In addition to the capsule and menisci, the stability, strength, and movement of the knee depend on 4 ligaments: 2 intracapsular ligaments (ACL and PCL) and 2 extracapsular ligaments (MCL and LCL). These ligaments are the most important passive stabilizers of the joint. They maintain smooth joint motion and guide the movement of the femur and tibia as they move through flexion and extension. They play a critical role in guiding the kinematics of movement and preventing excessive joint motion, which can damage the articular cartilage, menisci, and other soft tissue structures [ 8].

The extracapsular collateral ligaments of the knee provide stability to the medial and lateral sides of the joint. The medial collateral ligament (MCL) is a strong, flat band that extends from the medial condyle of the femur to the medial condyle of the tibia, with some deep fibers attaching to the medial meniscus. It provides medial stability against valgus stress, forces that would push the knee joint inward (knock-kneed stance). The lateral collateral ligament (LCL) is a rounded cord that runs from the lateral condyle of the femur to the head of the fibula. It provides lateral restraint against varus stress, forces that would push the knee joint outward (bow-legged stance). Both the MCL and LCL also prevent anterior translation of the tibia on the femur, prevent lateral rotation of the tibia on the femur, and work with the anterior cruciate ligament to provide restraint to axial rotation. Any ligament injury of the knee can lead to one of the many types of instabilities in the knee (Fig. 3).

Fig. (3). Instabilities about the knee. Abbreviations: ACL = anterior cruciate ligament; ITB = iliotibial band; LCL = lateral collateral ligament; PT = popliteal tendon; LG = lateral gastrocnemius; PCL = posterior cruciate ligament; MG medial gastrocnemius; ST = semitendinosus; SM = semimembranosus; G = gracilis; S = sartorius; MCL = medial collateral ligament. Modified from Magee DJ. Orthopedic Physical Assessment. 6th Edition. St Louis, 2014, Elsevier Saunders, p. 811.

Fig. (4). Knee ligaments. ( A). Lateral view. ( B). Medial view. ( C). Anterior view. ( D). Posterior view. ( E). Superior view.

Fig. (5). Any tension on the quadriceps muscle/tendon directs forces to extend the knee and stabilize the patellofemoral joint.

The anterior cruciate ligament (ACL) and the posterior cruciate ligament (PCL) form a crisscross in the center of the joint. The ACL runs from the anterior to the intercondylar eminence of the tibia to the posterior medial surface of the lateral condyle of the femur. The PCL runs from just posterior to the intercondylar eminence of the tibia to the anterior portion of the medial surface of the medial condyle of the femur (Fig. 4). The ACL and PCL are different from ligaments of other joints because they restrict normal, rather than abnormal, motion. The ACL is one of the most important contributors to the knee’s stability. It provides 85% of the restraint against the anterior translational force of the tibia relative to the femur when the knee is flexed 90°. It also acts as a secondary restraint to both internal and external rotations in the non-weight-bearing knee. Along with the resistance of the posterior muscles crossing the knee joint, the ACL also prevents the healthy knee from hyperextending. The PCL is the strongest ligament in the knee, as it has anterior and posterior fibers that differ in orientation. The PCL provides 95% of the restraint to posterior translation of the tibia on the femur during 90° flexion, prevents hyperextension, and limits rotation of the tibia. Together, the ACL and PCL are secondary stabilizers and provide some resistance to varus stress, which helps provide medial/lateral stability if the primary lateral structures have been disrupted. They also have a role to play in stabilizing the knee during rotation.

A fifth structure that contributes to knee stability is the quadriceps tendon. The quadriceps tendon includes the patellar tendon, which passes over the front of the knee and attaches to the patella. At the site of attachment, the patellar tendon continues as the patellar ligament, a strong, flat ligament that attaches the apex of the patella to the tibial tuberosity. The medial and lateral portions of the quadriceps tendon line, on either side of the patella, are inserted into the upper part of the tibia and joined with the joint capsule. The patellar ligament directs the force of the quadriceps femoris muscles to the tibia during the extension of the knee to stabilize the patellofemoral joint (Fig. 5).

