A differential-targeting core-shell microneedle patch with coordinated and prolonged release of mangiferin and MSC-derived exosomes for scarless skin regeneration.

Microneedles for skin regeneration are conventionally restricted by uncontrollable multi-drug release, limited types of drugs, and poor wound adhesion. Here, a novel core-shell microneedle patch is developed for scarless skin repair, where the shell is composed of hydrophilic gelatin methacryloyl (GelMA) loaded with mangiferin, an anti-inflammatory small molecule, and the core is composed of hydrophobic poly (lactide-co-propylene glycol-co-lactide) dimethacrylates (PGLADMA) loaded with bioactive macromolecule and human mesenchymal stromal cell (hMSC)-derived exosomes. This material choice provides several benefits: the GelMA shell provides a swelling interface for tissue interlocking and rapid release of mangiferin at an early wound healing stage for anti-inflammation, whereas the PGLADMA core offers long-term encapsulation and release of exosomes (30% release in 3 weeks), promoting sustained angiogenesis and anti-inflammation. Our results demonstrate that the core-shell microneedle possesses anti-inflammatory properties and can induce angiogenesis both in vitro in terms of macrophage polarization and tube formation of human umbilical vein endothelial cells (HUVECs), and in vivo in terms of anti-inflammation, re-epithelization, and vessel formation. Importantly, we also observe reduced scar formation in vivo. Altogether, the degradation dynamics of our hydrophilic/hydrophobic materials enable the design of a core-shell microneedle for differential and prolonged release, promoting scarless skin regeneration, with potential for other therapies of long-term exosome release.

Going below and beyond the surface: Microneedle structure, materials, drugs, fabrication, and applications for wound healing and tissue regeneration.

Microneedle, as a novel drug delivery system, has attracted widespread attention due to its non-invasiveness, painless and simple administration, controllable drug delivery, and diverse cargo loading capacity. Although microneedles are initially designed to penetrate stratum corneum of skin for transdermal drug delivery, they, recently, have been used to promote wound healing and regeneration of diverse tissues and organs and the results are promising. Despite there are reviews about microneedles, few of them focus on wound healing and tissue regeneration. Here, we review the recent advances of microneedles in this field. We first give an overview of microneedle system in terms of its potential cargos (e.g., small molecules, macromolecules, nucleic acids, nanoparticles, extracellular vesicle, cells), structural designs (e.g., multidrug structures, adhesive structures), material selection, and drug release mechanisms. Then we briefly summarize different microneedle fabrication methods, including their advantages and limitations. We finally summarize the recent progress of microneedle-assisted wound healing and tissue regeneration (e.g., skin, cardiac, bone, tendon, ocular, vascular, oral, hair, spinal cord, and uterine tissues). We expect that our article would serve as a guideline for readers to design their microneedle systems according to different applications, including material selection, drug selection, and structure design, for achieving better healing and regeneration efficacy.

An anti-bacterial and anti-cancer fibrous membrane with multiple therapeutic effects for prevention of pancreatic cancer recurrence.

Adjuvant systemic chemotherapy with gemcitabine (GEM) is recognized as the standard of care to improve the prognosis of patients with resected pancreatic cancer (PC); however, it is greatly limited by poor absorption of chemotherapy agents. Moreover, surgical site infection and Gammaproteobacteria-induced GEM resistance further decrease the chemotherapy efficacy and increase the risk of recurrence and even mortality. Here, we develop an implantable anti-bacterial and anti-cancer fibrous membrane (AAFM) to inhibit PC recurrence in a well-coordinated manner. Our AAFM can be readily prepared via simple co-electrospinning of GEM and poly-L-lactic acid (PLLA) and subsequent tannic acid (TA)-mediated in-situ generation of silver nanoparticles (AgNPs). The resultant membrane presents highly porous fibrous morphology and appropriate mechanical performance. Most importantly, we find the surface-deposited TA/AgNP complexes can exert multiple therapeutic effects: (1) they can act as a fence to extend GEM diffusion route, achieving a sustained drug release; (2) they can fight the pathogenic microorganisms in the local microenvironment and prevent infectious complications and alleviate Gammaproteobacteria-induced chemotherapy resistance; (3) they can combat residual cancer cells to synchronously strengthen the effectiveness of GEM-based chemotherapy. Altogether, our AAFM provides a proof-of-concept demonstration of the integrated anti-cancer and anti-bacterial strategy for enhanced therapeutic efficacy and will inspire the design of other high-performance implants for prevention of tumor relapse.

