Morphometric assessment of tibial nerve and its branches around the ankle.

It is essential to understand the considerable variations in bifurcation patterns of the tibial nerve (TN) and its peripheral nerves at the level of the tarsal tunnel to prevent iatrogenic nerve injury during surgical nerve release or nerve block. A total of 16 ankles of 8 human cadavers were dissected to investigate the branching patterns of the TN, using 2 imaginary lines passing through the tip of the medial malleolus (MM) as reference lines. Bifurcation patterns and detailed information on the relative locations of the medial plantar, lateral plantar, medial calcaneal, and inferior calcaneal nerves to the reference lines were recorded. The most common bifurcation pattern was Type 1 in 12 ankles (75%), followed by Type 2 in 2 ankles (13%). One medial calcaneal nerve (MCN) was seen in 11 (69%) specimens and 2 MCN branches were seen in 5 (31%) specimen. 88% of the MCN branches bifurcated from the TN, whereas 6% originated from both TN and lateral plantar nerve (LPN). At the level of the tip of the MM, 2 of 7 parameters showed statistically significant difference between both sexes (P < .05). There was a statistically significant difference between left and right ankles in 2 of 7 measurements (P < .05). Further morphometric analysis of the width, distance, and angle between the TN branches and the tip of MM showed a highly variable nature of the location of the peripheral nerve branches.

Biophysical interplay between extracellular matrix remodeling and hypoxia signaling in regulating cancer metastasis.

Mechanical properties of the tumor microenvironment play a critical role in cancer progression by activation of cancer mechano-responses. The biophysical interactions between cancer cells and their dynamic microenvironment are attributed to force-dependent alterations in molecular pathways that trigger the structural reorganization of intracellular organelles and their associated genetic modifications. Recent studies underscore the role of oxygen concentration in cancer metastasis. Suppressed oxygen levels promote the development of invasive phenotypes and aggressive proliferation of cancer cells, accompanied by remodeling of tumor microenvironment encompassing the modulation of physical settings of extracellular matrix. This review summarizes the role of biophysical interactions between cancer cells and their surroundings in determining cancer progression. Biophysical interpretation of the tumor microenvironment and cancer progression could provide further insights into the development of novel biomedical technologies for therapeutic cancer treatment.

Selective Suppression of Integrin-Ligand Binding by Single Molecular Tension Probes Mediates Directional Cell Migration.

Cell migration interacting with continuously changing microenvironment, is one of the most essential cellular functions, participating in embryonic development, wound repair, immune response, and cancer metastasis. The migration process is finely tuned by integrin-mediated binding to ligand molecules. Although numerous biochemical pathways orchestrating cell adhesion and motility are identified, how subcellular forces between the cell and extracellular matrix regulate intracellular signaling for cell migration remains unclear. Here, it is showed that a molecular binding force across integrin subunits determines directional migration by regulating tension-dependent focal contact formation and focal adhesion kinase phosphorylation. Molecular binding strength between integrin αvß3 and fibronectin is precisely manipulated by developing molecular tension probes that control the mechanical tolerance applied to cell-substrate interfaces. This data reveals that integrin-mediated molecular binding force reduction suppresses cell spreading and focal adhesion formation, attenuating the focal adhesion kinase (FAK) phosphorylation that regulates the persistence of cell migration. These results further demonstrate that manipulating subcellular binding forces at the molecular level can recapitulate differential cell migration in response to changes of substrate rigidity that determines the physical condition of extracellular microenvironment. Novel insights is provided into the subcellular mechanics behind global mechanical adaptation of the cell to surrounding tissue environments featuring distinct biophysical signatures.

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 10 days 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.

Photonic control of ligand nanospacing in self-assembly regulates stem cell fate.

