ECM stiffness regulates calcium influx into mitochondria via tubulin and VDAC1 activity.

Calcium ions (Ca2+) play pivotal roles in regulating numerous cellular functions, including metabolism and growth, in normal and cancerous cells. Consequently, Ca2+ signaling is a vital determinant of cell fate and influences both cell survival and death. These intracellular signals are susceptible to modulation by various factors, including changes in the extracellular environment, which leads to mechanical alterations. However, the effect of extracellular matrix (ECM) stiffness variations on intracellular Ca2+ signaling remains underexplored. In this study, we aimed to elucidate the mechanisms of Ca2+ regulation through the mitochondria, which are crucial to Ca2+ homeostasis. We investigated how Ca2+ regulatory mechanisms adapt to different levels of ECM stiffness by simultaneously imaging the mitochondria and endoplasmic reticulum (ER) in live cells using genetically encoded biosensors. Our findings revealed that the uptake of mitochondrial Ca2+ through Voltage-Dependent Anion Channel 1 (VDAC1), facilitated by intracellular tubulin, is influenced by ECM stiffness. Unraveling these Ca2+ regulatory mechanisms under various conditions offers a novel perspective for advancing biomedical studies involving Ca2+ signaling.

RAB13 regulates macrophage polarization in sepsis.

To select the core target (RAB13) in sepsis patients' peripheral blood and investigate its molecular functions and possible mechanisms. The peripheral blood of sepsis patients (n = 21) and healthy individuals (n = 9) within 24 h after admission were collected for RNA-seq, and differential gene screening was performed by iDEP online analysis software (P < 0.01; log2FC ≥ 2) and enrichment analysis, the potential core target RAB13 was screened out. The association between RAB13 expression and sepsis severity was explored using multiple datasets in the GEO database, and survival analysis was conducted. Subsequently, peripheral blood mononuclear cells (PBMCs) from sepsis and control groups were isolated, and 10 × single-cell sequencing was used to identify the main RAB13-expressing cell types. Finally, LPS was used to stimulate THP1 cells to construct a sepsis model to explore the function and possible mechanism of RAB13. We found that RAB13 was a potential core target, and RAB13 expression level was positively associated with sepsis severity and negatively correlated with survival based on multiple public datasets. A single-cell sequencing indicated that RAB13 is predominantly localized in monocytes. Cell experiments validated that RAB13 is highly expressed in sepsis, and the knockdown of RAB13 promotes the polarization of macrophages towards the M2 phenotype. This mechanism may be associated with the ECM-receptor interaction signaling pathway. The upregulation of RAB13 in sepsis patients promotes the polarization of M2-like macrophages and correlates positively with the severity of sepsis.

Research on jet electrochemical machining with coaxial megasonic assistance.

In order to address the problem of poor localization in electrochemical machining (ECM), a coaxial megasonic assisted jet ECM method was proposed. Based on theoretical analysis, experiments were conducted to compare the effects of various electrolyte flow rates, electrolytic voltage and megasonic power levels on pit ECM. The results indicate that, in the range of experimental parameters, the increase of electrolyte flow rate and megasonic power can increase the machining depth, so as to improve the depth-diameter ratio of ECM pits. The use of coaxial megasonic-assisted jet ECM can enhance the depth-diameter ratio of etched pits compared to the without megasonic one. When applying a megasonic power of 22 W, the dimensions of the ECM pit were measured as 0.81 mm in depth and 5.73 mm in diameter, resulting in an depth-diameter ratio of 0.140. Under the same conditions, without megasonic assistance, the pit diameter is reduced to 0.65 mm while the pit depth increases to 6.36 mm, resulting in a depth-diameter ratio of 0.102. Additionally, The results also demonstrate that, the increase of electrolytic voltage makes the depth to diameter ratio of pit further increase on the original basis. With an electrolyte flow rate of 0.9 L/min and a megasonic power of 22 W, the use of electrolysis voltage of 50 V increased the depth-diameter ratio of etched pits to 0.173. Using the above preferred parameters, electrolytic milling of the wide groove is carried out. The depth-diameter ratio of the wide groove is increased from 0.039 to 0.059 by appending coaxial megasonic. This further verified the effectiveness of the coaxial megasonic-assisted jet ECM method.

