Lecture 2b Healing and Repair PDF

HEALING HEALING HEALING HEALING PROCESSES OF HEALING A N D R E PA I R R E PA I RBSc Podiatry (Hons) Program – Year 1 R E PA I R Pathology R E PA I R LEARNING OBJECTIVES Define and explain wound healing phases Define and explain bone healing phases Discuss factors which improve and worsen healin...

HEALING HEALING HEALING HEALING PROCESSES OF HEALING A N D R E PA I R R E PA I RBSc Podiatry (Hons) Program – Year 1 R E PA I R Pathology R E PA I R LEARNING OBJECTIVES Define and explain wound healing phases Define and explain bone healing phases Discuss factors which improve and worsen healing Determine types of chronic wounds 2  WHAT IS IT MEANT BY “WOUND HEALING”? Wound healing refers to the process by which destroyed or damaged tissue is replaced by newly produced tissue. It is a physiological process which also restores function to the previously damaged tissues. WOUNDS result from: Cell death or damage due to a traumatic episode Loss of skin continuity due to an injury or planned surgery AND Soft tissue and bones may be affected May be confined to the epidermis or may involve deeper structures 3  WOUNDS – KEY POINTS Wound healing is dependent upon several interrelated factors… may include Oxygenation Medications Infection Drug use Age Nutrition Medical history An understanding of “normal” physiological stages of wound healing is essential for effective management… but WHY is this the case? Enables us to identify exact phases of wound healing for selection of appropriate management Helps us evaluate the effectiveness of treatment 4  PURPOSE OF WOUND HEALING Restore the epithelial barrier Restore tissue strength and function Ensure viability of the tissue Prevent infection Avoid fluid loss Prevent entry of foreign objects 5  HOW DO WOUNDS HEAL? Following cell damage/death, the body acts to regenerate new tissue – to regain original tissue structure and function  Specialised surrounding tissue proliferates to replace lost tissue OR repair of the damaged tissue occurs by creating new scar tissue The result if both of these processes occur is called restoration 6  WOUND HEALING - R E G E N E RAT I O N Regeneration is limited to specific types of cells which have the ability to divide and replace themselves. Body cells are labelled in relation to their ability to regenerate. The 3 types of cells are as follows:  Labile: These are cells that regenerate throughout life such as epithelial cells of the skin  Stable: These cells can regenerate but under certain stimuli/conditions such as hepatocytes with hepatocyte growth factor  Permanent: These are unable to regenerate such as nerve, skeletal muscle and cardiac cells 7  LABILE CELLS: Continuously dividing e.g. Germ cells of hematopoietic tissues; epithelial surfaces (Skin, GI Tract, Respiratory tree, Lymphoid tissues inc. spleen, lymph nodes) TYPES OF CELLS THAT PERMANENT CELLS: Non-dividing cells i.e. Cardiac muscle cells and neurons AID HEALING STABLE CELLS (Quiescent Cells): Do not normally divide but can under the control of specific growth factors. Most glandular organs e.g. liver, kidney, pancreas. Certain cell lines: Smooth muscle, fibroblasts, vascular endothelium 8  CAUSES OF TISSUE EXTERNAL TRAUMA INTERNAL Self-Induced Poor dressings Peripheral Vascular disease (PVD) Friction Chemical burns Infection Excessive pressure Electrical burns Anaemia Uneven pressure Radiation Neuropathy Severe cold Infection Malnutrition Severe heat Surgical 9  WOUND HEALING Wound healing depends on many factors The type of wound present is a critical factor for wound healing as not all wounds will heal equally Remember… full resolution is only able to occur in tissue whereby stable or labile cells are present To classify wounds, we often use wound 10  W O U N D C L A S S I F I C AT I O N Classification and scoring systems aid our clinical decision making and are useful for auditing healing outcomes Many systems exist Meggit-Wagner Wound Classification is one of the oldest and was previously very commonly used BUT WIfI is the recognised system currently There are many newer systems which are favoured in Diabetic Foot Ulcer (DFU) and wound management including: WIfI, SINBAD, TEXAS, 11 PEDIS 12 13 14  WOUND HEALING Wounds with minimal tissue loss heal by primary intention e.g. surgical incision Wounds with substantial tissue loss from injury or infection heal by secondary intention e.g. ulceration, burns, graze wounds  Generally, a slower process than primary intention Repair of a wound and regeneration of healthy tissue should commence within a short time from the initial injury 15 WOUND HEALING 16 WOUND HEALING 17  P R I M A RY I N T E N T I O N These wounds will heal with minimal production of granulation tissue