Physiological Microenvironment Research Articles

In-situ electret scaffolds with controllable electric fields printed by MEW for bone tissue regeneration

Physiologically relevant electrical microenvironments play an integral role in manipulating bone metabolism. Although implanted biomaterials using conductive or piezoelectric materials to mimic natural tissue electrical properties have been introduced into the field of bone regeneration, the use of electret materials to provide stable and durable electrical stimulation has rarely been studied in biomaterial design. In this study, the ZnO/PCL composite scaffolds with in-situ electret were fabricated using melt electro-writing to explore its efficacy in bone regeneration. By adjusting the electret concentration, the surface potential of the composite scaffolds could be tuned to the biopotential for promoting bone regeneration, and the prepared scaffolds exhibited good electrical stability over an observation period of up to 42 days. In vitro biological experiments showed that the in-situ electret scaffolds promoted the cell viability and osteogenic differentiation of mesenchymal stem cells. At the same time, the in-situ electret composite scaffolds can induce the phenotype transformation of RAW 264.7 cells from M1 to M2, creating a favorable microenvironment for bone tissue regeneration. The composite scaffolds significantly promoted bone regeneration in vivo through sustained endogenous electrical stimulation. These findings suggest that the in-situ electret scaffolds that maintain a stable and physiological electrical microenvironment are promising candidates for enhanced bone regeneration.

Visible Light‐Responsive Polyphenolic Bio‐Glues for Oral Mucosal Wound Healing

AbstractAlthough bio‐adhesives have achieved many progresses, creating robust bio‐glues that could withstand the complex physiological microenvironment remains a significant challenge such as limited bioadhesion strength and stability, as well as slow adhesion speed caused by pH, enzymes, salt, and bacteria. Herein, a series of strong bio‐glues are successfully fabricated using a polyphenol–acrylamide–ruthenium crosslinking (PARC) reaction under visible light irradiation, involving acrylamides radical polymerization, polyphenols (extracts) coupling reaction, and ruthenium‐mediated photochemistry. The resulting bio‐glues underwent rapid sol–gel transition and exhibited adhesive properties within a short of time (≈5 s), which could quickly bond to various bio‐tissues. Moreover, these bioadhesives demonstrate high adhesion strength and stability with mucosal tissue in the oral environment, effectively promoting rat and pig oral mucosal wound healing. It is anticipated that this class of visible light‐responsive polyphenolic bio‐glues could serve as a robust tool for addressing oral mucosal defects in the clinic, offering a promising alternative to traditional treatments for oral mucosal disorders.

HHLA2: An Emerging Immune Checkpoint for Cancer Immunotherapy.

HHLA2, a member of the B7 family of co-signaling molecules, is aberrantly expressed in various human cancers and has emerged as a promising target for cancer immunotherapy. It exhibits a unique structure and tissue distribution pattern compared to other B7 family members, where its expression is regulated by the complex physiological and tumor microenvironment. HHLA2 plays a crucial but contradictory role in immune modulation, and is thereby associated with heterogeneous prognostic implications across different cancer types. It interacts with two distinct receptors: TMIGD2, which is predominantly expressed on naïve T and NK cells to deliver co-stimulatory signals to T cells and NK cells; and KIR3DL3, which is prevalent on terminally differentiated T and CD56dim CD16+ NK cells to transmit inhibitory signals. The expression dynamics of these receptors on immune cells contribute to the maintenance of immune response homeostasis. Therapeutic strategies targeting the HHLA2 immune checkpoint aim to selectively inhibit the immunosuppressive HHLA2-KIR3DL3 pathway while preserving the HHLA2-TMIGD2 signaling. Several anti-HHLA2 and anti-KIR3DL3 antibodies are currently under investigation in early clinical trials, building upon encouraging results observed in humanized mouse models. Notably, the non-overlapping expression of HHLA2 and PD-L1 in tumors suggests potential synergistic benefits of combining HHLA2-KIR3DL3 targeted therapies with PD-1/PD-L1 blockade or anti-CTLA-4 to augment antitumor activity.

