A subset of specialized natural scaffolds that may hold promise as organotypic matrices are acellularized tissues. The process of acellularization has been studied extensively, with acellularized tissues as scaffolds for tissue engineering currently in clinical use, for example as natural matrices for cardiac valve replacement [61, 62]. Similarly, acellularized tissue-based scaffolds made from SIS are currently being considered for the repair of damaged myocardium after cardiac heart failure [63]. All of these acellularized scaffolds are created by using a combination of hypotonic lysis buffers, detergents, and/or proteolytic enzymes to remove cells and their constituents from native tissues, while leaving behind the maximal amount of intact ECM proteins and preserving as much as possible the native organizational structure [64]. The nature and bioactivity of the residual ECM proteins retained upon acellularization depend largely on the specific methodologies used to generate these acellularized tissues. Indeed, if performed carefully, acellularized tissue can also retain vascular conduits, thus facilitating homogeneous seeding of the constructs through the vascular pedicles. For all these approaches, different methodologies are being used to disrupt cell membranes, to rupture the intracellular organelles, and finally to remove residual intracellular debris and nucleic acids. As an example, Zhong et al. [65] used a two-step approach, in which detergent (sodium dodecyl sulfate, SDS) extraction was followed by a proteolytic (trypsin) digestion yielding acellularized porcine aortic scaffolds, comprised mainly of collagen and elastin. Such acellularized blood vessels are currently being tested in preclinical studies as scaffolds for vascular grafts [66]. Using a similar approach, we have recently generated acellularized murine hearts and lungs. Figure 1.3 shows light microscopy (Fig. 1.3A) and SEM (Fig. 1.3B) images of acellularized heart tissue. The complete acellularization of heart tissue is demonstrated in Figure 1.3A. Of interest, this gentle gradual acellularization process retains the nanofibrous morphology of the cardiac ECM (Fig. 1.3B) and tissue specificity in terms of suitability for cell seeding, as assessed by the mechanical properties and the patterns of cell growth and differentiation (C. D. Koharski et al., unpublished results).

In conclusion, a number of novel platform technologies have been developed in recent years that permit fine tuning of the physico-chemical characteristics (fibrous versus porous, mechanical properties, porosity, etc.) of natural and synthetic scaffolds for tissue engineering purposes. The choice of these technologies and of the particular scaffold properties is driven by the need optimally to emulate the native ECM in a particular target tissue.

Following the introduction of some of the most frequently used natural and synthetic biomaterials and platform technologies for creating "intelligent" matrices for tissue engineering, we will now discuss four different applications (liver, heart, lung, BBB), in which the use of these scaffolds is critical for engineering high-fidelity tissue constructs, which might serve as 3D in vitro models for drug discovery and toxicity testing.

Fig. 1.3 Typical images of acellularized scaffolds for tissue engineering. (A) Nuclear staining with bisbenzimide, (B) scanning electron microscopy image of acellularized heart tissue.
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