The biology of fracture healing is a complex process that involves both intramembranous and endochondral bone formation. It begins with an acute inflammatory response after trauma that recruits mesenchymal stem cells. These cells generate a cartilaginous callus and periosteal bony callus through endochondral and intramembranous ossification, respectively. The cartilaginous callus then undergoes revascularization and is remodeled into bone through resorption and replacement with woven bone. This process recapitulates bone development and allows fractures to heal without scarring.
Given the high and rising figures of people with osteoarthritis, knowledge of new factors defining course and evolution of the disease are important, when considering new pharmacological targets. IL-1 is a very important cytokine in the early steps
of osteoarthritis, giving the high sensitivity of the chondrocytes to this cytokine, and it can be considered the bridge allowing the dialogue between the different structures of the articulation, in such a way that the cartilage is not the only tissue affected in OA. IL-1 increases the destruction of the extracellular matrix of the cartilage increasing the collagenolytic activity of metalloproteases, increasing activity of nytric oxide ON, wich can induce apoptosis of chondrocytes. Interestingly, IL-1 further induces changes in the homeostasis of the cartilage, lessening activity of growth factors, such as TGF-beta.
This document discusses osteoporosis and bone fragility. It begins by defining key terms like osteoporosis, bone fragility, and T-scores. It then discusses the importance of both bone quantity and quality in determining fracture risk. The document outlines the key regulators of bone remodeling like RANK, RANKL, and OPG. It explains how chronic immune activation can uncouple the bone remodeling process and lead to increased fragility through a diversion of stem cell differentiation toward osteoclast formation. Finally, it discusses how biomarkers can help evaluate nutritional interventions aimed at reducing inflammation and supporting bone health.
This document summarizes a study that investigated the effects of total knee arthroplasty (TKA) and neuromuscular electrical stimulation (NMES) on mitochondrial subpopulations in skeletal muscle. The study found that TKA caused significant muscle atrophy and loss of both subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria. NMES prevented muscle atrophy and maintained IMF mitochondrial content but not SS mitochondrial content. Specifically, TKA reduced IMF mitochondrial area by 19% and SS mitochondria per unit of sarcolemma by 64%, while NMES maintained IMF mitochondrial area above baseline and reduced the SS mitochondrial loss to 55%. The results suggest that decreased neural activation following TKA leads to mitochondrial
The document discusses how gene therapy can be used to better understand and treat musculoskeletal disorders and injuries by promoting tissue regeneration through localized delivery of growth factors and cytokines. It outlines how viral and non-viral vectors can be used to introduce therapeutic genes into tissues to accelerate healing and reduce recovery time for conditions like fractures, osteoarthritis, tendon injuries, and muscular dystrophy.
This document discusses critical illness-acquired weakness (ICUAW), including its prevalence, risk factors, outcomes, and diagnostic criteria. The main points are:
First, ICUAW occurs in approximately 50% of adult ICU patients receiving prolonged mechanical ventilation or those with sepsis/multiple organ failure.
Second, while hyperglycemia is associated with ICUAW, studies have not consistently supported other accepted risk factors like glucocorticoids or neuromuscular blockers.
Third, ICUAW increases duration of mechanical ventilation and hospitalization, and may cause long-term neuromuscular weakness, though it does not reliably predict mortality. Diagnosis is challenging due to heterogeneity.
Early rehabilitation and mobil
We report the 11-year follow-up of a premenopausal woman with osteogenesisimperfecta (OI) who
was treated with alendronate. A 41-year-old Japanese premenopausal woman with OI type I who had
frequently experienced painful fragility fractures consulted our clinic because of chronic back pain associated
with spinal osteoporosis. She had undergone heart surgery (aortic valve replacement) because of aortic
regurgitation 5 years before her first consultation with our clinic. After surgery, she began taking warfarin (3
mg/day), and this treatment was continued during our follow-up period. She was treated with alendronate (5
mg/day or 35 mg/week) for 11 years. The patient’s urinary cross-linked N-terminal telopeptides of type I
collagen and serum alkaline phosphatase levels decreased, while the bone mineral density of her lumbar
spine (L2–L4) increased, as measured using dual energy X-ray absorptiometry. The serum calcium and
phosphorus levels stayed within the normal ranges. Three non-vertebral fractures occurred at the hip, ankle,
and ring finger during the 11-year treatment period, but no adverse effects were observed. Thus, the present
case report showed the long-term outcome and safety of alendronate treatment in a premenopausal woman
with OI type I.
Bone fracture healing is a complex process that proceeds through several stages: inflammation and hematoma formation, cellular proliferation and soft callus formation, hard callus formation and consolidation. It is influenced by local, chemical, vascular, systemic and treatment factors. Recent advances to enhance healing include bone grafts, bone marrow aspirate, growth factors, platelet rich plasma, laser therapy, and tissue engineering techniques.
Adult Stem cells in Orthopaedics present and future perspectives.
Παρουσίαση του Δρ. Σταύρου Αλευρογιάννη που έγινε στο ξενοδοχείο Χίλτον, στις 12/06/15 στα πλαίσια Ημερίδας της Ελληνικής Εταιρείας Αναγεννητικής Ιατρικής, Αντιγήρανσης και Βιοτεχνολογίας, στο 41ο Πανελλήνιο Ιατρικό Συνέδριο.
"H θέση της αναγεννητική Ιατρικής στις παθήσεις Οστών και Αρθρώσεων"
Given the high and rising figures of people with osteoarthritis, knowledge of new factors defining course and evolution of the disease are important, when considering new pharmacological targets. IL-1 is a very important cytokine in the early steps
of osteoarthritis, giving the high sensitivity of the chondrocytes to this cytokine, and it can be considered the bridge allowing the dialogue between the different structures of the articulation, in such a way that the cartilage is not the only tissue affected in OA. IL-1 increases the destruction of the extracellular matrix of the cartilage increasing the collagenolytic activity of metalloproteases, increasing activity of nytric oxide ON, wich can induce apoptosis of chondrocytes. Interestingly, IL-1 further induces changes in the homeostasis of the cartilage, lessening activity of growth factors, such as TGF-beta.
This document discusses osteoporosis and bone fragility. It begins by defining key terms like osteoporosis, bone fragility, and T-scores. It then discusses the importance of both bone quantity and quality in determining fracture risk. The document outlines the key regulators of bone remodeling like RANK, RANKL, and OPG. It explains how chronic immune activation can uncouple the bone remodeling process and lead to increased fragility through a diversion of stem cell differentiation toward osteoclast formation. Finally, it discusses how biomarkers can help evaluate nutritional interventions aimed at reducing inflammation and supporting bone health.
This document summarizes a study that investigated the effects of total knee arthroplasty (TKA) and neuromuscular electrical stimulation (NMES) on mitochondrial subpopulations in skeletal muscle. The study found that TKA caused significant muscle atrophy and loss of both subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria. NMES prevented muscle atrophy and maintained IMF mitochondrial content but not SS mitochondrial content. Specifically, TKA reduced IMF mitochondrial area by 19% and SS mitochondria per unit of sarcolemma by 64%, while NMES maintained IMF mitochondrial area above baseline and reduced the SS mitochondrial loss to 55%. The results suggest that decreased neural activation following TKA leads to mitochondrial
The document discusses how gene therapy can be used to better understand and treat musculoskeletal disorders and injuries by promoting tissue regeneration through localized delivery of growth factors and cytokines. It outlines how viral and non-viral vectors can be used to introduce therapeutic genes into tissues to accelerate healing and reduce recovery time for conditions like fractures, osteoarthritis, tendon injuries, and muscular dystrophy.