In the healthy knee, compressive forces are absorbed by soft tissue structures, which help to stabilize the articulation of the femur and tibia. During flexion, the top of the patella is pulled by the quadriceps tendon, while the bottom of the bone is simultaneously pulled by the patellar tendon, causing the patella to put compressive force on the posterior condyles of the femur. As the surface area of the patella is small in relation to the force applied to it, the compressive force on the patellofemoral joint is very high. At maximum flexion, the compressive force across the patellofemoral joint can be very high [ 9] (Table 2).

To ensure the femur remains on the tibial plateau, the compressive force needs to be strong enough to counter the force of the femur as it glides and rolls anteriorly while the knee flexes. As flexion increases, the compressive force that the quadriceps and patellar tendons apply to the patella becomes greater, preventing displacement of the femur (Fig. 6). As the compressive force of the patella increases, contact between the patella and femoral condyles also increases. This helps to spread the compressive force by transmitting some of it to the femur [ 9].

Fig. (7). Unfavorable biomechanical conditions about the knee joint and the mechanisms by which they result in relative overloading of the articular cartilage. Modified from: Heijink A, et al. Biomechanical considerations in the pathogenesis of osteoarthritis of the knee. Knee Surg Sports Traumatol Arthrosc. 2012 Mar; 20(3): 423-435. Table 2.

Compressive force, or load of gravity, is also essential for the nourishment and healing of the articular cartilage since it has no blood supply. When compressive force is applied, synovial fluid is pushed into the articular cartilage for nourishment, and once relieved, fluid goes out of the articular cartilage. Physiologic loading, including dynamic compression during motion, also causes an increase in anabolic growth factors and cytokines that stimulate the building of the extracellular matrix and aid in the health and maintenance of articular cartilage, menisci, and other joint structures. When mild injury occurs, these same forces induce an anabolic healing reaction to assist the body in repair.

Compressive joint forces stabilize the knee as long as the tibia and fibula are in proper alignment. If the articular surfaces are out of alignment, the center of force shifts to the periphery of the joint. This contact stress is then distributed into the thin cartilage of the condyle. The change in the site of contact alters the distribution, direction, and magnitude of load applied to the joint [ 12]. Such changes in the biomechanics of the joint complex result in increased gliding of the articular surfaces of the femur and tibia on one another, causing excessive motion about the joint.

When the kinematics between the tibia and femur are changed by misalignment, the integrity of the ligaments is disrupted, and the muscles’ ability to stabilize the joint is decreased, resulting in joint instability. This provides an unfavorable biomechanical condition around the knee joint. (Fig. 7). To accommodate the strain of force, healthy ligaments elongate slightly. If the force exceeds the strength of the ligament, permanent ligament damage can occur, with resultant instability [ 12]. The ACL, for example, receives 75% of the anterior force on the knee at full knee extension and an additional 10% at up to 90 ^o of knee flexion [ 13]. The ACL is normally 40 mm in length. Only 2 mm separate ACL injury and total rupture. Microscopic injury to the ligament occurs at approximately 5 mm of stretch and total rupture at 7 mm (Fig. 8). Sharp, cutting-type movements (such as those done when playing soccer or football) apply sudden rotational force, which can strain the ACL up to 8 mm (20%) and cause multi-planar knee laxity, which alters the joint biomechanics [ 14, 15].

Fig. (8). Load-elongation curve of cadaver human anterior cruciate ligament. As the ligament is stretched at a physiologic strain rate, damage begins at 5 mm of elongation (stretch) and completely tears at 7 mm. The Prolotherapy zone (areas 2 and 3) is the point where Prolotherapy is able to repair the ligament damage so that complete joint stabilization results. If complete failure of the ligament occurs, surgery is typically required. Used with permission from: Nordin M, et al. Basic Biomechanics of the Musculoskeletal System. 4th Edition. Lippincott Williams & Wilkins. Baltimore, MD. 2012.

