Because cartilage has no vascular supply, it lacks the rich source of progenitor cells and growth factors needed for tissue regeneration. Unless a defect is quite small, in which case it can self-repair, cartilage-forming cells must be provided in bulk, and must be delivered in a manner that assures full integration with surrounding tissue.
Several strategies have been used to grow new cartilage in damaged knee joints. One method on the market involves isolating a patient's cartilage cells (chondrocytes), stimulating them to reproduce in the laboratory, and injecting them back into the patient's damaged joint. The limited supply of chondrocytes re-stricts this procedure to small cartilage defects rather than resurfacing entire joints.
Other pioneers in the bioengineering field are making headway in overcoming the shortage of patient cartilage cells by seeding chondrocytes into polylactic-polyglycolic acid templates that have been shaped to fit large defects. This method has been used to grow the replica of a human ear on the back of a mouse and make a rib cage for a young boy born with part of his chest missing. Similar experiments are in the works to develop a cosmetic breast, and to shore up weakened urinary passages.
One NIDCR grantee is experimenting with the more available bone marrow stromal cells to repair damaged joints. These cells can be readily replicated in the laboratory, and when added to a collagen carrier gel and placed into a cartilage defect, they proceed to differentiate into both cartilage and bone. This is a particularly advantageous feature for treating "full-thickness" joint defects where both the surface cartilage and underlying bone are affected. Like chondrocytes, stromal cells also look like a promising source for growing pre-shaped cartilage scaffolds in the laboratory prior to placing them in the patient. By incorporating the growth factor TGF-beta 1, the NIDCR grantees were able to direct the bone marrow stromal cells into a strictly cartilage-forming mode.
Another advance by NIDCR scientists has added an additional weapon to the cartilage bioengineering arsenal. Intramural scientists discovered a group of proteins closely related to the BMPs. Designated cartilage derived morphogenetic proteins (CDMPs), these compounds differ from the BMPs in two very important aspects -- they appear to play a prominent role in the development of certain joints and they induce the formation of cartilage that only very slowly progresses to bone. These features make the CDMPs a promising component of a biomimetic system for replacing damaged joint cartilage. NIDCR has patented two of these morphogens, CDMP-1 and CDMP-2, and licensed them to the private sector for clinical development. Oral health researchers are also interested in possible application to TMJ disorders.
Temporomandibular disorders (TMD) can also result from trauma to the masticatory muscles that operate the jaw. Most skeletal muscle has an innate capacity to regenerate after injury. Muscle-forming cells (myoblasts) can migrate from healthy muscle fibers to a damaged site where they initiate repair. However, an NIDCR grantee has discovered that not all skeletal muscle is equal in this ability. A study of the jaw's masseter muscle found fewer myoblasts relative to limb muscle and revealed that these myoblasts grew more slowly in culture than their limb counterparts. The inability of masseter muscle to regenerate as effectively as limb muscle may underlie the link between muscle trauma and TMD.
Tissue engineering procedures are being explored for another muscle tissue that lacks the ability to recoup from injury, and may likewise be applicable to masticatory muscles. Cardiac muscle of the heart dies after injury, with no ability to regenerate. A study in rabbits restored function to damaged heart muscle by transplanting myoblasts from leg muscle. Another group of researchers has taken a different approach to repairing muscle and enhancing muscle strength. The investigators used a viral vector to introduce the protein, insulin-like growth factor-1 (IGF-1) into the leg muscles of aging mice. Muscle cells started producing high levels of IGF-1, which stimulated satellite cells (muscle stem cells) to become myoblasts and ultimately produce new muscle. NIDCR investigators are evaluating which growth factors increase the proliferative ability of masseter muscle satellite cells and are also exploring gene therapeutics as a means of regulating growth factors in ways that enhance muscle regeneration.
Another type of "muscle", the marine mussel Mytilus edulis, has yielded the secrets of its super-tough tendon -- information that may someday have human bioengineering applications. The mussel uses its tendon, or byssus, to anchor itself to solid surfaces under the harshest of marine environments. NIDCR grantees have identified the protein structure of this remarkable thread-like appendage. The byssal threads contain the first known protein to have both a solid, collagenous region and stretchy, elastin-like regions. The elastin regions resemble both spider silk and the human elastin protein that gives skin and arteries their pliability. This unique structure of the byssal protein provides the toughness and exibility that could prove invaluable in the design of artificial skin or tendons.
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