Hypoxia in Bone and Oxygen Releasing Biomaterials in Fracture Treatments Using Mesenchymal Stem Cell Therapy: A Review

Abstract

Bone fractures have a high degree of severity. This is usually a result of the physical trauma of diseases that affect bone tissues, such as osteoporosis. Due to its highly vascular nature, the bone is in a constant state of remodeling. Although those of younger ages possess bones with high regenerative potential, the impact of a disrupted vasculature can severely affect the recovery process and cause osteonecrosis. This is commonly seen in the neck of femur, scaphoid, and talus bone. In recent years, mesenchymal stem cell (MSC) therapy has been used to aid in the regeneration of afflicted bone. However, the cut-off in blood supply due to bone fractures can lead to hypoxia-induced changes in engrafted MSCs. Researchers have designed several oxygen-generating biomaterials and yielded varying degrees of success in enhancing tissue salvage and preserving cellular metabolism under ischemia. These can be utilized to further improve stem cell therapy for bone repair. In this review, we touch on the pathophysiology of these bone fractures and review the application of oxygen-generating biomaterials to further enhance MSC-mediated repair of fractures in the three aforementioned parts of the bone.

Harnessing the potential of oxygen-generating materials and their utilization in organ-specific delivery of oxygen

“…74 Such injuries are either healed by natural regeneration processes or corrected by clinical interventions such as caste wrapping, internal fixation, surgeries, or bone grafting. 75,76 Although grafting is the currently used gold standard approach for repairing critical sized bone defects, availability of the grafts is limited, and the demand far outweighs the supply. As such, there is a lot of ongoing research seeking to make oxygen-releasing engineered tissues for grafting out of more readily available materials to solve these challenges.…”

Construction of Bone Hypoxic Microenvironment Based on Bone-on-a-Chip Platforms

“…In a normal oxygen environment, the oxygen-dependent domain (ODD) of α subunits is hydroxylated by proline hydroxylase domain enzymes (PHDs, including PHD 1, PHD 2, and PHD 3). Among these enzymes, PHD2 plays an important physiological function and PHD1 and PHD3 play a role in mitochondrial energy metabolism and innate immune responses, respectively ( Figure 1 C) [ 12 , 27 ]. HIF-α is ubiquitinated by the ubiquitin enzyme von Hippel Lindau tumor suppressor protein, and degraded, leading to a decline in intracellular HIF levels, which shapes the different sensing states of the cell in response to oxygen under different oxygen content environments: In a hypoxic environment, HIF-α levels are elevated, resulting in the nuclear β dimerization of subunits.…”

ETV2 regulating PHD2-HIF-1α axis controls metabolism reprogramming promotes vascularized bone regeneration

“…Microcirculation disruption caused by bone fractures leads to a critical hypoxic microenvironment [ 14 ]. Under hypoxic conditions, reactive hypoxia-inducible factor-1α (HIF-1α) activation induces metabolic reprogramming in osteoblasts, shifting from aerobic respiration to anaerobic glycolysis [ 15 ].…”