1

Biomaterials Biomaterials
II1 II1--K RLACH Symposium 2007 K RLACH Symposium 2007
1heme 1heme: Materials of 1omorrow : Materials of 1omorrow
Dhirendra Dhirendra S. S. Katti Katti
Dept. o Biological Sciences and Bioengineering ,BSBL, Dept. o Biological Sciences and Bioengineering ,BSBL,
II1 II1--Kanpur Kanpur
What is Biomaterial Science ? What is Biomaterial Science ?
Biomaterial Science Biomaterial Science`` is the physical and is the physical and
biologi cal study o materials and thei r biologi cal study o materials and thei r
interactions with the biological eni ronment . interactions with the biological eni ronment .
What are Biomaterials ? What are Biomaterials ?
AA biomaterial biomaterial is a noniable material used in a is a noniable material used in a
medical dei ce, int ended to int eract with medical dei ce, int ended to int eract with
biologi cal systems ,\illiams, 198, biologi cal systems ,\illiams, 198,
I the words I the words nonviable nonviable`` ,incapabl e o growing ,incapabl e o growing
and deeloping i ndependent ly, or and deeloping i ndependent ly, or medical medical`` are are
remoed, the deinit ion becomes broader and remoed, the deinit ion becomes broader and
can encompass a wide range o applicat ions can encompass a wide range o applicat ions
!ittiav ., D.., Pr oce eaivg. of a Cov .e v.v . Covf er evc e of tbe vr oeav ociet, for iovat er iat., Cb e.t er ,
vgtava, Mar c b :, 1.
What is Biocompatibility ? What is Biocompatibility ?
Biocompatibility Biocompatibility is the ability o a material to perorm is the ability o a material to perorm
with an appropriate host response in a speciic with an appropriate host response in a speciic
application ,\illiams, 198, application ,\illiams, 198,
appropriate host response appropriate host response``
resistance to blood clotting , resistance to blood clotting ,eg eg. . hemodialysis hemodialysis membrane membrane -- in in
contact with the patients blood or 3 hrs.,, contact with the patients blood or 3 hrs.,,
resistance to bacterial colonization , resistance to bacterial colonization ,eg eg. urinary catheter . urinary catheter -- may may
be inserted or a week or hip be inserted or a week or hip--joint replacement prosthesis joint replacement prosthesis --
may be or the lie o the patient,, and may be or the lie o the patient,, and
normal, uncomplicated healing , normal, uncomplicated healing ,eg eg. tissue engineering . tissue engineering
applications,. applications,.
!ittiav ., D.., Pr oce eaivg. of a Cov .e v.v . Covf er evc e of tbe vr oeav ociet, for iovat er iat., Cb e.t er ,
vgtava, Mar c b :, 1.
Cell Biomaterial Interaction Cell Biomaterial Interaction
Design Considerations Design Considerations
1he 1he bulk bulk`` and and surface surface`` properties o biomaterials properties o biomaterials
used or medical implants hae been shown to directly used or medical implants hae been shown to directly
inluence, and in some cases, control the dynamic inluence, and in some cases, control the dynamic
interactions that take place at the tissue interactions that take place at the tissue--implant implant
interace. interace.
1hese characteristics and the 1hese characteristics and the changes in these changes in these
characteristics characteristics that may take place oer time that may take place oer time in uiuo in uiuo
should be known or designing biomaterials or speciic should be known or designing biomaterials or speciic
applications, applications,
eg eg. Cardioascular ,lowing blood contact,, . Cardioascular ,lowing blood contact,,
Orthopaedic Orthopaedic ,unctional load bearing,. ,unctional load bearing,.
2
Some examples of Some examples of
Biomaterials Biomaterials
Intraocular Lens Intraocular Lens
Basic materials PMMA (Acrylic), Silicone
Challenges Combining long term biocompatibility with
optical properties
Vascular Grafts Vascular Grafts
Basic Material:
Polyurethane, 1elon
& Dacron
Challenges:
Maintenance o
mechanical integrity
Long term blood
compatibility
,aoidance o blood
clotting,.
Artificial Hip Joints Artificial Hip Joints
http://www.totaIjoints.info/Hip.jpg
Basic material: Stainless Steel,
titanium and its alloys, and
UlM\PL.
