Implant-related infections reduce mesenchymal stem cell accumulation near implant sites while suppressing the viability and osteogenic capacity of these stem cells. Here, we show that pH-responsive biomaterial interfaces exploit infection-induced acidification to coordinate antimicrobial action with stem and immune cell functional reprogramming. The system can release bactericidal peptides for direct bacterial elimination, whereas indirect bactericidal enhancement occurs in the presence of magnesium ions and cell-targeting peptides, which enable a positive modulation of immune responses and recruitment of bone marrow mesenchymal stem cells, respectively. This feature results in robust osteogenic differentiation at the implant interfaces, achieving a 280% increase in the interfacial bone volume in rat infection models. Through transcriptomic analysis, we also show that Wnt-activated stem cells and alternatively activated macrophages jointly upregulate antimicrobial effector programs along with osteogenic genes, contributing to the observed >4-log bacterial reduction through combined material- and cell-mediated suppression. The coordinated infection clearance and interface regeneration demonstrate that infection-responsive biomaterials can transform endogenous cells to bifunctional therapeutic agents, defining a strategy that addresses infection and regeneration as integrated biological processes.

Cancer cachexia leads to decreases in body mass, lean mass and fat mass, decreased therapeutic potential and ~20% of cancer-related deaths. While several studies have demonstrated changes to components of the muscle microenvironment with cancer cachexia, none have comprehensively assessed changes to cellular dynamics across the duration of cachexia development.

Successful hematopoietic stem cell transplantation relies on the collection of a sufficient number of CD34+ hematopoietic progenitor cells (HPCs). While acid citrate dextrose solution A (ACD-A) is a common anticoagulant (AC) for HPC apheresis [HPC(A)], recent evidence suggests that concomitant heparin may enhance intra-apheresis recruitment (IAR) of CD34+ cells and improve collection efficiency. This study aimed to compare citrate-only and citrate-heparin protocols in routine HPC(A) procedures, with a focus on their effects on IAR and efficiency outcomes. A retrospective analysis was performed on 266 HPC(As) from 193 apheresis donors in autologous and allogeneic settings. Donor demographics, procedural parameters, and collection outcomes were compared between the ACD-A-only and ACD-A plus heparin protocols. The study endpoints included apheresis yield (AY/kg), collection efficiencies (CE1, CE2, and cruCE), recruitment ratio (RR), and performance ratio (PR). Statistical analyses included Mann-Whitney U tests, effect sizes, and partial least squares (PLS) regression. Heparinized procedures demonstrated higher processed total blood volume ratios, lower AC volumes, and superior outcomes across CE1 (83.8% vs. 72.5%, p = 0.00027), CE2 (70.8% vs. 64.2%, p = 0.0055), cruCE (77.0% vs. 72.4%, p < 0.0001), RR (2.3 vs. 1.7, p < 0.0001), PR (239.3% vs. 208.2%, p < 0.0001), and AY/kg (6.75 vs. 5.23 × 106 CD34+ cells/kg, p = 0.0025). The effect size and PLS analyses confirmed the contribution of heparin as an adjunct AC enhancing multiple apheresis outcomes. In summary, citrate-heparin anticoagulation was found to be a feasible strategy that improved key collection efficiency and IAR metrics during HPC(A).

Laceration is one of the most common meniscus injuries, which can cause knee joint dysfunction. The treatment of meniscus injuries remains one of the greatest challenges in orthopedics. In this study, a three-dimensional sponge-like Poly(lactic acid)/Poly(3-hydroxybutyrate-co-4-hydroxybutyrate) (PLA/P(3HB-co-4HB)) scaffold with oriented microtubules was fabricated using an improved gradient thermal phase separation technique. The scaffold surface was modified by adsorbing gelatin. The surface-modified scaffolds and the unmodified scaffolds were divided into two groups. All preparation parameters were adjusted to meet tissue engineering requirements. The prepared scaffolds were tested for porosity, compression modulus, hydrophilicity, and degradability. Following scaffold preparation, induced differentiated rabbit bone marrow mesenchymal stem cells (BMSCs) were seeded to evaluate scaffold cytocompatibility. Cell proliferation was observed in the two scaffold groups, and cell viability was analyzed using CCK-8 assay, scanning electron microscopy (SEM), and confocal microscopy. Histological staining was performed to comparatively study cell synthetic function. Subsequently, tissue reconstruction and regeneration were evaluated following subcutaneous implantation of gelatin/PLA/P(3HB-co-4HB) scaffolds loaded with induced differentiated BMSCs in the dorsal regions of athymic nude mice. Results demonstrated that the gelatin/PLA/P(3HB-co-4HB) scaffold exhibited good cell compatibility, providing a suitable microenvironment for cell proliferation and differentiation. Furthermore, the scaffold supported the growth of seeded induced differentiated rabbit MSCs in vivo, maintaining meniscus cell phenotyping and function. The cell-laden scaffold has the potential to generate meniscus fibrocartilage.

