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.

FIG. 1.

The process of amphibian epimorphic regeneration. An intact limb consists of tissues of various types, including dermal, skeletal, neural, and vascular. After amputation, the wound heals to form an epidermal layer, the underlying tissues undergo matrix remodeling, and cells in the region secrete soluble factors. A heterogeneous cell mass, or blastema, forms from the proliferation and migration of cells from the adjacent tissues. The blastema then gives rise to the various new tissues that are spatially patterned to reconstruct the original limb structure. Color images available online at www.liebertpub.com/teb

FIG. 2.

Regeneration in the murine digit model. Epimorphic regeneration in the murine digit is level-specific and provides an opportunity for comparative studies of mammalian epimorphic regeneration. Transection through the P2 element results in the frequent outcome of fibrotic scar tissue formation. Transection through the more distal P3 element instead results in the regeneration of missing tissue. Color images available online at www.liebertpub.com/teb

FIG. 3.

Opportunities for engineering epimorphic regeneration. Epimorphic regeneration has been observed in distal finger tips of children and young adults. Converting such stochastic events into designed clinical outcomes will require altering the default postamputation progression. Engineering the epimorphic regeneration process may include the transplantation of cells, scaffolds, and/or soluble factors, as well as controlling microenvironmental aspects, such as oxygen concentration, tissue hydration, mechanical, and electrical cues. Color images available online at www.liebertpub.com/teb