BEH.462/3. 962J Molecular Principles of Biomaterials Spring 2003 Lecture 1: Molecular Design and Synthesis of Biomaterials 1: 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 Readin Third-Generation Biomedical Materials. "LL 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? model systems for studying biology a. Both in vitro and in vivo models(SLIDE) (Lauffenburger/Griffith labs: clustered 来必 Fig 1 Schematic illustration of star polymer as a tether to presemt in which homogeneous to highly clustered (left to nght), can be independently Lecture 1-Introduction
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 labs1 :) Lecture 1 – Introduction
BEH.462/3. 962J Molecular Principles of Biomaterials Spring 2003 2. Therapeutic devices (SLIDE) rug delivery 1. small molecules, peptides, and proteins, and dNa (gene therapy) b. tissue engineering/regenerative medicine Porous matrix VEGF Time(days) 3. Analy 1. glucose sensors 2. toxin detection or something in between (1),(2), and (3): (SLIDE) Cells organized into tissue-like structures Culture ilter control一■■■ 3 mm Perfusion through "tissue Fig. 2. A microfabricated bioreactor for perfus ngi- nels. (C)Hepatocytes seeded onto the scaffold of the eered in vitro(54, 55).(A) growing attached to he inside walls of the 3D structures that are reminiscent of liver cords Bile ulture medium flows across the top of the scaffold nctions can be seen with high-power microscopy(54, 55). Live cells are 0. 2-mm-thick silicon-chip scaffold etched with 03-mm-diameter chan- the bioreactor channels [Illustration: Preston Morrighanl (Prof. Giffith's lab) Overview of topics and viewpoint (syllabus summary )(SLIDE) 1. Biodegradable polymeric solids 2. Controlled release from solid polymers 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 2. Therapeutic devices (SLIDE) a. Drug delivery 1. small molecules, peptides, and proteins, and DNA (gene therapy) b. tissue engineering/regenerative medicine (Mooney2 ) 3. Analytical devices a. Biosensors 1. glucose sensors 2. toxin detection b. …or something in between (1), (2), and (3): (SLIDE) (Prof. Giffith’s lab3 ) 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 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 Artificial hips, artificial hearts, pacemakers, etc. Injected or implanted devices o Tissue engineering Delivery of cells In vivo tissue engineering: materials that guide invading cells into proper position and function o Biosensors 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-allergen Toxicity of synthetic materials Few generalities can be made, typically determined by empirical studies Cost and time involved in developing new biomaterials extremely high 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 biodegradable: breaks down into metabolic products(most attractive )-mechanisms? o Hydrolysis o Enzymatic action bioeliminible: dissolves into low molecular weight compounds that can be excreted by natural pathways removable: a retrieveable implant (least attractive) o FDA APPROVAL 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 Artificial hips, artificial hearts, pacemakers, etc. o Drug delivery Injected or implanted devices o Tissue engineering Delivery of cells In vivo tissue engineering: materials that guide invading cells into proper position and function o Biosensors 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 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 biodegradable: breaks down into metabolic products (most attractive) - mechanisms? o Hydrolysis o Enzymatic action bioeliminible: dissolves into low molecular weight compounds that can be excreted by natural pathways removable: a retrieveable implant (least attractive) o FDA APPROVAL… Lecture 1 – Introduction
