BACKGROUND AND AIMS:Wound healing remains a demanding medical problem despite significant advances in regenerative medicine. Mesenchymal, hair follicle and pluripotent stem cells are candidate populations for therapeutically relevant applications. Hair follicle bulge stem cells with scaffolds and growth factors can promote the healing of wounds. METHODS:This study explores a dual-layer electrospun nanofibrous wound dressing composed of PCL/SSD and PCL/COLL, enhanced with chitosan nanoparticles loaded with EGF and bFGF growth factors. Hair follicle bulge stem cells were seeded onto the scaffold and transplanted into rat skin wounds. RESULTS:FE‑SEM confirmed that the chitosan microspheres were uniformly spherical, ranging from nanoscale to ~1 µm. Thermal analysis showed a 28% weight loss up to 250°C and major degradation between 230°C and 450°C, indicating good thermal stability. About 50% of the encapsulated EGF and bFGF (6.5 ng from 2 mg microspheres) was released within 24 h, followed by sustained release. Biological assays demonstrated strong cell attachment, enhanced collagen deposition, and rapid tissue remodeling, with complete skin regeneration achieved by day 14. CONCLUSION:These findings suggest that a two-layered electrospun nanofibrous mat incorporating chitosan nanoparticles, growth factors, and hair follicle bulge stem cells significantly enhances wound healing in a rat model.
Over the past four decades, significant advances in stem cell transplantation (SCT) have expanded its use in metabolic diseases. The therapeutic efficacy of SCT relies on the capacity of hematopoietic stem and progenitor cells (HSPCs) and their committed progeny to engraft, migrate, and differentiate within target tissues including the liver, spleen, bone, and hematopoietic system, thereby serving as a continuous source of functional enzyme for cross-correction of enzyme-deficient cells. Within the central nervous system, donor-derived cells can differentiate into microglia, enabling partial correction of neurological pathology. Long-term outcomes of SCT in metabolic diseases vary according to the underlying disorder and the extent to which transplantation can arrest or modify disease progression, with differential responses observed across organ systems. Despite its benefits, SCT is limited by transplant-related morbidity and mortality, as well as restricted access to suitable HLA-matched donors. Recent technological advances have led to the emergence of autologous hematopoietic stem cell gene therapy (HSC-GT) as a promising alternative therapeutic strategy for several metabolic diseases, with encouraging early clinical outcomes. In this narrative review, we evaluate the present landscape of SCT and the evolving role of autologous HSC-GT in the treatment of metabolic diseases, and highlight the key challenges that must be addressed to advance future applications.
The Informed Consent Standards for Human Fetal Tissue Donation for Research, published by the International Society for Stem Cell Research, provide important guidance for ethical research. They are particularly relevant in countries such as Japan, where clear legal frameworks for the use of human fetal and associated tissues obtained through induced abortion are lacking. However, because such guidelines do not fully account for national regulatory and legal frameworks, additional considerations are required to support their effective global implementation. Here, we describe three ethical, legal, and social issues in Japan - also shared in part by other countries - as examples of considerations relevant to the wider implementation of internationally recognized ethical standards. We discuss possible approaches to these issues, including: (1) appropriate selection of medical institutions capable of minimizing the burden on potential donors, (2) consideration of whether consent from the male partner should be obtained, and (3) clarification of the "Ena (placenta)" ordinance related to the use and disposal of dead fetuses. Ensuring appropriate integration between such ethical standards and local regulations is essential for the sustainable and ethical development of fetal tissue research.
