PHT 5237: Cell Injury and Cell Death PDF

PHT 5237: Cell Injury and Cell Death Over the next few slides, we will be going over the following topics: agents that can cause cell injury, the difference between reversible and irreversible cell injury, the stages of cell damage, adaptations to cell injury, the mechanisms of cell death, the diffe...

PHT 5237: Cell Injury and Cell Death Over the next few slides, we will be going over the following topics: agents that can cause cell injury, the difference between reversible and irreversible cell injury, the stages of cell damage, adaptations to cell injury, the mechanisms of cell death, the difference between necrosis and apoptosis, types and causes of necrosis, and the topic of pathological calcification. Cell injury may be reversible or irreversible. When the cell is unable to adapt, injury can occur. With reversible injuries, the stress is sufficiently small in magnitude or short enough in duration that the cell is able to restore homeostasis and recovers the original form. In other words, it will recover its normal cell structure and function. With an irreversible injury, on the other hand, the stress is larger in magnitude or long in duration and this results in cell death, otherwise known as necrosis. When cell injury is irreversible the intracellular proteins will be denatured. There is damage to the cell nucleus and autolysis. So, in other words, the cell will swell and then rupture and release its destructive contents into the extracellular fluid and it will be picked up into the body's circulation system. And what is being released? It's the lysosomal enzymes. Those enzymes will damage the surrounding healthy cells. Irreversible cell injury is synonymous with cell death. When the cell is being exposed to certain types of agents, the reversible cell injury process begins with an increase in intracellular ions coming into the cell. With that influx of ions, what follows is the interstitial fluids from the extracellular space merge into the cytosol and the cell organs. So, the cell volume increases, and the cell membrane starts to bleb. There's also swelling of the organelles. While there are multiple causes of cell injury, this is a list of the main causes to cell injury for reference, each of these causes are covered generally on the next slides. Note that these will be covered more fully in the coming units. Let us address ischemia as a cause for cell injury. Ischemia means blood flow is insufficient to maintain homeostasis and metabolic functions or absent (hypoxia or anoxia). The causes include circulatory, metabolism, inadequate respiratory transport, and inadequate transport in the cardiovascular system for example. 1 Loss of aerobic metabolism, reduction in ATP synthesis, accumulation of ions and fluid intracellularly, all cause cells to swell and their function is compromised. Infections are a cause of cell injury, and the most common types are bacterial and viral though note there is a third category: immune reactions which are caused by hypersensitivities or an autoimmune disorder. With bacterial infections, once they penetrate the body, the infection can get to multiple structures and they have in a sense, invaded the host. The first line of defense for the body are things like skin or mucosal membranes, also known as the barriers of the host. The bacteria are then met with an inflammatory response once they have invaded. The byproducts of an inflammatory response are cell injury and death in that local area of infection from the bacteria. But bacteria also produce endotoxins and exotoxins. The endotoxins will induce the synthesis of cytokines like tumor necrosis factor in the interleukins and those are responsible for the systemic manifestations of sepsis. Next, you have the exotoxins and those damage the host cells directly or they disrupt the normal cellular processes of the host cell. Viral infections have a direct or indirect effect on the cell depending on whether they are RNA or DNA viruses. RNA viruses, which have direct cytopathic effects disrupt the integrity of the cell itself while DNA viruses signal the cell to be destroyed by the host’s body. Chemical factors can include carbon monoxide, ammonia, heavy metals (for example mercury and aluminum), alkylating agents in pharmaceutical drugs, and free radicals. Carbon monoxide and ammonia are the cause of most injuries and death in this category. Free radical formation is an unstable byproduct of oxidation which destroys cell membranes. Free radicals are associated with cancer, atherosclerosis, Alzheimer’s disease, and Parkinson’s disease. Physical factors will include blunt trauma, temperature extremes like hypothermia or hyperthermia, radiation and electricity. Mechanical factors fall under physical factors, and these will depend on the characteristics of the load and the tissue tolerance. The result of physical injury can lead to damage to the cell membranes or the intracellular structures. When we're looking at mechanical factors that cause pathology, these are different than the controlled increase in physical stress from exercise