Hyaluronic Acid Polymer Research Articles

Incorporating GSE4 peptide in PEG/hyaluronic acid hydrogels to promote the alveolar epithelial differentiation of mesenchymal stem cells

Because of the shortage of donors, alveolar stem cells transplantation is under development as an important and promising treatment for end-stage lung disease. Currently, the acquisition of functional lung cells is mostly performed by two dimensional (2D) culture and suffers from low directed differentiation efficiency. It is particularly critical to replicate the three dimensional (3D) growth of lung cells, as cells grow in 3D microenvironment in vivo. In this work, we develop a 3D biomimetic composite hydrogel system based on the in situ crosslinking of the synthetic polymer 4 arm acrylated-poly(ethylene glycol) (4PEG-AC), the thiolated natural polymer hyaluronic acid (HA-SH), and the thiolated polypeptide (GSE4-SH) via a Michael-type “click” reaction under physiological conditions at pH 7.8. The PEG/HA/GSE4 hydrogel with a sheer modulus of 104.1 ± 9.9 Pa was used for 3D growth of bone marrow mesenchymal stem cells (BMSCs), displaying excellent biocompatibility. Covalent conjugation of GSE4 peptide in hydrogel promoted the differentiation of BMSCs into alveolar epithelial type 2 cells (AEC2s) with a AEC2s-differentiation rate of 58.6 ± 3.3%. Overall, this study provides a suitable 3D biomimetic platform to enable the efficient differentiation of stem cells into lung cells for lung tissue engineering.

Formulation Variables Effect on Gelation Temperature of Nefopam Hydrochloride intranasal in Situ Gel (Conference Paper) #

Nefopam (N.F.) HCl is a non-narcotic centrally-acting, non-opioid benzoxazocine analgesic to relieve acute and chronic pain. It exhibits low bioavailability (about 36%) due to its first-pass degradation in the liver.
 Intranasal administration has been used as a new route for targeting active brain sites and enhancing the bioavailability of N.F. HCl bypassing hepatic metabolism.
 In situ gel of N.F. HCl was prepared by the cold method using different concentrations of Poloxamer 407, Poloxamer 188, HPMC K4M, Carbapol 934, and Hyaluronic acid polymers.
 The results show that identification tests are superimposed with references, solubility study shows that N.F. HCl is suitable to be administered intranasally; Compatibility studies reveal incompatibility of Nefopam HCl with HPMC K4M and Carbapol 934; meanwhile, no interaction with Methylcellulose and Hyaluronic acid.
 In conclusion, the obtained results revealed the incredible ability of the produced N.F. HCl intranasal in situ gel is intended to enhance drug bioavailability bypassing the metabolizing effect of the liver that N.F. HCl is facing when given orally.

Hyaluronan-Cyclodextrin Conjugates as Doxorubicin Delivery Systems.

In the last years, nanoparticles based on cyclodextrins have been widely investigated for the delivery of anticancer drugs. In this work, we synthesized nanoparticles with a hyaluronic acid backbone functionalized with cyclodextrins under green conditions. We functionalized hyaluronic acid with two different molecular weights (about 11 kDa and 45 kDa) to compare their behavior as doxorubicin delivery systems. We found that the new hyaluronan-cyclodextrin conjugates increased the water solubility of doxorubicin. Moreover, we tested the antiproliferative activity of doxorubicin in the presence of the new cyclodextrin polymers in SK-N-SH and SK-N-SH-PMA (over-expressing CD44 receptor) cancer cells. We found that hyaluronan-cyclodextrin conjugates improved the uptake and antiproliferative activity of doxorubicin in the SK-N-SH-PMA compared to the SK-N-SH cell line at the ratio 8/1 doxorubicin/polymer. Notably, the system based on hyaluronan (45 kDa) was more effective as a drug carrier and significantly reduced the IC50 value of doxorubicin by about 56%. We also found that hyaluronic acid polymers determined an improved antiproliferative activity of doxorubicin (IC50 values are on average reduced by about 70% of free DOXO) in both cell lines at the ratio 16/1 doxorubicin/polymer.

