Microencapsulation to reduce mechanical loss of microspheres: implications in myocardial cell therapy
ABSTRACT Previous regenerative studies have demonstrated massive cell losses after intramyocardial cellular delivery. Therefore, efforts at reducing mechanical losses may prove more successful in optimising cellular therapy. In this study, we hypothesized that escalating mesenchymal stem cells (MSCs) dose will not produce corresponding improvement in cardiac function due to washout of the small cells in microcirculation. Using microspheres similar in size to MSCs, that are encapsulated in alginate-poly-l-lysine-alginate (APA), we tested the hypothesis that size is an important factor in early losses.
In experiment I, five groups of rats (n=9 each) underwent coronary ligation; group I had no treatment; the other groups received escalating 0.5 × 10(6), 1.5 × 10(6), 3 × 10(6) and 5 × 10(6) of MSCs each. Echocardiogram was performed at baseline, 2 days and 7 weeks after surgery. In experiment II, cell-sized microspheres (10 μm) were encapsulated in APA microcapsules. In group I (n=16), rats received bare microspheres, group II (n=16) microspheres within 200 μm microcapsules and in group III (n=16), microspheres within 400 μm microcapsules. After 20 min, hearts were quantified for the amount retained.
Myocardial function did not improve further with escalating cell doses beyond an initial response at 1.5 × 10(6) cells. Encapsulated microspheres in 200 μm and 400 μm microcapsules demonstrated a fourfold increase in retention rate compared with 10 μm microspheres.
We concluded that suboptimal functional improvement in this animal model starts at 1.5 × 10(6) cells and does not respond to escalating cell doses. Improving mechanical retention is possible by increasing the size of the injectate. Microencapsulation could be used to encapsulate donor cells and facilitate functional improvement in cellular heart failure therapy.
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ABSTRACT: Human umbilical vein endothelial cells (HUVECs) were successfully entrapped in polyethylene oxide (PEO) core /polycaprolactone (PCL) shell electrospun fibers thus creating a "bioactive fiber." The viability and release of biomolecules from the entrapped cells in the bioactive fibers were characterized. A key modification to the core solution was the inclusion of 50% fetal bovine serum (FBS), which improved cell viability substantially. The fluorescein diacetate (FDA) staining revealed that the entrapped cells were intact and viable immediately after the electrospinning process. A long-term cell viability assay using AlamarBlue® showed that cells were viable for over two weeks. Secreted Interleukin-8 (IL-8) was monitored as a candidate released protein, which can also act as an indicator of HUVEC stress. These results demonstrated that HUVECs could be entrapped within the electrospun scaffold with the potential of controllable cell deposition and the creation of a bioactive fibrous scaffold with extended functionality.02/2014; 4(1). DOI:10.4161/biom.28238
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ABSTRACT: Heart failure remains a major cause of death and disability, requiring rapid development of new therapies. Bone marrow-derived mesenchymal stem cell (MSC)-based therapy is an emerging approach for the treatment of both acute and chronic heart failure. Following successful experimental studies in a range of models, more than 40 clinical trials of MSC-based therapy for heart failure have now been registered, and the results of completed clinical trials so far have shown feasibility and safety of this approach with therapeutic potential suggested (though preliminarily). However, there appear to be several critical issues to be solved before this treatment could become a widespread standard therapy for heart failure. In this review, we comprehensively and systemically summarize a total of 73 preclinical studies and 11 clinical trial reports published to date. By analyzing the data in these reports, (1) improvement in the cell delivery method to the heart in order to enhance donor cell engraftment, (2) elucidation of mechanisms underpinning the therapeutic effects of the treatment differentiation and/or treatment secretion, and (3) validation of the utility of allogeneic MSCs which could enhance the efficacy and expand the application/indication of this therapeutic approach are highlighted as future perspectives. These important respects are further discussed in this review article with referencing latest scientific and clinical information.Heart Failure Reviews 05/2014; DOI:10.1007/s10741-014-9435-x · 3.99 Impact Factor
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ABSTRACT: Objective: The aim of the present study was to construct a new drug delivery system for milrinone using microparticles. This novel technology enhances drug bioavailability and decreases toxicity, with future implications for the treatment of end-stage heart failure. Methods: Polylactic-co-glycolic acid microparticles (PLGA-MPs) loaded with milrinone were prepared using a double emulsion-solvent evaporation technique. In vitro release kinetics was evaluated at physiologic conditions. A total of 24 female Lewis rats underwent left coronary artery ligation. One week after ligation, all rats were randomized to 1 of 3 groups (n = 8 per group). Group I received an intravenous injection of PLGA-MPs alone; group II, a bolus intravenous injection of milrinone; and group III an intravenous injection of milrinone-PLGA-MPs. All injections were administrated slowly by way of the tail vein over 10 minutes. Transthoracic echocardiography, noninvasive heart rate monitoring, and blood pressure measurements were performed at different predetermined intervals before and for 24 hours after the injection. All rats survived for 24 hours and were then killed by euthanasia. Serum plasma was taken for cytokine assays and determination of milrinone levels using high-performance liquid chromatography. Results: Group III had a significantly greater left ventricular ejection fraction at 90 minutes and 3, 6, and 12 hours after treatment compared with the other groups. The milrinone plasma level was significantly greater in group III than in the other groups (group I, 0 ng/mL; group II, 1.7 +/- 2.4 ng/mL; group III, 9.1 +/- 2.2 ng/mL; P < .05). The intercellular adhesion molecule and cytokine-induced neutrophil chemoattractant-1 levels were significantly lower in group III than in the other 2 groups (P < .05). Conclusions: Drug encapsulation using microparticles can prolong the effects of milrinone. We propose a new strategy for future drug delivery in patients with end-stage heart failure.Journal of Thoracic and Cardiovascular Surgery 07/2014; 148(5). DOI:10.1016/j.jtcvs.2014.07.033 · 3.99 Impact Factor