Challenges: Preention o wear
& loosening oer extended
periods ,10-15 yrs.,.
Substitute Heart Valves Substitute Heart Valves Indian - Chitra Heart Valve
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Chitra Chitra Heart Valve Heart Valve What Material What Material
1he disc which is 1he disc which is tiltably tiltably mounted has to lutter more than mounted has to lutter more than JJS,000 JJS,000
times per day times per day in a normal personhaing 2 to 80 beats per minute in a normal personhaing 2 to 80 beats per minute
,translates to the disc opening and closing ,translates to the disc opening and closing 40 million times a year 40 million times a year at at
an aerage,, causing an aerage,, causing tremendous strain tremendous strain on the material. 1hereore, on the material. 1hereore,
the material used should be extremely durable in terms o the material used should be extremely durable in terms o wear wear
resistance and fatigue strength resistance and fatigue strength. .
A ale may hae to operate inside the human body up A ale may hae to operate inside the human body up--to 25 years or to 25 years or
more which necessitates the material to hae excellent more which necessitates the material to hae excellent chemical and chemical and
structural stability structural stability. .
1he 1he bio bio--compatibility compatibility ,both tissue compatibility and blood ,both tissue compatibility and blood
compatibility, o the material is also a major requirement. compatibility, o the material is also a major requirement.
linally the material should be linally the material should be processable processable to achiee the required to achiee the required
surace inish and dimensional stability surace inish and dimensional stability
UlM\PL UlM\PL has all the adantageous properties such as durability, has all the adantageous properties such as durability,
longeity, high stress resistance, wear resistance, tissue and b longeity, high stress resistance, wear resistance, tissue and blood lood
compatibility, atigue strength, and toughness. compatibility, atigue strength, and toughness.
Ventricular Assist Device ( Ventricular Assist Device (VADs VADs))
VADs VADs that can be considered as one that can be considered as one
hal o a total artiicial heart, hae hal o a total artiicial heart, hae
eoled rom a daring experimental eoled rom a daring experimental
concept to a lie concept to a lie--prolonging tool. prolonging tool.
1hey are now used to maintain a 1hey are now used to maintain a
patient with a ailing heart while patient with a ailing heart while
waiting or a heart transplantation. waiting or a heart transplantation.
Challenges Challenges: :
maint ain pr op er electro maint ain pr op er electro--m echanical m echanical
unction ing unction ing
pre enti on o in ectio n and clotti ng o pre enti on o in ectio n and clotti ng o
blood blood
http:,, http:,,www.worldheart.com,products,noacor_las.cm www.worldheart.com,products,noacor_las.cm
LVADs LVADs
BIOMA1LRIALS
ML1ALS POLYMLRS CLRAMICS
COMBINA1IONS both
WI1HIN A CLASS & BL1WLLN CLASSLS
Biomaterials Biomaterials
A multidisciplinary science A multidisciplinary science
Asic Asic Asic Asic
ScicNccs ScicNccs ScicNccs ScicNccs
ENciNccniNc ENciNccniNc ENciNccniNc ENciNccniNc
ScicNccs ScicNccs ScicNccs ScicNccs
McoicAL ScicNccs McoicAL ScicNccs McoicAL ScicNccs McoicAL ScicNccs
From IDEA
To
PATIENT !!
AC1ION IACILI1A1OR
Ide ntify a need Clinician / Researcher
/ Inventor
Device design Clinician / Lngineer
Material synthesis Materials Scientist
Materials testing Materials Scientist /
Bioengineer /
Veterinarian
Iabrication Lngineer / Mac hinist
Device testing Bioengineer /
Clinician /
Regulatory Age ncy
Clinical Use Clinician
Lxplant a nalysis Pathologist /
Bioengineer
Personal Research Personal Research
Biomaterials
1issue
Lngineering
Applications
Drug Deliery
Applications
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1issue Lngineering 1issue Lngineering
1issue engi neering 1issue engi neering is an interdiscipl inary ield
that appli es the principles o engineering and
life sciences toward the deelopment o
biological substitutes that restore, maintain or
improe tissue uncti on.