as there is little disruption to the tissues. Granulation tissue is highly vascular containing erythrocytes, neutrophils, macrophages, plasma and fibroblasts. An epidermal and dermal 18 P R I M A RY I N T E N T I O N - E P I D E R M I S In a wound where primary intention healing occurs, the edges are held together by a fibrin clot The clot forms a protective barrier on the surface Lysosomes, macrophages and neutrophils act on any damaged tissue Within 24-48hrs, the cells within the basal layer adjoining the wound will commence mitosis The cells seek “like” cells and upon encountering each other move in different directions 19 P R I M A RY I N T E N T I O N - E P I D E R M I S Eventually the whole surface area of the wound will be covered in a layer of basal cells Basal cells of the epidermis move quickly to the wound edges and form an immature epidermis in place of the lost epidermal cells which occurred upon wound occurrence After this initial rapid process, the immature epithelial cells will keratinise in the usual way and eventually the scab will shed 20 1. 2. Surgical incision Spur of epithelium forms Wound fills with blood clot Scab is formed Minimal granulation tissue Epithelium joins together grows into the wound in about 2 days 3. 4. Fibroblasts in Narrow fibrous granulation tissue scar gradually form collagen becomes less This unites wound vascular edges 21 Epithelial spur  P R I M A RY A N D S E C O N DA RY WOUNDS The entire wound healing process is complex and follows a series of events which begins with the occurrence of the initial injury The process can continue from months to years The process is broadly the same for primary and secondary healing but differs in cases where there are different degrees of wound contraction, types and levels of scarring. 22  P R I M A RY A N D S E C O N DA RY WOUNDS STAGES OF WOUND HEALING:  Haemostasis and Inflammatory phase (slides 24-26)  Proliferation and Migratory phase (slides 27-37)  Remodelling and Maturation phase (slides 38-40) 23 24  1 - I N F L A M M AT O RY P H A S E This phase starts immediately after injury and lasts 2-5 days Enables wound closure and removal of dead cells, debris and exudate 1. Haemostasis (coagulation) - Vasoconstriction - Platelet aggregation - Fibrin clot 2. Inflammation - Vasodilation - Activation of WBCs (white blood cells) in tissues - Phagocytosis 25  1 - I N F L A M M AT O RY P H A S E Cont. Haemostasis (Coagulation) and Inflammation During this phase; platelets, neutrophils, macrophages and lymphocytes are the predominant cells present. They function to kill bacteria and clear the wound site of cellular debris and foreign material before repair stages commence The cells, especially platelets also synthesise and release growth factors which regulate the proliferation and remodelling stages of healing. Summary: Initial blood loss occurs and clot formation prevents further blood loss Inflammatory response  vasodilation of surrounding arterioles Plasma  tissues bringing neutrophils / macrophages to 26 27  2 - P R O L I F E RAT I O N P H A S E This phase starts after the inflammatory phase, may begin as soon as 2 days after the injury and may last up to 3 weeks. Enables replacement of lost cells and tissues Takes place largely by two processes: 1. Cell migration 2. Cell division (proliferation) In cutaneous wounds, 3 types of cells proliferate and migrate including:  Fibroblasts  Endothelial cells (cells migrate in arcs and form new vessels i.e. angiogenesis)  Epithelial cells (migrate in sheets to reestablish epithelial surface)  The direction of fibres formed are determined by the amount of 28  C E L L M I G RAT I O N The cells at the edges of the damaged tissue respond to a glycoprotein called fibronectin which is found in connective tissues (on cell surfaces and in plasma) Fibronectin is involved in many cellular processes including tissue repair, embryogenesis, blood clotting and cell migration/adhesion Fibronectin is an insoluble glycoprotein dimer that serves as a link protein in the extracellular matrix Serves as a general cell adhesion molecule by anchoring cells such as keratinocytes to collagen or proteoglycan substrates Keratinocytes bind and thus move through a fibrin-rich matrix 29 CELL PROLIFERATION 30  ANGIOGENESIS Capillaries near the damaged tissue bud and grow toward the repair zone Loops and arcades are formed together with anastomoses which rapidly reestablish a blood flow through the area This provides oxygen and nutrients while removing metabolic and repair waste products Oxygen is critical for many reparative processes but especially for collagen production Many angiogenic growth factors and chemical mediators have been identified which exert influences on the developing