Development and in vitro assessment of injectable, adhesive, and self-healing chitosan-based hydrogels for treatment of spinal cord injury.

Injured spinal cords have a limited ability to regenerate because of the inhibitory environment formed in situ that affects neuronal regrow. Ensuring stable contact between the injuried nerves to support neural regeneration in the lesion microenvironment remains a significant challenge. To address this challenge, we have engineered a new injectable and adhesive hydrogel to treat spinal cord injuries. This hydrogel was produced by functionalizing chitosan with catechol groups and crosslinking it with different amounts of ß-glycerophosphate to obtain adhesive hydrogels with tunable mechanical properties. The softest hydrogel (G' ~ 300 Pa) demonstrated strong adhesion to different biological soft tissues, including porcine skin (adhesion strength of 3.4 ± 0.9 kPa) and spinal cord, as well as injectability and self-healing abilities, making it ideal for a minimally invasive administration in difficult-to-reach areas. Additionally, this composition promoted the attachment, viability, proliferation, and the expression of neuronal marker ß-III tubulin (Tuj-1) by the neuroblastoma SH-SY5Y cells. Moreover, SH-SY5Y cells cultured on the hydrogel modulated its mechanical properties (G' ~ 3500 Pa). In summary, we propose a material that is compatible with different therapies for soft tissue healing, including repairing injured nerve tissue.

Deciphering Collagen Phenotype Dynamics Regulators: Insights from In-Silico Analysis.

Collagen (Col) types I and III are integral components in wound healing and tissue regeneration, influencing tissue development, homeostasis, and related pathologies. Col I and Col III expression changes during different stages of wound healing and understanding the regulation of collagen phenotype determination is crucial for unraveling the complexities of these processes. Transcription factors and microRNAs, directly and indirectly, play a critical role in regulating collagen expression, however, a comprehensive understanding of the factors regulating Col I and III phenotypes remains elusive. This critically analyzed published reports with focuses on various factors regulating the expression of Col I and Col III at the transcriptional and translational levels. We performed bioinformatics analysis with an input of proinflammatory mediators, growth factors, elastases, and matrix metalloproteinases and predicted transcription factors and microRNAs involved in the regulation of collagen expression. Network analysis revealed an interaction between genes, transcription factors, and microRNAs and provided a holistic view of the regulatory landscape governing collagen expression and unveils intricate interconnections. This analysis lays a founda-tional framework for guiding future research and therapeutic interventions to promote extracellular matrix remodeling, wound healing, and tissue regeneration after an injury by modulating collagen expression. In essence, this scientific groundwork offers a comprehensive exploration of the regulatory dynamics in collagen synthesis, serving as a valuable resource for advancing both basic research and clinical interventions in tissue repair.

Epidermal Stem Cells: Interplay with the Skin Microenvironment During Wound Healing.

Skin undergoes everyday turnover while often challenged by injuries. The wound healing process in the skin is a dynamic sequence of events that involves various cell types and signaling pathways. Epidermal stem cells (EpdSCs), the tissue-resident stem cells in the skin tissue, are in the center of this complicated process due to their special ability to self-renew and differentiate. During this process, EpdSCs interact actively with the tissue microenvironment, which is essential for proper re-epithelialization and skin barrier restoration. This review describes the intricate interplays between EpdSCs and various components of their surroundings, including ECM/fibroblasts, vasculature/endothelial cells, and immune cells, as well as their roles in tissue repair.

Biomacromolecular hydrogel scaffolds from microfluidics for cancer therapy: A review.

Traditional cancer treatment is confronted with the problem of limited therapeutic effect, tissue defects, and lack of drug screening. Hydrogel scaffolds from biological macromolecules based on microfluidic technology are a promising candidate, which can mimic tumor microenvironments to screen personalized drugs, promote the regeneration of healthy tissues, and deliver drugs for enhanced localized antitumor treatment. This review summarizes the latest research on the composition of biomacromolecular hydrogel scaffolds, the architecture of hydrogel scaffolds from microfluidic technology, and their application in cancer therapy, including anti-tumor drug screening, anti-tumor treatment, and anti-tumor treatment and tissue repair. In addition, the potential breakthroughs of this innovative platform in the clinical transformation of cancer therapy are further discussed. The insights revealed in this review are intended to guide the utilization of microfluidic technology-based biomacromolecular hydrogel scaffolds in cancer therapy.