This document discusses critical illness-acquired weakness (ICUAW), including its prevalence, risk factors, outcomes, and diagnostic criteria. The main points are:
First, ICUAW occurs in approximately 50% of adult ICU patients receiving prolonged mechanical ventilation or those with sepsis/multiple organ failure.
Second, while hyperglycemia is associated with ICUAW, studies have not consistently supported other accepted risk factors like glucocorticoids or neuromuscular blockers.
Third, ICUAW increases duration of mechanical ventilation and hospitalization, and may cause long-term neuromuscular weakness, though it does not reliably predict mortality. Diagnosis is challenging due to heterogeneity.
Early rehabilitation and mobil
We report the 11-year follow-up of a premenopausal woman with osteogenesisimperfecta (OI) who
was treated with alendronate. A 41-year-old Japanese premenopausal woman with OI type I who had
frequently experienced painful fragility fractures consulted our clinic because of chronic back pain associated
with spinal osteoporosis. She had undergone heart surgery (aortic valve replacement) because of aortic
regurgitation 5 years before her first consultation with our clinic. After surgery, she began taking warfarin (3
mg/day), and this treatment was continued during our follow-up period. She was treated with alendronate (5
mg/day or 35 mg/week) for 11 years. The patient’s urinary cross-linked N-terminal telopeptides of type I
collagen and serum alkaline phosphatase levels decreased, while the bone mineral density of her lumbar
spine (L2–L4) increased, as measured using dual energy X-ray absorptiometry. The serum calcium and
phosphorus levels stayed within the normal ranges. Three non-vertebral fractures occurred at the hip, ankle,
and ring finger during the 11-year treatment period, but no adverse effects were observed. Thus, the present
case report showed the long-term outcome and safety of alendronate treatment in a premenopausal woman
with OI type I.
Bone fracture healing is a complex process that proceeds through several stages: inflammation and hematoma formation, cellular proliferation and soft callus formation, hard callus formation and consolidation. It is influenced by local, chemical, vascular, systemic and treatment factors. Recent advances to enhance healing include bone grafts, bone marrow aspirate, growth factors, platelet rich plasma, laser therapy, and tissue engineering techniques.
Adult Stem cells in Orthopaedics present and future perspectives.
Παρουσίαση του Δρ. Σταύρου Αλευρογιάννη που έγινε στο ξενοδοχείο Χίλτον, στις 12/06/15 στα πλαίσια Ημερίδας της Ελληνικής Εταιρείας Αναγεννητικής Ιατρικής, Αντιγήρανσης και Βιοτεχνολογίας, στο 41ο Πανελλήνιο Ιατρικό Συνέδριο.
"H θέση της αναγεννητική Ιατρικής στις παθήσεις Οστών και Αρθρώσεων"
Understanding the molecular biology of intervertebral disc degeneration and p...CarlosAlbertoMontesM
This document reviews gene therapy strategies for treating intervertebral disc degeneration. It discusses the molecular biology and etiology of disc degeneration, which involves an imbalance between catabolism and anabolism leading to loss of extracellular matrix. Current treatments only relieve symptoms and do not address the underlying pathology. The review examines growth factor therapy, cell therapy, and gene therapy approaches for regeneration. Gene therapy was initially mediated by viral vectors but recent advances allow for non-viral methods to avoid risks of mutagenesis and infection. With further progress, non-viral gene therapy may prove effective for treating disc degeneration.
This document discusses collagen and its role in connective tissues, specifically in the extra-articular environment of joints. It notes that collagen Type I makes up the majority of structures like ligaments, tendons and joint capsules that provide stability and containment of joints. Deficiencies or damage to collagen Type I can lead to joint laxity and hypermobility, causing pain and impaired movement. The document reviews clinical studies on the use of injectable collagen medical devices to treat algic and degenerative diseases of the musculoskeletal system by supplementing damaged collagen in joints.
This document discusses fracture healing and bone repair. It describes the complex cellular and molecular processes involved, including inflammation, soft and hard callus formation, and remodeling. Failure of healing can occur through atrophic, hypertrophic, oligotrophic, or delayed nonunion. Treatment options to promote healing include autografts, allografts, bone graft substitutes, growth factors, and mechanical or electrical stimulation techniques.
1. Critical illness myopathy and neuropathy are common complications experienced by ICU patients that can last for years, increasing mortality, length of stay, and reducing quality of life.
2. They are caused by factors like prolonged immobilization, infections, medications, and underlying illnesses and can involve both nerve and muscle damage.
3. Diagnosis involves electromyography and assessing for denervation and reduced nerve and muscle potentials, while treatment focuses on minimizing harmful factors and improving recovery.
This document discusses the use of adult stem cells, specifically mesenchymal stem cells (MSCs), in orthopedics. It provides several examples of how MSCs derived from bone marrow have been used to treat orthopedic injuries and conditions. These include using bone marrow concentrate to treat non-unions, avascular necrosis, and promote healing in ACL reconstruction, spinal fusions, and rotator cuff injuries. Studies show MSCs can reduce healing times and promote stronger tissue regeneration compared to other treatments like corticosteroids or autografts. The document also discusses how MSCs may help regenerate cartilage and treat osteoarthritis by reducing pain and slowing degeneration.
Bone healing is a complex process involving four main elements: osteogenic cells, growth factors, an osteoconductive scaffold, and mechanical stability. It can occur through either direct bone healing with contact between bone ends and no callus formation, or indirect bone healing which involves four phases - inflammatory, granulation, hard callus formation, and remodeling. Complications of fractures can arise from associated pathologies and aggressive treatment is needed to minimize disabilities.
Healing of Bone - Dr. Shweta Yadav - Oral and Maxillofacial SurgeryDr. Shweta Yadav
Bone healing is a complex process that occurs in multiple stages to restore injured bone. It involves inflammation, cell proliferation, callus formation, consolidation, and remodeling. There are two main types: healing by direct union, which occurs when fracture ends are close together; and healing by callus formation, which involves five stages over several months. Many local and systemic factors can influence bone healing, and treatment aims to properly position fragments, stabilize fractures, and use grafting when needed. Complications include malunion, delayed healing, non-union, and infection.
Cytotherapy for osteonecrosis of hip.acta medica internationalSanjeev kumar Jain
The document discusses the use of cytotherapy, specifically autologous bone marrow transplantation, for the treatment of osteonecrosis of the hip. It provides background on how osteonecrosis leads to a decrease in mesenchymal stem cells and impaired bone remodeling. The document then reviews studies that have found autologous bone marrow transplantation can help increase stem cell levels and promote bone repair, potentially preventing the need for hip replacement surgery.
This document summarizes current and newer therapies for osteoporosis. It describes the FDA-approved pharmacologic options including bisphosphonates, estrogens, raloxifene, calcitonin, parathyroid hormone, and denosumab. It then discusses the efficacy of these current treatments in reducing vertebral and non-vertebral fractures. The document notes the need for newer agents due to safety concerns with long-term bisphosphonate use. It introduces several promising new therapies in development including denosumab, anti-sclerostin antibodies, and cathepsin K inhibitors which have shown increases in bone mineral density and reductions in fracture risk in clinical trials.
Xuhui Liu is an experienced physician-scientist specializing in biomedical research. He has over 20 years of experience conducting clinical and preclinical research focused on musculoskeletal and neurological diseases. Currently, he is an Associate Professor at UCSF leading multiple research programs investigating bone regeneration, rotator cuff injuries, and neuro-musculoskeletal trauma. He has published extensively in peer-reviewed journals and serves as a reviewer for several orthopedic research publications.
