CHAPTER 1
The ultimate determinant for a biomaterial to perform its intended in vivo function is the host response
to the biomaterial. The host response over time determines the performance of the biomaterial. The
host response starts immediately upon implantations and consists of:
- Inevitable iatrogenic tissue injury. Iatrogenic: Veroorzaakt door medische handeling
Short response, normal wound healing
- Response to the material.
Long response, as long as the device is in the host
Materials which induce pro-inflammatory responses are associated with abundant fibrous connective
tissue deposition and the downstream of effector molecules.
Materials which either rapidly degrade or reach steady state are associated with minimal scarring,
population of resident inflammatory cells and appropriate tissue types for the location in the body.
The host response is initiated with the activation of the innate immune system as a result of cell and
tissue damage during biomaterial implantation. During contact the surface of the biomaterial is coated
with blood and plasma proteins, this is called the Vroman-effect. As a result of the Vroman-effect, cells
interact with the adsorbed protein layer instead of the biomaterial. The protein layer is a temporary
matrix that mediates interaction between the biomaterial and the host tissue. The protein layer is
dependant on the material:
- Degradable material
The protein layer serves as a matrix that facilitates cellular access and promotes infiltration
towards the material.
- Nondegradable material
The adsorbed protein layer serves as interface, sites for cell attachment. Furthermore, the
protein layer will serve as mediator between host and the implanted construct.
The cellular response is predominated by neutrophils at the host-biomaterial interface. The neutrophil
response is the hallmark of the acute innate immune response. Neutrophils play an important role in
eliminating pathogenes at the treatment site. Neutrophils establish signaling gradients that attract
components of the innate immune system, initiate granulation tissue and secretion of enzymes
(degradable materials).
As a result of signaling gradients (due to neutrophils) the innate immune response transitions to a
macrophage dominant infiltrate which replaces the neutrophils at the interface. The macrophage
response will depend primarily on the material and host factors.
- Degradable material
Promotes a pro-remodeling M2 macrophage-associated response that leads to tissue
deposition.
- Nondegradable material
Promotes pro-inflammatory processes that lead to foreign body reaction, scar tissue formation
and chronic inflammatory processes associated with M1 macrophages.
- Permanent nondegradable material (metallic plates/screws)
Frustrated phagocytosis: promote inflammation, seroma formation and encapsulation.
,Host factors that can affect the host response:
- Age
The aging process affects functions of organs including immunocompetence. The numbers of
neutrophils and macrophages are not affected by aging, but there are functional changes.
Furthermore, the aging process alters adult stem cell function and behavior (not the absolute
number of stem cells).
- Nutritional status
Malnutrition can result in increased accessibility to infections. M1 Macrophages
- Anatomic factors - Pro-inflammatory processes
Every anatomic location has its own anatomic site. including foreign body reaction,
cytotoxicity and encapsulation.
Comorbidities that can affect the host response: M2 Macrophages
- Obesity (pro-inflammatory disease) - Constructive tissue remodeling
M1 Macrophages and site-appropriate tissue
- Diabetes (pro-inflammatory disease) deposition.
- Chemotherapy and Radiation therapy
Cell proliferation is affected.
CHAPTER 3
Biocompatibility: ‘The ability of a material to perform with an appropriate host response in a specific
application’
Biocompatibility can be assessed using in vitro and in vivo assays. An important expect of
biocompatibility is that no material can be biocompatible if it leaches cytotoxic substances.
- In vivo
Mild inflammatory reaction: no toxic leachables measured in vitro and virtually free of
endotoxin. After weeks this reaction resolves into a thin fibrous capsule surrounding the
implant with macrophages and giant cells present at the implant surface.
Foreign body response (FBR): The composite reaction after implantation.
Nowadays, an uncomplicated FBR with a thin, non-adherent capsule surrounding the
implant is considered he hallmark of a biocompatible biomaterial.
Foreign body response, five factors that impact the FBR are:
1. Toxicology
The measurement and study of the effects of material leaching from biomaterials.
2. Reactions related to products from extrinsic microbiologic organisms colonizing the biomaterial,
for example endotoxin contamination.
3. Mechanical effects such as rubbing, irritation, compression and modulus mismatch.
4. Size of the implant impacts the FBR including its size comparable to the organism receiving the
implant an relative to the size of macrophages.
