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BIODEGRADABLE POLYMERS: PROPERTIES AND BIOMEDICAL
APPLICATIONS Laura Elomaa 17.9.2015 [email protected]
Outline
1. Biodegradable polymers: definiLons 2. Mechanism of biodegradaLon 3. Origin of biodegradable polymers – Natural polymers – SyntheLc polymers
4. Polymers in biomedical applicaLons – Tissue engineering and 3D prinLng – Controlled drug delivery – Injectable materials
5. Take home messages
DefiniLons
According to Vert el al. (1992): • Biodegradable polymer
– Breaks down enzymaLcally or non-‐enzymaLcally through polymer chain cleavage when in contact with body fluids or water
• Bioresorbable polymer – A\er biodegradaLon, resorbs in body through natural pathways
• Bioabsorbable polymer – Does not degrade through chain cleavage but can be excreted from a body by natural pathways in their intact form
Vert M, Li SM, Spenlehauer G, Guerin P. Bioresorbability and biocompaLbility of aliphaLc polyesters. J. Mater. Sci: Mater. Med. 1992; 3:432-‐446.
Terms in this lecture: Polymer matrix consists of polymer chains
Biomedical applicaLons
• Where would we need biodegradable polymers? • What kind of applicaLons can benefit from biodegradaLon?
Biomedical applicaLons
• Surgical sutures, orthopedic devices such as bone cements, screws, and plates, dental applicaLons, scaffolds for Lssue engineering, drug delivery devices
• What kind of biodegradable polymer would be opLmal for biomedical applicaLons?
Ideal biodegradable polymer in biomedical applicaLons
Ideal biodegradable polymer in biomedical applicaLons
• Nontoxic (both polymer and its degradaLon products) • BiocompaLble • Immunologically inert • Does not cause inflammatory reacLon • In Lssue implants, mechanical properLes should match the
surrounding Lssue • DegradaLon rate can be controlled
BiodegradaLon
• One of the most significant properLes in biomedical applicaLons – Ensures that the material gradually disappears from the body a\er fulfilling its funcLon
– No addiLonal removal surgery is needed • Biodegradable polymers contain hydrolyLcally labile chemical
bonds, including ester, anhydride, carbonate, or pepLde bonds
• Some biodegradable polymers can degrade in water in absence of enzymes (polyesters, polyanhydrides), others require presence of enzymes (polypepLdes)
HydrolyLcally sensiLve biodegradable bonds
R OR
R O R
RNH
R
RNH
OR
RO O
R
OR
RO O
R
O
O O
O
O
O ester
anhydride
amide
urethane
orthoester
carbonate
Hydrolysis of labile bonds
• Bonds with carbonyl group and a heteroatom are parLcularly labile • Nucleophilic water or hydroxyl ion afacks the electron-‐
withdrawing carbonyl group à Breaks the bond through nucleophilic subsLtuLon
• Enzymes catalyze hydrolysis (esterases, proteases, etc.): bring specific polymer and water together and lower acLvaLon energy
• Cleavage of the polymer chain decreases the polymer molecular weight
• Short oligomer or monomer chains are metabolized in a body
R1 XR2
O H2O
R1 OH
O
XH R2+
X = O, N, S
BiodegradaLon
Example: PoylacLde
Citric acid cycle
H2O
Eliminationfrom body
O O OO
O
O
OO
O OH OO
O
O
OOHO
OHO
HO
H2O+
Polymer
extracellular
polymer cleavage
oligomer, monomer
intracellular
metabolism
H2O(enzymes)
CO2 + H2O
ProperLes affecLng biodegradaLon
• Chemical structure of the polymer: – Type and amount of labile chemical bonds – Hydrophobicity à Wegng properLes – Molecular weight – Crystallinity – Presence of ionic groups – Size and surface area of the polymer matrix
• Environment: – pH – Temperature – Presence of enzymes
Methods for studying biodegradaLon
• Weight measurements • Molecular weight: gel permeaLon chromatography (GPC),
mass spectroscopy • Thermal behavior and crystallinity changes: differenLal
scanning calorimetry (DSC) • Changes in chemistry (new end groups): nuclear magneLc
resonance (NMR), infrared (IR) spectroscopy • Morphological changes: swelling, deformaLon,
