We describe, for the first time the use of hydrogel-forming microneedle (MN) arrays for minimally-invasive extraction and quantification of drug substances and glucose from skin in vitro and in vivo. MN prepared from aqueous blends of hydrolysed poly(methyl-vinylether-co-maleic anhydride) (11.1% w/w) and poly(ethyleneglycol) 10,000 daltons (5.6% w/w) and crosslinked by esterification swelled upon skin insertion by uptake of fluid. Post-removal, theophylline and caffeine were extracted from MN and determined using HPLC, with glucose quantified using a proprietary kit. In vitro studies using excised neonatal porcine skin bathed on the underside by physiologically-relevant analyte concentrations showed rapid (5 min) analyte uptake. For example, mean concentrations of 0.16 μg/mL and 0.85 μg/mL, respectively, were detected for the lowest (5 μg/mL) and highest (35 μg/mL) Franz cell concentrations of theophylline after 5 min insertion. A mean concentration of 0.10 μg/mL was obtained by extraction of MN inserted for 5 min into skin bathed with 5 μg/mL caffeine, while the mean concentration obtained by extraction of MN inserted into skin bathed with 15 μg/mL caffeine was 0.33 μg/mL. The mean detected glucose concentration after 5 min insertion into skin bathed with 4 mmol/L was 19.46 nmol/L. The highest theophylline concentration detected following extraction from a hydrogel-forming MN inserted for 1 h into the skin of a rat dosed orally with 10 mg/kg was of 0.363 μg/mL, whilst a maximum concentration of 0.063 μg/mL was detected following extraction from a MN inserted for 1 h into the skin of a rat dosed with 5 mg/kg theophylline. In human volunteers, the highest mean concentration of caffeine detected using MN was 91.31 μg/mL over the period from 1 to 2 h post-consumption of 100 mg Proplus® tablets. The highest mean blood glucose level was 7.89 nmol/L detected 1 h following ingestion of 75 g of glucose, while the highest mean glucose concentration extracted from MN was 4.29 nmol/L, detected after 3 hours skin insertion in human volunteers. Whilst not directly correlated, concentrations extracted from MN were clearly indicative of trends in blood in both rats and human volunteers. This work strongly illustrates the potential of hydrogel-forming MN in minimally-invasive patient monitoring and diagnosis. Further studies are now ongoing to reduce clinical insertion times and develop mathematical algorithms enabling determination of blood levels directly from MN measurements.
Diabetic mellitus (DM) is a significant public health concern worldwide with an increased incidence of morbidity and mortality, which is particularly due to the diabetic vascular complications. Several pivotal underlying mechanisms are associated with vascular complications, including hyperglycemia, mitochondrial dysfunction, inflammation, and most importantly, oxidative stress. Oxidative stress triggers defective angiogenesis, activates pro-inflammatory pathways and causes long-lasting epigenetic changes to facilitate the development of vascular complications. Therefore, therapeutic interventions targeting oxidative stress are promising to manage diabetic vascular complications. Sirtuin1 (SIRT1), a class III histone deacetylase belonging to the sirtuin family, plays critical roles in regulating metabolism and ageing-related pathological conditions, such as vascular diseases. Growing evidence has indicated that SIRT1 acts as a sensing regulator in response to oxidative stress and attenuates vascular dysfunction via cooperating with adenosine-monophosphate-activated protein kinase (AMPK) to activate antioxidant signals through various downstream effectors, including peroxisome proliferator-activated receptor-gamma co-activator 1 (PGC-1α), forkhead transcription factors (FOXOs), and peroxisome proliferative-activated receptor α (PPARα). In addition, SIRT1 interacts with hydrogen sulfide (H2S), regulates NADPH oxidase, endothelial NO synthase, and mechanistic target of rapamycin (mTOR) to suppress oxidative stress. Furthermore, mRNA expression of sirt1 is affected by microRNAs in DM. In the current review, we summarize recent advances illustrating the importance of SIRT1 in antagonizing oxidative stress. We also discuss whether modulation of SIRT1 can serve as a therapeutic strategy to treat diabetic vascular complications.
Amphibian skin is a rich and unique source of novel bioactive peptides most of which are endowed with either antimicrobial or pharmacological properties. Here, we report the identification and structural characterization of a novel peptide, named senegalin, which possesses both activities. Senegalin is a hexadecapeptide amide (FLPFLIPALTSLISSL-NH2) of unique primary structure found in the skin secretion of the African running frog, Kassina senegalensis. The structure of the biosynthetic precursor of senegalin, deduced from cloned skin cDNA, consists of 76 amino acid residues and displays the typical domain organization of an amphibian skin peptide precursor. Both natural senegalin and its synthetic replicate displayed antimicrobial and myotropic activities. Senegalin was active against Staphylococcus aureus (MIC 50 μM) and Candida albicans (MIC 150 μM) but was non-haemolytic at concentrations up to and including 150 μM. In contrast, senegalin induced a dose-dependent contraction of rat urinary bladder smooth muscle (EC50 2.9 nM) and a dose-dependent relaxation of rat tail artery smooth muscle (EC50 37.7 nM). Senegalin thus represents a prototype biologically active amphibian skin peptide and illustrates the fact that amphibian skin secretion peptidomes continue to be unique sources of such molecules.
Granular hydrogels are a kind of bulk hydrogel that are densely assembled by microparticles, showing great potential in 3D bioprinting. To develop a granular hydrogel-based bioink with enhanced strength, the present study combined methacryloylated gelatin (GelMA) with granular hydrogel to fabricate a compound bioink. Poly (γ-glutamic acid) (PG) microspheres and hydroxy propyl chitosan (CSPO) microspheres were fabricated, respectively, and self-assembled via charge interaction between microspheres to form a granular hydrogel after adding GleMA solution. However, its assembly ability decreased with the increase of the content of CSPO microspheres. The composite granular hydrogel with same mass content of PG microspheres and CSPO microspheres showed superior storage modulus, shear-thinning and self-healing ability. The composite granular hydrogels carrying adiposed derived stem cells (ASCs) showed well-performed extrudability and fidelity. In addition, after printing, UV light was used for further cross-linking GelMA, forming multi-networks that significantly improve the strength of the printed engineered tissue. ASCs proliferated significantly in bioink. The composite granular hydrogel thus showed great potential as bioink with enhanced strength for cell printing.
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