Delivery Of Dexamethasone Research Articles

DDEL-17. INTRA-TUMORAL CONVECTION ENHANCED DELIVERY OF DEXAMETHASONE REDUCES INFLAMMATORY SIGNATURES AND EXTENDS SURVIVAL IN GBM MODEL

Abstract Dexamethasone is the most widely utilized drug for glioblastoma (GBM). However, systemic delivery of dexamethasone in GBM patients is associated with significant side effects and increasing doses with worse survival. Convection-enhanced delivery (CED) can deliver high doses of immunotherapy directly into the tumor microenvironment (TME) while avoiding systemic toxicity. Here, we report that high doses of dexamethasone can be delivered locally by CED without side effects and increase survival in a GBM model along with reduced inflammatory myeloid signatures. We investigated CED of dexamethasone treatment on survival(n=40), adverse side effects, and the immunological TME through peripheral analyses, liquid chromatography–mass spectrometry, and histology in a preclinical syngeneic mouse model. Additionally, we assessed the transcriptional responses of human GBM slices and stem-cell-derived human microglia after steroid treatment through bulk and single-cell RNA sequencing. We found that 7-day treatment with CED of dexamethasone produced a significant survival advantage in glioma-bearing mice compared to non-treated control(p=0.03). Systemic dexamethasone achieved low levels of drug in the TME and caused dysregulated blood glucose, blood counts, and peripheral organ weights, while high CED doses avoided these side effects(p< 0.05 each). Steroid treatment of acute GBM slices and lipopolysaccharide-activated microglia in-vitro both reversed inflammatory myeloid signatures associated with poor survival and recurrence on RNA sequencing analyses. We demonstrate the preclinical efficacy of delivering high local doses of dexamethasone in a GBM model through CED and observed prolonged survival along with reduced adverse inflammatory myeloid signatures. No side effects were demonstrated after chronic CED treatment of dexamethasone while systemic delivery achieved poor tumor penetration and caused known hematologic and metabolic side effects supporting the potential to optimize the clinical use of this therapy. CED of dexamethasone provides us a new treatment paradigm to locally control inflammatory signatures in the glioma TME in a controlled fashion.

Dexamethasone-loaded chitosan-decorated PLGA nanoparticles: a step forward in attenuating the COVID-19 cytokine storm?

This study aims to develop and characterize poly (lactic-co-glycolic acid) (PLGA) nanoparticles decorated with chitosan (CS) for the encapsulation of dexamethasone (DEX) (NP-DEX-CS), targeting improved efficacy in the treatment of severe acute respiratory syndrome (SARS) associated with COVID-19. The nanoparticles were systematically characterized for size, zeta potential (ZP), morphology, encapsulation efficiency, and in vitro drug release. Incorporation of CS resulted in significant modifications in the nanoparticles' physical properties, notably an increase in size (from 207.3 ± 6.7nm to 264.4 ± 4.4nm) and a shift in ZP to positive values (from -11.8 ±1.4mV to +30.0 ± 1,6mV). The NP-DEX-CS formulation achieved a high encapsulation efficiency (~79%) and a drug loading capacity of 6.53 ± 0.02%.In addition, the in vitro release rate of DEX from NP-DEX-CS was lower compared to undecorated nanoparticles, with a reduction from approximately 64% to 37% within 24h. Microscopy analyses revealed a smoother surface on the CS-decorated nanoparticles. FTIR and XRD analyses confirmed successful chitosan coating and DEX encapsulation. The CS coating enhanced the tolerability of J774.A1 cells to the nanoparticles, particularly evident at the highest concentration (400ug/mL), resulting in a cell viability ≥70%. Importantly, the NP-DEX-CS significantly reduced levels of nitric oxide and inflammatory cytokines (IL-1, IL-6, IL-12, and TNF-α). These findings suggest that CS-decorated PLGA nanoparticles hold promise as an effective dexamethasone delivery system for treating SARS related to COVID-19.