Langer et al. , Science, 260 (1993)
Katti et al Directions (2005)
Our Approach Our Approach
Deelopment o a Deelopment o a Nanoiberous Nanoiberous scaold scaold or cartilage or cartilage
tissue engineering tissue engineering
More than More than 43 mil lion 43 mil lion people have some Iorm oI arthritis. people have some Iorm oI arthritis.
OA aIIecting over 10 oI the USA population OA aIIecting over 10 oI the USA population
OA will i nIlict OA will i nIlict 70 70--100 million Indians 100 million Indians (~ 10 oI population) (~ 10 oI population)
No effective treatment today No effective treatment today !!!! !!!!
ww www. boneandjointdecade. org w. boneandjointdecade. org
Mujor unmeL medIcuI need Mujor unmeL medIcuI need
Age
Weight
Cartilage dama ge
Genetics
Osteoarthritis
Trauma
Articolur Curtiluge Biology Articolur Curtiluge Biology
Composition Composition
CIondrocyLes 1- %
WuLer 6-8o%
CoI Iugen 1o-zo%
ProLeogIycuns q-;%
Dense connecLIve LI ssue LIuL I orms LIe I oud beurIng
surIuces oI synovIuI joInLs
Brighton CT Brighton CT edt edt. . Clin ical Clin ical orthopaedics orthopaedics and related and related
research research, 2001 , 2001
Because of
(i) Small quantity of chondrocyte
(ii) The reduced availability of progenitor cells in the
local environment
(iii) Cartilage being a avascular and alymphatic tissue
~articular cartilage has limited capacity to regenerate
ArLIcuIur CurLIIuge ArLIcuIur CurLIIuge
Brighton CT Brighton CT edt edt. . Clin ical Clin ical Orthopaedics Orthopaedics and Related Research and Related Research, 2001 , 2001
A tough , elastic , fibrous
connective tissue
Avascular, Aneural,
alymphatic tissue
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Hierarchical Structure of Cartilage:
Collagen fibers have nanometer dimensions
Macro: 0.S-JS cm
1issue: J0
-4
-J0
-2
m
Micro: J0
-7
-J0
-4
m Ultra: J0
-8
-J0
-6
m Nano: J0
-J0
-J0
-9
m
Molecular and f ibrillar
structure of collagen
15 A 1.5 nm
Filament 200 A 20 nm
Fibril 2,000 A 200 nm
Primitive Fiber 20,000 A
2000 nm or 2 m
Fiber bundle
100,000 - 200,000 A
10-20 m
Hypothesis Hypothesis
We hypothesize that We hypothesize that fibers fibers made Iro m made Iro m
biodegradable and biocompatible polymers such biodegradable and biocompatible polymers such
as as poly(lactide poly(lactide--co co--glycolide glycolide) (PLAGA) ) (PLAGA) that that
have nanometer dimensions will mimic the have nanometer dimensions will mimic the
collagen f ibrils present in native human collagen f ibrils present in native human
tissue tissue and that these polymeric and that these polymeric nanoIibers nanoIibers can can
be engineered into porous three be engineered into porous three--dimensional dimensional
(3 (3--D) scaff olds D) scaff olds that are appropriate Ior tissue that are appropriate Ior tissue
engineering engineering
DeveIopmenL oI NunoIIber ous scuIIoId Ior DeveIopmenL oI NunoIIber ous scuIIoId Ior
curLIIuge L Issue engIneerIng curLIIuge L Issue engIneerIng
Mimics natural ECM Mimics natural ECM
composition composition
High porosity High porosity
Higher surIace area Ior Higher surIace area Ior
cell adhesion cell adhesion
Better mechanical strength Better mechanical strength
Synthesis of Nanof iber: Synthesis of Nanof iber:
Electrospinning Electrospinning
Biomaterials : Poly (l Biomaterials : Poly (l--
lactic acid), poly (lactide lactic acid), poly (lactide--
co co--glycolide), glycolide), chitosan chitosan. .
