Two essential prerequisites to aid this process are angiogenesis (the development of a viable blood circulation) and the establishment of cellular communication among the three resident cell populations: the fibroblasts, fibrochondrocytes, and osteoblasts. Angiogenesis and cellular communication are absolutely vital to achieving homeostasis under in vivo conditions. It is proposed that multiphasic scaffolds for ACL-to-bone integration may be fabricated as a cylinder that can be inserted directly into the bone tunnels for smooth interface formation. For rotator cuff repair of the shoulder, scaffold patches could be surgically sutured to the tendon to facilitate repair and bridge the gap between the tendon and bone.
The structure of an interface is naturally organized to reduce stress and optimize load bearing at the joint. The angle of attachment and the gross shape of the insertion are critical factors in preventing stress at the interface, and reducing the angle has been shown to aid the process. Interlocking of the tissues by interdigitation increases the strength and toughness of the graft. The orientation/alignment of the collagen fibers and mineral deposition has also been shown to be critical for functional repair of the interface. The transition between the unmineralized and mineralized tissues at the graded interface is particularly challenging and is key to attaining the mechanical properties of the interface.
Another requirement for a functionally graded transition between tendon and bone is physiologic muscle loading. Experiments have shown that reduction in muscle loading impaired mineralization and fibrocartilage formation, leading to disorganized fiber distribution and inferior mechanical properties at the interface. It becomes imperative to achieve a fine balance between excessive loads, which can cause microdamage, and insufficient loads so that healing is faster.
Tissue engineering brings with it several ethical, medical, and regulatory issues that will need to be addressed for clinical progress to continue. Considerable success has been achieved in animal models and the results have to be replicated in human subjects. A clinical trial enrolled six subjects for mesenchymal stem cell injections in an attempt at resurfacing of the articular cartilage in osteoarthritis. The results are not known, even though the study is over. Similar clinical trials for evaluation of a resorbable PLLA implant for regeneration of the ACL interface, bone marrow stem cells on protein scaffolds to heal the articular cartilage of the knee, and the impact of platelet-rich plasma on healing of rotator cuffs are in various stages of study.
Research inputs ranging from the ideal scaffold material (material science), growth factors (biochemistry), in vivo transition for structural (histology) and functional integration (biophysics) will have to be effectively incorporated for successful tissue regeneration. It follows that techniques for sterilization and long-term storage of stratified scaffolds will also need to be developed. The strategy for soft tissue and integrative orthopedic repair through tissue regeneration and implantation thus has wide-ranging implications.
Ruby A. Singh
Independent Scholar
See Also: Cartilage, Tendons, and Ligaments: Current Research on Isolation or Production of Therapeutic Cells; Cartilage, Tendons, and Ligaments: Existing or Potential Regenerative Medicine Strategies; Cartilage, Tendons, and Ligaments: Stem and Progenitor Cells in Adults; Mesenchymal: Current Research on Isolation or Production of Therapeutic Cells.
Further Readings
Dormer, Nathan H., Cory J. Berkland, and Michael S. Detamore. “Emerging Techniques in Stratified Designs and Continuous Gradients for Tissue Engineering of Interfaces.” Annals of Biomedical Engineering, v.38 (2010).
Erisken, Cevat, Xin Zhang, Kristen L. Moffat, William N. Levine, and Helen H. Lu. “Scaffold Fiber Diameter Regulates Human Tendon Fibroblast Growth and Differentiation.” Tissue Engineering, v.19 (2013).
Lu, Helen H. and Stavros Thomopoulos. “Functional Attachment of Soft Tissue to Bone: Development, Healing, and Tissue Engineering.” Annual Review of Biomedical Engineering, v.15 (2013).
Subramony, Siddarth D., Booth R. Dargis, Mario Castillo, Evren U. Azeloglu, Michael S. Tracey, Amanda Su, and Helen H. Lu. “The Guidance of Stem Cell Differentiation by Substrate Alignment and Mechanical Stimulation.” Biomaterials, v.34 (2013).
Cartilage, Tendons, and Ligaments: Existing or Potential Regenerative Medicine Strategies
Cartilage, Tendons, and Ligaments: Existing or Potential Regenerative Medicine Strategies
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Cartilage, Tendons, and Ligaments: Existing or Potential Regenerative Medicine Strategies
Cartilage is a flexible connective tissue that is attached to the bone. The cartilage is more flexible than the bone but less flexible than the muscle. Presence of cartilage in the joints increases the flexibility of the joints and also increases their load-bearing ability. They have enormous mechanical ability, as the cartilage tissue is pliable. It is made up of cells called tenocytes. Cartilage is different from bone in that cartilage does not contain vasculature and it receives blood by diffusion. This makes the regeneration process slower, necessitating cell replacement and regeneration therapy.
Tendons and ligaments are also connective tissue. Tendons connect the muscle to the bone, and the ligaments connect bone to other bone segments. Tendons and ligaments serve to hold the support structure in place; in addition, they provide flexibility.
Cartilage Regeneration
Osteoarthritis is a degenerative disease that is a result of cartilage destruction and is widespread in the United States. As mentioned above, cartilage has a limited potential to self-renew as it is not supplied with blood vessels like other connective tissues. Cartilage is a more flexible connective tissue that is made up of cells called chondrocytes. Current treatment options for cartilage regeneration are autologous grafting, in which cartilage from the patient is grafted from other sites for wound-healing purposes.
The cartilages are usually surgically removed from sites of minimal load bearing. The isolated cartilage tissue is then expanded ex vivo to be applied to the site of the wound. The chondrocytes that are part of this graft mixture proliferate and they regenerate the cartilage. One of the famous applications of this technology is the knee replacement technology whereby the cartilage in the knee is replaced.
As in bone regeneration, stem cells can be used for the regeneration of cartilage tissue as well, the major difference being induction to produce chrondrocytes. The stem cells can be pluripotent stem cells that are isolated from embryonic tissue. Major concerns about this involve ethics as well as their tumorigenicity and immunogenicity. In order to avoid issues of immunogenicity, it is best to derive stem cells from the patients themselves. Some of the major sources of these stem cells are bone marrow, adipose tissue, and the synovial membrane. The bone marrow consists of a heterogeneous population of pluripotent hematopoietic stem cells, which can be induced to form chondrocytes. Similarly, pluripotent stem cells can be isolated from adipose tissue by liposuction.
The lipo aspirate contains a higher yield of pluripotent stem cells that have the capacity to differentiate into chondrocytes. This process is much faster and the concentration of the cells is much higher; it is also noninvasive and less painful. However, the quality of the stem cells and their ability to self-renew is not as robust as those from the synovial membrane. Similarly, synovial tissue also contains stem cells that can be aspirated and it is thought to be the best source for stem cells. Although it is the best source as the concentration for the cells is much higher, however, synovial tissue has tumorigenicity potential. The stem cells are then grown in vitro, whereby the population is expanded to obtain a sufficient number of cells for the therapy.
Induced pluripotent cells are also a method by which the cells can be differentiated into chondrocytes. This is a technology in which the cells that are terminally differentiated are isolated from the body. In these cells, pluripotency is induced in vitro and maintained in this state until a significant cell count is reached. The induced pluripotent