Biodegradation and Bioresorption.
hello
everyone ah welcome to the course on a medical
biomaterials now we are going to talk about
ah properties just as a biodegradation or
bioresorption we are going to see what is
the difference between these ah biodegradation
and bioresorption in the human body and hm
how it is going to help because in many systems
we do not want the material to stay inside
the body we want the material to leave ah
body after it has done its function so the
properties of a biodegradation or bioresorption
are incorporated into the material ok
so when do you need a biodegradable polymers
in chemical biotechnology for example if you
look ah wound management area um sutures we
want that sutures to completely disappear
after the wound has yield or staples clips
adhesives surgical meshes all these once it
has den its job for example the wound has
yield ah there is no infection and tissue
has grown we want this material to completely
degraded we do want ah a material which does
not degrade and remain in the body forever
and ever orthopedic devices they use quite
a lot pins in orthopedic implants to keep
ah ah the ah stainless steel or a titanium
ah in its position we want the pins to degrade
once ah the um ah the implant ah got ah ah
in line with the ah bone rods lots of rods
are used screws are used so you want all these
to degrade after it is done its job tax ligaments
in orthopedic area
if you look at dental area um guided tissue
regeneration membrane void filling so after
a tooth extraction we are filling the void
and um we want slowly um ah the material to
grow on its own so we want degradation cardiovascular
application stents [cu/currently] currently
um metal stents and drug eluting stents are
used um and ah quite used ideally we would
like the stent to degrade after a few months
um so that there is no titanium or stainless
steel in inside if the stents d not degrade
and we have placed a stent the doctor is not
able to place another stent ah inside the
body that is one problem another problem could
be sometimes starts migrating that means they
move from one place to another and they may
block ah some artery so ideally we want the
stent to completely degrade after a few months
ah and so on
then intestinal applications anastomosis rings
drug delivery system you are delivering drug
ah to a targeted side um and then once the
drug has delivered we want the polymeric material
to completely [de/degrade] degrade and disappear
tissue engineering applications um use ah
ah scaffolds to tissue to grow what is the
tissue has grown and grown and then it has
occupied the void then the scaffold material
should completely disappear we do not know
want the scaffold to remain so in all these
areas um we would ah like the material to
completely ah degrade and come out of the
system or get completely resorbed ok
now what is the difference between biodegradation
and bioresorption ok there are lot differences
are there biodegradation so if you have a
polymer a large molecular weight polymer um
when it degrades it becomes [ma/macromolecule]
macromolecule so a sixty kilo dalton ah say
um ultrahigh molecular weight polyethylene
for example um may degrade into smaller molecular
weight may be about ah ten thousand or five
thousand or fifteen thousand they are called
macro molecules ok um but they may stay inside
the body and migrate so it is degraded into
smaller molecules but ah it might not be completely
eliminated they may be in the circulation
but still it is biodegradation so from may
be about sixty thousand like i said it may
come down to ten thousand or five thousand
of ah molecules of macromolecules of front
molecular weights for example ultrahigh molecular
weight polyethylene this is used quite a lot
in joint prosthesis suppose there is joint
replacement they use metal and um metal metal
ah interaction is not very good because it
rubs and it leads to release of ah fine metals
so the use ultrahigh molecular weight polyethylene
um which acts sort of a lubricant so e even
that gets degraded um weights that is called
biodegradation
what is this bioresorption so the entire material
gets degraded in vivo and it is eliminated
from the body into low molecular weight molecules
ok so if there is a twenty thousand molecular
weight material it get resorbed in very very
small molecular weight material and that is
gets eliminated completely for example if
you take polylactic acid polylactic acid is
a f d a approved polymer and is used in ah
quite a lot of implant especially in drug
delivery and so on so it gets completely bioresorbed
and um there is nothing left inside it goes
into live and lactic acid and that gets eliminated
that is called bioresorption um
so sometimes metals are also classified as
bioresorbable so if ah for exam ah rubbing
of metal or corrosion leads to the elimination
