Nederlandse Vereniging voor Klinische Chemie en Laboratoriumgeneeskunde
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Project 56 Prevention of major Amputation by Autologous Transplantation of bone marrow Stemcells in end stage chronic limb ischemia
Onderzoekslijn Tissue Engineering
Omschrijving Collateral vessel formation could be induced in ischemic nude rats hindlimbs by supplying blood mononuclear cells and platelets producing angiogenic factors and cytokines, suggesting that this cell therapy is useful as a novel strategy for therapeutic angiogenesis . Recently, Tateishi et al . demonstrated that angiogenesis could be induced with autologous transplantation of bone-marrow cells in patients with end stage CLI. After a pilot study in 25 patients, a randomised study was performed in 22 patients with bilateral stage 4, 5 or 6 CLI. This means patients with chronic rest pain and or non-healing ischemic ulcerations and no vascular reconstructive options. Diabetes mellitus was present in 65% of the patients although poorly controlled diabetic patients were excluded. The 22 patients were randomly allocated to implantation of either bone marrow-mononuclear cells (active treatment) or peripheral blood mononuclear cells (controls) into the right or left leg in a simultaneous within-patient trial fashion. The mononuclear cells were implanted by intramusculair injection into the gastrocnemius muscle. Primary outcomes were safety and feasibility of treatment defined as improvements in ankle brachial index (ABI), transcutaneous oxygen pressure (TcO2) and development of restpain. After 4 weeks both the ABI, and TcO2 were significantly increased and in 16 ot of 20 patients the vascular rest pain was resolved. Improvements were maintained during 24 weeks of follow up. Results of angiography showed a striking increase in number of visible collateral vessels in 12 out of 25 patients. An independent review committee noticed no adverse events. Also in a general hospital setting successful therapeutic angiogenesis is reported in a patientcohort with Buerger?s disease
The Tateishi study was the first report showing real clinical improvement in the treatment of patients with non-reconstructive end stage CLI on short term. Minor critiques of this study are the necessity of bone marrow harvest, that both diabetics and non-diabetics are included without any stratification and that the most important clinical endpoint, durable leg salvage after woundhealing pluripotent monocytes, was not reported.
Therapeutic angiogenesis is stimulated with agiogenic proteins. In the TRAFFIC study 190 patients with claudication were randomly assigned to received intra arterial infusion in the common femoral artery of recombinant fibroblast growth factor. In the active treatment leg the peak walking time was statistical significant increased .
Recently, also in the cardiac area the potential benefits of pluripotent monocytes induced neovascularisation is reported , The autologous mononuclear bone marrow cells are delivered directly into the ischaemic myocardium with percutaneous catheter procedures.
We hypothesize that the direct delivery of mononuclear cells in the capillary bed of the ischemic tissue itself in combination with local delivery of angiogenic proteins might improve the results of Tateishi-Yuyama et al. In order to achieve that goal we want to explore the possibility of intra-arterial injection in the inflow vessel of the ischaemic tissue of pluripotent monocytes in combination with angiogenic proteins encapsulated in a degradable nanoparticle. Encapsulating pluripotent monocytes induces the possibility for selective delivery of the stemcells in the microcirculation, even in the vasa vasorum of small vessels A clinical study assessing this aspects with formal clinical endpoints has not been performed yet.

2. Objectives
2.1. Part A
To study the efficacy and safety of using mononuclear cells harvested from bone marrow and injected in gastrocnemic muscle nearby the ischaemic area in a clear defined population with non-reconstructive end stage CLI. V and VI (?the Tateishi study?).

Projectleider Dr. J.(Jennita) Slomp
Instituut Medlon BV Enschede
Trefwoorden Stem cells, autologous transplantation of bon marrow, end stage chronic limb ischemia
Status Lopend
Periode 1-2005 - 1-2012
Partners Dr R.H. Geelkerken
T. Kahraman
M. Blokhuis, nurse practitioner
Department of Vascular Surgery.

Prof. dr I. Vermes
Department of Clinical Chemistry.

Dr M. de Groot
Department of Internal Medicine, Div. Haematology.

Dr J. van der Palen
Drs E. Monninkhof
Department of Epidemiology

Research Bureau Heelkunde
Dr D.W. Grijpma
W. Steenbergen
Prof. dr J. Feijen
Institute for Biomedical Technology, Faculty of Science & Technology
University of Twente
Medewerkers H. Weekamp, PhD student, University of Twente
M. Kamphuis, Technician, University of Twente
dr. A.A. Poot, University of Twente
N. Rosendahl-Kiens, technician
A. Heijs, technician
Financiering 1e Geldstroom - Intern