Tendon injuries pose a significant global health challenge due to the poor innate healing capacity of the tissue. Current clinical interventions report limited treatment efficacy, typically resulting in a fibrotic scar that is mechanically inferior to native tissue and predisposed to future re-rupture. Tendon tissue engineering, leveraging advances of biomimetic scaffolds, offers a promising path toward functional regeneration rather than fibrotic repair. The design of these biomimetic scaffolds is a complex, interdisciplinary challenge that has evolved from a simple structural replacement to a sophisticated, bio-instructive strategy. Literature searches were conducted using PubMed, Scopus, and R Discovery with the terms "tendon tissue engineering scaffold" or "tendon regenerative medicine scaffold," and studies published between 2020 and 2025 were included. In this review, we outline four key design principles identified to enhance tissue engineering solutions constructed for tendon: 1) Biomechanical compatibility, 2) Biocompatibility and Integration, 3) Porosity and Mass Transport, and 4) Mechanobiological Stimuli. Together, these core parameters mediate the production of hierarchical, bio-instructive scaffolds that integrate cellular components, growth factors, and mechanical stimulation to produce intelligent therapeutic systems for functional, long-lasting tendon regeneration.
BACKGROUND:Human induced pluripotent stem cells (iPSCs) are a promising starting material that can be differentiated into therapeutic cell products for clinical trials. The production of clinically applicable drug products requires good manufacturing practice (GMP)-compliant iPSCs as the initial starting material. Under the framework of the Korean Ministry of Food and Drug Safety, we generated a master cell bank (MCB) of a human iPSC line, KNIH01-MCB, from peripheral blood mononuclear cells obtained from a healthy female donor under a GMP system. MATERIAL AND METHODS:To verify cell identity and quality, we performed a risk assessment of genetic stability, pluripotency, cell line identity, and sterility. For this purpose, we used validated methods, including polymerase chain reaction, karyotyping, short tandem repeat analysis, ABO/human leukocyte antigen (HLA) typing, and bacterial growth testing. After material qualification, the cells underwent comprehensive quality testing, including viral screening, ABO/HLA typing, and sterility testing. RESULTS:We successfully established an MCB of the iPSC line, enabling clinical readiness, including full traceability and donor eligibility for clinical applications. The MCB met the quality control criteria of our in-house GMP system. CONCLUSION:These iPSCs provide a GMP-compliant and clinically applicable starting material for therapeutic cell manufacturing intended for human use.
INTRODUCTION:Acellular dermal matrices are increasingly applied in regenerative medicine and wound healing because they mimic native dermal structure and exhibit low immunogenicity. However, decellularization methods vary, and no consensus exists on the optimal protocol for human full-thickness dermis. This study compared three decellularization approaches to identify the most effective method for generating biocompatible, structurally preserved acellular dermis suitable for clinical use. METHODS:Full-thickness human dermis was processed using: (1) alkaline NaOH treatment, (2) Triton X-100 followed by mild alkali, and (3) freeze-thaw cycling with surfactant and sonication. The resulting scaffolds were assessed macroscopically, histologically, and through cytocompatibility assays. In vivo wound healing was evaluated in a murine full-thickness wound model. RESULTS:Alkaline treatment effectively removed cells but damaged the extracellular matrix, reducing mechanical strength and biocompatibility. Triton X-100-based and freeze-thaw/surfactant protocols preserved dermal architecture and mechanical integrity while ensuring complete decellularization and cytocompatibility. Both supported improved cellular infiltration and tissue remodeling in vivo. Neoangiogenesis and graft orientation showed minimal influence on healing. CONCLUSION:Triton X-100-based and freeze-thaw/surfactant protocols achieved optimal balance between cell removal and matrix preservation, offering promising strategies for producing clinically applicable acellular dermal scaffolds.
AIMS:Stem cell interventions (SCIs) are an exciting area of regenerative medicine (RM) that may offer improved outcomes for many patients, including those suffering from musculoskeletal conditions. They can also raise regulatory tensions and policy challenges, including how to manage direct-to-consumer markets where nonstandard SCIs - those falling outside the standard of care and lacking sufficient evidence of safety or efficacy - are sold. Ongoing regulatory reform efforts in several countries, including Canada, to address these and other related issues would benefit from insights regarding what is important to patients for trust in SCIs and their providers. MATERIALS AND METHODS:Through interviews involving eight participants with musculoskeletal conditions, this qualitative, constructivist grounded theory study presents a preliminary model of factors that influence some patients' trust in nonstandard SCIs. RESULTS AND CONCLUSIONS:Participants' anticipated approaches to nonstandard SCIs were rooted in their lived experiences of pain and frustration, shaped through interactions with healthcare providers, and framed by assumptions about regulatory protection. Healthcare providers play a pivotal role in helping navigate and interpret information. These results highlight the importance of evidence-based approaches to governance that integrate patient voices, practitioner education, and regulatory accountability to protect patients and help advance responsible RM innovation.
