Over the past decade, autologous and allogeneic grafts

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1 TISSUE ENGINEERING: Part B Volume 22, Number 3, 2016 ª Mary Ann Liebert, Inc. DOI: /ten.teb REVIEW ARTICLE Cell-Derived Extracellular Matrix: Basic Characteristics and Current Applications in Orthopedic Tissue Engineering Weixiang Zhang, MS, 1 Yun Zhu, BS, 2 Jia Li, MS, 3 Quanyi Guo, MD, 2 Jiang Peng, MD, 2,4 Shichen Liu, MS, 1 Jianhua Yang, MS, 1 and Yu Wang, MD 2,4 The extracellular matrix (ECM) is a dynamic and intricate microenvironment with excellent biophysical, biomechanical, and biochemical properties, which can directly or indirectly regulate cell proliferation, adhesion, migration, and differentiation, as well as plays key roles in homeostasis and regeneration of tissues and organs. The ECM has attracted a great deal of attention with the rapid development of tissue engineering in the field of regenerative medicine. Tissue-derived ECM scaffolds (also referred to as decellularized tissues and whole organs) are considered a promising therapy for the repair of musculoskeletal defects, including those that are widely used in orthopedics, although there are a few shortcomings. Similar to tissue-derived ECM scaffolds, cell-derived ECM scaffolds also have highly advantageous biophysical and biochemical properties, in particular their ability to be produced in vitro from a number of different cell types. Furthermore, cell-derived ECM scaffolds more closely resemble native ECM microenvironments. The products of cell-derived ECM have a wide range of biomedical applications; these include reagents for cell culture substrates and biomaterials for scaffolds, hybrid scaffolds, and living cell sheet coculture systems. Although cell-derived ECM has only just begun to be investigated, it has great potential as a novel approach for cell-based tissue repair in orthopedic tissue engineering. This review summarizes and analyzes the various types of cell-derived ECM products applied in cartilage, bone, and nerve tissue engineering in vitro or in vivo and discusses future directions for investigation of cell-derived ECM. Introduction Over the past decade, autologous and allogeneic grafts have proven to be the effective treatments for orthopedic injuries and degenerative diseases. However, the development of autologous graft technology has been severely restricted by the small number of autologous graft tissues and complications associated with donor sites. Although allografts are able to overcome many of the drawbacks associated with autologous grafts, they are much more likely to exhibit poor histocompatibility and are more susceptible to the spread of disease. 1 These persistent complications have led to the development of tissue engineering grafts as an alternative to autologous or allogeneic grafts. Tissue engineering is the application of engineering as well as the basic principles and techniques of life sciences to build artificial substitutes with biological function in vitro, which can be used to repair tissue defects and replace the loss of function or failure of the organization and part of or all the functions of organs. 2,3 Tissue engineering usually consists of seed cells, scaffolds, and cytokines. Seed cells are the key to tissue engineering construct because most sites of injury can be restored using renewable seed cells. Experimental studies have shown that culture and expansion of the cells to produce large amounts of extracellular matrix (ECM) and growth factors increase the flexibility of scaffolds and promote the proliferation and differentiation of autologous progenitor cells, thus enhancing tissue repair. Cytokines are also important factors as they exert a wide variety of biological effects through combination with receptors on the surface of the target cell membranes and transfer the signals to the cell interior, thus regulating cell behaviors as well as reinforcing ECM formation. Scaffolds can provide a suitable three-dimensional (3D) microenvironment to sustain the growth of seed cells and cytokines; they supply mechanical support for tissue defects and show 1 First Department of Orthopedics, First Affiliated Hospital of Jiamusi University, Jiamusi, China. 2 Institute of Orthopedics, Chinese PLA General Hospital, Beijing, China. 3 Department of Acupuncture and Moxibustion, The Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China. 4 The Neural Regeneration Co-innovation Center of Jiangsu Province, Nantong, Jiangsu Province, China. 193

2 194 ZHANG ET AL. good histocompatibility when implanted. Therefore, there is a great deal of interest in the development of scaffold materials in the field of tissue engineering research. During the past decade, scaffold use in tissue engineering includes polymerized materials and biological materials. In biological scaffolds, include biomaterials using one or two components of ECM to mimic the native ECM, such as collagen, fibronectin, and hyaluronan, those scaffolds, were unsuitable as the dynamic and intricate microenvironment with various functions of the nature ECM. 4 Therefore, there remains a strong interest in developing biological scaffolds that use native ECM substrates as biomaterials, allowing for greater preservation of tissue-specific ECM compositions and tissue structure, compared to individual ECM component scaffolds. Recently, it has been proposed that the ECM should be considered as the fourth important element in the development of tissue engineering. The ECM is mainly divided into tissuederived ECM and cell-derived ECM. Tissue-derived ECM consists of decellularized ECM derived from allogenic or xenogenic tissues or organs in combination with tissue-derived ECM scaffolds, such as cartilage, nerve, ligament, or heart tissue engineering grafts. These products have been granted Food and Drug Administration approval and have been widely applied in tissue engineering 5 7 ; however, experimental animal studies and clinical trials have identified several disadvantages, including potential pathogen transfer, inflammatory or antihost immune responses, uncontrollable degradation, and other issues In contrast, cell-derived ECM can be obtained from autologous cells cultured under sterile conditions in vitro, thereby avoiding the shortcomings of decellularized ECM derived from tissue. In addition, cell-derived ECM scaffolds are more readily customizable through the use of different types of cells, as opposed to tissue-derived ECM scaffolds, which require patient-specific cells, such as chondrocytes, mesenchymal stem cells (MSCs), fibroblasts, osteoblasts, and other