Human cartilage progenitor cells from ear, nose, rib, and joint have a robust, stable phenotype for cartilage repair

Ghavimi, Soheila Ali Akbari; Gehret, Paul M; Giordano, Terri; Smith, Kyra W.Y.; Gottardi, Riccardo

doi:10.1101/2022.06.30.498323

Cited by 3 publications

(3 citation statements)

References 57 publications

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“…All pig surgeries were approved by the Children's Hospital of Philadelphia IACUC (Approval 21‐001407). Surgery was conducted on 4 Yucatan pigs, similarly to how it was previously described for rabbits 31 . Briefly, a 10‐cm midline incision was performed from above the hyoid bone to the sternal notch.…”

Section: Methodsmentioning

confidence: 99%

“…MEND was generated as described previously. 31 Briefly, porcine menisci ($8 month) were obtained from a local scientific butcher (Animal Biotech Industries; Doylestown, PA) and frozen upon arrival at À80 C until use, when menisci were partially thawed for 5 minutes and sliced in half, radially. Then, 10-15 sections of 1 mm in thickness were obtained using a scalpel from each half of the meniscus.…”

Section: Decellularized Meniscal Cartilage (Mend) Synthesismentioning

confidence: 99%

“…Surgery was conducted on 4 Yucatan pigs, similarly to how it was previously described for rabbits. 31 Briefly, a 10-cm midline incision was performed from above the hyoid bone to the sternal notch. The subplatysmal flaps were elevated and tied back with silk sutures, and the strap muscles were divided at the midline.…”

Section: Pig Laryngotracheal Reconstructionmentioning

confidence: 99%

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A Pilot Study of Decellularized Cartilage for Laryngotracheal Reconstruction in a Neonatal Pig Model

Gehret,

Dumas,

Jacobs

et al. 2023

The Laryngoscope

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ObjectiveSevere subglottic stenosis develops as a response to intubation in 1% of the >200,000 neonatal intensive care unit infants per year and may require laryngotracheal reconstruction (LTR) with autologous hyaline cartilage. Although effective, LTR is limited by comorbidities, severity of stenosis, and graft integration. In children, there is a significant incidence of restenosis requiring revision surgery. Tissue engineering has been proposed to develop alterative grafting options to improve outcomes and eliminate donor‐site morbidity. Our objective is to engineer a decellularized, channel‐laden xenogeneic cartilage graft, that we deployed in a proof‐of‐concept, neonatal porcine LTR model.MethodsMeniscal porcine cartilage was freeze–thawed and washed with pepsin/elastase to decellularize and create microchannels. A 6 × 10‐mm decellularized cartilage graft was then implanted in 4 infant pigs in an anterior cricoid split. Airway patency and host response were monitored endoscopically until sacrifice at 12 weeks, when the construct phenotype, cricoid expansion, mechanics, and histomorphometry were evaluated.ResultsThe selective digestion of meniscal components yielded decellularized cartilage with cell‐size channels. After LTR with decellularized meniscus, neonatal pigs were monitored via periodic endoscopy observing re‐epithelization, integration, and neocartilage formation. At 12 weeks, the graft appeared integrated and exhibited airway expansion of 4 mm in micro‐CT and endoscopy. Micro‐CT revealed a larger lumen compared with age‐matched controls. Finally, histology showed significant neocartilage formation.ConclusionOur neonatal porcine LTR model with a decellularized cartilage graft is a novel approach to tissue engineered pediatric LTR. This pilot study sets the stage for “off‐the‐shelf” graft procurement and future optimization of MEND for LTR.Level of EvidenceNA Laryngoscope, 2023

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Section: Methodsmentioning

confidence: 99%

Section: Decellularized Meniscal Cartilage (Mend) Synthesismentioning

confidence: 99%

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A Pilot Study of Decellularized Cartilage for Laryngotracheal Reconstruction in a Neonatal Pig Model

