Open access peer-reviewed chapter

Current Tissue Engineering Approaches for Cartilage Regeneration

Written By

He Huang, Hongyao Xu and Jianying Zhang

Submitted: September 11th, 2018 Reviewed: January 15th, 2019 Published: February 11th, 2019

DOI: 10.5772/intechopen.84429

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Cartilage is one of the critical tissues existed in human and animal bodies. Unlike most tissues, cartilage does not have blood vessels, nerves, and lymphatics. Most cartilage tissues in vivo are subjected to large mechanical loads, and its principal function is to provide a smooth and lubricated surface to facilitate the transmission of mechanical loads with a low frictional coefficient. As a result, cartilage tissues are easily injured. Cartilage defects are frequently caused by trauma, aging, congenital diseases (osteochondritis), and many more factors such as endocrine pathologies and cancer. The damaged cartilage has a limited capacity for healing and repairing. Thus, restoration of normal structure and function to damaged cartilage is one of the most challenging areas in orthopedic research and sports medicine. Tissue engineering provides a prospective alternative strategy by seeding chondrogenic cells into or onto biocompatible scaffolds to produce engineer cartilage for damaged cartilage repair. This book chapter has summarized recent progress in cartilage tissue engineering including stem cells, growth factors, bioactive molecules, and biomaterial scaffolds used for cartilage regeneration. The procedures for some new approaches have also been described.


  • chondrogenesis
  • cartilage tissue engineering
  • stem cells
  • growth factors
  • platelet-rich plasma
  • bioactive molecules
  • biomaterial scaffold

1. Introduction

Cartilage is one of the critical tissues existed in human and animal bodies, such as rib cage, ear, nose, bronchial tubes, intervertebral discs, meniscus, and the joints between bones [1]. Cartilage injuries are the most common diseases. According to National Health Interview Survey (NHIS), in 2010–2012, about 52.5 million adults in the USA had doctor-diagnosed arthritis, and by 2040, the number of US adults with doctor-diagnosed arthritis is projected to increase 49% to 78.4 million. That means about 25.9% of all adults have arthritis [2, 3]. Degeneration of the intervertebral disc, a fibrocartilaginous joint residing between adjacent vertebrae in the vertebral column, is the most frequent cause of low back pain and another significant cartilage-related disease [4]. The overall cost of chronic low back pain exceeds the combined costs of stroke, respiratory infection, diabetes, coronary artery disease, and rheumatoid disease [5]. However, the damaged cartilage has little ability for repairing itself due to the lack of blood supply, nerves, and lymphangion [1], and the effective therapeutic treatments for cartilage regeneration are very few.

Tissue engineering is an interdisciplinary field that applies the principles of engineering and the life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function [6]. Stem cells, scaffold, and biologic active molecules are three key components in tissue engineering [7]. Successful tissue engineering relies on multiple factors including obtaining appropriate cells for implantation, directing the development of those cells on an appropriate differentiated pathway using growth factors and/or cytokines, supporting the growing cells on a three-dimensional matrix, and having that matrix remains in the injured tissue area, at least until healing is completed [6, 8]. This book chapter highlights the recent developments of tissue engineering approaches including stem cells, biomaterials, bioactive compounds, and reagents used for cartilage regeneration and repair.


2. Stem cells used for cartilage regeneration

Stem cells have multidifferentiation potential, which can differentiate into distinctive end-stage cell types including bone, cartilage, muscle, bone marrow stroma, tendon/ligament, fat, dermis, and other connective tissues [9]. There are many cell types that have been manipulated in vitro and subsequently implanted to repopulate a cartilage defect. It must be ensured that the implanted cells are immunoprivileged or provide immunosuppressive agents to avoid rejection by the host immune system.

2.1 Autologous chondrocytes

Autologous chondrocytes were first used for the treatment of cartilage defects of the patients by a Swedish group in 1994 [10]. This approach needs a slice of healthy articular cartilage obtained arthroscopically from proximal part of the medical femoral condyle of the affected knee joint during the first operation [11]. The chondrocytes were isolated from this healthy articular cartilage and cultured for 2–3 weeks to prepare enough cells (about 5 × 106) for damaged cartilage repair [11]. The clinical studies have shown that the treatment of autologous chondrocytes prompts pain reduction, improves quality of life, and delays the need of joint replacement in many cases [12, 13, 14]. Despite the encouraging clinical results, there are still limitations to the use of autologous chondrocyte transplantation. The conventional technique is accompanied with periosteum harvest and fixation over the cartilage defects via large skin incisions. Autologous chondrocytes were injected underneath the periosteal flap. Hypertrophy of the periosteum with high rate of revision arthroscopies and the risk of transplant failure of up to 20% are major drawbacks of the conventional autologous chondrocyte transplantation [14]. Moreover, the complexity and the cost of the two surgical procedures, the biological response of the periosteal flap, and the de-differentiation and consequent capacity loss associated with in vitro expansion of isolated chondrocytes are also the limitations [15].

2.2 Bone marrow-derived mesenchymal stem cells (BMSCs)

Mesenchymal stem cells (MSCs) are multipotent stromal cells first identified and described in 1966 by Alexander Fridenstein [16, 17]. Adult MSCs were originally isolated from bone marrow in 1999 by Pittenger and his colleagues [18]. Subsequent studies have demonstrated that MSCs present in various parts of the body including bone marrow (BM), peripheral blood, umbilical cord blood, fatty tissues, skeletal and cardiac muscles, Wharton’s Jelly of umbilical cord, facet joints, interspinous ligaments, and ligamentum flavum [19, 20, 21, 22, 23]. Many studies have shown that MSCs can migrate to injury sites, induce peripheral tolerance, and inhibit the release of proinflammatory cytokines. It has been demonstrated that MSCs can also promote tissue repair and survival of damaged cells [24]. However, it is not clear which adult tissue-derived MSCs should be used as a good source for cartilage repair.

Autologous bone marrow mesenchymal stem cell (BMSCs) transplantation was first used for the repair of full-thickness articular cartilage defects in human patellae by a Japanese group [25]. BMSCs were aspirated from iliac crest and the nucleated cells were cultured. Adherent cells were subsequently collected, embedded in a collagen gel, transplanted into the articular cartilage defect in patellae, and covered with autologous periosteum. Six months after transplantation, clinical symptoms (pain and walking disability) were improved and the improvement was persisted for 9 years post-transplantation [26]. Sixteen years after transplantation, no clinical problem has been reported. Human autologous BMSCs have been used successfully to treat articular cartilage defects. Twelve months after BMSC transplantation, magnetic resonance imaging (MRI) revealed complete defect fill and complete surface congruity with native cartilage [27]. Currently, autologous BMSC transplantation has been widely used for cartilage repair [26, 28, 29]. Although BMSC treatment did not require any cell expansion or manipulation, reducing costs, and risks involved, the quantity of bone marrow cells was somewhat unsatisfactory [16].

2.3 Adipose-derived stem cells (ADSCs)

Among MSCs, adipose-derived stem cells (ADSCs) have been recognized as an appropriate cell type with chondrogenic potential and high proliferation capacity [30, 31]. Approximately 400,000 liposuction surgeries are performed in the USA each year, and these procedures yield anywhere from 100 ml to 3 liters of lipoaspirate tissue [32]. This material is routinely discarded. It is well known that adipocytes are developed from mesenchymal cells via a complex cascade of transcriptional and non-transcriptional events that occur throughout the human life. Thus, adipose tissue is a good stem cell source.

