biocompabilitypathways - uts
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Essen%al Biomaterials Science: Professor David Williams
Biocompa(bility Pathways Overview of defini4ons of biocompa4bility and basic ground
rules Overarching biocompa4bility paradigm
Biocompa4bility scenarios:
A: Mechanisms that do not rely on chemical interac4ons B: Mechanisms that do rely on chemical interac4ons at macroscale
C: Microscale biocompa4bility D: Nanoscale biocompa4bility
E: Mechanisms influenced by pharmacological agents
The Williams Defini4on of Biocompa4bility
‘The ability of a material to perform with an appropriate host response in
a specific applica6on’
The Williams Dic4onary of Biomaterials Liverpool University Press, 1999
Williams D.F. On the mechanisms of biocompa4bility
Biomaterials, 2008, 29, 2941
The Consequences of Biocompa(bility Failures Death of the Pa4ent Thromboembolic complica4ons
Anaphylac4c shock Organ failure
Major Disease Cancer
Central nervous system damage Autoimmunity Incon4nence Peripheral nerve damage Reproduc4ve errors Loss of sensory func4on Viral disease transmission
Minor – major Complaints Allergy
Inflamma4on / edema Hyperplasia Hypoplasia / resorp4on
Failure to Achieve Desired Osteolysis Outcome Loss of patency of vessel
Infec4on
Intensity
Injury 1 Day 1 Week 1 Month
A
B1 C1 D1
B2 C2 D2
Phases of wound healing
Hemostasis Acute Inflamma4on Chronic inflamma4on Repair / scar
Fibrosis Blood biocompatibility -thrombosis -embolus -endocarditis
Microtoxicology Nanotoxicology
Ocular biocompatibility - cornea - lens -retina
Bioreactor biocompatibility
Problems with Conven4onal Treatment of Biocompa4bility Mechanisms
• Biocompa4bility of biomaterials has usually been discussed as a perturba4on of wound healing, which is based on inflamma4on, repair and remodelling, but most biomaterials are not placed in
contact with cells / 4ssues by surgical implanta4on. Biocompa4bility mechanisms and tes4ng procedures have been based on experiences
with implantable devices • Blood compa4bility has been treated separately to all other aspects of
biocompa4bility. In fact, we have wrongly tried to compartmentalize different aspects of biocompa4bility instead of considering them as
parts of an over-‐arching phenomenological system. • There has been an over-‐reliance on in vitro, non-‐physiological, protein
adsorp4on and cell adhesion data. • There are been major misunderstandings of the roles of innate and
adap4ve immunity in biocompa4bility. • ESPECIALLY, BIOCOMPATIBILITY HAS WRONGLY BEEN CONSIDERED AS
A PROPERTY OF A MATERIAL; IT IS A PROPERTY OF A BIOMATERIAL-‐HOST SYSTEM
The Basic Ground Rules of Biocompa(bility The introduc4on of a biomaterial into the human body represents a physiologically
stressful event and we must expect the body to present some adap4ve response.
The default posi4on is that there is inherent incompa4bility between foreign materials and the 4ssues of the body.
Biocompa4bility is not a property of a material; it is a characteris4c of a material –
4ssue system.
In biocompa4bility, an event may be triggered spontaneously, at any 4me, the effect of which can be powerfully amplified by one or more mechanisms, changing
the whole nature of the response in a short space of 4me. Mechanisms of biocompa4bility do not necessarily show a linear progression with 4me.
The consequences of interac4ons may be localized to the vicinity of the material,
oben referred to as the foreign body response, or they may be seen at some distant site, or they may be truly systemic.
Biocompa4bility phenomena vary from pa4ent to pa4ent and may vary with the
techniques used to administer the biomaterial to the pa4ent.
T
NN
BiomaterialSolid, Immobile
Chemically unreactiveUnchanging with time
Tissue EnvironmentSolid, or fluid, or collection of cells +/- ECMDynamic environment, changing with time
The conceptual starting point is that biocompatibility concerns the effect of the physical presence of the material on the dynamic
response of the tissue.