Lysyl Oxidase (LOX) Family Proteins: Key Players in Breast Cancer Occurrence and Progression.

The lysyl oxidase (LOX) family proteins are secreted copper-dependent amine oxidases, comprised of five paralogues: LOX and LOX-like 1-4 (LOXL1-4), which are characterized by catalytic activity contributing to the remodeling of the cross-linking of the structural extracellular matrix (ECM). ECM remodeling plays a key role in the angiogenesis surrounding tumours, whereby a corrupt tumour microenvironment (TME) takes shape. Additionally, dysregulation and aberrant expression of LOX family proteins have been implicated in the occurrence and progression of various types of human cancers, including lung cancer, hepatocellular carcinoma, gastric cancer, renal cell carcinoma, and colorectal cancer. Breast cancer is the most prevalent malignant tumour in women worldwide, and its incidence rate is increasing annually. In recent years, a growing body of evidence has revealed significant upregulation of LOX family proteins in breast cancer, which contributes to cancer cell proliferation, invasion, and metastasis. Furthermore, elevated expression of LOX family proteins is closely associated with poor prognosis in breast cancer patients. We herein review the structure, regulation, function, and mechanisms of LOX family proteins in the occurrence and progression of breast cancer. In addition, we highlight recent insights into their mechanisms and their potential involvement in the clinical value and novel biological roles of LOX family members in tumour progression and the TME of breast cancer. This review will provide a theoretical basis and reference for clinical diagnosis and treatment of breast cancer, as well as for the screening of effective LOX-specific inhibitors.

Adipocyte-secreted PRELP promotes adipocyte differentiation and adipose tissue fibrosis by binding with p75NTR to activate FAK/MAPK signaling.

Adipocyte-secreted factors intricately regulate adipose tissue function, and the underlying molecular mechanisms are only partially understood. However, the function of PRELP, which is a key component of the extracellular matrix (ECM) in adipocytes, remains largely unknown. In this study, we demonstrate that PRELP was upregulated in both obese humans and mice, which exhibited a positive correlation with metabolic disorders. PRELP knockout could resist HFD-induced obesity and inhibit adipocyte differentiation. PRELP knockout improved glucose tolerance, insulin sensitivity and alleviated adipose tissue fibrosis. Mechanistically, PRELP was secreted into the ECM and bound to the extracellular domain of its receptor p75NTR in adipocytes, which further activated the FAK/MAPK (JNK, p38 MAPK, ERK1/2) signaling pathway, promoting adipocyte differentiation and exacerbating adipocyte fibrosis. Adipocyte PRELP plays a pivotal role in regulating obesity and adipose tissue fibrosis through an autocrine manner, and PRELP may be a therapeutic target for obesity and its related metabolic disorders.

ALKBH5-mediated m6A demethylation ameliorates extracellular matrix deposition in cutaneous pathological fibrosis.

