NORMAL HEALING IN OTHER SPECIFIC TISSUES Bone

NORMAL HEALING IN OTHER SPECIFIC TISSUES Bone

Bone healing occurs in similar phases to those for skin but with some di ff erences ( Figure 3.3 ). Most fractures heal by callus formation, which involves intramembranous and endo - chondral ossifi cation. This is known as indirect or secondar y bone healing and typically occurs in non-operative fracture management. A haematoma forms at the fracture site and - there is an infl ammatory response. T he fracture haematoma is gradually replaced by a soft callus. This fibrocartilage callus then undergoes endochondral ossifi cation to form hard callus, which is woven bone helping to stabilise the fracture. Intramembranous ossifi cation also occurs directly adjacent to the distal and proximal fracture ends. Hard callus formation is

Plasma kallikrein Pre-kallikrein HK Intrinsic pathway HK of coagulation FXII FXIIa (contact system) 2+ Ca FXIa FXI 2+ Ca FIX FIXa FVIIIa FVIII 2+ Ca FXa FX FVa FV Ca FII (Prothrombin) Common pathway of coagulation Figure 3.2 Schematic representation of the coagulation cascade and the /f_i brinolytic system. The coagulation cascade (blue arrows) can be activated during haemostasis via the intrinsic pathway (contact system; red arrows) or the extrinsic pathway (black arrows), which ultimately converge on the common pathway of coagulation. Both pathways lead to the activation of factor X and subsequently of thrombin, which is required for the conversion of /f_i brinogen into /f_i brin and for activation of factor XIII. The /f_i brin clot is cross-linked and stabilised by factor XIII. Fibrinolysis (green arrows) is activated at the same time as the coagulation system but operates more slowly and is important for the regulation of haemostasis. During /f_i brinolysis, plasminogen is converted into plasmin, which degrades the /f_i brin network. Coagulation by ‘F’ followed by a roman numeral; an additional ‘a’ denotes the activated form. HK, high-molecular-weight kininogen; tP activator; uPA, urokinase plasminogen activator. (Adapted with permission from Loof TG, Deicke C, Medina E. The role of coagulation/ /f_i brino lysis during Streptococcus pyogenes infection. Front Cell Infect Microbiol (a) Medullary cavity Fibrocartilage Haematoma Soft callus New blood vessel Periosteum Compact bone Figure 3.3 Common stages of bone healing. (a) callus formation. (c) Hard callus formation from osteoblasts forming woven bone. osteoblasts facilitating the conversion of woven bone into lamellar bone shape. (Adapted with permission from Li J, Kacena MA, Stocum DL. Fracture healing. In: Burr DB, Allen MR (eds). applied bone biology , 2nd edn. London: Academic Press, 2019: 235–53.) Extrinsic pathway of coagulation Tissue factor FVIIa FVII Fibrinolysis uPA,tPA Plasminogen Plasmin Fibrinogen 2+ FIIa Fibrin (Thrombin) Cross-linked Fibrin fibrin clot degradation products FXIIIa FXIII factors are indicated A, tissue plasminogen

2014; 4 : 128. 2014. http://creativecommons.org/licenses/by/4.0/) (b) (c) (d) Spongy bone Bony callus At the fracture site, haematoma formation and in /f_l ammation lead to (b) soft (d) Remodelling proceeds with osteoclasts and and eventually recreating the appropriate anatomical Basic and

by lamellar bone. Primary bone healing is a direct bone union process involv ing intramembranous ossifi cation without callus formation. It does not commonly occur in the natural process of healing since it requires fracture ends to be directly apposed and rigidly fi xed with absolute stability . If a gap exists, then secondary healing may lead to delay ed union, non-union or malunion. Primary healing is therefore the aim of open reduction and internal fi xation surgery . (See also Chapter 32 ) . Augustus Volney Waller , 1816–1870, general practitioner of Kensington, London, UK (1842–1851), subsequently worked as a physiologist in Bonn, Germany; Paris, France; Birmingham, UK; and Geneva, Switzerland. Louis Antoine Ranvier , 1835–1922, physician and histologist who was a professor in the College of France, Paris, France Peripheral nerve degeneration and regeneration are - summarised in Figure 3.4 . Distal to nerve injury (neurotmesis), Wallerian degeneration occurs. Proximally , the nerve su ff ers degeneration as far as the nearest node of Ranvier. The regenerating nerve fi bres are attracted to their receptors by neur otropism, which is mediated by growth factors, hormones and the extracellular matrix. Injury of the perineurium and inflammation can lead to neuroma formation, where the disorganised nerve regeneration leads to a painful lump.