Extracellular matrix (ECM) undergoes dynamic inflation that dynamically changes ligand nanospacing but has not been explored. Here we utilize ECM-mimicking photocontrolled supramolecular ligand-tunable Azo+ self-assembly composed of azobenzene derivatives (Azo+) stacked via cation-π interactions and stabilized with RGD ligand-bearing poly(acrylic acid). Near-infrared-upconverted-ultraviolet light induces cis-Azo+-mediated inflation that suppresses cation-π interactions, thereby inflating liganded self-assembly. This inflation increases nanospacing of "closely nanospaced" ligands from 1.8 nm to 2.6 nm and the surface area of liganded self-assembly that facilitate stem cell adhesion, mechanosensing, and differentiation both in vitro and in vivo, including the release of loaded molecules by destabilizing water bridges and hydrogen bonds between the Azo+ molecules and loaded molecules. Conversely, visible light induces trans-Azo+ formation that facilitates cation-π interactions, thereby deflating self-assembly with "closely nanospaced" ligands that inhibits stem cell adhesion, mechanosensing, and differentiation. In stark contrast, when ligand nanospacing increases from 8.7 nm to 12.2 nm via the inflation of self-assembly, the surface area of "distantly nanospaced" ligands increases, thereby suppressing stem cell adhesion, mechanosensing, and differentiation. Long-term in vivo stability of self-assembly via real-time tracking and upconversion are verified. This tuning of ligand nanospacing can unravel dynamic ligand-cell interactions for stem cell-regulated tissue regeneration.

Sticky and Strain-Gradient Artificial Epineurium for Sutureless Nerve Repair in Rodents and Nonhuman Primates.

The need for the development of soft materials capable of stably adhering to nerve tissues without any suturing followed by additional damages is at the fore at a time when success in postoperative recovery depends largely on the surgical experience and/or specialized microsuturing skills of the surgeon. Despite fully recognizing such prerequisite conditions, designing the materials with robust adhesion to wet nerves as well as acute/chronic anti-inflammation remains to be resolved. Herein, a sticky and strain-gradient artificial epineurium (SSGAE) that overcomes the most critically challenging aspect for realizing sutureless repair of severely injured nerves is presented. In this regard, the SSGAE with a skin-inspired hierarchical structure entailing strain-gradient layers, anisotropic Janus layers including hydrophobic top and hydrophilic bottom surfaces, and synergistic self-healing capabilities enables immediate and stable neurorrhaphy in both rodent and nonhuman primate models, indicating that the bioinspired materials strategy significantly contributes to translational medicine for effective peripheral nerve repair.

Protective effect of alpha-lipoic acid and epalrestat on oxaliplatin-induced peripheral neuropathy in zebrafish.

INTRODUCTION/AIMS: Oxaliplatin is a platinum-based anti-cancer drug widely used in colorectal cancer patients, but it may cause peripheral neuropathy. As one of the main causes of oxaliplatin-induced peripheral neuropathy (OPN) is oxidative stress, which is also a key factor causing diabetic peripheral neuropathy (DPN), the aim of this study was to evaluate the preventive effects of alpha-lipoic acid (ALA) and epalrestat (EP), which are used for the treatment of DPN, in an OPN zebrafish model. METHODS: Tg(nbt:dsred) transgenic zebrafish, with sensory nerves in the peripheral lateral line, were treated with oxaliplatin, oxaliplatin/EP, and oxaliplatin/ALA for 4 days. A confocal microscope was used to visualize and quantify the number of axon bifurcations in the distal nerve ending. To analyze the formation of synapses on sensory nerve terminals, quantification of membrane-associated guanylate kinase (MAGUK) puncta was performed using immunohistochemistry. RESULTS: The number of axon bifurcations and intensity of MAGUK puncta were significantly reduced in the oxaliplatin-treated group compared with those in the embryo medium-treated group. In both the oxaliplatin/EP and oxaliplatin/ALA-treated groups, the number of axon bifurcations and intensity of MAGUK puncta were greater than those in the oxaliplatin-treated group (p < .0001), and no significant difference was observed between larvae treated with oxaliplatin/ALA 1 µM and oxaliplatin/EP 1 µM (p = .4292). DISCUSSION: ALA and EP have protective effects against OPN in zebrafish. Our findings show that ALA and EP can facilitate more beneficial treatment for OPN.

Micro-syringe chip-guided intratumoral administration of lipid nanoparticles for targeted anticancer therapy.

