Neutrophils in Biomaterial-Guided Tissue Regeneration: Matrix Reprogramming for Angiogenesis

Biomaterial-guided in situ tissue regeneration uses biomaterials to stimulate and guide the body's endogenous, regenerative processes to drive functional tissue repair and regeneration. To be successful, cell migration into the biomaterials is essential, which requires angiogenesis to maintain cell viability. Neutrophils, the first cells responding to an implanted biomaterial, are now known to play an integral part in angiogenesis in multiple tissues and exhibit considerable potential for driving angiogenesis in the context of tissue regeneration. In terms of biomaterial-guided in situ tissue regeneration, harnessing the proangiogenic potential of the neutrophil through its robust secretion of matrix metalloproteinase 9 (MMP-9) may provide a mechanism to improve biomaterial performance by initiating matrix reprogramming. This review will discuss neutrophils as matrix reprogrammers and what is currently known about their ability to create a microenvironment that is more conducive for angiogenesis and tissue regeneration through the secretion of MMP-9. It will first review a set of ground-breaking studies in tumor biology and then present an overview of what is currently known about neutrophils and MMP-9 in biomaterial vascularization. Finally, it will conclude with potential strategies and considerations to engage neutrophils in biomaterial-guided angiogenesis and in situ tissue regeneration. Impact statement This review draws attention to a highly neglected topic in tissue engineering, the role of neutrophils in biomaterial-guided tissue regeneration and angiogenesis. Moreover, it highlights their abundant secretion of matrix metalloproteinase 9 (MMP-9) for matrix reprogramming, a topic with great potential yet to be vetted in the literature. It presents strategies and considerations for designing the next generation of immunomodulatory biomaterials. While there is literature discussing the overall role of neutrophils in angiogenesis, there are a limited number of review articles focused on this highly relevant topic in the context of biomaterial integration and tissue regeneration, making this a necessary and impactful article.