Inflammation and Wound Healing

1 8 April 2015

Inflammation and wound healing Yashveer Singh, PhD

Department of Chemistry

CYL458: Biomaterials

2

Biomaterial tissue interactions

Wound healing responses under

normal injury and

implantation

Anderson, Semin Immunol 2008, 20, 86

3 BT Ratner, Biomaterials Science: An Introduction to Materials in Medicine, CRC Press

Biomaterial tissue interactions

The wound healing processes has following phases

Inflammatory (Acute and Chronic) Proliferative/Repair Remodeling/maturation

PMN: polymorphonuclear leukocytes or neutrophils

4

Leukocytes

Granulocytes: cells with granular appearance, are subdivided into

neutrophils, eosinophils, and basophils. Function is to phagocytose

foreign invaders and aid in inflammatory responses

Monocytes: Cells with no nuclei, differentiate into macrophages. Have large phagocytosis capability and play a central role in

inflammatory response

Lymphocytes / plasma cells: T and B cells, part of acquired immune response

Megakaryocytes: Found in bone marrow. It fragments to form platelets

Granulocytes live for 4-5 days, whereas macrophages may survive for months to year

BT Ratner, Biomaterials Science: An Introduction to Materials in Medicine, CRC Press

5 Wikipedia

Leukocytes

Granulocytes Monocytes

Lymphocytes Megakaryocytes Platelets

Leukocytes

6 Lodish, Molecular Cell Biology, WH Freeman

Phagocytosis

Three common mechanism of

phagocytosis

shown:

phagocytosis;

endocytosis; and

autophagy

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Acute inflammation

During inflammation, neutrophils predominate during the first few days of injuries, which are short-lived and disappear after 24-48 hours

Neutrophils emigration is of short duration and chemotactic factors are activated early in the inflammatory response

The size, shape, and chemical, and physical properties of biomaterials will influence the above process. While injury initiates inflammatory

response, the chemicals are released from plasma, cells, and injured tissue

to mediate the response

Neutrophils are replaced by monocytes, which differentiates into macrophages and these cells are very long lived (months). Monocyte

migration continues for days to weeks

Mast cells degranulate and release histamine (recruitment of phagocytosis) release along with interleukins (IL 4 and 13, induces foreign

body reaction) and fibrinogen is adsorbed


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There is exudation of fluids and plasma proteins and emigration of leukocytes (primarily neutrophils), from blood vessels to

perivascular tissues and then to the injury site

Migration is assisted by adhesion molecules present on leukocytes and endothelial surfaces, which is induced, enhanced or altered by

inflammatory agents and chemical mediators


Acute inflammation

Layer of neutrophils

adhering to the inner

surface of the blood vessel

bme.ucdavis.edu

9

Following localization at the injury site, phagocytosis and release of enzymes occurs. Neutrophils phagocytose microorganism and foreign

materials. Phagocytosis has following steps- injurious agent undergo

recognition and neutrophil attachment, engulfment, and killing or

degradation

In general, biomaterials are not phagocytosed because of disparity in size

The process of recognition and attachment will be more if the injurious agent is coated with serum factor called opsonin (IgG and

complement-activated fragment C3b)

Since phagocytosis cannot occur, leukocytes degradation products are released (frustrated phagocytosis)


Acute inflammation

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Characterized by the presence of macrophages, monocytes, and lymphocytes with proliferation of blood vessels and connective

tissue

Persistent inflammatory stimuli lead to chronic inflammation, caused by the chemical and physical property of the biomaterial

and motion in the implant site by the biomaterial

Monocytes differentiates into macrophages, and belong to mononuclear phagocytic system (MPS), also termed as

reticuloendothelial system (RES)