The initial methods to isolate cells from adipose tissue were developed by Rodbell and colleagues [33]. They isolated adipose-derived stromal cells from rat fat pads by four steps. Step 1: Adipose tissue was minced into small pieces. Step 2: The adipose tissue pieces were digested with collagenase. Step 3: The cell pellet was obtained by centrifuge. Step 4: The cell pellet was cultured for future use. This protocol has been widely used for the isolation of adipose-derived stem cells (ADSCs) from human adipose tissues with some modifications [34, 35].

The adipose tissue can be collected by needle biopsy or liposuction aspiration. The collected adipose tissues should be washed with 5% penicillin/streptomycin (P/S)-containing phosphate-buffered saline (PBS) twice, and then the tissue samples should be put in a sterile tissue culture plate and cut into small pieces. The minced tissues are digested with 0.075% collagenase at 37°C for 30 min; the collagenase is removed by centrifuging the digested solution (adipose tissue and collagenase mixture) at 1200 g for 10 min; the adipose-derived stem cells-containing pellet is then resuspended with culture medium (alpha-MEM, Mediatech, Herndon, VA) supplemented with 20% of fetal bovine serum (FBS), 1% L-glutamine (Mediatech, Herndon, VA), and 1% penicillin/streptomycin (Mediatech, Herndon, VA). The cell suspension is filtered through 70-μm cell strainer and cultured in a humidified tissue culture incubator at 37°C with 5% CO2. The medium is changed every second day until the cells reach 80–90% confluence. It is important that the adipose tissue should be treated within 24 hours, and the cells isolated from about 500 mg of adipose tissue should be added into one well of 12-well plates.

Adipose-derived stem cells (ADSCs) are readily accessible with no morbidity and display the capability to differentiate into several cell lineages, including the spontaneous chondrogenic differentiation [30]. Compared with bone marrow-derived MSCs, adipose-derived MSCs from lipoaspirates are acquired using a less invasive procedure and are in large amounts [36]. ADSCs have been used for the repair of articular cartilage defect in nonweight-bearing areas [37].

2.4 Synovial-derived stem cells (SDSCs)

Synovial-derived MSCs have been isolated from human synovial fluid and synovium of the knee and the hip using the following protocols [38, 39]. The synovial tissue samples (wet weight 10–50 mg) were obtained aseptically from the joints and rinsed twice with Hanks’ balanced salt solution (HBSS; Life Technologies, Carlsbad, CA) supplemented with antibiotic-antimycotic solution (100 units/ml penicillin, 100 μg/ml streptomycin, and 0.25 μg/ml amphotericin B; Life Technologies; Carlsbad, CA). The washed tissues were minced into small pieces and digested with 0.5 ml of 0.2% collagenase (Life Technologies, Carlsbad, CA) in high-glucose Dulbecco’s Modified Eagle’s Medium (DMEM; Life Technologies, Carlsbad, CA) at 37°C for 1 hour. The digested solution were removed by centrifugation at 1500 g for 10 min; the SDSCs-containing pellet was resuspended in growth medium (high-glucose DMEM supplemented with 10% FBS and 100 units/ml penicillin, 100 μg/ml streptomycin) and cultured in a humidified tissue culture incubator at 37°C with 5% CO2. The medium was first changed at day 7 and changed every 3 days until the cells reach 80–90% confluence. It is important that the synovial tissue should be treated within 24 hours.

SDSCs obtained by above procedures have a higher proliferative capacity and chondrogenic potential than the MSCs derived from other sources [39, 40]. A small synovial tissue biopsy is an easily accessible source of autologous MSCs in the context of an explorative or therapeutic arthroscopy. These cells can be subsequently used for the regeneration of damaged cartilage. Autologous chondrocyte transplantation used for cartilage defect repair is limited by the availability of cells, particularly in elderly individuals, and by the well-known dedifferentiation events associated with chondrocyte expansion [39, 41]. Furthermore, SDSCs can be harvested relatively in a minimally invasive manner from synovial fluid and retain a particularly high capacity for chondrogenic differentiation and proliferation compared with MSCs obtained from other tissues, such as bone marrow or cartilage, those have second injury on healthy tissues. SDSCs may be an optimal alternative source of chondrogenic cells for cartilage defect repair.

A recent research has shown that xenogenic implantation of equine SDSCs into rat cartilage defect area leads to articular cartilage regeneration [42]. Horse joints are anatomically equivalent to the human knee and ankle; as a result, horses are widely used as large animal preclinical models for cartilage repair studies. However, large animal studies pose logistical and financial challenges, and small animal rodent models are cost-effective and have proven to be useful for proof-of-concept studies. There was no any immune response to the equine cells in the treated rat knees [42]. This result was also confirmed by a xenogenic transplantation of human MSCs in a critical size defect of the sheep tibia for bone regeneration [43]. Another xenogenic transplantation study has shown that human MSCs can enhance damaged pig intervertebral disc regeneration [44].


3. Growth factors used for cartilage regeneration

Growth factors play an important role in cartilage regeneration. Although some growth factors used in cartilage repair have been well documented [45], it is necessary to summarize the most important chondrogenic differentiation-related growth factors in this chapter.

3.1 Transforming growth factor-beta family (TGF-β)

In cartilage repair, the four most thoroughly investigated members of TGF-β superfamily are TGF-β1, TGF-β3, bone morphogenetic protein-2 (BMP-2), and bone morphogenetic protein-7 (BMP-7) [45, 46]. It has been reported that TGF-beta 1 stimulates chondrocyte synthetic activity and decreases the catabolic activity of IL-1 [47]. TGF-β3 has been used to simulate extracellular matrix (ECM) synthesis in rabbit cartilage injury [48]. Bone morphogenetic proteins (BMPs) play an important role in the development of bone and cartilage. They are involved in the hedgehog pathway, TGF beta signaling pathway, and in cytokine-cytokine receptor interaction. Animal studies have shown that BMP-2 enhanced cartilage matrix production and blocked the IL-1-induced cartilage degeneration [49].

BMP-7 is another gold standard growth factor for cartilage repair [50]. It has been reported that BMP-7 inhibits cell proliferation but stimulates ECM synthesis in both SDSCs and BMSCs [51, 52].

3.2 Insulin-like growth factor-I (IGF-I)

IGF-1 is a multifunctional growth factor. The studies have found that IGF-1 play an important role in maintaining articular cartilage integrity. IGF-I deficiency has led to the development of articular lesions [53]. IGF-1 can not only enhance the synthesis of proteoglycans and upregulate the gene expression of collagen II but also can reduce the degradation of extracellular matrixes by decreasing the production of matrix metallopetidase-13 (MMP-13) [54, 55, 56]. The research has shown that IGF-1 exerts these functions in a dose-dependent manner [57]. Low dose of IGF-1 has a beneficial effect on bone remodeling by increasing bone formation markers in serum [58]. Higher IGF-1 levels in osteoarthritis (OA) osteoblasts could be correlated with bone sclerosis [59].