Development and evaluation of nanostructured systems for cutaneous delivery of H2S-releasing corticosteroids for skin inflammatory diseases

Psoriasis is an immune-mediated chronic inflammatory disease that causes major psychosocial impact. Topical corticosteroids represent the standard pharmacological treatment for mild-to-moderate disease, but their local and systemic adverse effects reinforce the need for treatment innovations. Here we developed lamellar phase-based formulations for topical delivery of a hybrid dexamethasone and hydrogen sulfide (H2S) donor molecule (Dexa-TBZ), aiming to potentiate the effects of the glucocorticoid with H2S. They offer the possibility to obtain precursor formulations free of water that originate lamellar phases upon water addition, preventing drug hydrolysis during storage. Two groups of formulations were developed varying the surfactants and oil phase types and content. Systems containing 20 and 70 % of water formed, respectively, bulk lamellar phase and a more fluid formulation consisting of dispersed droplets (< 1000 nm) stabilized by lamellar phase. Both presented pseudoplastic behavior. Dexa-TBZ was incorporated at 1 %, remaining stable for 8 h. Drug content decreased to ∼80 % after 1 week in precursor formulations free of water, but remained stable after that. Without causing changes to the cutaneous barrier function ex vivo or to the histological structure of the skin in vivo, the formulation containing phosphatidylcholine as surfactant and 70 % of water promoted 1.8- and 2.7-fold increases in Dexa-TBZ penetration in the stratum corneum and epidermis+dermis, respectively, compared to a control solution, demonstrating their potential applicability as topical delivery systems.

Molded Round Window Niche Implant as a Dexamethasone Delivery System in a Cochlear Implant-Trauma Animal Model.

Preserving residual hearing after cochlear implant (CI) surgery remains a crucial challenge. The application of dexamethasone (DEX) has been proven to positively affect residual hearing. To deliver DEX in a localized and controlled way, a round window niche implant (RNI), allowing drug diffusion via the round window membrane into the cochlea, may be used. To prove this concept, an RNI for guinea pigs as a CI-trauma model was manufactured by molding and tested for its drug release in vitro and biological effects in vivo. The RNIs were molded using silicone containing 10% DEX. Release was analyzed over time using high-performance liquid chromatography (HPLC). Fourteen adult guinea pigs were randomly assigned to two groups (CI or CI + RNI group). All animals received a unilateral CI electrode insertion trauma followed by CI insertion. The CI + RNI group was additionally implanted with an RNI containing 10% DEX. Animals were followed up for 4 weeks. Acoustically evoked auditory brainstem response and impedance measurement, micro-computed tomography (µCT) imaging, and histology were performed for evaluation. DEX was released for more than 250 days in vitro, with an initial burst followed by a slower release over time. Comparing the hearing threshold shift (from day 0 to day 28) of the CI and CI + RNI groups, significant differences were observed at 32 and 40 kHz. The impedance shift at basal contacts was lower in the CI + RNI group than in the CI group. Moreover, the fibrosis in the lower basal turn was reduced in the CI + RNI group in contrast to the CI group. The RNI containing 10% DEX has anti-inflammatory potential concerning fibrosis inhibition and has beneficial effects on hearing preservation at high frequencies.

Controlled Transdermal Delivery of Dexamethasone for Pain Management via Photochemically 3D-Printed Bioresorbable Microneedle Arrays.

Microneedle array patches (MAPs) are extensively studied for transdermal drug delivery. Additive manufacturing enables precise control over MAP customization and rapid fabrication. However, the scope of 3D-printable, bioresorbable materials is limited. Dexamethasone (DXM) is widely used to manage inflammation and pain, but its application is limited by systemic side effects. Thus, it is crucial to achieve high local drug concentrations while maintaining low serum levels. Here, poly(propylene fumarate-co-propylene succinate) oligomers are fabricated into DXM-loaded, bioresorbable MAPs via continuous liquid interface production 3D printing. Thiol-ene click chemistry yields MAPs with tailorable mechanical and degradation properties. DXM-loaded MAPs exhibit controlled elution of drug in vitro. Transdermal application of DXM-loaded MAPs in a murine tibial fracture model leads to substantial relief of postoperative pain. Pharmacokinetic analysis shows that MAP administration is able to control pain at a significantly lower dose than intravenous administration. This work expands the material properties of 3D-printed poly(propylene fumarate-co-propylene succinate) copolyesters and their use in drug delivery applications.