BACKGROUND: Elevated extracellular matrix (ECM) accumulation is a major contributing factor to the pathogenesis of fibrotic diseases. Recent studies have indicated that N6-methyladenosine (m6A) RNA modification plays a pivotal role in modulating RNA stability and contribute to the initiation of various pathological conditions. Howbeit, the precise mechanism by which m6A influences ECM deposition remains unclear. METHODS: In this study, we used hypertrophic scars (HTSs) as a paradigm to investigate ECM-related diseases. We focused on the role of ALKBH5-mediated m6A demethylation within the pathological progression of HTSs and examined its correlation with clinical stages. The effects of ALKBH5 ablation on ECM components were studied both in vivo and in vitro. Downstream targets of ALKBH5, along with their underlying mechanisms, were identified using integrated high-throughput analysis, RNA-binding protein immunoprecipitation and RNA pull-down assays. Furthermore, the therapeutic potential of exogenous ALKBH5 overexpression was evaluated in fibrotic scar models. RESULTS: ALKBH5 was decreased in fibroblasts derived from HTS lesions and was negatively correlated with their clinical stages. Importantly, ablation of ALKBH5 promoted the expression of COL3A1, COL1A1, and ELN, leading to pathological deposition and reconstruction of the ECM both in vivo and in vitro. From a therapeutic perspective, the exogenous overexpression of ALKBH5 significantly inhibited abnormal collagen deposition in fibrotic scar models. As determined by integrated high-throughput analysis, key ECM components including COL3A1, COL1A1, and ELN are direct downstream targets of ALKBH5. By means of its mechanism, ALKBH5 inhibits the expression of COL3A1, COL1A1, and ELN by removing m6A from mRNAs, thereby decreasing their stability in a YTHDF1-dependent manner. CONCLUSIONS: Our study identified ALKBH5 as an endogenous suppressor of pathological ECM deposition, contributing to the development of a reprogrammed m6A-targeted therapy for HTSs.

Tunable Hybrid Hydrogels of Alginate and Cell-Derived dECM to Study the Impact of Matrix Alterations on Epithelial-to-Mesenchymal Transition.

Epithelial-to-mesenchymal transition (EMT) is crucial for tumor progression, being linked to alterations in the extracellular matrix (ECM). Understanding the ECM's role in EMT can uncover new therapeutic targets, yet replicating these interactions in vitro remains challenging. It is shown that hybrid hydrogels of alginate (ALG) and cell-derived decellularized ECM (dECM), with independently tunable composition and stiffness, are useful 3D-models to explore the impact of the breast tumor matrix on EMT. Soft RGD-ALG hydrogels (200 Pa), used as neutral bulk material, supported mammary epithelial cells morphogenesis without spontaneous EMT, allowing to define the gene, protein, and biochemical profiles of cells at different TGFß1-induced EMT states. To mimic the breast tumor composition, dECM from TGFß1-activated fibroblasts (adECM) are generated, which shows upregulation of tumor-associated proteins compared to ndECM from normal fibroblasts. Using hybrid adECM-ALG hydrogels, it is shown that the presence of adECM induces partial EMT in normal epithelial cells, and amplifes TGF-ß1 effects compared to ALG and ndECM-ALG. Increasing the hydrogel stiffness to tumor-like levels (2.5 kPa) have a synergistic effect, promoting a more evident EMT. These findings shed light on the complex interplay between matrix composition and stiffness in EMT, underscoring the utility of dECM-ALG hydrogels as a valuable in vitro platform for cancer research.

PALMD haploinsufficiency aggravates extracellular matrix remodeling in vascular smooth muscle cells and promotes calcification.

BACKGROUND: Reduced PALMD expression is strongly associated with the development of calcified aortic valve stenosis; however, the role of PALMD in vascular calcification remains unknown. METHODS: Calcified arteries were collected from mice to detect PALMD expression. Heterozygous Palmd knockout (Palmd+/-) mice were established to explore the role of PALMD in subtotal nephrectomy-induced vascular calcification. RNA sequencing was applied to detect molecular changes in aortas from Palmd+/- mice. Primary Palmd+/- vascular smooth muscle cells (VSMCs) or PALMD silenced VSMCs by short interfering RNA (siRNA) were used to analyze PALMD function in phenotypic changes and calcification. RESULTS: PALMD haploinsufficiency aggravated subtotal nephrectomy-induced vascular calcification. RNA sequencing analysis showed that loss of PALMD disturbed the synthesis and degradation of the extracellular matrix (ECM) in aortas, including collagens and matrix metalloproteinases (Col6a6, Mmp2, Mmp9, etc.). In vitro experiments revealed that PALMD deficient VSMCs were more susceptible to high phosphate induced calcification. Downregulation of SMAD6 expression and increased levels of p-SMAD2 were detected in Palmd+/- VSMCs, suggesting that TGF-ß signaling may be involved in PALMD haploinsufficiency-induced vascular calcification. CONCLUSION: Our data revealed that PALMD haploinsufficiency causes ECM dysregulation in VSMCs and aggravates vascular calcification. Our findings suggest reduced PALMD expression is also linked to vascular calcification, and PALMD maybe a potential therapeutic target for this disease.

