Sequence‐Optimized Peptide Nanofibers as Growth Stimulators for Regeneration of Peripheral Neurons

There is an urgent need for biomaterials that support tissue healing, particularly neuronal regeneration. In a medium throughput screen novel self‐assembling peptide (SAP) sequences that form fibrils and stimulated nerve fiber growth of peripheral nervous system (PNS)‐derived neurons are identified. Based on the peptide sequences and fibril morphologies and by applying rational data‐mining, important structural parameters stimulating neuronal activity are elucidated. Three SAPs (SAP^1e, SAP^2e, and SAP^5c) enhance adhesion and growth of PNS neurons. These SAPs form 2D and 3D matrices that serve as bioactive scaffolds stimulating cell adhesion and growth. The newly discovered SAPs also support the growth of CNS neurons and glia cells. Subsequently, the potential of SAPs to enhance PNS regeneration in vivo is analyzed. For this, the facial nerve driving whisker movement in mice is injured. Notably, SAPs persist for up to 3 weeks in the injury site indicating highly adhesive properties and stability. After SAP administration, more motor neurons incorporating markers for successive regeneration are observed. Recovery of whisker movement is elevated in SAP‐injected mice. In summary, short peptides that form fibrils are identified and the adhesion, growth, and regeneration of neurons have been efficiently enhanced without the necessity to attach hormones or growth factors.     

Peripheral Nerve Regeneration with 3D Printed Bionic Scaffolds Loading Neural Crest Stem Cell Derived Schwann Cell Progenitors

Peripheral nerve injuries are one of the most common types of traumatic damage to the nervous system. Treatment of peripheral nerve injuries aims to promote axon regrowth by imitating and improving the microenvironment for sciatic nerve regeneration. In this study, regeneration efficiency and behavior of peripheral nerves are compared under three treatment strategies: 1) transplantation of Schwann cell progenitors induced from purified neural crest stem cells; 2) implantation of a multiscale scaffold based on high-resolution 3D printing; and 3) implantation of this bionic scaffold loading Schwann cell progenitors. The results of structural, electrophysiological, and behavioral tests demonstrate that the three treatment strategies result in different degrees of regeneration. The purified neural crest stem cells differentiate into functional Schwann cells and promote axon regeneration. The multifunctional 3D printed scaffold promotes oriented growth and myelination, and the myelinated nerve regrows with increased density and without visible scaffolds after six months. For the regeneration, scaffold treatment produces better performance than cell graft alone. Finally, it is shown that implantation of multiscale scaffolds preloaded with neural crest stem cell derived Schwann cell progenitors is the best strategy to promote peripheral nerve regeneration with improved anatomy and function among the three different strategies.     

3D Printed Anatomical Nerve Regeneration Pathways

A 3D printing methodology for the design, optimization, and fabrication of a custom nerve repair technology for the regeneration of complex peripheral nerve injuries containing bifurcating sensory and motor nerve pathways is introduced. The custom scaffolds are deterministically fabricated via a microextrusion printing principle using 3D models, which are reverse engineered from patient anatomies by 3D scanning. The bifurcating pathways are augmented with 3D printed biomimetic physical cues (microgrooves) and path‐specific biochemical cues (spatially controlled multicomponent gradients). In vitro studies reveal that 3D printed physical and biochemical cues provide axonal guidance and chemotractant/chemokinetic functionality. In vivo studies examining the regeneration of bifurcated injuries across a 10 mm complex nerve gap in rats showed that the 3D printed scaffolds achieved successful regeneration of complex nerve injuries, resulting in enhanced functional return of the regenerated nerve. This approach suggests the potential of 3D printing toward advancing tissue regeneration in terms of: (1) the customization of scaffold geometries to match inherent tissue anatomies; (2) the integration of biomanufacturing approaches with computational modeling for design, analysis, and optimization; and (3) the enhancement of device properties with spatially controlled physical and biochemical functionalities, all enabled by the same 3D printing process.     

