Gelatin methacryloyl granular scaffolds for localized mRNA delivery

Messenger RNA(mRNA)therapy is the intracellular delivery of mRNA to produce desired therapeutic proteins.Developing strategies for local mRNA delivery is still required where direct intra-articular injections are inappropriate for targeting a specific tissue.The mRNA delivery efficiency depends on protecting nucleic acids against nuclease-mediated degradation and safe site-specific intracellular delivery.Herein,novel mRNA-releasing matrices based on RGD-moiety-rich gelatin methacryloyl(GelMA)microporous annealed particle(MAP)scaffolds are reported.GelMA concentration in aerogel-based microgels(μgels)produced through a microfluidic process,MAP stiffnesses,and microporosity are crucial parameters for cell adhesion,spreading,and proliferation.After being loaded with mRNA complexes,MAP scaffolds composed of 10%GelMAμgels display excellent cell viability with increasing cell infiltration,adhesion,proliferation,and gene transfer.The intracellular delivery is achieved by the sustained release of mRNA complexes from MAP scaffolds and cell adhesion on mRNA-releasing scaffolds.These findings highlight that hybrid systems can achieve efficient protein expression by delivering mRNA complexes,making them promising mRNA-releasing biomaterials for tissue engineering.

Tissue adhesive hemostatic microneedle arrays for rapid hemorrhage treatment

Blood loss by hemorrhaging wounds accounts for over one-third of~5 million trauma fatalities worldwide every year.If not controlled in a timely manner,exsanguination can take lives within a few minutes.Developing new biomaterials that are easy to use by non-expert patients and promote rapid blood coagulation is an unmet medical need.Here,biocompatible,and biodegradable microneedle arrays(MNAs)based on gelatin methacryloyl(GelMA)biomaterial hybridized with silicate nanoplatelets(SNs)are developed for hemorrhage control.The SNs render the MNAs hemostatic,while the needle-shaped structure increases the contact area with blood,synergistically accelerating the clotting time from 11.5 min to 1.3 min in vitro.The engineered MNAs reduce bleeding by~92%compared with the untreated injury group in a rat liver bleeding model.SN-containing MNAs outperform the hemostatic effect of needle-free patches and a commercial hemostat in vivo via combining micro-and nanoengineered features.Furthermore,the tissue adhesive properties and mechanical interlocking support the suitability of MNAs for wound closure applications.These hemostatic MNAs may enable rapid hemorrhage control,particularly for patients in developing countries or remote areas with limited or no immediate access to hospitals.

Tunable hybrid hydrogels with multicellular spheroids for modeling desmoplastic pancreatic cancer

The tumor microenvironment consists of diverse,complex etiological factors.The matrix component of pancreatic ductal adenocarcinoma(PDAC)plays an important role not only in physical properties such as tissue rigidity but also in cancer progression and therapeutic responsiveness.Although significant efforts have been made to model desmoplastic PDAC,existing models could not fully recapitulate the etiology to mimic and understand the progression of PDAC.Here,two major components in desmoplastic pancreatic matrices,hyaluronic acid-and gelatin-based hydrogels,are engineered to provide matrices for tumor spheroids composed of PDAC and cancer-associated fibroblasts(CAF).Shape analysis profiles reveals that incorporating CAF contributes to a more compact tissue formation.Higher expression levels of markers associated with proliferation,epithelial to mesenchymal transition,mechanotransduction,and progression are observed for cancer-CAF spheroids cultured in hyper desmoplastic matrix-mimicking hydrogels,while the trend can be observed when those are cultured in desmoplastic matrix-mimicking hydrogels with the presence of transforming growth factor-β1(TGF-β1).The proposed multicellular pancreatic tumor model,in combination with proper mechanical properties and TGF-β1 supplement,makes strides in developing advanced pancreatic models for resembling and monitoring the progression of pancreatic tumors,which could be potentially applicable for realizing personalized medicine and drug testing applications.