[This corrects the article DOI: 10.1177/20417314231196275.].

Hair regrowth through mechano-stimulation and other therapeutic approaches has emerged as a significant area of research in regenerative medicine. This review examines recent advances in hair regeneration strategies, with a particular focus on mechanical stimulation and complementary treatments. Studies have demonstrated that skin stretching can activate hair follicle stem cells and promote hair growth under specific conditions and durations. This process involves intricate signaling interactions, particularly through the WNT and BMP pathways, and follows a two-stage mechanism that recruits and modulates the function of macrophages. Mechanical stimulation induces the release of growth factors such as HGF and IGF-1, which activate stem cells and support hair follicle regeneration. Beyond mechanical activation, emerging hair restoration therapies, including MSC transplantation, MSC secretome therapy, and platelet-rich plasma treatments, have shown promising results. These innovative strategies overcome the limitations of conventional therapies, offering effective solutions for various types of hair loss. Additionally, here we discuss the molecular mechanisms underlying hair follicle growth and repair, the influence of external factors, and novel hair follicle formation processes, such as chimeric follicle development and follicular neogenesis. Special attention is given to the roles of dermal papilla cells and their interactions with mesenchymal cells in promoting hair regrowth. The key strategies and underlying mechanisms discussed in this review will drive future research and potential clinical applications.

The plasticity of blood mononuclear cells (MCs) and their role in vascular remodeling have been the focus of many studies; however, their differentiation efficiency remains poorly understood. Herein, we demonstrate that the inflammatory response accelerates the efficiency of MCs differentiation into endothelial-like cells through chemical cues . RT-PCR and RNA sequencing revealed that the differentiated cells exhibited upregulated pathways associated with vascular remodeling and regeneration. In contrast, MCs collected from normal blood showed a differentiation bias toward macrophages. Notably, under inflammatory conditions, primarily monocytes transitioned into the CD14++/CD16+/CD163+ subset, which contributed significantly to vascular remodeling. This transition was triggered by inflammation, as confirmed by cytokine treatment.

NK cell mimics are assemblies of a cell membrane and a template that replicate biomimetic features and physicochemical properties, respectively. To develop this targeted drug delivery system, gelatin microspheres (cG) were fabricated using a water-in-oil emulsion and reinforced via DMTMM cross-linking to exhibit tunable Young's modulus, a critical parameter for cell-material interactions. These microspheres were subsequently coated with membranes derived from the human NK cell line KHYG-1 to form biomimetic NK cell mimics (cGCM), combining physicochemical control with bioinspired functionality. These engineered cGCM were non-toxic, non-inflammatory, and capable of reducing macrophage uptake by ~10% when incubated with differentiated THP-1 cells. In vitro studies demonstrated significant interaction/ proximity of the cGCM with cancer cells in 2D cultures of breast cancer cells (MDA-MB-231), 3D spheroids of liver (HepG2), and colon (HT-29) cancer cell models, and a zebrafish breast cancer xenograft (MDA-MB-231) model. The cGCM also evaded macrophage detection in a Kdrl:EGFP Spil:Ds Red zebrafish model. Furthermore, in a pilot assessment, loading and release of the sialyltransferase inhibitor (STI, 3Fax-Peracetyl Neu5Ac) using cGCM significantly reduced α-2,6 sialylation in 2D cultures of MDA-MB-231 cells, demonstrating the STI's intact functionality in inhibiting sialylation. By integrating bioinspired membranes with mechanically tunable gelatin-based carriers, our system demonstrates a multifunctional immune-mimicking platform with relevance to tissue engineering, tumour modelling, immune modulation, and drug delivery. These findings offer a promising foundation for future therapeutic strategies in cancer research and immuno-engineering.

