Cartilage tissue engineering requires biomaterial surfaces that support mesenchymal stem cell (MSC) adhesion and chondrogenic differentiation. This study investigated the effects of nanogrooved polydimethylsiloxane (PDMS) functionalized with Argiope modesta spider silk extract (SSE) following oxygen plasma treatment on the behavior of human Wharton’s Jelly-derived MSCs (hWJ-MSCs). Surface characterization by scanning electron microscopy (SEM), atomic force microscopy (AFM), water contact angle analysis, and X-ray photoelectron spectroscopy (XPS) confirmed the preservation of the nanogroove architecture, increased surface wettability following plasma treatment, and surface chemical changes associated with SSE functionalization. Liquid chromatography-high resolution mass spectrometry (LCHRMS) analysis provisionally identified 189 protein accessions in the SSE. SSE-coated plasma-treated nanogrooved PDMS exhibited increased protein adsorption and higher cellular metabolic activity during early culture compared with uncoated controls, with 50 µg/mL SSE showing optimal cytocompatibility. SEM and confocal microscopy demonstrated enhanced cell attachment, spreading, and alignment along the nanogrooves, particularly on the 350-nm pattern. Under chondrogenic culture conditions, the NG-350-P-SSE substrate showed greater glycosaminoglycan accumulation, increased expression of SOX9, COL2A1, and ACAN, relatively lower COL10A1 expression, and stronger collagen II immunoreactivity than the control substrates. Collectively, these findings suggest that plasma-treated nanogrooved PDMS functionalized with SSE provides a favorable surface for hWJ-MSC chondrogenic differentiation and represents a promising biomaterial platform for further investigation in cartilage tissue engineering.
Mesenchymal stem cells (MSCs) have gained considerable attention in tissue engineering due to their remarkable multilineage differentiation potential, recruitment of endogenous cells, and orchestration of a regenerative microenvironment via the secretion of trophic factors. Contemporary research increasingly underscores that, rather than direct differentiation into injured tissue cells, MSCs primarily facilitate tissue repair through the secretion of bioactive paracrine factors. Notably, the physical properties of scaffold materials have emerged as key regulators of MSC paracrine function. This review provides a comprehensive overview of how diverse physical characteristics of scaffold materials modulate the composition and concentration of MSC-derived paracrine factors, thereby shaping the cellular microenvironment to enhance tissue regeneration. By elucidating the mechanistic interplay between scaffold physicality and MSC paracrine function, we aim to inform the rational design of biomaterials for optimized regenerative therapies.
Traditional thrombolytic drugs such as urokinase and tissue plasminogen activator for vascular blockage remain large challenging due to their off-target side effects, low bioavailability and limited penetration abilities in blood clots, leading to the limited therapeutic effect. Considering the rapid developments of nanotechnology, the exploration of an innovative nanomaterials-based thrombolytic strategy for treating venous thromboembolism is highly demanded. Here, we present a polydopamine nanoparticles integrated microneedle patch for near-infrared-II light triggered thrombolysis in vitro and in vivo. Polydopamine nanoparticles with the near-infrared-II photothermal conversion performance were prepared at room temperature in the dark, and then were integrated into microneedle patch using the common polydimethylsiloxane microneedle mold. Polydopamine nanoparticles integrated microneedle patch not only showed good mechanical performance to easily insert into the skin without breaking, but also showed outstanding near-infrared-II photothermal conversion abilities. In vitro thrombolytic results proved that polydopamine nanoparticles integrated microneedle patch could induce the blood clot lysis in vitro under 1064 nm light irradiation for 5 min. Also, this microneedle patch showed effective thrombolysis effect by near-infrared-II light induced local overheating against the femoral vein thrombi model of female BALB/c mice. Overall, this microneedle patch has the great potential to treat venous thromboembolism.
