Engineering Dendritic-Cell-Based Vaccines and PD-1 Blockade in Self-Assembled Peptide Nanofibrous Hydrogel to Amplify Antitumor T-Cell Immunity.

Dendritic cells (DCs) are increasingly used in cancer vaccines due to their ability to regulate T-cell immunity. Major limitations associated with the present DC adoptive transfer immunotherapy are low cell viability and transient duration of transplanted DCs at the vaccination site and the lack of recruitment of host DCs, leading to unsatisfactory T-cell immune response. Here, we developed a novel vaccine nodule comprising a simple physical mixture of the peptide nanofibrous hydrogel, anti-PD-1 antibodies, DCs, and tumor antigens. Upon subcutaneous injection, the vaccine nodule maintained the viability and biological function including the antigen uptake and maturation of encapsulated DCs and simultaneously recruited a number of host DCs and promoted the drainage of activated DCs to lymph nodes, resulting in enhanced proliferation of antigen-specific splenocytes and provoking potent cellular immune responses. Compared with adoptive transfer of DCs and subcutaneous administration of antigen vaccine, such a vaccine nodule shows superior antitumor immunotherapy efficiency in both prophylactic and therapeutic tumor models including delayed tumor growth and prolonged mice survival due to effective stimulation of antitumor T-cell immunity and increased infiltration of activated CD8+ effector T-cells in the tumor. Our findings provide a simple and robust vaccination strategy for DC-based vaccines and also a unique vaccine product for stimulating and enhancing T-cell immunity, holding great promise for immunotherapy against cancer and infectious diseases.

Self-Assembly of Partially Alkylated Dextran- graft-poly[(2-dimethylamino)ethyl methacrylate] Copolymer Facilitating Hydrophobic/Hydrophilic Drug Delivery and Improving Conetwork Hydrogel Properties.

Key issues of injectable hydrogels are incapability of loading hydrophobic drugs due to insolubility of drugs in aqueous prepolymer solution as well as in hydrogel matrix, and high water swelling, which leads to poor mechanical and bioadhesive properties. Herein, we report that self-assembly of partially long-chain alkylated dextran- graft-poly[(2-dimethylamino)ethyl methacrylate] copolymer in aqueous solution could encapsulate pyrene, a hydrophobic probe, griseofulvin, a hydrophobic antifungal drug, and ornidazole, a hydrophilic antibiotic. Addition of activated chloride terminated poly(ethylene glycol) (PEG) into the guest molecules loaded copolymer solution produced an injectable dextran- graft-poly[(2-dimethylamino)ethyl methacrylate]-linked-PEG conetwork hydrogel. The alkylated hydrogels exhibited zero order release kinetics and were mechanically tough (50-54 kPa storage modulus) and bioadhesive (8-9 kPa). The roles of alkyl chains and dextran on the drug loading-release behavior, degradation behavior, gelation time, and the mechanical property of the hydrogels have been studied in details. Additionally, DNA hybrid composite hydrogel was formed owing to the cationic nature of the prepolymer solution and the hydrogel. Controlled alkylation of a prepolymer thus highlights the potential to induce and enhance the hydrogel property.

Macromolecule-Network Electrostatics Controlling Delivery of the Biotherapeutic Cell Modulator TIMP-2.

Tissue inhibitor of metalloproteinase 2 (TIMP-2) is an endogenous 22 kDa proteinase inhibitor, demonstrating antitumorigenic, antimetastatic and antiangiogenic activities in vitro and in vivo. Recombinant TIMP-2 is currently undergoing preclinical testing in multiple, murine tumor models. Here we report the development of an inert, injectable peptide hydrogel matrix enabling encapsulation and sustained release of TIMP-2. We studied the TIMP-2 release profile from four ß-hairpin peptide gels of varying net electrostatic charge. A negatively charged peptide gel (designated AcVES3) enabling encapsulation of 4 mg/mL of TIMP-2, without effects on rheological properties, facilitated the slow sustained release (0.9%/d) of TIMP-2 over 28 d. Released TIMP-2 is structurally intact and maintains the ability to inhibit MMP activity, as well as suppress lung cancer cell proliferation in vitro. These findings suggest that the AcVES3 hydrogel will be useful as an injectable vehicle for systemic delivery of TIMP-2 in vivo for ongoing preclinical development.