Nanotherapeutic kidney cell-specific targeting to ameliorate acute kidney injury

Acute kidney injury (AKI) increases the risk of in-hospital death, adds to expense of care, and risk of early chronic kidney disease. AKI often follows an acute event such that timely treatment could ameliorate AKI and potentially reduce the risk of additional disease. Despite therapeutic success of dexamethasone in animal models, clinical trials have not demonstrated broad success. To improve the safety and efficacy of dexamethasone for AKI, we developed and characterized a novel, kidney-specific nanoparticle enabling specific within-kidney targeting to proximal tubular epithelial cells provided by the megalin ligand cilastatin. Cilastatin and dexamethasone were complexed to H-Dot nanoparticles, which were constructed from generally recognized as safe components. Cilastatin/Dexamethasone/H-Dot nanotherapeutics were found to be stable at plasma pH and demonstrated salutary release kinetics at urine pH. In vivo, they were specifically biodistributed to the kidney and bladder, with 75% recovery in the urine and with reduced systemic toxicity compared to native dexamethasone. Cilastatin complexation conferred proximal tubular epithelial cell specificity within the kidney in vivo, and enabled dexamethasone delivery to the proximal tubular epithelial cell nucleus in vitro. The Cilastatin/Dexamethasone/H-Dot nanotherapeutic improved kidney function and reduced kidney cellular injury when administered to male C57BL/6 mice in two translational models of AKI (rhabdomyolysis and bilateral ischemia reperfusion). Thus, our design-based targeting and therapeutic loading of a kidney-specific nanoparticle resulted in preservation of the efficacy of dexamethasone, combined with reduced off-target disposition and toxic effects. Hence, our study illustrates a potential strategy to target AKI and other diseases of the kidney.

Design of colon-targeted drug delivery of dexamethasone: Formulation and in vitro characterization of solid dispersions

Colon-targeted drug delivery continues to generate increasing attention for its prospects in treating inflammatory bowel disease (IBD). This study aimed to develop and evaluate colon-targeted solid dispersions of dexamethasone (DEX-SDs) in vitro to reduce its systemic exposure. This would ultimately improve the therapeutic efficacy of DEX while minimizing its adverse effects. Different DEX-SDs formulations were prepared utilizing Eudragit S100 (EU S100) and a combination of hydroxypropyl methyl cellulose (HPMC) and EU S100 to tune its drug release profile suitable for colonic delivery. The fabricated formulations were extensively characterized via Attenuated Total Reflectance – Fourier Transform Infrared Spectroscopy (ATR-FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and polarized light microscopy (PLM). The different characterization techniques strongly suggest preparing solid solution-type solid dispersions of DEX with the other polymers (DEX-SDs). In addition, the in vitro dissolution of DEX-SDs was evaluated using two dissolution media (pH 1.2 and 7.4). The in vitro release of DEX-SDs was low in the acidic media and higher and sustained in the basic medium, leading to the conclusion that the developed DEX-SDs may represent an effective technology can overcome challenges related to poor drug solubility and bioavailability.

Magnetically Controlled Intraocular Delivery of Dexamethasone Using Silica-Coated Magnetic Nanoparticles.

Although the number of patients with eye diseases is increasing, efficient drug delivery to the posterior segment of the eyeball remains challenging. The reasons include the unique anatomy of the eyeball, the blood-aqueous barrier, the blood-retina barrier, and drug elimination via the anterior chamber and uveoscleral routes. Solutions to these obstacles for therapeutic delivery to the posterior segment will increase the efficacy, efficiency, and safety of ophthalmic treatment. Micro/nanorobots are promising tools to deliver therapeutics to the retina under the direction of an external magnetic field. Although many groups have evaluated potential uses of micro/nanorobots in retinal treatment, most experiments have been performed under idealized in vitro laboratory conditions and thus do not fully demonstrate the clinical feasibility of this approach. This study examined the use of magnetic nanoparticles (MNPs) to deliver dexamethasone, a drug widely used in retinal disease treatment. The MNPs allowed sustainable drug release and successful magnetic manipulation inside bovine vitreous humor and the vitreous humor of living rabbits. Therefore, controlled drug distribution via magnetic manipulation of MNPs is a promising strategy for targeted drug delivery to the retina.