of the material so it may slowly come out
of the body but this could be a much longer
when compared to polylactic acid bioresorption
which is very fast so although ah metal we
cannot call it bioresorbable but it is still
called because ah corrosion may lead to total
elimination of the material or even rubbing
of material ah metals um can lead to final
powder which may be get eliminated but it
could be much longer duration
then we have bioerosion materials are first
degraded on the surface and then it is resorbed
in vivo ok that is called bioerosion and then
bioabsorption so materials could dissolve
in the body without modification of their
molecular weight ah unlike the bioresorption
please um understand in bioresorption the
materials degraded into smaller weight and
then gets eliminated whereas in bioabsorption
ah the material um may get the resorbed without
actually ah degrading into smaller molecular
weight material so these are the different
types of ah changes that could happen ah materials
that are placed in the body and as i said
ah it is very important in ah many situations
to have a biodegraded or bioresorbed polymeric
um material as a implant
so the [res/resorption] resorption of a material
consists of several factors um how much water
gets um absorbed because water may get involved
in the ah hydrolysis reaction ah so after
it starts getting slowly degraded there could
be a reduction in mechanical properties that
means the stren[gth ]- that means ah the tensile
strength may change ah modulus may change
reduction of molecular mass ah that means
the material may be ah lost in the weight
complete loss of weight so the material could
be completely ah losing its weight then it
may be becoming smaller and smaller um and
then finally disappearing so that is what
it means resorption
for example i just wanted to show you a few
pictures look at this hm this is ah surgery
or orthopedic surgery ah what they do is ah
because there could be lot of infection that
could be happening after placing a metal orthopedic
implant so what they do is they use a poly
methyl methacrylate beads which are um impregnate
with the an antibiotic like a meropenem for
example so they keep these beads inside and
close it after doing the implant um so the
polymer slowly releases the drug the meropenem
thereby it prevents ah the um infection and
bio filling formation
but the problem is their p m m a is it does
not get degraded so it has to be removed later
on so they will do a small surgery to remove
that so this is bit a painful because it is
non biodegradable or bio non bioresorbable
so ideally one would like to have a nice polymer
which is able to take in lot of ah drug encapsulate
lot of drug it releases the drug say for example
within ah six to eight weeks and then it also
starts ah getting resorbed or biodegraded
so the doctor does not have to a perform a
second surgery so ideally ah this is a courtesy
this picture is a courtesy from ah c m c e
vellur in tamilnad
now look at this ah this is a poly urethane
ureteral stent ok this is a called a ureteral
stent it is placed inside ah the ureter region
which connects about the um um the kidney
and the ureter so the urine flows nicely um
down sometimes this ureter can get blocked
[de/because] because of infection or if there
is stones in the urine ah um sonication is
performed to break the stones so you need
a nice opening so that the small broken powder
stones can flow down so they place ah this
particular ah material called a ureteral stent
it is quite flexible ah it is made up of poly
urethane um so after about five to six week
ah the doctor has to perform another surgery
to remove this ideally if we have a biodegradable
material so the doctor places the material
stent inside um it performs its duty and once
it is performed its duty it should degrade
or bioresorbed completely so this is another
example of where i would like to have a biodegradable
material um like an ureteral stent this ah
picture this x ray is a courtesy from ah um
doctor shraf of a shri ramachandra medical
college in ah chennai
look at this these are stainless steel bone
plates ok so after an orthopedic um [su/surgery]
surgery these ah bone plates are placed inside
to connect the bones here ah using a screw
as you can see and pins here you see um so
it is placed like this so the bone starts
healing the bones starts growing so ideally
um after a few months if ah the bone plate
completely um resorbed then ah it will be
nice they it the person will not have a foreign
material plates inside but as you know currently
stainless steel and titanium plates are used
which are not biodegradable so they remain
inside the body forever and ever this is another
place where we would like to have ah ah biodegradable
bone plate but ah it could be after three
to six months whereas if you look at ah the