Dextrose Prolotherapy for Chronic Musculoskeletal Pain Ade Wijaya
Chronic pain persists for more than three months and musculoskeletal disorders are a common cause. Prolotherapy involves injecting irritant solutions like dextrose to promote tissue growth and reduce pain. Dextrose prolotherapy is a safe and non-surgical option for moderate to severe chronic musculoskeletal pain that has failed to improve with other treatments. It works by causing a controlled local injury that stimulates healing.
The document discusses several topics related to bone physiology, healing, and sterilization. It questions why we wait longer periods of time to load implants in the maxilla versus mandible. It also asks if augmenting a site and placing implants later or doing both at the same time is better. The document discusses the differences between immediate and delayed loading and their effects on bone health. It covers biology, mechanobiology, bone quality determinants like thickness, porosity and connectivity. Principles of bone response, remodeling, microdamage and fragility are discussed. Procedures like drilling, sinus lifts and ridge splits are mentioned. Models of bone injury and repair are presented. Studies on implant survival rates and the mechanostat theory are
Xuhui Liu is an experienced physician-scientist specializing in biomedical research. He has over 20 years of experience conducting clinical and preclinical research focused on musculoskeletal and neurological diseases. Currently, he is an Associate Professor at UCSF leading research programs in bone health, rotator cuff injuries, and neuro-musculoskeletal trauma. He has published over 30 peer-reviewed papers and is an active reviewer for several academic journals.
This document discusses a study that evaluated early changes in cartilage biomarkers following arthroscopic meniscectomy in young Egyptian adults. The study measured three biomarkers - COMP, Col II, and PIICP - in patients before and after surgery, and in a control group. It found significantly higher levels of COMP and PIICP in patients compared to controls after surgery, indicating increased cartilage breakdown and synthesis. This suggests meniscectomy may promote early cartilage changes detectable through biochemical markers.
This document discusses osteoporosis, its pathogenesis, current treatment options, and potential future therapies. It describes how osteoporosis results from an imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Current treatments either inhibit osteoclastic activity to decrease bone resorption or stimulate osteoblastic activity to increase bone formation. First-line therapies are bisphosphonates and calcitonin, while PTH is used for high-risk patients. Emerging drugs combine anti-resorptive and anabolic mechanisms or target new pathways like sclerostin inhibition. Future therapies aim to have better safety profiles and reliable biomarkers for prevention.
Conference of the Tense Active Motor Control in the Shoulder. XIVth Federation of European Societies for Surgery of the Hand, FESSH Congress 3rd to 6th of June 2009 Poznan, Poland. The author explain how the connective system is determinant to control the motions in the shoulder, an special joint deeply dependent of the tissue deformation of the connective and sof tissues to build the adequate movements. Are the connective tissues a passive sub system? Dr. López proposed a new vision how understand the role of Fascias, ligaments, Capsules and other connective tissues during the movements and posture.
This document summarizes research on the effects of COX-2 inhibitors on fracture healing and implications for patient recovery. The main points are:
1) Past research has found that COX-2 inhibitors like celecoxib can impair fracture healing in animal models by reducing callus strength and increasing nonunion rates.
2) A recent study in rats found celecoxib administration was associated with weaker fracture calluses, more nonunions, and duration of inhibition correlated with decreased healing.
3) The investigators concluded NSAID use after fractures may negatively affect healing in humans, though more research is needed, and COX-2 drug use should be avoided in fusion patients for now.
The document discusses the process of fracture healing. It begins with an inflammatory phase where hematoma forms and inflammatory cells degrade necrotic tissue. This is followed by a reactive phase where new capillaries form granulation tissue (procallus) and osteogenic cells lay down a soft callus of collagen and fibrocartilage. Finally, there is a remodeling phase where the callus is calcified to form hard callus, then remodeled over years into the original bone shape through the action of osteoblasts and osteoclasts. Growth factors and cytokines that regulate each phase of healing are also outlined.
Understanding the molecular biology of intervertebral disc degeneration and p...CarlosAlbertoMontesM
This document reviews gene therapy strategies for treating intervertebral disc degeneration. It discusses the molecular biology and etiology of disc degeneration, which involves an imbalance between catabolism and anabolism leading to loss of extracellular matrix. Current treatments only relieve symptoms and do not address the underlying pathology. The review examines growth factor therapy, cell therapy, and gene therapy approaches for regeneration. Gene therapy was initially mediated by viral vectors but recent advances allow for non-viral methods to avoid risks of mutagenesis and infection. With further progress, non-viral gene therapy may prove effective for treating disc degeneration.
This document discusses collagen and its role in connective tissues, specifically in the extra-articular environment of joints. It notes that collagen Type I makes up the majority of structures like ligaments, tendons and joint capsules that provide stability and containment of joints. Deficiencies or damage to collagen Type I can lead to joint laxity and hypermobility, causing pain and impaired movement. The document reviews clinical studies on the use of injectable collagen medical devices to treat algic and degenerative diseases of the musculoskeletal system by supplementing damaged collagen in joints.
This document discusses fracture healing and bone repair. It describes the complex cellular and molecular processes involved, including inflammation, soft and hard callus formation, and remodeling. Failure of healing can occur through atrophic, hypertrophic, oligotrophic, or delayed nonunion. Treatment options to promote healing include autografts, allografts, bone graft substitutes, growth factors, and mechanical or electrical stimulation techniques.
1. Critical illness myopathy and neuropathy are common complications experienced by ICU patients that can last for years, increasing mortality, length of stay, and reducing quality of life.
2. They are caused by factors like prolonged immobilization, infections, medications, and underlying illnesses and can involve both nerve and muscle damage.
3. Diagnosis involves electromyography and assessing for denervation and reduced nerve and muscle potentials, while treatment focuses on minimizing harmful factors and improving recovery.
This document discusses the use of adult stem cells, specifically mesenchymal stem cells (MSCs), in orthopedics. It provides several examples of how MSCs derived from bone marrow have been used to treat orthopedic injuries and conditions. These include using bone marrow concentrate to treat non-unions, avascular necrosis, and promote healing in ACL reconstruction, spinal fusions, and rotator cuff injuries. Studies show MSCs can reduce healing times and promote stronger tissue regeneration compared to other treatments like corticosteroids or autografts. The document also discusses how MSCs may help regenerate cartilage and treat osteoarthritis by reducing pain and slowing degeneration.
Bone healing is a complex process involving four main elements: osteogenic cells, growth factors, an osteoconductive scaffold, and mechanical stability. It can occur through either direct bone healing with contact between bone ends and no callus formation, or indirect bone healing which involves four phases - inflammatory, granulation, hard callus formation, and remodeling. Complications of fractures can arise from associated pathologies and aggressive treatment is needed to minimize disabilities.
Healing of Bone - Dr. Shweta Yadav - Oral and Maxillofacial SurgeryDr. Shweta Yadav
Bone healing is a complex process that occurs in multiple stages to restore injured bone. It involves inflammation, cell proliferation, callus formation, consolidation, and remodeling. There are two main types: healing by direct union, which occurs when fracture ends are close together; and healing by callus formation, which involves five stages over several months. Many local and systemic factors can influence bone healing, and treatment aims to properly position fragments, stabilize fractures, and use grafting when needed. Complications include malunion, delayed healing, non-union, and infection.