cell types. Cell-derived ECM scaffolds can be prepared using cellderived ECM substrates, cell-derived ECM pellets, cell-derived ECM scaffold or hybrid scaffolds, and scaffold-free living cell sheet culture systems in vitro. These can provide the appropriate microenvironment to promote amplification and differentiation of cells or can act as scaffolds to maintain the desired biological elasticity, geometry, biomechanical characteristics, and porosity that enhance seed cell proliferation, adhesion, and differentiation and speed up the repair of damaged tissues Moreover, cell-derived ECM can be used as a scaffold-free living cell sheet culture system to establish coculture and directly increase interactions of viable and new seed cells, which more closely mimics the natural cell growth microenvironment compared to hybrid scaffolds. The cell-derived ECM scaffolds are considered a feasible new scaffold within the regenerative medicine community. This review discusses the basic construction and characteristics of ECM along with the preparation of cell-derived ECM products. Furthermore, we address the potential applications of these products in orthopedic tissue engineering. Overview of the ECM Basic components of the ECM The ECM is a highly specialized structure that provides both structural and biomechanical support for all cell types. 17,18 Although the composition of these structures varies considerably among bone, cartilage, nervous tissues, and skeletal muscle, the ECM consists mainly of organic compounds, such as collagens, proteoglycans, glycosaminoglycan (GAG), hyaluronic acid, and other macromolecular substances along with various inorganic compounds that constitute a complex and dynamic network structure with excellent biophysical and biochemical properties. 18,19 The ECM is an important component of the cell growth microenvironment. The ECM provides not only structural support and attachment sites for cells but is also rich in natural and intrinsic biological information that can provide signals for cell growth and therefore influences cell adhesion, migration, proliferation, and differentiation, as well as regulation of gene expression. 20,21 Characteristics of the ECM The diversity of ECM components provides a number of advantageous physical properties, including bulk stiffness, porosity, surface topography, and other physical characteristics that influence cell growth, differentiation, and migration. 19,22,23 The biomechanical properties of the ECM can regulate cell behavior as the cells sense the external forces and stiffness of the surrounding ECM and adapt to the local environment. 24 Aging is known to influence not only tissue elasticity 25 but also the elasticity of the ECM. 26 Recently, Li et al. reported that fetal stem cell-derived ECM has lower elasticity due to enhanced stem cell differentiation compared to that derived from adult stem cells. 26 Sun et al. reported that aging was disadvantageous for formation of the ECM, 21 they found that the mineral content was higher in the aged ECM compared to the young ECM, while young ECM included more collagen. 21 These findings provide a theoretical basis for designing optimal scaffolds for tissue repair. The key features of the ECM reflect not only its physical properties but also its protein components. It has been known for many decades that the ECM can anchor cell surface receptors, such as integrins and other noncanonical receptors, as well as directly regulate cell behavior. 27 Integrins are the major cell surface transmembrane receptors that connect protein components of the ECM to the intracellular cytoskeleton and play key roles in mediating cell migration, proliferation, adhesion, and differentiation. 28 For example, integrins have been shown to regulate the proliferation, adhesion, and regeneration of stem cells by activating the focal adhesion kinase and phosphoinositide 3-kinase signaling pathways. 28,29 In turn, the signaling pathways can also modulate integrin delivery. 30 Various integrins are involved in the interaction between the ECM and cells, such as a6b1 integrin, a9 integrin, b1 integrin, and avb3 integrin, which may regulate the proliferation and homing of stem cells Some nonintegrin receptors, such as CD44, are also actively involved in the homing of hematopoietic stem cells. 36 The function of integrins may be hindered by antibodies or small-molecule drugs. All these characteristics regulate the various functions of the ECM, and changing one property inevitably affects the others. The dynamic interaction between the ECM and cells represents a mutually beneficial relationship, and cells continually remodel the ECM to adapt to changes in the surrounding environment. In turn, these modifications of the

3 CELL-DERIVED ECM 195 FIG. 1. Schematic preparation of cell-derived extracellular matrix (ECM) as a cell culture substrate. The ECM may contain several types of growth factor after decellularization. Indeed, the integrity of the ECM may be relatively good, and the ECM components are preserved. Color images available online at ECM can also markedly affect the phenotype and behavior of the cells Preparation of Cell-Derived ECM Substrates and Scaffolds An optimal method for preparation of cell-derived ECM substrates or scaffolds should remove cell components as much as possible, thus minimizing the immune response, and also minimize loss of major matrix components and retain relatively good biocompatibility and biomechanical strength to fulfill the requirements for cell growth or tissue reconstruction. 7 At present, the most commonly used methods for preparation of the ECM can be mainly divided into physical methods (freezing and thawing, mechanical shock, and pressure methods), chemical agents (detergents, hypotonic and hypertonic solutions, and acid and alkali solutions), and biological agents (enzyme and nonenzyme reagents). However, each decellularization method influences both the components of the ECM, as well its structure, meaning there are currently no unified criteria for decellularization. Normally, a specific decellularization method is chosen according to the requirements of a specific cell type, cell density, ECM thickness, or water content. 41 The most basic method of preparing cell-derived ECM substrate involves treatment with a combination of mild chemical and/or biological reagents (enzymatic) 42 (Fig. 1); preparation of 3D cell-derived ECM pellets uses only the physical method (Fig. 2). These approaches are by far the most commonly used and most effective means of cellderived ECM substrate preparation. To increase ECM adhesion, fibronectin is often used to coat the surfaces of culture dishes. A recent study indicated that addition of a certain amount of ascorbic acid to the medium facilitates ECM deposition and cell sheet formation. 