BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 Lecture 1: Molecular Design and Synthesis of Biomaterials I: Biodegradable Solid Polymeric Materials Today: course overview and administrative details Intro to concepts covered Chemistry and physical chemistry of biodegradable polymeric solids Hand-outs: course syllabus Course administrative details Reading: “Third-Generation Biomedical Materials,” L.L. Hench and J.M. Polak, Science 295, 1014 (2002) Ratner, 64-72 Ratner 243-259 Supplementary Reading: Young and Lovell, ‘Introduction to Polymers,’ Ch.4 Polymer Structure Course Overview Definition of Biomaterials for this course: Materials designed for application to problems in biological engineering or biotechnology. This includes materials comprised of purely ‘synthetic’ or ‘natural’/’biological’ components, but will focus primarily on hybrid materials that make are composed of both. -not ‘off the shelf’ -our objective is to cover the chemistry and physics of these materials How can biomaterials solve problems in Biological Engineering? 1. Model systems for studying biology a. Both in vitro and in vivo models (SLIDE) (Lauffenburger/Griffith labs 1 :) Lecture 1 – Introduction BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 2. Therapeutic devices (SLIDE) a. Drug delivery 1. small molecules, peptides, and proteins, and DNA (gene therapy) b. tissue engineering/regenerative medicine (Mooney 2 ) 3. Analytical devices a. Biosensors 1. glucose sensors 2. toxin detection b. …or something in between (1), (2), and (3): (SLIDE) (Prof. Giffith’s lab 3 ) Overview of topics and viewpoint (syllabus summary) (SLIDE) 1. Biodegradable polymeric solids 2. Controlled release from solid polymers 3. hydrogels 4. bioceramics and biocomposites 5. hybrid biological/synthetic molecules 6. stimuli-responsive biomaterials -we’ll try to remain complementary to other biomaterials courses: 2.79J/3.96J/BE.441J Biomaterials-Tissue Interactions BE.342 Molecular Structure of Biological Materials Lecture 1 – Introduction BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 Course administration ? 2 dates when there is no class – out of town ? Course grading o Weekly problem sets o 3 1-hour exams o term projects ? website ? office hours ? discuss term projects Materials that can be used in vivo Basic considerations ? Many applications require to materials to function inside the body: (SLIDE) o Mechanical implants null Artificial hips, artificial hearts, pacemakers, etc. o Drug delivery null Injected or implanted devices o Tissue engineering null Delivery of cells null In vivo tissue engineering: materials that guide invading cells into proper position and function o Biosensors null In situ measurements of pH, molecule concentrations, etc. If a device is to be applied in vivo, what characteristics must it have in addition to fulfilling the device requirements? -non-toxic (acute or chronic), non-carcinogenic, non-mutagenic, and non-allergenic ? Toxicity of synthetic materials ? Few generalities can be made, typically determined by empirical studies ? Cost and time involved in developing new biomaterials extremely high null Industry and clinicians further motivated by fear of malpractice cases ? E.g., the case of silicone breast implants ? A very small number of FDA-approved materials has been intensively studied due to this hurdle -biodegradable, bioeliminible, or removable null biodegradable: breaks down into metabolic products (most attractive) - mechanisms? o Hydrolysis o Enzymatic action null bioeliminible: dissolves into low molecular weight compounds that can be excreted by natural pathways null removable: a retrieveable implant (least attractive) o FDA APPROVAL… Lecture 1 – Introduction BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 Examples: Biodegradable Bioeliminible Removable