This is an update with explanatory notes for the general reader from our 2011 paper on ligament healing.
How ligaments heal: An Introduction
Ligament injuries are among the most common causes of musculoskeletal joint pain and disability encountered in primary practice today. Ligament injuries create disruptions in the balance between joint mobility and joint stability, causing abnormal force transmission throughout the joint resulting in damage to other structures in and around the joint. Osteoarthritis is the long-term consequence of a non-healed ligament injury that is the most common joint disorder globally.
Ligaments heal through a distinct sequence of cellular events that occur through three consecutive phases: the acute inflammatory phase, the proliferative or regenerative phase, and the tissue remodeling phase. The whole process can occur over months, and despite advances in therapeutics, many ligaments do not regain their normal tensile strength.
Numerous strategies have been employed over the years attempting to improve ligament healing after injury or surgery
We heal soft tissue and joint injuries through the process of inflammation. Motion, adequate blood flow, and progressing through normal stages of healing are necessary to optimize the healing of injured tissue. This does not just involve relieving pain. The goal of therapy should be the restoration of tissue strength. To heal injured tissue, it needs to be induced to do so. All joint tissues need weight-bearing and motion for health, maintenance, and repair after injury.
When a ligament is injured, gentle movement and weight-bearing are necessary for this inflammatory phase to occur unimpeded. What injured ligaments need is gentle motion, as in swimming or cycling, and walking as tolerated. Articular cartilage is dependent also on gentle compressive forces to repair and heal. Exercise done correctly can induce changes on joints that actually increase cartilage ECM and health. Exercise done correctly causes even the articular cartilage to repair that has been injured.
Numerous strategies have been employed over the years attempting to improve ligament healing after injury or surgery. One of the most important advances in the treatment of ligament injuries has come from the understanding that controlled early resumption of activity can stimulate repair and restoration of function, and that treatment of ligament injuries with prolonged rest may delay recovery and adversely affect the tissue repair. Likewise, although steroid injections and nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be effective in decreasing inflammation and pain of ligament injuries for up to six to eight weeks, the histological, biochemical, and biomechanical properties of ligament healing are inhibited. For this reason, their use is cautioned in athletes who have ligament injuries. As such, NSAIDs are no longer recommended for chronic soft tissue (ligament) injuries, and acute ligament injuries should be used for the shortest period of time if used at all. Regenerative medicine techniques, such as Prolotherapy, have been shown in case series and clinical studies, to resolve ligament injuries of the spine and peripheral joints. More Prolotherapy studies in more controlled settings with larger numbers would further prove the effectiveness of this therapy.
In 2013 we published our own research in The Open Rehabilitation Journal (1) NSAIDs have been a mainstay treatment in ligament injuries for many years, especially in the case of acute sports injuries, but new research has shown that these anti-inflammatory drugs are only mildly effective in relieving the symptoms of most muscle, ligament, and tendon injuries and are potentially deleterious to soft tissue healing.
In our article, When NSAIDs make the pain worse we cite 2021 research (2) led by the University of Oxford says: “Use of specific medications (NSAIDs) may accelerate the progression of radiographic knee osteoarthritis.”
Here are the learning points of this research:
- A the start of the study people with radiological evidence of knee osteoarthritis, greater than grade 2 level were selected. Data from patient medication habits were collected. Those who took medications prior to the x-ray were assessed for up to six years.
- Study conclusion: In current users of NSAIDs, (knee joint space) loss was increased compared with current non-users in participants with radiographic knee osteoarthritis.
Formation of scar tissue – chronic ligament injury is usually healed by the creation of scar tissue that is not as good as the tissue it is replacing
Ligaments are dense bands of fibrous connective tissue that serve to join two or more bones of the musculoskeletal system. Ligaments cross joints with wide ranges of motion as well as joints with little motion and may appear as long sheets of opaque tissue or short thickened strips in joint capsules. Although they vary in size, shape, orientation, and location, ligaments primarily function to provide stabilization of joints both at rest and during normal range of motion. While ligaments were once thought to be inactive structures, they are, in fact, complex tissues that respond to many local and systemic influences. (3)
The research cited is from 2004, what was also suggested is that when ligaments are injured they heal by creating scar tissue. Here is what was noted: “Injury to a ligament results in a drastic change in its structure and physiology and creates a situation where ligament function is restored by the formation of scar tissue that is biologically and biomechanically inferior to the tissue it replaces.”
In other words, chronic ligament injury is usually healed by the creation of scar tissue that is not as good as the tissue it is replacing.