An Evaluation of Photoengraved Microelectrodes for Extracellular Single-Unit Recording

Microelectrodes fabricated using integrated-circuit technology are shown to be suitable for extracellular single-unit recording, and the factors influencing electrode-cell coupling are discussed. Electrode tip size as well as location is found to be critical in recording high spike amplitudes, suggesting that the paths for current flow in central nervous system (CNS) tissue may be extremely small.     

3D Printed Neural Regeneration Devices

Neural regeneration devices interface with the nervous system and can provide flexibility in material choice, implantation without the need for additional surgeries, and the ability to serve as guides augmented with physical, biological (e.g., cellular), and biochemical functionalities. Given the complexity and challenges associated with neural regeneration, a 3D printing approach to the design and manufacturing of neural devices can provide next‐generation opportunities for advanced neural regeneration via the production of anatomically accurate geometries, spatial distributions of cellular components, and incorporation of therapeutic biomolecules. A 3D printing‐based approach offers compatibility with 3D scanning, computer modeling, choice of input material, and increasing control over hierarchical integration. Therefore, a 3D printed implantable platform can ultimately be used to prepare novel biomimetic scaffolds and model complex tissue architectures for clinical implants in order to treat neurological diseases and injuries. Further, the flexibility and specificity offered by 3D printed in vitro platforms have the potential to be a significant foundational breakthrough with broad research implications in cell signaling and drug screening for personalized healthcare. This progress report examines recent advances in 3D printing strategies for neural regeneration as well as insight into how these approaches can be improved in future studies.     

Silk Hydrogels as Soft Substrates for Neural Tissue Engineering

There is great need for soft biomaterials that match the stiffness of human tissues for tissue engineering and regeneration. Hydrogels are frequently employed for extracellular matrix functionalization and to provide appropriate mechanical cues. It is challenging, however, to achieve structural integrity and retain bioactive molecules in hydrogels for complex tissue formation that may take months to develop. This work aims to investigate mechanical and biochemical characteristics of silk hydrogels for soft tissue engineering, specifically for the nervous system. The stiffness of 1 to 8% silk hydrogels, measured by atomic force microscopy, is 4 to 33 kPa. The structural integrity of silk gels is maintained throughout embryonic chick dorsal root ganglion (cDRG) explant culture over 4 days whereas fibrin and collagen gels decrease in mass over time. Neurite extension of cDRGs cultured on 2 and 4% silk hydrogels exhibit greater growth than softer or stiffer gels. Silk hydrogels release <5% of neurotrophin‐3 (NT‐3) over 2 weeks and 11‐day old gels show maintenance of growth factor bioactivity. Finally, fibronectin‐ and NT‐3‐functionalized silk gels elicit increased axonal bundling suggesting their use in bridging nerve injuries. These results support silk hydrogels as soft and sustainable biomaterials for neural tissue engineering.     

Fuel-Cell Hybrid Powertrain: Toward Minimization of Hydrogen Consumption

In this paper, the powertrain sizing of a fuel-cell hybrid vehicle (FCHV) is investigated. The goal is to determine the fuel-cell system (FCS) size, together with the energy storage system (ESS) size, which leads to the lowest hydrogen consumption. The power source (FCS $+$ ESS) capabilities should also respect the vehicle driveability constraints. Batteries and supercapacitors are considered as ESSs. The power management strategy is a global optimization algorithm respecting charge sustaining of the ESS. The impacts of the driving cycle (urban, outer urban, and highway), ESS technology, and vehicle driveability constraints on hydrogen consumption are analyzed in detail.      

Microwave biological effects: An overview

Although most investigators accept the fact that "high power density" of microwaves can result in pathophysiological manifestations of a thermal nature, some reports have suggested that "low power density" microwave (MW) energy can affect neural and immunologic function in animals and man. Most of these reports have emanated from the USSR and other Eastern European countries. Since most reported "low-level" effects relate to behavioral and central nervous system changes, studies are needed to determine the nature and mechanism(s) of the nervous system's reactions, if any, to electromagnetic fields and to investigate the degree to which the individual's performance capabilities may be affected. Because of their important integrative and regulatory functions, the neuroendocrine and central nervous system should receive attention as possible sensitive areas. Neurochemical assays and immunologic reactivity could indicate basic mechanisms of interaction. A critical review of studies into the biological effects of MW's indicates that many of the investigations suffer from inadequacies of either technical facilities and energy measurement skills or insufficient control of the biological specimens and the criteria for biological change. There is a great need for systematic and quantitative comparative investigations, using well-controlled experiments. This should be done by using sound biomedical and biophysical approaches at the various organizational levels from the whole animal to the subcellular level on an integrated basis, with full recognition of the multiple associated and interdependent variables. Above all there is a need for scientific competence and integrity. It is important to maintain a proper perspective and assess realistically the biomedical effects of microwave exposure, so that the worker or general public will not be unduly exposed nor will research, development and benficial utilization of this energy be hampered or unecessarily restricted.     

