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    • A number of animal models of CLI including the hindlimb

    2018-11-08

    A number of animal models of CLI, including the hindlimb ischemia model after femoral artery ligation in rats (Rochester et al., 1994) and rabbits (Hao et al., 2014), have been proven useful to assess the effects of various cell types and to study potential mechanisms of action. For instance, IM injections of culture-expanded ADSCs increased flow and induced a higher systemic presence of EPCs (Kondo et al., 2009). Iwase et al. (2005) demonstrated the superior angiogenic potential of bone marrow-derived MSCs over MNCs; the former were able to differentiate into both endothelial procyanidin b2 and vascular smooth muscle cells. Finally, Hao et al. (2014) reported the neovascularization effect of both ADSCs and bone marrow-derived MNCs. In these and other studies, ADSCs came to be recognized as a source for angiogenic factors acting through a paracrine mechanism, and in concert with other cellular players (e.g.: EPCs and macrophages) (Nakagami et al., 2005; Rehman et al., 2004; Sumi et al., 2007). Pre-clinical data have prompted multiple groups to explore the feasibility, safety and efficacy of bone marrow-derived cell-based therapy for PVD, through the design and execution of small clinical trials (summarized in Lawall et al., 2011, 2010; Liew and O\'brien, 2012; Raval and Losordo, 2013). Powell et al. (2011) reported the interim results of the RESTORE-CLI trial, where IM injections of tissue repair cells (analogous to a MNC mixture) proved no serious adverse effects, with increased amputation-free survival of patients and improved wound healing. In addition to the IM route, intra-arterial (IA) administration (through a femoral artery catheter) has been also safely and efficaciously used to inject allogeneic, expanded, bone marrow-derived MSCs (Das et al., 2013). In sum, adult stem cell transplantation constitutes a paradigm shift in the treatment of chronic limb ischemia (CLI), especially for diabetic patients (O\'Neill et al., 2012; Powell, 2012; Weck et al., 2011). The safety and efficacy of culture-expanded ADSCs derived from SVF for the treatment of CLI has been documented (Bura et al., 2014; Lee et al., 2012) and reviewed (Zhi et al., 2014), although further studies with more rigorous designs, including randomization, standard-of-care or placebo controls, are still needed. However, to the best of our knowledge, no report has been made so far with fresh, non-fractionated, un-cultured, point-of-care administered SVF in CLI. Therefore, an open label, non-randomized study to assess the safety and efficacy of non-culture-expanded adipose-derived SVF cells administered IM to ten patients with nonreconstructable CLI was designed, approved, and executed at the National Autonomous University of Nicaragua in Leon.
    Materials and methods
    Results
    Discussion This study describes clinical outcomes obtained when fresh, non-fractionated, not culture-expanded, adipose tissue-derived SVF was used to treat patients with CLI. The rationale for using SVF instead of expanded ADSCs was twofold: first, to test the feasibility of a point-of-care administration of a cell-based therapy approach; and second, to take advantage of the presence of additional regenerative cell populations within the SVF (e.g.: EPCs, hemopoietic progenitors and pericytes), documented as having angiogenic and blood vessel-stabilizing properties. This pilot, small, open-label, non-randomized, no control group safety/feasibility study documented the clinical outcomes, evaluated both clinically and by imaging, of 10 patients with CLI (Rutherford stage 3–6) treated with multiple IM injections of SVF. One patient was dropped from the study due to sudden cardiac death at 4months post-treatment, leaving nine patients for full analysis. Despite a wide range of cell doses (viable cells injected), the patients demonstrated positive clinical responses in all assessments. In fact, of the nine patients that were followed completely, at the end of the study all had experienced significant improvement in terms of pain control and in the ability to ambulate without claudication (in the seven patients in which the evaluation was feasible). ABI ratios were increased in all patients but the significance of this finding is unclear. Four of the five patients with non-healing ulcers had a complete closure in eight to nine months with no reported ulcerations after 18months. Angiographies showed evidence of neovascularization in five of the six patients in whom the imaging procedure was feasible. No particular pattern, either by localization (e.g. proximal, middle, or distal 1/3 of the leg), or by responding artery (e.g. peroneal, tibialis anterior and posterior, dorsalis pedis, etc.) was seen in the angiograms. Most importantly, the degree of revascularization in the leg was not as striking as the overall clinical response. We recognize the limitations of angiography, as these studies may be subject to variations by ambient temperature, heart rate, other medications (no patient was taking vasodilators), and technical difficulties with assessing collaterals (Gates and Hartnell, 2000). Our impression was that angiography in cases of severe distal disease involving small-vessels is not very sensitive as was expected and is of limited clinical use.