Background and Objectives: Soft tissue regeneration in oral surgery has undergone remarkable progress in the last decade, supported by the development of innovative laser technologies, advanced biomaterials, platelet-rich plasma (PRP), mesenchymal stem cells (MSCs), and three-dimensional (3D) printing. Lasers are increasingly used not only for incision and coagulation but also for photobiomodulation, promoting cellular proliferation, angiogenesis, and tissue healing. The purpose of this review is to analyze the current advances in soft tissue regeneration, with a particular focus on the clinical use of lasers and their integration with other regenerative strategies. In parallel, hard tissue regeneration has evolved through the synergistic use of bioactive scaffolds, recombinant human growth factors (rhBMP-2, rhPDGF-BB), MSCs, and 3D-printed constructs. These innovations have enhanced alveolar bone regeneration, implant osseointegration, and periodontal tissue repair, offering predictable clinical outcomes. Materials and Methods: A review of the literature published between 2015 and 2025 was conducted through PubMed, Scopus, Web of Science, Embase, and Google Scholar. Clinical and preclinical studies on the use of CO2, Nd:YAG, Er:YAG, diode, and 445 nm lasers, biomaterials, PRP, MSCs, growth factors, and 3D-printed scaffolds were included. Results: Laser applications demonstrated significant benefits in epithelialization, biostimulation, and reduction in postoperative discomfort in soft tissues. For hard tissues, the combined use of MSCs, bioactive scaffolds, and growth factors promoted osteogenic differentiation, bone volume preservation, and improved mechanical stability. Photobiomodulation enhanced osteoblastic activity and accelerated bone remodeling, while 3D-printed scaffolds provided personalized architecture for optimal integration. Conclusions: Regenerative approaches integrating lasers, biomaterials, PRP, MSCs, growth factors, and 3D printing represent safe, minimally invasive, and effective strategies for the regeneration of both soft and hard oral tissues. These multidisciplinary techniques improve healing quality, functional recovery, and esthetic outcomes, reflecting the growing trend toward precision and technology-driven regenerative oral surgery.

The provincial-level registered superior cultivar Camellia chekiangoleosa 'Ganhongyou 1' boasts superior economic traits coupled with significant ornamental value, driving demand for an efficient propagation system. Consequently, this study aimed to develop a rapid micropropagation protocol by investigating culture conditions using semi-woody nodal segments with axillary buds as explants on Hyponex basal medium supplemented with varying combinations of plant growth regulators. Contamination was effectively minimized to 18% by a combined approach of surface sterilization (75% ethanol, 0.1% HgCl2, and 20% NaClO) and incorporating 1 mL/L bactericide into the induction medium. For bud induction, the optimal medium was 2 g/L Hyponex supplemented with 1.0 mg/L 6-benzylaminopurine (6-BA) and 0.2 mg/L indole-3-acetic acid (IAA), achieving an 86.67% induction rate. The best proliferation was achieved on the medium containing 2 g/L Hyponex, 1.0 mg/L 6-BA, 0.15 mg/L 3-indolebutyric acid (IBA), and 0.5 mg/L gibberellic acid (GA3), yielding a proliferation coefficient of 6.53. A combined strategy, integrating in vitro pre-culture with ex vitro treatment, proved most effective for rooting and acclimatization: shoots were first pre-cultured for 20 days on 1/2 strength Hyponex medium supplemented with 0.5 mg/L 1-naphthaleneacetic acid (NAA) and 2.0 mg/L IBA, followed by ex vitro base treatment with 1.0 g/L ABT (a rooting powder complex) solution before transplantation into seedling bags. This approach resulted in an 88% survival rate. Furthermore, anatomical analysis revealed the origin of adventitious root primordia from phloem parenchyma cells, thereby confirming a phloem-rooting pattern for this species. In conclusion, this study establishes a practical and efficient micropropagation protocol for 'Ganhongyou 1', providing a reliable technical foundation for its commercial-scale seedling production.

