Sports Medicine Arthroscopic Review September 2005; Vol. 13; No. 3; pp. 136 – 144 Kevin A. Hildebrand, MD, Corrie L. Gallant-Behm, BSc, Alison S. Kydd, BSc, andDavid A. Hart, PhD: From the University of Calgary, Alberta, Canada. KEY POINTS FROM THIS ARTICLE: 1) Wound healing following overt injury to a tissue follows general rulesirrespective of the tissue involved. 2) Wound healing and repair of injured tissues follows several steps in thehealthy individual. The process is initiated by the inflammatory response andsubsequent steps are based on this initial response. 3) Whereas wound healing generally leads to a repair of the injured site, it doesnot lead to tissue regeneration. This difference between repair and regeneration hasinfluence on tissues such as ligaments and tendons that function in a mechanicallyactive environment. 4) The dynamic interface between mechanics and biology influence theeffectiveness of the healing response. [Important] 5) Factors that impact the outcome of the healing response include the biologyof the host, such as: A)) Age B)) Sex C)) Genetics D)) Tissue history (prior injuries, scar tissue, and disease states) 6) The repair process can lead to a loss of function, primarily from scar tissue,and this can occur in both musculoskeletal and visceral tissue (heart, lung, kidney,liver). 7) Recent investigations have detailed the healing response of many connectivetissues (ligaments, tendons, menisci, joint capsules) that function in mechanicallydiverse environments. 8) The functional outcome of the healing process depends on the extent ofrepair versus regeneration. 9) The basic steps in the repair or healing of a tissue following overt injury are: A)) Hemostasis and a rapid inflammatory phase B)) A phase of cell proliferation and matrix deposition 2 C)) A slow remodeling phase, which may take months to years A)) The Inflammatory Phase *Following acute injury there is bleeding into the area of injury and pain. *Hemostasis is restored by the formation of a fibrin clot, which prevents furtherbleeding and serves as a provisional matrix for migrating cells. *This clotting cascade results in the release of inflammatory molecules andinflammatory cytokines from cells such as platelets. *There is an influx of fibroblasts, which sets the stage for the second phase (B) ofthe repair process. B)) The Matrix Deposition Phase *Deposition of matrix molecules [fibroblasts] produce collagen proteins that bridgethe damaged area with the residual endogenous ligament tissue. *If the matrix deposited early during the healing or repair process is alteredcompared with normal, the organization of the repair tissue is also likely to bealtered. [Important: early best treatment is critical for ultimate quality of healing] *The organization of the matrix deposited early following injury is disorganizedcompared with normal tissue. [The Fibrosis Of Repair] *The tissue deposited early after injury appears to be an attempt to bridge thedamaged area without regard to what was present before injury. *Not only does this provisional matrix have a different structural and cellularcomposition as compared with normal tissue, but in the case of ligament injury, thistissue is not necessarily even localized to the injury gap but also may extend tosurround the entire remaining ligament midsubstance. *This somewhat amorphous material, resulting from the initiation of an overtinflammatory response and subsequent events is compromised at both theorganizational and functional levels, independent of whether it is a ligament,tendon, or skin. C)) The Remodeling Phase *The remodeling phase is a slow process and is accompanied by alterations notonly in matrix remodeling, but also gene expression, cellularity, vascularity, andinnervation. *The scar tissue in a ligament undergos a protracted process where the initiallydeposited material seems to be turning over and the organization of collagen fibrilsbecome more oriented along the long axis of the ligament. *Because the remodeling phase occurs slowly, and may take months (i.e., skin) oryears (i.e., tendon and ligament). [Important] *A number of variables seem to influence the rate of remodeling and the finaloutcome, and it is not always possible to assign potential cause and effectrelationships. *Even after protracted time post-injury, the mechanical properties of a scar tissuein a ligament … is still compromised compared with normal. *The scar tissue may be functional for most activities even though it is notnormal. [Fails during high demand activities] 10) Normal tissues are organized with respect to collagen alignment and collagenfibril assembly, whereas collagen expressed early following injury is not aligned andheterogeneous with regard to orientation in the tissue. Because the latter is criticalfor function in a mechanically active environment such as a ligament, it is notsurprising that the mechanical properties of the healing ligament are severelycompromised compared with normal tissue. [The Fibrosis Of Repair] 11) The scar cells in the healing ligament are different from normal cells andtherefore the scar is intrinsically different. [Key Point] 12) Tissues that do not have an influx of new microvasculature, like the disc andmeniscus, do not heal well. [Very Important] 13) Not all ligaments heal to the same degree, and healing of ligament injuriesseems to be influenced by various factors including location (i.e. extra-articular vs.intra-articular), intrinsic aspects (which are largely unknown), mechanicalenvironment, as well as factors discussed in more detail in the following sections. 