capillaries including: VEGF, PDGF, IL-8 and fibroblast growth factor (Vernon- Roberts, 1988) Some of these mediators are produced during the inflammatory 31  P R O L I F E RAT I O N P H A S E C O N T. Fibroblasts, keratinocytes and vascular endothelial cells are all active in producing granulation tissue which is essential for restoring the epithelium and vascular integrity Granulation tissue to the naked eye appears as an aggregation of tiny pink granules which consist of:  Newly formed capillaries  Fibroblasts elaborating connective tissue  Many macrophages The granulation tissue has the following properties:  It bleeds freely (if touched slightly)  It is insensitive to pain (no nerves are present)  Quite resistant to infection 32 G RA N U L AT I O N T I S S U E 33  P R O L I F E RAT I O N P H A S E C O N T. Fibroblasts convert to myofibroblasts which are:  Responsible for wound contraction and strength of the repair site  Draw the edges of the wound together, particularly in skin lesions, thus reducing the size of the final scar Granulation tissue gradually matures with nerve fibre growth and mast cell invasion Collagen fibres are orientated in response to local stress and provide necessary strength in the required directions As granulation continues to mature, there is a process of devascularisation with obliteration of the lumen of the vessels 34  G RA N U L AT I O N T I S S U E Fibroblast action and angiogenesis normally occurs by about the third day after the tissue injury The combination of capillary budding and collagen production results in a very vascular repair site The fibroblasts initially produce mainly type III collagen which becomes type I as the repair matures Fibroblasts are the most important cell in this phase- they also produce fibronectin and proteoglycans which are essential components of the ground substance of connective tissue 35  R E - E P I T H E L I A L I S AT I O N This process begins almost immediately following the injury and runs in conjunction with the inflammatory and proliferative stages. For deliberate surgical wounds; where wounds heal by first intention this process can be completed in as little as 48 hours (primary intention epidermal healing slide has this information to refer back to) In more complex and/or chronic wounds it may take many weeks or even months for this to occur The process continues on the next slides  36  R E - E P I T H E L I A L I S AT I O N Intact epithelial cells at the peripheral areas of the damaged tissue zone begin to replicate within hours of the initial injury The stimuli for this increased activity could be the loss of restraint that cells exert over each other while in contact The process is a regenerative one where replacement cells are true epidermal cells rather than scar tissue Epidermal cells move in from the periphery and then move out from the islands of regeneration to cover the wound surface. The advancing edge of the epithelial sheet seeks out moist oxygen rich tissue 37  R E - E P I T H E L I A L I S AT I O N If the advancing epithelial sheet meets any foreign material (e.g. eschar, blood clots) it will “dive downwards” to maintain contact with the vascular bed to lift these foreign materials away from the wound bed where possible When migrating epithelial cells meet oncoming cells, movement ceases through a mechanism of contact inhibition Even when initial covering is complete it may still take many weeks for the skin covering to mature Replaced tissue will always be thinner and less strong than original tissue Epidermal growth factor (EGF) is thought to influence various aspects of this process 38  3- RE-MODELLING PHASE This phase after the proliferation phase, may begin at about 3 weeks and may continue for up to 2 years Enables new collagen to form, increasing tensile strength of the site Scar tissue is only 80% as strong as the original tissue Continuous synthesis and degradation of collagen occurs and relies upon a balance between factors that promote synthesis of extracellular material (ECM) components and enzymes that degrade these components Growth factors are synthesised and released locally at the wound site & regulate the functions of each of the cell types Growth factors involved include; platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-beta), epidermal growth factor (EGF), insulin-like growth factor (IGF-1) and interleukin- 39  3- RE-MODELLING PHASE Collagen is the most abundant protein in the body and has a very strong triple helical formation as seen below 40 F O R M AT I O N O F C O L L A G E N A N D S C A R T I S S U E Cicatrisation  The conversion of granulation tissue to scar tissue (via gradual closing of small vessels) Adhesions  Fibrous “connections” between two