Oral squamous cell carcinoma (OSCC) represents a major global health burden and remains one of the most prevalent and aggressive malignancies of the head and neck region. Despite significant advances in surgical techniques, chemotherapy, and radiotherapy, patient outcomes have improved only modestly over recent decades. The high recurrence rate, metastatic potential, and resistance to therapy underscore the complexity of OSCC biology and the limitations of conventional treatment approaches. In recent years, the concept of cancer stem cells (CSCs) has reshaped the understanding of tumor initiation, progression, and therapeutic failure in OSCC. These cells, characterized by self-renewal capacity and phenotypic plasticity, are believed to sustain tumor growth, drive recurrence, and mediate resistance to therapy. Parallel to this, insights into epigenetic regulation, including DNA methylation, histone modifications, and non-coding RNAs, have revealed new layers of molecular heterogeneity and adaptability in oral carcinogenesis. The integration of CSC biology with epigenetic modulation offers a promising foundation for the development of targeted and personalized therapeutic strategies. Novel approaches aim to eradicate CSCs, induce their differentiation, or reprogram their malignant phenotype through the use of epigenetic inhibitors and molecular modulators. This review summarizes current knowledge on the molecular and cellular mechanisms driving OSCC pathogenesis, highlights the emerging role of CSCs and epigenetic regulators, and discusses the challenges and perspectives of translating these findings into effective clinical therapies.

Background: Preterm birth is a leading cause of neonatal mortality and long-term disability worldwide. Injury in premature infants is demonstrated by disrupted organ development from inflammation, oxidative stress, hypoxia, and impaired vascular maturation. Current therapies largely provide supportive care and do not directly promote tissue regeneration. Mesenchymal stem cell (MSC)-based therapies have emerged as a potential strategy to enhance endogenous repair across organ systems commonly affected by prematurity. Results: Evidence indicates that MSCs exert therapeutic effects primarily through transient paracrine signaling rather than long-term engraftment. Following administration, MSCs release cytokines, growth factors, and extracellular vesicles that reduce inflammation, promote angiogenesis, and support tissue repair. In preclinical models of neonatal brain injury, MSC therapy has been associated with improved oligodendrocyte maturation and reduced white matter injury. Early clinical trials in neonatal encephalopathy demonstrate feasibility and short-term safety of both autologous and allogeneic cell products. However, studies remain limited by small sample sizes and short follow-up. Cell-free approaches using MSC-derived extracellular vesicles may offer similar biological benefits with potentially lower safety and regulatory concerns. Conclusions: MSC-based therapies represent a promising regenerative approach for complications of prematurity. Rigorous, large-scale trials with standardized protocols and long-term follow-up are necessary to clarify efficacy, optimize delivery strategies, and define safety in this vulnerable population.

Background: Advanced therapy medicinal products (ATMPs) require strict control of critical process parameters (CPPs) to ensure manufacturing efficiency. The relative impact of donor systemic factors, such as vitamin D status, versus technical process parameters on dental pulp-derived stem cell (DPSC) production remains unclear. Methods: In this prospective observational study, 250 adults undergoing extraction of impacted mandibular third molars were included. Dental pulp was processed under a standardized SOP using different preparation methods and enzyme conditions. Primary endpoints were serum 25(OH)D concentration and cell yield; secondary endpoints included number of passages and cryovials. Results: Mean 25(OH)D concentration was 30.1 ± 14.5 ng/mL and was higher in supplemented individuals (38.2 ± 14.0 vs. 25.6 ± 12.7 ng/mL; p < 0.0001) but was not associated with cell yield (ρ = 0.14, p = 0.168) or passages (ρ = 0.07, p = 0.406). In contrast, process parameters showed strong effects: scissor preparation resulted in a substantially higher yield than mechanical methods (median 5.00 vs. 1.00 million cells; p = 3.6 × 10-13), and type II collagenase was independently associated with a higher yield (+2.04 million cells; p = 0.026). The number of passages was the strongest predictor of yield (β = 2.28 million per passage; p < 10-26). Post-thaw viability remained high (mean 90.1% and range 81-98%). Conclusions: Manufacturing efficiency of DPSCs is primarily determined by critical process parameters, particularly preparation method, enzyme selection, and passage control, whereas donor vitamin D status did not significantly influence outcomes under the studied SOP. These findings highlight process standardization as the key driver of reproducible ATMP manufacturing.

