Combined intra-arterial and intra-muscular transfer 
of Wharton’s jelly mesenchymal stem/stromal cells in 
no-option critical limb ischemia – the CIRCULATE N-O CLI Pilot Study

Tomasz Kwiatkowski; Katarzyna Zbierska-Rubinkiewicz; Jerzy Krzywon; Marcin Majka; Danuta Jarocha; Jacek Kijowski; Andrzej Brzychczy; Piotr Musialek; Mariusz Trystula

doi:10.5114/aic.2022.120963

eISSN: 1897-4295
ISSN: 1734-9338

Advances in Interventional Cardiology/Postępy w Kardiologii Interwencyjnej

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abstract:

Original paper

Combined intra-arterial and intra-muscular transfer of Wharton’s jelly mesenchymal stem/stromal cells in no-option critical limb ischemia – the CIRCULATE N-O CLI Pilot Study

Tomasz Kwiatkowski

¹

,

Katarzyna Zbierska-Rubinkiewicz

¹

,

Jerzy W. Krzywon

¹

,

Marcin Majka

²

,

Danuta Jarocha

³

,

Jacek Kijowski

²

,

Andrzej Brzychczy

¹

,

Piotr Musialek

⁴

,

Mariusz Trystula

¹

Department of Vascular Surgery, John Paul II Hospital, Krakow, Poland
Department of Transplantation, Jagiellonian University, Krakow, Poland
Division of Hematology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
Department of Cardiac and Vascular Diseases, Jagiellonian University, John Paul II Hospital, Krakow, Poland

Adv Interv Cardiol 2022; 18, 4 (70): 439–445

DOI: https://doi.org/10.5114/aic.2022.120963

Online publish date: 2022/11/07

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AMA

Kwiatkowski T, Zbierska-Rubinkiewicz K, Krzywon JW, et al. Combined intra-arterial and intra-muscular transfer 
of Wharton’s jelly mesenchymal stem/stromal cells in 
no-option critical limb ischemia – the CIRCULATE N-O CLI Pilot Study. Advances in Interventional Cardiology/Postępy w Kardiologii Interwencyjnej. 2022;18(4):439-445. doi:10.5114/aic.2022.120963.

APA

Kwiatkowski, T., Zbierska-Rubinkiewicz, K., Krzywon, J. W., Majka, M., Jarocha, D.,  & Kijowski, J. et al. (2022). Combined intra-arterial and intra-muscular transfer 
of Wharton’s jelly mesenchymal stem/stromal cells in 
no-option critical limb ischemia – the CIRCULATE N-O CLI Pilot Study. Advances in Interventional Cardiology/Postępy w Kardiologii Interwencyjnej, 18(4), 439-445. https://doi.org/10.5114/aic.2022.120963

Chicago

Kwiatkowski, Tomasz, Katarzyna Zbierska-Rubinkiewicz, Jerzy W Krzywon, Marcin Majka, Danuta Jarocha, Jacek Kijowski,  and Andrzej Brzychczy et al. 2022. "Combined intra-arterial and intra-muscular transfer 
of Wharton’s jelly mesenchymal stem/stromal cells in 
no-option critical limb ischemia – the CIRCULATE N-O CLI Pilot Study". Advances in Interventional Cardiology/Postępy w Kardiologii Interwencyjnej 18 (4): 439-445. doi:10.5114/aic.2022.120963.

