Multispectral Imaging-Based System for Detecting Tissue Oxygen Saturation With Wound Segmentation for Monitoring Wound Healing.

OBJECTIVE: Blood circulation is an important indicator of wound healing. In this study, a tissue oxygen saturation detecting (TOSD) system that is based on multispectral imaging (MSI) is proposed to quantify the degree of tissue oxygen saturation (StO2) in cutaneous tissues. METHODS: A wound segmentation algorithm is used to segment automatically wound and skin areas, eliminating the need for manual labeling and applying adaptive tissue optics. Animal experiments were conducted on six mice in which they were observed seven times, once every two days. The TOSD system illuminated cutaneous tissues with two wavelengths of light - red ([Formula: see text] nm) and near-infrared ([Formula: see text] nm), and StO2 levels were calculated using images that were captured using a monochrome camera. The wound segmentation algorithm using ResNet34-based U-Net was integrated with computer vision techniques to improve its performance. RESULTS: Animal experiments revealed that the wound segmentation algorithm achieved a Dice score of 93.49%. The StO2 levels that were determined using the TOSD system varied significantly among the phases of wound healing. Changes in StO2 levels were detected before laser speckle contrast imaging (LSCI) detected changes in blood flux. Moreover, statistical features that were extracted from the TOSD system and LSCI were utilized in principal component analysis (PCA) to visualize different wound healing phases. The average silhouette coefficients of the TOSD system with segmentation (ResNet34-based U-Net) and LSCI were 0.2890 and 0.0194, respectively. CONCLUSION: By detecting the StO2 levels of cutaneous tissues using the TOSD system with segmentation, the phases of wound healing were accurately distinguished. This method can support medical personnel in conducting precise wound assessments. Clinical and Translational Impact Statement-This study supports efforts in monitoring StO2 levels, wound segmentation, and wound healing phase classification to improve the efficiency and accuracy of preclinical research in the field.

Ultrahigh frequency transcutaneous electrical nerve stimulation for neuropathic pain alleviation and neuromodulation.

A challenging complication in patients with peripheral compressive neuropathy is neuropathic pain. Excessive neuroinflammation at the injury site worsens neuropathic pain and impairs function. Currently, non-invasive modulation techniques like transcutaneous electrical nerve stimulation (TENS) have shown therapeutic promise with positive results. However, the underlying regulatory molecular mechanism for pain relief remains complex and unexplored. This study aimed to validate the therapeutic effect of ultrahigh frequency (UHF)-TENS in chronic constriction injury of the rat sciatic nerve. Alleviation of mechanical allodynia was achieved through the application of UHF-TENS, lasting for 3 days after one session of therapy and 4 days after two sessions, without causing additional damage to the myelinated axon structure. The entire tissue collection schedule was divided into four time points: nerve exposure surgery, 7 days after nerve ligation, and 1 and 5 days after one session of UHF therapy. Significant reductions in pain-related neuropeptides, MEK, c-Myc, c-FOS, COX2, and substance P, were observed in the injured DRG neurons after UHF therapy. RNA sequencing of differential gene expression in sensory neurons revealed significant downregulation in Cables, Pik3r1, Vps4b, Tlr7, and Ezh2 after UHF therapy, while upregulation was observed in Nfkbie and Cln3. UHF-TENS effectively and safely relieved neuropathic pain without causing further nerve damage. The decreased production of pain-related neuropeptides within the DRG provided the therapeutic benefit. Possible molecular mechanisms behind UHF-TENS may result from the modulation of the NF-κB complex, toll-like receptor-7, and phosphoinositide 3-kinase/Akt signaling pathways. These results suggest the neuromodulatory effects of UHF-TENS in rat sciatic nerve chronic constriction injury, including alleviation of neuropathic pain, amelioration of pain-related neuropeptides, and regulation of neuroinflammatory gene expression. In combination with the regulation of related neuroinflammatory genes, UHF-TENS could become a new modality for enhancing the treatment of neuropathic pain in the future.