which is specifically used to increase tissue tolerance so that you can have muscle hypertrophy 2 or to be able to generate greater forces. Mechanical factors include factors such as these listed. When speaking of nutritional causes of cell injury for example, Vitamin B12 deficiency can lead to neuropathy which is a general term for a grouping of pathologies that cause nerve death or injury. Calcium deficiency for example, can result in poor bone quality, and protein malnutrition can cause weight loss and edema because of the low protein levels in the blood, and diminished capacity for activities and tasks. When speaking of psychosocial factors, those can really impact health as you learn in the Societal Health course. When there are factors present such as fear, tension, anxiety, depression or isolation it impacts the activity level and the participation level of the individual and this will influence and impact thresholds for tissue adaptation and injury In the typical clinical manifestations of inflammation, tissues exhibit redness, swelling, increased temperature, pain, and there could be a decrease in function of the affected tissues. Once the agent is removed or resolved from the system, acute inflammation typically subsides. If there is very little cell death, structure and function remains intact in the tissue. Examples of acute inflammation are blisters, a cut or a scratch, but acute inflammation can also be linked to other pathologies such as atherosclerosis, diabetes and obesity There are local signs and symptoms of inflammation, also known as cardinal signs. Rubor – or redness - comes from a Latin origin. It's due to the vasodilation which gives rise to redness in that local area. There is an increase in blood flow due to histamine and prostaglandins. This also causes vascular permeability, so protein and cellular components will seep out of the vessels and into the injured area which his called exudate and that leads to edema. The next cardinal sign is calor or heat, and that is due to the increased blood flow from the core of the body, which is now a palpable heat on the surface of the tissue. Then there's tumor, which is swelling, and that is due to the capillary fluid shift mechanism. The capillaries become more permeable, then there is a movement of protein and water from the circulation into the interstitial spaces. 3 The last of the Goodman book signs is dolor, which is pain, and there are two classifications of pain in this context. These may be different than when you are in your other courses which may speak of it in a tissue specific way. The first is mechanical pain, which occurs when the swelling or edema causes a pressure on a tissue and the second is biochemical pain. Biochemical pain is the result of inflammatory mediators at the site irritating bare nerve endings. Examples of these mediators are substance P, ions, prostaglandins, and bradykinin. On this slide is an example of cell death Necrosis is the term that refers to the end point of a pathological process. It occurs when there is cell injury and is an irreversible cell injury. Apoptosis on the other hand is programmed cell death. It's genetically mediated like the leaves falling off the tree in the autumn. There is no activation or trigger. In this case the cells will shrink during apoptosis or shrivel. Some of the components of the cells are recycled by other cells and some are absorbed by phagocytes. It's yellow, soft, granular, and it has a cheesy appearance. This is due to the release of lipids from the cell walls of that specific pathogen which is called mycobacterium tuberculosis. The lipases which break down lipids can also combine with calcium, magnesium, and sodium ions and they create soaps or what’s called saponification. That’s an instance where within the necrotic tissue you're going to see opaque and chalk like substances. The remainder of the types of necrosis are on table 6.2 of your Goodman and Fuller textbook for your reference. 4 PHT 5237: Cell Injury and Cell Death Over the next few slides, we will be going over the following topics: agents that can cause cell injury, the difference between reversible and irreversible cell injury, the stages of cell damage, adaptations to cell injury, the mechanisms of cell death, the difference between necrosis and apoptosis, types and causes of necrosis, and the topic of pathological calcification. Cell injury may be reversible or irreversible. When the cell is unable to adapt, injury can occur. With reversible injuries, the stress is sufficiently small in magnitude or short enough in duration that the cell is able to restore homeostasis and recovers the original form. In other words, it will recover its normal cell structure and function. With an irreversible injury, on the other hand, the stress is larger in magnitude or long in duration and this results in cell death, otherwise known as necrosis. When cell injury is irreversible the intracellular proteins will be denatured. There is damage to the cell nucleus and autolysis. So, in other words, the cell will swell and then rupture and release its destructive