1. Biodegradable Polymers

2. Nomenclature
There is a confusion between biodegradation, bioerosion, bioabsorption and bioresorption!
Degradation: Typically= Cleavage of covalent bonds
Erosion: Typically= physical change (size, shape, mass)-dissolution
ex: sugar dissolves in water but not degrades!
Biodegradable: Degradation by a biological agent
enzyme, microorganism, cell,…
Bioerodable: Erosion under physiological condition
physical (ex: dissolution) and/or chemical (ex. Backbone cleavage
Bioresorbable /Bioabsorbable: may dissolve and/or degrade and products are removed from the body
cleared by kidneys, phagocytosis, etc

3. Why degradable? No need to remove (no second surgery)
When needed only for a transient period of time
Reduce chronic foreign body response
Body’s natural material is better and safer
Allows normal tissue function to take over
Allows gradual healing/tissue to gain strength
Eliminates additional surgery to remove an implant after it serves its function
Ideal when the “temporary presence” of the implant is desired
replaced by regenerated tissue as the implant degrades
orthopaedic fixation devices (requires exceptionally strong polymers)
adhesion prevention (requires polymers that can form soft membranes or films)
temporary vascular grafts (development stage, blood compatibility is a problem
Degradation rate must match the healing time of the tissue
Must have non-toxic degradation products

4. Applications Drug delivery Tissue scaffolds Stents Staples Sutures
Adhesives
Fracture fixation (requires exceptionally strong polymers)
adhesion prevention (requires polymers that can form soft membranes or films)
temporary vascular grafts (development stage, blood compatibility is a problem

5. Main types of degradable implants
the temporary support
the temporary barrier
the drug delivery device
multifunctional devices
Tissue engineering

6. Temporary Support provides mechanical support until the tissue heals
tissue weakened by disease, injury or surgery
healing wound, broken bone, damaged blood vessel
sutures, bone fixation devices (nail, screw, plate), vascular grafts
Rate of degradation = gradual stress transfer
implant should degrade at the rate the tissue heals
Major challange!
Nothing new commercially
Sutures are most widely used and most successful
polyglycolic acid (PGA) - Dexon® (1970)
copolymers of PGA/PLA (90/10), Vicryl® 1974
polydioxanone (PDS) 1981

7. Temporary Barrier
Prevent adhesion caused by clotting of blood in the extravascular tissue space
clotting  inflammation
adhesions are most significant problems after cardiac, spinal and tendon surgery
Barrier in the form of thin membrane or film
Another barrier use is artificial skin for treatment of burns
Stimulate regrowth of functional dermis: collagen/glycosaminoglycans
Can cause pain, functional impairment
Film adhacent to adhesion prone tissue
Artificila skin can be preseeded with fibroblast!

8. Biodegradable: Drug Delivery
Most widely investigated application
PLA, PGA used frequently
Polyanhydrides for administering chemotherapeutic agents to patients suffering from brain cancer

9. Tissue Engineering Artificial extracellular matrix
Provide space for cells to grow and reorganize into functional tissue
Ideally:
Restore lost function
Maintain function
Enhance function
Forms:
Foam
Sponge
BUT pore connectivity is critical! (OPEN pores)
Pre-seeded with cells or not

10. Multifunctional Devices
Combination of several functions
mechanical function + drug delivery
biodegradable bone nails and screws made of ultrahigh-strength PLA and treated with BMP & TGF- for stimulation of bone growth

11. Biodegradable: Multifunctional Devices
mechanical support + drug delivery: biodegradable stents to prevent collapse and restenosis (reblocking) of arteries opened by balloon angioplasty and treated with anti-inflammatory or anti-thrombogenic agents
Biodegradable intravascular stent molded from a blend of polylactide and trimethylene carbonate. Photo: Cordis Corp. Prototype Molded by Tesco Associates, Inc.

