Table of Contents Author Guidelines Submit a Manuscript
BioMed Research International
Volume 2018, Article ID 8472309, 15 pages
https://doi.org/10.1155/2018/8472309
Review Article

Biochemical Stimulus-Based Strategies for Meniscus Tissue Engineering and Regeneration

1Institute of Orthopedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, No. 28 Fuxing Road, Haidian District, Beijing 100853, China
2Center for Biomaterial and Tissue Engineering, Academy for Advanced Interdisciplinary Studies, No. 5 Yiheyuan Road, Haidian District, Peking University, Beijing 100871, China
3Institute of Anesthesiology, Chinese PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing 100853, China
4Department of Bone and Joint Surgery, The Affiliated Hospital of Southwest Medical University, No. 25 Taiping Road, Luzhou 646000, China
5First Department of Orthopedics, First Affiliated Hospital of Jiamusi University, No. 348 Dexiang Road, Xiangyang District, Jiamusi 154002, China
6School of Medicine, Nankai University, Tianjin 300071, China
7Shanxi Traditional Chinese Hospital, No. 46 Binzhou West Street, Yingze District, Taiyuan 030001, China

Correspondence should be addressed to Shuyun Liu; moc.361@nna_raelc and Quanyi Guo; moc.361@103_ougrotcod

Received 28 September 2017; Accepted 19 December 2017; Published 17 January 2018

Academic Editor: Haining Zhang

Copyright © 2018 Mingxue Chen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Meniscus injuries are very common and still pose a challenge for the orthopedic surgeon. Meniscus injuries in the inner two-thirds of the meniscus remain incurable. Tissue-engineered meniscus strategies seem to offer a new approach for treating meniscus injuries with a combination of seed cells, scaffolds, and biochemical or biomechanical stimulation. Cell- or scaffold-based strategies play a pivotal role in meniscus regeneration. Similarly, biochemical and biomechanical stimulation are also important. Seed cells and scaffolds can be used to construct a tissue-engineered tissue; however, stimulation to enhance tissue maturation and remodeling is still needed. Such stimulation can be biomechanical or biochemical, but this review focuses only on biochemical stimulation. Growth factors (GFs) are one of the most important forms of biochemical stimulation. Frequently used GFs always play a critical role in normal limb development and growth. Further understanding of the functional mechanism of GFs will help scientists to design the best therapy strategies. In this review, we summarize some of the most important GFs in tissue-engineered menisci, as well as other types of biological stimulation.

1. Introduction

Meniscus injuries are very common in athletes and middle-aged and older people [1]. The blood supply and nerve distribution to the meniscus are variable. The meniscus can be subdivided into three areas: the inner white region, which lacks a blood supply; the outer red region, which has a blood supply; and the middle red–white region, which shows transitional features. Meniscus injuries to the inner white region or middle red–white region remain hard to repair [2]. Orthopedic surgeons usually use a partial meniscectomy to treat these meniscus injuries. However, this inevitably leads to osteoarthritis (OA) of the injured knee [3]. Meniscus allograft transplantation can overcome this dilemma to an extent. However, there are some limitations to transplantation, such as viral transmission, graft preservation, and mismatching [4].

The development of tissue engineering and regeneration medicine provides a new avenue for meniscus repair. By combining cells and scaffolds, we can form tissue-engineered constructs. However, it is difficult to use these constructs to repair the injury tissues. Biomechanical or biochemical stimulation can enhance the maturation and remodeling of these constructs. Hence, we usually regard the seed cells, scaffolds, and biomechanical and biochemical stimulation as the three indispensable elements of tissue engineering. Meniscal fibrochondrocytes and stem cells are the two most important kinds of seed cell [5]. They all play critical roles in meniscus regeneration. Scaffolds can be roughly divided into scaffolds derived from synthetic polymers or from biological materials [5]. It is very hard to regenerate the injured tissue solely with a combination of seed cells and scaffold. However, biomechanical and biochemical stimulation can build a bridge between the tissue-engineered construct and the functional tissue. The biomechanical stimulation usually mimics the native meniscus biomechanical microenvironment, such as the compressive loading or tensile strength [6, 7]. However, this review focuses on the effects of biochemical stimulation of the tissue-engineered meniscus.

The most familiar biochemical stimulation is growth factor (GF). The GFs used usually play a significant role in normal limb development and growth [811]. They can influence cell migration, proliferation, differentiation, and apoptosis. When used for tissue regeneration, they may also play important roles in tissue maturation and remodeling. Finally, we summarize other forms of biological stimulation that are used in the tissue-engineered meniscus.

2. Growth Factors and Gene Therapy for Meniscus Tissue Engineering

The desirable properties and functions of the native meniscus are largely dependent on the maintenance of the unique extracellular matrix (ECM) and its structure, which is generally modulated by the anabolic and catabolic activities of meniscal cells [74]. Growing evidence indicates that in addition to genetic factors, growth factors play a key role in the metabolic activity of fibrochondrocytes and further affect development, homeostasis, and regeneration [7578]. By binding to specific receptors on the target cell surface, growth factors may initiate signal transduction cascades and further affect cellular processes and metabolic activity. Growth factors may promote meniscus repair and regeneration via multiple mechanisms, including recruitment of fibrochondrogenic cells, enhancement of fibrochondrogenic cell proliferation, and stimulation of ECM production. Thus, local administration of growth factors may create a favorable microenvironment and further promote meniscus repair. Growth factors commonly used for meniscus and cartilage regeneration are summarized in Table 1. Of the numerous bioactive molecules, the most important and thoroughly studied growth factors include the transforming growth factor-β (TGF-β) superfamily, basic fibroblast growth factor (bFGF), and insulin-like growth factor-1 (IGF-1). The effects of other growth factors, such as connective tissue growth factor (CTGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), and platelet-rich plasma (PRP), on meniscus regeneration have also been evaluated.

Table 1: Commonly used growth factors for cartilage and meniscus tissue engineering and regeneration.
2.1. The TGF-β Superfamily

The TGF-β superfamily consists of more than 30 members and includes TGF-βs, activins, and bone morphogenetic proteins (BMPs) [79, 80]. Growth factors from the TGF-β superfamily are involved in regulating various cellular processes, including cell survival, growth, proliferation, migration, differentiation, and apoptosis, as well as synthesis and degradation of the ECM [8082]. TGF-βs and BMPs have been studied most extensively and have shown great potential in the field of tissue engineering and regenerative medicine over the past few decades [77]. Thus, it is possible that local administration of these factors may benefit functional meniscus regeneration.

2.1.1. TGF-βs

There are three different isoforms of TGF-β in mammals: TGF-β1, TGF-β2, and TGF-β3 [83]. The most thoroughly studied TGF-βs in the musculoskeletal system are TGF-β1 and TGF-β3 [77]. TGF-β is very effective for stimulating collagen production and glycosaminoglycan (GAG) synthesis by meniscal cells [12, 14, 18, 19]. For example, Pangborn and Athanasiou [13, 15] evaluated the effects of four common growth factors (TGF-β1, PDGF-AB, IGF-I, and bFGF) on meniscal fibrochondrocyte ECM synthesis in monolayers or in three-dimensional (3D) cultures. These studies found that treatment with TGF-β1 led to the greatest amount of collagen and GAG production compared to other growth factors. Similarly, Imler et al. [16] demonstrated that TGF-β1 was the most potent stimulator of both collagen and GAG synthesis. In addition, a combination of TGF-β1 and chondroitinase ABC (C-ABC) improved the biochemical and biomechanical properties of an agarose scaffold seeded with bovine meniscus cells and articular chondrocytes [17, 18]. TGF-β1 also markedly increased the amount of alpha-smooth muscle actin (α-SMA) in meniscal cells, which plays a crucial role in the contraction of the collagen–GAG matrix [20]. Not only does TGF-β enhance ECM synthesis, but it also blocks matrix degradation via downregulation of proteases such as matrix metalloproteases (MMPs) or upregulation of inhibitors of MMPs (TIMPs) [21, 22]. In addition, TGF-β is a chief anticatabolic agent counteracting the deleterious effects of catabolic cytokines. For example, several studies [21, 22, 84] have reported that TGF-β may effectively suppress the catabolic effects mediated by interleukin (IL)-1 and tumor necrosis factor (TNF)-α, including the upregulation of MMPs (MMP-1, MMP-3, MMP-8, MMP-13, and MMP-14) and downregulation of ECM-related genes. In addition, TGF-β may increase TIMP production [21].

In addition to regulating matrix metabolism, another chief function of TGF-β in meniscus tissue engineering is the recruitment, proliferation, and fibrochondrogenic differentiation of mesenchymal stem cells (MSCs) [23, 24, 85]. In general, TGF-β plays a crucial role in chondrogenesis [25, 86], and studies have revealed that TGF-β3 has the strongest chondrogenic effects of all isoforms [26, 87, 88]. The synergistic effects of TGF-β and IGF-1 on the induction of dedifferentiated articular chondrocytes from their original phenotype were also observed [27]. Kulyk et al. revealed that, in this process, TGF-β upregulates transcription factor SOX9 through the Smad pathway, followed by enhancement of cartilage gene expression, such as type II collagen and aggrecan.

Furthermore, several studies have demonstrated that TGF-β supplementation can promote cartilage and meniscus repair and has promise for meniscus regeneration [2830]. For example, Lee et al. [89] investigated the potential of anatomically correcting TGF-β3-infused bioscaffolds for articular cartilage regeneration. Histological and mechanical results showed that TGF-β3-infused bioscaffolds promoted hyaline cartilage formation in the articular surface with excellent mechanical properties similar to those of native articular cartilage 4 months after implantation in a rabbit model. Moreover, this study was the first to demonstrate that TGF-β3 stimulates articular cartilage regeneration through the recruitment of endogenous stem or progenitor cells, chondrogenic differentiation, and histogenesis and provided evidence that complex tissues may regenerate by homing of endogenous cells without cell transplantation. Similarly, McNulty and Guilak [90] found that applying TGF-β1 enhanced cellular accumulation and increased the shear strength of the repaired tissue, which suggests that TGF-β1 is essential for cartilage integrity and may be a potent alternative for enhancing meniscal repair.

In general, TGF-β is likely to push cells toward a more chondrocytic phenotype and to induce hyaline cartilage formation. Freymann et al. [91] revealed that TGF-β enhanced the production of specific cartilage and collagen type II proteoglycans by mesenchymal or meniscus cells but did not significantly increase the formation of type I collagen in meniscus 3D micromass or scaffold cultures, which is the main component of fibrocartilage tissue and plays a crucial role in the tensile strength of the native meniscus. Because the unique inhomogeneous feature of the meniscus presents a tremendous challenge for total meniscus regeneration, the use of various combinations of growth factors may be a promising solution. Lee et al. [31] spatiotemporally delivered a combination of CTGF and TGF-β3 to regenerate the meniscus in a sheep model. They demonstrated that spatiotemporally delivered CTGF and TGF-β3 could lead to heterogeneous meniscus regeneration by inducing endogenous stem/progenitor cells to differentiate and synthesize zone-specific types I and II collagen.

However, several unfavorable side effects of TGF-β1 treatment must be mentioned, such as induction of synovial fibroplasias and fibrosis, stimulation of osteophyte formation, and recruitment of inflammatory leukocytes [84, 92, 93]. Fortunately, studies have reported that applying local inhibitors of TGF-β may help block these undesirable side effects [84].