contents into the extracellular fluid and it will be picked up into the body's circulation system. And what is being released? It's the lysosomal enzymes. Those enzymes will damage the surrounding healthy cells. Irreversible cell injury is synonymous with cell death. When the cell is being exposed to certain types of agents, the reversible cell injury process begins with an increase in intracellular ions coming into the cell. With that influx of ions, what follows is the interstitial fluids from the extracellular space merge into the cytosol and the cell organs. So, the cell volume increases, and the cell membrane starts to bleb. There's also swelling of the organelles. While there are multiple causes of cell injury, this is a list of the main causes to cell injury for reference, each of these causes are covered generally on the next slides. Note that these will be covered more fully in the coming units. Let us address ischemia as a cause for cell injury. Ischemia means blood flow is insufficient to maintain homeostasis and metabolic functions or absent (hypoxia or anoxia). The causes include circulatory, metabolism, inadequate respiratory transport, and inadequate transport in the cardiovascular system for example. 1 Loss of aerobic metabolism, reduction in ATP synthesis, accumulation of ions and fluid intracellularly, all cause cells to swell and their function is compromised. Infections are a cause of cell injury, and the most common types are bacterial and viral though note there is a third category: immune reactions which are caused by hypersensitivities or an autoimmune disorder. With bacterial infections, once they penetrate the body, the infection can get to multiple structures and they have in a sense, invaded the host. The first line of defense for the body are things like skin or mucosal membranes, also known as the barriers of the host. The bacteria are then met with an inflammatory response once they have invaded. The byproducts of an inflammatory response are cell injury and death in that local area of infection from the bacteria. But bacteria also produce endotoxins and exotoxins. The endotoxins will induce the synthesis of cytokines like tumor necrosis factor in the interleukins and those are responsible for the systemic manifestations of sepsis. Next, you have the exotoxins and those damage the host cells directly or they disrupt the normal cellular processes of the host cell. Viral infections have a direct or indirect effect on the cell depending on whether they are RNA or DNA viruses. RNA viruses, which have direct cytopathic effects disrupt the integrity of the cell itself while DNA viruses signal the cell to be destroyed by the host’s body. Chemical factors can include carbon monoxide, ammonia, heavy metals (for example mercury and aluminum), alkylating agents in pharmaceutical drugs, and free radicals. Carbon monoxide and ammonia are the cause of most injuries and death in this category. Free radical formation is an unstable byproduct of oxidation which destroys cell membranes. Free radicals are associated with cancer, atherosclerosis, Alzheimer’s disease, and Parkinson’s disease. Physical factors will include blunt trauma, temperature extremes like hypothermia or hyperthermia, radiation and electricity. Mechanical factors fall under physical factors, and these will depend on the characteristics of the load and the tissue tolerance. The result of physical injury can lead to damage to the cell membranes or the intracellular structures. When we're looking at mechanical factors that cause pathology, these are different than the controlled increase in physical stress from exercise which is specifically used to increase tissue tolerance so that you can have muscle hypertrophy 2 or to be able to generate greater forces. Mechanical factors include factors such as these listed. When speaking of nutritional causes of cell injury for example, Vitamin B12 deficiency can lead to neuropathy which is a general term for a grouping of pathologies that cause nerve death or injury. Calcium deficiency for example, can result in poor bone quality, and protein malnutrition can cause weight loss and edema because of the low protein levels in the blood, and diminished capacity for activities and tasks. When speaking of psychosocial factors, those can really impact health as you learn in the Societal Health course. When there are factors present such as fear, tension, anxiety, depression or isolation it impacts the activity level and the participation level of the individual and this will influence and impact thresholds for tissue adaptation and injury In the typical clinical manifestations of inflammation, tissues exhibit redness, swelling, increased temperature, pain, and there could be a decrease in function of the affected tissues. Once the agent is removed or resolved from the system, acute inflammation typically subsides. If there is very little cell death, structure and function remains intact in the tissue. Examples of acute inflammation are blisters, a cut or a scratch, but acute inflammation can also be linked to other pathologies such as