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Extracellular Matrix Scaffolds for Tissue Engineering and Regenerative Medicine

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Extracellular Matrix Scaffolds for Tissue Engineering and Regenerative Medicine Send Orders for Reprints to [email protected] 233 Current Stem Cell Research & Therapy, 2017, 12, 233-246 REVIEW ARTICLE ISSN: 1574-888X eISSN: 2212-3946 Current Stem Cell Research & Therapy Extracellular Matrix Scaffolds for Tissue Engineering and Regenerative Medicine BENTHAM SCIENCE Sheng Yi, Fei Ding, Leiiei Gong and Xiaosong Gu* Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China Abstract: The extracellular matrix is produced by the resident cells in tissues and organs, and secreted into the surrounding medium to provide biophysical and biochemical support to the surrounding cells due to its content of diverse bioactive molecules. Recently, the extracellular matrix has been used as a promis- A R T I C L E H I S T O R Y ing approach for tissue engineering. Emerging studies demonstrate that extracellular matrix scaffolds are Received: June 10, 2016 able to create a favorable regenerative microenvironment, promote tissue-specific remodeling, and act as Revised: August 26, 2016 Accepted: August 28, 2016 an inductive template for the repair and functional reconstruction of skin, bone, nerve, heart, lung, liver, DOI: kidney, small intestine, and other organs. In the current review, we will provide a critical overview of the 10.2174/1574888X11666160905092 structure and function of various types of extracellular matrix, the construction of three-dimensional ex- 513 tracellular matrix scaffolds, and their tissue engineering applications, with a focus on translation of these novel tissue engineered products to the clinic. We will also present an outlook on future perspectives of the extracellular matrix in tissue engineering and regenerative medicine. Keywords: The extracellular matrix, biological scaffold, microenviroment, tissue repair and regeneration, clinical application, tissue engineering. 1. INTRODUCTION individuals of the same species. Currently, it is most com- monly used for replacing damaged kidney, liver, heart, lung, Transplantation of living cells, tissues and/or organs is and other diseased organs. The extensive clinical application generally used as an ultimate means of replacing damaged or of allotransplantation, however, is robustly challenged by an absent cells, tissues and/or organs. To date, various organs increasing shortage of available donor organs. In the United (including heart, kidney, liver, lung, pancreas, intestine, and States, more than 54,000 patients were waiting for a kidney, thymus) and tissues (including bone, tendon, cornea, skin, 12000 for a liver, 2200 for a heart, and 1300 for a lung trans- heart valve, nerve, and vein) have been transplanted to the plant in 2013, and the situation is worrisome due to scarce patients for restoring their essential physiological functions donor organs—only over 17000 kidney, 6000 liver, 1900 and even saving their lives. heart, and 1800 lung transplants are performed annually [1]. Transplantation is mainly classified into 3 types: auto- Accordingly, the United Network for Organ Sharing transplantation, allotransplantation, and xenotransplantation. (UNOS) wait list continues to grow and now more than Autotransplantation refers to the transplantation from one 120,000 people await transplantation in the United States [2]. part of the body to another part in the same individual. Since Besides, allotransplantation will lead to transplant rejection, the donor and the recipient are the same person, autotrans- and the patients receiving transplantation surgery need to plantation does not trigger immune response, but it is limited adhere to lifelong immunosuppressant medication [3]. to the use of surplus tissues and/or organs that are able to Xenotransplantation is the transplantation between two dif- regenerate, typical examples of which are bone and skin. ferent species. The transplantation of animal organs to hu- Generally, autotransplantation requires a second surgery to man recipients overcomes the limitation of donor source; obtain the donor tissues and/or organs, thus inflicting the however, this strategy may face concerns about the long- patient with extra pain and surgical risk. Allotransplantation term stability, transplant rejection, introduction of xenoge- is the transplantation between genetically non-identical neic infectious agents, and ethics dilemma. Hence, consider- able efforts have been recently devoted to the development of newly genetically modified animal donors and new im- *Address correspondence to this author at the Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong munosuppressive approaches to expand the application of University, Nantong, Jiangsu, China; Tel:/Fax: 