Biomimetic Approaches in Scaffold-Based Blood Vessel Tissue Engineering.

Cardiovascular diseases remain a leading cause of mortality globally, with atherosclerosis representing a significant pathological means, often leading to myocardial infarction. Coronary artery bypass surgery, a common procedure used to treat coronary artery disease, presents challenges due to the limited autologous tissue availability or the shortcomings of synthetic grafts. Consequently, there is a growing interest in tissue engineering approaches to develop vascular substitutes. This review offers an updated picture of the state of the art in vascular tissue engineering, emphasising the design of scaffolds and dynamic culture conditions following a biomimetic approach. By emulating native vessel properties and, in particular, by mimicking the three-layer structure of the vascular wall, tissue-engineered grafts can improve long-term patency and clinical outcomes. Furthermore, ongoing research focuses on enhancing biomimicry through innovative scaffold materials, surface functionalisation strategies, and the use of bioreactors mimicking the physiological microenvironment. Through a multidisciplinary lens, this review provides insight into the latest advancements and future directions of vascular tissue engineering, with particular reference to employing biomimicry to create systems capable of reproducing the structure-function relationships present in the arterial wall. Despite the existence of a gap between benchtop innovation and clinical translation, it appears that the biomimetic technologies developed to date demonstrate promising results in preventing vascular occlusion due to blood clotting under laboratory conditions and in preclinical studies. Therefore, a multifaceted biomimetic approach could represent a winning strategy to ensure the translation of vascular tissue engineering into clinical practice.

Development of an Azobenzene-Based Cell Culture Photoresponsive Platform for In Situ Modulation of Surface Topography in Wet Environments.

Azopolymers are light-responsive materials that hold promise to transform in vitro cell culture systems. Through precise light illumination, they facilitate substrate pattern formation and erasure, allowing for the dynamic control and creation of active interfaces between cells and materials. However, these materials exhibit a tendency to locally detach from the supporting glass in the presence of aqueous solutions, such as cell culture media, due to the formation of blisters, which are liquid-filled cavities generated at the azopolymer film-glass interface. These blisters impede precise structurization of the surface of the azomaterial, limiting their usage for surface photoactivation in the presence of cells. In this study, we present a cost-effective and easily implementable method to improve the azopolymer-glass interface stability through silane functionalization of the glass substrate. This method proved to be efficient in preventing blister formation, thereby enabling the dynamic modulation of the azopolymer surface in situ for live-cell experiments. Furthermore, we proved that the light-illumination conditions used to induce azopolymer surface variations do not induce phototoxic effects. Consequently, this approach facilitates the development of a photoswitchable azopolymer cell culture platform for studying the impact of multiple in situ inscription and erasure cycles on cell functions while maintaining a physiological wet microenvironment.

3D Cell Migration Chip (3DCM-Chip): A New Tool toward the Modeling of 3D Cellular Complex Systems.

3D hydrogel-based cell cultures provide models for studying cell behavior and can efficiently replicate the physiologic environment. Hydrogels can be tailored to mimic mechanical and biochemical properties of specific tissues and allow to produce gel-in-gel models. In this system, microspheres encapsulating cells are embedded in an outer hydrogel matrix, where cells are able to migrate. To enhance the efficiency of such studies, a lab-on-a-chip named 3D cell migration-chip (3DCM-chip) is designed, which offers substantial advantages over traditional methods. 3DCM-chip facilitates the analysis of biochemical and physical stimuli effects on cell migration/invasion in different cell types, including stem, normal, and tumor cells. 3DCM-chip provides a smart platform for developing more complex cell co-cultures systems. Herein the impact of human fibroblasts on MDA-MB 231 breast cancer cells' invasiveness is investigated. Moreover, how the presence of different cellular lines, including mesenchymal stem cells, normal human dermal fibroblasts, and human umbilical vein endothelial cells, affects the invasive behavior of cancer cells is investigated using 3DCM-chip. Therefore, predictive tumoroid models with a more complex network of interactions between cells and microenvironment are here produced. 3DCM-chip moves closer to the creation of in vitro systems that can potentially replicate key aspects of the physiological tumor microenvironment.

