Surgical resection of hepatocellular carcinoma suffers from a high recurrence rate. Ozone directly kills tumor cells by generating reactive oxygen species , but its high reactivity and short half-life severely limit its tumor accumulation and penetration for the treatment of tumors . Herein, a thermoresponsive ozone-enriched spray gel is developed to suppress the tumor recurrence of hepatocellular carcinoma (Huh-7 tumors). Briefly, a perfluorocarbon nanoemulsion (PFTBA@LIP) consisting of a perfluorotributylamine core and a lipid monolayer is fabricated, which is encapsulated in the thermoresponsive hydrogel. Ozone is then dissolved in the nanoemulsion owing to its high affinity to PFTBA (O/PFTBA@LIP@Gel), which effectively improves its stability. Of note is that O/PFTBA@LIP@Gel induces both ferroptosis and apoptosis by regulating the expression of relevant genes (GPX4, ACSL4, CDKN1A, .) and inducing considerable lipid peroxidation, which significantly reduces the tumor recurrence of the Huh-7 tumor by spraying the gel in the surgical cavity and prolongs the survival of tumor-bearing mice.

To date, skin wounds are still an issue for healthcare professionals. Although numerous approaches have been developed over the years for skin regeneration, recent advances in regenerative medicine offer very promising strategies for the fabrication of artificial skin substitutes, including 3D bioprinting, electrospinning or spraying, among others. In particular, skin sprays are an innovative technique still under clinical evaluation that show great potential for the delivery of cells and hydrogels to treat acute and chronic wounds. Skin sprays present significant advantages compared to conventional treatments for wound healing, such as the facility of application, the possibility to treat large wound areas, or the homogeneous distribution of the sprayed material. In this article, we review the latest advances in this technology, giving a detailed description of investigational and currently commercially available acellular and cellular skin spray products, used for a variety of diseases and applying different experimental materials. Moreover, as skin sprays products are subjected to different classifications, we also explain the regulatory pathways for their commercialization and include the main clinical trials for different skin diseases and their treatment conditions. Finally, we argue and suggest possible future trends for the biotechnology of skin sprays for a better use in clinical dermatology.

Treatment of diabetic foot ulcers (DFU) needs to reduce inflammation, relieve hypoxia, lower blood glucose, promote angiogenesis, and eliminate pathogenic bacteria, but the therapeutic efficacy is greatly limited by the diversity and synergy of drug functions as well as the DFU microenvironment itself. Herein, an ultrasound-augmented multienzyme-like nanozyme hydrogel spray was developed using hyaluronic acid encapsulated l-arginine and ultrasmall gold nanoparticles and CuO nanoparticles coloaded phosphorus doped graphitic carbon nitride nanosheets (ACPCAH). This nanozyme hydrogel spray possesses five types of enzyme-like activities, including superoxide dismutase (SOD)-, catalase (CAT)-, glucose oxidase (GOx)-, peroxidase (POD)-, and nitric oxide synthase (NOS)-like activities. The kinetics and reaction mechanism of the sonodynamic/sonothermal synergistic enhancement of the SOD-CAT-GOx-POD/NOS cascade reaction of ACPCAH are fully investigated. Both in vitro and in vivo tests demonstrate that this nanozyme hydrogel spray can be activated by the DFU microenvironment to reduce inflammation, relieve hypoxia, lower blood glucose, promote angiogenesis, and eliminate pathogenic bacteria, thus accelerating diabetic wound healing effectively. This study highlights a competitive approach based on multienzyme-like nanozymes for the development of all-in-one DFU therapies.

Traumatic heterotopic ossification (THO) represents one of the most prominent contributors to post-traumatic joint dysfunction, which currently lacks an effective and definitive preventative approach. Inflammatory activation due to immune dyshomeostasis during the early stages of trauma is believed to be critical in initiating the THO disease process. This study proposes a dual-homeostatic modulation (DHM) strategy to synergistically prevent THO without compromising normal trauma repair by maintaining immune homeostasis and inducing stem cell homeostasis. A methacrylate-hyaluronic acid-based hydrogel spray device encapsulating a curcumin-loaded zeolitic imidazolate framework-8@ceric oxide (ZIF-8@CeO2, CZC) nanoparticles (CZCH) is designed. Photo-crosslinked CZCH is used to form hydrogel films fleetly in periosteal soft tissues to achieve sustained curcumin and CeO2 nanoparticles release in response to acidity and reactive oxygen species (ROS) in the inflammatory microenvironment. In vitro experiments and RNA-seq results demonstrated that CZCH achieved dual-homeostatic regulation of inflammatory macrophages and stem cells through immune repolarization and enhanced efferocytosis, maintaining immune cell homeostasis and normal differentiation. These findings of the DHM strategy are also validated by establishing THO mice and rat models. In conclusion, the CZCH hydrogel spray developed based on the DHM strategy enables synergistic THO prevention, providing a reference for a standard procedure of clinical operations.

A novel sprayable adhesive is established (ZnMet-PF127) by the combination of a thermosensitive hydrogel (Pluronic F127, PF127) and a coordination complex of zinc and metformin (ZnMet). Here we demonstrate that ZnMet-PF127 potently promotes the healing of traumatic skin defect and burn skin injury by promoting cell proliferation, angiogenesis, collagen formation. Furthermore, we find that ZnMet could inhibit reactive oxygen species (ROS) production through activation of autophagy, thereby protecting cell from oxidative stress induced damage and promoting healing of skin wound. ZnMet complex exerts better effects on promoting skin wound healing than ZnCl or metformin alone. ZnMet complex also displays excellent antibacterial activity against or which could reduce the incidence of skin wound infections. Collectively, we demonstrate that sprayable PF127 could be used as a new drug delivery system for treatment of skin injury. The advantages of this sprayable system are obvious: (1) It is convenient to use; (2) The hydrogel can cover irregular skin defect sites evenly in a liquid state. In combination with this system, we establish a novel sprayable adhesive (ZnMet-PF127) and demonstrate that it is a potential clinical treatment for traumatic skin defect and burn skin injury.

Hydrogel microparticles (HMPs) are promising for biomedical applications, ranging from the therapeutic delivery of cells and drugs to the production of scaffolds for tissue repair and bioinks for 3D printing. Biologics (cells and drugs) can be encapsulated into HMPs of predefined shapes and sizes using a variety of fabrication techniques (batch emulsion, microfluidics, lithography, electrohydrodynamic (EHD) spraying and mechanical fragmentation). HMPs can be formulated in suspensions to deliver therapeutics, as aggregates of particles (granular hydrogels) to form microporous scaffolds that promote cell infiltration or embedded within a bulk hydrogel to obtain multiscale behaviours. HMP suspensions and granular hydrogels can be injected for minimally invasive delivery of biologics, and they exhibit modular properties when comprised of mixtures of distinct HMP populations. In this Review, we discuss the fabrication techniques that are available for fabricating HMPs, as well as the multiscale behaviours of HMP systems and their functional properties, highlighting their advantages over traditional bulk hydrogels. Furthermore, we discuss applications of HMPs in the fields of cell delivery, drug delivery, scaffold design and biofabrication.