In tissue engineering fields, recent interest has been focused on stem cell therapy to replace or repair damaged or worn-out tissues due to congenital abnormalities, disease, or injury. In particular, the repair of articular cartilage degeneration by stem cell-based tissue engineering could be of enormous therapeutic and economic benefit for an aging population. Bone marrow-derived mesenchymal stem cells (MSCs) that can induce chondrogenic differentiation would provide an appropriate cell source to repair damaged cartilage tissues; however, we must first understand the optimal environmental conditions for chondrogenic differentiation. In this review, we will focus on identifying the best combination of MSCs and functional extracellular matrices that provides the most successful chondrogenesis.
Tissue loss or degeneration caused by congenital abnormalities, disease, or injury is of great consequence given human tissue’s limited intrinsic potential for healing [
Tissue engineering strategy. (a) Basic principles of tissue engineering. (b) General methods of cell culture using a scaffold.
For this reason, the appropriate selection of cells and materials as scaffolds is one of the most important factors for successful, cell-based cartilage tissue engineering because the reconstruction and regeneration of damaged tissues occurs via an ordered pathway of cellular events affected by biological and mechanical factors [
ESCs derived from totipotent cells of an early mammalian embryo can proliferate indefinitely and can give rise to virtually any cell type. Therefore, the use of ESCs to replace damaged cells and tissues promises future hope for the treatment of many diseases. However, many countries now face complex ethical and legal questions as a result of the research to develop these cell therapies [
In this review, we will focus on the use of synthetic polymeric scaffolds in articular cartilage therapy and discuss the strategies for specific targeting. In particular, we will describe the potential use of MSCs to deliver these scaffolds.
In cell-based tissue engineering fields, selection of the source cells is required for consideration of several criteria, including ease of access and availability, a capacity for differentiation, and a lack of minimal immunogenic or tumourigenic ability. For cartilage repair in cell-based tissue engineering applications, source cells have included committed chondrocytes, ESCs, and adult stem cells. Each cell type has its limitations and advantages due to its intrinsic biological properties. However, chondrocytes have shown limited redifferentiation capability after
Among the adult stem cells, specifically multipotent adult stem cells, MSCs are considered to be the cell type of choice for cell-based cartilage tissue engineering because of (1) the ease with which they can be isolated and expanded and (2) their multilineage differentiation capabilities [
Although MSCs have shown great promise in cartilage repair and regeneration, several requirements should be examined to allow them to effectively differentiate into chondrocytes and maintain this differentiated phenotype prior to implantation or delivery. These would involve the methods and materials for culture conditions of MSCs to repair or restore full functions of damaged cartilage. Upon proper culture conditions containing certain exogenous factors, MSCs can be directed towards chondrogenic differentiation. Growth factors that promote chondrogenesis or demonstrate a chondrogenic effect both
The 3D culture system for cell differentiation and proliferation may improve our understanding of the structure-function relationship under both normal and pathological conditions. With regard to cell-based cartilage tissue engineering, successfully reconstructed cartilage tissue formation would be structurally reunited with the peripheral cartilage and would suggest biomechanical properties necessary for permanence and efficacy under 3D environmental conditions [
The successful outcome of cell-based cartilage tissue engineering using a 3D culture of MSCs ultimately depends on the design of synthetic artificial ECMs for the proper differentiation of MSCs into chrondrocytes [
Other challenges are associated with the biomaterial scaffolds designed to guide tissue growth and differentiation. These biomaterials must meet several criteria to maximise the chances of a successful repair, including biodegradability and/or biocompatibility, facilitating functional tissue growth, and appropriate biomechanical properties [
Polymercross-linked scaffolds have been used for cell entrapment in cell-based tissue engineering applications, due to their 3D networks, tissue-like water content, structure stability, and biocompatibility [
For long-term retention of cells
In addition to porous scaffolds, the biofunctional constructs have been developed for better chondrogenesis of MSCs. In the application of cartiliage formation in the research field, for instance, fully thermoreversible gelling polymers have attracted considerable attention for use as scaffold materials to hold cells
Biodegradable micro- and nanocomposite materials that can provide the appropriate strength, integrate the desirable biological cues, and provide for the controlled sequential delivery of multiple growth factors would help fulfill the promise of regenerative medicine. Also the development of relevant scaffold design using suitable biomaterials and incorporation of appropriate biomolecules and the selection of cell types plays a vital role in tissue repair. Recent conceptual advances, which have taken advantage of new and practical techniques for size distribution and stabilisation control, have created novel routes for the synthesis of nanoparticle-based materials, in which nanoparticle building blocks can be spatially ordered in a controlled manner [
(a) Diagram of heparinized nanoparticles coated onto PLGA microsphere for stem cell delivery. (b) The SEM images of PLGA microspheres (upper (left) and bottom (right)) fabricated with heparin/poly(l-lysine) nanoparticles [
In another example using the nanoconstructs composed of fibrin hydrogels containing MSCs mixed with heparinised BMP-2, the bioactivities of entrapped MSCs mixed with growth factors were maintained for long term [
Although PLGA has proved to be an excellent material for cartilage tissue engineering due to its biodegradable properties, mechanical strength, and ease of fabrication into a considerably complex formation, the principle usage of PLGA as a delivery vehicle has problems as it does not offer a desirable environment for cell adhesion due to its limitation of binding sites mediated by biological recognition and high hydrophobicity. Based upon an early fundamental step in which positive cell-substrate interactions enable cell proliferation, migration, and differentiation on the surface of materials, many studies have focused on modifying the matrix surface in an effort to increase cell-substrate interaction for cell delivery [
Schematic diagram of RGD-modified PLGA microspheres containing growth factors and dexamethasone. Using a layer-by-layer (LBL) technique, positively charged, PEI precoated PLGA microspheres coated with negatively charged RGD molecules were fabricated for hMSC delivery and regeneration of injured tissues. The combination of growth factors, DEX, and RGD was an effective scaffold for cell delivery and differentiation of embedded hMSCs [
Culture methods are deeply considerable to improve the chondrogenetic potential of MSCs, because MSCs markedly decrease with the increase of passage number. If cultured in a medium that is not supplemented with factors facilitating the maintenance of plural differentiation potential, MSCs can hardly differentiate into chondrocytes after repeated passages. Some strong inductive signals for chondrogenesis are required to differentiate the passage-cultured MSCs into chondrocytes [
In addition, transfection of MSCs with growth factor genes has been proposed and practiced. However, the outcomes are not completely desirable not only due to the damage caused by the invasive procedure of transfection but also because long-term overexpression of a growth factor may result in undesirable changes in the transfected cells. To overcome these challenges, effective chondrogenesis in MSCs can be achieved by coculturing them with autologous chondrocytes transfected with growth factor genes [
The clinical need for cartilage repair technologies is unmistakable. Many people over the age of 40 suffer from degeneration or injury of their cartilage, leading to a reduced workforce and increased medical expenses. Thus, improvements in cartilage repair using a cell-based tissue engineering approach will greatly benefit public health and the economy. Personalised cell therapy for cartilage repair using cell-based tissue engineering technologies would provide clinically practical methods for producing a cartilage tissue equivalent. A number of biomaterials are available as scaffolds, and research continues to help us understand more details about how tissues develop and which cell type should be applied. These studies have provided details of how tissues grow
This research was financially supported by the Fundamental R&D Program for Core Technology of Materials (K0006028) Republic of Korea, the Gyeonggi Regional Research Center (GRRC), the Ministry of Knowledge Economy (MKE), and the Korea Industrial Technology Foundation (KOTEF) through the Human Resource Training Project for Strategic Technology, Republic of Korea.