43 Subsequent treatment with detergents and alkaline reagents (ammonium hydroxide) induces decellularization and more effectively removes cellular components from thin tissues, such as cell layers, compared to enzymatic and osmotic methods. 44 Mild detergents, such as Triton X-100, are preferable to compounds, such as sodium dodecyl sulfate, as they effectively remove cell residues, with only minimal disruption of other components, including GAG, growth factors, and collagen, and help maintain ECM ultrastructure. 45,46 These milder detergents also retain greater ECM bioactivity and reduce adverse immune responses. Alternatively, physical methods, such as repeated freeze thaw cycling, are sufficient to induce cell lysis in tissues and organs via the production of intracellular ice crystals, while retaining both intracellular and membranous contents. However, despite the retention of some ECM components, this approach does result in some disruption of the ECM ultrastructure. 47 Finally, biological agents, particularly nucleases (DNase and RNase solutions), are sometimes applied to degrade residual DNA or RNA. Hence, ECM preparation via a combination of chemical and biological digestions effectively removes cellular components, although some damage to the structure of the ECM does occur. Future studies are necessary to assess the effects of different preparation methods on ECM components and disruption of ECM structure, along with the effects of these structures on cell behavior. Significant efforts have been made to improve both the quality and efficiency of 3D cell-derived ECM scaffold generation. Part of this effort involves harvesting FIG. 2. Schematic illustration shows the process of producing a cellderived ECM pellet culture system. Color images available online at

4 196 ZHANG ET AL. FIG. 3. The process of preparing a threedimensional cell-derived ECM scaffold by physical and chemical techniques. Color images available online at cell-derived ECM membranes, which can then be fabricated into 3D scaffolds through the use of various physical and chemical techniques (Fig. 3). 48 Generation of 3D cell-derived ECM scaffolds with superior biological elasticity and porosity permits greater exchange of nutrients and waste products, which is conducive to cell proliferation, adhesion, and differentiation. 49 Alternative shaped 3D cell-derived ECM scaffolds, which rely on polymers, such as poly(l-lactide-co-glycolide) (PLGA) and polylactic acid (PLA) as templates, have also been developed. In these models, cells are seeded directly onto the polymer surface, which in turn stimulates ECM deposition to form cell ECM template architecture. Physical methods, such as freeze dry cycling, are then used to induce decellularization, after which the polymer can be removed through the use of chemical reagents, leaving only the shaped 3D cell-derived ECM scaffold behind (Fig. 4). Cell-derived ECM scaffolds prepared by this method exhibit mild host immune responses and excellent biocompatibility when transplanted in vivo. 50,51 Similar to the shaped 3D cell-derived ECM scaffolds, this novel cell-derived ECM hybrid scaffold is generated by coating template surfaces with cell-derived ECM, followed by retention of the templates in the scaffolds, thus conferring bioactivity to these templates (Fig. 4). The surface bioactivity of hybrid scaffolds provides a more beneficial FIG. 4. Preparation of ECM hybrid scaffolds or ECM scaffolds in vitro. In an ECM hybrid scaffold, the ECM may be present on the scaffold surface after decellularization, affording the stiffness, porosity, and surface topography required for cell growth. Both ECM scaffolds and ECM hybrid scaffolds exhibit superior bioactivity and biocompatibility when transplanted in vivo, which will aid future clinical applications. Color images available online at interaction between cells and biomaterials, with greater control of cellular density. Moreover, the cell-derived ECM hybrid scaffolds have stronger mechanical properties compared to tissue- and cell-derived ECM scaffolds, thereby increasing the number of potential applications in tissue engineering, particularly those associated with bone tissue engineering. Application of Cell-Derived ECM in Cartilage, Bone, Nerve, and Skeletal Muscle Tissue Engineering Application of cell-derived ECM in cartilage tissue engineering Cartilage injury is a common orthopedic issue as the lack of blood vessels and nerves in cartilage means that nutrient supply is derived mainly from the joint fluid, and cartilage therefore has a very poor self-repair capacity (Table 1). Once damaged, it is difficult for the cartilage to repair by itself, and so the repair of articular cartilage injury is a major clinical challenge in the field of orthopedics. 52 The emergence of cartilage tissue engineering may facilitate the clinical repair of articular cartilage damage and the development of novel treatment strategies for joint cartilage defects. Autologous chondrocyte implantation (ACI) was first

5 Table 1. Applications of Cell-Derived ECM in Cartilage Tissue Engineering ECM type Seed cell Growth factors Culture conditions Outcome Reference Cell-derived ECM substrate Pig SDSC-derived ECM Pig articular chondrocytes Pig SDSC-derived ECM Pig SDSC TGF-b1 and TGF-b3 HDF, HAC, human mesenchymal stem cell (MSC)-derived ECM Human fetal MSC-derived ECM, adult human MSC-derived ECM Human fetal SDSC-derived ECM, adult human SDSC-derived ECM TGF-b1 In vitro Suppressed chondrocyte dedifferentiation and retained redifferentiation In vitro and in vivo (5 pigs) Enhanced SDSC expansion, chondrogenic potential, and repair of cartilage defects HAC None In vitro HAC ECM enhanced chondrocyte adhesion, HDF ECM or hmsc ECM improved chondrocyte proliferation Human adult MSC and late-stage adult MSCs None In vitro Fetal MSC ECM promoted adult MSC proliferation, multipotency, and stemness Adult human SDSCs TGF-b3 In vitro Fetal SDSC ECM was superior to adult SDSC ECM in promoting adult SDSC proliferation and chondrogenic differentiation Pig SDSC-derived ECM Minipig SDSCs FGF-2 In vitro Provided large-scale and high-quality stem cells for cartilage tissue engineering Minipig ASC-derived ECM, minipig SDSC-derived ECM Rat osteoblast-derived ECM, rabbit articular chondrocyte-derived ECM Cell-derived ECM scaffolds Rabbit BMSC-derived ECM scaffolds Rabbit articular chondrocytes Pig articular chondrocyte-derived ECM