Potential factors to be superimposed on the basic concept
Adsorption
Mechanical forces
Effects of topography
Systems approach to biocompatibility
The essential biocompatibility paradigm
§ Resolution of response§ Clinically acceptable§ Tolerable to patient
Mechanical forcesProtein adsorption
Cell adhesionPolymer degradation
InflammationHyperplasia
Tissue resorptionThrombus formation
Surgical implantationInfusion / injection
Extracorporeal circuitIn vitro bioreactor
§ Inadequate resolution§ Clinically relevant effects§ Not tolerable
Causative event
Material and tissue come into contact
Progression of host response
Generic Biocompatibility Pathways
Essen(al Cells in Biocompa(bility Phenomena
Cells of inflamma6on and the Immune Response Basophils, Eosinophils, Monocytes, Mast cells Polymorphonuclear leukocytes (neutrophils)
B-‐lymphocytes, T-‐lymphocytes, Plasma cells, Dendri4c cells Macrophages, Foreign body giant cells
NK cells Platelets
Cells of Repara6ve and Hyperplas6c responses
Epithelial cells Endothelial cells
Fibroblasts Myoblasts, Myofibroblasts
Odontoblasts Osteoblasts
Smooth muscle cells
Cells of Tissue Resorp6on Chondroclasts Odontoclasts Osteoclasts
Biocompa4bility Scenarios
Scenario A; Mechanisms of biocompa(bility that do not rely on direct chemical interac(ons
Scenario B; Mechanisms of biocompa(bility involving chemical reac(ons between macroscale biomaterials and their soluble
deriva(ves with the host Scenario C; Mechanisms of biocompa(bility involving microscale
biomaterials and micropar(cles Scenario D; Mechanisms of biocompa(bility involving nanoscale
biomaterials and nanopar(cles Scenario E; Mechanisms of biocompa(bility involving delivery of pharmaceu(cal agents from macroscale biomaterial to the host
Scenario A Mechanisms of biocompa(bility that do not rely on direct
chemical interac(ons
• This does not mean that chemical reac4ons do not take place, but chemistry is not the driving force
• The first involves the effects of mechanical forces and the phenomenon of mechanotransduc4on
Moshayedi P et al “The rela4onship between glial cell mechanosensi4vity and foreign body reac4ons in the central nervous system” Biomaterials 2014;35:3919
• The second involves the biophysical forces associated with macromolecular adsorp4on and cell ac4va4on on biomaterials surfaces.
Wilson C J et al “Media4on of biomaterial-‐cell interac4ons by adsorbed proteins; a review” Tissue Engineering 2005;11:1-‐18.
Nucleusgene expression
I. Force transmission
II. Force transduction
Mechanosensitive ion channels
Force-induced exposure of molecular
recognition sites
Force regulation of protein activity
Effect of strain on integrin adhesions
III. Signal propagation
Intermediate filaments
Signaling molecules in cytoskeleton, changes to protein conformation, protein recruitment, cytoskeletal contraction, calcium signaling
Cell membrane IV. Cell responseECM production, change of phenotype, altered motility and shape
Actin filaments
Microtubules
Cell shape dynamics as a regulator of cell fate. Regulation of cell shape is a complex and dynamic process. Classically, in vitro cell shape was thought to be the output of variables such as adhesive ligands or more recently substrate stiffness..
