Enhancing Diabetic Wound Healing Through Improved Angiogenesis: The Role of Emulsion-Based Core-Shell Micro/Nanofibrous Scaffold with Sustained CuO Nanoparticle Delivery.

Attempts are made to design a system for sustaining the delivery of copper ions into diabetic wounds and induce angiogenesis with minimal dose-dependent cytotoxicity. Here, a dual drug-delivery micro/nanofibrous core-shell system is engineered using polycaprolactone/sodium sulfated alginate-polyvinyl alcohol (PCL/SSA-PVA), as core/shell parts, by emulsion electrospinning technique to optimize sustained delivery of copper oxide nanoparticles (CuO NP). Herein, different concentrations of CuO NP (0.2, 0.4, 0.8, and 1.6%w/w) are loaded into the core part of the core-shell system. The morphological, biomechanical, and biocompatibility properties of the scaffolds are fully determined in vitro and in vivo. The 0.8%w/w CuO NP scaffold reveals the highest level of tube formation in HUVEC cells and also upregulates the pro-angiogenesis genes (VEGFA and bFGF) expression with no cytotoxicity effects. The presence of SSA and its interaction with CuO NP, and also core-shell structure sustain the release of the nanoparticles and provide a non-toxic microenvironment for cell adhesion and tube formation, with no sign of adverse immune response in vivo. The optimized scaffold significantly accelerates diabetic wound healing in a rat model. This study strongly suggests the 0.8%w/w CuO NP-loaded PCL/SSA-PVA as an excellent diabetic wound dressing with significantly improved angiogenesis and wound healing.

Dendrimers as nanoscale vectors: Unlocking the bars of cancer therapy.

Chemotherapy is the first choice in the treatment of cancer and is always preferred to other approaches such as radiation and surgery, but it has never met the need of patients for a safe and effective drug. Therefore, new advances in cancer treatment are now needed to reduce the side effects and burdens associated with chemotherapy for cancer patients. Targeted treatment using nanotechnology are now being actively explored as they could effectively deliver therapeutic agents to tumor cells without affecting normal cells. Dendrimers are promising nanocarriers with distinct physiochemical properties that have received considerable attention in cancer therapy studies, which is partly due to the numerous functional groups on their surface. In this review, we discuss the progress of different types of dendrimers as delivery systems in cancer therapy, focusing on the challenges, opportunities, and functionalities of the polymeric molecules. The paper also reviews the various role of dendrimers in their entry into cells via endocytosis, as well as the molecular and inflammatory pathways in cancer. In addition, various dendrimers-based drug delivery (e.g., pH-responsive, enzyme-responsive, redox-responsive, thermo-responsive, etc.) and lipid-, amino acid-, polymer- and nanoparticle-based modifications for gene delivery, as well as co-delivery of drugs and genes in cancer therapy with dendrimers, are presented. Finally, biosafety concerns and issues hindering the transition of dendrimers from research to the clinic are discussed to shed light on their clinical applications.

Molecularly Imprinted Polymer-Based Sensors for the Detection of Skeletal- and Cardiac-Muscle-Related Analytes.

Molecularly imprinted polymers (MIPs) are synthetic polymers with specific binding sites that present high affinity and spatial and chemical complementarities to a targeted analyte. They mimic the molecular recognition seen naturally in the antibody/antigen complementarity. Because of their specificity, MIPs can be included in sensors as a recognition element coupled to a transducer part that converts the interaction of MIP/analyte into a quantifiable signal. Such sensors have important applications in the biomedical field in diagnosis and drug discovery, and are a necessary complement of tissue engineering for analyzing the functionalities of the engineered tissues. Therefore, in this review, we provide an overview of MIP sensors that have been used for the detection of skeletal- and cardiac-muscle-related analytes. We organized this review by targeted analytes in alphabetical order. Thus, after an introduction to the fabrication of MIPs, we highlight different types of MIP sensors with an emphasis on recent works and show their great diversity, their fabrication, their linear range for a given analyte, their limit of detection (LOD), specificity, and reproducibility. We conclude the review with future developments and perspectives.

Cost-effectiveness analysis of text messaging to support health advice for smoking cessation.