ureteral ah stent you would like to have it
about six to eight weeks whereas if you look
at ah the p m m a loaded um drug loaded p
m m a in this area i would like the material
to [grade/degrade] degrade in about fifteen
days
so you can see different types of time duration
are required here you would like the material
to degrade in about fifteen days here we would
like to de ah material to degrade after about
six to eight weeks um and here you would like
to have the material degrading after about
ah around six months ok so um if you you have
a biodegradable bone plate ok we will not
require another surgery for removing the bone
plate generally you cannot remove the bone
plate because ah the bone nicely grows um
and ah muscles grows so absolutely it not
possible we can also avoid stress shielding
ah if the stainless steel material is not
there because there will be one material that
is the bone instead of having bone um made
up of hydroxyapatite and stainless steel um
we can also have a control drug delivery so
if we have a polymeric material which may
degrade over a period of time um which can
be coated drug drug gets ah released slowly
so um it prevents the biofilm formation and
infection ok so um the plate take care of
the mechanical strength initially with time
it degrades so the plate is completely useless
in the mean time the bone starts growing so
the bones take care of ah the mechanical ah
strength requirements ah for the rest of the
life of the patient so ideally we would like
to have the plate slowly degrading and later
on the bone takes care of ah the weight and
um other mechanical requirements ok so these
are few situations i showed you examples where
we would like to have ah um this type of ah
biodegradable bioresorbable material ok these
are courtesy the photograph which is showed
are courtesy from various places like a c
m c vellur and shri ramachandra medical college
ah in chennai ok
so what type of ah bones in the polymer could
degrade um oxygen nitrogen sulphur for example
look at this is an ester bond you will say
ester bond ok so um or this could be in amide
bond or this could be thioester bond so we
have c double bond o x could be oxygen c double
o x could be nitrogen c double o x could be
sulphur so these bonds are um easily hydrolysable
that means water can react with that ah may
be little bit of acid or we have some enzymes
so it can generate acid like this ok so um
if you have polymers which has backbones like
this ah or linkers which has ah like this
type of set up um they can get hydrolyzed
and they can degrade ok slowly over a period
of time um ok so ester bond amide bond thioester
bonds can degrade if ah the polymer in the
backbone has these type of ah bonds ok um
or we can have ah these type of situations
ok carbonate these are slowly degradable unlike
the ah previous case where we have these are
more faster degradable where as these ok will
degrade much slowly ah so we can have o and
o this is called carbonate we have c double
o o and o or we can have urethane c double
o o n h or we can have urea n h n h and c
double bond o so these are also hudroge hydrolysable
um that means they can react with water but
but they are slowly ah reacting like the previous
case or we can have other situations like
imide anhydride again anhydride imide they
can be degrade much faster so we have c double
o connected by o another c double bond o or
c double o connected by nitrogen and other
c double o or c c double o connected by s
another c c double o um so they can also hydrolyzed
from acid and an ester like this ok so imide
is an example anhydride is an example
so here um we can have a o o on both sides
or nitrogen on both sides s on both sides
with the key tone c double o so this can give
you ah acid ok um and ah another ah ok hydrocarbon
here whereas these one we have c double o
and both sides connected by an oxygen or a
nitrogen or a sulphur ok so these are various
types of bonds systems which are biodegradable
so if you are designing polymers with these
type of ah um backbones then they are hydrolysable
that means they can react with water to slowly
um and as i mentioned some of these bonds
are ah degradedable faster rates some of these
bonds are degradable at slow slower rate so
if i am thinking about ah two weeks three
weeks degradation or if i am thinking about
six months nine months degradation i can design
polymers a with these different backbones
ok
so we have acetal some open some examples
ok acetyls ok ah oxygen on both side like
this they can degrade hemiacetal ok you have
the ring system which are degradable ethers
like i showed you here right ah ethers like
i showed you here oxygen these are ok ethers
um which can degrade nitriles ok so the c
triple bond n they can degrade phosphonate
they can degrade polycyanocrylate so [diff/different]