Assessment of Tilapia Skin Collagen for Biomedical Research Applications in Comparison with Mammalian Collagen.

Collagen is an important material for biomedical research, but using mammalian tissue-derived collagen carries the risk of zoonotic disease transmission. Marine organisms, such as farmed tilapia, have emerged as a safe alternative source of collagen for biomedical research. However, the tilapia collagen products for biomedical research are rare, and their biological functions remain largely unexamined. In this study, we characterized a commercial tilapia skin collagen using SDS-PAGE and fibril formation assays and evaluated its effects on skin fibroblast adhesion, proliferation, and migration, comparing it with commercial collagen from rat tails, porcine skin, and bovine skin. The results showed that tilapia skin collagen is a type I collagen, similar to rat tail collagen, and has a faster fibril formation rate and better-promoting effects on cell migration than porcine and bovine skin collagen. We also confirmed its application in a 3D culture for kidney cells' spherical cyst formation, fibroblast-induced gel contraction, and tumor spheroid interfacial invasion. Furthermore, we demonstrated that the freeze-dried tilapia skin collagen scaffold improved wound closure in a mouse excisional wound model, similar to commercial porcine or bovine collagen wound dressings. In conclusion, tilapia skin collagen is an ideal biomaterial for biomedical research.

Histone Trimethylations and HDAC5 Regulate Spheroid Subpopulation and Differentiation Signaling of Human Adipose-Derived Stem Cells.

Human adipose-derived stem cells (ASCs) have shown immense potential for regenerative medicine. Our previous work demonstrated that chitosan nano-deposited surfaces induce spheroid formation and differentiation of ASCs for treating sciatic nerve injuries. However, the underlying cell fate and differentiation mechanisms of ASC-derived spheroids remain unknown. Here, we investigate the epigenetic regulation and signaling coordination of these therapeutic spheroids. During spheroid formation, we observed significant increases in histone 3 trimethylation at lysine 4 (H3K4me3), lysine 9 (H3K9me3), and lysine 27 (H3K27me3), accompanied by increased histone deacetylase (HDAC) activities and decreased histone acetyltransferase activities. Additionally, HDAC5 translocated from the cytoplasm to the nucleus, along with increased nuclear HDAC5 activities. Utilizing single-cell RNA sequencing (scRNA-seq), we analyzed the chitosan-induced ASC spheroids and discovered distinct cluster subpopulations, cell fate trajectories, differentiation traits, and signaling networks using the 10x Genomics platform, R studio/language, and the Ingenuity Pathway Analysis (IPA) tool. Specific subpopulations were identified within the spheroids that corresponded to a transient reprogramming state (Cluster 6) and the endpoint cell state (Cluster 3). H3K4me3 and H3K9me3 were discovered as key epigenetic regulators by IPA to initiate stem cell differentiation in Cluster 6 cells, and confirmed by qPCR and their respective histone methyltransferase inhibitors: SNDX-5613 (a KMT2A inhibitor for H3K4me3) and SUVi (an SUV39H1 inhibitor for H3K9me3). Moreover, H3K9me3 and HDAC5 were involved in regulating downstream signaling and neuronal markers during differentiation in Cluster 3 cells. These findings emphasize the critical role of epigenetic regulation, particularly H3K4me3, H3K9me3, and HDAC5, in shaping stem cell fate and directing lineage-specific differentiation.

