Alopecia is highly prevalent and debilitating, yet current drugs provide limited, reversible benefit with notable side effects. We established a rapid protocol to generate human induced pluripotent stem cell-derived dermal papilla cells (hiPSC-DPCs) and demonstrated that their conditioned medium (CM) acts as a potent, cell-free hair-regenerative therapy. Transdermal delivery of hiPSC-DPCs or CM accelerated anagen re-entry and hair regrowth in depilated mice, and hiPSC-DPC CM outperformed minoxidil in promoting ex vivo hair-shaft elongation and in vitro proliferation and migration of primary DPCs and keratinocytes. Proteomic and metabolomic profiling revealed enrichment of growth factors, antioxidants, and immunomodulatory metabolites linked to TNF and PI3K-Akt signaling, conferring superior anti-inflammatory and cytoprotective properties relative to primary DPC CM. Moreover, hiPSC-DPC CM mitigated dihydrotestosterone (DHT)-induced pathology by suppressing androgen receptor expression and nuclear translocation. These findings position hiPSC-DPC secretome as a dual-functional, regenerative, and anti-androgenic biologic with translational potential for durable alopecia treatment.

While conductive nanomaterials have primarily been studied for neuronal modulation, their effects on astrocytic physiology and the underlying physicochemical determinants remain largely unexplored. In particular, how conductivity, along with other physicochemical properties, is linked to astrocyte function remains unclear. We engineered conductive and non-conductive nanotube platforms with comparable nanotopographies, differing in conductivity and material composition. Both platforms enhanced primary astrocyte adhesion, consistent with their shared nanotopography. However, only the conductive platform was associated with increased intracellular Ca2+ activity. Elevated Ca2+ coincided with enhanced glutamate uptake on the conductive platform. Astrocytic passive conductance was also increased on conductive substrates, accompanied by elevated TASK1 expression. Consistently, whole-cell patch-clamp recordings revealed a reduced neuronal firing probability in slices incubated with conductive nanotube, whereas non-conductive substrates had no effect. Collectively, this study highlights conductivity as a physicochemical parameter associated with astrocytic functional modulation and neuron-glia interaction, suggesting the potential of glia-targeted nanomaterial strategies.

Engineering multicellular constructs through biophysical cues, independent of soluble biochemical factors, is a promising strategy to boost the therapeutic potential of stem cells for regenerative medicine. However, the mechanisms by which spatially organized cell-cell and cell-matrix interfaces govern multicellular signaling and subsequent behavioral outcomes remain poorly understood. Here, we elucidate these mechanistic events by introducing 2D nanoplates (~350 nm) compartmentalized within the intercellular space of mesenchymal stem cell (MSC) spheroids to form de novo cell-matrix spatial interfaces. These interfaces redistribute internal stress across the spheroid, amplifying integrin-cytoskeleton-nucleus force transmission and restoring YAP-dependent mechanotransduction to achieve spatial mechanopriming. Cells within these mechanoprimed spheroids exhibit profound nuclear deformation, epigenetic remodeling, and spatially patterned metabolic activation. Finite element modeling and spatial transcriptomic analyses further reveal a spheroid-wide reorganization of cytoskeletal and transcriptional networks. Mechanistically, elevated cytoskeletal tension across the reorganized interfaces stabilizes HIF-1α-dependent pseudo-hypoxic signaling, establishing a mechanometabolic niche that robustly enhances angiogenic secretion. Consequently, mechanoprimed spheroids demonstrate superior engraftment, accelerated vascular regeneration, and improved perfusion recovery in a murine ischemia model. Collectively, this work establishes spatial mechanopriming as an effective strategy to remodel cytoskeletal-to-nuclear mechanics and enhance the therapeutic potential of 3D multicellular system.

