Biodegradable Polymers: Chemistry, Degradation and Applications

Transcription

1 Biodegradable Polymers: Chemistry, Degradation and Applications 1

2 Definition A biodegradable product has the ability to break down, safely, reliably, and relatively quickly, by biological means, into raw materials of nature and disappear into nature. Nature s way: every resource made by nature returns to nature. 2

3 How long does it take? Cotton rags Paper Rope Orange peels Wool socks Cigarette butts Plastic coated paper milk cartons Plastic bags Nylon fabric Aluminum cans Plastic 6-pack holder rings Glass bottles Plastic bottles 1-5 months 2-5 months 3-14 months 6 months 1 to 5 years 1 to 12 years 5 years 10 to 20 years 30 to 40 years 80 to 100 years 450 years 1 million years May be never

4 What is Polymer Degradation? polymers were synthesized from glycolic acid in 1920s At that time, polymer degradation was viewed negatively as a process where properties and performance deteriorated with time.

5 Medical Applications of Biodegradable Polymers Wound management Sutures Staples Clips Adhesives Surgical meshes Orthopedic devices Pins Rods Screws Tacks Ligaments Dental applications Guided tissue regeneration Membrane Void filler following tooth extraction Cardiovascular applications Stents Intestinal applications Anastomosis rings Drug delivery system Tissue engineering

6 Why We Use Biodegradable Materials? 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 6

7 Biodegradable Materials Degradation Short term applications sutures drug delivery 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) 7

8 Biodegradable Materials Four main types of degradable implants: the temporary scaffold the temporary barrier the drug delivery device multifunctional devices 8

9 Biodegradable: Scaffold provides support until the tissue heals weakened by disease, injury or surgery healing wound, broken bone, damaged blood vessel sutures, bone fixation devices, vascular grafts Rate of degradation: implant should degrade at the rate the tissue heals Sutures are most widely used polyglycolic acid (PGA) - Dexon copolymers of PGA and PLA (polylactic acid), Vicryl polydioxanone (PDS) 9

10 Biodegradable: Barrier Prevent adhesion caused by clotting of blood in the extravascular tissue space clotting inflammation fibrosis adhesions are common 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 10

11 Biodegradable: Drug Delivery Most widely investigated application PLA, PGA used frequently Polyanhydrides for administering chemotherapeutic agents to patients suffering from brain cancer 11

12 Biodegradable: Multifunctional Devices Combination of several functions mechanical support + drug delivery: biodegradable stents to prevent collapse and restenosis (reblocking) of arteries opened by balloon angioplasty and treated with antiinflammatory or antithrombogenic agents Biodegradable intravascular stent molded from a blend of polylactide and trimethylene carbonate. Photo: Cordis Corp. Prototype Molded by Tesco Associates, Inc. 12

13 Biodegradable: Terminology Confusion between biodegradation, bioerosion, bioabsorption and bioresorption! Consensus Conference of the European Society for Biomaterials: Biodegradation: A biological agent (an enzyme, microbe or cell) responsible for degradation Bioerosion: Bioerosion contains both physical (such as dissolution) and chemical processes (such as backbone cleavage). A water-insoluble polymer that turns watersoluble under physiological conditions. Bioresorption, Bioabsorption: Polymer or its degradation products removed by cellular activity (e.g. phagocytosis) 13

14 Biodegradable Polymers: Bioerosion Bioerosion cause: changes in the appearance of the device changes in the physicomechanical properties swelling deformation structural disintegration weight loss loss of function 14

15 Biodegradable Polymers: Bioerosion Bioerosion is due to chemical degradation cleavage of backbone cleavage of crosslinks side chains physical processes (e.g. changes in ph) Two types of erosion bulk erosion surface erosion 15

16 Biodegradable Polymers: Bioerosion bulk erosion (homogeneous) uniform degradation throughout polymer H 2 O H 2 O water enters polymer causes hydrolytic degradation component hollowed out finally crumbles (like sugar cube in water) releases acid groups (possible inflammation) characteristic of hydrophilic polymers 16

17 Biodegradable Polymers: Bioerosion surface erosion (heterogeneous) polymer degrades only at polymer-water interface water penetration limited degradation occurs on the surface thinning of the component over time integrity is maintained over longer time when compared to bulk erosion hydrophobic polymers experience surface erosion since water intake limited acidic byproducts are released gradually acid burst less likely, lower chance of inflammation surface erosion can also occur via enzymatic degradation H 2 O H 2 O 17