atherosclerosis, diabetes and obesity There are local signs and symptoms of inflammation, also known as cardinal signs. Rubor – or redness - comes from a Latin origin. It's due to the vasodilation which gives rise to redness in that local area. There is an increase in blood flow due to histamine and prostaglandins. This also causes vascular permeability, so protein and cellular components will seep out of the vessels and into the injured area which his called exudate and that leads to edema. The next cardinal sign is calor or heat, and that is due to the increased blood flow from the core of the body, which is now a palpable heat on the surface of the tissue. Then there's tumor, which is swelling, and that is due to the capillary fluid shift mechanism. The capillaries become more permeable, then there is a movement of protein and water from the circulation into the interstitial spaces. 3 The last of the Goodman book signs is dolor, which is pain, and there are two classifications of pain in this context. These may be different than when you are in your other courses which may speak of it in a tissue specific way. The first is mechanical pain, which occurs when the swelling or edema causes a pressure on a tissue and the second is biochemical pain. Biochemical pain is the result of inflammatory mediators at the site irritating bare nerve endings. Examples of these mediators are substance P, ions, prostaglandins, and bradykinin. On this slide is an example of cell death Necrosis is the term that refers to the end point of a pathological process. It occurs when there is cell injury and is an irreversible cell injury. Apoptosis on the other hand is programmed cell death. It's genetically mediated like the leaves falling off the tree in the autumn. There is no activation or trigger. In this case the cells will shrink during apoptosis or shrivel. Some of the components of the cells are recycled by other cells and some are absorbed by phagocytes. It's yellow, soft, granular, and it has a cheesy appearance. This is due to the release of lipids from the cell walls of that specific pathogen which is called mycobacterium tuberculosis. The lipases which break down lipids can also combine with calcium, magnesium, and sodium ions and they create soaps or what’s called saponification. That’s an instance where within the necrotic tissue you're going to see opaque and chalk like substances. The remainder of the types of necrosis are on table 6.2 of your Goodman and Fuller textbook for your reference. 4 PHT 5237: Cellular Adaptations After Injury When injury to the cell is sub lethal or chronic in nature, adaptations can take place within the affected cells, tissues and organs, and this enables the cells to function in an altered environment and avoid injury. Cellular adaptations are a result of a type of stressor or demand on a cell and over time, the cells alter to be able to function. Atrophy is the reduced cell or tissue organ size and examples would be bone loss, muscle wasting, brain cell loss associated with aging. Hypertrophy, on the other hand is the increased size of the cell tissue or organ. Hyperplasia is the increase in number of cells. For example, the endometrium during the menstrual cycle becomes thick under a hormonal regulation and a callous when it's under persistent mechanical pressure is also representative of hyperplasia it's an increase in number of cells in that particular tissue. Metaplasia is a change in cell morphology; in other words, a conversion of one cell type for another due to a persistent stimulus. A great example is the respiratory system of a chronic smoker. The ciliated pseudo stratified columnar cells are replaced and the new cells are stratified squamous epithelial cells capable of withstanding that type of environment. And finally, dysplasia- When sublethal stress remains over a long period of time, it will alter the cell morphology and histology so there will be an increase in cell number and a loss of histological organization and this is considered preneoplastic or pre-cancer. In acute inflammation, the main characteristics are exudation of fluid and plasma proteins and the migration of leukocytes, primarily neutrophils, to the site of injury. The causes can include an infection or an immune reaction. It could be from a foreign body or a reaction to a noxious substance. In chronic inflammation, the inflammation does not resolve, but persists over time. This can also be defined as repeated episodes of acute inflammation. The predominant cells involved in a chronic inflammation are the lymphocytes and the macrophages. In chronic inflammation, the vascular reaction is prolonged. Without resolution, that 1 vascular reaction goes on. Fluid continues to seep into the area and there is proliferation of blood vessels to the region with lymphocytes and macrophages invading the region. When fluid leaks into the anatomic space, it is called an effusion. Effusion is a general term that refers to the escape of fluid and encompasses both transudate and exudate. Transudate occurs with a capillary vessel that is intact and only has imbalances, so fluid