BACKGROUND: Smoking in one of the most serious public health problems. It is well known that it constitutes a major risk factor for chronic diseases and the leading cause of preventable death worldwide. Due to high prevalence of smokers, new cost-effective strategies seeking to increase smoking cessation rates are needed. METHODS: We performed a Markov model-based cost-effectiveness analysis comparing two treatments: health advice provided by general practitioners and nurses in primary care, and health advice reinforced by sending motivational text messages to smokers' mobile phones. A Markov model was used in which smokers transitioned between three mutually exclusive health states (smoker, former smoker and dead) after 6-month cycles. We calculated the cost-effectiveness ratio associated with the sending of motivational messages. Health care and society perspectives (separately) was adopted. Costs taken into account were direct health care costs and direct health care cost and costs for lost productivity, respectively. Additionally, deterministic sensitivity analysis was performed modifying the probability of smoking cessation with each option. RESULTS: Sending of text messages as a tool to support health advice was found to be cost-effective as it was associated with increases in costs of €7.4 and €1,327 per QALY gained (ICUR) for men and women respectively from a healthcare perspective, significantly far from the published cost-effectiveness threshold. From a societal perspective, the combined programmed was dominant. CONCLUSIONS: Sending text messages is a cost-effective approach. These findings support the implantation of the combined program across primary care health centres.

Use of autologous plasma rich in growth factors fibrin membrane in the surgical management of ocular surface diseases.

PURPOSE: To evaluate the safety and efficacy of the surgical use of autologous plasma rich in growth factors fibrin membrane (mPRGF) in improving corneal wound healing and regeneration in a variety of complex ocular surface defects. METHODS: Chart review on 15 eyes of 14 included patients undergoing ocular surface intervention using intraoperative mPRGF at the Bascom Palmer Eye Institute and at the Instituto Oftalmológico Fernández-Vega was performed. Patients were grouped based on type of intervention or condition (penetrating keratoplasty, superficial keratectomy, neurotrophic or persistent corneal ulcers, and corneal perforation). Patients were followed for an average of 11 ± 5 months. Main outcomes measured were mPRGF dissolving time, best-corrected visual acuity, and evidence of any persistent epithelial defects, rejections, or complications. RESULTS: All 15 eyes underwent successful placement of mPRGF. Average dissolving time for fibrin membrane was 21 ± 3 days. mPRGF resulted in total healing of the corneal defects in 13/15 (86.7%) of the treated eyes and partial healing in 2/15 (13.3%) eyes in which persistent epithelial defects were noted on follow-up. Visual acuity improvement was seen in 9/15 (60%) of the cases. CONCLUSION: The use of autologous mPRGF in the healing and regeneration of the ocular surface is a secure and efficacious surgical option. Our data demonstrate that PRGF fibrin membrane should be contemplated as an important tool to optimize ocular surface regeneration in complex cases.

Potential Effect of Plasma Rich in Growth Factors-Endoret in Stromal Wound Healing in Additive Surgery.

PURPOSE: To compare the clinical and histological outcomes after intrastromal corneal ring segment (ICRS) implantation with and without plasma rich in growth factors (PRGF) in an experimental animal model. MATERIALS AND METHODS: First, the toxicity of PRGF was tested in hen's keratocyte cultures. Then, an animal model with 18 hens was randomly divided into 2 groups. In the first group, one ICRS was implanted in each eye (ICRS group). In the second group, the ICRS was firstly immersed 30 min in PRGF-Endoret solution, then implanted and, finally, PRGF-Endoret was inoculated into the channel (PRGF-ICRS group). Animals of each group were also separated into 3 groups regarding the time they were sacrificed, and corneal tissue was fixed for histological analysis at 2, 7 and 30 days. Cell death was detected by terminal uridine nick end labelling (TUNEL) assay. Proliferation was labelled by 5-bromo-2-deoxyuridine (BrdU) incorporation and myofibroblast differentiation by alpha-smooth muscle actin (αSMA) immunodetection. Clinical examination, analyzing epithelial wound closure, deposits and stromal haze, was carried out at the different study times. RESULTS: No toxic effect was observed by PRGF in hen stromal cell cultures. Clinically, in PRGF-ICRS corneas at 7 days, there were more deposits with higher intensity than in ICRS group. Histologically, at day 2 there was less epithelial damage over the segment in the PRGF-ICRS group, corneal oedema around the segment disappeared earlier and, at day 7, there was also double the number of cells around the segment than in the ICRS group displaying different morphologies. The number of TUNEL-positive cells was statistically higher in the PRGF-ICRS group at 7 and 30 days, and the number of BrdU-positive cells was statistically higher at all analyzed times. However, there were no differences in the number of αSMA-positive cells at 30 days between both groups. CONCLUSIONS: The ICRS immersion in PRGF-Endoret prior and after to its corneal implantation, in an experimental animal model, enhances clinical deposits and histological cell turnover without increasing myofibroblast differentiation reducing stromal wound-healing time after surgery.

