No abstract

Transplantation of adipose-derived stem cells (ADSCs) is an emerging therapeutic option for addressing intractable diseases such as critical limb ischemia (CLI). Evidence suggests that therapeutic effects of ADSCs are primarily mediated through paracrine mechanisms rather than transdifferentiation. These secreted factors can be captured in conditioned medium (CM) and concentrated to prepare a therapeutic factor concentrate (TFC) composed of a cocktail of beneficial growth factors and cytokines that individually and in combination demonstrate disease-modifying effects. The ability of a TFC to promote reperfusion in a rabbit model of CLI was evaluated. A total of 27 adult female rabbits underwent surgery to induce ischemia in the left hindlimb. An additional five rabbits served as sham controls. One week after surgery, the ischemic limbs received intramuscular injections of either (1) placebo (control medium), (2) a low dose of TFC, or (3) a high dose of TFC. Limb perfusion was serially assessed with a Doppler probe. Blood samples were analyzed for growth factors and cytokines. Tissue was harvested postmortem on day 35 and assessed for capillary density by immunohistochemistry. At 1 month after treatment, tissue perfusion in ischemic limbs treated with a high dose of TFC was almost double (p < 0.05) that of the placebo group [58.8 ± 23 relative perfusion units (RPU) vs. 30.7 ± 13.6 RPU; mean ± SD]. This effect was correlated with greater capillary density in the affected tissues and with transiently higher serum levels of the angiogenic and prosurvival factors vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF). The conclusions from this study are that a single bolus administration of TFC demonstrated robust effects for promoting tissue reperfusion in a rabbit model of CLI and that a possible mechanism of revascularization was promotion of angiogenesis by TFC. Results of this study demonstrate that TFC represents a potent therapeutic cocktail for patients with CLI, many of whom are at risk for amputation of the affected limb.

The utilization of NMR method for BP absorption kinetics evaluation is a useful tool, which may be widely adopted to test other biodegradable implants. Further, it may substantially improve their safety and efficacy by facilitating programmed polymer and drugs elution.

Background: New paclitaxel coated balloons (PCB) developments have been proposed to maintain therapeutic levels of drug in the tissue while decreasing particle release. In this series of studies, we evaluated the pharmacokinetic profile and biological effects after paclitaxel delivery via novel microcrystalline PCB coating (mcPCB, Pax V R , Balton) in porcine iliofemoral arteries. Methods: Ten domestic swine were enrolled yielding 24 iliofemoral segments for evaluation. In the pharmacokinetic study, nine mcPCBs were dilated for 60 sec and animals sacrificed after 1 hr, 3 and 7 days. Studied segments were harvested and tissue paclitaxel concentration was analyzed utilizing HPLC. In the biological response evaluation, self-expandable stents were implanted followed by post dilation with either mcPCB (n 5 10) or POBA (n 5 5). After 28 days, angiography was performed, animals were sacrificed and stented segments harvested for histopathological evaluation. Results: The 1-hr, 3 and 7 days vessel paclitaxel concentrations were 152.9 6 154.5, 36.5 6 49.5, and 0.9 6 0.7 ng/mg respectively. In the biological response study, stents in the mcPCB group presented lower angiographic measures of neointimal hyperplasia as expressed by late loss when compared to POBA (20.43 6 0.9 vs. 0.23 6 1.2; P 5 0.24) at 28 days. In the histopathological evaluation, percent area of stenosis (%AS) was reduced by 42% in the mcPCB group (P < 0.05). The healing process in mcPCB group was comparable to POBA with regard to fibrin deposition (0.7 vs. 0.7; P 5 ns), neointimal maturity (1.97 vs. 1.93; P 5 ns), inflammation score (0.92 vs. 1; P 5 ns) and endothelialization score (1.77 vs. 1.73; P 5 ns). The mcPCB group did however display a greater tendency of medial cell loss and mineralization (60% vs. 0; P 5 0.08). Conclusions: Delivery of paclitaxel via a novel mcPCB resulted in low long-term tissue retention of paclitaxel.