Background: Despite extensive preclinical evidence that statins enhance osteogenesis and the widespread clinical use of platelet-rich fibrin (PRF), the clinical effectiveness of statin-incorporated PRF (SIM-PRF) in limiting peri-implant crestal bone loss remains insufficiently validated. Objectives: To address the mentioned gap, we integrated in vitro assays on human periodontal ligament stem cells (hPDLSCs) with a controlled clinical trial to test whether SIM-PRF reduces early and 12-month marginal bone loss versus PRF alone and PRF with bone graft. Methods: In vitro, cytotoxicity, migration and osteogenic differentiation were assessed, in addition to the effect on basal inflammatory markers. Clinically, 24 immediate-implant cases were randomized to receive PRF, PRF+SIM, or PRF+bone graft, with CBCT-based crestal bone change measured at 0-3, 3-6, and 6-12 months. Results: Flow cytometry confirmed the mesenchymal identity of the isolated hPDLSCs, which exhibited dose-dependent responses to SIM treatment. Lower SIM concentrations (0.1 μM) enhanced osteogenic differentiation, as evidenced by increased mineralization, alkaline phosphatase activity, and expression of osteogenic markers (RUNX2 and osteocalcin), while maintaining cell viability and migration. Both SIM concentrations (0.1 μM and 1 μM) significantly reduced basal pro-inflammatory cytokine expression (TNF-α and IL-6). Radiographic analysis revealed significantly reduced crestal bone loss (p < 0.001) in the PRF-SIM and PRF-Bone groups compared to PRF alone, particularly during early postoperative intervals (0-3 and 3-6 months). Notably, no significant difference was observed between the PRF-SIM and PRF-Bone groups (p > 0.05) in preserving the peri-implant bone. Conclusions: These findings highlight the potential of SIM-loaded PRF as an effective, biocompatible, and patient-friendly approach to enhance bone regeneration and implant success.

Background/Objectives: Toothpaste ingredients such as strontium chloride (SrCl2) and potassium carbonate (K2CO3) are recognized for their desensitizing and remineralizing effects but may be absorbed through the oral mucosa. Their potential cytotoxic and cardiotoxic properties, however, remain inadequately characterized. Here, we investigated the effects of SrCl2 and K2CO3 on mouse-induced pluripotent stem cells (iPSCs) and iPSC-derived cardiomyocytes (iPSC-CMs). Methods: Cells were exposed to varying concentrations of each compound for up to 72 h. Real-time cell analysis (xCELLigence RTCA Cardio system) was used to assess proliferation, and flow cytometry was used to evaluate cell viability. Functional properties of iPSC-CMs were examined using multi-electrode array (MEA) recordings and xCELLigence-based impedance measurements. Cardiac marker expression was examined via immunofluorescence and quantitative RT-PCR. Results: Both SrCl2 and K2CO3 affected iPSC proliferation and reduced viability in a dose- and time-dependent manner, accompanied by altered embryoid body (EB) morphology and increased cell death. In iPSC-CMs, both compounds downregulated key cardiac genes and disrupted spontaneous beating activity, with effects intensifying at higher concentrations. Conclusions: These results demonstrate that SrCl2 and K2CO3 induced dose-dependent cytotoxic and arrhythmogenic effects on iPSCs and iPSC-CMs. At elevated concentrations, these compounds impair iPSC-CM function and may pose safety concerns upon chronic exposure. Further mechanistic and long-term in vivo studies are warranted to assess their potential cardiotoxic risk in consumer oral care products.

