Advanced Functional Materials

Two-dimensional boron offers unique advantages in bone tissue engineering, unlocking capabilities that conventional additives struggle to achieve. In this study, we leverage the 2D morphology and intrinsic bioactivity of boron nanoplatelets, incorporated into collagen-based scaffolds, to simultaneously achieve osteogenic, neurogenic, angiogenic, anti-inflammatory, mechanically reinforcing, and anti-microbial effects. We synthesize boron nanoplatelets from non- layered precursors using liquid-phase exfoliation and combine them with collagen to form boron- collagen scaffolds (BColl). Boron significantly reinforces the collagen matrix, beneficial for mechanoresponsive bone cells. Osteoblasts and mesenchymal stem cells exhibit healthy morphology and proliferation on BColl films and scaffolds, with extended culture leading to increased alkaline phosphatase release and significantly increased calcium deposition, indicating enhanced osteogenesis. E. coli viability decreases significantly on BColl films, demonstrating their potential to limit post-implantation infections. Finally, we observe angiogenic, neurogenic and anti-inflammatory effects, with dose-dependent upregulation of vascular endothelial growth factor-A, nerve growth factor-beta and interleukin-10, and downregulation of interleukin-6 highlighting borons potential to drive pro-reparative processes. Taken together, these data showcase borons potential in developing next-generation bone biomaterials, by offering multifunctional benefits to clinically relevant aspects of bone regeneration such as mineralization, angiogenesis, and innervation, while improving the mechanical and anti-microbial properties of natural polymer scaffolds. Graphical Abstract & ToC TextAn ideal bone scaffold would enhance osteogenesis, angiogenesis, and neurogenesis, while preventing inflammation, infection, and stiffness mismatch. 2D materials unlock diverse properties arising from the nanoplatelet morphology, while simultaneously leveraging the intrinsic properties of the material, enabling such multifunctional scaffolds. In this study, we combine 2D boron nanoplatelets with a bioactive collagen matrix to form a multifunctional, versatile bone repair scaffold with osteogenic, angiogenic, neurogenic, anti-inflammatory, and anti-microbial behaviour. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=175 SRC="FIGDIR/small/673512v1_ufig1.gif" ALT="Figure 1"> View larger version (68K): org.highwire.dtl.DTLVardef@1611344org.highwire.dtl.DTLVardef@37f0bcorg.highwire.dtl.DTLVardef@9e044dorg.highwire.dtl.DTLVardef@2c6bf5_HPS_FORMAT_FIGEXP M_FIG C_FIG

A major challenge in bone tissue engineering is the embedding of osteocyte-like cells at high density within a mineralized matrix at the micro-scale and a trabecular-like architecture at the macro-scale. Volumetric bioprinting (VBP) enables rapid creation of complex cell-laden constructs through tomographic light projections. However, integrating both high cell densities and inorganic mineral precursors into VBP processes poses challenges due to light scattering, which can compromise print fidelity. In this study, we aim to combine bioinspired polymer-induced liquid-phase precursor (PILP) mineralization with VBP to fabricate cell-laden gelatin methacryloyl hydrogel constructs with amorphous mineral precursors. By stabilizing amorphous mineral precursors with poly-aspartic acid, light scattering is sufficiently reduced to enable printing. Tuning the refractive index of this mineralizing bioresin allows fast VBP of mineralized bone-like constructs with cell densities of up to 3 million cells ml-1. The constructs display high cell viability (>90%) and enhanced mineralization when cultured in osteogenic conditions with {beta}-glycerophosphate. Encapsulated human mesenchymal stromal cells exhibit an early osteocytic phenotype after 28 days of differentiation. Collectively, this PILP-assisted VBP platform holds promise for the development of advanced in vitro bone models with more physiologically relevant architecture and cellular composition.

