8SM20 Biomaterials
Lecture 1
Definitions
Biomaterial = a nonviable material used in a medical device, intended to interact with biological systems.
• Everything you bring into the body that is nonliving and you make a medical device of that is a
biomaterial
• This nonviable material can be any matter, surface or construct (e.g., synthetic material on which
we put cells and that total construct is put in body; or ceramic material that has been coated with
other polymer coating in which we have embedded drugs) that interacts with biological systems.
This biomaterial has to be biocompatible, non-toxic.
Biocompatible = ability of a material to perform with an appropriate host response in a specific
application.
• It is not realistic to create material with no reaction at all when implanted in body, so there will
be a response but it is considered biocompatible if there is an appropriate host response and you
have an intended application for that. E.g., bone implant will act differently than heart valve.
• So biocompatibility of your biomaterial has to be tested at the site of application
o In the past biocompatibility of biomaterial was tested by implanting material under the
skin (=subcutaneous implantation). But here you get response to biomaterial that is
implanted under skin, so local response. Does not say anything if you would plant this
material as a heart valve or as a bone implant.
o So biocompatibility at site where you want to use it has to be tested.
To get FDA approval, you have to show that your material is nontoxic and biocompatible at a certain site
of application for intended use. A material itself is not FDA approved, so saying that a certain type of
polymer has FDA approval does not hold. There are no materials that are FDA approved, a material is
approved for a specific application and for a specific intended use.
History of biomaterials
First generation, inert materials = invoke a reaction, but are not intended to steer regeneration or steer
specific responses in body.
• Bees wax (fatty acid esters) used as dental fillings (6500 b.Chr.)
• Iron (metal) used for dental implants (200 a.Chr.)
• Nacre (parelmoer; calciumcarbonate), a ceramics. Was also used for dental implants (600 n.Chr.)
Thereafter, synthetic materials were developed.
• PMMA: a polymer, used in WOII as glass windows in airplanes.
o Polymers can be in glass state
o Shreds of PMMA would enter eyes of pilots when windows shredded did not invoke
any reaction, so inert material. So from here, lenses were made = first synthetic
biomaterial.
o PMMA, still used polymer; very clear; by changing cross link density in network that
polymer forms, you change the refracted index (desirable for lens)
• Cellulose: natural polymer.
o Dialysis machine was developed using cellulose
o Also quite inert
• First valves 1960s
o PMMA/nylon
1
,Second and third generation, degradable and bioactive materials
• Sutures made of PGA (degradable)
o Degrade over time so you don’t have to remove them
o Polyglycolic acids (PGA) contain ester bonds, these are unstable, can be hydrolyzed and
oxidized hence degradable
• Stents can be made out of nitinol, a metal (bioactive)
o Bioactivity can be induced by making a coating of a polymer with a drug. E.g. a drug that
reduces thrombogenicity, so no clot formation in stent occurs.
• Heart valve made of two kinds of materials, nitinol and super molecular polymer
o Degradable, and can be made bioactive
Solutions for medical problems
• From inert to degradable and bioactive material
• Steer regeneration of body and not only repair
• Can we use biomaterials to fight pandemic?
Myth of Prometheus
• Our body has regeneration potential
• Learn from body to make biomaterials more complex
Fourth generation: Regenerative medicine vs. tissue engineering
Regenerative medicine
• Body is used as bioreactor where tissue is formed in or by body
• So in vivo / in situ regeneration
• In body tissue will regenerate (so not just repair)
• Biomaterial plays an important role
o Steers in situ regeneration
o Can be modified with drugs/bioactive
molecules/peptides/anti-thrombogenic
molecules, like heparin, that prevent
blood clot formation
• Use with or without cells (cells can be attracted
in body itself)
Tissue engineering
• Make tissue in lab, in vitro, e.g. test tube or culture disk
• Make use of similar components as with regenerative medicine
• Implantation in body or use in vitro
Tissue engineering was stated to be the way for organ repair, but now it is thought that this only holds for
complex tissues such as kidneys, where you need to steer tissue formation from stem cells towards this
very complex kidney. You might want to do this in vitro. But if you want to regenerate heart valve, it would
be preferable to not make complete autologous heart valve in lab, but make scaffold in form of heart
valve and then implant that in body and regenerate tissue in situ.
2
,Fifth generation?
We want to go to fifth generation biomaterials. These are materials, still in fundamental state where we
would like to introduce all the complexity from ECM in that material.
When looking at natural ECM, you see it is very complex.
• Many molecules all with different functions; some form fiber aggregates, some bind to cell surface
receptors
• Cells interact with ECM through receptors
• Soluble factors are present as well which can signal to the cells.
• Bidirectional process between matrix and your cells, so real interactive material. Can we remake
this synthetically? Going towards fifth generation material.
• Very complex, in a way that it gives complex signals to cells but also complex in a way that it is
formed by complex aggregates of molecules together into fiber structures. So this complexity is
not only on level of bioactivity, but also the morphology and geometry, as well as the mechanical
properties of this ECM is different for every tissue which also steers cells to form certain tissue
type.