scaffolds Human autologous MSCs, NHAC, NHDF, and mouse autologous fibroblasts cultured in PLGA template Human MSCs and mouse fibroblasts cultured in PLGA template Rabbit autologous BMSC-derived ECM scaffolds Pig articular chondrocyte-derived ECM scaffolds Rat chondrocytes cultured in electrospun PCL scaffolds Rabbit BMSC-derived ECM scaffolds and porcine chondrocyte-derived ECM scaffolds Minipig ASCs TGF-b3 and BMP-6 In vitro ASC ECM or SDSC ECM increased ASC proliferation and chondrogenic differentiation hmscs BMP-2 In vitro Osteoblast ECM and chondrocyte ECM promoted osteogenic and chondrocyte differentiation, respectively Rabbit articular chondrocytes None In vitro and in vivo (12 nude mice) None In vivo (18 nude mice) None None In vitro and in vivo (5 mice) None None In vitro and in vivo (6 mice) None None In vivo (12 rabbits) Show better cartilage-like tissue formation 48 Generated hyaline-like cartilage tissue 63 Autologous ECM scaffolds displayed great biocompatibility 50 Freeze thaw cycling with NH 4 OH and Triton X-100 with 1.5 M KCl can successfully prepare cell-derived ECM template scaffold and induce wild immune response Improved repair effect of articular cartilage 62 Rabbit chondrocytes None In vitro Produced high-quality cartilage 64 Rabbit MSCs TGF-b1 In vitro Improved chondrogenic differentiation 10 Rabbit chondrocytes None In vitro Both scaffolds supported attachment and proliferation of chondrocytes ASCs, adipose-derived stem cells; BMP, bone morphogenetic protein; BMSCs, bone marrow mesenchymal stem cells; ECM, extracellular matrix; FGF, fibroblast growth factor; HAC, human articular chondrocyte; HDF, human dermal fibroblast; MSC, mesenchymal stem cell; PCL, poly-e-caprolactone; PLGA, poly(l-lactide-co-glycolide); SDSCs, synovium-derived stem cells; TGF-b, transforming growth factor-beta. 197

6 198 ZHANG ET AL. reported in 1994 and resulted in successful healing of articular cartilage defects. 53 Although the ACI technique shows promise, a number of difficulties and bottlenecks limit the widespread clinical application of the technology, including age, disease status, and gender of individual donors, as well as a limited number of autologous cells. A monolayer culture technique that stimulates cellular proliferation without inducing their dedifferentiation or hypertrophic differentiation is important for a clinical application of chondrocyte-based therapy. Methods of improving the quantity and quality of seed cells have become key factors in the development of cartilage tissue engineering. As both chondrocytes and MSCs have been shown to play a vital role in the process of native cartilage formation, they are often used as seed cells for cartilage tissue engineering. Some investigators have shown that cell-derived ECM derived from different cell types, such as adult MSCs, fetal MSCs, chondrocytes, and fibroblasts, is able to maintain the stemness of MSCs and delay chondrocyte senescence in 2D monolayer and 3D pellet culture systems. Pei et al. reported that the ECM deposited by synovium-derived stem cells (SDSCs) efficiently provided high-quality chondrocytes in large quantities. 54 Pig cartilage chondrocytes were seeded on plastic flasks, SDSC-derived ECM, substrate transition from plastic to ECM, or ECM to plastic in the absence or presence of transforming growth factor beta 1 (TGF-b1), followed by characterizing the differentiation status and redifferentiation capacity of chondrocytes by pathological and biochemical methods. The results indicated that SDSCderived ECM formed a suitable microenvironment that not only significantly extended chondrocyte expansion, with 4- to 10-fold greater numbers of chondrocytes by culture on the SDSC-derived ECM compared to that on plastic dishes, but also inhibited chondrocyte dedifferentiation with redifferentiation capacity, as identified by the ratio of CD90 to CD105 expression. They reported that the rate of dual-positive cells (CD90 + /CD105 + ) decreased from 79.67% at P0 to 42.43% at P2 and 18.74% at P6 when chondrocytes were cultured on plastic dishes, while the rates were 79.67%, 68.99%, and 50.10%, respectively, in the ECM group, indicating a reduction in the decrease of CD90 + /CD105 + cell numbers compared with the plastic group. The SDSCs cultured on either SDSC-derived ECM or in plastic flasks were separately injected into partial-thickness knee cartilage defects in minipigs. The 3-month in vivo study showed that the cartilage defect sites were surfaced with a whitish tissue in both the tissue culture polystyrene (TCPS)-expanded group and the SDSC-derived ECM group, but only SDSCs cultured on SDSC-derived ECM showed intensified staining for GAG and collagen II and negative staining for collagen I. This suggested that SDSC-derived ECM promoted the proliferation and differentiation of SDSCs and achieved hyaline cartilage repair. 55 Cell-derived ECM as a promising cell expansion system enhanced the quantity and quality of seed cells. Recent studies have shown that ECM derived from human fetal MSCs can provide conditions more appropriate for cell growth and maintaining the stemness of MSCs compared to that derived from human adult MSCs or other tissue-derived ECMs. Ng et al. reported that fetal MSCderived ECM was superior to other substrates, including ECM derived from adult MSCs or human neonatal dermal fibroblasts and TCPS for promoting adult MSC proliferation and multipotency. Indeed, fetal MSC-derived ECM had effects on late-passage adult MSCs in terms of proliferation and differentiation. 56 In addition, Ng s group also compared the contents of ECM derived from fetal MSCs, adult MSCs, and neonatal dermal fibroblasts and found that fetal MSCs produced significantly greater amounts of ECM than adult MSCs and neonatal dermal fibroblasts, suggesting that the added fetal MSC-derived ECM likely contained greater quantities of growth factors and specific proteins conducive to cell proliferation and chondrogenic differentiation. Furthermore, compared to ECM deposited by adult SDSCs, ECM deposited by fetal SDSCs facilitated cell proliferation and chondrogenic potential as well as rejuvenation of adult SDSCs. Li et al. reported that P3 adult SDSCs cultured on fetal SDSC-derived ECM produced the greatest number of cells and the lowest percentage of apoptotic cells compared to those cultured on adult SDSC-derived ECM or plastic substrates. They reported the use of fetal SDSC-derived ECM as a promising cell culture microenvironment to modulate ECM-mediated adult SDSC rejuvenation by the mitogen-activated protein kinases and Wnt signaling pathways, and the lower elasticity of fetal SDSC-derived ECM may facilitate the proliferation and chondrogenic potential of SDSCs. 