Intravascular Stem Cell Bioreactor for Prevention of Adverse Remodeling After Myocardial Infarction

Peter V Johnston, Chao-Wei Hwang, Virginia Bogdan, Kevin J. Mills, Elliott R. Eggan, Aleksandra Leszczynska, Katherine Chih-Ching Wu, Daniel Herzka, Jeffrey A Brinker, Steven P Schulman, Monisha Banerjee, Victoria Florea, Makoto Natsumeda, Bryon Tompkins, Wayne Balkan, Joshua M. Hare, Gordon F. Tomaselli, Robert George Weiss, Gary Gerstenblith

Research output: Contribution to journalArticle

Abstract

Background Prevention of adverse remodeling after myocardial infarction (MI) is an important goal of stem cell therapy. Clinical trial results vary, however, and poor cell retention and survival after delivery likely limit the opportunity to exert beneficial effects. To overcome these limitations, we built an implantable intravascular bioreactor (IBR) designed to protect contained cells from washout, dilution, and immune attack while allowing sustained release of beneficial paracrine factors. Methods and Results IBRs were constructed using semipermeable membrane adhered to a clinical-grade catheter shaft. Mesenchymal stem cell (MSC) viability in and paracrine factor release from IBRs were assessed in vitro and IBR biocompatibility and immune protection confirmed in vivo. In a porcine anterior MI model, IBRs containing 25 million allogeneic MSCs (IBR-MSCs) were compared with IBRs containing media alone (IBR-Placebo; n=8 per group) with adverse remodeling assessed by magnetic resonance imaging. Four weeks after MI, IBR-MSCs had no significant change in end-diastolic volume (+0.33±4.32 mL; P=0.89), end-systolic volume (+2.14±4.13 mL; P=0.21), and left ventricular ejection fraction (-2.27±2.94; P=0.33) while IBR-Placebo had significant increases in end-diastolic volume (+10.37±3.84 mL; P=0.01) and ESV (+11.35±2.88 mL; P=0.01), and a significant decrease in left ventricular ejection fraction (-5.78±1.70; P=0.025). Eight weeks after MI, adherent pericarditis was present in 0 of 8 IBR-MSCs versus 4 of 8 IBR-Placebo (P=0.02), suggesting an anti-inflammatory effect. In a separate study, 25 million allogeneic pig MSCs directly injected in the peri-infarct zone 3 days after MI (n=6) showed no significant benefit in adverse remodeling at 4 weeks compared with IBR-MSCs. Conclusions MSCs deployed inside an implantable, removable, and potentially rechargeable bioreactor in a large animal model remain viable, are immunoprotected, and attenuate adverse remodeling 4 weeks after MI.

Original languageEnglish (US)
Pages (from-to)e012351
JournalJournal of the American Heart Association
Volume8
Issue number15
DOIs
StatePublished - Aug 6 2019

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Bioreactors
Stem Cells
Myocardial Infarction
Placebos
Stroke Volume
Cell Survival
Swine
Pericarditis
Cell- and Tissue-Based Therapy
Mesenchymal Stromal Cells
Anti-Inflammatory Agents
Catheters
Animal Models
Magnetic Resonance Imaging
Clinical Trials
Membranes

Keywords

  • cytokines
  • growth factors
  • myocardial infarction
  • remodeling heart failure
  • stem cell

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Intravascular Stem Cell Bioreactor for Prevention of Adverse Remodeling After Myocardial Infarction. / Johnston, Peter V; Hwang, Chao-Wei; Bogdan, Virginia; Mills, Kevin J.; Eggan, Elliott R.; Leszczynska, Aleksandra; Wu, Katherine Chih-Ching; Herzka, Daniel; Brinker, Jeffrey A; Schulman, Steven P; Banerjee, Monisha; Florea, Victoria; Natsumeda, Makoto; Tompkins, Bryon; Balkan, Wayne; Hare, Joshua M.; Tomaselli, Gordon F.; Weiss, Robert George; Gerstenblith, Gary.

In: Journal of the American Heart Association, Vol. 8, No. 15, 06.08.2019, p. e012351.

