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29 pages, 1434 KB  
Review
Evolving Landscape of Regenerative Therapies: Cell-Based and Cell-Free Approaches for Chronic Low Back Pain
by Courtney E. Bartlett, Pareeshe Bansal, Siddhant Bhattacharya, Abhi Dhote, Bruna B. Nicoletto, Joana R. N. Lemos and Rahul Mittal
J. Clin. Med. 2026, 15(13), 5235; https://doi.org/10.3390/jcm15135235 (registering DOI) - 4 Jul 2026
Abstract
Background: Chronic low back pain (CLBP) is the leading cause of years lived with disability globally, affecting over 600 million individuals. Intervertebral disc degeneration (IVDD) is a principal structural contributor, yet conventional treatments, including pharmacotherapy, physical therapy, and surgical intervention, do not reverse [...] Read more.
Background: Chronic low back pain (CLBP) is the leading cause of years lived with disability globally, affecting over 600 million individuals. Intervertebral disc degeneration (IVDD) is a principal structural contributor, yet conventional treatments, including pharmacotherapy, physical therapy, and surgical intervention, do not reverse the underlying degenerative pathology. Regenerative medicine has introduced a spectrum of biological therapies for IVDD, including cell-based mesenchymal stromal cell (MSC) therapy, platelet-derived products such as platelet-rich plasma (PRP) and platelet lysate, extracellular vesicle-based approaches using MSC-derived extracellular vesicles (EVs), and secretome-based therapies using MSC-derived secretomes. However, these approaches have largely been studied in isolation, without a unified framework to compare their respective advantages and limitations in CLBP secondary to IVDD. Accordingly, this narrative review aims to provide an integrated and comparative evaluation of these regenerative strategies within a single translational and clinical context. Methods: For this narrative review, PubMed, Scopus, and Web of Science were searched from January 2000 to January 2026 using terms combining regenerative modalities with intervertebral disc degeneration, and chronic low back pain. Randomized controlled trials (RCTs), prospective cohort studies, systematic reviews, and preclinical studies with translational relevance were included. Results: Intradiscal MSC therapy has demonstrated safety across multiple phase I–III trials, but two recent landmark RCTs (RESPINE and the Mesoblast phase III trial) failed to meet primary efficacy endpoints, highlighting the gap between preclinical promise and clinical outcomes. PRP has the largest clinical evidence base, with level II evidence supporting short- to medium-term pain relief for discogenic pain, although standardization remains a critical barrier. Platelet lysate, MSC-derived EVs, and MSC-derived secretomes show compelling preclinical data, including extracellular matrix restoration, anti-inflammatory modulation, and attenuation of nucleus pulposus cell apoptosis, but remain at early translational stages for spinal applications, with no completed RCTs. The hostile disc microenvironment (avascular, hypoxic, acidic, and nutrient-poor) poses unique challenges for all regenerative modalities, differing fundamentally from other musculoskeletal applications. Conclusions: The studies included in this narrative review suggest that no single regenerative modality has yet shown consistent and unequivocal efficacy for CLBP secondary to IVDD across clinical trials. Cell-free approaches offer manufacturing, scalability, and safety advantages over cell-based therapies, but lack clinical validation. Future progress requires standardized preparation protocols, disc-specific delivery systems, patient phenotyping strategies, and rigorously designed comparative clinical trials. This narrative review provides a framework for researchers and clinicians to evaluate these therapies in context rather than isolation. Full article
(This article belongs to the Section Clinical Rehabilitation)
18 pages, 3440 KB  
Article
MSC-Derived Extracellular Vesicles Mitigate Ischemia-Induced Energetic Dysfunction During Ex Situ Perfusion of Rat Livers
by Caterina Lonati, Michele Battistin, Andrea Carlin, Michela Ripolone, Francesco Fortunato, Valentina Fonsato, Alessia Brossa, Alberto Zanella, Giovanni Camussi and Daniele Eliseo Dondossola
Antioxidants 2026, 15(7), 843; https://doi.org/10.3390/antiox15070843 (registering DOI) - 4 Jul 2026
Abstract
Despite advances in liver machine perfusion (MP), ischemia–reperfusion injury (IRI) remains a major challenge in liver transplantation, with energetic stress and mitochondrial dysfunction recognized as key drivers of damage exacerbation. We investigated whether fractions enriched with extracellular vesicles (EVs) derived from mesenchymal stromal [...] Read more.