Biophysical-driven piezoelectric and aligned nanofibrous scaffold promotes bone regeneration by re-establishing physiological electrical microenvironment

Biophysical-driven piezoelectric and aligned nanofibrous scaffold promotes bone regeneration by re-establishing physiological electrical microenvironment

Interleukin 6 at menstruation promotes the proliferation and self-renewal of endometrial mesenchymal stromal/stem cells through the WNT/β-catenin signaling pathway.

At menstruation, the functional layer of the human endometrium sheds off due to the trigger of the release of inflammatory factors, including interleukin 6 (IL-6), as a result of a sharp decline in progesterone levels, leading to tissue breakdown and bleeding. The endometrial mesenchymal stem-like cells (CD140b+CD146+ eMSC) located in the basalis are responsible for the cyclical regeneration of the endometrium after menstruation. Endometrial cells from the menstruation phase have been proven to secrete a higher amount of IL-6 and further enhance the self-renewal and clonogenic activity of eMSC. However, the IL-6-responsive mechanism remains unknown. Thus, we hypothesized that IL-6 secreted from niche cells during menstruation regulates the proliferation and self-renewal of eMSC through the WNT/β-catenin signaling pathway. In this study, the content of IL-6 across the menstrual phases was first evaluated. Coexpression of stem cell markers (CD140b and CD146) with interleukin 6 receptor (IL-6R) was confirmed by immunofluorescent staining. In vitro functional assays were conducted to investigate the effect of IL-6 on the cell activities of eMSC, and the therapeutic role of these IL-6- and WNT5A-pretreated eMSC on the repair of injured endometrium was observed using an established mouse model. The endometrial cells secrete a high amount of IL-6 under hypoxic conditions, which mimic the physiological microenvironment in the menstruation phase. Also, the expression of IL-6 receptors was confirmed in our eMSC, indicating their capacity to respond to IL-6 in the microenvironment. Exogenous IL-6 can significantly enhance the self-renewal, proliferation, and migrating capacity of eMSC. Activation of the WNT/β-catenin signaling pathway was observed upon IL-6 treatment, while suppression of the WNT/β-catenin signaling impaired the stimulatory role of IL-6 on eMSC activities. IL-6- and WNT5A-pretreated eMSC showed better performance during the regeneration of the injured mouse endometrium. We demonstrate that the high level of IL-6 produced by endometrial cells at menstruation can induce the stem cells in the human endometrium to proliferate and migrate through the activation of the WNT/β-catenin pathway. Treatment of eMSC with IL-6 and WNT5A might enhance their therapeutic potential in the regeneration of injured endometrium.

Allogeneic bone marrow mesenchymal stem cell-derived exosomes alleviate human hypoxic AKI-on-a-Chip within a tight treatment window

BackgroundAcute hypoxic proximal tubule (PT) injury and subsequent maladaptive repair present high mortality and increased risk of acute kidney injury (AKI) - chronic kidney disease (CKD) transition. Human bone marrow mesenchymal stem cell-derived exosomes (hBMMSC-Exos) as potential cell therapeutics can be translated into clinics if drawbacks on safety and efficacy are clarified. Here, we determined the real-time effective dose and treatment window of allogeneic hBMMSC-Exos, evaluated their performance on the structural and functional integrity of 3D microfluidic acute hypoxic PT injury platform.MethodshBMMSC-Exos were isolated and characterized. Real-time impedance-based cell proliferation analysis (RTCA) determined the effective dose and treatment window for acute hypoxic PT injury. A 2-lane 3D gravity-driven microfluidic platform was set to mimic PT in vitro. ZO-1, acetylated α-tubulin immunolabelling, and permeability index assessed structural; cell proliferation by WST-1 measured functional integrity of PT.ResultshBMMSC-Exos induced PT proliferation with ED50 of 172,582 µg/ml at the 26th hour. Hypoxia significantly decreased ZO-1, increased permeability index, and decreased cell proliferation rate on 24–48 h in the microfluidic platform. hBMMSC-Exos reinforced polarity by a 1.72-fold increase in ZO-1, restored permeability by 20/45-fold against 20/155 kDa dextran and increased epithelial proliferation 3-fold compared to control.ConclusionsThe real-time potency assay and 3D gravity-driven microfluidic acute hypoxic PT injury platform precisely demonstrated the therapeutic performance window of allogeneic hBMMSC-Exos on ischemic AKI based on structural and functional cellular data. The novel standardized, non-invasive two-step system validates the cell-based personalized theragnostic tool in a real-time physiological microenvironment prior to safe and efficient clinical usage in nephrology.