Diffusive Memristor with CuS Nanoparticles Embedded in Polymeric Film as Artificial Nociceptor.

The threshold behavior and the ion diffusion dynamics in diffusive volatile memristors have a very uncanny resemblance to the transduction process of biological nociceptors. Hence, the diffusive memristors are considered the most suited for making artificial nociceptive systems. To facilitate their widespread adoption, it is imperative to develop polymeric or organic-inorganic hybrid material-based diffusive memristors that are economical, biocompatible, and easily processable. In this study, we present a cluster-type polymeric diffusive memristor where copper is used as the active top electrode. The switching medium comprises copper(II) sulfide (CuS) nanoparticles embedded in poly(ethylene oxide) (PEO). The devices show electrochemical metalization (ECM)-type and bidirectional diffusive volatile memory with high nonlinearity (104) and turn-on slope (5.6 mV/dec). They reliably remain diffusive volatile with up to 10 wt % CuS in PEO and for a wide range of compliance (10-6 to 10-2 A) without transitioning to the bipolar nonvolatile type. The low reduction potential of CuS and optimal segmental dynamics of PEO work synergistically to ensure stable and reproducible diffusive memory. The CuS nanoparticles act as bipolar electrodes, undergoing local oxidation and reduction under the influence of the bias. The switching of resistance states in the CuS-PEO memristors is attributed to the formation of cluster-type filaments between CuS nanoparticles within the PEO matrix supported by the participation of copper ions from the top Cu electrode. The observation of low filament temperature and the independence of on-state resistance with respect to the device area and temperature further corroborate the cluster-type filament in CuS-PEO memristors. Using a 5 wt % CuS-based device, an artificial nociceptor is realized, which successfully mimics most of the nociceptive plasticities such as threshold, relaxation, no adaptation, and sensitization.

CircRELL1 promotes osteoarthritis progression by regulating miR-200c-3p.

Background: There is a growing body of evidence indicating a potential association between circular RNA and the pathogenesis of human osteoarthritis (OA). Nevertheless, the precise extent of their involvement in OA remains largely unexplored. Hence, the objective of this investigation is to elucidate the function of Circular (Circ) RELL1 in the context of OA. Methods: 24 OA tissue samples and 11 normal tissue samples were collected. The inflammatory OA-like conditions were established by Destabilized Medial Meniscus (DMM) operation in mice and LPS-induced C28/I2 cells. OA severity and articular cartilage degradation were assessed by Safranin-O staining, hematoxylin-eosin (H&E) staining, and International Society for Osteoarthritis Research (OARSI) criteria. CircRELL1, miR-200c-3p, and TCF4 were measured by RT-qPCR and Immunoblot. The cell viability and apoptosis rate were measured by MTT and flow cytometry, respectively. The levels of cytokines interleukin (IL)-1ß, IL-6, and TNF-α were determined by ELISA. Apoptosis-associated proteins (cleaved caspase-3, Bax, and Bcl-2) and extracellular matrix (ECM) degradation-associated proteins (MMP13, collagen II, and Aggrecan) were detected by Immunoblot. The interaction between miR-200c-3p and circRELL1 or TCF4 was verified by dual luciferase reporter assay and RIP assay. Results: CircRELL1 expression was upregulated in OA patients, and the results were consistent in DMM mice and LPS-treated C28/I2 cells. Silencing circRELL1 improved cartilage injury caused by DMM and contributed to a lower OARSI score. Silencing CircRELL1 increased the activity of OA chondrocytes in vivo and in vitro and inhibited cellular inflammatory responses and ECM degradation. In terms of mechanism, circRELL1 functioned by targeting miR-200c-3p, leading to the suppression of inflammatory factor production, cell apoptosis, and ECM degradation, thus inhibiting the progression of OA. Conclusion: CircRELL1 may promote the progression of OA by regulating the miR-200c-3p.