3D Bioprinting in Skeletal Muscle Tissue Engineering.

Skeletal muscle tissue engineering (SMTE) aims at repairing defective skeletal muscles. Until now, numerous developments are made in SMTE; however, it is still challenging to recapitulate the complexity of muscles with current methods of fabrication. Here, after a brief description of the anatomy of skeletal muscle and a short state-of-the-art on developments made in SMTE with "conventional methods," the use of 3D bioprinting as a new tool for SMTE is in focus. The current bioprinting methods are discussed, and an overview of the bioink formulations and properties used in 3D bioprinting is provided. Finally, different advances made in SMTE by 3D bioprinting are highlighted, and future needs and a short perspective are provided.

Hyaluronic Acid Promotes Differentiation of Mesenchymal Stem Cells from Different Sources toward Pancreatic Progenitors within Three-Dimensional Alginate Matrixes.

Islet transplantation has shown to be a successful alternative in type 1 diabetes treatment, but donor scarcity precludes its worldwide clinical translation. Stem cells are an unlimited source that could circumvent the lack of donors if complete differentiation into insulin-producing cells (IPCs) could be accomplished. We have performed the differentiation of mesenchymal stem cells (MSCs) from different sources into IPCs within three-dimensional (3D) alginate matrixes. We quantified an increased insulin release at the final stage of differentiation compared to undifferentiated MSCs, which is more pronounced in IPCs differentiated from pancreatic-derived MSCs tissues. Moreover, the addition of hyaluronic acid (HA) in alginate microcapsules enhanced, even more, the insulin release from the final IPCs, independent of the MSC source. We can conclude that MSCs can be differentiated into IPCs within alginate microcapsules, enhancing insulin release when HA is present in the 3D alginate matrixes.

Cellular acidification as a new approach to cancer treatment and to the understanding and therapeutics of neurodegenerative diseases.

During the last few years, the understanding of the dysregulated hydrogen ion dynamics and reversed proton gradient of cancer cells has resulted in a new and integral pH-centric paradigm in oncology, a translational model embracing from cancer etiopathogenesis to treatment. The abnormalities of intracellular alkalinization along with extracellular acidification of all types of solid tumors and leukemic cells have never been described in any other disease and now appear to be a specific hallmark of malignancy. As a consequence of this intracellular acid-base homeostatic failure, the attempt to induce cellular acidification using proton transport inhibitors and other intracellular acidifiers of different origins is becoming a new therapeutic concept and selective target of cancer treatment, both as a metabolic mediator of apoptosis and in the overcoming of multiple drug resistance (MDR). Importantly, there is increasing data showing that different ion channels contribute to mediate significant aspects of cancer pH regulation and etiopathogenesis. Finally, we discuss the extension of this new pH-centric oncological paradigm into the opposite metabolic and homeostatic acid-base situation found in human neurodegenerative diseases (HNDDs), which opens novel concepts in the prevention and treatment of HNDDs through the utilization of a cohort of neural and non-neural derived hormones and human growth factors.

Subconjunctival PRGF Fibrin Membrane as an Adjuvant to Nonpenetrating Deep Sclerectomy: A 2-Year Pilot Study.

PURPOSE: To evaluate the potential role of the autologous PRGF (plasma rich in growth factors) fibrin membrane in tissue regeneration after glaucoma filtering surgery. MATERIALS AND METHODS: Ten patients with medically uncontrolled primary open-angle glaucoma underwent nonpenetrating deep sclerectomy and were treated with PRGF fibrin membrane as adjuvant. Intraocular pressure reduction was the primary outcome. This variable was measured preoperatively and also at each follow-up visit. Secondary outcomes included the number of antiglaucoma medications, anterior segment optical coherence tomography bleb examination, photographic bleb evaluation, and subjective clinical symptomatology evaluation. RESULTS: The surgical technique showed a significant reduction (p < 0.05) in intraocular pressure in relation to preoperative values at each time of the study, decreasing from 23.3 ± 6.4 to 15.2 ± 4.6 mm Hg at 2 years. Furthermore, the number of antiglaucoma medications consumed showed a significant reduction at the end point of the study compared with the preoperative situation. Optical coherence tomography and photographic filtering bleb variables experienced a progressive reduction during the follow-up. Subjective symptoms showed a reduction from 8.3 ± 4.5 to 4.2 ± 5.3 at 2 years. CONCLUSIONS: PRGF-Endoret treatment could promote ocular surface regeneration after glaucoma surgery, enhancing the surgery success rates and reducing the need for postoperative medications. It is important to highlight that this is a preliminary study and some large clinical studies are necessary to verify these results.