86-513-85511585; E-mail: xenotransplantation [4, 5]. Overall, the clinical utility of [email protected] transplantation is largely restricted [6-9], and there is a press- 2212-3946/17 $58.00+.00 © 2017 Bentham Science Publishers Current Stem Cell Research & Therapy 234 Current Stem Cell Research & Therapy, 2017, Vol. 12, No. 3 Yi et al. ing need to seek promising alternatives to donor organs used ing connective tissue [20]. The extracellular matrix consti- for transplantation. tutes a three-dimensional mechanical support for surround- ing cells to maintain tissue and organ structure. Besides these Tissue engineering and regenerative medicine is a rapidly biophysical properties, the extracellular matrix establishes advancing interdisciplinary field that combines the principles of life sciences, materials sciences, and engineering to con- and maintains cellular microenvironment, provides structural information and biochemical cues to surrounding cells, regu- struct tissue engineered grafts, which are transplanted to the lates the activity of signaling molecules, and affects cell be- body as replacements for the missing or severely damaged havior, including cell shape, survival, proliferation, migra- tissues and/or organs [10, 11]. Emerging researches and pre- tion, and differentiation through cell-extracellular matrix liminary clinical studies have demonstrated that tissue engi- interaction, thus playing pivotal roles in tissue morphogene- neered grafts are promising substitutes of donor organs [12, 13]. A typical tissue engineered graft consists of a scaffold sis and organ development [21, 22]. (or called a template) and biochemical cues that are fur- The extracellular matrix is generally composed of three nished by support cells and growth-stimulating signals (in- categories of molecules: fibrous proteins (e.g. collagen, cluding growth factors, cytokines and chemokines) [14, 15]. elastin, fibrillin, and fibulin), adhesive glycoproteins (e.g. A biomaterial-based scaffold plays a fundamental role in laminin, fibronectin, tenasin, thrombospondin, and integrin), tissue engineering because it provides mechanical property and glycosaminoglycans. These basic components of the and structural support for cell attachment and tissue devel- extracellular matrix are introduced in the following sessions. opment, creates a permissive environment for cell survival, proliferation and differentiation, and eventually promotes 2.1. Collagen tissue regeneration [16, 17]. An ideal scaffold needs to have In the human body, collagen is the most abundant pro- many specific architectural, mechanical, physicochemical, tein, making up 2535% of total protein mass [23]. Collagen and biological properties. Firstly, the scaffold should have a porous spongy structure to facilitate cell adhesion and migra- also constitutes the major component of the extracellular matrix [24], and comprises a large family of insoluble fi- tion and to stimulate angiogenesis and metabolic exchange. brous proteins. Totally, 28 collagen isoforms have been iden- Secondly, the scaffold should have a certain shape stability tified in the collagen superfamily, and all members of the and intrinsic mechanical property that are similar to that of collagen superfamily contain a common triple-helical do- defect tissues. Thirdly, the scaffold needs to be biocompati- main [25]. According to domain structure and supra- ble to the body and biodegradable with a controllable rate in the body. Fourthly, the scaffold needs to show no or low structural organization, the large family of collagen can be divided into several sub-families: (1) fibril-forming colla- immunogenicity. Finally, the scaffold needs to be able to gens (also called fibrillar collagens) including collagen I, II, include biological and/or physical cues that affect cell phe- III, V, XI, XXIV, and XXVII; (2) fibril-associated and fibril- notype and promote directed cellular regrowth [18, 19]. A associated-like collagens with interrupted triple helix, includ- large variety of biomaterials have been investigated, which ing collagen IX, XII, XIV, XVI, XIX, XXI, and XXII; (3) are generally divided into naturally derived materials (e.g. chitosan, alginate, and collagen) and synthetic polymers (e.g. network-forming collagens, including collagen IV, VI, VII, VIII, and X; (4) transmembrane collagens, including colla- polylactic acid, polyglycolic acid, and polycaprolactone) gen XVII, XXIII, XXV, gilomedins, and ectodysplasin; (5) [17]. Interestingly, several natural biomaterials commonly multiplexin collagens, including endostatin XV and XVIII, used for preparing scaffolds, such as collagen, fibrin, and other protein molecules with collagenous domains [26]. laminin, fibronectin, and hyaluronan, are major components Despite their remarkable diversity in molecular
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