Poly(lactide-co-glycolide) [PLGA] poly(ethylene glycol) 4 < 10KD CH 3 O CH 3 O O O -(CH-C-O-CH-C-O-) x -(CH 2 -C-O-CH 2 -C-O) y - -(CH 2 -CH 2 -O) n poly(ethylene-co-vinyl acetate) Polypeptides dextran metal/semiconductor devices Extracellular environment O H O H O H O + H 3 N-CH-C-N-CH-C-N-CH-C-N-CH-C-O - Surface oxide layer R 1 R 2 R 3 R 4 Metal/semiconductor lattice Characteristics of materials from each category: Hydrophilic or hydrophobic hydrophilic (water soluble) hydrophobic/insoluble Chemically unstable in water chemically stable in water chemically stable in water Biodegradable Solid Polymeric Materials Our definition: Biodegradable = solid polymer reduced to soluble fragments that are either excretable or metabolized under physiological conditions (saline environement, pH 7.4, 37°C) Why biodegradable? ? Generally desirability of one-time surgeries where a device does not need to be retrieved after living out its useful lifetime 1. Temporary needs a. E.g. fill and support bone defect until natural bone grows back (TE) b. Provide drug delivery until a condition is corrected 2. Avoid chronic inflammation and long-term complications e.g. loosening in artificial hip 3. Limited alternatives in eliminable materials devices poly(ethylene glycol) dextran First use of biodegradable sutures: 1962 PGA Produced by American Cyanamid Co. under name Dexon TM Vicryl introduced in 1966 (PLGA) Arch. Surg. 93, 839 (1966) Lecture 1 – Introduction BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 Chemistry of biodegradable solid polymers Pathways of solid polymer erosion (SLIDE) Used for biodegradable I hydrogels II Main mechanism exploited in solid III polymers (Ratner, Biomaterials Science) Example Materials- Common hydrolytically unstable linkages: Mechanism I: Crosslinked polyanhydrides 5-7 : Lecture 1 – Introduction BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 Mechanism II: o Poly(methyl vinyl ether-co-maleic anhydride) -> carboxyl group generation 8 ionizes to 2 carboxyl groups o Poly(alkyl cyanoacrylates) C≡N C≡N -(CH 2 -C-) n - H 2 O -(CH 2 -C-) n - C=O C=O O O - R Mechanism III: o poly(α-hydroxy, β-hydroxy esters) ? acid or base catalyzed CH 3 O CH 3 O O O H 2 O CH 3 O O -(CH-C-O-CH-C-O-) x -(CH 2 -C-O-CH 2 -C-O) y - HO-CH-C-OH + HO-CH 2 -C-OH Kreb?s cycle CO 2 + H 2 O o polyamides ? e.g. polypeptide hydrolysis O H O H O H O enzymes O H O O H O + H 3 N-CH-C-N-CH-C-N-CH-C-N-CH-C-O - + H 3 N-CH-C-N-CH-C-O - + + H 3 N-CH-C-N-CH-C-O - R 1 R 2 R 3 R 4 R 1 R 2 R 3 R 4 o polyanhydrides H 2 O =O O = = O O = -C-O-H H-O-C- -C-O-C _ _ _ _ _ _ _ Lecture 1 – Introduction BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 o poly(ortho esters) (SKIP?) H 2 O R? n O O R? O + O O O R? O R HO HO OH OH R? O R Medically-applied polymers are chosen for metabolizable or excretable final degradation products: PLGA: CH 3 O CH 3 O O O H 2 O CH 3 O O -(CH-C-O-CH-C-O-) x -(CH 2 -C-O-CH 2 -C-O) y - HO-CH-C-OH + HO-CH 2 -C-OH Kreb?s cycle CO 2 + H 2 O Kreb’s cycle = citric acid cycle (conversion of pyruvate from glycolytic cycle into energy) (D.H. Lewis in “Biodegradable polymers as drug delivery systems,” 1990 p. 1-41 M. Chasin, ed.) PCL: O H 2 O O Citric acid cycle -((CH 2 ) 5 -C-O-) n - HO-((CH 2 ) 5 -C-OH CO 2 + H 2 O 6-hydroxycaproic acid poly(hydroxybutyrate): O H 2 O O -(-C-O-CH(CH 3 )-CH 2 -) n - HO-CH(CH 3 )-CH 2 -C-OH D-3-hydroxybutyrate (normal blood constituent) Holmes, Phys. Technol. 