Contribution of Tregs to the promotion of constructive remodeling after decellularized extracellular matrix material implantation.

Host remodeling of decellularized extracellular matrix (dECM) material through the appropriate involvement of immune cells is essential for achieving functional organ/tissue regeneration. As many studies have focused on the role of macrophages, only few have evaluated the role of regulatory T cells (Tregs) in dECM remodeling. In this study, we used a mouse model of traumatic muscle injury to determine the role of Tregs in the constructive remodeling of vascular-derived dECM. According to the results, a certain number of Tregs could be recruited after dECM implantation. Notably, using anti-CD25 to reduce the number of Tregs recruited by the dECM was significantly detrimental to material remodeling based on a significant reduction in the number of M2 macrophages. In addition, collagen and elastic fibers, which maintain the integrity and mechanical properties of the material, rapidly degraded during the early stages of implantation. In contrast, the use of CD28-SA antibodies to increase the number of Tregs recruited by dECM promoted constructive remodeling, resulting in a decreased inflammatory response at the material edge, thinning of the surrounding fibrous connective tissue, uniform infiltration of host cells, and significantly improved tissue remodeling scores. The number of M2 macrophages increased whereas that of M1 macrophages decreased. Moreover, Treg-conditioned medium further enhanced material-induced M2 macrophage polarization in vitro. Overall, Treg is an important cell type that influences constructive remodeling of the dECM. Such findings contribute to the design of next-generation biomaterials to optimize the remodeling and regeneration of dECM materials.

Bioprinted, spatially defined breast tumor microenvironment models of intratumoral heterogeneity and drug resistance.

Cellular, extracellular matrix (ECM), and spatial heterogeneity of tumor microenvironments (TMEs) regulate disease progression and treatment efficacy. Developing in vitro models that recapitulate the TME promises to accelerate studies of tumor biology and identify new targets for therapy. Here, we used extrusion-based, multi-nozzle 3D bioprinting to spatially pattern triple-negative MDA-MB-231 breast cancer cells, endothelial cells (ECs), and human mammary cancer-associated fibroblasts (HMCAFs) with biomimetic ECM inks. Bioprinted models captured key features of the spatial architecture of human breast tumors, including varying-sized dense regions of cancer cells and surrounding microvessel-rich stroma. Angiogenesis and ECM stiffening occurred in the stromal area but not the cancer cell-rich (CCR) regions, mimicking pathological changes in patient samples. Transcriptomic analyses revealed upregulation of angiogenesis-related and ECM remodeling-related signatures in the stroma region and identified potential ligand-receptor (LR) mediators of these processes. Breast cancer cells in distinct parts of the bioprinted TME showed differing sensitivities to chemotherapy, highlighting environmentally mediated drug resistance. In summary, our 3D-bioprinted tumor model will act as a platform to discover integrated functions of the TME in cancer biology and therapy.

Mitochondrial DNA D-loop SNPs unveil molecular signatures of milk production variation in Murrah buffalo.