2.1.2. Bone Morphogenetic Proteins (BMPs)

BMPs also belong to the TGF-β superfamily and play a crucial role in bone and cartilage formation and repair [9496]. They share several functions with TGF-βs and have potential for meniscal regeneration [97]. The distinct and key function of BMPs is osteogenic differentiation of human MSCs (hMSCs), but they are not restricted to bone and also induce osteoblastic [98, 99], tenogenic [100], and chondrogenic [101] differentiation of MSCs. For instance, a study examined the capacity of BMP-2, BMP-4, and BMP-6 to promote chondrogenic differentiation of MSCs and encourage cartilage formation in vitro. It found that BMP-2 is more effective than others for chondrogenic differentiation of MSCs [39]. Gouttenoire et al. [32] reported the specific capability of BMP-2 to reverse chondrocyte dedifferentiation by increasing cartilage-specific collagen type II production in dedifferentiated chondrocytes. In addition, Shintani and Hunziker [42] evaluated the potential of BMP-2, BMP-7, and TGF-β1 for inducing chondrogenic differentiation of synovial explants. In that study, all three growth factors induced chondrogenic differentiation of synovial MSCs and enhanced the formation of cartilaginous tissue. However, BMP-7 was more potent and effective than the other growth factors in inducing chondrogenesis. In addition, Miyamoto et al. [41] reported that the effects of BMP-7 on chondrogenic differentiation of MSCs were enhanced when it was combined with TGF-β3.

BMPs have a clear role in modulating tissue homeostasis and blocking degradation processes [102, 103]. Chubinskaya compared the anabolic activity of BMPs (BMP-2, BMP-4, BMP-6, and BMP-7) and cartilage-derived morphogenetic proteins (CDMP-1 and CDMP-2) in human articular chondrocytes [40]. BMP-2, BMP-4, and BMP-7 were more potent in upregulating proteoglycan production than the other three growth factors, with the highest proteoglycan content on day 9 in the presence of BMP-7. Furthermore, under simultaneous treatment with IL-1β and the aforementioned growth factors, only BMP-7 effectively antagonized the inhibition of proteoglycan synthesis mediated by IL-1β. Similar studies have also demonstrated that BMP-7 effectively counteracted chondrocyte catabolism induced by various proinflammatory cytokines such IL-1, IL-6, IL-8, MMP-1, MMP-13, and TNF-α [35, 36, 67, 104]. The prominent proanabolic and anticatabolic properties of growth factors are essential to their clinical application, particularly under local inflammatory conditions triggered by trauma, degenerative disease, or surgery. In addition, BMP-7 increases matrix synthesis without stimulating uncontrolled fibroblast proliferation and osteophyte formation [105, 106]. It is interesting that BMP-2 may enhance matrix turnover in native and IL-damaged cartilage, as evidenced by upregulated collagen type II and aggrecan expression and increased aggrecan degradation, which suggests that BMP-2 treatment may lead to a reparative response in chondrocytes after cartilage injury or osteoarthritis [33].

BMPs effectively promote cartilage and osteochondral regeneration [107, 108]. BMPs have also been evaluated for their potential in meniscus repair and regeneration. For example, Forriol et al. [37] investigated the effects of BMP-7 treatment on meniscal defects in a sheep model. In that study, defects were made in the avascular region of the medial meniscus and treated with Putty® (control group) or osteogenic protein-1 (OP-1) Putty, which contains BMP-7 (experimental group). After 12 weeks, meniscal defects in the experimental group were filled with cellular fibrous tissue that connected both edges of the defects. In addition, Minehara et al. [34] developed a chemotactic cell-seeding technique with a solvent-preserved human meniscus scaffold to improve meniscal repair. They found that rhBMP-2 stimulated chondrocyte migration and proliferation as well as proteoglycan production throughout the meniscus tissue, which suggests a potential application of rhBMP-2 as a chemokinetic factor for loading into a scaffold for cartilage and meniscus tissue engineering. In another study, the Achilles tendon was treated with BMP-7 and transplanted into a rat meniscal defect model [38]. After 12 weeks, regenerated meniscus-like tissue was observed; this may effectively prevent cartilage degeneration.

In general, BMP-2 and BMP-7, which are approved by the Food and Drug Administration (FDA) for clinical use, have shown promising effects on chondrocyte differentiation, ECM production, and fibrocartilaginous tissue regeneration. Synergistic effects have been observed when BMP-7 is combined with other growth factors such as IGF-1 and TGF-β1 [109], which suggests that the addition of these factors may lead to greater improvements in meniscus repair and regeneration.

2.2. Basic Fibroblast Growth Factor (bFGF)

The fibroblast growth factor (FGF) family is composed of 18 structurally related signaling molecules [110, 111]. Basic FGF, also known as bFGF, FGF2, or FGF-β, is an important member of the FGF family and is found in the cartilaginous matrix [78, 102, 112, 113]. The mitogenic effects of FGF on MSCs were first reported by Oliver more than 27 years ago [114]. FGF is a powerful mitogen for a variety of cell types, including chondrocytes, fibrochondrocytes, osteoblasts, and adipocytes [102]. Numerous studies [45, 115, 116] have demonstrated the strong stimulating effects of bFGF on meniscal cell proliferation in monolayer cultures as well as in tissue-engineered constructs. For example, one study [44] evaluated the effects of nine growth factors (EGF, NGF, IGF-1, TGF-α, TGF-β, a-FGF, b-FGF, PDGF-AA, and PDGF-AB) on meniscal fibrochondrocyte proliferation in a monolayer culture. EGF, bFGF, TGF-α, and PDGF-AB stimulate cell proliferation, with bFGF having the greatest effect. Cucchiarini et al. [46] investigated the effects of bFGF on proliferation and metabolic activities of meniscal cells using a gene-based approach in which bFGF was vectored with a recombinant adeno-associated virus; increased cell proliferation and alpha-smooth muscle actin (α-SMA) expression were observed. Sotiropoulou et al. [47] also demonstrated that adding bFGF to culture media enhanced the proliferative capacity of hMSCs. In addition, FGF maintains the multilineage differentiation potential of MSCs during proliferation, including chondrogenic, osteogenic, adipogenic, and neurogenic differentiation [48, 49, 117, 118].

Monolayer expansion may result in loss of expression of collagen type II and matrix-forming phenotypes of meniscal cells. However, Adesida et al. [50] demonstrated the ability of bFGF to restore the chondrogenic phenotype of passaged meniscal cells based on reexpression of collagen type II and proteoglycan at both the gene and protein levels. In that study, supplementation with bFGF upregulated expression of collagen type II 200-fold in subsequent 3D pellet cultures. Moreover, this favorable effect was further enhanced under 5% oxygen culture conditions.

The specific role of bFGF in anabolic and catabolic processes remains controversial. Studies have demonstrated the capacity of bFGF to stimulate the anabolic activity of cartilage and meniscus [13]. For example, Tumia and Johnstone [115] demonstrated that meniscal cells from all zones responded positively to bFGF supplementation by enhancing DNA synthesis and ECM formation. Cheng et al. [119] also demonstrated that bFGF boosted the kinetics of MSC chondrogenesis, resulting in faster differentiation and leading to enhanced ECM accumulation. However, several studies [16, 51] revealed that bFGF was the least effective stimulator of both protein and proteoglycan production. In addition, Loeser et al. [54] reported that bFGF had dramatic antagonistic effects on proteoglycan accumulation promoted by IGF-1 and/or BMP-7. bFGF is also an antagonist of collagen type II and decorin production induced by IGF-1 and TGF-β in porcine articular chondrocytes [52]. Moreover, some evidence suggests that bFGF leads to the upregulation of MMPs and aggrecanases and increases reactive oxygen species such as nitric oxide (NO) and the superoxide anion [53]. The role of two members of the FGF family, FGF-2 and FGF-18, in cartilage homeostasis was evaluated by Ellman et al. [120, 121], who concluded that bFGF is a catabolic mediator in human cartilage via increased matrix-degrading enzyme activity and decreased ECM production, whereas FGF-18 is likely an anabolic regulator in human articular chondrocytes, enhancing ECM formation and chondrogenic differentiation and inhibiting cell proliferation.

Despite its controversial effects on cartilage homeostasis, the effects of bFGF on tissue regeneration and repair were investigated and revealed positive results [43, 55, 122, 123]. Deng et al. [55] developed gelatin microspheres in combination with controlled-release bFGF for cartilage repair in a rabbit model. Histological results showed that defects were filled with hyaline-like cartilage after 24 weeks, which indicates the great potential of a bFGF-loaded scaffold for promoting cartilage regeneration. In another study [56], meniscal cells were cultured on poly L-lactic acid (PLLA) scaffolds with bFGF under hypoxic conditions. After 4 weeks, histological results demonstrated synergic effects of hypoxia and bFGF on enhancing GAG production and compressive properties of tissue-engineered meniscus constructs in vitro. In addition, Ionescu et al. [57] investigated the effects of bFGF as a promitotic manager and TGF-β3 as a promatrix formation manager on meniscus repair and integration with electrospun polycaprolactone (PCL) scaffolds. This study biochemically, histologically, and mechanically showed that short-term delivery of bFGF or sustained delivery of TGF-β3 enhanced integration for bovine meniscus tissues, which suggests that both bFGF and TGF-β3 have the potential to promote meniscus repair.

Miyakoshi et al. [124] reported that local administration of bFGF led to inflammatory responses and osteophyte formation in a rabbit model. bFGF was also closely associated with synovial proliferation and hyperplasia in rheumatoid arthritis joints [120]. Given the potentially deleterious effects and controversial role of bFGF in articular development, the use of bFGF for meniscus repair and regeneration must be further explored. Although there is less literature on the role of FGF-18 in meniscus repair, it has shown promising anabolic effects on chondrocytes [121, 125]. More detailed studies are necessary to define the exact effects of FGF on meniscal cells, explants, and engineered constructs and to provide evidence for meniscus regeneration.

2.3. Insulin-Like Growth Factors (IGFs)

Two distinct forms of IGFs, IGF-1, and IGF-2 play a pivotal role in tissue metabolism [126]. IGF-1 is a vital anabolic growth factor of cartilaginous tissue under normal conditions and has been studied most in cartilage and meniscus tissue engineering [67, 127]. In general, IGF-1 enhances anabolic effects and inhibits catabolic responses. Puetzer et al. [58] explored the effects of IGF-1 on the mechanical and biochemical properties of meniscal constructs. After 4 weeks, IGF-1 treatment led to a 26-fold increase in GAG production, a 10-fold increase in collagen production, and a 3-fold increase in the equilibrium modulus of engineered meniscal constructs compared to 0-week controls, providing evidence for IGF-1 as a potential treatment in meniscal regeneration. A mixture of bFGF, TGF-β1, and IGF-1 elevates expression of collagen type II and aggrecans in fibroblast-like synoviocytes in vitro [66]. In another study [59], IGF-1 applied to monolayer cultures for 48 h enhanced fibrochondrocyte proliferation and formation of ECM in all zones of the meniscus. What is interesting is that the meniscal cells from the avascular region responded more favorably than those from the vascular region. This indicates that fibrochondrocytes from avascular meniscal tissue are able to express their intrinsic potential to regenerate when exposed to suitable growth factors. In addition, IGF-1 effectively decreases expression of aggrecanase-1 and reduces the release of degrading molecules such as MMPs [67]. For example, Im et al. [67] demonstrated the prominent suppressive effects of the combination of IGF-1 and BMP-7 on MMP-13 expression: IGF-1 and BMP-7 decreased inflammatory cytokine expression and/or their intermediate gene products. However, chondrocyte responsiveness to IGF-1 may diminish with age and under conditions of inflammation due to overexpression of IGF binding proteins [128131]. BMP-7 seems attractive for counteracting these effects because of its robust anticatabolic actions. Therefore, synergistic effects resulting in enhanced ECM production were observed when BMP-7 and IGF-I were used in combination [109, 132].