Harvard

Kwiatkowski, T., Zbierska-Rubinkiewicz, K., Krzywon, J., Majka, M., Jarocha, D., Kijowski, J., Brzychczy, A., Musialek, P.,  and Trystula, M. (2022). Combined intra-arterial and intra-muscular transfer 
of Wharton’s jelly mesenchymal stem/stromal cells in 
no-option critical limb ischemia – the CIRCULATE N-O CLI Pilot Study. Advances in Interventional Cardiology/Postępy w Kardiologii Interwencyjnej, 18(4), pp.439-445. https://doi.org/10.5114/aic.2022.120963

MLA

Kwiatkowski, Tomasz et al. "Combined intra-arterial and intra-muscular transfer 
of Wharton’s jelly mesenchymal stem/stromal cells in 
no-option critical limb ischemia – the CIRCULATE N-O CLI Pilot Study." Advances in Interventional Cardiology/Postępy w Kardiologii Interwencyjnej, vol. 18, no. 4, 2022, pp. 439-445. doi:10.5114/aic.2022.120963.

Vancouver

Kwiatkowski T, Zbierska-Rubinkiewicz K, Krzywon J, Majka M, Jarocha D, Kijowski J et al. Combined intra-arterial and intra-muscular transfer 
of Wharton’s jelly mesenchymal stem/stromal cells in 
no-option critical limb ischemia – the CIRCULATE N-O CLI Pilot Study. Advances in Interventional Cardiology/Postępy w Kardiologii Interwencyjnej. 2022;18(4):439-445. doi:10.5114/aic.2022.120963.

Introduction
Despite progress in pharmacologic and revascularization therapies, no-option critical limb ischemia poses a major clinical and societal problem. Prior cell-based strategies involved mainly autologous (limited) cell sources. Aim: To evaluate the safety and feasibility of a novel ischemic tissue reparation/regeneration strategy using Wharton’s jelly mesenchymal stem/stromal cells (WJMSCs) as an “unlimited” cell source in N-O CLI (first-in-man study, FIM).

Material and methods
Enrollment criteria included Rutherford-4 to Rutherford-6 in absence of anatomic/technical feasibility for revascularization and adequate inflow via the common femoral artery with patency of at least one below-the-knee artery. 30 × 106 WJMSCs were administered intra-arterially and intra-muscularly (50%/50%) over 3–6-week intervals (3–6 administrations). Safety, feasibility and potential signals of efficacy were assessed at 12 and 48 months.

Results
Five patients (age 61–71, 60% male, Rutherford-6 20%, Rutherford-5 60%, Rutherford-4 20%) were enrolled. WJMSCs were administered per protocol in absence of administration technique-related adverse events. Hyperemia, lasting 12–24 h, occurred in 4/5 subjects. Transient edema and pain (reactive to paracetamol) occurred in 3 (60%) patients. Amputation-free survival was 80% after 12 and 48 months. In those who avoided amputation, ischemic ulcerations healed and Rutherford stage improved. 4/5 patients were free of resting pain after 3–6 doses.

Conclusions
This FIM study demonstrated the safety and feasibility of WJMSCs use in patients with N-O CLI and suggested treatment efficacy with ≥ 3 doses. Our findings provide a basis for a randomized, double-blind clinical trial to assess the efficacy of WJMSC-based therapeutic strategy in N-O CLI patients.

keywords:

Combined intra-arterial and intra-muscular transfer of Wharton’s jelly mesenchymal stem/stromal cells in no-option critical limb ischemia – the CIRCULATE N-O CLI Pilot Study

Tomasz Kwiatkowski 1 , Katarzyna Zbierska-Rubinkiewicz 1 , Jerzy W. Krzywon 1 , Marcin Majka 2 , Danuta Jarocha 3 , Jacek Kijowski 2 , Andrzej Brzychczy 1 , Piotr Musialek 4 , Mariusz Trystula 1

Wharton’s jelly mesenchymal stem cells, critical limb ischemia, no-option limb ischemia, CIRCULATE

Tomasz Kwiatkowski

¹

,

Katarzyna Zbierska-Rubinkiewicz

¹

,

Jerzy W. Krzywon

¹

,

Marcin Majka

²

,

Danuta Jarocha

³

,

Jacek Kijowski

²

,

Andrzej Brzychczy

¹

,

Piotr Musialek

⁴

,

Mariusz Trystula

¹