BACKGROUND: The Murrah buffalo, pivotal in Asian agriculture, faces challenges in maximizing milk production despite significant breeding efforts. Recognizing its economic importance, this study investigates mtDNA D-loop variations in Murrah buffalo as potential indicators of milk production variability, addressing challenges in maximizing yield despite significant breeding efforts. METHODS AND RESULTS: Analyzing mtDNA D-loop sequences from 50 buffaloes, we categorized them into Low (Group 1), Medium (Group 2), and High ECM (Group 3) groups based on milk yields, fat and protein percentage of a 30-day period data. Somatic cell mtDNA D-loop analysis revealed distinct genetic variations, with significant differences among ECM groups. Group 2 showed higher SNP prevalence, group 3 had more insertions/deletions, and Group 1 exhibited the highest transition frequency. Notably, a consistent "C" deletion at the 714th position occurred in Groups 1 and 3, prevalent in 68% of Group 2. A G-A variation at the 93rd position was specific to the medium ECM group. Negative Tajima D values indicated unique variations in each group, with Group 1 having the highest number, and a specific SNP linked to Group 2 was identified. These SNPs in the D-loop region could impact mtDNA replication, influencing mitochondrial content among animals. Our results provide valuable insights into the role of mtDNA D-loop polymorphisms in milk production traits in Murrah buffalo. CONCLUSIONS: Our research highlights the potential for valuable markers of cellular energy efficiency in Murrah buffalo. Exploring diverse cytoplasmic backgrounds opens avenues for mtDNA-based selection strategies, enhancing milk production and optimizing genetic traits for the dairy industry.

An In Vitro Model of the Blood-Brain Barrier for the Investigation and Isolation of the Key Drivers of Barriergenesis.

The blood-brain barrier (BBB) tightly regulates substance transport between the bloodstream and the brain. Models for the study of the physiological processes affecting the BBB, as well as predicting the permeability of therapeutic substances for neurological and neurovascular pathologies, are highly desirable. Existing models, such as Transwell utilizing-models, do not mimic the extracellular environment of the BBB with their stiff, semipermeable, non-biodegradable membranes. To help overcome this, we engineered electrospun membranes from poly L-lactic acid in combination with a nanometric coating of poly(ethyl acrylate) (PEA) that drives fibrillogenesis of fibronectin, facilitating the synergistic presentation of both growth factors and integrin binding sites. Compared to commercial semi-porous membranes, these membranes significantly improve the expression of BBB-related proteins in brain endothelial cells. PEA-coated membranes in combination with different growth factors and extracellular protein coatings reveal nerve growth factor (NGF) and fibroblast growth factor (FGF-2) caused formation of better barriers in vitro. This BBB model offers a robust platform for studying key biochemical factors influencing barrier formation that marries the simplicity of the Transwell model with the highly tunable electrospun PEA-fibronectin membranes. This enables the generation of high-throughput drug permeability models without the need of complicated co-culture conditions.

Expression of insulin-like growth factor binding protein 5 in the vaginal wall tissues of older women with pelvic organ prolapse.

This study aimed to investigate the expression and significance of insulin-like growth factor binding protein 5 (IGFBP5) and extracellular matrix (ECM) related proteins in anterior vaginal wall tissues among aged pelvic organ prolapse (POP) patients. Tissues from the anterior vaginal wall were collected from 28 patients with POP and 20 patients without POP. The expression of protein and mRNA levels of IGFBP5 and ECM related proteins were evaluated in the vaginal wall tissues using immunohistochemistry, western blotting, and RT-qPCR techniques. The expression levels were then compared with clinical parameters. The expression levels of protein and mRNA of IGFBP5, collagen I, and collagen III were significantly lower in the POP group. Protein and mRNA expression levels of MMP2 were significantly higher in the POP group. IGFBP5 protein and mRNA expression levels were negatively correlated with age and significantly lower in older POP patients (≥ 65 years old) compared to younger POP patients (< 65 years old). IGFBP5 protein and mRNA expression levels were also significantly lower in POP-Q stage IV patients compared to POP-Q stage III patients. IGFBP5 expression level is negatively correlated with the age and severity of prolapse. The significant decrease in IGFBP5 expression may play a crucial part in the aging process and the occurrence of POP.

The function of the inter-alpha-trypsin inhibitors in the development of disease.