Comparison of a thiolated demineralized bone matrix hydrogel to a clinical product control for regeneration of large sheep cranial defects

Regeneration of calvarial bone remains a major challenge in the clinic as available options do not sufficiently regenerate bone in larger defect sizes. Calvarial bone regeneration cases involving secondary medical conditions, such as brain herniation during traumatic brain injury (TBI) treatment, further exacerbate treatment options. Hydrogels are well-positioned for severe TBI treatment, given their innate flexibility and potential for bone regeneration to treat TBI in a single-stage surgery. The current study evaluated a photocrosslinking pentenoate-modified hyaluronic acid polymer with thiolated demineralized bone matrix (i.e., TDBM hydrogel) capable of forming a completely interconnected hydrogel matrix for calvarial bone regeneration. The TDBM hydrogel demonstrated a setting time of 120 s, working time of 3 to 7 days, negligible change in setting temperature, physiological setting pH, and negligible cytotoxicity, illustrating suitable performance for in vivo application. Side-by-side ovine calvarial bone defects (19 mm diameter) were employed to compare the TDBM hydrogel to the standard-of-care control material DBX®. After 16 weeks, the TDBM hydrogel had comparable healing to DBX® as demonstrated by mechanical push-out testing (∼800 N) and histology. Although DBX® had 59% greater new bone volume compared to the TDBM hydrogel via micro-computed tomography, both demonstrated minimal bone regeneration overall (15 to 25% of defect volume). The current work presents a method for comparing the regenerative potential of new materials to clinical products using a side-by-side cranial bone defect model. Comparison of novel biomaterials to a clinical product control (i.e., standard-of-care) provides an important baseline for successful regeneration and potential for clinical translation.

Enhancing Intradermal Delivery of Lidocaine by Dissolving Microneedles: Comparison between Hyaluronic Acid and Poly(Vinyl Pyrrolidone) Backbone Polymers.

Lidocaine hydrochloride (LiH), an amide-type local anesthetic agent, is commonly used in dermatological procedures. LiH is categorized as a BCS (biopharmaceutics classification system) class III group, which has high solubility and poor permeability. It should be noted that, in this context, LiH is intended as a local anesthetic, so the level of LiH in systemic circulation should be minimized to avoid toxicity and unwanted side effects such as hypotension and bradycardia. This study aimed to formulate and evaluate LiH-loaded dissolving microneedles (DMNs) with different polymer bases. Moreover, an in vitro permeation study using Franz diffusion cells and in vivo study were also performed. LiH-loaded DMNs were prepared using polymer groups of poly(vinyl pyrrolidone) (PVP-K30) and hyaluronic acid (HA). DMNs were created using the micro-molding method with centrifugation. The formulations selected based on the evaluation were F3 (HA 10%) and F5 (PVP-K30 25%). Based on the in vitro permeation study, the amount of drug permeated and deposited in the skin at F3 (HA 10%) was 247.1 ± 41.85 and 98.35 ± 12.86 μg, respectively. On the other hand, the amount of drug permeated and deposited in the skin at F5 (PVP-K30 25%) was 277.7 ± 55.88 and 59.46 ± 9.25 μg, respectively. Our in vivo drug-permeation study showed that only one rat from the PVP-K30 polymer group-with a concentration of 150.32 ng/mL-was detected on rat plasma. Therefore, LiH can be formulated into a DMN and can be deposited in the skin with a safe concentration of the drug permeating into systemic circulation.

Polymer in hemostasis and follow‐up wound healing

AbstractPolymers offer unique functional properties that lead to some novel applications every other day. Bioactive polymers with high degree of biodegradability, nonimmunogenicity, and biocompatibility are considered for applications in wound healing. The most basic form of wound protection is by gauge dressing that isolates the wound from contaminants. Natural polymers for example, cellulose, alginate, chitosan, starch, dextran, gelatin, hyaluronic acid, glycan, collagen, and synthetic polymers including polymethyl methacrylate (PMMA), polyvinyl alcohol (PVA), polyethylene glycol (PEG), polyvinyl pyrrolidone (PVP) are candidates for these applications. Biopolymers, when applied as wound dressing promote tissue healing and repair by (i) regulating the moist environment, and (ii) providing the needed growth factors, while offering anti‐inflammatory, immune‐modulatory, and cell proliferative properties. It induces hemostasis via direct interaction with erythrocytes and platelets. These polymers in cross linked state offer a scaffold for cell proliferation, differentiation, and cell migration. Further, these polymeric materials can be utilized to form permeable envelopes around the hemostatic and wound healing agents to leverage a favorable release kinetics. The fabrication strategies and their reported efficacy are reviewed in this article.