Apart from its anabolic effects on cartilaginous tissue, IGF-1 promoted the chondrogenic differentiation of MSCs, which may be further enhanced when combined with TGF-β1 [60, 64]. IGF-1 also stimulated cell migration in specific regions of the meniscus [61]. Together, these findings support the regenerative potential of IGF for cartilage and meniscus tissue engineering. Zhang et al. [62] studied the ability of human IGF-1- (hIGF-1-) meshed bone marrow stromal cells (BMSCs) to promote the repair of full-thickness meniscal defects and found that defects were completely filled with white tissue 16 weeks after treatment in a goat model that was histologically and biochemically similar to normal meniscal fibrocartilage. In another study, Goodrich et al. [63] investigated the ability of chondrocytes modified by an adenovirus vector encoding equine IGF-1 to enhance cartilage healing in an equine model. Histological results showed that defects were filled with a more hyaline-like tissue at 8 months, whereas control defects were covered with irregular and more fibrous tissue. Izal et al. [65] also reported that treatment with TGF-β1 and IGF-1 in combination improved repair of the meniscus avascular zone by enhancing meniscal cell proliferation and tissue attachment.

2.4. Other Growth Factors and Small Bioactive Molecules

In addition to the aforementioned growth factors, other growth factors, such as CTGF, VEGF, PDGF, HGF, and PRP, have been studied for their ability to improve meniscal repair and regeneration. Inducing angiogenesis may be essential to enhancing the healing capacity of the meniscus tissue. Thus, VEGF seems to be attractive for improving meniscus repair by stimulating angiogenesis. However, Petersen et al. [68, 133] demonstrated that VEGF failed to promote healing in the meniscus in a sheep meniscal longitudinal injury model treated with VEGF-coated sutures. In addition, HGF induces blood vessel formation in engineered meniscal fibrochondrocyte-polyglycolic acid (PGA) constructs without increasing any mechanical properties [69]. The effects of CTGF were also assessed. He et al. [70] studied the reparative effects of CTGF on enhancing meniscal repair in the meniscal avascular zone in a rabbit model and demonstrated that CTGF might promote healing of defects by stimulating ECM deposition within the repair zone. Nishida et al. [71] also reported that CTGF-hydrogel collagen scaffolds enhanced articular cartilage regeneration in a rat model. PDGF also enhanced wound healing and ECM production as well as cell proliferation; thus, it was believed to be capable of enhancing tissue regeneration and repair [126]. Tumia and Johnstone [72] investigated the capacity of PDGF-AB to improve meniscal tissue regeneration in all three zones of the meniscus and found that it enhanced fibrochondrocyte proliferation and new matrix formation, which suggests that PDGF may be of benefit in meniscus regeneration. PRP is the source of multiple growth factors, including TGF-β, PDGF, VEGF, IGF-1, bFGF, and EGF [73, 134]. Because growth factors are effective in meniscal healing, PRP may be a potent agent for meniscal repair. PRP promoted cartilage regeneration by increasing ECM content in a rabbit model [134]. Ishida [73] also demonstrated the ability of PRP to encourage matrix deposition and proliferation of meniscal cells in a monolayer culture, histologically enhancing the healing of meniscal defects with tissue that resembled the inner region of the meniscus in a rabbit model. However, Zellner et al. [135] reported no improvements in the healing of a meniscus defect after treatment with PRP-loaded hyaluronan-collagen composite matrices.

Several small bioactive molecules, such as kartogenin (KGN), aptamer, Y-27632, and E7 peptide, have also attracted great interest and shown promising results in cartilage and meniscus regeneration. For example, Huang et al. [136] reported that KGN not only promoted chondrogenic differentiation of tendon stem cells in vitro but also enhanced meniscus-like tissue formation in a rabbit model. Hu et al. [137] demonstrated that an aptamer-bilayer scaffold could specifically recognize and bind with MSCs, while efficiently recruiting them to enrich the MSCs around the osteochondral defect, successfully achieving osteochondral regeneration. A biphasic scaffold functionalized with E7 peptide was also demonstrated to enhance cartilage regeneration via the specific homing of endogenous stem cells [138]. The rho-kinase inhibitor Y-27632 also favors the differentiation of chondroprogenitors and prevents the dedifferentiation of articular chondrocytes [139, 140].

2.5. Gene Therapy

Gene therapy is a novel approach to meniscus tissue engineering that aims to transfer specific genes into an organism or tissue using viral or nonviral vectors or direct injection [102, 141]. Because growth factor concentration gradients and the duration of treatment may play a crucial role in meniscus repair, an important aspect of growth factor treatment is their delivery, given their short biological half-life and rapid clearance potential. To achieve controlled and extended growth factor release, gene transfer techniques may be favored for the local administration of specific factors. The major advantage of gene therapy is high-concentration delivery and persistent expression of these growth factors at the repair site [141144]. A variety of vectors are currently used for gene transfer in meniscus tissue engineering, including nonviral vectors, adenoviral vectors, retroviral/lentiviral vectors, herpes simplex virus (HSV) vectors, and recombinant adeno-associated virus (rAAV) vectors. Each exhibits specific characteristics [46, 62, 69, 145149]. In general, nonviral vectors are safe because of their lack of inherent replication capability, but their lower efficiency limits their widespread application [150, 151]. Adenoviral vectors are characterized by high transduction efficiency and a low risk of carcinogenesis, but they are immunogenic and fail to maintain long-term transgene expression [147, 152, 153]. Retroviral/lentiviral vectors permit prolonged transgene expression by integrating into the host cell genome. Although retroviral vectors only transduce actively replicating cells, this obstacle can be overcome with the application of lentiviral vectors, which are most effective for transduction in nondividing cells [153156]. However, the potential for insertional mutagenesis and tumor gene activation makes them unattractive candidates for clinical application. The advantage of HSV vectors is their ability to deliver long transgenes and a relatively high level of transduction efficiency in nondividing cells. Nevertheless, several studies have revealed that they are toxic and mediate only short-term transgene expression [154]. rAAV vectors are promising gene vehicles because they not only exhibit high transduction efficacy in both dividing and nondividing cells but also allow for long-term transgene expression [46, 148, 149, 154, 157]. In addition, these vectors demonstrate fewer immunogenic effects and are not pathogenic. All of these features make them an attractive choice for tissue engineering. Currently, there are two primary methods of gene transfer: direct injection of a gene into the target tissue and implantation of a genetically modified cell into the body. Numerous experiments have shown the feasibility of gene transfer to several tissues of the musculoskeletal system. Thus, gene transfer of regenerative factors appears to be a promising option for promoting meniscal repair and regeneration.

To date, only a few studies have used gene therapy strategies for meniscus tissue engineering. Growth factors used for gene transfer, including TGF-β1, HGF, and bFGF, have demonstrated the potential to enhance meniscus repair and regeneration. For example, bFGF vectored with rAAV enhanced cell proliferation, cell survival, and α-SMA expression in human meniscal fibrochondrocytes in vitro. This study demonstrated the feasibility of gene transfer for aiding in the repair of meniscal defects [158]. In another study [149], human meniscal fibrochondrocytes modified using a TGF-β rAAV enhanced cell proliferation and matrix synthesis. The TGF-β rAAV vectors were injected directly into the defects in meniscal explants and promoted repair of the meniscus lesions. In addition, meniscal cells and MSCs transduced with adenoviral vectors encoding TGF-β1 and seeded type I collagen–GAG matrices were transplanted into the injured avascular region of bovine menisci. After 3 weeks of in vitro culture, the constructs showed enhanced cellularity, collagen and proteoglycan production, and repair of the meniscal lesions with new tissue [147]. Previously, we also mentioned a study in which BMSCs with the transfected hIGF-1 gene were mixed with calcium alginate gel and aided in the repair of meniscus defects [151]. In general, gene therapy has the potential to enhance meniscus repair and regeneration, but more work is needed to identify the best candidate genes and ideal combinations of genes for meniscus regeneration.

2.6. Other Types of Biological Stimulation

Because a lack of blood supply creates a hypoxic environment in the inner region of the meniscus, scientists have attempted to mimic this environment in in vitro cultures to restore a differentiated phenotype. For example, Adesida et al. [50] demonstrated that low oxygen tension may enhance the matrix-forming phenotype of meniscal cells. Meniscal cells from the inner and outer regions responded differently to hypoxia culture. Indeed, cells from the outer meniscus showed greater sensitivity to lowered oxygen tension than cells from the inner meniscus. The response of meniscal cells to hypoxia was mediated by transcription factor hypoxia inducible factor-1α (HIF-1α), which may play a crucial role in determining the phenotype of inner meniscus cells [159]. Additive and synergistic effects of bFGF and hypoxia were also found on the enhancement of GAG accumulation and the compressive properties of engineered meniscus constructs in vitro [56].

Coculture systems have also been used for meniscus tissue engineering. Gunja and Athanasiou [160] used cocultures of second-passage meniscus cells and primary articular chondrocytes at varying ratios (100 : 0, 75 : 25, 50 : 50, 25 : 75, and 0 : 100) to enhance the biochemical and biomechanical properties of engineered constructs. Coculture systems with a higher percentage of chondrocytes led to significantly greater production of collagen type I, collagen type II, and GAG as well as compressive properties, whereas constructs with a higher percentage of meniscus cells resulted in a greater collagen type I content. This study illustrates that it is possible to achieve matrix content and mechanical properties close to native values of the meniscal inner and outer regions using a variety of coculture ratios. In another study, Cui et al. [161] investigated the use of coculture systems of human meniscal cells with MSCs at different ratios (100 : 0, 75 : 25, 50 : 50, 25 : 75, and 0 : 100) for meniscus tissue engineering and regeneration. The 75% meniscal cell/25% MSC coculture system showed optimal meniscus ECM production and the lowest hypertrophic expression of MSC genes such as COL10A1 and MMP13 during chondrogenic differentiation. This study indicates that coculture of meniscal cells with MSCs has the potential to expand the limited supply of meniscal cells with enhanced ECM production without hypertrophy.

3. Conclusion, Challenges, and Future Perspectives

Currently, there is no ideal treatment for the meniscus injuries. Tissue engineering is an attractive and promising strategy for repairing or regenerating the meniscus defects. However, regeneration of the functionally engineered meniscus remains challenging because of its complicated structure and functions. This review clearly demonstrates that biochemical stimulus plays a crucial role in the repair and regeneration of the engineered meniscus. There seems to be great potential for growth factors loading to promote regeneration of the engineered meniscus.

