Bioactive Materials

Articular cartilage repair is limited by the poor regenerative capacity of chondrocytes and their rapid dedifferentiation during in vitro expansion. This study investigated whether a decellularized and lyophilized cell-secreted matrix (CSM) could function as a bioactive material to regulate cell behavior, promote chondrogenic differentiation, and attenuate or reverse chondrocyte dedifferentiation without exogenous growth factor supplementation. CSM was generated from rabbit auricular perichondrial cells, decellularized, lyophilized, and characterized by histology, biochemical assays, and proteomic analysis. The resulting matrix was enriched in structurally and functionally relevant extracellular matrix proteins, including collagens, fibronectin, fibrillin, proteoglycans, and matricellular regulators, with minimal intracellular contamination and good batch-to-batch reproducibility. Functionally, CSM supported robust adhesion and proliferation of allogeneic and xenogeneic cells. Human articular chondrocytes cultured on CSM exhibited enhanced proliferation, sustained expression of cartilage-specific markers, and preserved type II collagen production over serial passages compared with standard plastic culture. CSM also promoted chondrogenic differentiation of human progenitor cells and partially reversed established chondrocyte dedifferentiation, as evidenced by increased expression of COL2A1, ACAN, SOX9, and COMP, with reduced COL1 expression and no induction of hypertrophic markers. These findings demonstrate that lyophilized CSM is a stable, off-the-shelf biomaterial capable of directing chondrocyte fate through intrinsic matrix-derived cues, highlighting its potential for cartilage tissue engineering and cell manufacturing applications.

Controlled delivery of growth factors and viable cells remains a significant challenge in bone tissue engineering. In this study, a 3D-printed hydrogel scaffold system was developed for the co-delivery of bone morphogenetic protein-9 (BMP-9) and preosteoblasts to enhance bone regeneration. The system consisted of a 3D-printed base scaffold containing BMP-9-coated calcium sulfate (CaS) microparticles and a photocurable hydrogel coating layer encapsulating viable cells. The scaffold design exploited electrostatic interactions between BMP-9 and gelatin matrices by incorporating gelatin type B in the base scaffold and gelatin type A in the coating layer. Differences in the isoelectric points of these gelatin types were utilized to regulate protein binding and release. Release studies demonstrated that CaS microparticles alone exhibited rapid burst release, with nearly 80% of BMP-9 released within 24 h. Encapsulation of BMP-9 coated CaS particles in the 3D-printed scaffolds reduced the release rate, while the addition of the coating layer significantly improved sustained release, limiting BMP-9 release to approximately 50-60% by day 5. Bioactivity studies showed enhanced cell attachment in BMP-9 containing scaffolds compared with controls. Live/Dead cytotoxicity assays demonstrated high cell viability (>80%) within the coating layer over the culture period, confirming that the encapsulation and photocuring processes did not adversely affect cell survival. Cell proliferation and differentiation were further evaluated using WST-1 and alkaline phosphatase assays. The results demonstrate that electrostatic interactions governed by gelatin type selection can regulate BMP-9 release while maintaining high cell viability, providing a promising platform for growth factors and cell delivery in bone tissue engineering.

Hypertrophic cartilage is a promising bone repair strategy by producing a mineralizable matrix that transitions to bone through endochondral ossification. Current approaches require large cell numbers and costly recombinant factors to induce chondrogenesis. Here, we developed a composite granular scaffold using photocrosslinkable alginate microgels, cell-secreted decellularized extracellular matrix (dECM), and mesenchymal stromal cell (MSC) spheroids under dynamic compressive loading for hypertrophic cartilage formation. Incorporation of dECM into MSC spheroids enhanced expression of chondrogenic markers and supported the hypertrophic phenotype, evidenced by increased VEGFA and SPP1 expression and ALP activity. Dynamic loading further increased spheroid sprouting and scaffold mineralization. Histology confirmed mature hypertrophic cartilage conducive to bone formation. Upregulation of hypertrophic and osteogenic markers was associated with YAP1 activation, linking compressive loading to mechanotransduction to drive hypertrophic cartilage formation. These results demonstrate that dynamic compressive loading, cell aggregates, and scaffold granular macroporosity synergistically yield hypertrophic cartilage.