Shear force, which is negligible in the healthy knee joint (only 1-2%), is harmful in the unstable joint and increases as ligaments become laxer. For example, knees with a deficient ACL will experience 3 times as much force in the MCL and increased shear force on the tibia [ 16]. In addition to mechanical changes, shear force causes biomolecular alterations in the joint. They increase destructive inflammatory mediators, including nitric oxide, interleukin-1, tumor necrosis factor-a, metalloproteinases, and excessive reactive oxygen species (oxidation) in the synovial fluid [ 17, 18]. These inflammatory substances cause pain and swelling in the joint, and the long-term net effect of these mediators is the breakdown of the articular cartilage extracellular matrix if the excessive forces from joint instability are not resolved [ 19-21] (Fig. 9). Passive and static biomechanics that were previously well managed by the joint before the ligaments were injured now produce destructive shear forces.

Ligament injury causes destructive forces upon the knee. It is not just the magnitude of the force that damages the joint structures when the ligaments are injured but also the location and direction of the force as well [ 19, 22]. When the femur shifts backward, and the tibia shifts forward, the patella gets pulled away from the tibia. Less lubrication leads to an increase in shear strain on the articular cartilage [ 17, 22]. High tension or shear at the edges of the joint contact regions predisposes the cartilage to splitting, tears, or fibrillation over time [ 23]. When ligaments are injured, unaligned shear forces push one part of the joint cartilage in one direction while another part of the articular cartilage is pushed in the opposite direction (Fig. 10).Continued movement, in this case, will induce pathologic loading. Excessive joint motion leads to synovitis and the production of excessive inflammatory fluid, which, if left unchecked, causes articular cartilage breakdown, dysregulated bone remodeling, and other characteristics of osteoarthritis [ 24] (Fig. 11).

Fig. (9). Joint instability-induced synovitis in osteoarthritis. The low level inflammatory physiology of the synovial fluid has a long-term net effect of breaking down the articular cartilage extracellular matrix. Adipocyte image modified from: https://pt.wikipedia.org/wiki/Ficheiro:Yellow_adiposetissue_in_paraffin_section_-_lipids_washed_out.jpg. Macrophage image modified from: https://commons.wikimedia.org/wiki/File:Macrophage.jpg

Fig. (10). The destructive joint shear and torsional motions. Ligament injury ending in joint instability induces significant shear and torsional motions on the joint, which amplifies diffuse joint destruction.

Fig. (11). Healthy vs. osteoarthritic joint. Shown is a healthy joint, in which physiological loading (magnitude of loadxfrequency of loading) is managed by the joint. Healthy subchondral blood vessels and blood perfusion, and a putative healthy crosstalk between the subchondral bone and articular cartilage lead to coupled bone remodeling to maintain homeostasis and repair microdamage in the bone matrix. In the OA joint, chronic overloading results in failed repair mechanisms. Bone within a bone marrow lesion (BML) zone, imaged by MRI, contains the most severe bony manifestations, in which dysregulated bone remodeling results in both bone attrition and sclerosis. The cartilage overlying the BML is degraded, with increased matrix proteases and decreased production of cartilage matrix. A putative unhealthy crosstalk between the bone and cartilage compartments exacerbates the failure of repair mechanisms, in the face of continued unfavorable biomechanics. Findlay DM, Kuliwaba JS. Bone-cartilage crosstalk: a conversation for understanding osteoarthritis. Bone Res. 2016;4:16028. Published 2016 Sep 20. doi: 10.1038/boneres.2016.28. Copyright © 2016 The Author(s). http://creativecommons.org/licenses/by/4.0/

Osgood-Schlatter disease is one of the most common knee joint conditions of adolescence [ 47, 48] and is believed to result from a traction apophysitis of the tibial tuberosity that occurs due to repeated tensile extension forces from the quadriceps on the weak apophyseal cartilage of the tibial tuberosity. This apophysitis, in turn, results in the avulsion of segments of the anterior cartilage and anterior bone if left untreated [ 49]. While most patients recover with conservative treatment and regain normal patellar length and diameter, some patients at the 2-year follow-up have been shown to continue to suffer from lower endurance, power, and strength compared to healthy controls [ 47].

Knee ligament injury is a lesser-known risk factor for apophyseal and other growth plate injuries [ 50, 51]. Increased external tibial torsion, consistent with the instability of the knee, has also been shown to be a predisposing mechanical factor in the development of Osgood-Schlatter disease [ 52]. Quadriceps muscle tightness, along with increased peak quadriceps torque, is a known compensatory mechanism for joint instability, especially in the ACL-deficient knee [ 53]. ACL laxity causes the quadriceps tendon to become tighter to compensate for an unstable knee, resulting in traction apophysitis of the tibial tuberosity and traumatic avulsion at the open growth plate.

