Autologous Cell-derived Tissue Engineered Cartilage for Repairing Articular Cartilage Lesions: a Protocol for a Prospective, Randomized, Controlled Clinical Trial

Injured articular cartilage has limited capacity for self repair. Without timely, early and effective treatment, damage to the articular cartilage progressively worsens, resulting in joint swelling, pain and dysfunction. The patient ultimately develops osteoarthritis and will be required to undergo artificial joint replacement. Clinical therapy for cartilage damage includes microfracture surgery and autologous osteochondral transplantation. However, the microfracture technique is limited to small-scale damage, and autologous osteochondral transplantation is hindered by limited supply. With advances in material science, cell biology, biomechanics and bioreactor technology, the new generation of biomimetic tissue engineered osteochondral composites display great potential for the repair of cartilage damage.

Currently, in cartilage tissue engineering, seed cells are derived from autologous or allogeneic chondrocytes, mesenchymal stem cells, embryonic stem cells or pluripotent stem cells. Increasing evidence indicates that bone marrow mesenchymal stem cells can be induced to differentiate into chondrocytes, and these cells have been successfully used in the treatment of large-size bone defects, cartilage lesions and spinal cord injury. The quality and quantity of bone mesenchymal stem cells gradually decrease with age, especially in patients with degenerative diseases. Adipose stem cells and umbilical cord mesenchymal stem cells are abundant and have similar characteristics to bone mesenchymal stem cells, and both of these cell types can be induced to differentiate into chondrocytes. Adipose stem cells and umbilical cord mesenchymal stem cells have been used to repair cartilage defects, but the findings are still preliminary, and these cells cannot be harvested or cultured in large quantities. Furthermore, the use of embryonic stem cells is complicated by ethical considerations. As a consequence, autologous chondrocytes are optimal seed cells for cartilage tissue engineering.

The transplantation of autologous chondrocytes in combination with tissue engineered cartilage scaffolds to repair cartilage damage requires researchers to focus on two major issues, namely, (i) the in vitro amplification of chondrocytes and (ii) the preparation of biocompatible chondrocyte scaffolds. The preparation of chondrocyte scaffolds requires advanced technique, and currently, only the Institute of Orthopedics at the Chinese PLA General Hospital has the capacity to produce acellular cartilage; there is no other source of tissue engineered cartilage scaffolds in China.

A proprietary allogeneic acellular cartilage-oriented scaffold was successfully created by the Cartilage Tissue Engineering Research Group, Institute of Orthopedics, Chinese PLA General Hospital (with intellectual property rights). The innovative scaffold simulates the composition and spatial structural characteristics of normal cartilage. The preparation methods are as follows: articular cartilage is pulverized to obtain natural cartilage extracellular matrix, which is identical in biochemical composition to extracellular matrix of natural articular cartilage. Then, a porous sponge-like scaffold is prepared using the freeze-drying technique. In vitro experiments and large-animal articular cartilage injury repair experiments have produced good results. Using this material, our research group prepared biomimetic cartilage tissue engineered scaffolds, which mimic the structural characteristics of natural articular cartilage extracellular matrix. This allogeneic acellular cartilage scaffold has the following characteristics: (1) it is derived from allogeneic cartilage, and the extracellular matrix remains intact after allografting, helping to maintain the numerous components of normal cartilage, particularly type II collagen and proteoglycans, resulting in enhanced repair. Cartilage scaffolds used outside of China are mainly composed of types I and III collagen or hyaluronic acid, and vary greatly from natural cartilage components. The original cartilage structure is difficult to reproduce with these types of scaffolds, and fibrous cartilage may affect treatment outcome. (2) The biomimetic scaffold has a similar three-dimensional structure to that of normal articular cartilage, which is the oriented scaffold structure. The scaffold imitates the orientation of normal cartilage cells, which are arranged perpendicular to the surface, and provides a paratactic columnar structure that contributes to the columnar arrangement of cells. This structure in combination with type II collagen and proteoglycans derived from normal articular cartilage results in a scaffold structure that is extremely close to that of normal joint cartilage. Consequently, the repaired cartilage will have normal structure and function. (3) The oriented scaffold has a good biomechanical property. Its compressive stress is better than the non-oriented scaffold in wet and dry conditions. (4) The oriented scaffold has good biocompatibility. Preliminary experiments have investigated the immune responses of the oriented scaffold of heterogeneous (porcine) and conspecific (rabbit) acellular cartilage. After the oriented scaffold was implanted into the rabbit, its immune responses were observed from the aspects of cellular immunity and humoral immunity. Results suggested that its immunogenicity was low. Thus, it is verified that the oriented scaffold of acellular cartilage has good biocompatibility.

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