moves from the blood vessel to the tissues, this is NOT associated with inflammation. There will be few plasma proteins or leukocytes in that fluid. Transudate is described as clear fluid. The reasons for transudate are usually an increase in hydrostatic pressure or a decrease in colloidal osmotic pressure. With the increase in hydrostatic pressure, more fluid is pushing out, and this resists fluid reabsorption. This is the case for conditions like right sided congestive heart failure which leads to fluid accumulation in the extremities or left congestive heart failure which leads to pulmonary edema. Exudate, which has a higher protein and leukocyte content will be grouped into sub- types next. Exudate, on the other hand, is the result of inflammation. There will be vasodilation and an increase in vascular permeability, and that permeability means that the fluid will be higher in plasma proteins and leukocytes. Now we will take a look at the five different types of inflammatory exudate that are listed. They are typically described based on color, viscosity, odor, amount, and the type of cells that are present in the exudate. Sanguineous exudate is bloody drainage. An example of this type of exudate is a hematoma. Serous exudate is thin, clear, watery fluid. It contains plasma proteins and immunoglobulins, and it is very common in the early stages of most inflammatory responses. An example of serous exudate is a fluid-filled blister. Serosanguinous is blood-tinged, so it's got the serous, which is the clear watery fluid, and a little bit of blood. Cattarhal is a thin and clear mucus like liquid. It is usually seen within mucous membranes like with an upper respiratory infection. 2 Purulent exudate is viscous, cloudy, pussy, and that is filled with leukocytes and debris of dead cells. Abscesses are a great example of purulent exudate and can evolve into more complications and inflammation. A systemic inflammation involves the entire body rather than a single organ or body part and is called septicemia. Septicemia could be caused by bacteria, a virus, or toxins in the blood. It is also commonly referred to as blood poisoning or sepsis and is confused with bacteremia which is the presence of bacteria in the blood. The individual will typically complain of malaise, nausea, loss of appetite, fatigue, amongst other symptoms and is a medial emergency. Fever occurs with systemic inflammation and the fever will cause chills, sweats, and discomfort, and make patients report feeling flushed and warm. It will lead to significantly decreased blood pressure and a raised respiratory rate above 22rpm. Leukocytes and cytokines are released that were triggered by a cascade type effect from damage and those mediate fever, tumor necrosis factor, and interleukin-1. These cause the hypothalamus to upregulate the thermostat and the temperature in the body goes up. Just note that temperatures above 108 Fahrenheit cause brain damage. Sepsis/septicemia categorization continues to evolve and not everyone uses the same definitions or categories. 3 PHT 5237: Role of PT and Tissue Healing As physical therapists, we will play a vital role in addressing pathologies from the perspective of movement and overall well-being. The ICF model, otherwise known as International Classification Framework, provides us with a comprehensive perspective of our patient. We want to know how particular diseases or conditions effect the individual's functional abilities (activities) and if there will be an impact on functional outcomes (participation). We need to be familiar with pathophysiology and understand the precautions and contraindications so we can carefully choose the right interventions for our patients. We also need to understand the disease process and how it can affect the goals and treatment plan for our patients. 1 PHT 5237: Bone Injury and Healing A significant injury to a bone is referred to as a fracture. Some different types of Hematoma formation (inflammatory) phase. Initially, the tissue volume in which new A decision on the part of the physician whether to do surgery or not, depends on the degree of injury and involvement of supporting tissues. Percutaneous Pinning. Percutaneous pinning is a minimally invasive form of internal fixation in which fractures are pinned using Kirschner wires. The pins are driven through the skin and cortex of the bone, across the reduced fracture, and into the opposite cortex. This mode is commonly used in fractures of the phalanges, metacarpals, distal radius, proximal humerus, and metatarsals. The disadvantage of this type of treatment is that the pins can bend or break, not providing absolute stability. External Fixation.This mode of treatment maintains traction and alignment of the bone without the need to confine the patient to a bed. The threaded traction pins are inserted into the bone proximal and distal to the fracture site, and the fracture is manually reduced and fixed in position with carbon fiber bars spanning the fracture site outside the skin. Using fine wires in a circular fixator across the subchondral metaphysis is the least damaging to