Cell surface engineering offers a powerful strategy to modulate cellular behaviors, including adhesion, migration, and differentiation. While cell fate is typically governed by extracellular cues such as matrix ligands, engineered cell surfaces can reshape how these signals are sensed and transduced. Here, we present a facile and robust approach to cell surface engineering via mild chemical reduction. Using tris(2-carboxyethyl)phosphine (TCEP), a gentle reducing agent, we modulated surface-exposed disulfide bonds to induce adhesion-dependent signaling without genetic manipulation. This strategy was applied to preadipocytes to investigate its effects on cell adhesion, mechanotransduction, and adipogenic differentiation. Mild surface reduction induced pronounced morphological changes, including increased spreading, elongation, and cytoskeletal reorganization. Notably, TCEP treatment enhanced focal adhesion kinase (FAK)-associated adhesion and mechanotransductive signaling, accompanied by elevated cell-matrix traction forces, increased intracellular tension, and enhanced cytoskeletal-nuclear force transmission. These multiscale mechanical responses were quantified using traction force microscopy, intracellular force microscopy, and nuclear envelope wrinkling analysis. Functionally, these coordinated mechanobiological changes suppressed adipogenic differentiation, even under adipogenic induction conditions. Taken together, our findings demonstrate that mild chemical reduction of the cell surface modulates adhesion-dependent mechanotransduction through a FAK-centered force-transmission pathway, reinforcing cytoskeletal and nuclear mechanics to inhibit adipogenesis. This work highlights surface redox modulation as a non-genetic strategy to regulate cellular mechanics and lineage commitment.

Oral and dental tissues are continuously challenged by a dynamic microbial milieu and recurrent inflammatory insults. Microbiota-driven dysbiosis establishes a self-reinforcing pathogenic cycle, and spontaneous reversion to homeostasis after injury is uncommon. Contemporary care is largely reparative, restoring only limited structure and function. Durable regeneration, by contrast, requires a staged and integrated program: (i) antimicrobial debulking of pathogenic biofilms, (ii) balanced immunomodulation to resolve inflammation, (iii) pro-angiogenic support to perfuse the remodeling matrix, and (iv) recruitment and lineage-directed differentiation of endogenous stem/progenitor cells. Multifunctional nanomaterials are uniquely positioned to deliver spatially and temporally programmed biochemical and biophysical cues for each phase. By integrating antibacterial components with immune-regulating, angiogenic, and stem cell-activating functions, nanoengineered platforms can reconstruct a pro-regenerative microenvironment that approximates native dental tissue. This review outlines the dental indications most in need of regeneration, delineates the synergistic mechanisms that underlie successful repair, and highlights emerging nanomaterial designs that activate these mechanisms. We also discuss design principles, efficacy readouts, and translational considerations to accelerate clinically durable restoration of dental structure and function, ultimately improving patients’ quality of life.

Burn wounds require dual therapeutic strategies: removing pro-inflammatory damage-associated molecular patterns (DAMPs) while delivering regenerative signals. Here, we report a nanounit-assembled hydrogel embodying a "pull-and-push" approach for immune modulation and tissue repair. The hydrogel integrates cationic components (chitosan and PAMAM dendrimer) that scavenge ('pull') cell-free DNA (cfDNA), a critical inflammatory DAMP, while simultaneously initiating regenerative programs through thermosensitive release ('push') of plerixafor (a CXCR4 antagonist) and bioactive ions (Ca2+ and SiO4 4-) via NIPAAm polymer. The thermosensitive system responds to localized hyperthermia in burn-wounded inflammation, while activating macrophage repolarization and angiogenesis. In vitro studies demonstrated efficient cfDNA scavenging, downregulation of pro-inflammatory cytokines, and M2 polarization. In murine burn models, hydrogels accelerated re-epithelialization, granulation tissue formation, and neovascularization. Spatial transcriptomic profiling reveals macrophage niches as functional hubs where pull-and-push mechanisms converge, driving stepwise reconfiguration from inflammatory suppression to repair-permissive environments. By integrating cfDNA scavenging with thermally-responsive dual delivery of therapeutics and bioactive ions, these multifunctional hydrogels provide a blueprint for next-generation regenerative biomaterials.