Aberrant expression of interleukin-17A in mast cells contributes to the pathogenesis of hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) significantly diminishes the quality of life for patients. Delayed diagnosis represents a significant challenge in effectively managing HS. OBJECTIVES: To identify and characterize the key mediator in HS. METHODS: Bioinformatic transcriptomic analysis was applied to identify potential candidates contributing to the disease process of HS. Skin samples from 40 patients with HS, four with psoriasis and 29 with normal skin were included. The expression of interleukin (IL)-17A was evaluated and compared among samples of normal skin, psoriatic skin and skin from different stages of HS by immunohistochemistry or dual-colour immunofluorescence. In vitro experiments and RNA sequencing analysis were also conducted to validate the expression of IL-17A and its pathogenic effect in HS. RESULTS: Transcriptomic database analyses identified IL-17 signalling as a potential contributor to HS. In HS, the predominant IL-17A+ cell population was identified as mast cells. IL-17A+ mast-cell density was significantly elevated in HS, especially in samples with advanced Hurley stages, compared with normal skin and psoriasis samples. The close contact between IL-17A+ mast cells and IL-17 receptor A (IL-17RA)-expressing keratinocytes was demonstrated, along with the significant effects of IL-17A on keratinocyte cell proliferation and HS pathogenic gene expression. Treatment with biologics (brodalumab or adalimumab) reduced the severity of the disease and the number of IL-17A+ mast cells in affected tissues. CONCLUSIONS: The presence of high-density IL-17A+ mast cells may serve as a valuable pathological marker for diagnosing HS. Moreover, developing therapeutic drugs targeting IL-17A+ mast cells may provide a new approach to treating HS.

Adipose-derived stem cells modulate neuroinflammation and improve functional recovery in chronic constriction injury of the rat sciatic nerve.

Introduction: Compressive neuropathy, a common chronic traumatic injury of peripheral nerves, leads to variable impairment in sensory and motor function. Clinical symptoms persist in a significant portion of patients despite decompression, with muscle atrophy and persistent neuropathic pain affecting 10%-25% of cases. Excessive inflammation and immune cell infiltration in the injured nerve hinder axon regeneration and functional recovery. Although adipose-derived stem cells (ASCs) have demonstrated neural regeneration and immunomodulatory potential, their specific effects on compressive neuropathy are still unclear. Methods: We conducted modified CCI models on adult male Sprague-Dawley rats to induce irreversible neuropathic pain and muscle atrophy in the sciatic nerve. Intraneural ASC injection and nerve decompression were performed. Behavioral analysis, muscle examination, electrophysiological evaluation, and immunofluorescent examination of the injured nerve and associated DRG were conducted to explore axon regeneration, neuroinflammation, and the modulation of inflammatory gene expression. Transplanted ASCs were tracked to investigate potential beneficial mechanisms on the local nerve and DRG. Results: Persistent neuropathic pain was induced by chronic constriction of the rat sciatic nerve. Local ASC treatment has demonstrated robust beneficial outcomes, including the alleviation of mechanical allodynia, improvement of gait, regeneration of muscle fibers, and electrophysiological recovery. In addition, locally transplanted ASCs facilitated axon remyelination, alleviated neuroinflammation, and reduced inflammatory cell infiltration of the injured nerve and associated dorsal root ganglion (DRG). Trafficking of the transplanted ASC preserved viability and phenotype less than 7 days but contributed to robust immunomodulatory regulation of inflammatory gene expression in both the injured nerve and DRG. Discussion: Locally transplanted ASC on compressed nerve improve sensory and motor recoveries from irreversible chronic constriction injury of rat sciatic nerve via alleviation of both local and remote neuroinflammation, suggesting the promising role of adjuvant ASC therapies for clinical compressive neuropathy.

Physical processing for decellularized nerve xenograft in peripheral nerve regeneration.

In severe or complex cases of peripheral nerve injuries, autologous nerve grafts are the gold standard yielding promising results, but limited availability and donor site morbidity are some of its disadvantages. Although biological or synthetic substitutes are commonly used, clinical outcomes are inconsistent. Biomimetic alternatives derived from allogenic or xenogenic sources offer an attractive off-the-shelf supply, and the key to successful peripheral nerve regeneration focuses on an effective decellularization process. In addition to chemical and enzymatic decellularization protocols, physical processes might offer identical efficiency. In this comprehensive minireview, we summarize recent advances in the physical methods for decellularized nerve xenograft, focusing on the effects of cellular debris clearance and stability of the native architecture of a xenograft. Furthermore, we compare and summarize the advantages and disadvantages, indicating the future challenges and opportunities in developing multidisciplinary processes for decellularized nerve xenograft.