Background/Objectives: Bone marrow adipose tissue (BMAT) serves multiple physiological roles but accumulates with age, compromising skeletal health. This expansion is largely driven by an adipogenic drift of bone marrow mesenchymal stromal cells (BMSCs), shifting attention toward stromal cell fate regulation as a target to preserve bone marrow homeostasis. Preventing adipogenic commitment may be as relevant as directly inducing osteogenesis for maintaining a bone-permissive marrow microenvironment. Here, we investigated whether olive leaf extract (OLE) and its purified secoiridoid components, oleacin (OC) and oleuropein aglycone (OA), modulate the adipogenic differentiation and proliferative capacity of human BMSCs. Methods: Human BMSCs were induced to undergo adipogenic differentiation and treated with OLE, OC, or OA. Intracellular lipid accumulation and the expression of key adipogenic regulators were assessed. Proliferative capacity was evaluated under both maintenance and adipogenic conditions. Results: Under adipogenic conditions, OLE markedly reduced intracellular lipid accumulation and induced a coordinated downregulation of PPARγ, PLIN1, FABP4, ADIPOQ, LEP and the adipogenesis-associated miR-422a. In contrast, OC and OA exerted more selective and specific effects on biomarkers, indicating the partial and complementary modulation of adipogenic programs. Notably, OLE also increased BMSC proliferation under both maintenance and adipogenic conditions, suggesting the preservation of a less committed stromal cell pool. Although the relative contribution of enhanced proliferation versus the direct inhibition of adipogenic pathways cannot be fully disentangled, the combined molecular and functional data support a dual action of OLE on stromal cell fate. Conclusions: OLE limits adipogenic commitment while maintaining stromal cell proliferative competence, processes that are critically involved in BMAT expansion and bone marrow dysfunction. OC and OA contribute to OLE bioactivity deserving further investigation, particularly in combination, as potential modulators of BMAT expansion.

Acute myeloid leukemia (AML) remains a therapeutically challenging malignancy due to high relapse rates driven by leukemic stem cells (LSCs) and adaptive resistance mechanisms. Emerging evidence positions autophagy as a central regulator of AML pathobiology, exerting context-dependent effects that suppress leukemogenesis during disease initiation yet sustain LSC survival and chemoresistance in established AML. Mechanistically, autophagy integrates mitochondrial quality control, lipid droplet turnover, and metabolic rewiring to support oxidative phosphorylation, particularly under hypoxic bone marrow conditions. Lipophagy-driven fatty acid oxidation has emerged as a key metabolic vulnerability distinguishing LSCs from normal hematopoietic stem cells. Furthermore, non-coding RNAs critically modulate autophagy networks, reinforcing therapy resistance. Preclinical and clinical studies demonstrate that both inhibition and activation of autophagy may yield therapeutic benefit depending on genetic context, mutational landscape, and disease stage. We propose that integrating multi-omics approaches, particularly lipidomics, with artificial intelligence and machine learning will enable precise identification of autophagy-dependent AML subsets. Rational, biomarker-guided modulation of autophagy may overcome resistance while preserving normal hematopoiesis, offering a path toward personalized metabolic targeting in AML.

Objectives: pH-responsive zeolite imidazolate framework-8 (ZIF-8) enables selective release of 5-fluorouracil (5-FU) within the acidic tumor microenvironment. However, the direct effects of ZIF-8 itself on cancer cells or surrounding tissues remain unclear. Since oral cancer involves interactions between epithelial tumor cells and stromal cells, comparing the effects of ZIF-8 on epithelial cancer cells and orofacial mesenchymal stem/stromal cells (OMSCs) is critical to understanding its broader biological impact. Methods: The effects of ZIF-8 on SCC7 epithelial cancer cells and OMSCs, including periodontal ligament stem cells (PDLSCs) and dental pulp stem cells (DPSCs), were evaluated using RNA sequencing, nuclear staining, live/dead assays, and immunocytochemistry. Cells were treated with 0, 1, 10, or 100 μg/mL ZIF-8. Based on nuclear staining results, live/dead viability assays were conducted on SCC7 and DPSCs treated with 0 or 100 μg/mL ZIF-8. Apoptosis-related markers (Bax, caspase-3, caspase-6, and caspase-10) were assessed following exposure to 100 μg/mL ZIF-8. Results: Transcriptomic analysis revealed that ZIF-8 not only facilitates selective 5-FU release but also directly induces apoptosis in SCC7 cells compared with 5-FU alone. At 100 μg/mL ZIF-8, SCC7 viability was significantly reduced, whereas OMSC viability was preserved. Nonviable SCC7 cells increased markedly compared with controls, while DPSCs showed no significant change. Apoptosis-related signaling was also elevated in SCC7 cells compared with DPSCs. Conclusions: ZIF-8 at 100 μg/mL selectively inhibits SCC7 growth while sparing OMSC viability and apoptosis.