Spatiotemporal tracking of intracellular nanoparticles using complementary imaging systems reveals acute ferroptosis triggered by burst reduction of ferric ions

Uptake and intracellular trafficking of nanoparticles are tightly regulated by their interactions with cellular organelles and physiological microenvironment. Although the dynamic physicochemical reactions at the interface of nanoparticles and cells ultimately determine the intracellular distribution and fate, microscopic tracing and quantitative analysis of the nanoparticles have been hampered by the limited resolution associated with individual nanoparticle trafficking. Herein, we report spatiotemporal investigations on autophagic clearance of biodegradable iron oxide-silica core-shell nanoparticles in terms of intracellular trafficking and ionic dissolution at a single cell level using multimodal imaging systems. By combining transmission electron microscopy and super-resolution confocal laser scanning microscopy with fluorescence correlation spectroscopy, the complementary imaging analysis exclusively shows the intracellular uptake, endosomal fusion and biodegradative clearance, leading to identify the step-by-step endocytic transport pathway and autophagic degradation pathways. Tracing the intracellular trafficking of nanoparticles reveals that they are spontaneously transported from endosomes to lysosomes, and transiently stimulate autophagy while maintaining cell viability. While protecting iron oxide core, the silica shell is gradually degraded during endocytosis and autophagic clearance, resulting in ionic dissolution of iron oxide in acidic environment. Moreover, burst reduction of ferric ions by adding ascorbic acid readily triggers acute ferroptosis owing to rapid supplement of ferrous ions and Fenton reaction in cancer cells. The complementary imaging strategy provides insights into the design of biocompatible nanomedicines for cellular delivery and the degradative mechanisms beyond the intracellular fate.

The Keratinocyte in the Picture Cutaneous Melanoma Microenvironment.

Melanoma progression is a multistep evolution from a common melanocytic nevus through a radial superficial growth phase, the invasive vertical growth phase finally leading to metastatic dissemination into distant organs. Melanoma aggressiveness largely depends on the propensity to metastasize, which means the capacity to escape from the physiological microenvironment since tissue damage due to primary melanoma lesions is generally modest. Physiologically, epidermal melanocytes are attached to the basement membrane, and their adhesion/migration is under the control of surrounding keratinocytes. Thus, the epidermal compartment represents the first microenvironment responsible for melanoma spread. This complex process involves cell-cell contact and a broad range of secreted bioactive molecules. Invasion, or at the beginning of the microinvasion, implies the breakdown of the dermo-epidermal basement membrane followed by the migration of neoplastic melanocytic cells in the superficial papillary dermis. Correspondingly, several experimental evidences documented the structural and functional rearrangement of the entire tissue surrounding neoplasm that in some way reflects the atypia of tumor cells. Lastly, the microenvironment must support the proliferation and survival of melanocytes outside the normal epidermal-melanin units. This task presumably is mostly delegated to fibroblasts and ultimately to the self-autonomous capacity of melanoma cells. This review will discuss remodeling that occurs in the epidermis during melanoma formation as well as skin changes that occur independently of melanocytic hyperproliferation having possible pro-tumoral features.

How murine neutrophils are hijacked within the microenvironment of pancreatic cancer.