Metabolomics analysis reveals four biomarkers associated with the gouty arthritis progression in patients with sequential stages.

OBJECTIVES: The gouty arthritis (GA) progression was multistage, yet the GA clinical diagnosis guidelines were more inclined to suitable for acute gouty arthritis (AGA), thus neglecting of the progress of GA. This study aimed to identify specific biomarkers that were competent for reflecting the progression of GA and attempted to provide evidence for seasonable intervention of appropriate clinical treatment. METHODS: A total of 547 patients with GA at sequential stages and healthy volunteers were divided into a training set (n = 347) and a validation set (n = 200). Serum metabolic profiles were determined by UHPLC-QTOF-MS-MS untargeted metabolomics, and biomarkers were identified by logistic regression and receiver operating characteristic analysis. Further, UHPLC-QE-MS was applied for accurate quantitative validation of identified potential biomarkers in the validation set samples. RESULTS: After serum metabolic profiles analysis by untargeted metabolomics, 12 metabolites with monotonous change trend were screened, and were verified by targeted metabolomics subsequently. The quantitative results showed the serum concentration of kynurenic acid(KYNA), N1-Methyl-2-pyridone-5-carboxamide(2PY), DL-2-Aminoadipic acid(2AMIA) and 5-hydroxyindole acetic acid(5-HIAA) of patients with sequential stages showed a strictly monotonic trend, and AUC was 0.97, 0.97, 0.96 and 0.95, respectively. CONCLUSIONS: KYNA and 5-HIAA are related to acute inflammation of GA, while 2PY and 2AMIA are related to renal function damage caused by long-term HUA. Therefore, we believe it is inappropriate to use a single biomarker to define the phase of GA. Actually, four biomarkers obtained in this paper should be integratedly adopted to evaluate the progression of GA with sequential stages.

Establishment of a clinical diagnostic model for gouty arthritis based on the serum biochemical profile: A case-control study.

ABSTRACT: The disease progression of gouty arthritis (GA) is relatively clear, with the 4 stages of hyperuricemia (HUA), acute gouty arthritis (AGA), gouty arthritis during the intermittent period (GIP), and chronic gouty arthritis (CGA). This paper attempts to construct a clinical diagnostic model based on blood routine test data, in order to avoid the need for bursa fluid examination and other tedious steps, and at the same time to predict the development direction of GA.Serum samples from 579 subjects were collected within 3 years in this study and were divided into a training set (n = 379) and validation set (n = 200). After a series of multivariate statistical analyses, the serum biochemical profile was obtained, which could effectively distinguish different stages of GA. A clinical diagnosis model based on the biochemical index of the training set was established to maximize the probability of the stage as a diagnosis, and the serum biochemical data from 200 patients were used for validation.The total area under the curve (AUC) of the clinical diagnostic model was 0.9534, and the AUCs of the 5 models were 0.9814 (Control), 0.9288 (HUA), 0.9752 (AGA), 0.9056 (GIP), and 0.9759 (CGA). The kappa coefficient of the clinical diagnostic model was 0.80.This clinical diagnostic model could be applied clinically and in research to improve the accuracy of the identification of the different stages of GA. Meanwhile, the serum biochemical profile revealed by this study could be used to assist the clinical diagnosis and prediction of GA.

LC-MS Analysis of Serum for the Metabolomic Investigation of the Effects of Pulchinenoside b4 Administration in Monosodium Urate Crystal-Induced Gouty Arthritis Rat Model.