Individual growth factors are potent stimulators and have significant effects on many cellular processes, such as cell proliferation, differentiation, and metabolic activity, as well as meniscus repair and regeneration. Numerous experimental studies have demonstrated the synergistic effects of combinations of growth factors on meniscus repair and regeneration. Future investigations are warranted to explore the effects on meniscus tissue engineering of small bioactive molecules, which have already been shown to promote cartilage regeneration. The design of a good growth factor application strategy needs to consider the spatiotemporal specificity of meniscus regeneration. Nevertheless, it is easier than ever to achieve a spatial-specific growth factors distribution using a 3D printing approach. It is also important to develop a sequential release model for multiple growth factors that mimics cell migration and proliferation in the early regeneration stage, differentiation in the middle regeneration stage, and tissue remodeling in the final maturation stage. Gene therapy approaches may help to achieve this in the future.

Physical mechanical loading also plays a vital role in the development, remolding, and regeneration of the meniscus. The combination of mechanical stimulation and growth factors may yield great benefits for meniscus tissue engineering in the future.

Abbreviations

GF:Growth factor
ECM:Extracellular matrix
GAG:Glycosaminoglycan
TGF-β:Transforming growth factor-β
FGF:Fibroblast growth factor
bFGF:Basic fibroblast growth factor
IGF-1:Insulin-like growth factor-1
CTGF:Connective tissue growth factor
VEGF:Vascular endothelial growth factor
PDGF:Platelet-derived growth factor
HGF:Hepatocyte growth factor
PRP:Platelet-rich plasma
BMP:Bone morphogenetic protein
OP-1:Osteogenic protein-1
EGF:Epidermal growth factor
NGF:Nerve growth factor
HIF-1:Hypoxia inducible factor-1α
C-ABC:Chondroitinase ABC
α-SMA:Alpha-smooth muscle actin
3D:Three-dimensional
MMP:Matrix metalloprotease
TIMP:Inhibitors of matrix metalloprotease
IL:Interleukin
TNF:Tumor necrosis factor
OA:Osteoarthritis
MSC:Mesenchymal stem cell
BMSC:Bone marrow stromal cell
hMSC:Human mesenchymal stem cell
CDMP:Cartilage-derived morphogenetic protein
PLLA:Poly L-lactic acid
PCL:Polycaprolactone
PGA:Polyglycolic acid
HSV:Herpes simplex virus
rAAV:Recombinant adeno-associated virus
KGN:Kartogenin
FDA:Food and Drug Administration.

Conflicts of Interest

The authors declare no conflicts of interest.

Authors’ Contributions

All authors were involved in the study and approved its final version. Mingxue Chen and Weimin Guo contributed equally to this work.

Acknowledgments

This work was supported by the National Key R&D Program of China (2017YFC1103404), the High Technology Research and Development Program of China (2012AA020502, 2015AA020303), the National Natural Science Foundation of China (81472092), the Beijing Science and Technology Development Foundation (Z161100005016059), and the Natural Science Foundation of Beijing (7172203).