Skin photoaging, primarily induced by chronic ultraviolet (UV) irradiation, is characterized by wrinkle formation, skin laxity, and collagen loss. As a traditional Chinese medicine, the potential of Asini Corii Colla (ACO) in protecting against skin photoaging has not been systematically investigated. This study aimed to comprehensively evaluate the anti-photoaging efficacy of ACO and elucidate its underlying mechanisms. Cytotoxicity and in vitro bioactivity of ACO were initially assessed in cultured human keratinocytes and dermal fibroblasts, followed by examination of its effects on cell proliferation and migration under normal conditions, and on SA-β-Gal activity, collagen, and elastin synthesis under UV-induced photoaging. Subsequently, a UV-induced skin photoaging mouse model was established to further validate the efficacy in vivo. Pathological changes, collagen content, and senescence-related markers in skin tissues were analyzed. In vitro results demonstrated that ACO, within a safe concentration range below 20 mg/mL, significantly promoted cell proliferation and migration, inhibited cellular senescence, enhanced collagen synthesis, and suppressed extracellular matrix (ECM) degradation. In vivo experiments confirmed that intervention with ACO markedly ameliorated UV-induced photoaging phenotypes in mice, including wrinkle formation and epidermal thickening, while maintaining dermal collagen density and content, and reducing oxidative stress in skin tissue. Collectively, ACO effectively mitigates UV-induced skin photoaging by promoting skin cell repair and regeneration, enhancing collagen synthesis, and maintaining redox homeostasis. These findings provide a solid scientific foundation for its potential application as an anti-photoaging agent.
Hydrogel microfibers resemble native biological filaments due to their hierarchical structure, tunable physicochemical properties, and biocompatibility, thus holding transformative potential in biomedical sensing. Conventional fabrication methods are limited in topological precision, spatiotemporal functionalization, and controllability. Recent microfluidic technology is advancing programmable microfiber engineering through functional units, including hydrodynamic focusing, laminar flow control, and in situ polymerization modules. In this review, we introduce common hydrogel materials used in microfiber fabrication and summarize microfluidic chip design strategies that enable spatial control and assembly. Furthermore, we comprehensively highlight the recent progress in hydrogel microfibers for biomedical sensing applications, and discuss how to advance hydrogel microfiber-based intelligent sensing ecosystems through multidisciplinary integration.
Hair follicles are dynamic mini-organs that cyclically regenerate through coordinated epithelial–mesenchymal interactions and precisely regulated molecular signalling. Reconstructing this complexity in vitro remains a central challenge in regenerative dermatology. This review reframes hair-follicle morphogenesis through the Tissue Engineering Triad (TET), which consists of cells, signals, and materials, to provide a design-oriented perspective for organoid construction. Each hair-cycle phase (anagen, catagen, telogen) is analysed in terms of its cellular composition, signalling environment, and extracellular matrix (ECM) dynamics, emphasizing how these triadic components govern homeostasis and regeneration. The telogen-to-anagen transition is highlighted as a natural model of reactivation, linking cellular reprogramming, morphogen signalling, and matrix remodelling. Building on these biological insights, recent advances in hair-follicle organoid engineering are reviewed, covering cell sources, morphogen combinations, ECM scaffolds, and the developmental fidelity of resulting structures. Finally, the challenges of maintaining dermal papilla inductivity, achieving vascularization, and ensuring translational scalability are discussed. Framing hair development through the TET paradigm offers a unifying roadmap for transforming developmental principles into practical strategies for hair regeneration.
The oral mucosa relies on constant salivary lubrication as well as on epithelial and immune barriers to maintain its homeostasis and normal function. Disruption of these can be triggered by salivary gland (SG) damage following radiotherapy and/or chemotherapy for head and neck cancer (HNC) patients. This SG injury leads to major complications, particularly dry mouth (also known as xerostomia, XM) and oral mucositis (OM). Xerostomia with hyposalivation is associated with oral complications such as dental caries, dysphagia, candidiasis, and taste disturbances. In contrast, OM develops as a result of epithelial injury and inflammatory cascades, leading to pain, burning, altered dietary intake, and poor nutrition. Together, XM and OM severely compromise the quality of life of HNC patients worldwide. Currently, effective curative treatments remain limited due to the lack of functional SG tissue after HNC therapy, highlighting the urgent need for innovative strategies. Artificial salivary substitutes, ranging from biological to synthetic, provide a safe and effective means of enhancing oral hydration and lubrication. These formulations encompass traditional components like mucins and growth factors, as well as emerging agents based on lipids, carbohydrates, and plant-derived compounds. In this narrative review, we provide current insights into the protective biochemistry barriers of the oral mucosa elicited by XM and OM, and discuss emerging salivary mimetic compounds aimed at restoring mucosal homeostasis and immunoepithelial barrier functions.