3.3 Fibroblast growth factor (FGF)

There are two FGF members used in cartilage regeneration. One of them is called as basic FGF (bFGF) or FGF-2, and the other one is called as FGF-18. FGF-2 increases anabolic material levels and decreases aggrecanase levels in cartilage. In vivo study has indicated that bFGF can promote cartilage repair [60]. However, some study indicated that the concentration of FGF-2 in synovial fluid samples of OA patients is approximately twice that of normal healthy knee joints [61]. Further studies found that FGF-2 promoted the repair of partial thickness defects of articular cartilage in immature rabbits but not in mature rabbits [62].

A rat model study has shown that FGF-18 stimulates chondrogenesis and cartilage repair in a concentration-dependent manner [63]. More studies have demonstrated that FGF-18 may present a therapeutic agent for osteoarthritis [64, 65]. A recombinant form of human FGF-18 has been used for cartilage injury treatment [66].

3.4 Platelet-rich plasma (PRP)

Platelets play a fundamental role in hemostasis and are a natural source of growth factors. More than 30 growth factors have been identified in PRP; among them, the following six growth factors play an important role in cartilage regeneration. They are TGF-β1, platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), insulin-like growth factor 1 (IGF-1), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF) [67, 68].

The concentration of platelet in PRP used for cartilage repair should be two to three times higher than that of baseline [69]. PRP can be prepared by the following five procedures (Figure 1). Step 1: blood (9 parts) is added into 3.8% sodium citrate solution (1 part) in a centrifuge tube and centrifuged at 500 g for 5 min to obtain three layers. Step 2: The supernatant at the top layer is transferred into a new tube, which is called as platelets-containing plasma, and the middle layer is transferred into another new tube, which is called leukocytes-containing plasma. Step 3: The platelets-containing plasma is centrifuged at 2000 g for 5 min to separate platelet-poor plasma (PPP) from the platelet pellet. Step 4: The platelet pellet is resuspended with appropriate amount of PPP to make pure PRP (P-PRP). Step 5: The leukocytes-containing plasma is mixed with platelet pellet and resuspended with appropriate amount of PPP to make leukocytes-containing PRP (L-PRP). Both P-PRP and L-PRP can be used for cartilage tissue engineering [70].

Figure 1.

Scheme of preparation of P-PRP and L-PRP from whole blood using five steps.


4. Bioactive molecules used for cartilage tissue engineering

Bioactive molecules used in cartilage tissue engineering include two kinds of materials: one is small molecular weight bioactive compound and the other one is high molecular weight materials including some nature biomaterials and synthetic polymers. Both of them play critical role in cartilage tissue engineering.

4.1 Kartogenin (KGN)

Kartogenin (KGN), a small heterocyclic molecule, has been discovered to enhance chondrogenic differentiation of human MSCs by regulating the CBFbeta-RUNX1 transcriptional program [71, 72]. Animal studies have shown that KGN can promote rabbit meniscus regeneration [73] and wounded rat enthesis repair [70, 74]. In vitro and ex vivo experiments showed that KGN can reduce nucleus pulposus cell degeneration induced by interleukin-1beta (IL-1β) and tumor necrosis factor-alpha [75]. More recent studies indicated that KGN inhibited pain behavior, chondrocyte inflammation, and attenuated osteoarthritis progression in mice [76]; enhanced collagen organization and mechanical strength of the repaired enthesis of mouse rotator cuff [77]; and induced chondrogenic differentiation of dental pulp stem cells [78].

These findings invigorate research into small-molecule therapy and regenerative medicine for cartilage diseases. It also provides new insights into the control of chondrogenesis that may ultimately lead to a stem cell-based therapy for osteoarthritis (OA). KGN and other structurally related small molecules that can promote selective differentiation of MSCs into chondrocytes may prove to be extremely useful for improving the outcome of cell-based therapy by stimulating endogenous mechanisms for repair of damaged cartilage, thus enhancing the joint’s intrinsic capacity for cartilage regeneration [79].

4.2 Simvastatin

Simvastatin is a kind of HMG-CoA reductase inhibitor, which is widely used therapeutically to reduce morbidity and mortality in patients with hyperlipidemic cardiovascular disease [80]. In addition to lowing low-density lipoprotein (LDL) cholesterol, statins have broad-range pleiotropic effects, including anti-inflammatory effects, which could exert an effect on synovium and cartilage [81]. Animal studies found that simvastatin markedly inhibited not only developing but also established collagen-induced arthritis [82]. Simvastatin inhibited the IL-6 and TNF-α production of human chondrocytes and cartilage explants in a concentration-dependent manner. Higher concentrations of simvastatin decreased nitric oxide (NO) production in both of human chondrocytes and cartilage explants [83]. Statin treatment has also been shown to positively regulate components of the extracellular matrix in a rabbit OA model [84]. More studies have shown that local application of simvastatin enhanced tendon-bone interface healing in rabbits [85]. These studies have shown that the effect of simvastatin on articular chondrocytes may provide novel insight regarding the role of cholesterol homeostasis and signaling during cartilage development.

4.3 Biomaterial scaffolds for cartilage tissue engineering

Biomaterial scaffolds play an important role in cartilage tissue engineering, which act as a carrier to deliver the cells and bioactive molecules to the damaged tissue areas and also work as a template for tissue regeneration, to guide the growth of new tissue.

There are two groups of biomaterial scaffolds used for cartilage tissue engineering. They are synthetic polymers and natural polymers. Commonly used natural materials in cartilage repair are agarose, alginate, chitosan, collagen, fibrin, and hyaluronan.

Agarose is a galactose polymer, which is suitable for cell encapsulation, especially for chondrocytes. When the ADSCs were cultured in agarose, they were differentiated into chondrocytes as evidenced by upregulation of the production of glycosaminoglycan (GAG) [86]. Moreover, dynamically loaded cell-seeded agarose hydrogel provided better graft tissues in a repair model of full thickness defects in rabbit joint cartilage [87]. PRP combined with agarose as a bioactive scaffold has shown to enhance cartilage repair [88].

Another extensively studied natural scaffold used for cartilage tissue engineering is alginate, which is a polysaccharide extracted from brown algae. Generally, alginate is hydrophilic and water-soluble, thickening in neutral conditions, which is of great importance for in situ hydrogel formation [89]. The good gelling properties of alginate-based scaffolds allowed them to be used as an injectable scaffold for the damaged cartilage repair. Human dental pulp stem cells were cultured in 3% alginate hydrogel and implanted in a rabbit damaged cartilage area. Three months after surgery, significant cartilage regeneration was observed [90]. More studies have been done by mixing the cells or/and growth factors with alginate solution to form gel microspheres in an isotonic CaCl2 solution (Figure 2). The findings have shown that the cells are distributed homogeneously inside the gel microspheres. Those cell-containing alginate beads can be used as chondrogenesis-promoting scaffolds for cartilage regeneration [91, 92].

Figure 2.

The intermolecular network of alginate molecules is formed in calcium chloride solution. Alginate can be dissolved with sodium chloride (left image), but cross-linked each other in calcium ions-containing solution to form hydrogel (right image).

Chitosan is another natural polysaccharide extracted from crustacean shells, particularly from shrimps and crabs. Chitosan contains glucosamine and hyaluronic acid (HA), which are basic components of the native cartilage. Therefore, chitosan is widely used for cartilage tissue engineering. The recent studies have shown that chitosan-hyaluronic acid hydrogel promoted wounded cartilage healing in a rabbit model [93, 94].

