The role of oxygen in bone regeneration

Abstract

One in every 200 people in the U.S. will suffer an amputation. Amputation has protracted effects on vocational outcome, individual productivity, and personal independence far beyond the initial trauma. Amputation of the digit tip within the terminal phalangeal bone of rodents, monkeys, and humans results in near‐perfect regeneration from a cell population called the blastema, which has been well characterized in both adult and neonatal mice. However, it remains unclear why amputations within the more proximal phalangeal elements, or within limbs, fail to produce the same regenerative result. The objective of this study is to gain insight into the role of oxygen in bone regeneration by manipulating oxygen to alter the regenerative process. Using the murine amputation model, we have developed a novel multi‐tissue in vitro slice culture model that is used with mixed gas to control oxygen tension in vitro. To our knowledge, this is the first time such a model has been used in digit regeneration and shows promise as a model for studies involving bone remodeling. Using this model we have determined that 3% oxygen delays bone redifferentiation while 20% oxygen promotes redifferentiation into bone. Incubation of the blastema at 3% oxygen, prior to incubation at 20% oxygen, further accelerated the rate of bone formation. Our results show that the use of sequential incubation in 3% and 20% oxygen can be used to accelerate the regenerative process of bone when used at the correct temporal interval during the regenerative process. Research enabled by this work will lead to a defined mechanistic understanding of oxygen's role in bone regeneration and identify therapeutic targets to enhance regenerative capacity.