5. A broad range of biospecific interactions with surrounding proteins and cells that might direct
long-term in vivo bioreaction. (less well developed than 4 point before)
, 1. Toxicology
Polymeric materials often contain extractable (leachable) components such as unreacted
monomer, oligomers, initiator fragments etc. If these substances negatively impact cells,
adjacent tissue or an organism systemically, these are toxicology considerations.
2. Organisms colonizing biomaterials and their impact on bio reaction
Bacteria and their cell wall components are intense inflammatory activators. When an implant is
contaminated an intense and usually long-term biological reaction is seen (lots of leukocytes).
The leukocytes are mostly neutrophils and macrophages, called ‘pus’ in the neighborhood of the
implant. Pain, redness and heat are associated with this response, this can lead to a thick foreign
body capsule. These are characteristics for poor biocompatibility. Surface endotoxin can convert
a biocompatible material to one that is not.
3.
4. Cell-biomaterial interactions
All “biocompatible” materials, whether hydrophilic, hydrophobic, metallic, polymeric, or
ceramic, will heal similarly with a classic (and largely quiet) FBR if there are (1) no leachables, (2)
no contaminating products from extrinsic organisms, and (3) minimal mechanical irritation.
The phenomena of frustrated phagocytosis and cytokine release are important. Frustrated
phagocytosis occurs when the macrophage is incapable of engulfing some mass of material
considerably larger than its size. The macrophage is spread thin on the surface of the implant as
it tries to engulf it, in the process the macrophage may release the contents of lysosomes into
the adjacent tissues causing local tissue damage and inflammation. In trying to spread over the
surface, a macrophage might fuse with other macrophages and form multinucleated foreign
body giant cells (FBGCs), there are markers for the FBR. Macrophages also release cytokines in
response to biomaterials (pro-inflammatory (IL-1, TNF-alpha) ór anti-inflammatory (IL-4, IL-10)).
Recap Phagocytosis:
Phagocytosis occurs when the foreign body has surface molecules that trigger receptors on the
surface of the macrophage. The macrophage then engulfs the foreign body. Once inside this
phagocyte, the foreign particle is trapped in a lipid–membrane compartment called a
lysosome in which a battery of chemicals attempts to degrade the foreign material.
The ultimate determinant for a biomaterial to perform its intended in vivo function is the host response
to the biomaterial. The host response over time determines the performance of the biomaterial. The
host response starts immediately upon implantations and consists of:
- Inevitable iatrogenic tissue injury. Iatrogenic: Veroorzaakt door medische handeling
Short response, normal wound healing
- Response to the material.
Long response, as long as the device is in the host
Materials which induce pro-inflammatory responses are associated with abundant fibrous connective
tissue deposition and the downstream of effector molecules.
Materials which either rapidly degrade or reach steady state are associated with minimal scarring,
population of resident inflammatory cells and appropriate tissue types for the location in the body.
The host response is initiated with the activation of the innate immune system as a result of cell and
tissue damage during biomaterial implantation. During contact the surface of the biomaterial is coated
with blood and plasma proteins, this is called the Vroman-effect. As a result of the Vroman-effect, cells
interact with the adsorbed protein layer instead of the biomaterial. The protein layer is a temporary
matrix that mediates interaction between the biomaterial and the host tissue. The protein layer is
dependant on the material:
- Degradable material
The protein layer serves as a matrix that facilitates cellular access and promotes infiltration
towards the material.
- Nondegradable material
The adsorbed protein layer serves as interface, sites for cell attachment. Furthermore, the
protein layer will serve as mediator between host and the implanted construct.
The cellular response is predominated by neutrophils at the host-biomaterial interface. The neutrophil
response is the hallmark of the acute innate immune response. Neutrophils play an important role in
eliminating pathogenes at the treatment site. Neutrophils establish signaling gradients that attract
components of the innate immune system, initiate granulation tissue and secretion of enzymes
(degradable materials).
As a result of signaling gradients (due to neutrophils) the innate immune response transitions to a
macrophage dominant infiltrate which replaces the neutrophils at the interface. The macrophage
response will depend primarily on the material and host factors.
- Degradable material
Promotes a pro-remodeling M2 macrophage-associated response that leads to tissue
deposition.
- Nondegradable material
Promotes pro-inflammatory processes that lead to foreign body reaction, scar tissue formation
and chronic inflammatory processes associated with M1 macrophages.