Scaling engineered living materials to clinically relevant dimensions is limited by diffusion-dependent depletion of oxygen and nutrients, which rapidly induces metabolic failure. We introduce glycogen as nutritional nanoparticle that provides cell-mediated, autonomous nutrient release to support long-term survival under extreme metabolic stress. We demonstrate that human mesenchymal stromal cells (hMSCs) survive for weeks in anoxia and serum deprivation when provided extracellular glycogen. Contrary to long-held assumptions, hMSCs secrete glycogen-degrading enzymes, enabling cell-density controlled extracellular glycogenolysis and sustained release of glucose and metabolic intermediates, positioning glycogen as the first-of-its-kind metabolic battery. This cell-responsive process maintains metabolic activity, limits glycolytic acidosis, and enhances pro-angiogenic signaling. To translate this mechanism into a versatile materials platform, we engineered core-shell dextran-tyramine microcapsules that stably encapsulate glycogen while permitting diffusion of enzymes and degradation products. Integrated into centimeter-scale GelMA constructs, these microcapsules maintained hMSC viability and function for at least one month under anoxia. In vivo, glycogen-loaded implants promote deep cellular infiltration, enhanced matrix remodeling, increased M2 macrophage polarization, and orchestrated accelerated vascularization. This work establishes the novel concept of glycogen-based nutritional nanoparticles as metabolic batteries to endow engineered tissues with autonomous self-feeding capacity, enabling scalable and functional living materials for regenerative medicine and related technologies.

Engineered neural tissues serve as models for studying neurological conditions and drug screening. Besides observing the cellular physiological properties, in situ monitoring of neurochemical concentrations with cellular spatial resolution in such neural tissues can provide additional valuable insights in models of disease and drug efficacy. In this work, we demonstrate the first three-dimensional (3D) tissue cultures with embedded optical dopamine (DA) sensors. We developed an alginate/Pluronic F127 based bio-ink for human dopaminergic brain tissue printing with tetrapodal-shaped-ZnO microparticles (t-ZnO) additive as the DA sensor. DA quenches the autofluorescence of t-ZnO in physiological environments, and the reduction of the fluorescence intensity serves as an indicator of the DA concentration. The neurons that were 3D printed with the t-ZnO showed good viability, and extensive 3D neural networks were formed within one week after printing. The t-ZnO can sense DA in the 3D printed neural network with a detection limit of 0.137 M. The results are a first step toward integrating tissue engineering with intensiometric biosensing for advanced artificial tissue/organ monitoring.

Chronic wounds and severe burns pose a major clinical challenge, as they often heal slowly or fail to respond to conventional treatments. In addition, there is a critical lack of tools for personalized, continuous monitoring of the healing process. Although progress has been made in both regenerative biomaterials and wearable biosensors, their integration into a unified platform that enables in situ, real-time monitoring of wound healing remains a major challenge. Here, we present a multifunctional bioelectronic scaffold that combines regenerative capability with real-time sensing of cellular activity. The scaffold was fabricated by electrospinning polycaprolactone (PCL) functionalized with the bioactive, self-assembling peptide fluorenylmethoxycarbonyl-phenylalanine-arginine-glycine-aspartic acid (Fmoc-FRGD) to promote cell adhesion and proliferation. For electrical sensing, biocompatible MXene (Ti3C2TX) electrodes were conformally deposited onto the nanofibrous matrix, preserving its biological functionality. This system enables label-free, real-time monitoring of cell viability and coverage using electrical impedance spectroscopy (EIS), offering continuous and quantitative insight into cellular adhesion and proliferation. Extracted impedance parameters at low frequencies exhibit a strong correlation with both cell viability and coverage, providing a non-destructive indicator of wound closure and healing dynamics. This platform offers a promising strategy for advanced wound care, integrating real-time monitoring with biologically supportive materials.

Implantable polymeric biodegradable devices, such as biodegradable vascular stents or scaffolds, cannot be fully visualized using standard X-ray-based techniques, compromising their performance due to malposition after deployment. To address this challenge, we describe composites of methacrylated poly(1,12 dodecamethylene citrate) (mPDC) and MoS2 nanosheets to fabricate novel X-ray visible radiopaque and photocurable liquid polymer-ceramic composite (mPDC-MoS2). The composite was used as an ink with micro continuous liquid interface production (CLIP) to fabricate bioresorbable vascular scaffolds (BVS). Prints exhibited excellent crimping and expansion mechanics without strut failures and, importantly, required X-ray visibility in air and muscle tissue. Notably, MoS2 nanosheets displayed physical degradation over time in a PBS environment, indicating the potential for producing bioresorbable devices. mPDC-MoS2 is a promising bioresorbable X-ray-visible composite material suitable for 3D printing medical devices, particularly vascular scaffolds or stents, that require non-invasive X-ray-based monitoring techniques for implantation and evaluation. This innovative composite system holds significant promise for the development of biocompatible and highly visible medical implants, potentially enhancing patient outcomes and reducing medical complications. TOC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/564364v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@58cb6aorg.highwire.dtl.DTLVardef@192d2b1org.highwire.dtl.DTLVardef@4699a3org.highwire.dtl.DTLVardef@110d7f8_HPS_FORMAT_FIGEXP M_FIG C_FIG