Modification and Functionalization of Polymers for Targeting to Bone Cancer and Bone Regeneration.

Bone is one of the most complex, inaccessible body structures, responsible for calcium storage and haematopoiesis. The second highest cause of death across the world is cancer. Amongst all the types of cancers, bone cancer treatment modalities are limited due to the structural complexity and inaccessibility of bones. The worldwide incidence of bone diseases and bone defects due to cancer, infection, trauma, age-related bone degeneration is increasing. Currently different conventional therapies are available for bone cancer such as chemotherapy, surgery and radiotherapy, but they have several disadvantages associated with them. Nanomedicine is being extensively researched as viable therapeutics to mitigate drug resistance in cancer therapy and promote bone regeneration. Several natural polymers such as chitosan, dextran, alginate, hyaluronic acid, and synthetic polymers like polyglycolic acid, poly(lactic-co-glycolic acid), polycaprolactone are investigated for their application in nanomedicine for bone cancer treatment and bone regeneration. Nanocarriers have shown promising results in preclinical experimental studies. However, they still face a major drawback of inadequate targetability. The paper summarizes the status of research and the progress made so far in modifications and functionalization of natural polymers for improving their site specificity and targeting for effective treatment of bone cancer and enhancing bone regeneration.

Novel Crosslinked HA Hydrogel Films for the Immediate Release of Active Ingredients

Novel crosslinked hyaluronic acid (HA) hydrogel films were previously invented by reacting the HA polymer with the PT (Pentaerythritol Tetra-acrylate) crosslinker over basic pH conditions in the oven. HA is considered a natural polymer present in cosmetic as well as pharmaceutical formulations. This current study aimed to highlight the effect of loading method (post-loading and in situ) of selected actives (salicylic acid and niacinamide B3) in the hydrogel films and then study their release kinetics. Differential scanning colometry (DSC) and Fourier transform infrared spectroscopy (FTIR) analysis evidenced the loading of the actives and full release from the HA hydrogel films, while the scanning electron microscopy (SEM) demonstrated the morphological changes to the films during the study by comparing the average molecular weight between crosslinks (M¯c), gel fraction, crosslinking density (Ve) and mesh size (ξ) of the films. The loading percentage of the SA and B3 showed high percentage loading of actives via both loading methods. In conclusion, the (95–100%) release of the actives achieved from the HA hydrogel films within 10 min revealed that the films are an efficient immediate release system of actives.

1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic Acid Acetoxymethyl Ester Loaded Reactive Oxygen Species Responsive Hyaluronic Acid-Bilirubin Nanoparticles for Acute Kidney Injury Therapy via Alleviating Calcium Overload Mediated Endoplasmic Reticulum Stress.

Calcium overload is one of the early determinants of the core cellular events that contribute to the pathogenesis of acute kidney injury (AKI), which include oxidative stress, ATP depletion, calcium overload, and inflammatory response with self-amplifying and interactive feedback loops that ultimately lead to cellular injury and renal failure. Excluding adjuvant therapy, there are currently no approved pharmacotherapies for the treatment of AKI. Using an adipic dihydride linker, we modified the hyaluronic acid polymer chain with a potent antioxidant, bilirubin, to produce an amphiphilic conjugate. Subsequently, we developed a kidney-targeted and reactive oxygen species (ROS)-responsive drug delivery system based on the flash nanocomplexation method to deliver a well-known intracellular calcium chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM, BA), with the goal of rescuing renal cell damage via rapidly scavenging of intracellularly overloaded Ca2+. In the ischemia-reperfusion (I/R) induced AKI rat model, a single dose of as-prepared formulation (BA 100 μg·kg-1) 6 h post-reperfusion significantly reduced renal function indicators by more than 60% within 12 h, significantly alleviated tissular pathological changes, ameliorated tissular oxidative damage, significantly inhibited apoptosis of renal tubular cells and the expression of renal tubular marker kidney injury molecule 1, etc., thus greatly reducing the risk of kidney failure. Mechanistically, the treatment with BA-loaded NPs significantly inhibited the activation of the ER stress cascade response (IRE1-TRAF2-JNK, ATF4-CHOP, and ATF6 axis) and regulated the downstream apoptosis-related pathway while also reducing the inflammatory response. The BA-loaded NPs hold great promise as a potential therapy for I/R injury-related diseases.

