Advancements in stimulation therapies for peripheral nerve regeneration.

Soft-tissue injuries affecting muscles, nerves, vasculature, tendons, and ligaments often diminish the quality of life due to pain, loss of function, and financial burdens. Both natural healing and surgical interventions can result in scarring, which potentially may impede functional recovery and lead to persistent pain. Scar tissue, characterized by a highly disorganized fibrotic extracellular matrix, may serve as a physical barrier to regeneration and drug delivery. While approaches such as drugs, biomaterials, cells, external stimulation, and other physical forces show promise in mitigating scarring and promoting regenerative healing, their implementation remains limited and challenging. Ultrasound, laser, electrical, and magnetic forms of external stimulation have been utilized to promote soft tissue as well as neural tissue regeneration. After stimulation, neural tissues experience increased proliferation of Schwann cells, secretion of neurotropic factors, production of myelin, and growth of vasculature, all aimed at supporting axon regeneration and innervation. Yet, the outcomes of healing vary depending on the pathophysiology of the damaged nerve, the timing of stimulation following injury, and the specific parameters of stimulation employed. Increased treatment intensity and duration have been noted to hinder the healing process by inducing tissue damage. These stimulation modalities, either alone or in combination with nerve guidance conduits and scaffolds, have been demonstrated to promote healing. However, the literature currently lacks a detailed understanding of the stimulation parameters used for nerve healing applications. In this article, we aim to address this gap by summarizing existing reports and providing an overview of stimulation parameters alongside their associated healing outcomes.

Stimuli-responsive peptide assemblies: Design, self-assembly, modulation, and biomedical applications.

Peptide molecules have design flexibility, self-assembly ability, high biocompatibility, good biodegradability, and easy functionalization, which promote their applications as versatile biomaterials for tissue engineering and biomedicine. In addition, the functionalization of self-assembled peptide nanomaterials with other additive components enhances their stimuli-responsive functions, promoting function-specific applications that induced by both internal and external stimulations. In this review, we demonstrate recent advance in the peptide molecular design, self-assembly, functional tailoring, and biomedical applications of peptide-based nanomaterials. The strategies on the design and synthesis of single, dual, and multiple stimuli-responsive peptide-based nanomaterials with various dimensions are analyzed, and the functional regulation of peptide nanomaterials with active components such as metal/metal oxide, DNA/RNA, polysaccharides, photosensitizers, 2D materials, and others are discussed. In addition, the designed peptide-based nanomaterials with temperature-, pH-, ion-, light-, enzyme-, and ROS-responsive abilities for drug delivery, bioimaging, cancer therapy, gene therapy, antibacterial, as well as wound healing and dressing applications are presented and discussed. This comprehensive review provides detailed methodologies and advanced techniques on the synthesis of peptide nanomaterials from molecular biology, materials science, and nanotechnology, which will guide and inspire the molecular level design of peptides with specific and multiple functions for function-specific applications.

Pentosan polysulfate regulates hepcidin expression in native Mongolian horses.

The aim of this study was to investigate the anti-hepcidin effect of pentosan polysulfate (PPS) in Mongolian horses. Twenty-six healthy horses were randomly allocated in to two-groups; one group was treated with a PPS once a week for 4-weeks while another group keeping as placebo. Blood samples at day 0 (D0), before race (BR; day 28) and after race (AR; day 28) were analyzed for serum biochemistry, hepcidin and iron concentrations. Significant reduction of hepcidin was observed at AR in PPS group when compared with BR placebo (P<0.05) and AR placebo (P<0.01). Mean hepcidin concentration difference of D0-BR and BR-AR in PPS was greater than the placebo whereas the iron concentration difference is reduced compared to placebo. Results indicate a novel therapeutic application of PPS as an anti-hepcidin compound to control hepcidin in horses while emphasizing further molecular studies.

Pentosan polysulfate regulates hepcidin 1-facilitated formation and function of osteoclast derived from canine bone marrow.

Hepcidin which is the crucial regulator of iron homeostasis, produced in the liver in response to anemia, hypoxia, or inflammation. Recent studies have suggested that hepcidin and iron metabolism are involved in osteoporosis by inhibiting osteoblast function and promoting osteoclastogenesis. Pentosan polysulfate (PPS) is a heparin analogue and promising novel therapeutic for osteoarthritis (OA). This study was undertaken to determine whether PPS inhibits hepcidin-facilitated osteoclast (OC) differentiation and iron overload. Canine (n = 3) bone marrow mononuclear cells were differentiated to OC by macrophage colony-stimulating factor and receptor-activator of nuclear factor kappaB ligand with the treatment of hepcidin1 (200, 400, 800, 1200 nmol/L) and PPS (1, 5, 10, 20, 40 µg/mL). Differentiation and function of OC were accessed using tartrate-resistant acid phosphate staining and bone resorption assay while monitoring ferroportin1 (FPN1) and iron concentration by immunocytochemistry. Gene expression of OC for cathepsin K (CTK), matrix metallopeptidase-9, nuclear factor of activated-T-cells cytoplasmic 1 and FPN1 was examined. Hepcidin1 showed significant enhancement of OC number at 800 nmol/L (p<0.01). PPS impeded hepcidin-facilitated OC at 1, 5 and 10 µg/mL and reduction of resorption pits at 5 and 10 µg/mL (p< 0.01). All OC specific genes were downregulated with PPS, specifically in significant manner with CTK at higher concentrations. However, heparin induced FPN1 internalization and degradation was inhibited at higher concentrations of PPS while restoring iron-releasing capability of OC. We demonstrate for the first time that PPS is a novel-inhibitor of hepcidin-facilitated OC formation/function which might be beneficial for treatment of OA and osteoporosis.

Chronological differential effects of pro-inflammatory cytokines on RANKL-induced osteoclast differentiation of canine bone marrow-derived macrophages.

The aim of this study was to investigate osteoclastogenic properties of inflammatory cytokines at different time-points of osteoclastogenesis. Bone marrow-derived macrophages from five healthy dogs were stimulated with the macrophage colony-stimulating factor, receptor activator of nuclear factor-κB ligand and inflammatory cytokines such as interleukin (IL)-1ß, tumor necrosis factor (TNF)-α and IL-17. Osteoclasts (OC) formation and function were enhanced with TNF-α regardless of temporal differences. But in contrast, IL-1ß suppressed the osteoclastogenesis at early phase of the process while upregulating at the late phase. Furthermore, differentiation of OC precursors into OC was suppressed at high concentrations of IL-17. Collectively, the results revealed that suppressing TNF-α would be a promising strategy to inhibit inflammation-associated bone destruction in dogs.