Cartilage Tissue Engineering: An Update on Multi-Component Approach

Abstract

Cartilage injury and osteoarthritis are big clinical challenges as self-healing potential of cartilaginous tissue is very limited. The need for a multi-disciplinary approach in order to establish new strategies for cartilage healing has been addressed by many scientists from the fields of orthopaedic surgery or biomedical engineering in the last two decades. With a focus on the very preclinical research in this field, this review covers the multitude of approaches, ranging from cellbased to scaffold-based strategies and also including growth factors, precondition approach, mechanical stimulation-that have been combined to assess their potential to develop effective concepts for the treatment of cartilage injury or osteoarthritis. Citation: Zong Z, Wu X, Su Z, Wang Z, Zhao Z, et al. Cartilage Tissue Engineering: An Update on Multi-Component Approach. J Orthopedics Rheumatol. 2019; 6(1): 9. J Orthopedics Rheumatol 6(1): 9 (2019) Page 02 ISSN: 2334-2846 scenarios [14]. Amount of all, operations like arthroscopic lavage, debridement, microfracture, Autologous Chondrocyte Implantation (ACI), and Osteochondral Autograft Transplantation (OAT) are most widely used nowadays encountering to the cartilage lesions [15]. These reparative methods are tended to stimulate the formation of new fibrocartilage tissue by facilitating access to the vascular system and bringing new progenitor cells capable of chondrogenesis (e.g., microfracture procedure and drilling). Reconstructive methods fill up the defects with autologous, homologous, or other tissue (e.g., autologous chondrocyte implantation and osteochondral autologous transplantation) [16,17]. Such methods may associated with good outcomes after surgery, but according to a systematic review of level I and II studies on OAT procedures and microfracture surgery showing that, patients with small lesions who returned to higher-demand activities had an higher progressive failure rate and only 52% of athletes returned to sports after received microfracture surgery, 37% of them retained their same level of sports 10-year after operation [18,19]. Besides, another systematic review reported by Filardo et al. revealed that 33.7% failure rate at a mean was recorded follow-up of 8.5 years after ACI surgeries (5-12 years post-surgery) in 193 patients [20]. The therapeutic strategies for OA are distinct from acute cartilage injuries. Chronic pain relief could be achieved with lifestyle modification and medication such as Non-Steroidal AntiInflammatory Drugs (NSAIDs) or glucocorticoid. NSAIDs are the most widely prescribed pharmacological medications and were recommended in the guidelines in the treatment of OA but longterm administration are associated with serious side effects including bleeding and perforated gastric ulcers [21-23]. Long-term use of glucocorticoid may cause several side effects such as immunodeficiency, osteoporosis, peptic ulcer disease or gastrointestinal bleeding [24,25]. Viscosupplementation with hyaluronic acid through intra-articular injection helps to reduce OA caused pain through its lubricating action, but recent clinical studies showed that the use of hyaluronic acid did not improve clinical outcomes compared to the placebo group significantly [26,27]. However, these current treatments are not promising solution to prevent articular cartilage from further progressive destruction, thus OA patients may need joint replacement to regain reasonable joint movement at the expense of potential complications. Although the shelf life of prosthetics for joint replacement is significantly improved, this surgery remains less suitable for young OA patients [28,29]. Thus, there is a burning need for alternative approaches to manage cartilage lesions, which would prevent the early onset of OA and to reduce the need for total joint replacement. Biological Solutions for Cartilage Repair Autologous Chondrocyte Implantation (ACI) is a convincing and effective method for the treatment of cartilage lesions [30,31]. The usefulness of allogeneic chondrocytes as alternative source was constrained because of the reported immunogenicity [32]. Furthermore, in vitro expansion of chondrocytes can lead to rapid dedifferentiation and a fibroblastic phenotype [30], resulting in an inferior tissue-engineered cartilage. Mesenchymal Stem Cells (MSCs) are a promising and readily available cell source showing chondrogenic differentiation potential and forming cartilage-like tissues in vitro induced by specific growth factors without compromising its low immunogenicity [33-37]. MSCs can be derived from various types of tissues, including bone marrow [38,39], adipose tissue [40], tendon [41,42], synovial membrane [43], dental pulp [44], umbilical cord blood [45], placenta [46,47], etc. Autologous MSCs are currently the major cell source because of ethical and immunological concerns. However, a major drawback of their clinical use is the aging-related decline