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 cells are then differentiated into chondrocytes for therapeutic purposes. While the cells are obtained in a painless, noninvasive fashion, the induction process to form pluripotent cells is not half as efficient; and if fibroblasts mix with the population of chondrocytes, it leads to the formation of scar tissue that interferes with the healing process.
The BMP and TGF-β family of proteins induce the differentiation into chondrocytes. Once the chondrocytes are ready for application, the periostal flap from a different bone site is resected. The cartilage to be healed is closed off with this periosteal flap and the chondrocytes are injected into the gap. The chondrocytes proliferate and mineralize the matrix to completely regenerate the cartilage. While this is an efficient mechanism, there are some cases in which the use of scaffolds are necessary. In using scaffolds, biomimetic osteoinductive biomaterials are used as substrates. The chondrocytes are then applied to the scaffold, which provides a support structure and network for the chondrocytes to proliferate. The scaffolds are then surgically inserted at the site of regeneration.
Some of the polymers that are used in bioengineering of tissue scaffolds are protein based, such as fibrin, collagen, and gelatin. Some carbohydrate-based polymers include hyaluranon, chitason, agarose, and others. Synthetic polymers are also used. A significant advantage of using such scaffolds is that they prevent immunogenic reaction and eliminate the time required for acceptance of the scaffold by the body—a significant decrease in the healing process.
Tendon Regeneration
Tendons are made of cells called tenocytes. Repair of the tendons takes place mainly due to the formation of scar tissue in the adult and it takes about a year or two to mature. The healed tissue contains fibroblast and fibrous tissue that form the scar tissue and that are not essentially the tendon cell type. Therefore, to hasten this process and to make them more robust, tendon wounds are treated through various methods.
As described above, in cartilage regeneration, stem cells that are derived from various sources are used. The cells then differentiate into tenocytes in vitro. With BMP-12, which is a subclass in the family of BMP proteins, the stem cells differentiate into tenocytes. BMP12 is transferred into the cells by using gene therapy, and this triggers the differentiation using the pluripotency network. The tenocytes are applied to the site of the wound directly where the wound environment provides