The influence of neutrophils and of neutrophil extracellular traps (NETs) on post-traumatic tendon-to-bone healing was studied in a murine model. The impact of neutrophil infiltration on macrophage polarization and peritendinous fibrosis in early-stage Achilles tendon injury is reported. Mice underwent Achilles tendon-bone injury and divided into four groups: sham operation, tendon injury (TI) treated with acetylcellulose (vehicle control), TI treated with a Protein arginine deiminase-4 (PAD4) inhibitor GSK484, and TI treated with a neutrophil elastase inhibitor Sivelestat. Each group was monitored for 21 days. Post-traumatic neutrophil infiltration and NET formation were assessed using flow cytometry and immunofluorescence. Immunohistochemistry, Western blot, and qPCR were used to evaluate macrophage polarization. Peritendinous fibrosis was assessed using Masson staining and Western blot. Neutrophil infiltration and NET formation increased significantly in the tendon following injury. A significant increase in M1-related markers and a decrease in M2-related markers were associated with NET formation. NET Inhibition using GSK484 or sivelestat reduced M1 markers and increased M2 markers. Furthermore, NET inhibition during the early stage suppressed peritendinous fibrosis and reduced inflammation during the healing process. In co-culture experiments, NETs induced proinflammatory cytokine secretion and upregulated M1 markers in bone marrow-derived macrophages while downregulating M2 markers. nlsNETs promote early-phase tendon-bone injury by inducing M1 macrophage polarization and peritendinous fibrosis. Targeting NETs during the initial phase of tendon injury could potentially facilitate the healing process.

Over 30% of polytrauma patients with bone fractures suffer from impaired healing and nonunion due to persistent systemic inflammation. Existing biologic strategies for bone repair primarily focus on osteogenesis but are not designed to modulate systemic immune dysregulation, limiting their utility in the polytrauma setting. To overcome this, we developed a hyaluronic acid-based hydrogel (HA) incorporating osteogenic intrinsically disordered peptides (P2) and mesenchymal stem cells (MSCs) to promote bone regeneration and modulate inflammation simultaneously. MSCs entrapped in hydrogels containing P2 (HA + P2) exhibited increased cell viability, alkaline phosphatase activity, and calcium deposition under in vitro polytrauma conditions compared to MSCs in hydrogels alone (HA). We utilized a murine polytrauma model (4 mm femoral osteotomy + blunt chest trauma) in mice. We studied the inflammatory response and bone formation over 21 days in mice treated with (1) HA, (2) HA + P2, or (3) HA + P2 + MSCs. We observed that adding P2 enhanced bone mineralization at the fracture site, yet transplantation of MSCs with P2 further increased mineralization. Both HA + P2 and HA + P2 + MSCs groups attenuated the systemic inflammatory response to near healthy baseline values. The HA + P2 group significantly accelerated the first stages of fracture healing by upregulating genes encoding for collagen biosynthesis, modifying enzymes, and extracellular matrix (ECM)-receptor interaction. Mice treated with HA + P2 + MSCs exhibited transcriptional regulation resulting in the upregulation of key repair genes related to cell cycle control, E2F transcriptional regulation, and TP53-mediated DNA repair, alongside downregulation of inflammatory pathways (IL-2, IL-3, and IL-5 signaling) and improved fracture healing. This study demonstrated that the combination of intrinsically disordered peptides and mesenchymal stem cells in HA-based hydrogels enhances bone formation, modulates both local and systemic inflammation, and improves structural organization at the fracture site in polytrauma conditions.

Intervertebral disc degeneration (IDD) is a common condition and a leading cause of chronic low back pain, affecting millions of individuals worldwide. Human Umbilical Cord Mesenchymal Stromal Cell (hUCMSC)-derived extracellular vesicles (EVs) are emerging as a promising therapeutic strategy for IDD. However, the limited production yield and unclear mechanisms by which EV contents mediate their therapeutic effects have hindered the clinical application of EVs. In this study, using transcriptomic data and single-cell RNA sequencing, we identify PANoptosis as a key mechanism driving the progression of IDD. Furthermore, parathyroid hormone (PTH) enhances the secretion of hUCMSC-derived EVs and alters their cargo composition, which may contribute to their improved therapeutic effects. Mechanistically, PTH-preconditioned EVs, enriched with ZDHHC5, ameliorate PANoptosis by modulating ZBP1 transcription through competitive inhibition of YBX1 phosphorylation via palmitoylation. Our findings provide strong support for a cell-free therapeutic strategy utilizing EVs from PTH-preconditioned MSCs for IDD treatment and propose the ZDHHC5/YBX1/ZBP1 axis as a novel molecular target for inhibiting PANoptosis, thus paving the way for clinical translation and broader healthcare applications.