The regulation of cellular signaling relies fundamentally on molecular recognition. However, the direct application of natural biomolecules is often limited by poor stability, insufficient specificity, and inadequate controllability. Rational molecular design has therefore emerged as an effective approach to bridge chemical structure and biological function, enabling the development of engineered systems with programmable recognition and tunable bioactivity. This review provides a function-oriented perspective on molecular imprinting, affinity screening, dynamic combinatorial chemistry, and biomolecular modification. These approaches enable the construction of synthetic or semi-synthetic macromolecules with tailored affinity, multivalency, and environmental responsiveness. Such engineered systems generate diverse biofunctional outputs, including signal interception, receptor clustering, and adaptive regulation, thereby enabling precise modulation of cellular signaling pathways. Furthermore, this review highlights the recent advances in applying these design principles to biomedical scenarios, including intelligent drug delivery, immunotherapy, and tissue engineering. Finally, the current technological challenges are summarized in vivo stability, insufficient spatiotemporal control, and barriers to clinical translation. Future efforts will likely focus on the development of adaptive and integrative molecular systems with enhanced precision and controllability, enabling the rational programming of biological functions and accelerating their clinical translation.
Four-dimensional (4D) bioprinting offers a facile strategy for generating dynamic tissue constructs with physiologically relevant geometries for disease modeling. Here, we extend a previously established visible-light-crosslinkable hydrogel system to fabricate self-folding, duct-mimetic tubular constructs for triple-negative breast cancer (TNBC) modeling under dynamic culture conditions. Systematic optimization of photoinitiator concentration in bioink, scaffold thickness and length, cell density, and solvent conditions identified parameters that enabled robust self-folding of TNBC cell-laden constructs into closed thin-walled (≤ 0.8 mm) tubes with an internal diameter of ≈2.1 mm, comparable to those of mammary ducts. Nanoindentation confirmed a stable mechanical gradient in the tubular scaffolds over 14 days, with a softer outer surface (≈0.5 kPa) and a stiffer inner surface (≈20 kPa). Under rocker-based dynamic culture, MDA-MB-231-laden tubular constructs showed improved viability and a 1.4-fold increase in metabolic activity compared with their static culture counterparts at Day 14. Dynamic culture also promoted the appearance of mesenchymal-like spindle morphology by Day 7 and cellular aggregation by Day 14. Following doxorubicin treatment at Day 14, dynamically cultured tubes exhibited enhanced chemoresistance compared to static constructs, with lower cell death (65%vs. 75%) at approximately 10-fold higher half-maximal inhibitory concentration (IC50) (10 µM). Together, these findings establish a 4D-bioprinted TNBC model with a duct-like architecture and mechanical anisotropy to investigate the role of passive (stiffness gradients) and dynamic (interstitial flow) biophysical cues on tumor cell behavior and therapeutic response.
Granular materials, comprising discrete macro/micro-particles exhibiting both solid- and fluid-like behaviors, have emerged as a transformative class of biomaterials owing to their tunable multiscale architectures and stimuli-responsive dynamics. Unlike bulk materials, their jamming-to-flow transition and shear-thinning behavior enable minimally invasive delivery through injection or spraying. These unique features drive transformative applications in biomedical area: (1) Tissue engineering and cell encapsulation leverage injectable granular scaffolds that endow porosity for nutrient diffusion and cell migration; (2) 3D bioprinting employs granular suspensions as self-supportive bioinks or self-healing matrices to stabilize fragile bioinks; (3) Drug delivery utilizes their modular feature for payload release with enhanced spatiotemporal precision; (4) Immunotherapy exploits engineered granular materials as synthetic antigen-presenting platforms to direct immune cell activation in vitro and in vivo. Key challenges in the application of granular materials include scalable monodisperse production of particles with designed microstructure, collective property prediction emerging from inter-particle interactions, expansion of their biomedical applications and translation of these materials to clinical practice. Emerging computational models and biohybrid designs promise advances in applying granular materials in organ-on-chip systems and adaptive medical implants. This review highlights the mechanistic synergy between granular physics and biomedical requirements, proposing a roadmap for designing next-generation therapeutic biomaterials.