Research output: Contribution to journalArticle

Johnston, Peter V ; Hwang, Chao-Wei ; Bogdan, Virginia ; Mills, Kevin J. ; Eggan, Elliott R. ; Leszczynska, Aleksandra ; Wu, Katherine Chih-Ching ; Herzka, Daniel ; Brinker, Jeffrey A ; Schulman, Steven P ; Banerjee, Monisha ; Florea, Victoria ; Natsumeda, Makoto ; Tompkins, Bryon ; Balkan, Wayne ; Hare, Joshua M. ; Tomaselli, Gordon F. ; Weiss, Robert George ; Gerstenblith, Gary. / Intravascular Stem Cell Bioreactor for Prevention of Adverse Remodeling After Myocardial Infarction. In: Journal of the American Heart Association. 2019 ; Vol. 8, No. 15. pp. e012351.
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title = "Intravascular Stem Cell Bioreactor for Prevention of Adverse Remodeling After Myocardial Infarction",
abstract = "Background Prevention of adverse remodeling after myocardial infarction (MI) is an important goal of stem cell therapy. Clinical trial results vary, however, and poor cell retention and survival after delivery likely limit the opportunity to exert beneficial effects. To overcome these limitations, we built an implantable intravascular bioreactor (IBR) designed to protect contained cells from washout, dilution, and immune attack while allowing sustained release of beneficial paracrine factors. Methods and Results IBRs were constructed using semipermeable membrane adhered to a clinical-grade catheter shaft. Mesenchymal stem cell (MSC) viability in and paracrine factor release from IBRs were assessed in vitro and IBR biocompatibility and immune protection confirmed in vivo. In a porcine anterior MI model, IBRs containing 25 million allogeneic MSCs (IBR-MSCs) were compared with IBRs containing media alone (IBR-Placebo; n=8 per group) with adverse remodeling assessed by magnetic resonance imaging. Four weeks after MI, IBR-MSCs had no significant change in end-diastolic volume (+0.33±4.32 mL; P=0.89), end-systolic volume (+2.14±4.13 mL; P=0.21), and left ventricular ejection fraction (-2.27±2.94; P=0.33) while IBR-Placebo had significant increases in end-diastolic volume (+10.37±3.84 mL; P=0.01) and ESV (+11.35±2.88 mL; P=0.01), and a significant decrease in left ventricular ejection fraction (-5.78±1.70; P=0.025). Eight weeks after MI, adherent pericarditis was present in 0 of 8 IBR-MSCs versus 4 of 8 IBR-Placebo (P=0.02), suggesting an anti-inflammatory effect. In a separate study, 25 million allogeneic pig MSCs directly injected in the peri-infarct zone 3 days after MI (n=6) showed no significant benefit in adverse remodeling at 4 weeks compared with IBR-MSCs. Conclusions MSCs deployed inside an implantable, removable, and potentially rechargeable bioreactor in a large animal model remain viable, are immunoprotected, and attenuate adverse remodeling 4 weeks after MI.",
keywords = "cytokines, growth factors, myocardial infarction, remodeling heart failure, stem cell",
author = "Johnston, {Peter V} and Chao-Wei Hwang and Virginia Bogdan and Mills, {Kevin J.} and Eggan, {Elliott R.} and Aleksandra Leszczynska and Wu, {Katherine Chih-Ching} and Daniel Herzka and Brinker, {Jeffrey A} and Schulman, {Steven P} and Monisha Banerjee and Victoria Florea and Makoto Natsumeda and Bryon Tompkins and Wayne Balkan and Hare, {Joshua M.} and Tomaselli, {Gordon F.} and Weiss, {Robert George} and Gary Gerstenblith",
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TY - JOUR

T1 - Intravascular Stem Cell Bioreactor for Prevention of Adverse Remodeling After Myocardial Infarction

AU - Johnston, Peter V

AU - Hwang, Chao-Wei

AU - Bogdan, Virginia

AU - Mills, Kevin J.

AU - Eggan, Elliott R.

AU - Leszczynska, Aleksandra

AU - Wu, Katherine Chih-Ching

AU - Herzka, Daniel

AU - Brinker, Jeffrey A

AU - Schulman, Steven P

AU - Banerjee, Monisha

AU - Florea, Victoria

AU - Natsumeda, Makoto

AU - Tompkins, Bryon

AU - Balkan, Wayne

AU - Hare, Joshua M.

AU - Tomaselli, Gordon F.

