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In Vitro Regeneration of Patient-specific Ear-shaped Cartilage and Its First Clinical Application for Auricular Reconstruction.

ABSTRACT: Microtia is a congenital external ear malformation that can seriously influence the psychological and physiological well-being of affected children. The successful regeneration of human ear-shaped cartilage using a tissue engineering approach in a nude mouse represents a promising approach for auricular reconstruction. However, owing to technical issues in cell source, shape control, mechanical strength, biosafety, and long-term stability of the regenerated cartilage, human tissue engineered ear-shaped cartilage is yet to be applied clinically. Using expanded microtia chondrocytes, compound biodegradable scaffold, and in vitro culture technique, we engineered patient-specific ear-shaped cartilage in vitro. Moreover, the cartilage was used for auricle reconstruction of five microtia patients and achieved satisfactory aesthetical outcome with mature cartilage formation during 2.5years follow-up in the first conducted case. Different surgical procedures were also employed to find the optimal approach for handling tissue engineered grafts. In conclusion, the results represent a significant breakthrough in clinical translation of tissue engineered human ear-shaped cartilage given the established in vitro engineering technique and suitable surgical procedure. This study was registered in Chinese Clinical Trial Registry (ChiCTR-ICN-14005469).

SUBMITTER: Zhou G

PROVIDER: S-EPMC5835555 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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In Vitro Regeneration of Patient-specific Ear-shaped Cartilage and Its First Clinical Application for Auricular Reconstruction.

Zhou Guangdong G Jiang Haiyue H Yin Zongqi Z Liu Yu Y Zhang Qingguo Q Zhang Chen C Pan Bo B Zhou Jiayu J Zhou Xu X Sun Hengyun H Li Dan D He Aijuan A Zhang Zhiyong Z Zhang Wenjie W Liu Wei W Cao Yilin Y

EBioMedicine 20180113

Microtia is a congenital external ear malformation that can seriously influence the psychological and physiological well-being of affected children. The successful regeneration of human ear-shaped cartilage using a tissue engineering approach in a nude mouse represents a promising approach for auricular reconstruction. However, owing to technical issues in cell source, shape control, mechanical strength, biosafety, and long-term stability of the regenerated cartilage, human tissue engineered ear ...[more]

PMID: 29396297

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Project description:In vitro construction is a major trend involved in cartilage regeneration and repair. Satisfactory in vitro cartilage regeneration depends on a suitable culture system. Current chondrogenic culture systems with a high content of transforming growth factor beta-1 effectively promote cartilaginous extracellular matrix (ECM) production but inhibit chondrocyte survival. As is known, inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway acts in blocking the progression of osteoarthritis by reducing chondrocyte apoptosis and cartilage destruction. However, whether inhibiting JNK signaling resists the inhibitory effect of current chondrogenic medium (CM) on cell survival and affects in vitro auricular cartilage regeneration (including cell proliferation, ECM synthesis, and degradation) has not been investigated. In order to address these issues and optimize the chondrogenic culture system, we generated a three-dimensional in vitro auricular cartilage regeneration model to investigate the effects of SP600125 (a JNK-specific inhibitor) on chondrocyte proliferation and ECM metabolism. SP600125 supplementation efficiently promoted cell proliferation at both cellular and tissue levels and canceled the negative effect of our chondrogenic culture system on cell survival. Moreover, it significantly inhibited ECM degradation by reducing the expressions of tumor necrosis factor-alpha, interleukin-1-beta, and matrix metalloproteinase 13. In addition, SP600125 inhibited ECM synthesis at both cellular and tissue levels, but this could be canceled and even reversed by adding chondrogenic factors; yet this enabled a sufficient number of chondrocytes to be retained at the same time. Thus, SP600125 had a positive effect on in vitro auricular cartilage regeneration in terms of cell proliferation and ECM degradation but a negative effect on ECM synthesis, which could be reversed by adding CM. Therefore, a combination of SP600125 and CM might help in optimizing current chondrogenic culture systems and achieve satisfactory in vitro cartilage regeneration by promoting cell proliferation, reducing ECM degradation, and enhancing ECM synthesis.

Project description:PURPOSE:The significant shortcomings associated with current autologous reconstructive options for auricular deformities have inspired great interest in a tissue engineering solution. A major obstacle in the engineering of human auricular cartilage is the availability of sufficient autologous human chondrocytes. A clinically obtainable amount of auricular cartilage tissue (ie, 1 g) only yields approximately 10 million cells, where 25 times this amount is needed for the fabrication of a full-scale pediatric ear. It is thought that repeated passaging of chondrocytes leads to dedifferentiation and loss of the chondrogenic potential. However, little to no data exist regarding the ideal number of times that human auricular chondrocytes (HAuCs) can be passaged in a manner that maximizes the cellular expansion while minimizing dedifferentiation. METHODS:Human auricular chondrocytes were isolated from discarded otoplasty specimens. The HAuCs were then expanded, and cells from passages 3, 4, and 5 were encapsulated into discs 8 mm in diameter made from type I collagen hydrogels with a cell density of 25 million cells/mL. The constructs were implanted subcutaneously in the dorsa of nude mice and harvested after 1 and 3 months for analysis. RESULTS:Constructs containing passages 3, 4, and 5 chondrocytes all maintained their original cylindrical geometry. After 3 months in vivo, the diameters of the P3, P4, and P5 discs were 69 ± 9%, 67 ± 10%, and 73 ± 15% of their initial diameter, respectively. Regardless of the passage number, all constructs developed a glossy white cartilaginous appearance, similar to native auricular cartilage. Histologic analysis demonstrated development of an organized perichondrium composed of collagen, a rich proteoglycan matrix, cellular lacunae, and a dense elastin fibrin network by Safranin-O and Verhoeff stain. Biochemical analysis confirmed similar amounts of proteoglycan and hydroxyproline content in late passage constructs when compared with native auricular cartilage. CONCLUSIONS:These data indicate that late passage HAuCs (up to passage 5) form elastic cartilage that is histologically, biochemically, and biomechanically similar to native human elastic cartilage and have the potential to be used for auricular cartilage engineering.

Dataset Information

In Vitro Regeneration of Patient-specific Ear-shaped Cartilage and Its First Clinical Application for Auricular Reconstruction.

Publications

In Vitro Regeneration of Patient-specific Ear-shaped Cartilage and Its First Clinical Application for Auricular Reconstruction.

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