Tissue regeneration and remodeling involve many complex stages. Macrophages are critical in maintaining micro-environmental homeostasis by regulating inflammation and orchestrating wound healing. They display high plasticity in response to various stimuli, showing a spectrum of functional phenotypes that vary from M1 (pro-inflammatory) to M2 (anti-inflammatory) macrophages. While transient inflammation is an essential trigger for tissue healing following an injury, sustained inflammation (e.g., in foreign body response to implants, diabetes or inflammatory diseases) can hinder tissue healing and cause tissue damage. Modulating macrophage polarization has emerged as an effective strategy for enhancing immune-mediated tissue regeneration and promoting better integration of implantable materials in the host. This article provides an overview of macrophages\' functional properties followed by discussing different strategies for modulating macrophage polarization. Advances in the use of synthetic and natural biomaterials to fabricate immune-modulatory materials are highlighted. This reveals that the development and clinical application of more effective immunomodulatory systems targeting macrophage polarization under pathological conditions will be driven by a detailed understanding of the factors that regulate macrophage polarization and biological function in order to optimize existing methods and generate novel strategies to control cell phenotype.

Due to their tissue structure similar to mammalian skin and their close evolutionary relationship with chordates, holothurians (Echinodermata: Holothuroidea) are particularly interesting for studies on wound healing. However, previous studies dealing with holothuroid wound healing have had limited approaches, being restricted to tissue repair or perivisceral immune response. In this study, we combined tissue, cellular and humoral parameters to study the wound healing process of Holothuria grisea. The immune responses of the perivisceral coelom were assessed by analyzing the number, proportion and viability of coelomocytes and the volume and protein concentration of the coelomic fluid. Additionally, the morphology of the healing tissue and number of coelomocytes in the connective tissue of different body wall layers were examined over 30 days. Our results showed that perivisceral reactions started 3 h after injury and decreased to baseline levels within 24 h. In contrast, tissue responses were delayed, beginning after 12 h and returning to baseline levels only after day 10. The number of coelomocytes in the connective tissue suggests a potential cooperation between these cells during wound healing: phagocytes and acidophilic spherulocytes act together in tissue clearance/homeostasis, whereas fibroblast-like and morula cells cooperate in tissue remodeling. Finally, our results indicate that the major phases observed in mammalian wound healing are also observed in H. grisea, despite occurring at a different timing, which might provide insights for future studies. Based on these data, we propose a model that explains the entire healing process in H. grisea.

Intervertebral disc (IVD) herniation is a leading cause of disability and lower back pain, causing enormous socioeconomic burdens. The standard of care for disc herniation is nucleotomy, which alleviates pain but does not repair the annulus fibrosus (AF) defect nor recover the biomechanical function of the disc. Existing bioadhesives for AF repair are limited by insufficient adhesion and significant mechanical and geometrical mismatch with the AF tissue, resulting in the recurrence of protrusion or detachment of bioadhesives. Here, we report a composite hydrogel sealant constructed from a composite of a three-dimensional (3D)-printed thermoplastic polyurethane (TPU) mesh and tough hydrogel. We tailored the fiber angle and volume fraction of the TPU mesh design to match the angle-ply structure and mechanical properties of native AF. Also, we proposed and tested three types of geometrical design of the composite hydrogel sealant to match the defect shape and size. Our results show that the sealant could mimic native AF in terms of the elastic modulus, flexural modulus, and fracture toughness and form strong adhesion with the human AF tissue. The bovine IVD tests show the effectiveness of the composite hydrogel sealant for AF repair and biomechanics recovery and for preventing herniation with its heightened stiffness and superior adhesion. By harnessing the combined capabilities of 3D printing and bioadhesives, these composite hydrogel sealants demonstrate promising potential for diverse applications in tissue repair and regeneration.