disappearance, soluLon viscosity
Material erosion
• DegradaLon of the polymer chains results in mass loss of the polymer matrix
• Mechanism depends on the rate of water diffusion into a polymer matrix:
a) Surface erosion – Water diffusion into the polymer matrix is slower than polymer chain degradaLon
à Polymer matrix undergoes surface erosion – Mass loss happens on the matrix surface
b) Bulk erosion – Water diffusion into the polymer matrix is faster than polymer chain degradaLon
à Polymer matrix undergoes bulk erosion – Mass loss happens throughout the matrix
Surface vs. bulk erosion
Change of polymer properLes in bulk degradaLon
• In ideal surface erosion, properLes change only on the surface and remain intact inside the polymer matrix
• In bulk erosion, properLes change through the polymer matrix
ORIGIN OF BIODEGRABLE POLYMERS
I) Natural biopolymers
• Are extracted from natural resources 1. Plant origin:
Polysaccharides: Cellulose, starch, alginate
2. Animal origin: Polysaccharides: ChiLn, hyaluronate Proteins: Collagen, gelaLn, albumin
3. Microbe origin Polyesters: Poly(3-‐hydroxyalkanoate) Polysaccharides: Hyaluronate
Natural biopolymers
Benefits: • Inherently biodegradable • Abundant natural resources • Great diversity in chemistry • Typically have good cell afachment properLes; BioacLvity • Hydrophilic à Suitable for water-‐absorbing hydrogels
Drawbacks: • Complex chemical structure à Poor lot-‐to-‐lot uniformity • Chemical modificaLon can be difficult without changing bioacLvity • PurificaLon can be difficult and expensive • Typically temperature sensiLve à Challenging processing
properLes
Examples of natural biopolymers
• Collagen: Long polypepLde composed of various amino acids
• Chitosan: PosiLvely charged polysaccharide à AnLmicrobial, good blood coagulant and wound healer
Examples of natural polymer applicaLons
• Apligra\®: – ArLficial skin for treatment of ulcers – Contains collagen type 1 from bovine and
human fibroblasts and keraLnocytes à Together accelerate the wound healing – First living cell-‐based Lssue regeneraLon
product with FDA approval
• KytoCel® (AspenMedical) • Chitosan derived from shellfish • Wound healer: Biodegradable chitosan fibers
bond with wound exudate to form a water-‐absorbing gel à Accelerates wound healing
• Absorbs pathogens
II) SyntheLc biodegradable polymers
• Polyesters, polyamides, polyanhydrides, poly(ortho ester)s, polyphosphates
Benefits: • ProperLes can be readily modified by changing its monomer,
molecular weight, or funcLonal groups • Straighlorward synthesis à Great lot-‐to-‐lot uniformity • No concerns of immunogenicity • Befer mechanical strength Drawbacks: • Low bioacLvity à Poor cell afachment if not funcLonalized • Most of them are highly hydrophobic à Poor wegng
Commonly used syntheLc biodegradable polyesters
OO
OO
O
O
O
O
O
O
OO
O
O
OO
O
O
H OOH
O
HO OH
O
n
n
HO
OH
O
n
HO
O
nO
OH
O m
glycolide
lactide
poly(clycolic acid) or polyglycolide (PGA)
poly(lactic acid) orpolylactide (PLA)
glycolic acid
lactic acid
glycolide lactide
caprolactone polycaprolactone (PCL)
OHHO
O
OHHO
O
or
or
poly(lactide-co-glycolide) (PLGA)
+
• PolycondensaLon of acid monomers gives lower molecular weight than ring-‐opening polymerizaLon of cyclic monomers
Ring-‐opening polymerizaLon: Polycaprolactone
Commonly used syntheLc biodegradable polyesters
1. Polyglycolide (PGA)
• High crystallinity à Not soluble in most organic solvents • High melLng point: around 225-‐230 °C • More hydrophilic than PLA of CL and degrades faster; degradaLon Lme 6-‐12
months • In body, degrades into glycolic acid à Can be excreted in the urine or
converted into carbon dioxide and water via citric acid cycle • High modulus and tensile strength à Suitable for load-‐bearing applicaLons
OO
O
O
HO OH
O
n
glycolidepoly(clycolic acid) or polyglycolide (PGA)glycolic acid
OHHO
Oor
Commonly used syntheLc biodegradable polyesters
2. PolylacLde (PLA)