Hyperosmolar Hyperglycemic Crisis After Burn Injury in a Patient With Advanced Amyotrophic Lateral Sclerosis: A Case Report.

ABSTRACT: Metabolic disturbance in patients of amyotrophic lateral sclerosis is a rare presentation that might be related to disease progression and outcomes. Hypermetabolic status after major burn injury remains a critical issue in the modern medical care. Here, we present a rare case of a patient sporadic amyotrophic lateral sclerosis who suffered from minor burn injury (8% total body surface area), developing critical hyperosmolar hyperglycemic state during early hospitalization. Newly diagnosed diabetes is established and found related to the underlying disease of this patient. The accumulative metabolic alteration among vulnerable patients of amyotrophic lateral sclerosis and burn injury is noteworthy. Judicious monitoring of fluid and metabolic status helps to prevent the occurrence of acute hyperosmolar hyperglycemic state.

Autologous Platelet-Rich Growth Factor Reduces M1 Macrophages and Modulates Inflammatory Microenvironments to Promote Sciatic Nerve Regeneration.

The failure of peripheral nerve regeneration is often associated with the inability to generate a permissive molecular and cellular microenvironment for nerve repair. Autologous therapies, such as platelet-rich plasma (PRP) or its derivative platelet-rich growth factors (PRGF), may improve peripheral nerve regeneration via unknown mechanistic roles and actions in macrophage polarization. In the current study, we hypothesize that excessive and prolonged inflammation might result in the failure of pro-inflammatory M1 macrophage transit to anti-inflammatory M2 macrophages in large nerve defects. PRGF was used in vitro at the time the unpolarized macrophages (M0) macrophages were induced to M1 macrophages to observe if PRGF altered the secretion of cytokines and resulted in a phenotypic change. PRGF was also employed in the nerve conduit of a rat sciatic nerve transection model to identify alterations in macrophages that might influence excessive inflammation and nerve regeneration. PRGF administration reduced the mRNA expression of tumor necrosis factor-α (TNFα), interleukin-1ß (IL-1ß), and IL-6 in M0 macrophages. Increased CD206 substantiated the shift of pro-inflammatory cytokines to the M2 regenerative macrophage. Administration of PRGF in the nerve conduit after rat sciatic nerve transection promoted nerve regeneration by improving nerve gross morphology and its targeted gastrocnemius muscle mass. The regenerative markers were increased for regrown axons (protein gene product, PGP9.5), Schwann cells (S100ß), and myelin basic protein (MBP) after 6 weeks of injury. The decreased expression of TNFα, IL-1ß, IL-6, and CD68+ M1 macrophages indicated that the inflammatory microenvironments were reduced in the PRGF-treated nerve tissue. The increase in RECA-positive cells suggested the PRGF also promoted angiogenesis during nerve regeneration. Taken together, these results indicate the potential role and clinical implication of autologous PRGF in regulating inflammatory microenvironments via macrophage polarization after nerve transection.

Electroceuticals for peripheral nerve regeneration.

Electroceuticals provide promising opportunities for peripheral nerve regeneration, in terms of modulating the extensive endogenous tissue repair mechanisms between neural cell body, axons and target muscles. However, great challenges remain to deliver effective and controllable electroceuticals via bioelectronic implantable device. In this review, the modern fabrication methods of bioelectronic conduit for bridging critical nerve gaps after nerve injury are summarized, with regard to conductive materials and core manufacturing process. In addition, to deliver versatile electrical stimulation, the integration of implantable bioelectronic device is discussed, including wireless energy harvesters, actuators and sensors. Moreover, a comprehensive insight of beneficial mechanisms is presented, including up-to-datein vitro, in vivoand clinical evidence. By integrating conductive biomaterials, 3D engineering manufacturing process and bioelectronic platform to deliver versatile electroceuticals, the modern biofabrication enables comprehensive biomimetic therapies for neural tissue engineering and regeneration in the new era.

Intramuscular delivery of neural crest stem cell spheroids enhances neuromuscular regeneration after denervation injury.

