A mismatch in the activity of regulatory factors and an imbalance in their interactions at one stage or another of repair may lead to impaired healing of a bone wound. The literature contains many studies devoted to disorders of osteoreparation. Of particular interest is the work of a team of authors from the SI «Kharkiv Institute of Spine and Joint Pathology», which summarizes clinical and experimental data on disorders of bone fragment union. Considering reparative osteogenesis as a multilevel and multiphase process of cellular response to injury, the authors note that most causes of delayed union or nonunion of fractures are associated with the early stage of regeneration, where a «biological failure» of the genetically programmed tissue restoration process may occur. Disturbances in the formation of tissue regenerate may also arise at later stages. Among the causes that disrupt osteoreparation, the authors distinguish three groups. The first group includes causes that negatively affect the functional state of bone tissue before and after trauma. The second group includes causes associated with the trauma itself. The third group includes causes that affect the course of reparative osteogenesis during treatment.
The condition of bone tissue before and after trauma is significantly influenced by age, nutrition, hormonal status, vitamin deficiency, and other factors. A number of studies have shown that fracture healing slows with increasing biological age. Experiments in mice showed that periosteal reaction formation is more pronounced in young animals than in old ones. This is associated with the fact that the periosteum in young animals has greater cellularity and vascularization, while in adult animals it is represented by a fibrous layer. Slower reparative processes with age are linked to a decrease in the number of progenitor cells in bone marrow and a reduction in their proliferative and osteoblastic activity. It has been noted that in children one stromal cell is found per 10 thousand bone marrow cells, whereas in adults one stromal cell is found per 2 million cells. Reduced activity of progenitor cells is associated with decreased collagen biosynthesis and disruption of collagen fiber formation in the intercellular substance. Literature data indicate that with age proteoglycan biosynthesis decreases, the crystalline and amorphous structure of bone tissue changes, and the level of biochemical markers of bone metabolism – Gla protein and alkaline phosphatase – decreases. This, in turn, has a significant effect on the rate of formation of bone regenerate components. Some studies also show that gene activity involved in regenerative processes decreases in cells with age.
The rate of regenerate formation and mineralization is significantly influenced by deficiency of calcium, phosphorus, and proteins. Vitamin A deficiency slows osteoid formation by osteoblasts, while vitamin C deficiency disrupts collagen formation and intercellular substance formation, inhibiting bone formation. Delayed regeneration may be associated with vitamin D3 deficiency, which directly affects metabolic processes and osteoblast differentiation, as well as with vitamin K deficiency, which is necessary for the biosynthesis of liver proteins involved in coagulation. Bone non-collagenous proteins – osteocalcin and Gla protein – produced by osteoblasts and involved in forming the regenerate matrix and its mineralization, are vitamin K-dependent proteins. Therefore, a decreased vitamin K level disrupts the formation of a complete bone regenerate. Bone tissue is also significantly influenced by a number of hormones and hormone-like substances. Parathyroid hormone reduces the content of type I collagen, alkaline phosphatase, osteocalcin, and osteonectin, slowing bone tissue formation. Increased blood cortisone enhances bone tissue destruction and disrupts the synchrony of regenerate structure formation. Thyroxine deficiency slows mineralization, while sex hormone deficiency contributes to reduced mechanical properties of the regenerate.
In addition to the functional state of bone tissue before trauma, the type of traumatic agent and the nature of bone tissue damage have a significant effect on the reparative process. In the philosophical article «Fracturology – some aspects of theorizing the doctrine of bone fractures. Part 1. On the genesis of fracture syndrome», B.I. Simenach places «injury» first in the «genesis of bone fracture», considering it the factor that carries the cause of «fracture syndrome». In other words, a bone fracture, as a pathological condition, develops according to laws characteristic of any disease. Any disease can arise only in the presence of an etiological factor, and the intensity of its effect plays a determining role in the development and course of the disease. The etiological factor of bone fractures is an external force that exceeds the strength limits of bone tissue. Therefore, the course of a disease such as bone fracture depends on the severity of the etiological factor – mechanical force. Studies by A.V. Kalashnikov showed that in 55% of patients with impaired reparative osteogenesis, trauma occurred due to a high-energy traumatic agent (road traffic accidents and industrial injuries involving moving mechanisms). In 24% of cases the trauma was medium-energy, and in 21% it was low-energy (falling on the side or unsuccessful extension of the limb).
Although mechanical force as the etiological factor of fracture, which triggers a cascade of pathological and adaptive mechanisms, is important in the course of reparative osteogenesis, detailed literature sources on the relationship between traumatic energy and the duration of bone wound healing could not be found. There are also no data in the literature on the morphofunctional state of cellular sources of osteoreparation depending on the intensity of the traumatic agent acting on them.