26 These studies suggest that in vitro-derived fetal SDSC-derived ECM is an excellent culture substrate and may better preserve both the biophysical and biochemical properties of ECM, an important consideration in terms of both the proliferation and lineage-specific differentiation of seeded MSCs. The observations outlined above raised questions regarding whether ECMs derived from different cell types have different effects on cell growth. Hoshiba et al. investigated three types of cell-derived ECM produced from chondrocytes, fibroblasts, and MSCs by chemical or enzymatic methods and examined their effects on the behavior of articular chondrocytes. Cell-derived ECM obtained by the chemical method was significantly superior to that produced enzymatically with regard to cell adhesion, and the number of chondrocytes adhering to the chondrocyte-derived ECM was markedly higher than that to fibroblast- or MSC-derived ECM; however, chondrocyte-derived ECM did not enhance proliferation of chondrocytes compared to acellular ECM derived from fibroblasts or MSCs. 57 ECM produced from the same cell lineage has been shown to provide a more suitable microenvironment for cellular growth due to the presence of distinctive molecules and lacuna of appropriate size, which are more conducive to reseeded cell adhesion. However, other factors, such as the method of decellularization, are also known to affect cell adhesion. The high density of 3D pellet culture provided by cellderived ECM plays a crucial role in inducing chondrogenic differentiation of human MSCs by providing a microenvironment that promotes both cell cell and cell ECM interactions and by inducing human MSC chondrogenesis, a process similar to precartilage compression during embryonic development. 58 He et al. used SDSC-derived ECM as a model to reconstruct a 3D stem cell microenvironment in vitro. When SDSCs were seeded on the SDSC-derived ECM, they showed a thin and spindle-like morphology. The number and chondrogenic potential of SDSCs were markedly increased but exhibited weak adipogenic or osteogenic

7 CELL-DERIVED ECM 199 differentiation potential, which suggested that the tissuespecific stem cell microenvironment can improve both proliferation of its own stem cells and lineage-specific stemness in vitro. 42 Li et al. compared the effects of three crucial parameters of the stem cell microenvironment SDSC-derived ECM, hypoxia, and basic fibroblast growth factor-2 (FGF-2) on the proliferation and stemness of MSCs. SDSCs were cultured on either SDSC-derived ECM or in plastic flasks with or without FGF-2 and incubated under hypoxia (5% O 2 ) or normoxia (21% O 2 ), followed by culture in a 3D pellet culture system in chondrogenic induction medium. They found that SDSC-derived ECM expansion was superior in terms of SDSC proliferation and maintenance of SDSC stemness than FGF-2. In addition, pretreatment with SDSC-derived ECM pellets resulted in a higher chondrogenic index (ratio of GAG to DNA) compared to FGF-2 pretreatment, but both showed significantly higher chondrogenic indices than SDSCs cultured in plastic flasks. FGF-2 pretreatment may yield higher GAG and DNA contents than other treatments. 59 FGF-2 can promote the proliferation and differentiation of MSCs and maintain MSCs in a young state via the MAPK and Wnt signaling pathways. 60 The combination of hypoxia and SDSC-derived ECM pellet pretreatment may decrease the expression of hypertrophic marker genes. 59 Studies have shown that hypoxia is likely to suppress the differentiation of cells and contribute to the retention of stem or progenitor cell stemness similar to a hypoxic microenvironment during the early stages of embryonic development. 61 Therefore, the use of FGF-2 in combination with low oxygen levels and cellderived ECM resulted in the establishment of a 3D pellet culture system that provided high-quality stem cells on a large scale for use in cartilage tissue engineering and regenerative medicine. The 3D porous scaffolds that comprise cell-derived ECM derived from different cell types, including autologous bone marrow mesenchymal stem cells (BMSCs) and chondrocytes, may provide a favorable biological environment for chondrocytes and promote hyaline cartilage-like tissue regeneration. Tang et al. evaluated the effects of autologous BMSC-derived ECM scaffolds on engineered cartilage in vitro as well as in vivo following implantation into nude mice, relative to atelocollagen scaffolds, which were used as controls. The BMSC-derived ECM scaffold formed a thicker cartilage tissue layer with elevated cartilaginous gene and protein expression levels compared to the atelocollagen scaffold after 1 month in vitro. After 3 weeks, the in vivo BMSC-derived ECM scaffold implant group also exhibited smooth white cartilage formation accompanying homogeneity, higher cartilage matrix content, and higher compressive modulus. 48 In a follow-up study, the authors tested the effects of BMSC-derived ECM scaffolds on damaged cartilage repair after bone marrow stimulation and reported superior outcomes in terms of gross histology, immunohistochemistry, GAG, and DNA content relative to the bone marrow stimulation group. 62 However, these outcomes were not exclusive to BMSC-derived ECM scaffolds, with chondrocyte-derived ECM scaffolds able to provide a uniform porous microstructure base for chondrocyte development, enabling the formation of high-quality cartilage both in vivo 63 and in vitro. 64 The compressive strength and size of neocartilage tissue gradually increased over time in the chondrocyte-derived ECM scaffold group and were consistently higher than those in the control group. These studies suggest that 3D cell-derived ECM scaffolds loaded with seed cells result in the formation of high-quality engineered cartilage, with potential for application across a wide range of cartilage tissue engineering applications. Application of cell-derived ECM in bone tissue engineering Autologous or allogeneic bone grafts are used in therapeutic approaches in cases of large and complex bone defects, such as wounds, infections, tumors, or congenital disorders (Table 2). However, serious donor site morbidity and high risks of infection hinder their use for bone tissue repair. 