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

      research-article
      Author(s): a , b , d , 1 , c , 1 , a , b , 1 , a , b , 1 , c , e , c , c , c , c , a , b , a , b , a , b , a , b , a , b , a , b , c , *
      Publication date (Electronic):
      Journal: EBioMedicine
      Publisher: Elsevier
      Keywords: MC, microtia chondrocyte, PCL, polycaprolactone, ChiCTR, Chinese clinical trial registry, ICTRP, International Clinical Trial Registry Platform, SOP, standard operating procedures, PGA, polyglycolic acid, PLA, polylactic acid, GMP, good manufacturing procedure, PBS, phosphate buffered saline, DMEM, Dulbecco's modified Eagle's medium, bFGF, basic fibroblast growth factor, FBS, fetal bovine serum, CAD, computer aided design, CAM, computer aided manufacturing, SEM, scanning electron microscopy, ECM, extracellular matrices, TGF-β1, transforming growth factor-beta1, IGF-I, insulin-like growth factor-I, MRI, magnetic resonance imaging, HE, hematoxylin and eosin, SO/FG, Safranin-O/Fast Green, EvG, Verhoeff van Gieson, HRP, horseradish peroxidase, DAB, diaminobenzidine tetrahydrochloride, Mn, number-average molecular weight, Mw, weight-average molecular weight, SEC, size exclusion chromatography, GAG, glycosaminoglycan, Microtia chondrocytes, Human ear-shaped cartilage, In vitro engineering, 3D printing, Polycaprolactone (PCL), Clinical trial

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          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 2.5 years 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).

          Highlights

          • •

            Patient-specific ear-shaped cartilage was engineered in vitro using expanded MCs and compound biodegradable scaffold.

          • •

            The first microtia case treated with the tissue engineered ear-shaped cartilage was follow-up for 2.5 years.

          • •

            Other four cases with similar and different surgical procedures were also presented.

          Microtia is a congenital external ear malformation that can seriously influence the psychological and physiological well-being of affected children. Using expanded microtia chondrocytes, compound biodegradable scaffold, and in vitro culture technique, we engineered patient-specific ear-shaped cartilage in vitro, and performed a pilot clinical trial of auricle reconstruction using the engineered ear cartilage on five patients. Satisfactory aesthetical outcome with mature cartilage formation was achieved with the longest follow-up of 2.5 years.

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          Mechanical properties and cell cultural response of polycaprolactone scaffolds designed and fabricated via fused deposition modeling.

          D W Hutmacher, T Schantz, I Zein … (2001)
          A number of different processing techniques have been developed to design and fabricate three-dimensional (3D) scaffolds for tissue-engineering applications. The imperfection of the current techniques has encouraged the use of a rapid prototyping technology known as fused deposition modeling (FDM). Our results show that FDM allows the design and fabrication of highly reproducible bioresorbable 3D scaffolds with a fully interconnected pore network. The mechanical properties and in vitro biocompatibility of polycaprolactone scaffolds with a porosity of 61 +/- 1% and two matrix architectures were studied. The honeycomb-like pores had a size falling within the range of 360 x 430 x 620 microm. The scaffolds with a 0/60/120 degrees lay-down pattern had a compressive stiffness and a 1% offset yield strength in air of 41.9 +/- 3.5 and 3.1 +/- 0.1 MPa, respectively, and a compressive stiffness and a 1% offset yield strength in simulated physiological conditions (a saline solution at 37 degrees C) of 29.4 +/- 4.0 and 2.3 +/- 0.2 MPa, respectively. In comparison, the scaffolds with a 0/72/144/36/108 degrees lay-down pattern had a compressive stiffness and a 1% offset yield strength in air of 20.2 +/- 1.7 and 2.4 +/- 0.1 MPa, respectively, and a compressive stiffness and a 1% offset yield strength in simulated physiological conditions (a saline solution at 37 degrees C) of 21.5 +/- 2.9 and 2.0 +/- 0.2 MPa, respectively. Statistical analysis confirmed that the five-angle scaffolds had significantly lower stiffness and 1% offset yield strengths under compression loading than those with a three-angle pattern under both testing conditions (p < or = 0.05). The obtained stress-strain curves for both scaffold architectures demonstrate the typical behavior of a honeycomb structure undergoing deformation. In vitro studies were conducted with primary human fibroblasts and periosteal cells. Light, environmental scanning electron, and confocal laser microscopy as well as immunohistochemistry showed cell proliferation and extracellular matrix production on the polycaprolactone surface in the 1st culturing week. Over a period of 3-4 weeks in a culture, the fully interconnected scaffold architecture was completely 3D-filled by cellular tissue. Our cell culture study shows that fibroblasts and osteoblast-like cells can proliferate, differentiate, and produce a cellular tissue in an entirely interconnected 3D polycaprolactone matrix. Copyright 2001 John Wiley & Sons, Inc.
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            A new method of total reconstruction of the auricle for microtia.