Immunomodulatory Biomaterials: Tailoring Surface Properties to Mitigate Foreign Body Reaction and Enhance Tissue Regeneration.

The immune cells have demonstrated the ability to promote tissue repair by removing debris, breaking down the extracellular matrix, and regulating cytokine secretion profile. If the behavior of immune cells is not well directed, chronic inflammation and foreign body reaction (FBR) will lead to scar formation and loss of biomaterial functionality. The immunologic response toward tissue repair or chronic inflammation after injury and implantation can be modulated by manipulating the surface properties of biomaterials. Tailoring surface properties of biomaterials enables the regulation of immune cell fate such as adhesion, proliferation, recruitment, polarization, and cytokine secretion profile. This review begins with an overview of the role of immune cells in tissue healing and their interactions with biomaterials. It then discusses how the surface properties of biomaterials influence immune cell behavior. The core focus is reviewing surface modification methods to create innovative materials that reduce foreign body reactions and enhance tissue repair and regeneration by modulating immune cell activities. The review concludes with insights into future advancements in surface modification techniques and the associated challenges.

Immunomodulation of Macrophages in Diabetic Wound Individuals by Structurally Diverse Bioactive Phytochemicals.

Diabetes-related ulcers and slow-healing wounds pose a significant health risk to individuals due to their uncertain causes. Mortality rates for diabetes foot ulcers (DFUs) range from 10% after 16 months to 24% after five years. The use of bioactive phytochemicals can play a key role in healing wounds in a predictable time. Recent literature has demonstrated that various natural substances, including flavonoids, saponins, phenolic compounds, and polysaccharides, play key roles at different stages of the wound-healing process through diverse mechanisms. These studies have categorized the compounds according to their characteristics, bioactivities, and modes of action. In this study, we evaluated the role of natural compounds derived from plant sources that have been shown to play a crucial role in immunomodulation. Macrophages are closely involved in immunomodulation within the wound microenvironment and are key players in efferocytosis, inflammation resolution, and tissue regeneration, all of which contribute to successful wound healing. Phytochemicals and their derivatives have shown capabilities in immune regulation, including macrophage migration, nitric oxide synthase inhibition, lymphocyte and T-cell stimulation, cytokine activation, natural killer cell enhancement, and the regulation of NF-κß, TNF-α, and apoptosis. In this review, we have studied the role of phytochemicals in immunomodulation for the resolution of diabetic wound inflammation.

Isoorientin Improves Excisional Skin Wound Healing in Mice.

Background/Objectives: Wound healing relies on a coordinated process with the participation of different mediators. Natural products are a source of active compounds with healing potential. Isoorientin is a natural flavone recognized as having several pharmacological properties, such as anti-inflammatory effects, making it a potential treatment for wounds. We investigated the effect of isoorientin on the healing of excisional skin wounds. Methods: Male Swiss mice were subjected to the induction of excisional skin wounds (6 mm diameter) and treated with a vehicle (2% dimethyl sulfoxide in propylene glycol) or 2.5% isoorientin applied topically once a day for 14 days. The wound area was measured on days 0, 3, 7, and 14. Histopathological analyses were performed on the cicatricial tissue after 14 days. The myeloperoxidase activity and the interleukin-1ß, tumoral necrosis factor (TNF)-α, and interleukin-6 concentrations were determined on the third day. Results: We observed that 3 days after the topical application of isoorientin, the lesion area was significantly smaller when compared to those of the vehicle (p < 0.01) and control (p < 0.05) groups. No difference was observed after 7 and 14 days of induction. Despite this, on day 14, histological analysis of cicatricial tissue from the animals treated with isoorientin showed reduced epidermal thickness (p < 0.001) and increased collagen deposition (p < 0.001). These effects were accompanied by decreased myeloperoxidase activity and interleukin-1ß concentration on the third day of induction, without alteration in TNF-α and interleukin-6. Conclusions: The treatment with isoorientin promoted better tissue repair in excisional wounds in mice, which may be linked to the modulation of the early inflammatory response.