Traumatic brain injury (TBI) is a major cause of mortality and morbidity, commonly leading to long-term impairments in cognition, sensorimotor function, and personality. While neuroprotective drugs have demonstrated some efficacy cultures and animal models, their clinical applications remain debated. Intranasal delivery to the brain parenchyma, bypassing the blood-brain barrier for more direct access to target sites, offers a favorable and safe approach. This review illuminates current advancements in intranasal delivery systems for TBI treatment. We begin with an overview of TBI and its current clinical treatment options. We then outline recent developments in intranasal delivery systems of molecules and cells, emphasizing their efficacy in animal models. Finally, we discuss future clinical perspectives on emerging trends, offering insights into leveraging intranasal delivery for effective TBI therapeutics.

Bone tissue regeneration and fracture healing remain a significant challenge for physicians, with nonunion failures occurring in an estimated 5%-10% of bone-healing treatments. The autologous bone graft has long been the gold standard of treatment. However, these procedures suffer from persistent donor-site morbidity and extended surgery times, while still having high revision and nonunion failure rates. Cell therapies and tissue engineering strategies utilizing stem cells have been considered as promising alternatives to autologous bone grafts. Here, we explore the concept of using CRISPR-activation (CRISPRa) as a cell-engineering tool to drive osteogenesis without exogenous growth factors. We present a genome-wide CRISPRa screen in adipose-derived stem cells (ASCs) to identify upregulation targets that drive osteogenesis. Top targets from the screen, SPRED2 and ATXN7L3B, demonstrated significant increases in alkaline phosphatase activity and mineralization in monolayer and 3D culture. These results are the first evidence of these genes as osteogenic targets in ASCs.

Pancreatic islet transplantation offers great promise for the treatment of type 1 diabetes, yet the functional decline of islets after isolation remains a major obstacle. Increasing evidence highlights the endoplasmic reticulum (ER) as a critical regulator of islet cell survival under stress. We explored how ex vivo culture conditions affect encapsulated islet resilience under ER-stress. Two conditions were assessed: (i) incorporation of decellularized porcine pancreatic extracellular matrix (ECM) into alginate microcapsules, and (ii) free-fall dynamic pre-conditioning culture. Human islets were encapsulated in alginate with or without ECM, cultured under static or dynamic conditions, and exposed to acute ER-stress followed or not by a recovery period. Dynamic culture preserved viability and enhanced glucose responsiveness. ECM-containing capsules showed reduced inflammatory marker expression, while encapsulation in alginate-only capsules led to more pronounced changes associated with ECM remodeling. Under ER-stress, the dynamic culture, especially combined with ECM, maintained cell function and reduced cell death. Gene profiles indicated improved stress adaptation and ECM remodeling. These results highlight ECM enrichment and dynamic culture as good strategies to maintain islet survival and functionality.

Peripheral nerve injuries (PNIs) affect thousands of patients yearly, often resulting in loss of function, sensation, and chronic pain. In critical-size defects, advanced surgical repair strategies often fail to restore full function. A key limitation is the lack of sustained, localized delivery of biological cues for axonal regeneration, such as growth factors. Glial-cell line-derived neurotrophic factor (GDNF) is known to promote axonal growth, Schwann cell migration, and neuronal survival, but uncontrolled release may cause axonal entrapment. We previously developed tissue-engineered nerve grafts (TENGs) composed of two neuronal populations connected by stretch-grown axons. In this study, we genetically modified the distal population to express human GDNF under a Tet-on inducible promoter, temporally controlling GDNF release through doxycycline administration. Modified TENGs survived implantation in a 1.5-cm rat sciatic nerve defect, supporting future studies. This approach offers a promising platform for spatially and temporally controlled neurotrophic factor delivery from tissue-engineered living scaffolds.