Set up design criteria based on natural ECM and from that make synthetic material
• Goal: make synthetic material that mimics natural ECM
• But synthetic material is complex, so also more difficult
to get granted by FDA to use that material in that certain
application in the body. So also difficult to get it into
clinical use.
• Solution: simplify this material, resulting in biomedical
material = used in the body with biomedical application,
so with biomedical function.
• As opposed to a biomedical material, a biomaterial can
also be used in vitro, in a test tube and interact with cells,
so then you also have an interaction with the biological system (=definition of biomaterial is met).
Classes of biomaterials
Classes of materials used in medicine
• Polymers & polymer properties
• Metals
• Ceramics & glasses
• Carbons
• Composites
Natural polymers
• Silk
o Can be taken from animals, is a natural polymer.
o Composed of aminoacids, so it’s a protein
o Contains amide bonds that can form hydrogen bonds
• Gelatin
o Gelatin is also a protein
o Made of aminoacids
o Derived from ECM of slaughterhouse waste, so pig tail of cows
o Denatured collagen (also protein)
3
, • Cotton
o Has complex structure when comparing it to silk
o Carbohydrate, a lot of hydroxy groups so binds a lot of water
• Alginate also used as biomaterials
o Made from seaweed
o Carbohydrate, a lot of hydroxy groups so binds a lot of water
Synthetic polymers
• Such as a plastic bag (PE polymer), a lens (PHEMA polymer), etc. (see image below)
• Nylon is a polyamide, has amide bond which is also found in gelatin and silk.
• Kevlar is a polyaramide, again amide bond is seen. But Kevlar is used for bullet proof vest, this is
because of the aromatic rings and that takes care of ordering the fibers in very dense structures.
• PP (polypropylene) is only based of carbon and hydrogen atoms. Also used in plastic bags.
• Water bottles are made of PET. Contains ester bonds, these are hydrolytically more unstable than
amide bond. So you would think PET degrades more easily than nylon. BUT: PET also contains
aromatic ring which prevents water from attacking the ester bonds, so it is quite a stable bond.
But if this ring was removed it would become less stable.
• PHEMA contains ester bond, so can be hydrolyzed. It also contains hydroxy group, so material
very hydrophilic which means water can bind. Therefore you can make lenses that have this water
layer.
Natural vs. synthetic polymers
Materials
Chemical structures
4
Lecture 1
Definitions
Biomaterial = a nonviable material used in a medical device, intended to interact with biological systems.
• Everything you bring into the body that is nonliving and you make a medical device of that is a
biomaterial
• This nonviable material can be any matter, surface or construct (e.g., synthetic material on which
we put cells and that total construct is put in body; or ceramic material that has been coated with
other polymer coating in which we have embedded drugs) that interacts with biological systems.
This biomaterial has to be biocompatible, non-toxic.
Biocompatible = ability of a material to perform with an appropriate host response in a specific
application.
• It is not realistic to create material with no reaction at all when implanted in body, so there will
be a response but it is considered biocompatible if there is an appropriate host response and you
have an intended application for that. E.g., bone implant will act differently than heart valve.
• So biocompatibility of your biomaterial has to be tested at the site of application
o In the past biocompatibility of biomaterial was tested by implanting material under the
skin (=subcutaneous implantation). But here you get response to biomaterial that is
implanted under skin, so local response. Does not say anything if you would plant this
material as a heart valve or as a bone implant.
o So biocompatibility at site where you want to use it has to be tested.
To get FDA approval, you have to show that your material is nontoxic and biocompatible at a certain site
of application for intended use. A material itself is not FDA approved, so saying that a certain type of
polymer has FDA approval does not hold. There are no materials that are FDA approved, a material is
approved for a specific application and for a specific intended use.
History of biomaterials
First generation, inert materials = invoke a reaction, but are not intended to steer regeneration or steer
specific responses in body.
• Bees wax (fatty acid esters) used as dental fillings (6500 b.Chr.)
• Iron (metal) used for dental implants (200 a.Chr.)
• Nacre (parelmoer; calciumcarbonate), a ceramics. Was also used for dental implants (600 n.Chr.)
Thereafter, synthetic materials were developed.
• PMMA: a polymer, used in WOII as glass windows in airplanes.
o Polymers can be in glass state
o Shreds of PMMA would enter eyes of pilots when windows shredded did not invoke
any reaction, so inert material. So from here, lenses were made = first synthetic
biomaterial.
o PMMA, still used polymer; very clear; by changing cross link density in network that
polymer forms, you change the refracted index (desirable for lens)
• Cellulose: natural polymer.
o Dialysis machine was developed using cellulose
o Also quite inert
• First valves 1960s
o PMMA/nylon
1
,Second and third generation, degradable and bioactive materials
• Sutures made of PGA (degradable)
o Degrade over time so you don’t have to remove them
o Polyglycolic acids (PGA) contain ester bonds, these are unstable, can be hydrolyzed and
oxidized hence degradable
• Stents can be made out of nitinol, a metal (bioactive)
o Bioactivity can be induced by making a coating of a polymer with a drug. E.g. a drug that
reduces thrombogenicity, so no clot formation in stent occurs.