Consequently repaired ligament has decreased strength and durability
This idea was still being discussed in a 2018 research study that suggested disorganized healing of the ligaments. (4)
“Ligament wound healing involves the proliferation of a dense and disorganized fibrous matrix (collagen-based repair fibers) that slowly remodels into scar tissue at the injury site. This remodeling process does not fully restore the highly aligned collagen network that exists in native tissue, and consequently repaired ligament has decreased strength and durability.
Ligament injuries are among the most common causes of musculoskeletal joint pain and disability encountered in primary practice today. Ligament injuries create disruptions in the balance between joint mobility and joint stability, which can lead to abnormal transmission of forces throughout the joint, resulting in damage to other structures in and around the joint. Knees, hips, shoulders, ankles, elbows, and wrists are among some of the joints most commonly affected by ligament injuries. While there is a vast body of knowledge available regarding the structure and function of normal ligaments, understanding the structure and function of injured ligaments becomes more complicated due to the variability and unpredictable nature of ligament healing.
The incomplete healing and persisting differences in the new ligament tissue result in ligament laxity, which predisposes the joint to further injury
This may be due to the dramatic physiological and structural changes that ligaments sustain as a result of injury, as well as the complex and dynamic cellular processes that occur during healing. These processes create alterations in the biology and biomechanics of the injured ligament, leading to inadequate healing and tissue formation that is inferior to the tissue it replaces. The incomplete healing and persisting differences in the new ligament tissue result in ligament laxity, which predisposes the joint to further injury. Ligament injury and subsequent laxity cause joint instability, which leads to chronic pain, diminished function, and ultimately osteoarthritis of the affected joint. (5, 6, 7,8)
Despite the numerous strategies that have been employed over the years attempting to improve ligament healing after injury, osteoarthritis, the long-term consequence of ligament injury, continues to be the most common joint disorder in the world. (9) Therefore, understanding the complex cellular processes that occur as a result of ligament injury, along with determining and implementing strategies that optimize ligament restoration are necessary to reduce the enormous individual and public health impacts of osteoarthritis.
Understanding the complex cellular processes that occur as a result of ligament injury, along with determining and implementing strategies that optimize ligament restoration are necessary to reduce the enormous individual and public health impacts of osteoarthritis.
Ligament structure and function
Ligaments are primarily composed of water, collagen, and various amino acids. Approximately two-thirds of total ligament mass can be attributed to water and one-third can be attributed to solids. (3) Collagen represents approximately 75% of the dry weight of ligaments, while the remaining 25% contains proteoglycans, elastin, and other proteins and glycoproteins. Type I collagen accounts for nearly 85% of the total collagen within ligaments and the remaining balance consists of types III, V, VI, XI, and XIV collagen. (3, 10)
Microscopic studies of ligament tissues have shown that bundles of collagen fibers are composed of smaller fibrils arranged in a parallel fashion along the long axis of the ligament. The collagen fibers appear to have a characteristic, specially designed cross-linked formation, which contributes to the incredible strength of ligaments. Under a microscope, the collagen bundles appear undulated or crimped along their length and it is believed that the crimping is present in relation to the loading capacity or tension applied to ligaments. With load-bearing, certain areas of the ligament uncrimp, which allows the ligament to elongate without sustaining structural damage. (3, 11) It appears that some fibers tighten or loosen depending on musculoskeletal positioning and applied forces, which support the joint through various tensions and ranges of motion.
Fibroblasts, which produce and maintain the extracellular matrix, are located between the rows of collagen fibers. Recent studies suggest that fibroblast cells in normal ligaments may be capable of cell-to-cell communication allowing the coordination of cellular and metabolic processes throughout the tissue. (3, 12, 13)
Update: The movement of cells dictated by messages
A March 2019 study from the McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Washington University published in the journal Nature Reviews Rheumatology (14) continued along this line of study: The authors wrote: “Connective tissues (like ligaments) within the synovial joints are characterized by their dense extracellular matrix and sparse cellularity (There are not many cells within them). With injury or disease, however, tissues commonly experience an influx of cells owing to proliferation and migration of endogenous mesenchymal cell populations, as well as invasion of the tissue by other cell types, including immune cells. (In other words, when there is an injury there is a cell migration to the site of the injury. As you will see in the next line, too many cells, especially the immune cells can lead to chronic swelling). Although this process is critical for successful wound healing, aberrant immune-mediated cell infiltration can lead to pathological inflammation of the joint.”
Therefore cell-to-cell communication is critical to ligament healing.