Water-resistant adhesives are indispensable for biomedical applications, from surgical wound closure to internal hemostasis. While poly(-lipoic acid)-based adhesives show promise for their strong underwater adhesion, their clinical utility has been limited by uncontrolled polymerization-depolymerization dynamics. Here we present a visible light-controllable adhesive system enabled by a simple mix of -lipoic acid (LA) and vitamin B12 (i.e., adenosylcobalamin or AdoB12)--a photolabile compound--without resorting to any chemical modification. Benign visible light irradiation facilitates the cleavage of the C-Co bond and the subsequent formation of B12-thiolate complexes that stabilize LA polymers against depolymerization. The photoresponsive LA-AdoB12 adhesive system has proven highly effective in a wide range of surgical applications, achieving (1) strong bonding in porcine skin models in vitro, (2) reliable sealing of punctured organs (lung, heart and stomach) ex vivo, and (3) immediate hemostasis in active bleeding models such as topical, esophageal, and intestinal wounds in vivo. This work highlights a simple yet powerful strategy for creating visible light-controllable bioglues well-suited for diverse surgical applications.

We design and validate a novel electrotherapy platform without electronic components, using printed abundant, environmentally benign materials. Whereas existing electrotherapy devices use an independent power source and electronics to generate and control stimulation currents, our design eliminates the need for these components. Device production relies only on scalable additive manufacturing and common materials, minimizing cost and environmental impact. The disposable single-use platform (as discreet as adhesive bandages) is activated simply by placement on the body. A prescribed electrotherapy discharge is regulated by a flexible 3D electrochemical architecture tailored to each application by a novel operational theory. The single-dose usability of this platform is a categorical shift from existing approaches with durable equipment that require programming and assembly to disposable electrodes for each use. Our Wearable Disposable Electrotherapy technology can be distributed like pharmacotherapy, with indications spanning neuromodulation of brain disorders, wound healing, transcutaneous drug delivery, bioelectronic medicine, and aesthetics.

AbstractsDiabetes poses a significant global health burden, with complications such as cardiovascular disease, stroke, and kidney failure. While insulin therapy is central to type 2 diabetes (T2D) management, its limitations--including rapid degradation and the need for frequent injections--highlight the demand for non-invasive alternatives. Here, we present an ultrasound (US)-mediated approach to enhance insulin release by selectively stimulating pancreatic {beta}-cells via targeted microbubbles (MBs). In vitro experiments using RINm5F {beta}-cells demonstrated that US-MB stimulation induces significant calcium influx and subsequent insulin release. In addition, this method effectively decreased blood glucose levels in mice by promoting insulin release. Mechanistic studies revealed that mechanosensitive ion channels play a pivotal role, as their inhibition (via GdCl3) abolished the ultrasonic effect. Importantly, the approach exhibited high biosafety, with no detectable cell death or tissue damage. Our findings establish ultrasound-stimulated {beta}-cell targeting as a promising non-invasive strategy for diabetes treatment, offering a potential alternative to conventional insulin therapy.

Bioprinting increasingly requires biomaterials that are not only printable, but structurally adaptive and biologically instructive. Here we establish an ovoprotein-derived microgel platform that couples intrinsic protein bioactivity with orthogonal interparticle photocrosslinking for modular bioprinting. Methacrylated ovoproteins yielded a photoresponsive protein-rich hydrogel matrix with retained proteomic complexity, tunable mechanics, and cell-regulatory biofunction. Endogenous tyrosine chemistry drove interparticle dityrosine coupling between ovoprotein microgels, producing cohesive, microporous, and intrinsically autofluorescent granular networks. The resulting systems displayed programmable rheology and broad compatibility across digital light processing, extrusion-based and aspiration-assisted bioprinting. Functionally, the ovoprotein microgel matrices attenuated sustained pro-inflammatory macrophage activation, promoted endothelial organization and host angiogenic invasion, and supported spheroid-mediated vascular morphogenesis with progressive sprouting, lumenization, branching and inosculation. It further enabled bioprinted osteogenic constructs with long-term maturation into bone-like mineralized tissues in vitro. These findings establish ovoprotein microgel-spheroid bioassembly as an adaptive, bioinstructive strategy for engineering vascularized and mineralized tissue constructs.