16, 32 (1985) ? What doesn’t work? o e.g. poly(ethylene terephthalate) (PET) – used for soda bottles null breaks down to aromatic oligomers which form deposits in body null therefore more than just a hydrolysis-susceptible bond is needed! = = = = Lecture 1 – Introduction BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 Mechanisms of Hydrolysis One example, for polyesters: 9 Acid-catalyzed hydrolysis: Base-catalyzed hydrolysis (saponification): Example Structures, Properties, and Applications: (solid polymers, not water soluble) (SLIDE) Polymer (class) Structure Current Applications Polylactide: (polyester) Poly(L-lactide) [PLLA] Poly(D,L-lactide) [PDLLA] ? Monomer can be obtained from fermentation of corn ? First investigated by Carothers (DuPont) in 30s 10 CH 3 O CH 3 O -(CH-C-O-CH-C-O-) n ? Resorbable sutures ? bone fixtures ? tissue engineering scaffolds for bone 11 , liver, nerve ? PDLLA – Atrix laboratories in situ precipitation for scaffolds ? Drug delivery (various) Lecture 1 – Introduction BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 Poly(lactide-co-glycolide) (polyester) CH 3 O CH 3 O O O -(CH-C-O-CH-C-O-) x -(CH 2 -C-O-CH 2 -C-O) y - ? Controlled release devices (protein and small molecule drugs) 12 ? Tissue engineering scaffolds ? Drug delivery (various) ? Gene delivery Poly(ε-caprolactone) [PCL] (polyester) ? Slow controlled release devices – drug delivery (e.g. > 1 year) Polyanhydrides ? First synthesized in 1909 ? Orthopaedic reconstruction 5 ? Drug delivery Poly(β-hydroxy butyrate) (polyester) ? Lemoigne (1920) discovered production of polyester by Bacillus Megaterium (bacteria) 13 ? Ocular drug delivery 14,15 Poly(ortho esters) ? Ocular drug delivery 16 ? Periodontal antibiotic delivery and guided tissue regeneration 16 ? Bone tissue regeneration 16 Polyphosphazenes ? Insulin delivery 17 ? New tissue engineering scaffolds (current research) Polycarbonates ? ADD polycarbonates? PPF? Refs: Biomat. 8, 311 (1987); Biomat 8,70 (1987); Biomat 8,289 (1987); J Contr Rel 2,167 (1985); Prog. Polym. Sci. 14, 679 (1989); J. Bioact. Compat. Polym. 6(1) 64 (1991); Polymer 34, 942(1993) Lecture 1 – Introduction BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 Lecture 1 – Introduction (Ratner, Biomaterials Science) *Semicrystalline materials highlighted Physical chemistry of hydrolysis Mechanisms of Dissolution ? two modes of erosion: surface and bulk surface erosion – degradation from exterior only with little/no water penetration into bulk bulk erosion – water penetrates entire structure and degrades entire device simultaneously BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 o Polymers hydrolyzing by mechanisms II or III can be either surface or bulk eroding. (SLIDE) Bulk Erosion Surface Erosion Scanning electron micrographs of PLA and PLGA polymer samples undergoing bulk or surface erosion by altering degradation conditions 18-20 Lecture 1 – Introduction BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 ? typical weight loss profiles for these modes (SLIDE) Bulk (normal erosion at pH 7.4): Surface (pH > 12): SEM shown previously (Fig. 13) confirms transition to surface mode o common polyesters composed of lactide and glycolide only soluble for oligomers Mn ≤ 1100 g/mole 21 ? schematic illustration ? networks show retarded breakdown compared to linear polymers: need to break more bonds to create free water- soluble oligomers Molecular structure effects on hydrolytic breakdown -hydrolysis requires water to access the bonds: so structure has a strong effect on hydrolysis rates -factors influencing hydrolysis rate: SUMMARY: 1. relative bond stability 2. hydrophobicity 3. steric effects 4. production of autocatalytic products 5. microstructure (phase separation) Lecture 1 – Introduction BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 1. relative bond stability representative examples: bond half-lives at physiological pH/temperature: ? intrinsic stability of polyamide bond: o polypeptides and proteins are degradable due to action of enzymes o …whereas nylon isn’t a biodegradable polymer (SLIDE) polyesters poly(ortho esters) reasonable hydrolytic stability low hydrolytic stability THIS DOESN’T MAKE THE POINT Lecture 1 – Introduction BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 