Engineered extracellular vesicles for tissue repair and regeneration.

Extracellular vesicles (EVs) are heterogeneous membrane-like vesicles secreted by living cells that are involved in many physiological and pathological processes and act as intermediaries of intercellular communication and molecular transfer. Recent studies have shown that EVs from specific sources regulate tissue repair and regeneration by delivering proteins, lipids, and nucleic acids to target cells as signaling molecules. Nanotechnology breakthroughs have facilitated the development and exploration of engineered EVs for tissue repair. Enhancements through gene editing, surface modification, and content modification have further improved their therapeutic efficacy. This review summarizes the potential of EVs in tissue repair and regeneration, their mechanisms of action, and their research progress in regenerative medicine. This review highlights their design logic through typical examples and explores the development prospects of EVs in tissue repair. The aim of this review is to provide new insights into the design of EVs for tissue repair and regeneration applications, thereby expanding their use in regenerative medicine.

Monocytes/Macrophages in Helminth Infections: Key Players in Host Defence, Inflammation, and Tissue Repair.

Monocytes/macrophages are pivotal in host defense, inflammation, and tissue repair. They are actively engaged during helminth infections, playing critical roles in trapping pathogens, eliminating them, repairing tissue damage, and mitigating type 2 inflammation. These cells are indispensable in preserving physiological equilibrium and overseeing pathogen resistance as well as metabolic processes. Furthermore, these immune cells are influenced by cellular metabolism, which adjusts in response to host-derived factors and environmental cues. They secrete effector molecules crucial for anti-helminthic immunity and healing tissues damaged by parasites. Helminth parasites manipulate the immune regulatory capabilities of monocytes/macrophages by secreting anti-inflammatory mediators to dodge host defenses. Infections, especially with helminths, induce metabolic adaptations involving monocytes/macrophages that can lead to enhanced insulin sensitivity. This review provides a synthesis of the activation and diversity of monocytes/macrophages, their involvement in inflammation, and the latest insights into the strategies of monocyte/macrophage-mediated host defense against helminth infections. It also sheds light on recent discoveries concerning the immune regulatory interactions between monocytes/macrophages and helminth parasites.

A rapid and robust organ repair polyacrylamide/alginate adhesive hydrogel mediated via interfacial adhesion-trigger molecules.

Adhesive hydrogels have been widely explored as tissue adhesives for wound sealing and repair. However, developing adhesive hydrogels with simple preparation techniques and strong adhesion to internal organs in a short time remains a challenge. In this study, we developed a strategy for robust and rapid tissue adhesion of internal organ sealing and repair by an interfacial adhesion-molecule triggered hydrogel system. In this system, polyphenol molecules act as adhesion-trigger reagents to achieve fast and strong adhesion of polyacrylamide/alginate hydrogels on the surface of wound tissue by rapidly forming abundant hydrogen bonds at the interface. The adhesion energy is significantly enhanced by 45 times under the mediation of polyphenol adhesion-trigger molecules, resulting in a robust (> 600 J m-2) tissue adhesion in just 30 s. This interfacial adhesion system demonstrates good biocompatibility, strong sealing performance on multiple organs (porcine heart, lung, stomach, and intestine), and excellent repair properties in gastric perforation wounds of rabbits in vivo. Moreover, immunocytochemical and transcriptomic analyses reveal that this interfacial adhesion system significantly promotes vascular regeneration and inhibits inflammatory responses during wound repairing. The proposed hydrogel provides a facile strategy for rapid and robust tissue adhesion, and shows potential applications in organ sealing and repair.

Electrically-stimulated cellular and tissue events are coordinated through ion channel-mediated calcium influx and chromatin modifications across the cytosol-nucleus space.

