Repairing traumatic injuries to the skin and bones of the face and skull is difficult due to the many layers of different tissue types involved, but now researchers have repaired these defects in a rat model using bioprinting. during surgery, and their work can lead to faster and better methods of healing the skin and bones.
“This work is clinically significant,” said Ibrahim T. Ozbolat, Hartz Family Career Development Associate Professor in Engineering and Mechanical Sciences, Biomedical Engineering and Neurosurgery, Penn State. “Treating composite defects, fixing hard and soft tissue at the same time, is difficult. And for the craniofacial area, the results must be aesthetic.”
Currently, fixing a hole in the skull involving both bone and soft tissue requires the use of bone from another part of the patient’s body or from a cadaver. The bone must be covered with soft tissue with blood flow, also taken from elsewhere, otherwise the bone will die. Next, surgeons must repair the soft tissue and skin.
Ozbolat and his team used extrusion bioprinting and droplet bioprinting of mixtures of cells and support materials to print both bone and soft tissue. They report their results in Advanced functional materials.
“There is no surgical method to repair both soft and hard tissue,” Ozbolat said. “This is why we sought to demonstrate a technology that allows us to reconstruct the entire defect – from bone to epidermis – in one go.”
The researchers first tackled the problem of bone replacement, starting in the lab and moving to an animal model. They needed something that was printable and non-toxic and could fix a 5 millimeter hole in the skull. The “hard tissue ink” consisted of collagen, chitosan, nano-hydroxyapatite and other compounds, and mesenchymal stem cells – multipotent cells found in the bone marrow that create bone, cartilage and fat. bone marrow.
Hard tissue ink extrudes at room temperature but heats up to body temperature when applied. This creates physical cross-linking of collagen and other parts of the ink without any chemical changes or the need for a cross-linking additive.
Researchers used droplet printing to create soft tissue with layers thinner than bone. They used collagen and fibrinogen in alternate layers with crosslinking and growth compounds. Each layer of skin, including the epidermis and dermis, differs, so the bio-imprinted soft tissue layers differ in composition.
Experiments in repairing 6mm holes in full thickness skin have proven to be successful. Once the team understood the skin and bones separately, they moved on to repairing both in the same surgery.
“This approach was an extremely difficult process and we actually spent a lot of time finding the right material for the bones, skin and the right bioprinting techniques,” said Ozbolat.
After careful imaging to determine the geometry of the defect, the researchers deposited the bone layer. They then deposited a barrier layer mimicking the periosteum, a highly vascularized tissue layer that surrounds the skull bone.
“We needed a barrier to ensure that the cells in the skin layers didn’t migrate into the bone area and start growing there,” Ozbolat said.
After placing the barrier, the researchers printed the layers of dermis and then the epidermis.
“It took less than 5 minutes for the bioprinter to deposit the bone layer and soft tissue,” Ozbolat said.
The researchers performed over 50 defect closures and achieved 100% soft tissue closure within four weeks. The rate of bone closure was 80% in six weeks, but Ozbolat noted that even with a bone replacement taken, bone closure generally did not reach 100% in six weeks.
Blood flow to bone is especially important, according to Ozbolat, and the inclusion of vascularizing compounds is a next step.
The researchers are also keen to translate this research into human applications and continue to work with neurosurgeons, craniomaxillofacial surgeons, and plastic surgeons at Penn State Hershey Medical Center. They use a larger bioprinting device on larger animals.
Other Penn State researchers working on this project include Kazim K. Moncal, recent doctoral student; Hemanth Gudapati, doctorate recipient; and Youngnam Kang, postdoctoral fellow; all in engineering and mechanics. Kevin P. Godzik, recent bachelor’s degree in biomedical engineering; Jason Z. Moore, associate professor in mechanical and biomedical engineering; and David F. Pepley, PhD in Mechanical Engineering. At Penn State Hershey Medical Center were Hwa Bok Wee, research associate, and Gregory S. Lewis, assistant professor, orthopedics and rehabilitation; Elias Rizk, associate professor of neurosurgery, Thomas D. Samson, associate professor of plastic surgery, and Dino J. Ravnic, assistant professor of plastic surgery; all at the College of Medicine.
Others were Dong N. Heo, former postdoctoral fellow and now dental materials research professor, Kyung Hee University, Seoul, Republic of Korea; Veli Ozbolat, former postdoctoral fellow and now assistant professor, Cukorova University, Adana, Turkey; and Ryan R. Driskell, assistant professor of molecular biosciences, Washington State University.
The National Institute for Dental and Craniofacial Research, the National Science Foundation, the Osteology Foundation and the international implantology team have supported this work.
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