the medullary blood supply. This type of fixation may provide enough stability to allow rapid endosteal healing without external callus. Open Reduction and Internal Fixation.This mode of treatment aims to reduce anatomically and provide absolute stability to as many of the fracture fragments as possible. A rigidly internally fixed fracture produces no periosteal callus and heals by a combination of endosteal callus and primary cortical union. Locking Plates.Locking plates are fracture fixation devices with threaded screw holes, which allow screws to thread to the plate and function as a fixed-angle scaffold. Intramedullary Nailing.Fracture fixation with intramedullary nails provides relative stability—unless the nail is locked proximally and distally and has tight fixation at the fracture site, the fixation may have rotational and angular instability. An intermedullary nail blocks endosteal healing but allows enough movement to trigger periosteal callus. Early mobilization of patients after femoral and tibial rodding is a major advance compared to the prolonged immobilization in traction 1 Splints and fracture braces are devices that lie along one or more surfaces of an extremity. They are made of prefabricated material (molded plastic) or plaster and secured with an elastic bandage. The splinting/bracing aims to immobilize or passively correct stable fractures, and their use is usually temporary, used for days to a few weeks. Casting provides rigid circumferential support into which appropriate holes and three- point fixation can be incorporated. Casting more effectively immobilizes fracture fragments than either splinting or bracing. Casting is particularly useful for maintaining the reduction of the ankle, tibia, pediatric forearm, and distal radius fractures. Skeletal, also called Buck’s traction is applied either manually or via weights and pulleys to overcome the shortening force of muscles across the fracture site. The configuration of the skeletal traction varies according to the specific bone involved, but its use is dwindling due to the successful development of surgical reduction and internal fixation. Continuous immobilization of connective and skeletal muscle tissues can cause some undesirable consequences. These include the following: Cartilage degeneration. Immobilization of a joint causes atrophic changes in articular cartilage by reducing matrix proteoglycans and cartilage softening. Softened articular cartilage is vulnerable to damage during weight bearing. The reduction of the matrix proteoglycan concentration has been demonstrated to be highest in the superficial zone and occurs throughout the uncalcified cartilage, diminishing with distance from the surface of the articular cartilage. Decreased mechanical and structural properties of ligaments. Following a period of immobilization, CTs are more vulnerable to deformation and breakdown than normal tissues subjected to similar amounts of stress. Decreased bone density. Mechanical forces acting on bone stimulate osteogenesis, and the absence of such forces inhibits osteogenesis. Weakness or atrophy of muscles. Muscle atrophy is an imbalance between protein synthesis and degradation. General and selective muscle atrophy can occur with immobilization. General muscle atrophy typically occurs in one-joint muscles, as two- joint muscles are “less” immobilized by typical immobilization methods. Selective 2 muscle atrophy occurs more often in type I fibers as they are more susceptible to the effects of inactivity, and as their numbers decline, the proportion of type IIa fibers 3 PHT 5237: Periarticular Tissues Injury and Healing There are three principal structures that closely surround, connect, and stabilize the joints of the skeletal system: ligaments, joint capsules, and tendons. None of these structures actually produce active motion, but each play an essential role in joint motion biomechanics. Ligaments and joint capsules guide motion by providing mechanical stability and preventing excessive motion. Function of tendons is to attach muscle to bone and to transmit tensile loads from muscle to bone- thus producing joint motionBoth tendons and ligaments are made up of Type 1 regular collagen in a parallel alignment to protect against tensile loads The joint capsule is made up of Type 1 dense irregular collagen which affords its ability to resist loads in multiple directions. Injury to the joint capsule can result in joint laxity due to injury of the connective tissue and decreased synovium. Synovial fluid gives adds to the joint stability. The joint capsule and the synovium create a fluid filled container that creates joint stability. If the synovium or synovial fluid are altered in any way this can lead to joint instability. The joint capsule does have the capability of healing due to its vascular supply and the joint can regain stability from the capsular healing. The key is treating the joint capsule correctly through appropriate immobilization and dynamic stability training. Th key with joint capsule injury is to prevent scar tissue to obtain better function al results along with managing