Electrical stimulation (ES) through biomaterials and devices has been implicated in activating diverse cell behaviors while facilitating tissue healing process. Despite its significance in modulating biological events, the mechanisms governing ES-activated cellular phenomena remain largely elusive. Here, we demonstrated that millisecond-pulsed temporal ES profoundly impacted a spectrum of cellular events across the membrane-cytosol-nuclear space. These include activated ion channels, intracellular calcium influx, actomyosin contractility, cell migration and proliferation, and secretome release. Such events were coordinated mainly through ES-activated ion channels and calcium oscillation dynamics. Notably, ES increased the chromatin accessibility of genes, particularly those associated with the ES-activated cellular events, underscoring the significance of epigenetic changes in ES-induced behavioral outcomes. We identified histone acetylation (mediated by histone acetyltransferases), among other chromatin modifications, is key in reshaping the chromatin landscape upon ES. These observations were further validated through experiments involving ex vivo skin tissue samples, including activated ion channels and calcium influx, increased cell proliferation and actomyosin contractility, elevated secretome profile, and more accessible chromatin structure following ES. This work provides novel insights into the mechanisms underlying ES-activated cell and tissue events, ultimately guiding design principles for the development of electrical devices and materials effective for tissue repair and wound healing.

Photobiomodulation on Full-Thickness Skin Graft Survival in Rats.

OBJECTIVE: To evaluate the photobiomodulation effects on the receptor area for full-thickness skin graft integration. METHODS: Thirty-Six Wistar rats were divided: red laser (660 nm), infrared laser (808 nm), and control. A skin segment with 5 × 3 cm was removed. In the control, the skin was reallocated after a 180° rotation. For the 660 nm and 808 nm, the receptor area was first irradiated, and then the skin was reallocated the same as the control. Euthanasia occurred on the third and seventh days after the procedure, and macroscopical of necrosis and histological analysis were realized. RESULTS: The 660 nm reached the lowest necrosis percentage on Day 7. In the 808 nm, necrosis increased between the two periods. Similar morphological findings were observed for the control and 660 nm; however, the 808 nm showed significant alterations in fibrosis and inflammatory infiltrate. CONCLUSION: The infrared wavelength showed inferior performance on skin graft integration compared to the control and the red wavelength.

The Role of Platelet-Rich Plasma in the Management of Sensorineural Hearing Loss: Current Evidence and Emerging Trends.

Sensorineural hearing loss (SNHL) is a common form of hearing impairment characterized by damage to the inner ear or auditory nerve, resulting in significant communication difficulties and reduced quality of life. Current treatment options, including hearing aids, cochlear implants, and corticosteroids, primarily focus on symptom management and do not address the underlying pathophysiological damage. Platelet-rich plasma (PRP), an autologous concentrate rich in platelets and growth factors, has emerged as a potential regenerative therapy due to its ability to promote tissue repair and cellular regeneration. This review provides a comprehensive overview of the role of PRP in the management of SNHL, examining the current evidence from preclinical and clinical studies. We discuss the mechanisms through which PRP may promote auditory tissue regeneration and repair, analyze its efficacy and safety profile, and explore innovative approaches and future directions in its application for SNHL. Despite promising preliminary findings, further research is needed to optimize PRP protocols, establish standardized treatment guidelines, and conduct large-scale randomized controlled trials to validate efficacy. This review aims to highlight the potential of PRP as a novel therapeutic strategy in treating SNHL and its possible integration into current clinical practices, offering new hope for patients with this debilitating condition.

Discovery of bioactive peptides as therapeutic agents for skin wound repair.