Injectable Maltodextrin-Based Micelle/Hydrogel Composites for Simvastatin-Controlled Release.

Injectable hydrogels have shown great potential in bone tissue engineering. Simvastatin (SIM), a common hypolipidemic drug, has been suggested as a potential agent to promote bone regeneration. However, due to its hydrophobic nature, the compatibility between SIM and hydrogels is rather poor, thereby greatly affecting the drug release behavior, the mechanical properties, and dimensional stability of the hydrogels. Herein, we presented a novel design to entrap SIM in an injectable maltodextrin-based micelle/hydrogel composite system. Maltodextrin-based micelles were prepared to solubilize and encapsulate SIM. The SIM-loaded aldehyde-modified micelles were anchored to the hydrogel network and served as a cross-linker to realize improved mechanical strength of hydrogel, controlled release, and osteogenic capability of SIM. In all, this study demonstrated a strategy to incorporate drug loaded carriers into hydrogels for drug delivery and tissue engineering applications.

Multifunctional Tannic Acid/Silver Nanoparticle-Based Mucoadhesive Hydrogel for Improved Local Treatment of HSV Infection: In Vitro and In Vivo Studies.

Mucoadhesive gelling systems with tannic acid modified silver nanoparticles were developed for effective treatment of herpes virus infections. To increase nanoparticle residence time after local application, semi solid formulations designed from generally regarded as safe (GRAS) excipients were investigated for their rheological and mechanical properties followed with ex vivo mucoadhesive behavior to the porcine vaginal mucosa. Particular effort was made to evaluate the activity of nanoparticle-based hydrogels toward herpes simplex virus (HSV) type 1 and 2 infection in vitro in immortal human keratinocyte cell line and in vivo using murine model of HSV-2 genital infection. The effect of infectivity was determined by real time quantitative polymerase chain reaction, plaque assay, inactivation, attachment, penetration and cell-to-cell assessments. All analyzed nanoparticle-based hydrogels exhibited pseudoplastic and thixotropic properties. Viscosity and mechanical measurements of hydrogels were found to correlate with the mucoadhesive properties. The results confirmed the ability of nanoparticle-based hydrogels to affect viral attachment, impede penetration and cell-to-cell transmission, although profound differences in the activity evoked by tested preparations toward HSV-1 and HSV-2 were noted. In addition, these findings demonstrated the in vivo potential of tannic acid modified silver nanoparticle-based hydrogels for vaginal treatment of HSV-2 genital infection.

Effects of Hydrogel With Enriched Sodium Alginate in Wounds of Diabetic Patients.

Objective of this study was to evaluate the efficacy of the autolytic debridement promoted by hydrogel with sodium alginate enriched with fatty acids and vitamins A and E in the healing of foot wounds in diabetic patients. A clinical study was conducted at an outpatient clinic of medical specialties. The sample comprised 8 patients supervised for a 3-month period, from April to July 2017, by means of a clinical history, photographic record, planimetry, and classification of the wound severity by the Pressure Ulcer Scale for Healing (PUSH) system. Of the 8 patients supervised, 1 dropped out and 7 were followed up for 12 weeks. Only 2 had complete wound healing, but all presented a reduction of the lesion area of approximately 22.2% and PUSH score of 9.8 to 6.6. This study found that hydrogel showed good results for the treatment of diabetic feet, reducing the area and overall PUSH score of the wounds.

Single-stage cell-based cartilage repair in a rabbit model: cell tracking and in vivo chondrogenesis of human umbilical cord blood-derived mesenchymal stem cells and hyaluronic acid hydrogel composite.