Despite advances in liver machine perfusion (MP), ischemia–reperfusion injury (IRI) remains a major challenge in liver transplantation, with energetic stress and mitochondrial dysfunction recognized as key drivers of damage exacerbation. We investigated whether fractions enriched with extracellular vesicles (EVs) derived from mesenchymal stromal cells can preserve energetic homeostasis in rat livers undergoing normothermic MP (NMP). An established NMP rat model was used (n = 5 per group). After procurement, livers underwent NMP for 4 h, preceded or not by 30 min cold ischemia (CI). EVs (NMP + EVs and CI + NMP + EVs) or saline (NMP and CI + NMP) were randomly administered to the perfusion fluid. Perfusate samples were collected throughout the procedure, and biopsies were taken at the end of NMP. Ischemic livers exhibited succinate accumulation, flavin mononucleotide (FMN) release, activation of reverse electron transport, and adenosine triphosphate (ATP) depletion. EV treatment effectively counteracted these effects, restoring a metabolic profile comparable to that of non-ischemic livers. Moreover, EVs improved adenosine monophosphate/ATP ratios and prevented AMP-activated protein kinase activation, a key energy-stress sensor. Furthermore, EVs reduced oxidative stress markers, cell death mediators, and pro-inflammatory cytokines, indicating a broad cytoprotective and anti-inflammatory effect. These findings support the potential of EVs to preserve mitochondrial function, restore energy balance, and reduce inflammation, thereby improving liver cell viability during NMP. Full article
(This article belongs to the Special Issue Oxidative Stress in Hepatic Diseases)
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19 pages, 1955 KB  
Article
Probabilistic Risk Assessment of Tunnel Seismic Damage Under Physically Based Non-Stationary Earthquakes
by Li Guo, Zhongkai Huang, Nianchen Zeng and Wei Zhang
Mathematics 2026, 14(13), 2382; https://doi.org/10.3390/math14132382 - 3 Jul 2026
Abstract
The seismic performance of tunnel structures is significantly influenced by the randomness of ground motions. Traditional probabilistic risk assessments, which rely on limited recorded ground-motion data, often suffer from small-sample bias and fail to capture the full distribution of seismic input. To overcome [...] Read more.
The seismic performance of tunnel structures is significantly influenced by the randomness of ground motions. Traditional probabilistic risk assessments, which rely on limited recorded ground-motion data, often suffer from small-sample bias and fail to capture the full distribution of seismic input. To overcome this limitation, this study employs a physically based stochastic ground-motion model to generate a large and statistically representative sample ensemble. A probabilistic seismic risk assessment framework is then developed using the stochastic finite element method, explicitly incorporating ground-motion uncertainty. Four statistical criteria, namely practicality, correlation, efficiency, and proficiency, are systematically applied to evaluate candidate intensity measures (IMs) and identify the optimal one. Among all candidates, PGA exhibits the best overall performance, with the highest regression fitness (R2 = 0.873) and the lowest dispersion (βD = 0.197), followed by PGV (R2 = 0.848, βD = 0.215). Fragility curves for different damage states are subsequently derived. Results indicate that structural responses vary considerably under stochastic ground-motion excitation, and the failure probability follows a typical S-shaped curve as intensity increases. Moreover, the failure probabilities for different damage states exhibit nonlinear growth at higher intensity levels. These findings provide a mathematical basis for probability-based seismic design and risk assessment of tunnel structures. Full article
26 pages, 1001 KB  
Review
Engineered Extracellular Vesicles as Programmable Immune Interfaces: Surface and Cargo Engineering for Cancer Immunotherapy and Tolerance
by Tomoyoshi Yamano and Rikinari Hanayama
Cells 2026, 15(13), 1213; https://doi.org/10.3390/cells15131213 - 3 Jul 2026
Abstract
Extracellular vesicles (EVs) are membrane-enclosed nanoparticles that mediate intercellular communication in the immune system by transferring proteins, nucleic acids, and lipids. Their biocompatibility, nanoscale size, and capacity for cell-type-selective delivery have stimulated growing interest in engineering EVs as therapeutic platforms. In this review, [...] Read more.
Extracellular vesicles (EVs) are membrane-enclosed nanoparticles that mediate intercellular communication in the immune system by transferring proteins, nucleic acids, and lipids. Their biocompatibility, nanoscale size, and capacity for cell-type-selective delivery have stimulated growing interest in engineering EVs as therapeutic platforms. In this review, we discuss recent advances in EV engineering for immune regulation, focusing on surface display, cellular targeting, and cargo loading strategies. A central concept is that engineered EVs should not be viewed simply as delivery vehicles, but as programmable immune interfaces. EVs can integrate antigen specificity, target-cell recognition, therapeutic cargo delivery, and defined immunostimulatory or tolerogenic signals within a single nanoscale particle. By combining these modular elements, engineered EVs can be designed to direct immune responses in a context-dependent manner. We examine how this principle is being applied to cancer immunotherapy, immune suppression, and antigen-specific tolerance induction, including antigen-presenting EVs, cytotoxic and RNA-loaded EVs, checkpoint-modulatory EVs, MSC-derived EVs, and engineered platforms for autoimmune and inflammatory diseases. We also discuss the clinical translation of engineered EV therapeutics, with emphasis on manufacturing, characterization, potency assays, biodistribution, safety, and regulatory challenges. Together, current advances suggest that programmable EV immune interfaces may provide a versatile foundation for next-generation cancer immunotherapy and antigen-specific immune regulation. Full article
(This article belongs to the Special Issue Translating Extracellular Vesicle Science)
39 pages, 3781 KB  
Article
Fair Marking in the Generative AI Era: Introducing the Master’s Dissertation Marking Framework
by Mireilla Bikanga Ada
AI Educ. 2026, 2(3), 23; https://doi.org/10.3390/aieduc2030023 - 2 Jul 2026
Viewed by 90
Abstract
This paper presents the Master’s Dissertation Marking Framework (MDMF), a longitudinally developed framework designed to support fairer and more transparent master’s dissertation assessment. The framework was developed through a multi-phase, design-based research framework, comprising a literature review, a survey and in-depth interviews (2022) [...] Read more.