Short sequences of amino acids called peptides have a wide range of biological functions and the potential to treat a number of diseases. Bioactive peptides can be derived from different sources, including marine organisms, and synthetic design, making them versatile candidates for production of therapeutic agents. Their therapeutic effects span across areas such as antimicrobial activity, cells proliferation and migration, synthesis of collagen, and more. This current review explores the fascinating realm of bioactive peptides as promising therapeutic agents for skin wound healing. This review focuses on the multifaceted biological effects of specific peptides, shedding light on their potential to revolutionize the field of dermatology and regenerative medicine. It delves into how these peptides stimulate collagen synthesis, inhibit inflammation, and accelerate tissue regeneration, ultimately contributing to the effective repair of skin wounds. The findings underscore the significant role several types of bioactive peptides can play in enhancing wound healing processes and offer promising insights for improving the quality of life for individuals with skin injuries and dermatological conditions. The versatility of peptides allows for the development of tailored treatments catering to specific wound types and patient needs. As continuing to delve deeper into the realm of bioactive peptides, there is immense potential for further exploration and innovation. Future endeavors may involve the optimization of peptide formulations, elucidation of underlying molecular and cellular mechanisms.

An Innovative Approach of Utilizing the Digastric Tendon for Lower Lip Soft Tissue Repair: A Case Report.

Lower lip reconstruction following oral and neck oncosurgery presents significant challenges in maintaining function and esthetics. This case report describes a novel application of the digastric tendon for repairing the soft tissue of the lower lip in a patient undergoing wide excision of a lesion, bilateral modified radical neck dissection, segmental mandibulectomy, and free fibula flap repair. This innovative approach aims to maintain oral competence, strengthen the flap, and enhance esthetics. The digastric tendon was chosen due to its accessibility and effectiveness in strengthening the lower lip.

Current advances in the development of microRNA-integrated tissue engineering strategies: a cornerstone of regenerative medicine.

Regenerative medicine is an innovative scientific field focused on repairing, replacing, or regenerating damaged tissues and organs to restore their normal functions. A central aspect of this research arena relies on the use of tissue-engineered scaffolds, which serve as structural supports that mimic the extracellular matrix, providing an environment that orchestrates cell growth and tissue formation. Remarkably, the therapeutic efficacy of these scaffolds can be improved by harnessing the properties of other molecules or compounds that have crucial roles in healing and regeneration pathways, such as phytochemicals, enzymes, transcription factors, and non-coding RNAs (ncRNAs). In particular, microRNAs (miRNAs) are a class of tiny (20-24 nt), highly conserved ncRNAs that play a critical role in the regulation of gene expression at the post-transcriptional level. Accordingly, miRNAs are involved in a myriad of biological processes, including cell differentiation, proliferation, and apoptosis, as well as tissue regeneration, angiogenesis, and osteogenesis. On this basis, over the past years, a number of research studies have demonstrated that miRNAs can be integrated into tissue-engineered scaffolds to create advanced therapeutic platforms that precisely modulate cellular behavior and offer a controlled and targeted release of miRNAs to optimize tissue repair and regeneration. Therefore, in this current review, we discuss the most recent advances in the development of miRNA-loaded tissue-engineered scaffolds and provide an overview of the future outlooks that should be aborded in this area of study in order to lay the groundwork for the clinical translation of these tissue engineering approaches.

BioMOF@cellulose Glycerogel Scaffold with Multifold Bioactivity: Perspective in Bone Tissue Repair.

The development of new biomaterials for musculoskeletal tissue repair is currently an important branch in biomedicine research. The approach presented here is centered around the development of a prototypic synthetic glycerogel scaffold for bone regeneration, which simultaneously features therapeutic activity. The main novelty of this work lies in the combination of an open meso and macroporous nanocrystalline cellulose (NCC)-based glycerogel with a fully biocompatible microporous bioMOF system (CaSyr-1) composed of calcium ions and syringic acid. The bioMOF framework is further impregnated with a third bioactive component, i.e., ibuprofen (ibu), to generate a multifold bioactive system. The integrated CaSyr-1(ibu) serves as a reservoir for bioactive compounds delivery, while the NCC scaffold is the proposed matrix for cell ingrowth, proliferation and differentiation. The measured drug delivery profiles, studied in a phosphate-buffered saline solution at 310 K, indicate that the bioactive components are released concurrently with bioMOF dissolution after ca. 30 min following a pseudo-first-order kinetic model. Furthermore, according to the semi-empirical Korsmeyer-Peppas kinetic model, this release is governed by a case-II mechanism, suggesting that the molecular transport is influenced by the relaxation of the NCC matrix. Preliminary in vitro results denote that the initial high concentration of glycerol in the NCC scaffold can be toxic in direct contact with human osteoblasts (HObs). However, when the excess of glycerol is diluted in the system (after the second day of the experiment), the direct and indirect assays confirm full biocompatibility and suitability for HOb proliferation.