12. Biodegradable Polymers
Variety of available degradable polymers is limited due to stringent requirements
biocompatibility
free from degradation related toxic products (e.g. monomers, stabilizers, polymerization initiators, emulsifiers)

13. FDA approved ones As of 1999: poly(lactic acid) poly(glycolic acid)
polydioxanone
polycaprolactone
poly(PCPP-SA anhydride)
degradable polymers have been approved for use in a narrow
range of clinical applications

15. Biodegradable Polymers

16. Chemistry of Biodegradable Polymers
Most degradable polymers are polyesters
ester is a covalent bond with polar nature, more reactive
can be broken down by hydrolysis
the C-O bond breaks
ESTER BOND

17. Chemistry of Biodegradable Polymers
Amide link
can be broken down by hydrolysis
the C-N bond breaks
can be spun into fibers for strength

18. What causes degradation?
solid structural polymer --> soluble stuff and goes away
Simple hydrolytic cleavage of backbone
Enzymatic cleavage (biodegradation)
not guaranteed same in each patient
Naturally derived materials have established degradation pathways

19. bioerosion changes in the appearance of the device,
in its physicomechanical properties
in physical processes such as swelling, deformation, or structural disintegration, weight loss, and the eventual depletion of drug or loss of function.
bioerosion of a solid device
chemical cleavage of the polymer backbone or the chemical cleavage of cross-links or side chains.
simple solubilization of the intact polymer (due to changes in pH, etc)

20. Degradation
• Cleavage of crosslinks
– Yield smaller soluble chains
• Cleavage of side chains/pendant grps
– Change polarity, charge, solubility
• Cleavage of the backbone
Chemical degradation mediated by water, enzymes, microorganisms

21. HOW DOES IT DEGRADE ? Bulk vs. surface • Rates vary according to :
– Time (seconds -months)
– In vitro, in vivo
– Anatomic location
– Human variability

22. Degradation throughout the whole sample!
Bulk erosion
Degradation throughout the whole sample!
water enters polymer (faster than degradation rate)
characteristic of hydrophilic polymers
causes hydrolytic degradation
component hollowed out
finally crumbles
releases acid groups (acid bursting)  possible inflammation
(PLA,PGA,PLGA, PCL)

23. degradation occurs on the surface water penetration limited !
Surface erosion
degradation occurs on the surface
water penetration limited !
hydrophobic polymers experience surface erosion since water intake limited
thinning of the component over time
integrity is maintained over longer time when compared to bulk erosion
surface erosion can also occur via enzymatic degradation
Differ from patient to patient, tisuue to tisuue
acidic byproducts are released gradually  acid burst less likely, lower chance of inflammation
(poly(ortho)esters and polyanhydrides)

24. Before factors…… Steps of erosion/degradation
water sorption
reduction of mechanical properties (modulus & strength)
reduction of molar mass
weight loss

25. Factors that determine rate of erosion
chemical stability of the polymer backbone
erosion rate: anhydride > ester > amide
hydrophobicity of the monomer
hydrophobic comonomers reduce
erosion rate
morphology of polymer
crystalline vs. amorphous
packing density
Polymer less permeable to water in glassy state: Tg of the polymer should be greater than 37 C to maintain resistance to hydrolysis under physiological conditions
Amorphous degrades faster

26. Factors that determine rate of erosion
initial molecular weight of the polymer
fabrication process
Porous, dense…
presence of catalysts, additives or plasticizers
geometry of the implanted device (surface/volume ratio)
defects

27. Biodegradable Polymers: Storage, Sterilization and Packaging
minimize premature polymer degradation during fabrication and storage
moisture can seriously degrade
controlled atmosphere facilities

28. Biodegradable Polymers: Storage, Sterilization and Packaging
-irradiation vs ethylene oxide
both methods degrade physical properties
choose lesser of two evils for a given polymer
-irradiation dose at 2-3 Mrad (standard level to reduce HIV) can induce significant backbone damage
ethylene oxide highly toxic
PLA, PGA
Need to degass for long period of time before use

29. Biodegradable Polymers: Storage, Sterilization and Packaging
Packed in airtight, aluminum-backed, plastic foil pouches.
Refrigeration may be necessary

30. Scaffolds incubated with viable cells…
No way to sterilize
Prepare under sterile conditions
No shelf life

31. Synthetic Degradable Polymers

32. Polydioxanone (PDS) Poly(ether-ester) Low modulus Tg: −10 - 0 °C
crystallinity of about 55%
Monofilment sutures
1st commercialized one
Suture clips
Bone pin
flexibility

