The knee meniscus: structure-function, pathophysiology, current repair techniques, and prospects for regeneration

Abstract

Extensive scientific investigations in recent decades have established the anatomical, biomechanical, and functional importance that the meniscus holds within the knee joint. As a vital part of the joint, it acts to prevent the deterioration and degeneration of articular cartilage, and the onset and development of osteoarthritis. For this reason, research into meniscus repair has been the recipient of particular interest from the orthopedic and bioengineering communities. Current repair techniques are only effective in treating lesions located in the peripheral vascularized region of the meniscus. Healing lesions found in the inner avascular region, which functions under a highly demanding mechanical environment, is considered to be a significant challenge. An adequate treatment approach has yet to be established, though many attempts have been undertaken. The current primary method for treatment is partial meniscectomy, which commonly results in the progressive development of osteoarthritis. This drawback has shifted research interest toward the fields of biomaterials and bioengineering, where it is hoped that meniscal deterioration can be tackled with the help of tissue engineering. So far, different approaches and strategies have contributed to the in vitro generation of meniscus constructs, which are capable of restoring meniscal lesions to some extent, both functionally as well as anatomically. The selection of the appropriate cell source (autologous, allogeneic, or xenogeneic cells, or stem cells) is undoubtedly regarded as key to successful meniscal tissue engineering. Furthermore, a large variation of scaffolds for tissue engineering have been proposed and produced in experimental and clinical studies, although a few problems with these (e.g., byproducts of degradation, stress shielding) have shifted research interest toward new strategies (e.g., scaffoldless approaches, self-assembly). A large number of different chemical (e.g., TGF-β1, C-ABC) and mechanical stimuli (e.g., direct compression, hydrostatic pressure) have also been investigated, both in terms of encouraging functional tissue formation, as well as in differentiating stem cells. Even though the problems accompanying meniscus tissue engineering research are considerable, we are undoubtedly in the dawn of a new era, whereby recent advances in biology, engineering, and medicine are leading to the successful treatment of meniscal lesions.

Figure 1. Anatomy of the knee joint: anterior view

The knee meniscus is situated between the femur and the tibia. Crossing the meniscus are various ligaments, which aid in stabilizing the knee joint.

Figure 2. Anatomy of the meniscus: superior view of the tibial plateau

This view of the tibial plateau highlights the ligaments of Humphrey and Wrisberg, which attach the meniscus to the femur. The menisci are attached to each other via the transverse ligament. The horn attachments connect the tibial plateau to the meniscus.

Figure 3. Regional variations in vascularization and cell populations of the meniscus

Left: Though fully vascularized at birth, the blood vessels in the meniscus recede during maturity. In adulthood, the red-red region contains the overwhelming majority of blood vessels. Right: Cells in the outer, vascularized section of the meniscus (red-red region) are spindle-shaped, display cell processes, and are more fibroblast-like in appearance, while cells in the middle section (white-red region) and inner section (white-white region) are more chondrocyte-like, though they are phenotypically distinct from chondrocytes. Cells in the superficial layer of the meniscus are small and round.

Figure 4. How force is transduced upon and throughout the knee meniscus

Free body diagram of the forces acting on the knee meniscus during loading (for simplicity, only the lateral meniscus is shown). During everyday activity, the menisci are compressed by the downward force of the femur. Since the meniscus is a wedge, the femoral force is enacted at an angle, and thus a vertical component exists which is countered by the upward force of the tibia. Additionally, a horizontal component of the femoral force exists, which is exerted radially outward on each meniscus. This horizontal force is in turn countered by the anchoring force of the attachments at the posterior and anterior horns of the meniscus. Additionally, as this compression occurs, circumferential stress is created along the meniscus. Therefore, the menisci function by converting compressive loads to circumferential tensile loads. At the same time, shear forces are developed between the collagen fibers within the meniscus while the meniscus is deformed radially.

Figure 5. The classical, scaffold-based approach for meniscus tissue engineering

Generation of a functional meniscus requires several key considerations. Characterization of the meniscus is essential for establishing design parameters. Following this, judicious choice of cell type(s), scaffold material(s), and exogenous stimuli must be made. Implantation in vivo may be substituted for, or performed subsequent to, bioreactor culture. Using these tools, tissue engineering aims to regenerate or replace the meniscus.

Figure 6. The strategy of tissue self-assembly for meniscus tissue engineering

This approach utilizes a hydrogel mold to form completely biologic tissue constructs. Selection of cells is of paramount importance. Following isolation from allogeneic or xenogeneic sources, articular chondrocytes (ACs) and meniscus cells (MCs) are expanded to achieve the high numbers needed for robust tissue engineering. Mesenchymal stem cells, but also potentially embryonic stem cells, are a promising alternative cell source for subsequent differentiation into meniscus cells. Cells are then seeded in high density in a non-adherent biomaterial mold, secreting ECM that coalesces into a continuous tissue over several days. Exogenous stimuli are added during culture to increase the synthetic activity and functional properties of neotissue, which is eventually implanted in vivo.