65,66 As an alternative to autologous or allogeneic bone transfer, tissue-engineered hybrid scaffolds are prepared by combining cell-derived ECM cultured in vitro with inorganic materials or synthetic polymers, which can be formed using patient-specific cells to eliminate donor site morbidity and anti-host immune response. Different types of cell-derived ECM, such as MSCderived ECM, chondrocyte-derived ECM, fibroblast-derived ECM, and osteoblast-derived ECM, exhibit a variety of effects when applied in bone tissue engineering and will facilitate significant advances in this field. The reconstitution of a native decellularized ECM derived from human bone marrow cells in vitro, which consists mainly of collagen types I and III, fibronectin, and other small proteoglycans, such as biglycan and decorin, was reported. The ECM-based culture system significantly promoted the proliferation of mesenchymal progenitors and retained their multilineage differentiation potential, in addition to lower levels of reactive oxygen species and higher sensitivity to bone morphogenetic protein-2 (BMP-2). Furthermore, an in vivo transplantation assay indicated that MSCs retained the capacity to form a high volume of bone tissue after expanding for multiple passages on the ECM-based culture platform. 20,67 Cell-derived ECM preparations rich in collagen and proteoglycans are beneficial for the proliferation and osteogenic differentiation of MSCs for bone regeneration. Sun et al. reported that aging negatively affects the replication and osteogenesis of MSCs. However, aged MSCs can be rejuvenated by culturing on an ECM generated by bone marrow cells from young (3 months) C57BL mice. The frequency of MSCs from both young and aged mice, measured in mesenchymal colony-forming units, was significantly increased after culture on young ECM compared to those cultured on aged ECM. Young ECM may enhance the adhesion of bone marrow cells and the bone-forming capacity of MSCs from both young and aged mice, accompanied by high levels of adenosine triphosphate and telomerase activity. 21 Decellularized ECM derived from human bone marrow stromal cells induced the osteogenic potential of adipose-derived stem cells both in vitro and in vivo. 68 The complex compositions of decellularized ECM derived from osteoblasts and chondrocytes may contribute to osteogenic and chondrogenic differentiation of hmscs in the presence of BMP In addition, Zeitouni et al. reported that an inhibitor of peroxisome proliferator can substantially reinforce the bone repair capacity of hmscs at a specific bone-remodeling phase with engraftment of

8 Table 2. Applications of Cell-Derived ECM in Bone Tissue Engineering ECM type Seed cell Growth factors Culture condition Outcome Reference Cell-derived ECM substrate Mouse BMSC-derived ECM Mice BMSCs None In vitro and in vivo (6 SCID mice) Human BMSC-derived ECM Human BMSCs None In vitro and in vivo (SCID mice) Young or old mouse BMSC-derived ECM Young or old mice BMSCs None In vitro and in vivo (SCID mice) Human BMSC-derived ECM Human ASCs None In vitro and in vivo (SCID mice) Rat osteoblast-derived ECM and rabbit articular chondrocytederived ECM Human MSC-derived ECM hmscs and inhibitortreated hmscs Human MSC-derived ECM and transferred human MSC-derived ECM Promoted expansion of mesenchymal colony-forming units and retained their stemness Large-scale expansion of MSCs and preservation of their properties Aging negatively affects ECM formation, and young ECM can rejuvenate old BMSCs Induced hasc osteogenesis 68 Human MSCs BMP-2 In vitro Induced osteogenic and chondrogenic differentiation of hmscs in the presence of BMP-2, respectively None In vivo (calvarial bone defect mice) Enhanced the effectiveness of bone repair 70 hmscs None In vitro Cell-derived ECM can be effectively transferred and retain the ability to instruct cell fate Human MSC-derived ECM hmscs None In vitro Regulated osteogenic differentiation of hmscs, correlated with culture duration, cell seeding density, media supplementation, and surrounding oxygen tension Cell-derived ECM scaffold Human bone marrow mononuclear cells and Col/HA scaffolds Rat MSC-derived ECM and Ti fiber mesh Human lung fibroblast-derived ECM and PLGA/PLA mesh Rat MSC-derived ECM and Ti fiber mesh hmscs None In vitro and in vivo (3 SCID mice) Promoted the proliferation and osteogenic differentiation of MSCs Rat MSCs None In vitro Enhanced osteoblastic differentiation of 75 MSCs Promoted osteogenesis and bone healing 76 Human placentaderived MSCs BMP-2 In vitro and in vivo (5 SCID mice and 4 calvarial bone defect rats) Rat MSCs None In vitro Enhanced marrow stromal osteoblast differentiation (continued) 200

9 Table 2. (Continued) ECM type Seed cell Growth factors Culture condition Outcome Reference Rat calvarial osteoblasts, dermal fibroblasts, and HA scaffolds Rabbit BMSC ECM marrow clots complex scaffolds and marrow clots Rat MSC ECM PCL scaffolds Rat MSCs or MSCs and whole bone marrow cells Rat MSC-derived ECM and Ti fiber mesh Mesenchymal progenitor cells ( MPCs) from human embryonic stem cells and human induced pluripotent stem cells (hipscs) and nanofiber layers (NFLs) Human bone marrow-derived MSC ECM-coated polymeric scaffolds Mouse preosteoblast cell-derived ECM and fibrous scaffolds Scaffold-free living cell sheet Porcine living chondrocytes and chondrocyte-derived ECM None None In vitro and in vivo (5 calvarial bone defect rats) Facilitated cell adhesion, growth, and calvarial bone repair None None In vitro Enhanced chondrogenesis and supported the adherence and proliferation of cells None In vitro Promoted the osteogenic differentiation of MSCs with or without dexamethasone in medium Rat MSCs None In vitro Affected MSC differentiation and osteoblastic gene expression Human MPCs None In vitro and in vivo (SCID mice and rats) hmscs or osteogenically induced hmscs None In vitro and in vivo (6 nude rats) hmscs None In vitro and in vivo (SCID mice) Human fetal osteoblasts and hmscs None In vitro and in vivo (6 nude mice) Rat MSCs and MSC-derived ECM None None In vitro and in vivo (calvarial bone defect rats) Supported the adhesion, migration, and proliferation of MPCs and showed excellent biocompatibility and biodegradability ECM retains the capacity to regulate cell phenotype in the 3D ECM polymeric scaffold Promoted hmsc migration, differentiation, and bone formation Promoted cell attachment and bone formation Effectively induced new bone regeneration and blood vessel formation BMSCs, bone marrow mesenchymal stem cells; Col/HA, collagen/hydroxyapatite; PLA, polylactic acid. 201