OBJECTIVE: Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) have gained popularity as a promising cell source for regenerative medicine, but limited in vivo studies have reported cartilage repair. In addition, the roles of MSCs in cartilage repair are not well-understood. The purpose of this study was to investigate the feasibility of transplanting hUCB-MSCs and hyaluronic acid (HA) hydrogel composite to repair articular cartilage defects in a rabbit model and determine whether the transplanted cells persisted or disappeared from the defect site. DESIGN: Osteochondral defects were created in the trochlear grooves of the knees. The hUCB-MSCs and HA composite was transplanted into the defect of experimental knees. Control knees were transplanted by HA or left untreated. Animals were sacrificed at 8 and 16 weeks post-transplantation and additionally at 2 and 4 weeks to evaluate the fate of transplanted cells. The repair tissues were evaluated by gross, histological and immunohistochemical analysis. RESULTS: Transplanting hUCB-MSCs and HA composite resulted in overall superior cartilage repair tissue with better quality than HA alone or no treatment. Cellular architecture and collagen arrangement at 16 weeks were similar to those of surrounding normal articular cartilage tissue. Histological scores also revealed that cartilage repair in experimental knees was better than that in control knees. Immunohistochemical analysis with anti-human nuclear antibody confirmed that the transplanted MSCs disappeared gradually over time. CONCLUSION: Transplanting hUCB-MSCs and HA composite promote cartilage repair and interactions between hUCB-MSCs and host cells initiated by paracrine action may play an important role in cartilage repair.

Synthesis and Evaluation of a Sodium Alginate-4-Aminosalicylic Acid Based Microporous Hydrogel for Potential Viscosupplementation for Joint Injuries and Arthritis-Induced Conditions.

A microporous hydrogel was developed using sodium alginate (alg) and 4-aminosalicylic acid (4-ASA). The synthesized hydrogel was characterized using various analytical techniques such as Fourier transform infrared spectroscopy (FTIR), Carbon-13 nuclear magnetic resonance (13C-NMR), X-ray powder diffraction (XRD), scanning electron microscopy (SEM), and differential scanning calorimetry (DSC). Additonal carboxyl and hydroxyl functional groups of 4-ASA provided significant lubrication and stress-triggered sol-gel transition to the conjugated hydrogel. In addition, cytotoxicity analysis was undertaken on the conjugated hydrogel using human dermal fibroblast-adult (HDFa) cells, displaying non-toxic characteristics. Drug release profiles displaying 49.6% in the first 8 h and 97.5% within 72 h, similar to the native polymer (42.8% in first 8 h and 90.1% within 72 h). Under applied external stimuli, the modified hydrogel displayed significant gelling properties and structure deformation/recovery behaviour, confirmed using rheological evaluation (viscosity and thixotropic area of 8095.3 mPas and 26.23%, respectively). The modified hydrogel, thus, offers great possibility for designing smart synovial fluids as a biomimetic aqueous lubricant for joint-related injuries and arthritis-induced conditions. In addtion, the combination of thixotropy, non-toxicity, and drug release capabilities enables potential viscosupplementation for clinical application.

Development and In Vivo Evaluation of a Novel Histatin-5 Bioadhesive Hydrogel Formulation against Oral Candidiasis.

Oral candidiasis (OC), caused by the fungal pathogen Candida albicans, is the most common opportunistic infection in HIV(+) individuals and other immunocompromised populations. The dramatic increase in resistance to common antifungals has emphasized the importance of identifying unconventional therapeutic options. Antimicrobial peptides have emerged as promising candidates for therapeutic intervention due to their broad antimicrobial properties and lack of toxicity. Histatin-5 (Hst-5) specifically has exhibited potent anticandidal activity indicating its potential as an antifungal agent. To that end, the goal of this study was to design a biocompatible hydrogel delivery system for Hst-5 application. The bioadhesive hydroxypropyl methylcellulose (HPMC) hydrogel formulation was developed for topical oral application against OC. The new formulation was evaluated in vitro for gel viscosity, Hst-5 release rate from the gel, and killing potency and, more importantly, was tested in vivo in our mouse model of OC. The findings demonstrated a controlled sustained release of Hst-5 from the polymer and rapid killing ability. Based on viable C. albicans counts recovered from tongues of treated and untreated mice, three daily applications of the formulation beginning 1 day postinfection with C. albicans were effective in protection against development of OC. Interestingly, in some cases, Hst-5 was able to clear existing lesions as well as associated tissue inflammation. These findings were confirmed by histopathology analysis of tongue tissue. Coupled with the lack of toxicity as well as anti-inflammatory and wound-healing properties of Hst-5, the findings from this study support the progression and commercial feasibility of using this compound as a novel therapeutic agent.