Discoveries made in the past decades have brought out that, in addition to their classical primary defensive functions against infections, polymorphonuclear neutrophils play key effector roles not only in chronic inflammatory and immune-mediated diseases but also in cancer. In addition, depending on their differentiation/activation status and/or on the physiological or pathological microenvironment in which they reside, neutrophils have been shown to behave as highly plastic cells, able to acquire new phenotypes/functional states. All these features are well manifested in cancer and modulated during tumor progression. Herein, we discuss intriguing data by Lai Ng's group that have shed light on the origin and development of terminally differentiated, proangiogenic, tumor-associated neutrophils, facilitating tumor growth in a murine orthotopic model of pancreatic ductal adenocarcinoma. These findings help to progress toward the ambitious goal of selectively targeting only the skewed pathological neutrophil populations present within the tumor microenvironment.

Assessment of the proteome profile of decellularized human amniotic membrane and its biocompatibility with umbilical cord-derived mesenchymal stem cells.

Extracellular matrix-based bio-scaffolds are useful for tissue engineering as they retain the unique structural, mechanical, and physiological microenvironment of the tissue thus facilitating cellular attachment and matrix activities. However, considering its potential, a comprehensive understanding of the protein profile remains elusive. Herein, we evaluate the impact of decellularization on the human amniotic membrane (hAM) based on its proteome profile, physicochemical features, as well as the attachment, viability, and proliferation of umbilical cord-derived mesenchymal stem cells (hUC-MSC). Proteome profiles of decellularized hAM (D-hAM) were compared with hAM, and gene ontology (GO) enrichment analysis was performed. Proteomic data revealed that D-hAM retained a total of 249 proteins, predominantly comprised of extracellular matrix proteins including collagens (collagen I, collagen IV, collagen VI, collagen VII, and collagen XII), proteoglycans (biglycan, decorin, lumican, mimecan, and versican), glycoproteins (dermatopontin, fibrinogen, fibrillin, laminin, and vitronectin), and growth factors including transforming growth factor beta (TGF-β) and fibroblast growth factor (FGF) while eliminated most of the intracellular proteins. Scanning electron microscopy was used to analyze the epithelial and basal surfaces of D-hAM. The D-hAM displayed variability in fibril morphology and porosity as compared with hAM, showing loosely packed collagen fibers and prominent large pore areas on the basal side of D-hAM. Both sides of D-hAM supported the growth and proliferation of hUC-MSC. Comparative investigations, however, demonstrated that the basal side of D-hAM displayed higher hUC-MSC proliferation than the epithelial side. These findings highlight the importance of understanding the micro-environmental differences between the two sides of D-hAM while optimizing cell-based therapeutic applications.

Acid and Glutathione Dual-Responsive, Injectable and Self-Healing Hydrogels for Controlled Drug Delivery.

Considering the complexity of physiological microenvironments and the risks of surgical infection, there still remains critical demand to develop a hydrogel as a drug release platform with multifunctional properties, including good neutral stability and sensitive multiple stimuli-responsive behaviors, as well as injectable and self-healing properties. Herein, we present a facile preparation of injectable, self-healing hydrogels with acid and glutathione (GSH) dual-responsiveness for controlled drug delivery. Initially, the anticancer drug camptothecin (CPT) was premodified with disulfide bonds and attached to poly(ethylenimine) (PEI) via the Schiff base reaction, resulting in PEI-CPT. Subsequently, OSA-IR780 was synthesized through the Schiff base reaction involving IR780 with amine groups (IR780-NH2) and oxidized sodium alginate with aldehyde groups (OSA). The formation of PEI-CPT/OSA-IR780 hydrogels with various solid contents occurred rapidly within 40 s through a simple mixing process of the aqueous solution of PEI-CPT and OSA-IR780. These hydrogels exhibited remarkable stability under neutral conditions and controlled release of CPT upon exposure to simulated tumor environments characterized by acidic conditions and elevated GSH concentrations. Furthermore, they had significant injectable and self-healing properties due to the dynamically imine-cross-linked networks. In addition, the prepared hydrogels exhibited long-term biodegradability and biocompatibility. Collectively, these features indicate the great potential of PEI-CPT/OSA-IR780 hydrogels as therapeutic delivery vehicles.

