inflammation and wound healing Flashcards
Platelet activation via adsorbed proteins
trigger: adsorption of plasma proteins on material surfaces
effect: platelet adhesion, activation, aggregation
primary players: platelets and adsorbed proteins (fibrinogen, vWF)
end product: platelet plug formation
hemostasis phase: primary
material properties driving it: protein adsorptive surfaces
contact activation of intrinsic clotting cascade
trigger: direct activation of factor XII by the material surface
effect: initiates fibrin formation via the intrinsic coagulation cascade
primary players: coagulation factors, fibrin formation
end product: fibrin clot stabilization
hemostasis phase: secondary
material properties driving it: reactive/negatively charged surfaces
competitive protein binding in biomaterial-tissue interactions
describes how proteins from body fluids (eg blood plasma) compete to adsorb onto the surface of an implanted biomaterial
protein adsorption and cellular response (biomaterial-tissue interactions)
Upon implantation, proteins rapidly adsorb onto the material surface, forming a “protein corona” that acts as the interface between the biomaterial and the biological environment. The composition of the protein corona determines cellular behavior, immune responses, and biocompatibility. Examples:
* Fibrinogen promotes immune cell adhesion and triggers inflammation.
* Albumin supports a more biocompatible surface.
vroman effect
Initially adsorbed proteins (often abundant, low-affinity proteins) are displaced by higher-affinity proteins over time, altering the biological response to the material.
material properties (competitive biomaterial-tissue interactions)
Surface features like charge, hydrophobicity, and roughness dictate protein binding and downstream biological effects.
improving blood compatibility of article surfaces
hydrophilic coatings, anticoagulant coating, NO releasing surfaces, protein immobilization, drug-eluting surfaces, biomimetic materials, nanostructured surfaces
Approach: hydrophilic coatings
Create a hydrated layer to repel protein and platelet adhesion (e.g., PEG-based).
approach: anticoagulant coating
e.g., heparin, which binds antithrombin III to inhibit thrombin and reduce clot formation.
approach: NO releasing surfaces
Mimic endothelial cells by releasing NO, which inhibits platelet activation and aggregation.
approach: protein immobilization
Immobilize proteins like albumin to form a non-thrombogenic interface.
approach: drug-eluting surfaces
Release antiplatelet or anticoagulant drugs (e.g., sirolimus, paclitaxel).
approach: biomimetic materials
Incorporate endothelial-like molecules (e.g., thrombomodulin) to mimic natural blood vessel surfaces.
approach: nanostructured surfaces
Modify surface roughness to reduce platelet adhesion and activation.
biological responses to materials ex. tissue reactions
Beneficial: A vascularized tissue reaction, a thin fibrous capsule, and integration of the material with the surrounding tissue resulting in a seamless continuity within the tissue.
Deleterious: Thick fibrous and avascular capsule, scar formation, and chronic inflammatory response.
tissue homeostasis
Tissues operate best within specific physiological ranges (e.g., pH,
temperature, nutrition, pressure).
The body maintains homeostasis (optimal conditions) by dynamically adapting to internal and external changes.
mechanisms of adaptation (tissue homeostasis)
achieved through:
- soluble signaling molecules (eg hormones, cytokines)
- cell-cell and cell-ECM interactions
ECM role
three-dimensional network of proteins, glycoproteins, and polysaccharides that provides structural and biochemical support to surrounding cells in tissues.
Tissue homeostasis depends critically on cellular interactions with the extracellular matrix (ECM).
Extracellular matrix (ECM)
In most tissues, the ECM is constantly turning over and being remodeled in a coordinated, regulated manner.
ECM turnover is generally quite low in normal mature (i.e. stable) tissues, but rapid and extensive remodeling characterizes embryological development, adaptation to changing environmental conditions, and wound repair.
Tissues with high regenerative capacity
- Epithelial, lymphoid, hematopoietic, and mesenchymal tissues (cell types include fibroblasts, smooth muscle cells, osteoblasts, chondrocytes, and endothelial cells)
- Highly vascularized
Tissues with low regenerative capacity
Nerve, muscle (esp. cardiac), cartilage
homeostasis and hemostasis
Hemostasis is a critical part of homeostasis because it helps maintain blood pressure and other factors that are important for survival.
The coagulation system, which is responsible for blood clotting, is tightly controlled to ensure a balance between clotting and vascular integrity.