Electrically Conductive Hydrogel Nerve Guidance Conduits for Peripheral Nerve Regeneration

Peripheral nerve injuries are serious conditions, and surgical treatment has critical limitations. Therefore, nerve guidance conduits (NGCs) are proposed as an alternative. In this study, multifunctional NGCs are fabricated for the regeneration of injured peripheral nerves. Graphene oxide (GO) and gelatin‐methacrylate (GelMA) are polymerized and chemically reduced to form reduced (GO/GelMA) (r(GO/GelMA)). The prepared materials present good electrical conductivity, flexibility, mechanical stability, and permeability, which are suitable for use as NGCs. In vitro studies show 2.1‐ and 1.4‐fold promotion of neuritogenesis of PC12 neuronal cells on r(GO/GelMA) compared to GelMA and unreduced GO/GelMA, respectively. Animal studies using a rat sciatic nerve injury model with a 10 mm gap between the proximal and distal regions of the defect reveal that r(GO/GelMA) NGCs significantly enhance peripheral nerve regeneration, indicated by improved muscle weight increase, electro‐conduction velocity, and sciatic nerve function index. Specifically, r(GO/GelMA) NGCs are utilized to potentiate regrowth with myelination in rat sciatic nerves followed by histological, immunohistological, and morphometrical analyses. This study successfully shows the feasibility of electrically conductive hydrogel NGCs as functional conduits for improved nerve regeneration in a preclinical study, where these NGCs can not only mimic nerve tissues but also strongly promote nerve regeneration.     

电镜在中枢神经系统小圆细胞肿瘤诊断中的作用

本文报道９８例中枢神经系统小圆细胞肿瘤电镜诊断资料。常规透射电镜确诊７９例（８０．６％）,加免疫组化后确诊１５例（１５．３％）,但仍有４例（４．１％）不能确诊。确诊后的肿瘤类型包括胶母细胞瘤、少突胶质细胞瘤、室管膜瘤、髓母细胞瘤、神经母细胞瘤、松果体细胞瘤、原始神经外胚层瘤、恶性淋巴瘤、转移性未分化鳞癌和未分化腺癌、以及黑色素瘤。对上述肿瘤的主要超微结构特征进行了描述,并结合文献阐明了电镜检查对中枢神经系统小圆细胞肿瘤诊断和鉴别诊断有七个方面的作用。     

PNS modules for the synthesis of parallel self-organizing hierarchical neural networks

The PNS module is discussed as the building block for the synthesis of parallel, self-organizing, hierarchical, neural networks (PSHNNs). The PNS module contains three submodules (units), the first two of which are created as simple neural network constructs and the last of which is a statistical unit. The first two units are fractile in nature, meaning that each such unit may itself consist of a number of parallel PNS modules in a fractile fashion. Through a mechanism of statistical acceptance or rejection of input vectors for classification, the sample space is divided into a number of regions. The input vectors belonging to each region are classified by a dedicated set of PNS modules. This strategy results in considerably higher accuracy of classification and better generalization as compared to previous neural network models. If the delta rule network is used to generate the first two units, each region approximates a linearly separable region. In this sense, the total system becomes similar to a piecewise linear model. The various regions are determined nonlinearly by the first and third units of the PNS modules.     