Platelet-Rich Plasma Gel Matrix (PRP-GM): Description of a New Technique.

Several musculoskeletal conditions are triggered by inflammatory processes that occur along with imbalances between anabolic and catabolic events. Platelet-rich plasma (PRP) is an autologous product derived from peripheral blood with inherent immunomodulatory and anabolic properties. The clinical efficacy of PRP has been evaluated in several musculoskeletal conditions, including osteoarthritis, tendinopathy, and osteonecrosis. When used in combination with hyaluronic acid (HA), a common treatment alternative, the regenerative properties of PRP are significantly enhanced and may provide additional benefits in terms of clinical outcomes. Recently, a new PRP-derived product has been reported in the literature and is being referred to as "plasma gel". Plasma gels are obtained by polymerizing plasmatic proteins, which form solid thermal aggregates cross-linked with fibrin networks. Plasma gels are considered to be a rich source of growth factors and provide chemotactic, migratory, and proliferative properties. Additionally, clot formation and the associated fibrinolytic reactions play an additional role in tissue repair. There are only a few scientific articles focusing on plasma gels. Historically, they have been utilized in the fields of aesthetics and dentistry. Given that the combination of three products (PRP, HA, and plasma gel) could enhance tissue repair and wound healing, in this technical note, we propose a novel regenerative approach, named "PRP-HA cellular gel matrix" (PRP-GM), in which leukocyte-rich PRP (LR-PRP) is mixed with a plasma gel (obtained by heating the plasma up) and HA in one syringe using a three-way stopcock. The final product contains a fibrin-albumin network entangled with HA's polymers, in which the cells and biomolecules derived from PRP are attached and released gradually as fibrinolytic reactions and hyaluronic acid degradation occur. The presence of leukocytes, especially monocytes and macrophages, promotes tissue regeneration, as type 2 macrophages (M2) possess an anti-inflammatory feature. In addition, HA promotes the viscosuplementation of the joint and induces an anti-inflammatory response, resulting in pain relief. This unique combination of biological molecules may contribute to the optimization of regenerative protocols suitable for the treatment of degenerative musculoskeletal diseases.

Cancer cells targeting H2O2-responsive MXene-integrated hyaluronic acid polymer dots coated sensor

We successfully developed a reactive oxygen species (ROS)-responsive electrochemical sensor based on a substrate coated with cancer cell-targeted hyaluronic acid polymer dot-integrated ROS-degradable MXene particles [MXene-PD(HA)] for identifying cancer conditions in vitro. Exposure to high H2O2 concentration of cancer cells selectively controls the electroconductivity and photothermal conversion of the MXene-PD(HA) due to the involvement of oxidation reaction, changing MXene into TiO2. The resistance of the sensor increases with accumulation of H2O2, elevating the resistance from 225.4 ± 62.39 kΩ (0 mM) to 3418 ± 39.22 kΩ after treatment with 1 mM H2O2. In vitro treatment with CHO-K1 and HeLa cells adjusted the morphology of MXene-PD(HA)-coated surfaces and electrochemical sensing performance through the degradation of MXene by intracellular ROS. The sensor could differentiate normal and cancer cells by displaying an increase in resistance from 147.4 ± 16.00 kΩ (control) to 994.4 ± 152.6 kΩ (CHO-K1) and 2040 ± 460.1 kΩ (HeLa). Besides, the MXene-PD(HA) is uptaken after 1 h treatment for CHO-K1 cells and as early as 0.5 h for HeLa, displaying a rapid detection. In conclusion, the MXene-PD(HA) electrode exhibited the ability to distinguish between normal and cancer cells and showed promising potential for the detection of tumor microenvironment.