This study presents the development of biodegradable intra-arterial drug delivery (IADD) devices for focal treatment of targeted organs, to enhance therapeutic efficacy while minimizing systemic toxicity. The IADD devices are fabricated using magnesium (Mg) and poly(glycerol sebacate) (PGS), leveraging their biocompatibility and tunable biodegradability, and are loaded with two model drugs, i.e., dexamethasone (DEX) or cisplatin (CIS). The IADD devices with helical and linear designs were fabricated for focal drug delivery to targeted organs and characterized for their microstructure and composition using scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), thermogravimetric analysis (TGA), and Fourier-transform infrared spectroscopy (FTIR). The results confirmed the successful incorporation and stability of the drugs within the device. The IADD devices demonstrated a sustained release of DEX and CIS over 30 days in vitro, with cumulative release of 373.11 {+/-} 1.41 {micro}g and 64.73 {+/-} 0.06 {micro}g, respectively. The IADD devices demonstrated cytocompatibility with endothelial cells and sustained pharmacological activity against glioma cells throughout the in vitro release period. We implanted DEX-loaded IADD devices into the artery upstream of a target organ in rat models. The devices implanted into the renal artery to target the kidney and the carotid artery to target the brain achieved 109-fold and 68-fold improvements, respectively, in organ vs systemic drug levels compared to oral drug administration. These results proved the safety and efficacy of the IADD devices for sustained, focal drug delivery of different drugs to the target organs, with reduced systemic drug exposure. Overall, the results demonstrated the potential of the IADD devices as a valuable platform technology to achieve focal drug delivery to targeted organs for a wide range of clinical applications, especially for delivering drugs with high efficacy, high systemic side-effects, and narrow therapeutic window.

Polysaccharides are often used to mimic physiological environments such as for cancer research models. However, established polysaccharides can display limited long-term stability and high batch-to-batch variability. To overcome this, biomanufactured polysaccharides are increasingly utilized in biomaterials. Here, we produced and characterized Rhodotorula toruloides yeast exopolysaccharides (EPS) and used it to engineer hydrogel for culturing cancer cells. Yeast fermentation of glucose, mannose, and xylose yielded varying EPS amounts (1.68, 1.44, and 0.48 g/L, respectively) with similar compositions, suggesting a common biosynthetic pathway. The glucose-derived EPS characterization identified multiple linkage types and three molecular weight fractions (1.75, 30.0, and 1000 kDa), and its solutions exhibited Newtonian behavior, indicating minimal chain-chain interactions. Solubilizing this polydisperse EPS with polyethylene glycol diacrylate and UV-crosslinking it enabled the engineering of semi-interpenetrating polymer network hydrogel that efficiently embedded cancer spheroids. Our study introduces an integrated biomanufacturing strategy to generate stable and consistent biomaterials, applicable for tissue engineering. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/703759v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@110d079org.highwire.dtl.DTLVardef@e6e390org.highwire.dtl.DTLVardef@662540org.highwire.dtl.DTLVardef@17afd5_HPS_FORMAT_FIGEXP M_FIG C_FIG

In vitro reconstruction of human tissue microenvironments that integrate native biochemical and biomechanical cues is essential for disease modelling, regenerative medicine, and personalized therapeutic approaches. However, most currently available engineered matrices fail to recapitulate the complexity and tissue specificity of the human extracellular matrix (ECM). To address this limitation, we developed a novel hydrogel derived from decellularized human adipose tissue (atdECM) designed to support three-dimensional culture of human cells. The decellularization and delipidation processes were first validated, and the biochemical composition and biomechanical properties of atdECM were comprehensively characterized. Human pancreatic organoids were then cultured within atdECM hydrogel, and their structural organization and transcriptional profiles were analyzed and compared with those obtained in Matrigel, the current gold-standard matrix for organoid culture. Proteomic and cytokine analyses demonstrated efficient decellularization while preserving collagen-rich ECM architecture and a diverse repertoire of soluble bioactive factors. AtdECM exhibited physiological stiffness and retained tissue-specific extracellular cues. Pancreatic organoids cultured in atdECM displayed morphological similarities with those grown in Matrigel but exhibited transcriptional profiles more consistent with physiological epithelial homeostasis, with reduced activation of inflammatory and stress-related pathways. Altogether, these findings indicate that atdECM provides a human-derived, tissue-relevant, and permissive microenvironment for human organoid generation. This platform represents a promising alternative to Matrigel for studying human tissue biology and for developing physiologically relevant in vitro models.