Silk-Inspired In Situ Hydrogel with Anti-Tumor Immunity Enhanced Photodynamic Therapy for Melanoma and Infected Wound Healing

Easy cancer recurrence and wound infections have been clinical challenges after surgical treatment of melanoma. Herein, a silk-inspired in situ gelation system containing methacrylated silk fibroin (SF) and chlorine e6 for improved cancer therapy with enhanced wound healing is developed. Favored by the macrophage recruitment capacity of the SF hydrogel, promising antitumor immune responses can be turned “on” via near infrared irradiation in a controllable manner to achieve combination therapy with photodynamic therapy to significantly suppress melanoma recurrence. Moreover, the effective photodynamic antibacterial activity of this bioactive system with the capacity of light-controllable modulating macrophage phenotype promotes remarkable tissue ingrowth with hair follicle regeneration for Staphylococcus aureus infected wound healing. Thus, this multifunctional silk-based hydrogel system, as a desirable wound dressing, provides a new platform for promising melanoma therapy and skin regeneration.     

Glycopeptide-Based Multifunctional Hydrogels Promote Diabetic Wound Healing through pH Regulation of Microenvironment

Excessive inflammation, bacterial infection, and blocked angiogenesis make diabetic wound healing challenging. Multifunctional wound dressings have several advantages in diabetic wound healing. In addition, the pH regulation of the microenvironment is shown to be a key factor that promotes skin regeneration through cellular immune regulation. However, few reports have focused on the development of functional dressings with the ability to regulate the pH microenvironment and promote diabetic wound healing. This study presents a novel approach for regulating the pH microenvironment of diabetic wound sites using a glycopeptide-based hydrogel consisting of modified hyaluronic acid and poly(6-aminocaproic acid). This hydrogel forms a network through Schiff base interactions and metal complexation, which suppresses inflammation and accelerates angiogenesis during wound healing. Hydrogels not only have adequate mechanical properties and self-healing ability but can also support tissue adhesion. They can also promote the secretion of inducible cAMP early repressor, which promotes the polarization of macrophages toward the M2 type. The in vivo results confirm that hydrogel promotes diabetic wound repair and skin regeneration by exerting rapid anti-inflammatory effects and promoting angiogenesis. Therefore, this hydrogel system represents an effective strategy for treating diabetic wounds.     

Teaching ethics in the engineering design process: a legal scholar's view

Engineering ethics are a critical "gap filler" in the regulation of technology. Engineers, as "professionals," are given professional autonomy in promoting risky activities, based on a promise that they will act in the public interest. The legal system, both in regulation and liability, puts constraints on the design process, but often leaves gaps that must be filled by ethical precepts. The conflict between the public interest and the private interest of the engineer is often most acute in the acceptance or rejection of relatively rare risks in the design of products. Rare risks normally involve the greatest uncertainty of injury. These rare risks of catastrophic injury can fall "under the radar" of regulatory systems, or technological advances may make regulatory systems obsolete. The other major risk category are "system risks," in which individual engineers assume that some other party will take care of the risk. Teaching engineers to recognize and deal with these risks is critical. In particular, reliance on regulatory approval may be inadequate. Designing products that hold paramount the public safety must be the benchmark for engineering ethics.     

A characterization of the effects on neuronal excitability due toprolonged microstimulation with chronically implanted microelectrodes

Localized, long-lasting stimulation-induced depression of neuronal excitability (SIDNE) is a consequence of prolonged, high-frequency microstimulation in the central nervous system (CNS). It represents a persisting refractory state in the neurons and axons near the stimulating microelectrode, that occurs in the absence of histologically detectable tissue injury. It does not involve a change in synaptic efficacy and, in this respect, it differs from the more familiar phenomenon of long-term depression (LTD). Although SIDNE is ultimately reversible (after several days), it must be taken into account in the design of neural prostheses based on microstimulation in the central nervous system and in animal studies that require prolonged microstimulation in the CNS. In this study, we have characterized the phenomenon, using as the paradigm, iridium microelectrodes implanted chronically in the cat's posteroventral cochlear nucleus. Although the SIDNE may persist for several days after the end of the stimulation protocol, it does not become more severe from day to day when the stimulation protocol is repeated on successive days. The severity of the SIDNE is strongly dependent upon both the instantaneous frequency and the duty cycle of the electrical stimulation. The character of the SIDNE, including its localization to the immediate vicinity of the stimulating microelectrodes, suggests that the phenomenon is a direct consequence of the prolonged electrical excitation of the neurons close to the microelectrode. The problem of designing microstimulation systems that allow high-frequency stimulation of a neural substrate, while minimizing SIDNE are discussed     

