Ye Wu

Stimuli-responsive hydrogels possess unique advantages in drug delivery due to their variable performance and status based on the external environment. In the present study, a dual-responsive (pH and reactive oxygen species (ROS)) hydrogel was prepared to realize drug release properties under inflammatory stimulation. By grafting 3-carboxy-phenylboronic acid to the gelatin molecular backbone and cross-linking with poly(vinyl alcohol), we successfully synthesized the inflammation-responsive drug-loaded hydrogels after encapsulation with vancomycin-conjugated silver nanoclusters (VAN-AgNCs) and pH-sensitive micelles loaded with nimesulide (NIM). This novel design not only retained the dynamic functions of hydrogels, such as injectability, self-healing, and remodeling, but also realized sequential and on-demand drug delivery at diabetic-infected wound sites. In this work, we found that the hydrogel exhibited excellent biocompatibility and hemostasis properties owing to the enhanced cell-adhesive property of the gelatin component. The significant antibacterial and anti-inflammatory effect of the hydrogel was demonstrated in an in vitro experiment. Moreover, in the in vivo experiment, the hydrogel was found to play a role in promoting infected wound healing through sequential hemostasis and antibacterial and anti-inflammatory processes. Collectively, this inflammation-responsive hydrogel design containing VAN-AgNCs and NIM-loaded micelles has great potential in the application of chronically infected diabetic wound treatment, as well as in other inflammatory diseases.

A preliminary report of clinical study revealed that chronic discogenic low back pain could be treated by intradiscal methylene blue (MB) injection. We investigated the effect of intradiscal MB injection for the treatment of chronic discogenic low back pain in a randomized placebo-controlled trial. We recruited 136 patients who were found potentially eligible after clinical examination and 72 became eligible after discography. All the patients had discogenic low back pain lasting longer than 6 months, with no comorbidity. Thirty-six were allocated to intradiscal MB injection and 36 to placebo treatment. The principal criteria to judge the effectiveness included alleviation of pain, assessed by a 101-point numerical rating scale (NRS-101), and improvement in disability, as assessed with the Oswestry Disability Index (ODI) for functional recovery. At the 24-month follow-up, both the groups differed substantially with respect to the primary outcomes. The patients in MB injection group showed a mean reduction in pain measured by NRS of 52.50, a mean reduction in Oswestry disability scores of 35.58, and satisfaction rates of 91.6%, compared with 0.70%, 1.68%, and 14.3%, respectively, in placebo treatment group (p<0.001, p<0.001, and p<0.001, respectively). No adverse effects or complications were found in the group of patients treated with intradiscal MB injection. The current clinical trial indicates that the injection of methylene blue into the painful disc is a safe, effective and minimally invasive method for the treatment of intractable and incapacitating discogenic low back pain.

Microenvironment-responsive hydrogels present high potential in treating refractory wounds due to their capability of on-demand drug release. In this study, a specially designed hydrogel with smart targeting of refractory wound characteristics was designed to treat chronically infected diabetic wounds. Aminated gelatin reacted with oxidized dextran, forming a hydrogel cross-linked with a dynamic Schiff base, which is sensitive to the low-pH environment in refractory wounds. Nano-ZnO was loaded into the hydrogel for killing microbes. A Paeoniflorin-encapsulated micelle with a ROS-responsive property was fixed to the skeleton of the hydrogel via a Schiff base bond for low-pH- and ROS-stimulated angiogenic activity. The sequential responsiveness of the novel hydrogel enabled smart rescue of the deleterious microenvironment in refractory wounds. This highly biocompatible hydrogel demonstrated antibacterial and angiogenic abilities in vitro and significantly promoted healing of chronically infected diabetic wounds via sequential hemostatic, microbe killing, and angiogenic activities. This microenvironment-responsive hydrogel loaded with nZnO and Pf-encapsulated micelles holds great potential as a location-specific dual-response delivery platform for curing refractory, chronically infected diabetic wounds.