Transzonular moxifloxacin and dexamethasone delivery in phacoemulsification: A novel dropless regimen.

To assess the safety and efficacy of transzonular moxifloxacin and dexamethasone versus standard postoperative topical drug regimen in phacoemulsification. Nonrandomized prospective study. The study included 100 eyes of 100 age and gender-matched individuals with senile cataract undergoing routine phacoemulsification. The patients were consecutively divided into transzonular (TZ = 50) and topical (TP = 50) groups. Both the groups were followed up for 4 weeks and assessed for intraocular inflammation, visual acuity, changes in intraocular pressure (IOP), and any adverse events. The grades of inflammation were significantly lower in TZ as compared to the TP group ( P < 0.001). The IOP remained normal and comparable in both the groups. Most of the patients in the two groups attained a visual acuity of 0.2 or better at the end of the follow-up. No adverse effects and increased rate of endophthalmitis were noted in TZ group. A one-time peroperative TZ moxifloxacin and dexamethasone combination is a safe and effective method to control postoperative inflammation after cataract surgery. A word of caution though, due precautions to be exercised to prevent the risk of inflammation and endophthalmitis.

Remote-controlled dexamethasone-duration on eye-surface with a micelle-magnetic nanoparticulate co-delivery system for dry eye disease

Dexamethasone (DEX) is used to treat ocular surface diseases. However, regulating DEX duration in tears while preventing its absorption into the anterior chamber is critical for balancing its therapy effects and the side effects. In this study, a novel magnetic nanoparticle (MNP)-micelle (MC) co-delivery system (MMDS) was developed. The MC moiety in the MMDS served as the carrier for DEX and the MNP part endowed the MMDS with magnetic-responsive properties. To extend its residency, the MMDS was magnetically attracted by an external magnet after instilling, which acted as a precorneal drug-depot enabling a sustainable release of DEX in tears. With combination of magnet treatment, the topical instillation of MMDS@DEX significantly prolonged the DEX-retention in tears and increased the DEX-concentration in the cornea and conjunctiva, as well as concurrently reduced the DEX-level in the aqueous humor, when compared with the commercial DEX eye drop treatment. The combination of MMDS@DEX and magnet treatment exerted significantly better therapeutic effects against DED with smaller side effects than conventional treatments including DEX suspension, commercial DEX eye drops, as well as the MMDS@DEX treatment alone. The present work provided a new method for the effective delivery of DEX to ocular surface tissues while reducing its side effects, which will be beneficial to the treatments of a wide range of ocular surface diseases.

Electrospun composite-coated endotracheal tubes with controlled siRNA and drug delivery to lubricate and minimize upper airway injury

Endotracheal Tubes (ETTs) maintain and secure a patent airway; however, prolonged intubation often results in unintended injury to the mucosal epithelium and inflammatory sequelae which complicate recovery. ETT design and materials used have yet to adapt to address intubation associated complications. In this study, a composite coating of electrospun polycaprolactone (PCL) fibers embedded in a four-arm polyethylene glycol acrylate matrix (4APEGA) is developed to transform the ETT from a mechanical device to a dual-purpose device capable of delivering multiple therapeutics while preserving coating integrity. Further, the composite coating system (PCL-4APEGA) is capable of sustained delivery of dexamethasone from the PCL phase and small interfering RNA (siRNA) containing polyplexes from the 4APEGA phase. The siRNA is released rapidly and targets smad3 for immediate reduction in pro-fibrotic transforming growth factor-beta 1 (TGFϐ1) signaling in the upper airway mucosa as well as suppressing long-term sequelae in inflammation from prolonged intubation. A bioreactor was used to study mucosal adhesion to the composite PCL-4APEGA coated ETTs and investigate continued mucus secretory function in ex vivo epithelial samples. The addition of the 4APEGA coating and siRNA delivery to the dexamethasone delivery was then evaluated in a swine model of intubation injury and observed to restore mechanical function of the vocal folds and maintain epithelial thickness when observed over 14 days of intubation. This study demonstrated that increase in surface lubrication paired with surface stiffness reduction significantly decreased fibrotic behavior while reducing epithelial adhesion and abrasion.