This paper presents the Master’s Dissertation Marking Framework (MDMF), a longitudinally developed framework designed to support fairer and more transparent master’s dissertation assessment. The framework was developed through a multi-phase, design-based research framework, comprising a literature review, a survey and in-depth interviews (2022) conducted prior to the emergence of generative AI, and follow-up empirical phases between 2023 and 2025. Across these phases, the framework evolves from an initial focus on procedural consistency and bias mitigation to a broader sociotechnical perspective that incorporates ethical boundaries, professional judgement, institutional responsibility, and the disruptive effects of generative AI on assessment practice. The paper traces the progression of the framework to MDMF Version 5, the final iteration, which consolidates six interdependent components: ethical boundaries and AI policy clarity; fairness and equity issues; pre-marking tasks and calibration; marker allocation; marking processes, culture, and well-being; and technology as both enabler and disruptor. Drawing on empirical evidence from academic staff involved in MSc dissertation marking in the post-generative-AI context, the framework brings together these components to address both longstanding and emerging challenges in assessment. The findings demonstrate that fairness in dissertation marking cannot be achieved through procedural mechanisms or technological solutions alone. Instead, the MDMF supports fairer assessment by structuring human judgement, enabling calibration, and clarifying ethical boundaries in AI-mediated contexts. The framework offers a coherent yet adaptable model for institutions seeking to maintain valid and defensible assessment practices in the age of generative AI. Full article
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22 pages, 10962 KB  
Article
Transplantation of Mesenchymal Stem Cell-Derived Hepatocytes Primed with Quercetin Alone or in Combination with Rutin and LiCl Enhances Liver Regeneration
by Tuba Shakil Malick, Rida-E-Maria Qazi, Aisha Ishaque, Abiha Fatima, Irfan Khan, Shaheen Faizi, Asmat Salim and Farasat Zaman
Cells 2026, 15(13), 1206; https://doi.org/10.3390/cells15131206 - 2 Jul 2026
Viewed by 160
Abstract
Inhibition of Wnt/β-catenin signaling differentiates mesenchymal stem cells (MSCs) into hepatocytes. However, there is lack of data on whether transplanting these cells can enhance liver regeneration. Additionally, it remains unknown if the flavonoids quercetin and rutin and the clinically used drug lithium chloride [...] Read more.
Inhibition of Wnt/β-catenin signaling differentiates mesenchymal stem cells (MSCs) into hepatocytes. However, there is lack of data on whether transplanting these cells can enhance liver regeneration. Additionally, it remains unknown if the flavonoids quercetin and rutin and the clinically used drug lithium chloride (LiCl) can effectively differentiate MSCs into hepatocytes and promote liver regeneration. To address this, the rat bile duct ligation (BDL) fibrosis model was used. Male Wistar rats were surgically ligated. Liver function tests, histological analysis and cell tracking were also conducted to validate liver regeneration. Treatment with quercetin inhibited the Wnt pathway, while rutin and LiCl activated it. Hepatic differentiation was noted in three treatment groups: quercetin, quercetin with rutin and LiCl. We observed that the initial downregulation of the Wnt pathway, followed by its upregulation, facilitated the differentiation of MSCs into hepatocytes. Transplantation of quercetin-treated MSC-derived hepatocytes into the rat BDL fibrosis model resulted in complete restoration of liver function, normalization of elevated systemic liver enzymes and reduction of inflammation and fibrosis. Interestingly, quercetin-treated hepatocytes resulted in enhanced liver regeneration compared to rutin and LiCl. Finally, tracking of labeled hepatocytes confirmed their main localization in the liver. In conclusion, MSC-derived hepatocytes, generated through ex vivo treatment with quercetin, exhibit enhanced liver regeneration. These findings provide a novel ex vivo treatment strategy with flavonoids and the clinically used drug LiCl to achieve enhanced liver regeneration in vivo. Full article
(This article belongs to the Section Cells of the Cardiovascular System)
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22 pages, 2186 KB  
Article
High-Content Analysis of 3D Chondrogenic Pellets Derived from Primary Cells In Vitro
by Lucija Voga, Tilen Burnik, Maša Kandušer, Matjaž Jeras, Janja Zupan and Andreja Trojner Bregar
Biomedicines 2026, 14(7), 1496; https://doi.org/10.3390/biomedicines14071496 - 1 Jul 2026
Viewed by 218
Abstract
Background: Primary cells derived from connective tissues contain mesenchymal stem/stromal cell (MSC)–like progenitors with chondrogenic potential relevant for cartilage repair. However, donor- and tissue-specific variability and the lack of robust, high-content analytical methods limit their translational use. Objectives: This study aimed [...] Read more.