Gouty arthritis (GA) is commonly caused by deposition of monosodium urate (MSU) crystals within the joint capsule, bursa, cartilage, bone, or other periarticular tissues after chronic hyperuricemia. Clinically, GA is characterized by acute episodes of joint inflammation, which is most frequently encountered in the major joints, and also has a significant impact on quality of life. Pulchinenoside b4(P-b4) has a wide range of biological activities, including antitumor, anti-inflammatory, antiviral and immunomodulatory activities. Currently, the anti-GA activity and metabolomic profiles after being treated by P-b4 have not been reported. In this paper, for the first time, we have performed a non-targeted metabolomics analysis of serum obtained from an MSU crystal-induced GA rat model intervened by P-b4, using ultra-performance liquid chromatography coupled to quadrupole time-of-flight tandem mass spectrometry. In this study, the main pharmacodynamics of different dosing methods and dosages of P-b4 was firstly investigated. Results have shown that P-b4 possesses high anti-inflammatory activity. These results demonstrated changes in serum metabolites with 32 potential biomarkers. Arachidonic acid, sphingolipid, and glycerophospholipid metabolism are considered to be the most relevant metabolic pathway with P-b4 treatment effect in this study. Moreover, the changes of metabolites and the self-extinction of model effects within 24 h reveals important information for GA diagnostic criteria: The regression of clinical symptoms or the decline of some biochemical indicators cannot be regarded as the end point of GA treatment. Furthermore, our research group plans to conduct further metabolomics research on the clinical course of GA.

[Application of metabolomics and related technologies in research and development field of traditional Chinese medicine].

Internal environment of metabolism of traditional Chinese medicine (TCM) is a dynamic process, which is in line with the "holistic-dynamic-comprehensive-analytic" characteristics of metabonomics, therefore metabonomics have a unique advantage to reveal the metabolic pattern of TCM. The application of metabonomics in TCM has great practical significance in understanding the pharmacodynamic/toxic effect material basis, mechanisms and guiding for determination of dosage and treatment course; At the same time, the scientific compatibility of TCM prescription, the germplasm resources of TCM and the preclinical safety/toxicity can be widely researched. At present, metabolomics has become a leading technology in many industries and fields including the research and development of TCM. The core of metabolomics is analytical technology, because comprehensive metabolite profiles or accurate identification of known metabolites can be obtained from complex biological samples only by appropriate analytical techniques. At the same time, a series of bioinformatics/chemical informatics/stoichiometry methods are needed to process the data, so as to obtain the potential law and information in the mass data. In this paper, the concept of metabolomics, relevant analytical techniques, data processing methods and applications were explained and analyzed clearly. In addition, the core problems and countermeasures of metabolomics were summarized, and the future development of metabolomics was prospected as well.

Methanol decomposition reactions over a boron-doped graphene supported Ru-Pt catalyst.

The decomposition of methanol is currently attracting research attention due to the potential widespread applications of its end products. In this work, density functional theory (DFT) calculations have been performed to investigate the adsorption and decomposition of methanol on a Ru-Pt/boron doped graphene surface. We find that the most favorable reaction pathway is methanol (CH3OH) decomposition through O-H bond breaking to form methoxide (CH3O) as the initial step, followed by further dehydrogenation steps which generate formaldehyde (CH2O), formyl (CHO), and carbon monoxide (CO). The calculations illustrate that CH3OH and CO groups prefer to adsorb at the Ru-top sites, while CH2OH, CH3O, CH2O, CHO, and H2 groups favor the Ru-Pt bridge sites, indicating the preference of Ru atoms to adsorb the active intermediates or species having lone-pair electrons. Based on the results, it is found that the energy barrier for CH3OH decomposition through the initial O-H bond breaking is less than its desorption energy of 0.95 eV, showing that CH3OH prefers to undergo decomposition to CH3O rather than direct desorption. The study provides in-depth theoretical insights into the potentially enhanced catalytic activity of Ru-Pt/boron doped graphene surfaces for methanol decomposition reactions, thereby contributing to the understanding and designing of an efficient catalyst under optimum conditions.