Fmoc-FF hydrogels and nanogels for improved and selective delivery of dexamethasone in leukemic cells and diagnostic applications

Dexamethasone (DEX) is a synthetic analogue of cortisol commonly used for the treatment of different pathological conditions, comprising cancer, ocular disorders, and COVID-19 infection. Its clinical use is hampered by the low solubility and severe side effects due to its systemic administration. The capability of peptide-based nanosystems, like hydrogels (HGs) and nanogels (NGs), to serve as vehicles for the passive targeting of active pharmaceutical ingredients and the selective internalization into leukemic cells has here been demonstrated. Peptide based HGs loaded with DEX were formulated via the “solvent-switch” method, using Fmoc-FF homopeptide as building block. Due to the tight interaction of the drug with the peptidic matrix, a significant stiffening of the gel (G′ = 67.9 kPa) was observed. The corresponding injectable NGs, obtained from the sub-micronization of the HG, in the presence of two stabilizing agents (SPAN®60 and TWEEN®60, 48/52 w/w), were found to be stable up to 90 days, with a mean diameter of 105 nm. NGs do not exhibit hemolytic effects on human serum, moreover they are selectively internalized by RS4;11 leukemic cells over healthy PBMCs, paving the way for the generation of new diagnostic strategies targeting onco-hematological diseases.

An injectable thermosensitive hyaluronic acid/pluronic F-127 hydrogel for deep penetration and combination therapy of frozen shoulder

Frozen shoulder (FS) is a common and progressive shoulder disorder that causes glenohumeral joint stiffness, characterized by inflammation and fibrosis. The treatment options are quite limited, and the therapeutic response is hindered by the fibrous membrane formed by excessive collagen and the rapid removal by synovial fluid. To address these challenges, we designed a hyaluronic acid/Pluronic F-127 (HP)-based injectable thermosensitive hydrogel as a drug carrier loaded with dexamethasone and collagenase (HPDC). We screened for an optimal HP hydrogel that can sustain drug release for approximately 10 days both in vitro and in vivo. In the meanwhile, we found that HP hydrogel could inhibit the proliferation and diminish the adhesion capacity of rat synovial cells induced by transforming growth factor-β1. Furthermore, using an established immobilization rat model of FS, intra-articular injection of HPDC significantly improved joint range of motion compared to medication alone. Relying on sustained drug release, the accumulated collagen fibers were degraded by collagenase to promote the deep delivery of dexamethasone. These findings showed a positive combined treatment effect of HPDC, providing a novel idea for the comprehensive treatment of FS.

Sex-dependent improvement in traumatic brain injury outcomes after liposomal delivery of dexamethasone in mice.

Traumatic brain injury (TBI) can have long-lasting physical, emotional, and cognitive consequences due to the neurodegeneration caused by its robust inflammatory response. Despite advances in rehabilitation care, effective neuroprotective treatments for TBI patients are lacking. Furthermore, current drug delivery methods for TBI treatment are inefficient in targeting inflamed brain areas. To address this issue, we have developed a liposomal nanocarrier (Lipo) encapsulating dexamethasone (Dex), an agonist for the glucocorticoid receptor utilized to alleviate inflammation and swelling in various conditions. In vitro studies show that Lipo-Dex were well tolerated in human and murine neural cells. Lipo-Dex showed significant suppression of inflammatory cytokines, IL-6 and TNF-α, release after induction of neural inflammation with lipopolysaccharide. Further, the Lipo-Dex were administered to young adult male and female C57BL/6 mice immediately after controlled cortical impact injury (a TBI model). Our findings demonstrate that Lipo-Dex can selectively target the injured brain, thereby reducing lesion volume, cell death, astrogliosis, the release of pro-inflammatory cytokines, and microglial activation compared to Lipo-treated mice in a sex-dependent manner, showing a major impact only in male mice. This highlights the importance of considering sex as a crucial variable in developing and evaluating new nano-therapies for brain injury. These results suggest that Lipo-Dex administration may effectively treat acute TBI.

Biosafety and potency of high-molecular-weight hyaluronic acid with intratympanic dexamethasone delivery for acute hearing loss.

