Hydrogels in regenerative medicine

Abstract

Hydrogels, due to their unique biocompatibility, flexible methods of synthesis, range of constituents, and desirable physical characteristics, have been the material of choice for many applications in regenerative medicine. They can serve as scaffolds that provide structural integrity to tissue constructs, control drug and protein delivery to tissues and cultures, and serve as adhesives or barriers between tissue and material surfaces. In this work, the properties of hydrogels that are important for tissue engineering applications and the inherent material design constraints and challenges are discussed. Recent research involving several different hydrogels polymerized from a variety of synthetic and natural monomers using typical and novel synthetic methods are highlighted. Finally, special attention is given to the microfabrication techniques that are currently resulting in important advances in the field.

Figure 1

Neutrally charged synthetic monomers typically used in tissue engineering.

Figure 2

Network structure of a hydrogel showing junctions, entanglements, and covalent linkages. Not all tie points (crosslink) types shown here are necessarily present in a given hydrogel.

Figure 3

Multimembrane gels: a) Macroscopic vessel. b) Microscopic capsule. c) Macroscopic onionlike structure section. Reproduced with permission from [54]. Copyright 2008 Nature Publishing Group.

Figure 4

Three reaction schemes that can be used to make synthetic hydrogels from hydrophilic macromers. A) A diacrylate macromer undergoes free radical polymerization. B) A thiol and acrylate group undergo conjugate addition to crosslink two macromers. C) A pendant alkyne and azide ‘click’ together to crosslink two macromers via a 1,2,3-triazole group.

Figure 5

Molecular structure of typical natural macromer repeat units used in hydrogels for tissue engineering: A) Hyaluronic acid is composed of disaccharide repeat units of d-glucuronic acid and d-N-acetylglucosamine, linked together via alternating β-1,4 and β-1,3 glycosidic bonds. B) Chitosan is composed of randomly distributed N-acetyl-d-glucosamine (acetylated unit) and β-1,4-linked d-glucosamine (deacetylated unit), where x is usually much smaller than y. Chitosan is a partial deacetylation product of chitin which is composed entirely of N-acetyl-d-glucosamine (acetylated units). C) Agarose is an alternating 1,4-linked 3,6-anhydro-α-l-galactopyranose and 1,3-linked β-d-galactopyranose. Some residues are replaced by methylated, sulphated, or other sugar units, which affect gel formation. D) Alginate consists of varying number of α-l-guluronic acid (x) and β-d-mannuronic acid (y) residues connected via 1,4-linkages.

Figure 6

Schematic diagram showing the hierarchical structure of collagen fibrils. Three polypeptide strands (A) form a right-handed triple helix of collagen type II (B), and these helical molecules are interconnected with pyridinium crosslinks (C). The collagen fibrils (D) are mainly composed of staggered collagen type II molecules which are connected with other fibrils via collagen type IX molecules. A–C adapted with permission from [203]. Copyright 2007 IOP Publishing. Figure 6D reproduced with permission from [204]. Copyright 1998 Wiley-Liss.

Figure 7

Structure of peptide amphiphile nanofiber for self-assembly into a fibrous crosslinked scaffold for bone tissue engineering applications. Reproduced with permission from [229]. Copyright 2001 American Association for the Advancement of Science.

Figure 8

Various microfabrication techniques for hydrogels. Images adapted with permission from [,–240]. From top to bottom respectively, copyright 2005 Royal Society of Chemistry, 2006 Elsevier, 2001 American Chemical Society (ACS), 2006 Wiley-VCH, 2006 ACS, and 2003 Elsevier.