different types of ah bond systems that are
degradable so polymers ah natural polymers
or synthetic polymers natural polymers like
fibrin collagen chitosan gelatin hyaluronic
acid um cyclic glucones ok um alpha cyclic
glucones and beta cylclic glucones and so
on if you got to synthetic polymers ah poly
lactic poly um p g a that is ah glycolic poly
glycolic acid or combination of lactic and
glycolic polycaprolactone polyorthoesters
poly dioxanone poly anhydrides poly trimethylene
carbonates polyphosphazenes so lot of synthetic
polymer that can also degrade ok lot of natural
polymers lot of synthetic polymers that can
be degrading so we can consider ah designing
ah may be drug delivery systems or scaffolds
ah or bone plates using these polymers and
of course we need to match the other mechanical
and physical chemical requirements and initially
for the material to ah hold
so you can also have enzymatic degradation
hm apart from the normal hydrolysis type of
[deb/degradation] degradation ok ah so hydrolysis
like a it is anhydride um or very easily degradable
ah esters come next and so on ok um of course
enzymatic you can have live phases we can
esterases ah all these (( )) present in the
in vivo system they can also aid in the degradation
some of the degradation is called [homoge/homogenous]
homogenous degradation we can heterogeneous
degradation homogenous means uniformly material
the backbone gets degraded heterogeneous means
indicates degradaded only at the specific
location where we have the sides favorable
bonds for it to degrade and if the bond is
not favorable for degradation then it will
not degrade ok ah
bioresoption we can ah ah initiate ah by first
solubilization like dextran polyvinyl alcohol
polyethylene oxide so the it the polymer solubilizes
ok and then later you can have a ionization
poly acrylic acid poly vinyl acetate for example
some of the polymer ah ah poly lactic acid
ah you can have ionization you can have enzymatic
reaction ok polysaccharides polyamides you
have amides or you have esters or it could
be simple ah hydrolysis like aliphatic polyesters
and get simple hydrolyzed and completely get
absorbed so these are various situations we
can have solubilization which can lead to
um bioresorption solubilization followed by
ionization we can have enzymatic reaction
after ah hydrolysis ok or simple hydrolysis
without enzymes all these can lead to bioresorption
ok so we have ah a polymer and this bond is
there so ah it can get hydrolyzed um just
plain hydrolysis or we can enzyme that is
catalyzing the hydrolysis of this particular
polymeric material we can have two situations
surface erosion that means the surface slowly
gets ah eroded or degraded or the bulk the
entire polymer gets degraded and the polymer
sort of dissolves or it is not dissolved it
is completely ah loses its molecular mass
so ok um so two situations surface erosion
takes place that means the sample is eroded
from the surface ah then mass loss is greater
than ingress of water into the bulk whereas
if the water ingress is much more and degradation
takes place and that is called bulk degradation
so example of surface erosion poly ortho esters
polyanhydrides um that means if mass gets
lost very fast and compared to water ingress
into the polymer ah bulk degradation like
p l a p g a p l g a p c l so the ingress of
water is much faster than the rate of degradation
so the water goes inside and the material
starts degrading ok that is called the bulk
degradation so we have surface degradation
ah
so in bulk degradation the degradation takes
place throughout the material whereas surface
degradation mit ah ah degradation takes place
at the surface because the water ingress is
much lower than the mass loss whereas in bulk
ah ingress of water is much faster than rate
of degradation so um ah if we have a surface
erosion situation may be like this material
may be becoming thinner thinner thinner thinner
thinner um its time whereas in bulk erosion
material may be getting lost inside it may
be start forming pores inside material may
be crumbling material may be breaking into
pieces so all these can happen in bulk erosion
whereas surface erosion material will be uniformly
getting thinner bulk erosion material may
break into pieces mil material may form um
pores inside material may break um at various
places ah getting chipped because of bulk
erosion so situations depending upon the type
of situations even depending upon the thickness
of the material um it could have surface erosion
or bulk erosion
so pictorially we can show it like that surface
only and the surface materials gets degraded
so it is very nice to have if you are talking
about ah ah slow drug release whereas bulk
erosion as the water starts growing in an
suddenly there could be degradation taking
place at various places inside ah the material
