Advanced Healthcare Materials

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.

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.

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.

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.

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.

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.

Cellular therapy, such as beta cell transplantation for Type 1 diabetes, is a promising approach to durably alleviate disease states. Implanting cells within porous scaffolds is beneficial as they distribute the cells and mechanically support implantation; however, scaffolds can exacerbate foreign body responses (FBR). While the geometric features of a scaffold are known to impact FBR, there is limited consensus on what makes an ideal implant. Some have explored the role of pore size and interconnectivity; however, the impact of rung thickness between pores on FBR is broadly understudied. To investigate this parameter, we created a scaffold with reproducible geometric features and high biostability by combining 3D-printing with the polymer polydimethylsiloxane (PDMS). We tested 3D-printed scaffold prototypes with identical pore sizes but distinct PDMS rung thicknesses ranging from 150 to 300 {micro}m. Upon transplantation, biocompatibility screening in a mouse model revealed that scaffolds with thicker PDMS rungs led to increased intra-device fibrosis. Additional spatio-proteomic analysis revealed distinct differences in host responses to rung changes, with alterations in macrophage and adaptive immune cell markers, as well as fibrotic proteins, within scaffolds containing thicker rungs. Selecting the optimized rung size, we evaluated its efficacy in rat syngeneic and allogeneic islet transplant models. In the allogeneic model, 3D-printed scaffold islet implants demonstrated robust efficacy and stability, yielding improved outcomes compared to PDMS scaffolds without optimized geometric features. Results from this study reveal how specific geometric scaffold features critically influence FBR to biomaterial implants, accelerating or mitigating fibrotic responses, and ultimately determining transplant success.

Thrombogenicity causes significant complications in the application of blood-contacting implants, requiring strategies to prevent adverse coagulation reactions. The thrombotic responses to the foreign surfaces are mainly driven by surficial factors such as surface energy, topography, and electrochemical interactions. Although anticoagulation therapies reduce the risks of clotting, patients might still encounter bleeding complications. Therefore, rather than high-risk anticoagulation therapies to counteract coagulation, it is essential to ensure hemocompatibility through the materials intrinsic properties. Endothelialization is crucial in preventing thrombotic complications, with various strategies explored for facilitating endothelial cell adhesion and proliferation. We investigated the impact of crystallographic anisotropy on endothelial and blood cell interactions on four main planes (A-, C-, M-, and R-planes) of single crystalline alumina (-Al2O3, sapphire). Employing advanced surface characterization techniques, including SIMS, KPFM and Zeta potential measurements, our study sheds light on the hemocompatibility of biomaterials considering anisotropic effects. We elucidated that the A-plane of alumina promotes endothelialization and suppresses platelet activation in contrast to other crystallographic planes. Our investigation into cell-surface interactions provides valuable insights and contributes to the advanced biomaterial design, ultimately leading to enhanced clinical outcomes.

Critical-sized craniomaxillofacial (CMF) defects affect the skull, face, and jaw, arising from conditions such as cleft palate, oncologic resections, and high energy impacts, and due to their large size and irregular geometry, cannot heal naturally by the body, thus requiring surgery. The field of biomedical research has long recognized the need to develop higher order biomaterial model systems for improved disease characterization and translational therapeutic/material progress. There is, however, difficulty in developing these workflows at the scale of conventional two-dimensional cell culture screening systems while simultaneously approaching a level of complexity necessary to consider translation to in vivo animal models. Here, we describe a three-dimensional (3D), in vitro model system to investigate the impact of stromal cell migration from one microenvironment to another at a medium-throughput scale. Importantly, we demonstrate the ability of this workflow to be utilized as a screening tool for collagen-based biomaterial motifs of interest in promoting craniomaxillofacial bone defect repair. Taken together we provide a strategy for interpreting cell-to-cell, cell-to-material, and material-to-material interactions across a multidimensional spatiotemporal scale.

