Hydrogel may help tiny skulls heal

GEORGIA TECH / EMORY (US) — Engineers and surgeons are working together to improve the treatment of babies born with craniosynostosis, a condition that causes the bone plates in the skull to fuse too soon.

Treating craniosynostosis typically requires surgery after birth to remove portions of the fused skull bones, and in some cases the bones again grow together too quickly—requiring additional surgeries.

“Babies are usually only a few months old during the first operation, which lasts more than three hours and requires a unit of blood and a stay in the intensive care unit,” says Joseph Williams, clinical assistant professor of plastic and reconstructive surgery at Emory University and clinical director of craniofacial plastic surgery at Children’s Healthcare of Atlanta at Scottish Rite. “So our goal is to develop technologies that will simplify the initial surgery and limit affected babies to this one operation.”

Craniosynostosis affects approximately one in every 2,500 babies in the United States. The condition is caused by the premature closure of sutures with bone. Sutures, which are made of tissue that is more flexible than bone, play an important role in brain growth by providing a method for the skull to increase in size. If the sutures close too soon and get replaced with bony tissue, the skull may limit the normal expansion of the brain. Untreated, it can cause a range of developmental problems.

If treated using the standard treatment course, surgeons remove the fused skull bones, break them up, reposition them, and hold them in place with plates and screws. This usually slows bone growth between the bone pieces, allowing room for expansion of the brain. Studies show, however, that more than six percent of babies need a second operation to separate the bones again and 25 percent of those require a third operation.

“Following the first surgery, there’s a clinical need to be able to screen children on a regular basis to predict when their skull bones are going to fuse together again so that the surgeons can determine if additional intervention will be required,” says Barbara Boyan, the chair in tissue engineering in the department of biomedical engineering at Georgia Institute of Technology (Georgia Tech) and Emory University and associate dean for research and innovation in the Georgia Tech College of Engineering.

Researchers developed a non-invasive technique to monitor bone growth with computed tomography images. Software identifies bone, quantifies the distance between the bones, the mass of bone in the gap, and the area and volume of the gap.

The utility of this “snake” algorithm was demonstrated using a mouse model of cranial development and recently presented at the 2011 Plastic Surgery Education Foundation conference.

“Using our snake algorithm to analyze computed tomography images of developing skulls in mice, we were able to monitor different types and speeds of bone growth on a daily basis for many weeks,” says PhD student Chris Hermann. “While one suture fused between 12 and 20 days and then significantly increased in mass for the next 20 days, another came closer together and increased in mass but remained largely open.”

Researchers recently adapted the technology for use in children and began a clinical study to determine the effectiveness of the algorithm to diagnose cases of craniosynostosis, improving physicians’ ability to diagnose and determine the severity of the condition.

The researchers are also studying the biological basis of the condition and developing technologies they hope will delay bone growth and eliminate the need for additional operations.

In one project, Williams and research scientist Rene Olivares-Navarrete are examining individuals with craniosynostosis to identify genes that influence suture fusion. Determining the genes that control suture closure may help identify potential therapeutic targets to prevent premature suture fusion.

The research team has also designed a gel to be injected into the gap created between skull bones during the first surgery. The hydrogel would deliver specific proteins to the area to delay, but not prevent, bone growth.

“The hydrogel cross-links spontaneously because of a reaction between a polyethylene-glycol monomer and a cross-linking molecule, allowing for polymerization without the use of chemical initiators or the production of free radicals,” explains Hermann.

Preliminary results in a mouse model of cranial development indicate that the gel, developed in collaboration with professor Niren Murthy, can be injected into a gap between skull bones, firm up rapidly, and not injure underlying soft tissues or impair bone healing.

“During the initial surgery, injecting the gel may reduce the operation’s severity if it eliminates the need for plates and screws to hold the skull bones in place afterward,” explains Boyan. “After the surgery, if the computed tomography images tell us that the skull is closing too quickly, we may be able to inject the gel through the skin overlying the skull without surgery to further delay the bones from fusing.”

The researchers are currently improving the protein release kinetics of the hydrogel and conducting pre-clinical experiments to determine which proteins successfully delay bone growth when included in the gel. Approval from the Food and Drug Administration will be required before this system and hydrogel can be used as a treatment for craniosynostosis.

The research was sponsored by the the Center for Pediatric Healthcare Technology Innovation, which is supported by Children’s Healthcare of Atlanta in collaboration with Georgia Tech.

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