also so bulk erosion when water diffuses rapidly
into polymer leading to hydrolysis so this
is the function of rate of hydrolysis of the
functional groups rate of diffusion inside
the matrix dimensions of the matrix all these
play very important role ah in deciding the
the material is bulk or surface degradation
so what is the critical thickness for [rebor/resorbable]
resorbable polymers above which ah it is bulk
or surface ok so if for these polymers if
thickness is less than this it will be a bulk
degradation so what it means is ah water has
to ingress with the water can ingress inside
then ah you can have a very good ah ah bulk
degradation if the water cannot ingress into
it then degradation is faster then it will
be a surface degradation ok so if the material
is very thin um then obviously you are going
to have a ah surface degradation if the merity
sorry obviously you are going to have bulk
degradation if the material is very thick
um water is not able to ingress inside then
you are going to have a surface degradation
and this dimension tells you whether it is
going to be ah surface degradation or bulk
degradation ok
we can also have autocatalysis because for
example if you take poly lactic acid um when
it degrades ah it releases lactic acid um
which is acidic and which may enhance the
degradation further and further for example
if you look at this ah particular picture
the rate of degradation was ah time initially
the degradation is slow so may be acids are
produced or may be some functional groups
are produced in degradation which enhances
the degradation very fast so the degradation
can sudden shoot up like this this is called
autocatalysis
so oligomeric hydrolysis products like carboxylic
acids or other acids which may aid the degradation
much faster and these material is retained
inside they are not thrown out so its get
retained inside so it crosses localized decrease
in p h that means material becomes acidic
p h at different places which can accelerate
the rate of degradation so we may form hollow
structures within the polymer ok and because
of these acids um then this leads to rapid
deterioration of the mechanical properties
and sudden loss of structural integrity like
p l g a or p l a autocatalysis takes place
because the acids that are produced in various
places can enhance the degradation further
and further um so there could be these are
sides where degradation are going to be much
faster called autocatalysis based degradation
ok
now um we can have different types of degradation
if you look at type one a so we have polymers
ok they are connected ah by certain cross
linkers ok so the polymer is stable it is
not soluble in water the cross linkers could
be covalently ionically cross linked monomers
so what happens after digestion of these linkages
ok the suppose these linkages ah degrade then
the fragments which are formed could be water
soluble ok the ah so if i have say for example
collagen or gelatin which are cross linked
collagen and gelatin may be water soluble
but ah ah the linkages prevents them from
degrading or water [so/solubilizing] solubilizing
so once the linkages ah disappear then the
remaining portions could be ah soluble ok
so that it is called a type one degradation
if you have one b um the digestion of the
polymer backbone ok some portions ah could
be degrading that means they have a relatively
low molecular weight because of either chemical
or enzymatic cleavage then the resulting fragments
are water soluble and have a lower molecular
weight so ah some portions of the back bone
could be degrading because of presence of
low molecular weight once they disappear because
of ah degradation ah through enzymatic or
chemical ah the resulting fragments are water
soluble because they have lower molecular
weight that is type one b
type two initially water insoluble the may
have some pendant group which may get ionized
or hydrolysis ah degrader once these pendent
group degrade because of hydrolysis then the
remaining polymer could be water soluble that
is type two type three ah we have addition
cleavage in the backbone so the backbone um
some portions um can get degraded so you can
have combinations of type one a with type
three so initial cleavage of the cross linkers
and then remaining backbone could be degrading
later actually for example aliphatic poly
esters um poly amides poly cyanoacrylates
poly anhydrides poly acetals poly orthoesters
so they have cross linkers um which may initially
gets cleaved then the remaining polymer could
be degrading in that ok so you can have combinations
so these are various situation um by which
we can create biodegradable polymers which
may degrade with different mechanisms at different
time periods so we have lot of ah flexibility
in designing ah polymeric systems with that
biodegradable properties um
so when we talk about hydrolytic degradation