joint effusion and loading. Remember the joint capsule creates a closed container that is dependent on the right amount of synovial fluid withing the joint to maintain the stability and extensibility of the joint. The physical stress theory was described in MS 1 and is a good framework for all visoelastic tissues in the body where an appropriate load on a tissue will keep it healthy whereas not enough of a load will lead to atrophy and too much load can lead to injury and death of tissues. This is an example of a load deformation curve that you will see again in Biomechanics. Figure 3-5 A stress-strain curve for a tendon loaded until failure. The load (force) applied to the tissue has been divided by the cross-sectional area to calculate the 1 stress, while the increase in length is divided by the original length to give the strain (ΔL/L × 100). In the toe region of the curve, the crimped collagen fibers straighten, which requires little force. In the linear region, the tendon resists deformation through cross-linking between molecules and friction between fibrils. The slope of this part of the curve is the stiffness of the tissue, and it reflects the material properties of the tissue. Less physical deformation should reduce the likelihood of injury, which occurs in the region of 6% to 10% strain. After the linear region, the stress-strain curve becomes irregular as fibrils begin to fail. Figure A Top, a direct insertion with its four morphological zones: tendon (T), uncalcified fibrocartilage (UF), calcified cartilage (CF), and bone (B). The femoral insertion of the medial collateral ligament is an example of a direct insertion. Figure B, an indirect insertion where the deep fibers of the ligament (L) pass into bone through a well-defined zone of fibrocartilage (F). The arrow represents the line of calcification Ligament attachment to bone is by direct or indirect transition. Direct ligament insertion into bone represents a gradual change from specific ligament fiber to fibrocartilage to calcified fibrocartilage to bone. With indirect insertion, the superficial layers of ligament fibers attach directly in the periosteum, whereas the deep fibers transition to bone by way of Sharpey's perforating fibers. (Shankman, 2004) There appears to be a gradual change in ligament architecture as the ligament approaches bone that involves a modification of both the cellular and extracellular matrix. Collagen fibers that make up the ligament appear to be cemented into the bone during ligament growth and development, forming “Sharpey's fibers” at the ligament insertions. The cells at the bone–soft tissue interface in ligaments are different from those in the midsubstance. It appears that the ligament cells undergo a transition from fibroblasts (cells that produce and maintain the ligament midsubstance), through fibrocartilaginous cells (producing fibrocartilaginous material withi n 100 μm of the bone interface), to an area where fibrocartilage calcifies (at the surface of the bone), finally merging into an area with bone as depicted in A. From a functional point of view, this transition permits a progressive stiffening of the ligament, thus decreasing the likelihood of concentration of stresses at the ligament–bone interface and minimizing the chance of failure at this site. (Magee, 2007) There are three grades or classification of ligament injuries 2 In Grade I tears have some collagen fibers torn but no laxity is present but there is pain associated with the injury In Grade II tears laxity is now present with some increased number of fibers torn with pain In Grade III complete tear, typically no symptoms however there is marked laxity Ligamentous healing is dependent on controlled movement and low cyclical loads to promote scar proliferation. This is a chart that represents tissue response to injury and the time to maturation ( remodeling). Note in the proliferative phase around two weeks after injury you get a decrease in the GAG's, decrease in type III collagen and replaced with Type I collagen along with an increase in cross linking. Controlled mobility and loading is vital to promoting ligamentous healing. Not all ligaments heal at the same rate or to the same degree. Three conditions are needed to promote ligament healing. Ligament ends must be in contact with each other. A progressive controlled loading or stress must be applied to the healing tissue to orient scar tissue formation. The ligament must be protected against excessive forces during the remodeling phase. A decision on the part of the physician whether to do surgery or not, depends on the degree of injury and involvement of supporting tissues. Ligament tears or injuries that are not managed correctly will be biomechanically inferior and generally are not healed even at 40 weeks after injury. When an intraarticular ligament, such as the ACL, is injured, the intra- articular environment interferes with the formation of the fibrin clot, which in turn disrupts the healing process. Therefore, intra-articular ligaments do not heal spontaneously and will require surgery to heal especially in high performance