wound repair

lecture given 10/11/2026

repair

replacement of the lost tissue by granulation tissue

regeneration

replacement by similar type tissue

what are physical causes of tissue damage?

compromised blood flow

crushing

desiccation

incision

irradiation

overcooling

overheating

what are chemical causes of tissue damage?

agents with unphysiologic pH

agents with unphysiologic tonicity

proteases

vasoconstrictors

thrombogenic agents

mild, superficial injury

damages epithelium but not the underlying tissue, resolution occurs by regeneration

severe injury

damage to the connective tissue, repair is by scar formation

what is the sequence of events in an inflammatory reaction?

microbes enter and are recognized by macrophages, dendritic cells, and mast cells (tissue resident sentinel cells)

cells create mediators like amines and cytokines

this recruits leukocytes (monocytes, granulocytes), plasma proteins (complement, kinins, others), and platelets

cells eliminate micrones and dead tissue that lead to repair

platelets increase vasodilation and vascular permeability which leads to edema

epithelialization

injured epithelium has genetically programmed regenerative ability that allows it to reestablish its integrity through proliferation, migration, and contact inhibition

edge of normal epithelium will begin and continue to migrate until it comes into contact with another free edge of epithelium, where it is signaled to stop growing laterally

epithelium in wounds in which the subepithelial tissue is also damaged proliferates across whatever vascularized tissue bed is available and stays under the portion of the superficial blood clot that desiccates until it reaches another epithelium margin

once the wound is fully epithelialized, the scab loosens and eventually dislodges

what are the 3 basic stages of wound healing?

inflammatory

fibroplastic

remodeling

inflammatory stage

wound fills with clotted blood, inflammatory cells, and plasma

adjacent epithelium begins to migrate into the wound

undifferentiated mesenchymal cells begin to transform into fibroblasts

migratory stage

first stage of fibroplastic stage

continued epithelial migration

leukocytes dispose of foreign and necrotic materials

capillary ingrowth

fibroblasts migrate into wound along fibrin strands

proliferative stage

second stage of fibroplastic stage

proliferation increases epithelial thickness

collagen fibers are haphazardly laid down by fibroblasts

budding capillaries begin to establish contact with their counterparts from other sites in wound

remodeling stage

epithelial stratification is restored

collagen is remodeled into efficiently organized patterns

fibroblasts slowly disappear

vascular integrity is reestablished

*hemostasis

immediately to 2 days

vasoconstriction

blood clot stabilization through clotting factors release and thrombus formation

*inflammation

24 hrs to 2 weeks

infiltration of neutrophil granulocytes, macrophages, lymphocytes

migration of keratinocytes

microbe removal and phagocytosis of debris

*proliferation

3 days to weeks

migration and proliferation of endothelial cells, fibroblasts, and epithelial cells

formation of granulation tissue and re-epithelialization via keratinocytes

angiogenesis

wound contraction

collagen synthesis and deposition

*maturation/remodeling

3 weeks to years

continued deposition of collagen

secretion of growth factors, matrix metalloproteinases

what factors affect healing of oral wounds?

location- wounds in area with a good vascular bed heal considerably more rapidly than wounds in an area which is relatively avascular

immobilization- particularly important in the healing of bone fractures, as bony union may be delayed or even completely inhibited, resulting in fibrous union

steroid therapy- pts receiving ACTH or cortisone, the growth of granulation tissue was inhibited, apparently because of inhibition of proliferation of new fibroblasts and new endothelial sprouts

what are physical factors that can affect healing?

severe trauma

local temperature

radiation

vascularity and circulation

nutrition and viability

age of the person

presence or absence of infection

hormonal factors that affect healing

diabetes mellitus- one of the most widely recognized diseases in which there is significant, clinically evident retardation in repair of wounds after surgical procedures, including tooth extraction

metabolic aberrations in dental wounds

metabolic disruptions include chronic hyperglycemia, insulin resistance, and dysregulated lipid and amino acid metabolism

these factors initiate a cascade of events that interfere with normal wound healing stages- hemostasis, inflammation, proliferation, and remodeling

hyperglycemia leads to the formation of advanced glycation end-products (AGEs) which alter extracellular matrix (EMC) structure and trap immune cells

insulin resistance reduced glucose uptake, impairing energy production necessary for cell migration and proliferation

dysregulated lipid metabolism results in toxic lipid intermediates that impair immune cell function and promote chronic inflammation

altered amino acid metabolism, particularly arginine deficiency, compromises nitric oxide (NO) synthesis, essential for vasodilation and angiogenesis

what is the impact of hyperglycemia on healing?

