Vascularization Strategies in the Prevention of Nonunion Formation

Abstract

Delayed healing and nonunion formation are major challenges in orthopedic surgery, which require the development of novel treatment strategies. Vascularization is considered one of the major prerequisites for successful bone healing, providing an adequate nutrient supply and allowing the infiltration of progenitor cells to the fracture site. Hence, during the last decade, a considerable number of studies have focused on the evaluation of vascularization strategies to prevent or to treat nonunion formation. These involve (1) biophysical applications, (2) systemic pharmacological interventions, and (3) tissue engineering, including sophisticated scaffold materials, local growth factor delivery systems, cell-based techniques, and surgical vascularization approaches. Accumulating evidence indicates that in nonunions, these strategies are indeed capable of improving the process of bone healing. The major challenge for the future will now be the translation of these strategies into clinical practice to make them accessible for the majority of patients. If this succeeds, these vascularization strategies may markedly reduce the incidence of nonunion formation.

Strategies for Enhancing Vascularization of Biomaterial‐Based Scaffold in Bone Regeneration

“…[159] FDA-approved pulsed EMF/electrical stimulation can also enhance the pro-angiogenic qualities, density in conjunction with SC differentiation probably via Ca 2 + Wnt/βcatenin, MAPK, FGF, VEGF getaways by induction coupling. [84,160,161] Good vascularization and EC adhesion were observed at 400 mV/cm of electric stimulation. [162] Another non-invasive technique for therapeutic effects of sound waves < 20kHz allows the repair of bone defects; most proposed mechanisms hypothesized are oscillatory motion of regenerative cells, 'fluidization' of the cytoskeleton, cell bilayer model, optimum stress-induced onto the defected ECM.…”

“…[143] Although GF application into biomaterial scaffolds is restricted with the short half-lives, cost of production, and administration pharmacodynamics, thus, needs advanced techniques of gene incorporation. [144] Adenoviral and lentiviral vectors are commonly put into use for transfection of stem [125] cells for VEGF, BMP gene expression, apart from viral-free implants carrying plasmid DNA, and micro RNA's potential to signal reaction cascade. [66,120] Scaffolds with such plasmid DNA for VEGF (pVEGF)/chitosan/BMP combination enhanced the cell's penetration and transfection into the implant with prolonged VEGF expression for almost 28 days, in vitro.…”

“…on rabbit femur implanted with HA/Collagen/BMSC composite, was applied with sinusoidal EMF of 15 Hz/mT; demonstrated better scaffold unification [159] . FDA‐approved pulsed EMF/electrical stimulation can also enhance the pro‐angiogenic qualities, density in conjunction with SC differentiation probably via Ca 2+ Wnt/β‐catenin, MAPK, FGF, VEGF getaways by induction coupling [84,160,161] . Good vascularization and EC adhesion were observed at 400 mV/cm of electric stimulation [162] …”

The vascularization paradox of non-union formation

“…There is strong evidence that a disturbance in the angiogenic response after skeletal injury leads to detrimental consequences for bone regeneration [10]. Various experimental animal studies indicate that the blockade of vascularization by TNP-470, non-steroidal anti-inflammatory drugs (NSAIDs) or fumagillin, hampers fracture repair and may eventually lead to atrophic non-union formation [49][50][51][52].…”

“…Bone regeneration involves multiple biological and biochemical processes. Among these, vascularization is supposed to be essential for successful fracture healing [ 10 , 11 ]. Bone is a highly vascularized tissue, which crucially depends on the close spatial and temporal interaction between blood vessels and osteogenic cells to maintain bone development and remodeling [ 12 ].…”