BEH.462/3. 962J Molecular Principles of Biomaterials Spring 2003 Biodegradable le Bioeliminible Removable Poly(lactide-co-glycolide)[PLGA] poly(ethylene glycol)< 10KD poly(ethylene-co-vinyl acetate) 8。88o):cH8oc8oy -CH2 CH2 CH2 CH)CH -(CH2-CH2 -O) Polypeptides extran metal/semiconductor devices Extrace lular environm 早?早O N-CH-C-N-CH-C-o 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, 37C) Why biodegradable? Generally desirability of one-time surgeries where a device does not need to be retrieved after living out its useful lifetime 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) First use of biodegradable sutures: 1962 PGA Produced by American Cyanamid Co under name Dexon Vicryl introduced in 1966(PLGA) Arch.Surg.93.839(1966) 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 CH3 O CH3O O O -(CH-C-O-CH-C-O-) x-(CH2-C-O-CH2-C-O)y- -(CH2-CH2-O)npoly(ethylene-co-vinyl acetate) Polypeptides dextran metal/semiconductor devices Extracellular environment O H O H O H O + H3N-CH-C-N-CH-C-N-CH-C-N-CH-C-O- Surface oxide layer R1 R2 R3 R4 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 DexonTM 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) I5 BIOaF SORRARTE AND BEOFRDDO L MATIHIALY Used fo biodegradable hydrogels Main mechanism exploited in solid (Ratner, Biomaterials Science) Example Materials- Common hydrolytically unstable linkages Mechanism Crosslinked polyanhydrides buffer solution ∞ 人+ p=3 MCPP P=6 MCPH 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 polyanhydrides5-7: Lecture 1 – Introduction
BEH.462/3. 962J Molecular Principles of Biomaterials Spring 2003 mechanism lI: o Poly(methyl vinyl ether-co-maleic anhydride)-> carboxyl group generation CH2 CH ionizes to 2 carboxyl groups o Poly(alkyl cyanoacrylates) -(CH2C-) MechanismⅢ o poly(a-hydroxy, B-hydroxy esters) acid or base catalyzed R CHaR -(CH-C-O-CH-C-0-x(CH2-C-O-CH2-C-O)y OH+ HO-CH-C-OH KrebS cycle e.g. polypeptide hydrolysis t +H N-CH-C-N-CH-C-O polyanhydrides -C-O-C C-O-H H-0-C 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 generation8 ionizes to 2 carboxyl groups o Poly(alkyl cyanoacrylates) C≡N C≡N -(CH2-C-)n- H2O -(CH2-C-)n- C=O C=O O OR Mechanism III: o poly(α-hydroxy, β-hydroxy esters) • acid or base catalyzed CH3 O CH3O O O H2O CH3 O O -(CH-C-O-CH-C-O-)x-(CH2-C-O-CH2-C-O)y- HO-CH-C-OH + HO-CH2-C-OH KrebÕs cycle CO2 + H2O o polyamides • e.g. polypeptide hydrolysis O H O H O H O enzymes O H O O H O + H3N-CH-C-N-CH-C-N-CH-C-N-CH-C-O- + H3N-CH-C-N-CH-C-O- + + H3N-CH-C-N-CH-C-OR1 R2 R3 R4 R1 R2 R3 R4 o polyanhydrides O O H2 O= = = O =O -C-O-C -C-O-H H-O-C- _ _ _ _ _ _ _ Lecture 1 – Introduction
BEH.462/3. 962J Molecular Principles of Biomaterials Spring 2003 o poly(ortho esters)(SKIP?) ooO RO H-O Ho、OH Medically-applied polymers are chosen for metabolizable or excretable final degradation products HO -(CH-C-O-CH-C-O-x(CH2-C-0-CH2-C-O)y HO-CH-C-OH HO-C Kreb@ cycle CO2+ H2O 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 H2o Citric acid cycle -(CH2)5-C-O-) HO-((CH2)5-C-OH Co2 +H2o 6-hydroxycaproic acid polyhydroxybutyrate: ( C-O-CH(CH3)CH2h、o HO-CH(CH3)-CH2 -C-OH D-3-hydroxybutyrate (normal blood constituent Holmes, Phys. Technol. 16, 32(1985) · What doesnt work? o e.g. poly(ethylene terephthalate)(PET)-used for soda bottles breaks down to aromatic oligomers which form deposits in body therefore more than just a hydrolysis-susceptible bond is needed CRYSTALLINE, T INELASTIC 256·T.67 Lecture 1-Introduction