(a) Normal nerve (b) Wallerian degeneration (c) Phagocytosis and reconstruction (d) Axonal regeneration and remyelination Myelin debris Schwann cell Macrophage Figure 3.4 Schematic diagram illustrating the process of degeneration and regeneration after peripheral nerve injury. When normal nerves (a) suffer a physical injury, the portion of the lesion site and its distal stump undergo destruction and break down to produce myelin debris. This degenerative process is called Wallerian degeneration (b) Schwann cells (SCs) recruit macrophages to scavenge degenerated myelin fragments (c) . Meanwhile, SCs proliferate and migrate alone to the basal lamina to form bands of Büngner, which guide the axon to reinnervate towards the corresponding target (d) . (Adapted from Li R, Li DH, Zhang HY et al . Growth factor-based therapeutic strate gies and their underlying signaling mechanisms for peripheral nerve regeneration. Acta Pharmacol Sin 2020; 41 : 1289–300. 2020. http:// creativecommons.org/licenses/by/4.0/)

NORMAL HEALING IN OTHER SPECIFIC TISSUES Bone

Bone healing occurs in similar phases to those for skin but with some di ff erences ( Figure 3.3 ). Most fractures heal by callus formation, which involves intramembranous and endo - chondral ossifi cation. This is known as indirect or secondar y bone healing and typically occurs in non-operative fracture management. A haematoma forms at the fracture site and - there is an infl ammatory response. T he fracture haematoma is gradually replaced by a soft callus. This fibrocartilage callus then undergoes endochondral ossifi cation to form hard callus, which is woven bone helping to stabilise the fracture. Intramembranous ossifi cation also occurs directly adjacent to the distal and proximal fracture ends. Hard callus formation is

Plasma kallikrein Pre-kallikrein HK Intrinsic pathway HK of coagulation FXII FXIIa (contact system) 2+ Ca FXIa FXI 2+ Ca FIX FIXa FVIIIa FVIII 2+ Ca FXa FX FVa FV Ca FII (Prothrombin) Common pathway of coagulation Figure 3.2 Schematic representation of the coagulation cascade and the /f_i brinolytic system. The coagulation cascade (blue arrows) can be activated during haemostasis via the intrinsic pathway (contact system; red arrows) or the extrinsic pathway (black arrows), which ultimately converge on the common pathway of coagulation. Both pathways lead to the activation of factor X and subsequently of thrombin, which is required for the conversion of /f_i brinogen into /f_i brin and for activation of factor XIII. The /f_i brin clot is cross-linked and stabilised by factor XIII. Fibrinolysis (green arrows) is activated at the same time as the coagulation system but operates more slowly and is important for the regulation of haemostasis. During /f_i brinolysis, plasminogen is converted into plasmin, which degrades the /f_i brin network. Coagulation by ‘F’ followed by a roman numeral; an additional ‘a’ denotes the activated form. HK, high-molecular-weight kininogen; tP activator; uPA, urokinase plasminogen activator. (Adapted with permission from Loof TG, Deicke C, Medina E. The role of coagulation/ /f_i brino lysis during Streptococcus pyogenes infection. Front Cell Infect Microbiol (a) Medullary cavity Fibrocartilage Haematoma Soft callus New blood vessel Periosteum Compact bone Figure 3.3 Common stages of bone healing. (a) callus formation. (c) Hard callus formation from osteoblasts forming woven bone. osteoblasts facilitating the conversion of woven bone into lamellar bone shape. (Adapted with permission from Li J, Kacena MA, Stocum DL. Fracture healing. In: Burr DB, Allen MR (eds). applied bone biology , 2nd edn. London: Academic Press, 2019: 235–53.) Extrinsic pathway of coagulation Tissue factor FVIIa FVII Fibrinolysis uPA,tPA Plasminogen Plasmin Fibrinogen 2+ FIIa Fibrin (Thrombin) Cross-linked Fibrin fibrin clot degradation products FXIIIa FXIII factors are indicated A, tissue plasminogen

