Currently, surgical operations, followed by systemic drug delivery, are the prevailing treatment modality for most diseases, including cancers and trauma-based injuries. Although effective to some extent, the side effects of surgery include inflammation, pain, a lower rate of tissue regeneration, disease recurrence, and the non-specific toxicity of chemotherapies, which remain significant clinical challenges. The localized delivery of therapeutics has recently emerged as an alternative to systemic therapy, which not only allows the delivery of higher doses of therapeutic agents to the surgical site, but also enables overcoming post-surgical complications, such as infections, inflammations, and pain. Due to the limitations of the current drug delivery systems, and an increasing clinical need for disease-specific drug release systems, hydrogels have attracted considerable interest, due to their unique properties, including a high capacity for drug loading, as well as a sustained release profile. Hydrogels can be used as local drug performance carriers as a means for diminishing the side effects of current systemic drug delivery methods and are suitable for the majority of surgery-based injuries. This work summarizes recent advances in hydrogel-based drug delivery systems (DDSs), including formulations such as implantable, injectable, and sprayable hydrogels, with a particular emphasis on stimuli-responsive materials. Moreover, clinical applications and future opportunities for this type of post-surgery treatment are also highlighted.

Smart nanomaterials with stimuli-responsive behavior are considered as promising platform for various drug delivery applications. Regarding their specific conditions, such as acidic pH, drug carriers to treatment of tumor microenvironment need some criteria to enhance drug delivery efficiency. In this study, for the first time, pH-sensitive BSA-stabilized graphene (BSG)/chitosan nanocomposites were synthesized through electrostatic interactions between the positively charged chitosan nanoparticles and negatively charged BSG and used for Doxorubicin (DOX) encapsulation as a general anticancer drug. Physicochemical characterization of the nanocomposites with different concentrations of BSG (0.5, 2, and 5wt%) showed effective decoration of chitosan nanoparticles on BSG. Comparing DOX release behavior from the nanocomposites and free BSG-chitosan nanoparticles were evaluated at two pHs of 7.4 and 4.5 in 28 days. It was shown that the presence of BSG significantly reduced the burst release observed in chitosan nanoparticles. The nanocomposite of 2wt% BSG was selected as the optimal nanocomposite with a release of 84% in 28 days and with the most uniform release in 24 h. Furthermore, the fitting of release data with four models including zero-order, first-order, Higuchi, and Korsmeyer-Peppas indicated that the addition of BSG changed the release mechanism of the drug, enabling uniform release for the optimal nanocomposite in first 24 h, compared to that for pure chitosan nanoparticles. This behavior was proved using metabolic activity assay of the SKBR-3 breast cancer cell spheroids exposed to DOX release supernatant at different time intervals. It was also demonstrated that DOX released from the nanocomposite had a significant effect on the suppression of cancer cell proliferation at acidic pH.

Glioblastoma multiforme (GBM) is a rapidly progressive and deadly form of brain tumor with a median survival rate of ~15 months. GBMs are hard to treat and significantly affect the patient’s physical and cognitive abilities and quality of life. Temozolomide (TMZ)—an alkylating agent that causes DNA damage—is the only chemotherapy choice for the treatment of GBM. However, TMZ also induces autophagy and causes tumor cell resistance and thus fails to improve the survival rate among patients. Here, we studied the drug-induced programmed cell death and invasion inhibition capacity of TMZ and a mevalonate cascade inhibitor, simvastatin (Simva), in a three-dimensional (3D) microfluidic model of GBM. We elucidate the role of autophagy in apoptotic cell death by comparing apoptosis in autophagy knockdown cells (Atg7 KD) against their scrambled counterparts. Our results show that the cells were significantly less sensitive to drugs in the 3D model as compared to monolayer culture systems. An immunofluorescence analysis confirmed that apoptosis is the mechanism of cell death in TMZ- and Simva-treated glioma cells. However, the induction of apoptosis in the 3D model is significantly lower than in monolayer cultures. We have also shown that autophagy inhibition (Atg7 KD) did not change TMZ and Simva-induced apoptosis in the 3D microfluidic model. Overall, for the first time in this study we have established the simultaneous detection of drug induced apoptosis and autophagy in a 3D microfluidic model of GBM. Our study presents a potential ex vivo platform for developing novel therapeutic strategies tailored toward disrupting key molecular pathways involved in programmed cell death and tumor invasion in glioblastoma.

Self-filling microwell arrays hold great promise for the production of 3D tumor spheroids and organoids for disease modeling and drug discovery.

To treat and manage chronic diseases, it is necessary to continuously monitor relevant biomarkers and modify treatment as the disease state changes. Compared to other bodily fluids, interstitial skin fluid (ISF) is a good choice for identifying biomarkers because it has a molecular composition most similar to blood plasma. Herein, a microneedle array (MNA) is presented to extract ISF painlessly and bloodlessly. The MNA is made of crosslinked poly(ethylene glycol) diacrylate (PEGDA), and an optimal balance of mechanical properties and absorption capability is suggested. Besides, the effect of needles’ cross-section shape on skin penetration is studied. The MNA is integrated with a multiplexed sensor that provides a color change in a biomarker concentration-dependent manner based on the relevant reactions for colorimetric detection of pH and glucose biomarkers. The developed device enables diagnosis by visual inspection or quantitative red, green, and blue (RGB) analysis. The outcomes of this study show that MNA can successfully identify biomarkers in interstitial skin fluid in a matter of minutes. The home-based long-term monitoring and management of metabolic diseases will benefit from such practical and self-administrable biomarker detection.