Advancements in Hydrogels for Corneal Healing and Tissue Engineering.

Hydrogels have garnered significant attention for their versatile applications across various fields, including biomedical engineering. This review delves into the fundamentals of hydrogels, exploring their definition, properties, and classification. Hydrogels, as three-dimensional networks of crosslinked polymers, possess tunable properties such as biocompatibility, mechanical strength, and hydrophilicity, making them ideal for medical applications. Uniquely, this article offers original insights into the application of hydrogels specifically for corneal tissue engineering, bridging a gap in current research. The review further examines the anatomical and functional complexities of the cornea, highlighting the challenges associated with corneal pathologies and the current reliance on donor corneas for transplantation. Considering the global shortage of donor corneas, this review discusses the potential of hydrogel-based materials in corneal tissue engineering. Emphasis is placed on the synthesis processes, including physical and chemical crosslinking, and the integration of bioactive molecules. Stimuli-responsive hydrogels, which react to environmental triggers, are identified as promising tools for drug delivery and tissue repair. Additionally, clinical applications of hydrogels in corneal pathologies are explored, showcasing their efficacy in various trials. Finally, the review addresses the challenges of regulatory approval and the need for further research to fully realize the potential of hydrogels in corneal tissue engineering, offering a promising outlook for future developments in this field.

Crosstalk between macrophages and immunometabolism and their potential roles in tissue repair and regeneration.

Immune metabolism is a result of many specific metabolic reactions, such as glycolysis, the tricarboxylic acid (TCA) pathway, the pentose phosphate pathway (PPP), mitochondrial oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), fatty acid biosynthesis (FAs) and amino acid pathways, which promote cell proliferation and maintenance with structural and pathological energy to regulate cellular signaling. The metabolism of macrophages produces many metabolic intermediates that play important regulatory roles in tissue repair and regeneration. The metabolic activity of proinflammatory macrophages (M1) mainly depends on glycolysis and the TCA cycle system, but anti-inflammatory macrophages (M2) have intact functions of the TCA cycle, which enhances FAO and is dependent on OXPHOS. However, the metabolic mechanisms of macrophages in tissue repair and regeneration have not been well investigated. Thus, we review how three main metabolic mechanisms of macrophages, glucose metabolism, lipid metabolism, and amino acid metabolism, regulate tissue repair and regeneration.

Histomorphometric analysis of excisional cutaneous wounds with different diameters in an animal model.

The skin wound model in rats is a fundamental stage in preclinical trials, but there is a lack of standardization in these trials regarding the initial wound area, making analysis and comparison between studies difficult. Therefore, this study evaluates the healing progression of excisional skin lesions of varying diameters in Wistar rats, aiming to identify the optimal wound size for monitoring treatment effects on wound healing. Excisions of 0.8, 1.5, 2.0 and 3.0 cm in diameter were made on the back of the animals. Thirty animals were used per treatment and evaluated on days 3, 7, 10, 14 and 21 after surgery. The lesions were cleaned daily with saline solution until they were completely closed. The 0.8 cm group showed complete repair on D14, while in the other groups, the wounds persisted until day 21, with a reddened surface and no complete epidermal coverage, but with greater keratinization and presence of appendages in the 1.5 cm lesions. Therefore, as a standardization model for creating skin wounds, we suggest using 1.5 or 2.0 cm excisions, considering that 0.8 cm wounds close very early and 3.0 cm wounds, although behaving similarly to 2.0 cm wounds, are more invasive for the animals. The 1.5 cm model proved to be suitable for closure within 21 days. When evaluating a product intended to accelerate wound healing, 2.0 cm lesions are recommended to assess the effectiveness of the treatment.