14) The large scar tissue mass gradually remodels, likely under the influence ofthe mechanical environment. [Very Important: supports the contention thatthe mechanics of the chiropractic adjustment can enhance the timing andquality of scar remodeling] 15) Scar-like tissue is functionally ineffective. 16) Maturation of the scar tissue requires mechanical loading to continue theremodeling phase of healing. [Very Important] 17) Normal connective tissues that function in a mechanically active environment(actually most tissues) subscribe to the use it or lose it paradigm of tissue integrity. Increased loading leads to adaptation, whereas decreased loadingbelow a threshold leads to atrophy. The same principle likely also holds for scartissue and immobilization beyond the initial phases of healing could have adetrimental impact on outcome. [Very Important] 18) Too much loading of a scar at too early a time point may have a detrimentalimpact on the maturation of the scar. 19) Post healing joint instability and the loss of function leads to increasedexpression of inflammatory mediators, likely caused by microinjuries to the scartissue, and resulted in a protracted healing response. There is a delicate balancebetween biology and mechanical environment when it comes to optimizing the basichealing response in tissues such as ligaments, tendons, or skin. 20) Some tendon and ligament injuries lead to formation of scar tissue that ispartially functional, but to regain as much function as possible requiresphysiotherapy to facilitate the return to function after the scar tissue has formed.[Very Important] 21) The inflammatory response associated with overt injury or surgery can lead toformation of adhesions, where the ligament/tendon scar tissue is bonded to thesurrounding tissue and thus, such restrictions compromise function in situationswhere movement is required. [Adhesions, Fibrosis Of Repair] 22) This emphasizes the need to minimize the induction of a vigorousinflammatory response in some environments to assist in the repair process withoutside effects such as adhesions. [Very Important: the resolution ofinflammation is fibrosis; reducing inflammation reduces the fibrosis] 23) It is clear that the outcome is repair and not regeneration in all softconnective tissues, except for muscle and of course the hard tissue, bone.[Most Important: ligaments and tendons repair (with scar tissue) ratherthan regenerate (heal with normal pre-injury tissue)]. 24) Writings from ships captains from the 17th to 19th centuries whose mensuffered from scurvy noted: Under conditions of vitamin C deficiency, scars on menthat had formed greater than 20 years prior seemed to dissolve before normal skinwas affected, leaving gaping wounds where once there were scars. Thus, even aftermany years, scar tissue is more ascorbate dependent than normal skin formaintenance of integrity in humans. [Both acute injury and the long-termintegrity of healed tissues are Vitamin C dependent]. 25) The healing process is influenced by age. 26) It is known that the biomechanical properties of ligaments and tendonschange with age (become stiffer) because of accumulated stresses and theincidence of injuries, and degenerative processes in many of these tissues increasewith age (aside from those associated with athletics). [Very Important] 27) The authors present evidence that indicates that different tissues anddifferent individual [animals] have phenotypes that allow them to genetically healbetter or worse. Apparently, genetics in part, determines if the healing occurs by regeneration or by scar tissue, which is linked to the severity and extent of theinflammatory response. [Very Important] 28) Women tend to have a more vigorous inflammatory response than males,[and therefore more fibrotic and mechanical (scar) healing residuals]. This responseis probably linked to estrogen levels. 29) Normal ligament and joint function (laxity) can be influenced by themenstrual cycle in some women. 30) Pregnancy is associated with changes in several hormones qualitatively andquantitatively, impairing the metabolism of cells in the healing ligament, and alsoaffecting the functioning of the normal ligament (i.e. laxity). 31) Genetic factors play a role in some pathologic scarring or wound healing suchas keloid formation. 32) It is apparent from talking with orthopedic surgeons that there is a body ofanecdotal information that has implicated genetics in wound healing followingligament injuries and surgical interventions. 33) The quality of the tissue prior to overt injury may play a role in the woundhealing process and the final outcome, and therefore should be considered. Thepresence of previous injury, either overt or subclinical, could also impact thehealing outcome. The healing outcome following re-injury could impact both thequality of the outcome and the functioning of the healed tissue.