interposition conduits in 2 groups of C57BL/6 mice (n = 25/group): unseeded grafts and unseeded grafts with TGF-βR1 inhibitor systemic treatment for the first 2 wk. The TGF-βR1 inhibitor treatment effectively improved TEVG patency at 6 mo compared to the untreated control group (91.7 vs. 48%, P < 0.001), which is associated with a reduction in classic activation of mononuclear phagocytes. Consistent with these findings, the addition of rTGF-β to LPS/IFN-γ-stimulated monocytes enhanced secretion of inflammatory cytokines TNF-α, IL-12, and IL-6; this effect was blocked by TGF-βR1 inhibition (P < 0.0001). These findings suggest that the TGF-β signaling pathway contributes to TEVG stenosis by inducing classic activation of host monocytes. Furthermore, blocking monocyte activation by TGF-βR1 inhibition provides a viable strategy for preventing TEVG stenosis while maintaining Neotissue Formation.-Lee, Y.-U., de Dios Ruiz-Rosado, J., Mahler, N., Best, C. A., Tara, S., Yi, T., Shoji, T., Sugiura, T., Lee, A. Y., Robledo-Avila, F., Hibino, N., Pober, J. S., Shinoka, T., Partida-Sanchez, S., Breuer, C. K. TGF-β receptor 1 inhibition prevents stenosis of tissue-engineered vascular grafts by reducing host mononuclear phagocyte activation.

Cameron A Best - One of the best experts on this subject based on the ideXlab platform.

  • the role of myeloid cell derived pdgf b in Neotissue Formation in a tissue engineered vascular graft
    Regenerative Medicine, 2017
    Co-Authors: Ekene Onwuka, Christopher K. Breuer, Cameron A Best, Andrew J Sawyer, Eric Heuer, Malik Sams, Matthew Wiet, Hong Zheng, Themis R Kyriakides
    Abstract:

    Aim: Inflammatory myeloid lineage cells mediate Neotissue Formation in tissue-engineered vascular grafts, but the molecular mechanism is not completely understood. We examined the role of vasculogenic PDGF-B in tissue-engineered vascular graft Neotissue development. Materials & methods: Myeloid cell-specific PDGF-B knockout mice (PDGF-KO) were generated using bone marrow transplantation, and scaffolds were implanted as inferior vena cava interposition grafts in either PDGF-KO or wild-type mice. Results: After 2 weeks, grafts from PDGF-KO mice had more remaining scaffold polymer and less intimal Neotissue development. Increased macrophage apoptosis, decreased smooth muscle cell proliferation and decreased collagen content was also observed. Conclusion: Myeloid cell-derived PDGF contributes to vascular Neotissue Formation by regulating macrophage apoptosis, smooth muscle cell proliferation and extracellular matrix deposition.

  • Intravascular Ultrasound Characterization of a Tissue-Engineered Vascular Graft in an Ovine Model
    Journal of Cardiovascular Translational Research, 2017
    Co-Authors: Victoria K. Pepper, Shinka Miyamoto, Cameron A Best, Tadahisa Sugiura, Hideki Miyachi, Elizabeth S. Clark, Ekene A. Onwuka, Eric D. Heuer, Lilamarie E. Moko, Darren P. Berman
    Abstract:

    Patients who undergo implantation of a tissue-engineered vascular graft (TEVG) for congenital cardiac anomalies are monitored with echocardiography, followed by magnetic resonance imaging or angiography when indicated. While these methods provide data regarding the lumen, minimal inFormation regarding Neotissue Formation is obtained. Intravascular ultrasound (IVUS) has previously been used in a variety of conditions to evaluate the vessel wall. The purpose of this study was to evaluate the utility of IVUS for evaluation of TEVGs in our ovine model. Eight sheep underwent implantation of TEVGs either unseeded or seeded with bone marrow-derived mononuclear cells. Angiography, IVUS, and histology were directly compared. Endothelium, tunica media, and graft were identifiable on IVUS and histology at multiple time points. There was strong agreement between IVUS and angiography for evaluation of luminal diameter. IVUS offers a valuable tool to evaluate the changes within TEVGs, and clinical translation of this application is warranted.

