Effects of BMP‐2 dose and delivery of microvascular fragments on healing of bone defects with concomitant volumetric muscle loss

Abstract

Traumatic composite bone‐muscle injuries, such as open fractures, often require multiple surgical interventions and still typically result in long‐term disability. Clinically, a critical indicator of composite injury severity is vascular integrity; vascular damage alone is sufficient to assign an open fracture to the most severe category. Challenging bone injuries are often treated with bone morphogenetic protein 2 (BMP‐2), an osteoinductive growth factor, delivered on collagen sponge. Previous studies in a composite defect model found that a minimally bridging dose in the segmental defect model was unable to overcome concomitant muscle damage, but the effect of BMP dose on composite injuries has not yet been studied. Here, we test the hypotheses that BMP‐2‐mediated functional regeneration of composite extremity injuries is dose dependent and can be further enhanced via co‐delivery of adipose‐derived microvascular fragments (MVF), which have been previously shown to increase tissue vascular volume. Although MVF did not improve healing outcomes, we observed a significant BMP‐2 dose‐dependent increase in regenerated bone volume and biomechanical properties. This is the first known report of an increased BMP‐2 dose improving bone healing with concomitant muscle damage. While high dose BMP‐2 delivery can induce heterotopic ossification (HO) and increased inflammation, the maximum 10 μg dose used in this study did not result in HO and was associated with a lower circulating inflammatory cytokine profile than the low dose (2.5 μg) group. These data support the potential benefits of an increased, though still moderate, BMP‐2 dose for treatment of bone defects with concomitant muscle damage. Published 2019. This article is a U.S. Government work and is in the public domain in the USA. J Orthop Res

The vascularization paradox of non-union formation

“…However, the data of this study shows that these highly angiogenic vascularization units did not improve but even impaired the formation of new bone within the defects [102]. These findings are supported by an experimental studies of Ruehle et al [103,104], which evaluated the effects of BMP-2 compared to BMP-2 in combination with MVFs in bone defects with concomitant muscle loss. The results showed a decreased bending stiffness and larger areas of non-mineralized, marrow-like tissue in bone defects additionally treated with MVFs [103].…”

“…These findings are supported by an experimental studies of Ruehle et al [ 103 , 104 ], which evaluated the effects of BMP-2 compared to BMP-2 in combination with MVFs in bone defects with concomitant muscle loss. The results showed a decreased bending stiffness and larger areas of non-mineralized, marrow-like tissue in bone defects additionally treated with MVFs [ 103 ]. These observations imply that extensive angiogenesis and vascularization may not support, but, paradoxically, may even hamper adequate fracture repair and, therefore, aggravate non-union formation.…”

Tibial bone strength is negatively affected by volumetric muscle loss injury to the adjacent muscle in male mice

“…However, the extent to which less forceful contractions (lower mechanical loads applied to bone) influence bone morphological and functional changes after VML injury are not established. We are not aware of any data from human studies directly addressing this, and the data from animal studies are sparse and indirect (i.e., involve VML plus bone fracture 27–29 ).…”

Encapsulated vaterite-calcite CaCO3 particles loaded with Mg2+ and Cu2+ ions with sustained release promoting osteogenesis and angiogenesis

“…Vascular endothelial growth factor (VEGF) is widely used in bone tissue engineering research for the improvement of tissue vascularization, either alone or in combination with BMP-2 ( Liu et al, 2020 ; Fitzpatrick et al, 2021 ). However, significant disadvantages are associated with these protein growth factors-based therapeutics, including the sever complications caused by the supraphysiological dose applied, the instability in the fabrication process, and the high cost ( Ruehle et al, 2019 ; Gelebart et al, 2022 ). Repeated clinical applications of BMP-2 have not been approved as safe and effective by the United States Food and Drug Administration (FDA) ( SSED, 2022 ).…”