HA-PEG-PCL Nanoparticles With Paclitaxel Loaded For Targeted Delivery To Colon Cancer

For improved treatment efficacy with no or few adverse effects and higher patient compliance, novel delivery techniques with selective dispersion are required. The biodegradable and biocompatible polymers hyaluronic acid (HA), polyethylene glycol (PEG), and polycaprolactone (PCL) were used to create paclitaxel-loaded nanoparticles. The development and characterisation of a Paclitaxel-loaded HA-PEG-PCL polymeric nanoparticulate drug delivery system were the goals of the current study work in order to increase the therapeutic efficacy and targeted Paclitaxel distribution. The copolymers were chemically created, and IR spectroscopies were used to identify them. Transmission electron microscopy, particle size, percentage of drug entrapment, cell viability studies, stability, and in vitro drug release profile were used to describe the nanoparticles' structure and morphology. To determine whether PTX was crystalline or amorphous inside the polymer matrix, experiments using differential scanning calorimetry and X-ray diffraction were also carried out. Zeta potentials for blank NPs and PTX-HA-PEG-PCL NPs were respectively -15.4±1.23 mV and -18±2.35 mV. In 144 hours, PTX-HA-PEG-PCL NPs demonstrated a 58.08±3.8 release of PTX at pH 7.4. Because HA functions as a ligand for the CD44 receptors that are over expressed on HT-29 cells, the PTX-HA-PEG-PCL NPs demonstrated noticeably more cytotoxicity as a result of better formulation internalization. The proposed nanotechnology’s-controlled drug release behavior showed its potential for colon cancer cell lines

A novel chitosan-hyaluronic acid-pullulan composite film wound dressing for effectively inhibiting bacteria and accelerating wound healing

The wound healing process involves not only the recovery of skin barrier integrity, but also reducing the risk of infection and secondary complications. Therefore, utilizing an appropriate antibacterial method plays a key role in accelerating wound healing. In this paper, chitosan (CS) was chosen due to its inherent antibacterial property. Succinyl chitosan grafted hyaluronic acid and pullulan (CS-st-HA-Pu) polymer for wound healing was successfully prepared and characterized. Scanning electron microscopy (SEM) observation showed that the CS-st-HA-Pu film had a three-dimensional cavity junction, which could absorb a large amount of liquid and keep the wound environment moist. The results of skin irritation, cytotoxicity, cell proliferation and hemolysis tests indicated that CS-st-HA-Pu material had good biocompatibility. Moreover, CS-st-HA-Pu material exhibited a certain antibacterial capability against E. coli and S. aureus . In a wound healing of rat, CS-st-HA-Pu film outperformed the control or market band-aid group with respect to acceleration of wound closure. • A series of hyaluronic acid grafted pullulan (HA-st-Pu) polymers were synthesized. • The novel CS/HA-st-Pu wound dressing prepared by physical mixture method . • CS/HA-st-Pu exhibited a certain antibacterial capability. • CS/HA-st-Pu films can promote the wound healing.

Design of a bactericidal hydrogel scaffold containing genipin crosslinked HF-18 peptide.

Wound healing is a process getting affected by internal and external factors and might be interrupted by infections. To overcome infections during wound healing, novel antibacterial agents such as antimicrobial peptides have gained popularity because of the rising antibiotic resistance. Therefore, in this study, a three-dimensional polymeric scaffold was designed for the controlled release of HF-18 peptide, with the contribution of hyaluronic acid, chondroitin sulfate, and chitosan polymers with the crosslinker genipin. The obtained scaffold structure (OPT) was found to have interconnected pores, was pH-responsive and swelled more in acidic conditions (5446.5% at pH: 5.0). It was observed that HF-18-loaded OPT (P-OPT) was able to release HF-18 peptide both in acidic and neutral conditions in a controlled release manner. This study also demonstrated that both OPT and P-OPT were biocompatible and promoted L929 cell attachment and migration. Antimicrobial activity assessments demonstrated that P-OPT was effectively bactericidal on Staphylococcus aureus and methicillin-resistant S. aureus. Moreover, OPT produced a synergistic effect on the antimicrobial activity of HF-18 peptide, as P-OPT showed activity below the reported MIC value. As a result, OPT is considered a promising scaffold as a carrier for HF-18 for wound healing.

Microgel-Assisted Delivery of Adenosine to Accelerate Fracture Healing.