  • tissue engineered small diameter arterial vascular grafts from cell free nanofiber pcl chitosan scaffolds in a sheep model
    PLOS ONE, 2016
    Co-Authors: Takuma Fukunishi, Toshiharu Shinoka, Tai Yi, Cameron A Best, Toshihiro Shoji, Tadahisa Sugiura, Brooks V Udelsman, Devan Ohst, Huaitao Zhang, Christopher K. Breuer
    Abstract:

    Tissue engineered vascular grafts (TEVGs) have the potential to overcome the issues faced by existing small diameter prosthetic grafts by providing a biodegradable scaffold where the patient’s own cells can engraft and form functional Neotissue. However, applying classical approaches to create arterial TEVGs using slow degrading materials with supraphysiological mechanical properties, typically results in limited host cell infiltration, poor remodeling, stenosis, and calcification. The purpose of this study is to evaluate the feasibility of novel small diameter arterial TEVGs created using fast degrading material. A 1.0mm and 5.0mm diameter TEVGs were fabricated with electrospun polycaprolactone (PCL) and chitosan (CS) blend nanofibers. The 1.0mm TEVGs were implanted in mice (n = 3) as an unseeded infrarenal abdominal aorta interposition conduit., The 5.0mm TEVGs were implanted in sheep (n = 6) as an unseeded carotid artery (CA) interposition conduit. Mice were followed with ultrasound and sacrificed at 6 months. All 1.0mm TEVGs remained patent without evidence of thrombosis or aneurysm Formation. Based on small animal outcomes, sheep were followed with ultrasound and sacrificed at 6 months for histological and mechanical analysis. There was no aneurysm Formation or calcification in the TEVGs. 4 out of 6 grafts (67%) were patent. After 6 months in vivo, 9.1 ± 5.4% remained of the original scaffold. Histological analysis of patent grafts demonstrated deposition of extracellular matrix constituents including elastin and collagen production, as well as endothelialization and organized contractile smooth muscle cells, similar to that of native CA. The mechanical properties of TEVGs were comparable to native CA. There was a significant positive correlation between TEVG wall thickness and CD68+ macrophage infiltration into the scaffold (R2 = 0.95, p = 0.001). The fast degradation of CS in our novel TEVG promoted excellent cellular infiltration and Neotissue Formation without calcification or aneurysm. Modulating host macrophage infiltration into the scaffold is a key to reducing excessive Neotissue Formation and stenosis.

  • tgf β receptor 1 inhibition prevents stenosis of tissue engineered vascular grafts by reducing host mononuclear phagocyte activation
    The FASEB Journal, 2016
    Co-Authors: Yong Ung Lee, Cameron A Best, Juan De Dios Ruizrosado, Nathan Mahler, Shuhei Tara, Toshihiro Shoji, Tadahisa Sugiura, Avione Y Lee, Frank Robledoavila, Narutoshi Hibino
    Abstract:

    Stenosis is a critical problem in the long-term efficacy of tissue-engineered vascular grafts (TEVGs). We previously showed that host monocyte infiltration and activation within the graft drives stenosis and that TGF-β receptor 1 (TGF-βR1) inhibition can prevent it, but the latter effect was attributed primarily to inhibition of mesenchymal cell expansion. In this study, we assessed the effects of TGF-βR1 inhibition on the host monocytes. Biodegradable TEVGs were implanted as inferior vena cava interposition conduits in 2 groups of C57BL/6 mice (n = 25/group): unseeded grafts and unseeded grafts with TGF-βR1 inhibitor systemic treatment for the first 2 wk. The TGF-βR1 inhibitor treatment effectively improved TEVG patency at 6 mo compared to the untreated control group (91.7 vs. 48%, P < 0.001), which is associated with a reduction in classic activation of mononuclear phagocytes. Consistent with these findings, the addition of rTGF-β to LPS/IFN-γ-stimulated monocytes enhanced secretion of inflammatory cytokines TNF-α, IL-12, and IL-6; this effect was blocked by TGF-βR1 inhibition (P < 0.0001). These findings suggest that the TGF-β signaling pathway contributes to TEVG stenosis by inducing classic activation of host monocytes. Furthermore, blocking monocyte activation by TGF-βR1 inhibition provides a viable strategy for preventing TEVG stenosis while maintaining Neotissue Formation.-Lee, Y.-U., de Dios Ruiz-Rosado, J., Mahler, N., Best, C. A., Tara, S., Yi, T., Shoji, T., Sugiura, T., Lee, A. Y., Robledo-Avila, F., Hibino, N., Pober, J. S., Shinoka, T., Partida-Sanchez, S., Breuer, C. K. TGF-β receptor 1 inhibition prevents stenosis of tissue-engineered vascular grafts by reducing host mononuclear phagocyte activation.