Objective: This study evaluated the potential of high-molecular-weight hyaluronic acid (HHA) as an intratympanic (IT) drug delivery vehicle for dexamethasone (D) in treating acute hearing loss. We compared the efficacy, safety, and residence time of HHA to the standard-of-care IT drug delivery method. Methods: Endoscopic examinations were used to track tympanic membrane (TM) healing post-IT injection. Micro-computed tomography (CT) was used to gauge drug/vehicle persistence in the bulla air space. Histological analyses covered the middle ear, TM, and hair cell counts. Auditory brainstem responses (ABR) were used to measure hearing thresholds, while high-performance liquid chromatography (HPLC) was employed to quantify cochlear perilymph dexamethasone concentrations. Results: The HHA + D group had a notably prolonged drug/vehicle residence time in the bulla (41 ± 27days) compared to the saline + D group (1.1 ± 0.3days). Complete TM healing occurred without adverse effects. Histology revealed no significant intergroup differences or adverse outcomes. Hearing recovery trends favored the HHA + D group, with 85.0% of ears showing clinically meaningful improvement. D concentrations in cochlear perilymph were roughly double in the HHA group. Conclusion: HHA is a promising vehicle for IT drug delivery in treating acute hearing loss. It ensures extended residence time, augmented drug concentrations in targeted tissues, and safety. These results highlight the potential for HHA + D to excel beyond existing standard-of-care treatments for acute hearing loss.

Dexamethasone eluting polydopaminated polycaprolactone-poly (lactic-co-glycolic) acid for treatment of tracheal stenosis.

Tracheal stenosis is commonly caused by injury, resulting in inflammation and fibrosis. Inhibiting inflammation and promoting epithelization can reduce recurrence after initial successful treatment of tracheal stenosis. Steroids play an important role in tracheal stenosis management. This study in vitro evaluated effectiveness of a polydopaminated polycaprolactone stent coated with dexamethasone-eluting poly(lactic-co-glycolic) acid microparticles (μPLGA) for tracheal stenosis management. Polydopamination was characterized by Raman spectroscopy and promoted epithelialization while dexamethasone delivery reduced macrophage activity, assessed by individual cell area measurements and immunofluorescent staining for inducible nitric oxide synthase (iNOS). Dexamethasone release was quantified by high-performance liquid chromatography over 30 days. Activation-related increase in cell area and iNOS production by RAW 264.7 were both reduced significantly (p < .05) through dexamethasone release. Epithelial cell spreading was higher on polydopaminated polycaprolactone (PCL) than PCL-alone (p < .05). Force required for stent migration was measured by pullout tests of PCL-μPLGA stents from cadaveric rabbit and porcine tracheas (0.425 ± 0.068 N and 1.082 ± 0.064 N, respectively) were above forces estimated to occur during forced respiration. Biomechanical support provided by stents to prevent airway collapse was assessed by comparing compressive circumferential stiffness, and stiffness of the stent was about 1/10th of the rabbit trachea (0.156 ± 0.023 N/mm vs. 1.420 ± 0.194 N/mm, respectively). A dexamethasone-loaded PCL-μPLGA stent platform can deliver dexamethasone and exhibits sufficient mechanical properties to anchor within the trachea and polydopamination of PCL is conducive to epithelial layer formation. Therefore, a polydopaminated PCL-μPLGA stent is a promising candidate for in vivo evaluation for treatment of tracheal restenosis.

Pulmonary delivery of remdesivir and dexamethasone encapsulated nanostructured lipid carriers for enhanced inflammatory suppression in lung

Pulmonary delivery of remdesivir and dexamethasone encapsulated nanostructured lipid carriers for enhanced inflammatory suppression in lung

Unveiling pro-angiogenesis and drug delivery using dual-bio polymer with bio-ceramic based nanocomposite hydrogels

