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Engineered cartilaginous tubes for tracheal tissue replacement via self-assembly and fusion of human mesenchymal stem cell constructs.

ABSTRACT: There is a critical need to engineer a neotrachea because currently there are no long-term treatments for tracheal stenoses affecting large portions of the airway. In this work, a modular tracheal tissue replacement strategy was developed. High-cell density, scaffold-free human mesenchymal stem cell-derived cartilaginous rings and tubes were successfully generated through employment of custom designed culture wells and a ring-to-tube assembly system. Furthermore, incorporation of transforming growth factor-?1-delivering gelatin microspheres into the engineered tissues enhanced chondrogenesis with regard to tissue size and matrix production and distribution in the ring- and tube-shaped constructs, as well as luminal rigidity of the tubes. Importantly, all engineered tissues had similar or improved biomechanical properties compared to rat tracheas, which suggests they could be transplanted into a small animal model for airway defects. The modular, bottom up approach used to grow stem cell-based cartilaginous tubes in this report is a promising platform to engineer complex organs (e.g., trachea), with control over tissue size and geometry, and has the potential to be used to generate autologous tissue implants for human clinical applications.

SUBMITTER: Dikina AD

PROVIDER: S-EPMC4379457 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Engineered cartilaginous tubes for tracheal tissue replacement via self-assembly and fusion of human mesenchymal stem cell constructs.

Dikina Anna D AD Strobel Hannah A HA Lai Bradley P BP Rolle Marsha W MW Alsberg Eben E

Biomaterials 20150318

There is a critical need to engineer a neotrachea because currently there are no long-term treatments for tracheal stenoses affecting large portions of the airway. In this work, a modular tracheal tissue replacement strategy was developed. High-cell density, scaffold-free human mesenchymal stem cell-derived cartilaginous rings and tubes were successfully generated through employment of custom designed culture wells and a ring-to-tube assembly system. Furthermore, incorporation of transforming gr ...[more]

PMID: 25818451

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Project description:Biological approaches to intervertebral disc (IVD) restoration and/or regeneration have become of increasing interest. However, the IVD comprises a viscoelastic system whose biological replacement remains challenging. The present study sought to design load-sharing two-component model systems of circular, nested, concentric elements reflecting the nucleus pulposus and annulus fibrosus. Specifically, we wanted to investigate the effect of architectural design variations on (1) model system failure loads when testing the individual materials either separately or homogeneously mixed, and (2) also evaluate the potential of modulating other mechanical properties of the model systems. Two sets of softer and harder biomaterials, 0.5% and 5% agarose vs. 0.5% agarose and gelatin, were used for fabrication. Architectural design variations were realized by varying ring geometries and amounts while keeping the material composition across designs comparable. Variations in the architectural design, such as lamellar width, number, and order, combined with choosing specific biomaterial properties, strongly influenced the biomechanical performance of IVD constructs. Biomechanical characterization revealed that the single most important parameter, in which the model systems vastly exceeded those of the individual materials, was failure load. The model system failure loads were 32.21- and 84.11-fold higher than those of the agarose materials and 55.03- and 2.14-fold higher than those of the agarose and gelatin materials used for system fabrication. The compressive strength, dynamic stiffness, and viscoelasticity of the model systems were always in the range of the individual materials. Relevant architecture-promoted biomechanical performance-tuning of tissue-engineered constructs for biological IVD replacement can be realized by slight modifications in the design of constructs while preserving the materials' compositions. Minimal variations in the architectural design can be used to precisely control structure-function relations for IVD constructs rather than choosing different materials. These fundamental findings have important implications for efficient tissue-engineering of IVDs and other load-bearing tissues, as potential implants need to withstand high in situ loads.

Project description:BACKGROUND:Stem-cell-based, tissue engineered transplants might offer new therapeutic options for patients, including children, with failing organs. The reported replacement of an adult airway using stem cells on a biological scaffold with good results at 6 months supports this view. We describe the case of a child who received a stem-cell-based tracheal replacement and report findings after 2 years of follow-up. METHODS:A 12-year-old boy was born with long-segment congenital tracheal stenosis and pulmonary sling. His airway had been maintained by metal stents, but, after failure, a cadaveric donor tracheal scaffold was decellularised. After a short course of granulocyte colony stimulating factor, bone marrow mesenchymal stem cells were retrieved preoperatively and seeded onto the scaffold, with patches of autologous epithelium. Topical human recombinant erythropoietin was applied to encourage angiogenesis, and transforming growth factor ? to support chondrogenesis. Intravenous human recombinant erythropoietin was continued postoperatively. Outcomes were survival, morbidity, endoscopic appearance, cytology and proteomics of brushings, and peripheral blood counts. FINDINGS:The graft revascularised within 1 week after surgery. A strong neutrophil response was noted locally for the first 8 weeks after surgery, which generated luminal DNA neutrophil extracellular traps. Cytological evidence of restoration of the epithelium was not evident until 1 year. The graft did not have biomechanical strength focally until 18 months, but the patient has not needed any medical intervention since then. 18 months after surgery, he had a normal chest CT scan and ventilation-perfusion scan and had grown 11 cm in height since the operation. At 2 years follow-up, he had a functional airway and had returned to school. INTERPRETATION:Follow-up of the first paediatric, stem-cell-based, tissue-engineered transplant shows potential for this technology but also highlights the need for further research. FUNDING:Great Ormond Street Hospital NHS Trust, The Royal Free Hampstead NHS Trust, University College Hospital NHS Foundation Trust, and Region of Tuscany.

Project description:Recent efforts to tissue engineer long-segment tracheal grafts have been complicated by stenosis and malacia. It has been proposed that both the mechanical characteristics and cell seeding capacity of TETG scaffolds are integral to graft performance. Our aim was to design a tracheal construct that approximates the biomechanical properties of native sheep trachea and optimizes seeding with bone marrow derived mononuclear cells prior to preclinical evaluation in an ovine model.A solution of 8% polyethylene terephthalate (PET) and 3% polyurethane (PU) was prepared at a ratio of either 8:2 or 2:8 and electrospun onto a custom stainless steel mandrel designed to match the dimensional measurements of the juvenile sheep trachea. 3D-printed porous or solid polycarbonate C-shaped rings were embedded within the scaffolds during electrospinning. The scaffolds underwent compression testing in the anterior-posterior and lateral-medial axes and the biomechanical profiles compared to that of a juvenile ovine trachea. The most biomimetic constructs then underwent vacuum seeding with ovine bone marrow derived mononuclear cells. Fluorometric DNA assay was used to quantify scaffold seeding.Both porous and solid rings approximated the biomechanics of the native ovine trachea, but the porous rings were most biomimetic. The load-displacement curve of scaffolds fabricated from a ratio of 2:8 PET:PU most closely mimicked that of native trachea in the anterior-posterior and medial-lateral axes. Solid C-ringed scaffolds had a greater cell seeding efficiency when compared to porous ringed scaffolds (Solid: 19 × 104 vs. Porous: 9.6 × 104 cells/mm3, p = 0.0098).A long segment tracheal graft composed of 2:8 PET:PU with solid C-rings approximates the biomechanics of the native ovine trachea and demonstrates superior cell seeding capacity of the two prototypes tested. Further preclinical studies using this graft design in vivo would inform the rational design of an optimal TETG scaffold.

Dataset Information

Engineered cartilaginous tubes for tracheal tissue replacement via self-assembly and fusion of human mesenchymal stem cell constructs.

Publications

Engineered cartilaginous tubes for tracheal tissue replacement via self-assembly and fusion of human mesenchymal stem cell constructs.

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