Background: Primary cells derived from connective tissues contain mesenchymal stem/stromal cell (MSC)–like progenitors with chondrogenic potential relevant for cartilage repair. However, donor- and tissue-specific variability and the lack of robust, high-content analytical methods limit their translational use. Objectives: This study aimed to develop and optimize a high-content imaging workflow for quantitative evaluation of chondrogenesis in three-dimensional (3D) pellets derived from primary cells. Methods: Primary human cells isolated from cartilage were chondrogenically differentiated in vitro. A systematic optimization of immunofluorescence staining parameters was performed, including staining platform, enzymatic matrix digestion, non-specific site blocking, membrane permeabilization, and nuclear counterstaining. Type II collagen was detected using an Alexa Fluor 488–conjugated antibody, and pellets were analyzed using high-content non-confocal imaging. Fluorescence intensities were adjusted to the pellet area to account for size-dependent effects. Results: Staining directly in imaging plates enabled streamlined high-content analysis. Controlled pepsin-mediated matrix digestion markedly enhanced antibody penetration, while excessive digestion compromised pellet integrity. Extended bovine serum albumin blocking improved type II collagen signal intensity and homogeneity. Triton X-100 permeabilization increased detection sensitivity but occasionally induced structural disruption in weakly organized control pellets. The optimized protocol enabled clear discrimination between chondrogenic pellets and controls, with approximately threefold higher type II collagen signal in chondrogenic samples. Conclusions: This study establishes a high-content imaging–based workflow for quantitative assessment of 3D chondrogenesis from primary cells. The approach provides a rapid, scalable platform with direct relevance for in vitro screening, potency testing, and quality control in cartilage-oriented advanced therapy development. Full article
(This article belongs to the Special Issue Stem Cell Therapy: Traps and Tricks)
24 pages, 47922 KB  
Article
Superior In Vitro Osteo-Supportive Properties of Trabecular Titanium vs. Chromium–Cobalt Scaffolds
by Andrea Massimiliano Nebuloni, Roberta Lauro, Michela Maria Taiana, Gaetano Sorano, Piero Costa, Enrico Ragni and Laura de Girolamo
Prosthesis 2026, 8(7), 70; https://doi.org/10.3390/prosthesis8070070 - 1 Jul 2026
Viewed by 86
Abstract
Background: Degenerative joint diseases are a major cause of disability and drive the increasing demand for joint arthroplasty. Long-term prosthesis success depends on rapid and stable bone–implant integration, which is influenced by the osteo-inductive and osteo-conductive properties of implant materials. Chromium–cobalt (CrCo) and [...] Read more.
Background: Degenerative joint diseases are a major cause of disability and drive the increasing demand for joint arthroplasty. Long-term prosthesis success depends on rapid and stable bone–implant integration, which is influenced by the osteo-inductive and osteo-conductive properties of implant materials. Chromium–cobalt (CrCo) and titanium (Ti) alloys are widely used in reconstructive orthopedics, but direct comparative data on their biological performance, particularly for trabecular titanium (T-Ti), remain limited. This study aimed to directly compare the biocompatibility and osteogenic potential of CrCo and T-Ti using human mesenchymal stromal cells (MSCs). Methods: Human MSCs were characterized by immunophenotyping and cultured on CrCo and T-Ti scaffolds under control and osteogenic conditions for up to 28 days. Cell adhesion and morphology were assessed by scanning electron microscopy. Proliferation and viability were quantified, and osteogenic differentiation was evaluated using alkaline phosphatase activity, calcium deposition assays, and gene expression profiling of osteogenic markers. Results: Both materials supported MSC adhesion and proliferation, confirming cytocompatibility. Under control conditions, T-Ti significantly increased alkaline phosphatase activity and osteogenic gene expression. Under osteogenic stimulation, T-Ti accelerated differentiation and mineralized matrix deposition. CrCo exhibited limited stimulation of the osteogenic-supportive microenvironment and delayed differentiation responses. Conclusions: Trabecular titanium, in terms of morphology and topology, provides a biologically active scaffold that both induces and conducts osteogenic differentiation of human MSCs, whereas CrCo acts primarily as a mechanically optimized but biologically passive material. These findings support the use of trabecular titanium at bone-contact interfaces in joint prostheses to enhance osteointegration and potentially improve long-term implant stability. Full article
(This article belongs to the Special Issue Joint Prostheses: Innovations in Shoulder, Hip, and Knee Replacement)
18 pages, 1115 KB  
Systematic Review
Comparative Efficacy and Safety of Intra-Articular Adipose-Derived, Bone Marrow-Derived, and Peripheral Blood-Derived Stem Cell Injections for Knee Osteoarthritis: A Systematic Review
by Se Yeong Jeon, Min Woo Kim and Dong Ha Lee
Bioengineering 2026, 13(7), 771; https://doi.org/10.3390/bioengineering13070771 - 1 Jul 2026
Viewed by 230
Abstract
Background: Intra-articular (IA) stem cell injection is an emerging treatment for knee osteoarthritis (KOA). Three principal cell sources—adipose-derived mesenchymal stem cells (ADMSCs), bone marrow-derived MSCs (BMMSCs), and peripheral blood-derived stem cells (PBSCs)—have been evaluated independently; however, a systematic review comprehensively comparing all [...] Read more.