An Injectable Hydrogel Prepared Using a PEG/Vitamin E Copolymer Facilitating Aqueous-Driven Gelation.

Hydrogels have been widely explored for biomedical applications, with injectable hydrogels being of particular interest for their ability to precisely deliver drugs and cells to targets. Although these hydrogels have demonstrated satisfactory properties in many cases, challenges still remain for commercialization. In this paper, we describe a simple injectable hydrogel based on poly(ethylene glycol) (PEG) and a vitamin E (Ve) methacrylate copolymer prepared via simple free radical polymerization and delivered in a solution of low molecular weight PEG and Ve as the solvent instead of water. The hydrogel formed immediately in an aqueous environment with a controllable gelation time. The driving force for gelation is attributed to the self-assembly of hydrophobic Ve residues upon exposure to water to form a physically cross-linked polymer network via polymer chain rearrangement and subsequent phase separation, a spontaneous process with water uptake. The hydrogels can be customized to give the desired water content, mechanical strength, and drug release kinetics simply by formulating the PEGMA-co-Ve polymer with an appropriate solvent mixture or by varying the molecular weight of the polymer. The hydrogels exhibited no significant cytotoxicity in vitro using fibroblasts and good tissue compatibility in the eye and when injected subcutaneously. These polymers thus have the potential to be used in a variety of applications where injection of a drug or cell containing depot would be desirable.

Sequential Thiol-Ene and Tetrazine Click Reactions for the Polymerization and Functionalization of Hydrogel Microparticles.

Click chemistry is a versatile tool for the synthesis and functionalization of polymeric biomaterials. Here, we describe a versatile new strategy for producing bioactive, protein-functionalized poly(ethylene glycol) (PEG) hydrogel microparticles that is based on sequential thiol-ene and tetrazine click reactions. Briefly, tetra-functional PEG-norbornene macromer and dithiothreitol (SH) cross-linker were combined at a 0.75:1 [SH]:[norbornene] ratio, emulsified in a continuous Dextran phase, and then photopolymerized to form PEG hydrogel microparticles that varied from 8 to 30 µm in diameter, depending on the PEG concentration used. Subsequently, tetrazine-functionalized protein was conjugated to unreacted norbornene groups in the PEG microparticles. Tetrazine-mediated protein tethering to the microparticles was first demonstrated using fluorescein-labeled ovalbumin as a model protein. Subsequently, bioactive protein tethering was demonstrated using alkaline phosphatase (ALP) and glucose oxidase (GOx). Enzyme activity assays demonstrated that both ALP and GOx maintained their bioactivity and imparted tunable bioactivity to the microparticles that depended on the amount of enzyme added. ALP-functionalized microparticles were also observed to initiate calcium phosphate mineralization in vitro when incubated with calcium glycerophosphate. Collectively, these results show that protein-functionalized hydrogel microparticles with tunable bioactive properties can be easily synthesized using sequential click chemistry reactions. This approach has potential for future applications in tissue engineering, drug delivery, and biosensing.

Assessment of Photodynamic Inactivation against Periodontal Bacteria Mediated by a Chitosan Hydrogel in a 3D Gingival Model.