Cytotherapy for osteonecrosis of hip.acta medica internationalSanjeev kumar Jain
The document discusses the use of cytotherapy, specifically autologous bone marrow transplantation, for the treatment of osteonecrosis of the hip. It provides background on how osteonecrosis leads to a decrease in mesenchymal stem cells and impaired bone remodeling. The document then reviews studies that have found autologous bone marrow transplantation can help increase stem cell levels and promote bone repair, potentially preventing the need for hip replacement surgery.
This document summarizes current and newer therapies for osteoporosis. It describes the FDA-approved pharmacologic options including bisphosphonates, estrogens, raloxifene, calcitonin, parathyroid hormone, and denosumab. It then discusses the efficacy of these current treatments in reducing vertebral and non-vertebral fractures. The document notes the need for newer agents due to safety concerns with long-term bisphosphonate use. It introduces several promising new therapies in development including denosumab, anti-sclerostin antibodies, and cathepsin K inhibitors which have shown increases in bone mineral density and reductions in fracture risk in clinical trials.
Xuhui Liu is an experienced physician-scientist specializing in biomedical research. He has over 20 years of experience conducting clinical and preclinical research focused on musculoskeletal and neurological diseases. Currently, he is an Associate Professor at UCSF leading multiple research programs investigating bone regeneration, rotator cuff injuries, and neuro-musculoskeletal trauma. He has published extensively in peer-reviewed journals and serves as a reviewer for several orthopedic research publications.
Dextrose Prolotherapy for Chronic Musculoskeletal Pain Ade Wijaya
Chronic pain persists for more than three months and musculoskeletal disorders are a common cause. Prolotherapy involves injecting irritant solutions like dextrose to promote tissue growth and reduce pain. Dextrose prolotherapy is a safe and non-surgical option for moderate to severe chronic musculoskeletal pain that has failed to improve with other treatments. It works by causing a controlled local injury that stimulates healing.
The document discusses several topics related to bone physiology, healing, and sterilization. It questions why we wait longer periods of time to load implants in the maxilla versus mandible. It also asks if augmenting a site and placing implants later or doing both at the same time is better. The document discusses the differences between immediate and delayed loading and their effects on bone health. It covers biology, mechanobiology, bone quality determinants like thickness, porosity and connectivity. Principles of bone response, remodeling, microdamage and fragility are discussed. Procedures like drilling, sinus lifts and ridge splits are mentioned. Models of bone injury and repair are presented. Studies on implant survival rates and the mechanostat theory are
Xuhui Liu is an experienced physician-scientist specializing in biomedical research. He has over 20 years of experience conducting clinical and preclinical research focused on musculoskeletal and neurological diseases. Currently, he is an Associate Professor at UCSF leading research programs in bone health, rotator cuff injuries, and neuro-musculoskeletal trauma. He has published over 30 peer-reviewed papers and is an active reviewer for several academic journals.
This document discusses a study that evaluated early changes in cartilage biomarkers following arthroscopic meniscectomy in young Egyptian adults. The study measured three biomarkers - COMP, Col II, and PIICP - in patients before and after surgery, and in a control group. It found significantly higher levels of COMP and PIICP in patients compared to controls after surgery, indicating increased cartilage breakdown and synthesis. This suggests meniscectomy may promote early cartilage changes detectable through biochemical markers.
This document discusses osteoporosis, its pathogenesis, current treatment options, and potential future therapies. It describes how osteoporosis results from an imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Current treatments either inhibit osteoclastic activity to decrease bone resorption or stimulate osteoblastic activity to increase bone formation. First-line therapies are bisphosphonates and calcitonin, while PTH is used for high-risk patients. Emerging drugs combine anti-resorptive and anabolic mechanisms or target new pathways like sclerostin inhibition. Future therapies aim to have better safety profiles and reliable biomarkers for prevention.
Conference of the Tense Active Motor Control in the Shoulder. XIVth Federation of European Societies for Surgery of the Hand, FESSH Congress 3rd to 6th of June 2009 Poznan, Poland. The author explain how the connective system is determinant to control the motions in the shoulder, an special joint deeply dependent of the tissue deformation of the connective and sof tissues to build the adequate movements. Are the connective tissues a passive sub system? Dr. López proposed a new vision how understand the role of Fascias, ligaments, Capsules and other connective tissues during the movements and posture.
This document summarizes research on the effects of COX-2 inhibitors on fracture healing and implications for patient recovery. The main points are:
1) Past research has found that COX-2 inhibitors like celecoxib can impair fracture healing in animal models by reducing callus strength and increasing nonunion rates.
2) A recent study in rats found celecoxib administration was associated with weaker fracture calluses, more nonunions, and duration of inhibition correlated with decreased healing.
3) The investigators concluded NSAID use after fractures may negatively affect healing in humans, though more research is needed, and COX-2 drug use should be avoided in fusion patients for now.
The document discusses the process of fracture healing. It begins with an inflammatory phase where hematoma forms and inflammatory cells degrade necrotic tissue. This is followed by a reactive phase where new capillaries form granulation tissue (procallus) and osteogenic cells lay down a soft callus of collagen and fibrocartilage. Finally, there is a remodeling phase where the callus is calcified to form hard callus, then remodeled over years into the original bone shape through the action of osteoblasts and osteoclasts. Growth factors and cytokines that regulate each phase of healing are also outlined.
This document summarizes research on the pathophysiology and pharmacologic control of osseous mandibular condylar resorption. It describes how while different diagnoses may cause condylar resorption, the underlying bone loss process is the same. This involves the activation of osteoblasts by cytokines and other factors, leading to osteoclast recruitment and bone matrix degradation. The document reviews literature on the cellular mechanisms of resorption and conditions that increase susceptibility. It discusses how medications targeting cytokines, antioxidants, and other inflammatory pathways have potential to prevent further condylar resorption by disrupting the bone loss process. More clinical research is still needed but current evidence is encouraging.
Fracture healing is a complex physiological process involving inflammation, repair, and remodeling phases. During inflammation, the fracture site fills with hematoma and swelling occurs. In repair, granulation tissue forms and a fibrocartilaginous callus develops. Remodeling involves mineralization of callus and Haversian remodeling. Many factors like nutrition, comorbidities, medications, and local/systemic inflammation can affect fracture healing. Adequate calories, protein, and other nutrients are important for providing the body with energy and materials to synthesize new proteins and tissues during healing. Both local and systemic inflammation can impair healing depending on factors like the specific inflammatory conditions and cells involved.
Biochemical mediators. kavitha /certified fixed orthodontic courses by Indian...Indian dental academy
This document discusses various biochemical mediators involved in orthodontic tooth movement. It begins by describing the periodontal ligament and bone remodeling processes in response to orthodontic forces. It then discusses various first messengers like prostaglandins, leukotrienes, cytokines, and nitric oxide that are released during tooth movement. These first messengers activate second messengers like cAMP, cGMP, and inositol phosphates. Finally, it discusses various chemical mediators involved in the inflammatory response and pain associated with orthodontic tooth movement.
Fracture Healing,Introduction,Pathology&Stages,Factors influencing osteogenesis,differences in healing of fractured bone by conservative&operative management.
Fracture healing is a complex physiological process involving inflammation, repair, and remodeling phases. Many factors can influence fracture healing including nutrition, comorbidities, medications, and systemic inflammation. Adequate protein, calorie, mineral, and vitamin intake is important to meet the increased nutritional demands of healing. Specifically, antioxidants, zinc, copper, calcium, phosphorus, and silicon may help accelerate fracture healing by reducing inflammation and supporting new bone formation. Both local and systemic inflammation can impair healing, though local inflammation alone does not necessarily cause impaired healing. Optimizing nutrition is one approach to enhance and speed the natural fracture healing process.