Background: Myocardial ischemic injury, encompassing acute myocardial infarction (MI) and ischemia/reperfusion (I/R) injury, remains a major cause of cardiac morbidity and mortality worldwide, and is driven by interconnected molecular and cellular processes, including cardiomyocyte apoptosis, inflammatory activation, mitochondrial dysfunction, oxidative stress, and impaired angiogenesis. Mesenchymal stem cell (MSC)-derived exosomes have emerged as a promising cell-free nanotherapeutic strategy for cardiac repair due to their ability to transfer bioactive molecules that modulate multiple signaling networks involved in myocardial survival and regeneration. This systematic review aimed to synthesize evidence on the mechanistic basis of MSC-derived exosome mediated cardioprotection in myocardial ischemic injury. Methods: A systematic search of Ovid MEDLINE, Scopus, and Web of Science was conducted to identify studies investigating the effects of MSC-derived exosomes on myocardial ischemic injury. Eligible studies included clinical and preclinical models of MI or I/R injury assessing functional, biochemical, and molecular outcomes. Results: Seven preclinical studies published between 2015 and 2025 met the inclusion criteria. Exosome administration consistently improved cardiac function, reduced infarct size, and preserved myocardial architecture. Biochemical analyses revealed decreased cardiac injury markers, alongside suppressed apoptosis, inflammation, and oxidative stress. Mechanistically, MSC-derived exosomes delivered regulatory miRNAs (e.g., miR-19a, miR-125b, miR-205, miR-294) and lncRNAs (HAND2-AS1) that modulated key signaling pathways including PI3K/Akt, JAK2/STAT3, HAND2-AS1/miR-17-5p/Mfn2, and HIF-1α/VEGF. These molecular effects collectively inhibited apoptotic and inflammatory responses, enhanced mitochondrial integrity, and promoted angiogenesis and myocardial repair. Conclusions: MSC-derived exosomes confer robust cardioprotection against myocardial ischemic injury through integrated anti-apoptotic, anti-inflammatory, antioxidant, and pro-angiogenic mechanisms. Their multifaceted bioactivity, low immunogenicity, and potential for targeted delivery highlight their potential as a next-generation nanomedicine for ischemic heart disease. Future studies should emphasize standardized exosome production, mechanistic profiling, and translational validation in large-animal and clinical models.

Environmental exposure to heavy metals, particularly cadmium (Cd), has been increasingly associated with obesity, metabolic dysfunction, chronic inflammation, and related disorders such as type 2 diabetes and cardiovascular diseases. Adipose tissue (AT), a paracrine and endocrine organ central to systemic energy and inflammatory homeostasis, is a major site of heavy metal accumulation and a key target of Cd toxicity. However, the mechanisms by which Cd disrupts adipocyte function, especially through epigenetic pathways, remain poorly understood. In this study, we investigated the effects of Cd on epigenetic regulators, antioxidant enzyme activity, inflammatory mediators, and adipogenic programming in human adipose-derived stromal/stem cells (hASCs) and differentiated adipocytes. Cd exposure altered histone modifiers associated with lysine 27 of histone 3 (H3K27), disrupted redox balance in a concentration-dependent manner, impaired adipogenic differentiation and lipid accumulation, and modulated inflammatory and adipokine responses according to differentiation stage and Cd concentration. Our findings suggest that Cd compromises adipose cell homeostasis through mechanisms involving epigenetic dysregulation, oxidative stress imbalance, and altered adipogenic and inflammatory signalling. These observations point to possible long-term metabolic consequences of environmental Cd exposure due to its accumulation in adipose tissue.