Bioactive glasses (BGs) have emerged as multifunctional biomaterials with distinctive therapeutic and targeting capabilities, positioning them as promising candidates for regenerative medicine and disease treatment. This review traces the evolution of BGs from their conventional use in tissue regeneration to their integration into advanced therapeutic platforms. We first examine the intrinsic physicochemical properties that underpin their bioactivity and targeting functions. Recent technological innovations, including nanofibrous scaffolds, injectable formulations, nanostructured coatings, drug delivery systems, and 3D-printed bioinks, have significantly expanded the biomedical applications of BGs. Both in vitro and in vivo studies demonstrate their capacity to promote tissue regeneration under various pathological conditions, stimulate osteogenesis while inhibiting osteoclastogenesis, and modulate inflammatory, infectious, and ischemic microenvironments. Furthermore, BG-based systems enable synergistic therapeutic outcomes through controlled drug release. Emerging research highlights their potential in cancer therapy via ion-mediated cytotoxicity, stimuli-responsive modalities such as photothermal/photodynamic therapy and hyperthermia, and combinatorial treatment approaches. This review provides a comprehensive overview of the therapeutic versatility and targeted functionalities of BGs, underscoring their potential in next-generation biomedical applications.

Biomaterials have played pivotal roles in restoring the functions of damaged and diseased tissues. Beyond traditional considerations, their dynamic interactions with tissues and cells, particularly in response to mechanobiological stimuli, have emerged as critical determinants of cell fate and secretory profiles during healing and disease progression. Materials exhibiting intrinsic mechanobiological dynamics, such as tunable viscoelasticity and mechanoresponsive adaptation to physiological mechanical forces, are of particular interest. Additionally, biomaterials engineered to trigger mechanobiological responses under external stimuli, including light, electricity, ultrasound, and magnetic fields, offer exciting opportunities for on-demand tissue engineering, moving beyond passive functionality. This review highlights the emerging importance of mechanobiologically dynamic materials as active platforms for tissue healing and disease treatment. We discuss their roles in cellular behaviors, explore the underlying mechanisms of material dynamics, review representative examples of intrinsic and externally activated platforms, and present future perspectives for next-generation regenerative therapies.

Chronic diabetic wounds present a critical clinical challenge due to persistent inflammation and compromised healing. Here, we report a sprayable nanozyme hydrogel that epigenetically remodels macrophages (Mφ) to suppress inflammation and coordinate regeneration. Ultrasmall copper-based nanozymes (CuNZ, ~4 nm) synthesized via an eco-friendly one-pot method demonstrated potent multi-radical scavenging activity. When integrated into gelatin methacryloyl (Gel), CuNZ@Gel exhibited sprayability, conformal skin coverage, and storage stability, offering potential for clinical translation. Notably, the nanozyme hydrogel induced distinct epigenetic modifications in Mφ by remodeling chromatin accessibility, thereby shifting gene expression from a pro-inflammatory to an anti-inflammatory profile. This epigenetic modulation sustained under oxidative stress, actively suppressing inflammation while facilitating regenerative responses. In rat diabetic wound models, CuNZ@Gel significantly accelerated healing through its coordinated antioxidant, anti-inflammatory, and pro-regenerative actions. Unlike conventional passive dressings, this sprayable nanozyme hydrogel proactively remodels the wound microenvironment via epigenetic control of inflammation, providing a promising therapeutic strategy for managing chronic diabetic wounds and inflammatory skin complications.

