Wound Healing and the
Presence of Biomaterials
Topics:
•Formation of Granulation Tissue
•Foreign Body Reaction
•Fibrous Encapsulation
•Chronic Inflammation
•Types of Implant Resolution
•Repair vs. Regeneration
•In Vivo Assays for Inflammatory Response
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Responses following injury:
1. Blood clotting and formation of fibrin
network
2. Acute inflammation:
• activation of neutrophils
• phagocytosis of foreign bodies
•release of hyaluronic acid and glycosaminoglycan
(chemoattractants) into ECM.
3. Inflammatory response:
influx of fibroblasts into ECM
beginnings of granulation tissue formation
generation of new blood vessels
deposition of type III collagen fibers (thin and
randomly oriented)
fibrin clot is dissolved, enzymes released and
phagocytosis continues
4. Remodeling and scar
formation:
•Type III collagen replaced by
type I collagen: collagen
bundles are larger and oriented
with principal lines of stress in
tissue
•Increased amounts of
chemicals such as chrondroitin
and dermatan sulfate
•Scar tissue continues to form
for several months
•Blood vessels that are
unattached are resorbed
•Scar becomes pale and
avascular
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Definition:
Granulation Tissue: characterized by a pebbly,
granular appearance caused by the creation of
many vascular buds sprouting from existing blood
vessels. This process is called
neovascularization or angiogenesis.
Fibroblasts: committed cell type found in many
tissues. Fibroblasts synthesize and maintain
connective tissues by producing and extracellular
matrix (ECM) rich in collagen and proteoglycans.
Fibroblasts with features of smooth muscle cells
are called myofibroblasts and are responsible for
wound contraction.
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Formation of Granulation Tissue
Wound-healing response of the
body after injury or biomaterial
implantation
Granulation tissue formation at
the tissue/material interface. (G)
zone of granulation tissue
separates the spleen (S) from
the polymer implant (I)
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Foreign Body Reaction
Definition:
Foreign Body Giant Cells (FBGCs): multinucleated cells
formed by fusion of monocytes/macrophages in an attempt to
phagocytose biomaterials much larger than a single cell.
Factors affecting Foreign
Body Composition:
1. Topography
2. Surface Chemistry
Factors affecting Foreign
Body Reaction:
Large cells:
FGGCs
Small Cells:
macrophages
Bright particles:
polypropylene
1. Shape
2. Surface/Volume Ratio
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(a) Foreign body reaction to embedded PMMA. Arrow points to
macrophages in tissue
(b) Foreign body reaction to large particles of UHMWPE showing
macrophages and FBGCs
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Fibrous Encapsulation
In vivo response to a biodegradable, polymeric
biomaterial implanted in a rat for 12 weeks. (a) 4
days (b) 3 weeks (c) 12 weeks. P indicates polymer,
or space left by polymer; N: neutrophils, FC: fibrous
capsule, M: macrophages, PF: polymer fragments
embedded in fibrous capsule. Infiltration of
neutrophils into implantation area is seen within a few
days, followed by slower development of fibrous
capsule surrounding implant. Because material is
biodegradable, polymer fragmentation is present at
later times.
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Fibrous Encapsulation, cont.
Final stage of healing for implants made of nondegradable
materials.
Steps in granulation tissue
maturation:
•Presence of larger blood vessels
•Alignment of collagen fibers in
response to local mechanical forces
•Collapse of capsule surrounding
implant and formation of a scar
Factors affecting capsule formation:
•Degree of original injury during
implantation
•Amount of subsequent cell death
•Location of implant site
•Degradation time of implant
Factors affecting capsule thickness:
•Amount and composition of small particulates produced
•Mechanical factors at implant site
•Shape of implant
•Electrical currents
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Chronic Inflammation
Characterized by the presence
of mononuclear cells, including
lymphocytes and plasma cells
Can include presence of
granulomas – a layered
structure comprised of a
nonphagocytosable particle
surrounded by a layer of
FBGCs, a layer of modified
macrophages called Epithelioid
cells, and surrounded by a layer
of lymphocytes
Subcutaneous model showing:
•Polymer hydrogel implant (h)
•Macrophages (right arrow)
•Lymphocytes (left arrow)
•C: beginning of fibrous capsule
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Four types of implant response
resolution:
1. Extrusion: material forced out of the
body (e.g. splinter)
2. Resorption: material biodegrades,
no fibrous capsule forms
3. Integration: implant and host tissue
grow together (e.g. porous titanium
implant in bone)
4. Encapsulation: implant surrounded
by fibrous tissue
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Repair vs. Regeneration
Wound healing in Skin
Repair involves healing of the
internal dermal layer
Regeneration is regrowth of
thin outer epidermal layer
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Skin Regeneration
In the epidermis, this process is
called reepithelilization.
Cells at edge of wound flatten to
cover more of the wound,
releasing attachment to ECM to
migrate across wound
Epithelial cells gradually cover the
entire wound site
ECM attachments are
reestablished, and cells recover
original shape
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In vivo Assays for Inflammatory
Response
Items in the table at right
may cause biological
response through:
•Interactions of biomolecules
(e.g. proteins and ions) or
cells with implant
•Interactions of biomolecules
or cells with soluble agents
leached from implant
•Interactions of biomolecules
or cells with insoluble
particulates
•Alterations in load or strain in
the area around the implant
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Biocompatibility: the ability of a medical
device to perform with an appropriate host
response in a specific application.
Biocompatible assessment: a
measurement of the magnitude and duration
of the adverse alterations in homeostatic
mechanisms that determine the host
response.
Evaluation of biocompatibility usually
involves exposing a small animal to the
selected biomaterial or its extract through
injection or implantation.
Two primary reasons to carry out biocompatibility tests:
1. Screen novel materials to learn degree & type of inflammation
response
2. Assess inflammation response to the material in a form very
similar to that which will be implanted
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Choice of Animal:
•Select on similarity of physiology
and healing response to that of
humans in a given application
•Start with a small animal (e.g., rat,
rabbit) and scale up as warranted
Choice of Implant Site:
•As close as possible to that used in
final application
•Use accessible site (subcutaneous
pouch) to check for inflammation
response.
•Identify parameters that may affect
degree of inflammation
Length of Study:
Dose: should be same shape as
•Subacute toxicity: 14-28 days
final product.
•Acute toxicity: up to 24 hours
•Subchronic toxicity: up to first 90
days
•Chronic: > 90 days
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Factors that can affect dose in
addition to shape in direct implants
1. Implant weight/bulk size
2. Implant surface area
3. Implant roughness
4. Number of implants per animal
Biomaterials may be introduced via:
1. Direct implantation
2. Injection of soluble products
3. Placing in a “cage” to isolate
biomaterial – cage may affect
inflammatory response. l
Stainless steel cage implant model.
This allows investigators to examine
inflammatory response without direct
contact between biomaterial and
surrounding tissue.
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The End
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