Evangelia Bellas, Christopher S Chen
Forms, forces, and stem cell fate
Current Opinion in Cell Biology, Volume 31, 2014, 92–97
http://dx.doi.org/10.1016/j.ceb.2014.09.006
Forces on bone
Forces on soft tissue
Shear stressesin fluids in vivo
Shear stressesin fluids in vitro
Forces on cells
at surfaces
Signal propagation
Compressive forces Tensile forces
Fluid shear stresses
Fibrosis
Phenotype change
Intimal hyperplasia
Osteoporosis
Hemolysis
Exposure of peptide sequences
Regulation of proteinsChanges to ion channels
Cytoskeletal filaments
Signaling molecules
Force transduction
Force transmission
Gene expression – cell responses
The essence of mechanotransduc4on-‐mediated biocompa4bility
BloodExtra-
cellular fluidCulture mediumCytoplasm CSF
Molecular re-arrangement
Molecular activationCell interactions
Coagulationcascade
ComplementcascadeActivationAdhesion Proliferation Phenotype
change
Cross-talk
Physiological / pathological outcomes
HydrodynamicsFluid characteristics
HydrophilicityTopographyElasticityFunctional groups
Macromolecular adsorption
The essence of surface biocompa4bility mechanisms
Extrinsic Pathway Intrinsic Pathway
Tissue factor Foreign surface
TF + Factor VII → TF-VIIa (extrinsic tenase)
Factor X → Factor Xa
Factor XII → Factor XIIa
Kallikrein
Factor XI → Factor XIa
Prekallikrein
Factor IX → Factor IXa
Factor II (Prothrombin ) → Thrombin
Factor Va
Fibrinogen → Fibrin monomer
Fibrin polymer
Factor XIII
Factor XIIIa
Cross-linked blood clot
Factor VIIIa
Coagula4on cascade
Alternative Pathway
Foreign surface
C3
C5b
Terminal Complement Complex (TCC)
C4
C4b2a (C3 convertase)
C4b
C3a (An*)
C3b
C5
C5a (An*)
C6 C7
C8 C9
C3b C3
C3a
C3bBb(C3 convertase)
fD
fB
C2
C1
Classical Pathway
Antigen-antibody complex
C1q / C1r / C1s
Complement ac4va4on
•
Cell membrane with receptors, GPIb and GPIIb/IIIa
Microtubules
Surface connected
canalicular system
Mitochondrion
Glycogen
Dense granule
Lysosomal granule
Dense tubular system
Dense bodyα-granules
Platelet
�
Endothelial cell / subendothelium / collagen
vWF
GP Ib
Thrombin
Thrombin receptor
GP IIb-IIIa of other platelet
GP IIb-IIIa
Fibrinogen
α degranulation
Platelet Factor 4,β thromboglobulin,other soluble factors, platelet microparticles
Serotonin, ADP, Factor V,Thromboxane A, etc.
Gorbet and Sebon, “Biomaterials-‐associated thrombosis; roles of coagula4on factors, complement, platelets and leukocytes: Biomaterials 2004;25:5681
Scenario B; Mechanisms of biocompa(bility involving chemical reac(ons between macroscale biomaterials and their soluble
deriva(ves with the host
• Recognizes that virtually all monolithic biomaterials have chemically-‐reac4ve surfaces and / or release chemically-‐reac4ve moie4es into an aqueous biological environment
• The human body has well-‐developed mechanisms to deal with many foreign substances. These mechanisms are based on the immune system that has evolved to provide defense to micro-‐organisms
• There are two types of immune response • Innate immunity is non-‐specific, involving leukocytes (including natural killer cells,
mast cells, eosinophils, basophils) and phagocy4c cells (including macrophages and neutrophils)
• Adap4ve immunity is an4gen-‐specific, laregly mediated by lymphocytes. B cells are ac4vated to secrete an4bodies ( immunoglobulins) which bind specifically to the foreign an4gen that s4mulated their produc4on
• Biomaterials are generally considered to evoke innate immunity but adap4ve immunity may also be involved
C
Gene expression
Ligand
Receptor
Cell membrane
Signal initiation
Signal transduction A cascade of events such as phosphorylation
ProliferationDifferentiation
ApoptosisEtc.