A b s t r a c tBackground: Fast releasing, rapamycin-eluting stents, although safe, showed inferior results with regard to inhibition of restenosis.Aim: Therefore, we report vascular effects of a novel, biodegradable polymer stent matrix with elevated sirolimus dose and fast release kinetics (ed-frSES, Alex, Balton) in the porcine coronary in-stent restenosis model. Methods:A total of 19 stents were implanted with 120% overstretch in the coronary arteries of seven domestic pigs: seven ed-frSES with 1.3 μg/mm 2 of sirolimus, eight frSES with 1 μg/mm 2 of sirolimus, and eight bare metal stents (BMS). For the following 28 days, coronary angiography was performed, animals were sacrificed, and the stented segments harvested for histopathological evaluation. Results:In angiography at 28 days the late lumen loss was lowest in the elevated dose sirolimus eluting stent (SES) (ed-frSES: 0.20 ± 0.2 vs. frSES: 0.80 ± 0.5 vs. BMS: 0.96 ± 0.5 mm, p < 0.01). This was confirmed in the morphometric evaluation in histopathology as represented by a significant and dose-dependent decrease in the percentage area of stenosis (ed-frSES: 22.4 ± 12.7% vs. frSES: 35 ± 10.7% vs. BMS: 47.5 ± 12.5%, p < 0.01). There was no peri-strut inflammation in any of the groups. However, the endothelialisation score was numerically not meaningfully decreased in ed-frSES (ed-frSES: 2.93 vs. frSES: 3. vs. BMS: 3, p = 0.05). Signs of fibrin were also noted in ed-frSES (ed-frSES: 0.4 vs. frSES: 0 vs. BMS: 0, p = 0.05). Conclusions:Sirolimus dose-dependent vascular response was reported. The elevated dose, fast releasing SES shows satisfactory vascular healing, similar to regular dose, fast release SES, with improved efficacy in restenosis inhibition.

We aimed to compare the vascular effects exclusive to antiproliferative agents by using identical stent and biodegradable polymeric matrices eluting everolimus (BP-EES) (Carlo; Balton) and paclitaxel (BP-PES) (Luc-Chopin2; Balton) in the porcine model of coronary injury. A total of 37 stents were implanted with 110% overstretch in the coronary arteries of 14 domestic pigs: 13 BP-PES, 16 BP-EES and eight bare metal stents (BMS) (Chopin2; Balton). Coronary angiography was performed after 28 and 90 days, the animals were sacrificed and the stented segments harvested for histopathological evaluation. At 28 days, BP-PES most effectively limited angiographic late loss (LL PES: 0.15±0.1 vs. EES: 0.40±0.3 vs. BMS: 0.5±0.2 mm; p=0.04) and neointimal thickness (NT) in histology (PES: 0.12 [0.1-0.2] vs. EES: 0.38 [0.3-0.4] vs. BMS: 0.35 [0.3-0.4] mm; p<0.01). The BP-PES had lower endothelialisation (EES: 100% vs. PES: 40±4% vs. BMS: 97.5±5%; p<0.01) and slightly higher inflammation scores (EES: 1 vs. PES: 2.1±0.3 vs. BMS: 1; p<0.01). At three months, LL remained unchanged in the EES and BMS groups in contrast to an increase in the PES group (EES: 0.38±0.3 vs. PES: 0.52±0.4 vs. BMS: 0.51±0.3 mm; p=0.69). NT stabilised at 90 days in the EES group in comparison to a fourfold increase in the PES group and a 30% increase in the BMS group (EES: 0.35 [0.3-0.5] vs. PES: 0.53 [0.5-0.8] vs. BMS: 0.46 [0.4-0.5] mm: p=0.07). Stent endothelialisation and inflammation were comparable at 90 days in all groups. Temporal differences in vascular response were seen by the delivery of different antiproliferative agents. In contrast to everolimus, paclitaxel seems to induce a slightly higher degree of inflammation in the short term, potentially leading to further neointimal hyperplasia in the long term.

No abstract

The study proved safety, feasibility, and biocompatibility of PDVG formed on the basis of a silicone-coated, latex catheter in an SDF-1 chemokine-enriched environment. These biological grafts effectively integrated with the native high-pressure arterial environment in an ovine model and provided favorable vascular profile. The potential clinical value of this technology needs to be further elucidated in long-term preclinical and clinical studies.