Plasma Rich in Growth Factors for the Treatment of Dry Eye after LASIK Surgery.

PURPOSE: The aim of this study was to evaluate the use of plasma rich in growth factors (PRGF) eye drops in patients with dry eye disease after laser-assisted in situ keratomileusis (LASIK) surgery. MATERIAL AND METHODS: This is a longitudinal, retrospective, comparative, and descriptive study of 77 eyes of 42 patients with dry eye disease following LASIK surgery. This study was designed to evaluate the efficacy of PRGF treatment compared to conventional therapy (control group). Outcome measures including signs and symptoms of dry eye disease were evaluated before and after treatment. The percentage of change before and after treatment for each clinical variable measured was compared between both groups. RESULTS: There were 1-4 treatment cycles with PRGF eye drops (1 cycle = 6 weeks). Results showed a statistically significant improvement in the Ocular Surface Disease Index (38.12%), visual analogue scale scores for frequency (41.89%) and severity (42.47%), and the Schirmer test scores (88.98%) after PRGF treatment (p < 0.05). No adverse events were reported after PRGF treatment. CONCLUSIONS: These results suggest that PRGF eye drops are effective for the improvement of dry eye symptoms in patients who underwent LASIK surgery in comparison to the conventional therapy. The treatment with PRGF is an alternative for patients who suffer from postoperative dry eye.

Two cycles of plasma rich in growth factors (PRGF-Endoret) intra-articular injections improve stiffness and activities of daily living but not pain compared to one cycle on patients with symptomatic knee osteoarthritis.

PURPOSE: To assess the clinical efficacy and safety of a treatment based on one cycle versus two cycles of intra-articular injections of plasma rich in growth factors (PRGF-Endoret) on patients with knee osteoarthritis (OA). METHODS: Ninety patients with knee OA were included and evaluated. A total of 48 patients received one cycle (OC group) (3 injections on a weekly basis), while 42 patients received two cycles of PRGF-Endoret (TC group) spaced 6 months between them. Patients were evaluated with LEQUESNE and WOMAC scores before treatment and after 48 weeks. Safety assessment was also performed. RESULTS: A significant reduction of all assessed outcome measures was shown for both groups at 48 weeks compared with baseline values (P < 0.001). Patients of TCs group showed a significantly higher reduction (P < 0.05) in WOMAC stiffness subscales. Regarding LEQUESNE INDEX, a significantly higher reduction was observed in the TC group in all subscales except in pain score. In the maximum walking distance subscale (MCD), the improvement rate was 31.8% higher for the TCs group compared with the OC group (P < 0.01). In addition, the TC group showed a significant improvement in LEQUESNE activities of daily living (ADV) and global subscales of 14.7 and 11.8% (P < 0.05) higher, respectively, than the OC group. CONCLUSIONS: Treatment with two cycles of PRGF did not show a significantly higher pain reduction compared with one cycle treatment. However, two cycles of PRGF showed a significant improvement in WOMAC stiffness, LEQUESNE MCD, LEQUESNE ADV and LEQUESNE global subscales. Therefore, patients treated with two cycles present an improvement in quality of life. LEVEL OF EVIDENCE: II.

Treatment of patients with neurotrophic keratitis stages 2 and 3 with plasma rich in growth factors (PRGF-Endoret) eye-drops.

PURPOSE: To provide preliminary data about efficacy and safety of plasma rich in growth factors (PRGF) eye-drops in neurotrophic keratitis (NK) and to analyze the possible influence of certain variables on treatment outcomes. METHODS: This retrospective study included patients with stages 2-3 of NK treated with PRGF eye-drops. Primary endpoint was the resolution time of corneal ulcer defect. Outcome measures including percentage of ulcer closure at 4 weeks, Ocular Surface Disease Index (OSDI), Best-Corrected Visual Acuity (BCVA) and Visual Analogue Scale (VAS) were also evaluated before and after treatment with PRGF. The influence of some patients' clinical variables on results was assessed. Safety assessment was also performed reporting all adverse events. RESULTS: Thirty-eight treated eyes in a total of thirty-one patients were evaluated, of which five cases had no prior response to autologous serum treatment. Most cases (97.4%) achieved the complete resolution of corneal defect/ulcer. Mean resolution time was 11.4 weeks (SD = 13.7). A statistical significant (p < 0.05) reduction in OSDI (60.9%), VAS frequency (59.9%), VAS severity (57.0%) and improvement in BCVA (52.8%) was observed. The results were stratified according to the pathology stage and to the identified potential effect modifiers variables. Only one adverse event was reported in one patient (2.6%). CONCLUSIONS: PRGF eye-drops could be a safe and effective therapeutic option for patients with stages 2-3 of NK, showing high rates of corneal defect/ulcer resolution in short times, either in reducing signs and symptoms of NK, and therefore preventing the progression of NK to greater ocular complications.