  • Tissue-Engineered Small Diameter Arterial Vascular Grafts from Cell-Free Nanofiber PCL/Chitosan Scaffolds in a Sheep Model.
    Public Library of Science (PLoS), 2026
    Co-Authors: Takuma Fukunishi, Chin Siang Ong, Cameron A Best, Toshihiro Shoji, Tadahisa Sugiura, Devan Ohst, Huaitao Zhang, Brooks Udelsman, Toshiharu Shinoka
    Abstract:

    Tissue engineered vascular grafts (TEVGs) have the potential to overcome the issues faced by existing small diameter prosthetic grafts by providing a biodegradable scaffold where the patient's own cells can engraft and form functional Neotissue. However, applying classical approaches to create arterial TEVGs using slow degrading materials with supraphysiological mechanical properties, typically results in limited host cell infiltration, poor remodeling, stenosis, and calcification. The purpose of this study is to evaluate the feasibility of novel small diameter arterial TEVGs created using fast degrading material. A 1.0mm and 5.0mm diameter TEVGs were fabricated with electrospun polycaprolactone (PCL) and chitosan (CS) blend nanofibers. The 1.0mm TEVGs were implanted in mice (n = 3) as an unseeded infrarenal abdominal aorta interposition conduit., The 5.0mm TEVGs were implanted in sheep (n = 6) as an unseeded carotid artery (CA) interposition conduit. Mice were followed with ultrasound and sacrificed at 6 months. All 1.0mm TEVGs remained patent without evidence of thrombosis or aneurysm Formation. Based on small animal outcomes, sheep were followed with ultrasound and sacrificed at 6 months for histological and mechanical analysis. There was no aneurysm Formation or calcification in the TEVGs. 4 out of 6 grafts (67%) were patent. After 6 months in vivo, 9.1 ± 5.4% remained of the original scaffold. Histological analysis of patent grafts demonstrated deposition of extracellular matrix constituents including elastin and collagen production, as well as endothelialization and organized contractile smooth muscle cells, similar to that of native CA. The mechanical properties of TEVGs were comparable to native CA. There was a significant positive correlation between TEVG wall thickness and CD68+ macrophage infiltration into the scaffold (R2 = 0.95, p = 0.001). The fast degradation of CS in our novel TEVG promoted excellent cellular infiltration and Neotissue Formation without calcification or aneurysm. Modulating host macrophage infiltration into the scaffold is a key to reducing excessive Neotissue Formation and stenosis

Takuma Fukunishi - One of the best experts on this subject based on the ideXlab platform.

  • regenerative and durable small diameter graft as an arterial conduit
    Proceedings of the National Academy of Sciences of the United States of America, 2019
    Co-Authors: Morgan B Elliott, Takahiro Inoue, Brian Ginn, Takuma Fukunishi, Djahida Bedja, Abhilash Suresh, Theresa Chen, Harry C Dietz
    Abstract:

    Despite significant research efforts, clinical practice for arterial bypass surgery has been stagnant, and engineered grafts continue to face postimplantation challenges. Here, we describe the development and application of a durable small-diameter vascular graft with tailored regenerative capacity. We fabricated small-diameter vascular grafts by electrospinning fibrin tubes and poly(e-caprolactone) fibrous sheaths, which improved suture retention strength and enabled long-term survival. Using surface topography in a hollow fibrin microfiber tube, we enable immediate, controlled perfusion and Formation of a confluent endothelium within 3–4 days in vitro with human endothelial colony-forming cells, but a stable endothelium is noticeable at 4 weeks in vivo. Implantation of acellular or endothelialized fibrin grafts with an external ultrathin poly(e-caprolactone) sheath as an interposition graft in the abdominal aorta of a severe combined immunodeficient Beige mouse model supports normal blood flow and vessel patency for 24 weeks. Mechanical properties of the implanted grafts closely approximate the native abdominal aorta properties after just 1 week in vivo. Fibrin mediated cellular remodeling, stable tunica intima and media Formation, and abundant matrix deposition with organized collagen layers and wavy elastin lamellae. Endothelialized grafts evidenced controlled healthy remodeling with delayed and reduced macrophage infiltration alongside neo vasa vasorum-like structure Formation, reduced calcification, and accelerated tunica media Formation. Our studies establish a small-diameter graft that is fabricated in less than 1 week, mediates Neotissue Formation and incorporation into the native tissue, and matches the native vessel size and mechanical properties, overcoming main challenges in arterial bypass surgery.