2. Hydrophobicity a) Degradation rate decreases with increasing hydrophobicity Polyesters: cleavage rate of PCL < PDLLA < PLGA poly(anhydrides) of varying hydrophobicity 5 : effect of PLGA composition (varied hydrophobicity): Biomaterials 16, 1123 (1995) b) as we will see later, hydrogels containing polyester segments degrade much more rapidly than their solid polymer counterparts (water intimately in contact with structure) 3. Steric effects null Local structure ? Bulky substituents o PLA degrades more slowly than PGA due to bulky methyl group blocking water access SHOW SPACE-FILLING MODEL TO MAKE POINT? null Glass transition (Tg) ? Rubbery polymers above Tg have more chain mobility; easier for water to penetrate the solid null Crystallinity ? Stereoisomers: Lactide has 3 stereoisomers: Lecture 1 – Introduction BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 o Pure poly(D-lactide) or poly(L-lactide) are semicrystalline o Copolymers of D- and L-monomer or meso-lactide are amorphous, but have similar Tg to isotactic polymers ? (SLIDE) Fibers of PLLA can be highly crystalline with sharp WAXS patterns 22 : crystal structure: NEED PDLLA VS. PLLA Lecture 1 – Introduction BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 amorphous regions degrade faster, causing total crystallinity remaining in solids to increase 23 : (SLIDE) 4. Production of autocatalytic products b) polyesters produce acid chain ends on breakdown and auto-catalyze acidic breakdown i. pH as low as 1.8 has been measured inside PLA structures immersed in pH 7.4 buffer c) polyanhydrides, producing 2 acid chain ends autocatalyze even more rapidly and also show dramatic pH drops in their environment d) self-destroying polymers constituent of polymer chain attacks backbone: hydrolyzing side group attacks backbone: e.g. polyphosphazenes: Lecture 1 – Introduction BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 constitutive attack: e.g. Lim et al. 24,25 : primary amine side chains attack backbone) Cbz structure: MECHANISM? rapid degradation in water: (SLIDE) pH change as polymer breaks down: d) catalytic degradation products cannot be removed from the interior of the solid until a percolation threshold is reached Lecture 1 – Introduction BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 Lecture 1 – Introduction 5. Phase separation in Composite materials and blends a. Formation of blends and phase separation has dramatic effects on mechanical, electrical, optical, magnetic properties of solids; we’ll focus here on the effect on degradation b. Effect of blending with a hydrophilic polymer: case study of adding poly(ethylene glycol) to poly(L- lactide) 26,27 : i. PLLA and PEG both semicrystalline ii. Polymers are miscible in the amorphous phase, but crystallization forces phase separation: (SLIDE) Amorphous state - miscible Incompatible crystal lattices HH O H H O If PEO amount is low enough to avoid much crystallization, water absorption is elevated in amorphous regions and degradation can be speeded up significantly: (SLIDE) peak in water sorption shifts left as blend becomes more hydrophilic and water uptake kinetics are speeded up (PLLA MW = 800K g/mol, PEO MW = 20K g/mol) BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 Addition of large amounts of PEG allows the hydrophilic component to crystallize as well: comparison of blend degradation with a triblock copolymer of PLLA-PEG-PLLA: PLLA (40K)-PEG (20K)-PLLA (40K) (SLIDE) Constrained mass loss: triblock copolymers Network polymers degrade more slowly: break down to soluble fragments requires multiple bond cleavages controlling degradation behavior of solids for devices by choosing the right chemical structure: Lecture 1 – Introduction BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 References 1. 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