AIMS:Deep second-degree burns often require autografting, but donor-site limitations highlight the need for alternative biological coverings. This study evaluated the safety and feasibility of allogeneic cultured keratinocyte sheets for acute burn wounds. PATIENTS AND METHODS:Five patients with 20-50% total body surface area burns were enrolled. A 60 cm2 wound site in each patient received the sheet, while the remaining areas were treated with standard autologous grafts. Patients were followed for 6 months. Primary endpoints were safety and feasibility; secondary endpoints included graft take, wound closure time, and scar quality assessed by Vancouver Scar Scale (VSS) and Patient and Observer Scar Assessment Scale (POSAS). Histopathology was performed at baseline and 6 months. RESULTS:No serious adverse events occurred; only minor, self-limited reactions were observed. Keratinocyte sheets demonstrated near-complete take without immune responses. Wound closure occurred within 1 month in two patients and by 3 months in the others. POSAS patient scores improved from 28.4 ± 9.8 to 19.2 ± 6.0, and observer scores from 21.2 ± 3.8 to 14.2 ± 5.1. VSS decreased from 5.0 ± 2.1 to 3.6 ± 2.4. Histology confirmed favorable epithelialization. CONCLUSIONS:Allogeneic keratinocyte sheets were safe, feasible, and improved healing and scar quality. CLINICAL TRIAL REGISTRATION:Iranian Registry of Clinical Trials (IRCT), https://irct.ir/trial/62833; identifier is IRCT20080728001031N31.
The global shortage of donor organs and the limitations of conventional in vitro models stress the urgent need for advanced liver tissue engineering and regenerative medicine strategies. These approaches aim to create physiologically relevant platforms for drug testing and develop transplantable tissues to restore liver function. Decellularization offers unique advantages by providing native extracellular matrix architecture and biochemical cues that support cell adhesion, differentiation, and vascularization. Complementary technologies such as three-dimensional (3D) bioprinting and microfluidics enable precise spatial organization of multiple cell types and dynamic perfusion, improving tissue functionality and disease modeling. Together, these innovations facilitate the development of high-fidelity liver constructs and organ-on-chip systems for studying pathologies like fibrosis and steatosis, as well as for preclinical drug screening. In this review we summarize current methods for liver decellularization and explore its role as a regenerative medicine strategy. We also examine applications in disease modeling, with emphasis on 3D bioprinting and microfluidic platforms, and discusses emerging vascularization techniques. Collectively, these insights highlight the progress and remaining challenges in engineering functional liver tissues for clinical and research applications.
Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by the destruction of pancreatic β-cells and the subsequent loss of insulin production. The regeneration of pancreatic β-cells from induced pluripotent stem cells (iPSCs) represents a promising therapeutic approach for restoring β-cell function in T1DM patients. However, ensuring the safety, functionality, and genetic stability of iPSC-derived β-cells is crucial for their clinical application. To address this challenge, a comprehensive literature review was conducted using PubMed/MEDLINE, Web of Science, and Scopus databases to identify relevant studies published up to October 2025. It included an analysis of key regulatory documents from the U.S. Food and Drug Administration (FDA), the European Medicines Agency on Advanced Therapy Medicinal Products (EMA ATMP), and the International Organization for Standardization (ISO). This article proposes a comprehensive quality control (QC) strategy for differentiating iPSCs into pancreatic β-cells, emphasizing a tiered approach with multiple checkpoints throughout the process. The strategy integrates advanced molecular and functional assays to evaluate cell identity, viability, stability, and microbiological safety. The proposed QC framework allows for continuous monitoring, early detection of potential issues, and real-time adjustments to optimize the differentiation process. The flexibility of this approach ensures its adaptation to emerging scientific advancements and regulatory requirements. This integrated and adaptable QC strategy enhances the likelihood of success in generating functional β-cells, laying a solid foundation for the clinical application of iPSC-derived β-cell therapies and offering hope for effective, long-term treatments for T1DM.