Nanofiber Iabrication Nanofiber Iabrication
Llectrospinning Llectrospinning
lli gh electri cal i gh electri cal
potential appl ied to potential appl ied to
a polymer solut ion a polymer solut ion
to cause jet to cause jet
ormati on that ormati on that
progressiel y thins progressiel y thins
to orm to orm
nanofibers nanofibers
HV Po wer Supply
Gro unded
Needle
Sy ringe
Po ly mer 1et
Po ly mer
Substrate
So lution
Llectrospinning Llectrospinning
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Stable Jet
Increased
instabilities
Initiationof
instabilities
Lxamples of Lxamples of Nanofibers Nanofibers
Poly(lactic acid) Poly(styrene) Poly(lactide-co-glycolide)
Poly(lactide-co-glycolide)
& Poly(vinyl alcohol)
Poly(styrene) Aligned Poly(styrene) Aligned
Cosmetics
Iilter
media
Protective
clothing
Material
reinforcement
Optical
applications
Llectrical
conductors
Sensor
Devices
Polymer
Nanofibers
Possibilities Possibilities
Personal Research Personal Research
Biomaterials
1issue
Lngineering
Applications
Drug Deliery
Applications
Drug Delivery Systems Drug Delivery Systems
lormulation or deice that deliers therapeutic lormulation or deice that deliers therapeutic agent,s agent,s, to , to
desired body desired body location,s location,s, and,or proides timely release o , and,or proides timely release o
therapeutic therapeutic agent,s agent,s,. ,.
1he system, on its own, is not a therapy, but improes the 1he system, on its own, is not a therapy, but improes the
eicacy and,or saety o the therapeutic eicacy and,or saety o the therapeutic agent,s agent,s, that it , that it
carries. carries.
http:/ /www.drugdel.com/
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Drug Delivery Systems Drug Delivery Systems
1ransdermal Drug Delivery
Liposomes
Conventional Approaches of drug Conventional Approaches of drug
administration administration
Oral ,pil ls, tablets, Oral ,pil ls, tablets,
Injection o Injection o solubli zed solubli zed drug drug
,intraenous,intramuscular,subcutaneous, ,intraenous,intramuscular,subcutaneous,
Disadvantages Disadvantages
Rapid breakdown o the drug Rapid breakdown o the drug iv riro. iv riro.
lydrophobic drugs may precipitat e in aqueous lydrophobic drugs may precipitat e in aqueous
media. media.
Unaorable pharmacokineti cs. Unaorable pharmacokineti cs.
Poor Poor biodist ributi on biodist ributi on -- dose limiti ng side eects. dose limiti ng side eects.
Lack o selectiity or target tissues. Lack o selectiity or target tissues.
39
Possible Solution Possible Solution
Drug deliery systems Drug deliery systems
Maintenance o Maintenance o optimum therapeutic drug optimum therapeutic drug
concentration concentration ,Improed bioaailability,. ,Improed bioaailability,.
Predetermined release rates or extended periods o Predetermined release rates or extended periods o
time. time.
Llimination o side eects and requent dosing Llimination o side eects and requent dosing --
hence proiding optimized therapy. hence proiding optimized therapy.
Better patient compliance. Better patient compliance.
Drug rel ease kinetics
Therap eutic
Rang e of drug
concen tration
1arget Specific
Duration specific
Drug Delivery Systems
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Development of Development of intratumoral intratumoral drug drug
delivery system for the treatment of delivery system for the treatment of
lung cancer lung cancer
Our Research
44
Iung cuncer is the
leuJing cuuse jor cuncer
reluteJ Jeuths not only in
InJiu, but in rest oj the
uorlJ too!!
45
Disadvantages of Systemic Disadvantages of Systemic
Chemotherapy Chemotherapy
Low bioaailabil ity at target site Low bioaailabil ity at target site
Side eects Side eects
li gh Cost li gh Cost
Intratumoral Chemotherapy Intratumoral Chemotherapy
Lnhances antitumor actiity by ocusing therapy at Lnhances antitumor actiity by ocusing therapy at
the tumor site. the tumor site.
Local administration o drugs preents systemic Local administration o drugs preents systemic
toxicity. toxicity.