BACKGROUND: Nano-sized drug delivery system has been widely studied as a potential technique to promote tumor-specific delivery of anticancer drugs due to its passive targeting property, but resulting in very restricted improvements in its systemic administration so far. There is a requirement for a different approach that dramatically increases the targeting efficiency of therapeutic agents at targeted tumor tissues. METHODS: To improve the tumor-specific accumulation of anticancer drugs and minimize their undesirable toxicity to normal tissues, a tumor-implantable micro-syringe chip (MSC) with a drug reservoir is fabricated. As a clinically established delivery system, six liposome nanoparticles (LNPs) with different compositions and surface chemistry are prepared and their physicochemical properties and cellular uptake are examined in vitro. Subsequently, MSC-guided intratumoral administration is studied to identify the most appropriate for the higher tumor targeting efficacy with a uniform intratumoral distribution. For efficient cancer treatment, pro-apoptotic anticancer prodrugs (SMAC-P-FRRG-DOX) are encapsulated to the optimal LNPs (SMAC-P-FRRG-DOX encapsulating LNPs; ApoLNPs), then the ApoLNPs are loaded into the 1 µL-volume drug reservoir of MSC to be delivered intratumorally for 9 h. The tumor accumulation and therapeutic effect of ApoLNPs administered via MSC guidance are evaluated and compared to those of intravenous and intratumoral administration of ApoLNP in 4T1 tumor-bearing mice. RESULTS: MSC is precisely fabricated to have a 0.5 × 4.5 mm needle and 1 µL-volume drug reservoir to achieve the uniform intratumoral distribution of LNPs in targeted tumor tissues. Six liposome nanoparticles with different compositions of 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (PC), 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (PS), 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)2000] (PEG2000-DSPE) are prepared with average sizes of 100-120 nm and loaded into the 1 µL-volume drug reservoir in MSC. Importantly negatively charged 10 mol% of PS-containing LNPs are very slowly infused into the tumor tissue through the micro-syringe of the MSC over 6 h. The intratumoral targeting efficiency of MSC guidance is 93.5%, effectively assisting the homogeneous diffusion of LNPs throughout the tumor tissue at 3.8- and 2.7-fold higher concentrations compared to the intravenous and intratumoral administrations of LNPs, respectively. Among the six LNP candidates 10 mol% of PS-containing LNPs are finally selected for preparing pro-apoptotic SMAC-P-FRRG-DOX anticancer prodrug-encapsulated LNPs (ApoLNPs) due to their moderate endocytosis rate high tumor accumulation and homogenous intratumoral distribution. The ApoLNPs show a high therapeutic effect specifically to cathepsin B-overexpressing cancer cells with 6.6 µM of IC50 value while its IC50 against normal cells is 230.7 µM. The MSC-guided administration of ApoLNPs efficiently inhibits tumor growth wherein the size of the tumor is 4.7- and 2.2-fold smaller than those treated with saline and intratumoral ApoLNP without MSC, respectively. Moreover, the ApoLNPs remarkably reduce the inhibitor of apoptosis proteins (IAPs) level in tumor tissues confirming their efficacy even in cancers with high drug resistance. CONCLUSION: The MSC-guided administration of LNPs greatly enhances the therapeutic efficiency of anticancer drugs via the slow diffusion mechanism through micro-syringe to tumor tissues for 6 h, whereas they bypass most hurdles of systemic delivery including hepatic metabolism, rapid renal clearance, and interaction with blood components or other normal tissues, resulting in the minimum toxicity to normal tissues. The negatively charged ApoLNPs with cancer cell-specific pro-apoptotic prodrug (SMAC-P-FRRG-DOX) show the highest tumor-targeting efficacy when they are treated with the MSC guidance, compared to their intravenous or intratumoral administration in 4T1 tumor-bearing mice. The MSC-guided administration of anticancer drug-encapsulated LNPs is expected to be a potent platform system that facilitates overcoming the limitations of systemic drug administration with low delivery efficiency and serious side effects.

Recent Studies and Progress in the Intratumoral Administration of Nano-Sized Drug Delivery Systems.

Over the last 30 years, diverse types of nano-sized drug delivery systems (nanoDDSs) have been intensively explored for cancer therapy, exploiting their passive tumor targetability with an enhanced permeability and retention effect. However, their systemic administration has aroused some unavoidable complications, including insufficient tumor-targeting efficiency, side effects due to their undesirable biodistribution, and carrier-associated toxicity. In this review, the recent studies and advancements in intratumoral nanoDDS administration are generally summarized. After identifying the factors to be considered to enhance the therapeutic efficacy of intratumoral nanoDDS administration, the experimental results on the application of intratumoral nanoDDS administration to various types of cancer therapies are discussed. Subsequently, the reports on clinical studies of intratumoral nanoDDS administration are addressed in short. Intratumoral nanoDDS administration is proven with its versatility to enhance the tumor-specific accumulation and retention of therapeutic agents for various therapeutic modalities. Specifically, it can improve the efficacy of therapeutic agents with poor bioavailability by increasing their intratumoral concentration, while minimizing the side effect of highly toxic agents by restricting their delivery to normal tissues. Intratumoral administration of nanoDDS is considered to expand its application area due to its potent ability to improve therapeutic effects and relieve the systemic toxicities of nanoDDSs.