Chitosan hydrogels containing hydroxypropyl methylcellulose (HPMC) and toluidine blue O were prepared and assessed for their mucoadhesive property and antimicrobial efficacy of photodynamic inactivation (PDI). Increased HPMC content in the hydrogels resulted in increased mucoadhesiveness. Furthermore, we developed a simple In Vitro 3D gingival model resembling the oral periodontal pocket to culture the biofilms of Staphylococcus aureus (S. aureus), Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans), and Porphyromonas gingivalis (P. gingivalis). The PDI efficacy of chitosan hydrogel was examined against periodontal biofilms cultured in this 3D gingival model. We found that the PDI effectiveness was limited due to leaving some of the innermost bacteria alive at the non-illuminated site. Using this 3D gingival model, we further optimized PDI procedures with various adjustments of light energy and irradiation sites. The PDI efficacy of the chitosan hydrogel against periodontal biofilms can significantly improve via four sides of irradiation. In conclusion, this study not only showed the clinical applicability of this chitosan hydrogel but also the importance of the light irradiation pattern in performing PDI for periodontal disease.

Debridement for venous leg ulcers.

BACKGROUND: Venous ulcers (also known as varicose or venous stasis ulcers) are a chronic, recurring and debilitating condition that affects up to 1% of the population. Best practice documents and expert opinion suggests that the removal of devitalised tissue from venous ulcers (debridement) by any one of six methods helps to promote healing. However, to date there has been no review of the evidence from randomised controlled trials (RCTs) to support this. OBJECTIVES: To determine the effects of different debriding methods or debridement versus no debridement, on the rate of debridement and wound healing in venous leg ulcers. SEARCH METHODS: In February 2015 we searched: The Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE and EBSCO CINAHL. There were no restrictions with respect to language, date of publication or study setting. In addition we handsearched conference proceedings, journals not cited in MEDLINE, and the bibliographies of all retrieved publications to identify potential studies. We made contact with the pharmaceutical industry to enquire about any completed studies. SELECTION CRITERIA: We included RCTs, either published or unpublished, which compared two methods of debridement or compared debridement with no debridement. We presented study results in a narrative form, as meta-analysis was not possible. DATA COLLECTION AND ANALYSIS: Independently, two review authors completed all study selection, data extraction and assessment of trial quality; resolution of disagreements was completed by a third review author. MAIN RESULTS: We identified 10 RCTs involving 715 participants. Eight RCTs evaluated autolytic debridement and included the following agents or dressings: biocellulose wound dressing (BWD), non-adherent dressing, honey gel, hydrogel (gel formula), hydrofibre dressing, hydrocolloid dressings, dextranomer beads, Edinburgh University Solution of Lime (EUSOL) and paraffin gauze. Two RCTs evaluated enzymatic preparations and one evaluated biosurgical debridement. No RCTs evaluated surgical, sharp or mechanical methods of debridement, or debridement versus no debridement. Most trials were at a high risk of bias.Three RCTs assessed the number of wounds completely debrided. All three of these trials compared two different methods of autolytic debridement (234 participants), with two studies reporting statistically significant results: one study (100 participants) reported that 40/50 (80%) ulcers treated with dextranomer beads and 7/50 (14%) treated with EUSOL achieved complete debridement (RR 5.71, 95% CI 2.84 to 11.52); while the other trial (86 participants) reported the number of ulcers completely debrided as 31/46 (76%) for hydrogel versus 18/40 (45%) for paraffin gauze (RR 0.67, 95% CI 0.45 to 0.99). One study (48 participants) reported that by 12 weeks, 15/18 (84%) ulcers treated with BWD had achieved a 75% to 100% clean, granulating wound bed versus 4/15 (26%) treated with non-adherent petrolatum emulsion-impregnated gauze.Four trials assessed the mean time to achieve debridement: one (86 participants) compared two autolytic debridement methods, two compared autolytic methods with enzymatic debridement (71 participants), and the last (12 participants) compared autolytic with biosurgical debridement; none of the results achieved statistical significance.Two trials that assessed autolytic debridement methods reported the number of wounds healed at 12 weeks. One trial (108 participants) reported that 24/54 (44%) ulcers treated with honey healed versus 18/54 (33%) treated with hydrogel (RR (adjusted for baseline wound diameter) 1.38, 95% CI 1.02 to 1.88; P value 0.037). The second trial (48 participants) reported that 7/25 (28%) ulcers treated with BWD healed versus 7/23 (30%) treated with non-adherent dressing.Reduction in wound size was assessed in five trials (444 participants) in which two autolytic methods were compared. Results were statistically significant in one three-armed trial (153 participants) when cadexomer iodine was compared to paraffin gauze (mean difference 24.9 cm², 95% CI 7.27 to 42.53, P value 0.006) and hydrocolloid compared to paraffin gauze (mean difference 23.8 cm², 95% CI 5.48 to 42.12, P value 0.01). A second trial that assessed reduction in wound size based its results on median differences and, at four weeks, produced a statistically significantly result that favoured honey over hydrogel (P value < 0.001). The other three trials reported no statistically significant results for reduction in wound size, although one trial reported that the mean percentage reduction in wound area was greater at six and 12 weeks for BWD versus a non-adherent dressing (44% versus 24% week 6; 74% versus 54% week 12).Pain was assessed in six trials (544 participants) that compared two autolytic debridement methods, but the results were not statistically significant. No serious adverse events were reported in any trial. AUTHORS' CONCLUSIONS: There is limited evidence to suggest that actively debriding a venous leg ulcer has a clinically significant impact on healing. The overall small number of participants, low number of studies and lack of meta-analysis in this review precludes any strong conclusions of benefit. Comparisons of different autolytic agents (hydrogel versus paraffin gauze; Dextranomer beads versus EUSOL and BWD versus non-adherent dressings) and Larvae versus hydrogel all showed statistically significant results for numbers of wounds debrided. Larger trials with follow up to healing are required.

