W BIOENGINEERING. Nanomaterials Applications in Biology and Medicine. Topics:

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1 Nanomaterials Applications in Biology and Medicine Obejctive: Develop a firm understanding of the fundamental materials science and engineering principles underlying synthetic/engineered materials used in biology, biotechnology, and medicine Topics: 1. Chemistry and physical chemistry of degrading polymeric solids for biomaterials 2. Factors controlling polymer degradation and erosion - Theory of polymer erosion 3. Molecular design of degradable solid polymers Next time: Integrating biological knowledged into biomaterial design for vaccines 1

2 Motivation: Tissue regeneration and tissue engineering Development of tissues and organs is typically driven by the the action of multiple growth factors Nature (2000) 407, 242. Role of vascular growth factors in vessel formation. Stage A: Vasculogenesis Stage B: Angiogenic remodelling Stage C: Stabilization and maturation Stage D: Destabilization Stage E: Regression Stage F: Sprouting Nature Biotechnology (2001) 19, Polymer scaffold fabrication for growth factor release. Growth factors incorporated into polymer scaffolds by either (1) mixing with polymer particles before processing into scaffolds, or (2) pre-encapsulating the factors into polymer microspheres that are then used to form scaffolds. Scaffold fabrications results in rapid release of the growth factor (1) or release that is controlled by the degradation of the polymer micospheres (2). 2

3 Degradable solid polymers: In vivo applications Active Lifetime Application Examples 8-10 years Implants Artificial hips, artificial heart, pacemaker, etc. 1 year Tissue engineering, cell therapy Delivery of cells, scaffolds for in vivo tissue guidance 6 months Drug delivery Injected or implanted devices Hours - days Biosensors In situ measurement of ph, analyte concentrations, etc. 3

4 Design criteria for biomaterials: Characteristics required for use in vivo In addition to fulfilling the device requirments, biomaterials must be: Non-toxic Non-carcinogenic Non-mutagenic Non-allergenic Results: Very few number of FDA-approved materials Cost of clinicatl trials increases as device approaches approval FDA standards scales with the risk releated to treatment 4

5 Classes of materials used in vivo: Biodegradable: Breaks down by hydrolysis or enzymatic cleavage to form metabolized products Bioeliminable: Do not degrade; water-soluble, excretable Permanent or retrievable materials: Not degradable or excretable; requires surgery for removal 8

6 Biodegradable solid polymers: Definition: Initially solid or gel-phase material reduced to soluble fragements that are metabolized or excreted under physiological conditions (saline environment, ph 7.4, 37 C) Why use biodegradable materials? Bonds that are susceptible to hydrolysis: Anhydrides Esters Carbonates Amides (generally stable in vivo without catalysis) Mechanisms of polymer degradation 9

7 Mechanisms of solid polymer degrdation Mechanism I: Crosslink degradation water soluble crosslinks WATER INSOLUBLE Cleavage of crosslinks between water soluble polymer chains WATER SOLUBLE Example: Degradation of polyanhydride networks 10

8 Mechanisms of solid polymer degrdation Mechanism II: Sidechain degradation X Y X Y X Y X X Transformation or cleavage of side chains (X) leading to the formation of polar or charged groups (Y) Y Y WATER INSOLUBLE WATER SOLUBLE Examples: Degradation of PMV/MA 11

9 Mechanisms of solid polymer degrdation Mechanism III: Backbone degradation Cleavage of backbone linkages between polymer repeat units. WATER INSOLUBLE WATER SOLUBLE Examples: Degradation of polyphosphazenes 12

10 Factors controlling solid polymer degradation Bond stability Hydrophobicity Steric effects Production of autocatalytic breakdown fragments Microstructure (crystallinity, porosity, phase separation) 13

11 Effect of polymer hydrophobicity on solid polymer erosion rate Sebacic acid --> poly(sebacic acid) - hydrophilic 1,6-bis(o-carboxyphenoxy)hexane (o-cph) - hydrophobic Copolymers of PSA and PCPH Degradation Rate Constant, k (mm h -1 ) poly(sa) 72:25 poly(sa:cph) 50:50 poly(sa:cph) poly(cph) Percent Mass Loss poly(sa) 72:25 poly(sa:cph) 50:50 poly(sa:cph) poly(cph) Polyanhydride Time (hour) 14

12 Steric effects controlling polymer hydrolysis rates Local Structure: Glass transition (Tg): V molar volume k degradation rate constant T g eff T g T T g T 15

13 Production of autocatalytic products Mechanisms of hydrolysis 1. No acid catlysis: What does this look like? 2. Acid/base-catalyzed hydrolysis of esters: What does this look like? 3. What is observed? What is the measurable? 16

14 Predicting polymer erosion: Why does it matter and how do we do it? 30 years ago: Polyesters made of glycolic acid were among the first biodegradable polymers applied in medicine Today: New biodegradable polymers and new applications Mechanism of polymer erosion controls essential processes: (1) release of drugs from polymer implants and (2) mechanical stability of the material 18

15 Göpferich theory of polymer erosion: Definitions Polymer Degradation: cleavage of polymer chain Polymer Erosion: loss of mass from degradable polymers Assumptions 1. Polymers are water insoluble 2. Degradation causes erosion and is initated by hydrolysis 3. Other processes that cause degradation do not lead to erosion Two processes dominate erosion behavior Diffusion of water in the polymer bulk Degradation rate of polymer backbone 19

16 Göpferich theory of polymer erosion: ε = t diff t c = 4D H 2O x 2 πk ln x + 1 ln bn AV ρ 3 M o e >>1 surface erosion e <<1 bulk erosion e ~1 bulk <--> surface 20

17 Göpferich theory of polymer erosion: Estimated values of e and Lcritical for selected degradable polymers Chemical Structure Polymer k (s -1 ) e L critical Poly(anhydrides) 1.9 x , mm Poly(ketal) 6.4 x mm Poly(ortho esters) 4.8 x mm Poly(acetal) 2.7 x cm Poly(e-caprolacctone) 9.7 x cm Poly(a-hydroxy esters) 6.6 x x cm Poly(amides) 2.6 x x m 21