An important condition for the course of any wound process, including a bone wound, is the completed inflammatory phase and the creation of conditions for normalization of energy production and the possibility of excessive anabolism. The timing of this state is significantly influenced by blood circulation in the damaged area and in the limb segment as a whole. Disintegration of blood supply caused by trauma leads to impaired tissue oxygenation. The severity and extent of vascular disorders, destabilization of microangioarchitectonic ultrastructures, and especially venous outflow pathways are directly dependent on the energy of the traumatic agent. Progression of dystrophic processes in limb tissues after trauma largely depends on post-traumatic microangiopathies that develop against the background of disorders in the venous part of the microcirculatory bed. This leads to the formation of transendothelial channels and openings, plasma impregnation of vessel walls, hyalinosis, and sclerosis. As a result, transcapillary exchange is disrupted, hypoxia increases, and trophic support of limb tissues significantly worsens. At the same time, a decrease in volumetric blood flow in the microcirculatory bed of the damaged area disrupts information processes between the injury zone and lymphoid organs and, consequently, slows or reduces the inflammatory process. The duration of the stage of destruction and cell dedifferentiation is significantly affected by imbalance of energy processes. Due to hypoxia in damaged tissues, the ratio of cyclic nucleotides (cAMP and cGMP), through which neurohumoral regulation of biochemical processes in the cell is mediated, is disturbed. As a result, regulatory mechanisms of cellular energy consumption are disrupted and no longer correspond to the rate of energy production. The result of this energy imbalance is the predominance of ergotropic processes over trophotropic ones and assimilation over dissimilation.
Among the third group of factors (causes affecting the course of reparative osteogenesis during treatment), the greatest importance is attributed to unjustified changes in treatment methods, instability in the «bone-bone» system, mismatch between treatment methods and fixation techniques and the nature of traumatic injury, tissue defects in the fracture area, impaired bone metabolism, delayed vascularization, and bone atrophy. These factors may be supplemented by biomechanical mismatch syndrome, which means that the load on the injured segment (insufficient or excessive load) does not correspond to the course of reparative processes. This may lead to deformation of the regenerate and the development of secondary hemodynamic and local metabolic disorders, and consequently to dysregeneration. A number of studies based on in-depth research into human lower limb biomechanics and experimental data have shown that bone regenerate at different stages of formation has a certain resistance to shear, rotational, and compressive loads. Experimental models have shown that if any of these loads exceed the maximum permissible values during fracture treatment, regenerate formation slows sharply or stops altogether. According to some authors, failures in bone fragment union are most often associated with an inadequate choice of treatment method and insufficient consideration of the biological and biomechanical characteristics of bone tissue.
A mismatch in the activity of regulatory factors and an imbalance in their interactions at one stage or another of repair may lead to impaired healing of a bone wound. The literature contains many studies devoted to disorders of osteoreparation. Of particular interest is the work of a team of authors from the SI «Kharkiv Institute of Spine and Joint Pathology», which summarizes clinical and experimental data on disorders of bone fragment union. Considering reparative osteogenesis as a multilevel and multiphase process of cellular response to injury, the authors note that most causes of delayed union or nonunion of fractures are associated with the early stage of regeneration, where a «biological failure» of the genetically programmed tissue restoration process may occur. Disturbances in the formation of tissue regenerate may also arise at later stages. Among the causes that disrupt osteoreparation, the authors distinguish three groups. The first group includes causes that negatively affect the functional state of bone tissue before and after trauma. The second group includes causes associated with the trauma itself. The third group includes causes that affect the course of reparative osteogenesis during treatment.
The condition of bone tissue before and after trauma is significantly influenced by age, nutrition, hormonal status, vitamin deficiency, and other factors. A number of studies have shown that fracture healing slows with increasing biological age. Experiments in mice showed that periosteal reaction formation is more pronounced in young animals than in old ones. This is associated with the fact that the periosteum in young animals has greater cellularity and vascularization, while in adult animals it is represented by a fibrous layer. Slower reparative processes with age are linked to a decrease in the number of progenitor cells in bone marrow and a reduction in their proliferative and osteoblastic activity. It has been noted that in children one stromal cell is found per 10 thousand bone marrow cells, whereas in adults one stromal cell is found per 2 million cells. Reduced activity of progenitor cells is associated with decreased collagen biosynthesis and disruption of collagen fiber formation in the intercellular substance. Literature data indicate that with age proteoglycan biosynthesis decreases, the crystalline and amorphous structure of bone tissue changes, and the level of biochemical markers of bone metabolism – Gla protein and alkaline phosphatase – decreases. This, in turn, has a significant effect on the rate of formation of bone regenerate components. Some studies also show that gene activity involved in regenerative processes decreases in cells with age.