Acute respiratory distress syndrome (ARDS) is the most severe manifestation of acute lung injury (ALI), characterized by diffuse pulmonary inflammation, impaired gas exchange, and high morbidity and mortality. Despite its clinical significance, no specific or effective pharmacological therapies are currently available for its treatment. In this study, we developed a lung -targeted mRNA-sulfonium lipid nanoparticle (mRNA/sLNP) delivery system for the treatment of ALI in a mouse model. We first optimized sulfonium lipid structures, and the optimized sLNP was comprehensively characterized and subsequently loaded with interleukin-10 (IL-10) mRNA. In a lipopolysaccharide (LPS)-induced ALI mousemodel, IL-10/sLNPdemonstrated both prophylactic and therapeutic efficacy, significantly attenuating pulmonary and systemic inflammation, restoring barrier integrity, and reducing tissue injury.

The clinical success of vascular grafts relies on three main prerequisites: artery-tuned mechanics, cell-supportive microstructure, and a thromboresistant interface. Most current solutions address only a subset of this triad and equate mechanical matching with compliance alone, which can lead to disturbed hemodynamics, maladaptive mechanobiology, and adverse graft-host biochemical interactions that frequently culminate in clinical complications and graft failure. This study presents polyurethane-based heparin-functionalized elastomeric nanofibrillar grafts (H-ENGs) that integrate all three prerequisites while allowing multi-parameter mechanical mimicry. To address the principal failure mode of early thrombosis, a small fraction of polyethyleneimine (PEI) is added to the ENG electrospinning solution to form P-ENGs, enabling one-step covalent heparin conjugation to form H-ENGs. The decoupled design of the ENG platform preserves the biomimetic microstructure and mechanics following PEI incorporation and heparinization, enabling adaptable, indication-specific optimization. In vitro, H-ENGs exhibit good cytocompatibility with minimal hemolysis, platelet adhesion, and whole blood clotting. Pilot porcine abdominal aorta interposition studies demonstrate feasibility: H-ENGs exhibit favorable surgical handling, intact suture-line integrity, and anastomotic hemostasis under dynamic flow, and retain artery-tuned mechanics and surface heparin at two weeks. While further testing is warranted, these results indicate that H-ENGs satisfy the three prerequisites for vascular graft clinical success. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=68 SRC="FIGDIR/small/701857v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@1e09f2aorg.highwire.dtl.DTLVardef@1f1b5baorg.highwire.dtl.DTLVardef@1d1fba6org.highwire.dtl.DTLVardef@e066ca_HPS_FORMAT_FIGEXP M_FIG C_FIG

Critical sized craniomaxillofacial bone defects do not heal naturally and often exhibit chronic inflammatory responses that restrict regeneration. It is increasingly apparent that biomaterials must facilitate dynamic crosstalk between immune cells, such as macrophages, and osteoprogenitors to resolve inflammation and accelerate regeneration. Here, we evaluate interactions between macrophages in a neutral (M0) or pro-inflammatory (M1) state with mesenchymal stem cells (MSCs) in a basal or licensed state within a mineralized collagen scaffold. We reveal that MSC-macrophage crosstalk influences significant changes in osteoprogenitor cell differentiation and immune cell polarization. Notably, crosstalk between MSCs and macrophages drives an early-stage inflammatory response, which enhances the immunomodulatory activity of MSCs via secretion of IL-6, an effect that is heightened for already licensed MSCs. The presence of macrophages in the co-cultures upregulated osteogenic (ALPL, BMP2, COL1A2, and RUNX2) and angiogenic genes (ANGPT1) in basal MSC groups. Further, MSC-macrophage interactions subsequently drive increased M2-like macrophage polarization as early as 7 days of culture, as indicated by surface marker expression. These findings show that biomaterial scaffolds can be leveraged as mediators of MSC-mediated immunomodulation with an emphasis on achieving early-stage pro-inflammatory phenotypes that drive subsequent macrophage polarization and markers of increased regenerative potency.