Proteoglycans allow ligaments to progressively lengthen
Proteoglycans, also found in the extracellular matrix, store water and contribute to the viscoelastic properties of ligaments. These viscoelastic features allow ligaments to progressively lengthen when under tension and return to their original shape when the tension is removed. Ligaments attach to bones at specific sites on the bone called “insertions.” Both ligaments and their insertion sites can vary in configuration and their geometric shape appears to relate to the manner in which the fibers within the ligament are engaged as the joint moves. The direction of joint movement determines which fibers within a particular ligament are recruited for the performance of the specific movement. Ligaments are covered by a more vascular and cellular overlying layer called the epiligament, which is often indistinguishable from the actual ligament. The epiligament contains sensory and proprioceptive nerves with more nerves located closer to the boney ligament insertion sites. (3, 15, 16) When ligaments are strained, the proprioceptive nerves initiate neurological feedback signals that activate muscle contraction around the joint, which allows the body to protect and stabilize the joint after injury.
Ligaments prevent excessive motion of joints by providing passive stabilization and guiding joints through a normal range of motion under tensile load. In doing so, ligaments transfer force to and from the skeleton while dynamically distributing the loads applied to them in order to perform specific movement patterns. (17) Ligaments also function to provide joint homeostasis through their viscoelastic properties that reflect the complex interactions between collagens, proteoglycans, water, and other proteins. (3, 18) The viscoelastic properties, along with the recruitment of crimped collagen, contribute to the mechanical behavior of the structure under loading conditions. When tension is applied, ligaments deform, or elongate, in a non-linear fashion through the recruitment of crimped collagen fibers. As the tension placed on the ligament increases, the collagen fibers progressively un-crimp, or elongate, until all fibers are nearly linear.
As the fibers become increasingly linear, the ligament structure becomes increasingly stiff. Varying degrees of ligament stiffness is necessary for various loads and various ranges of joint motion. Ligaments can lose their ability to retain their original shape when stretched or elongated past a certain point for a prolonged period of time. When this occurs, the ligament becomes lax and unable to properly support the joint, leading to instability, pain, and eventual osteoarthritis of the joint. When an applied load causes all fibers to become nearly linear, the ligament continues to absorb energy until tensile failure or disruption of the tissue. Just as overstretched ligaments cause joint instability, ligament disruptions, or tears, will also create joint instability. In an attempt to prevent overstretching and disruption, ligaments utilize their viscoelastic properties to exhibit both creep and relaxation behaviors. Creep and load relaxation behaviors help to prevent fatigue failure of the tissue when ligaments are loaded in tension. Creep is defined as the deformation, or elongation, of the ligament over time under a constant load or stress. Load relaxation refers to a decrease in the stress of the tissue over time when the ligament is subjected to a constant elongation. (19, 20, 21)
In this image
Ligament structural strength graph. As the load is increased, more ligament fibers are recruited (straight lines), and the slack or creep in the fibers is removed until the entire ligament tears. The load at the complete failure of the ligament represents its maximum structural strength.
An update on CREEP
Creep signifies the slow stretching of soft tissue. Ligament creep most commonly occurs because of forward head posture from hours of computer work, playing on mobile devices, or texting on a smartphone. Keeping the head and neck in this position stretches the neck ligaments beyond the point they should be stretched while stabilizing the head. For every inch of forward head posture, the force on the spine increases by an additional 10-12 pounds. Therefore, a 12-pound head held 3 inches forward can put 42 pounds of pressure on the spinal ligaments. Hunching over a cell phone or computer for as little as 20 minutes can increase the laxity of these ligaments. Many tech activities encourage this forward head posture and put the cervical vertebral ligaments in a stretched position.
Creep can cause a chronic cycle of neck pain and headaches. As the ligaments become weaker, the head-forward position increases because the ligaments can no longer keep the cervical vertebrae in proper alignment. Then the neck muscles start to tighten, to limit the range of motion and decrease the load on the ligaments, resulting in muscle spasms. In this pain scenario, muscles can atrophy in a relatively short time. Unfortunately, injured ligaments heal very slowly because they have a minimal blood supply, which limits the necessary nourishment to promote healing. The result is acute pain, followed by chronic pain, and possibly nerve pathologies. Muscle, posture, and realignment therapies may only be temporarily beneficial since the ligament tissue that holds the vertebrae in alignment is weak.
