The present study illustrates the progress of the wheat grass bioactive-reinforced collagen-based aerogel system as an instructive scaffold for collagen turnover and angiogenesis for wound healing applications. The reinforcement of wheat grass bioactives in collagen resulted in the design and development of aerogels with enhanced physicochemical and biomechanical properties due to the intermolecular interaction between the active growth factors of wheat grass and collagen fibril. Differential scanning calorimetry analysis revealed an enhanced denaturation temperature when compared to those of native collagen aerogels. Fourier transform infrared spectroscopy analysis confirmed that the reinforcement of bioactives in the wheat grass did not affect the structural integrity of the collagen molecule. Additionally, the reinforced biomaterial with a systematic absorptive morphology resulted in a three-dimensional (3D) sponge-like aerogel exhibiting a potent highly oriented 3D structural assembly that showed increased water retention ability and substance permeability that would enable the passage of nutrients and gaseous components for cellular growth. Furthermore, the cumulative effect of the growth factors in wheat grass and the collagen molecule augments the angiogenic ability and collagen production of the aerogel by restoration of the damaged tissue thereby making it a potential 3D wound dressing scaffold. The results were confirmed by in vivo wound healing assays. This study shows the possibility for progress of a biocompatible, biodegradable, and nonadhesive nutraceutical-reinforced collagen aerogel as an instructive scaffold with good antimicrobial properties for collagen turnover and angiogenic response for wound healing applications.

The present study describes the fabrication of collagen reinforced with praseodymium−cobaltite nanoparticles for wound healing applications. Praseodymium−cobaltite nanoparticles (PCNP) reinforced with collagen resulted in an increased thermal stability and decreased proteolytic susceptibility to collagen. Circular dichroism spectroscopy and ATR-FTIR (attenuated total reflection Fourier transform infrared) spectroscopy analyses confirm the intact structural integrity of the collagen sheets after cross-linking with praseodymium−cobaltite nanoparticles. Cross-linked collagen has shown to possess biocompatibility, less protein adsorption behavior, and hemocompatibility, which are the desirable properties of a wound dressing material. The nanoparticle cross-linked collagen sheets provided a proper matrix elasticity that promotes mesenchymal stem cell attachment and angiogenesis. Further, the scaffold promoted tube formation in endothelial cells. The enhancement of angiogenesis is considered to be brought about by the therapeutic potential of nanoparticle formulation. Praseodymium− cobaltite nanoparticle cross-linking increased the ductility of collagen sheets for the pro-angiogenic and stem cell differentiation ability. Also, the praseodymium−cobaltite cross-linked collagen sheets have been shown to induce a mild level of ROS (reactive oxygen species) generation in the DCFH-DA (2′,7′-dichlorodihydrofluorescein diacetate) assay, which is beneficial for angiogenesis as well as wound healing. This study paves the way for exploring the therapeutic potential of rare-earth-based nanoparticles for tissue engineering applications as an alternative for traditional wound healing materials.

The redox state of the endothelial cells plays a key role in the regulation of the angiogenic process. The modulation of the redox state of endothelial cells (ECs) could be a viable target to alter angiogenic response. In the present work, we synthesized a redox modulator by caging 5‐hydroxy 2‐methyl 1, 4‐napthoquinone (Plumbagin) on silver nano framework (PCSN) for tunable reactive oxygen species (ROS) inductive property and tested its role in ECs during angiogenic response in physiological and stimulated conditions. In physiological conditions, the redox modulators induced the angiogenic response by establishing ECs cell–cell contact in tube formation model, chorio allontoic membrane, and aortic ring model. The molecular mechanism of angiogenic response was induced by vascular endothelial growth factor receptor 2 (VEGFR2)/p42‐mitogen‐activated protein kinase signaling pathway. Under stimulation, by mimicking tumor angiogenic conditions it induced cytotoxicity by generation of excessive ROS and inhibited the angiogenic response by the loss of spatiotemporal regulation of matrix metalloproteases, which prevents the tubular network formation in ECs and poly‐ADP ribose modification of VEGF. The mechanism of opposing effects of PCSN was due to modulation of PKM2 enzyme activity, which increased the EC sensitivity to ROS and inhibited EC survival in stimulated condition. In normal conditions, the endogenous reactive states of NOX4 enzyme helped the EC survival. The results indicated that a threshold ROS level exists in ECs that promote angiogenesis and any significant enhancement in its level by redox modulator inhibits angiogenesis. The study provides the cues for the development of redox‐based therapeutic molecules to cure the disease‐associated aberrant angiogenesis.

The current work describes the development of a nanoscaled biodegradable metal polymeric three-dimensional framework with controlled nanotherapeutic release for endothelial cell patterning and sustained angiogenesis for biomedical applications. Biocompatible polymers gelatin and PLGA were used as polymeric nanofibrous three-dimensional framework in a core–shell manner with the gelatin core containing a biodegradable and bioactive metal nanoframework of cobalt caged with PEGylated curcumin by coaxial electrospinning. FTIR results confirmed the presence of nanobioactives in the core region of a coaxial nanofiber. Scanning electron microscopic analysis of the coaxial nanofibrous system showed a three-dimensional architecture that favored endothelial cell adhesion, patterning, migration, and proliferation. The as-synthesized nanoscaled biodegradable metal polymeric three-dimensional core–shell nanofibers exhibited potent antibacterial efficacy. Further, it improved the endothelial cell patterning promoting angiogenesis. The high therapeutic potential of cobalt nanoframework in the nanofibers enhanced the production of vascular endothelial growth factor promoting angiogenesis that resulted in the earlier restoration of wounded tissue compared with untreated control in vivo animal models. The study opens up a new horizon in exploring biodegradable biosorbable metal nanoframework for biomaterial applications. Additionally, the present study opens up a new strategy in developing biodegradable biosorbable biomaterial with enhanced vascularization efficacy to the biomaterial, which is important for acceptance of these biomaterials into the host tissue.

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