Part II: Foreign Body

Response
 Outline for Part II
• How does today’s lecture relate to what we have
learned so far?
• What is the foreign body response?
• What are the physiological processes?
• Cell adhesion (parts and models)
• Cell migration (parts and models)
• Introduction to developmental biology
• Integration of above for tissue engineering and
regenerative medicine
 Biomaterial-Tissue Interactions
Effects of implant on host:
– Local
• Part I: Blood-material interactions: protein adsorption,
coagulation, fibrinolysis, platelet adhesion/activation
• Foreign body response: modification of normal
healing, encapsulation, foreign body reaction
– Systemic and remote
• Part I: Embolization, thrombus, biomaterial
 Outline for Today’s lecture*
• Physiological Processes
– Inflammation
• Acute vs. Chronic
– Wound Healing
• Granulation Tissue
– Foreign Body Response
• Fibrosis and Fibrous Encapsulation

*Source: Ratner “Biomaterials Science”

 Implantation leads to…
• Injury**
• Acute inflammation
• Chronic inflammation
time • Granulation tissue
• Foreign body reaction
• Fibrosis

** What are possible types of injury? Name

examples of implantation. What are
examples of injury not related to implantation?
 What is inflammation?
• Definition: reaction of vascularized living
tissue to local injury
• Functions:
– Contain, neutralize, dilute, or wall off injurious
agent/process
– Triggers series of events that may lead to
• Healing and proper integration of implant, OR
• Scar tissue formation, OR
• Combination of the two
Inflammation video 1
Inflammation video 2
Example of inflammation:
 Common Themes
• Normal physiological process / homeostasis
can impact host response to biomaterials
• Response can vary temporally and spatially
• Identifying specific cell types and receptor-
ligand pairs can give leads for diagnosis and
treatment

How do biomaterial properties impact specific

physiological processes? How can we manipulate the
processes to promote our desired response?
 Host reactions are tissue/organ-specific

but have the same types

of immune cells. The
parenchyma is different.
 Cells and Components of Vascularized Connective Tissue:
• Intravascular (blood) cells
– neutrophils, monocytes, eosinophils, lymphocytes, basophils,
platelets
• Connective tissue cells
– mast cells, fibroblasts, macrophages, lymphocytes
• Extracellular matrix components
– collagens, elastins, proteoglycans, fibronectin, laminin
Important chemical mediators of inflammation derived from
plasma, cells, and injured tissue

• Mediator systems provide checks and balances

• Chemical mediators act locally because they are quickly inactivated or destroyed
• Can degrade biomaterials (especially lysosomal proteases and oxygen-derived
free radicals)
Temporal variation in host response
 Acute Inflammation
• Initial event
• Relatively short in duration (mins – days)
• Main characteristics (mainly determined histologically)
– Fluid exudate, plasma proteins (edema), emigration of leukocytes (neutrophils)
guided by chemotaxis
• Some chemical mediators are chemotactic agents

• Cellular processes
– Phagocytosis, activation and release of enzymes
• Recognition of agent and neutrophil attachment
• Engulfment
• Degradation (may or may not occur)

• Relevance to biomaterials
– Serum factors (opsonins, e.g. IgG and complement) can adsorb to biomaterials
– Neutrophils and macrophages have receptors that recognize opsonins
– Phagocytosis may or may not occur (clearance; low bioavailability)
– Frustrated phagocytosis can lead to release of enzymes to degrade biomaterials
*** Biomaterials properties (e.g. porosity, shape, stiffness, size) have been shown to
be able to modulate inflammatory response.
 A closer look at ‘emigration’*

* Stay tuned for lectures on cell adhesion

 Neutrophil in action*

* Stay tuned for lectures on cell migration

 Chronic Inflammation
• Results from persistent inflammatory stimuli
• Main characteristics
– Macrophages, monocytes, lymphocytes
– Proliferation of blood vessels and connective tissue
• Some chemical mediators are chemotactic agents
• MPS (mononuclear phagocytic system) or RES
(reticuloendothelial system)
– Cells of this system can release factors that
can…
• Stimulate production of a wide variety of cells
• Initiate cell migration, differentiation, and tissue
remodeling
• Be involved in various stages of wound healing
• Relevance to biomaterials
– Motion in implant site may produce chronic
inflammation
 Granulation Tissue
• Depends on extent of injury, but ~ 3 – 5 days after implantation
• Formed from fibroblasts and vascular endothelial cells
• Characterized by pink, soft granular appearance on surface of
healing wounds
– Histological features: proliferation of small blood vessels and fibroblasts
• Cellular processes
– Neovascularization or angiogenesis
• Proliferation, maturation, organization of ECs into capillary tubes
– Fibroblasts proliferate and synthesize collagen and PGs
• Type III collagen is predominant in fibrous capsule
– Some fibroblasts are smooth muscle cell-like (myofibroblasts)
• Wound contraction
– Wound healing (primary, secondary union)
 Foreign Body Reaction
• Main components
– Foreign body giant cells
– Components of granulation tissue (macrophages, fibroblasts, capillaries)
– Depends on form and topography of biomaterial surface

Monocyte Macrophage Foreign Body Giant Cell

Courtesy Prof. J. Anderson, CWRU, Cleveland

 Fibrosis and Fibrous Encapsulation
• Last stage
• Cellular processes (2 distinct processes):
– Regeneration
– Connective tissue (scar, fibrous capsule)
** Depends on proliferative capacity of cells, extent of injury

**We will discuss more when we discuss regeneration

Figure 19-31 The connective tissue underlying an
epithelial cell sheet. It consists largely of
extracellular matrix that is secreted by the
fibroblasts.
© 1994 by Bruce Alberts, Dennis Bray, Julian Lewis, Martin Raff,
Keith Roberts, and James D. Watson.
Wound Healing by First Intention

• little or no loss of tissue (surgical incision)

• wound heals primarily by connective tissue deposition
• sutures, staples, skin closure strips
Wound Healing by Second Intention

• production of granulation tissue

• wound contraction
Phases of Normal Wound Healing

• Coagulation
• Inflammation
• Fibroplasia (Proliferation)
• Remodeling
 Step 1: Coagulation

Fibrin

Red Blood Cell

Blood Vessel

Fixed Tissue Monocyte

Fibroblast

Mast Cell

• platelet activation
• thrombin, fibrin, clot production
• fibrin matrix serves as scaffold for cell migration
• growth factors released (PDGF, TGF-b, etc.)
 Step 2: Inflammation

Fibrin Neutrophil

Fibroblast

Fixed Tissue Monocyte

• occurs within hours of injury and lasts 5-7 days

• neutrophils and macrophages (bacteria, damaged tissue)
• more growth factors released
 Step 3: Proliferation (Fibroplasia)

Epithelial
Macrophage
Bridge
Fibrin

Fixed Tissue
Monocyte Fibroblast

• angiogenesis (migration and proliferation of endothelial cells)

• matrix formation (fibroblast proliferation and deposition of
fibronectin, laminin, collagen, GAGs)
• epithelialization (migration, proliferation, differentiation of
keratinocytes)
Steps in Angiogenesis
 Epithelialization

• model of wound closure by migration of epithelial cells

 Step 4: Remodeling
• excess collagen and matrix removed by collagenase
and other proteolytic enzymes
• wound contraction (fibroblasts? myofibroblasts?)
Summary of Cell Types involved in Wound Healing
 Next time
• Discuss details on cellular
processes, including molecular
level details, in context of
physiology and pathophysiology
described today