Clinical, Electrophysiological, and Sonographic Findings in Patients With Nerve Injury After Vessel Puncture.

BACKGROUND AND PURPOSE: This study aimed to describe the clinical, electrophysiological, and ultrasonographic findings of patients with nerve injury after vessel puncture. METHODS: Data on ten patients (three males and seven females) with nerve injury after vessel puncture were reviewed. Demographic and clinical data were analyzed retrospectively. Bilateral electrophysiological studies were performed based on clinical findings. Ultrasonographic examinations were performed on both the affected and unaffected sides of the injured nerve. RESULTS: The nerves of nine patients were injured following vein puncture, and injury occurred following arterial sampling in one patient. Seven patients had superficial radial sensory nerve injury: five medial, one lateral, and one at both branches. One patient had injury to the dorsal ulnar cutaneous nerve, one to the lateral antebrachial cutaneous nerve, and one to the median nerve. Nerve conduction studies produced abnormal findings in 80% of patients, whereas ultrasonographic examinations produced abnormal findings in all of the patients. Spearman's coefficient for the correlation between the amplitude ratio and nerve cross-sectional area ratio was not significant, at -0.127 (95% confidence interval=-0.701 to 0.546, p=0.721). CONCLUSIONS: Ultrasonography supported by electrodiagnosis was found to be a useful method for identifying the lesion location and structural abnormalities of vessel-puncture-related neuropathy.

Ultrasonographic Evaluation of the Optimal Needle Position in the Supinator Muscle.

BACKGROUND AND PURPOSE: Investigating the supinator muscle (SUP) is important for diagnosing radial neuropathy or cervical radiculopathy in needle electromyography (EMG). However, different authors have proposed several locations for needle EMG placement in the SUP. This study aimed to determine the optimal needle insertion position for examining the SUP via needle EMG under ultrasonographic guidance. METHODS: This study included 16 male (32 upper limbs) and 15 females (30 upper limbs). In the supine position, the line connecting the midpoint of the dorsal wrist to the upper margin of the radial head (RH) (RH_WRIST line) was measured while the forearm was pronated. Under ultrasonographic guidance, the thickness of the SUP was measured at 1-cm intervals from the RH to 4 cm along the RH_WRIST line. Moreover, the horizontal distance (HD) from the RH_WRIST line to the posterior interosseous nerve (PIN) and the distance from the RH to the point where the RH_WRIST line and the PIN intersected (VD_PIN_CROSS) were measured. RESULTS: VD_PIN_CROSS was 51.25±7.0 mm (mean±SD). The muscle was the thickest at 3 cm (5.6±0.8 mm) and 4 cm (5.4±1.0 mm) from the RH. The distances from the PIN to these points were 14.1±3.9 mm and 9.0±4.3 mm, respectively. CONCLUSIONS: Our findings suggest that the optimal needle placement is at 3 cm from the RH.

Ultrasonographic features of ulnar nerve instability around the elbow in fresh cadavers.

Ultrasound (US) is commonly used to evaluate ulnar nerve instability (UNI) and snapping of the medial head of the triceps brachii muscle (ST). We aimed to determine the diagnostic accuracy of US in evaluating UNI, through cadaveric dissection, and to evaluate the US features and relationships of UNI and ST according to elbow flexion. Dynamic US was performed with elbow extension, 90° flexion, and full flexion positions on 18 elbows from 9 fresh cadavers. UNI was classified into N (normal), S (subluxation), and D (dislocation) types. On US exams, the following findings and parameters were evaluated: the presence of UNI and ST; the horizontal distance from the apex of the medial epicondyle (ME) to the margins of the UN and medial head of the triceps brachii muscle (ME_UN and ME_TB, respectively); cross-sectional area and flattening ratio (FR) of UN. After US, all cadavers were dissected to expose the UN and TB, and elbow flexion and extension were simulated to confirm UNI and ST. The gross anatomic findings of UNI and ST were consistent with the US findings. In extension and 90° flexion positions, all cases were type N. In full flexion position, types N and S occurred in 10 (56%) and 8 (44%) elbows, respectively. FR and ME_UN in 90° flexion position, FR, ME_UN, and ME_TB in full flexion position differed significantly between types S and N. Positive correlations were found between ME_UN and ME_TB in 90° flexion and full flexion positions. Dynamic US accurately assessed UNI and ST. UNI was positively correlated to medial TB movement.