Hydrogels that mimic the extracellular matrix can create a microenvironment with various physicochemical cues, which significantly influence stem cell fate with particular emphasis on their immunoregulatory and pro-regenerative functions. However, elucidating how biomaterial cues regulate cell fate is invariably confronted with complexities such as multi-parameter interactions and nonlinear relationships, thereby necessitating a large number of samples and consuming substantial labor and resources. This research introduces a materiomics platform that utilizes high-throughput data and artificial intelligence for the systematic evaluation and accurate prediction of optimal stem cell niche features, aiming to boost the immunomodulatory functions of mesenchymal stem cells (MSC). Specifically, binary hydrogels composed of methacrylated alginate and gelatin (AMGM) were employed, allowing the establishment of a comprehensive materiomics database with seven critical physicochemical cues as indicators of MSC immunomodulatory capacity in mediating macrophage polarization. Machine learning algorithms based on this materiomics database not only successfully predicted the most effective hydrogel formulations to promote stem cells immunoregulatory efficacy but also revealed that matrix stiffness is the most dominant environmental cue mediating macrophage phenotype. In summary, this study demonstrates the utility of artificial intelligence in identifying core microenvironment cues and establishes a data-driven research paradigm for investigating microenvironmental signals.

Macrophages play a central role in early immune response after injury that can shape the success or failure of craniomaxillofacial (CMF) bone repair. While mineralized collagen glycosaminoglycan (GAG) scaffolds have been developed to support osteogenesis, here we define how scaffold pore size, pore alignment, and glycosaminoglycan (GAG) composition influence human monocyte-derived macrophage polarization. We establish flow cytometry, secretome, and gene expression benchmarks to assess primary macrophage polarization toward M1 versus M2 phenotypes in response to cytokine cocktails in 2D culture and 3D scaffolds. We then define the kinetics macrophage polarization in response to scaffold pore architecture and composition in the absence of exogenous cytokines. All scaffold variants support an early pro-inflammatory response followed by a shift toward M2-like phenotypes over seven days reflected by increased CD206 expression, secretion of pro-healing factors such as CCL18, and upregulation of M2a- and M2c-associated genes. Anisotropic scaffolds with smaller pores more robustly drove angiogenic and extracellular matrix related gene expression as well as earlier emergence of M2-like phenotypes. Scaffold GAG chemistry provided an additional tuning mechanism, with chondroitin-6-sulfate variants promoting the greatest late-stage M2 surface marker expression, heparin variants accelerating early M2 and pro-angiogenic phenotypes, and chondroitin-4-sulfate variants dampening both M1 and M2 phenotypes at early timepoints. These findings demonstrate that mineralized collagen scaffolds intrinsically guide macrophage polarization toward pro-regenerative states but that scaffold structure and composition can be used to shape the kinetics and intensity of these responses. These insights provide a critical foundation for immuno-instructive biomaterial designs that enhance CMF bone repair.

Tissue engineering scaffolds such as collagen-based biomaterials have long been used to mimic native extracellular matrix in a wide range of regenerative applications. Their high porosity, tunable degradation and mechanics, and cell adhesion sites provide a structure upon which cells can grow and differentiate, while they also have the potential to act as carriers for loading and release of biomolecules to aid in healing. Here we describe the inclusion of a second lyophilization step in the fabrication process to enable improved loading efficiency of bone morphogenic protein 2 as well as increased ease of end-user handling. We report mineralized collagen scaffolds demonstrate maintained microarchitecture and mechanical properties post-relyophilization with reduced variability in biomolecule loading. Relyophilization allows consistent loading and release profiles and suggests the potential to improve the translational potential of collagen scaffold biomaterials for regenerative medicine applications.

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.

Miniaturized neural interfaces for research, diagnostics, and neuromodulation therapies require electrode materials that maintain low impedance and high charge injection capacity as device dimensions shrink to ensure high-quality recordings and safe stimulation. Conventional interfaces rely on metals like platinum (Pt), which are limited by intrinsically high impedance and low charge transfer capacity, reducing their performance in sub-100 {micro}m applications. Ti3C2Tx MXene has emerged as a promising alternative for high-density recording and stimulation interfaces, though the fundamental charge transfer mechanisms governing its performance remain poorly understood. This study evaluates Ti3C2Tx MXene microelectrodes across a range of diameters (25 - 500 {micro}m) and systematically elucidates the mechanisms governing their recording and stimulation capabilities. Electrochemical impedance spectroscopy, cyclic voltammetry, and voltage transient measurements - supported by equivalent-circuit modeling - revealed enhanced recording and stimulation capabilities of the MXene microelectrodes over size-matched Pt microelectrodes, attributed to reduced charge-transfer resistance and increased double-layer capacitance. Finally, varying the volume and concentration of the spray-coated Ti3C2Tx films showed that increased MXene concentration and volume enhanced performance by creating thicker, rougher interfaces. Together, these results establish Ti3C2Tx MXene as a promising electrode material with exceptional performance at the microscale.