Collagen is a main component of the extracellular matrix (ECM) of chondrocytes. Collagen gel has been widely used as substrates for articular cartilage substitutes [95, 96]. Injectable type II collagen gel has been used to treat full-thickness articular cartilage defects [97]. Clinical study has demonstrated that collagen gel can be used to replace cartilage and subchondral bone [98].

Fibrin hydrogels used for articular cartilage repair has been well documented by a review paper [99]. It has been reported that chondrocytes survived in the fibrin gel and enhanced their synthetic activity as evidenced by the increase of the production of GAG and collagen type II [100]. Human fibrin hydrogels have been approved by the Food and Drug Administration (FDA) for cartilage tissue engineering [101].

Hyaluronan is a main component of native cartilage. Similarly to the other native biomaterial scaffold, hyaluronan is the most widely used scaffold for cartilage tissue engineering. The studies have shown that hyaluronan upregulated collagen II expression and downregulated collagen I expression in human MSCs when they were cultured in hyaluronan gel [102].

Although bioactive natural scaffolds have very good biocompatibilities, their mechanical properties still need to be improved. In addition to natural bioactive scaffolds, synthetic materials provide good mechanical properties suitable for cartilage tissue engineering. These synthetic polymers are either used alone or combined with natural biomaterials for cartilage research.

The most famous synthetic polymers for cartilage regeneration are polylactic acid (PLA), polyglycolic acid (PGA), and their copolymer polylactic-co-glycolic acid (PLGA). These polymers have a beneficial range of mechanical characteristics and high biocompatibility. Owing to the fact that PLA-PGA polymers have been successfully used in the clinics including sutures, screws, and pins [103, 104, 105], they are also used for articular cartilage defect repair in rabbits [106] and meniscal lesion repair in dogs [107]. Currently, two PLA-based scaffolds have been clinically used for cartilage repair: one is BioSeed ®-C and the other one is TRUFIT CB™. The PLA-based polymer scaffolds have shown significant improvement in patient outcomes for the treatment of post-traumatic OA and focal degenerative cartilage defects [108, 109].

Polyethylene glycol (PEG), a nontoxic synthetic polymer, is widely used with other natural materials to enhance their mechanical strength for cartilage tissue engineering. The studies have indicated that PEG-based hydrogel can promote chondrogenic differentiation of MSCs in vitro and in vivo [110, 111]. Injectable hydrogels used for cartilage tissue engineering have been well summarized by several review papers [112]. PEG-HA scaffold-treated patients achieved significantly higher levels of tissue fill in cartilage defects [113].


5. New surgical techniques for cartilage regeneration

Surgical techniques are more important for cartilage repair. In any cartilage repair techniques, the preparation of the defect bed to receive the implant is essential [114]. In order to promote cartilage regeneration, several new surgical techniques have been developed.

5.1 Arthroscopic surgery

Arthroscopic surgery is a common orthopedic procedure that is used in the diagnosis and treatment of problems inside a joint. Generally, the cartilage defect is measured with an arthroscopic graded probe, and the size and the shape of the defect are templated using sterile paper or aluminum that is subsequently used to prepare the graft if it is not an injectable gel form [114]. Besides the defect preparation and measurement, most operations can be done under an arthroscopy. Currently, arthroscopic surgery has been widely used for various damaged cartilage treatments such as degenerative meniscal tear [115] and osteoarthritis of the knee [116].

5.2 Open surgery

Open surgery is used for some arthroscopically inaccessible cartilage defects such as patella, trochlea, posterior femoral condyle, and some scaffolds that cannot be implanted arthroscopically [114]. This technique has been widely used in cartilage tissue engineering for animal surgery and clinical practice.

5.3 Microfracture surgery

Microfracture surgery is a surgical technique used to repair damaged cartilage by making multiple small holes in the surface of the joint to stimulate a healing response. This technique was developed in the early 1980s by Steadman and his colleagues. The technical details of microfracture have been well summarized [117]. Several animal studies have been completed to assess the microfracture technique [118, 119]. The functional outcomes of patients treated with microfracture for traumatic chondral defects have shown significant improvement [120]. Currently, microfracture surgical technique is considered to be an effective arthroscopic treatment for full-thickness cartilage defect [121]. However, some studies have shown that the younger patients have better clinical outcomes and quality cartilage repair than older patients [122].

5.4 Mosaicplasty surgery

Mosaicplasty surgery is another common cartilage restoration technique in standard clinical practice. This technique was introduced into clinical application in 1992 [123]. Mosaicplasty surgical technique is based on the mosaic-like transplantation of several small, cylindrical plugs of bone and cartilage to provide an even resurfaced area. The long-term clinical follow-up results have shown that the mosaicplasty-treated patients can regain their pre-injury activity level [124].

The studies have demonstrated that the treatment of mosaicplasty in a single cartilage defect size one to five square centimeters of the femoral condyle resulted in clinically relevant better outcome than microfracture [125, 126].


6. Conclusions and future research on cartilage tissue engineering

Cartilage tissue engineering is to use a biomaterial scaffold, bioactive molecules, and cells to produce new cartilage under special conditions. The rapid progress in material science, life science, and engineering has resulted in advancements in the treatment options for various illnesses and diseases, especially for cartilage defects. However, the field of cartilage tissue engineering is still in developing stage. The number of potential variables in cartilage tissue engineering strategy is vast, and the key challenges remain to be addressed. As cartilage tissue engineering incorporates the fields of cell biology, nuclear transfer, and material science, personnel who have mastered the techniques of cell harvest, culture, expansion, transplantation, and polymer design is essential for the successful application of these technologies to build new cartilage and extend human life. The future research on cartilage tissue engineering should thus be aimed at investigating and evaluating tissue engineering approaches, as well as surgical techniques for cartilage repair in disease-compromised animal models to gain a better understanding of clinically feasible design. It is necessary to develop a model system for the study of normal and pathological cartilage tissues.


Conflict of interest

The authors declared no potential conflicts of interest with respect to the research authorship and/or publication of this article.



This work was financially supported by the Department of Orthopedic Surgery, University of Pittsburgh School of Medicine.