Botulinum Toxin Injection for the Treatment of Compression of Lateral Plantar Nerve by Flexor Digitorum Accessorius Longus.

ABSTRACT: The flexor digitorum accessorius longus is an anomalous muscle with a reported prevalence of 1.6%-12.2% in cadaveric studies. Flexor digitorum accessorius longus courses through the tarsal tunnel and has been reported as an etiology of tarsal tunnel syndrome in previous case reports. The flexor digitorum accessorius longus is intimately related to the neurovascular bundle and may impinge on the lateral plantar nerves. However, very few cases of lateral plantar nerve compression by the flexor digitorum accessorius longus have been reported. Herein, we report a case of lateral plantar nerve compression caused by the flexor digitorum accessorius longus muscle in a 51-year-old man who complained of insidious pain at the lateral sole and hypoesthesia at the left third-fifth toe and lateral sole, and the pain improved after treatment of botulinum toxin injection into the flexor digitorum accessorius longus muscle.

A Cadaveric Study of a Safe and Accurate Electromyographic Needle Approach to the Rhomboid Major.

OBJECTIVE: This study aimed to investigate a safe and accurate electromyographic needle insertion site of the rhomboid major (RM) muscle using cadaver dissection. DESIGN: Dissection of the trapezius and rhomboid major muscles around the scapula was performed in 18 scapulae from nine fresh cadavers. The point (point A) at which the lateral margin of the lower trapezius muscle crossed the medial border of the scapula and the distal insertion point (point DI) of the rhomboid major muscle to the medial scapula were determined. The midpoint (point M) between points A and DI was also determined. The distance from the inferior angle of the scapula to each point was measured. RESULTS: The length of the medial scapula was 12.9 ± 1.2 cm from the root of the scapular spine to the inferior angle of the scapula. Points A, DI, and M were located at a mean distance of 8.4 ± 0.7, 1.8 ± 0.4, and 5.1 ± 0.5 cm proximal to the inferior angle of the scapula, respectively. CONCLUSIONS: Needle electromyographic examination of the rhomboid major muscle can be performed safely and accurately using the lower part of the rhomboid major muscle, as investigated in this anatomical study.

Subcellular mechano-regulation of cell migration in confined extracellular microenvironment.

Cell migration is a highly coordinated cellular event that determines diverse physiological and pathological processes in which the continuous interaction of a migrating cell with neighboring cells or the extracellular matrix is regulated by the physical setting of the extracellular microenvironment. In confined spaces, cell migration occurs differently compared to unconfined open spaces owing to the additional forces that limit cell motility, which create a driving bias for cells to invade the confined space, resulting in a distinct cell motility process compared to what is expected in open spaces. Moreover, cells in confined environments can be subjected to elevated mechanical compression, which causes physical stimuli and activates the damage repair cycle in the cell, including the DNA in the nucleus. Although cells have a self-restoring system to repair damage from the cell membrane to the genetic components of the nucleus, this process may result in genetic and/or epigenetic alterations that can increase the risk of the progression of diverse diseases, such as cancer and immune disorders. Furthermore, there has been a shift in the paradigm of bioengineering from the development of new biomaterials to controlling biophysical cues and fine-tuning cell behaviors to cure damaged/diseased tissues. The external physical cues perceived by cells are transduced along the mechanosensitive machinery, which is further channeled into the nucleus through subcellular molecular linkages of the nucleoskeleton and cytoskeleton or the biochemical translocation of transcription factors. Thus, external cues can directly or indirectly regulate genetic transcriptional processes and nuclear mechanics, ultimately determining cell fate. In this review, we discuss the importance of the biophysical cues, response mechanisms, and mechanical models of cell migration in confined environments. We also discuss the effect of force-dependent deformation of subcellular components, specifically focusing on subnuclear organelles, such as nuclear membranes and chromosomal organization. This review will provide a biophysical perspective on cancer progression and metastasis as well as abnormal cellular proliferation.

A Proposed Safe Electromyographic Needle Insertion Technique for the Flexor Pollicis Longus Muscle Using Arterial Pulse Palpation: Preliminary Study with Ultrasonography.