• Heart valve made of two kinds of materials, nitinol and super molecular polymer
o Degradable, and can be made bioactive
Solutions for medical problems
• From inert to degradable and bioactive material
• Steer regeneration of body and not only repair
• Can we use biomaterials to fight pandemic?
Myth of Prometheus
• Our body has regeneration potential
• Learn from body to make biomaterials more complex
Fourth generation: Regenerative medicine vs. tissue engineering
Regenerative medicine
• Body is used as bioreactor where tissue is formed in or by body
• So in vivo / in situ regeneration
• In body tissue will regenerate (so not just repair)
• Biomaterial plays an important role
o Steers in situ regeneration
o Can be modified with drugs/bioactive
molecules/peptides/anti-thrombogenic
molecules, like heparin, that prevent
blood clot formation
• Use with or without cells (cells can be attracted
in body itself)
Tissue engineering
• Make tissue in lab, in vitro, e.g. test tube or culture disk
• Make use of similar components as with regenerative medicine
• Implantation in body or use in vitro
Tissue engineering was stated to be the way for organ repair, but now it is thought that this only holds for
complex tissues such as kidneys, where you need to steer tissue formation from stem cells towards this
very complex kidney. You might want to do this in vitro. But if you want to regenerate heart valve, it would
be preferable to not make complete autologous heart valve in lab, but make scaffold in form of heart
valve and then implant that in body and regenerate tissue in situ.
2
,Fifth generation?
We want to go to fifth generation biomaterials. These are materials, still in fundamental state where we
would like to introduce all the complexity from ECM in that material.
When looking at natural ECM, you see it is very complex.
• Many molecules all with different functions; some form fiber aggregates, some bind to cell surface
receptors
• Cells interact with ECM through receptors
• Soluble factors are present as well which can signal to the cells.
• Bidirectional process between matrix and your cells, so real interactive material. Can we remake
this synthetically? Going towards fifth generation material.
• Very complex, in a way that it gives complex signals to cells but also complex in a way that it is
formed by complex aggregates of molecules together into fiber structures. So this complexity is
not only on level of bioactivity, but also the morphology and geometry, as well as the mechanical
properties of this ECM is different for every tissue which also steers cells to form certain tissue
type.
Set up design criteria based on natural ECM and from that make synthetic material
• Goal: make synthetic material that mimics natural ECM
• But synthetic material is complex, so also more difficult
to get granted by FDA to use that material in that certain
application in the body. So also difficult to get it into
clinical use.
• Solution: simplify this material, resulting in biomedical
material = used in the body with biomedical application,
so with biomedical function.
• As opposed to a biomedical material, a biomaterial can
also be used in vitro, in a test tube and interact with cells,
so then you also have an interaction with the biological system (=definition of biomaterial is met).
Classes of biomaterials
Classes of materials used in medicine
• Polymers & polymer properties
• Metals
• Ceramics & glasses
• Carbons
• Composites
Natural polymers
• Silk
o Can be taken from animals, is a natural polymer.
o Composed of aminoacids, so it’s a protein
o Contains amide bonds that can form hydrogen bonds
• Gelatin
o Gelatin is also a protein
o Made of aminoacids
o Derived from ECM of slaughterhouse waste, so pig tail of cows
o Denatured collagen (also protein)
3
, • Cotton
o Has complex structure when comparing it to silk
o Carbohydrate, a lot of hydroxy groups so binds a lot of water
• Alginate also used as biomaterials
o Made from seaweed
o Carbohydrate, a lot of hydroxy groups so binds a lot of water
Synthetic polymers
• Such as a plastic bag (PE polymer), a lens (PHEMA polymer), etc. (see image below)
• Nylon is a polyamide, has amide bond which is also found in gelatin and silk.
• Kevlar is a polyaramide, again amide bond is seen. But Kevlar is used for bullet proof vest, this is
because of the aromatic rings and that takes care of ordering the fibers in very dense structures.
• PP (polypropylene) is only based of carbon and hydrogen atoms. Also used in plastic bags.
• Water bottles are made of PET. Contains ester bonds, these are hydrolytically more unstable than
amide bond. So you would think PET degrades more easily than nylon. BUT: PET also contains
aromatic ring which prevents water from attacking the ester bonds, so it is quite a stable bond.
But if this ring was removed it would become less stable.
• PHEMA contains ester bond, so can be hydrolyzed. It also contains hydroxy group, so material
very hydrophilic which means water can bind. Therefore you can make lenses that have this water
layer.
Natural vs. synthetic polymers
Materials
Chemical structures
4
