Repair and tissue engineering techniques for articular cartilage

Abstract

Chondral and osteochondral lesions due to injury or other pathology commonly result in the development of osteoarthritis, eventually leading to progressive total joint destruction. Although current progress suggests that biologic agents can delay the advancement of deterioration, such drugs are incapable of promoting tissue restoration. The limited ability of articular cartilage to regenerate renders joint arthroplasty an unavoidable surgical intervention. This Review describes current, widely used clinical repair techniques for resurfacing articular cartilage defects; short-term and long-term clinical outcomes of these techniques are discussed. Also reviewed is a developmental pipeline of acellular and cellular regenerative products and techniques that could revolutionize joint care over the next decade by promoting the development of functional articular cartilage. Acellular products typically consist of collagen or hyaluronic-acid-based materials, whereas cellular techniques use either primary cells or stem cells, with or without scaffolds. Central to these efforts is the prominent role that tissue engineering has in translating biological technology into clinical products; therefore, concomitant regulatory processes are also discussed.

Figure 1

Cartilage regeneration techniques. a | A full-thickness focal chondral lesion. b | The lesion is debrided to ensure healthy, stable margins for integration of the host tissue with the neotissue. c | Microfracture. Channels are created using a 45° awl, spaced 3–4 mm apart, and 3–4 mm deep to penetrate the subchondral bone, allowing MSCs to migrate from the marrow to the cartilage defect. d | ACI. The debrided lesion is filled with 12–48 million autologous chondrocytes and covered with a periosteal flap or mixed collagen type I and type III membrane. e | MACI. The autologous chondrocyte population is expanded in vitro and then seeded for 3 days onto an absorbable 3D (collagen types I and III or hyaluronic acid) matrix prior to implantation. The cell-seeded scaffold is then secured into the lesion with fibrin glue. Abbreviations: ACI, autologous chondrocyte implantation; MACI, matrix-assisted autologous chondrocyte implantation; MSCs, mesenchymal stem cells.

Figure 2

Algorithm for treatment of cartilage defects. If rehabilitation is not a viable option for a patient with a symptomatic cartilage lesion, the surgeon should assess both the size and location of the defect, determine whether the patient desires a more active (high demand) or sedentary (low demand) lifestyle, and consider if the patient has undergone previous cartilage repair treatments. *Recommended treatment options for a given situation.

Figure 3

New tissue engineering techniques for treating cartilage lesions. a | Technically mimicking ACI, a debrided chondral lesion is filled with bone-marrow-derived or chondroinduced MSCs, not autologous chondrocytes, and covered with a collagen type I/III membrane. b | Intra-articular injection of MSCs with or without injectable matrices is a single-stage procedure. c | AMIC is a cell-free, scaffold-based single surgery. Microfracture releases blood and bone marrow MSCs, then collagen type I/III, hyaluronic acid or fibrin matrix are sutured or glued into the defect. d | MACI uses scaffolds plus either primary articular chondrocytes or bone-marrow-derived MSCs. e | Neotissue can be formed by combining particulated native cartilage with fibrin glue. Limited autodigestion of ECM releases superficial chondrocytes, which then produce additional ECM that integrates the cartilage particles and fills the defect. f | Scaffold-free techniques include a self-assembling process or chondrospheres. Without a scaffold to interrupt cell–cell signalling and stress shielding, cells are able to respond to stimuli and promote integration of neotisssue ECM with the surrounding tissue. Resulting neotissue is thought to be a bioactive microenvironment. Abbreviations: ACI, autologous chondrocyte implantation; AMIC, autologous matrix-induced chondrogenesis; ECM, extracellular matrix; MACI, matrix-induced autologous chondrocyte implantation; MSCs, mesenchymal stem cells.

Figure 4

The tissue engineering paradigm. Cells, signals and scaffolds are the major elements of tissue engineering approaches to cartilage repair. For this purpose, many different cell sources (autologous cells, allogeneic cells or stem cells) have been tested in vitro. Neotissue has been cultured ex vivo with various stimuli and chemicals to enhance synthesis and chondrogenic potential. To further improve the integrity of neotissues, scaffolds have been used to create a 3D environment to maintain the phenotype of, and carry, integrated cells in vivo, and to recruit cells from the host environment. Combinations of these factors drive the three major cartilage engineering strategies that exist: cell-free, scaffold-based implants that promote cell recruitment with chemoattractants; cell-seeded scaffolds that mimic the structure of native tissues; and scaffold-free, cell-based biomimetic techniques. Abbreviations: AMIC, autologous matrix-induced chondrogenesis; ECM, extracellular matrix; GAG, glycosaminoglycans; MACI, matrix-assisted autologous chondrocyte implantation.