Microfragmented adipose tissue (MFAT) has emerged as a minimally manipulated, autologous orthobiologic for musculoskeletal disorders, with the Lipogems system representing one of the most widely studied platforms. By preserving the stromal vascular niche and pericyte-rich microenvironment, MFAT provides a ready-to-use biologic without enzymatic digestion or ex vivo expansion. This narrative review synthesizes the biological rationale, clinical applications, and comparative effectiveness of MFAT across major orthopedic indications. We review action mechanisms, patient selection factors, procedural considerations, and regulatory context, with emphasis on outcomes, durability, and imaging correlations. Across joints, MFAT has demonstrated consistent improvements in pain and function, particularly in early to moderate osteoarthritis. However, radiographic findings are heterogeneous and often discordant with clinical outcomes. Studies suggest MFAT offers outcomes comparable to platelet-rich plasma and bone marrow aspirate concentrate rather than clear superiority. Overall, the evidence base is dominated by low- to moderate-level studies with small sample sizes, protocol variability, and limited follow-up. This review provides a cross-joint clinical synthesis to contextualize MFAT's current role in orthopedic practice, highlighting its procedural simplicity and favorable safety profile. Despite encouraging clinical signals, we strongly underscore the need for future high-quality trials, standardized methodologies, and cost-effectiveness analyses to define its long-term clinical utility.
Limbal stem cell deficiency (LSCD) is a severe ocular surface disorder that remains a major therapeutic challenge, particularly in bilateral disease where autologous limbal tissue is unavailable. Over the past three decades, stem cell-based interventions have transformed LSCD management, evolving from large limbal grafts to refined ex vivo expansion techniques and alternative stem cell sources. Despite these advances, long-term clinical outcomes remain variable and are strongly influenced by disease severity, immune rejection, stem cell quality, and optimization of the ocular surface microenvironment. This report examines the current landscape of surgical and stem cell-based therapies for LSCD, including autologous and allogeneic limbal epithelial transplantation, simple limbal epithelial transplantation, oral mucosa-derived approaches, mesenchymal stem cell therapies, and emerging induced pluripotent stem cell-derived corneal epithelium. We highlight key clinical outcomes, biological limitations, and translational challenges. Finally, we discuss future directions required to improve therapeutic efficacy and accessibility, including improved stem cell characterization and the development of hypoimmune or universal donor cell products.
BACKGROUND/AIMS:Mesenchymal stem/stromal cells (MSCs) are known to secrete wound healing factors. However, the delivery of the MSCs and their secretomes remains a barrier to the development of a successful regenerative medicine. Therefore, we examined the content and paracrine activity of serum free MSC conditioned media (MSC CM) generated in routine tissue culture and when cultured on a plasma polymerized membrane previously used clinically in cell therapies for skin wounds. METHODS:Serum free MSC CM from murine and human MSC cultures were subjected to proteomic analysis by mass spectrometry and quantitative immunoassays and their paracrine effects were tested on dermal fibroblasts in vitro. RESULTS:MSC CM contained multiple wound healing factors, including extracellular matrix proteins and soluble factors. MSC CM harvested from flask cultures and plasma polymerized membrane cultures significantly increased dermal fibroblast adhesion, proliferation, and scratch wound closure (for mouse MSC CM) compared to control media. CONCLUSION:This study has: (i) shown that MSC secreted factors increased dermal fibroblast activities seen in wound healing; (ii) identified target factors potentially responsible for these paracrine effects; (iii) shown that MSC secretomes generated on a plasma polymerized membrane used in skin cell therapies also have wound healing paracrine effects.
