The vascularization paradox of non-union formation

Abstract

Despite major research efforts to elucidate mechanisms of non-union formation, failed fracture healing remains a common complication in orthopedic surgery. Adequate vascularization has been recognized as a crucial factor for successful bone regeneration, as newly formed microvessels guarantee the supply of the callus tissue with vital oxygen, nutrients, and growth factors. Accordingly, a vast number of preclinical studies have focused on the development of vascularization strategies to stimulate fracture repair. However, recent evidence suggests that stimulation of blood vessel formation is an oversimplified approach to support bone regeneration. This review discusses the role of vascularization during bone regeneration and delineates a phenomenon, for which we coin the term “the vascularization paradox of non-union-formation”. This view is based on the results of a variety of experimental studies that suggest that the callus tissue of non-unions is indeed densely vascularized and that pro-angiogenic mediators, such as vascular endothelial growth factor, are sufficiently expressed at the facture site. By gaining further insights into the molecular and cellular basis of non-union vascularization, it may be possible to develop more optimized treatment approaches or even prevent the non-union formation in the future.

The human clavicle's nutrient foramen's prevalence, number, location, and direction: A systematic review and meta-analysis

“…35e37 Another explanation is that vascularization may only play a small part in the still largely unclear and complex mechanism that is fracture healing. 38 Lastly, it should be kept in mind, that the nutrient foramen is a surrogate marker for the nutrient artery and does not provide direct evidence of its prevalence, location, or functional role in the clavicular blood supply and fracture management. Another clinically relevant aspect of delineating the clavicle vascular tree is the use of clavipectoral osteomyocutaneus flaps in oromandibular reconstruction.…”

Bone Healing Gone Wrong: Pathological Fracture Healing and Non-Unions—Overview of Basic and Clinical Aspects and Systematic Review of Risk Factors

“…The importance of vascularization for the healing fracture has been highlighted in several studies [35,75,76]. Indeed, microparticle-delivered VEGF and bone morphogenetic proteins (BMP)-2 improved bone healing in murine atrophic non-unions, evidenced by enhanced stiffness and bone volume within the callus [35].…”

Influence of Scaffold Microarchitecture on Angiogenesis and Regulation of Cell Differentiation during the Early Phase of Bone Healing: A Transcriptomics and Histological Analysis

“…A deeper understanding of the causes of unsuccessful healing is essential in current treatment and may even lead to new treatment strategies. More precisely, a better and deeper understanding of the early phase of bone healing in the context of the microarchitecture of bone substitutes, with the help of transcriptomic analysis, could increase our understanding of the interplay between scaffold microarchitecture [ 7 ] and angiogenesis [ 8 ] in bone regeneration [ 9 ]. Moreover, such results might even be transferred to other scaffold-based tissue regeneration concepts since the majority are dependent on angiogenesis.…”