Proposed Proposed Intratumoral Intratumoral
Chemotherapy: Chemotherapy: Polymer based, Polymer based,
micro/ micro/nanoparticle nanoparticle
Importance of Importance of nanocarriers nanocarriers
Blood essels and cells hae diamet er in range o Blood essels and cells hae diamet er in range o
500nm 500nm-- 20 20m. m.
Nanoscale Nanoscale carri ers oer adantage o easy cel l carri ers oer adantage o easy cel l
and tissue uptake. and tissue uptake.
li gh surace area to olume rati o. li gh surace area to olume rati o.
47
http://www.csir.co.za/websource/ptl0002/ima ges/m&mtek/cpt/nano particles.jpg
Combination Chemotherapy Combination Chemotherapy
1umor cel l death in a 1umor cel l death in a heterogenous heterogenous tumor cel l tumor cel l
populat ion can be achieed in a more eect ie populat ion can be achieed in a more eect ie
way when drugs working on dierent principles way when drugs working on dierent principles
are combi ned. are combi ned.
Proposed Combination Proposed Combination
Chemotherapy Chemotherapy
Paclitaxel and 1opotecan Paclitaxel and 1opotecan
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Paclitaxel Paclitaxel
Paclitaxel is a microtubule Paclitaxel is a microtubule
interfering agent which interfering agent which
antagonizes the disassembly antagonizes the disassembly
of of pp--tubulin tubulin..
Mitotic arrest follow in G2M Mitotic arrest follow in G2M
phase of cell cycle. phase of cell cycle.
A portion of these arrested A portion of these arrested
cells undergo apoptosis, cells undergo apoptosis,
remainder portion of non remainder portion of non--
lethally injured cells move lethally injured cells move
forward in the cell forward in the cell--cycle after cycle after
a period of latency. a period of latency.
1opotecan 1opotecan
A camptothecin analog A camptothecin analog
1opotecan binds to the topoisomerase I 1opotecan binds to the topoisomerase I--DNA DNA
complex and prevents re complex and prevents re--ligat ion of these single ligat ion of these single
strand breaks. strand breaks.
1he cytotoxicity of topotecan is due to irreversible 1he cytotoxicity of topotecan is due to irreversible
double strand DNA damage produced during DNA double strand DNA damage produced during DNA
synthesis. synthesis.
Sequential Chemotherapy Sequential Chemotherapy
In many cases o combination chemotherapy, In many cases o combination chemotherapy,
sequential admi nistrat ion is more eectie than sequential admi nistrat ion is more eectie than
simultaneous del iery. simultaneous del iery.
Proposed Sequent ial Chemotherapy Proposed Sequent ial Chemotherapy
Synergism leads to: Synergism leads to:
Reduction in total dose hence reduced toxicity Reduction in total dose hence reduced toxicity
Improed patient compliance Improed patient compliance
Cost Cost--eectie treatment eectie treatment
Proposed Sequential Proposed Sequential
Chemotherapy: Chemotherapy:
Paclitaxel : 3 Paclitaxel : 3--S hours S hours
Drug free incubation period : J7 Drug free incubation period : J7--J9 hours J9 hours
1opotecan : S days 1opotecan : S days
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Our Approach Our Approach
Intratumoral
chemotherapy
Combination
chemotherapy
Sequential
chemotherapy
Hypothesis Hypothesis
\e hypothesize that \e hypothesize that sequentiul Jeliuery sequentiul Jeliuery o paclitaxel o paclitaxel
and topotecan using a and topotecan using a polymeric purticulute Jeliuery polymeric purticulute Jeliuery
system system when administered when administered intrutumorully intrutumorully will lead to will lead to
better permeability into the tumor, higher local better permeability into the tumor, higher local
concentration o the drugs and better toxicity proile. concentration o the drugs and better toxicity proile.
\e urther hypothesize that this deliery system will \e urther hypothesize that this deliery system will
eentually proide or eentually proide or improueJ loco improueJ loco--regi onul regi onul
control control and hence and hence increuseJ suruiuul rutes increuseJ suruiuul rutes o lung o lung
cancer patients. cancer patients.