References

  1. R. W. B. Wyatt, M. C. S. Inacio, K. D. Liddle, and G. B. Maletis, “Prevalence and incidence of cartilage injuries and meniscus tears in patients who underwent both primary and revision anterior cruciate ligament reconstructions,” The American Journal of Sports Medicine, vol. 42, no. 8, pp. 1841–1846, 2014. View at Publisher · View at Google Scholar · View at Scopus
  2. C. Starke, S. Kopf, W. Petersen, and R. Becker, “Meniscal repair, Arthroscopy,” Journal of Arthroscopic & Related Surgery: Official Publication of the Arthroscopy Association of North America and the International Arthroscopy Association, vol. 25, no. 9, pp. 1033–1044, 2009. View at Google Scholar
  3. J. D. Lamplot and R. H. Brophy, “The role for arthroscopic partial meniscectomy in knees with degenerative changes: a systematic review,” The Bone & Joint Journal, vol. 98-b, no. 7, pp. 934–938, 2016. View at Google Scholar
  4. M. G. Hannon, M. K. Ryan, and E. J. Strauss, “Meniscal allograft transplantation a comprehensive historical and current review,” Bulletin of the Hospital for Joint Diseases, vol. 73, no. 2, pp. 100–108, 2015. View at Google Scholar · View at Scopus
  5. T. Trzeciak, M. Richter, W. Suchorska et al., “Application of cell and biomaterial-based tissue engineering methods in the treatment of cartilage, menisci and ligament injuries,” International Orthopaedics, vol. 40, no. 3, pp. 615–624, 2016. View at Publisher · View at Google Scholar · View at Scopus
  6. D. J. Huey and K. A. Athanasiou, “Tension-compression loading with chemical stimulation results in additive increases to functional properties of anatomic meniscal constructs,” PLoS ONE, vol. 6, no. 11, Article ID e27857, 2011. View at Publisher · View at Google Scholar · View at Scopus
  7. M. Petri, K. Ufer, I. Toma et al., “Effects of perfusion and cyclic compression on in vitro tissue engineered meniscus implants,” Knee Surgery, Sports Traumatology, Arthroscopy, vol. 20, no. 2, pp. 223–231, 2012. View at Publisher · View at Google Scholar · View at Scopus
  8. N. Itoh, “FGF10: A multifunctional mesenchymal-epithelial signaling growth factor in development, health, and disease,” Cytokine & Growth Factor Reviews, vol. 28, pp. 63–69, 2016. View at Publisher · View at Google Scholar · View at Scopus
  9. D. M. Ornitz and P. J. Marie, “Fibroblast growth factor signaling in skeletal development and disease,” Genes & Development, vol. 29, no. 14, pp. 1463–1486, 2015. View at Publisher · View at Google Scholar · View at Scopus
  10. G. D. Agrogiannis, S. Sifakis, E. S. Patsouris, and A. E. Konstantinidou, “Insulin-like growth factors in embryonic and fetal growth and skeletal development (Review),” Molecular Medicine Reports, vol. 10, no. 2, pp. 579–584, 2014. View at Publisher · View at Google Scholar · View at Scopus
  11. L. Jin and X. Li, “Growth differentiation factor 5 regulation in bone regeneration,” Current Pharmaceutical Design, vol. 19, no. 19, pp. 3364–3373, 2013. View at Publisher · View at Google Scholar · View at Scopus
  12. T. Tanaka, K. Fujii, and Y. Kumagae, “Comparison of biochemical characteristics of cultured fibrochondrocytes isolated from the inner and outer regions of human meniscus,” Knee Surgery, Sports Traumatology, Arthroscopy, vol. 7, no. 3, pp. 75–80, 1999. View at Publisher · View at Google Scholar · View at Scopus
  13. C. A. Pangborn and K. A. Athanasiou, “Effects of growth factors on meniscal fibrochondrocytes,” Tissue Engineering Part A, vol. 11, no. 7-8, pp. 1141–1148, 2005. View at Publisher · View at Google Scholar · View at Scopus
  14. S. Collier and P. Ghosh, “Effects of transforming growth factor beta on proteoglycan synthesis by cell and explant cultures derived from the knee joint meniscus,” Osteoarthritis and Cartilage, vol. 3, no. 2, pp. 127–138, 1995. View at Publisher · View at Google Scholar · View at Scopus
  15. C. A. Pangborn and K. A. Athanasiou, “Growth factors and fibrochondrocytes in scaffolds,” Journal of Orthopaedic Research, vol. 23, no. 5, pp. 1184–1190, 2005. View at Publisher · View at Google Scholar · View at Scopus
  16. S. M. Imler, A. N. Doshi, and M. E. Levenston, “Combined effects of growth factors and static mechanical compression on meniscus explant biosynthesis,” Osteoarthritis and Cartilage, vol. 12, no. 9, pp. 736–744, 2004. View at Publisher · View at Google Scholar · View at Scopus
  17. R. F. MacBarb, E. A. Makris, J. C. Hu, and K. A. Athanasiou, “A chondroitinase-ABC and TGF-β1 treatment regimen for enhancing the mechanical properties of tissue-engineered fibrocartilage,” Acta Biomaterialia, vol. 9, no. 1, pp. 4626–4634, 2013. View at Publisher · View at Google Scholar · View at Scopus
  18. D. J. Huey and K. A. Athanasiou, “Maturational growth of self-assembled, functional menisci as a result of TGF-β1 and enzymatic chondroitinase-ABC stimulation,” Biomaterials, vol. 32, no. 8, pp. 2052–2058, 2011. View at Publisher · View at Google Scholar · View at Scopus
  19. N. J. Gunja, R. K. Uthamanthil, and K. A. Athanasiou, “Effects of TGF-β1 and hydrostatic pressure on meniscus cell-seeded scaffolds,” Biomaterials, vol. 30, no. 4, pp. 565–573, 2009. View at Publisher · View at Google Scholar · View at Scopus
  20. J. M. Zaleskas, B. Kinner, T. M. Freyman, I. V. Yannas, L. J. Gibson, and M. Spector, “Growth factor regulation of smooth muscle actin expression and contraction of human articular chondrocytes and meniscal cells in a collagen-GAG matrix,” Experimental Cell Research, vol. 270, no. 1, pp. 21–31, 2001. View at Publisher · View at Google Scholar · View at Scopus
  21. W. Hui, A. D. Rowan, and T. Cawston, “Modulation of the expression of matrix metalloproteinase and tissue inhibitors of metalloproteinases by TGF-β1 and IGF-1 in primary human articular and bovine nasal chondrocytes stimulated with TNF-α,” Cytokine, vol. 16, no. 1, pp. 31–35, 2001. View at Publisher · View at Google Scholar · View at Scopus
  22. N. Takahashi, K. Rieneck, P. M. van der Kraan et al., “Elucidation of IL-1/TGF-β interactions in mouse chondrocyte cell line by genome-wide gene expression1,” Osteoarthritis and Cartilage, vol. 13, no. 5, pp. 426–438, 2005. View at Publisher · View at Google Scholar · View at Scopus
  23. Y. I. Kim, J.-S. Ryu, J. E. Yeo et al., “Overexpression of TGF-β1 enhances chondrogenic differentiation and proliferation of human synovium-derived stem cells,” Biochemical and Biophysical Research Communications, vol. 450, no. 4, pp. 1593–1599, 2014. View at Publisher · View at Google Scholar · View at Scopus
  24. H. Jian, X. Shen, I. Liu, M. Semenov, X. He, and X. F. Wang, “Smad3-dependent nuclear translocation of beta-catenin is required for TGF-beta1-induced proliferation of bone marrow-derived adult human mesenchymal stem cells,” Genes & Development, vol. 20, no. 6, pp. 666–674, 2006. View at Google Scholar
  25. E. Augustyniak, T. Trzeciak, M. Richter, J. Kaczmarczyk, and W. Suchorska, “The role of growth factors in stem cell-directed chondrogenesis: a real hope for damaged cartilage regeneration,” International Orthopaedics, vol. 39, no. 5, pp. 995–1003, 2015. View at Publisher · View at Google Scholar · View at Scopus
  26. Q. O. Tang, K. Shakib, M. Heliotis et al., “TGF-β3: a potential biological therapy for enhancing chondrogenesis,” Expert Opinion on Biological Therapy, vol. 9, no. 6, pp. 689–701, 2009. View at Publisher · View at Google Scholar · View at Scopus
  27. P. C. Yaeger, T. L. Masi, J. L. B. De Ortiz, F. Binette, R. Tubo, and J. M. McPherson, “Synergistic action of transforming growth factor-β and insulin-like growth factor-I induces expression of type II collagen and aggrecan genes in adult human articular chondrocytes,” Experimental Cell Research, vol. 237, no. 2, pp. 318–325, 1997. View at Publisher · View at Google Scholar · View at Scopus
  28. H. Diao, J. Wang, C. Shen et al., “Improved cartilage regeneration utilizing mesenchymal stem cells in TGF-beta1 gene-activated scaffolds.,” Tissue Engineering Part A, vol. 15, no. 9, pp. 2687–2698, 2009. View at Publisher · View at Google Scholar · View at Scopus
  29. H. Fan, H. Tao, Y. Wu, Y. Hu, Y. Yan, and Z. Luo, “TGF-β3 immobilized PLGA-gelatin/chondroitin sulfate/hyaluronic acid hybrid scaffold for cartilage regeneration,” Journal of Biomedical Materials Research Part A, vol. 95, no. 4, pp. 982–992, 2010. View at Publisher · View at Google Scholar · View at Scopus
  30. A. I. Bochyńska, G. Hannink, R. Verhoeven, D. W. Grijpma, and P. Buma, “The effect of tissue surface modification with collagenase and addition of TGF-β3 on the healing potential of meniscal tears repaired with tissue glues in vitro,” Journal of Materials Science: Materials in Medicine, vol. 28, no. 1, article no. 22, 2017. View at Publisher · View at Google Scholar · View at Scopus
  31. C. H. Lee, S. A. Rodeo, L. A. Fortier, C. Lu, C. Erisken, and J. J. Mao, “Protein-releasing polymeric scaffolds induce fibrochondrocytic differentiation of endogenous cells for knee meniscus regeneration in sheep,” Science Translational Medicine, vol. 6, no. 266, article 266ra171, 2014. View at Publisher · View at Google Scholar
  32. J. Gouttenoire, U. Valcourt, M.-C. Ronzière, E. Aubert-Foucher, F. Mallein-Gerin, and D. Herbage, “Modulation of collagen synthesis in normal and osteoarthritic cartilage,” Biorheology, vol. 41, no. 3-4, pp. 535–542, 2004. View at Google Scholar · View at Scopus
  33. E. N. B. Davidson, E. L. Vitters, P. L. E. M. van Lent, F. A. J. van de Loo, W. B. van den Berg, and P. M. van der Kraan, “Elevated extracellular matrix production and degradation upon bone morphogenetic protein-2 (BMP-2) stimulation point toward a role for BMP-2 in cartilage repair and remodeling,” Arthritis Research & Therapy, vol. 9, no. 5, article no. R102, 2007. View at Publisher · View at Google Scholar · View at Scopus
  34. H. Minehara, K. Urabe, K. Naruse et al., “A new technique for seeding chondrocytes onto solvent-preserved human meniscus using the chemokinetic effect of recombinant human bone morphogenetic protein-2,” Cell and Tissue Banking, vol. 12, no. 3, pp. 199–207, 2011. View at Publisher · View at Google Scholar · View at Scopus
  35. A. M. Elshaier, A. A. Hakimiyan, L. Rappoport, D. C. Rueger, and S. Chubinskaya, “Effect of interleukin-1β on osteogenic protein 1-induced signaling in adult human articular chondrocytes,” Arthritis & Rheumatology, vol. 60, no. 1, pp. 143–154, 2009. View at Publisher · View at Google Scholar · View at Scopus
  36. K. Huch, B. Wilbrink, J. Flechtenmacher et al., “Effects of recombinant human osteogenic protein 1 on the production of proteoglycan, prostaglandin E2, and interleukin-1 receptor antagonist by human articular chondrocytes cultured in the presence of interleukin-1β,” Arthritis & Rheumatology, vol. 40, no. 12, pp. 2157–2161, 1997. View at Publisher · View at Google Scholar · View at Scopus
  37. F. Forriol, P. Ripalda, J. Duart, R. Esparza, and A. R. Gortazar, “Meniscal repair possibilities using bone morphogenetic protein-7,” Injury, vol. 45, no. 4, pp. S15–S21, 2014. View at Publisher · View at Google Scholar · View at Scopus
  38. N. Ozeki, T. Muneta, H. Koga et al., “Transplantation of achilles tendon treated with bone morphogenetic protein 7 promotes meniscus regeneration in a rat model of massive meniscal defect,” Arthritis & Rheumatology, vol. 65, no. 11, pp. 2876–2886, 2013. View at Publisher · View at Google Scholar · View at Scopus
  39. I. Sekiya, B. L. Larson, J. T. Vuoristo, R. L. Reger, and D. J. Prockop, “Comparison of effect of BMP-2, -4, and -6 on in vitro cartilage formation of human adult stem cells from bone marrow stroma,” Cell and Tissue Research, vol. 320, no. 2, pp. 269–276, 2005. View at Publisher · View at Google Scholar · View at Scopus
  40. S. Chubinskaya, D. Segalite, D. Pikovsky, A. A. Hakimiyan, and D. C. Rueger, “Effects induced by BMPS in cultures of human articular chondrocytes: Comparative studies,” Growth Factors, vol. 26, no. 5, pp. 275–283, 2008. View at Publisher · View at Google Scholar · View at Scopus
