Repurposing protein aggregation into a biofunctional BMP-2–hyaluronic acid hydrogel for sustained drug release and accelerated wound healing

Abstract

Hydrogels have emerged as highly versatile biomaterials in biomedical science owing to their intrinsic biocompatibility, biodegradability, and tunable mechanical properties, enabling their widespread application in drug delivery, wound healing, tissue engineering, and corneal prostheses. In the present study, we have developed a composite hydrogel by incorporating hyaluronic acid (HA) into an unfolded, aggregation-driven bone morphogenetic protein-2 (BMP-2) network to enhance its functional performance for biomedical use. The inclusion of HA induced significant modifications in both physicochemical and biological properties of the system. Notably, the composite hydrogel exhibited a markedly improved pore architecture, with an average pore size of ∼15 µm, compared to the denser BMP-2-only hydrogel, thereby creating a more favorable microenvironment for cellular infiltration. In parallel, a substantial increase in water retention capacity was observed, attributable to the hydrophilic nature of HA and its influence on gelation behavior, resulting in a hydrated, extracellular matrix (ECM)-mimetic scaffold. Furthermore, the BMP-2/HA hydrogel demonstrated enhanced hemocompatibility and reduced cytotoxicity relative to the BMP-2 system, alongside sustained antibiotic release, which is critical for infection control during wound healing. Importantly, in vivo wound healing studies using Drosophila melanogaster revealed that the composite hydrogel accelerates wound closure by approximately 40–45% compared to BMP-2 alone. This improvement highlights the synergistic interplay between HA-driven biological activity and the structural support provided by the aggregated BMP-2 network, underscoring the potential of this composite hydrogel as a promising candidate for advanced biomedical and translational applications.