Peripheral nerve injuries remain a major clinical burden, as current surgical and biomaterial strategies primarily restore anatomical continuity but fail to adequately modulate the immune microenvironment required for complete functional recovery. Here, we report a nanozyme-integrated hydrogel designed to modulate redox balance and immune responses to promote peripheral nerve repair. The nanozyme-integrated hydrogel (USCu@GelMA) was engineered by encapsulating ultrasmall copper nanozymes (USCu) within Gelatin methacryloyl (GelMA), which serves as a biocompatible carrier enabling localized and sustained nanozyme-driven redox regulation. In vitro, USCu@GelMA enhances Schwann cell (SC) migration, survival under oxidative stress, and secretion of TGF-beta 1 and BDNF, while reprogramming the SC secretome through FAK-ROCK-YAP-linked mechanotransduction and metabolic priming to establish an anti-inflammatory, proregenerative profile. SC-conditioned media derived from USCu@GelMA cultures subsequently drive macrophage polarization toward an M2-dominant state characterized by elevated IL-10 secretion and increased CD206 expression, reflecting a balanced yet M2-biased activation rather than a binary switch. In a rat facial nerve transection model, local USCu@GelMA implantation accelerates M2 macrophage accumulation, reduces oxidative DNA damage, and enhances axonal regeneration in both proximal and distal segments, resulting in higher compound muscle action potential amplitudes, improved facial palsy scores, and sustained recovery without detectable systemic toxicity in major organs. Collectively, these findings identify USCu@GelMA as a multifunctional, clinically translatable hydrogel platform that integrates nanozyme-driven redox control, matrix mechanics, and SC-macrophage immunoregulation to coordinate the complex cellular programs required for peripheral nerve regeneration.

Abstract Multifunctional surface engineering of titanium implants that integrates osteogenic activity with localized antibacterial function is highly desirable yet remains challenging. Here, we report a nanostructured graphene oxide/mesoporous bioactive glass nanoparticle (GO/MBGN) nanocoating fabricated via electrophoretic deposition (EDP) using a chitosan-assisted strategy. An amine-functionalized mesoporous bioactive glass nanoparticle (MBGN-NH2) enables co-deposition with negatively charged GO, resulting in uniform and stable coatings with tunable nanotopography and composition. Structural and microscopic analyses confirm homogeneous incorporation of MBGN within the GO matrix while preserving the amorphous mesoporous structure, essential for ion release and drug loading. The GO/MBGN nanocoatings significantly enhance cellular responses in a composition-dependent manner. Notably, GO-10MBGN promotes improved cell spreading, focal adhesion, and proliferation of rat bone marrow-derived mesenchymal stem cells. Osteogenic differentiation is markedly upregulated, as evidenced by increased expression of alkaline phosphatase (ALP), collagen type I (COL I), and osteocalcin (OCN), attributed to combined effects of nanoscale surface features and sustained release of Ca2+ and SiO44– ions. Furthermore, gentamicin sulfate (GENT)-loaded MBGN endow controlled drug release, exhibiting an initial burst followed by sustained delivery over 6 weeks. This results in effective antibacterial activity against Staphylococcus aureus, with enhanced inhibition observed for higher MBGN content. Collectively, this work establishes that GO/MBGN nanocoatings possess both osteoinductive and antibacterial functionalities, offering a promising strategy for advanced titanium implants.

Mechanical forces are central determinants of development, homeostasis, and pathology in oral and maxillofacial tissues, yet most regenerative strategies continue to prioritize biochemical signaling over mechanical control. In anatomically and functionally heterogenous tissues such as dentin-pulp, periodontium, temporomandibular joint, oral mucosa, and salivary glands, mechanics is not a secondary cue but a primary regulator of cell fate, immune responses, and tissue integration. This review reframes oral and maxillofacial regeneration through a mechanobiological engineering lens, summarizing how region-specific mechanical loading is sensed and transduced through focal adhesions, mechanosensitive ion channels, cytoskeletal tension, and nuclear mechanotransduction to coordinate tissue-specific repair programs. We organize recent advances into two complementary strategies. Intrinsic mechanobiological design exploits biomaterial stiffness, hierarchical topography, anisotropic and modular architectures, and piezoelectric functionality to recreate tissue-appropriate mechanical niches. Extrinsic mechanotherapy leverages engineered in vitro platforms and clinically adaptable physical modalities including vibration, low-intensity ultrasound, electrical stimulation, and magnetic fields - to activate endogenous regenerative pathways. We further discuss critical barriers to clinical translation, including the lack of physiologically realistic testbeds, insufficient standardization of mechanical dose, fatigue and durability under cyclic loading, and challenges in scalable manufacturing. Finally, we highlight emerging opportunities in adaptive biomaterials coupled with multiscale modeling and AI-assisted, data-driven design to integrate mechanical, biological, and functional outcome data. By positioning mechanics as a design and dosing variable rather than a passive property, this review provides a framework for developing reproducible, clinically relevant therapies that restore both biological function and mechanical performance in oral and maxillofacial tissues.