The document discusses the potential impacts of fibroblast growth factor 2 (FGF2) on osteogenesis and bone recovery. Studies in rats found that FGF2 improved the expression of osteogenic markers and differentiation when bone marrow stem cells were cultured in a hyaluronate-based polymer scaffold with FGF2. Another study in rabbits found that a gelatin hydrogel delivering FGF2 promoted new bone growth and mechanical strength in a skull defect model. Further, a composite scaffold delivering FGF2 supported bone and cartilage regeneration in a rabbit knee osteochondral defect model. While FGF2 enhanced osteoblast proliferation, it also inhibited alkaline phosphatase activity and differentiation in some studies.
Mediators of Periodontal Osseous Destruction.pptxUzmaAnsari27
This document discusses mediators of periodontal osseous destruction. It begins by introducing bone remodeling and the coupling of bone resorption by osteoclasts and formation by osteoblasts. It then describes the bone remodeling cycle and key cells involved - osteoclasts which resorb bone and are derived from hematopoietic precursors, and osteoblasts which form bone. Critical mediators that stimulate bone resorption in periodontal disease are discussed, including proinflammatory cytokines like IL-1, IL-6, TNF-α, as well as PGE2, vitamin D3, PTH, and RANKL which stimulates osteoclastogenesis. Matrix metalloproteinases are also discussed which degrade the
Fracture healing, complication & factors promotes the fracture healingAdnan Sabir
This document summarizes fracture healing, complications that can occur, and factors that promote fracture healing. It discusses the goals of fracture healing as encouraging healing, restoring function, and achieving a cosmetically acceptable appearance. It outlines the phases of fracture healing as the reactive, reparative, and remodeling phases. Complications that can occur include delayed union, non-union, osteomyelitis, and mal-union. Factors that promote fracture healing include growth hormones, thyroid hormone, calcitonin, immobilization, anabolic steroids, young age, nutrition, minerals, and exercise.
What is fixation?
Fixation in orthopedics is the process by which an injury is rendered immobile. This may be accomplished by internal fixation, or by external fixation.
What is internal fixation?
Internal fixation is an operation in orthopedics that involves the surgical implementation of implants for the purpose of repairing a bone
What is osteosynthesis?
Osteosynthesis is the reduction and internal fixation of a bone fracture with implantable devices that are usually made of metal. It is a surgical procedure with an open or per cutaneous approach to the fractured bone. Osteosynthesis aims to bring the fractured bone ends together and immobilize the fracture site while healing takes place. In a fracture that is rigidly immobilized the fracture heals by the process of intramembranous ossification
INDICATIONS for internal fixation
History of Fracture Treatment and Development Of Modern Osteosynthesis
In the Preantibiotic era, closed reduction of fractures was understandably the rule for most fractures. However, when closed reduction was insufficient, external fixation appliances served to maintain skeletal units in position, frequently without the need for MMF (Maxillo-mandibular fixation) .Following the development of antibiotics, the open treatment of fractures began to be used on a more frequent basis.
Rigid internal fixation (RIF) is “Any form of fixation applied directly to the bones which is strong enough to permit active use of the skeletal structure during the healing phase and also helps in healing”.
Bone fractures have been treated with various conservative techniques for centuries and it was not until the eighteenth century that internal fixation was first documented.
Icart, a French surgeon in Castres, performed ligature fixation with brass wire on a young man with a humeral fracture.
1886, when Hansmann of Hamburg published a technique using retrievable metal bone plates with transcutaneous screws.
Soon after, a Belgian surgeon, Albin Lambotte, improved these techniques and coined the term internal fixation.
Lambotte developed and manufactured a variety of bone plates and screws and much of his armamentarim remained in use until the 1950s.
In the twentieth century, Sherman improved on Lambotte’s designs and created parallel, threaded, finepitched, self-tapping screws. This hardware was made of corrosion-resistant vanadium steel, which was a strength improvement over silver and ivory fixation materials.
BIOLOGY OF BONE AND BONE HEALING
Bone is a complex and ever-evolving connective tissue and serves multiple purposes. Besides being the main constituent of the human skeletal system, bone is highly metabolically active and essential for the regulation of serum electrolytes—namely, calcium and phosphate.
Marrow cavities are filled with hematopoietic elements necessary to manufacture and maintain blood components and regulate the immune system. Bone is comprised
Implants for the aged patient: biological, clinical and sociological considerations.
The biological considerations in treating elderly patients with dental implants is the possibility of compromised wound healing following implant placement, as well as the effect of aging on the long-term integrity of osseointegration.
Tooth movement induced by orthodontic force application is
characterized by changes in the cells and tissue. When exposed to varying degrees of magnitude, frequency,
and duration of mechanical loading, cells and tissue show
extensive macroscopic and microscopic changes.
Functional appliances harness natural muscle forces to move teeth and bone in a desired direction. They have been used for over half a century but their principles and limitations are not fully understood, leading to controversy. Research shows that the lateral pterygoid muscle plays a role in regulating condylar cartilage growth rate. Cybernetics, the study of control systems, provides a framework for understanding craniofacial growth mechanisms and how appliances work through feedback loops. Functional matrices theory and servosystem theory describe how craniofacial growth is controlled through interactions between soft tissue and skeletal structures.
Mesenchymal stem cells (MSCs) show potential in treating various orthopaedic conditions. MSCs can differentiate into bone, cartilage, and other tissues, helping repair fractures and cartilage/meniscus injuries. They also secrete factors that promote angiogenesis, regulate inflammation, and induce tissue regeneration through paracrine effects. Clinical studies show MSCs may effectively treat non-union fractures, osteoarthritis, and femoral head necrosis by differentiating into local tissues or secreting factors that aid repair. However, larger high-quality studies are still needed to confirm efficacy, especially for late-stage conditions.
This document discusses the development of treatment pathways for returning athletes to sport after knee injuries. It explains that rehabilitation progression is dependent on factors like biologic healing rates of soft tissues in the knee as well as surgical techniques used. Treatment guidelines are criterion-based and use indicators like pain, swelling, quadriceps strength and function on tests to determine when to advance rehabilitation. The principles discussed can be applied to create treatment pathways for various knee pathologies.
This document summarizes the process of distraction osteogenesis, which involves surgically separating bone segments and using an external fixator to slowly pull the segments apart, inducing new bone growth in the gap. It describes the three phases of distraction osteogenesis - the latent phase involving inflammation and recruitment of stem cells; the distraction phase where mechanical strain promotes new bone formation; and the consolidation phase where the new bone matures. Key cellular processes involving osteoblasts and osteoclasts during bone formation and remodeling are also summarized. Potential future approaches to improve distraction osteogenesis outcomes through modulating these cells are outlined.
Proposal to National Science Foundation co-authored by Ian Nieves and James Earthman. It describes using FEA simulation and advanced computer-assisted fabrication techniques to develop materials for bone regeneration.
