Electrospun nanofibrous scaffolds as a platform to reduce melanoma tumour growth, recurrence, and promote post-resection wound repair.

Wound healing following skin tumour surgery still remains a major challenge. To address this issue, polysaccharide-loaded nanofibrous mats have been engineered as skin patches on the wound site to improve wound healing while simultaneously eliminating residual cancer cells which may cause cancer relapse. The marine derived polysaccharides kappa-carrageenan (KCG) and fucoidan (FUC) were blended with polydioxanone (PDX) nanofibers due to their inherent anti-cancer activity conferred by the sulphate groups as well as their immunomodulatory properties which can reduce inflammation resulting in accelerated wound healing. KCG and FUC were released sustainably from the blend nanofibers via the Korsmeyer-Peppas kinetics. MTT assays, live/dead staining and SEM images demonstrated the toxicity of KCG and FUC towards skin cancer MP 41 cells. In addition, MP 41 cells showed reduced metastatic potential when grown on KCG or FUC containing mats. Both KCG and FUC were non- cytotoxic to healthy L 929 fibroblast cells. In vivo studies on healthy Wistar rats confirmed the non-toxicity of the nanofibrous patches as well as their improved and scarless wound healing potential. In vivo studies on tumour xenograft model further showed a reduction of 7.15 % in tumour volume in only 4 days following application of the transdermal patch.

Nanomedicine-based strategies to improve treatment of cutaneous leishmaniasis.

Nanomedicine strategies were first adapted and successfully translated to clinical application for diseases, such as cancer and diabetes. These strategies would no doubt benefit unmet diseases needs as in the case of leishmaniasis. The latter causes skin sores in the cutaneous form and affects internal organs in the visceral form. Treatment of cutaneous leishmaniasis (CL) aims at accelerating wound healing, reducing scarring and cosmetic morbidity, preventing parasite transmission and relapse. Unfortunately, available treatments show only suboptimal effectiveness and none of them were designed specifically for this disease condition. Tissue regeneration using nano-based devices coupled with drug delivery are currently being used in clinic to address diabetic wounds. Thus, in this review, we analyse the current treatment options and attempt to critically analyse the use of nanomedicine-based strategies to address CL wounds in view of achieving scarless wound healing, targeting secondary bacterial infection and lowering drug toxicity.

Polysucrose hydrogel and nanofiber scaffolds for skin tissue regeneration: Architecture and cell response.

Scaffolds capable of mediating overlapping multi-cellular activities to support the different phases of wound healing while preventing scarring are essential for tissue regeneration. The potential of polysucrose as hydrogels and electrospun mats for wound healing was evaluated in vitro by seeding fibroblasts, endothelial cells and macrophages either singly or in combination. It was found that the scaffold architecture impacted cell behaviour. Electrospun mats promoted fibroblasts flattened morphology while polysucrose methacrylate (PSucMA) hydrogels promoted fibroblast spheroids formation, accentuated in the presence of endothelial cells. Hydrogels exhibited lower inflammatory response than mats and curcumin loaded scaffolds reduced TNF-α production. In vivo biocompatibility of the hydrogels tested on Wistar rats was superior to electrospun mats. In vivo wound healing studies indicated that PSucMA hydrogels integrated the surrounding tissue with better cellular infiltration and proliferation throughout the entire wound region. PSucMA hydrogels led to scarless wound closure comparable with commercially available gels.

Piezoelectric core-shell PHBV/PDX blend scaffolds for reduced superficial wound contraction and scarless tissue regeneration.

The use of non-invasive scaffold materials which can mimic the innate piezoelectric properties of biological tissues is a promising strategy to promote native tissue regeneration. Piezoelectric and cell instructive electrospun core-shell PDX/PHBV mats have been engineered to promote native tissue and skin regeneration. In depth physicochemical characterisation, in vitro and in vivo studies of a rat model showed that the 20/80 PDX/PHBV composition possessed the right balance of physicochemical and piezoelectric properties leading to enhanced fibroblast stimulation, proliferation and migration, reduced fibroblast-mediated contraction and macrophage-induced inflammation, improved keratinocyte proliferation, proper balance between endothelial cell phenotypes, decreased in vivo fibrosis and accelerated in vivo scarless wound regeneration. Overall, this study highlights the importance of exploiting cell-material interactions to match tissue biological needs to sustain the wound healing cascade.

Caffeic Acid, One of the Major Phenolic Acids of the Medicinal Plant Antirhea borbonica, Reduces Renal Tubulointerstitial Fibrosis.