Ultraviolet A (UVA) radiation, a principal driver of skin photoaging, generates excessive reactive oxygen species (ROS) in dermal fibroblasts, causing oxidative stress, loss of viability, inflammatory signaling, and extracellular matrix (ECM) degradation. Hyaluronic acid (HA) and polynucleotides (PN) are clinically used dermal biomaterials; however, their protection against UVA injury remains insufficiently defined. We evaluated HA, PN, and their combination in human dermal fibroblasts (HDFs) subjected to photodamage. HDFs were pretreated with HA, PN, or both, irradiated with 20 J/cm2 UVA, and then maintained in treated media to mimic therapeutic recovery. UVA reduced viability and proliferation, downregulated ECM genes (COL1A1, FN1), and increased intracellular and mitochondrial ROS and proinflammatory cytokine gene (TNF-α). Monotherapy partially alleviated these changes. In contrast, combined HA + PN synergistically improved survival and proliferation, lowered ROS to near baseline, restored ECM transcription, and upregulated antioxidant enzymes (GPX1, SOD2). HA + PN also increased fibroblast invasion, indicating regenerative activity beyond cytoprotective effects. Under basal conditions, neither HA nor PN showed cytotoxicity or prooxidant effects, while modestly enhancing ECM transcription. These findings demonstrate that HA and PN act synergistically to counter UVA-induced oxidative stress and support dermal regeneration, highlighting a combinatorial bioactive strategy for photoaged skin.

Mechanobiology investigates how mechanical forces influence cellular behavior across scales, from molecular interactions to tissue-level responses. Advances in force measurement, high-resolution imaging, and multiomic profiling have generated datasets of increasing dimensionality, modality, and scale. Artificial intelligence (AI) and machine learning (ML) methods are well suited to analyzing such data, predicting cellular responses to mechanical stimuli, and identifying candidate mechanistic relationships. Here we review key applications of AI and ML in mechanobiology, including force inference from imaging data, tissue stiffness mapping, cell phenotype classification, chromatin-based prediction of protein localization, and computational modeling of mechanosensitive protein dynamics. We discuss emerging tools such as foundation models for cell segmentation and protein structure prediction, as well as the integration of AI-predicted mechanical properties with spatial transcriptomics. We also examine current limitations—including data scarcity, the gap between proof-of-concept and validated tools, and the challenge of causal interpretation—and identify opportunities for real-time closed-loop systems, therapeutic translation, and multiscale modeling.

Skeletal muscle regeneration is essential in conditions like muscle injury and muscular dystrophy, primarily relying on the activation and differentiation of myogenic progenitors. This study explores the role of redox‐modulated surface thiol modification in myogenesis, using tris(2‐carboxyethyl)phosphine hydrochloride (TCEP) to reduce disulfide bonds and generate free thiol groups on the cell surface. The findings show that TCEP treatment significantly increases cell surface thiols, activating the focal adhesion kinase (FAK)‐phosphoinositide 3‐kinase (PI3K)‐protein kinase B (AKT) signaling pathway, and promoting cell spreading, adhesion, and actin cytoskeleton remodeling. This biochemical modulation upregulates myogenic and fusion‐related markers, facilitating multinucleated myotube formation. Biophysical analysis using traction force microscopy (TFM), intracellular force microscopy (IFM), and monolayer stress microscopy (MSM) demonstrates that TCEP‐treated cells, particularly at muscle‐relevant stiffness (20 kPa), exhibit increased traction, intracellular, and monolayer stresses compared to untreated cells. These results suggest that redox‐modulated surface thiol modification, combined with specific stiffness conditions, enhances myogenic differentiation and myotube maturation through biomechanical signaling. This proof‐of‐concept study advances the understanding of how redox‐modulated surface engineering and substrate stiffness regulate myogenesis, offering novel therapeutic strategies for muscle regeneration and optimization of stem cell‐based therapies for muscle tissue repair

