TISSUE ENGINEERING: Part A Volume 22, Numbers 3 and 4, 2016 ª Mary Ann Liebert, Inc. DOI: 10.1089/ten.tea.2015.0514


Tissue Engineering for Pediatric Applications Corin Williams, PhD,1 and Robert E. Guldberg, PhD 2

Severe birth defects occur in *2–3% of live-born infants and are a leading cause of death in the young. Structural malformations can occur in just about any major organ system and often their causes are unknown. The pediatric population presents a unique set of opportunities to the field of tissue engineering and regenerative medicine (TERM). Infants and young children have significantly greater regenerative capacity than adults, which could be leveraged in TERM strategies. Children also arguably stand to benefit the most from TERM. Although the lack of growth potential and relatively short life span of synthetic materials may be suitable for adults, it is unacceptable for children. Furthermore, given that there is a particular scarcity of pediatric donor organs, the need for living functional tissue replacements that can grow with the child is quite evident. There is enormous potential for the TERM community to address the needs of the pediatric population.


his special collection gives a glimpse of the vast array of challenges and opportunities in pediatric tissue engineering and regenerative medicine (TERM). The methods article by Jiang et al.1 presents an interesting concept of ‘‘perinatal tissue engineering’’ by deriving induced pluripotent stem cells from the placental chorion, a tissue that is genetically identical to that of the baby and usually discarded at birth. Benavides et al.2 show that amniotic fluid-derived stem cells, which can be harvested before birth, are capable of generating blood vessel-like networks. In addition, Duan et al.3 emphasize the need to consider appropriate cell sources either for implantation or for comparison, as pediatric and adult cells can behave quite differently. The articles by Caballero et al.,4 Paniagua Gutierrez et al.,5 Shakir et al.,6 Santa Maria et al.,7 and Ott et al.8 highlight the importance of using young animal models to test pediatric TERM strategies. For TERM to see widespread clinical translation, it must be cost-effective. To this end, work from the laboratories of Toshiharu Shinoka and Christopher Breuer, who have made some of the most significant advances in pediatric TERM, presents a ‘‘closed system’’ approach for engineered vascular grafts as an alternative to the ‘‘open’’ clean room.9 Target applications represented in this collection are equally varied, although far from exhaustive. Craniofacial defects present at birth or due to trauma result in significant morbidity in children and are addressed by the work of Caballero et al.4 and Shakir et al.6 Heart valves are one of the most desperately needed engineered tissues for children born with congenital heart defects; some interesting findings in cell-based and decellularized scaffold-based approaches are

presented by Duan et al.3 and Paniagua Gutierrez et al.,5 respectively. Santa Maria et al.7 show promising results from a growth factor-loaded hydrogel for nonsurgical repair of chronic perforation of the tympanic membrane, a major cause of hearing loss in children in developing countries. Finally, Ott et al.8 demonstrate a functional tissue-engineered solution for tracheal stenosis, a life-threatening condition that can be congenital or acquired in children. Many of these challenges, opportunities, and applications could also be extended more broadly to adult disease. The recent advances in pediatric TERM that have been collected in this special issue are exciting. Nevertheless, there are several major hurdles to success, which need to be addressed in future work. Some birth defects are due to genetic mutations that result in impaired cell and tissue function. Gene editing or other creative approaches to overcome inherent defects will likely need to be combined with TERM for autologous cell-based repair and regeneration for these patients. Children with severe structural defects require surgical reconstruction of large portions of tissue or even whole organ transplant. The generation of thick vascularized grafts that recapitulate the complex structure and function of native tissue remains a major challenge to the field of tissue engineering. Finally, it must be noted that the physiology and pathology of diseases in children are often much different than those in adults. Therapies that have been developed for adults often fail or cannot be readily adapted to children. Therefore, demonstration of safety is also paramount for pediatric TERM applications, as it is often unknown how children will respond to certain