BACKGROUND: Muscle denervation from trauma and motor neuron disease causes disabling morbidities. A limiting step in functional recovery is the regeneration of neuromuscular junctions (NMJs) for reinnervation. Stem cells have the potential to promote these regenerative processes, but current approaches have limited success, and the optimal types of stem cells remain to be determined. Neural crest stem cells (NCSCs), as the developmental precursors of the peripheral nervous system, are uniquely advantageous, but the role of NCSCs in neuromuscular regeneration is not clear. Furthermore, a cell delivery approach that can maintain NCSC survival upon transplantation is critical. METHODS: We established a streamlined protocol to derive, isolate, and characterize functional p75+ NCSCs from human iPSCs without genome integration of reprogramming factors. To enhance survival rate upon delivery in vivo, NCSCs were centrifuged in microwell plates to form spheroids of desirable size by controlling suspension cell density. Human bone marrow mesenchymal stem cells (MSCs) were also studied for comparison. NCSC or MSC spheroids were injected into the gastrocnemius muscle with denervation injury, and the effects on NMJ formation and functional recovery were investigated. The spheroids were also co-cultured with engineered neuromuscular tissue to assess effects on NMJ formation in vitro. RESULTS: NCSCs cultured in spheroids displayed enhanced secretion of soluble factors involved in neuromuscular regeneration. Intramuscular transplantation of spheroids enabled long-term survival and retention of NCSCs, in contrast to the transplantation of single-cell suspensions. Furthermore, NCSC spheroids significantly improved functional recovery after four weeks as shown by gait analysis, electrophysiology, and the rate of NMJ innervation. MSC spheroids, on the other hand, had insignificant effect. In vitro co-culture of NCSC or MSC spheroids with engineered myotubes and motor neurons further evidenced improved innervated NMJ formation with NCSC spheroids. CONCLUSIONS: We demonstrate that stem cell type is critical for neuromuscular regeneration and that NCSCs have a distinct advantage and therapeutic potential to promote reinnervation following peripheral nerve injury. Biophysical effects of spheroidal culture, in particular, enable long-term NCSC survival following in vivo delivery. Furthermore, synthetic neuromuscular tissue, or "tissues-on-a-chip," may offer a platform to evaluate stem cells for neuromuscular regeneration.

High-Frequency Ultrasound Elastography for Assessing Elastic Properties of Skin and Scars.

Scars are a type of fibrous tissue that typically forms during the wound healing process to replace damaged skin. Because studies have indicated a high correlation between scar stiffness and clinical symptoms, assessing the mechanical properties of scar is crucial for determining an appropriate treatment strategy and evaluating the treatment's efficacy. Shear wave elastography (SWE) is a common technique for measuring tissue elasticity. Because scars are typically a few millimeters thick, they are thin-layer tissues, and therefore, the dispersion effect must be considered to accurately estimate their elasticity. In this study, high-frequency ultrasound (HFUS) elastography was proposed for estimating the elastic properties of scars by using the Lamb wave model (LWM). An external vibrator was used to generate elastic waves in scar tissue and skin, and the propagation of the elastic waves was tracked through 40-MHz ultrafast ultrasound imaging. The elasticity was estimated through shear wave models (SWMs) and LWMs. The effectiveness of using HFUS elastography was verified through phantom and human studies. The phantom experiments involved bulk phantoms with gelatin concentrations of 7% and 15% and 2-4-mm-thick thin-layer 15% gelatin phantoms. The studies of three patients with eight cases of scarring were also conducted. The phantom experimental results demonstrated that the elasticity estimation biases for the thin-layer mediums were approximately -36% to -50% and 3% to -9% in the SWMs and LWMs, respectively, and the estimated shear moduli were 12.8 ± 5.4 kPa and 74.8 ± 26.8 kPa for healthy skin and scar tissue, respectively. All the results demonstrated that the proposed HFUS elastography has a great potential for improving the accuracy of elasticity estimations in clinical dermatological diagnoses.