  1. 1. Sophia Fox AJ, Bedi A, Rodeo SA. The basic science of articular cartilage: Structure, composition, and function. Sports Health. 2009;1:461-468
  2. 2. Hootman JM, Helmick CG, Barbour KE, Theis KA, Boring MA. Updated projected prevalence of self-reported doctor-diagnosed arthritis and arthritis-attributable activity limitation among US adults, 2015-2040. Arthritis & Rhematology. 2016;68:1582-1587
  3. 3. Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis and Rheumatism. 2008;58:15-25
  4. 4. Paesold G, Nerlich AG, Boos N. Biological treatment strategies for disc degeneration: potentials and shortcomings. European Spine Journal. 2007;16:447-468
  5. 5. Walker BF. The prevalence of low back pain: A systematic review of the literature from 1966 to 1998. Journal of Spinal Disorders. 2000;13:205-217
  6. 6. Langer R, Vacanti JP. Tissue engineering. Science. 1993;260:920-926
  7. 7. Fuchs JR, Nasseri BA, Vacanti JP. Tissue engineering: A 21st century solution to surgical reconstruction. The Annals of Thoracic Surgery. 2001;72:577-591
  8. 8. Kessler MW, Grande DA. Tissue engineering and cartilage. Organogenesis. 2008;4:28-32
  9. 9. Caplan AI. Review: Mesenchymal stem cells: Cell-based reconstructive therapy in orthopedics. Tissue Engineering. 2005;11:1198-1211
  10. 10. Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. The New England Journal of Medicine. 1994;331:889-895
  11. 11. Horas U, Pelinkovic D, Herr G, Aigner T, Schnettler R. Autologous chondrocyte implantation and osteochondral cylinder transplantation in cartilage repair of the knee joint. A prospective, comparative trial. The Journal of bone and joint surgery American. 2003;85-A:185-192
  12. 12. Brittberg M. Cell carriers as the next generation of cell therapy for cartilage repair: A review of the matrix-induced autologous chondrocyte implantation procedure. American Journal of Sports Medicine. 2010;38:1259-1271
  13. 13. Peterson L, Vasiliadis HS, Brittberg M, Lindahl A. Autologous chondrocyte implantation: A long-term follow-up. American Journal of Sports Medicine. 2010;38:1117-1124
  14. 14. Mardones R, Jofre CM, Minguell JJ. Cell therapy and tissue engineering approaches for cartilage repair and/or regeneration. International Journal of Stem Cells. 2015;8:48-53
  15. 15. Mobasheri A, Kalamegam G, Musumeci G, Batt ME. Chondrocyte and mesenchymal stem cell-based therapies for cartilage repair in osteoarthritis and related orthopaedic conditions. Maturitas. 2014;78:188-198
  16. 16. Kristjansson B, Honsawek S. Mesenchymal stem cells for cartilage regeneration in osteoarthritis. World Journal of Orthopedics. 2017;8:674-680
  17. 17. Friedenstein AJ, Piatetzky S, II, Petrakova KV. Osteogenesis in transplants of bone marrow cells. Journal of Embryology and Experimental Morphology 1966;16:381-390
  18. 18. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143-147
  19. 19. Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS, et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell. 2008;3:301-313
  20. 20. Chin S, Furukawa K, Ono A, Asari T, Harada Y, Wada K, et al. Immunohistochemical localization of mesenchymal stem cells in ossified human spinal ligaments. Biochemical and Biophysical Research Communications. 2013;436:698-704
  21. 21. Schieker M, Gulkan H, Austrup B, Neth P, Mutschler W. Telomerase activity and telomere length of human mesenchymal stem cells. Changes during osteogenic differentiation. Der Orthopäde. 2004;33:1373-1377
  22. 22. Li S, Huang KJ, Wu JC, Hu MS, Sanyal M, Hu M, et al. Peripheral blood-derived mesenchymal stem cells: Candidate cells responsible for healing critical-sized calvarial bone defects. Stem Cells Translational Medicine. 2015;4:359-368
  23. 23. Sibov TT, Severino P, Marti LC, Pavon LF, Oliveira DM, Tobo PR, et al. Mesenchymal stem cells from umbilical cord blood: Parameters for isolation, characterization and adipogenic differentiation. Cytotechnology. 2012;64:511-521
  24. 24. Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nature Reviews. Immunology. 2008;8:726-736
  25. 25. Wakitani S, Mitsuoka T, Nakamura N, Toritsuka Y, Nakamura Y, Horibe S. Autologous bone marrow stromal cell transplantation for repair of full-thickness articular cartilage defects in human patellae: Two case reports. Cell Transplantation. 2004;13:595-600
  26. 26. Yamasaki S, Mera H, Itokazu M, Hashimoto Y, Wakitani S. Cartilage repair with autologous bone marrow Mesenchymal stem cell transplantation: Review of preclinical and clinical studies. Cartilage. 2014;5:196-202
  27. 27. Haleem AM, Singergy AA, Sabry D, Atta HM, Rashed LA, Chu CR, et al. The clinical use of human culture-expanded autologous bone marrow Mesenchymal stem cells transplanted on platelet-rich fibrin glue in the treatment of articular cartilage defects: A pilot study and preliminary results. Cartilage. 2010;1:253-261
  28. 28. Wakitani S, Imoto K, Yamamoto T, Saito M, Murata N, Yoneda M. Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees. Osteoarthritis and Cartilage. 2002;10:199-206
  29. 29. Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M, Karli D. Regeneration of meniscus cartilage in a knee treated with percutaneously implanted autologous mesenchymal stem cells. Medical Hypotheses. 2008;71:900-908
  30. 30. Bielli A, Scioli MG, Gentile P, Cervelli V, Orlandi A. Adipose-derived stem cells in cartilage regeneration: Current perspectives. Regenerative Medicine. 2016;11:693-703
  31. 31. Im GI. Regeneration of articular cartilage using adipose stem cells. Journal of Biomedical Materials Research Part A. 2016;104:1830-1844
  32. 32. Katz AJ, Llull R, Hedrick MH, Futrell JW. Emerging approaches to the tissue engineering of fat. Clinics in Plastic Surgery. 1999;26:587-603
  33. 33. Rodbell M. Metabolism of isolated fat cells. II. The similar effects of phospholipase C (Clostridium perfringens alpha toxin) and of insulin on glucose and amino acid metabolism. The Journal of Biological Chemistry. 1966;241:130-139
  34. 34. Zhu M, Heydarkhan-Hagvall S, Hedrick M, Benhaim P, Zuk P. Manual isolation of adipose-derived stem cells from human lipoaspirates. Journal of Visualized Experiments. 2013;79:e50585
  35. 35. Bunnell BA, Flaat M, Gagliardi C, Patel B, Ripoll C. Adipose-derived stem cells: Isolation, expansion and differentiation. Methods. 2008;45:115-120
  36. 36. Peng L, Jia Z, Yin X, Zhang X, Liu Y, Chen P, et al. Comparative analysis of mesenchymal stem cells from bone marrow, cartilage, and adipose tissue. Stem Cells and Development. 2008;17:761-773