Traumatic cranial defects often involve concurrent loss of soft and hard tissues and can progress to chronic defects due to delayed healing associated with infection or other co-morbidities. Despite autologous reconstruction remaining the clinical standard, it requires staged procedures using heterogeneous tissues, increasing operative time, costs, and surgical risks. Moreover, current tissue engineering approaches focus on single tissues or acute tissue defect models, limiting their clinical applications. Herein, we describe an acellular, material-driven 3D-printed composite scaffold designed to regenerate both bone and skin within composite cranial defects. The scaffold integrates controlled copper ion release from both organic and inorganic components with 3D-printed citrate polymer and citrate polymer-ceramic composites. Integrated thermoresponsive citrate-based hydrogels further enable spatially defined dermoconductive and osteoconductive properties, supporting a one-step surgical approach. At 12 weeks post-implantation, our scaffold enhanced keratinocyte organization, collagen deposition, and defect coverage with mature bone, achieving histological outcomes comparable to autografts. Furthermore, the system suppressed bacterial burden. Thus, this acellular platform represents a clinically promising synchronized strategy to address the complex demands of traumatic craniofacial composite defects.

The precise control of mechanochemical activation within deep tissues via non-invasive ultrasound holds profound implications for advancing our understanding of fundamental biomedical sciences and revolutionizing disease treatments. However, a theory-guided mechanoresponsive materials system with well-defined ultrasound activation has yet to be explored. Here we present the concept of using porous hydrogen-bonded organic frameworks (HOFs) as toolkits for focused ultrasound programmably triggered drug activation to control specific cellular events in the deep brain, through on-demand scission of the supramolecular interactions. A theoretical model is developed to visualize the mechanochemical scission and ultrasound mechanics, providing valuable guidelines for the rational design of mechanoresponsive materials at the molecular level to achieve programmable and spatiotemporal activation control. To demonstrate the practicality of this approach, we encapsulate designer drug clozapine N-oxide (CNO) into the optimal HOF nanoparticles for FUS gated release to activate engineered G-protein-coupled receptors in the mice and rat ventral tegmental area (VTA), and hence achieved targeted neural circuits modulation even at depth 9 mm with a latency of seconds. This work demonstrates the capability of ultrasound to precisely control molecular interaction and develops ultrasound programmable HOFs to minimally invasive and spatiotemporally control cellular events, thereby facilitating the establishment of precise molecular therapeutic possibilities. We anticipate that this research could serve as a source of inspiration for precise and non-invasive molecular manipulation techniques, potentially applicable in programming molecular robots to achieve sophisticated control over cellular events in deep tissues.

Controlled biomineralization is central to engineering physiologically relevant hard-tissue models, yet achieving spatially organized, three-dimensional (3D) mineral deposition in microfluidic on-chip systems remains challenging. While cell-based bone-on-chip platforms offer biological complexity, they intrinsically couple mineral initiation to confounding factors such as matrix remodeling and paracrine signaling, obscuring the earliest biochemical drivers of nucleation. Drawing inspiration from bottom-up synthetic biology, we engineered an enzymatically active granular matrix that recapitulates a key osteogenic function within a perfusable 3D microenvironment. Alkaline phosphatase (ALP), the key driver of native bone formation, was covalently conjugated to poly(ethylene glycol)-based (PEG) microgels via thiol-ene photochemistry, retaining over 90% enzymatic activity after 48 h. These monodisperse microgels were assembled into a jammed, perfusable matrix within an on-chip chamber, enabling independent control over enzyme loading and substrate delivery. The system supported rapid in situ mineralization (24-48 h), yielding a carbonated, calcium-deficient, apatite-like phase characteristic of early-stage bone mineral. We demonstrate that the spatial 3D localization of enzymatic activity to discrete microscale compartments, coupled with interstitial perfusion, enables localized and near-physiological mineral formation. This mechanistically defined, acellular platform provides a programmable foundation for investigating ALP-driven 3D mineralization and establishes a modular route toward hybrid biosynthetic models of (patho)physiological tissue mineralization.

Successful hematopoietic stem cell transplantation (HSCT) critically depends on efficient T cell recovery, which is limited by compromised bone marrow niches following irradiation. While various factors influence the regeneration of bone and bone marrow niches, the dynamics of this process remain elusive. Here, we explore the kinetics of de novo bone and bone marrow development under varying BMP-2 doses, host immune status, and biological sex, using a cryogel of covalently crosslinked alginate and gelatin releasing BMP-2. Bone formation was monitored by ultrasonography and microcomputed tomography (microCT) analysis, while histological analysis provided insights into the relation between mineralized tissue and bone marrow formation. Bone developed within 2-4 weeks, resulting in cortical bone around the cryogels, and a trabecular bone network with hematopoietic tissue within the cryogels. Higher BMP-2 doses significantly accelerated mineralization kinetics and doubled the resident hematopoietic stem cell population. Notably, immunocompromised status delayed niche development by two weeks and reduced hematopoietic stem cells fourfold. We also found that female mice exhibited enhanced niche formation compared to males under the identical conditions. These findings provide insights into the factors that govern the spatiotemporal regulation of bone and bone marrow niche development and establish this hybrid click cryogel system as a promising platform for improving T cell reconstitution in HSCT patients.