1 Hauser RA, Dolan EE, Phillips HJ, Newlin AC, Moore RE, Woldin BA. Ligament injury and healing: a review of current clinical diagnostics and therapeutics. The Open Rehabilitation Journal. 2013 Jan 23;6(1). [Google Scholar]
2 Perry TA, Wang X, Nevitt M, Abdelshaheed C, Arden N, Hunter DJ. Association between current medication use and progression of radiographic knee osteoarthritis: data from the Osteoarthritis Initiative. Rheumatology. 2021 Jan 27. [Google Scholar]
3 Frank C. Ligament structure, physiology and function. Journal of Musculoskeletal and Neuronal Interactions. 2004;4(2):199-201. [Google Scholar]
4 Frahs SM, Oxford JT, Neumann EE, Brown RJ, Keller-Peck CR, Pu X, Lujan TJ. Extracellular matrix expression and production in fibroblast-collagen gels: Towards an in vitro model for ligament wound healing. Annals of biomedical engineering. 2018 Nov;46(11):1882-95. [Google Scholar]
5 Fleming BC, Hulstyn MJ, Oksendahl HL, Fadale PD. Ligament injury, reconstruction, and osteoarthritis. Current opinion in orthopaedics. 2005 Oct;16(5):354. [Google Scholar]
6 Koh J, et al. Osteoarthritis in other joints (hip, elbow, foot, toes, wrist) after sports injuries. Clinical Sports Medicine. 2005;24:57-70. [Google Scholar]
7 Connell D, et al. MR imaging of thumb carpometacarpal joint ligament injuries. Journal of Hand Surgery. 2004;29:46-54. [Google Scholar]
8 Martou G, et al. Surgical treatment of osteoarthritis of the carpometacarpal joint of the thumb: a systematic review. Plastic and Reconstructive Surgery. 2004;114:1-32. [Google Scholar]
9 Arden N, et al. Osteoarthritis: epidemiology. Best Practice & Research Clinical Rheumatology. 2006;20(1):3-25. [Google Scholar]
10 Vereeke, et al. Soft-tissue physiology and repair. In: Vaccaro A, ed. Orthopaedic Knowledge Update 8. Rosemont, IL: American Academy of Orthopaedic Surgeons; 2005:15-27.
11 Amiel D, Constance C, Lee J. Repetitive motion disorders of the upper extremity: effect of loading on metabolism and repair of tendons and ligaments. American Academy of Orthopaedic Surgery. 1995:217-3.
12 Benjamin M, et al. The cell and developmental biology of tendons and ligaments. International Review of Cytology. 2000;196:85-130. [Google Scholar]
13 Lo I, et al. The cellular matrix: a feature of tensile bearing dense soft connective tissues. Histology and Histopathology. 2002;17:523-537. [Google Scholar]
14 Qu F, Guilak F, Mauck RL. Cell migration: implications for repair and regeneration in joint disease. Nature Reviews Rheumatology. 2019 Mar;15(3):167-79. [Google Scholar]
15 Chowdhury P, et al, The “epiligament” of the rabbit medial collateral ligament: a quantitative morphological study. Connective Tissue Research. 1991;27:33-50. [Google Scholar]
16 Bray R. Blood supply of ligaments: a brief overview. Orthopaedics. 1995;3:39-48.
17 Benjamin,M, et al. Where tendons and ligaments meet bone: attachment sites (‘entheses’) in relation to exercise and/or mechanical load. Journal of Anatomy. 2006;208:471-490. [Google Scholar]
18 Jung HJ, Fisher MB, Woo SL. Role of biomechanics in the understanding of normal, injured, and healing ligaments and tendons. BMC Sports Science, Medicine and Rehabilitation. 2009 Dec;1(1):1-7. [Google Scholar]
19 Akeson WH, Frank CB, Amiel D, Woo SL. Ligament biology and biomechanics. In Symposium on Sports Medicine: the knee 1985 (pp. 111-151). [Google Scholar]
20 Andriacchi T, et al. Ligament injury and repair. In: Woo SL-Y Buckwalter JA, eds. Injury and Repair of the Musculoskeletal Soft Tissues. Park Ridge, IL: Am Acad Orthop Surg; 1988:103. Woo SL, Buckwalter JA. Injury and repair of the musculoskeletal soft tissues. Savannah, Georgia, June 18–20, 1987. Journal of Orthopaedic Research. 1988 Nov;6(6):907-31. [Google Scholar]
21 Shrive N, Chimich D, Marchuk L, Wilson J, Brant R, Frank C. Soft‐tissue “flaws” are associated with the material properties of the healing rabbit medial collateral ligament. Journal of Orthopaedic Research. 1995 Nov;13(6):923-9. [Google Scholar]