L1: Introductory lecture
Biomaterials= a material that can be implanted into the body and is designed to interact with the body.
Why study the host response to biomaterials? Device safety!
What can go wrong?
● Systemic interactions: embolization, hypersensitivity, the elevation of implant elements in blood,
lymphatic particle transport.
● Local interactions (at the biomaterial-tissue interface):
○ Effect of material on host tissues: blood-material interactions, toxicity, modification of healing,
inflammation, infection, tumorigenesis.
○ Effect of environment on materials: (physical-mechanical effects) wear, fatigue, corrosion,
stress-corrosion cracking, (biological effects) tissue absorption of implant constituents,
enzymatic degradation, calcification.
● Device-patiënt complications: thrombosis, infection, biomaterial failure, adverse local tissue reaction,
adverse systemic effect.
Immunomodulatory biomaterials/ immune engineering:
● Are made to have an interaction with the body.
● Also called ‘smart biomaterials’.
● Examples: regenerative stenting technology, in situ engineered heart valves, nanoparticles that attack
tumor cells (immunotherapy for cancer), and artificial lymph nodes.
● Nano, macro and nano are possible.
Applications:
● Replacement (permanent): joint prosthesis, dental implants, artificial heart valves, pacemaker, vascular
stent, etc.
● Regenerative (degradable): in situ tissue engineering, cancer treatment, synthetic immune niches,
targeted drug delivery, etc.
Factors that influence the host response:
● Biomaterial-related factors: composition (material), degradability, mechanical properties, sterility,
antigenicity, active ingredients (drugs).
● Host-related factors: age (absolute numbers of neutrophils and macrophages are not typically affected,
functional changes, e.g. ability to mobilize, establish chemical gradients, are observed), nutritional status
(malunion can result in infections, impaired healing ability, altered metabolic state), gender, anatomic
location (different conditions, e.g. air interface, blood contact, mechanical loading), previous
interventions, comorbidities (diabetes and obesity; pro-inflammatory disease), immune response,
medications.
L2: The foreign body response
Innate immune system (recap)
The immune system
1. First line of defense: mechanical barriers (skin, mucus
membranes).
2. Second line of defense: innate immune system
3. Third line of defense: adaptive immune system
Innate immune response Adaptive immune response
Nonspecific (react to everything) Specific (antigens)
Responds quickly, intense Slowly the 1st time.
, Cells: macrophage, dendritic cell, mast cell, NK cell, Memory.
complement protein, granulocytes (neutrophil,
eosinophil, basophil). Cells: B cell, T cell (CD4+ T cell, CDB+ T cell),
antibodies, natural killer T cell.
(Synthetic, acellular) biomaterials are typically not
antigenic. Antigen presentation (DCs, macrophages) →
- Mainly innate immune response adaptive immune cells).
- Adaptive immune cells play a role in the Instructing adaptive immune system → targeting
FBR specific pathologies.
Phagocytes: (innate immune response)
= cells that protect the body by ingesting
(phagocytosis) harmful particles, bacteria, or
dead or dying cells. Types:
- Granulocytes (or
polymorphonucleated cells, PMNs)
- “Eat or detonate”
- Robust siege cells, weird
looking nucleus
- Short-lived; hours.
- Monocytes → macrophages
- “Eat or encapsulate”
- Precursor of macrophages
- Nucleus looks like a kidney
Neutrophils: try to eat and if they cannot, they will explode.
How do they know what to eat?
1. Pattern-recognition receptors (PRRs)
○ You should know this very well!!
○ They recognize danger signals.
○ Two types:
■ PAMPs (=Pathogen-Associated Molecular Patterns)
● Exogenous; outside your body (bacteria)
● Example of PAMPs: lipopolysaccharides (LPS).
■ DAMPs (=Damage-Associated Molecular Patterns) = alarmins:
● Endogenous; inside your body (stuff inside a cell, intracellular parts, e.g.
when cells die, this will come out. E.g.:
● Necrotic cells → cytoplasmic & nuclear components (e.g. heat shock protein
(HSP), high-mobility group protein 1 (HMGP1), ATP).
● Damaged extracellular matrix → ECM fragments.
○ Example: tattoo ink. The ink will be uptaken by macrophages (eat) and they bring this to the
lymph nodes and try to activate the adaptive immune system (because they cannot eat it; they
need help).
2. Integrins
○ Bind to the substrate (ECM/biomaterial) and form an integrin complex, which activates the
cells.
Antigen presentation - macrophages & dendritic cells
, Cascade of the host response to biomaterial implantation
What happens when a biomaterial is implanted? Activation of the innate immune system due to injury → alarmins
→ inflammation!!
Implantation/ injury → Protein absorption
activate the immune system
(e.g. via alarmins) Coagulation
Complement system
1 2
Inflammatory cell infiltration: After days: adhered cell
- Polymorphonucleate releases cytokines and
d cells (e.g. chemokines.
neutrophils)
- Monocytes,
macrophages.
- Other signaling cells
(dendritic cells, mast
cells). 4
3
Recruitment of tissue repair Foreign body giant cells.
cells: fibroblasts, MSC. Fibrous encapsulation
and granuloma tissue
Stem cell homing. formation
If the cells cannot break it
ECM formation. down, you get a collagen
wall around it = fibrous
encapsulation.
5
6
Purpose: degrade and/or encapsulate material!!
Cellular players:
Dynamic process: neutrophils → macrophages → giant body cells.
, Cascade!! The outcome is dependent on the implant properties. So, the outcome can be controlled by
engineering the implant properties.
Steps: injury → blood-material interactions (protein adsorption) → acute inflammation → chronic inflammation →
granulation tissue → FBR → fibrosis/fibrous encapsulation.
More into detail:
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1. Injury
is typically a surgical procedure.
Material independent:
1. Release of histamine by mast cells
→ vasolidation of capillary vessels
(blood vessels will open up, increase
blood flow, cells can go through the
walls). Splinter; finger becomes
swollen and red.
2. Release of cytokines:(by activated
platelets, endothelial cells, mast cells,
local tissue macrophages) → activate
endothelium & attract immune cells
(‘homing signals’ attracts endothelium. Chemokines are cytokines that attract immune cells.
3. Danger signals (DAMPs) (by necrotic cells and damaged cells) → activate immune cells.
Hallmark signs of inflammation:
1. Pain (‘do not use this body part anymore’)
2. Heat (helps cells recover (metabolism increases), stops pathogens)
3. Redness (due to increased blood flow)
4. Swelling (due to vasodilation (blood plasma → hemostasis))
5. (Sometimes: loss of function)
Leukocyte extravasation= the movement of leukocytes out of the circulatory system and
towards the site of tissue damage or infection. There are 4 steps:
1. Endothelial activation: resident macrophages in the affected tissue release
cytokines (IL-1, TNF-a, and chemokines). This cause the endothelial cells to
express cellular adhesion molecules (such as selectins). Circulating leukocytes
are localized toward the site of injury.
2. Rolling adhesion/ weak adhesion: leukocytes slow down and begin rolling along
the inner surface of the vessel wall. Bonds are formed and broken between
selectins and their ligands.
3. Tight/ firm adhesion: chemokines released by macrophages activate the rolling leukocytes and cause
surface integrin molecules to switch to a high-affinity state. This causes immobilization of the
leukocytes.
4. Transmigration: leukocytes are spread out over the endothelial cells. Leukocytes pass through the gaps
between endothelial cells. Diapedesis= blood vessel escape.