surfaces may occur Keloid Scarring  Does not occur in all cases. Represents a post-traumatic repair where connective tissue proliferation in the dermis drastically exceeds the amounts necessary  Macroscopically it is a red, raised and firm lesion with sharp, often irregular outline and a smooth, shiny surface 41 42 W H Y D O E S W O U N D H E A L I N G M AT T E R T O U S ? Helps with   Identification of the type and the cause/s of a wound  Recognition of a wound which is healing well or not healing well i.e. acute vs chronic  Understanding of the intervention/s needed to aid tissue healing  Consideration of a successful intervention or one that is unsuccessful or inappropriate  Let's go over some common wounds in the following slides: 43  PRESSURE ULCERS Caused by unrelieved pressure to tissue over time Also known as decubitus ulcers or bed sores Range in severity from mild (minor skin reddening) to severe (deep craters which can tunnel to muscle and bone) Cause:  Continued pressure restricts blood vessels which are required to supply the skin with nutrients and oxygen  Tissue dies and a pressure ulceration forms  The affected area may feel warmer than the surrounding tissue Q: Which anatomical areas may be at risk? 44 PRESSURE ULCERS 45  VENOUS ULCERS Most common type of ulcer affecting lower extremities Cause/process/signs:  Caused by venous stasis which is a result of valve dysfunction within the veins  Haemoglobin from erythrocytes leak into the extravascular space, causing hemosiderosis pigmentation (brown pigments on legs)  Transcutaneous oxygen pressure of the skin surrounding a venous ulceration is decreased which suggests that there are forces obstructing the normal vascularity of the area  Usually seen around gaiter areas and medial malleolus is also common  Typically seen with an oedematous and indurated lower extremity  Ulcers tend to be shallow, not overly painful and produce exudate 46 VENOUS ULCERS 47 FAC T O R S A F F E C T I N G H E A L I N G L O C A L FA C T O R S S Y S T E M I C FA C T O R S Blood supply Dressing choice Age Immunosuppression Adhesion to bone Temperature Nutrition Systemic disease ( e.g. PAD, Diabetes) Infection Drying Vitamin and trace element deficiencies – Malignancy Foreign bodies vitamin C, A, zinc for Hypoxia Excessive movement example Drugs such as steroids, chemotherapy 48 O T H E R C O M P L I C AT I O N S O F H E A L I N G Perfect restoration of function is unlikely. Some degree of scar formation almost always occurs, even with surgical sutures. Depending on the tissue and amount of scar tissue produced any of the following may occur: Risk of interference with normal function Disfigurement Limitation of movement at joints (flexion or extension) Scar tissue is non-functional Scar tissue is not elastic Adhesions to adjacent structures may occur 49 BONE HEALING 50  R E PA I R O F B O N E All treatment forms related to broken bones follows a basic rule:  The broken pieces must be put back into position and prevented from moving out of place until they are healed. 51  F RA C T U R E H E A L I N G Most broken bones can heal successfully once they have been repositioned and held in place Bones heal relatively rapidly when placed relatively accurately (usually in 6 weeks) but bear in mind, the immediate ends of a fracture are dead, so we are reliant upon surrounding active bone. Healed bone is often stronger than the original (opposite to cutaneous healing) due to external calcification > may also mean that the area appears more hypertrophic or osteophytic In certain cases, often as a result of age or ill health, broken bones will not heal regardless of successful repositioning and correct immobilisation 52 Initial fixation: radial head excision and coronoid screw fixation. Two years later, asymptomatic non-union. This is not optimal, but no intervention is indicated. 53  BONE Bone is a dynamic organ which is continuously remodelling by resorption and reformation These processes are dependant on:  Osteoblasts: bone forming cells  Osteocytes: bone maintaining cells (mature bone cells)  Osteoclasts: bone destroying (break-down) and resorbing cells STAGES OF FRACTURE HEALING are as follows:  Stage 1: Inflammation  Stage 2: Repair and Formation of Soft (Provisional) Callus  Stage 3: Bone Remodelling 54  S TA G E S O F F RA C T U R E H E A L I N G Stage 1: Inflammation Bleeding from the fractured bone and surrounding tissue occurs The fractured area swells and a haematoma forms Acute inflammation and oedema follows soon after injury  This stage begins the day you fracture the bone and lasts about 2-3 weeks Osteocytes are deprived of their nutrition and die; hence the immediate ends of a fracture are dead and contribute to the presence of necrotic