BACKGROUND: Bone marrow-derived mesenchymal stem cell (BMMSC)-based therapy has become a major focus for treating liver fibrosis/cirrhosis. However, although these cell therapies promote the treatment of this disease, the heterogeneity of BMMSCs, which causes insufficient efficacy during clinical trials, has not been addressed. In this study, we describe a novel Percoll-Plate-Wait procedure (PPWP) for the isolation of an active cell subset from BMMSC cultures that was characterized by the expression of neuroglial antigen 2 (NG2/BMMSCs).
METHODS: By using the key method of PPWP and other classical biological techniques we compared NG2/BMMSCs with parental BMMSCs in biological and functional characteristics within a well-defined diethylnitrosamine (DEN)-induced liver fibrosis/cirrhosis injury male C57BL/6 mouse model also in a culture system. Of note, the pathological alterations in the model is quite similar to humans\'.
RESULTS: The NG2/BMMSCs revealed more advantages compared to parentalBMMSCs. They exhibited greater proliferation potential than parental BMMSCs, as indicated by Ki-67 immunofluorescence (IF) staining. Moreover, higher expression of SSEA-3 (a marker specific for embryonic stem cells) was detected in NG2/BMMSCs than in parental BMMSCs, which suggested that the \"stemness\" of NG2/BMMSCs was greater than that of parental BMMSCs. In vivo studies revealed that an injection of NG2/BMMSCs into mice with ongoing DEN-induced liver fibrotic/cirrhotic injury enhanced repair and functional recovery to a greater extent than in mice treated with parental BMMSCs. These effects were associated with the ability of NG2/BMMSCs to differentiate into bile duct cells (BDCs). In particular, we discovered for the first time that NG2/BMMSCs exhibit unique characteristics that differ from those of parental BMMSCs in terms of producing liver sinusoidal endothelial cells (LSECs) to reconstruct injured blood vessels and sinusoidal structures in the diseased livers, which are important for initiating hepatocyte regeneration. This unique potential may also suggest that NG2/BMMSCs could be an novel off-liver progenitor of LSECs. Ex vivo studies revealed that the NG2/BMMSCs exhibited a similar trend to that of their in vivo in terms of functional differentiation responding to the DEN-diseased injured liver cues. Additionally, the obvious core role of NG2/BMMSCs in supporting the functions of BMMSCs in bile duct repair and BDC-mediated hepatocyte regeneration might also be a novel finding.
CONCLUSIONS: Overall, the PPWP-isolated NG2/BMMSCs could be a novel effective cell subset with increased purity to serve as a new therapeutic tool for enhancing treatment efficacy of BMMSCs and special seed cell source (BDCs, LSECs) also for bioliver engineering.

To evaluate the effects of red and infrared wavelengths, separately and combined, on the inflammatory process and collagen deposition in muscle damage caused by B. leucurus venom. 112 mice were inoculated with diluted venom (0.6mg/kg) in the gastrocnemius muscle. The animals were divided into four groups: one control (CG) and three treatments, namely: 1) red laser (λ=660 nm) (RG), 2) infrared laser (λ=808 nm) (IG) and 3) red laser (λ=660 nm) + infrared (λ=808 nm) (RIG). Each group was subdivided into four subgroups, according to the duration of treatment application (applications every 24 hours over evaluation times of up to 144 hours). A diode laser was used (0.1 W, CW, 1J/point, ED: 10 J/cm2). Both wavelengths reduced the intensity of inflammation and the combination between them significantly intensified the anti-inflammatory response. Photobiomodulation also changed the type of inflammatory infiltrate observed and RIG had the highest percentage of mononuclear cells in relation to the other groups. Hemorrhage intensity was significantly lower in treated animals and RIG had the highest number of individuals in which this variable was classified as mild. As for collagen deposition, there was a significant increase in RG in relation to CG, in RIG in relation to CG and in RIG in relation to IG. Photobiomodulation proved to be effective in the treatment of inflammation and hemorrhage caused by B. leucurus venom and stimulated collagen deposition. Better results were obtained with the combined wavelengths.

UNASSIGNED: This study examined the anti-inflammatory and antioxidant properties of Capparis spinosa L. (caper) in order to determine its medicinal potential in the treatment of acute colitis.
UNASSIGNED: Sixty male rats were divided into six groups. After the experimental period, distal colonic extension was collected for determination of colonic damage, oxidative stress markers, along with antioxidant markers. The impact of altered levels of inflammatory cytokines in colon tissues on the underlying mechanisms examined.
UNASSIGNED: The results showed that administering different doses of caper led to significant decreases in TNF-α and IL-6 levels when compared to the control colitis group (p < 0.001). Caper treatment effectively lowered elevated oxidative stress factors (MDA, NO, and MPO) compared to the control colitis group (p < 0.001). Caper treatment resulted in a significant increase in antioxidant factors (CAT, SOD, and GSH) compared with the control colitis group (p < 0.001).Significant improvements in tissue repair were observed in caper-treated groups compared to positives and control colitis (p < 0.001).
UNASSIGNED: The study highlights caper may be useful in the treatment of acute colitis due to its ameliorative effects on inflammation, oxidative stress, and tissue repair.