[Very Important] 34) Mechanobiology is likely important in the healing outcome in tissues such asligaments, tendons, and related tissues. That is, depriving healing ligaments ofmechanical loading likely has a detrimental impact on healing outcome.[Very Important: improved with chiropractic adjustments] 35) Ligaments and tendons adapt to increases in mechanical loading within aphysiologic window; therefore, decreased loading decreases function. [Important] 36) When loading is consistently decreased, the quality of the tissue is decreased;this may influence the ability of these injuries to heal and their functional residuals. 37) Aging influences healing outcomes. [Very Important] 38) Re-injury of an acutely healing ligament increases inflammatory molecules,which could worsen the long-term consequence of the mechanical properties of thetissue. [Very Important] 39) Because not all injuries to a tissue are overt, it is possible that theaccumulated cycles of injury and repair to a tissue could impact the startingmaterial following an overt injury. If one extends this to the situation of a secondacute injury, the starting material following a second injury is really scar tissuerather than normal tissue. This could impact the functional outcome in at least ways; first, the quality of the scar may be compromised compared with the originalscar tissue; and second, the size of the scar may be increased and thus couldimpact the functional outcome. [Very Important] 40) The size of the wound and the resulting scar tissue has a dramatic impact onthe biomechanical outcome. 41) Diabetes can impact the healing outcome. 42) Many patients with diabetes have a compromised wound healing responsedue in part to an impaired inflammatory response and elaboration of growthfactors. 43) In conditions such as diabetes, the disease could affect the quality of theconnective tissue directly via derivatization of the tissues and formation ofadvanced glycation endproducts [AGEs] by carbohydrates. 44) Many individuals with diabetes exhibit impaired wound healing and candevelop chronic wounds that do not readily heal. 45) In animals, a single local glucocorticoid treatment of a healing ligamentresulted in reduced biomechanical properties of the scar, possibly because of adelay in the maturation/remodeling of the healing tissue. 46) It is readily apparent that wound healing in the adult under the most optimalconditions should be considered tissue repair not regeneration. For tissues like aligament or tendon, the mechanical outcome may be less than ideal, depending onthe expectations of tissue use post-injury and the occurrence of side-effects such asadhesions. [Very Important] 47) Improved understanding and application of the regulation of the inflammatoryresponse may improve the subsequent healing processes improving thefunctionality of the reparative outcome. [Lasers, Omega-3, Antioxidant Status, etc.] 48) Regulation of the interface between biology and biomechanics (i.e.mechanobiology) may also affect the functionality of the reparative outcome.[Chiropractically Very Important] 7 COMMENTS FROM DAN MURPHY This article reiterates that ligaments are important sources of proprioception. This isimportant because proprioceptive afferents control joint muscle tone; there isappreciative evidence from other sources that indicate that joint proprioceptioninfluences sympathetic autonomic tone and immunology. This article reiterates that soft tissue healing occurs over a period of 12 months ormore. Ligaments and tendons heal with scar tissue (repair) as a rule, and not with normalpre-injury tissue (regeneration). This scar tissue causes permanent loss of function. Scar tissue is mechanically and neurologically functionally inferior to normal tissue. Its inherent weakness makes the tissue prone to failure at previously normal loadlevels, and subsequent new trauma to scarred tissue will result in greater injury. Scar tissue (fibrosis) is linked to the intensity of the initial inflammatory response. Consequently, early inflammation control could improve the timing and quality ofhealing. Scar tissue, to varying degrees, is remodelable with the application of controlledmotion, which I believe includes and even requires chiropractic adjustment. Mechanical loading is critical for scar tissue remodeling and maturation. Lack of symptoms is not synonymous with full healing and functional recovery. There are definitive reasons as to why some patients heal slowly or incompletelywith functional residuals. These reasons include: A)) Age B)) Female Sex C)) Genetics D)) Tissue history (prior injuries, scar tissue, and disease states) E)) Diabetes F)) Disc injuries heal poorly, primarily as a consequence of poor blood supply G)) Pregnancy H)) Vitamin C levels I)) Menstrual cycle hormonal changes J)) Any reason that deprives the healing tissues from mechanical loading K)) Re-injury of a prior injury or prior tissue that has sustained repetitive stress L)) Excess carbohydrates that increase glycation (AGEs) [Hb-A1c] M)) Any treatment with corticosteroids N)) Anything that exaggerates the inflammatory response[omega-6/omega-3 or AA/EPA ratio]