  37. 37. Cui L, Wu Y, Cen L, Zhou H, Yin S, Liu G, et al. Repair of articular cartilage defect in non-weight bearing areas using adipose derived stem cells loaded polyglycolic acid mesh. Biomaterials. 2009;30:2683-2693
  38. 38. Hatakeyama A, Uchida S, Utsunomiya H, Tsukamoto M, Nakashima H, Nakamura E, et al. Isolation and characterization of synovial Mesenchymal stem cell derived from hip joints: A comparative analysis with a matched control knee group. Stem Cells International. 2017;2017:9312329
  39. 39. De Bari C, Dell'Accio F, Tylzanowski P, Luyten FP. Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis and Rheumatism. 2001;44:1928-1942
  40. 40. Yao Y, Li ZY, Zhang H, Zheng YH, Mai LX, Liu WJ, et al. Synovial fluid-derived synovial fragments represent an improved source of synovial mesenchymal stem cells in the temporomandibular joint. International Journal of Molecular Medicine. 2018;41:173-183
  41. 41. Benya PD, Shaffer JD. Dedifferentiated chondrocytes reexpress the differentiated collagen phenotype when cultured in agarose gels. Cell. 1982;30:215-224
  42. 42. Zayed M, Newby S, Misk N, Donnell R, Dhar M. Xenogenic implantation of equine synovial fluid-derived Mesenchymal stem cells leads to articular cartilage regeneration. Stem Cells International. 2018;2018:1073705
  43. 43. Niemeyer P, Schonberger TS, Hahn J, Kasten P, Fellenberg J, Suedkamp N, et al. Xenogenic transplantation of human mesenchymal stem cells in a critical size defect of the sheep tibia for bone regeneration. Tissue Engineering Parts A. 2010;16:33-43
  44. 44. Henriksson HB, Svanvik T, Jonsson M, Hagman M, Horn M, Lindahl A, et al. Transplantation of human mesenchymal stems cells into intervertebral discs in a xenogeneic porcine model. Spine. 2009;34:141-148
  45. 45. Fortier LA, Barker JU, Strauss EJ, McCarrel TM, Cole BJ. The role of growth factors in cartilage repair. Clinical Orthopaedics and Related Research. 2011;469:2706-2715
  46. 46. Chubinskaya S, Segalite D, Pikovsky D, Hakimiyan AA, Rueger DC. Effects induced by BMPS in cultures of human articular chondrocytes: Comparative studies. Growth Factors. 2008;26:275-283
  47. 47. Davidson TS, DiPaolo RJ, Andersson J, Shevach EM. Cutting edge: IL-2 is essential for TGF-beta-mediated induction of Foxp3+ T regulatory cells. Journal of Immunology. 2007;178:4022-4026
  48. 48. Lee CH, Cook JL, Mendelson A, Moioli EK, Yao H, Mao JJ. Regeneration of the articular surface of the rabbit synovial joint by cell homing: A proof of concept study. Lancet. 2010;376:440-448
  49. 49. Blaney Davidson EN, Vitters EL, van Lent PL, van de Loo FA, van den Berg WB, van der Kraan PM. 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. 2007;9:R102
  50. 50. Chubinskaya S, Hurtig M, Rueger DC. OP-1/BMP-7 in cartilage repair. International Orthopaedics. 2007;31:773-781
  51. 51. Miyamoto C, Matsumoto T, Sakimura K, Shindo H. Osteogenic protein-1 with transforming growth factor-beta1: Potent inducer of chondrogenesis of synovial mesenchymal stem cells in vitro. Journal of Orthopaedic Science. 2007;12:555-561
  52. 52. Shen B, Wei A, Whittaker S, Williams LA, Tao H, Ma DD, et al. The role of BMP-7 in chondrogenic and osteogenic differentiation of human bone marrow multipotent mesenchymal stromal cells in vitro. Journal of Cellular Biochemistry. 2010;109:406-416
  53. 53. Ekenstedt KJ, Sonntag WE, Loeser RF, Lindgren BR, Carlson CS. Effects of chronic growth hormone and insulin-like growth factor 1 deficiency on osteoarthritis severity in rat knee joints. Arthritis and Rheumatism. 2006;54:3850-3858
  54. 54. Mullen LM, Best SM, Ghose S, Wardale J, Rushton N, Cameron RE. Bioactive IGF-1 release from collagen-GAG scaffold to enhance cartilage repair in vitro. Journal of Materials Science Materials in Medicine. 2015;26:5325
  55. 55. Tyler JA. Insulin-like growth factor 1 can decrease degradation and promote synthesis of proteoglycan in cartilage exposed to cytokines. Biochemical Journal. 1989;260:543-548
  56. 56. Zhang M, Zhou Q, Liang QQ, Li CG, Holz JD, Tang D, et al. IGF-1 regulation of type II collagen and MMP-13 expression in rat endplate chondrocytes via distinct signaling pathways. Osteoarthritis and Cartilage. 2009;17:100-106
  57. 57. Ortved KF, Begum L, Mohammed HO, Nixon AJ. Implantation of rAAV5-IGF-I transduced autologous chondrocytes improves cartilage repair in full-thickness defects in the equine model. Molecular Therapy. 2015;23:363-373
  58. 58. Crane JL, Cao X. Function of matrix IGF-1 in coupling bone resorption and formation. Journal of Molecular Medicine. 2014;92:107-115
  59. 59. Massicotte F, Fernandes JC, Martel-Pelletier J, Pelletier JP, Lajeunesse D. Modulation of insulin-like growth factor 1 levels in human osteoarthritic subchondral bone osteoblasts. Bone. 2006;38:333-341
  60. 60. Cuevas P, Burgos J, Baird A. Basic fibroblast growth factor (FGF) promotes cartilage repair in vivo. Biochemical and Biophysical Research Communications. 1988;156:611-618
  61. 61. Im HJ, Muddasani P, Natarajan V, Schmid TM, Block JA, Davis F, et al. Basic fibroblast growth factor stimulates matrix metalloproteinase-13 via the molecular cross-talk between the mitogen-activated protein kinases and protein kinase Cdelta pathways in human adult articular chondrocytes. The Journal of Biological Chemistry. 2007;282:11110-11121
  62. 62. Yamamoto T, Wakitani S, Imoto K, Hattori T, Nakaya H, Saito M, et al. Fibroblast growth factor-2 promotes the repair of partial thickness defects of articular cartilage in immature rabbits but not in mature rabbits. Osteoarthritis and Cartilage. 2004;12:636-641
  63. 63. Moore EE, Bendele AM, Thompson DL, Littau A, Waggie KS, Reardon B, et al. Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat model of injury-induced osteoarthritis. Osteoarthritis and Cartilage. 2005;13:623-631
  64. 64. Mori Y, Saito T, Chang SH, Kobayashi H, Ladel CH, Guehring H, et al. Identification of fibroblast growth factor-18 as a molecule to protect adult articular cartilage by gene expression profiling. The Journal of Biological Chemistry. 2014;289:10192-10200
  65. 65. Huang L, Yi L, Zhang C, He Y, Zhou L, Liu Y, et al. Synergistic effects of FGF-18 and TGF-beta3 on the Chondrogenesis of human adipose-derived Mesenchymal stem cells in the pellet culture. Stem Cells International. 2018;2018:7139485
  66. 66. Barr L, Getgood A, Guehring H, Rushton N, Henson FM. The effect of recombinant human fibroblast growth factor-18 on articular cartilage following single impact load. Journal of Orthopaedic Research. 2014;32:923-927
