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Advances in Biogels Support Stem Cell Viability and Regeneration for Neurologic Diseases

CHICAGO—Stem cells transplanted into the brain must be nourished by growth factors and guided by chemical signals that direct their development. They also must avoid an inflammatory response launched by the host's immune system. Only then do they stand a chance of surviving, differentiating, and integrating into pre-existing circuits where they can replace tissue lost to disease, stroke, or traumatic brain injury.

German researchers have attempted to provide a hospitable environment for transplanted stem cells by developing a versatile biogel that can be laced with growth factors and other biomaterials, and then injected into the brain to create a flexible matrix that can support transplanted stem cells in various parts of the brain without provoking an immune reaction.

Their biogel matrix consists of heparin, a biological material, linked to star-shaped polyethylene glycols, a synthetic product. The heparin, the researchers note, has an affinity for a wide variety of important signaling molecules, while “star-PEG” — their name for star-shaped polyethylene glycols — forms a flexible mesh that conforms comfortably to surrounding tissue. The resulting “biohybrid biogel,” as the researchers call it, can be customized to carry different growth factors, and to have varying degrees of flexibility, permeability, and swelling.

The biogel provides options for neuronal cell replacement therapies, such as those required to treat Parkinson disease or Huntington disease, according to the researchers, who presented their work as a poster at the Society for Neuroscience annual meeting here.

“We have demonstrated that different neuronal cell types respond differently to the biomolecular functions and physical properties of biohybrid materials,” said Carsten Werner, PhD, lead author of an article on the new biogel in the October issue of Biomaterials. “This allows us to trigger cell fate transitions desired in various therapeutic strategies.”

The incorporation of heparin into the biogel makes it more versatile, according to Dr. Werner, head of the department of biomaterials at the Leibniz Institute of Polymer Research, and founding member of the Max Bergmann Center of Biomaterials in Dresden.

The high heparin content allows for changes in the cross linking with the star-PEG, producing alterations in elasticity, permeability and swelling of the gel. Such versatility allows the gel to be customized for placement in various parts of the brain. It also allows it to be flexible enough to carry various quantities and types of growth factors and other biomaterials needed to promote the survival and integration of the cells. Experiments with neurons in culture, as well as with other cell types including endothelial cells and mesenchymal cells, have demonstrated the viability of this technique, Dr. Werner said.

PROBLEMS WITH HYDROGELS

The researchers have taken an interesting approach toward overcoming the problems of hydrogels, according to Ning Zhang, PhD, assistant professor of bioengineering, microbiology and immunology, and cell biology & regenerative medicine at Clemson University.

“One problem is the poor ability of hydrogels to maintain the viability of cells,” said Dr. Zhang, who is involved in an effort to develop a similar biogel. “Another problem is the poor integration of the hydrogel with surrounding tissue. The goal is to overcome the interface between the lesion site and the tissue so the hydrogel will not only fill in the space, but also serve as a bridge between the host tissue and the hydrogel.”

She does not believe the hydrogel developed by the German researchers overcomes these problems. “I don't see integration of their gel with the surrounding tissue, especially in vivo,” she said. “When they implanted the gel, there was no cell infiltration into the gel. That surprised me.”

Although Dr. Zhang cannot discuss the materials used in the gel she is helping to develop, which is under patent protection, she said it is similar to the concept used by the German researchers.

“A hydrogel for neuronal regeneration requires two basic components,” she said. “The hydrophilic component, the star-shaped polyethylene glycol, serves as the structural framework that makes this material a hydrogel, and the cell adhesive component — the heparin conjugated with the RGD peptide — which decorates the hydrogel with cell adhesive domains to attract cell infiltration and the neuronal growth factors.”

Despite her reservations, “I consider this a breakthrough because they do seem to be going in right direction,” Dr. Zhang said. “However, I think they have not done enough engineering of the gel so it will exhibit properties that would dictate cell response. In other words, there is further engineering they could do.”

Dr. Zhang's own research, sponsored by the U.S. Department of Defense, has focused more on traumatic brain injury (TBI). “We have tested our hydrogel for TBI, and we've seen significant functional recovery in adult rats,” she said.

REFERENCE

• Lanfer B, Seib FP, Werner C, et al.The growth and differentiation of mesenchymal stem and progenitor cells cultured on aligned collagen matrices. Biomaterials 2009;30(30):5950–5958. E-pub 2009 Aug 11.