ABSTRACT

Table 5a.1 Several types of scaffold-based cardiac patches that have been implanted in animal models of HF Materials Types Cell sourcesSynthetic PGA Mesh Mouse ESCs [3]

PLGA Mesh Human dermal fibroblasts [4-10]

PGCL Sponge Rat bone marrow-derived MNCs [11] PLCL

Sponge Rat MSCs [12]Rat vascular SMCs

[13-15]

Materials Types Cell sourcesPU Sponge Rat myoblasts [16-22] NaturalAlginateAgarose SpongeHydrogel Rat cardiac cells [23-25]Human ADSCs [26]Collagen Hydrogel

Sponge Mouse ESCs [27]Human MSCs [28]Human ESC-derived mesenchymal cells [29]HUCBCs [34-36]Collagen plus Matrigel Hydrogel Rat cardiomyocytes [30-32] Rat myoblasts [33]Gelatin Sponge Rat cardiomyocytes [37, 38]Human myoblasts [39]Fibrin Hydrogel Pig MSCs [40]Human ESC-derived ECs and SMCs [41]SIS Sheet Rabbit MSCs [42]UBM Sheet Human MSCs [43]Pericardial matrix Sponge Rat MSCs [44-47]Myocardial matrix Sheet Human MPCs [48]

5a.3.1 Poly(Glycolic Acid)PGA is a biocompatible and biodegradable polymer that has been a very popular scaffold material since the early days of tissue engineering. The degradation rate of PGA, typically a few weeks, depends on the molecular weight of the polymer and the environmental conditions during the degradation process. Ke et al. implanted nonwoven PGA meshes seeded with ES-D3 cells from a mouse ESC line on the ventricular surface of infarcted hearts in mice [3]. After eight weeks, cellular PGA grafts improved blood pressure and left ventricular (LV) function, which resulted in an increased survival rate in mice after myocardial infarction (MI). In addition, immunostaining of the cardiac α-myosin heavy chain (α-MHC) was positive in the graft area. 5a.3.2 Poly(Lactide-co-Glycolide) PLGA is a biodegradable elastic copolymer of lactic acid (LA) and glycolic acid (GA), having the advantage of being able to tailor degradation by manipulating the ratio of LA/GA. Specifically, a higher percentage of GA results in an increased degradation rate. Therefore, PLGA copolymers are of great interest to make scaffolds for various applications. These copolymers degrade in vivo and eventually disappear at a desired rate, while native tissues grow and degradation residues are discharged through rental filtration. Kellar et al. applied a scaffold-based 3D human dermal fibroblast culture (3DFC), commercially available as Dermagraft, for cardiac repair in a mouse model of acute MI [4, 5]. Dermagraft is a cryopreserved dermal replacement template produced by culturing allogeneic neonatal human fibroblasts in a knitted PLGA mesh. Viable 3DFC patches stimulated mature blood vessel formation and attenuated a reduction in LV function of infarcted hearts. Moreover, these 3DFC grafts also stimulated angiogenesis and increased myocardial blood flow through sustained local delivery of angiogenic cytokines, such as vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), in rat models of acute and chronic MI [6-8]. Furthermore Kellar et al. reported the safety and biological effects of 3DFC to treat chronically ischemic canine hearts in compliance

with the Food and Drug Administration Good Laboratory Practice Regulations [9]. Recently, the regenerative medicine company Theregen Inc. reported clinical studies using 3DFC, renamed Anginera, for the treatment of heart disease [10]. In 2006 a phase I safety study was initiated of Anginera used as an adjunct therapy in patients with reversible myocardial ischemia undergoing coronary artery bypass graft (CABG) surgery. In 2009, a phase I study in patients who received a left ventricular-assist device (LVAD) as a bridge to heart transplantation was conducted. Theregen Inc. concluded that Anginera has the potential for growing mature blood vessels in underperfused cardiac tissue, which improves perfusion, and thus stimulates heart tissue repair. 5a.3.3 Poly(Glycolide-co-Caprolactone)

PGCL is a copolymer synthesized from glycolide and ε-caprolactone, possessing properties of rubber-like elasticity and biodegradability. Piao et al. implanted rat bone marrow-derived mononuclear cell (BMMNC)-seeded porous PGCL scaffolds onto the epicardial surface in a rat MI model [11]. As a result, they observed BMMNC migration into the epicardial region, differentiation to cardiomyocytes, induction of neovascularization, and the improvement of lessened LV remodeling and progressive LV systolic dysfunction. 5a.3.4 Poly(Lactide-co-Caprolactone)PLCL is a synthetic biocompatible copolymer of L-lactide and ε-caprolactone, which has elastic and biodegradable characteristics. Jin et al. investigated the effect of rat bone marrow-derived MSC implantation with porous PLCL scaffolds in a rat acute MI model [12]. MSC-seeded PLCL patches attenuated LV dilation and improved cardiac function. Moreover, implanted MSCs survived in the injured myocardium and expressed cardiac markers such as MHC, α-actin, troponin-I, and GATA-4. Additionally, Ozawa et al. showed that rat aortic SMCs could be seeded onto a PLCL sponge reinforced with knitted poly-L-lactide fabric. The SMC-seeded patches were then employed to replace a surgically created defect in the right ventricular outflow tract (RVOT) of rats [13, 14]. At right weeks after implantation, degradation of the patches, the presence of elastin fibers, and endothelialization were all observed in the grafts. Even

at 22 weeks the thickness of the grafts had been maintained. In the same manner, Matsubayashi et al. also demonstrated the feasibility of endoventricular circular patch plasty (EVCPP) repair using these SMC-seeded patches in a rat MI model [15]. 5a.3.5 PolyurethanePU is a synthetic biocompatible elastomer and displays excellent mechanical properties such as high tensile strength and abrasion resistance. Hence it has been used for a variety of medical implants, particularly for long-term implants. Siepe et al. created a cardiac patch by seeding neonatal rat skeletal myoblasts on a porous PU scaffold and evaluated the functional benefit of these constructs in rat MI models [16, 17]. The LV function was stabilized when the infarcted hearts were treated with cellular PU biografts. However, this beneficial effect on the LV function was only observed up to nine months following implantation [18]. On the other hand, for enhanced angiogenesis and reduction of the infarction zone in the ischemic myocardium, PU scaffolds have been seeded with transduced myoblasts, which overexpress paracrine growth factors or signaling factors involved in angiogenic, antifibrotic, and antiapoptotic processes [19-22].