Using a combination of 3-D printing and cultured cells, scientists in China have grown new ears for five children born with a defect in one ear called microtia, which impacts the shape and function of the ear.
In a first-of-its-kind study, researchers describe how they collected cartilage cells called chondrocytes from the children’s microtia ears and used them to grow new ear-shaped cartilage. The new cartilage was based on 3-D-printed models of the children’s healthy ears.
Then, the researchers transferred the newly engineered ears to the children and performed ear reconstruction, according to a study published this month in the journal EBioMedicine.
“We were able to successfully design, fabricate, and regenerate patient-specific external ears,” the researchers wrote in their study, which followed each child for up to 2½ years.
“Nevertheless, further efforts remain necessary to eventually translate this prototype work into routine clinical practices,” they wrote. “In the future, long-term (up to 5 years) follow-up of the cartilage properties and clinical outcomes … will be essential.”
Microtia is a condition in which a child is born with structural abnormalities or even the complete absence of the ear, which can result in hearing impairment.
The condition is estimated to occur in about one in every 5,000 live births, depending on ethnic background. The prevalence of microtia is higher in Hispanic, Asian, Native American and Andean populations.
Typically, microtia treatment options include reconstructive surgery involving various approaches, such as sculpting an artificial “plastic ear” that attaches to the body or using the patient’s rib cartilage to create an ear.
“The delivery of shaped cartilage for the reconstruction of microtia has been a goal of the tissue engineering community for more than two decades,” said Lawrence Bonassar, a professor of biomedical engineering and mechanical and aerospace engineering at Cornell University in Ithaca, New York, who was not involved in the new study but separately has studied 3-D-printed ears in microtia patients.
“This work clearly shows tissue engineering approaches for reconstruction of the ear and other cartilaginous tissues will become a clinical reality very soon,” he said of the new study. “The aesthetics of the tissue produced are on par with what can be expected of the best clinical procedures at the present time.”
‘The concept is not novel’
The approach featured in the new study has been around as an idea for a while, said Dr. Tessa Hadlock, chief of facial plastic and reconstructive surgery at Massachusetts Eye and Ear in Boston, who was not involved in the new research.
In 1997, for instance, researchers grew tissue-engineered cartilage in the shape of a human ear using chondrocytes and then implanted them on the backs of mice.
“Surgeons have been toying with the idea of removing cartilage tissue from a patient and distilling that tissue into individual cellular components and then expanding those cellular components. In other words, having the cells divide so you have a bigger piece or more cells to make a new part with,” Hadlock said.
“For many years, we have tried to harvest cells from people and expand those cells on polymer to grow kind of a new structure, and we’ve done it in animals for a long time, and it also was FDA-approved for some studies here in the United States where we were trying to fix problems with the bladder in a condition called vesicoureteral reflux.”
So, “the concept is not novel,” Hadlock said.
As for the new study, “the thing that is novel about this is that for the first time, they have done it in a series of five patients, and they have good long-term followup that shows the results of the ears that were grown from that harvested cartilage,” she said.
The study involved a 6-year-old girl, a 9-year-old girl, an 8-year-old girl, a 7-year-old boy and a 7-year-old girl, all with unilateral microtia.
The researchers used CT scanning and 3-D printing to build a biodegradable scaffold that replicated the exact 3-D structure of each patient’s healthy ear. After the researchers derived chondrocytes from the cartilage in each patient’s microtia ear, those cells were seeded onto the scaffold and cultured for three months.
Next, once the cartilage frameworks were generated with each patient’s specific ear shape, they were implanted to reconstruct ears in the five patients. Each patient was monitored for various amounts of time after implantation, with the longest follow-up being 2½ years.
Of all of the cases, four showed obvious cartilage formation by six months after the new ear implantation, the researchers found, and among three of the patients, the shape, size and angle of the new ear all matched the other ear, which was healthy.
The new ears stayed intact as the researchers followed up with the children after surgery, but two of the cases showed slight distortion after surgery, the researchers said.
The researchers described their results as “a significant breakthrough” in the clinical application of engineering human ear-shaped cartilage, but the approach comes with several limitations.
“The part about this work that is dangerous is when you remove cells from someone’s body and you grow them in culture, you have to apply stimulating compounds to the cells to get them to divide,” Hadlock said.
“When you apply those stimulating compounds, you are running the risk of allowing those cells to go haywire from a division standpoint. It’s another way of saying that you can actually create like a cancerous type of uncontrolled growth,” she said. “In the United States, we have been extremely wary of doing that.”
Another limitation relates to how the researchers used the children’s own chondrocytes, the cartilage cells within their ears, even though their ears had been diagnosed with microtia, Hadlock added.
“Because the ear is not normal, they in and of themselves may be diseased. They may be different than a totally healthy chondrocyte,” Hadlock said. “That’s something about which we don’t have enough information.”
Many challenges remain
More research is needed before the approach described in the new study could be widely used among microtia patients in a clinical setting.
Though there has been no recent review of the average medical costs of microtia treatment options, they are expected to be steep since hearing impairment care and multiple surgeries for reconstruction are often needed.
So the approach described in the new study could come with a hefty price tag as well.
The researchers noted in their study that they plan to continue to intermittently follow up with the children in the study for up to five years and to continue reporting on their results as data are collected.
“The main challenges for the widespread use of this particular approach for microtia are manufacturing and regulatory surveillance,” said Bonassar, who cofounded 3-D Bio Corp., a company developing tissue-engineered cartilage for multiple applications.
“The method for making these constructs is quite complicated, involving three distinct biomaterials that are combined into a scaffold, seeded with cells, then cultured for three months before implantation to ensure proper cell distribution throughout the construct,” he said.
So scaling up that process to help the tens of thousands of patients who need such implants remains a real challenge, Bonassar said.
“Secondly, the materials that are used for these scaffolds remain in the body for a long time: up to four years,” he said. “Such implants would likely need to be monitored for four or five years before the ultimate fate of these materials in the body is known.”