The precise replication of native tissue microarchitecture remains a key challenge in biofabrication. While extrusion-based bioprinting fabricates multicellular constructs for regenerative medicine and drug testing, its typical resolution (∼100 μm) is insufficient to reproduce <50 μm features such as capillaries, aligned myofibres, etc. Electrohydrodynamic (EHD) approaches, such as melt electrowriting (MEW), address this limitation by producing polymer fibres of 1–500 μm in diameter by applying high voltages. Cell electrowriting (CEW) expands this principle to living systems, aiding the direct deposition of cell-laden hydrogel fibres with diameters of 5–40 μm, thereby supporting microscale cell placement and architectures that are unachievable with conventional methods. This review discusses the principles of CEW, strategies for bioink formulation, and assessments of biological performance, with emphasis on recent advances in CEW-based printing approaches. The potential applications, challenges, and outlook of CEW for tissue engineering are also discussed.
This comprehensive review explores integrative approaches combining decellularized extracellular matrix (dECM) with exosome-based therapies to target structural integrity and biochemical signaling to promote cartilage regeneration. dECM is a biomimetic scaffold that retains essential components such as collagen and proteoglycans, which are crucial for cellular adhesion, matrix maintenance, and cartilage formation. Exosomes, on the other hand, derived from mesenchymal stem cells, enhance intercellular communication by delivering bioactive molecules such as growth factors and microRNAs. Combining dECM with exosomes can precisely mimic the cartilage matrix microenvironment, simultaneously promoting cell growth and the production of matrix components and modulating responses. This review delves into the mechanisms of dECM-exosome interactions, innovative integration technologies, and their impact on gene expression and cartilage-specific cellular responses. We demonstrate the potential of dECM-exosome therapy to enhance cartilage repair through in vitro and in vivo studies. Ultimately, these findings lay the foundation for the next-generation of cell-matrix-based therapeutics, which will provide advanced therapeutic strategies to improve clinical outcomes for cartilage damage and degenerative joint diseases.
Tendon injuries are common musculoskeletal disorders characterized by limited natural healing capacity and inability to restore the original structure and function of tendons. Tendon tissue engineering based on tendon stem/progenitor cells (TSPCs) offers a potential strategy for tendon injury treatments. The function regulation of TSPCs is influenced by both in vivo and in vitro microenvironmental factors. Here, we provide a concise summary of the various subpopulations of TSPCs identified thus far. Additionally, we explore the current research progress on the in vivo microenvironment of TSPCs. Notably, we first introduce the concept of a ''degeneration loop,'' which highlights the intricate interplay between the tendon microenvironment and TSPCs. Developing from this concept, we derive the theory and strategic framework of ''Remodel niche - Disrupt Degeneration Loop - Tendon Healing'' for effective tendon regeneration. Furthermore, we present an overview of the latest advances in the regulation of TSPCs expansion and differentiation through manipulation of the microenvironment in vitro and in vivo. Lastly, we address the challenges and related prospects encountered in the regenerative application of TSPCs subpopulations. A deeper multi-scale understanding of the interplay between distinct TSPCs subpopulations and their microenvironment will greatly contribute to the development of innovative tissue engineering strategies for successful tendon regeneration.
