Journals
2025 EN
Pfaff Morgan R. · Wague Aboubacar · Davies Michael
+9 more
Abstract Rotator cuff tears are common musculotendinous injuries with a high risk of permanent functional disability. Following surgical repair, sub‐optimal patient outcomes are directly correlated with poor muscle quality; namely, injury site fatty infiltration, fibrosis, and muscle atrophy. Muscle resident fibro‐adipogenic progenitor cells (FAPs) have been identified as key regulators of post‐injury skeletal muscle regeneration and repair by maintaining a pro‐myogenic environment. In this work, human FAPs (hFAPs) were encapsulated into hyaluronic acid (HyA)‐based hydrogels functionalized with bsp‐RGD(15) cell adhesion peptide, heparin, and a matrix metalloproteinase (MMP)‐cleavable crosslinker. Hydrogel‐encapsulated hFAPs increased expression of the pro‐myogenic marker UCP1 and production of the anti‐inflammatory cytokine IL‐10 while downregulating the expression of the fibrotic marker αSMA over time. A murine model of unilateral rotator cuff transection, denervation, and delayed repair was treated with the HyA hydrogel or PBS and compared to a contralateral, non‐injured control limb. Muscle histology 6 weeks post‐repair revealed that the hydrogel reduced fibrosis, FI, and muscle atrophy while supporting vascularization of the injured tissue region. Collectively, these results suggest that the HyA hydrogel alone can promote muscle regeneration in a clinically relevant delayed repair model of rotator cuff tear, which is hypothesized due to controlled FAP differentiation into pro‐myogenic lineages.
Journals
2025 EN
Lee EunJin · Lialios Peter · Curtis Micaila
+8 more
Abstract Glucocorticoids (GCs) are standard‐of‐care treatments for inflammatory and immune disorders, and their long‐term use increases the risk of osteoporosis. Although GCs decrease bone functionality, their role in bone microvasculature is incompletely understood. Herein, the study investigates the mechanisms of bone microvascular barrier function via osteoblast‐endothelial interactions in response to GCs. The animal data shows that prednisolone (Psl) downregulated the osteoblast function and microvessel number and size. To investigate the role of GCs in bone endothelial barrier function further, a bicellular microfluidic in vitro system is developed and utilized, which consists of three‐dimensional (3D) perfusable microvascular structures embedded in collagen I/osteoblast matrix. Interestingly, it is demonstrated that GCs significantly inhibit osteogenesis and microvascular barrier function by interfering with endothelial‐osteoblast interactions. This effect is triggered by MAPK‐induced phosphorylation of connexin43 (Cx43) at Ser282. Collectively, this study sheds light on microvascular function in bone disorders, as osteoporosis, and permits to capture dynamic changes in endothelial‐bone interactions under GCs by dissecting the MAPK/Cx43 mechanism and proposing this as a potential target for bone diseases.
Journals
2025 EN
Martin Ellie · Doidge Sean P. · Aleem Eiman
+4 more
Abstract Bioconjugation is a pillar of modern medicine, enabling the likes of targeted therapeutics and sensitive diagnostics by exploiting synergies between biomolecules and functional materials. Conjugation techniques have expanded to match an evolving materials discovery landscape, fueling a new wave of bioconjugates. Despite the breadth of conjugate literature, most reviews describe common and relatively simple substrates such as metal nanoparticles or polymers. This review therefore centers around novel materials including biological (e.g., viral capsids, live cells), hybrid (e.g., gold‐decorated nanoparticles, covalent‐organic frameworks), and synthetic (e.g., piezoelectrics, upconverting nanoparticles) substrates. Applications in cancer and viral therapy, tissue engineering, optogenetics, antimicrobials, diagnostics, advanced imaging, and related topics are explored, revealing trends in conjugation approach. This review also compares characterization techniques used to confirm and optimize conjugation before offering perspectives on the future of the field. By shedding light on the latest materials, applications, and analytical methods, we hope to empower researchers to harness bioconjugation for transformative medical innovations.