Prolotherapy treatment of Osgood-Schlatter disease is directed at the weakened soft tissue structures, including the patellar tendon and any involved ligaments. In one double-blinded study, young athletes aged 9-17 years with Osgood–Schlatter disease were randomized to dextrose injection, control injection, or a non-injection (supervised exercise) group. Dextrose prolotherapy patients had substantially greater pain reduction during sports activity than either group at follow-up, with many pain-free during sports involvement. At 1 year, 84% of the dextrose-treated knees were pain-free with sports compared to 46% of the lidocaine-treated knees [ 54]. Other clinicians have found dextrose prolotherapy to be safe and effective, aiding in a quicker return to sport for adolescent athletes with recalcitrant Osgood-Schlatter disease [ 55].

Patellar pain syndromes are not usually precipitated by trauma but rather occur due to ligamentous injuries, meniscal tears, bony aberrations, muscle imbalances, or a combination of these events. Patellar syndromes, also called patellofemoral pain syndromes, such as patellar subluxation, patellar instability, patellar tendonitis/-osis (jumper’s knee), Osgood-Schlatter disease (tibial apophysitis), and osteochondritis dissecans, can be caused by trauma, but are primarily due to anatomic or biomechanical conditions that are prone to “failure” either in an osseous or soft tissue component. Failing soft tissues, bony aberrations, and lack of sufficient ligament support can produce both static and dynamic instability [ 56]. Patellar instability is often associated with patellofemoral subluxation, misalignments, or dislocation.

Joint instability due to ligament laxity precipitates excessive movement and altered tracking of the patella [ 57]. Physical therapy, patellar taping, orthoses, ice applications, and soft braces are common conservative treatments for patellar pain syndromes [ 58]. They do not address, however, the underlying issues of joint instability secondary to ligamentous injury, tendon injury, or meniscal tears. Prolotherapy can potentially promote nonsurgical repair of the ligament, tendon, and meniscus and has been employed with positive outcomes for patellar pain syndromes associated with joint instability [ 56] (Fig. 21).

Tendonitis is a frequent diagnosis in sports medicine that has traditionally been viewed as a tendon injury resulting from repetitive mechanical load with a subsequent inflammatory response [ 59]. While some tendon injuries heal well, others linger, potentially because the underlying joint instability causes too much force on them [ 60]. Chronic tendinopathies have been found to be degenerative in nature rather than primarily inflammatory and appropriately termed “tendinosis,” reflecting a focus on damage rather than inflammation. Tendinopathy is remarkable for mucoid degeneration and a loss of collagen continuity, which requires appropriate treatment and management regimens consistent with the degenerative pathology [ 61, 62]. Through the ligamento-muscular reflex, muscles, and thus their corresponding tendons around the knee, are recruited for stability. The most common ones are the hamstrings and quadriceps for anterior knee instability, pes anserine for medial instability, iliotibial band for posterolateral instability, and popliteus when posterior knee instability is present (Fig. 22).

Fig. (21). Typical injection sites for H3 Prolotherapy of the knee. Injecting the ligament attachment sites is the most important part of comprehensive Prolotherapy.

Fig. (22). Various tendinopathies from ligamentous knee joint instability. ( A). Medial collateral ligament injury. ( B). Lateral collateral ligament injury. ( C). Anterior cruciate ligament injury. ( D). Posterior cruciate ligament injury. Knee ligament injuries via the ligamento-muscular reflex cause tightening and increase forces on various muscles and tendons to stabilize the knee, ultimately making these soft tissue structures prone to breaking down.

Pes anserine tendonitis is one of the most frequent types of chronic knee injuries [ 63]. The pes anserine tendon group prevents the lower leg from twisting outward while running. The tendinosis of this structure is characterized by inflammation of the medial knee and often coexists with other knee disorders [ 64]. During walking, pressure from the weight of the body is medial to the knee rather than lateral, applying a varus torque at the knee, increasing the compressive force and subsequent breakdown at the medial aspect [ 65]. Chronic stress from activity or contusion to the pes anserine bursa near the tibial insertion may precipitate the inflammation. An underlying or coexisting medial collateral ligament injury causing joint instability would put additional stressors on the pes anserine tendons as they try to stabilize the medial joint line. Prolotherapy can be used in the medial knee joint line, including the pes anserine area, to relieve pain and stabilize the knee [ 66].