Extracellular adenosine plays a key role in promoting bone tissue formation. Local delivery of adenosine could be an effective therapeutic strategy to harness the beneficial effect of extracellular adenosine on bone tissue formation following injury. Herein, we describe the development of an injectable in situ curing scaffold containing microgel-based adenosine delivery units. The two-component scaffold includes adenosine-loaded microgels and functionalized hyaluronic acid (HA) molecules. The microgels were generated upon copolymerization of 3-acrylamidophenylboronic acid (3-APBA)- and 2-aminoethylmethacrylamide (2-AEMA)-conjugated HA (HA-AEMA) in an emulsion suspension. The PBA functional groups were used to load the adenosine molecules. Mixing of the microgels with the HA polymers containing clickable groups, dibenzocyclooctyne (DBCO) and azide (HA-DBCO and HA-Azide), resulted in a 3D scaffold embedded with adenosine delivery units. Application of the in situ curing scaffolds containing adenosine-loaded microgels following tibial fracture injury showed improved bone tissue healing in a mouse model as demonstrated by the reduced callus size, higher bone volume, and increased tissue mineral density compared to those treated with the scaffold without adenosine. Overall, our results suggest that local delivery of adenosine could potentially be an effective strategy to promote bone tissue repair.

Effect of hyaluronic acid on milk properties: Rheology, protein stability, acid and rennet gelation properties

Hyaluronic acid (HA) is gaining popularity and acceptance as a food ingredient. HA has certain properties such as water binding, viscosity manipulation which can be exploited in food products. However, there are limited studies available for the effect of HA on the properties of food, especially in milk and milk products. Studying the effect of HA treatments on milk properties such as viscosity, heat stability, phase separation, rennet, and acid gelation would be beneficial to the processors. The objective was to study the effect of HA at different concentrations on various physico-chemical properties of milk. Whole milk treated with HA showed increased viscosity as a function of HA concentration in both cold and pasteurized milk samples. The frequency sweep results indicated that only a higher HA concentration (0.5%) was able to achieve the viscoelastic solid behavior (G′ > G″), which was stable over the entire frequency sweep range of 10–150 rad/s. Heat stability of skim milk was negatively impacted as a function of HA concentration. The gravimetric protein phase separation during skim milk storage was also negatively impacted as a function of HA concentrations up to 0.25%. However, higher HA concentration (0.5%) reduced the phase separation. In the case of rennet gel and acid gel studies, the gelation properties and the gel structure was negatively impacted as a function of HA concentration. The negative effect of HA on rennet and acid gelation properties could be as a result of depletion–flocculation mechanism leading to micro-phase separation interference by HA polymer in the formation of continuous protein gel network.

Safety and efficacy of a new hydrogel based on hyaluronic acid as cosmeceutical for xerosis.

Hyaluronic acid (HA) is among the most effective and safe ingredients frequently used in cosmetics. However, a more economical and efficient formulation is still required. We sought to assess the safety and efficacy of a novel hydrogel manufactured only by irradiation containing cross-linked HA and polyethylene glycol polymers with addition of polysiloxane. The study included 30 people with normal skin and 30 patients with xerosis. In the normal skin group, to evaluate the safety, a patch test and a photopatch test were performed, and patients' discomfort was investigated. In those with xerosis, to assess the efficacy, a skin barrier function test was performed at baseline and at 2, 4, and 8 weeks after the application of the novel hydrogel. Additionally, the xerosis severity scale (XSS), patient satisfaction, Investigator's Global Assessment (IGA), and adverse responses were evaluated. In the safety study, there was no significant discomfort in the experimental group compared with the control group. In the efficacy study, at 2, 4, and 8 weeks after the application of the novel hydrogel, the mean value of skin hydration and sebum content increased and the mean value of XSS decreased with time in the experimental group, and a difference was observed when compared with the control group. IGA showed improvement in 97%, 77%, and 80% at each visit and the proportions of satisfied patients were 90%, 87%, and 90%, respectively. The novel HA-based hydrogel tested herein could be a safe and effective therapeutic remedy for xerosis.

XA pH-Responsive and Colitis-Targeted Nanoparticle Loaded with Shikonin for the Oral Treatment of Inflammatory Bowel Disease in Mice.

