Zwitterionic Hydrogel Activates Autophagy to Promote Extracellular Matrix Remodeling for Improved Pressure Ulcer Healing

Abstract

Pressure ulcer (PU) is a worldwide problem that is hard to heal because of its prolonged inflammatory response and impaired ECM deposition caused by local hypoxia and repeated ischemia/reperfusion. Our previous study discovered that the non-fouling zwitterionic sulfated poly (sulfobetaine methacrylate) (SBMA) hydrogel can improve PU healing with rapid ECM rebuilding. However, the mechanism of the SBMA hydrogel in promoting ECM rebuilding is unclear. Therefore, in this work, the impact of the SBMA hydrogel on ECM reconstruction is comprehensively studied, and the underlying mechanism is intensively investigated in a rat PU model. The in vivo data demonstrate that compared to the PEG hydrogel, the SBMA hydrogel enhances the ECM remolding by the upregulation of fibronectin and laminin expression as well as the inhibition of MMP-2. Further investigation reveals that the decreased MMP-2 expression of zwitterionic SBMA hydrogel treatment is due to the activation of autophagy through the inhibited PI3K/Akt/mTOR signaling pathway and reduced inflammation. The association of autophagy with ECM remodeling may provide a way in guiding the design of biomaterial-based wound dressing for chronic wound repair.

Self-Adhesive, Strong Antifouling, and Mechanically Reinforced Methacrylate Hyaluronic Acid Cross-Linked Carboxybetaine Zwitterionic Hydrogels

“…Hydrogels of natural and synthetic polymers that facilitate wound healing are unrivaled candidates for wound dressings. Hyaluronic acid, a natural linear polysaccharide existing in the extracellular matrix, can conduce to reducing inflammatory cell infiltration and promoting the formation of blood vessels, thus improving skin regeneration. − Zwitterionic polymer hydrogels are novel synthetic materials with a strong hydration effect that can promote wound closure and angiogenesis, rapid reconstruction of the extracellular matrix (ECM), and regulation of macrophage polarization to reduce inflammatory responses. − Carboxybetaine (CB) and sulfobetaine (SB) are common zwitterionic groups with similar electroneutral structure, and carboxybetaine zwitterionic polymer (PCB) hydrogels could promote skin wound healing more efficiently than sulfobetaione zwitterionic polymer (PSB) hydrogels for their disparate cationic and anionic groups . Although hyaluronic acid (HA) hydrogels and PCB hydrogels possessed eminent advantages as wound dressings, the crux of lacking satisfying mechanical strengths to adapt to limb movement and provide wound protection was still pendent.…”

Photopolymerized Zwitterionic Hydrogels with a Sustained Delivery of Cerium Oxide Nanoparticle-miR146a Conjugate Accelerate Diabetic Wound Healing

“…34−42 Additionally, ZW hydrogels have been shown to enhance extracellular matrix remodeling by the upregulation of fibronectin and laminin when compared to a poly(ethylene glycol) (PEG) hydrogel, as well as decreasing expression of MMP-2, indicating that ZW gels have an intrinsic ability to improve wound healing through a variety of biochemical pathways. 43 The most commonly used ZW monomers are [2-(methacryloyloxy)ethyl]dimethyl-(3sulfopropyl)ammonium hydroxide (SBMA) and 3-{[2-(methacryloyloxy)ethyl]dimethylammonio}propionate (CBMA), which are often polymerized using different ZW or non-ZW biocompatible monomers or crosslinkers, such as hydroxyethyl methacrylate (HEMA). 44−46 Our previous work investigated ZW cryogelation (i.e., hydrogels polymerized below freezing temperature conditions) and found that our novel cryogels could release proteins or CNP-miR146a for several months with sustained behavior.…”

“…Our group has developed zwitterionic (ZW) hydrogels which exhibit many of the properties mentioned. , ZW hydrogels have strong antifouling properties due to closely repeating positive and negative charges, and they have been shown to avoid the foreign body response. − Research shows that ZW materials can also reduce inflammation by resisting nonspecific protein adsorption and promoting pro-healing macrophage phenotypes. − Additionally, ZW hydrogels have been shown to enhance extracellular matrix remodeling by the upregulation of fibronectin and laminin when compared to a poly­(ethylene glycol) (PEG) hydrogel, as well as decreasing expression of MMP-2, indicating that ZW gels have an intrinsic ability to improve wound healing through a variety of biochemical pathways . The most commonly used ZW monomers are [2-(methacryloyloxy)­ethyl]­dimethyl-(3-sulfopropyl)­ammonium hydroxide (SBMA) and 3-{[2-(methacryloyloxy)­ethyl]­dimethylammonio}­propionate (CBMA), which are often polymerized using different ZW or non-ZW biocompatible monomers or crosslinkers, such as hydroxyethyl methacrylate (HEMA). − …”

Highly Adhesive Antibacterial Bioactive Composite Hydrogels With Controllable Flexibility and Swelling as Wound Dressing for Full-Thickness Skin Healing

“…Zwitterionic polymers such as poly [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl) ammonium hydroxide (PolySBMA) have widely been used as wound repair materials, attributing to their attractive biological and mechanical properties ( Pei et al, 2020 ; Zhu et al, 2016 ; Wang J. et al, 2020 ; Li et al, 2021 ). For example, the PolySBMA can bond to the skin surface through the ion–dipole and dipole–dipole interactions between the zwitterionic groups of PolySBMA and the functional groups on the tissues.…”