3D bioprinting spatiotemporally defined patterns of growth factors to tightly control tissue regeneration

Abstract

Therapeutic growth factor delivery typically requires supraphysiological dosages, which can cause undesirable off-target effects. The aim of this study was to 3D bioprint implants containing spatiotemporally defined patterns of growth factors optimized for coupled angiogenesis and osteogenesis. Using nanoparticle functionalized bioinks, it was possible to print implants with distinct growth factor patterns and release profiles spanning from days to weeks. The extent of angiogenesis in vivo depended on the spatial presentation of vascular endothelial growth factor (VEGF). Higher levels of vessel invasion were observed in implants containing a spatial gradient of VEGF compared to those homogenously loaded with the same total amount of protein. Printed implants containing a gradient of VEGF, coupled with spatially defined BMP-2 localization and release kinetics, accelerated large bone defect healing with little heterotopic bone formation. This demonstrates the potential of growth factor printing, a putative point of care therapy, for tightly controlled tissue regeneration.

Vascularized organoids on a chip: strategies for engineering organoids with functional vasculature

“…This mechanism can be more robustly established by precise control over the spatiotemporal distribution of pro-angiogenic factors in the matrix with advanced bioengineering techniques. 88 Alternatively, functional anastomosis could be obtained through an opposite 'outside-in' mechanism, which is driven by angiogenesis as well (Fig. 3).…”

Advances in Growth Factor Delivery for Bone Tissue Engineering

“…The released GFs induced bone repair in a critical-size rat calvaria model and promoted local bone formation by bridging a critical-size defect [ 33 ]. Freeman et al [ 168 ] utilized a 3D bioprinting technique to print alginate-based hydrogels containing a spatial gradient of bioactive molecules directly within polycaprolactone scaffolds. They created two distinct growth factor patterns: peripheral and central localizations.…”

Printing the Pathway Forward in Bone Metastatic Cancer Research: Applications of 3D Engineered Models and Bioprinted Scaffolds to Recapitulate the Bone–Tumor Niche

“…Recently, 3D bioprinted scaffolds have been developed that are capable of the controlled release of growth factors that affect angiogenesis and osteogenesis in the bone microenvironment. Specifically, Freeman et al developed 3D bioprinted constructs to deliver VEGF and BMP-2 with distinct spatiotemporal release profiles to enhance the regeneration of large bone defects [ 228 ]. Importantly, the properties of the 3D bioprinted constructs were “tunable” in that (1) the release of VEGF and BMP-2 could be slowed or accelerated, and (2) the distribution of release of VEGF and BMP-2 could be localized or eluted in a spatial gradient [ 228 ].…”

“…Specifically, Freeman et al developed 3D bioprinted constructs to deliver VEGF and BMP-2 with distinct spatiotemporal release profiles to enhance the regeneration of large bone defects [ 228 ]. Importantly, the properties of the 3D bioprinted constructs were “tunable” in that (1) the release of VEGF and BMP-2 could be slowed or accelerated, and (2) the distribution of release of VEGF and BMP-2 could be localized or eluted in a spatial gradient [ 228 ]. In a similar fashion, Sun et al developed a 3D bioprinted scaffold loaded with connective tissue growth factor and transforming growth factor beta 3, then seeded with mesenchymal stromal cells and implanted into mice to facilitate the regeneration of an intervertebral disc [ 229 ].…”