Self-Healing Hydrogel Containing Decellularized Liver Matrix and Endothelial Cell-Covered Hepatocyte Spheroids for Rescue of Injured Hepatocytes.

Liver fibrosis occurs in many chronic liver diseases, while severe fibrosis can lead to liver failure. A chitosan-phenol based self-healing hydrogel (CP) integrated with decellularized liver matrix (DLM) is proposed in this study as a 3D gel matrix to carry hepatocytes for possible therapy of liver fibrosis. To mimic the physiological liver microenvironment, DLM is extracted from pigs and mixed with CP hydrogel to generate DLM-CP self-healing hydrogel. Hepatocyte spheroids coated with endothelial cells (ECs) are fabricated using a customized method and embedded in the hydrogel. Hepatocytes injured by exposure to CCl4-containing medium are used as the in vitro toxin-mediated liver fibrosis model, where the EC-covered hepatocyte spheroids embedded in the hydrogel are co-cultured with the injured hepatocytes. The urea synthesis of the injured hepatocytes reaches 91% of the normal level after 7 days of co-culture, indicating that the hepatic function of injured hepatocytes is rescued by the hybrid spheroid-laden DLM-CP hydrogel. Moreover, the relative lactate dehydrogenase activity of the injured hepatocytes is decreased 49% by the hybrid spheroid-laden DLM-CP hydrogel after 7 days of co-culture, suggesting reduced damage in the injured hepatocytes. The combination of hepatocyte/EC hybrid spheroids and DLM-CP hydrogel presents a promising therapeutic strategy for hepatic fibrosis.

Enhanced solute transport and steady mechanical stimulation in a novel dynamic perifusion bioreactor increase the efficiency of the in vitro culture of ovarian cortical tissue strips.

Introduction: We report the development and preliminary evaluation of a novel dynamic bioreactor to culture ovarian cortical tissue strips that leverages tissue response to enhanced oxygen transport and adequate mechanical stimulation. In vitro multistep ovarian tissue static culture followed by mature oocyte generation, fertilization, and embryo transfer promises to use the reserve of dormant follicles. Unfortunately, static in vitro culture of ovarian tissue does not promote development of primordial to secondary follicles or sustain follicle viability and thereby limits the number of obtainable mature oocytes. Enhancing oxygen transport to and exerting mechanical stimulation on ovarian tissue in a dynamic bioreactor may more closely mimic the physiological microenvironment and thus promote follicle activation, development, and viability. Materials and Methods: The most transport-effective dynamic bioreactor design was modified using 3D models of medium and oxygen transport to maximize strip perifusion and apply tissue fluid dynamic shear stresses and direct compressive strains to elicit tissue response. Prototypes of the final bioreactor design were manufactured with materials of varying cytocompatibility and assessed by testing the effect of leachables on sperm motility. Effectiveness of the bioreactor culture was characterized against static controls by culturing fresh bovine ovarian tissue strips for 7days at 4.8 × 10-5m/s medium filtration flux in air at -15% maximal total compressive strain and by assessing follicle development, health, and viability. Results and Conclusions: Culture in dynamic bioreactors promoted effective oxygen transport to tissues and stimulated tissues with strains and fluid dynamic shear stresses that, although non-uniform, significantly influenced tissue metabolism. Tissue strip culture in bioreactors made of cytocompatible polypropylene preserved follicle viability and promoted follicle development better than static culture, less so in bioreactors made of cytotoxic ABS-like resin.

Stretching of porous poly (l-lactide-co-ε-caprolactone) membranes regulates the differentiation of mesenchymal stem cells.