  41. C. Miyamoto, T. Matsumoto, K. Sakimura, and H. Shindo, “Osteogenic protein-1 with transforming growth factor-β1: Potent inducer of chondrogenesis of synovial mesenchymal stem cells in vitro,” Journal of Orthopaedic Science, vol. 12, no. 6, pp. 555–561, 2007. View at Publisher · View at Google Scholar · View at Scopus
  42. N. Shintani and E. B. Hunziker, “Chondrogenic differentiation of bovine synovium: Bone morphogenetic proteins 2 and 7 and transforming growth factor β1 induce the formation of different types of cartilaginous tissue,” Arthritis & Rheumatology, vol. 56, no. 6, pp. 1869–1879, 2007. View at Publisher · View at Google Scholar · View at Scopus
  43. A. Hiraide, N. Yokoo, K.-Q. Xin et al., “Repair of articular cartilage defect by intraarticular administration of basic fibroblast growth factor gene, using adeno-associated virus vector,” Human Gene Therapy, vol. 16, no. 12, pp. 1413–1421, 2005. View at Publisher · View at Google Scholar · View at Scopus
  44. C. Kasemkijwattana, J. Menetrey, H. Goto, C. Niyibizi, F. H. Fu, and J. Huard, “The use of growth factors, gene therapy and tissue engineering to improve meniscal healing,” Materials Science and Engineering C: Materials for Biological Applications, vol. 13, no. 1-2, pp. 19–28, 2000. View at Publisher · View at Google Scholar · View at Scopus
  45. K. Stewart, M. Pabbruwe, S. Dickinson, T. Sims, A. P. Hollander, and J. B. Chaudhuri, “The effect of growth factor treatment on meniscal chondrocyte proliferation and differentiation on polyglycolic acid scaffolds,” Tissue Engineering Part A, vol. 13, no. 2, pp. 271–280, 2007. View at Publisher · View at Google Scholar · View at Scopus
  46. M. Cucchiarini, S. Schetting, E. F. Terwilliger, D. Kohn, and H. Madry, “rAAV-mediated overexpression of FGF-2 promotes cell proliferation, survival, and α-SMA expression in human meniscal lesions,” Gene Therapy, vol. 16, no. 11, pp. 1363–1372, 2009. View at Publisher · View at Google Scholar · View at Scopus
  47. P. A. Sotiropoulou, S. A. Perez, M. Salagianni, C. N. Baxevanis, and M. Papamichail, “Characterization of the optimal culture conditions for clinical scale production of human mesenchymal stem cells,” Stem Cells, vol. 24, no. 2, pp. 462–471, 2006. View at Publisher · View at Google Scholar · View at Scopus
  48. C. T. Buckley and D. J. Kelly, “Expansion in the presence of FGF-2 enhances the functional development of cartilaginous tissues engineered using infrapatellar fat pad derived MSCs,” Journal of the Mechanical Behavior of Biomedical Materials, vol. 11, pp. 102–111, 2012. View at Publisher · View at Google Scholar · View at Scopus
  49. I. Martin, A. Muraglia, G. Campanile, R. Cancedda, and R. Quarto, “Fibroblast growth factor-2 supports ex vivo expansion and maintenance of osteogenic precursors from human bone marrow,” Endocrinology, vol. 138, no. 10, pp. 4456–4462, 1997. View at Publisher · View at Google Scholar · View at Scopus
  50. A. B. Adesida, L. M. Grady, W. S. Khan, and T. E. Hardingham, “The matrix-forming phenotype of cultured human meniscus cells is enhanced after culture with fibroblast growth factor 2 and is further stimulated by hypoxia,” Arthritis Research & Therapy, vol. 8, article R61, 2006. View at Publisher · View at Google Scholar · View at Scopus
  51. X. Li, H. S. An, M. Ellman et al., “Action of fibroblast growth factor-2 on the intervertebral disc,” Arthritis Research & Therapy, vol. 10, no. 2, article no. R48, 2008. View at Publisher · View at Google Scholar · View at Scopus
  52. D. Sonal, “Prevention of IGF-1 and TGFβ stimulated type II collagen and decorin expression by bFGF and identification of IGF-1 mRNA transcripts in articular chondrocytes,” Matrix Biology, vol. 20, no. 4, pp. 233–242, 2001. View at Publisher · View at Google Scholar · View at Scopus
  53. P. Muddasani, J. C. Norman, M. Ellman, A. J. Van Wijnen, and H.-J. Im, “Basic fibroblast growth factor activates the MAPK and NFκB pathways that converge on Elk-1 to control production of matrix metalloproteinase-13 by human adult articular chondrocytes,” The Journal of Biological Chemistry, vol. 282, no. 43, pp. 31409–31421, 2007. View at Publisher · View at Google Scholar · View at Scopus
  54. R. F. Loeser, S. Chubinskaya, C. Pacione, and H.-J. Im, “Basic fibroblast growth factor inhibits the anabolic activity of insulin-like growth factor 1 and osteogenic protein 1 in adult human articular chondrocytes,” Arthritis & Rheumatology, vol. 52, no. 12, pp. 3910–3917, 2005. View at Publisher · View at Google Scholar · View at Scopus
  55. T. Deng, S. Huang, S. Zhou, L. He, and Y. Jin, “Cartilage regeneration using a novel gelatin-chondroitin-hyaluronan hybrid scaffold containing bFGF-impregnated microspheres,” Journal of Microencapsulation, vol. 24, no. 2, pp. 163–174, 2007. View at Publisher · View at Google Scholar · View at Scopus
  56. N. J. Gunja and K. A. Athanasiou, “Additive and synergistic effects of bFGF and hypoxia on leporine meniscus cell-seeded PLLA scaffolds,” Journal of Tissue Engineering and Regenerative Medicine, vol. 4, no. 2, pp. 115–122, 2010. View at Publisher · View at Google Scholar · View at Scopus
  57. L. C. Ionescu, G. C. Lee, K. L. Huang, and R. L. Mauck, “Growth factor supplementation improves native and engineered meniscus repair in vitro,” Acta Biomaterialia, vol. 8, no. 10, pp. 3687–3694, 2012. View at Publisher · View at Google Scholar · View at Scopus
  58. J. L. Puetzer, B. N. Brown, J. J. Ballyns, and L. J. Bonassar, “The effect of IGF-I on anatomically shaped tissue-engineered menisci,” Tissue Engineering Part: A, vol. 19, no. 11-12, pp. 1443–1450, 2013. View at Publisher · View at Google Scholar · View at Scopus
  59. N. S. Tumia and A. J. Johnstone, “Regional regenerative potential of meniscal cartilage exposed to recombinant insulin-like growth factor-I in vitro,” The Journal of Bone & Joint Surgery (British Volume), vol. 86, no. 7, pp. 1077–1081, 2004. View at Publisher · View at Google Scholar · View at Scopus
  60. L. Longobardi, L. O'Rear, S. Aakula et al., “Effect of IGF-I in the chondrogenesis of bone marrow mesenchymal stem cells in the presence or absence of TGF-β signaling,” Journal of Bone and Mineral Research, vol. 21, no. 4, pp. 626–636, 2006. View at Publisher · View at Google Scholar · View at Scopus
  61. M. M. Bhargava, E. T. Attia, G. A. C. Murrell, M. M. Dolan, R. F. Warren, and J. A. Hannafin, “The effect of cytokines on the proliferation and migration of bovine meniscal cells,” The American Journal of Sports Medicine, vol. 27, no. 5, pp. 636–643, 1999. View at Publisher · View at Google Scholar · View at Scopus
  62. H. Zhang, P. Leng, and J. Zhang, “Enhanced meniscal repair by overexpression of hIGF-1 in a full-thickness model,” Clinical Orthopaedics and Related Research, vol. 467, no. 12, pp. 3165–3174, 2009. View at Publisher · View at Google Scholar · View at Scopus
  63. L. R. Goodrich, C. Hidaka, P. D. Robbins, C. H. Evans, and A. J. Nixon, “Genetic modification of chondrocytes with insulin-like growth factor-1 enhances cartilage healing in an equine model,” The Journal of Bone & Joint Surgery (British Volume), vol. 89, no. 5, pp. 672–685, 2007. View at Publisher · View at Google Scholar · View at Scopus
  64. A. A. Worster, B. D. Brower-Toland, L. A. Fortier, S. J. Bent, J. Williams, and A. J. Nixon, “Chondrocytic differentiation of mesenchymal stem cells sequentially exposed to transforming growth factor-β1 in monolayer and insulin-like growth factor-I in a three-dimensional matrix,” Journal of Orthopaedic Research, vol. 19, no. 4, pp. 738–749, 2001. View at Publisher · View at Google Scholar · View at Scopus
  65. I. Izal, P. Ripalda, C. A. Acosta, and F. Forriol, “In vitro healing of avascular meniscal injuries with fresh and frozen plugs treated with TGF-beta1 and IGF-1 in sheep,” International Journal of Clinical and Experimental Pathology, vol. 1, no. 5, pp. 426–434, 2008. View at Google Scholar
  66. D. B. Fox, J. J. Warnock, A. M. Stoker, J. K. Luther, and M. Cockrell, “Effects of growth factors on equine synovial fibroblasts seeded on synthetic scaffolds for avascular meniscal tissue engineering,” Research in Veterinary Science, vol. 88, no. 2, pp. 326–332, 2010. View at Publisher · View at Google Scholar · View at Scopus
  67. H.-J. Im, C. Pacione, S. Chubinskaya, A. J. Van Wijnen, Y. Sun, and R. F. Loeser, “Inhibitory effects of insulin-like growth factor-1 and osteogenic protein-1 on fibronectin fragment- and interleukin-1β-stimulated matrix metalloproteinase-13 expression in human chondrocytes,” The Journal of Biological Chemistry, vol. 278, no. 28, pp. 25386–25394, 2003. View at Publisher · View at Google Scholar · View at Scopus
  68. W. Petersen, T. Pufe, C. Stärke et al., “The effect of locally applied vascular endothelial growth factor on meniscus healing: gross and histological findings,” Archives of Orthopaedic and Trauma Surgery, vol. 127, no. 4, pp. 235–240, 2007. View at Publisher · View at Google Scholar · View at Scopus
  69. C. Hidaka, C. Ibarra, J. A. Hannafin et al., “Formation of vascularized meniscal tissue by combining gene therapy with tissue engineering,” Tissue Engineering Part A, vol. 8, no. 1, pp. 93–105, 2002. View at Publisher · View at Google Scholar · View at Scopus
  70. W. He, Y.-J. Liu, Z.-G. Wang, Z.-K. Guo, M.-X. Wang, and N. Wang, “Enhancement of meniscal repair in the avascular zone using connective tissue growth factor in a rabbit model,” Chinese Medical Journal, vol. 124, no. 23, pp. 3968–3975, 2011. View at Publisher · View at Google Scholar · View at Scopus
  71. T. Nishida, S. Kubota, S. Kojima et al., “Regeneration of defects in articular cartilage in rat knee joints by CCN2 (connective tissue growth factor),” Journal of Bone and Mineral Research, vol. 19, no. 8, pp. 1308–1319, 2004. View at Publisher · View at Google Scholar · View at Scopus
  72. N. S. Tumia and A. J. Johnstone, “Platelet derived growth factor-AB enhances knee meniscal cell activity in vitro,” The Knee, vol. 16, no. 1, pp. 73–76, 2009. View at Publisher · View at Google Scholar · View at Scopus
  73. K. Ishida, R. Kuroda, M. Miwa et al., “The regenerative effects of platelet-rich plasma on meniscal cells in vitro and its in vivo application with biodegradable gelatin hydrogel,” Tissue Engineering Part A, vol. 13, no. 5, pp. 1103–1112, 2007. View at Publisher · View at Google Scholar · View at Scopus
  74. E. A. Makris, P. Hadidi, and K. A. Athanasiou, “The knee meniscus: structure-function, pathophysiology, current repair techniques, and prospects for regeneration,” Biomaterials, vol. 32, no. 30, pp. 7411–7431, 2011. View at Publisher · View at Google Scholar · View at Scopus
  75. S. Font Tellado, E. R. Balmayor, and M. Van Griensven, “Strategies to engineer tendon/ligament-to-bone interface: Biomaterials, cells and growth factors,” Advanced Drug Delivery Reviews, vol. 94, pp. 126–140, 2015. View at Publisher · View at Google Scholar · View at Scopus
  76. N. Bhardwaj, D. Devi, and B. B. Mandal, “Tissue-engineered cartilage: The crossroads of biomaterials, cells and stimulating factors,” Macromolecular Bioscience, vol. 15, no. 2, pp. 153–182, 2015. View at Publisher · View at Google Scholar · View at Scopus
  77. L. A. Fortier, J. U. Barker, E. J. Strauss, T. M. McCarrel, and B. J. Cole, “The role of growth factors in cartilage repair,” Clinical Orthopaedics and Related Research, vol. 469, no. 10, pp. 2706–2715, 2011. View at Publisher · View at Google Scholar · View at Scopus
  78. F. Forriol, “Growth factors in cartilage and meniscus repair,” Injury, vol. 40, pp. S12–S16, 2009. View at Publisher · View at Google Scholar · View at Scopus