Department of Biomedical Engineering, Tufts University, Medford, Massachusetts. Parker H. Pedit Institute for Bioengineering & Bioscience, Georgia Institute of Technology; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University; George W. Woodurff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia. 2



therapies or what the appropriate dose should be. The development of appropriate animal models for pediatric defects and diseases will be necessary for the preclinical testing and eventual clinical translation of promising TERM strategies that will improve the survival and quality of life of many children. Disclosure Statement

No competing financial interests exist. References

1. Jiang, G., Di Bernardo, J., DeLong, C.J., Monteiro da Rocha, A., O’Shea, K.S., Kunisaki, and S.M. Induced pluripotent stem cells from human placental chorion for perinatal tissue engineering applications. Tissue Eng Part C Methods 20, 731, 2014. 2. Benavides, O.M., Quinn, J.P., Pok, S., Connell, J.P., Ruano, R., and Jacot, J.G. Capillary-like network formation by human amniotic fluid-derived stem cells within fibrin/poly(ethylene glycol) hydrogels. Tissue Eng Part A 21, 1185, 2015. 3. Duan, B., Hockaday, L.A., Das, S., Xu, C., and Butcher, J.T. Comparison of mesenchymal stem cell source differentiation toward human pediatric aortic valve interstitial cells within 3D engineered matrices. Tissue Eng Part C Methods 21, 795, 2015. 4. Caballero, M., Morse, J.C., Halevi, A.E., Emodi, O., Pharaon, M.R., Wood, J.S., and van Aalst, J.A. Juvenile swine surgical alveolar cleft model to test novel autologous stem cell therapies. Tissue Eng Part C Methods 21, 898, 2015. 5. Paniagua Gutierrez, J.R., Berry, H., Korossis, S., Mirsadraee, S., Lopes, S.V., da Costa, F., Kearney, J., Watterson, K., Fisher, J., and Ingham, E. Regenerative potential of lowconcentration SDS-decellularized porcine aortic valved conduits in vivo. Tissue Eng Part A 21, 332, 2015.


6. Shakir, S., MacIsaac, Z.M., Naran, S., Smith, D.M., Bykowski, M.R., Cray, J.J., Craft, T.K., Wang, D., Weiss, L., Campbell, P.G., Mooney, M.P., Losee, J.E., and Cooper, G.M. Transforming growth factor beta 1 augments calvarial defect healing and promotes suture regeneration. Tissue Eng Part A 21, 939, 2015. 7. Santa Maria, P.L., Kim, S., Varsak, Y.K., and Yang, Y.P. Heparin binding-epidermal growth factor-like growth factor for the regeneration of chronic tympanic membrane perforations in mice. Tissue Eng Part A 21, 1483, 2015. 8. Ott, L.M., Vu, C.H., Farris, A.L., Fox, K.D., Galbraith, R.A., Weiss, M.L., Weatherly, R.A., and Detamore, M.S. Functional reconstruction of tracheal defects by protein-loaded, cell-seeded, fibrous constructs in rabbits. Tissue Eng Part A 21, 2390, 2015. 9. Kurobe, H., Maxfield, M.W., Naito, Y., Cleary, M., Stacy, M.R., Solomon, D., Rocco, K.A., Tara, S., Lee, A.Y., Sinusas, A.J., Snyder, E.L., Shinoka, T., and Breuer, C.K. Comparison of a closed system to a standard open technique for preparing tissue-engineered vascular grafts. Tissue Eng Part C Methods 21, 88, 2015.

Address correspondence to: Corin Williams, PhD Department of Biomedical Engineering Tufts University 4 Colby Street Medford, MA 02155 E-mail: [email protected] Received: November 12, 2015 Accepted: November 12, 2015 Online Publication Date: December 18, 2015

Tissue Engineering for Pediatric Applications.

Severe birth defects occur in ∼ 2-3% of live-born infants and are a leading cause of death in the young. Structural malformations can occur in just ab...
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