The growing prevalence of obesity necessitates innovative treatments. This study investigates a spray-dried konjac glucomannan-montmorillonite (KGM-MMT) hybrid designed to combine the fermentable, satiety-promoting effects of KGM with the lipid-binding and anti-inflammatory properties of MMT. In HFD-fed mice treated for 42 days with 2% w/w KGM-MMT, body weight gain was reduced by 7.6%, with an AUC of 5094[{+/-}[52.95, compared to 5513[{+/-}[81.35 in HFD controls (p < 0.0001). Serum IL-6 concentrations were reduced by 97% (p = 0.0002), while blood glucose decreased by 46% (p < 0.0001), outperforming reductions seen with MMT (24%, p = 0.0271) and KGM (16%, ns). Gut microbiota profiling demonstrated a significant 6.2-log[ fold increase in Lactobacillaceae (p = 0.023) and a 2.4-log[ fold increase in Enterococcaceae (p = 0.015) with KGM-MMT treatment. Predicted functional shifts revealed a 1.9-fold increase in short-chain fatty acid synthesis pathways and a 5.4-fold increase in bile acid deconjugation. Although the KGM-MMT hybrid did not consistently outperform its individual components in all measurements within the current study, it generally consolidated their metabolic benefits within a single dosage form. These findings support the utility of spray-dried KGM-MMT as a gut-targeted dietary strategy with additive effects on metabolic health. Future studies should explore underlying mechanisms and dosage effects of the hybrid formulation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/701163v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@738445org.highwire.dtl.DTLVardef@1f0d465org.highwire.dtl.DTLVardef@86e5aorg.highwire.dtl.DTLVardef@184fba8_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LISpray-dried KGM-MMT reduced HFD-induced weight gain by 7.6% in obese mice C_LIO_LISerum IL-6 and glucose levels decreased by 97% and 46%, respectively C_LIO_LI6.2-log[J and 2.4-log[J increases in Lactobacillaceae & Enterococcaceae relative abundance C_LIO_LIBile acid deconjugation and SCFA pathways increased 5.4- and 1.9-fold C_LIO_LIKGM-MMT microparticles offer additive gut-targeted benefits in metabolic disease C_LI

Apatite-based bone graft materials are widely used for bone regeneration; however, their limited bioactivity and slow remodeling often hinder complete replacement by newly formed bone. Electrical surface polarization has emerged as a promising non-chemical strategy to modify biomaterial surface properties without altering bulk characteristics. In this study, we investigated the effects of electrical surface polarization on apatite-based biomaterials using synthesized carbonate apatite (CA) for mechanistic in vitro evaluation and a clinically relevant xenograft material for in vivo validation. Material characterization confirmed the formation of B-type carbonate apatite with bone-like mineral composition. Thermally stimulated depolarization current measurements verified successful induction of surface charges, with polarization intensity dependent on treatment conditions. In vitro studies using human peripheral blood-derived osteoclast precursors demonstrated that electrically polarized CA surfaces significantly enhanced osteoclast differentiation and resorptive activity compared to non-polarized controls, with the strongest effects observed on positively polarized surfaces. Three-dimensional analysis revealed increased resorption pit depth and volume, indicating enhanced osteoclast functionality. In vivo implantation of polarized xenograft materials into rat femoral defects resulted in significantly increased new bone formation and improved implant-bone integration compared to non-polarized materials. Higher polarization conditions promoted more mature bone tissue formation and greater bone-material affinity. These results demonstrate that electrical surface polarization effectively modulates osteoclast-material interactions and enhances bone regeneration, highlighting its potential as a simple and translatable functionalization strategy for apatite-based bone graft materials.

ObjectiveEvaluate the effects of bioabsorbable magnesium wires on dermal wound healing and tissue regeneration in a murine full-thickness wound model. Approach6 mm diameter stented dorsal skin wounds were created in C57BL/6J mice and treated with implanted WE43B magnesium alloy wires or PBS control. Wound healing was evaluated on days 7 and 28 by histology, immunohistochemistry, and micro-CT. Finite element analysis modeled mechanical strain distribution due to wire degradation during healing. ResultsAt day 7, magnesium wire-treated wounds showed 100% improved granulation tissue formation, reduced inflammation (37% fewer CD45+ leukocytes and 37% fewer F4/80+ macrophages), increased neovascularization (91% more CD31+ lumens), and 74% more nerve bundles. Improved wound closure (mean difference -1.48 mm) did not reach statistical significance (d = 1.06). By day 28, magnesium-treated wounds showed improved collagen organization and normalized epidermal thickness. The increase in dermal appendages (247%), and vascular density (41%) did not reach statistical significance. Micro-CT confirmed progressive wire degradation. Modeling revealed that degrading wires dynamically altered strain gradients in healing tissue, thereby modulating the spatial mechanical cues that govern fibroblast migration and extracellular matrix (ECM) remodeling. InnovationMagnesium is an essential trace element involved in cellular processes critical to wound repair, including angiogenesis, nerve growth, inflammation modulation, and ECM remodeling. Previous magnesium delivery systems incorporated polymers or other confounding materials that degrade rapidly. We directly applied bioabsorbable pure magnesium metal to provide sustained ion release and favorable mechanical properties to support regenerative healing. ConclusionBioabsorbable magnesium wires support regenerative wound healing by reducing inflammation, enhancing neovascularization, and promoting favorable ECM remodeling without adverse inflammatory reactions. These findings provide a strong rationale to harness magnesium metal use in wound healing applications.