Two-dimensional (2D) cardiac models are widely used for cardiotoxicity screening but often lack structural and functional maturity of adult native tissue. Electrical stimulation (ES) enhances maturation, yet conventional waveforms (monophasic and symmetric biphasic) have shown limitations, including charge accumulation and possible cell hyperpolarization. Here, we introduce for the first time an asymmetric biphasic ES waveform that combines the advantages of monophasic and symmetric biphasic stimulation by reversing the current and reducing residual voltage. Asymmetric biphasic stimulation improved electrical functionality, calcium handling and contractility of neonatal rat cardiac cells, without triggering cellular stress. Additionally, cells subjected to asymmetric biphasic ES displayed a metabolic shift toward fatty acid oxidation, a hallmark of mature cardiomyocytes. Taken together, these findings highlight the novelty and efficacy of asymmetric biphasic stimulation in generating more physiologically relevant cardiac models, providing a promising alternative to standard ES protocols.

Coronary artery disease (CAD) encompasses a spectrum of pathologies driven by atherosclerosis, trauma, inflammation, or other etiologies that compromise coronary morphology and function, ultimately leading to myocardial ischemia and infarction. While organ-on-a-chip (OOC) technology has emerged as a transformative tool for cardiovascular research, existing reviews have consistently marginalized coronary-specific pathophysiology, treating it merely as a subset of generic vascular biology. This review presents the first dedicated, critical analysis of microphysiological system (MPS) engineered explicitly as CAD-on-a-chip platform. We deliberately depart from generalized vascular models by exclusively evaluating systems designed to recapitulate the unique coronary-specific hallmarks: distinct geometric constraints, pro-inflammatory microenvironments, and dynamic hemodynamic shear stress profiles inherent to human coronary arteries. Following a concise introduction to OOC fabrication materials and techniques, we systematically present vessel-on-a-chip (VOC) models derived from diverse cellular sources. We then emphasize the biomedical applications of VOC in CAD field and analyze key CAD-specific pathological processes, including flow-mediated endothelial dysfunction, atherosclerotic plaque formation, plaque rupture-induced atherothrombosis, and coronary artery aneurysm. Finally, we critically discuss current limitations and outline future directions of OOC technology in CAD research. This review by focusing on the specific pathological features of CAD and the requirements for in vitro modeling, aim to establish a targeted knowledge framework to promote the clinical transformation of VOC technology in CAD diagnosis and treatment.

Pathogenic mutations in Bcl2-associated athanogene 3 (BAG3) cause genetic dilated cardiomyopathy (DCM), a disease characterized by ventricular dilation, systolic dysfunction, and fibrosis. Previous studies have demonstrated that BAG3 mediates sarcomeric protein turnover through chaperone-assisted selective autophagy to maintain sarcomere integrity in the human heart. Although mouse models provide valuable insights into whole-organism effects of BAG3 knockout or pathogenic variants, their utility is limited by species-specific differences in pathophysiology, which often do not translate to humans and contribute to the failure of clinical trials. As a result, the development of induced pluripotent stem cell-derived cardiomyocytes (iCM) and engineered heart tissues presents a promising alternative for studying adult-onset cardiac diseases. Here, we used genome engineering to generate an isogenic pseudo-wild-type control cell line from a patient-derived iPSC line carrying a pathogenic BAG3 variant, clinically presenting with DCM. While monolayer iCMs recapitulated some features of BAG3-mediated DCM, such as reduced autophagy, mitochondrial membrane potential, and decreased HSPB8 stability, they failed to develop the age-associated impairment in sarcomere integrity. Therefore, we developed a mature, patient-specific, human engineered heart tissue model of BAG3-mediated DCM and compared it to its isogenic healthy control. We demonstrated successful recapitulation of adult-like features of the clinically observed disorganized sarcomeres and impaired tissue contractility, thereby providing a platform to investigate BAG3-related pathophysiology and therapeutic interventions.