in MSCs proliferation and chondrogenic differentiation potential from aged patients (donors) and in vitro cell culturing as several studies had reported that MSC isolated from older donors exhibited a slower proliferation rate throughout the entire in vitro expansion compared with the younger donors. And the shorter average length of telomere, loss of telomere length after cell passage and lower levels of telomerase activity may contribute to such phenomenon. Besides, the expression of p16INK4A is also strongly associated with cell senescence [4851]. Furthermore, instable MSCs phenotypes such as formation of mineralized deposits within cartilage. Current available strategies for enhancing plasticity of MSCs included genetic modification [5254], hypoxia stimulation [55,56], etc. However, safety and ethical concerns are existed for genetic modification approach, which is left far behind clinical use, and hypoxia could only promote cell proliferation at this stage. Hence, it is mandatory to find out a simple and feasible manipulation for promoting plasticity of MSCs including proliferation, chondrogenesis and viability. Dedifferentiation Reprogrammed MSCs for Tissue Regeneration Cellular dedifferentiation is cellular regression from a more differentiated stage back to a less differentiated stage from within its own lineage that confers pluripotency, giving rise to reminiscent of stem cells [57,58]. Based on this definition, cellular dedifferentiation is not only initiating from a completely differentiated stage, but also initiating from partially differentiated stage. Similarly, cellular dedifferentiation could result in partially or fully pluripotent cells, depends on the different time points. This process is more commonly studied in plants and more primitive creatures. Several non-mammalian vertebrate species, such as zebra fish and urodele amphibians [59-65], possess a remarkable capacity to regenerate heart tissue or limb, respectively. Apart from natural conditions, researchers found that inducible dedifferentiation is an appropriate strategy to promote regeneration in mammalian tissues that lack of this ability. Studies have reported the occurrence of cell dedifferentiation during tissue regeneration both in vitro and in vivo [66-70]. Recent studies have demonstrated that dedifferentiation reprogramming is a reliable method to improve properties of stem cells and promote lineage differentiation commitment [71-73]. Previous data revealed that a population of MSCs with enhanced viability in vitro and improved therapeutic efficacy in a cerebral ischemia model could be attained via neuronal differentiation and dedifferentiation reprogramming [72]. Recently we reported that, compared with untreated MSCs, MSCs which manipulated with osteogenic differentiation medium exhibited a better osteogenic differentiation potential, improved cell migratory capacity and upregulated expression of genes Nanog, Oct4 and Sox2 [74]. And we Citation: Zong Z, Wu X, Su Z, Wang Z, Zhao Z, et al. Cartilage Tissue Engineering: An Update on Multi-Component Approach. J Orthopedics Rheumatol. 2019; 6(1): 9. J Orthopedics Rheumatol 6(1): 9 (2019) Page 03 ISSN: 2334-2846 also proved that such improvements were inducted by decreased methylation and accrual of activating histone marks of promoters on Nanog and Oct4.Besides, after preconditioned with chondrogenic differentiation medium and complete medium, the Manipulated MSCs (M-MSCs) also showed an improved cell clonogenicity, proliferation, survivability and chondrogenic property. And the results of epigenetic analysis revealed the central role of Nanog in maintaining the multipotency of the manipulated MSCs [75]. Furthermore, we also revealed that neocartilage formation of M-MSC-laden constructs implanted in the nude mice was significantly promoted after dynamic compressive applied in the bioreactor and the constructs laden with M-MSCs were also significantly promoted the cartilage healing process of osteochondral defect of a rat model [76]. Growth Factors for Chondrogenic Differentiation In the hyaline cartilage, growth factors regulate homeostasis and integrity, as well as development [77]. Growth factors also play an important role in the process of chondrogenic differentiation of MSCs. Table 1 summarizes some representable endogenous bioactive cytokines, including Transforming Growth Factor β (TGF-β) superfamily with respect to cartilage tissue engineering are TGF-β1, TGF-β3, Bone Morphogenetic Protein 2(BMP-2), BMP-4, BMP-6, BMP-7, BMP-9 and Growth Differentiation factor-5 (GDF5) [78-81], which are reported to stimulate MSCs proliferation and differentiation. Among of these, TGF-β1 and TGF-β3 are the most frequently used cytokines in experimental studies to promote chondrogenic differentiation and synthesis of corresponding Extracellular Matrix (ECM) production [79,81-83] (Table 1). Biomaterials for Cartilage Repair Various materials in the form of sponges, hydrogels, electrospun fibers, and microparticles have been