Immune system
defends the body by protecting against harmful pathogens, maintaining self-tolerance, and coexisting with beneficial microbes.
complex network of cells, tissues, and molecules that protects the body from infections and maintains homeostasis.
Immunology is now recognized as vital for tissue homeostasis, influencing stem cells, local metabolism, and the microbiome.
Immune system main branches
- innate immune system
- first line of defense, providing a rapid but non-specific response.
- Includes physical barriers (skin, mucosa), cells (macrophages, neutrophils, natural killer cells), and soluble factors (cytokine, complement proteins) - adaptive immune system
- provides a slower, highly specific response
- involves T cells and B cells, which recognize and remember specific pathogens
- includes the production of antibodies by B cells
Complement system core functions
Complement activation through the classical, lectin, and alternative pathways, leading to the formation of the membrane attack complex (MAC) which can directly kill pathogens.
complement system beyond pathogen killing
Recent research highlights the Complement System’s role in regulating inflammation, influencing adaptive immune responses by interacting with T and B cells, and contributing to tissue homeostasis.
complement system emerging complexities
Further investigations include the role of complement receptors on immune cells and the potential for dysregulation in autoimmune diseases.
Complement system overview
complex cascade involving approximately 30 glycoproteins present in serum as well as cell surface receptors.
part of innate immune system to enhance the immune system’s ability to clear pathogens and damaged cells; it also bridges to the adaptive system by enhancing antibody responses.
complement system key functions
Opsonization: Coating pathogens to enhance phagocytosis.
Chemotaxis: Attracting immune cells to the infection site.
Lysis: Forming the membrane attack complex (MAC) to lyse pathogens.
Inflammation: Triggering the release of inflammatory molecules.
complement system activation pathways
Classical Pathway: Activated by antibodies binding to antigens.
Lectin Pathway: Triggered by mannose-binding lectin binding to microbial surfaces.
Alternative Pathway: Spontaneously activated on pathogen surfaces.
membrane attack complex (MAC)
structure formed by the complement system to lyse and kill target cells, such as bacteria or infected host cells.
membrane attack complex (MAC) formation
Triggered by the activation of the Complement cascade
(typically the terminal stage).
involves complement proteins C5b, C6, C7, C8 and multiple C9 assembling on the target cell membrane.
membrane attack complex (MAC) mechanism
Create a pore in the cell membrane, disrupting the cellular lipid
bilayer.
Leads to cell lysis (rupture) and death.
membrane attack complex (MAC) role
Provides a direct defense against pathogens.
A critical effector mechanism of the innate immune system.
Four stages of normal wound healing
Hemostasis: Blood clotting occurs to stop bleeding and create a temporary matrix.
Inflammation: Acute inflammation lasts for a few days, where immune cells (e.g., neutrophils and macrophages) clear debris and pathogens.
Proliferation: Fibroblasts, keratinocytes, and endothelial cells proliferate to rebuild tissue, form new blood vessels (angiogenesis), and deposit ECM.
Remodeling (Maturation): Collagen is reorganized, and the wound contracts to restore the tissue’s structural integrity.
normal healing vs. chronic inflammation
normal: Acute inflammation resolves within a few days, allowing proper
progression to subsequent healing stages.
chronic inflammation: Prolonged inflammation disrupts healing, causing delayed wound closure, tissue damage, or chronic wound formation.
Underlying Factors: Causes include infection, ischemia, diabetes, or prolonged presence of foreign materials.
five cardinal signs of inflammation
Heat: Localized warmth from elevated blood flow and metabolic activity.
Redness: Caused by increased blood flow due to vasodilation.
Swelling: Result of fluid and plasma proteins leakage into tissues (edema).
Pain: Triggered by inflammatory mediators activating pain receptors.
Loss of Function: Impairment caused by pain, swelling, or tissue damage.
inflammation
Acute inflammation in normal wound healing is mainly driven by innate immunity, with adaptive T cells contributing to inflammation resolution and tissue repair.
The initial response to cell and tissue damage is the cells of innate immunity, neutrophils and macrophages.
inflammation, at the site of injury
- Increased vascular permeability
- Infiltration of blood plasma proteins and leukocytes
- Opsonization and phagocytosis of
foreign material
cytokines
created by macrophages
Cytokine release is critical to mount inflammatory response and resolve inflammation.
general properties of cytokines
- Cytokines are often redundant, and actions are pleiotropic
- Cytokines often affect the production and action of other cytokines (sometimes self) —positive feedback
- Action is often local, but at high doses can be systemic (e.g., TNF- a).