Background: Intra-articular (IA) stem cell injection is an emerging treatment for knee osteoarthritis (KOA). Three principal cell sources—adipose-derived mesenchymal stem cells (ADMSCs), bone marrow-derived MSCs (BMMSCs), and peripheral blood-derived stem cells (PBSCs)—have been evaluated independently; however, a systematic review comprehensively comparing all three sources under unified eligibility criteria is absent from the literature. Methods: Systematic searches of MEDLINE, Embase, Cochrane CENTRAL, and Scopus were conducted from inception to December 2025, supplemented by manual reference screening and ClinicalTrials.gov. Eligible studies included randomized controlled trials (RCTs) and prospective comparative studies in adult KOA patients. Primary outcomes were pain (VAS/NRS) and function (WOMAC, KOOS) at ≥3 months. Risk of bias was assessed using RoB 2 and ROBINS-I; evidence certainty was rated using GRADE. Results: Thirty-one studies (n = 1247; ADMSC: 14 studies, n = 612; BMMSC: 12 studies, n = 487; PBSC: 5 studies, n = 148) met inclusion criteria. Pooled standardized mean differences (SMDs) for 6-month pain showed significant reduction versus comparators for ADMSCs (SMD −1.23; 95% CI −1.61 to −0.85; I2 = 62%) and BMMSCs (SMD −1.09; 95% CI −1.55 to −0.63; I2 = 70%). PBSCs demonstrated significant within-group improvement but were too few for formal pooling. Because no trial compared cell sources head-to-head, these estimates reflect within-source efficacy versus each study’s own comparator rather than comparative superiority between sources. Adverse events were mild and transient across all sources. GRADE certainty was moderate for ADMSCs, low for BMMSCs, and very low for PBSCs. Conclusions: IA injection of ADMSCs and BMMSCs provides pain reduction and functional improvement in KOA with point estimates reaching minimal clinically important difference thresholds, although the certainty of this evidence is only moderate (ADMSC) to low (BMMSC). PBSC evidence is insufficient for formal comparison. Adequately powered, three-arm head-to-head RCTs that share a common comparator and a core outcome set are needed to establish comparative efficacy. Because only indirect comparisons were possible, this review supports efficacy within each cell source but cannot establish the superiority of one source over another. Full article
(This article belongs to the Section Regenerative Engineering)
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16 pages, 5494 KB  
Article
Prosthesis-Based 3D Guide System for Maxillary Implant Placement: A Feasibility Study Using a Split-Mouth Evaluation
by Marco Tudts, Tashia Moodley, Rani D’haese and Stefan Vandeweghe
Dent. J. 2026, 14(7), 395; https://doi.org/10.3390/dj14070395 - 1 Jul 2026
Viewed by 143
Abstract
Background/Objectives: To evaluate the clinical feasibility and short-term radiographic outcomes of adapting a prosthesis-based guide system originally developed for single-implant placement for multi-implant placement in the edentulous maxilla, and to compare implant-level marginal bone change from prosthetic loading to one year between full-rough [...] Read more.