Epidemiology shows that more than 6.8 million people in the world are influenced by inflammatory bowel disease (IBD) each year. IBD is a refractory inflammatory disease, and the disease mainly affects the colon. Shikonin (SK) was originally extracted from traditional Chinese medicine "Zicao" (with an English name Lithospermum erythrorhizon) and found to inhibit inflammation, regulate immunity, and be involved in healing wounds. Herein, we used chitosan (CS), hyaluronic acid (HA), and pH-responsive polymer Eudragits S100 (ES100) to design SK-loaded ES100/HA/CS nanoparticles (SK@SAC) as an oral delivery system to treat the colitis mice. Particle size of SK@SAC was 190.3 nm and drug loading efficiency was 6.6%. SAC nanoparticles accumulated in RAW264.7 macrophages and exhibited colitis-targeted ability by increasing the local drug concentration as well as reducing nonspecific distribution after oral gavage. In TNBS-induced IBD mice, SK@SAC treatment had significant therapeutic effects, regulated of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) and anti-inflammatory cytokines (IL-10 and TGF-β), and also inhibited COX-2 and iNOS activity. SK@SAC also increased tight junction protein ZO-1 and occludin to some extent. These promising results showed that this novel oral SK-loaded nanoparticle drug delivery system for targeted treatment provides a new strategy for the management of IBD.

Independent control of molecular weight, concentration, and stiffness of hyaluronic acid hydrogels

Hyaluronic acid (HA) hydrogels have been used for a multitude of applications, perhaps most notably for tissue engineering and regenerative medicine, owing to the versatility of the polymer and its tunable nature. Various groups have investigated the impact of hydrogel parameters (e.g. molecular weight, concentration, stiffness, etc) in vitro and in vivo to achieve desired material performance characteristics. A limitation in the literature to date has been that altering one hydrogel parameter (a ‘manipulated variable’) to achieve a given hydrogel characteristic (a ‘controlled variable’) changes two variables at a time (e.g. altering molecular weight and/or concentration to investigate cell response to stiffness). Therefore, if cell responses differ, it may be possible that more than one variable caused the changes in observed responses. In the current study, we leveraged thiol-ene click chemistry with a crosslinker to develop a method that minimizes material performance changes and permitted multiple material properties to be independently held constant to evaluate a single variable at a time. Independent control was accomplished by tuning the concentration of crosslinker to achieve an effectively constant stiffness for different HA hydrogel molecular weights and polymer concentrations. Specific formulations were thereby identified that enabled the molecular weight (76–1550 kDa), concentration (2%–10%), or stiffness (∼1–350 kPa) to be varied while the other two were held constant, a key technical achievement. The response of rat mesenchymal stem cells to varying molecular weight, concentration, and stiffness demonstrated consistent upregulation of osteocalcin gene expression. The methodology presented to achieve independent control of hydrogel parameters may potentially be adopted by others for alternative hydrogel polymers, cell types, or cell culture medium compositions to minimize confounding variables in experimental hydrogel designs.

Novel Retro-Inverso Peptide Antibiotic Efficiently Released by a Responsive Hydrogel-Based System.

Topical antimicrobial treatments are often ineffective on recalcitrant and resistant skin infections. This necessitates the design of antimicrobials that are less susceptible to resistance mechanisms, as well as the development of appropriate delivery systems. These two issues represent a great challenge for researchers in pharmaceutical and drug discovery fields. Here, we defined the therapeutic properties of a novel peptidomimetic inspired by an antimicrobial sequence encrypted in human apolipoprotein B. The peptidomimetic was found to exhibit antimicrobial and anti-biofilm properties at concentration values ranging from 2.5 to 20 µmol L−1, to be biocompatible toward human skin cell lines, and to protect human keratinocytes from bacterial infections being able to induce a reduction of bacterial units by two or even four orders of magnitude with respect to untreated samples. Based on these promising results, a hyaluronic-acid-based hydrogel was devised to encapsulate and to specifically deliver the selected antimicrobial agent to the site of infection. The developed hydrogel-based system represents a promising, effective therapeutic option by combining the mechanical properties of the hyaluronic acid polymer with the anti-infective activity of the antimicrobial peptidomimetic, thus opening novel perspectives in the treatment of skin infections.