Electromyographic needle access to the flexor pollicis longus (FPL) is challenging because of the risk of injuries to the superficial radial nerve (SRN) or radial artery (RA), which run close to the FPL. This study aimed to investigate the safe electromyographic needle insertion point of the FPL using a newly proposed RA pulse palpation method. Fifty forearms of 25 healthy individuals were studied. At the junction of the middle and distal third of the forearm, an RA pulse was palpated, and 5 mm lateral to the pulse was determined as the preliminary needle insertion point. The distance from the vertical virtual needle pathway to the RA and SRN was measured using ultrasonography. In ultrasonography, the distances from the needle pathway to the RA and the SRN were 3.4 ± 0.8 (range, 2.1-6.0) and 5.9 ± 1.8 (range, 2.4-9.4) mm, respectively. The depth of the FPL muscle was 8.4 ± 1.7 mm. Electromyographic needle insertion into the FPL can be safely performed using the RA palpation method. The needle insertion point is 5 mm lateral to the RA pulse at the level between the middle and distal third of the forearm.

Micropattern-based nerve guidance conduit with hundreds of microchannels and stem cell recruitment for nerve regeneration.

Guiding the regrowth of thousands of nerve fibers within a regeneration-friendly environment enhances the regeneration capacity in the case of peripheral nerve injury (PNI) and spinal cord injury (SCI). Although clinical treatments are available and several studies have been conducted, the development of nerve guidance conduits (NGCs) with desirable properties, including controllable size, hundreds of nerve bundle-sized microchannels, and host stem-cell recruitment, remains challenging. In this study, the micropattern-based fabrication method was combined with stem-cell recruitment factor (substance P, SP) immobilization onto the main material to produce a size-tunable NGC with hundreds of microchannels with stem-cell recruitment capability. The SP-immobilized multiple microchannels aligned the regrowth of nerve fibers and recruited the host stem cells, which enhanced the functional regeneration capacity. This method has wide applicability in the modification and augmentation of NGCs, such as bifurcated morphology or directional topographies on microchannels. Additional improvements in fabrication will advance the regeneration technology and improve the treatment of PNI/SCI.

Nuclear transport of STAT6 determines the matrix rigidity dependent M2 activation of macrophages.

Alternatively activated or M2 macrophages, as opposed to the well characterized pro-inflammatory or M1 macrophages, vitally regulate anti-inflammation, wound healing, and tissue repair to maintain tissue homeostasis. Although ubiquitous presence of macrophages in diverse tissues, exposed to different physical environments, infers distinct immune responses of M2 macrophages with high phenotypic heterogeneity, the underlying mechanism of how the varying extracellular mechanical conditions alter their immunological activation remains unclear. Here, we demonstrate that M2 activation requires a threshold mechanical cue from the extracellular microenvironment, and matrix rigidity-dependent macrophage spreading is mediated by the F-actin formation that is essential to regulate mechanosensitive M2 activation of macrophages. We identified a new mechanosensing function of STAT6 (signal transducer and activator of transcription 6), a key transcription factor for M2 activation, whose intranuclear transportation is promoted by the rigid matrix that facilitates the F-actin formation. Our findings further highlight the critical role of mechanosensitive M2 activation of macrophages in long-term adaptation to the extracellular microenvironment by bridging nuclear mechanosensation and immune responses.

Injectable Hydrogel-Based Combination Cancer Immunotherapy for Overcoming Localized Therapeutic Efficacy.

Various immunotherapeutic agents that can elicit antitumor immune responses have recently been developed with the potential for improved efficacy in treating cancer. However, insufficient delivery efficiency at the tumor site, along with severe side effects after systemic administration of these anticancer agents, have hindered their therapeutic application in cancer immunotherapy. Hydrogels that can be directly injected into tumor sites have been developed to help modulate or elicit antitumor responses. Based on the biocompatibility, degradability, and controllable mechanochemical properties of these injectable hydrogels, various types of immunotherapeutic agents, such as hydrophobic anticancer drugs, cytokines, antigens, and adjuvants, have been easily and effectively encapsulated, resulting in the successful elicitation of antitumor immune responses and the retention of long-term immunotherapeutic efficacy following administration. This review summarizes recent advances in combination immunotherapy involving injectable hydrogel-based chemoimmunotherapy, photoimmunotherapy, and radioimmunotherapy. Finally, we briefly discuss the current limitations and future perspectives on injectable hydrogels for the effective combination immunotherapy of tumors.