33. Polyanhydrides Most hydrolytically unstable polymer !!!!
First proposed by Langer for use in drug delivery in 1993
Aliphatic ones degrade within days
Aromatic ones may take years
Fast surface erosion
Excellent in vivo compatability
Can react with amine containing drugs! But also biomolcules around the implant?!
Mostly used in drug delivery (microcapsule)
Gliadel was developed using the principles just outlined. Carmustine has a small effect on brain cancer patients when given systemically. The drug has limited passage through the blood brain barrier. It is relatively rapidly cleared, and its systemic toxicity (e.g., bone marrow suppression) limits dosing. CarmustineÕs mechanism of action is DNA and RNA alkylation. Once cellular DNA is alkylated, it cannot replicate, and the cell dies. Including carmustine in a PPCP-SA polymer allows the direct application of the Gliadel wafer to the surface of the tumor resection cavity. It has been demonstrated that most brain cancers recur within a 2-cm margin after resection and eventually lead to the death of the patient, not by distant metastasis, but by local growth, invasion, and compromise of brain function (3).

34. Gliadel® 1st commercial application: chemotherapy
Brain tumor treatment patch
Compression moulding of the spray-dried polyanhydride microspheres
Carmustine + Copolymer of 1,3-bis(p-carboxyphenoxy propane) (CPP) and sebacic acid (SA) (degrade in 6-8 wks)
Before implantation
1day after
5 day after
P(CPP-SA)
Carboxyphenoxypropane Sebacic acid
Excreted metabolized by
oxidative pathway (CO2)
Gliadel was developed using the principles just outlined. Carmustine has a small effect on brain cancer patients when given systemically. The drug has limited passage through the blood brain barrier. It is relatively rapidly cleared, and its systemic toxicity (e.g., bone marrow suppression) limits dosing. CarmustineÕs mechanism of action is DNA and RNA alkylation. Once cellular DNA is alkylated, it cannot replicate, and the cell dies. Including carmustine in a PPCP-SA polymer allows the direct application of the Gliadel wafer to the surface of the tumor resection cavity. It has been demonstrated that most brain cancers recur within a 2-cm margin after resection and eventually lead to the death of the patient, not by distant metastasis, but by local growth, invasion, and compromise of brain function (3).
D .S . Katti et al . / Advanced Drug Delivery Reviews
54 (2002) 933–961

36. Polyesters MOST WIDELY USED MATERIAL DEGRADATION BY HYDROLYSIS
BUT; ACID DEGRADATION PRODUCT

37. Biodegradable Polymers: Hydrolysis
Breakdown of a molecule in the presence of water
Hydrolysis of the ester bond results in formation of an acid and an alcohol
Inverse of reaction to hydrolysis is condensation (remember condensation polymerization)
Hydrolysis of ester
Hydrolysis of anhydride
hydrolysis
condensation

38. PLA and PGA POLYGLYCOLIC ACID Most studied and used ones!
More hydrophilic
highly crystalline
high melting point
low solubility
Degrades fast !!!!
Dexon ® sutures lose strength within 2-4 weeks sooner than desired
used as bone screws, Biofix®

39. Polylactic acid More hydrophobic Slower hydrolysis
D and L-PLA: differ in morphology!
L(+)-PLA: semicrystalline (natural) most common
mechanical applications (Good mechanical strength)
sutures or orthopaedic devices
D,L-PLA: Amorphous
Faster degradation rate
Drug delivery
Homogenous distribution of drug in matrix

40. PLA and PGA Tailor degradation rate and mechanical strength
Lactic acid decreases water uptake!
VICRYL® (1974) and Polyglactin 910® (90/10 PGA/PLA)
PANACRYL ® (3/97 PGA/PLA) (sutures)

42. Polymer Tm (°C) Tg Modulus Degr.Time
(°C) (Gpa)a (months)b
PGA 225—230 35— to 12
L-PLA 173—178 60— >24
DL-PLA Amorphous 55— to 16
85/15 DLPLG Amorp 50— to 6
75/25 DLPLG Amorph 50— to 5
65/35 DLPLG Amorph 45— to 4
50/50 DLPLG Amorph 45— to 2
a Tensile or flexural modulus.
b Time to complete mass loss. Rate also depends on part geometry.