Background/Objectives: To evaluate the clinical feasibility and short-term radiographic outcomes of adapting a prosthesis-based guide system originally developed for single-implant placement for multi-implant placement in the edentulous maxilla, and to compare implant-level marginal bone change from prosthetic loading to one year between full-rough (IBT/IBNT/IBR) and hybrid-surface (MSC-IBT/MSC-IBNT) implants in a split-mouth design. Patient-reported outcomes were assessed with the OHIP-14 questionnaire. Methods: Fifteen patients with an edentulous maxilla received four or five maxillary implants placed flaplessly using a 3D-printed prosthesis-based guide incorporating polyether-ether-ketone (PEEK) rails and interchangeable angulation-correction sleeves (0°, 12°, 24°). Implants had either a fully roughened or a hybrid (rough apical and middle third with a machined coronal collar) surface. Side allocation was non-randomized: the hybrid side was assigned by alternating sequence and three patients received only full-rough implants for prosthetic reasons. All patients followed a delayed loading protocol and received a screw-retained zirconia fixed bridge. Standardized periapical radiographs were obtained at definitive prosthetic loading (baseline) and at the 12-month follow-up. Implant-level marginal bone loss was calculated as the mean of mesial and distal measurements per implant. All radiographic measurements were performed by two independent examiners (M.T. and T.M.); intra-rater reliability (M.T., remeasurement of 10 radiographs) and inter-rater reliability (M.T. versus T.M., full dataset) were quantified by intraclass correlation coefficient (ICC; two-way mixed effects, absolute-agreement, single-measurement). The primary split-mouth surface comparison was performed at the patient level by averaging implant-level change scores within each surface for each patient and comparing the paired patient-level means with a Wilcoxon signed-rank test. No a priori sample-size calculation was performed; the study was designed as a feasibility pilot. Results: Sixty-one implants were placed in 15 patients (seven male, eight female; mean age 62.5 ± 8.9 years; three current smokers). Four implants in three patients required removal and replacement during the observation period (three early failures, one late failure; per-implant early-failure rate of 3/61, 4.9%); one patient (P7) withdrew from clinical follow-up. Paired baseline and 12-month radiographs were available for 53 implants from 14 patients. Median implant-level marginal bone level increased from 0.38 mm (IQR 0.20–0.54) at baseline to 0.78 mm (IQR 0.47–1.32) at 12 months (paired Wilcoxon signed-rank, p < 0.001); two implants exceeded 4 mm of bone change at 12 months. In the patient-level paired surface comparison (n = 8 patients contributing at least one full-rough and one hybrid implant with paired data), full-rough implants showed less 12-month marginal bone change than hybrid implants in every paired patient (median paired difference full-rough hybrid of −0.49 mm; Hodges–Lehmann pseudo-median of 0.55 mm; paired Wilcoxon p = 0.012). OHIP-14 scores at one year (n = 14) showed a pronounced floor effect, with most patients scoring zero across most domains. Both intra-rater (M.T.) and inter-rater (M.T. versus T.M.) reliability showed good agreement (ICC = 0.85). Conclusions: A prosthesis-based guide system originally validated for single-implant placement can be feasibly adapted for flapless multi-implant rehabilitation of the edentulous maxilla, with early clinical and radiographic outcomes broadly consistent with comparable published series. Contrary to the design rationale that a machined coronal collar would limit early crestal remodeling, full-rough implants showed less 12-month within-patient bone change than hybrid implants in the eight paired patients; this finding is preliminary and hypothesis generating given the small, unbalanced paired sample and the contrast with larger published series. The approach is best characterized as a reduced infrastructure alternative to proprietary guided-surgery platforms, remains operator dependent, and requires confirmation in formally powered, balanced split-mouth trials with concealed allocation, placement anchored bone level measurement, postoperative CBCT for deviation quantification, and longer follow-up. Full article
(This article belongs to the Section Dental Implantology)
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21 pages, 8592 KB  
Article
Scalable Isolation of Human Umbilical Cord MSC-Derived Exosomes and Their Therapeutic Potential in Osteoarthritis
by Chao Zhou, Shimei Wu, Yanyi Zeng, Xueyan Liu, Shiye Wu, Ke Chen, Junrong Wu, Haibin Yin and Yuanyuan Zhou
Bioengineering 2026, 13(7), 770; https://doi.org/10.3390/bioengineering13070770 - 30 Jun 2026
Viewed by 203
Abstract
Osteoarthritis (OA) is a prevalent degenerative joint disorder characterized by cartilage degradation, synovial inflammation, and osteophyte formation, yet effective therapies that alter disease progression remain absent. Mesenchymal stem cell-derived exosomes (MSC-EXOs), as a cell-free regenerative medicine strategy, have shown great potential in the [...] Read more.
Osteoarthritis (OA) is a prevalent degenerative joint disorder characterized by cartilage degradation, synovial inflammation, and osteophyte formation, yet effective therapies that alter disease progression remain absent. Mesenchymal stem cell-derived exosomes (MSC-EXOs), as a cell-free regenerative medicine strategy, have shown great potential in the treatment of osteoarthritis. In this study, we successfully isolated and purified exosomes derived from human umbilical cord mesenchymal stem cells using a scalable tangential flow filtration (TFF)–chromatography platform and evaluated their therapeutic effects on OA model induced by anterior cruciate ligament transection (ACLT). OARSI scores were significantly reduced compared with the ACLT group (p < 0.01). Exosomes administration markedly reduced osteophyte formation, preserved cartilage structure, enhanced collagen II expression (p < 0.01), and suppressed MMP13-mediated matrix degradation (p < 0.05) compared with the ACLT group. The treatment also significantly decreased pro-inflammatory cytokines, indicating alleviation of the inflammatory microenvironment. Transcriptomic profiling further revealed genes and pathways potentially associated with exosome treatment. These findings suggest that hUC-MSC-EXOs isolated and purified using TFF–chromatography exert robust chondroprotective and immunomodulatory effects, supporting their potential as an effective cell-free therapeutic candidate for OA. Full article
(This article belongs to the Special Issue Cell Therapy and Tissue Engineering for Orthopedic Applications)
23 pages, 10195 KB  
Article
Comparative Thermodynamic Analysis of CO2 Refrigeration Cycles with Internal Heat Exchanger, Mechanical Subcooling, and Ejector Configurations
by Muhsin Kılıç and Orhan Mert Duraner
Appl. Sci. 2026, 16(13), 6503; https://doi.org/10.3390/app16136503 - 30 Jun 2026
Viewed by 217
Abstract
This study presents a comparative thermodynamic assessment of four widely used CO2 refrigeration configurations, namely, the basic cycle (BC), internal heat exchanger cycle (IHEX), mechanical subcooling cycle (MSC), and ejector cooling cycle (ECS), operating under both subcritical and transcritical conditions. The investigated [...] Read more.