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Schematic of proposed model of sequential drug
delivery system
Outer Layer of D, L- PLA
containi ng Paclitaxel
(Degra dation time 3-S hours)
Drug Iree Middle Layer of D, L-
PLA ( Degradation time J7-J9
hours)
Inner Layer of Chitosan
containi ng 1opoteca n
( Degradation time S days)
10
55
Llectrospraying Llectrospraying
High
Voltage
Polymer Solution
56
Synthesis of Synthesis of chitosan chitosan micro/ micro/nanospheres nanospheres
by by electrospraying electrospraying..
S m
S m
Possibilities Possibilities
Diagnostic Diagnostic Micro, Micro,nanoparticles nanoparticles tagged with antibodies tagged with antibodies
that can detect speciic antigens in body luids such as urine that can detect speciic antigens in body luids such as urine
and blood as well as in cell culture. and blood as well as in cell culture.
Portable, simple, fast, specific and quantitative. Portable, simple, fast, specific and quantitative.
Magnetic Magnetic -- Contrast ehicle or MRI Contrast ehicle or MRI
1hermal 1hermal -- Improe eiciency o coolants by suspending Improe eiciency o coolants by suspending
metallic metallic nanoparticles nanoparticles in the heat transer luids. in the heat transer luids.
Llectronic Llectronic -- Langmuir Langmuir--Blodgett ilms o Blodgett ilms o nanoparticles nanoparticles..
http ://w ww. mal ver n.c o. uk; 1. K elly J . Ph ys. C he m (2 00 3); 2 . Mul de r N MR Bi omed (2 00 6) ;
3. C hoi (1 99 6) ; 4. P aul Na no Let t ( 20 03 ).
Iuture of Biomaterials Iuture of Biomaterials
An appropriate combinat ion o An appropriate combinat ion o engineers engineers, ,
clinicians clinicians and and basic science researchers basic science researchers will will
pae the way or the deelopment o better pae the way or the deelopment o better
biomaterials biomaterials and hence ,medical, dei ces that and hence ,medical, dei ces that
will help improe the qual ity o li e o humans. will help improe the qual ity o li e o humans.
1hanks to 1hanks to
Rajesh Rajesh Vasita Vasita
Neha Neha Arya Arya
1hank you for your attention !! 1hank you for your attention !!
1HL
LND
11
1hank You
1hank You
0epar tment of |o|og|ca| 8c|ences & |oeng|neer |ng,
|nd|an |nst|tute of Techno|ogy - Kanpur
Some Commonly used Biomaterials Some Commonly used Biomaterials
Material Material Applications Applications
Silicone rubber Catheters, tubing Silicone rubber Catheters, tubing
Dacron Vascular grats Dacron Vascular grats
Cellulose Dialysis membranes Cellulose Dialysis membranes
Poly,methyl Poly,methyl methacrylate methacrylate, Intraocular lenses, bone cement , Intraocular lenses, bone cement
Polyurethanes Catheters, pacemaker lea Polyurethanes Catheters, pacemaker leads ds
lydogels lydogels Opthalmological Opthalmological deices, deices,
Drug Deliery Drug Deliery
Stainless steel Orthopedic deices, Stainless steel Orthopedic deices, stents stents
1itanium Orthopedic and dental 1itanium Orthopedic and dental deices deices
Alumina Orthopedic and dental Alumina Orthopedic and dental deices deices
lydroxyapatite lydroxyapatite Orthopedic and dental deices Orthopedic and dental deices
Collagen ,reprocessed, Collagen ,reprocessed, Opthalmologic Opthalmologic applications, wound applications, wound
dressings dressings
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Nondegradable Homopolymers used as biomaterials
Degradable Homopolymers used as biomaterials
preention o inection and clotting o blood
Degradable Homopolymers used as biomaterials
In vitro Tissue Cult ure
Biodegradable
Polymer Scaffold
CeIIs
Osteoblasts
Chondrocytes
Hepatocytes
Enterocytes
Urothelial Cells
In Vivo Impla ntatio n
New
Bone
Cartilage
Liver
Intestine
Ureter
Inc ubation period
Increased 1opoisomerase I level
Increased BcL - xL phos phorylation
Paclitaxel
Paclitaxel and 1opotecan Paclitaxel and 1opotecan-- Sequence Sequence
in action! in action!
1opotecan
Apoptosis
Apoptosis