  • tissue engineered small diameter arterial vascular grafts from cell free nanofiber pcl chitosan scaffolds in a sheep model
    PLOS ONE, 2016
    Co-Authors: Takuma Fukunishi, Toshiharu Shinoka, Tai Yi, Cameron A Best, Toshihiro Shoji, Tadahisa Sugiura, Brooks V Udelsman, Devan Ohst, Huaitao Zhang, Christopher K. Breuer
    Abstract:

    Tissue engineered vascular grafts (TEVGs) have the potential to overcome the issues faced by existing small diameter prosthetic grafts by providing a biodegradable scaffold where the patient’s own cells can engraft and form functional Neotissue. However, applying classical approaches to create arterial TEVGs using slow degrading materials with supraphysiological mechanical properties, typically results in limited host cell infiltration, poor remodeling, stenosis, and calcification. The purpose of this study is to evaluate the feasibility of novel small diameter arterial TEVGs created using fast degrading material. A 1.0mm and 5.0mm diameter TEVGs were fabricated with electrospun polycaprolactone (PCL) and chitosan (CS) blend nanofibers. The 1.0mm TEVGs were implanted in mice (n = 3) as an unseeded infrarenal abdominal aorta interposition conduit., The 5.0mm TEVGs were implanted in sheep (n = 6) as an unseeded carotid artery (CA) interposition conduit. Mice were followed with ultrasound and sacrificed at 6 months. All 1.0mm TEVGs remained patent without evidence of thrombosis or aneurysm Formation. Based on small animal outcomes, sheep were followed with ultrasound and sacrificed at 6 months for histological and mechanical analysis. There was no aneurysm Formation or calcification in the TEVGs. 4 out of 6 grafts (67%) were patent. After 6 months in vivo, 9.1 ± 5.4% remained of the original scaffold. Histological analysis of patent grafts demonstrated deposition of extracellular matrix constituents including elastin and collagen production, as well as endothelialization and organized contractile smooth muscle cells, similar to that of native CA. The mechanical properties of TEVGs were comparable to native CA. There was a significant positive correlation between TEVG wall thickness and CD68+ macrophage infiltration into the scaffold (R2 = 0.95, p = 0.001). The fast degradation of CS in our novel TEVG promoted excellent cellular infiltration and Neotissue Formation without calcification or aneurysm. Modulating host macrophage infiltration into the scaffold is a key to reducing excessive Neotissue Formation and stenosis.

  • Tissue-Engineered Small Diameter Arterial Vascular Grafts from Cell-Free Nanofiber PCL/Chitosan Scaffolds in a Sheep Model.
    Public Library of Science (PLoS), 2026
    Co-Authors: Takuma Fukunishi, Chin Siang Ong, Cameron A Best, Toshihiro Shoji, Tadahisa Sugiura, Devan Ohst, Huaitao Zhang, Brooks Udelsman, Toshiharu Shinoka
    Abstract:

    Tissue engineered vascular grafts (TEVGs) have the potential to overcome the issues faced by existing small diameter prosthetic grafts by providing a biodegradable scaffold where the patient's own cells can engraft and form functional Neotissue. However, applying classical approaches to create arterial TEVGs using slow degrading materials with supraphysiological mechanical properties, typically results in limited host cell infiltration, poor remodeling, stenosis, and calcification. The purpose of this study is to evaluate the feasibility of novel small diameter arterial TEVGs created using fast degrading material. A 1.0mm and 5.0mm diameter TEVGs were fabricated with electrospun polycaprolactone (PCL) and chitosan (CS) blend nanofibers. The 1.0mm TEVGs were implanted in mice (n = 3) as an unseeded infrarenal abdominal aorta interposition conduit., The 5.0mm TEVGs were implanted in sheep (n = 6) as an unseeded carotid artery (CA) interposition conduit. Mice were followed with ultrasound and sacrificed at 6 months. All 1.0mm TEVGs remained patent without evidence of thrombosis or aneurysm Formation. Based on small animal outcomes, sheep were followed with ultrasound and sacrificed at 6 months for histological and mechanical analysis. There was no aneurysm Formation or calcification in the TEVGs. 4 out of 6 grafts (67%) were patent. After 6 months in vivo, 9.1 ± 5.4% remained of the original scaffold. Histological analysis of patent grafts demonstrated deposition of extracellular matrix constituents including elastin and collagen production, as well as endothelialization and organized contractile smooth muscle cells, similar to that of native CA. The mechanical properties of TEVGs were comparable to native CA. There was a significant positive correlation between TEVG wall thickness and CD68+ macrophage infiltration into the scaffold (R2 = 0.95, p = 0.001). The fast degradation of CS in our novel TEVG promoted excellent cellular infiltration and Neotissue Formation without calcification or aneurysm. Modulating host macrophage infiltration into the scaffold is a key to reducing excessive Neotissue Formation and stenosis