The skin of bony fish is the first physical barrier and is responsible for maintaining the integrity of the fish. Lesions make the skin vulnerable to potential infection by pathogens present in the aquatic environment. In this way, wound repair has barely been studied in gilthead sea bream. Thus, this study investigated the modulation of peripheral neuro-endocrine and tissue repair markers at the transcriptional level in the skin of teleost fish subjected to mechanical damage above or below the lateral line (dorsal and ventral lesions, respectively). Samples were evaluated using RT-qPCR at 2-, 4-, and 20-days post-injury. Fish with a ventral lesion presented a trend of progressive increase in the expressions of corticotropin-releasing hormone (crh), pro-opiomelanocortin-A (pomca), proenkephalin-B (penkb), cholecystokinin (cck), oxytocin (oxt), angiotensinogen (agt), and (less pronounced) somatostatin-1B (sst1b). By contrast, fish with a dorsal lesion registered no significant increase or biological trend for the genes evaluated at the different sampling times. Collectively, the results show a rapid and more robust response of neuro-endocrine and tissue repair markers in the injuries below than above the lateral line, which could be attributable to their proximity to vital organs.

Monodisperse nanoparticles of biodegradable polyhydroxyalkanoates (PHAs) polymers, copolymers of 3-hydroxybutyrate (3HB) and 4-hydroxybutyrate (4HB), are synthesized using a membrane-assisted emulsion encapsulation and evaporation process for biomedical resorbable adhesives. The precise control over the diameter of these PHA particles, ranging from 100 nm to 8 μm, is achieved by adjusting the diameter of emulsion or the PHA concentration. Mechanical properties of the particles can be tailored based on the 3HB to 4HB ratio and molecular weight, primarily influenced by the level of crystallinity. These monodisperse PHA particles in solution serve as adhesives for hydrogel systems, specifically those based on poly(N, N-dimethylacrylamide) (PDMA). Semi-crystalline PHA nanoparticles exhibit stronger adhesion energy than their amorphous counterparts. Due to their self-adhesiveness, adhesion energy increases even when those PHA nanoparticles form multilayers between hydrogels. Furthermore, as they degrade and are resorbed into the body, the PHA nanoparticles demonstrate efficacy in in vivo wound closure, underscoring their considerable impact on biomedical applications.

Infection is the most common complication after orthopedic surgery and can result in prolonged ailments such as chronic wounds, enlarged bone defects, and osteomyelitis. Iron, which is essential for bacterial metabolism and immune cell functions, is extremely important. Bacteria harness iron from nearby cells to promote biofilm formation, ensuring their survival. Iron deficiency within the infection microenvironment (IME) consequently hampers macrophage function, enabling further dissemination of the infection and hindering macrophage polarization to the M2 phenotype. Therefore, a novel approach is proposed to regulate macrophage polarization, aiming to restore the inflammatory immune environment. A composite hydrogel derived from natural polymers is developed to address infections and manage iron metabolism in macrophages. This IME-responsive hydrogel, named FCL-ECMH, is synthesized by encapsulating vermiculite functional core layers within a decellularized extracellular matrix hydrogel. It is noteworthy that FCL-ECMH can produce reactive oxygen species within the IME. Supplementary photothermal treatment enhances bacterial iron uptake, leading to ferroptosis-like death. This process also rejuvenates the iron-enriched macrophages around the IME, thereby enhancing their antibacterial and tissue repair functions. In vivo experiments confirmed the antibacterial and repair-promoting capabilities of FCL-ECMH, indicating its potential for clinical applications.

Tissue repair and regeneration, such as bone and nerve restoration, face significant challenges due to strict regulations within the immune microenvironment, stem cell differentiation, and key cell behaviors. The development of 3D scaffolds is identified as a promising approach to address these issues via the efficiently structural regulations on cell fates and behaviors. In particular, 3D-printed polymer scaffolds with diverse micro-/nanostructures offer a great potential for mimicking the structures of tissue. Consequently, they are foreseen as promissing pathways for regulating cell fates, including cell phenotype, differentiation of stem cells, as well as the migration and the proliferation of key cells, thereby facilitating tissue repairs and regenerations. Herein, the roles of structural functions of 3D-printed polymer scaffolds in regulating the fates and behaviors of numerous cells related to tissue repair and regeneration, along with their specific influences are highlighted. Additionally, the challenges and outlooks associated with 3D-printed polymer scaffolds with various structures for modulating cell fates are also discussed.