Alginate Microcapsules Incorporating Hyaluronic Acid Recreate Closer in Vivo Environment for Mesenchymal Stem Cells.

The potential clinical application of alginate cell microencapsulation has advanced enormously during the past decade. However, the 3D environment created by alginate beads does not mimic the natural extracellular matrix surrounding cells in vivo, responsible of cell survival and functionality. As one of the most frequent macromolecules present in the extracellular matrix is hyaluronic acid, we have formed hybrid beads with alginate and hyaluronic acid recreating a closer in vivo cell environment. Our results show that 1% alginate-0.25% hyaluronic acid microcapsules retain 1.5% alginate physicochemical properties. Moreover, mesenchymal stem cells encapsulated in these hybrid beads show enhanced viability therapeutic protein release and mesenchymal stem cells' potential to differentiate into chondrogenic lineage. Although future studies with additional proteins need to be done in order to approach even more the extracellular matrix features, we have shown that hyaluronic acid protects alginate encapsulated mesenchymal stem cells by providing a niche-like environment and remaining them competent as a sustainable drug delivery system.

Hybrid Alginate-Protein-Coated Graphene Oxide Microcapsules Enhance the Functionality of Erythropoietin Secreting C2C12 Myoblasts.

The beneficial effect of combining alginate hydrogel with graphene oxide (GO) on microencapsulated C2C12-myoblast viability has recently been described. However, the commercially available GO lacks homogeneity in size, this parameter being of high relevance for the cell fate in two-dimensional studies. In three-dimensional applications the capacity of this material for binding different kinds of proteins can result in the reduction of de novo released protein that can effectively reach the vicinity of the microcapsules. Undoubtedly, this could be an important hurdle in its clinical use when combined with alginate-PLL microcapsules. Here, we demonstrate that the homogenization of GO nanoparticles is not a mandatory preparation step in order to get the best of this material upon cell microencapsulation. In fact, when the superficial area of these particles is increased, higher amounts of the therapeutic protein erythropoietin (EPO) are adsorbed on their surface. On the other hand, we have been able to improve even more the favorable effects of this graphene derivative on microencapsulated cell viability by forming a protein biocorona. These proteins block the potential binding sites of EPO and, therefore, enhance the amount of therapeutic drug that is released. Finally, we prove that these hybrid alginate-protein-coated GO-microcapsules are functional in vivo.

The Effect of Plasma Rich in Growth Factors on Pattern Hair Loss: A Pilot Study.

BACKGROUND: Autologous growth factors have proved to promote tissue regeneration in various medical fields. Recent findings suggest that platelet rich plasma may also play an important role in hair follicle restoration. OBJECTIVE: The objective of this study was to evaluate the safety and clinical efficacy of plasma rich in growth factors (PRGFs) for the treatment of androgenetic alopecia (AGA). MATERIALS AND METHODS: Five PRGF injections were administered over 19 patients with AGA. Phototrichograms regarding follicle density/diameter and terminal/vellus hair ratio were performed at baseline and after 1 year follow-up period. Consenting participants underwent histologic scalp examination. At the end of the study, overall patient satisfaction and clinical improvement were determined. RESULTS: After PRGF therapy, mean hair density/diameter increased and terminal/vellus hair ratio was also improved. Patients presented epidermal thickness, perifollicular neoangiogenesis, cell proliferation, and terminal/miniaturized hair ratio improvement. Plasma rich in growth factors seemed to reduce the perivascular inflammatory infiltrate, promote the remodeling of dermo-epidermal tissue, and increase bulge stem cell niches. Patients declared an overall positive satisfaction, and a high clinical improvement score was achieved when comparing premacrophotographs and postmacrophotographs. CONCLUSION: Although randomized clinical trials are needed, this study provides preliminary data supporting the positive therapeutic effect of autologous growth factors on hair follicle regeneration.