This study presents a comparative thermodynamic assessment of four widely used CO2 refrigeration configurations, namely, the basic cycle (BC), internal heat exchanger cycle (IHEX), mechanical subcooling cycle (MSC), and ejector cooling cycle (ECS), operating under both subcritical and transcritical conditions. The investigated systems were analyzed using validated numerical models developed in the Engineering Equation Solver (EES) under evaporating temperatures ranging from −30 °C to +5 °C and gas cooler temperatures ranging from 30 °C to 50 °C. For each operating condition, the refrigeration cycles were thermodynamically optimized in order to maximize the coefficient of performance (COP). The results indicate that an increasing gas cooler temperature significantly reduces the COP of all investigated systems, whereas an increasing evaporating temperature improves cycle performance. Among the investigated configurations, the MSC system exhibited the highest thermodynamic performance improvement, particularly under severe transcritical operating conditions characterized by high gas cooler temperatures and low evaporating temperatures. The ECS configuration also provided considerable performance enhancement by reducing throttling-related thermodynamic losses and compressor pressure ratio. In contrast, the IHEX configuration yielded comparatively moderate but relatively stable performance improvement with lower system complexity. In addition to the thermodynamic comparison, a simplified engineering-oriented practical assessment framework based on a relative cost index (RCI) was introduced to comparatively evaluate implementation complexity, control requirements, maintenance considerations, and relative investment burden of the investigated systems. The results indicate that, although the MSC configuration provides the highest thermodynamic performance, it is also associated with the highest implementation complexity and relative investment requirement, whereas the IHEX configuration offers a simpler and lower-cost alternative with moderate performance enhancement. The present study provides engineering-oriented comparative guidance regarding the thermodynamic performance, practical applicability, and operational suitability of advanced CO2 refrigeration systems under varying climatic and operational conditions. Full article
(This article belongs to the Special Issue Advances in Thermal Engineering: From Fundamentals to Applications)
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35 pages, 2371 KB  
Review
Transcriptomics Insights into Spinal Cord Injury for Therapy Development
by Daria Chudakova, Olga Astakhova, Matthew Shkap, Ekaterina Levichkina, Alesya Soboleva, Artur Biktimirov and Vladimir Baklaushev
Int. J. Mol. Sci. 2026, 27(13), 5870; https://doi.org/10.3390/ijms27135870 - 29 Jun 2026
Viewed by 167
Abstract
Traumatic spinal cord injury (SCI) is a severe medical condition, often resulting in permanent disability, with significant impacts on patients’ quality of life and burden on healthcare systems. Current therapeutic approaches for SCI are insufficient, advocating for the development of more effective treatments. [...] Read more.
Traumatic spinal cord injury (SCI) is a severe medical condition, often resulting in permanent disability, with significant impacts on patients’ quality of life and burden on healthcare systems. Current therapeutic approaches for SCI are insufficient, advocating for the development of more effective treatments. As changes in transcriptome post-SCI can provide clues for novel treatment strategies and targets, substantial efforts have been made recently to characterize such transcriptional changes and their spatiotemporal features. This narrative review focuses on how transcriptomics, alone or in combination with other omics data, can contribute to understanding SCI pathobiology and the mechanisms of post-SCI regeneration and guide the development of novel SCI therapies. It covers an arsenal of tools for transcriptomics studies and provides a concise summary of findings from the latest relevant studies (predominantly from 2020 to 2025), representing the major directions in the field. Full article
18 pages, 2539 KB  
Article
Differential Effects of Mesenchymal Stem Cell- and Natural Killer Cell-Derived Extracellular Vesicles on Cisplatin Responsiveness in Endometrial Cancer Cells
by Ren-Jun Hsu, Cheng-Shuo Huang, Ming-Kung Yeh, Zheng-Zong Lai, Cheng-Ping Yu, Jar-Yi Ho and Fung-Wei Chang
Int. J. Mol. Sci. 2026, 27(13), 5842; https://doi.org/10.3390/ijms27135842 - 28 Jun 2026
Viewed by 176
Abstract
Cisplatin (cis-diamminedichloroplatinum(II) [DDP]) is a key chemotherapeutic agent for advanced endometrial cancer; however, chemoresistance substantially limits its clinical benefit. Extracellular vesicles (EVs) mediate intercellular communication and influence tumour cell behaviour and therapeutic response. We investigated whether mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) and [...] Read more.