Ortho: to make straight or right. The use of biologic substances to prompt, stimulate or support a “healing event” within the body.The use of biologic substances to promote healing or reduce pain.The use of platelets and stem cells in treatment and management of musculoskeletal conditions
TEST BANK For An Introduction to Brain and Behavior, 7th Edition by Bryan Kol...rightmanforbloodline
TEST BANK For An Introduction to Brain and Behavior, 7th Edition by Bryan Kolb, Ian Q. Whishaw, Verified Chapters 1 - 16, Complete Newest Versio
TEST BANK For An Introduction to Brain and Behavior, 7th Edition by Bryan Kolb, Ian Q. Whishaw, Verified Chapters 1 - 16, Complete Newest Version
TEST BANK For An Introduction to Brain and Behavior, 7th Edition by Bryan Kolb, Ian Q. Whishaw, Verified Chapters 1 - 16, Complete Newest Version
Cell Therapy Expansion and Challenges in Autoimmune DiseaseHealth Advances
There is increasing confidence that cell therapies will soon play a role in the treatment of autoimmune disorders, but the extent of this impact remains to be seen. Early readouts on autologous CAR-Ts in lupus are encouraging, but manufacturing and cost limitations are likely to restrict access to highly refractory patients. Allogeneic CAR-Ts have the potential to broaden access to earlier lines of treatment due to their inherent cost benefits, however they will need to demonstrate comparable or improved efficacy to established modalities.
In addition to infrastructure and capacity constraints, CAR-Ts face a very different risk-benefit dynamic in autoimmune compared to oncology, highlighting the need for tolerable therapies with low adverse event risk. CAR-NK and Treg-based therapies are also being developed in certain autoimmune disorders and may demonstrate favorable safety profiles. Several novel non-cell therapies such as bispecific antibodies, nanobodies, and RNAi drugs, may also offer future alternative competitive solutions with variable value propositions.
Widespread adoption of cell therapies will not only require strong efficacy and safety data, but also adapted pricing and access strategies. At oncology-based price points, CAR-Ts are unlikely to achieve broad market access in autoimmune disorders, with eligible patient populations that are potentially orders of magnitude greater than the number of currently addressable cancer patients. Developers have made strides towards reducing cell therapy COGS while improving manufacturing efficiency, but payors will inevitably restrict access until more sustainable pricing is achieved.
Despite these headwinds, industry leaders and investors remain confident that cell therapies are poised to address significant unmet need in patients suffering from autoimmune disorders. However, the extent of this impact on the treatment landscape remains to be seen, as the industry rapidly approaches an inflection point.
Local Advanced Lung Cancer: Artificial Intelligence, Synergetics, Complex Sys...Oleg Kshivets
Overall life span (LS) was 1671.7±1721.6 days and cumulative 5YS reached 62.4%, 10 years – 50.4%, 20 years – 44.6%. 94 LCP lived more than 5 years without cancer (LS=2958.6±1723.6 days), 22 – more than 10 years (LS=5571±1841.8 days). 67 LCP died because of LC (LS=471.9±344 days). AT significantly improved 5YS (68% vs. 53.7%) (P=0.028 by log-rank test). Cox modeling displayed that 5YS of LCP significantly depended on: N0-N12, T3-4, blood cell circuit, cell ratio factors (ratio between cancer cells-CC and blood cells subpopulations), LC cell dynamics, recalcification time, heparin tolerance, prothrombin index, protein, AT, procedure type (P=0.000-0.031). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and N0-12 (rank=1), thrombocytes/CC (rank=2), segmented neutrophils/CC (3), eosinophils/CC (4), erythrocytes/CC (5), healthy cells/CC (6), lymphocytes/CC (7), stick neutrophils/CC (8), leucocytes/CC (9), monocytes/CC (10). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).
Histololgy of Female Reproductive System.pptxAyeshaZaid1
Dive into an in-depth exploration of the histological structure of female reproductive system with this comprehensive lecture. Presented by Dr. Ayesha Irfan, Assistant Professor of Anatomy, this presentation covers the Gross anatomy and functional histology of the female reproductive organs. Ideal for students, educators, and anyone interested in medical science, this lecture provides clear explanations, detailed diagrams, and valuable insights into female reproductive system. Enhance your knowledge and understanding of this essential aspect of human biology.
- Video recording of this lecture in English language: https://youtu.be/kqbnxVAZs-0
- Video recording of this lecture in Arabic language: https://youtu.be/SINlygW1Mpc
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Adhd Medication Shortage Uk - trinexpharmacy.comreignlana06
The UK is currently facing a Adhd Medication Shortage Uk, which has left many patients and their families grappling with uncertainty and frustration. ADHD, or Attention Deficit Hyperactivity Disorder, is a chronic condition that requires consistent medication to manage effectively. This shortage has highlighted the critical role these medications play in the daily lives of those affected by ADHD. Contact : +1 (747) 209 – 3649 E-mail : sales@trinexpharmacy.com
These lecture slides, by Dr Sidra Arshad, offer a quick overview of the physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar lead (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
6. Describe the flow of current around the heart during the cardiac cycle
7. Discuss the placement and polarity of the leads of electrocardiograph
8. Describe the normal electrocardiograms recorded from the limb leads and explain the physiological basis of the different records that are obtained
9. Define mean electrical vector (axis) of the heart and give the normal range
10. Define the mean QRS vector
11. Describe the axes of leads (hexagonal reference system)
12. Comprehend the vectorial analysis of the normal ECG
13. Determine the mean electrical axis of the ventricular QRS and appreciate the mean axis deviation
14. Explain the concepts of current of injury, J point, and their significance
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. Chapter 3, Cardiology Explained, https://www.ncbi.nlm.nih.gov/books/NBK2214/
7. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Integrating Ayurveda into Parkinson’s Management: A Holistic ApproachAyurveda ForAll
Explore the benefits of combining Ayurveda with conventional Parkinson's treatments. Learn how a holistic approach can manage symptoms, enhance well-being, and balance body energies. Discover the steps to safely integrate Ayurvedic practices into your Parkinson’s care plan, including expert guidance on diet, herbal remedies, and lifestyle modifications.
Osteoporosis - Definition , Evaluation and Management .pdfJim Jacob Roy
Osteoporosis is an increasing cause of morbidity among the elderly.
In this document , a brief outline of osteoporosis is given , including the risk factors of osteoporosis fractures , the indications for testing bone mineral density and the management of osteoporosis
Promoting Wellbeing - Applied Social Psychology - Psychology SuperNotesPsychoTech Services
A proprietary approach developed by bringing together the best of learning theories from Psychology, design principles from the world of visualization, and pedagogical methods from over a decade of training experience, that enables you to: Learn better, faster!
2. biological process sometimes fails and fractures may heal in unfavorable anatomical
positions, show a delay in healing or even develop pseudo-arthrosis or non-unions.32
Investigations in both humans and animal models have provided insight into the pathways
that regulate the biologically optimized process of fracture healing and provide direction for
further research to prevent its failure.16 The use of animal models have made it possible to
investigate fracture healing from all perspectives such as histology, biochemistry and
biomechanics and has hence been a very important tool in understanding fracture biology.6
To better understand new concepts and strategies to enhance the healing of fractures this
review presents a basic summary of the current knowledge of the biology of fracture repair.