Bisphenol A (BPA), a widely used industrial chemical with endocrine-disrupting properties, raises developmental and cardiotoxicity concerns. We established a stage-specific cardiotoxicity platform using human pluripotent stem cell (hPSC)-derived cardiomyocytes in two-dimensional and three-dimensional (3D) cultures. BPA exposure at ⩾10 µM significantly reduced cell viability and downregulated pluripotency and cardiac lineage markers such as OCT4, NKX2-5, and cTnT in a stage-dependent manner. Electrophysiological analysis revealed that acute exposure to 10 µM BPA disrupted action potentials in hPSC-derived cardiomyocytes, inducing membrane depolarization and rhythm disturbances. Furthermore, 3D cardiac tissues treated with 10 or 50 µM BPA exhibited severe mitochondrial deformation and impaired contractile function, as observed by TEM and beating analysis. Reproducing these effects in a personalized hPSC line validated the platform's applicability for patient-specific toxicity assessment. These findings highlight the importance of integrating developmental stage-specific and 3D human-relevant models for comprehensive cardiotoxicity evaluation of environmental chemicals such as BPA.

Type 1 diabetes (T1D) results from the autoimmune destruction of pancreatic β cells, leading to lifelong insulin dependence and significant health complications. Human pluripotent stem cell-derived β cells (hPSC-β cells) have emerged as a promising therapeutic alternative for restoring endogenous insulin production; however, limitations such as functional immaturity, immune rejection, and biosafety concerns such as tumorigenic risk continue to hinder clinical application. Recent advances in gene editing technologies, particularly clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), offer precise tools to enhance or correct hPSC-β cell performance by improving glucose-stimulated insulin secretion (GSIS), reducing immune rejection, and reducing biosafety concerns. This review explores gene editing strategies developed to overcome the key barriers in hPSC-β cell-based therapy for T1D. We highlight how genetic modifications enhance or correct β cell function, promote immune evasion, and reduce biosafety concerns through precise and clinically relevant engineering. Finally, we discuss the current landscape of clinical trials and future directions for translating gene-edited hPSC-β cells into curative treatments for T1D.

Three-dimensional engineered muscle tissues (EMTs) are transformative tools for modeling skeletal muscle physiology and pathology in vitro. Here, we perform a comprehensive comparison of EMTs derived from primary human myoblasts (hP-Myo) and hiPS-derived myoblasts (hiPS-Myo) to evaluate their structural, functional, and transcriptional characteristics. Contractile performance was quantified using a magnetic force-sensing platform, revealing that hP-Myo EMTs generate ~2 fold higher twitch forces and enhanced tetanic responses compared to hiPS-Myo EMTs. Tissue architecture and maturation were assessed and demonstrated significant larger myofiber diameters in hP-Myo EMTs. Transcriptomic profiling highlighted that hP-Myo EMTs maintain a mature skeletal muscle-like signature, marked by enriched pathways linked to sarcomere organization and fast-/slow-twitch fiber specification. To model metabolic dysfunction, hiPS-Myo EMTs were subjected to lipid overload, recapitulating hallmarks of intracellular lipid (IMCL) accumulation, including impaired contractility, blunted force-frequency responses, and dysregulated lipid metabolism genes.