Cancer immunotherapy offers a promising long-term treatment for solid tumors by activating the immune system, but side effects and systemic toxicity limit its broad clinical translation. While intratumoral delivery addresses these limitations, elevated stiffness within solid tumors continues to hinder both intracellular and extracellular delivery. Here, a novel therapeutic platform, the Precision Ultrasound-Localized Sonoporation-Equipment (PULSE), is presented to enable spatiotemporally controlled, ultrasound-mediated gene and drug delivery for intratumoral immunotherapy. The PULSE incorporates forward and sideward-looking miniaturized ultrasound transducers, integrated into either a 7-French catheter (cPULSE) or a 16-gauge needle (nPULSE), to minimally invasively sonicate a centimeter-sized tumor. Following the design, prototyping, and characterization of PULSE, its dual capability for intracellular and extracellular delivery is demonstrated through comprehensive in vitro cell-based sonoporation tests and phantom-based drug penetration tests. Luciferase assays (activity: ~104 RLU/g level) in the cell studies confirm significantly enhanced gene transfection with cPULSE, while increased dye diffusion (width: ~1 cm level) in the phantom tests validates improved perfusion with nPULSE. The reported PULSE shows promise for spatiotemporally precise, controlled, and localized therapeutic delivery in early-stage tumors for intratumoral immunotherapy.

Electrical stimulation is a powerful tool for investigating and modulating brain activity, as well as for treating neurological disorders. However, understanding the precise effects of electrical stimulation on neural activity has been hindered by limitations in recording neuronal responses near the stimulating electrode, such as stimulation artifacts in electrophysiology or obstruction of the field of view in imaging. In this study, we introduce a novel stimulation device fabricated from conductive polymers that is transparent and therefore compatible with optical imaging techniques. The device is manufactured using a combination of microfabrication and inkjet printing techniques and is flexible, allowing better adherence to the brains natural curvature. We characterized the electrical and optical properties of the electrode and evaluated its performance in the brain of an anesthetized mouse. Furthermore, we combined experimental data with a finite-element model of the in-vivo experimental setup to estimate the maximum electric field that the highly transparent device can generate in the mouse brain. Our findings indicate that the device can generate an electric field as high as 300 V/m, demonstrating its potential for studying and manipulating neural activity using a range of electrical stimulation techniques relevant to human applications. Overall, this work presents a promising approach for developing versatile new tools to apply and study electrical brain stimulation.

Although recent wearable chronic wound (CWO) bandage technologies have opened up exciting opportunities for personalized CWO management, they still face significant obstacles due to the reliance on the wound bed exudate for sensing and delivering therapeutics. Flat, shallow, and desiccated wounds are difficult to collect wound exudate for sensing, and some wounds continuously exude, potentially washing delivered therapeutics out of the wound bed. Herein, we developed a hydrogel-forming microneedles (HFMNs) array-based multimodal transdermal dressing system that continuously monitors the on-site physiological conditions of CWOs in interstitial fluid (ISF) and offers healing capabilities. The unique polar array design enables the integration of six replaceable HFMNs sensing electrodes to target the desired wound-specific analytes in transdermal interstitial fluid (glucose, uric acid, pH, Na+, Cl-, K+, and temperature) based on their significance in reflecting the status of the CWOs. The hydrogel is composed of a biocompatible and swellable polymer - polyvinyl alcohol, and chitosan as a crosslinking agent, while the incorporation of MXene (Ti3C2Tx) nanosheets as conductive nanofillers facilitates the formation of 3D polymer hydrogel networks via hydrogen bonding. Further coating and functionalization of poly(3,4-ethylenedioxythiophene): polystyrene sulfate (PEDOT: PSS) and graphene oxide through a laser-scribed phase separation (LSPS) process improves the electrical conductivity and in-vivo water stability of the HFMNs as a result of the larger and interconnected PEDOT-rich domains. Importantly, anti-inflammatory and antibacterial properties of the hydrogel prevent wound infection and promote skin wound healing. Through the potential correlation between wound-affected ISF and wound bed exudate, this method bridges conventional and implantable dressing systems for commercialization.