            S Nagata (1993)
            This new method for total reconstruction of the auricle is a two-stage operation in which the first stage involves fabrication and grafting of a three-dimensional costal cartilage framework and the second stage is the ear elevation operation. The three-dimensional frame was designed with emphasis on the fabrication of the helical crus, intertragic notch, and antitragus and by extending the crus helicis and fixing it to the undersurface of the base frame. The reconstructed auricle will have four different floors: the cymba and cavum conchae are the bottom (fourth) level, the crus helicis is the third level, the fossa triangularis and the scapha are the second level, and the helix, anthelix, tragus, and antitragus are the top level. The skin incision was made in a W-shaped fashion to create skin flaps with ample surface area to cover the three-dimensional frame without skin grafting. Furthermore, the semilunar costal cartilage was utilized for ear elevation. Thus this new method for total reconstruction of the auricle eliminates the major problems encountered with the conventional method.
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              High-Fidelity Tissue Engineering of Patient-Specific Auricles for Reconstruction of Pediatric Microtia and Other Auricular Deformities

              Alyssa Reiffel, Concepcion Kafka, Karina A. Hernandez … (2013)
              Introduction Autologous techniques for the reconstruction of pediatric microtia often result in suboptimal aesthetic outcomes and morbidity at the costal cartilage donor site. We therefore sought to combine digital photogrammetry with CAD/CAM techniques to develop collagen type I hydrogel scaffolds and their respective molds that would precisely mimic the normal anatomy of the patient-specific external ear as well as recapitulate the complex biomechanical properties of native auricular elastic cartilage while avoiding the morbidity of traditional autologous reconstructions. Methods Three-dimensional structures of normal pediatric ears were digitized and converted to virtual solids for mold design. Image-based synthetic reconstructions of these ears were fabricated from collagen type I hydrogels. Half were seeded with bovine auricular chondrocytes. Cellular and acellular constructs were implanted subcutaneously in the dorsa of nude rats and harvested after 1 and 3 months. Results Gross inspection revealed that acellular implants had significantly decreased in size by 1 month. Cellular constructs retained their contour/projection from the animals' dorsa, even after 3 months. Post-harvest weight of cellular constructs was significantly greater than that of acellular constructs after 1 and 3 months. Safranin O-staining revealed that cellular constructs demonstrated evidence of a self-assembled perichondrial layer and copious neocartilage deposition. Verhoeff staining of 1 month cellular constructs revealed de novo elastic cartilage deposition, which was even more extensive and robust after 3 months. The equilibrium modulus and hydraulic permeability of cellular constructs were not significantly different from native bovine auricular cartilage after 3 months. Conclusions We have developed high-fidelity, biocompatible, patient-specific tissue-engineered constructs for auricular reconstruction which largely mimic the native auricle both biomechanically and histologically, even after an extended period of implantation. This strategy holds immense potential for durable patient-specific tissue-engineered anatomically proper auricular reconstructions in the future.
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                Author and article information