Journals
2025 EN
Mehrotra Dev R. · Cordova Carolina V. · Wang Tianbai
+8 more
Abstract A Raman spectroscopy‐based platform has tremendous potential to non‐destructively monitor the evolving composition of tissue‐engineered cartilage (TEC) responsible for its mechanical properties from in vitro cultivation to post‐implantation in vivo function. Raman spectroscopy, an inelastic light scattering technique, reflects the biochemical building blocks (amides, sulfates, and hydroxyls) comprising a tissue. Here, an arthroscopy‐compatible probe acquires Raman spectra, and a multivariate linear decomposition routine extracts the regression coefficient biomarkers that reflect the contribution of extracellular matrix (ECM) constituents (sulfated glycosaminoglycans [sGAG], collagen, water) and the scaffold biomaterial to the tissue spectra. Repeated Raman acquisitions during cultivation do not alter growth of chondrocyte‐seeded‐agarose constructs. The Raman‐derived ECM biomarkers portray the composition of the evolving neocartilage developed on agarose, hyaluronan, collagen, and polyethylene‐glycol scaffolds, accounting for 90%, 78%, and 87% of content variation in sGAG, collagen, and water, and 94% of the variation in stiffness. The ECM biomarkers reveal variability in sGAG and collagen content for constructs infused with donor chondrocytes from a 58‐year‐old/female, a 36‐year‐old/male, and a 53‐year‐old/male, accounting for 81% and 87% of the variation in stiffness and sGAG content. This Raman platform offers a transformative approach enabling optimization of construct fabrication, improving preclinical evaluation, and advancing cartilage regenerative therapies.
Journals
2025 EN
Mukthavaram Rajesh · Sagi Amit · Hong Hyojung
+12 more
Abstract Lipid nanoparticle (LNP) is a proven platform for the safe and efficacious delivery of nucleic acid‐based therapeutics. Regulatory approvals of Patisiran, and mRNA vaccines against Covid‐19 are testaments to this fact. A key requisite for enabling a safe and biocompatible delivery system is the quick degradation and elimination of the various lipid components comprising the LNPs. Here, a new family of ionizable cationic lipids called “Self‐Immolative Lipids” (SILs) is reported. This innovative lipid architecture is designed to overcome a critical challenge in non‐viral gene therapy: the need for a delivery vector that is both efficacious and stable during biodistribution while remaining biodegradable upon reaching the target cell. These lipids demonstrate high stability in serum, required for the efficient delivery of the cargo, and an efficient bio‐degradation profile under the reducing conditions of the cytosol through a sequence of initial disulfide reduction and subsequent self‐elimination reactions resulting in the complete degradation of the lipids to facilitate elimination. These lipids demonstrated improved or equal activity and increased biodegradability compared to MC3, the ionizable lipid used in the first clinically approved LNP called Patisiran.
Journals
2025 EN
Rui Kejie · Priyadarshani Priyanka · Liversage Adrian Ross
+3 more
Abstract Mesenchymal stromal cells (MSCs) exhibit significant immunomodulatory potential, making them promising candidates for cell‐based therapies in autoimmune and inflammatory diseases. However, the heterogeneity of MSC cultures and a lack of robust, predictive potency assays have hindered their clinical translation. In this study, the potential of single‐cell morphological imaging during MSC expansion is explored as a method to estimate indoleamine‐2,3‐dioxygenase (IDO) protein and enzyme activity, a common immunosuppressive capacity measure. Fluorescence and label‐free quantitative differential phase contrast (qDPC) imaging is employed to non‐invasively extract morphological features from live MSCs during biomanufacturing with machine learning (ML) regression models to predict single cell IDO activity. qDPC imaging characterization is extended to estimate a previously established consensus model of MSC potency based on their IDO activity and immune suppression on T cells. These findings establish a foundation for scalable, non‐destructive monitoring of MSC immunomodulatory capacity, facilitating the future development of quality control strategies for MSC manufacturing and clinical applications.
Journals
2025 EN
Gentry James L. · Caliari Steven R.
Abstract Thiol–ene click chemistry is a powerful tool for engineering tissue‐mimicking hydrogels permissive to 3D cell spreading. Thiol–norbornene chemistry allows precise control over crosslinking while seemingly avoiding alkene homopolymerization that can restrict 3D cell spreading. However, limited stress relaxation of a guest–host crosslinked norbornene‐modified hyaluronic acid (NorHA) hydrogel employing a thiol–norbornene photoclick reaction prompts investigation into unintended norbornene homopolymerization. Norbornene conversion exceeds 1:1 thiol–ene expectations across various formulations, implicating homopolymerization. Reducing the number of norbornenes per NorHA chain ( f ) mitigates network formation via norbornene homopolymerization. Guest–host hydrogels fabricated with Nor 8 HA ( f = 8) exhibit 93.0 ± 1.6% relaxation, while those fabricated with Nor 40 HA ( f = 40) achieve only 42.3 ± 0.1% relaxation. As early as day 3 of culture, Nor 8 HA hydrogels facilitate spreading of encapsulated human mesenchymal stromal cells (hMSCs) into a spindle‐like morphology (aspect ratio: 2.95 ± 0.38), while Nor 40 HA hydrogels appear to constrain cells into a spherical or compact star morphology (aspect ratio: 1.22 ± 0.01). Inference of a single‐cell morphological space validates the two distinct hMSC morphological phenotypes primarily associated with polymer f . These results demonstrate that thiol–norbornene crosslinking is not fully stoichiometric in dilute aqueous systems and that network topology, modulated by f , is critical for restoring hydrogel permissivity and enabling cell spreading.