Cells adapt their phenotypes in noisy microenvironments while maintaining robust decision-making. We develop a coarse-grained theoretical framework in which cellular phenotypic adaptation is described as Bayesian decision-making coupled to replication and diffusion. This leads to an effective Fokker-Planck equation with an emergent fitness landscape governing phenotypic dynamics. We identify distinct phenotypic regimes homeostatic fixation, bistable decision-making, critical switching, and runaway explosion and propose a biological interpretation in which homeostatic and bistable landscapes correspond to healthy differentiated cell states, whereas explosive landscapes capture stem-like or cancer-like behavior. In the Gaussian setting, the correlation between intrinsic and extrinsic states directly encodes mutual information and acts as a bifurcation parameter: high correlation produces shallow or explosive landscapes associated with phenotypic plasticity, while reduced correlation stabilizes differentiated fates by deepening potential wells. We further show that proliferation reshapes these landscapes in a nontrivial manner. Proliferation conditionally stabilizes local homeostasis without altering global confinement, or cooperates with biased environmental sensing to eliminate homeostasis/bistability and drive cancer-like phenotypic explosion even at high phenotypic fidelity. Finally, we show that negative intrinsic-extrinsic correlations suppress explosive dynamics but also reduce bistable plasticity, suggesting a robustness-plasticity trade-off. Together, our results suggest that development, tissue homeostasis, and carcinogenesis can be understood as information-driven deformations of a Bayesian phenotypic fitness landscape.

Cartilage is an important yet vulnerable tissue with limited self-healing capacity, where damage often progresses to joint degeneration, which eventually leads to severe osteoarthritis (OA). Current tissue engineering strategies focus on biocompatible scaffolds for cartilage regeneration, particularly amnion (or amniotic membrane), emerging as a promising biomaterial due to its wide availability, low immunogenicity, and naturally derived microenvironment that is advantageous for cartilage regeneration. This systematic review aims to evaluate the existing evidence on the efficacy of amnion as a tissue scaffolding material for cartilage regeneration in both preclinical and clinical studies. Using terms such as "cartilage damage", "cartilage injuries", "amnion" and "amniotic membrane", 19 relevant studies were identified across three major databases (PubMed, Scopus and Web of Science) until 25 December 2025. All preclinical and clinical studies that utilized amnion for cartilage repair or as cartilage tissue engineering scaffolding materials were included. Evidence quality was assessed using the OHAT and MINORS risk of bias tool. This study is prospectively registered in the PROSPERO database under the ID 1178444. The findings consistently indicate that amniotic scaffolds, regardless of processing methods or cell seeding, yield favorable outcomes without adverse effects across different species. In vitro analysis revealed that treatment groups with amnion show better cell attachment, viability, and proliferation, and higher content of cartilage-related markers expressed by the seeded cells, either chondrocyte, bone marrow-derived mesenchymal stem cells (MSCs), adipose tissue-derived MSCs, placenta-derived MSCs, umbilical cord-derived MSCs, amniotic MSCs or amniotic epithelial cells. In in vivo and ex vivo studies, amnion-treated groups demonstrated improved quality of the treated cartilage, with better integration, as indicated by higher histological scores and the presence of type II collagen (COL-II). There was an inconsistency in the reporting of cartilage defect dimensions in the in vivo models across the different studies. Nevertheless, the outcome measurements were consistently reported with histological analysis, with or without International Cartilage Repair Society (ICRS) scoring and immunohistochemistry (IHC) analysis, across the studies. Clinically, most subjects show improvement in the Knee Injury and Osteoarthritis Outcome Score (KOOS) Sports and Recreation score and KOOS Quality of Life score, as well as reduced Visual Analogue Scale (VAS) average and maximum pain scores. In conclusion, preclinical and clinical studies support amnion as an ideal scaffold material for cartilage tissue engineering and regeneration. Future research should focus on optimizing and standardizing amnion scaffold preparation at a production scale to facilitate the translation of these positive outcomes into clinical applications. This study is funded by the Ministry of Higher Education Malaysia via Prototype Research Grant Scheme (PRGS/1/2021/SKK01/UM/02/1) and UM International Collaboration Grant-2023 SATU Joint Research Scheme Program: ST007-2024.