- Cytokines bind receptors with very high affinity —only small amounts are necessary.
- Other signals regulate sensitivity to cytokines:
- Number of receptors on the cell surface
- Often cytokines increase the production of their own receptor — positive feedback
proinflammatory cytokines
Tumor Necrosis Factor-alpha (TNF-α): Activates endothelial cells and promotes recruitment of
immune cells; Induces fever and acute-phase responses.
Interleukin-1 (IL-1): Stimulates inflammation, fever, and production of acute-phase proteins; Activates endothelial cells and lymphocytes.
Interferon-gamma (IFN-γ): Enhances pro-inflammatory signaling and macrophage activation.
anti-inflammatory cytokines
Interleukin-10 (IL-10): Suppresses pro-inflammatory cytokine production; Regulates macrophage and dendritic cell activity.
Transforming Growth Factor-beta (TGF-β): Suppresses inflammation and promotes tissue repair; Contributes to extracellular matrix production and fibrosis.
Growth factors (support tissue remodeling, angiogenesis, and repair
Vascular Endothelial Growth Factor (VEGF): Promotes angiogenesis (formation of new blood
vessels).
Platelet-Derived Growth Factor (PDGF): Stimulates fibroblast proliferation and collagen production.
Insulin-like Growth Factor 1 (IGF-1): Enhances cell proliferation and tissue repair.
Fibroblast Growth Factor (FGF): Promotes fibroblast activity and angiogenesis.
Classical activation (M1 macrophages)
Induced by interferon-gamma (IFN-ɣ) and microbial signals (e.g.,
lipopolysaccharides, LPS)
Pro-inflammatory response to eliminate pathogens and infected cells
Cytokines produced: TNF-⍺, IL-1, IL-6, IL-12.
Classical activation (M1 macrophages) key features
Enhanced microbicidal activity
Produces reactive oxygen species (ROS) and reactive
nitrogen species (RNS)
Amplifies inflammation to recruit more immune cells.
Alternative activation (M2 macrophages)
Induced by interleukin-4 (IL-4) and interleukin-13 (IL-13).
Anti-inflammatory and tissue repair response.
Cytokines produced: IL-10, TGF-b
Alternative activation (M2 macrophages) key features
Resolves inflammation and promotes wound healing.
Stimulates ECM production and angiogenesis.
Regulates immune responses to avoid excessive damage.
M1 vs M2 macrophages
M1 macrophages focus on pathogen destruction and inflammation.
M2 macrophages prioritize healing, repairs, and inflammation resolution
The macrophage phenotype is not binary; macrophages exist on a spectrum between M1 and M2 states and can exhibit mixed or intermediate phenotypes.
Polarization if highly context-dependent, mediated by microenvironmental signals.
polarization process
The temporal control over the polarization process is crucial: dysregulation leads to excessive
inflammation and disease.
Inflammatory Response to Implanted Devices
Inflammation is Unavoidable
The extent of inflammation critically determines the device’s ability to
function effectively and avoid adverse host reactions.
Toleration thresholds differ based on the device type (e.g., artificial heart valve vs. prosthetic hip vs. microelectrode).
Unresolved or misregulated inflammation can lead to tissue damage and device failure.
Sequence of Local Events Following Device Implantation
ProteinAdsorption
Hemostasis and Clot Formation
Acute Inflammation: Neutrophils and macrophages are recruited to clear debris and pathogens, releasing inflammatory signals.
Chronic Inflammation (If Prolonged): Persistent inflammation may result in tissue damage or delayed healing.
Granulation Tissue (Fibroblast Activation and ECM Deposition): Fibroblasts deposit collagen and endothelial cells promote capillary growth to
form granulation tissue.
Foreign Body Reaction (FBR): Foreign Body Giant Cells (FBGCs) form on the implant surface, and a fibrous capsule develops around the device.
Integration or Failure: Successful integration supports functionality, while excessive inflammation or fibrosis may lead to device failure.
granulation tissue
The hallmark of an early stage of healing. It derives from the pink, soft granular appearance on the surface of healing wounds.
granulation tissue composition
Fibroblasts: Produce collagen and ECM for structural support.
Endothelial Cells: Promote angiogenesis (formation of new blood vessels).