hyperglycemia activates pathways that produce reactive oxygen species (ROS), causign oxidative stress and cellular damage

excessive ROS production overwhelms antioxidant defenses, leading to mitochrondrial dysfunction and reduced ATP production

mitochrondrial damage contributes to cellular apoptosis, further delaying wound healing

hyperglycemia also promotes the formation of AGEs, which trigger inflammatory responses and tissue damage

epigenetic modifications due to hyperglycemia suppress genes involved in antioxidant defense, exacerbating oxidative stress

what is the role of insulin resistance in wound healing?

insulin resistance complicates wound healing through chronic inflammation and impaired cellular responses

chronic inflammation from obesity releases pro-inflammatory cytokines that disrupt insulin signaling

insulin resistance reduces glucose uptake, forcing the pancreas to produce more insulin and exacerbating metabolic imbalances

elevated free fatty acids from altered lipid metabolism contribute to insulin resistance and hinder glucose metabolism

aging compounds the effects of insulin resistance, leadint to slower wound healing and increased chronic inflammation

how is wound healing impaired in diabetes?

chronic wounds resist healing, particularly in diabetic ulcers

fibroblasts are crucial for wound repair, but their activity is dysregulated in diabetes

distinct fibroblast populations in skin layers contribue differently to wound healing and scarring

metabolic reprogramming in fibroblasts is essential for their activation and function during repair

diabetic fibroblasts show increased glycolysis and abnormal metabolite accumulation, hindering migration and proliferation

pyruvate dehydrogenase kinase 4 (PDK4) is vital for fibroblast function; its lower expression in diabetic fibroblasts impairs healing

insulin resistance disrupts glucocorticoid regulation, leading to elevated levels that impair healing

impaired angiogenesis in diabetic wounds

elevated glucose causes oxidative damage and accumulation of advanced glycation end products (AGEs) in endothelial cells

impaired nitric oxide (NO) production reduces endothelial cell migration and proliferation

angiogenic signaling pathways like VEGF are disrupted leading to reduced neovascularization

chronic inflammation and oxidative stress contribute to dysfunctional blood vessels, compromising tissue oxygenation

abnormal ECM remodeling creates barriers to endothelial cell migration and blood vessel formation

neuropathy’s role in wound healing

sensory nerves and dendritic cells work together to maintain epithelial homeostasis and promote healing

diabetes leads to reduced epithelial proliferation and sensory neuropathy, delaying wound healing

neuropathy affects metabolic pathways like mTOR and AMPK, crucial for cellular processes

cell based treatments and modulation of growth factors show promise in addressing diabetic neuropathy

compromised epithelial regeneration in diabetes

elevated glucose levels lead to mitochondria dysfunction, reducing energy production and increasing oxidative stress

growth factors like ciliary neurotrophic factor (CNTF) are deficient in diabetes, hindering epithelial regeneration

calcium homeostasis imbalances disrupt metabolic processes essential for tissue repair

keratinocytes rely on glycolysis for energy during wound healing, especially in hypoxic conditions

what does prolonged hyperglycemia promote?

oxidative stress- cellular damage, impaired tissue regeneration

induces chronic inflammation- hampering immune system, prolonged transition to the proliferative phase of wound healing

dysregulated angiogenesis results in disrupted nutrient delivery, thereby further impairing reparative processes

diabetic neuropathy delays injury detection and compromises muscle function, hindering wound closure

a combination of disrupted cell signaling, continuous inflammation, and oxidative damage collectively impair reepithalization

miscellaneous factors that affect wound healing

presence or absence of tissue enzymes

suture materials

tissue adhesives

complex environment of the mouth

primary healing/first intention

edges of the wound are approximated, the healing process is fast

secondary intention

when there is tissue loss, and wound edges cannot be apposed, the wound contracts to reduce the size, granulation tissue fills the wound and epithelialization occurs across the wound surface

are extraction wounds primary or secondary wound repair?