Macrophages release neutral proteases, chemotactic factors, arachidonic acid metabolites, reactive oxygen metabolites,

complement components, coagulation factors, growth promoting

factors, and cytokines

Usually confined to the implant site

Chronic inflammation


11 http://courses.washington.edu/conj/inflammation/chronicinflam.htm

The figure shows macrophages distended with lipid from broken down myelin at the site of necrotic tissue due to a blocked blood

vessel in the brain

Persistence of chronic response beyond 2-3 weeks time will indicate infection

Chronic inflammation

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Within a day of implantation, healing

responses are initiated by the action of

monocytes and macrophages

Fibroblast and vascular endothelial cells proliferate at the site to form granulation

tissue

The new small blood vessels are formed by budding or sprouting of preexisting vessels

(neovascularization or angiogenesis)

Fibroblasts proliferates in granulation tissue and synthesize collagen and proteoglycans,

which causes wound contraction

Granulation tissue


Granulation tissue

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Formation of granulation tissue by proliferation of blood

vessels and fibroblast

Granulation tissue

edoc.hu-berlin.de

14

Wound healing by primary union or first intention: Healing of clean surgical incisions, where wound edges are approximated by surgical

sutures. Healing occurs without bacterial contamination and with minimum

tissue loss

Wound healing by secondary union or second intention: Healing of large tissue defects. Regeneration of parenchymal cells is unable to

completely reconstitute lost tissue and much larger amount of granulation

tissue are formed, leading to scar formation (fibrosis)

Granulation tissue


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Granulation tissue

Google images

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The foreign body reaction to implants involve formation of foreign

body giant cells and component of granulation tissue (macrophages,

fibroblasts, and capillaries)

Macrophages adhere to the implant surface using integrin receptors. The macrophages then undergo cytoskeleton remodeling to spread

over the implant surface. Finally, macrophages fuses to form foreign

body giant cells. IL-4 plays a key role in fusion

The macrophages and foreign body giant cells persists at the tissue-biomaterial interface for the life of implant

Foreign body reaction


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SEM images of an Elasthane 80A

polyurethane surface

(in vivo)

Monocytes adhere to surface (0 days, A),

monocyte differentiate

into macrophage (3

days, B), macrophages

undergoing fusion (7

days, C), foreign body

giant cells formed (14

days, D)

Anderson, Semin Immunol 2008, 20, 86

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Topology and form of implant influence this process. Smooth and

flat surfaces (breast prostheses) have macrophages 1-2 cells thick,

and rough surfaces (PTFE vascular prostheses) have macrophages

and foreign body giant cells at the surface

High surface-to-volume implants (fabrics/porous materials) have higher ratios of macrophages and giant cells than the smooth surface

implant


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When the foreign material is not phagocytosed or removed, the implant is encapsulated in a dense layer of connective tissue

(fibrous capsule) to isolate it from the surrounding tissues and

shield it from immune system

Repair of implant sites involve two distinct processes: regeneration of injured tissue by parenchymal cells of the same

type or replacement by connective tissue that constitute the fibrous

capsule

It depends on (i) proliferative capacity of cells in the tissue or organ receiving the implant and extent of injury as it related to

implants; and (ii) persistence of the tissue framework at the implant

site

Fibrosis/fibrous encapsulation


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Cells are classified into three groups based on regenerative

capacity:

Labile cells, which continue to proliferate (epithelial and lymphoid

cells)

Stable (expanding) cells, which retain the capacity but do not

replicate (parenchymal cells of liver, kidney, pancreas)

Permanent (static) cells, which do not reproduce after birth (nerve,

skeletal muscle, and cardiac muscle cells)

Tissues composed of permanent cells most likely undergo fibrosis (fibrous capsule formation) and those composed of stable or labile

cells may undergo fibrosis or restitution of normal tissue

vasculature



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The C-implant was removed before

histological studies. Fibrous

encapsulation of bone marrow part of

C-implant is shown. e-kjo.org

A normal and encapsulated breast implant.

www.cosmeticbreastsurgeon.co.uk

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www.nature.com

Inflammation and Wound Healing

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