Treating extensive full-thickness burn wounds remains difficult in clinical practice because available donor skin is often limited, the risk of infection is high, and many standard dressings do not perform well when defects are large or structurally complex. These limitations have shifted attention to decellularized extracellular matrix (dECM) scaffolds, which can provide physical coverage while preserving biochemical cues that may support tissue repair. Based on this rationale, we designed a decellularization method that improves reagent penetration to produce a full-thickness porcine decellularized small intestine (dSI) scaffold for use in burn wound coverage. The protocol removed most cellular material while leaving low levels of detergent residue, and it maintained the native three-layer structure of the intestinal wall. Most key ECM components, such as collagen and glycosaminoglycans, were also retained. In this study, the dSI showed several properties relevant to burn care, capacity to absorb large amounts of fluid, water vapor transmission rates similar to those reported for skin, and resisted microbial penetration in vitro. From a mechanical standpoint, the scaffold retained anisotropic behaviour and remained stable under cyclic loading. This pattern indicates that it could withstand repeated deformation instead of acting like a fragile membrane. Degradation tests under enzymatic and oxidative conditions indicate that the material breaks down in a controlled way over a period that appears consistent with typical wound-healing timelines. In vitro assays indicated that the scaffold was cytocompatible, as human dermal fibroblasts and keratinocytes both attached to its surface and continued to proliferate. Cell responses differed depending on surface orientation, suggesting that preserved intestinal layers may shape cell behaviour in ways that are often missing in thinner or more uniform matrices. Overall, full-thickness dSI appears to act as a biologically active scaffold and shows mechanical properties that exceed those of many currently used burn dressings.

Three-dimensional (3D) bioprinted liver scaffolds offer a promising platform for drug screening, disease modelling, and regenerative medicine, yet their broader adoption is limited by the absence of robust post-fabrication preservation strategies. This study aimed to evaluate the impact of -80{degrees}C (deep freezer) preservation and evaluate the structural integrity and hepatic functionality of GelMA-decellularized liver extra cellular matrix (dECM)-based 3D bioprinted liver scaffolds. Bioinks were formulated using synthesized GelMA and solubilized rat liver dECM, and 3D scaffolds were fabricated via extrusion bioprinting into rectilinear grid scaffolds. The 3D scaffold preservations was performed by immersion into two different medium (the culture DMEM media and the other FBS-DMSO cocktail) was evaluated using MTT viability assay, and albumin assay. Preserved 3D bioprinted scaffolds retained overall architecture and cell distribution in the FBS-DMSO cocktail demonstrated by the live dead assay. Together, the data demonstrate that -80{degrees}C storage can maintain the basic cell viability ([~]80%) and a substantial fraction of liver-specific functionality in 3D bioprinted scaffolds but also highlight sensitivity to preservation-induced injury. These findings underscore the need for further optimization of cryoprotectant formulations and freezing protocols tailored to 3D bioprinted liver scaffolds, and provide a foundational framework for developing ready-to-use, cryopreserved 3D liver models for translational applications.