2014; 4 : 128. 2014. http://creativecommons.org/licenses/by/4.0/) (b) (c) (d) Spongy bone Bony callus At the fracture site, haematoma formation and in /f_l ammation lead to (b) soft (d) Remodelling proceeds with osteoclasts and and eventually recreating the appropriate anatomical Basic and

by lamellar bone. Primary bone healing is a direct bone union process involv ing intramembranous ossifi cation without callus formation. It does not commonly occur in the natural process of healing since it requires fracture ends to be directly apposed and rigidly fi xed with absolute stability . If a gap exists, then secondary healing may lead to delay ed union, non-union or malunion. Primary healing is therefore the aim of open reduction and internal fi xation surgery . (See also Chapter 32 ) . Augustus Volney Waller , 1816–1870, general practitioner of Kensington, London, UK (1842–1851), subsequently worked as a physiologist in Bonn, Germany; Paris, France; Birmingham, UK; and Geneva, Switzerland. Louis Antoine Ranvier , 1835–1922, physician and histologist who was a professor in the College of France, Paris, France Peripheral nerve degeneration and regeneration are - summarised in Figure 3.4 . Distal to nerve injury (neurotmesis), Wallerian degeneration occurs. Proximally , the nerve su ff ers degeneration as far as the nearest node of Ranvier. The regenerating nerve fi bres are attracted to their receptors by neur otropism, which is mediated by growth factors, hormones and the extracellular matrix. Injury of the perineurium and inflammation can lead to neuroma formation, where the disorganised nerve regeneration leads to a painful lump.

(a) Normal nerve (b) Wallerian degeneration (c) Phagocytosis and reconstruction (d) Axonal regeneration and remyelination Myelin debris Schwann cell Macrophage Figure 3.4 Schematic diagram illustrating the process of degeneration and regeneration after peripheral nerve injury. When normal nerves (a) suffer a physical injury, the portion of the lesion site and its distal stump undergo destruction and break down to produce myelin debris. This degenerative process is called Wallerian degeneration (b) Schwann cells (SCs) recruit macrophages to scavenge degenerated myelin fragments (c) . Meanwhile, SCs proliferate and migrate alone to the basal lamina to form bands of Büngner, which guide the axon to reinnervate towards the corresponding target (d) . (Adapted from Li R, Li DH, Zhang HY et al . Growth factor-based therapeutic strate gies and their underlying signaling mechanisms for peripheral nerve regeneration. Acta Pharmacol Sin 2020; 41 : 1289–300. 2020. http:// creativecommons.org/licenses/by/4.0/)

NORMAL HEALING IN OTHER SPECIFIC TISSUES Bone

Bone healing occurs in similar phases to those for skin but with some di ff erences ( Figure 3.3 ). Most fractures heal by callus formation, which involves intramembranous and endo - chondral ossifi cation. This is known as indirect or secondar y bone healing and typically occurs in non-operative fracture management. A haematoma forms at the fracture site and - there is an infl ammatory response. T he fracture haematoma is gradually replaced by a soft callus. This fibrocartilage callus then undergoes endochondral ossifi cation to form hard callus, which is woven bone helping to stabilise the fracture. Intramembranous ossifi cation also occurs directly adjacent to the distal and proximal fracture ends. Hard callus formation is