Sodium phenylbutyrate inhibits Schwann cell inflammation via HDAC and NFκB to promote axonal regeneration and remyelination.

BACKGROUND: Epigenetic regulation by histone deacetylases (HDACs) in Schwann cells (SCs) after injury facilitates them to undergo de- and redifferentiation processes necessary to support various stages of nerve repair. Although de-differentiation activates the synthesis and secretion of inflammatory cytokines by SCs to initiate an immune response during nerve repair, changes in either the timing or duration of prolonged inflammation mediated by SCs can affect later processes associated with repair and regeneration. Limited studies have investigated the regulatory processes through which HDACs in SCs control inflammatory cytokines to provide a favorable environment for peripheral nerve regeneration. METHODS: We employed the HDAC inhibitor (HDACi) sodium phenylbutyrate (PBA) to address this question in an in vitro RT4 SC inflammation model and an in vivo sciatic nerve transection injury model to examine the effects of HDAC inhibition on the expression of pro-inflammatory cytokines. Furthermore, we assessed the outcomes of suppression of extended inflammation on the regenerative potential of nerves by assessing axonal regeneration, remyelination, and reinnervation. RESULTS: Significant reductions in lipopolysaccharide (LPS)-induced pro-inflammatory cytokine (tumor necrosis factor-α [TNFα]) expression and secretion were observed in vitro following PBA treatment. PBA treatment also affected the transient changes in nuclear factor κB (NFκB)-p65 phosphorylation and translocation in response to LPS induction in RT4 SCs. Similarly, PBA mediated long-term suppressive effects on HDAC3 expression and activity. PBA administration resulted in marked inhibition of pro-inflammatory cytokine secretion at the site of transection injury when compared with that in the hydrogel control group at 6-week post-injury. A conducive microenvironment for axonal regrowth and remyelination was generated by increasing expression levels of protein gene product 9.5 (PGP9.5) and myelin basic protein (MBP) in regenerating nerve tissues. PBA administration increased the relative gastrocnemius muscle weight percentage and maintained the intactness of muscle bundles when compared with those in the hydrogel control group. CONCLUSIONS: Suppressing the lengthened state of inflammation using PBA treatment favors axonal regrowth and remyelination following nerve transection injury. PBA treatment also regulates pro-inflammatory cytokine expression by inhibiting the transcriptional activation of NFκB-p65 and HDAC3 in SCs in vitro.

Investigation of Neuropathology after Nerve Release in Chronic Constriction Injury of Rat Sciatic Nerve.

Peripheral compressive neuropathy causes significant neuropathic pain, muscle weakness and prolong neuroinflammation. Surgical decompression remains the gold standard of treatment but the outcome is suboptimal with a high recurrence rate. From mechanical compression to chemical propagation of the local inflammatory signals, little is known about the distinct neuropathologic patterns and the genetic signatures after nerve decompression. In this study, controllable mechanical constriction forces over rat sciatic nerve induces irreversible sensorimotor dysfunction with sustained local neuroinflammation, even 4 weeks after nerve release. Significant gene upregulations are found in the dorsal root ganglia, regarding inflammatory, proapoptotic and neuropathic pain signals. Genetic profiling of neuroinflammation at the local injured nerve reveals persistent upregulation of multiple genes involving oxysterol metabolism, neuronal apoptosis, and proliferation after nerve release. Further validation of the independent roles of each signal pathway will contribute to molecular therapies for compressive neuropathy in the future.

Delayed Neurological Sequelae in an Infant After Carbon Monoxide Intoxication.

Delayed neurological sequelae are symptoms that appear over a period of time after an acute event of carbon monoxide poisoning. The incidence of delayed neurological sequelae is lower in children than in adults and is even more uncommon in infants. Here, we present a case of a 4-month-old infant who developed delayed neurological sequelae after carbon monoxide intoxication. She presented with neurological symptoms, including opisthotonus, athetoid movements, anterior tongue thrust, and opsoclonus. Because these symptoms are starkly different from those of adults, they should be compared with age-appropriate developmental milestones. Because of their faster metabolic rate and presence of fetal hemoglobin, infants with developing brains may be especially vulnerable to carbon monoxide toxicity. Therefore, thorough neurological examination and prompt treatment are critical for infants who experience carbon monoxide intoxication.