AU - Weiss, Robert George

AU - Gerstenblith, Gary

PY - 2019/8/6

Y1 - 2019/8/6

N2 - Background Prevention of adverse remodeling after myocardial infarction (MI) is an important goal of stem cell therapy. Clinical trial results vary, however, and poor cell retention and survival after delivery likely limit the opportunity to exert beneficial effects. To overcome these limitations, we built an implantable intravascular bioreactor (IBR) designed to protect contained cells from washout, dilution, and immune attack while allowing sustained release of beneficial paracrine factors. Methods and Results IBRs were constructed using semipermeable membrane adhered to a clinical-grade catheter shaft. Mesenchymal stem cell (MSC) viability in and paracrine factor release from IBRs were assessed in vitro and IBR biocompatibility and immune protection confirmed in vivo. In a porcine anterior MI model, IBRs containing 25 million allogeneic MSCs (IBR-MSCs) were compared with IBRs containing media alone (IBR-Placebo; n=8 per group) with adverse remodeling assessed by magnetic resonance imaging. Four weeks after MI, IBR-MSCs had no significant change in end-diastolic volume (+0.33±4.32 mL; P=0.89), end-systolic volume (+2.14±4.13 mL; P=0.21), and left ventricular ejection fraction (-2.27±2.94; P=0.33) while IBR-Placebo had significant increases in end-diastolic volume (+10.37±3.84 mL; P=0.01) and ESV (+11.35±2.88 mL; P=0.01), and a significant decrease in left ventricular ejection fraction (-5.78±1.70; P=0.025). Eight weeks after MI, adherent pericarditis was present in 0 of 8 IBR-MSCs versus 4 of 8 IBR-Placebo (P=0.02), suggesting an anti-inflammatory effect. In a separate study, 25 million allogeneic pig MSCs directly injected in the peri-infarct zone 3 days after MI (n=6) showed no significant benefit in adverse remodeling at 4 weeks compared with IBR-MSCs. Conclusions MSCs deployed inside an implantable, removable, and potentially rechargeable bioreactor in a large animal model remain viable, are immunoprotected, and attenuate adverse remodeling 4 weeks after MI.

AB - Background Prevention of adverse remodeling after myocardial infarction (MI) is an important goal of stem cell therapy. Clinical trial results vary, however, and poor cell retention and survival after delivery likely limit the opportunity to exert beneficial effects. To overcome these limitations, we built an implantable intravascular bioreactor (IBR) designed to protect contained cells from washout, dilution, and immune attack while allowing sustained release of beneficial paracrine factors. Methods and Results IBRs were constructed using semipermeable membrane adhered to a clinical-grade catheter shaft. Mesenchymal stem cell (MSC) viability in and paracrine factor release from IBRs were assessed in vitro and IBR biocompatibility and immune protection confirmed in vivo. In a porcine anterior MI model, IBRs containing 25 million allogeneic MSCs (IBR-MSCs) were compared with IBRs containing media alone (IBR-Placebo; n=8 per group) with adverse remodeling assessed by magnetic resonance imaging. Four weeks after MI, IBR-MSCs had no significant change in end-diastolic volume (+0.33±4.32 mL; P=0.89), end-systolic volume (+2.14±4.13 mL; P=0.21), and left ventricular ejection fraction (-2.27±2.94; P=0.33) while IBR-Placebo had significant increases in end-diastolic volume (+10.37±3.84 mL; P=0.01) and ESV (+11.35±2.88 mL; P=0.01), and a significant decrease in left ventricular ejection fraction (-5.78±1.70; P=0.025). Eight weeks after MI, adherent pericarditis was present in 0 of 8 IBR-MSCs versus 4 of 8 IBR-Placebo (P=0.02), suggesting an anti-inflammatory effect. In a separate study, 25 million allogeneic pig MSCs directly injected in the peri-infarct zone 3 days after MI (n=6) showed no significant benefit in adverse remodeling at 4 weeks compared with IBR-MSCs. Conclusions MSCs deployed inside an implantable, removable, and potentially rechargeable bioreactor in a large animal model remain viable, are immunoprotected, and attenuate adverse remodeling 4 weeks after MI.

KW - cytokines

KW - growth factors

KW - myocardial infarction

KW - remodeling heart failure

KW - stem cell

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