As mentioned previously, most attempts in the field of cardiac regeneration after MI have focused on cellular therapy. Clinically, the vast majority of reported studies, mostly using bone fragments marrow-derived mononuclear cells (revised in [ 41 ]), are intricate to compare because the delivered cells are possibly mixed or enriched populations, and the number of implanted cellular material, delivery methods, and injection time intervals are not generally comparable. Other experiences have included MSCs harvested through bone marrow aspirates [ 42 , 43 ], subcutaneous adipose cells [ 44 ], and Wharton’ s jelly [ 45 ]. In general, studies have commonly employed the intracoronary or intramyocardial cell delivery routes, and use of these routes continues to be associated with low ratios of cell engraftment and success. Hence, despite being safe and technologically feasible, regular cell therapy approaches in humans have not reproduced the advantages in cardiac function restoration observed in preclinical animal versions, because of the difficulties involved in repairing usually large myocardial marks and because of the low efficacy of administered cells, because of low retention rates, poor survival, and lack of difference. Consequently, increasingly more studies are based on techniques involving cardiac LO, which aims to combine stem cells with synthetic or even natural scaffolds with characteristics very similar to those of native myocardial tissue. Once locally delivered/implanted in the infarcted area, these types of innovative bioactive constructs can integrate effectively into focus on tissues to regenerate myocardial scars and improve heart function [ 46 , 47 ].
Regarding natural scaffolding materials for cardiac restoration after MI, collagen scaffold-associated benefits have been observed in various MI models using subcutaneous adipose tissue-derived MSCs [ 48 , 49 ]. In rats, MSCs from brown adipose cells also improved cardiac function and contractility when used into the infarcted area inside a chitosan scaffold [ 50 ]. Other in-vivo experiences have included the use of alginate, hyaluronic acid, gelatin, and matrigel (revised in [ 51 ]). Alternatively, our group has evaluated the implantation of fibrin as a scaffold material for cardiac restoration (revised in [ 37 ]). Thus, we created 3D engineered fibrin patches filled with cATMSCs or UCBMSCs and delivered them to postinfarcted myocardium in mice [ 36 , 40 , 52 ]. Fibrin patches filled with stem cells can be placed along with myocardium undergoing scarring. This procedure avoids many of the drawbacks associated with conventional cell-infusion systems. Fibrin has several advantages; it could be extracted from the patient’ s blood; it is easily readjusted; the implantation procedure is simple; it promotes viability plus early proliferation in delivered cells; and it provides advantages, even when a fibrin patch does not contain cells. Within our studies, new functional vascular growth and improved heart function were commonly observed in animals treated with fibrin– MSC patches. However , the fates of implanted cells seemed to depend on the cell type. Implanted UCBMSCs exclusively led to vascular growth, and implanted cATMSCs exhibited heart and endothelial properties. In some of these pioneering studies, we all employed noninvasive bioluminescence imaging to track the behavior and success of implanted cells [ 36 , 52 ]. We found that will, although fibrin patches enhanced MSC retention, their immigration toward injured myocardium and survival were limited, whatever the MSC origin. These restrictions limited the therapeutic results. In addition , we had to scale up the production of fibrin– cell patches to achieve comparable or better results in people.
Other correctly commonly employed swine as the translational model for providing microporous membranes filled with cATMSCs after MI. In particular, during these studies, scaffolds from porcine myocardium or human pericardium have been assessed [ 53 – 57 ]. Succinctly, these scaffolds made up a filamentous extracellular matrix, from which all cellular plus nuclear content are removed in a process called decellularization. After decellularization, these natural scaffolds preserved fiber predisposition and structure; promoted high levels of cell repopulation; carefully matched the native, physiological microenvironment; preserved the natural stiffness, composition, vasculature network, and 3-D framework associated with myocardium; and enabled electromechanical coupling with the host myocardium upon implantation. Moreover, once implanted in the ischemic myocardium, these engineered bioimplants improved cardiac function, reduced infarct size, attenuated fibrosis progression, and promoted both neovascularization and neoinnervation. Thus, we concluded that cardiac TE supplied promising beneficial effects without any identified adverse side effects, assisting its clinical translation.
As also mentioned previously, our laboratory was your first to describe the cardioreparative potential of the adipose cells that surrounds the heart and pericardium, and we proposed cATMSCs as a prospective source of MSCs and a biological matrix. We all also envisioned a novel approach (AGTP) for adding cardiac adipose tissue-derived cell therapy with TE to get repairing damaged myocardium. In the AGTP, a vascularized adipose flap was transpositioned over the infarcted area, which all of us demonstrated in the porcine MI model [ 58 , 59 ]. Nevertheless , recently, the risks associated with open chest surgery have caused the advent of alternative surgical approaches; in addition , it might be good for provide the AGTP to patients who do not need coronary artery bypass grafts. Consequently, we reasoned that a minimally intrusive AGTP approach (mi-AGTP) would be desirable for clinical configurations. Therefore , we assessed the mi-AGTP in the swine design with thoracoscopy [ 60 ]. This novel surgical method provided beneficial effects for left ventricular function plus inhibited myocardial remodeling following acute MI [ 58 ]. We then assessed the effect of postinfarction scar insurance with the AGTP in a pig model of chronic MI. Generally there, the flap was placed on the scar 2 days after artery occlusion with a coil. One month after the AGTP, histopathologic analysis confirmed a reduction in infarct size and the existence of vascular connections at the flap– myocardium interface. Even so, at the functional level, we did not detect significant adjustments in LV ejection fraction or end-systolic and end-diastolic volumes [ 59 ]. Thus, this innovative approach required advantage of local existing tissue to limit the size of the particular infarct scar, which simplified the surgical procedure and possibly avoided the risks associated with nonautologous cells manipulated ex vivo [ 61 ]. Thus, the AGTP intervention is anticipated to be readily adaptable to clinical practice; it is officially simple, it does not require additional or expensive material, and it also does not incur any ethical or social concerns which could constrain its employment. Of note, we reported the particular first-in-man clinical trial (ClinicalTrials. gov NCT01473433, AdiFLAP Trial— AGTP-I), which investigated the safety and efficacy from the AGTP in patients with chronic MIs who went through coronary artery bypass graft surgery [ 62 ]. Our own experience demonstrated that the AGTP was safe; treated sufferers showed trends of smaller left ventricular end-systolic quantity and smaller necrosis ratios. However , the AGTP failed to completely reverse myocardial dysfunction. These encouraging results resulted in an ongoing 1-year follow-up multicenter randomized controlled trial (ClinicalTrials. gov NCT02798276, AGTP-II) to test AGTP efficacy. Eligible sufferers included candidates for surgical revascularization in one or more myocardial areas with a nonrevascularizable area. The trial was designed in order to validate the ability of AGTP to reduce necrotic areas [ 63 ].