                Contributors
                Yilin Cao
                Journal
                Journal ID (nlm-ta): EBioMedicine
                Journal ID (iso-abbrev): EBioMedicine
                Title: EBioMedicine
                Publisher: Elsevier
                ISSN (Electronic): 2352-3964
                Publication date PMC-release: 13 January 2018
                Publication date Collection: February 2018
                Publication date (Electronic): 13 January 2018
                Volume: 28
                Pages: 287-302
                Affiliations
                [a ]Shanghai Tissue Engineering Research Key Laboratory, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
                [b ]National Tissue Engineering Center of China, Shanghai, PR China
                [c ]Auricular Center, Plastic Surgery Hospital, Chinese Academy of Medical Science, Beijing, PR China
                [d ]Research Institute of Plastic Surgery, Plastic Surgery Hospital, Wei Fang Medical College, Weifang, Shandong Province, PR China
                [e ]Department of Plastic Surgery, Xin Hua Hospital, Dalian University, Dalian, Liaoning Province, PR China
                Author notes
                [* ]Corresponding author at: Shanghai Tissue Engineering Research Key Laboratory, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; 639 Zhi Zao Ju Road, Shanghai 200011, PR China.Shanghai Tissue Engineering Research Key LaboratoryShanghai Ninth People's HospitalShanghai Jiao Tong University School of Medicine639 Zhi Zao Ju RoadShanghai200011PR China yilincao@ 123456yahoo.com
                [1]

                These authors are equal to this work.

                Article
                Publisher ID: S2352-3964(18)30016-1
                DOI: 10.1016/j.ebiom.2018.01.011
                PMC ID: 5835555
                PubMed ID: 29396297
                SO-VID: ae981e9e-b1a9-4eb1-8043-95bbb468ff81
                Copyright © © 2018 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 25 December 2017
                Date revision received : 11 January 2018
                Date accepted : 11 January 2018
                Categories
                Subject: Research Paper

                Keywords: mc, microtia chondrocyte,pcl, polycaprolactone,chictr, chinese clinical trial registry,ictrp, international clinical trial registry platform,sop, standard operating procedures,pga, polyglycolic acid,pla, polylactic acid,gmp, good manufacturing procedure,pbs, phosphate buffered saline,dmem, dulbecco's modified eagle's medium,bfgf, basic fibroblast growth factor,fbs, fetal bovine serum,cad, computer aided design,cam, computer aided manufacturing,sem, scanning electron microscopy,ecm, extracellular matrices,tgf-β1, transforming growth factor-beta1,igf-i, insulin-like growth factor-i,mri, magnetic resonance imaging,he, hematoxylin and eosin,so/fg, safranin-o/fast green,evg, verhoeff van gieson,hrp, horseradish peroxidase,dab, diaminobenzidine tetrahydrochloride,mn, number-average molecular weight,mw, weight-average molecular weight,sec, size exclusion chromatography,gag, glycosaminoglycan,microtia chondrocytes,human ear-shaped cartilage,in vitro engineering,3d printing,polycaprolactone (pcl),clinical trial
                Data availability:
                Keywords: mc, microtia chondrocyte, pcl, polycaprolactone, chictr, chinese clinical trial registry, ictrp, international clinical trial registry platform, sop, standard operating procedures, pga, polyglycolic acid, pla, polylactic acid, gmp, good manufacturing procedure, pbs, phosphate buffered saline, dmem, dulbecco's modified eagle's medium, bfgf, basic fibroblast growth factor, fbs, fetal bovine serum, cad, computer aided design, cam, computer aided manufacturing, sem, scanning electron microscopy, ecm, extracellular matrices, tgf-β1, transforming growth factor-beta1, igf-i, insulin-like growth factor-i, mri, magnetic resonance imaging, he, hematoxylin and eosin, so/fg, safranin-o/fast green, evg, verhoeff van gieson, hrp, horseradish peroxidase, dab, diaminobenzidine tetrahydrochloride, mn, number-average molecular weight, mw, weight-average molecular weight, sec, size exclusion chromatography, gag, glycosaminoglycan, microtia chondrocytes, human ear-shaped cartilage, in vitro engineering, 3d printing, polycaprolactone (pcl), clinical trial

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