A
B
The essence of cell signaling pathways and mechanisms of biocompa4bility concerned with biomaterial-‐released molecules
Rounding-up of cell, reduction of cell volume, chromatin condensation, nuclear fragmentation, retraction of pseudopodia
Increase in cell volume swelling of organelles, plasma membrane rupture, loss on intracellular content
Appearance of multiple-membrane enclosed vesicles, engulfment and loss of organelles
≅≅≈ ≈. ≅ ≈ ≈ + ≈ ≈ = ≈
NECROSIS APOPTOSIS AUTOPHAGY
Macrophage derived from monocytes or other progenitor cells
Exposure to cytokines such as Interferon γ and Tumor Necrosis Factor α
M1 macrophage Macrophage phenotypes : M2a M2b M2c
IL-4, IL-13 IC IL-1R IL-10
Pathogen killing Th2 response Th2 response ImmunosuppressionAntigen presentation Macrophage fusion ECM remodelingMatrix destructionTissue reorganization
IL-12
Macrophage polariza4on
TIME ZERO ; BIOMATERIAL-HOST CONTACT
RELEASE OF CHEMICALLY ACTIVE AGENTS FROM BIOMATERIAL
INITIATION OF CELL SIGNALING
Metal ions Monomers
ECM components Oligomers
Free radicals
Endotoxins
Additives Catalysts Impurities
CELL SIGNALING PATHWAYS
CELL DESTRUCTION
TISSUE GROWTH
DIRECTION CHANGE
Fibrosis Hyperplasia (Cancer)
Differentiation Phenotype shift
Granulation Necrosis Osteolysis
� �
� �
� �
Apoptosis Necrosis Autophagy
Innate immunity Inflammation Wound healing Adaptive immunity
Varia
ble
influ
ence
of t
ime
Intensity of host response
Time
Acute phase
Acute / sub-chronic destructive responses, e.g. thrombus, necrosis, hyperplasia, granuloma
Minor chronic inflammation and fibrosis
Equilibrium: The Foreign
Body Response
The Metastable Pathway
The Chronic Quiescent Pathway ofBenign Acceptance
The Chronic Anti-inflammatory Pathway
Chemically-‐driven biocompa4bility phenomena
The most chemically inert biomaterials are associated with minimal inflamma4on: PTFE, Titanium and Pla4num, Alumina
Degrada4on products of some polyesters produce late inflamma4on (pH, catalysts etc.)
Quantum dots may ini4ate toxicity because of metal ion (Cd) release Adap4ve immune response to some metallic nanopar4cles (e.g. Co-‐Cr
wear debris) Adap4ve immune response seen to some collagen products
Anaphylac4c response seen with some hemodialysis membranes Hydroxyl groups in some hydrogels ac4vate complement by alterna4ve
pathway
Scenario C; Mechanisms of biocompa(bility involving microscale biomaterials and micropar(cles
• Micropar4cles u Wear par4cles, corrosion products, degrada4on products, drug
delivery vehicles, porous coa4ngs u Mechanisms based on phagocytosis of bacteria (few micron
diameter) u Clinical experience with pneumoconiosis (esp asbestos) u No clear correla4on between biomaterial parameters and host
response Sheikh Z et al, Macrophages, foreign body giant cells and their response to implanted biomaterials, Materials 2015;8:5671
• Microtopography v Manufactured surface finish v Deliberate surface paoerning v Most interested in bone contact
Scenario D; Mechanisms of biocompa(bility involving nanoscale biomaterials and nanopar(cles
• Nanopar4cles Deliberate introduc4on of nanopar4cles into medical
technology, in drug and gene delivery systems and imaging contrast agents
Oh N, Endocytosis and exocytosis of nanopar4cles in mammalian cells, Int J Nanomedicine 2014;9(Suppl 1): S1
• Nanotopography
Possible effects on bone biocompa4bility Probable influence on stem cell differen4a4on
Toxicological effects of nanopar4cles This list represents the possible effects of nanopar4cles on the human body. There is clear experimental and clinical evidence for
some of them; in other cases the effects are theore4cal and not necessarily proven.