Immune Cells: Macrophages and lymphocytes regulate repair and prevent infection.
granulation tissue functions
Provides a scaffold for tissue regeneration.
Supports angiogenesis for oxygen and nutrient delivery.
Facilitates immune response to clear debris and pathogens.
granulation tissue, role of myofibroblasts
Generate contractile forces to close the wound.
Deposit collagen to strengthen the repair site.
granulation tissue, transition to remodeling
Granulation tissue matures into scar tissue through ECM reorganization and myofibroblast
apoptosis.
granulation tissue clinical relevance
Positive: Essential for healing and tissue integration.
Negative: Dysregulated granulation tissue can lead to fibrosis or chronic wounds.
Foreign Body reaction (FBR) key features
Cellular Responses: Macrophages dominate, with some fusing into foreign body giant cells (FBGCs).
Fibrous Capsule Formation: Fibroblasts deposit collagen, creating a capsule that isolates the material.
factors influenign Foreign Body reaction (FBR)
Material Properties: Surface chemistry, hydrophobicity, and roughness determine the intensity of the reaction.
Immune Modulation: Biocompatibility of the material affects macrophage and fibroblast responses.
Clinical implications of FBR
Challenges: Thick fibrous capsules and persistent inflammation can impair device function.
Strategies: Surface coatings (e.g., hydrophilic layers) or optimized material design reduce adverse reactions.
Possible Outcomes for the
Implant
Resorption: if the implant is resorbable then the implant site eventually resolves to a collapsed scar or, in the case of bone, may completely disappear.
Integration: very limited occurrence in practice; close approximation of normal host tissue to the implant without an intervening capsule (e.g. implantation of pure titanium in bone).
Encapsulation: the most common response to non-biodegradable or poorly integrated implants. A fibrous capsule forms around the implant as the body isolates the foreign material.
Wound Healing Without Scars (Regeneration)
In tissues capable of complete regeneration (e.g., liver, bone, or the epidermis under certain conditions), healing may occur without scar formation.
These tissues can:
* Restore their original structure and function by proliferation of native cells.
* Maintain tissue integrity without forming fibrotic tissue.
* Example: Superficial skin wounds where only the epidermis is damaged can heal without scars.
Wound Healing With Scar Formation (Fibrosis)
In tissues with limited regenerative capacity (e.g., cardiac muscle, dermis), scar formation is a compensatory mechanism.
Scars are essential in these cases because they:
* Provide structural stability by depositing collagen and other ECM components.
* Prevent the wound from reopening or becoming infected.
* Example: Deep wounds or injuries involving dermis and subcutaneous tissue often result in scarring.
goal in therapeutic wound healing
minimize scar formation while promoting functional tissue regeneration
Pathobiology of Foreign Body Tumorigenesis possible mechanisms
- Chronic Inflammation: Persistent immune activation (e.g., macrophages, FBGCs) creates a pro-inflammatory microenvironment.
- Fibrosis: Excessive ECM deposition and fibrous encapsulation may contribute to tumor-promoting conditions.
- Reactive Oxygen Species (ROS): Chronic inflammation generates ROS, causing DNA damage and mutations.
- Mechanical and Chemical Irritation: Physical properties or leachable substances from implants may promote carcinogenesis.
Pathobiology of Foreign Body Tumorigenesis risk factors
Poor biocompatibility or particle-shedding implants (e.g., nanoparticles).
Prolonged immune activation (macrophages, lymphocytes).
which of the following is NOT a key function of the immune system?
protecting against pathogens
maintaining tissue homeostasis
promoting uncontrolled cell proliferation
interacting with the extracellular matrix
promoting uncontrolled cell proliferation
which pathway of the complement system is activated by antigen-antibody complexes?
classical
lectin
alternative
direct
classical
which of the following cytokines is primarily anti-inflammatory?
IL-1
IL-6
TNF-alpha
IL-10
IL-10
what outcome is most common for implanted biomaterials?
complete integration with encapsulation
resorption into the body
formation of a fibrous capsule
complete tissue regeneration
formation of a fibrous capsule
true or false: fibrous encapsulation of an implant indicates successful integration with the surrounding tissue
false
true or false: cytokines such as TNF-alpha and IL-6 are primarily pro-inflammatory
true
true or false: granulation tissue formation involves the recruitment of macrophages, proliferation of fibroblasts, and angiogensis
true
true or false: heparin coating improves blood compatibility of biomaterial surfaces by reducing thrombus fomation
true
