Lecture 6 Spring 2006 1

Hydrogel Biomaterials: Structure and thermodynamics

Last Day: programmed/regulated/multifactor controlled release fordrug delivery and tissue engineering

Today: Applications of hydrogels in bioengineeringCovalent hydrogels structure and chemistry of biomedical

gelsThermodynamics of hydrogel swelling

Reading: N.A. Peppas et al., ‘Physicochemical foundations andstructural design of hydrogels in medicine and biology,’Annu. Rev. Biomed. Eng., 2, 9-29 (2000).

Supplementary Reading: P.J. Flory, ‘Principles of Polymer Chemistry,’ CornellUniversity Press, Ithaca, pp. 464-469, pp. 576-581(Statistical thermodynamics of networks and networkswelling)

Announcements:

Finish discussion of programmed release materialsStructure of hydrogels, basic chemistry of covalent hydrogelsPhysical properties of hydrogels for biomedical applications

Lecture 6 Spring 2006 2

Biodegradable programmed burst release chips

Richards-Grayson, A. C., I. S. Choi, B. M. Tyler, P. P. Wang, H. Brem, M. J. Cima, and R. Langer. "Multi-pulse Drug Delivery from a ResorbablePolymeric Microchip Device." Nature Materials 2 (2003): 767-772.

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Biodegradable programmed burst release chips

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Controlled release in tissue engineering/regenerative medicine

Nerve TE paradigms:

Figure by MIT OCW.

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Controlled release in tissue engineering/regenerative medicine

Skin TE paradigms:

(I. Yannas)

Figure by MIT OCW.

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Challenge of providing blood supply to macroscopic engineered tissues

O2

O2

O2

z

pO2

Extensive cell death in center of construct

blood vessel structure:

Blood flowIntima

(supportive ECM layer)

Endothelial cell lining

Smooth muscle cells

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Case study: controlled release of multiple cytokines from a TE scaffold to drive angiogenesis

Steps in angiogenesis:1. VEGF (vascular endothelial growth factor)

-attracts endothelial cells, induces proliferation-induces tube formation

2. PDGF (platelet-derived growth factor) -attracts smooth muscle cells, stabilizes new vessels

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Fabricating dual-factor delivery microstructures

Compression mold

PLGA particles

Lyophilized VEGF

PDGF-containing microspheres

NaCl particles

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Fabricating dual factor-delivery microstructures

1. Fill with high-pressure CO22. Rapidly depressurize

Soak with water to leach out NaCl

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Gas nucleation by generating thermodynamic instability in polymer/gas solution

Rapid drop to ambient pressure (1.01E+05 Pa)

Thermodynamically stable polymer/gas solution

unstable stable Gas bubble creates void in polymer matrix

High pressure

CO2 Gas molecules

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Release of cytokines from scaffolds

VEGF release PDGF release

Low MW PLGA

High MW PLGA

In vivo experiments:Scaffolds implanted subcutaneously (under skin) of Lewis rats

1) Compared bolus injection of free cytokines with release from scaffolds2) Compared dual cytokine delivery from scaffolds with single factor delivery

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II. HYDROGELS

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The structure of hydrogels

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Structure of hydrogels

CH3 CH3 CH3 CH3-CH2-CH-CH2-C-CH2-CH-CH2-CH- C=O C=O C=O C=O O O O O CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 OH O OH OH CH2 CH2 O C=O-CH2-CH-CH2-C-CH2-CH-CH2-CH- C=O C=O C=O O O O CH2 CH2 CH2 CH2 CH2 CH2 OH OH OH

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Representative monomers used for biological applications

CH3CH=C

C=OOCH2CH2NH2

CH3CH=C

C=OOCH2CH2NH2

2-aminoethyl methacrylate

CH3CH=C

C=OOH

CH3CH=C

C=OOH

Methacrylic acidHydroxyethyl methacrylate

Poly(vinyl alcohol)

N-isopropylacrylamide

Poly(ethylene glycol) diacrylate

Lecture 6 Spring 2006 15

Common biomedical hydrogel components

Table removed due to copyright reasons. Please see:

Table 1 in Peppas, N. A., Y. Huang, M. Torres-Lugo, J. H. Ward, and J. Zhang. “Physicochemical Foundations and Structural Design of Hydrogels in Medicine and Biology.”Annu Rev Biomed Eng 2 (2000): 9-29.

