Therapy for full-thickness skin wounds remains a clinical challenge [1]. Wound healing involves four overlapping processes when skin injuries occur for a variety of reasons: hemostasis, inflammation, proliferation, and dermal re-modelling [2]. Endothelial cells, macrophages, keratinocytes, and fibroblasts are all involved in the healing process. The migration, infiltration, proliferation, and differentiation of these cells are all linked to the inflammatory response, tissue regeneration, and, ultimately, wound healing [3]. Several growth factors (GFs), cytokines, and chemokines play roles in regulating the biological behavior of these cells as well as the complex healing process [4,5]. As a result, GFs have piqued the interest of researchers as the most easy therapeutic option for skin wounds, as they can directly operate on healing-related cells and induce the creation of functioning vascular networks [6].

Platelet-rich plasma (PRP) is a blood-derived product in which plasma containing high concentrations of platelets (PLTs) is obtained from whole blood after centrifugation and has been used clinically as an innovative tool of regenerative medicine [7]. PRR is a natural accumulation of several growth factors, including platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and epidermal growth factor (EGF) [8]. These growth factors are essential for controlling mesenchymal cell synthesis, proliferation, and extracellular matrix production [9]. PRP has been proven to block cytokine and inflammatory release, stimulate capillary development, and expedite wound epithelialization, hence boosting wound healing and tissue regeneration [10]. However, current PRP management approaches have many flaws, such as unstable biological fixation and burst release of growth factors, all of which will complicate its use in the regeneration of damaged tissues and limit its therapeutic efficacy [11]. Hydrogels filled with PRP have been utilized to avoid burst release of growth factors, stimulate angiogenesis, and repair injured tissues such as skin and bone tissues [12]. In addition, for patients with blood defects, the source of autologous PRP is limited, so PRP with low immunogenicity (such as PRP derived from human cord blood) can be applied to various types of patients, which will have greater research significance.

In recent years, a variety of wound dressings have been developed, including porous foams, electrospun nanofibers, lyophilized sponges, biocompatible films, and multifunctional hydrogels [[13], [14], [15]]. Due to the porous structure and good swelling properties, hydrogels are considered the most ideal biomaterial among these materials, as they can permeate oxygen, absorb wound exudates, maintain a moist environment, and cool the wound surface to reduce patient discomfort and promote wound healing [16]. Particularly, injectable hydrogels offer a number of benefits, including minimally invasive treatment, targeted medication administration, the capacity to treat wounds of arbitrary shape, adhesion to wound tissue, etc. [17]. The incorporation of reversible covalent chemical bonds into hydrogels is thought to be a potential strategy for developing injectable hydrogels. Schiff base connections, disulfide bonds, boronic esters, acylhydrazone bonds, and Diels-Alder reactions are examples of common covalent bonds [18,19]. Many dynamic bonds can be dissolved in response to stimuli such as glucose, pH, reactive oxygen species (ROS), temperature, and enzymes, making it possible for drugs to be regulated for release in specific environments [20,21]. Chronic wounds have prolonged inflammation, which causes ROS levels to be increased and sustained. The inflammatory response at the wound makes ROS levels rise and persist in the wound [22]. In addition, the physiological environment of the wound is acidic, and the bacteria in the infected wound metabolize lactic acid and acetic acid to further reduce the pH of the wound surface (pH 4.5–6.5) [23,24]. Therefore, designing an injectable hydrogel with pH/ROS responsiveness and drug release control is a good strategy for wound treatment. By crosslinking an aldehyde to a primary amine, the Schiff base reaction creates dynamic covalent imine bonds, which are regarded as strong covalent bonds [25]. As an acidic environment speeds up the hydrolysis of the imine link, Schiff bases are pH responsive [26]. The hydrogel based on imine link and boronic ester bond might dissolve and trigger the smart release of medicines in an acidic environment with a high level of ROS.

Antibacterial activity is considered to be an important property of wound dressings. A variety of antimicrobial agents, such as antibiotics, metal ions and inorganic nanoparticles, have been introduced into hydrogel dressings [[27], [28], [29]]. On the other hand, antibiotics have a narrow spectrum of bactericidal effectiveness and may cause bacterial resistance [30]. As a result, there is an urgent need to develop a hydrogel with inherent antibacterial activity that can effectively eliminate germs without the need of antibiotics. Oligomeric procyanidins (OPC) are natural polyphenolic compounds that contain catechol groups. OPC has been reported to have excellent antioxidant and antibacterial activities [31,32]. As one of the derivatives of chitosan, carboxymethyl chitosan (CMCS) has higher hydrophilicity and better biological activity, and has excellent biocompatibility, antibacterial activity and high moisture retention ability [33]. Dextran is a kind of natural polysaccharide with good biocompatibility and biodegradability, which has been widely used in tissue engineering [34,35].

In this study, we developed a novel dynamic Schiff base and hydrogen bond double cross-linked hydrogel with multiple functions including self-healing, injectable, antibacterial, and ROS/pH dual response to achieve spatio-temporal controlled release of GFs, thereby promoting wound healing (Scheme 1). The injectable and self-healing properties of these hydrogels are attributed to dynamic Schiff base bonds. Among them, Schiff base bonds are constructed by cross-linking the amino group on CMCS and PRP with the aldehyde group of the Odex chain. In addition, hydrogels have good self-healing properties due to the cross-linking of amino and carboxyl groups on CMCS, aldehyde group on Odex, and hydrogels formed hydrogen bonds between amino group on PRP and catechol group of OPC chain. When the hydrogel is applied to the wound, the Schiff base breaks in the acidic oxidation environment, resulting in continuous release of GFs. Combined with the inherent antioxidant and antibacterial properties of hydrogels, thus effectively promoting wound healing. The results of H&E, Masson's trichrome, and immunofluorescence staining revealed that this multifunctional hydrogel could reduce oxidative stress, ameliorate inflammation, and promote angiogenesis, indicating considerable promise in wound management.