material Macrophages, lysosomes start to clear debris 55  S TA G E S O F F RA C T U R E H E A L I N G Stage 2: Repair and Formation of Soft (provisional) Callus The haematoma becomes organised as a fibrin mesh acting as a scaffold for healing Granulation tissue is laid down as the basis for new bone formation Cells invade the granulation tissue (fibroblasts, chondrocytes) The site of the fracture stiffens as fibro- cartilaginous callus forms and splints the fractured bone The new bone cannot be seen on x-rays - This stage usually lasts until 3 weeks or 56 more after the injury  S TA G E S O F F RA C T U R E H E A L I N G Hard Callus Between 4 and 8 weeks, the new bone begins to bridge the fracture. The bone ends gradually become enveloped in a fusiform mass of callus which contains increasing amounts of bone. These fragments become more rigid and immobilise due to the internal and external callus formation. Eventually the fracture site is deemed to have clinically “united” or has “union”. The new bone starts to become more mineralised  a process called ossification (to ossify) The bridge and callus can now be noted on x-rays By 8-12 weeks after the injury, new bone has filled the fracture 57  S TA G E S O F F RA C T U R E H E A L I N G Stage 3: Bone Remodelling At about 8-12 weeks post injury the fracture site remodels itself and corrects any deformities that may still be present as a result of the initial injury. This process does not typically end at right at this point. The final remodelling and fracture healing can last several years beyond this point. Consider watching the below video post lecture: You tube video – bone modelling/remodelling https://www.youtube.com/watch?v=0dV1Bwe2v6c 58  S U M M A RY O F B O N E H E A L I N G 1. Haematoma occurs > blood filled swelling > coagulation occurs and increased inflammatory response 2. Granulation tissue and fibrocartilaginous callus form in an initial response to help knit area together and heal i.e. prevention of further bone disruption 3. Capillaries grow within break area and increase vascular permeability to continue healing 4. Collagen fibres span the break and start to seal and strengthen the area 5. Bone callus is formed, ossification occurs 6. The bone is remodelled and corrects any deformities and/or increases strength of the bone 59  C O M P L I C AT I O N S O F F RA C T U R E HEALING Neurovascular injury: Some fractures are so severe that the arteries and nerves around the injury are damaged. Complications could also arise and may not be apparent initially – such as an avascular necrosis. Infection: Open/compound fractures can become infected when the jagged bone ends are exposed to air where they have torn through the skin. Fractures where metalwork has been added to stabilise may also be predisposed due to rejection of the foreign material or less likely incorrect surgical prep. Vascular death of bone may also increase risk of infection (weakening of bone may cause cavities or break downs, immunosuppressed individuals are at greater risk). Post-traumatic arthritis: Fractures that extend into the joints (intraarticular fractures) or fractures that cause bone to meet at abnormal 60 angles may predispose or cause premature arthritis to occur to the joint.  C O M P L I C AT I O N S O F F RA C T U R E HEALING Growth abnormalities: A fracture in the growth plate (epiphysial growth plate) in a child or potentially teen, depending on the area/age can cause bone to stop growing prematurely, therefore they may end up with a discrepancy Delayed Union: A fracture that takes longer to heal is called a delayed-union Non-union: A fracture that fails to heal in a reasonable amount of time is called a non-union Mal-union: A fracture that does not heal in a typical or normal alignment is called a mal-union 61 C O M P L I C AT I O N S O F F RA C T U R E HEALING – NON-UNION 62  P O S T L E C T U R E C O N S O L I D AT I O N Post-lecture consolidation: 1. Review the lecture notes and supporting YouTube videos on angiogenesis and fracture healing 2. Attempt the MCQ quiz at the end of this learning unit and test your knowledge! Websites/Reading: http://www.youtube.com/watch?v=u7Ryg9nVFLI – (Stages of wound healing) VELNAR, T., T BAILEY AND V SMRKOLJ (2009) The Wound Healing Process: an Overview of the Cellular and Molecular Mechanisms. The Journal of International Medical Research 37(5): 1528-1542. Available from: http://docserver.ingentaconnect.com/deliver/connect/field/03000605/v37n5/s31.pdf?ex pires=1264354537&id=54579045&titleid=75001442&accname=Guest+User&checksu m=6A10B6A2C416016672785537F9343979 Wallace HA, Basehore BM, Zito PM. Wound Healing Phases. [Updated 2023 Jun 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470443/ 63