• Three isomeric forms: poly(L-‐lacLde) (PLLA), poly(D-‐lacLde) (PDLA), and poly(D,L-‐lacLde) (PDLLA)
• Tm = 170 °C (PLLA) • High molecular weight PLLA is semi-‐crystalline and degrades in 2 years • PDLLA is amorphous; degrades in 12-‐16 months • DegradaLon product lacLc acid à is metabolized via citric acid cycle • PLLA is typically used in load-‐bearing applicaLons and PDLLA in low
strength implants and drug release applicaLons
OO
O
O
HO
OH
O
n
lactide poly(lactic acid) orpolylactide (PLA)
lactic acid
OHHO
Oor
Bio-‐based monomer
Commonly used syntheLc biodegradable polyesters
3. Poly(ε-‐caprolactone) (PCL)
• Semi-‐crystalline polymer • Tm = 50-‐60 °C • Due to its hydrophobicity, has longer biodegradaLon Lme than PGA or
PLA, around 2-‐3 years • DegradaLon product 6-‐hydroxyicaproic acid à is metabolized in a body • Modulus is low à Typically used in long-‐term implantable drug delivery
systems and low strength applicaLons
O
O
H OOH
O
n
caprolactone polycaprolactone (PCL)
Petroleum-‐based monomer
SyntheLc biodegradable polymers in applicaLons
• Capronor® – Long-‐term subdermal contracepLve for hormone release – Made of slowly degradable polycaprolactone – Releases hormone for over a year; polymer remains intact during the first year of use
– Biodegrades during the second year – Clinically tested (already in 1983); However, has not made its way to the market
• Arthrex Bio-‐InterferenceTM screws – FixaLon of bone and so\ Lssue gra\s – Made of PLLA à Allows for controlled degradaLon over Lme
BIOMEDICAL APPLICATION FIELDS OF BIODEGRADABLE POLYMERS
I) Tissue engineering (TE)
• More than 120,000 people in a waiLng list for an organ donor in the US (2013); only 29,000 received a transplant – The gap is growing due to the shortage of suitable organ donors
• Use of animal tests is being restricted by laws à Need for alternaLve methods for tesLng drugs
• TE aims to provide paLents with temporary biological subsLtutes that mimic naLve Lssue – ArLficial Lssue constructs can be used for restoring or improving natural Lssue funcLon
• TE strategy supports cells that are naLvely found in the body to induce natural healing of Lssues and organs
• Tissue constructs grown in a lab can be used for efficient pharmaceuLcal research
Tissue engineering
A) In vitro TE approach 1. Culturing and mulLplying of cells 2. FabricaLon of a TE scaffold 3. Cell seeding on the scaffold 4. ProliferaLon and differenLaLon of cells within the scaffold in vitro 5. ImplantaLon into a body
B) In vivo TE approach 1. Culturing and mulLplying of cells 2. FabricaLon of a TE scaffold 3. Cell seeding on the scaffold 4. ImplantaLon into a body 5. ProliferaLon and differenLaLon of cells within the scaffold in vivo
Extracellular matrix (ECM)
• Highly porous 3D structure à Provides Lssue with structural integrity and directs cell behavior through biomechanical interacLons and mechanical cues
• Composed of interlocked fibrous proteins and polysaccharides secreted by cells
• Major ECM proteins are elasLn, collagen, fibronecLn, and laminin – ElasLn is responsible for the elasLc properLes of many Lssues like
arteries – Collagen gives tensile strength to Lssues like bone and skin – FibronecLn contains important collagen-‐, heparin-‐, and cell-‐binding
domains – Crosslinked laminin is the main component of basement membranes
à ECM is a highly organized 3D construct of natural biopolymers
Biodegradable TE scaffold
• Porous 3D structure fabricated of biodegradable polymers • ArLficial subsLtute for ECM à Provides cells with a local
environment that enhances and regulates cell proliferaLon • Key funcLon is to guide proliferaLon and growth of cells to form
healthy new Lssue • Mechanically supports regeneraLng Lssue and can deliver
therapeuLc agents to enhance Lssue growth or to treat diseases
Biodegradable TE scaffold
• What properLes are needed for an opLmal TE scaffold that mimics natural ECM?
