N.J. Kim, S.J. Lee and A. Atala, Wake Forest School of Medicine, USA
Abstract:
Tissue engineering aims to develop functional tissue substitutes that can be used for reconstructing damaged tissues or organs. To engineer a tissue construct, cells are generally seeded on biomaterial scaffolds that recapitulate the extracellular matrix (ECM) and microenvironment in order to enhance tissue development. Recently, it has been recognized that biomedical nanomaterials play a central role in tissue engineering as they may better support tissue regeneration. Here, we address various biomedical nanomaterials and their effects on cells and tissues. The considerations needed to create a scaffold material for tissue engineering applications are discussed. We will also review the current progress and future directions for nanomaterials in tissue engineering.
1.1 Introduction
Tissue engineering strategies combine the principles of cell transplantation, material science, and engineering to develop biological substitutes that can restore and maintain the normal function of diseased or injured tissues/organs (Atala, 2007). Despite the technical advance over the past decades, the use of these approaches has been restricted to research applications and few have been used in clinic. Many clinicians still employ biodegradable polyesters that were first approved for use in humans over 30 years ago. This is a serious concern because morphogenesis is strongly affected by the interactions between the cells and the extracellular environment during normal tissue development. While the simple synthetic polymers that have been in use provide support for neo-tissue development, they do not successfully mimic the complex interactions between the tissue-specific cells and the tissue-specific extracellular matrices (ECMs) that promote functional tissue regeneration. Therefore, āsmart biomaterialsā that actively participate in functional tissue regeneration (Furth et al., 2007) must be developed and used for future applications.
A biomedical nanomaterial is a nanostructured material that is used to construct a device designed to interface with tissues or tissue components in performance of its function (Williams, 2009). Currently, a biomedical nanomaterial in tissue engineering is considered a smart biomaterial due to its multi-functionality. Even though nanoscale is usually defined as being smaller than one-tenth of a micrometer in at least one dimension, this definition is also used to describe materials that are smaller than 1 μm in tissue engineering applications. These materials include nanoparticles, nanofibers, nanotubes, nanowires, and any other nanoscaled materials or devices. A nanomaterial has been commonly described and recognized as a nanostructured building block of biological replacements used to restore or improve physiological function of bioengineered tissues/organs. Nanomaterials are increasingly studied for tissue engineering and regenerative medicine because they can closely mimic natural biological environments. Using these materials, nanostructures and other properties of native tissues can be constructed. In addition, nanomaterials have better functional, mechanical, and physical characteristics as well as superior biocompatibility compared to macroscaled materials. These properties can be modified by varying methods of fabrication and assembly. The use of nanomaterials has opened up immense possibilities and facilitated significant progress in tissue engineering to date.
Since tissue engineering involves developing functional substitutes for damaged tissues/organs, materials need to be inert or biocompatible when in contact with living cells or tissues. Moreover, the interaction between a material and cells influences cellular behaviors such as migration, adhesion, proliferation, and differentiation. Molecular signals from the extracellular environment affect the functional properties and the physical integrity of a material. Thus, the interactions among materials, cells, and the neighboring environment determine the performance and outcome of the tissue engineering scaffolds. In this regard, nanostructured biomaterials play important roles in boosting cellāmaterial or cellācell interactions (Huppertz, 2011). This chapter will review biomedical nanomaterials that provide nanoscaled environments for tissue engineering applications and will describe the design considerations for these materials. The current progress and future directions for nanomaterials in tissue engineering will also be discussed.
1.2 Overview of nanomaterials in tissue engineering
This section will introduce fundamentals of nanomaterials in tissue engineering. Basic principles and utilization of nanomaterials in tissue engineering will be discussed.
1.2.1 Basic principles of nanomaterials
The basic requirements of scaffold materials for use in tissue engineering applications are biocompatibility, biodegradability, and low immunogenicity in order to assimilate cellular function and tissue formation with little adverse effect. Incompatible biomaterials are destined for inflammatory response or foreign-body reaction that eventually leads to rejection and/ or necrosis (Atala, 2008). While classic tissue-engineered scaffolds provide temporary mechanical support during the spatial tissue organization of cells, a smart biomaterial scaffold can maintain adequate mechanical integrity and simultaneously accelerate tissue formation during the early stages of development. Principally, a scaffold should facilitate the localization and the delivery of tissue-specific cells to designated sites in the body, maintain a three-dimensional architecture that permits the formation of neo-tissues, and guide the development of neo-tissues with appropriate function (Kim and Mooney, 1998). However, it has been recognized that most classic tissue-engineered scaffolds do not properly recapitulate the extracellular environment, because this environment is a dynamic and hierarchically organized nanoscaled composite that regulates essential cellular functions such as morphogenesis, migration, adhesion, proliferation, and differentiation (Dvir et al., 2011b). The extracellular environment encompasses the ECM proteins, soluble factors, and cytokines secreted from cells. In addition, ECM proteins consist of proteoglycans, structural proteins (e.g. collagens and elastin), and adhesive proteins (e.g. fibronectin and laminin).
In order to provide an effective extracellular environment using biomaterial scaffolds, there are critical factors that need to be taken into account including the biological, mechanical, and the physical properties of a target tissue/organ. Moreover, the significance of the nanoscaled configuration of the extracellular environment in promoting essential cellular interactions has been recognized and can be employed to engineer functional tissue constructs. For example, a scaffold composed of nanoscaled fibers provides excellent cellular interactions as well as tissue compatibility. There has been remarkable interest in exploring the potency of biomimetic fibers in tissue engineering. One important feature of these fibrous biomaterials is the vastly increased ratio of surface area to volume. These attractive aspects of advanced biomaterials enable improved mimicking of the extracellular environment and ultimately being used to engineer more complex tissues/organs when compared to traditional biomaterials.
1.2.2 Utilization of nanomaterials in tissue engineering
There is a need in tissue engineering to develop advanced biomaterial scaffolding systems, which could provide a proper extracellular environment for a regenerating tissue including biophysical (topography) and biochemical (delivery of bioactive molecules) cues. Such a material could mimic natural ECMs to regulate cellular behaviors for example, stem cell differentiation (McMurray et al., 2011). One major determinant of success or failure in tissue engineering is the physicochemical interaction between cells and materials. Cells interact with the neighboring environment by nanoscaled extracellular signals. The purpose of nanoscaled tissue engineering is to channel these interactions through nanostructured biomaterials and to guide cellular behaviors towards regeneration. To improve cellāmaterial and cellācell interactions for comprehensive tissue regeneration, nanomaterials have been fabricated and modified by various methods (Wheeldon et al., 2011).
Topographical cues generated by the ECM have signifi...