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Bonding in hydrogels

• Covalent

• Ionic

• Hydrogen bonding

• Polypeptide complexation (e.g., coiled coils)

• Hydrophobic effect

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Covalent hydrogel structure

Typical covalent hydrogel synthesis:

Interpenetrating networks:

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Physical gels: example- Hydrophobic interactions in physical gels

organic solution

Hydrophilic B blocks

Hydrophobic A blocks Poly(propylene oxide) (PPO)Poly(butylene oxide) (PBO)

Poly(ethylene glycol) (PEG)

Example blocks:Physical gels are formed by noncovalentcross-links

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Physical gels: ionically-crosslinked gels

alginate

Images removed due to copyright restrictions.Please see:

Rees, D. "Polysaccharide Shapes and Their Interactions - Some Recent Advances." Pure ApplChem 53 (1981): 1-14. http://www.iupac.org/publications/pac/1981/pdf/5301x0001.pdf

Alginate microspheresLoaded with fluorescent

nanoparticles

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Iso-octane

+ span 80

CaCl2 solution

homogenization

Chemokine(MIP-3α)

Antigen-loaded Hydrogel

nanoparticles

alginate

Washing

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Key properties of hydrogels for bioengineering applications:

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Further Reading

1. Nguyen, K. T. & West, J. L. Photopolymerizable hydrogels for tissue engineeringapplications. Biomaterials 23, 4307-14 (2002).

2. An, Y. & Hubbell, J. A. Intraarterial protein delivery via intimally-adherent bilayerhydrogels. J Control Release 64, 205-15 (2000).

3. Hubbell, J. A. Hydrogel systems for barriers and local drug delivery in the control ofwound healing. Journal of Controlled Release 39, 305-313 (1996).

4. Elisseeff, J. et al. Photoencapsulation of chondrocytes in poly(ethylene oxide)-basedsemi-interpenetrating networks. Journal of Biomedical Materials Research 51, 164-171(2000).

5. Jen, A. C., Wake, M. C. & Mikos, A. G. Review: Hydrogels for cell immobilization.Biotechnology and Bioengineering 50, 357-364 (1996).

6. Anseth, K. S. & Burdick, J. A. New directions in photopolymerizable biomaterials. MrsBulletin 27, 130-136 (2002).

7. Peppas, N. A., Huang, Y., Torres-Lugo, M., Ward, J. H. & Zhang, J. Physicochemicalfoundations and structural design of hydrogels in medicine and biology. Annu RevBiomed Eng 2, 9-29 (2000).

8. Hennink, W. E. et al. in Biomedical Polymers and Polymer Therapeutics (eds. Chiellini,E., Sunamoto, J., Migliaresi, C., Ottenbrite, R. M. & Cohn, D.) 3-18 (Kluwer, New York,2001).

9. Flory, P. J. & Rehner Jr., J. Statistical mechanics of cross-linked polymer networks. II.Swelling. J. Chem. Phys. 11, 521-526 (1943).

10. Flory, P. J. & Rehner Jr., J. Statistical mechanics of cross-linked polymer networks. I.Rubberlike elasticity. J. Chem. Phys. 11, 512-520 (1943).

11. Peppas, N. A. & Merrill, E. W. Polyvinyl-Alcohol) Hydrogels - Reinforcement of Radiation-Crosslinked Networks by Crystallization. Journal of Polymer Science Part a-PolymerChemistry 14, 441-457 (1976).

12. Flory, P. J. Principles of Polymer Chemistry (Cornell University Press, Ithaca, 1953).