The primary treatment for myocardial infarction (MI) is restoring blood flow to the obstructed coronary artery. However, this approach can paradoxically generate reactive oxygen species (ROS), leading to secondary ischemia-reperfusion (IR) injury. Multifunctional nanomaterials present a promising alternative for managing IR injury, offering benefits including cost-effectiveness, robust catalytic stability, and customizable properties that surpass traditional antioxidants. This study explores single-atom Pt-doped ceria nanozymes (Pt@CeNZ) with multi-enzyme mimetic functions facilitated by atomically dispersed Pt. The nanozymes effectively eliminate excess ROS in cardiomyocytes, thereby enhancing cell viability. Notably, Pt@CeNZ demonstrates significantly higher uptake in cardiomyocytes, underscoring its potential as a targeted nanotherapeutic for cardiac tissues. In vivo studies further confirm that Pt@CeNZ treatment substantially reduces infarct size and improves cardiac function following IR injury, without inducing long-term toxicity or inflammation. These findings position Pt@CeNZ as a highly promising heart-targeting nanotherapeutic with potential applications in the acute and long-term treatment of cardiac injuries.

Activating angiogenic and immunomodulatory potential of stem cells through optimized cultivation strategies presents significant opportunities for cell-based tissue therapeutics. Among others, hydrogels with tunable chemo-mechanical properties offer optimal 3D environments for stem cell functions. Here, we report rigidity sensing and mechanoresponses of mesenchymal stem cells (MSC) in 3D hydrogels drive therapeutic effects in ischemic injury. We introduce a silk-collagen (SC) binary-protein system, engineered for high viscoelasticity and cell adhesion, to facilitate mechanosensing through integrins and the actin cytoskeleton. Notably, MSC mechanoresponses, such as actomyosin contractility and cell spreading in SC hydrogels, closely correlate with their pro-angiogenic and anti-inflammatory capacity. We identified key mechanotransduction pathways, including Rho/Rho-associated protein kinase and focal adhesion kinase (FAK)/proto-oncogene tyrosine-protein kinase Src (Src) signaling, as critical regulators of these therapeutic functions. Pharmacological intervention revealed FAK-Src signaling is essential for cytoskeletal remodeling and angiogenesis while simultaneously mediating anti-inflammatory effects. These findings underscore the interplay between cell mechanophenotype, morphology, and function, providing a strategy to optimize hydrogel-based MSC therapies. In a mouse model of ischemic hindlimb injury, mechano-primed MSCs delivered via SC hydrogels significantly improved blood reperfusion, cell survival, and anti-inflammatory responses, ultimately preventing limb loss. This study highlights the importance of controlling hydrogel mechanics and cellular mechanophenotype to enhance stem cell functions for regenerative therapies.

The extracellular matrix (ECM) provides structural support and mechanical cues that profoundly influence cellular behavior via nuclear mechanotransduction. This review discusses how ECM biophysical properties, including stiffness, topology, and spatial confinement, regulate nuclear mechanics and chromatin organization to determine cell fate across diverse pathophysiological contexts. We describe how mechanical signals propagate from the plasma membrane through cytoskeletal networks to modulate nuclear envelope tension, chromatin accessibility, and epigenetic landscapes. These matrix-driven nuclear changes orchestrate cellular responses in cancer progression, inflammation, fibrosis, stem cell differentiation, and age-related tissue dysfunction. Building on this mechanistic insight, we highlight emerging therapeutic strategies targeting the matrix-nucleus axis, such as tuning matrix properties to modulate chromatin accessibility, mechano-priming cells to enhance therapeutic outcomes, and targeting mechanosensitive molecules in the cytoskeletal-nuclear interface. Collectively, these approaches represent a promising paradigm leveraging mechanically induced epigenetic regulation and nuclear mechanobiology for disease treatment and tissue regeneration.