Expectation-induced placebo responses fail to accelerate wound healing in healthy volunteers: results from a prospective controlled experimental trial.

Placebo responses have been shown to affect the symptomatology of skin diseases. However, expectation-induced placebo effects on wound healing processes have not been investigated yet. We analysed whether subjects' expectation of receiving an active drug accelerates the healing process of experimentally induced wounds. In 22 healthy men (experimental group, n = 11; control group, n = 11) wounds were induced by ablative laser on both thighs. Using a deceptive paradigm, participants in the experimental group were informed that an innovative 'wound gel' was applied on one of the two wounds, whereas a 'non-active gel' was applied on the wound of the other thigh. In fact, both gels were identical hydrogels without any active components. A control group was informed to receive a non-active gel on both wounds. Progress in wound healing was documented via planimetry on days 1, 4 and 7 after wound induction. From day 9 onwards wound inspections were performed daily accompanied by a change of the dressing and a new application of the gel. No significant differences could be observed with regard to duration or process of wound healing, either by intraindividual or by interindividual comparisons. These data document no expectation-induced placebo effect on the healing process of experimentally induced wounds in healthy volunteers.

Effects of a hydrogel patch on denture-related traumatic ulcers; an exploratory study.

PURPOSE: The aim of this exploratory study was to evaluate the effects of hydrogel patch wound dressing on healing time and pain level of denture-related lesions of the oral mucosa in edentulous individuals. MATERIALS AND METHODS: Twenty-three adults with newly fabricated complete sets of dentures who subsequently developed at least two ulcerative lesions related to their complete dentures were included in the study. For each participant, the smaller lesion (control lesion) was allocated to usual care, that is, adjustment of the denture's margins, whereas the larger lesion (test lesion) was assigned to receive usual care plus application of a hydrogel patch. In the latter, a patch was applied directly on the affected area three times within the first 24 hours, followed by application of three additional patches, namely one during each of the following 3 days. Participants were monitored until complete healing of all ulcers. The primary outcome measures were changes since baseline in each lesion's greatest dimension at days 1 and 7, as well as improvement in ulcer-related pain experienced. RESULTS: Participants were on average about 70 years old, about half were women, and just over 40% had type 2 diabetes. Lesions treated with the hydrogel patch extended between 4.3 and 10.2 mm (mean 7.1 mm) in their greatest dimension, and the smaller lesions receiving usual care were initially 4 mm on average, ranging from 2.0 to 7.0 mm. The hydrogel patch lesions attained 25% to 75% reductions in their greatest lesion extent from baseline to days 1 and 7, respectively, compared to 10% and just over 50% reduction in the lesions that received usual care. Healing rates were similar in patients with and without diabetes. The participants reported significant improvement in pain level 1 day following treatment initiation for 30% of the control lesions, compared to 65% of the lesions treated with the hydrogel patch. CONCLUSIONS: The results of this exploratory study suggest that application of hydrogel patches may represent a novel, effective treatment for accelerating the healing process and pain reduction in mucosal lesions associated with complete dentures also in people with type 2 diabetes; however, larger studies need to confirm these findings.

