Injection of growth factors
To skip the inflammatory phase and begin proliferation, primary growth factors, either singly or in various combinations, may be used for injection. Blood is a source of already produced common growth factors such as insulin-like growth factor 1 (IGF-1), platelet-derived growth factor (PDGF), and transforming growth factor (TGF). Taylor et al demonstrated that even normal ligaments can grow stronger with exposure to injected blood. A single injection of 0.15 ml of blood into the patellar tendon of rabbits resulted in a significantly stronger tendon (p < 0.014) with microscopic examination showing completely normal cells.14 Injection of the patient's own blood has been studied for treatment of tennis elbow in humans by Edwards et al. In that study, average pain levels improved from 7.8 to 2.3 on a 10-point visual analog scale after just one injection of the patients' own blood. Also, 23 of 28 patients with chronic symptoms not responsive to all usual treatments had no pain with vigorous activity after one to three injections.15
Single or multiple growth factors can also be produced en masse in the laboratory by genetic means and then injected. Forslund demonstrated the potential of a single injection of a growth factor on ligament/tendon tissue when he injected chondrocyte-derived morphogenetic protein-1 (CDMP-1) into rats' Achilles-equivalent tendon within hours of injury. By eight days postinjection, CDMP-1 injected tendons were 39% stronger than noninjected tendons. (P < 0.0002).16 Direct injection of growth factors in human ligaments have not been reported to this point but studies are under way.
Thus far, cartilage repair through the use of growth factor injection has been reported only in animals. Young (maturing) rats developed a thicker knee cartilage when injected just once during knee development with bFGF (basic fibroblast growth factor).17 Also, full thickness holes (3 to 4 mm) in rabbit knee cartilage have been shown to heal after injection of HGF (hepatocyte growth factor).18 Injection without inflammation
Dextrose in concentrations greater than 10% causes a reliable temporary inflammatory process, as evidenced by the need to put IV lines into bigger veins for hospital patients receiving concentrated dextrose. However, if dextrose concentration is kept at 10% or less, the osmotic pressure on surrounding cells does not exceed the cells' ability to compensate and inflammation does not occur.
A normal human cell contains only 0.1% dextrose. Upon culturing human cells in glucose concentrations, it has been found that an environment with as little as 0.6% glucose causes virtually all the main growth factors for cartilage, ligament, and tendon-not bone-to elevate within minutes to hours.19,20 In addition to elevating growth factors for cartilage, some research indicates that elevating dextrose concentration in a joint reduces cartilage-damaging protein (collagenase) levels.21
Why not just take dextrose orally? The stomach is designed to handle high dextrose loads without such growth reactions. Sustained high dextrose loads are not delivered to tissues except in patients with diabetes, for whom control of blood sugar is altered. It has been recognized that patients with diabetes develop extra blood vessels in their eyes, and extra cells in their kidneys and blood vessels. To bypass the stomach and place the dextrose in high concentration where it is therapeutically needed, injection is required.
Two double-blinded placebo-controlled clinical trials of 10% dextrose injection in arthritic joints have been conducted and involved both large and small human joints. One such study demonstrated that in 111 arthritic knees with a pretreatment average of only 2 mm of residual cartilage (35 knees had no residual cartilage in the medial compartment), small-needle injection of only 9 ml of 10% dextrose at zero, two, and four months led to improvements in pain and function significantly better than those achieved in the control group.19 Improvements in walking pain, swelling, and buckling are shown in Figure 1. In addition, range of motion in the dextrose-treated knees improved by 13.2 degrees . A second double-blinded study involved injecting moderate to severely arthritic fingers (150 joints in 27 patients). With injection of 0.5 ml of 10% dextrose in each joint at zero, two, and four months, subjects injected with dextrose demonstrated significantly better grip pain (p = 0.027) and flexion range of motion (p = 0.003) than control patients injected with the same bacteriostatic water/dilute lidocaine solution without dextrose (Figure 2).20 Injection of a solution that produces inflammation
The use of nonsteroidal anti-inflammatory drugs has been popular for decades. However, the potential folly of preventing natural inflammation after injury was pointed out by Elder, who demonstrated that administering anti-inflammatory medication after an acute injury to the medial collateral ligament of the knee in rats led to a 32% weaker ligament after healing.22 In contrast, nearly 20 years earlier, Liu in 1983 confirmed the ability of an inflammatory solution (sodium morrhuate) to thicken and strengthen normal medial collateral ligament in the rat and measured a 47% increase in medial collateral ligament mass after inflammatory solution injection.23
Chronic inflammation interferes with healing, but temporary inflammation facilitates healing. Injecting relatively high (greater than 10%) concentrations of dextrose, or any of a variety of other solutions such as dilute phenol, causes temporary inflammation. Nearly 50 years ago Hackett demonstrated that temporary inflammation not only thickens ligaments and tendons, but it also creates a bigger connection to bone.12 Hackett used an inflammatory solution called Sylnasol, which is not currently available.