43. Biodegradable Polymers

44. Acid degradation product
Issues
Acid degradation product
Relatively strong acids
Inflamation
Cells do not grow on PLA PGA that well
Limited use as tissue scaffolds
pKa : 3.83

45. Poly(caprolactone) semi-crystalline polymer
slower degradation than PLA
remains active as long as a year for drug delivery
Low Tm (60°C)
Low Tg (-60°C)
Rubbery at RT
Caprolactone is non-toxic
Wound dressing and controlled drug delivery

46. Polymer Tm (°C) Tg Modulus Degr.Time
(°C) (Gpa)a (months)b
PGA 225—230 35— to 12
L-PLA 173—178 60— >24
DL-PLA Amorphous 55— to 16
PCL 58— >24
PDO N/A -10— to 12
a Tensile or flexural modulus.
b Time to complete mass loss. Rate also depends on part geometry.

47. Capronor® implantable biodegradable contraceptive implanted under skin
the implant remains intact during the first year of use, thus could be removed if needed.
dissolve in the body and does not require removal
degradation of the poly(e-caprolactone) matrix occurs through bulk hydrolysis of ester linkages
autocatalyzed by the carboxylic acid end groups of the polymer, eventually forming carbon dioxide and water

49. Monocryl suture was developed as a shorter-term suture.
PGA/PCL (75/25) copolymer. It has been reported that the first block is a PCL/PGA (45/55) random copolymer while the end blocks are predominantly composed of PGA
Biosyn suture introduced in 1995
glycolide, TMC, and p-dioxanone in a 60/23/17 weight ratio
PTMC/PDO (65/35 w/w) copolymer while the end blocks are
random PGA/PDO (92/8 w/w) copolymers
Caprosyn, introduced in late 2002
glycolide, ε-caprolactone, l-lactide, and TMC
in a 68/17/7/7 weight ratio
Caprosyn loses all strength by 3 weeks and is absorbed by the body in 56 days, making it the fastest-absorbing synthetic monofilament.

51. Poly alkanoates
polyesters synthesized and used by microorganisms for intracellular energy and C storage
rate of degradation controlled by varying copolymer composition but all takes SEVERAL YEARS to be completely resorbed!
used in controlled drug release, suturing, artificial skin, and paramedical disposables

52. Poly alkanoates: Poly(4-hydroxybutyrate) PHB
crystalline/brittle
Slow degradation
Retains 80% of strength after 500days of implantation
in vivo degradation product :hydroxybutyric acid
normal constituent of human blood  biocompatible, nontoxic

53. Poly alkanoates: PHV, p(hydroxyvalerate)
PHV/PHB: more flexible, less crystalline, more processable
Biopol®: 70% PHB-30% PHV copolymer
Internal suture
• Heart valve- Mayer, Vacanti

54. polyorthoesters
formulated so that degradation occurs by surface erosion
drug release at a constant rate

55. polyaminoacids poly-L-lysine, polyglutamic acid
aminoacid side-chains offer sites for drug attachment
low-level systemic toxicity owing to their similarity to naturally occurring amino acids
investigated as suture materials
artificial skin subtitutes

56. polyaminoacids limited applicability as biomaterials!
limited solubility and processibility
difficult to predict drug release rate due to swelling
polymers containing more than three or more amino acids may trigger antigenic response
“pseudo”- polyaminoacids
backbone of polyaminoacids altered
tyrosine derived polycarbonates developed as high-strength degradable orthopaedic implants

57. Biodegradable Polymers
polycyanocrylates
used as bioadhesives (IIWW)
Dental adhesive (butyl derivative)
Drug delivery (newer!)
use as implantable material is limited due to significant inflammatory response (formaldehyde)
Very reactive monomer!
Superglue!

58. Biodegradable Polymers
polyphosphazenes
inorganic polymer
backbone consists of nitrogen-phosphorus bonds
High thermal properties
use for drug delivery under investigation