Cardiac fibroblasts play an important role in heart homeostasis, regeneration, and disease by producing extracellular matrix (ECM) proteins and remodeling enzymes. Under normal conditions, fibroblasts exist in a quiescent state and maintain homeostasis, such as tissue structure and ECM turnover. However, if they become activated upon stimuli, such as injury, aging, or mechanical stress, which can lead to disease through excessive cell proliferation and ECM production. In addition to their role in disease progression, it remains unclear how cardiac fibroblasts contribute to cardiac maturation during development and whether the mechanism driving cytokine and ECM production during development aligns with those observed in pathological conditions. In this study, we investigated the functional and structural maturation of engineered cardiac tissue by modulating fibroblast activity within a three-dimensional (3D) in vitro model. In this model, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and human primary cardiac fibroblasts (FBs) were co-cultured in a fibrin gel and their morphology, beating characteristics, beating force, and mRNA expression profiles were analyzed. The results demonstrate that functional and structural maturation were enhanced by fibroblast-driven tissue contraction and collagen deposition, while inhibition of ECM remodeling impaired both processes. However, excessive collagen accumulation reduced functional maturation by limiting contractile efficiency. Our data suggest that ECM remodeling by cardiac fibroblasts is essential for cardiac tissue maintenance and maturation. Additionally, the regulation of collagen deposition by fibroblast activity will be a key focus of future research, as it may critically influence both cardiac development and the progression of heart disease.

Angiogenesis is essential for successful tissue regeneration, particularly in clinical contexts such as ischemic injury, wound healing, and reconstructive therapies. However, the establishment of functional vasculature remains a major limitation in organoid-based systems. In this study, we developed vascularized organoid tissue modules (Angio-TMs) by incorporating human umbilical vein endothelial cells (HUVECs) into scaffold-free, self-organized constructs. Remarkably, the inclusion of HUVECs at 1% of the total cell population was sufficient to generate highly reproducible and structurally stable Angio-TMs, which exhibited clear endothelial differentiation and vascular functionality both in vitro and in vivo. Furthermore, inhibition of transforming growth factor (TGF)-β signaling in Angio-TMs led to a 2.5-fold increase in vessel length density, demonstrating a substantial enhancement in angiogenic potential. These findings highlight Angio-TMs as a robust and modular platform for engineering vascularized tissues and underscore their translational relevance in regenerative medicine and tissue transplantation.

Dry eye disease is a complex ocular surface disorder with multifactorial pathophysiology, including corneal epithelial damage, chronic inflammation, and corneal nerve dysfunction. Among these, impaired corneal innervation plays a particularly critical role, as it disrupts neurotrophic support and tear reflexes, perpetuating disease progression, and delaying healing. However, conventional treatments often provide only temporary symptom relief without addressing underlying tissue damage or promoting nerve regeneration. This shortcoming highlights the need for therapies that not only suppress inflammation but also restore corneal innervation. In this study, we evaluated the therapeutic potential of mesenchymal stem cell (MSC) spheroid-derived secretome-a cell-free solution rich in regenerative and anti-inflammatory factors-in a preclinical mouse model of dry eye disease. Compared with untreated controls, eyes treated with the MSC spheroid secretome presented faster corneal epithelial regeneration, improved corneal nerve reinnervation, and reduced inflammatory cell infiltration. These findings demonstrate that the MSC spheroid-derived secretome can simultaneously target multiple pathological features of dry eye to promote recovery of ocular surface integrity, underscoring its potential as a clinically relevant, cell-free regenerative therapy for dry eye and other ocular surface disorders.

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe inherited skin disorder caused by mutations in . Patient-derived induced pluripotent stem cells (iPSCs) enable the personalized study of RDEB pathogenesis and potential therapies. However, current skin cell differentiation protocols via 2D culture perform suboptimally when applied to engineered 3D skin constructs (ESC). Here, we present an approach to source fibroblasts (iFBs) and keratinocytes (iKCs) from iPSC-derived skin organoids using an optimized differentiation protocol, and utilize them to engineer ESCs modeling wild-type and RDEB phenotypes. The resulting iPSC-derived skin cells display marker expression consistent with primary counterparts and produce ESCs exhibiting significant extracellular matrix remodeling, protein deposition, and epidermal differentiation. RDEB constructs recapitulated hallmark disease features, including absence of collagen VII and reduced iFB proliferation. This work establishes a robust and scalable strategy for generating physiologically-relevant, iPSC-derived skin constructs, offering a powerful model for studying RDEB mechanisms and advancing personalized regenerative medicine.