INDIRECT FRACTURE HEALING
Indirect (secondary) fracture healing is the most common form of fracture healing, and
consists of both endochondral and intramembranous bone healing.17 It does not require
anatomical reduction or rigidly stable conditions. On the contrary, it is enhanced by micro-
motion and weight-bearing. However, too much motion and/or load is known to result in
delayed healing or even non-union.20 Indirect bone healing typically occurs in non-operative
fracture treatment and in certain operative treatments in which some motion occurs at the
fracture site such as intramedullary nailing, external fixation, or internal fixation of
complicated comminuted fractures.35, 36
The Acute Inflammatory Response
Immediately following the trauma, a hematoma is generated and consists of cells from both
peripheral and intramedullary blood, as well as bone marrow cells. The injury initiates an
inflammatory response which is necessary for the healing to progress. The response causes
the hematoma to coagulate in between and around the fracture ends, and within the medulla
forming a template for callus formation.18 Although it is known that inflammatory cytokines
have a negative effect on bone, joints and implanted material when prolonged or chronic
expression occur, a brief and highly regulated secretion of proinflammatory molecules
following the acute injury is critical for tissue regeneration.18 The acute inflammatory
response peaks within the first 24h and is complete after 7 days, although proinflammatory
molecules also play an important role later in the regeneration as is described later in this
article.12
The initial proinflammatory response involves secretion of tumor necrosis factor-α (TNF-α),
interleukin-1 (IL-1), IL-6, IL-11 and IL-18.18 These factors recruit inflammatory cells and
promote angiogenesis.40 The TNF-α concentration has been shown to peak at 24h and to
return to baseline within 72h post trauma.18 During this time-frame TNF-α is expressed by
macrophages and other inflammatory cells, and it is believed to mediate an effect by
inducing secondary inflammatory signals, and act as a chemotactic agent to recruit necessary
cells.28 TNF-α has also been shown in vitro to induce osteogenic differentiation of MSCs.11
These effects are mediated by activation of the two receptors TNFR1 and TNFR2 which are
expressed on both osteoblasts and osteoclasts. However, TNFR1 is always expressed in
bone whereas TNFR2 is only expressed following injury, suggesting a more specific role in
bone regeneration.3, 28 Among the different interleukins, IL-1 and IL-6 are believed to be
most important for fracture healing. IL-1 expression overlaps with that of TNF-α with a
biphasic mode. It is produced by macrophages in the acute phase of inflammation and
induces production of IL-6 in osteoblasts, promotes the production of the primary
cartilaginous callus, and also promotes angiogenesis at the injured site by activating either of
its two receptors, IL-1RI or IL-1RII.28, 29, 40 IL-6 on the other hand, is only produced during
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3. the acute phase and stimulates angiogenesis, vascular endothelial growth factor (VEGF)
production, and the differentiation of osteoblasts and osteoclasts.47
Recruitment of Mesenchymal Stem Cells (MSC)
In order for bone to regenerate, specific mesenchymal stem cells (MSCs) have to be
recruited, proliferate and differentiate into osteogenic cells. Exactly where these cells come
from is not fully understood. Although most data indicate that these MSCs are derived from
surrounding soft tissues and bone marrow, recent data demonstrate that a systemic
recruitment of circulating MSCs to the injured site might be of great importance for an
optimal healing response.19, 27 Which molecular events mediate this recruitment is still
under debate. It has long been suggested that BMP-2 has an important role in this
recruitment, but data from our group indicates that this is not the case.2 Indeed, BMP-2 is
essential for bone repair43 but other BMPs such as BMP-7 may play a more important role
in the recruitment of progenitor cells.2
Current data suggest that stromal cell-derived factor-1(SDF-1) and its G-protein-coupled
receptor CXCR-4 form an axis (SDF-1/CXCR-4) that is a key regulator of recruiting and
homing specific MSCs to the site of trauma.19, 27, 31 These reports show that SDF-1
expression is increased at the fracture site, and especially in the periosteum at the edges of
the fracture. They also demonstrate that SDF-1 has a specific role in recruiting CXCR-4
expressing MSCs to the injured site during endochondral fracture healing.27 The importance
of this axis has been further verified as treatment with an anti-SDF-1 antagonist or genetic
manipulation of SDF-1 and CXCR-4 impairs fracture healing. It has also been shown that
transplanted MSCs only home to the fracture site if they express CXCR-4, whereas CXCR-4
negative MSCs do not have this ability.19, 27 Furthermore, recent data also demonstrate an
important role for hypoxia inducible factor-1α (HIF-1α) in bone repair and its induction of
VEGF in the revascularization process show that hypoxic gradients regulate MSC progenitor
cell trafficking by HIF-1.9, 44
Generation of a Cartilaginous and a Periosteal Bony Callus
Although indirect fracture healing consists of both intramembranous and endochondral
ossification, the formation of a cartilaginous callus which later undergoes mineralization,
resorption and is then replaced with bone is its key feature of this process. Following the
formation of the primary hematoma, a fibrin-rich granulation tissue forms.37 Within this
tissue, endochondral formation occurs in between the fracture ends, and external to
periosteal sites. These regions are also mechanically less stable and the cartilaginous tissue
forms a soft callus which gives the fracture a stable structure.14 In animal models (rat,
rabbit, mouse) the peak of soft callus formation occurs 7–9 days post trauma with a peak in
both type II procollagen and proteoglycan core protein extracellular markers.15 At the same
time, an intramembranous ossification response occurs subperiostally directly adjacent to the
distal and proximal ends of the fracture, generating a hard callus. It is the final bridging of
this central hard callus that ultimately provides the fracture with a semi-rigid structure which
allows weight bearing.17
The generation of these callus tissues is dependent on the recruitment of MSCs from the
surrounding soft tissues, cortex, periosteum, and bone marrow as well the systemic
mobilization of stem cells into the peripheral blood from remote hematopoetic sites. Once
recruited, a molecular cascade involves collagen-I and collagen-II matrix production and the
participation of several peptide signaling molecules. In this process the transforming growth
factor-beta (TGF-β) superfamily members have been shown to be of great importance. TGF-
β2, -β3 and GDF-5 are involved in chondrogenesis and endochondral ossification, whereas
BMP-5 and -6 have been suggested to induce cell proliferation in intramembranous
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4. ossification at periosteal sites.12, 33 In addition, as noted above, BMP-2 has been shown to
be crucial for initiation of the healing cascade, as mice with inactivating mutations in
BMP-2 are not able to form callus in order to heal their fractures successfully.43 Whether
this is due to effects on mesenchymal stem cell proliferation and differentiation or effects on
cell migration is still under debate.