Osteoarthritis is characterized by a breakdown of articular cartilage. Articular cartilage is comprised of connective tissue nourished by the surrounding joint fluid. It lacks blood vessels, lymphatics, and nerves and has a limited ability for healing and repair. As such, the preservation of healthy articular cartilage is essential for joint health, and the health of the cartilage is dependent on the normal loading process that occurs through the usage of the joint [ 66, 67]. Articular cartilage has a great ability to withstand high cyclic loads [ 68]; excessive loading, rotational forces, and trauma, however, can cause cell death and result in damage to the extracellular matrix and cartilage. When damaged, the unique and complex structure of articular cartilage makes treatment and repair a significant challenge, especially considering that injury to articular cartilage is recognized as a cause of significant musculoskeletal morbidity [ 69].

The progression of chondral lesions ultimately results in osteoarthritis, a chronic degenerative joint disorder characterized by articular cartilage destruction and osteophyte formation. Although loss of articular cartilage plays a pivotal role in osteoarthritis, the condition is often preceded by joint instability due to soft tissue lesions, such as ligament injury (Fig. 23). Injured or overstretched ligaments alter joint biomechanics, and the resultant joint instability allows for an uneven gliding motion and increased pressure on the articulating bones, eventually leading to osteoarthritis [ 64] (Fig. 24). Studies in mouse models of osteoarthritis indicate that the progression of the disorder is related to the severity of joint instability [ 70, 71]. Subsequent injury to the knee is also one of the strongest predictors of the development of OA in that joint [ 72, 73]. In a Johns Hopkins University prospective cohort study on young adults with knee trauma, 13.9% developed radiographic and symptomatic osteoarthritis over a median follow-up of 36 years, compared to 6.0% of those without knee injury [ 74]. Notably, slightly more than half (57%) of people who have a traumatic knee injury will develop knee OA in their lifetime [ibid].

Prolotherapy studies with dextrose, platelet-rich plasma, and bone marrow have reported success with chondromalacia patella and osteoarthritis [ 75, 76] (Fig. 25). Randomized controlled studies have shown the effectiveness of dextrose prolotherapy in treating osteoarthritic knees. Of these 3 studies, those of Rabago et al. and Reeves and Hassanein were double-blinded, the latter study showing efficacy in patients with and without ACL laxity [ 77, 78]. The third study, conducted by Dumais et al., was a randomized crossover study in which prolotherapy and exercise therapy were combined in alternating sequences [ 79]. All 3 studies showed a significant gain from prolotherapy treatment with respect to both pain and functional capacity. Additionally, in a study on knee and hip osteoarthritis, Hauser and Woldin reported the results of a combined dextrose prolotherapy and bone marrow prolotherapy treatment regimen in patients with radiographic osteoarthritis and observed pain relief, improved joint function, and enhanced quality of life [ 80]. Prolotherapy injections target the multiple potential pain generators inside and around the knee joint [ 81] (Fig. 26).

Fig. (23). Pathophysiology of osteoarthritis: old view vs. new view.

Fig. (24). The progression of knee osteoarthritis. When a simple ligament injury (medial collateral ligament depicted here) is not resolved, the resultant joint instability can progress to the complete breakdown of the articular cartilage and the joint.

Fig. (25). Self-reported symptom levels in 69 patients with knee OA before and after Prolotherapy. Prolotherapy reduced all symptom levels to a statistically significant level. Modified from: Havil S. Maddela, BS, MPH, CPH & Ross Hauser, MD. The Use of Prolotherapy for Chondromalacia Patella (Patellofemoral Pain Syndrome). Journal of Prolotherapy. 2018;10:e1000-e1008.

Fig. (26). Chronic ligament injury vs. ligament treatment (Prolotherapy). Left unchecked, ligamentous joint instability is a progressive condition causing joint breakdown, but treatments such as Prolotherapy directed at joint instability can potentially stop the process.