Nanotopography-guided tissue engineering and regenerative medicine

Hong Nam Kim, Alex Jiao, Nathaniel S. Hwang, Min Sung Kim, Do Hyun Kang, Deok-Ho Kim, Kahp-Yang Suh
2013 Advanced Drug Delivery Reviews  
Human tissues are intricate ensembles of multiple cell types embedded in complex and welldefined structures of the extracellular matrix (ECM). The organization of ECM is frequently hierarchical from nano to macro, with many proteins forming large scale structures with feature sizes up to several hundred microns. Inspired from these natural designs of ECM, nanotopography-guided approaches have been increasingly investigated for the last several decades. Results demonstrate that the
more » ... itself can activate tissue-specific function in vitro as well as promote tissue regeneration in vivo upon transplantation. In this review, we provide an extensive analysis of recent efforts to mimic functional nanostructures in vitro for improved tissue engineering and regeneration of injured and damaged tissues. We first characterize the role of various nanostructures in human tissues with respect to each tissue-specific function. Then, we describe various fabrication methods in terms of patterning principles and material characteristics. Finally, we summarize the applications of nanotopography to various tissues, which are classified into four types depending on their functions: protective, mechano-sensitive, electro-active, and shear stress-sensitive tissues. Some limitations and future challenges are briefly discussed at the end. Mechano-sensitive tissues Mechano-sensitive tissues refer to those tissues that are continuously exposed to mechanical force while walking or exercising, including bone, ligament and tendon. To endure external forces and support the body's structure, bone (4.5-20 GPa) [15] [16] [17] and ligament/tendon (10 MPa-2 GPa) [9,10,18] have relatively high elastic moduli. Mechano-sensitive tissues also act mechanically as a damper, to absorb or diminish abrupt mechanical changes of the body system. Interestingly, mechano-sensitive tissues have hierarchical structures. As shown in Fig. 1 , the bone is composed of two distinct areas: cortical bone (also known as compact bone) which has concentric cylindrical features and cancellous bone (also known as spongy bone) which has a spongy-like structure. Especially, in cortical bone, such high mechanical rigidity originated from brick-and-mortar structures, comprising plate-like mineral crystals stacked within the collagen matrix [19, 20] . The mineral platelets (dahllite, also known as carbonated apatite) have average lengths and widths of 50×25 nm 2 , and thicknesses of 1.5-4 nm [21, 22] . The collagen fibers found in bone have a diameter of about 80-100 nm, comprised of triple helixes of collagen molecules with a diameter of ~1.5 nm and a length of ~300 nm which are organized in a staggered way [22, 23] . Since the mineral platelets are also stacked in a staggered manner and embedded in a collagen matrix, externally applied stresses can be redistributed and fracture energy can be absorbed or dissipated in daily activities such as walking and running [24] . In contrast, the cancellous bone is less dense, softer, and less stiff, and contains red bone marrow, where hematopoiesis, the production of blood cells, occurs. Similarly, ligaments and tendons, which are fibrous connective tissues, connecting two tissues together, also contain hierarchical nanostructures for their functions. Ligaments connect bone to bone at joints, with enough flexibility to allow the joint movement while containing sufficient rigidity to prevent dislocation, and are commonly observed in knees and shoulders. Tendons connect skeletal muscle to bone to transfer force for the movement. For ligaments and tendons, it is composed of four levels of hierarchy: collagen molecule, collagen fiber, fascicle, and tendon fiber. The collagen fibers are composed of bundles of collagen molecules in a triple helix (diameter of ~1.3 nm) which are packed in a staggered manner. The bundles of collagen fibers with a diameter of 50-500 nm are embedded in a proteoglycan-rich matrix [24] , forming a fascicle (diameter of 50-300 μm). Finally, fascicles form tendon fibers with a diameter of 100-500 μm [25] . Due to multilevel, hierarchical, and staggered organization, ligaments and tendons dissipate abruptly applied mechanical force by slippage between collagen molecules or fibers. These uni-directionally aligned hierarchical nanostructures provide sufficient compliance for dynamic action and mechanical impact by inter-fiber sliding which is aided by deformation of the proteoglycan layer [26,27]. Electro-active tissues Unlike the passive structures in mechano-sensitive tissues, electro-active tissues have active structures which respond to electrical stimuli. As can be inferred from the name 'electroactive', electro-active tissues respond to pulsatile or abrupt electrical stimuli. Brain tissue is an electro-active tissue in which information and stimulation received from the eyes, ears and skin are processed through the relay of signals by neurons. When these signals are Kim et al.
doi:10.1016/j.addr.2012.07.014 pmid:22921841 pmcid:PMC5444877 fatcat:e62tlaasgjbq7nny5uv5thohgu