Gehret,

Dumas,

Jacobs

et al. 2023

The Laryngoscope

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A Translational Tissue Engineering Approach to Airway Reconstruction Leveraging Decellularized Meniscus and Cartilage Progenitor Cells

Gehret

Ghavimi

Dumas

et al. 2022

Preprint

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Severe subglottic stenosis develops in over 20,000 infants per year and requires laryngotracheal reconstruction (LTR) to enlarge the airway by implanting autologous cartilage from a rib graft. However, young children often lack sufficiently sized costal cartilage resulting in increased donor site morbidity and operative time, as well as an elevated risk for airway restenosis necessitating revision surgery. To overcome these limitations, we have created a first-of-its-kind scaffold based on porcine meniscal cartilage decellularization (MEND) by selectively digesting the elastin and blood vessels uniquely present in the meniscus to create microchannels that support cellular re-invasion. Here we demonstrated that MEND can be fully recellularized in 3 days with ear-derived cartilage progenitor cells (eCPCs) and reaches structural and functional maturation suitable for implant within 3 weeks of chondrogenic differentiation, a time frame compatible with clinical translation, a first in airway tissue engineering. To further this therapy toward clinical translation, we validated the eCPCs-MEND grafts in a New Zealand white rabbit LTR model. Our results demonstrated airway expansion, graft re-epitheliazation, neocartilage formation, and integration with adjacent native laryngotracheal cartilage, notably at a higher degree than the standard of care of autologous costal cartilage. No instances of adverse events of extrusion, granulation, infection, or calcification were observed in any of the 38 rabbits of our 3 months study. These results demonstrate the feasibility of our translational tissue engineering approach to laryngotracheal reconstruction and could overcome the autograft-associated limitations in pediatric patients and a decrease the risk of invasive revision surgery.

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4D bioprinted self-folding scaffolds enhance cartilage formation in the engineering of trachea

Chiesa,

Esposito,

Vozzi

et al. 2023

Preprint

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Trachea defects that required surgical interventions are increasing in number in the recent years, especially for pediatric patients. However, current gold standards, such as biological grafts and synthetic prothesis, do not represent an effective solution, due to the lack of mimicry and regeneration capability. Bioprinting is a cutting-edge approach for the fabrication of biomimetic scaffold to empower tissue engineering toward trachea replacement. In this study, we developed a self-folding gelatin-based bilayer scaffold for trachea engineering, exploiting the 4D bioprinting approach, namely the fabrication of dynamic scaffolds, able to shape morph in a predefined way after the application of an environmental stimulus. Indeed, starting form a 2D flat position, upon hydration, this scaffold forms a closed tubular structure. An analytical model, based on Timoshenko’s beam thermostats, was developed, and validated to predict the radius of curvature of the scaffold according to the material properties and the scaffold geometry. The 4D bioprinted structure was tested with airway fibroblast, lung endothelial cells and ear chondral progenitor cells (eCPCs) toward the development of a tissue engineered trachea. Cells were seeded on the scaffold in its initial flat position, maintained their position after the scaffold actuation and proliferated over or inside it. The ability of eCPCs to differentiate towards mature cartialge was evaluated. Interestingly, real-time PCR revealed that differentiating eCPCs on the 4D bioprinted scaffold promote healthy cartilage formation, if compared with eCPCs cultured on 2D static scaffold. Thus, eCPCs can perceive scaffold folding and its final curvature and to react to it, towards the formation of mature cartilage for the airway.

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Human cartilage progenitor cells from ear, nose, rib, and joint have a robust, stable phenotype for cartilage repair

Cited by 3 publications

References 57 publications

A Pilot Study of Decellularized Cartilage for Laryngotracheal Reconstruction in a Neonatal Pig Model

A Pilot Study of Decellularized Cartilage for Laryngotracheal Reconstruction in a Neonatal Pig Model

A Translational Tissue Engineering Approach to Airway Reconstruction Leveraging Decellularized Meniscus and Cartilage Progenitor Cells

4D bioprinted self-folding scaffolds enhance cartilage formation in the engineering of trachea

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