Aptamer-Functionalized Fibrin Hydrogel Improves Vascular Endothelial Growth Factor Release Kinetics and Enhances Angiogenesis and Osteogenesis in Critically Sized Cranial Defects

Abstract

An aging population, decreased activity levels and increased combat injuries, have led to an increase in critical sized bone defects. As more defects are treated using allografts, which is the current standard of care, the deficiencies of allografts are becoming more evident. Allografts lack the angiogenic potential to induce sufficient vasculogenesis to counteract the hypoxic environment associated with critical sized bone defects. In this study, aptamer-functionalized fibrin hydrogels (AFH), engineered to release vascular endothelial growth factor (VEGF), were evaluated for their material properties, growth factor release kinetics, and angiogenic and osteogenic potential in vivo. Aptamer functionalization to native fibrin did not result in significant changes in biocompatibility or hydrogel gelation. However, aptamer functionalization of fibrin did improve the release kinetics of VEGF from AFH and, when compared to FH, reduced the diffusivity and extended the release of VEGF several days longer. VEGF released from AFH, in vivo, increased vascularization to a greater degree, relative to VEGF released from FH, in a murine critical-sized cranial defect. Defects treated with AFH loaded with VEGF, relative to nonhydrogel loaded controls, showed a nominal increase in osteogenesis. Together, these data suggest that AFH more efficiently incorporates and retains VEGF in vitro and in vivo, which then enhances angiogenesis and osteogenesis to a greater extent in vivo than FH.

Type I Collagen-Fibrin Mixed Hydrogels: Preparation, Properties and Biomedical Applications

“…At same time, myogenic genes showed a faster expression compared to original fibrin gel [ 105 ]. In the field of bioactive molecules delivery, aptamer-modified fibrin hydrogels were prepared that allowed for the controlled delivery of VEGF, enhancing the repair of critical size cranial defects [ 106 ]. As a final example related to cell delivery, thrombin was modified with cationic and surfactant moieties to enhance its affinity with biological membranes while avoiding its internalization.…”

Aptamer‐functionalized hydrogels: An emerging class of biomaterials for protein delivery, cell capture, regenerative medicine, and molecular biosensing

“…Both protein release and cell capture can be applied to regenerative medicine. The efficacy of sustained protein release has been examined in several in vivo models (Abune et al, 2019; Juhl et al, 2019; Zhao, Coyne, et al, 2019; Zhao, Suzuki, et al, 2019). For instance, aptamer‐functionalized fibrin (Ap‐Fn) hydrogels for sustained VEGF release were applied to treat murine skin wounds (Figure 6a) (Zhao, Coyne, et al, 2019).…”

“…Angiogenesis is important to not only for the regeneration of the skin, but also many other organs and tissues. Thus, Ap‐Fn hydrogels were further applied to treat critically sized cranial defects (Juhl et al, 2019). While the whole hydrogel system was not optimized, a moderate increase in new bone formation could be observed in mice treated with Ap‐Fn loaded with 10 μg/ml VEGF (Figure 6b) (Juhl et al, 2019).…”

Aptamer-Functionalized Natural Protein-Based Polymers as Innovative Biomaterials

“…The Wang group has developed several systems for this purpose [ 37 , 38 , 39 , 40 ]. Thus, they initially developed fibrinogen–aptamer macromers (Ap–Fgs) that gave rise to fibrin hydrogels with a molecular recognition capability, using an anti-VEGF aptamer for wound-healing applications [ 37 ].…”

“…After their success in wound healing, engineered fibrin hydrogels for the release of VEGF were also studied for bone regeneration purposes [ 39 ]. Thus, Juhl et al assayed bone regeneration promoted by the implant of different VEGF-loaded hydrogels with and without anti-VEGF aptamer in mice with critically sized calvarial bone defects.…”