Hepatic spheroids formed by the spontaneous self-aggregation of hepatocytes maintain better liver function than two-dimensional (2D) monolayer cultures. Although structural polarity and intercellular adhesion can be maintained in hepatic spheroids, cell-extracellular matrix (ECM) interactions cannot be reproduced in spheroid-based models. In this study, we leveraged customizable ECM component and fabricated hepatic by injecting a cell suspension supplemented with primary mouse hepatocytes and Matrigel into a high-density methylcellulose (MC) solution. Amongst other findings, gene expression analysis of hepatic spheroid aggregates containing Matrigel revealed elevated levels of drug-metabolizing enzymes (Phase I and II) and transporters (compared to spheroids without Matrigel). Furthermore, the induction of drug metabolism enzymes and activity in hepatic spheroids containing Matrigel also increased compared to those without Matrigel. Lastly, we demonstrated that hepatic spheroids containing Matrigel can maintain liver function by increasing HNF4α through activation of Hippo signaling. Overall, our results indicate that high-performance hepatic spheroids containing Matrigel can maintain liver function through cell-cell and cell-ECM interactions and can be used to increase the efficiency of drug screening.
Chronic inflammation of biomedical implants usually leads to fibrosis and device malfunction in the long term. To address these issues, a cell-crosslinked coating of red blood cells (RBCs) was developed to imitate a self-friendly biological membrane and camouflage the implants from immune system. Using the widely applied poly(dimethylsiloxane) (PDMS) as a model substrate, a natural polymer hyaluronic acid (HA) layer was constructed upon PDMS (PDMS-HA), which was further decorated with RBCs (PDMS-HA-RBC). Compared to pristine PDMS, both PDMS-HA and PDMS-HA-RBC notably polarized the original macrophages into an anti-inflammatory phenotype (M2) rather than a pro-inflammatory phenotype (M1). Especially, PDMS-HA-RBC exhibited the highest M2/M1 ratios of macrophages, suggesting efficient modulation effects of inflammation reactions by the RBCs coating. Moreover, in vivo results found that PDMS induced considerable foreign body reactions (FBRs) and extensive fibrosis formation. In contrast, PDMS-HA revealed a significantly thinner fibrotic layer while PDMS-HA-RBC induced the least amount of fibrosis. In addition, PDMS-HA-RBC exhibited the highest fluorescent intensity of CD206 (M2 antigen) and the lowest fluorescent intensity of CD86 (M1 antigen). It was speculated that the RBCs coating-mediated macrophage polarization was mainly attributed to the presence of immune escape antigens (such as CD47 and CD59) upon the cell coating. Altogether, our living RBCs coating demonstrated significant potentials in mitigating FBRs of PDMS, indicating their promising applications in surface engineering of various biomedical implants.
Mucoepidermoid carcinoma (MEC) is a rare malignancy of the salivary gland (SG) that poses significant treatment challenges. This highlights the need for in vitro cancer modeling platforms towards anti-cancer drug screening applications. Emerging organ-on-a-chip (OoC) microfluidic technologies represent promising new approach methodologies (NAMS) and a real alternative to animal testing. While tissue-specific decellularized extracellular matrix (ECM) can recapitulate in vivo-like microenvironments, its application in SG-on-a-chip (SGoC) is still underexplored. This study developed an injectable porcine decellularized submandibular gland (dSMG) hydrogel for bioengineering an SG MEC tissue chip. dSMG was prepared using a chemical and enzymatic decellularization process with 0.1% or 1% sodium dodecyl sulfate (SDS). Both treatments effectively removed DNA content while preserving key ECM components, including collagens, glycoproteins, and mucins. Proteomic analysis revealed that 1% SDS-treated dSMG contained a greater abundance of ECM components involved in matrix assembly and cell-ECM interactions compared to the 0.1% group. The 1% SDS-treated dSMG was subsequently digested with a pepsin-based buffer to form hydrogels. At 5 mg/mL, dSMG hydrogel exhibited nanofibrous architecture, thermo-responsive gelation, injectability into microfluidic devices, and minimal batch-to-batch biological variations. In static conditions, dSMG hydrogel significantly enhanced SG cell viability and mitochondria-dependent proliferation compared to Matrigel. Under gravity-driven flow, dSMG hydrogel promoted a ductal phenotype on human SG MEC cells, unlike on Matrigel. Additionally, dSMG hydrogel supported cholinergic-specific signaling and functional activity. These findings demonstrate the potential of dSMG hydrogel as a physiologically relevant matrix for SG cancer modeling towards drug screening applications in SGoC microfluidic systems.