Plasma kallikrein Pre-kallikrein HK Intrinsic pathway HK of coagulation FXII FXIIa (contact system) 2+ Ca FXIa FXI 2+ Ca FIX FIXa FVIIIa FVIII 2+ Ca FXa FX FVa FV Ca FII (Prothrombin) Common pathway of coagulation Figure 3.2 Schematic representation of the coagulation cascade and the /f_i brinolytic system. The coagulation cascade (blue arrows) can be activated during haemostasis via the intrinsic pathway (contact system; red arrows) or the extrinsic pathway (black arrows), which ultimately converge on the common pathway of coagulation. Both pathways lead to the activation of factor X and subsequently of thrombin, which is required for the conversion of /f_i brinogen into /f_i brin and for activation of factor XIII. The /f_i brin clot is cross-linked and stabilised by factor XIII. Fibrinolysis (green arrows) is activated at the same time as the coagulation system but operates more slowly and is important for the regulation of haemostasis. During /f_i brinolysis, plasminogen is converted into plasmin, which degrades the /f_i brin network. Coagulation by ‘F’ followed by a roman numeral; an additional ‘a’ denotes the activated form. HK, high-molecular-weight kininogen; tP activator; uPA, urokinase plasminogen activator. (Adapted with permission from Loof TG, Deicke C, Medina E. The role of coagulation/ /f_i brino lysis during Streptococcus pyogenes infection. Front Cell Infect Microbiol (a) Medullary cavity Fibrocartilage Haematoma Soft callus New blood vessel Periosteum Compact bone Figure 3.3 Common stages of bone healing. (a) callus formation. (c) Hard callus formation from osteoblasts forming woven bone. osteoblasts facilitating the conversion of woven bone into lamellar bone shape. (Adapted with permission from Li J, Kacena MA, Stocum DL. Fracture healing. In: Burr DB, Allen MR (eds). applied bone biology , 2nd edn. London: Academic Press, 2019: 235–53.) Extrinsic pathway of coagulation Tissue factor FVIIa FVII Fibrinolysis uPA,tPA Plasminogen Plasmin Fibrinogen 2+ FIIa Fibrin (Thrombin) Cross-linked Fibrin fibrin clot degradation products FXIIIa FXIII factors are indicated A, tissue plasminogen

2014; 4 : 128. 2014. http://creativecommons.org/licenses/by/4.0/) (b) (c) (d) Spongy bone Bony callus At the fracture site, haematoma formation and in /f_l ammation lead to (b) soft (d) Remodelling proceeds with osteoclasts and and eventually recreating the appropriate anatomical Basic and

by lamellar bone. Primary bone healing is a direct bone union process involv ing intramembranous ossifi cation without callus formation. It does not commonly occur in the natural process of healing since it requires fracture ends to be directly apposed and rigidly fi xed with absolute stability . If a gap exists, then secondary healing may lead to delay ed union, non-union or malunion. Primary healing is therefore the aim of open reduction and internal fi xation surgery . (See also Chapter 32 ) . Augustus Volney Waller , 1816–1870, general practitioner of Kensington, London, UK (1842–1851), subsequently worked as a physiologist in Bonn, Germany; Paris, France; Birmingham, UK; and Geneva, Switzerland. Louis Antoine Ranvier , 1835–1922, physician and histologist who was a professor in the College of France, Paris, France Peripheral nerve degeneration and regeneration are - summarised in Figure 3.4 . Distal to nerve injury (neurotmesis), Wallerian degeneration occurs. Proximally , the nerve su ff ers degeneration as far as the nearest node of Ranvier. The regenerating nerve fi bres are attracted to their receptors by neur otropism, which is mediated by growth factors, hormones and the extracellular matrix. Injury of the perineurium and inflammation can lead to neuroma formation, where the disorganised nerve regeneration leads to a painful lump.

(a) Normal nerve (b) Wallerian degeneration (c) Phagocytosis and reconstruction (d) Axonal regeneration and remyelination Myelin debris Schwann cell Macrophage Figure 3.4 Schematic diagram illustrating the process of degeneration and regeneration after peripheral nerve injury. When normal nerves (a) suffer a physical injury, the portion of the lesion site and its distal stump undergo destruction and break down to produce myelin debris. This degenerative process is called Wallerian degeneration (b) Schwann cells (SCs) recruit macrophages to scavenge degenerated myelin fragments (c) . Meanwhile, SCs proliferate and migrate alone to the basal lamina to form bands of Büngner, which guide the axon to reinnervate towards the corresponding target (d) . (Adapted from Li R, Li DH, Zhang HY et al . Growth factor-based therapeutic strate gies and their underlying signaling mechanisms for peripheral nerve regeneration. Acta Pharmacol Sin 2020; 41 : 1289–300. 2020. http:// creativecommons.org/licenses/by/4.0/)