Engineering Antioxidant and Oxygen-Releasing Lignin Composites to Promote Wound Healing

Abstract

The application of engineered biomaterials for wound healing has been pursued since the beginning of tissue engineering. Here, we attempt to apply functionalized lignosulfonates to confer antioxidation to tissue microenvironments and to deliver oxygen to accelerate vascularization and healing responses without causing inflammatory responses. The results from fibrosis array shows that thiolated lignosulfonate in methacrylated gelatin can effectively attenuate fibrotic responses of human dermal fibroblasts. Elemental analysis of oxygen releasing nanoparticles shows the positive incorporation of calcium peroxide. Composites including nanoparticles of lignosulfonate and calcium peroxide release around 0.05% oxygen per day at least for 7 days. Stiffness can be precisely modulated to avoid adverse inflammatory responses. Injection of lignin composites with oxygen generation nanoparticles enhanced the formation of blood vessels and promoted infiltration of alpha-smooth muscle actin+ fibroblasts over 7 days. At 30 days after surgery, the lignin composite with oxygen generating nanoparticles remodels the collagen architecture resembling to the reticular pattern of normal collagen and leave minimal scars. Thus, our study shows the potential of functionalized lignosulfonate for wound healing applications requiring balanced antioxidation and controlled release of oxygen.

Tailoring Physical Properties of Dual-Network Acrylamide Hydrogel Composites by Engineering Molecular Structures of the Cross-linked Network

“…Sulfonated lignin is a water-soluble, non-linear, and cluster-like natural polymer with several chemical functionalities for additional applications . TLS bears multiple sulfhydryl groups, enabling us to utilize the thiol–ene cross-linking reaction. , Therefore, TLS plays the role of nanoparticle cross-linker and filler in a hydrogel composite. Incorporation of TLS into PAAm and PNIPAm hydrogels with Alg, Gel, GelMA, and GelMA–DOPA (Figure b,d, summarized in Table S4) exhibited largely similar trends of stress–strain curves in comparison to the acrylamide hydrogel composites without TLS (Figure a,c, summarized in Table S3).…”

“…To form a dual-network acrylamide hydrogel composite with fillers, we incorporated several natural polymers including sodium alginate (polysaccharide), gelatins from porcine skin and fish skin (protein), and lignosulfonate with thiolation (phenolic polymer). Since the application of these additive natural polymers is advantageous due to their abundance, biocompatibility, and biodegradability, their applicability has been largely expanded in various fields including biomedical applications such as scaffold materials, wound dressing, antioxidant materials, and drug delivery devices. − Chemical modifications were performed on the polymeric backbone to incorporate reactive groups such as methacrylate to gelatin, 3,4-dihydroxyphenethylamine (dopamine) to methacrylated gelatin, or sulfhydryl to lignosulfonate. The dual-network acrylamide hydrogel composites with the chemically modified gelatin and/or lignosulfonate were formed to enhance Young’s modulus or toughness (the area under the stress–strain curve).…”

Lignin Composites with Sustained Oxygenation and Reactive Oxygen Species-Scavenging Improve Neovascularization and Healing of Diabetic Wounds

“…The coupling of SLS to PLGA (poly(lactic- co -glycolic) acid) was performed by acylation reaction in a mass ratio of 2 to 1 (57). CPO and CPOc nanoparticles were prepared using the same method of synthesis (58). We also confirmed the integration of CPO in SLS/CPO nanoparticles by Particle Induced X-ray Emission spectrometry (58).…”

“…CPO and CPOc nanoparticles were prepared using the same method of synthesis (58). We also confirmed the integration of CPO in SLS/CPO nanoparticles by Particle Induced X-ray Emission spectrometry (58).…”

“…Formation of lignin composites. Lignin composites were formed with 50 mg/mL methacrylated gelatin (GelMA) (56,58) plus i) TLS (3 mg/mL), ii) CPOc (4 mg/mL, CPO controlnanoparticles formed without CPO) or iii) CPO (4 mg/mL) reconstituted in PBS. Lithium phenyl 2,4,6-trimethylbenzoylphosphinate (LAP) photo-initiator (1mg/mL) was added to the composites for crosslinking with UV illumination for 1 min (365 nm, fixed).…”