10 202 ZHANG ET AL. inhibitor-treated hmscs in conjunction with hmsc-derived ECM into mouse calvarial lesions at specific times. 70 Extended cell retention time at the bone defect site has been shown to improve bone healing as part of a multistage process of osteogenesis. However, other studies testing the osteogenic properties of MSCs cultured on cell-derived ECM in vivo failed to observe a significant improvement, possibly due to a reduction in MSC retention signals, thereby preventing cells from progressing to the later boneremodeling phase. Cell-derived ECM has been used as a cell culture substrate in bone tissue engineering and regenerative medicine due to its excellent biocompatibility and biodegradability. Inorganic materials, including hydroxyapatite, glassceramics, and titanium, also induce differentiation of MSCs into osteoblasts and facilitate formation of mineralized tissue as a binding site for seed cells and that inorganic materials can provide mechanical support for seed cells and exhibit stronger osteoinductive properties than cell-derived ECM. 71,72 The osteoinductive properties of inorganic materials provide a new therapeutic approach to bone defects and will facilitate rapid development of bone tissue engineering. 73 Therefore, some investigators have shifted their efforts toward exploiting composite 3D hybrid scaffolds composed of various types of inorganic material in combination with cell-derived ECM. Antebi et al. incorporated stromal cell-derived ECM into a collagen/hydroxyapatite (Col/HA) scaffold to mimic the bone marrow niche and assessed the effects on MSCs. MSCs cultured on ECM Col/ HA scaffolds showed significantly faster proliferation than those cultured on Col/HA scaffolds, and the expression levels of osteogenic markers, such as alkaline phosphatase (ALP), osteopontin, and runx2, were higher than on Col/HA scaffolds alone. In a follow-up in vivo study, greater bone volume, higher trabecular number, and greater densities were observed in the Col/HA scaffold alone compared to the other three groups when two types of scaffold were subcutaneously implanted into the backs of mice with or without MSC loading. These data suggest that the ECM Col/HA scaffolds have lower osteoconductive potential than the Col/ HA scaffolds. 74 Datta et al. produced a complex scaffold consisting of titanium fibers and decellularized ECM derived from rat MSCs, onto which rat marrow stromal cells were seeded in the presence or absence of osteogenic supplementation in a static culture. The results indicated that MSCs cultured on the ECM titanium scaffolds in the presence of osteogenic supplementation had significantly higher ALP activity than the other three scaffold groups, but calcium content was markedly increased in the MSC ECM titanium with osteogenic supplementation compared to the other groups only on day Instead of inorganic materials, some researchers have fabricated hybrid scaffolds that incorporate cell-derived ECM into synthetic polymers. Kim et al. developed a PLGA/PLA mesh scaffold loaded with decellularized ECM derived from human lung fibroblasts in the presence of BMP-2, onto the surface of which human placenta-derived MSCs were seeded to induce osteogenic differentiation in vitro. After 4 weeks, human placentaderived MSCs cultured on the ECM PLGA/PLA scaffolds exhibited higher levels of ALP activity, mineralization, and osteogenic marker gene expression compared to the control groups. When a variety of complex scaffolds were implanted into rat calvarial bone defects, the ECM PLGA/ PLA scaffold with 1000 ng of BMP-2 induced significantly more newly formed bone, and the bone defect was more completely repaired compared to the controls. 76 These studies show that the cell-derived ECM hybrid scaffolds can enhance osteogenic differentiation of MSCs and bone formation. Furthermore, many of the properties of tissue engineering grafts may be open to customization through the use of diverse biomaterials as templates, a process that may help overcome many of the disadvantages of autografts and allografts. The recent emergence of 3D printing technology may be particularly useful in the field of tissue engineering and regenerative medicine. Using a digital model of the desired scaffold, it is now possible to create physical structures synthetically layer by layer. 77 Compared to conventional methods of scaffold preparation, 3D printing is able to produce scaffolds with higher accuracy and precision with stronger biomechanical properties in less time. Pati et al. created 3D printed hybrid scaffolds composed of poly-ecaprolactone, PLGA, and b-tricalcium phosphate in combination with mineralized ECM derived from human nasal inferior turbinate tissue-derived MSCs. The human nasal inferior turbinate tissue-derived MSCs were reseeded on the ECM-ornamented 3D printed hybrid scaffolds to evaluate their capacity for osteoblastic differentiation and bone formation. In vitro calcium deposition and osteoblastic gene expression, such as osteopontin, osteocalcin, ALP, and RUNX2, were significantly increased in the ECMornamented 3D printed hybrid scaffolds compared to the bare 3D printed scaffolds. The same research group, using both ectopic and orthotopic analyses, showed that ECMornamented scaffolds produce more new bone tissue in vivo compared to bare scaffolds. 78 These findings provide a proof of principle that 3D printed scaffolds combined with cellderived ECM are able to retain the biological properties of ECM without compromising the biomechanical strength of 3D printed scaffolds. In addition, some researchers have developed a novel approach for fabricating biomimetic 3D combined collagen ECM-based bioinks with preosteoblasts. These bioinks significantly enhance cell viability, proliferation, and osteogenic activities relative to conventional alginate-based bioinks. 79 They also result in a more uniform and accurate distribution of embedded cells, which is more conducive to the diffuse transport of nutrients and metabolic wastes. Further development of this type of 3D printing technology is therefore highly recommended, with the potential to revolutionize the fields of tissue engineering and regenerative medicine. A study indicated that under dynamic conditions, the flow perfusion bioreactor could markedly enhance marrow stromal osteoblast differentiation and mineralized deposition by fluid shear forces compared to statically cultured constructs. 80 The dynamic environment is more conducive to the flow of nutrients and removal of metabolites. The fluid shear forces and cell-derived ECM 3D scaffolds may have synergistic effects to promote osteoblastic differentiation, calcium content, ALP activity, and osteopontin secretion by MSCs in the presence or absence of osteogenic medium supplemented with dexamethasone. 81 Therefore, flow perfusion culture systems are important for the development of both bone biology and orthopedic tissue engineering.