18 Polymer Degradation by Erosion 18

19 Erodible Matrices or Micro/Nanospheres (a) Bulk-eroding system (b) Surface-eroding system

20 Degradation Schemes Surface erosion (poly(ortho)esters and polyanhydrides) Sample is eroded from the surface Mass loss is faster than the ingress of water into the bulk Bulk degradation (PLA,PGA,PLGA, PCL) Degradation takes place throughout the whole of the sample Ingress of water is faster than the rate of degradation

21 Biodegradable Polymers: Bioerosion Factors that determine rate of erosion: 1. chemical stability of the polymer backbone (erosion rate: anhydride > ester > amide parallel to the activity of functional group!!) 2. hydrophobicity of the monomer (addition of hydrophobic comonomers reduce erosion rate) 3. morphology of polymer crystalline vs. amorphous: crystallinity packing density water penetration erosion rate 21

22 Biodegradable Polymers: Bioerosion Factors that determine rate of erosion (cont.): 4. initial molecular weight of the polymer 5. fabrication process 6. presence of catalysts, additives or plasticizers 7. geometry of the implanted device (surface/volume ratio) 8. Annealing: Polymer less permeable to water in glassy state: T g of the polymer should be greater than 37 C to maintain resistance to hydrolysis under physiological conditions 22

23 Biodegradable Polymers: Bioerosion Factors that determine rate of erosion (cont.): 9. Method of Sterilization 10. Storage History 11. Site of Implantation 12. Absorbed Compounds 13. Mechanism of Hydrolysis (enzymes vs water) 23

24 Biodegradable Polymers: Chemical Degradation Chemical degradation mediated by water, enzymes, microorganisms Mechanisms of chemical degradation cleavage of crosslinks between chains cleavage of side chains cleavage of polymer backbone combination of above 24

25 Biodegradable Polymers: Chemical Degradation CLEAVAGE OF CROSSLINKS TRANSFORMATION OF SIDE CHAINS CLEAVAGE OF BACKBONE 25

26 Biodegradable Polymers: Storage, Sterilization and Packaging minimize premature polymer degradation during fabrication and storage moisture can seriously degrade, controlled atmosphere facilities sterilization γ-irradiation or ethylene oxide both methods degrade physical properties choose lesser of two evils for a given polymer γ-irradiation dose at 2-3 Mrad (standard level to reduce HIV) can induce significant backbone damage ethylene oxide highly toxic 26

27 Biodegradable Polymers: Storage, Sterilization and Packaging Packed in airtight, aluminum-backed, plastic foil pouches. Refrigeration may be necessary 27

28 Enzymatic Degradation Natural polymers degrade primarily via enzyme action collagen by collagenases, lysozyme glycosaminoglycans by hyaluronidase, lysozyme There is also evidence that degradation of synthetic polymers is due to or enhanced by enzymes. poly(ε-caprolactone) elastomers 80.0 % weight loss in vitro in vivo C.G. Pitt et al., J. Control. Rel. 1(1984) time (weeks) 28

29 Methods of Studying Polymer Degradation Morphological changes (swelling, deformation, bubbling, disappearance ) Weight lose Thermal behavior changes Differential Scanning Calorimetry (DSC) Molecular weight changes Dilute solution viscosity Size exclusion chromatograpgy(sec) Gel permeation chromatography(gpc) Change in chemistry Infared spectroscopy (IR) Nuclear Magnetic Resonance Spectroscopy (NMR) 29

30 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) Few approved by FDA PLA, PGA, PDS used routinely 30

31 Biodegradable Polymers 31

32 Biodegradable Polymers 32

33 Biodegradable Polymers Effect of molecular weight on the mechanical strength???? 33

34 Biodegradable Polymers Carbonyl bond to A. O N S O R 1 C X H 2 O R 2 R 1 C OH O + HX R 2 Where X= O, N, S O O O R 1 C O R 2 R 1 C NH R 2 R 1 C S R 2 Ester Amide Thioester

35 Biodegradable Polymers B. O O H 2 O R 1 X C X' R 1 X C OH + HX' R 2 R 2 Where X and X = O, N O O O R 1 O C O R 1 NH C O NH C NH R 2 Carbonate Urethane Urea R 2 R 1 R 2 O C. R 1 C X O C O R 2 H 2 O R 1 C OH + HX O C R 2 Where X and X = O, N O O O O R 1 C NH C R 2 R 1 C O C R 2 Imide Anhydride