The renal fibrotic process is characterized by a chronic inflammatory state and oxidative stress. Antirhea borbonica (A. borbonica) is a French medicinal plant found in Reunion Island and known for its antioxidant and anti-inflammatory activities mostly related to its high polyphenols content. We investigated whether oral administration of polyphenol-rich extract from A. borbonica could exert in vivo a curative anti-renal fibrosis effect. To this aim, three days after unilateral ureteral obstruction (UUO), mice were daily orally treated either with a non-toxic dose of polyphenol-rich extract from A. borbonica or with caffeic acid (CA) for 5 days. The polyphenol-rich extract from A. borbonica, as well as CA, the predominant phenolic acid of this medicinal plant, exerted a nephroprotective effect through the reduction in the three phases of the fibrotic process: (i) macrophage infiltration, (ii) myofibroblast appearance and (iii) extracellular matrix accumulation. These effects were associated with the mRNA down-regulation of Tgf-ß, Tnf-α, Mcp1 and NfkB, as well as the upregulation of Nrf2. Importantly, we observed an increased antioxidant enzyme activity for GPX and Cu/ZnSOD. Last but not least, desorption electrospray ionization-high resolution/mass spectrometry (DESI-HR/MS) imaging allowed us to visualize, for the first time, CA in the kidney tissue. The present study demonstrates that polyphenol-rich extract from A. borbonica significantly improves, in a curative way, renal tubulointerstitial fibrosis progression in the UUO mouse model.

Green seaweeds ulvan-cellulose scaffolds enhance in vitro cell growth and in vivo angiogenesis for skin tissue engineering.

Cellulose has been extracted from a wide range of land resources, whereas it has been scarcely exploited from marine resources. Cellulose from green seaweeds can be extracted together with smaller molecules called ulvans. We have successfully extracted and characterized cellulose from Ulva sp. Solid state 13C NMR indicated the presence of ulvans in the cellulose extracts. The extracted cellulose was blended with polylactide and polydioxanone and electrospun into nanofibrous mats with a range of physico-chemical properties. These cellulose-based scaffolds were assessed in vitro using fibroblast cells and showed accelerated cell growth. In vivo biocompatibility studies using a Wistar rat model indicated the absence of foreign body response and enhanced angiogenesis.

Sugar-cane bagasse cellulose-based scaffolds promote multi-cellular interactions, angiogenesis and reduce inflammation for skin tissue regeneration.

In a previous article, we reported on the physico-chemical properties of cellulose-based scaffolds derived from sugar-cane bagasse and their preliminary in vitro assessment. In view of skin tissue regeneration, we here present our findings of an extensive in vitro testing of these scaffolds using key cells involved in the wound healing cascade namely fibroblasts, keratinocytes, endothelial cells and macrophages either singly or in various combinations to mimic in vivo conditions. Inflammation was quantified using TNF-α. In vivo biocompatibility as well as wound healing potential of the scaffolds was demonstrated using Wistar rats. Finally, we discuss the effect of curcumin-loaded scaffolds on inflammation and angiogenesis in vitro and in vivo. Nanosilica extracted from sugar-cane bagasse ash was also loaded in the scaffolds and its effect on biological response was assessed.

Correlating in vitro performance with physico-chemical characteristics of nanofibrous scaffolds for skin tissue engineering using supervised machine learning algorithms.

The engineering of polymeric scaffolds for tissue regeneration has known a phenomenal growth during the past decades as materials scientists seek to understand cell biology and cell-material behaviour. Statistical methods are being applied to physico-chemical properties of polymeric scaffolds for tissue engineering (TE) to guide through the complexity of experimental conditions. We have attempted using experimental in vitro data and physico-chemical data of electrospun polymeric scaffolds, tested for skin TE, to model scaffold performance using machine learning (ML) approach. Fibre diameter, pore diameter, water contact angle and Young's modulus were used to find a correlation with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of L929 fibroblasts cells on the scaffolds after 7 days. Six supervised learning algorithms were trained on the data using Seaborn/Scikit-learn Python libraries. After hyperparameter tuning, random forest regression yielded the highest accuracy of 62.74%. The predictive model was also correlated with in vivo data. This is a first preliminary study on ML methods for the prediction of cell-material interactions on nanofibrous scaffolds.

Synthesis and Automated Labeling of [18F]Darapladib, a Lp-PLA2 Ligand, as Potential PET Imaging Tool of Atherosclerosis.