Requirements for scaffold polymer
• Biodegradable: Scaffold degrades when cells no longer need addiLonal support
• Should encourage cell afachment and proliferaLon • Polymer and degradaLon products need to be biocompaLble à No
cytotoxicity allowed • Scaffold needs to be sterilizable and reproducible
– Polymer should endure heat or radiaLon • Mechanical properLes should ideally match the properLes of the
target Lssue: – Load-‐bearing bone Lssue à Strong polymer like PLA – So\ Lssue à Hydrogel-‐forming polymers like gelaLn
• Should allow for processing into a highly porous scaffold
AddiLve manufacturing (3D prinLng)
• Allows for fabricaLon of defined pore architecture designs à Highly interconnected pores ensure free nutrient flow within the scaffold
• Free-‐form parts are defined in CAD models à Liquid, powder, or sheet polymers are joined in a layer-‐by-‐layer manner to form a desired 3D structure
• CAD file can be obtained by using 3D modeling so\ware or by using clinical imaging techniques such as CT, MRI, or ultrasound imaging
• Since no molds are used, shape of the scaffold is not limited à Scaffold can be customized to each paLent individually =
personalized medicine • Allows for fabricaLon of mechanically graded scaffolds à Fulfills
the requirements of various cell and Lssue types within the same scaffold
AddiLve manufacturing and TE
A) Fused deposiLon modeling (FDM)
• Nozzle-‐based AMT system: deposits thin polymer filaments through an extrusion head
• ThermoplasLc polymer is heated in the temperature-‐controlled extrusion head à Melt polymer is extruded onto a plalorm following a computer-‐generated model
• Extrusion nozzle operates in x-‐ and y-‐ axis; build plalorm moves in z-‐axis for each new layer
• Polymer solidifies onto the plalorm à Adjacent rods form a scaffold layer
• Allows for change of direcLon of every second layer à Scaffold has a woven type pafern
• A support material can be used to improve the quality of resulLng scaffold
Fused deposiLon modeling (FDM)
!
!
Polymers in FDM
• Before FDM, polymer is processed into homogenous long filaments à ThermoplasLc polymer is needed
• MelLng and cooling properLes have to be well controlled • Polymer is heated in the syringe à Doesn’t allow for incorporaLon
of living cells or acLve proteins into the material • Cooling process has to be fast to achieve a high resoluLon • High-‐molecular weight polymers typically used à High mechanical
strength • Polymers are thermoplasLcs: Scaffold can be melted or dissolved
and polymer used again
B) Stereolithography (SLA)
• Photocrosslinking-‐based AMT • 3D structure is built using UV or visible light exposure in a layer-‐by-‐
layer manner
• Computer-‐controlled laser beam or a digital light projector is directed into liquid polymer resin à Photocrosslinks the desired pafern
• A\er photocrosslinking one layer, a build plalorm moves in z-‐direcLon à Photocrosslinking is repeated layer-‐by-‐layer to form a 3D structure
• Scaffold fabricaLon at room temperature à Allows for encapsulaLon of living cells or heat-‐sensiLve pepLdes into the scaffold
• Great spaLal and temporal control à High resoluLon
Stereolithography
!
!