The rate of regenerate formation and mineralization is significantly influenced by deficiency of calcium, phosphorus, and proteins. Vitamin A deficiency slows osteoid formation by osteoblasts, while vitamin C deficiency disrupts collagen formation and intercellular substance formation, inhibiting bone formation. Delayed regeneration may be associated with vitamin D3 deficiency, which directly affects metabolic processes and osteoblast differentiation, as well as with vitamin K deficiency, which is necessary for the biosynthesis of liver proteins involved in coagulation. Bone non-collagenous proteins – osteocalcin and Gla protein – produced by osteoblasts and involved in forming the regenerate matrix and its mineralization, are vitamin K-dependent proteins. Therefore, a decreased vitamin K level disrupts the formation of a complete bone regenerate. Bone tissue is also significantly influenced by a number of hormones and hormone-like substances. Parathyroid hormone reduces the content of type I collagen, alkaline phosphatase, osteocalcin, and osteonectin, slowing bone tissue formation. Increased blood cortisone enhances bone tissue destruction and disrupts the synchrony of regenerate structure formation. Thyroxine deficiency slows mineralization, while sex hormone deficiency contributes to reduced mechanical properties of the regenerate.
In addition to the functional state of bone tissue before trauma, the type of traumatic agent and the nature of bone tissue damage have a significant effect on the reparative process. In the philosophical article «Fracturology – some aspects of theorizing the doctrine of bone fractures. Part 1. On the genesis of fracture syndrome», B.I. Simenach places «injury» first in the «genesis of bone fracture», considering it the factor that carries the cause of «fracture syndrome». In other words, a bone fracture, as a pathological condition, develops according to laws characteristic of any disease. Any disease can arise only in the presence of an etiological factor, and the intensity of its effect plays a determining role in the development and course of the disease. The etiological factor of bone fractures is an external force that exceeds the strength limits of bone tissue. Therefore, the course of a disease such as bone fracture depends on the severity of the etiological factor – mechanical force. Studies by A.V. Kalashnikov showed that in 55% of patients with impaired reparative osteogenesis, trauma occurred due to a high-energy traumatic agent (road traffic accidents and industrial injuries involving moving mechanisms). In 24% of cases the trauma was medium-energy, and in 21% it was low-energy (falling on the side or unsuccessful extension of the limb).
Although mechanical force as the etiological factor of fracture, which triggers a cascade of pathological and adaptive mechanisms, is important in the course of reparative osteogenesis, detailed literature sources on the relationship between traumatic energy and the duration of bone wound healing could not be found. There are also no data in the literature on the morphofunctional state of cellular sources of osteoreparation depending on the intensity of the traumatic agent acting on them.
An important condition for the course of any wound process, including a bone wound, is the completed inflammatory phase and the creation of conditions for normalization of energy production and the possibility of excessive anabolism. The timing of this state is significantly influenced by blood circulation in the damaged area and in the limb segment as a whole. Disintegration of blood supply caused by trauma leads to impaired tissue oxygenation. The severity and extent of vascular disorders, destabilization of microangioarchitectonic ultrastructures, and especially venous outflow pathways are directly dependent on the energy of the traumatic agent. Progression of dystrophic processes in limb tissues after trauma largely depends on post-traumatic microangiopathies that develop against the background of disorders in the venous part of the microcirculatory bed. This leads to the formation of transendothelial channels and openings, plasma impregnation of vessel walls, hyalinosis, and sclerosis. As a result, transcapillary exchange is disrupted, hypoxia increases, and trophic support of limb tissues significantly worsens. At the same time, a decrease in volumetric blood flow in the microcirculatory bed of the damaged area disrupts information processes between the injury zone and lymphoid organs and, consequently, slows or reduces the inflammatory process. The duration of the stage of destruction and cell dedifferentiation is significantly affected by imbalance of energy processes. Due to hypoxia in damaged tissues, the ratio of cyclic nucleotides (cAMP and cGMP), through which neurohumoral regulation of biochemical processes in the cell is mediated, is disturbed. As a result, regulatory mechanisms of cellular energy consumption are disrupted and no longer correspond to the rate of energy production. The result of this energy imbalance is the predominance of ergotropic processes over trophotropic ones and assimilation over dissimilation.
Among the third group of factors (causes affecting the course of reparative osteogenesis during treatment), the greatest importance is attributed to unjustified changes in treatment methods, instability in the «bone-bone» system, mismatch between treatment methods and fixation techniques and the nature of traumatic injury, tissue defects in the fracture area, impaired bone metabolism, delayed vascularization, and bone atrophy. These factors may be supplemented by biomechanical mismatch syndrome, which means that the load on the injured segment (insufficient or excessive load) does not correspond to the course of reparative processes. This may lead to deformation of the regenerate and the development of secondary hemodynamic and local metabolic disorders, and consequently to dysregeneration. A number of studies based on in-depth research into human lower limb biomechanics and experimental data have shown that bone regenerate at different stages of formation has a certain resistance to shear, rotational, and compressive loads. Experimental models have shown that if any of these loads exceed the maximum permissible values during fracture treatment, regenerate formation slows sharply or stops altogether. According to some authors, failures in bone fragment union are most often associated with an inadequate choice of treatment method and insufficient consideration of the biological and biomechanical characteristics of bone tissue.