Through the formation of covalent connections with hyaluronic acid (HA), the inter-α-trypsin inhibitor (IαI) family collaborates to preserve the stability of the extracellular matrix (ECM). The five distinct homologous heavy chains (ITIH) and one type of light chain make up the IαI family. ITIH alone or in combination with bikunin (BK) has been proven to have important impacts in a number of earlier investigations. This implies that BK and ITIH might be crucial to both physiological and pathological processes. The functions of BK and ITIH in various pathophysiological processes are discussed independently in this paper. In the meanwhile, this study offers suggestions for further research on the roles of BK and ITIH in the course of disease and summarizes the plausible mechanisms of the previous studies.

CX3C chemokine: Hallmarks of fibrosis and ageing.

Fibrosis refers to the progressive tissue lesion process characterized by excessive secretion and deposition of extracellular matrix (ECM). Abnormal fibrous tissue deposition distorts tissue architecture and leads to the progressive loss of organ function. Notably, fibrosis is one of the primary pathological appearances of many end stage illnesses, and is considered as a lethal threat to human health, especially in the elderly with ageing-related diseases. CX3C ligand 1 (CX3CL1) is the only member of chemokine CX3C and binds specifically to CX3C receptor 1 (CX3CR1). Different from other chemokines, CX3CL1 possesses both chemotactic and adhesive activity. CX3CL1/CX3CR1 axis involves in various physiological and pathological processes, and exerts a critical role in cells from the immune system, vascular system, and nervous system etc. Notably, increasing evidence has demonstrated that CX3CL1/CX3CR1 signaling pathway is closely related to the pathological process of fibrosis in multiple tissue and organs. We reviewed the crucial role of CX3CL1/CX3CR1 axis in fibrosis and ageing and systematically summarized the underlying mechanism, which offers prospective strategies of targeting CX3C for the therapy of fibrosis and ageing-related diseases.

The extracellular matrix in solid tumor immunotherapy.

The extracellular matrix (ECM) of solid tumors impacts the antitumor activities of CD8+ T and natural killer (NK) cells in a variety of ways. Cell motility is restricted by the tumor ECM which creates physical barriers. The tumor ECM directly alter the phenotypes and functions of cytotoxic lymphocytes, and indirectly influences immunological synapse-mediated interactions between cytotoxic lymphocytes and cancer cells. Therefore, strategies to improve solid tumor immunotherapy should be established by considering complex ternary interactions between cytotoxic lymphocytes, cancer cells, and the tumor ECM. Novel bioengineering tools approximating key characteristics of the tumor ECM, such as in vitro reconstituted 3D ECMs and microfluidics are valuable from a fundamental study viewpoint and from a translational perspective, aiming to enable systematic screening approaches.

Harnessing Peptide-Based Hydrogels for Enhanced Cartilage Tissue Engineering.

Cartilage tissue engineering remains a formidable challenge due to its complex, avascular structure and limited regenerative capacity. Traditional approaches, such as microfracture, autografts, and stem cell delivery, often fail to restore functional tissue adequately. Recently, there has been a surge in the exploration of new materials that mimic the extracellular microenvironment necessary to guide tissue regeneration. This review investigates the potential of peptide-based hydrogels as an innovative solution for cartilage regeneration. These hydrogels, formed via supramolecular self-assembly, exhibit excellent properties, including biocompatibility, ECM mimicry, and controlled biodegradation, making them highly suitable for cartilage tissue engineering. This review explains the structure of cartilage and the principles of supramolecular and peptide hydrogels. It also delves into their specific properties relevant to cartilage regeneration. Additionally, this review presents recent examples and a comparative analysis of various peptide-based hydrogels used for cartilage regeneration. The review also addresses the translational challenges of these materials, highlighting regulatory hurdles and the complexities of clinical application. This comprehensive investigation provides valuable insights for biomedical researchers, tissue engineers, and clinical professionals aiming to enhance cartilage repair methodologies.