Polymers in SLA
• Requires polymer with double bond end groups – MethacrylaLon is typically used:
• Polymer has to be liquid before crosslinking – Solvents or heaLng can be used
• Low molecular weight polymers are typically used – Can be liquid and highly reacLve at RT; However, mechanical strength is limited
• Polymer needs to crosslink fast under exposure to UV or visible light à ReacLve mulL-‐arm polymers typically used
• Thermosegng polymers: Scaffold cannot be melted or dissolved a\er fabricaLon
H
OO
O+R
R
R
OO
nR
R
R
OO
n
O
Photocrosslinking in SLA
• PhotoiniLator molecule splits into radicals under exposure to UV or visible light à Starts polymerizaLon by opening double bonds à Forms covalent bonds between two polymer chains à Crosslinking
C) Bioplogng
• For fabricaLon of so\ Lssue hydrogels with encapsulated cells • Viscous plogng material is dispensed through a pressure-‐
controlled syringe into a liquid medium • The scaffold is built layer by layer à Polymer solidifies into a woven
type 3D structure • Wide variety of different materials
– Polymer melts, swollen polymers, thermoset resins, polymer soluLons, sensiLve natural biopolymers
• Especially for fabricaLon of cell-‐laden hydrogels with complex architectures
Bioplogng
!
Polymers in bioplogng
• Cells are encapsulated in the hydrogel while prinLng à Polymer has to be sterile in the fabricaLon process
• Cells and proteins are sensiLve: No strong organic solvents or heaLng is allowed
• Hydrophilic polymer is needed to obtain a water-‐absorbing hydrogel
II) Controlled drug delivery
• In tradiLonal drug delivery (tablets), drug concentraLon varies from high to ineffecLve level; drug molecules spread everywhere in body
• Controlled drug delivery: Biodegradable polymer is used as an implanted or injected drug delivery vehicle
• Drug level remains in a therapeuLc range and can be localized in a body à Safer and more convenient to the paLent
• Drug release is controlled by tuning the degradaLon of polymer
DegradaLon-‐controlled drug release (w/o diffusion)
• Bulk erosion vs. surface erosion A. Bulk erosion:
– Drug release non-‐linear – Burst of drug is possible
B. Surface erosion: – Linear release kineLcs – Constant drug release rate
• Especially for large proteins that cannot diffuse out of the polymer matrix
Surface erosion and zero-‐order pepLde release
Hakala R. et al. Biomacromolecules 2011, 12, 2806–2814.
Bulk erosion and non-‐linear drug release
Schmif EA. et al. J. Pharm. Sci., 1993, 82, 326–329.
III) In situ solidifying injectable biodegradable polymers
• InjecLon of liquid polymer into Lssue • Polymer solidifies due to changes in environment (pH, T, chemicals)
or sLmulus from outside (light, magneLc field) • No need for surgery • Photorosslinking allows for solidifying the polymer transdermally
– Light penetraLon limited à Material has to be close to the skin surface
Summary
• Biodegradable polymers degrade in contact with body fluids or water with or without enzymes
• Cleavage of hydrolyLcally labile bonds, such as ester, anhydride, or pepLde bonds, causes decrease in molecular weight à Results in mass erosion
• Polymer matrix can lose mass on the surface or throughout the bulk
• Both natural and syntheLc biodegradable polymers are used in biomedical applicaLons
• Tissue engineering and controlled drug delivery are important applicaLon fields of biodegradable polymers
Further reading in case you’re interested
• Nair, L.S.; Laurencina, C.T. Biodegradable polymers as biomaterials. Prog. Polym. Sci. 32 (2007) 762–798
• Ulery, B.D.; Nair, L.S.; Laurencin, C.T. Biomedical applicaLons of biodegradable polymers. J. Polym. Sci. B Polym. Phys. 49 (2011) 832-‐864.
• Vroman, I.; Tighzert, L. Biodegradable polymers. Materials 2 (2009) 307-‐344.
• GunaLllake, P.A.; Adhikari, R. Biodegradable syntheLc polymers for Lssue engineering. Eur. Cells Mater. 5 (2003) 1-‐16.
• Uhrich, K.E.; Cannizzaro, S.M.; Langer, R.S.; Shakesheff, M. Polymeric systems for controlled drug release. Chem. Rev. 99 (1999) 3181-‐3198.