BEH.462/3.962J Molecular Principles of Biomaterials Spring 2003 o poly(ortho esters) (SKIP?) H2O RÕ n O RÕ O O + O O O RÕ O R HO HO OH OH RÕ O R Medically-applied polymers are chosen for metabolizable or excretable final degradation products: PLGA: CH3 O CH3O O O H2O CH3 O O -(CH-C-O-CH-C-O-)x-(CH2-C-O-CH2-C-O)y- HO-CH-C-OH + HO-CH2-C-OH KrebÕs cycle CO2 + H2O 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 H2O O Citric acid cycle -((CH2)5-C-O-)n- HO-((CH2)5-C-OH CO2 + H2O 6-hydroxycaproic acid poly(hydroxybutyrate): O H2O O -(-C-O-CH(CH3)-CH2-)n- HO-CH(CH3)-CH2-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 breaks down to aromatic oligomers which form deposits in body 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 H O-H Base-catalyzed hydrolysis( saponification) ACM Example Structures, Properties, and Applications: (solid polymers, not water soluble) (SLIDE) olymer(class) Structur Current Applications Polylactide:(polyester) Resorbable sutures Poly(L-lactide)[PLLA bone fixtures oly(D, L-lactide)[PDLLA Monomer can be obtained -(cH-C-o-CH-E-O-H tissue engineering scaffolds for bone. liver, nerve from fermentation of corn DLLA -Atrix laboratories in First investigated by Carothers situ precipitation for scaffolds (DuPont) in 30s Drug delivery(various) 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 30s10 CH3 O CH3O -(CH-C-O-CH-C-O-)n • Resorbable sutures • bone fixtures • tissue engineering scaffolds for bone11, 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 oly(lactide-co-glycolide)(polyester) Controlled release devices *8。:8 (protein and small molecule O-)(CH2-C-o Tissue engineering scaffolds Drug delivery(various Gene delivery oly (E-caprolactone)[PCL](polyester) Slow controlled release devices-drug delivery (e.g Polyfe-caprolactone) Polyanhydrides Orthopaedic reconstruction First synthesized in 1909 一cH Drug delivery te add IS Poly(SA-HDA anhydride) Poly(B-hydroxy butyrate)(polyester) Ocular drug deliver Lemoigne(1920) discovered production of polyester by Bacillus Megaterium (bacteria oly(ortho esters) Ocular drug deliver Periodontal antibiotic delivery and guided tissue LE-iD PolyDETOSU-1. 6 HD-t-CDM ortho ester egeneration Bone tissue regeneration polyphosphazenes Insulin delivery lew tissue engineering scaffolds(current research) polycarbonates ADD polycarbonates? PPF? Refs: Biomat.8,311(1987); Biomat8,70(1987); Biomat8,289(1987); J Contr Rel2,167(1985)};Prog. Polym.sc.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 Poly(lactide-co-glycolide) (polyester) CH3 O CH3O O O -(CH-C-O-CH-C-O-) x-(CH2-C-O-CH2-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 reconstruction5 • Drug delivery Poly(β-hydroxy butyrate) (polyester) • Lemoigne (1920) discovered production of polyester by Bacillus Megaterium (bacteria)13 • Ocular drug delivery14,15 Poly(ortho esters) • Ocular drug delivery16 • Periodontal antibiotic delivery and guided tissue regeneration16 • Bone tissue regeneration16 Polyphosphazenes • Insulin delivery17 • 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 TABLE 2 Mechanical Properties of Some Degradable Polymers Tensile Tensile Flexural temperature Yield Polymer MPa) (%)(%) Polyglycolic acid)(MW: 50,000) 210 LPLA(MW:100,000) 2.63.3 3000 D,LPLA(Mw:107,000) 4.060 D, L-PLA(MW: 550,000 y(B-hydroxybutyrate)(MW: 422,000) oly(e-caprolactone)(MW: 44,000) 7.080 polyanhydrides SA-HDA anhydride)(MW: 142,000) Poly(ortho esters) DETOSU: t-CDM: 1, 6-HD (MW: 4.1220 Poly(BPa PA imidocarbonate)(MW 2150 TH iminocarbonate)(MW: 103, 000) 55 B, ..A100: 35: 65 copolymer of 3. 9-bistethylidene 2, 4.8, 10-tetraoxaspirol5, undecane)(DETOSU), trans-cyclohexane dimethanol (t-CDM)and hexanediol(1, 6-HD) was selected as a specific example. "BPA: Bisphenol A; DTH: desaminotyrosyl-tyrosine hexyl ester. For detailed structures, see Fig. 1 tner, 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 surface erosion bulk-erosion Fig. I. Schematic illustration of the changes a polymer matrix undergoes during surface erosion and bulk erosion. 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