In regenerative medicine, blood vessel development is of utmost importance as it enables the restoration of blood flow to tissues, and facilitate rapid vascularization in clinical tissue-engineered grafts. Herein, we fabricate the nanocomposite hydrogels from BG (clinophosinaite), alginate, Polyethylene glycol (PEG) and Dexamethasone (DEX) for the dual applications of drug delivery and angiogenesis assay. The hydrogels were fabricated through cross-linking approach and termed as alginate/PEG (A), alginate/PEG/clinophosinaite (AC), and alginate/PEG/clinophosinaite/DEX (ACD) that further subjected to structural characterization, using powder X-ray diffraction, and fourier-transform infrared spectroscopy. Porous nanostructures and sheets were imaged using field emission scanning electron microscopy (FESEM), which aid in nutrient and oxygen transport to support angiogenesis. The nanocomposite hydrogels evidently demonstrated good hemocompatibility and fully hydrophilic (30.20°). By means of liquid displacement technique, the nanocomposite hydrogel achieves 47% of porosity with the compressive strength about 0.04 MPa. In alginate/PEG/clinophosinaite and alginate/PEG/clinophosinaite/DEX systems, water absorption capacity reached 85% in 6 h and maintained 90% retention after 12 h. Further, leachable tests revealed that the hydrogel had not deformed even after 24 h. In vitro drug release studies evidently divulge sustainable delivery of DEX from alginate/PEG/clinophosinaite/DEX hydrogel with superior characteristics for drug release. The angiogenesis assay also evidently revealed that the AC and ACD hydrogels, demonstrated higher angiogenic properties with, promoted blood vessel development.

PEG hydrogel containing dexamethasone-conjugated hyaluronic acid reduces secondary injury and improves motor function in a rat moderate TBI model

Traumatic brain injury (TBI) leads to long-term impairments in motor and cognitive function. TBI initiates a secondary injury cascade including a neuro-inflammatory response that is detrimental to tissue repair and limits recovery. Anti-inflammatory corticosteroids such as dexamethasone can reduce the deleterious effects of secondary injury; but challenges associated with dosing, administration route, and side effects have hindered their clinical application. Previously, we developed a hydrolytically degradable hydrogel (PEG-bis-AA/HA-DXM) composed of poly (ethylene) glycol-bis-(acryloyloxy acetate) (PEG-bis-AA) and dexamethasone-conjugated hyaluronic acid (HA-DXM) for local and sustained dexamethasone delivery. In this study, we evaluated the effect of locally applied PEG-bis-AA/HA-DXM hydrogel on secondary injury and motor function recovery after moderate controlled cortical impact (CCI) TBI. Hydrogel treatment significantly improved motor function evaluated by beam walk and rotarod tests compared to untreated rats over 7 days post-injury (DPI). We also observed that the hydrogel treatment reduced lesion volume, inflammatory response, astrogliosis, apoptosis, and increased neuronal survival compared to untreated rats at 7 DPI. These results suggest that PEG-bis-AA/HA-DXM hydrogels can mitigate secondary injury and promote motor functional recovery following moderate TBI.

Magnetic Nanoemulsions for the Intra-Articular Delivery of Ascorbic Acid and Dexamethasone.

(1) Osteoarthritis (OA) is a progressive joint degenerative disease that currently has no cure. Limitations in the development of innovative disease modifying therapies are related to the complexity of the underlying pathogenic mechanisms. In addition, there is the unmet need for efficient drug delivery methods. Magnetic nanoparticles (MNPs) have been proposed as an efficient modality for the delivery of bioactive molecules within OA joints, limiting the side effects associated with systemic delivery. We previously demonstrated MNP's role in increasing cell proliferation and chondrogenesis. In the design of intra-articular therapies for OA, the combined NE-MNP delivery system could provide increased stability and biological effect. (2) Proprietary Fe3O4 MNPs formulated as oil-in-water (O/W) magneto nanoemulsions (MNEs) containing ascorbic acid and dexamethasone were tested for size, stability, magnetic properties, and in vitro biocompatibility with human primary adipose mesenchymal cells (ADSC), cell mobility, and chondrogenesis. In vivo biocompatibility was tested after systemic administration in mice. (3) We report high MNE colloidal stability, magnetic properties, and excellent in vitro and in vivo biocompatibility. By increasing ADSC migration potential and chondrogenesis, MNE carrying dexamethasone and ascorbic acid could reduce OA symptoms while protecting the cartilage layer.