  67. 67. Okuda K, Kawase T, Momose M, Murata M, Saito Y, Suzuki H, et al. Platelet-rich plasma contains high levels of platelet-derived growth factor and transforming growth factor-beta and modulates the proliferation of periodontally related cells in vitro. Journal of Periodontology. 2003;74:849-857
  68. 68. Lubkowska A, Dolegowska B, Banfi G. Growth factor content in PRP and their applicability in medicine. Journal of Biological Regulators and Homeostatic Agents. 2012;26:3S-22S
  69. 69. Hall MP, Band PA, Meislin RJ, Jazrawi LM, Cardone DA. Platelet-rich plasma: Current concepts and application in sports medicine. Journal of the American Academy of Orthopaedic Surgeons. 2009;17:602-608
  70. 70. Zhang J, Yuan T, Zheng N, Zhou Y, Hogan MV, Wang JH. The combined use of kartogenin and platelet-rich plasma promotes fibrocartilage formation in the wounded rat Achilles tendon entheses. Bone & Joint Research. 2017;6:231-244
  71. 71. Zhang J, Wang JH. Kartogenin induces cartilage-like tissue formation in tendon-bone junction. Bone Research. 2014;2:14008
  72. 72. Johnson K, Zhu S, Tremblay MS, Payette JN, Wang J, Bouchez LC, et al. A stem cell-based approach to cartilage repair. Science. 2012;336:717-721
  73. 73. Huang H, Xu H, Zhao J. A novel approach for meniscal regeneration using Kartogenin-treated autologous tendon graft. American Journal of Sports Medicine. 2017;45:3289-3297
  74. 74. Zhou Y, Zhang J, Yang J, Narava M, Zhao G, Yuan T, et al. Kartogenin with PRP promotes the formation of fibrocartilage zone in the tendon-bone interface. Journal of Tissue Engineering and Regenerative Medicine. 2017;11:3445-3456
  75. 75. Huang Y, Jiang T, Chen J, Yin GY, Fan J. Effects of kartogenin on the attenuated nucleus pulposus cell degeneration of intervertebral discs induced by interleukin-1beta and tumor necrosis factor-alpha. International Journal of Molecular Medicine. 2018;41:749-756
  76. 76. Kwon JY, Lee SH, Na HS, Jung K, Choi J, Cho KH, et al. Kartogenin inhibits pain behavior, chondrocyte inflammation, and attenuates osteoarthritis progression in mice through induction of IL-10. Scientific Reports. 2018;8:13832
  77. 77. Wang D, Tan H, Lebaschi AH, Nakagawa Y, Wada S, Donnelly PE, et al. Kartogenin enhances collagen organization and mechanical strength of the repaired Enthesis in a murine model of rotator cuff repair. Arthroscopy. 2018;34:2579-2587
  78. 78. Westin CB, Trinca RB, Zuliani C, Coimbra IB, Moraes AM. Differentiation of dental pulp stem cells into chondrocytes upon culture on porous chitosan-xanthan scaffolds in the presence of kartogenin. Materials Science and Engineering: C. 2017;80:594-602
  79. 79. Mobasheri A. The future of osteoarthritis therapeutics: Emerging biological therapy. Current Rheumatology Reports. 2013;15:385
  80. 80. Smith DA, Galin I. Statin therapy for native and peri-interventional coronary heart disease. Current Molecular Medicine. 2006;6:589-602
  81. 81. Lazzerini PE, Capecchi PL, Selvi E, Lorenzini S, Bisogno S, Baldari CT, et al. Statins and the joint: Multiple targets for a global protection? Seminars in Arthritis and Rheumatism. 2011;40:430-446
  82. 82. Leung BP, Sattar N, Crilly A, Prach M, McCarey DW, Payne H, et al. A novel anti-inflammatory role for simvastatin in inflammatory arthritis. Journal of Immunology. 2003;170:1524-1530
  83. 83. Dombrecht EJ, Van Offel JF, Bridts CH, Ebo DG, Seynhaeve V, Schuerwegh AJ, et al. Influence of simvastatin on the production of pro-inflammatory cytokines and nitric oxide by activated human chondrocytes. Clinical and Experimental Rheumatology. 2007;25:534-539
  84. 84. Akasaki Y, Matsuda S, Nakayama K, Fukagawa S, Miura H, Iwamoto Y. Mevastatin reduces cartilage degradation in rabbit experimental osteoarthritis through inhibition of synovial inflammation. Osteoarthritis and Cartilage. 2009;17:235-243
  85. 85. Oka S, Matsumoto T, Kubo S, Matsushita T, Sasaki H, Nishizawa Y, et al. Local administration of low-dose simvastatin-conjugated gelatin hydrogel for tendon-bone healing in anterior cruciate ligament reconstruction. Tissue Engineering Parts A. 2013;19:1233-1243
  86. 86. Awad HA, Wickham MQ, Leddy HA, Gimble JM, Guilak F. Chondrogenic differentiation of adipose-derived adult stem cells in agarose, alginate, and gelatin scaffolds. Biomaterials. 2004;25:3211-3222
  87. 87. Weisser J, Rahfoth B, Timmermann A, Aigner T, Brauer R, von der Mark K. Role of growth factors in rabbit articular cartilage repair by chondrocytes in agarose. Osteoarthritis and Cartilage. 2001;9(Suppl A):S48-S54
  88. 88. Yin Z, Yang X, Jiang Y, Xing L, Xu Y, Lu Y, et al. Platelet-rich plasma combined with agarose as a bioactive scaffold to enhance cartilage repair: An in vitro study. Journal of Biomaterials Applications. 2014;28:1039-1050
  89. 89. Sun J, Tan H. Alginate-based biomaterials for regenerative medicine applications. Materials. 2013;6:1285-1309
  90. 90. Mata M, Milian L, Oliver M, Zurriaga J, Sancho-Tello M, de Llano JJM, et al. In vivo articular cartilage regeneration using human dental pulp stem cells cultured in an alginate scaffold: A preliminary study. Stem Cells International. 2017;2017:8309256
  91. 91. Focaroli S, Teti G, Salvatore V, Orienti I, Falconi M. Calcium/cobalt alginate beads as functional scaffolds for cartilage tissue engineering. Stem Cells International. 2016;2016:2030478
  92. 92. Pleumeekers MM, Nimeskern L, Koevoet WL, Kops N, Poublon RM, Stok KS, et al. The in vitro and in vivo capacity of culture-expanded human cells from several sources encapsulated in alginate to form cartilage. European Cells & Materials. 2014;27:264-280; discussion 78-80
  93. 93. Mohan N, Mohanan PV, Sabareeswaran A, Nair P. Chitosan-hyaluronic acid hydrogel for cartilage repair. International Journal of Biological Macromolecules. 2017;104:1936-1945
  94. 94. Zhao M, Chen Z, Liu K, Wan YQ, Li XD, Luo XW, et al. Repair of articular cartilage defects in rabbits through tissue-engineered cartilage constructed with chitosan hydrogel and chondrocytes. Journal of Zhejiang University Science B. 2015;16:914-923
  95. 95. Mueller-Rath R, Gavenis K, Andereya S, Mumme T, Albrand M, Stoffel M, et al. Condensed cellular seeded collagen gel as an improved biomaterial for tissue engineering of articular cartilage. Bio-Medical Materials and Engineering. 2010;20:317-328
  96. 96. Kawamura S, Wakitani S, Kimura T, Maeda A, Caplan AI, Shino K, et al. Articular cartilage repair. Rabbit experiments with a collagen gel-biomatrix and chondrocytes cultured in it. Acta Orthopaedica Scandinavica. 1998;69:56-62
  97. 97. Funayama A, Niki Y, Matsumoto H, Maeno S, Yatabe T, Morioka H, et al. Repair of full-thickness articular cartilage defects using injectable type II collagen gel embedded with cultured chondrocytes in a rabbit model. Journal of Orthopaedic Science. 2008;13:225-232