Cisplatin (cis-diamminedichloroplatinum(II) [DDP]) is a key chemotherapeutic agent for advanced endometrial cancer; however, chemoresistance substantially limits its clinical benefit. Extracellular vesicles (EVs) mediate intercellular communication and influence tumour cell behaviour and therapeutic response. We investigated whether mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) and natural killer cell-derived extracellular vesicles (NK-EVs) modulate cisplatin responsiveness in endometrial cancer cells (RL95-2 and HEC-1A). MSC-EVs and NK-EVs were isolated and characterised using nanoparticle tracking analysis, scanning electron microscopy, and EV marker profiling. MSC-EVs and NK-EVs reduced RL95-2 and HEC-1A cell viability in a dose-dependent manner, with MSC-EVs exhibiting substantial effects at lower particle concentrations. In a cisplatin-resistant HEC-1A (HEC-1A DDP-R) model, MSC-EVs were associated with greater reductions in cell viability under cisplatin treatment conditions, whereas NK-EVs showed comparatively modest effects. Mechanistic analyses demonstrated altered expression of apoptosis- and cell cycle–related proteins, including increased cleaved poly(ADP-ribose) polymerase and cleaved caspase-3 levels and reduced cyclin A and cyclin D1 expression following MSC-EV treatment. Annexin V-fluorescein isothiocyanate/propidium iodide flow cytometry demonstrated increased apoptotic cell populations after MSC-EV treatment, with MSC-EV + DDP co-treatment resulting in the highest apoptotic fraction in chemoresistant HEC-1A cells. Collectively, these findings indicate that MSC-EVs are associated with altered cellular responses to cisplatin in chemoresistant endometrial cancer cells, accompanied by changes in apoptosis-related protein expression, apoptotic cell populations, and cell-cycle regulators. Further investigation is required to determine their mechanistic role and therapeutic potential in overcoming chemoresistance. Full article
29 pages, 1707 KB  
Article
Chondrogenic Potential of Human Adipose-Derived Stem/Stromal Cells (hAD-MSCs) and Human Dental Pulp Stem/Stromal Cells (hDPSCs) Growing on a Poly L-Lactide-Co-Caprolactone Scaffold (PLCL)
by Julia K. Bar, Aleksandra Klimczak, Piotr G. Grelewski, Anna Lis-Nawara, Sandra Stamnitz, Tomasz Kowalczyk, Kinga Demska, Maria Paprocka and Hanna Gerber
Cells 2026, 15(13), 1168; https://doi.org/10.3390/cells15131168 - 26 Jun 2026
Viewed by 155
Abstract
Cartilage engineering is a new therapeutic approach in regenerative medicine. This study explored the chondrogenic potential of human dental pulp stem/stromal cells (hDPSCs) and adipose-derived stem/stromal cells (hAD-MSCs) grown on a hydrolytically modified poly(L-lactide-co-caprolactone) (PLCL) electrospun scaffold in relation to the phenotype of [...] Read more.
Cartilage engineering is a new therapeutic approach in regenerative medicine. This study explored the chondrogenic potential of human dental pulp stem/stromal cells (hDPSCs) and adipose-derived stem/stromal cells (hAD-MSCs) grown on a hydrolytically modified poly(L-lactide-co-caprolactone) (PLCL) electrospun scaffold in relation to the phenotype of primary chondrocytes on PLCL. The effects of PLCL scaffold on the biological features of hDPSC, hAD-MSC, and their chondrogenic differentiation and chondrocytes biology were evaluated via flow cytometry, immunochemistry, biochemistry, and RT‒PCR. The results demonstrated that PLCL supported hDPSC, hAD-MSC, and chondrocyte viability and cellular attachment. The chondrogenic potential of hDPSCs and hAD-MSCs on PLCL scaffold was evidenced by the mRNA expression of the cartilage-specific genes. Collagen type II (Col II) and aggrecan (Acan) gene expression and their proteins significantly increased in chondrogenically differentiated hDPSCs and hAD-MSCs on PLCL compared with undifferentiated stem/stromal cells on PLCL. The phenotype of differentiated hDPSCs and hAD-MSCs was comparable to primary chondrocytes grown on PLCL. The results of this study showed that PLCL scaffold promoted chondrogenic differentiation of hAD-MSCs and hDPSCs toward chondrocytes with phenotypic similarities to native chondrocytes. The PLCL scaffold composition has a positive effect on hDPSC, hAD-MSC, and chondrocyte behavior, chondrogenic gene expression, and matrix protein synthesis. Full article
(This article belongs to the Special Issue Stem Cells and Beyond: Innovations in Tissue Repair and Regeneration)
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