Living Microneedle Patch with Adipose-Derived Stem Cells Embedding for Diabetic Ulcer Healing

Stem cells have demonstrated values in diabetic ulcer (DU) treatments. Challenges in this area are focused on enhancing the localized curative effects of stem cells and improving diabetic wound healing efficiently. Herein, a novel living microneedle (MN) patch is presented as a localized delivery system of bioactive platelet derived growth factor D (PDGF-D) and human adipose-derived stem cells (ADSCs) for DU wound treatment. Compared with traditional complicated stem cell carriers, the MN patch can keep stem cell viability for ADSCs encapsulation and delivery, and possesses good mechanical strengths to penetrate the local skin wounds noninvasively. It is demonstrated that the delivery ADSCs are with the abilities of angiogenesis promotion during the DU wound healing; while the additive PDGF-D can contribute significantly to the proliferation of ADSCs, strengthening the cell function of ADSCs and further facilitating the healing processes. Thus, living MN patches accelerate vascularization, tissue regeneration, and collagen deposition in a wounded diabetic mouse model, suggesting their potential application to DU wound healing and other therapeutic applications.     

Capacity optimization in multiservice mobile wireless networks with multiple fractional channel reservation

In this paper, the multiple fractional channel reservation (MFCR) strategy for service differentiation is proposed. MFCR overcomes the "integer nature" of traditional channel reservation schemes (also referred to as guard channel, trunk reservation, or cutoff priority) that precludes them to achieve maximum system capacity in single- and multiservice environments. Contrary to the rest of the channel reservation schemes previously proposed in the literature on the topic, MFCR reserves, on average, real numbers of channels to prioritize new and/or handoff calls in multiple service environments. Given a set of requirements on new call blocking and forced termination probabilities for each service type, MFCR maximizes system capacity while meeting the quality of service (QoS) constraints in multiservice mobile cellular networks. It finely controls the communication service quality, by varying the average numbers of reserved channels by a fraction of one. Determining the right amount of resources (cutoff threshold or number of reserved channels) to prioritize each call type and to satisfy all QoS constraints in multiservice environments, however, is a difficult task. Selecting the optimal prioritization order is not an easy process either, as it is affected by QoS constraints, system characteristics, and resource sharing. Thus, an heuristic algorithm to determine the optimum numbers of reserved (resources) channels to achieve maximum system capacity when using the MFCR is also proposed. To our knowledge, the capacity optimization problem considering individual QoS constraints had only been addressed in single service environments. Also, a comprehensive survey on channel reservation strategies proposed in the literature has been included.     

Self‐Healing Silk Fibroin‐Based Hydrogel for Bone Regeneration: Dynamic Metal‐Ligand Self‐Assembly Approach

Despite advances in the development of silk fibroin (SF)‐based hydrogels, current methods for SF gelation show significant limitations such as lack of reversible crosslinking, use of nonphysiological conditions, and difficulties in controlling gelation time. In the present study, a strategy based on dynamic metal‐ligand coordination chemistry is developed to assemble SF‐based hydrogel under physiological conditions between SF microfibers (mSF) and a polysaccharide binder. The presented SF‐based hydrogel exhibits shear‐thinning and autonomous self‐healing properties, thereby enabling the filling of irregularly shaped tissue defects without gel fragmentation. A biomineralization approach is used to generate calcium phosphate‐coated mSF, which is chelated by bisphosphonate ligands of the binder to form reversible crosslinkages. Robust dually crosslinked (DC) hydrogel is obtained through photopolymerization of acrylamide groups of the binder. DC SF‐based hydrogel supports stem cell proliferation in vitro and accelerates bone regeneration in cranial critical size defects without any additional morphogenes delivered. The developed self‐healing and photopolymerizable SF‐based hydrogel possesses significant potential for bone regeneration application with the advantages of injectability and fit‐to‐shape molding.