Extracellular matrix (ECM) remodeling is a fundamental determinant of neural tissue repair and implant integration, yet its conserved regulatory architecture remains undefined. While transcriptomic alterations following neural injury and implantation have been described, the ECM-centered programs that unify traumatic injury and neural implant responses remain unclear. Here, integrative systems-level transcriptomic analysis identifies a dominant and conserved ECM regulatory axis linking traumatic brain injury (BI), spinal cord injury (SCI), and neural implant-induced injury. By integrating transcriptomic datasets from brain and spinal cord injury models using weighted gene co-expression network analysis (WGCNA), six conserved ECM-associated gene modules are identified, with hyaluronan (HA)-centered networks emerging as the dominant and conserved regulatory axis across both injury types. Modules enriched for low-molecular-weight HA (LMW-HA) are linked to Toll-like receptor signaling and pro-inflammatory cytokine expression, whereas high-molecular-weight HA (HMW-HA)-associated modules correlate with Cd44 signaling, tissue stabilization and repair. Furthermore, independent validation in thin-film intracortical microelectrode datasets confirms robust activation of HA damage-associated molecular pattern (HA-DAMP) signaling following implantation, with 9/10 injury-derived modules preserved and 88% of transcripts exhibiting resolving temporal dynamics. These findings indicate that neural implants engage conserved trauma-associated ECM programs rather than a conventional foreign-body response, highlighting HA-related metabolisms. Given that HA fragments and HA-modifying enzymes are detectable in cerebrospinal fluid and peripheral circulation, HA-associated signatures may serve as minimally invasive biomarkers of neural injury and implant biocompatibility, enabling longitudinal monitoring and informing next-generation neural interface design.

The endothelialization of organ-on-chip platforms and vascular implants is often limited by slow cell attachment and unstable monolayer formation. This work presents a scalable workflow that imprints micro- and nano-gratings into elastin-like recombinamer (ELR)-based hydrogels, enabling rapid endothelial cell capture and accelerating monolayer formation within 14 days. Three gelatin-ELR formulations are engineered, with {superscript 1}H-NMR confirming incorporation of sequences designed to modulate bioactivity (ELR1: inert; ELR2: uPA-responsive; ELR3: RGD-adhesive). ELR incorporation generates fibrillar microstructures and enhances mechanical performance, yielding elastic-dominant networks suitable for high-fidelity pattern transfer and stable culture. Using this library, the combined effects of ELR bioactivity and groove geometry on human iPSC-derived endothelial cells (iPSC-ECs) are systematically evaluated. In a 15-minute attachment assay, patterned ELR composites markedly improve cell retention compared to gelatin, with ELR2 on [~]350 nm and [~]4 {micro}m grooves performing best, consistent with controlled, cell-mediated interfacial remodeling. This early advantage persists, as ELR2 and ELR3 hydrogels support rapid alignment and reach confluence by day 14, whereas gelatin remains sub-confluent. Cytoskeletal analysis confirms F-actin alignment. By combining enhanced early capture with protease-regulated remodeling, ELR2 identifies a favorable design window. These results establish a materials design framework linking programmable ELR chemistry with surface topography to engineer endothelial interfaces, providing a versatile platform for vascular biomaterials and microphysiological systems.