Four double-blinded studies have been conducted to investigate inflammatory injection in chronic low back and leg pain (Figure 3). Unfortunately, the low back has a complicated ligament/tendon structure and proportionally complex referral patterns. These four studies were well blinded, but did not have a true placebo control, since needling itself would be expected to result in microbleeding with release of natural growth factors from blood. Nevertheless, the two researchers who used complete injection for ligaments responsible for both back and leg pain found that including the inflammatory proliferant (phenol 1.25%, dextrose 12.5%, glycerine 12.5%) was significantly (p < 0.00124) or nearly significantly ( p = 0.05625) better than needling alone. In each study, six- to 12-month follow-up revealed an impressive 60% sustained reduction in pain and a comparable reduction in disability ratings. Yelland26 published a study showing sustainable benefit in both dextrose and control (saline) groups consistent with a therapeutic benefit from needling alone. However, his study was hampered by an incomplete injection method that did not introduce proliferant in key areas such as facet ligaments, multifidi, or, for the first four treatments, the deep SI ligament. Dechow27 published strikingly different results, which in retrospect was largely because patients were selected by a rheumatologist who excluded patients with leg pain. Patients were then injected by a different physician who was instructed to inject only certain areas without being allowed to examine the patients. These areas were those that would refer leg pain, not primarily back pain; the treating physician used leg-pain specific injection for patients without leg pain.
These low back pain studies therefore suggest that it is critical for the injecting physician to examine the patient, be familiar with referral patterns for ligaments and tendons, and to inject all sources of pain. It will also be important to consider that degenerative disks can themselves be sources of low back and leg pain. Indeed, Klein et al25 reported on lumbar intervertebral disk injection with an inflammatory solution (glucosamine + chondroitin sulfate + dextrose + dimethyl sulfoxide) in patients whose pain was reproduced by disk injection (discogram). They found that 57% of patients improved markedly after disk injection, achieving 72% improvement in disability scores and 76% in pain scores. A positive discogram did not perfectly predict who would and would not respond, and further research is indicated. A study on simple dextrose injection for pain from disk origin is nearing completion at this time. For sprain and strain to heal, tendons or ligaments need to both thicken and tighten, since they are both thinned and stretched when injured. To demonstrate the ability of simple dextrose injection to tighten loose ligament, a study was conducted on 16 consecutive patients with laxity of the ACL ligament as measured by a KT-1000 arthrometer.28 Ten percent to 25% dextrose was used in this study, depending on patient tolerance. Injection of 6 to 9 ml of dextrose solution (depending on comfort level with injection) using an inferomedial approach was performed every two months for a year, and then on an as-needed basis for knee pain. Fourteen out of 16 patients had moderate to severe knee osteoarthritis at study onset in addition to measured ACL laxity. At three years post study commencement, patients on average experienced a 44% improvement in pain, a 64% improvement in swelling, and a 72% improvement in looseness (KT1000 side-to-side difference) (Figure 4). Rather than losing range of motion over time, these patients experienced an average improvement in flexion range of motion of 10.5 degrees . For a condition typically associated with declining function, (either moderate to severe osteoarthritis or ACL laxity), these results are encouraging.