  79. X.-H. Feng and R. Derynck, “Specificity and versatility in TGF-β signaling through smads,” Annual Review of Cell and Developmental Biology, vol. 21, pp. 659–693, 2005. View at Publisher · View at Google Scholar · View at Scopus
  80. M. Y. Wu and C. S. Hill, “TGF-β superfamily signaling in embryonic development and homeostasis,” Developmental Cell, vol. 16, no. 3, pp. 329–343, 2009. View at Publisher · View at Google Scholar · View at Scopus
  81. C.-H. Heldin, K. Miyazono, and P. ten Dijke, “TGF-β signalling from cell membrane to nucleus through SMAD proteins,” Nature, vol. 390, no. 6659, pp. 465–471, 1997. View at Publisher · View at Google Scholar · View at Scopus
  82. Y. Shi and J. Massagué, “Mechanisms of TGF-β signaling from cell membrane to the nucleus,” Cell, vol. 113, no. 6, pp. 685–700, 2003. View at Publisher · View at Google Scholar · View at Scopus
  83. L. A. Poniatowski, P. Wojdasiewicz, R. Gasik, and D. Szukiewicz, “Transforming growth factor beta family: Insight into the role of growth factors in regulation of fracture healing biology and potential clinical applications,” Mediators of Inflammation, vol. 2015, Article ID 137823, 17 pages, 2015. View at Publisher · View at Google Scholar · View at Scopus
  84. E. N. Blaney Davidson, P. M. van der Kraan, and W. B. van den Berg, “TGF-β and osteoarthritis,” Osteoarthritis and Cartilage, vol. 15, no. 6, pp. 597–604, 2007. View at Publisher · View at Google Scholar · View at Scopus
  85. A. M. Mackay, S. C. Beck, J. M. Murphy, F. P. Barry, C. O. Chichester, and M. F. Pittenger, “Chondrogenic differentiation of cultured human mesenchymal stem cells from marrow,” Tissue Engineering Part A, vol. 4, no. 4, pp. 415–428, 1998. View at Publisher · View at Google Scholar · View at Scopus
  86. A. T. Mehlhorn, H. Schmal, S. Kaiser et al., “Mesenchymal stem cells maintain TGF-β-mediated chondrogenic phenotype in alginate bead culture,” Tissue Engineering Part A, vol. 12, no. 6, pp. 1393–1403, 2006. View at Publisher · View at Google Scholar · View at Scopus
  87. M. B. Mueller, M. Fischer, J. Zellner et al., “Hypertrophy in mesenchymal stem cell chondrogenesis: effect of TGF-β isoforms and chondrogenic conditioning,” Cells Tissues Organs, vol. 192, no. 3, pp. 158–166, 2010. View at Publisher · View at Google Scholar · View at Scopus
  88. T. A. Ahmed and M. T. Hincke, “Mesenchymal stem cell-based tissue engineering strategies for repair of articular cartilage,” Histology and Histopathology, vol. 6, pp. 669–689, 29. View at Google Scholar
  89. C. H. Lee, J. L. Cook, A. Mendelson, E. K. Moioli, H. Yao, and J. J. Mao, “Regeneration of the articular surface of the rabbit synovial joint by cell homing: a proof of concept study,” The Lancet, vol. 376, no. 9739, pp. 440–448, 2010. View at Publisher · View at Google Scholar · View at Scopus
  90. A. L. McNulty and F. Guilak, “Integrative repair of the meniscus: Lessons from in vitro studies,” Biorheology, vol. 45, no. 3-4, pp. 487–500, 2008. View at Publisher · View at Google Scholar · View at Scopus
  91. U. Freymann, M. Endres, U. Goldmann, M. Sittinger, and C. Kaps, “Toward scaffold-based meniscus repair: effect of human serum, hyaluronic acid and TGF-ß3 on cell recruitment and re-differentiation,” Osteoarthritis and Cartilage, vol. 21, no. 5, pp. 773–781, 2013. View at Publisher · View at Google Scholar · View at Scopus
  92. H. M. van Beuningen, P. M. van der Kraan, O. J. Arntz, and W. B. van den Berg, “Transforming growth factor-β1 stimulates articular chondrocyte proteoglycan synthesis and induces osteophyte formation in the murine knee joint,” Laboratory Investigation, vol. 71, no. 2, pp. 279–290, 1994. View at Google Scholar · View at Scopus
  93. A. C. Bakker, F. A. J. van de Loo, H. M. van Beuningen et al., “Overexpression of active TGF-beta-1 in the murine knee joint: evidence for synovial-layer-dependent chondro-osteophyte formation,” Osteoarthritis and Cartilage, vol. 9, no. 2, pp. 128–136, 2001. View at Publisher · View at Google Scholar · View at Scopus
  94. A. C. Carreira, G. G. Alves, W. F. Zambuzzi, M. C. Sogayar, and J. M. Granjeiro, “Bone morphogenetic proteins: structure, biological function and therapeutic applications,” Archives of Biochemistry and Biophysics, vol. 561, pp. 64–73, 2014. View at Publisher · View at Google Scholar · View at Scopus
  95. J. M. Wozney and V. Rosen, “Bone morphogenetic protein and bone morphogenetic protein gene family in bone formation and repair,” Clinical Orthopaedics and Related Research, no. 346, pp. 26–37, 1998. View at Google Scholar · View at Scopus
  96. A. C. Carreira, F. H. Lojudice, E. Halcsik, R. D. Navarro, M. C. Sogayar, and J. M. Granjeiro, “Bone morphogenetic proteins: facts, challenges, and future perspectives,” Journal of Dental Research, vol. 93, no. 4, pp. 335–345, 2014. View at Publisher · View at Google Scholar · View at Scopus
  97. J. Fan, Y. Gong, L. Ren, R. R. Varshney, D. Cai, and D.-A. Wang, “In vitro engineered cartilage using synovium-derived mesenchymal stem cells with injectable gellan hydrogels,” Acta Biomaterialia, vol. 6, no. 3, pp. 1178–1185, 2010. View at Publisher · View at Google Scholar · View at Scopus
  98. D. N. Kim, Y. H. Joung, P. Darvin et al., “Methylsulfonylmethane enhances BMP-2-induced osteoblast differentiation in mesenchymal stem cells,” Molecular Medicine Reports, vol. 14, no. 1, pp. 460–466, 2016. View at Publisher · View at Google Scholar · View at Scopus
  99. K. Lavery, P. Swain, D. Falb, and M. H. Alaoui-Ismaili, “BMP-2/4 and BMP-6/7 differentially utilize cell surface receptors to induce osteoblastic differentiation of human bone marrow-derived mesenchymal stem cells,” The Journal of Biological Chemistry, vol. 283, no. 30, pp. 20948–20958, 2008. View at Publisher · View at Google Scholar · View at Scopus
  100. L. Dai, X. Hu, and X. Zhang, “Different tenogenic differentiation capacities of different mesenchymal stem cells in the presence of BMP-12,” Journal of Translational Medicine, vol. 13, article 200, 2015. View at Publisher · View at Google Scholar
  101. H. Nochi, H. S. Jin, J. Lou, H. D. Adkisson, W. J. Maloney, and K. A. Hruska, “Adenovirus mediated BMP-13 gene transfer induces chondrogenic differentiation of murine mesenchymal progenitor cells,” Journal of Bone and Mineral Research, vol. 19, no. 1, pp. 111–122, 2004. View at Publisher · View at Google Scholar · View at Scopus
  102. U. G. Longo, M. Loppini, F. Forriol, G. Romeo, N. Maffulli, and V. Denaro, “Advances in meniscal tissue engineering,” Stem Cells International, vol. 2012, Article ID 420346, 7 pages, 2012. View at Publisher · View at Google Scholar · View at Scopus
  103. C. Merrihew, S. Soeder, D. C. Rueger, K. E. Kuettner, and S. Chubinskaya, “Modulation of endogenous osteogenic protein-1 (OP-1) by interleukin-1 in adult human articular cartilage,” The Journal of Bone & Joint Surgery, vol. 85, no. 3, pp. 67–74, 2003. View at Publisher · View at Google Scholar · View at Scopus
  104. S. Chubinskaya, L. Otten, S. Soeder et al., “Regulation of chondrocyte gene expression by osteogenic protein-1,” Arthritis Research & Therapy, vol. 13, no. 2, article no. R55, 2011. View at Publisher · View at Google Scholar · View at Scopus
  105. J. Flechtenmacher, K. Huch, E. J.-M. A. Thonar et al., “Recombinant human osteogenic protein 1 is a potent stimulator of the synthesis of cartilage proteoglycans and collagens by human articular chondrocytes,” Arthritis & Rheumatology, vol. 39, no. 11, pp. 1896–1904, 1996. View at Publisher · View at Google Scholar · View at Scopus
  106. Z. Fan, S. Chubinskaya, D. C. Rueger, B. Bau, J. Haag, and T. Aigner, “Regulation of anabolic and catabolic gene expression in normal and osteoarthritic adult human articular chondrocytes by osteogenic protein-1,” Clinical and Experimental Rheumatology, vol. 22, no. 1, pp. 103–106, 2004. View at Google Scholar · View at Scopus
  107. S. Chubinskaya, M. Hurtig, and D. C. Rueger, “OP-1/BMP-7 in cartilage repair,” International Orthopaedics, vol. 31, no. 6, pp. 773–781, 2007. View at Publisher · View at Google Scholar · View at Scopus
  108. S. Scarfi, “Use of bone morphogenetic proteins in mesenchymal stem cell stimulation of cartilage and bone repair,” World Journal of Stem Cells, vol. 8, no. 1, pp. 1–12, 2016. View at Publisher · View at Google Scholar
  109. R. F. Loeser, C. A. Pacione, and S. Chubinskaya, “The combination of insulin-like growth factor 1 and osteogenic protein 1 promotes increased survival of and matrix synthesis by normal and osteoarthritic human articular chondrocytes,” Arthritis & Rheumatology, vol. 48, no. 8, pp. 2188–2196, 2003. View at Publisher · View at Google Scholar · View at Scopus
  110. A. Beenken and M. Mohammadi, “The FGF family: biology, pathophysiology and therapy,” Nature Reviews Drug Discovery, vol. 8, no. 3, pp. 235–253, 2009. View at Publisher · View at Google Scholar · View at Scopus
  111. D. M. Ornitz and P. J. Marie, “FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease,” Genes & Development, vol. 16, no. 12, pp. 1446–1465, 2002. View at Publisher · View at Google Scholar · View at Scopus
  112. S.-L. Chia, Y. Sawaji, A. Burleigh et al., “Fibroblast growth factor 2 is an intrinsic chondroprotective agent that suppresses ADAMTS-5 and delays cartilage degradation in murine osteoarthritis,” Arthritis & Rheumatology, vol. 60, no. 7, pp. 2019–2027, 2009. View at Publisher · View at Google Scholar · View at Scopus
  113. T. L. Vincent, C. J. McLean, L. E. Full, D. Peston, and J. Saklatvala, “FGF-2 is bound to perlecan in the pericellular matrix of articular cartilage, where it acts as a chondrocyte mechanotransducer,” Osteoarthritis and Cartilage, vol. 15, no. 7, pp. 752–763, 2007. View at Publisher · View at Google Scholar · View at Scopus
  114. L. I. Oliver, D. B. Rifkin, J. Gabrilove, M.-J. Hannocks, and E. L. Wilson, “Long-term culture of human bone marrow stromal cells in the presence of basic fibroblast growth factor,” Growth Factors, vol. 3, no. 3, pp. 231–236, 1990. View at Publisher · View at Google Scholar · View at Scopus
  115. N. S. Tumia and A. J. Johnstone, “Promoting the proliferative and synthetic activity of knee meniscal fibrochondrocytes using basic fibroblast growth factor in vitro,” The American Journal of Sports Medicine, vol. 32, no. 4, pp. 915–920, 2004. View at Publisher · View at Google Scholar · View at Scopus
  116. R. J. Webber, M. G. Harris, and A. J. Hough, “Cell culture of rabbit meniscal fibrochondrocytes: Proliferative and synthetic response to growth factors and ascorbate,” Journal of Orthopaedic Research, vol. 3, no. 1, pp. 36–42, 1985. View at Publisher · View at Google Scholar · View at Scopus
  117. L. A. Solchaga, K. Penick, J. D. Porter, V. M. Goldberg, A. I. Caplan, and J. F. Welter, “FGF-2 enhances the mitotic and chondrogenic potentials of human adult bone marrow-derived mesenchymal stem cells,” Journal of Cellular Physiology, vol. 203, no. 2, pp. 398–409, 2005. View at Publisher · View at Google Scholar · View at Scopus
  118. M. Rodrigues, L. G. Griffith, and A. Wells, “Growth factor regulation of proliferation and survival of multipotential stromal cells,” Stem Cell Research & Therapy, vol. 1, no. 4, article 32, 2010. View at Publisher · View at Google Scholar · View at Scopus
  119. T. Cheng, C. Yang, N. Weber, H. T. Kim, and A. C. Kuo, “Fibroblast growth factor 2 enhances the kinetics of mesenchymal stem cell chondrogenesis,” Biochemical and Biophysical Research Communications, vol. 426, no. 4, pp. 544–550, 2012. View at Publisher · View at Google Scholar · View at Scopus
  120. M. B. Ellman, H. S. An, P. Muddasani, and H.-J. Im, “Biological impact of the fibroblast growth factor family on articular cartilage and intervertebral disc homeostasis,” Gene, vol. 420, no. 1, pp. 82–89, 2008. View at Publisher · View at Google Scholar · View at Scopus
