Excerpt: (IGF info in bold below)
Manipulating Growth Factors
Growth factors are proteins that stimulate cell proliferation and differentiation. Some growth factors can cause normal uninjured tendon fibroblasts to proliferate and synthesize more collagen and proteoglycans. Since growth factors play an important role in tissue healing, researchers have wondered if they could be used to improve the healing of tendons and ligaments.
Research into growth factor treatments is difficult because the effects of growth factors can be very different in vivo than in vitro and because fibroblast cells injured by repetitive motion can react differently to growth factors than normal cells. [1] In a study of carpal tunnel syndrome, wrist ligament cells from injured and uninjured people were exposed to four growth factors, including transforming growth factor beta (TGF-beta).[1] The cells from the injured patients produced abnormally high amounts of Type III collagen and low amounts of Type I collagen when exposed to the growth factors, as compared to the controls. The cells in the injured patients seemed to have been altered by the injury so that their response to growth factors was different. Therefore, studies that use growth factors to improve healing of acute tendon injuries might not apply to healing of tendinosis injuries.
Nevertheless, growth factors are worth studying to determine their potential for treating acute tendon and ligament injuries and to see if any of the growth factors have positive effects on repetitive motion injuries as well. If growth factor treatments don't seem to produce a good response from cells injured by repetitive motion, stem cell treatment could be combined with growth factor treatment; the stem cells would provide normal uninjured cells for the growth factors to stimulate, and the growth factors could stimulate them to produce healthy tendon/ligament collagen. See the previous section "Local Injection of Stem Cells" for more information about stem cells.
Another obstacle with growth factor therapy is that a fine line could exist between too little and too much of the growth factor; too little could cause inability to heal and too much could cause abnormal healing, scar formation, or other negative effects. When wounds and acute injuries heal normally, the body provides the correct balance of growth factors at the correct time in sequence as healing progresses from one stage to the next. More research is needed to investigate whether we can control the timing and the amount of added growth factors well enough to optimize healing. Researchers will need to investigate how the effects of various growth factors depend on the dose, the injury site, the stage in the healing process, and the interactions with other growth factors.
Various delivery methods for growth factors have been tried. Growth factors can be injected directly into the site of injury, but they tend to break down quickly. Researchers have had difficulty maintaining constant enough levels with the injection method. Other researchers have tried implanting controlled-release polymer matrices or microspheres into the injury site to slowly release growth factors into the tissue; these methods could be appropriate for some acute injuries, but a non-surgical method is better for tendinosis. Many researchers are now looking toward gene therapy delivery methods as being the most promising way to use growth factors to improve healing of injuries. See the section below on "Gene Therapy."
The following list of growth factors describes some of the studies that have been done to determine whether these substances can be used to help improve the healing of tendon and ligament injuries.
IGF-1
Insulin-like growth factor 1, or IGF-1, is a growth factor that is important for tissue healing. It can stimulate an increase in Type I collagen when added to normal fibroblasts.
One study showed that tenocytes from healthy equine tendon made more Type I collagen relative to Type III collagen when treated with IFG-1 in vitro.[31] The tendon samples had "greater numbers of larger and more metabolically active fibroblasts," and IGF-1 enhanced collagen synthesis in a dose dependant manner. The authors suggest that IGF-1 might help treat horses with tendinosis. A growth factor that helps promote Type I collagen relative to Type III collagen in tendon is certainly worth more study for its potential use in treating tendinosis.
Several other studies showed that a combination of IGF-1 and platlet-derived growth factor increased the rupture force, stiffness, and breaking energy in rat medial collateral ligaments.[32,33] Also, one study showed that treating injured rat Achilles tendons with IGF-1 reduced the "maximal functional deficit" and the "time to functional recovery."[34] Another study showed that IGF-1 and IGF-II stimulated collagen, proteoglycan, and DNA synthesis in a dose-dependent manner in rabbit flexor tendon in vitro.[35]
IGF-1 was not one of the growth factors tried in the previously mentioned carpal tunnel syndrome study[1], so it would be interesting to discover its effect on cells from tendinosis patients.
GDF-5
Growth and differentiation factor 5, or GDF-5, has been linked to tendon healing in several studies. One study showed that the tensile strength of healing rat tendons increased in a dose-dependent manner when treated with GDF-5.[36] Another study showed that GDF-5 deficiency caused mouse tail tendon to have a 17% increase in the proportion of medium diameter collagen fibrils at the expense of larger diameter fibrils, as well as a 33% increase in irregularly-shaped polymorphic fibrils.[37] These structural differences did not cause major differences in biomechanical properties of the tendon, but did cause the fibers to relax 11% more slowly than controls during time-dependent stress/relaxation tests. More research would be needed to see if GDF-5 could play a role in the treatment of tendinosis.
CDMP-2
One research group has investigated the potential for treating tendon injuries with cartilage derived morphogenetic protein, or CDMP-2.[25] This protein is a member of the TGF-beta super family. The researchers treated injured rat Achilles tendons with injections of CDMP-2 and found that the treated tendons were 39% stronger than controls after 8 days. The tendons were also mechanically loaded during healing because the researchers suspected that loading would help the CDMP-2 induce tendon-like tissue instead of bone or cartilage tissue. (The abstract didn't say if the control tendons were also mechanically loaded; if not, the improved healing could be from the loading rather than from the CDMP-2. Presumably, they loaded both the controls and the treated injuries.)
TGF-beta1
Transforming growth factor beta1, or TGF-beta1, is a growth factor important in wound and tissue healing. It has been associated with excessive scar tissue formation in some cases. A group of researchers studied the effect of reducing TGF-beta1 because they were looking for a way to reduce the adhesions and scar tissue that commonly form between the site of injured hand flexor tendon and the surrounding tissues.[26,27] These adhesions reduce normal range of motion. Injured rabbit flexor tendons treated with neutralizing antibody to TGF-beta1 had approximately twice as much range of motion as the controls after 8 weeks of healing. This research might not have direct implications for treating tendinosis, but it does show that sometimes lowering growth factors can lead to better healing; more is not always better when it comes to growth factors.
BMP-12
Bone morphogenic protein 12, or BMP-12, has been shown to improve tendon healing; researchers found that in vivo gene therapy delivery of BMP-12 caused a two-fold increase in tissue strength and stiffness of healing chicken tendons.[38] See the section below "Gene Therapy."