Genera4on of reac4ve oxygen species, leading to oxida4ve stress
Pro-‐inflammatory responses, including granuloma forma4on and acute phase protein expression
Effects on phagocy4c func4on, especially prolonga4on of chronic inflamma4on and inhibi4on of clearance of microorganisms and 4ssue debris
Effects on proteins, denatura4on and loss of enzyme ac4vity
Effects on mitochondria, including disrup4on of energy processes
Uptake by re4culo-‐endothelial system, sequestra4on in liver and spleen
Nuclear uptake, leading to DNA damage and mutagenesis
Uptake in neuronal 4ssue, damage to central and peripheral nerve systems
Cardiovascular effects, including thrombosis, myocardial infarc4on and stroke
Effects on cell cycle, including prolifera4on, senescence and apoptosis
Intensity of host response
Time
Acute phase
Acute / sub-chronic destructive responses, e.g. thrombus, necrosis, hyperplasia, granuloma
Minor chronic inflammation and fibrosis
Equilibrium: The Foreign
Body Response
The Metastable Pathway
The Chronic Quiescent Pathway ofBenign Acceptance
The Chronic Anti-inflammatory Pathway
Scenario E;
Mechanisms of biocompa(bility involving delivery of pharmaceu(cal agents from macroscale biomaterial to host
An4bio4c bone cements Drug elu4ng intravascular stents
Bone morphogene4c proteins in spinal fusion Bisphosphonates in bone
Drug elu4ng intraocular lenses
Without drug
With drug
Without drug
With drug
Acuteinflammation
Acute inflammation
Example 1 Intravascular stent
Acute Endothelial Smooth Stenosis inflammation response muscle cell response
Minimal endothelial response, anti-proliferativeeffect, delayed / minimal stenosis
Example 2 Bone fusion
Acute Chronic Fibrosis Delayed inflammation inflammation bone union
Reduced chronic inflammation, minimalfibrosis, accelerated, superior bone union
Pharmacologically-‐mediated biocompa4bility
Diagnosis of clinical condition êDecision to use procedure involving biomaterial ê Presentation of biomaterial to tissues
BIOCOMPATIBILITY PATHWAY
Adverse Neutral Idealoutcome outcome outcome
Summary of Biocompa4bility Pathways
Biomaterial
Molecular adsorption, mechanical or biophysical factors and chemical agents
Defensive
Cells Target
Interfering
No effects GOOD OUTCOME
Adverse effects ADVERSE OUTCOME
No interaction NEUTRAL
Required interaction GOOD OUTCOME
No interference GOOD OUTCOME
Interference POOR OUTCOME
Effects within cell
• Material destruction by cell environment
• Generation of reactive oxygen species and cell damage
• Alteration of organelle function• Interference with apoptotic and
necrotic pathways• Passage into nucleus affecting gene
expression• Passage into nucleus with gene
damage
Biomaterial components : metal ions, polymer additives, corrosion products, nanoparticle contrast agents, degradation products, contaminants etc
Internalization mechanisms : phagocytosis, endocytosis, pinocytosis
Mechanical and biophysicalmediators of interactionswith cells; forces, Electromagnetic fields etc
Material mediators of reactions: chemical structure, elasticity, shape and volume, topography etc
Summary of the control of biocompa4bility
Special Considera4ons
q Carcinogenicity q Reproduc4ve toxicity
q Infec4on
Biocompa4bility Tes4ng
Remember BIOCOMPATIBILITY HAS WRONGLY BEEN CONSIDERED AS A PROPERTY OF A MATERIAL; IT IS A PROPERTY OF A BIOMATERIAL-‐HOST SYSTEM
Williams D F
Leading Opinion Paper There is no such thing as a biocompa4ble material
Biomaterials 2014, 35(38), 10009-‐14
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