Revascularization and Neoangiogenesis at the Fracture Site
Fracture healing requires a blood supply and revascularization is essential for successful
bone repair.25 In endochondral fracture healing, this not only involves angiogenic pathways,
but also chondrocyte apoptosis and cartilaginous degradation as the removal of cells and
extracellular matrices are necessary to allow blood vessel in-growth at the repair site.1
Once this structural pattern is achieved, the vascularization process is mainly regulated by
two molecular pathways, an angiopoietin-dependent pathway, and a vascular endothelial
growth factor (VEGF)-dependent pathway.42 The angiopoietins, primarily angiopoetin-1
and 2, are vascular morphogenetic proteins. Their expression is induced early in the healing
cascade, suggesting that they promote an initial vascular in-growth from existing vessels in
the periosteum.30 However, the VEGF pathway is considered to be the key regulator of
vascular regeneration.25 It has been shown that both osteoblasts and hypertrophic
chondrocytes express high levels of VEGF, thereby promoting the invasion of blood vessels
and transforming the avascular cartilaginous matrix into a vascularized osseous tissue.25
VEGF promotes both vasculogenesis, i.e. aggregation and proliferation of endothelial
mesenchymal stem cells into a vascular plexus, and angiogenesis, i.e. growth of new vessels
from already existing ones.24 Hence, VEGF plays a crucial role in the neoangiogenesis and
revascularization at the fracture site. Its importance in these processes is further supported
by the observations that addition of excessive VEGF promotes fracture healing, whereas
blocking of VEGF-receptors inhibit vascular in-growth and delays or disrupts the
regenerative process.1, 25 Several other factors may also be involved in these responses,
having pro-angiogenic effects, such as the synergistic interactions of the BMPs with VEGF
and the role of mechanical stimuli to enhance angiogenic activities in a VEGFR2-dependent
manner.1, 24
Mineralization and Resorption of the Cartilaginous Callus
In order for bone regeneration to progress, the primary soft cartilaginous callus needs to be
resorbed and replaced by a hard bony callus. This step of fracture healing, to some extent,
recapitulates embryological bone development with a combination of cellular proliferation
and differentiation, increasing cellular volume and increasing matrix deposition.7 The
connection between bone regeneration and bone development has been further strengthened
by a recent understanding of the role of the Wnt-family of molecules, which is of great
importance in embryology and has also been shown to have an important role in bone
healing. The Wnt-family is thought to regulate the differentiation of pluripotent MSCs into
the osteoblastic lineage and, at later stages of development, to positively regulate
osteoblastic bone formation.10
As fracture callus chondrocytes proliferate, they become hypertrophic and the extracellular
matrix becomes calcified. A cascade orchestrated primarily by macrophage colony-
stimulating factor (M-CSF), receptor activator of nuclear factor kappa B ligand (RANKL),
osteoprotegerin (OPG) and TNF-α initiates the resorption of this mineralized cartilage.4, 18
During this process M-CSF, RANKL and OPG are also thought to help recruit bone cells
and osteoclasts to form woven bone. TNF-α further promotes the recruitment MSC with
osteogenic potential but its most important role may be to initiate chondrocyte apoptosis.18
The calcification mechanism involves the role of mitochondria, which accumulate calcium-
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5. containing granules created in the hypoxic fracture environment. After elaboration into the
cytoplasm of fracture callus chondrocytes, calcium granules are transported into the
extracellular matrix where they precipitate with phosphate and form initial mineral deposits.
These deposits of calcium and phosphate become the nidus for homogeneous nucleation and
the formation of apatite crystals.26 The peak of the hard callus formation is usually reached
by day 14 in animal models as defined by histomorphometry of mineralized tissue, but also
by the measurement of extracellular matrix markers such as type I procollagen, osteocalcin,
alkaline phosphatase and osteonectin.15 As the hard callus formation progresses and the
calcified cartilage is replaced with woven bone, the callus becomes more solid and
mechanically rigid.17
Bone Remodeling
Although the hard callus is a rigid structure providing biomechanical stability, it does not
fully restore the biomechanical properties of normal bone. In order to achieve this, the
fracture healing cascade initiates a second resorptive phase, this time to remodel the hard
callus into a lamellar bone structure with a central medullary cavity.18 This phase is
biochemically orchestrated by IL-1 and TNF-α, which show high expression levels during
this stage, as opposed to most members of the TGF-β family which have diminished in
expression by this time.1, 34 However, some BMPs such as BMP2, are seemingly also
involved in this phase with reasonably high expression levels.33
The remodelling process is carried out by a balance of hard callus resorption by osteoclasts,
and lamellar bone deposition by osteoblasts. Although the process is initiated as early as 3–4
weeks in animal and human models, the remodelling may take years to be completed to
achieve a fully regenerated bone structure.45 The process may occur faster in animals and
younger patients. Bone remodelling has been shown to be a result of production of electrical
polarity created when pressure is applied in a crystalline environment.5 This is achieved
when axial loading of long bones occur, creating one electropositive convex surface, and
one electronegative concave surface, activating osteoclastic and osteoblastic activity
respectively. By these actions the external callus is gradually replaced by a lamellar bone
structure, whereas the internal callus remodelling re-establishes a medullar cavity
characteristic of a diaphyseal bone.5
For bone remodelling to be successful, an adequate blood supply and a gradual increase in
mechanical stability is crucial.8 This is clearly demonstrated in cases where neither is
achieved, resulting in the development of an atrophic fibrous non-union. However, in cases
in which there is good vascularity but unstable fixation, the healing process progresses to
form a cartilaginous callus, but results in a hypertrophic non-union or a pseudoarthrosis.20
DIRECT FRACTURE HEALING
Direct healing does not commonly occur in the natural process of fracture healing. This
since it requires a correct anatomical reduction of the fracture ends, without any gap
formation, and a stable fixation. However, this type of healing is often the primary goal to
achieve after open reduction and internal fixation surgery. When these requirements are
achieved, direct bone healing can occur by direct remodeling of lamellar bone, the
Haversian canals and blood vessels. Depending on the species, it usually takes from a few
months to a few years, before complete healing is achieved.37
Contact Healing
Primary healing of fractures can either occur through contact healing or gap healing. Both
processes involve an attempt to directly re-establish an anatomically correct and
biomechanically competent lamellar bone structure. Direct bone healing can only occur
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6. when an anatomic restoration of the fracture fragments is achieved and rigid fixation is
provided resulting in a substantial decrease in interfragmentary strain. Bone on one side of
the cortex must unite with bone on the other side of the cortex to re-establish mechanical
continuity. If the gap between bone ends is less than 0.01 mm and interfragmentary strain is
less than 2%, the fracture unite by so-called contact healing.41 Under these conditions,
cutting cones are formed at the ends of the osteons closest to the fracture site.22 The tips of
the cutting cones consist of osteoclasts which cross the fracture line, generating longitudinal
cavities at a rate of 50–100 μm/day. These cavities are later filled by bone produced by
osteoblasts residing at the rear of the cutting cone. This results in the simultaneous
generation of a bony union and the restoration of Haversian systems formed in an axial
direction.23, 37 The re-established Haversian systems allow for penetration of blood vessels
carrying osteoblastic precursors.15, 21 The bridging osteons later mature by direct
remodelling into lamellar bone resulting in fracture healing without the formation of
periosteal callus.
Gap Healing
Gap healing differs from contact healing in that bony union and Haversian remodelling do
not occur simultaneously. It occurs if stable conditions and an anatomical reduction are
achieved, although the gap must be less than 800 μm to 1 mm.23 In this process the fracture
site is primarily filled by lamellar bone oriented perpendicular to the long axis, requiring a
secondary osteonal reconstruction unlike the process of contact healing.39 The primary bone
structure is then gradually replaced by longitudinal revascularized osteons carrying
osteoprogenitor cells which differentiate into osteoblasts and produce lamellar bone on each
surface of the gap.41 This lamellar bone, however, is laid down perpendicular to the long
axis and is mechanically weak. This initial process takes approximately 3 and 8 weeks, after
which a secondary remodelling resembling the contact healing cascade with cutting cones
takes place. Although not as extensive as endochondral remodelling, this phase is necessary
in order to fully restore the anatomical and biomechanical properties of the bone.41
CONCLUSION
There are several pathways through which bone can heal, yet the unique attribute of bony
repair is that it occurs without the development of a fibrous scar. This designates the process
of fracture healing as a form of tissue regeneration. In order to achieve a complete
regeneration of a fully functional bone, many interrelated anatomical, biomechanical and
biochemical processes must occur in a well orchestrated manner.
While this article describes the essential components of the process of fracture healing, other
mechanisms have also been shown to have important roles in bone regeneration: such as the
actions of metalloproteinases, the involvement of several endocrine systems affecting
phosphate and calcium homeostasis, and the hematopoetic system and its regulation of the
mesenchymal stem cell progenitors that are crucial for bone and vascular
regeneration.13, 38, 46
Although currently available data provide a detailed picture of the complex biological
pathways through which bone is regenerated, much remains to be understood and many
questions remain. It is anticipated that with the development of new imaging technologies
and advanced systems for molecular analysis many of these questions will be answered.
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