mostly secondary- even with sutures, the socket at the bottom is open

is fracture healing primary or secondary wound repair?

mostly primary

is implant osseointegration primary or secondary wound repair?

primary

are neural injuries and healing patterns primary or secondary wound repair?

depends on the type of injury

are alveolplastys primary or secondary wound repair?

primary

healing of extraction sockets

sockets heal by secondary intention and many months must pass before a socket heals to the degree to which it becomes difficult to distinguish from the surrounding bone when viewed radiographically

when a tooth is removed, the remaining empty socket consists of cortical bone (the radiographic lamina dura) covered by torn PDL, with a rim of oral epithelium (gingiva) left at the coronal portion

white blood cells enter the socket to remove contaminating bacteria from the area and begin to break down any debris such as bone fragments that are left in the socket

bone healing

in contrast to soft tissues, osteoblasts and osteoclasts are also involved to reconstitue and remodel the damaged ossified tissue

osteogenic cells (osteoblasts) important to bone healing and derived from periosteum, endosteum, and circulating pluripotent mesenchymal cells

osteoclasts, derived from monocyte precursor cells, function to resorb necrotic bone and bone that needs to be remodeled

osteoblasts then lay down osteoid, which, if immobile during healing, usually goes on to calcify

fracture healing

early phase of fibroplastic stage of bone repair

osteogenic cells from periosteum and marrow proliferate and differeniate into osteoblasts, osteoclasts, and chondroblasts, and capillary budding begins

late phase fibroplastic stage of bone repair

osteoclasts resorb necrotic bone, in areas of sufficient oxygen tension, osteoblasts lay down new bone; in areas of low oxygen tension, chondroblasts lay down cartilage

in addition capillary ingrowth continues and internal and external calluses form

remodeling stage of bone repair

osteoclasts remove unnecessary bone, and osteoblasts lay new bone tissue in response to stresses placed on bone

new haversian systems develop as concentric layers of cortical bone are deposited along blood vessels

calluses gradually decrease in size

implant osseointegration

wound healing involves healing of bone to the implant and healing of alveolar soft tissue to the implant

maximizing the likelihood of bone winning this race with soft tissue to cover the implant requires…

a short distance between bone and the implant

viable bone at or near the surface of bone along the implant

no movement of the implant while bone is attaching to its surface

an implant surface reasonably free of contamination by organic or inorganic materials

nerve healing

fortunately, most injured nerves spontaneously recover

advances in the understanding of how nerves heal and in the surgical means of repairing peripheral nerves provide pts with the possibility of partially or fully regaining normal nerve function

usually occurs in 2 phases- degeneration and regeneration

neural degeneration

partial segment degeneration and wallerian degeneration

segmental demyelination- myelin sheath is dissolved in isolated segments and a slowing of conduction velocity prevents the transmission of some nerve impulses

wallerian degeneration- the axons and myelin sheath of the nerve distal to the site of nerve trunk interruption undergo disintegration in their entirely

neurapraxia

least severe form of contusion injury, where continuity of the epineural sheath and the axons is maintained

blunt trauma or traction of a nerve, inflammation around a nerve, or local ischemia of a nerve can produce neurapraxia

spontaneous full recovery usually occurs in a few days or weeks

axonotmesis

occurs when the continuity of the axons, but not the epineural sheath is disrupted

beacause the epineural sheath is still intact, axonal regeneration can (but does not always) occur with a resolution of nerve dysfunction in 2 to 6 mo

neurotmesis

most severe type of nerve injury, involving a complete loss of nerve continuity

this form of damage can be produced by badly displaced fractures, severance by bullets or knives during an assault, or by iatrogenic transection

prognosis for spontaneous recovery is poor, except if the ends of the affected nerve have somehow been left in approximation and properly oriented

what are complications of wound healing?

infection

keloid and hypertrophic scar formation- not seen in oral cavity

pigmentary changes- both hyper and hypopigmented changes are possible

cicartrization- refers to late reduction in the size of the scar in contrast to immediate wound contraction

implantation cysts- epithelial cells may slide or get entrapped in the wound

healing after pulpal diseases

healing after periapical disease

keloids

overgrown scar tissues with no tendency for resolution

hypertrophic scar formation

occur in wounds where healing is delayed

more cellular and vascular