- Permanent nondegradable material (metallic plates/screws)
Frustrated phagocytosis: promote inflammation, seroma formation and encapsulation.
,Host factors that can affect the host response:
- Age
The aging process affects functions of organs including immunocompetence. The numbers of
neutrophils and macrophages are not affected by aging, but there are functional changes.
Furthermore, the aging process alters adult stem cell function and behavior (not the absolute
number of stem cells).
- Nutritional status
Malnutrition can result in increased accessibility to infections. M1 Macrophages
- Anatomic factors - Pro-inflammatory processes
Every anatomic location has its own anatomic site. including foreign body reaction,
cytotoxicity and encapsulation.
Comorbidities that can affect the host response: M2 Macrophages
- Obesity (pro-inflammatory disease) - Constructive tissue remodeling
M1 Macrophages and site-appropriate tissue
- Diabetes (pro-inflammatory disease) deposition.
- Chemotherapy and Radiation therapy
Cell proliferation is affected.
CHAPTER 3
Biocompatibility: ‘The ability of a material to perform with an appropriate host response in a specific
application’
Biocompatibility can be assessed using in vitro and in vivo assays. An important expect of
biocompatibility is that no material can be biocompatible if it leaches cytotoxic substances.
- In vivo
Mild inflammatory reaction: no toxic leachables measured in vitro and virtually free of
endotoxin. After weeks this reaction resolves into a thin fibrous capsule surrounding the
implant with macrophages and giant cells present at the implant surface.
Foreign body response (FBR): The composite reaction after implantation.
Nowadays, an uncomplicated FBR with a thin, non-adherent capsule surrounding the
implant is considered he hallmark of a biocompatible biomaterial.
Foreign body response, five factors that impact the FBR are:
1. Toxicology
The measurement and study of the effects of material leaching from biomaterials.
2. Reactions related to products from extrinsic microbiologic organisms colonizing the biomaterial,
for example endotoxin contamination.
3. Mechanical effects such as rubbing, irritation, compression and modulus mismatch.
4. Size of the implant impacts the FBR including its size comparable to the organism receiving the
implant an relative to the size of macrophages.
5. A broad range of biospecific interactions with surrounding proteins and cells that might direct
long-term in vivo bioreaction. (less well developed than 4 point before)
, 1. Toxicology
Polymeric materials often contain extractable (leachable) components such as unreacted
monomer, oligomers, initiator fragments etc. If these substances negatively impact cells,
adjacent tissue or an organism systemically, these are toxicology considerations.
2. Organisms colonizing biomaterials and their impact on bio reaction
Bacteria and their cell wall components are intense inflammatory activators. When an implant is
contaminated an intense and usually long-term biological reaction is seen (lots of leukocytes).
The leukocytes are mostly neutrophils and macrophages, called ‘pus’ in the neighborhood of the
implant. Pain, redness and heat are associated with this response, this can lead to a thick foreign
body capsule. These are characteristics for poor biocompatibility. Surface endotoxin can convert
a biocompatible material to one that is not.
3.
4. Cell-biomaterial interactions
All “biocompatible” materials, whether hydrophilic, hydrophobic, metallic, polymeric, or
ceramic, will heal similarly with a classic (and largely quiet) FBR if there are (1) no leachables, (2)
no contaminating products from extrinsic organisms, and (3) minimal mechanical irritation.
The phenomena of frustrated phagocytosis and cytokine release are important. Frustrated
phagocytosis occurs when the macrophage is incapable of engulfing some mass of material
considerably larger than its size. The macrophage is spread thin on the surface of the implant as
it tries to engulf it, in the process the macrophage may release the contents of lysosomes into
the adjacent tissues causing local tissue damage and inflammation. In trying to spread over the
surface, a macrophage might fuse with other macrophages and form multinucleated foreign
body giant cells (FBGCs), there are markers for the FBR. Macrophages also release cytokines in
response to biomaterials (pro-inflammatory (IL-1, TNF-alpha) ór anti-inflammatory (IL-4, IL-10)).
Recap Phagocytosis:
Phagocytosis occurs when the foreign body has surface molecules that trigger receptors on the
surface of the macrophage. The macrophage then engulfs the foreign body. Once inside this
phagocyte, the foreign particle is trapped in a lipid–membrane compartment called a
lysosome in which a battery of chemicals attempts to degrade the foreign material.