Mandibular reconstruction using a calcium phosphate/polyethylene glycol hydrogel carrier with BMP-2.

AIM: To test the hypothesis that a synthetic hydroxyapatite/ß-tricalcium phosphate (HA/TCP) construct combined with polyethylene glycol (PEG) hydrogel including recombinant human bone morphogenetic proteins-2 (rhBMP-2) enhances new bone formation compared with bone morphogenetic proteins-2 (BMP-2) delivered using the HA/TCP construct alone. MATERIAL AND METHODS: Bilateral mandibular partial thickness 20 × 8 × 8 mm (L × W × H) alveolar defects were surgically created in the edentulated posterior mandible in 18 female minipigs. Randomized into two groups of nine animals each, the alveolar defects either received HA/TCP or HA/TCP/PEG with or without BMP-2 (105 µg/defect) in contra-lateral sites using a split-mouth design. Primary outcome, bone density (%) within four regions of interest, was evaluated following a 4-week healing interval when the animals were killed for histometric analysis. RESULTS: Bone morphogenetic proteins-2 loaded onto HA/TCP constructs significantly enhanced new bone formation compared with HA/TCP controls. Adding PEG apparently obstructed BMP-2 induced bone formation. CONCLUSION: Polyethylene glycol compromises the osteogenic effect of BMP-2.

Dextran hydrogel scaffolds enhance angiogenic responses and promote complete skin regeneration during burn wound healing.

Neovascularization is a critical determinant of wound-healing outcomes for deep burn injuries. We hypothesize that dextran-based hydrogels can serve as instructive scaffolds to promote neovascularization and skin regeneration in third-degree burn wounds. Dextran hydrogels are soft and pliable, offering opportunities to improve the management of burn wound treatment. We first developed a procedure to treat burn wounds on mice with dextran hydrogels. In this procedure, we followed clinical practice of wound excision to remove full-thickness burned skin, and then covered the wound with the dextran hydrogel and a dressing layer. Our procedure allows the hydrogel to remain intact and securely in place during the entire healing period, thus offering opportunities to simplify the management of burn wound treatment. A 3-week comparative study indicated that dextran hydrogel promoted dermal regeneration with complete skin appendages. The hydrogel scaffold facilitated early inflammatory cell infiltration that led to its rapid degradation, promoting the infiltration of angiogenic cells into the healing wounds. Endothelial cells homed into the hydrogel scaffolds to enable neovascularization by day 7, resulting in an increased blood flow significantly greater than treated and untreated controls. By day 21, burn wounds treated with hydrogel developed a mature epithelial structure with hair follicles and sebaceous glands. After 5 weeks of treatment, the hydrogel scaffolds promoted new hair growth and epidermal morphology and thickness similar to normal mouse skin. Collectively, our evidence shows that customized dextran-based hydrogel alone, with no additional growth factors, cytokines, or cells, promoted remarkable neovascularization and skin regeneration and may lead to novel treatments for dermal wounds.

Multicenter cohort study to assess the impact of a silver-alloy and hydrogel-coated urinary catheter on symptomatic catheter-associated urinary tract infections.