Journals
2025 EN
Au Kin Man · Swinnea J. Steven · Wang Andrew Z.
Abstract Radiotherapy (XRT) is often utilized to improve the immune checkpoint blockade response in cancer management. Such combination treatment can enhance the abscopal effect, facilitating a prolonged and durable systemic response. However, despite intense research efforts, only a minority of patients respond to this approach, and novel strategies to increase the abscopal effect are urgently needed. Here, the development of an intratumoral (i.t.) injectable nanofiber (NF)‐based tumor immune niche (TIN) that converts XRT‐treated tumors into an in situ cancer vaccine, eliciting robust systemic antitumor immunity, is reported. This NF‐based immune niche incorporates redox‐degradable anti‐CTLA‐4 (α‐CTLA‐4) nanogels (NGs) and interleukin‐2 (IL‐2) NGs for controlled release in hypoxic irradiated tumors, reversing the immunosuppressive tumor microenvironment into a pro‐inflammatory microenvironment, and expanding the tumor‐infiltrating CD8 + T cell population. Additionally, it is functionalized with polyinosinic‐polycytidylic acid (poly(I:C)) to promote antigen‐presenting cell maturation and prime neoantigen‐specific CD8 + T cells. In vitro studies demonstrate TIN's ability to prime antigen‐specific CD8 + T cells and increase antigen‐specific cell‐killing efficiency under in vitro immunosuppressive conditions. In vivo studies confirm TIN's ability to elicit robust systemic anticancer activity in mouse melanoma and colorectal cancer models without inducing severe immune‐related adverse events.
Journals
2025 EN
Maganzini Nicolò · Reschke Agnes · Cartwright Alyssa P.
+11 more
Abstract For more than fifty years, the enzyme‐linked immunosorbent assay (ELISA) serves as the gold standard for protein biomarker detection. However, conventional ELISA requires considerable sample preparation including reagent addition, incubation, and washing steps, limiting its usefulness at the point‐of‐care. In this work, the “instant ELISA” (fluorophore‐linked immunosorbent assay) biosensor that can measure protein biomarkers in the picomolar range within 15 min in undiluted plasma or serum with no sample preparation is described. The sensor leverages a synthetic reagent termed the “monolithic dual‐antibody clamp” (MDAC) which preserves the specificity, sensitivity, and generalizability of an ELISA, but produces a fluorescence signal as two surface‐tethered antibodies form a “sandwich” by binding to two distinct epitopes on the target. As exemplars, picomolar quantification of tumor necrosis factor alpha (TNFα) and monocyte chemotactic protein (MCP)‐1, the latter of which is a useful prognostic indicator of cytokine release syndrome in patient plasma samples during chimeric antigen receptor T cell therapy are demonstrated.
Journals
2025 EN
Holstun Tucker · Mishra Tara P · Huang Liliang
+8 more
Abstract Mn‐rich disordered rocksalt materials with Li‐excess (DRX) materials have emerged as a promising class of earth‐abundant and energy‐dense next‐generation cathode materials for lithium‐ion batteries. Recently, an electrochemical transformation to a spinel‐like “δ” phase has been reported in Mn‐rich DRX materials, with improved capacity, rate capability, and cycling stability compared with previous DRX compositions. However, this transformation unfolds slowly over the course of cycling, complicating the development and understanding of these materials. In this work, it is reported that the transformation of Mn‐rich DRX materials to the promising δ phase can be promoted to occur much more rapidly by electrochemical pulsing at elevated temperature, rate, and voltage. To extend this concept, micron‐sized single‐crystal DRX particles are also transformed to the δ phase by the same method, possessing greatly improved cycling stability in the first demonstration of cycling for large, single‐crystal DRX particles. To shed light on the formation and specific structure of the δ phase, X‐ray diffraction, scanning electron nanodiffraction (SEND) and atomic resolution STEM‐HAADF are used to reveal a nanodomain spinel structure with minimal remnant disorder.