we so water ah is ah reacting with some functional
groups ok so we can have acids catalyzing
these bases catalyzing these enzymes so as
i mentioned before so these are the situations
where can have enzymes also catalyzing or
even bases may be catalyzing this type of
ah reactions ah so lot of these again what
as i showed again before ah the catalysis
could be taking place because of enzyme or
acids or bases ok we i showed you before also
so all these situations ok so we can have
a acids um for a water to react or bases or
even enzymes ah which are catalyzing this
reaction um
sometimes even ions could be catalyzing ah
you may wonder where are they ions in the
body but biological and cell cultured fluids
contained lot of ions ok h plus o h minus
sodium plus chlorine minus ok phosphate (( )) potassium
magnesium calcium sulphate two minus and so
on for example if you look at ah a blood or
extracellular fluid you can see ah c l minus
it contains lot of c l minus carbonates phosphates
sulphates ok hydro phosphates um sodium magnesium
calcium potassium so all ah you can see blood
contains all this as well as extracellular
fluid contains all these so these could be
catalyzing ah hydrolysis reaction ah these
could be breaking esters amides or ah ok um
and these could be ba ah breaking ah um orthoesters
um carbonates ok so these could be catalyzing
some of these reactions ok acid be acid catalyzed
base catalyzed or metal catalyzed reactions
hydrolysis type of reaction
so ah body contains so many mate ah metal
um irons both in the blood as well as in the
extracellular fluid so they could be catalyzing
ah many of the degradation process so even
if you do not want degradation sometimes you
may be surprised the material is degrading
because ah they are catalyzed by acids bases
and ions ok so ah lot of these ah materials
nitriles um ethers ok phosphates phosphonates
so all these are getting degraded because
of ah presence of a acid acidic ions or basic
ions and so on actually ok so quiet a lot
of situations where you can have sulfonamide
for example um produces acidic functions ok
polycyanoacrylate ok we have the cyan group
um ok so um c triple bond n and c triple bond
n ok and they are getting ah again hydrolyzed
in the presence of base ok ah sulfonamides
they are getting um hydrolyzed in the presence
of ah acidic or ah basic functional
now if you look degradation of a polymer ok
ah um this is an example picture i am showing
p l a starting from eighty milligrams going
down to fifty milligrams in thirty days p
l g a starting from seventy five milligrams
going down to twenty five milligrams in thirty
day gallic acid is more biodegradable than
lactic acid ok as you can see in these two
pictures ok so by modifying the amount of
glycolic acid in ah poly lactic system i can
um modify the weight loss ok as you can see
and we can assume a first order type of degradation
like this you know weight loss is equal to
weight loss at times zero exponent minus k
t k value for p l a poly lactic acid is point
zero two three k value for p l g a is point
zero six eight so i am having different ah
by having different amounts of [gla/glycolic]glycolic
acid i can achieve different degradation rate
which ah means i can have different k values
here
and um the degradation generally um we can
assume it as a first order as you can see
in this ah nice fit this is a experimental
and data is the squares um and diamonds on
the model fit is given by this straight line
um this (( )) shows you as a scanning electron
pictures of the degradation of both ah ply
lactic acid and poly lactic glycolic acids
system um nice ah um polymeric spheres here
as you can see and with time it goes down
you can see nice degradation and the polymers
of ah certain diameters two hundred and seventy
nanometers becomes almost hundred nanometers
in thirty day p l g a is starting from three
hundred and twenty five nanometers coming
down to seventy five nanometers ok nice ah
degradation profiles you can see and changes
in the size of this polymers also ok you can
see
so ah if i am using this ah system for drug
delivery obviously if i have drug incorporated
into this um as the polymers degrade losing
its ah um sized diameter ah it may be liberating
the drug may be antibiotic or anti inflammatory
drug so we can use p l a or p l g a both p
l a and p l g a are f d a approved (( )) ok
so we have very nice ah situation where um
we can ah have a drug loaded polymers and
as you can see within thirty days ah we achieve
ah um almost ah um two times reduction in
the size p l a and almost ah um four times
reduction in ah in the size of ah p l g a
ok
so we will continue in the next class more
on the biodegradation as well as bioresorption
of ah polymeric material
thank you very much for your time

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