Composite scaffold provides a cell delivery platform for cardiovascular repair

Abstract

Control over cell engraftment, survival, and function remains critical for heart repair. We have established a tissue engineering platform for the delivery of human mesenchymal progenitor cells (MPCs) by a fully biological composite scaffold. Specifically, we developed a method for complete decellularization of human myocardium that leaves intact most elements of the extracellular matrix, as well as the underlying mechanical properties. A cellmatrix composite was constructed by applying fibrin hydrogel with suspended cells onto decellularized sheets of human myocardium. We then implanted this composite onto the infarct bed in a nude rat model of cardiac infarction. We next characterized the myogenic and vasculogenic potential of immunoselected human MPCs and demonstrated that in vitro conditioning with a low concentration of TGF-β promoted an arteriogenic profile of gene expression. When implanted by composite scaffold, preconditioned MPCs greatly enhanced vascular network formation in the infarct bed by mechanisms involving the secretion of paracrine factors, such as SDF-1, and the migration of MPCs into ischemic myocardium, but not normal myocardium. Echocardiography demonstrated the recovery of baseline levels of left ventricular systolic dimensions and contractility when MPCs were delivered via composite scaffold. This adaptable platform could be readily extended to the delivery of other reparative cells of interest and used in quantitative studies of heart repair.biomaterial | cardiac repair | human stem cell | cardiac patch G iven the adult heart's minimal capacity for endogenous regeneration (1), cell therapy has emerged as a viable option for revascularization (2) and regeneration (3) of the infarct bed. Cell delivery methods are progressing through clinical trials, particularly in the setting of end-stage heart failure, where the lack of effective therapies leads to more than 500,000 deaths per year in the United States alone (4). Human mesenchymal stem cells (MSCs) were used with variable functional improvement and neovascularization (5-10). This outcome is thought to be largely due to the use of cell suspensions that are limited by poor cell retention (11), survival (12), engraftment (13), and differentiation (14). The underlying mechanisms (i.e., secretion of paracrine factors vs. cell incorporation) are not well defined and can be interrogated only through control over cell retention (e.g., by the use of scaffolding materials) and insight into cell phenotype (e.g., expression of functional markers). We introduce a cell delivery platform that combines a fully biological gel-matrix composite scaffold with biochemical preconditioning of human MPCs. The resulting vasculogenic and myogenic cell properties and functional benefits of the cell delivery platform were evaluated in an animal model of myocardial infarction (MI). Results and DiscussionCell Delivery Platform. Composite scaffolds for cell delivery were assembled from thin sheets of decellularized human myocardium and fibrin hydrogel. MPCs were imm...

Indirect three‐dimensional printing: A method for fabricating polyurethane‐urea based cardiac scaffolds

“…The created scaffolds fulfill both of these criteria: The elastic modulus of 15–132 kPa displayed by the scaffolds under tension fits well into the range measured for cardiac muscle 20–500 kPa,24 and resides within the interval (7.9–1200 kPa) that has been reported in previous cardiac biomaterial studies 25, 26, 27, 28, 29, 30…”

Cardiac Tissue Engineering

“…44 It is not clear at this point how the reported formation of new myocardium is compatible with the extremely low capacity of the adult mammalian heart to regenerate cardiac myocytes. 45 Most studies to date concluded that the reported beneficial effects of injecting alginate, 46 ECM, 47 or nanofibers 48 into infarcted hearts are likely independent of the formation of new heart muscle and potentially because of improved angiogenesis or mechanical stabilization of the ventricular wall. Similar mechanisms have been suggested to account for the beneficial effects of cell therapy.…”

“…An elaborated approach was developed by Godier-Furnémont et al 47 Scaffolds were made from decellularized human hearts, seeded with mesenchymal stem cell in a fibrin hydrogel, and implanted onto infarcted nude rat hearts. This promoted an arteriogenic response and improved functional recovery, particularly when mesenchymal stem cells had been in vitro preconditioned by transforming growth factor-β before cell seeding.…”

Spatial-temporal reorganization of activated integrins

“…Many recent studies have shown that decellularized tissues provide an excellent matrix for the differentiation of mesenchymal stem cells into the original tissue type. 54,55 Thus, the combination of different matrices appears to have a major effect on the differentiation process. It will be important to use a variety of different matrix ligands to determine how the synergy of different integrin binding components occurs.…”