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Injectable Hydrogel-based Medical Devices: “There's always room for Jell-O”

Although great advances have been made in developing chemistries to allow sufficient safety profiles, it is an intrinsic weakness of these systems that: 1) the reaction that generates the crosslinks results in a heat increase (exotherm) as the bond forms; 2) there will be unused materials remaining which are reactive and potentially toxic; and 3) a bond forming reaction results in reaction by-products that may have undesirable safety profiles.

Hydrogels formed from physical bonds present a broad class of materials. These physical bonds can be formed by crystalline junctions, hydrogen bonding, phase-separation, ionic bonds or other associations. (See Exhibit 1.) The strength of the hydrogel depends upon the strength of these physical bonds and their density. As one example, triblock copolymers can be constructed with hydrophobic end blocks and a hydrophilic center block. When placed in water, the end blocks associate into tight bundles, and the hydrophilic blocks absorb water and expand. A 3-dimensional, water containing structure can form. These hydrogels are sometimes reversible, in that changing the conditions (temperature, pH, salinity) can sometimes permit the gel material to go back into solution.

Exhibit 1: Schematic Diagram of a Hydrogel Formed by Physical Bonds

Schematic Diagram of a Hydrogel Formed by Physical Bonds

A well-researched polymer, polyvinyl alcohol (PVA), readily forms hydrogels by a variety of mechanisms. While PVA hydrogels can be crosslinked by chemical (covalent) bonds, they are normally processed by creating hydrogen bonds resulting from the interaction of a hydrogen atom with an electronegative atom, such as oxygen. Although this bond is weak relative to the covalent bond, it can still be structurally stable, and is the mechanism used to stabilize folded proteins and give water its unique properties. These hydrogen bonds create crystalline junction points in the material, generating a hydrogel. Researchers will commonly form PVA-based hydrogels by repeatedly freezing and thawing a PVA-solution, which allows the PVA chains to move into sufficiently close proximity as to form the hydrogen bonds and subsequent crystalline junction points. The more freeze-thaw cycles, the tougher the gel. PVA is used in a variety of biomedical applications including drug delivery, cell encapsulation, artificial tears, artificial vitreous humor, contact lenses and more recently as nerve cuffs.

In our laboratory, we have developed a method of creating a PVA-based hydrogel through the use of solvent manipulation. By carefully altering the solution conditions of a PVA solution through the selective use of a second component, termed a “gellant,” we can drive the polymer chains into forming the crystalline junction points without a freezing process. By using biocompatible materials, the PVA solution and gellant can be injected through a narrow gauge needle into a body cavity, where it will form a hydrogel without chemical reaction or toxic byproducts. The hydrogel solution can act as a transport mechanism for therapeutic drugs or cells as well, with a structure ranging from micro to macro-pores. (See Exhibit 2 for an example of a macro-porous hydrogel.)

Exhibit 2: Scanning Electron Micrograph of Porous Structure of PVA-based Hydrogel

Scanning Electron Micrograph of Porous Structure of PVA-based Hydrogel

This class of hydrogels, termed “injectable hydrogels,” has found an audience for minimally invasive procedures in both orthopaedic applications and soft tissue work. Researchers have focused on hydrogel formulations derived from silk proteins, thermally-responsive phase-change materials, such as poly-N-Isopropylacrylamide, and emulsion systems in an effort to deliver a low viscosity solution into a confined body space that will then form a load-bearing, biocompatible construct.

Application Areas for Hydrogels

Arguably the largest growth areas in injectable hydrogels have been in tissue bulking, cartilage repair, nucleus pulposus replacement and scaffolding. As opposed to pre-formed hydrogels that must be polymerized in controlled conditions, involving chemical crosslinkers, injectable hydrogels for tissue bulking must inject through narrow gauge needles and gel without initially toxic monomers or crosslinkers, and also must not yield potentially toxic polymerization byproducts, all while being able to form a hydrogel in the body environment. The systems considered here are all permanent implants; degradable hydrogel structures have been developed for other applications, including tissue scaffolding and drug release.

Nucleus Pulposus Augmentation

As a case study, it is interesting to discuss the materials currently considered for nucleus pulposus replacement in the spine. The human functional spinal unit, comprising vertebrae and intervertebral disc, is responsible for both the mobility of the spine and its ability to support the dynamic loads of the human body.


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