Looking Ahead to Engineering Epimorphic Regeneration of a Human Digit or Limb

Abstract

Approximately 2 million people have had limb amputations in the United States due to disease or injury, with more than 185,000 new amputations every year. The ability to promote epimorphic regeneration, or the regrowth of a biologically based digit or limb, would radically change the prognosis for amputees. This ambitious goal includes the regrowth of a large number of tissues that need to be properly assembled and patterned to create a fully functional structure. We have yet to even identify, let alone address, all the obstacles along the extended progression that limit epimorphic regeneration in humans. This review aims to present introductory fundamentals in epimorphic regeneration to facilitate design and conduct of research from a tissue engineering and regenerative medicine perspective. We describe the clinical scenario of human digit healing, featuring published reports of regenerative potential. We then broadly delineate the processes of epimorphic regeneration in nonmammalian systems and describe a few mammalian regeneration models. We give particular focus to the murine digit tip, which allows for comparative studies of regeneration-competent and regeneration-incompetent outcomes in the same animal. Finally, we describe a few forward-thinking opportunities for promoting epimorphic regeneration in humans.

Engineering multicellular systems: Using synthetic biology to control tissue self-organization

“…In many biological systems, it is thought that an endogenous regeneration potential is present, but impeded by competing blocking mechanisms [32–34]. Currently, the combination of stem cells, growth factors, and scaffolds is being explored as a possible therapeutic intervention in degenerative contexts.…”

New insight into functional limb regeneration: A to Z approaches

“…There is an essential demand to pursue investigations in the context of cell therapy and tissue engineering (Laurencin & Nair, ). The few studies that have specifically addressed the lack of tissue engineering and stem cell therapy in limb regeneration have not emphasized the critical issues needed for functional limb regeneration (Laurencin & Nair, ; Quijano, Lynch, Allan, Badylak, & Ahsan, ). Herein, we discuss a different attitude to the therapeutic approaches of limb/digit regeneration.…”

Fibroblast reticular cells engineer a blastema extracellular network during digit tip regeneration in mice

“…Current approaches to enhancing the regeneration of human limb structures involve the use of scaffolds that can be seeded with cells ex vivo or become populated with cells after implantation (Quijano, Lynch, Allan, Badylak, & Ahsan, 2016). Scaffolds are ECM structures that can be biological (Badylak, Freytes, & Gilbert, 2009) or synthetic (Wolf, Dearth, Sonnenberg, Loboa, & Badylak, 2015), and can be molded into distinct forms that approximate the target structure, or they can be derived from the decellularization of tissues or an entire organ, such as the heart, lung, or limb (Jank et al, 2015;Ott et al, 2008;Stabler et al, 2015).…”