Engineered cartilage grafts improve surgery for narrowed child airways

A study led by researchers at Children's Hospital of Philadelphia (CHOP) demonstrated a new method of using decellularized cartilage with patient-specific cells to help enlarge the pediatric airways narrowed as a result of severe subglottic stenosis. Researchers demonstrated that this new method was faster, more effective and able to overcome issues associated with the current standard grafts such as donor site morbidity, insufficient tissue volume and delayed timeline. The findings were published today by the journal Nature Communications.

Severe subglottic stenosis is a narrowing of the airway below the vocal cords and above the trachea. An estimated 20,000 infants per year are affected by this condition. The most severe cases require laryngotracheal reconstruction (LTR), an open airway surgery that is used to enlarge the airway by implanting cartilage taken from a rib cage. While LTR is used to successfully treat thousands of children with subglottic stenosis, in many cases, young children often lack enough costal cartilage – the cartilage connecting our ribs to the sternum – for these grafts. As a result, operations often need to be delayed, leaving the child attached to a tracheostomy tube until they are older, and there is a higher risk of needing follow-up surgery because the airway is at risk of narrowing again.

To improve this process and reduce the risk of these potential complications, a team led by Riccardo Gottardi, PhD, Assistant Professor with the Perelman School of Medicine at the University of Pennsylvania and leader of the Bioengineering and Biomaterials (Bio²) lab, and Ian Jacobs, MD, Medical Director of the Center for Pediatric Airway Disorders in the Division of Otolaryngology (ENT) at CHOP, has been looking at tissue engineering a laryngotracheal graft. However, the complexity of the trachea prevents the use of conventional cartilage engineering techniques for this procedure.

We needed something that could be equivalent to a piece of cartilage, integrate well with the surrounding tissue, be well tolerated by the patient, behave like native tissues and regrow and be part of the airway This required quite a bit of creative thinking because of the additional challenges in children who are so small and still growing."

Riccardo Gottardi, PhD, Assistant Professor, Perelman School of Medicine, University of Pennsylvania 

To overcome these limitations, the researchers, led by former Gottardi lab member Paul Gehret, PhD, created a first-of-its-kind scaffold based on meniscal cartilage decellularization (MEND – MENiscus Decellularization). They realized that if the cells, elastin, and blood vessels present in the meniscus are "digested" away, the meniscal cartilage becomes amenable to recellularization and integration while being less likely to provoke an immune response.

Using ear-derived cartilage progenitor cells (eCPCs), which can mature into cartilage-producing chondrocytes, the researchers demonstrated that MEND can be "recellularized" after the removal of elastin and blood vessels and suitable for implantation in less than a month. This technique was validated in a preclinical in vivo model and demonstrated better performance than costal cartilage, the standard of care, with no instances of adverse events reported.

Importantly, this method needed to work in a clinically relevant timeframe. In a real-world scenario, clinicians may only have one or two months to be able to perform the procedure when it can still benefit the patient. Harvesting seed cells within days and creating a scaffold within three to four weeks is significantly less time than the six months that was typically needed for engineered cartilage. These findings will be further validated prior to proposing the procedure for patients suffering from severe subglottic stenosis.

"This research shows really promising data that suggests this novel approach could overcome the autograft-associated limitations we sometimes encounter when attempting laryngotracheal reconstruction in infants," Jacobs said. "With more research, we expect this could decrease the need for invasive surgery, and we may be able to apply the technology to other conditions that require a cartilage graft."

This study was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health grant R21HL159521, Children's Hospital of Philadelphia Research Institute, the Frontier Program in Airway Disorders of Children's Hospital of Philadelphia, the National Science Foundation Graduate Research Fellowship No. DGE 1845298, the University of Pennsylvania University Scholars Program, and American Society of Pediatric Otolaryngology research grant, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health grant P3AR0069619.