11 CELL-DERIVED ECM 203 Recently, some groups have attempted to develop 3D cellular sheets made solely of living cells and autologous ECM components, with no artificial scaffold. Such a cellular sheet may adjust to the degree of cell differentiation and proliferation to a certain extent in vitro, as well as exhibit excellent handleability and biocompatibility. Lau et al. produced a cellular sheet model consisting of living chondrocytes and chondrocyte-derived ECM that they named living hyaline cartilaginous graft (LhCG). To assess the efficiency and function of LhCG, human fetal osteoblasts and hmscs were seeded onto LhCG templates to form constructs containing both osteoprogenitors and chondrocytes. They found that the LhCG could provide a suitable microenvironment to enhance maturation and osteogenic lineage differentiation of the human fetal osteoblasts and hmscs. In further research, LhCG constructs with or without hmscs were implanted subcutaneously into nude mice and bone formation examined. Osteogenesis was clearly observed in the two types of LhCG construct, but there were no obvious differences in calcium content, osteocalcin secretion, or osteogenic phenotype marker expression between LhCG with and without hmscs in the presence of osteogenic medium. These observations indicated the presence of large numbers of osteoprogenitor cells within the LhCG chondrocytes. 82 Compared to cell-derived ECM hybrid scaffolds, the use of LhCG as a cell-based scaffold-free platform presents a closer simulation of the natural endochondral niche, which appears to benefit bone development and formation. Additionally, LhCG may serve as a dynamic platform capable of overcoming several complications of cell-derived ECM hybrid scaffolds, including the production of harmful degradation products, as well as asynchronous scaffold absorption and bone regeneration. Coculture systems consisting of osteoprogenitor and chondrocytes have been shown to support osteogenesis via the simulation of natural endochondral ossification. Kittaka et al. cultured MSCs in growth medium supplemented with 50 mg/ml ascorbic acid for 7 days to generate a cell sheet consisting of MSCs and MSC-derived ECM. 83 An ascorbic acid concentration of 50 mg/ml in the medium, which is the optimal concentration for ECM deposition and cell sheet formation, facilitated retention of the activity and pluripotent differentiation potential of cells seeded on the cell sheets. 43 The cell sheets induced with osteoinductive medium showed higher levels of osteopontin mrna expression, elevated calcium contents, and increased ALP activity compared to those without osteoinductive medium treatment. The implantation of cell sheets that had been cultured in osteoinductive medium for 5 days into rat calvarial defects effectively induced new bone regeneration and blood vessel formation. 83 Use of such cell sheets represents a novel type of scaffold-free cell therapy for bone tissue engineering. Application of cell-derived ECM in nerve tissue engineering A recent study suggested that Schwann cell-derived ECM may contribute to the regulation of axonal growth and differentiation of dorsal root ganglion neurons in vitro; Gu et al. seeded dorsal root ganglion neurons from embryonic day 18 Sprague Dawley rats into Schwann cell-derived ECM- or poly-l-lysine-coated dishes and then performed labeling of axon neurofilaments with neurofilament 200 after culturing for 2 days (Table 3). They found that the axons of dorsal root ganglion neurons seeded onto Schwann cell ECM-coated dishes grew more rapidly and more bifurcate than those on poly-l-lysine-coated dishes. 84 Lin et al. demonstrated that 3D chitosan scaffolds with superior biodegradability and biofunctionality can facilitate secretion by Schwann cells of large amounts of laminin and collagen IV, components of the ECM that may be beneficial for promoting regeneration of injured nerve tissue. 85 In a follow-up study, Gu et al. developed a hybrid nerve scaffold by combining rat Schwann cell-derived ECM with both chitosan conduit and silk fibroin fibers to restore a sciatic nerve gap in rat. Following the cell-derived ECM hybrid scaffolds, tissue-derived ECM scaffolds (acellular nerve grafts) and blank chitosan/silk fibroin scaffolds were implanted into sciatic nerve gap sites in rats. The results revealed no obvious differences in regenerative outcome between acellular nerve grafts and cell-derived ECM hybrid scaffolds, but the experimental groups showed significantly better regeneration than the blank chitosan/silk fibroin scaffold groups. 84 Jian et al. cultured rat neural stem cells on rat glioma cell-derived ECM combined with chitosan scaffolds in the presence of SB The results showed that SB accelerated neural stem cell differentiation into ECM type Cell-derived ECM substrate Rat SCs Table 3. Applications of Cell-Derived ECM in Nerve Tissue Engineering Seed cell Rat DRG neuron Cell-derived ECM hybrid scaffolds Rat SC-derived ECM and chitosan conduit/silk fibroin fibers Rat glioma cell-derived ECM and chitosan scaffold Growth factors Culture condition Outcome Reference None In vitro Promoted axonal growth of DRG neuron None None In vitro and in vivo (rat sciatic nerve gap) Rat neural stem cells SB In vitro and in vivo (rat spinal cord injury) No obvious differences between acellular nerve grafts and cell-derived ECM scaffolds for nerve regeneration Strengthened the repair of spinal cord injury

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