Human pluripotent stem cell (hPSC)-derived alveolar organoids (ALOs) have emerged as a powerful tool for modeling human lung development and disease, and accelerating respiratory drug discovery. However, achieving the functional maturation of ALOs remains challenging. Polydopamine (PDA) is a mussel-inspired polyphenolic biomaterial with antioxidant and adhesive properties that can be deployed as surface coatings and nanoparticles (NPs) in cell culture systems. Here, we integrate PDA coatings and NPs sequentially in a stage-adaptive manner throughout the hPSC-derived ALOs differentiation system and study their contributions to ALOs maturation. Our results demonstrated PDA coating yielded more anterior foregut endoderm (AFE) spheroids by strengthening the interaction between Matrigel and substrate. Bulk RNA-seq revealed enrichment of cell-cell and cell-extracellular matrix interactions by PDA. The subsequent incorporation of PDA NPs in Matrigel at lung progenitor cells (LPCs) stage significantly mitigated reactive oxygen species (ROS) accumulation and enhanced LPCs generation. Functionally, AT2 cells in ALOs exhibit characteristic lysosome-to-lamellar body (LB) maturation due to the traffic of internalized PDA NPs to endolysosome. Transcriptomics further indicated enrichment of endocytic-phagosome and epithelium development pathways by PDA treatment. Together, our study establishes a stage-adaptive-integrated PDA strategy throughout hPSC-to-ALOs differentiation and demonstrates that PDA robustly enhances ALOs maturation and secretory function. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=178 SRC="FIGDIR/small/708928v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@88208dorg.highwire.dtl.DTLVardef@1111590org.highwire.dtl.DTLVardef@9ea9b0org.highwire.dtl.DTLVardef@969fad_HPS_FORMAT_FIGEXP M_FIG C_FIG

PurposeEndothelial cell (EC) activation, characterized by upregulation of adhesion molecules that drive monocyte recruitment, contributes to plaque progression while also providing an opportunity for targeted therapeutic delivery. Leveraging the cell membrane cloaking strategy, we recently developed a monocyte-mimetic nanoparticle (MoNP) platform that exploits the natural inflammatory tropism of monocytes for site-specific delivery to atherosclerotic vessels. Recognizing that integrin activation is a key determinant of monocyte adhesion to ECs, this study investigates whether pre-activating integrins on MoNP enhances their binding affinity and accumulation at atherosclerotic lesions. MethodsMouse bone marrow-derived monocytes were pretreated with CCL2 or Mn2{square} to activate membrane integrins. Isolated monocyte plasma membranes were cloaked onto fluorescently labeled polymeric cores to generate integrin-activated MoNPs (IA@MoNPs). The targeting capability of IA@MoNPs toward endothelial ligands, inflamed ECs, and atherosclerotic lesions was evaluated using in vitro and in vivo models. ResultsIA@MoNPs exhibited markedly enhanced binding to VCAM1, the primary endothelial ligand mediating integrin-dependent monocyte adhesion, and significantly increased uptake by ECs under atheroprone conditions compared to standard MoNPs. In vivo, IA@MoNPs demonstrated enhanced accumulation in atherosclerotic arteries without increasing nonspecific binding, and blocking {beta}1-integrins on IA@MoNPs abolished this targeting effect. Importantly, integrin activation on IA@MoNPs did not compromise circulatory stability or induce immune or organ toxicity. ConclusionIntegrin activation represents a simple yet effective strategy to enhance MoNP targeting to inflamed ECs and atherosclerotic lesions. This mechanism-driven approach improves targeting performance while maintaining specificity and safety, advancing the translational potential of the biomimetic nanomedicine platform for atherosclerosis.

Central nervous system (CNS) disease or injury might be treated by implanted devices, tissue regenerative scaffolds, or drug delivery platforms. However, inflammatory CNS responses limit these interventions and may worsen outcomes following damage to the CNS. Via the foreign body reaction (FBR), macrophages and glial cells trigger a "glial scar" around implants, reducing device performance, scaffold regenerative ability, or drug delivery potential. Previous studies have shown that stiffness of CNS implants significantly affects glial encapsulation, but few studies have investigated materials that truly match brain tissue stiffness. Porous precision-templated scaffolds (PTS) with uniform, interconnected, 40 {micro}m pores have shown favorable healing outcomes and a reduced FBR in numerous soft and hard tissue applications. To quantify the effects of both hydrogel compliance (stiffness) and pore size on glial encapsulation, we implanted poly(2-hydroxyethyl methacrylate-co-glycerol methacrylate) (pHEMA/GMA) PTS of varying stiffness and pore size for 4 weeks in rat brain. We observed reduced astrocyte encapsulation around PTS compared to solid hydrogel rods, reduced pro-inflammatory macrophage polarization for softer hydrogels versus stiffer hydrogels, and the presence of neuronal markers and neurogenesis within the pores. Utilizing soft, precision-porous hydrogels could provide a strategy for mitigating glial scarring and improving implant-based CNS treatments.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is marked by excessive hepatic lipid accumulation and is closely associated with hyperlipidemia. It poses significant health challenges and can progress to severe chronic liver disease if untreated. Several small-molecule pharmacological agents are either in clinical use (resmetirom) or advancing through preclinical development for the treatment of hepatic steatosis. However, some promising lead drug candidates have limited therapeutic potential due to poor solubility, low permeability, limited biocompatibility, and off-target effects. Cell membrane-derived nanoparticles (CMN), prepared from red blood cells, naturally exhibit immune-evasion properties and can overcome these limitations by encapsulating small molecules within their self-assembled structures. Further, CMN can be surface functionalized to enable precise targeting of liver hepatocytes. Here, we developed a hepatocyte-targeting CMN loaded with a model drug (resmetirom) for MASLD therapy. Using covalent bonds, we conjugated three different hepatocyte-targeting ligands to CMN and identified lactoferrin as the most effective ligand through comparative screening. We then confirmed the cellular internalization pathways of the selected ligand in both targeted CMN and non-functionalized CMN. Finally, in an in vitro hepatic steatosis model, the optimized targeted CMN demonstrated improved bioactivity, including significant reductions in lipid droplets, triglycerides, and liver enzyme levels. Altogether, this targeted CMN platform shows promising potential to enhance the therapeutic efficacy of small-molecule drugs for MASLD and may, overall, improve therapeutic outcomes in preclinical and clinical trials.