BACKGROUND:In burn-injured skin, the main goal is to accelerate wound healing and restore the barrier. In chemical burns, excessive inflammation and deep tissue damage complicate repair. Regenerative medicine approaches may modulate these processes. This study investigated the effects of human umbilical cord-derived mesenchymal stem cells (HucMSCs) and their exosomes (Exo-HucMSCs) on wound healing in a chemical burn model. METHODS:A chemical burn was induced on the dorsal skin of 24 Wistar rats using 2 M sodium hydroxide. Rats were randomly assigned to three groups (n = 8): HucMSC-treated, Exo-HucMSC-treated and control. Wound closure and histopathological changes were evaluated and compared among groups. RESULTS:Wound closure was higher in the HucMSC group (78.15% ± 9.19) than in the Exo-HucMSC (66.11% ± 7.33) and control groups (57.35% ± 4.54) (p < 0.05). Histologically, treatment groups showed early inflammatory changes on days 1 and 3 (p < 0.01), enhanced striated muscle regeneration on day 7 (p < 0.01) and narrower non-epithelialized areas on day 21 (p < 0.05). Neoangiogenesis was greater in the Exo-HucMSC group on day 3 (p < 0.01). CONCLUSION:Both HucMSC and Exo-HucMSC treatment accelerated chemical burn healing. Exosomes promoted early-phase angiogenesis, whereas HucMSCs provided superior long-term wound closure.
Latest developments in the field of Advanced Therapy Medicinal Products and regenerative medicine compiled from publicly available information and press releases from non-academic institutions in April 2026.
PURPOSE:This phase I clinical trial evaluated the safety and preliminary efficacy of three intra-articular injections of 20 × 106 allogeneic Umbilical Cord-derived Mesenchymal Stromal Cells (UC-MSCs) in patients with Knee Osteoarthritis (OA) at a two-month interval. METHODS:Six participants aged 40-70 years with Kellgren and Lawrence grade II-III were enrolled. They received three bilateral intra-articular injections of allogeneic UC-MSCs at two-month intervals. They were assessed for possible Adverse Events, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Visual Analogue Scale (VAS), Short Form Health Survey, and Magnetic Resonance Imaging (MRI) over 12 months. RESULTS:No serious adverse events occurred. Four participants (66%) reported at least one adverse event, most commonly transient injection-site pain or swelling. Exploratory analyses showed improvement in WOMAC scores from a median of 58.33 (IQR: 25-69.53) at baseline to 21.85 (IQR: 11.97-61.44) at 12 months, with pain and function improving in five patients (83%). VAS scores decreased by a median of 55% (IQR: -62.5 to -12.5). MRI showed no consistent structural changes, although mild tibial cartilage improvement was observed in two participants. CONCLUSION:Three intra-articular injections of allogeneic UC-MSCs appear to be safe and may provide functional benefits in patients with knee OA, supporting further investigation in larger, controlled trials. CLINICAL TRIAL REGISTRATION:https://irct.behdasht.gov.ir identifier is IRCT20211102052944N1.
Stimuli-responsive and bioinspired hydrogels have become the new promising biomaterials in regenerative medicine as they are capable of dynamically recreating the extracellular matrix (ECM) and reacting to physiological stimuli. Compared to traditional stationary scaffolds, these hydrogels combine bioinspired structural design with endogenous stimulus response, including pH, temperature, redox, and enzyme activity to allow adaptive mechanical response, targeted therapeutic release, and cell-instructive microenvironment. Though much research has shown potential preclinical efficacy in tissue engineering, wound healing and drug delivery, clinical implementation has been hampered by such factors as long term biocompatibility, mechanical instability, scalability of manufacturing, and regulatory complexity. This will be a critical review of the current developments in the design principles of hydrogel, molecular functionalization concepts, and multi-stimuli-responsive principles with specific consideration on how these characteristics can be applied to translational potential. Moreover, the new fabrication technologies, such as 3D and 4D bioprinting, are mentioned as the tools to allow spatially and temporally programmable hydrogel systems. The article offers a framework of translationally focused research, which also identifies the potential and constraints of bioinspired and stimuli-responsive hydrogels by combining material design with fabrication approaches and clinical aspects, providing a pathway toward the creation of clinically viable regenerative therapies.