The clinical translation of engineered skeletal muscle (eSM) for volumetric muscle regeneration is hindered by the challenge of establishing a functional vascular network capable of sustaining its high metabolic demand and ensuring graft survival. Here, we present a bottom-up biofabrication strategy to generate a pre-vascularized in vitro eSM model through the modular assembly of independently matured muscle and vascular compartments. C2C12 myoblasts were encapsulated within core-shell fibers using rotary wet-spinning (RoWS), yielding anisotropically aligned, multinucleated, and contractile myofibers expressing myosin heavy chain and sarcomeric -actinin. In parallel, gelatin methacryloyl (GelMA)-based microvascular seeds ({micro}VS), pre-endothelialized with human umbilical vein endothelial cells, were engineered to guide rapid and structurally stable vascular formation while preventing uncontrolled capillary self-organization. Fully endothelialized {micro}VS were incorporated into a pro-angiogenic bioink and processed via RoWS to generate tubular vascular fibers with physiological diameters (100-200 m) and continuous CD31-positive lumens. After independent maturation, muscle and vascular constructs were bioassembled into a hierarchically organized tissue and co-cultured. By decoupling myogenic and angiogenic differentiation, this strategy overcomes medium incompatibility typical of conventional co-cultures, preserving compartment-specific architecture and function and establishing a versatile platform for muscle-vascular modeling and translational muscle repair.

Vascularization remains a major obstacle in tissue engineering. Here, we introduce a developmentally inspired bioprinting strategy to generate centimeter-scale, self-organising "mother vessel" constructs from iPSC-derived human mesodermal progenitor cells (hiMPCs). By systematically optimizing the bioink composition, we identified a formulation that combines high print fidelity, mechanical stability and cell compatibility within a single-step bioprinting process. Within the first week after printing, hiMPCs in the "mother vessel" constructs underwent spontaneous differentiation and morphogenesis, forming intima-, media-, and adventitia-like layers containing CD31 endothelial, SMA mural and CD34/CD150 progenitor cells. Remarkably, Iba1 macrophage-like cells appeared despite their absence in the initial population, indicating intrinsic differentiation into both vascular and non-vascular lineages essential for angiogenesis, remodeling and tissue homeostasis. Surrounding the newly formed vessel wall-like structure was a broad, vascularized mesodermal tissue compartment that also contained the above-mentioned progenitors. Co-culture with prevascularized mesodermal organoids resulted in early structural interconnection of microvessels with the printed wall, representing a prerequisite for subsequent hierarchical vascular network formation. As a proof-of-concept, the mother vessel withstood controlled flow conditions in a bioreactor without detectable leakage, demonstrating its principal suitability for perfusion analyses. Together, these findings establish a biologically driven platform that bridges macro- and microvascularization. This may pave the way toward perfusable, vascularized larger tissue constructs, a major bottleneck in regenerative biofabrication.

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.

The brains complex network relies on both electrical and chemical signaling to support its physiological and cognitive functions. To fully understand neural circuit dynamics and their dysfunctions, it is crucial to simultaneously detect neurotransmitters and modulators alongside electrophysiological signals. The striatal dopamine circuits are integral to neurological processes such as movement, reward, learning, and circadian rhythm regulation, making it highly desirable to monitor both neural activity and dopamine (DA) levels in freely behaving animals. One promising approach involves the implantation of multimodal microelectrode arrays (MEAs). However, chronic electrochemical sensing of DA in freely moving animals faces significant challenges, including biofouling of sensing electrodes and the instability of Ag/AgCl reference electrodes. In this study, we developed two complementary strategies--surface grafting and photo crosslinking--to coat the MEA and implanted Ag/AgCl reference electrodes, respectively, with zwitterionic poly(sulfobetaine methacrylate) (PSB). The surface-grafted thin PSB coating effectively inhibits protein fouling and inflammatory responses to the MEA, while the PSB hydrogel protects the Ag/AgCl electrodes from delamination in vivo, ensuring a stable reference potential. By coating both the Ag/AgCl reference electrodes and flexible polyimide MEAs with PSB and PEDOT/CNT, we achieved stable DA detection and electrophysiological recordings in freely moving mice over a four-week period. Weekly electrochemical impedance spectroscopy confirmed the long-term stability of the implanted electrodes. Our method enables multidimensional analysis of behavioral patterns, electrophysiological activity, and DA dynamics, providing a comprehensive approach for neuroscience research. This work advances neurochemical and electrophysiological methodologies by offering reliable tools for longitudinal investigations of brain function in freely behaving animals.