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
MSE-536
 Responses following injury:
1. Blood clotting and formation of fibrin
network 4. Remodeling and scar
formation:
2. Acute inflammation:
Type III collagen replaced by
activation of neutrophils type I collagen: collagen
bundles are larger and oriented
phagocytosis of foreign bodies
with principal lines of stress in
release of hyaluronic acid and glycosaminoglycan tissue
(chemoattractants) into ECM.
Increased amounts of
chemicals such as chrondroitin
3. Inflammatory response: and dermatan sulfate
influx of fibroblasts into ECM Scar tissue continues to form
beginnings of granulation tissue formation for several months

generation of new blood vessels Blood vessels that are

unattached are resorbed
deposition of type III collagen fibers (thin and
randomly oriented) Scar becomes pale and
avascular
fibrin clot is dissolved, enzymes released and
phagocytosis continues
MSE-536
 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.
MSE-536
 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)

MSE-536
 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 Large cells:
FGGCs
2. Surface Chemistry Small Cells:
macrophages

Factors affecting Foreign Bright particles:

polypropylene
Body Reaction:
1. Shape
2. Surface/Volume Ratio
MSE-536
(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

MSE-536
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.
MSE-536
 Fibrous Encapsulation, cont.
Final stage of healing for implants made of nondegradable
materials.
Steps in granulation tissue Factors affecting capsule formation:
maturation: Degree of original injury during
Presence of larger blood vessels implantation
Alignment of collagen fibers in Amount of subsequent cell death
response to local mechanical forces
Location of implant site
Collapse of capsule surrounding
Degradation time of implant
implant and formation of a scar

Factors affecting capsule thickness:

Amount and composition of small particulates produced
Mechanical factors at implant site
Shape of implant
Electrical currents MSE-536
 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 Subcutaneous model showing:
cells, and surrounded by a layer Polymer hydrogel implant (h)
of lymphocytes Macrophages (right arrow)
Lymphocytes (left arrow)
C: beginning of fibrous capsule
MSE-536
 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

MSE-536
 Repair vs. Regeneration
Wound healing in Skin
Repair involves healing of the
internal dermal layer
Regeneration is regrowth of
thin outer epidermal layer

MSE-536
 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

MSE-536
 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

MSE-536
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
MSE-536
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 Length of Study:
degree of inflammation
Acute toxicity: up to 24 hours
Dose: should be same shape as Subacute toxicity: 14-28 days
final product.
Subchronic toxicity: up to first 90
days
Chronic: > 90 days MSE-536
 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.

MSE-536
The End

MSE-536