  121. M. B. Ellman, D. Yan, K. Ahmadinia, D. Chen, H. S. An, and H. J. Im, “Fibroblast growth factor control of cartilage homeostasis,” Journal of Cellular Biochemistry, vol. 114, no. 4, pp. 735–742, 2013. View at Publisher · View at Google Scholar · View at Scopus
  122. A. Inoue, K. A. Takahashi, Y. Arai et al., “The therapeutic effects of basic fibroblast growth factor contained in gelatin hydrogel microspheres on experimental osteoarthritis in the rabbit knee,” Arthritis & Rheumatism, vol. 54, no. 1, pp. 264–270, 2006. View at Publisher · View at Google Scholar · View at Scopus
  123. S. Miot, P. S. de Freitas, D. Wirz et al., “Cartilage tissue engineering by expanded goat articular chondrocytes,” Journal of Orthopaedic Research, vol. 24, no. 5, pp. 1078–1085, 2006. View at Publisher · View at Google Scholar · View at Scopus
  124. N. Miyakoshi, M. Kobayashi, K. Nozaka, K. Okada, Y. Shimada, and E. Itoi, “Effects of intraarticular administration of basic fibroblast growth factor with hyaluronic acid on osteochondral defects of the knee in rabbits,” Archives of Orthopaedic and Trauma Surgery, vol. 125, no. 10, pp. 683–692, 2005. View at Publisher · View at Google Scholar · View at Scopus
  125. E. E. Moore, A. M. Bendele, D. L. Thompson et al., “Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat model of injury-induced osteoarthritis,” Osteoarthritis and Cartilage, vol. 13, no. 7, pp. 623–631, 2005. View at Publisher · View at Google Scholar · View at Scopus
  126. M. B. Schmidt, E. H. Chen, and S. E. Lynch, “A review of the effects of insulin-like growth factor and platelet derived growth factor on in vivo cartilage healing and repair,” Osteoarthritis and Cartilage, vol. 14, no. 5, pp. 403–412, 2006. View at Publisher · View at Google Scholar · View at Scopus
  127. P. Buma, N. N. Ramrattan, T. G. Van Tienen, and R. P. H. Veth, “Tissue engineering of the meniscus,” Biomaterials, vol. 25, no. 9, pp. 1523–1532, 2004. View at Publisher · View at Google Scholar · View at Scopus
  128. J. A. Martin, S. M. Ellerbroek, and J. A. Buckwalter, “Age-related decline in chondrocyte response to insulin-like growth factor-I: The role of growth factor binding proteins,” Journal of Orthopaedic Research, vol. 15, no. 4, pp. 491–498, 1997. View at Publisher · View at Google Scholar · View at Scopus
  129. R. F. Loeser, G. Shanker, C. S. Carlson, J. F. Gardin, B. J. Shelton, and W. E. Sonntag, “Reduction in the chondrocyte response to insulin-like growth factor 1 in aging and osteoarthritis: Studies in a non-human primate model of naturally occurring disease,” Arthritis & Rheumatology, vol. 43, no. 9, pp. 2110–2120, 2000. View at Publisher · View at Google Scholar · View at Scopus
  130. J. Schalkwijk, L. A. B. Joosten, W. B. Van Den Berg, and L. B. A. Van De Putte, “Chondrocyte nonresponsiveness to insulin-like growth factor 1 in experimental arthritis,” Arthritis & Rheumatology, vol. 32, no. 7, pp. 894–900, 1989. View at Google Scholar · View at Scopus
  131. S. Doré, J. Pelletier, J. A. Dibattista, G. Tardif, P. Brazeau, and J. Martel‐Pelletier, “Human Osteoarthritic Chondrocytes Possess an Increased Number of Insulin‐Like Growth Factor 1 Binding Sites but are Unresponsive to its Stimulation,” Arthritis & Rheumatism, vol. 37, no. 2, pp. 253–263, 1994. View at Publisher · View at Google Scholar · View at Scopus
  132. S. Chubinskaya, A. Hakimiyan, C. Pacione et al., “Synergistic effect of IGF-1 and OP-1 on matrix formation by normal and OA chondrocytes cultured in alginate beads,” Osteoarthritis and Cartilage, vol. 15, no. 4, pp. 421–430, 2007. View at Publisher · View at Google Scholar · View at Scopus
  133. W. Petersen, T. Pufe, C. Stärke et al., “Locally applied angiogenic factors—a new therapeutic tool for meniscal repair,” Annals of Anatomy, vol. 187, no. 5-6, pp. 509–519, 2005. View at Publisher · View at Google Scholar · View at Scopus
  134. L. Brass, “Understanding and evaluating platelet function,” American Society of Hematology. Education Program, vol. 2010, pp. 387–396, 2010. View at Google Scholar · View at Scopus
  135. J. Zellner, M. Mueller, A. Berner et al., “Role of mesenchymal stem cells in tissue engineering of meniscus,” Journal of Biomedical Materials Research Part A, vol. 94, no. 4, pp. 1150–1161, 2010. View at Publisher · View at Google Scholar · View at Scopus
  136. H. Huang, H. Xu, and J. Zhao, “A novel approach for meniscal regeneration using kartogenin-treated autologous tendon graft,” The American Journal of Sports Medicine, vol. 45, no. 14, pp. 3289–3297, 2017. View at Publisher · View at Google Scholar
  137. X. Hu, Y. Wang, Y. Tan et al., “A Difunctional Regeneration Scaffold for Knee Repair based on Aptamer-Directed Cell Recruitment,” Advanced Materials, vol. 29, no. 15, Article ID 1605235, 2017. View at Publisher · View at Google Scholar · View at Scopus
  138. H. Huang, X. Zhang, X. Hu et al., “A functional biphasic biomaterial homing mesenchymal stem cells for invivo cartilage regeneration,” Biomaterials, vol. 35, no. 36, pp. 9608–9619, 2014. View at Publisher · View at Google Scholar · View at Scopus
  139. E. Matsumoto, T. Furumatsu, T. Kanazawa, M. Tamura, and T. Ozaki, “ROCK inhibitor prevents the dedifferentiation of human articular chondrocytes,” Biochemical and Biophysical Research Communications, vol. 420, no. 1, pp. 124–129, 2012. View at Publisher · View at Google Scholar · View at Scopus
  140. H.-C. Chou, L.-T. Huang, T.-F. Yeh, and C.-M. Chen, “Rho-kinase inhibitor Y-27632 attenuates pulmonary hypertension in hyperoxia-exposed newborn rats,” Acta Pharmacologica Sinica, vol. 34, no. 10, pp. 1310–1316, 2013. View at Publisher · View at Google Scholar · View at Scopus
  141. M. D. Kofron and C. T. Laurencin, “Orthopaedic applications of gene therapy,” Current Gene Therapy, vol. 5, no. 1, pp. 37–61, 2005. View at Publisher · View at Google Scholar · View at Scopus
  142. T. N. Vo, F. K. Kasper, and A. G. Mikos, “Strategies for controlled delivery of growth factors and cells for bone regeneration,” Advanced Drug Delivery Reviews, vol. 64, no. 12, pp. 1292–1309, 2012. View at Publisher · View at Google Scholar · View at Scopus
  143. M. Cucchiarini, A. L. McNulty, R. L. Mauck, L. A. Setton, F. Guilak, and H. Madry, “Advances in combining gene therapy with cell and tissue engineering-based approaches to enhance healing of the meniscus,” Osteoarthritis and Cartilage, vol. 24, no. 8, pp. 1330–1339, 2016. View at Publisher · View at Google Scholar · View at Scopus
  144. C. H. Evans and J. Huard, “Gene therapy approaches to regenerating the musculoskeletal system,” Nature Reviews Rheumatology, vol. 11, no. 4, pp. 234–242, 2015. View at Publisher · View at Google Scholar · View at Scopus
  145. H. Goto, F. D. Shuler, C. Niyibizi, F. H. Fu, P. D. Robbins, and C. H. Evans, “Gene therapy for meniscal injury: Enhanced synthesis of proteoglycan and collagen by meniscal cells transduced with a TGFβ1 gene,” Osteoarthritis and Cartilage, vol. 8, no. 4, pp. 266–271, 2000. View at Publisher · View at Google Scholar · View at Scopus
  146. H.-P. Lee, A. Rey-Rico, M. Cucchiarini, and H. Madry, “Nonviral gene transfer into human meniscal cells. Part II: Effect of three-dimensional environment and overexpression of human fibroblast growth factor 2,” International Orthopaedics, vol. 38, no. 9, pp. 1931–1936, 2014. View at Publisher · View at Google Scholar · View at Scopus
  147. A. F. Steinert, G. D. Palmer, R. Capito et al., “Genetically enhanced engineering of meniscus tissue using ex vivo delivery of transforming growth factor-β1 complementary deoxyribonucleic acid,” Tissue Engineering Part A, vol. 13, no. 9, pp. 2227–2237, 2007. View at Publisher · View at Google Scholar · View at Scopus
  148. H. Madry, M. Cucchiarini, G. Kaul, D. Kohn, E. F. Terwilliger, and S. B. Trippel, “Menisci are efficiently transduced by recombinant adeno-associated virus vectors in vitro and in vivo,” The American Journal of Sports Medicine, vol. 32, no. 8, pp. 1860–1865, 2004. View at Publisher · View at Google Scholar · View at Scopus
  149. M. Cucchiarini, K. Schmidt, J. Frisch, D. Kohn, and H. Madry, “Overexpression of TGF-β via rAAV-Mediated Gene Transfer Promotes the Healing of Human Meniscal Lesions Ex Vivo on Explanted Menisci,” The American Journal of Sports Medicine, vol. 43, no. 5, pp. 1197–1205, 2015. View at Publisher · View at Google Scholar · View at Scopus
  150. S. Elsler, S. Schetting, G. Schmitt, D. Kohn, H. Madry, and M. Cucchiarini, “Effective, safe nonviral gene transfer to preserve the chondrogenic differentiation potential of human mesenchymal stem cells,” The Journal of Gene Medicine, vol. 14, no. 7, pp. 501–511, 2012. View at Publisher · View at Google Scholar · View at Scopus
  151. H.-N. Zhang, P. Leng, Y.-Z. Wang, and J. Zhang, “Treating human meniscal fibrochondrocytes with hIGF-1 gene by liposome,” Clinical Orthopaedics and Related Research, vol. 467, no. 12, pp. 3175–3182, 2009. View at Publisher · View at Google Scholar · View at Scopus
  152. H. Goto, F. D. Shuler, C. Lamsam et al., “Transfer of LacZ marker gene to the meniscus,” The Journal of Bone & Joint Surgery, vol. 81, no. 7, pp. 918–925, 1999. View at Publisher · View at Google Scholar · View at Scopus
  153. V. Martinek, A. Usas, D. Pelinkovic, P. Robbins, F. H. Fu, and J. Huard, “Genetic engineering of meniscal allografts,” Tissue Engineering Part A, vol. 8, no. 1, pp. 107–117, 2002. View at Publisher · View at Google Scholar · View at Scopus
  154. T. G. Gerich, S. Ghivizani, F. H. Fu, P. D. Robbins, and C. H. Evans, “Gene transfer into the patellar tendon of rabbits: a preliminary study of locoregional expression of growth factors,” Wiener klinische Wochenschrift, vol. 109, no. 11, pp. 384–389, 1997. View at Google Scholar
  155. J. M. Brunger, N. P. T. Huynh, C. M. Guenther et al., “Scaffold-mediated lentiviral transduction for functional tissue engineering of cartilage,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 111, no. 9, pp. E798–E806, 2014. View at Publisher · View at Google Scholar · View at Scopus
  156. K. A. Glass, J. M. Link, J. M. Brunger, F. T. Moutos, C. A. Gersbach, and F. Guilak, “Tissue-engineered cartilage with inducible and tunable immunomodulatory properties,” Biomaterials, vol. 35, no. 22, pp. 5921–5931, 2014. View at Publisher · View at Google Scholar · View at Scopus
  157. M. Cucchiarini, M. Ekici, S. Schetting, D. Kohn, and H. Madry, “Metabolic activities and chondrogenic differentiation of human mesenchymal stem cells following recombinant adeno-associated virus-mediated gene transfer and overexpression of fibroblast growth factor 2,” Tissue Engineering Part A, vol. 17, no. 15-16, pp. 1921–1933, 2011. View at Publisher · View at Google Scholar · View at Scopus
  158. T. P. Lozito, P. G. Alexander, H. Lin, R. Gottardi, A. W.-M. Cheng, and R. S. Tuan, “Three-dimensional osteochondral microtissue to model pathogenesis of osteoarthritis,” Stem Cell Research & Therapy, vol. 4, no. 1, article no. S6, 2013. View at Publisher · View at Google Scholar · View at Scopus
  159. A. B. Adesida, L. M. Grady, W. S. Khan, S. J. Millward-Sadler, D. M. Salter, and T. E. Hardingham, “Human meniscus cells express hypoxia inducible factor-1α and increased SOX9 in response to low oxygen tension in cell aggregate culture,” Arthritis Research & Therapy, vol. 9, article R69, 2007. View at Publisher · View at Google Scholar · View at Scopus
  160. N. J. Gunja and K. A. Athanasiou, “Effects of co-cultures of meniscus cells and articular chondrocytes on PLLA scaffolds,” Biotechnology and Bioengineering, vol. 103, no. 4, pp. 808–816, 2009. View at Publisher · View at Google Scholar · View at Scopus
  161. X. Cui, A. Hasegawa, M. Lotz, and D. D'Lima, “Structured three-dimensional co-culture of mesenchymal stem cells with meniscus cells promotes meniscal phenotype without hypertrophy,” Biotechnology and Bioengineering, vol. 109, no. 9, pp. 2369–2380, 2012. View at Publisher · View at Google Scholar · View at Scopus