  98. 98. Kon E, Delcogliano M, Filardo G, Busacca M, Di Martino A, Marcacci M. Novel nano-composite multilayered biomaterial for osteochondral regeneration: A pilot clinical trial. American Journal of Sports Medicine. 2011;39:1180-1190
  99. 99. Peretti GM, Xu JW, Bonassar LJ, Kirchhoff CH, Yaremchuk MJ, Randolph MA. Review of injectable cartilage engineering using fibrin gel in mice and swine models. Tissue Engineering. 2006;12:1151-1168
  100. 100. Scotti C, Mangiavini L, Boschetti F, Vitari F, Domeneghini C, Fraschini G, et al. Effect of in vitro culture on a chondrocyte-fibrin glue hydrogel for cartilage repair. Knee Surgery, Sports Traumatology, Arthroscopy. 2010;18:1400-1406
  101. 101. Fussenegger M, Meinhart J, Hobling W, Kullich W, Funk S, Bernatzky G. Stabilized autologous fibrin-chondrocyte constructs for cartilage repair in vivo. Annals of Plastic Surgery. 2003;51:493-498
  102. 102. Lisignoli G, Cristino S, Piacentini A, Toneguzzi S, Grassi F, Cavallo C, et al. Cellular and molecular events during chondrogenesis of human mesenchymal stromal cells grown in a three-dimensional hyaluronan based scaffold. Biomaterials. 2005;26:5677-5686
  103. 103. Bostman O, Makela EA, Sodergard J, Hirvensalo E, Tormala P, Rokkanen P. Absorbable polyglycolide pins in internal fixation of fractures in children. Journal of Pediatric Orthopedics. 1993;13:242-245
  104. 104. Hirvensalo E, Bostman O, Partio E, Tormala P, Rokkanen P. Fracture of the humeral capitellum fixed with absorbable polyglycolide pins. 1-year follow-up of 8 adults. Acta Orthopaedica Scandinavica. 1993;64:85-86
  105. 105. Paivarinta U, Bostman O, Majola A, Toivonen T, Tormala P, Rokkanen P. Intraosseous cellular response to biodegradable fracture fixation screws made of polyglycolide or polylactide. Archives of Orthopaedic and Trauma Surgery. 1993;112:71-74
  106. 106. von Schroeder HP, Kwan M, Amiel D, Coutts RD. The use of polylactic acid matrix and periosteal grafts for the reconstruction of rabbit knee articular defects. Journal of Biomedical Materials Research. 1991;25:329-339
  107. 107. Klompmaker J, Jansen HW, Veth RP, de Groot JH, Nijenhuis AJ, Pennings AJ. Porous polymer implant for repair of meniscal lesions: A preliminary study in dogs. Biomaterials. 1991;12:810-816
  108. 108. Kreuz PC, Muller S, Ossendorf C, Kaps C, Erggelet C. Treatment of focal degenerative cartilage defects with polymer-based autologous chondrocyte grafts: Four-year clinical results. Arthritis Research & Therapy. 2009;11:R33
  109. 109. Kreuz PC, Muller S, Freymann U, Erggelet C, Niemeyer P, Kaps C, et al. Repair of focal cartilage defects with scaffold-assisted autologous chondrocyte grafts: Clinical and biomechanical results 48 months after transplantation. American Journal of Sports Medicine. 2011;39:1697-1705
  110. 110. Skaalure SC, Chu S, Bryant SJ. An enzyme-sensitive PEG hydrogel based on aggrecan catabolism for cartilage tissue engineering. Advanced Healthcare Materials. 2015;4:420-431
  111. 111. Wang J, Zhang F, Tsang WP, Wan C, Wu C. Fabrication of injectable high strength hydrogel based on 4-arm star PEG for cartilage tissue engineering. Biomaterials. 2017;120:11-21
  112. 112. Liu M, Zeng X, Ma C, Yi H, Ali Z, Mou X, et al. Injectable hydrogels for cartilage and bone tissue engineering. Bone Research. 2017;5:17014
  113. 113. Sharma B, Fermanian S, Gibson M, Unterman S, Herzka DA, Cascio B, et al. Human cartilage repair with a photoreactive adhesive-hydrogel composite. Science Translational Medicine. 2013;5:167ra6
  114. 114. Haleem AM, Chu CR. Advances in tissue engineering techniques for articular cartilage repair. Operative Techniques in Orthopaedics. 2010;20:76-89
  115. 115. Sihvonen R, Paavola M, Malmivaara A, Itala A, Joukainen A, Nurmi H, et al. Arthroscopic partial meniscectomy versus sham surgery for a degenerative meniscal tear. The New England Journal of Medicine. 2013;369:2515-2524
  116. 116. Kirkley A, Birmingham TB, Litchfield RB, Giffin JR, Willits KR, Wong CJ, et al. A randomized trial of arthroscopic surgery for osteoarthritis of the knee. The New England Journal of Medicine. 2008;359:1097-1107
  117. 117. Steadman JR, Rodkey WG, Briggs KK. Microfracture: Its history and experience of the developing surgeon. Cartilage. 2010;1:78-86
  118. 118. Frisbie DD, Morisset S, Ho CP, Rodkey WG, Steadman JR, McIlwraith CW. Effects of calcified cartilage on healing of chondral defects treated with microfracture in horses. American Journal of Sports Medicine. 2006;34:1824-1831
  119. 119. Frisbie DD, Oxford JT, Southwood L, Trotter GW, Rodkey WG, Steadman JR, et al. Early events in cartilage repair after subchondral bone microfracture. Clinical Orthopaedics and Related Research. 2003;407:215-227
  120. 120. Steadman JR, Briggs KK, Rodrigo JJ, Kocher MS, Gill TJ, Rodkey WG. Outcomes of microfracture for traumatic chondral defects of the knee: Average 11-year follow-up. Arthroscopy. 2003;19:477-484
  121. 121. Miller BS, Steadman JR, Briggs KK, Rodrigo JJ, Rodkey WG. Patient satisfaction and outcome after microfracture of the degenerative knee. The Journal of Knee Surgery. 2004;17:13-17
  122. 122. Kreuz PC, Erggelet C, Steinwachs MR, Krause SJ, Lahm A, Niemeyer P, et al. Is microfracture of chondral defects in the knee associated with different results in patients aged 40 years or younger? Arthroscopy. 2006;22:1180-1186
  123. 123. Hangody L, Kish G, Karpati Z, Szerb I, Udvarhelyi I. Arthroscopic autogenous osteochondral mosaicplasty for the treatment of femoral condylar articular defects. A preliminary report. Knee Surgery, Sports Traumatology, Arthroscopy. 1997;5:262-267
  124. 124. Cognault J, Seurat O, Chaussard C, Ionescu S, Saragaglia D. Return to sports after autogenous osteochondral mosaicplasty of the femoral condyles: 25 cases at a mean follow-up of 9 years. Orthopaedics & Traumatology: Surgery & Research. 2015;101:313-317
  125. 125. Solheim E, Hegna J, Inderhaug E. Long-term clinical follow-up of microfracture versus mosaicplasty in articular cartilage defects of medial femoral condyle. The Knee. 2017;24:1402-1407
  126. 126. Solheim E, Hegna J, Strand T, Harlem T, Inderhaug E. Randomized study of long-term (15-17 years) outcome after microfracture versus Mosaicplasty in knee articular cartilage defects. American Journal of Sports Medicine. 2018;46:826-831

Written By

He Huang, Hongyao Xu and Jianying Zhang

Submitted: September 11th, 2018 Reviewed: January 15th, 2019 Published: February 11th, 2019