Biophysical stimuli for promoting angiogenesis and vascularization in regenerative medicine and dentistry

Despite significant advancements in tissue engineering technologies for regenerative medicine applications in recent years, achieving sufficient vascularization and angiogenesis in tissue-engineered grafts upon in situ implantation continues to pose a formidable challenge. This challenge is particularly pronounced for thick and complex structures designed for larger defects that exceed the critical size and lack spontaneous self-regenerative capacity. An adequate vascular network is essential for delivering oxygen and nutrients, to ensure the survival, differentiation, and proliferation of cells within implanted tissue-engineered grafts. It also facilitates the removal of metabolic waste, promotes migration and infiltration of endogenous host cells, and enables anastomosis with the host vasculature. Often, a necrotic core develops in the deep interior of larger tissue-engineered constructs due to hypoxic conditions and inadequate nutrient supply arising from insufficient vascularization and angiogenesis. Several strategies have been developed to address this challenge, including pre-vascularization through the seeding of endothelial and smooth muscle precursors, incorporation and delivery of pro-angiogenic factors, and modulation of scaffold biomaterial properties such as porosity and stiffness gradients. Nevertheless, the use of various biophysical stimuli to enhance the vascularization of tissue-engineered grafts has been largely overlooked. These stimuli encompass mechanical, electrical, ultrasound, magnetic, light, and thermal modalities and will thus be critically examined. An advantage of these biophysical stimuli is that some of them can be applied non-invasively and localized specifically at the defect/injury site, unlike pro-angiogenic drugs or growth factors, which tend to diffuse away after delivery, reducing their therapeutic efficacy and exerting detrimental side effects at ectopic sites.