Implanted brain stimulators play a crucial role in treating various neurological disorders, including Parkinsons disease (PD), Alzheimers disease, epilepsy, and depression. However, none of the existing implanted brain stimulators can realize specific neuromodulation due to fundamental disparities in signal transmission between electrical signal-induced neuronal responses and neurotransmitter-evoked neural signalling in natural neural circuits, leading to persistent challenges in biosafety and therapeutic effectiveness. Inspired by the dopaminergic neural circuit, we report a biointegrated living brain stimulator (BBS) that integrates ferroelectric bioelectronics, dopaminergic cells, and a gelatin hydrogel matrix, enabling dopamine neurotransmitter-evoked neural signalling. In contrast to conventional brain stimulators, the BBS are capable of programmed secretion of physiological-level dopamine, specifically activating nigral dopamine pathways and restoring motor function in a rodent PD model. By integrating the advantages of both bioelectronics and medicine, this lifelike BBS offers a great promise for next-generation bioelectronics, medicine, and brain-machine interfaces.

Photothermal therapy (PTT) and photodynamic therapy (PDT) require nanostructures capable of efficiently converting red-light energy into both heat and reactive oxygen species (ROS). However, simultaneously achieving high photothermal conversion efficiency and strong ROS generation remains challenging. Here, we report zinc-doped Ag2S (ZSS) nanostructures, synthesized via controlled cation exchange, in which Zn incorporation modulates the electronic structure of Ag2S and improves charge separation, thereby enhancing red-light-activated PTT/PDT performance while preserving intrinsic biocompatibility. Among the series, ZSS(0.15) demonstrated optimized charge-carrier dynamics, a high photothermal conversion efficiency of 67.26%, and approximately four-fold higher singlet oxygen (1O2) generation relative to methylene blue under 660 nm irradiation. These physicochemical enhancements translated into potent therapeutic outcomes: in-vitro, ZSS(0.15) achieved an IC50 of 15 {micro}g/mL under irradiation, corresponding to approximately a 1.5-fold enhancement in cytotoxic potency compared to pristine Ag2S, and induced apoptosis via activation of the p53/Bax/Caspase pathway. In-vivo, ZSS(0.15) with laser irradiation achieved [~]97% tumor volume suppression without systemic toxicity. Extending evaluation across multiple breast cancer cell lines representing distinct molecular subtypes further confirmed broad-spectrum in-vitro efficacy. Altogether, these findings demonstrate that controlled Zn incorporation into Ag2S effectively enhances red-light-driven photothermal conversion and 1O2 generation, establishing a rational materials strategy for improving synergistic PTT/PDT performance. GRAPHICAL ABSTRACTA Zn-doped Ag2S nanoplatform (ZSS(0.15)) enables synergistic photothermal and photodynamic therapy under 660-nm laser irradiation, triggering p53-mediated mitochondrial apoptosis via ROS generation and caspase-3 activation, achieving [~]97% tumor regression in-vivo without detectable systemic toxicity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/684667v2_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@1d93519org.highwire.dtl.DTLVardef@12d18f4org.highwire.dtl.DTLVardef@1c14608org.highwire.dtl.DTLVardef@1dcd9f8_HPS_FORMAT_FIGEXP M_FIG C_FIG

Traditional bioelectronic devices are limited by poor biointerfacing due to their substantial mismatch in mechanical and biochemical properties. In tissue engineering, soft and bioactive materials support biointegration by harnessing or mimicking the natural extracellular matrix (ECM). Building bioelectronic devices from ECM should improve their biointegration, yet there are limited methods to fabricate them due to current manufacturing approaches. An additive manufacturing strategy is presented here for collagen-based bioelectronic interfaces that integrates conducting polymer electrodes with ECM-based substrates or encapsulation layers. Addition of poly(ethylene glycol) diglycidyl ether (PEGDE) to poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) colloidal dispersions enables direct extrusion-based patterning under mild conditions compatible with collagen substrates, and forms aqueous stable and highly conducting printed patterns (2788 S m-{superscript 1}). The resulting interfaces maintain stable electrochemical performance over 7 days in physiological environments, and support primary human cell adhesion, viability, and proliferation across both material regions. A sacrificial patterning strategy using 3D printed cacao butter further enables spatial control of collagen encapsulation. This approach establishes a framework for fabricating functional bioelectronic devices based on ECM to further enhance device biointerfaces for tissue models and implantable systems.