Research Article: A Modular Strategy to Engineer Complex Tissues and Organs

Date Published: February 14, 2018

Publisher: John Wiley and Sons Inc.

Author(s): Anna D. Dikina, Daniel S. Alt, Samuel Herberg, Alexandra McMillan, Hannah A. Strobel, Zijie Zheng, Meng Cao, Bradley P. Lai, Oju Jeon, Victoria Ivy Petsinger, Calvin U. Cotton, Marsha W. Rolle, Eben Alsberg.


Currently, there are no synthetic or biologic materials suitable for long‐term treatment of large tracheal defects. A successful tracheal replacement must (1) have radial rigidity to prevent airway collapse during respiration, (2) contain an immunoprotective respiratory epithelium, and (3) integrate with the host vasculature to support epithelium viability. Herein, biopolymer microspheres are used to deliver chondrogenic growth factors to human mesenchymal stem cells (hMSCs) seeded in a custom mold that self‐assemble into cartilage rings, which can be fused into tubes. These rings and tubes can be fabricated with tunable wall thicknesses and lumen diameters with promising mechanical properties for airway collapse prevention. Epithelialized cartilage is developed by establishing a spatially defined composite tissue composed of human epithelial cells on the surface of an hMSC‐derived cartilage sheet. Prevascular rings comprised of human umbilical vein endothelial cells and hMSCs are fused with cartilage rings to form prevascular–cartilage composite tubes, which are then coated with human epithelial cells, forming a tri‐tissue construct. When prevascular– cartilage tubes are implanted subcutaneously in mice, the prevascular structures anastomose with host vasculature, demonstrated by their ability to be perfused. This microparticle–cell self‐assembly strategy is promising for engineering complex tissues such as a multi‐tissue composite trachea.

Partial Text

Patients suffering from tracheal stenosis have a significantly reduced quality of life. The diseased region of the trachea cannot be resected when more than half of the airway is affected in adults.1 Thus, tracheal tissue engineering has the exciting potential to fill this gap and will have a tremendous impact for the patients in need. A variety of tracheal replacement strategies have been developed in vitro and implanted in vivo, both in animals and human patients, including cell‐free artificial prostheses,2 autografts,3 intact allografts or decellularized allografts often seeded with the recipient’s own cells,4 high‐cell density constructs derived from mature cell sources,5 and primarily scaffold‐based tissue engineered constructs.6 Despite the broad range of approaches, each has its own shortcomings ranging from the technical, such as restenosis,[[qv: 1c,3b]] to the practical, such as lack of tissue availability.

In this work, a modular, scaffold‐free approach for engineering complex tubular hollow organs was presented via the formation of a tri‐tissue engineered trachea. The three distinct tissues (i.e., cartilage, epithelial, and vascular) with defined spatial placement provide for luminal rigidity, a respiratory epithelium and prevascular structures to facilitate perfusion after implantation and anastomosis with host vasculature. Moving forward, prevascular–cartilaginous tubes may be epithelialized on the lumen with the aid of a tubular organ bioreactor.[[qv: 4d,f,41]] This modular, tubular tissue and organ engineering approach may also find great utility for regenerating other tissues such as large blood vessels and segments of the gastrointestinal (i.e., esophagus, intestines) and urinary (i.e., ureters) tract.

Experimental Design: Four research objectives were examined in this body of work (Figure 1). The goal of Part Ia was to tune the thickness of engineered cartilage rings. Part Ib aimed to develop cartilage rings and tubes with custom‐defined lumen diameters. In Part II, a respiratory epithelium was engineered on the cartilaginous surface of cartilage tissues. Lastly, Part III focused on developing multi‐tissue type tubular constructs comprised of prevascular rings fused with cartilaginous rings, which were ultimately seeded with epithelial cells.

The authors declare no conflict of interest.




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