Alginate hydrogels are widely used for biocompatible encapsulation due to their low cost, mild gelation conditions, and scalability; however, their limited mechanical strength and poor chemical stability under physiological conditions restrict their utility for oral delivery applications. In particular, the development of robust alginate formulations capable of surviving gastrointestinal salt and pH exposures is critical for advancing encapsulated microbial therapeutics for chronic kidney disease (CKD). In this study, we investigated the incorporation of ferric iron into calcium alginate networks as a strategy to enhance gel stability while maintaining biocompatibility. Using a three-ion competition approach, we achieved controlled introduction of ferric ions into calcium alginate gels without significantly altering bulk mechanical properties relative to standard calcium alginate. Although the initial ferric-containing gels displayed comparable modulus and structure, post-treatment with chitosan under mildly acidic conditions produced a dramatic increase in gel stability in physiological salt concentrations across both acidic and neutral pH environments. Ferric-containing gels formed at pH 4.6 absorbed negligible chitosan, in contrast to iron-free alginate gels, which incorporated substantial chitosan under identical conditions. These results support the formation of a thin, dense interfacial complex between chitosan, ferric ions, and alginate at the gel surface, which reinforces the matrix and inhibits dissolution. The resulting hybrid ferric-calcium alginate formulation enabled the production of sub-millimeter beads capable of encapsulating live Thauera aminoaromatica while preserving anaerobic p-cresol degradation activity at 37 {degrees}C using nitrate as an electron acceptor. Collectively, these findings establish ferric-modified alginate hydrogels as a promising, scalable platform for stable oral delivery of encapsulated microbial therapeutics.

Pancreatic ductal organoids (PDOs) generated from human induced pluripotent stem cells (iPSCs) can be used to model pancreatic diseases and to conduct drug screening/testing. However, current protocols for generating PDOs rely heavily on tumor-derived Matrigel, which has been shown to upregulate oncogenes. Furthermore, Matrigel has undefined composition and weak mechanical properties that hamper mechanistic studies of cell-material interactions. In this study, we explore photo-clickable decellularized small intestine submucosa-norbornene (dSIS-NB) hydrogels as a Matrigel replacement for generating human iPSC-derived PDOs. To achieve this, pancreatic progenitors (PP) were first differentiated in conventional two-dimensional (2D) culture, aggregated into spheroids, then encapsulated and differentiated within dSIS-NB hydrogels with tunable stiffness. The differentiated organoids were analyzed by morphology, expression of key pancreatic ductal markers, and single-cell RNA sequencing (scRNA-seq). Post-differentiation, PDOs generated in stiffer photo-clickable dSIS-NB hydrogels (shear moduli [~]2.5 kPa) maintained ductal epithelial phenotype and exhibited pronounced forskolin-induced swelling. In contrast, differentiation of PP spheroids in softer dSIS-NB gels (shear moduli [~]0.9 kPa) and Matrigel resulted in a persistent mesenchymal phenotype and failed to generate functional PDOs. Finally, scRNA-seq results revealed that stiffer dSIS-NB hydrogels strongly biased ductal cell differentiation, yielding greater than 97% ductal progeny.