Background: Among a variety of biomaterials supporting cell growth for therapeutic applications, poly (l-lactide-co-ε-caprolactone) (PLCL) has been considered as one of the most attractive scaffolds for tissue engineering owing to its superior mechanical strength, biocompatibility, and processibility. Although extensive studies have been conducted on the relationship between the microstructure of polymeric materials and their mechanical properties, the use of the fine-tuned morphology and mechanical strength of PLCL membranes in stem cell differentiation has not yet been studied. Methods: PLCL membranes were crystallized in a combination of diverse solvent-nonsolvent mixtures, including methanol (MeOH), isopropanol (IPA), chloroform (CF), and distilled water (DW), with different solvent polarities. A PLCL membrane with high mechanical strength induced by limited pore formation was placed in a custom bioreactor mimicking the reproducible physiological microenvironment of the vascular system to promote the differentiation of mesenchymal stem cells (MSCs) into smooth muscle cells (SMCs). Results: We developed a simple, cost-effective method for fabricating porosity-controlled PLCL membranes based on the crystallization of copolymer chains in a combination of solvents and non-solvents. We confirmed that an increase in the ratio of the non-solvent increased the chain aggregation of PLCL by slow evaporation, leading to improved mechanical properties of the PLCL membrane. Furthermore, we demonstrated that the cyclic stretching of PLCL membranes induced MSC differentiation into SMCs within 10days of culture. Conclusion: The combination of solvent and non-solvent casting for PLCL solidification can be used to fabricate mechanically durable polymer membranes for use as mechanosensitive scaffolds for stem cell differentiation.

Retraction Note to: Mechanical model of the physiological microenvironment of cardiomyocytes

Retraction Note to: Mechanical model of the physiological microenvironment of cardiomyocytes

ADVANCED TENDON REPAIR STRATEGIES: FROM EVS TO MRNA-BASED APPROACHES

Approximately 30% of general practice consultations for musculoskeletal pain are related to tendon disorders, causing substantial personal suffering and enormous related healthcare costs. Treatments are often prone to long rehabilitation times, incomplete functional recovery, and secondary complications following surgical repair. Overall, due to their hypocellular and hypovascular nature, the regenerative capacity of tendons is very poor and intrinsically a disorganized scar tissue with inferior biomechanical properties forms after injury. Therefore, advanced therapeutic modalities need to be developed to enable functional tissue regeneration within a degenerative environment, moving beyond pure mechanical repair and overcoming the natural biological limits of tendon healing.Our recent studies have focused on developing biologically augmented treatment strategies for tendon injuries, aiming at restoring a physiological microenvironment and boosting endogenous tissue repair. Along these lines, we have demonstrated that the local application of mesenchymal stromal cell-derived small extracellular vesicles (sEVs) has the potential to improve rotator cuff tendon repair by modulating local inflammation and reduce fibrotic scarring. In another approach, we investigated if the local delivery of the tendon ECM protein SPARC, which we previously demonstrated to be essential for tendon maturation and tissue homeostasis, has the potential to enhance tendon healing. Finally, I will present results demonstrating the utility of nanoparticle-delivered, chemically modified mRNAs (cmRNA) to improve tendon repair.

Advancing piezoelectric 2D nanomaterials for applications in drug delivery systems and therapeutic approaches.

Precision drug delivery and multimodal synergistic therapy are crucial in treating diverse ailments, such as cancer, tissue damage, and degenerative diseases. Electrodes that emit electric pulses have proven effective in enhancing molecule release and permeability in drug delivery systems. Moreover, the physiological electrical microenvironment plays a vital role in regulating biological functions and triggering action potentials in neural and muscular tissues. Due to their unique noncentrosymmetric structures, many 2D materials exhibit outstanding piezoelectric performance, generating positive and negative charges under mechanical forces. This ability facilitates precise drug targeting and ensures high stimulus responsiveness, thereby controlling cellular destinies. Additionally, the abundant active sites within piezoelectric 2D materials facilitate efficient catalysis through piezochemical coupling, offering multimodal synergistic therapeutic strategies. However, the full potential of piezoelectric 2D nanomaterials in drug delivery system design remains underexplored due to research gaps. In this context, the current applications of piezoelectric 2D materials in disease management are summarized in this review, and the development of drug delivery systems influenced by these materials is forecast.