Atherosclerosis and its associated clinical complications are major health issues in industrialized countries. Lipoprotein-associated phospholipase A2 (Lp-PLA2) was demonstrated to play an important role in atherogenesis and to be a potential risk prediction factor of plaque rupture. Darapladib is one of the most potent Lp-PLA2 inhibitors with an IC50 of 0.25 nM. Using its affinity for Lp-PLA2, we describe herein the total synthesis of darapladib radiolabeling precursor and the automated radiolabeling process for positron emission tomography (PET) imaging via an arylboronate moiety. The tracer thus obtained was tested in a mouse model of atherosclerosis (ApoE KO) and compared with the widely used [18F]fluorodeoxyglucose ([18F]FDG) PET tracer, known to label metabolically active cells. [18F]Darapladib showed a significant accumulation within mice aortic atheromatous plaques dissected out ex vivo compared to [18F]FDG. Incubation of the radiotracer with human carotid samples showed a strong accumulation within the atherosclerotic plaques and supports its potential for use in PET imaging.

Development, synthesis, and 68Ga-Labeling of a Lipophilic complexing agent for atherosclerosis PET imaging.

Cardiovascular disease is the leading cause of mortality and morbidity worldwide. Atherosclerosis accounts for 50% of deaths in western countries. This multifactorial pathology is characterized by the accumulation of lipids and inflammatory cells within the vascular wall, leading to plaque formation. We describe herein the synthesis of a PCTA-based 68Ga3+ chelator coupled to a phospholipid biovector 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), which is the main constituent of the phospholipid moiety of High-Density Lipoprotein (HDL) phospholipid moiety. The resulting 68Ga-PCTA-DSPE inserted into HDL particles was compared to 18F-FDG as a PET agent to visualize atherosclerotic plaques. Our agent markedly accumulated within mouse atheromatous aortas and more interestingly in human endarterectomy carotid samples. These results support the potential use of 68Ga-PCTA-DSPE-HDL for atherosclerosis PET imaging.

Enhanced effects of curcumin encapsulated in polycaprolactone-grafted oligocarrageenan nanomicelles, a novel nanoparticle drug delivery system.

One of the most effective strategies to enhance the bioavailability and the therapeutic effect of hydrophobic drugs is the use of nanocarriers. We have used κ-carrageenan extracted from Kappaphycus alvarezii to produce oligocarrageenan via an enzymatic degradation process. Polycaprolactone (PCL) chains were grafted onto the oligocarrageenans using a protection/deprotection technique yielding polycaprolactone-grafted oligocarrageenan. The resulting amphiphilic copolymers formed spherical nanomicelles with a mean size of 187 ± 21 nm. Hydrophobic drugs such as curcumin were efficiently encapsulated in the micelles and released within 24-72 h in solution. The micelles were non-cytotoxic and facilitated the uptake of curcumin by endothelial EA-hy926 cells. They also increased the anti-inflammatory effect of curcumin in TNF-alpha-induced inflammation experiments. Finally, in vivo experiments supported a lack of toxicity in zebrafish and thus the potential use of polycaprolactone-grafted oligocarrageenan to improve the delivery of hydrophobic compounds to different organs, including liver, lung and brain as shown in mice.

Improved Multicellular Response, Biomimetic Mineralization, Angiogenesis, and Reduced Foreign Body Response of Modified Polydioxanone Scaffolds for Skeletal Tissue Regeneration.

The potential of electrospun polydioxanone (PDX) mats as scaffolds for skeletal tissue regeneration was significantly enhanced through improvement of the cell-mediated biomimetic mineralization and multicellular response. This was achieved by blending PDX ( i) with poly(hydroxybutyrate- co-valerate) (PHBV) in the presence of hydroxyapatite (HA) and ( ii) with aloe vera (AV) extract containing a mixture of acemannan/glucomannan. In an exhaustive study, the behavior of the most relevant cell lines involved in the skeletal tissue healing cascade, i.e. fibroblasts, macrophages, endothelial cells and preosteoblasts, on the scaffolds was investigated. The scaffolds were shown to be nontoxic, to exhibit insignificant inflammatory responses in macrophages, and to be degradable by macrophage-secreted enzymes. As a result of different phase separation in PDX/PHBV/HA and PDX/AV blend mats, cells interacted differentially. Presumably due to varying tension states of cell-matrix interactions, thinner microtubules and significantly more cell adhesion sites and filopodia were formed on PDX/AV compared to PDX/PHBV/HA. While PDX/PHBV/HA supported micrometer-sized spherical particles, nanosized rod-like HA was observed to nucleate and grow on PDX/AV fibers, allowing the mineralized PDX/AV scaffold to retain its porosity over a longer time for cellular infiltration. Finally, PDX/AV exhibited better in vivo biocompatibility compared to PDX/PHBV/HA, as indicated by the reduced fibrous capsule thickness and enhanced blood vessel formation. Overall, PDX/AV blend mats showed a significantly enhanced potential for skeletal tissue regeneration compared to the already promising PDX/PHBV/HA blends.