36 Biodegradable Polymers H O Acetal: H 2 O R O C O R' R OH + C + H H H R' OH OH OH Hemiacetal: C C OH OH C O C OH C H 2 O C C OH OH C OH C C==O + H 2 O OH OH H Ether H H R C O C R' H H H 2 O H R C OH H + H R' C OH H

37 Biodegradable Polymers Nitrile H R C R C N O H 2 H R C R C O H 2 N O H 2 H R C R C O HO Phosphonate O RO P OR' OR'' H 2 O O R OH + H O P OH + HO OR'' R' Polycyanocrylate H CN H CN R C C C C R' H C H O C O H 2 O H CN H R C C C H C H O + CN OH C R' C O OR'' OR''' OR'' OR'''

38 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 38

39 Biodegradable Polymers contain a peptide (or amide) link can be broken down by hydrolysis the C-N bond breaks can be spun into fibres for strength AMIDE BOND 39

40 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 condensation is hydrolysis (remember condensation polymerization) Preparation of ester Preparation of anhydride 40

41 Biodegradable Polymers PGA and PLA most widely used biodegradable polymers PGA is the simplest aliphatic polyester highly crystalline, high melting point, low solubility appeared with the trade name Dexon Dexon sutures lose strength within 2-4 weeks sooner than desired used as bone screws, Biofix 41

42 Biodegradable Polymers PLA D,L-PLA amorphous polymer; thus, used for drug delivery L-PLA semicrystalline; thus, mechanical applications such as sutures or orthopaedic devices compare mechanical properties of D,L-PLA and L- PLA in the Table in slide # 33 42

43 Biodegradable Polymers PGA and PLA (cont.) PLA is more hydrophobic than PGA hydrophobicity of PLA limits water uptake of thin films to about 2% and reduces the rate of hydrolysis compared with PGA sutures with trade names Vicryl and Polyglactin

44 Biodegradable Polymers PGA and PLA (cont.) copolymers of PGA and PLA used to adapt material properties suitable for wider range of applications 44

45 Biodegradable Polymers polyhydroxybutyrate (PHB), polyhydroxyvalerate (PHV) and copolymers polyesters synthesized and used by microorganisms for intracellular energy storage 70% PHB-30% PHV copolymer commercially available as Biopol rate of degradation controlled by varying copolymer composition 45

46 Biodegradable Polymers polyhydroxybutyrate (PHB), polyhydroxyvalerate (PHV) and copolymers (cont) in vivo PHB degrades to hydroxybutyric acid which is a normal constituent of human blood biocompatible, nontoxic PHB homopolymer is highly crystalline and brittle copolymer of PHB with hydroxyvaleric acid is less crystalline, more flexible and more processible used in controlled drug release, suturing, artificial skin, and paramedical disposables 46

47 Biodegradable Polymers polycaprolactone semi-crystalline polymer slower degradation rate than PLA remains active as long as a year for drug delivery Capronor, implantable biodegradable contraceptive implanted under skin dissolve in the body and does not require removal degradation of the poly(epsilon-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 47

48 Biodegradable Polymers Polyesters 48

49 Biodegradable Polymers Capronor, implantable biodegradable contraceptive (cont.) Capronor II consists of 2 rods of poly(ecaprolactone) each containing 18 mg of levonorgestrel Capronor III is a single capsule of copolymer (caprolactone and trimethylenecarbonate) filled with 32 mg of levonorgestrel the implant remains intact during the first year of use, thus could be removed if needed. Over the second year, it biodegrades to carbon dioxide and water, which are absorbed by the body 49

50 Biodegradable Polymers polyanhydrides highly reactive and hydrolytically unstable degrade by surface degradation without the need for catalysts aliphatic (CH 2 in backbone and side chains) polyanhydrides degrade within days aromatic (benzene ring as the side chain) polyanhydrides degrade over several years 50

51 Biodegradable Polymers o ester bond o o c = anhydride 51

52 Biodegradable Polymers polyanhydrides (cont.) aliphatic-aromatic copolymers can be used to tailor degradation rate excellent biocompatibility used in drug delivery drug loaded devices prepared by compression molding or microencapsulation insulin, bovine growth factors, angiogenesis inhibitors, enzymes 52

53 Biodegradable Polymers polyorthoesters formulated so that degradation occurs by surface erosion drug release at a constant rate 53

54 Polyesters 54

55 Biodegradable Polymers 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 55

56 56

57 Biodegradable Polymers polycyanocrylates used as bioadhesives use as implantable material is limited due to significant inflammatory response polyphosphazenes inorganic polymer backbone consists of nitrogen-phosphorus bonds use for drug delivery under investigation 57