athletes. Whereas capsular ligaments or extra-articular ligaments like the collateral ligaments are able to heal with conservative management, depending on the extent of the injury. It is possible that synovial fluid, surrounding the intra-articular ligament, dilutes clot formation at the ends of the injured ligament (fibrolytic enzyme). What this means is that there is no clot or scaffolding holding the two ends of the ligament together 3 Pictured here is a Collagen-coated FiberTape outside of the native ulnar collateral ligament at the medial elbow to augment or strengthen the ligament repair in severe grade II or grade III injuries. This FiberTape can also be used to reconstruct a ligament that is unrepairable. With the emerging field of orthobiologics and regenerative therapies, innovative materials are being developed and are being more commonly used in the surgical treatment of ligaments. The collagen coated FiberTape and ligament augmentation surgeries are transforming rehabilitation because the fiber tape is stronger immediately postoperatively, allowing for a more aggressive rehab protocol and earlier return to competition as compared to a conventional repair or reconstructive surgery. When looking at the comparison of the rate of different tissue’s healing time frames, the main difference is that the fibroplasia and repair phase lasts until about 3-4 weeks- so most ligament repairs are going to be highly protected until that time- meaning although motion is often allowed- any direct stresses to the ligament will be minimized through bracing or orthotic devices usually. The same is true for tendon injuries. Extra articular ligaments Heal with the sequential cascade overlapping events Inflammatory phase - Ends of ligament retract and hematoma forms between the ends Chemical mediators released causing vasodilation and inflammation Repair – proliferation Production of type III collagen Neurovascularization. During the proliferative stage Type III collagen is laid down and replaced with Type I collagen and aligns in response to stress What are some of the chemical mediators of vasodilation, cell wall permeability, and pain? Prostaglandins, histamine, bradykinins, and serotonin are mobilized to the trauma site to increase capillary permeability Which cells migrate? inflammatory polymorphonuclear cells and lymphocytes to the injured tissue to initiate the action of phagocytosis. The predominant cell types present during the acute 4 inflammatory phase are neutrophils and lymphocytes. Monocytes are referred to as macrophages as they become phagocytes. 5 PHT 5237C: Periarticular Tissues Immobilization, Healing, and Safe Load Bearing Although the mechanisms are not clear, ligament complexes are extremely sensitive to load and load history. Load deprivation (joint immobilization) causes a rapid deterioration in ligament biochemical and mechanical properties, partially because of atrophy (a decrease in ligament mass), which causes a net loss in ligament strength and stiffness. Experimental evidence suggests that immobility causes a net shift in ligament cell metabolism from a balanced (homeostatic) state or a net anabolic (building) state to a more catabolic (destructive) state. A few weeks of immobilization causes the ligament matrix to decrease in quantity. Ligament cells also apparently produce inferior-quality ligament material, which contributes to the structural weakening of the ligament complex. Bone begins to resorb, causing a focal weakness at the sites of insertion. The loss of ligament complex strength with immobilization appears to be exponential over time. Although there is only slight weakening in the first few weeks, ligament complexes that have been completely immobilized for periods of 6 to 9 weeks are only about 50% as strong and stiff as normal controls. From a functional therapeutic view, this implies that periods of joint immobilization should ideally, for the sake of the ligaments at least, be minimized. Joint stiffness after immobilization is probably not caused by ligament deterioration; in fact, ligaments are less stiff after periods of immobilization. Magee, 2007 Muscle shortening, thickening joint capsule and cartilage; decreased capsular remodeling, pronounced reduction of GAGs, decreased water content, decreased tissue compliance, adhesion formation, fissures in cartilage all result in periarticular contracture development Figure 2-16 New Zealand white rabbit medial collateral ligament scars subject to immobilization (A) and exercise (B). Note that the scar from the immobilized ligament is small compared with the scar from the exercised ligament. (From Frank CB: Ligament 1 injuries: pathophysiology and healing. In Zachazewski JE, Magee DJ, Quillen WS, editors: Athletic injuries and rehabilitation, p 21, Philadelphia, 1996, WB Saunders.) As with normal ligaments, exercise has some powerful influences on ligament scars. Joint movement during ligament healing definitely has some beneficial effects on the joint tissues, the uninjured ligaments, and the healing ligament as long as forces on the healing tissues are not too great. 2