PURPOSE: The purpose of this study was to determine the effect of a silver-alloy hydrogel catheter on symptomatic catheter-associated urinary tract infections (CAUTIs). DESIGN: Multicenter before-after non-randomized cohort study. SUBJECTS AND SETTING: Seven acute care hospitals ranging in size from 124 to 607 beds participated in this study. The study population included adult patients with a positive urine culture 2 or more days after admission, who underwent Foley catheterization. METHODS: Catheter-associated urinary tract infection surveillance was conducted at each hospital for at least 3 months during the use of a standard catheter and 3 months during the use of the silver-alloy hydrogel catheter. Both the National Healthcare Safety Network (NHSN) surveillance and a clinical definition of CAUTI were used for rate calculation. RESULTS: A 47% relative reduction in the CAUTI rate was observed with the silver-alloy hydrogel catheter compared to the standard catheter when both infection definitions were used (0.945/1000 patient days vs 0.498/1000 patient days) (odds ratio = 0.53; P < .0001; 95% CI: 0.45-0.62). When only NHSN-defined CAUTIs were considered, a 58% relative reduction occurred in the silver-alloy hydrogel period (0.60/1000 patient days vs 0.25/1000 patient days) (odds ratio = 0.42; P < .0001; 95% CI: 0.34-0.53). Antimicrobial days for CAUTIs decreased from 1165 (standard catheter period) to 406 (silver-alloy hydrogel period). CONCLUSIONS: Use of a silver-alloy hydrogel urinary catheter reduced symptomatic CAUTI occurrences as defined by both NHSN and clinical criteria.

[The study of quality characteristics of the hydrogel ointments and films based on copolymers divinyl esters of diethylene glycol].

The possibility of using a hydrogel based on divinyl ether co- and terpolymer of diethylene glycol as the backbone polymer for incorporating water-soluble medicinal substances was examined. The character of the influence of emulsifiers, plasticizers, high-boiling liquids and bioactive substances is defined within the changes of physical-chemical properties of obtained hydrogels. The obtained polyelectrolyte hydrogels by their homogeneity, dehydration and rheological characteristics may be of concern in function of matrices to create external prolonged-action dosage forms.

Widely distributable and retainable in-situ gelling material for treating myocardial infarction.

Intramyocardial hydrogel injection is a promising therapy to prevent negative remodeling following myocardial infarction (MI). In this study, we report a mechanism for in-situ gel formation without external stimulation, resulting in an injectable and tissue-retainable hydrogel for MI treatment, and investigate its therapeutic outcomes. A liquid-like polymeric solution comprising poly(3-acrylamidophenylboronic acid-co-acrylamide) (BAAm), polyvinyl alcohol (PVA), and sorbitol (S) increases the viscous modulus by reducing the pre-added sorbitol concentration is developed. This solution achieves a sol-gel transition in-vitro in heart tissue by spontaneously diffusing the sorbitol. After intramyocardial injection, the BAAm/PVA/S with lower initial viscous modulus widely spreads in the myocardium and gelate compared to a viscoelastic alginate (ALG) hydrogel and is retained longer than the BAAm/S solution. Serial echocardiogram analyses prove that injecting the BAAm/PVA/S into the hearts of subacute MI rats significantly increases the fraction shortening and ejection shortening and attenuates the expansion of systolic LV diameter for up to 21 d after injection compared to the saline injection as a control, but the ALG injection does not. In addition, histological evaluation shows that only the BAAm/PVA/S decreases the infarct size and increases the wall thickness 21 d after injection. The BAAm/PVA/S intramyocardial injection is better at restraining systolic ventricular dilatation and cardiac failure in the rat MI model than in the control groups. Our findings highlight an effective injectable hydrogel therapy for MI by optimizing injectability-dependent distribution and retention of injected material. STATEMENT OF SIGNIFICANCE: In-situ gelling material is a promising strategy for intramyocardial hydrogel injection therapy for myocardial infarction (MI). Since the sol-gel transition of reported materials is driven by external stimulation such as temperature, pH, or ultraviolet, their application in vivo remains challenging. In this study, we first reported a synthetic in-situ gelling material (BAAm/PVA/S) whose gelation is stimulated by spontaneously reducing pre-added sorbitol after contacting the heart tissue. The BAAm/PVA/S solution spreads evenly, and is retained for at least 21 d in the heart tissue. Our study demonstrated that intramyocardial injection of the BAAm/PVA/S with more extensive distribution and longer retention had better effects on preventing LV dilation and improving cardiac function after MI than that of viscoelastic ALG and saline solution. We expect that these findings provide fundamental information for the optimum design of injectable biomaterials for treating MI.