Skeletal muscle regeneration via the chemical induction and expansion of myogenic stem cells in situ or in vitro.

Muscle loss and impairment resulting from traumatic injury can be alleviated by therapies using muscle stem cells. However, collecting sufficient numbers of autologous myogenic stem cells and expanding them efficiently has been challenging. Here we show that myogenic stem cells (predominantly Pax7+ cells)-which were selectively expanded from readily obtainable dermal fibroblasts or skeletal muscle stem cells using a specific cocktail of small molecules and transplanted into muscle injuries in adult, aged or dystrophic mice-led to functional muscle regeneration in the three animal models. We also show that sustained release of the small-molecule cocktail in situ through polymer nanoparticles led to muscle repair by inducing robust activation and expansion of resident satellite cells. Chemically induced stem cell expansion in vitro and in situ may prove to be advantageous for stem cell therapies that aim to regenerate skeletal muscle and other tissues.

Stretchable, dynamic covalent polymers for soft, long-lived bioresorbable electronic stimulators designed to facilitate neuromuscular regeneration.

Bioresorbable electronic stimulators are of rapidly growing interest as unusual therapeutic platforms, i.e., bioelectronic medicines, for treating disease states, accelerating wound healing processes and eliminating infections. Here, we present advanced materials that support operation in these systems over clinically relevant timeframes, ultimately bioresorbing harmlessly to benign products without residues, to eliminate the need for surgical extraction. Our findings overcome key challenges of bioresorbable electronic devices by realizing lifetimes that match clinical needs. The devices exploit a bioresorbable dynamic covalent polymer that facilitates tight bonding to itself and other surfaces, as a soft, elastic substrate and encapsulation coating for wireless electronic components. We describe the underlying features and chemical design considerations for this polymer, and the biocompatibility of its constituent materials. In devices with optimized, wireless designs, these polymers enable stable, long-lived operation as distal stimulators in a rat model of peripheral nerve injuries, thereby demonstrating the potential of programmable long-term electrical stimulation for maintaining muscle receptivity and enhancing functional recovery.

FGF9 induces functional differentiation to Schwann cells from human adipose derived stem cells.

Rationale: The formation of adipose-derived stem cells (ASCs) into spheres on a chitosan-coated microenvironment promoted ASCs differentiation into a mixed population of neural lineage-like cells (NLCs), but the underline mechanism is still unknown. Since the fibroblast growth factor 9 (FGF9) and fibroblast growth factor receptors (FGFRs) play as key regulators of neural cell fate during embryo development and stem cell differentiation, the current study aims to reveal the interplay of FGF9 and FGFRs for promoting peripheral nerve regeneration. Methods: Different concentration of FGF9 peptide (10, 25, 50, 100 ng/mL) were added during NLCs induction (FGF9-NLCs). The FGFR expressions and potential signaling were studied by gene and protein expressions as well as knocking down by specific FGFR siRNA or commercial inhibitors. FGF9-NLCs were fluorescent labeled and applied into a nerve conduit upon the injured sciatic nerves of experimental rats. Results: The FGFR2 and FGFR4 were significantly increased during NLCs induction. The FGF9 treated FGF9-NLCs spheres became smaller and changed into Schwann cells (SCs) which expressed S100ß and GFAP. The specific silencing of FGFR2 diminished FGF9-induced Akt phosphorylation and inhibited the differentiation of SCs. Transplanted FGF9-NLCs participated in myelin sheath formation, enhanced axonal regrowth and promoted innervated muscle regeneration. The knockdown of FGFR2 in FGF9-NLCs led to the abolishment of nerve regeneration. Conclusions: Our data therefore demonstrate the importance of FGF9 in the determination of SC fate via the FGF9-FGFR2-Akt pathway and reveal the therapeutic benefit of FGF9-NLCs.