Formulation of Neem and Echinacea Gel for Oral Health Along With the Evaluation of Antimicrobial, Cytotoxic, Anti-inflammatory, and Free Radical Scavenging Activity: An In Vitro Study.

Background Herbs have been used in medical practice for centuries and continue to play a significant role in modern complementary and alternative medicine. Phytochemicals in these herbs possess strong antioxidant and anti-inflammatory properties, which are beneficial in targeting oral health issues, such as dental plaque, gingivitis, and oral microbial infections. As research progresses, the challenge remains to translate these natural compounds into safe, effective, and accessible treatments for a wide range of diseases. Aim The aim of this research was to formulate the neem and echinacea gel along with the evaluation of antimicrobial, anti-inflammatory, free-radical scavenging activity, and cytotoxic potential. Materials and methods The neem and echinacea gel was prepared using a concentrated powdered mixture of neem and echinacea (5 grams each) to which 100 ml of distilled water was added, and the mixture was boiled for 30 minutes at 60°C. The 10 ml concentrate was mixed with 20 ml of a carbopol and carboxymethyl cellulose (CMC) mixture and mixed thoroughly, which resulted in neem and echinacea gel. Then, the antimicrobial, anti-inflammatory, cytotoxic potential, and free-radical scavenging activity of the gel were evaluated. The data obtained were statistically analyzed with the help of a paired t-test, where a p-value of less than 0.05 was considered statistically significant. Results The antimicrobial assay showed that neem and echinacea gel at the concentration of 100 micrograms showed a greater zone of inhibition against Staphylococcus aureus (3.15 ± 0.26), Streptococcus mutans (2.48 ± 0.45), Enterococcus faecalis (2.89 ± 0.15), and Candida albicans (4.28 ± 0.87). The cytotoxic test revealed that even at an 80 µg concentration of the extract, more than 70% of the nauplii were vital, which indicated that the gel was not cytotoxic. The highest anti-inflammatory activity (78.39 ± 1.82) of the gel was seen at 50 micrograms when compared with diclofenac sodium (73.16 ± 1.80). The free radical scavenging activity showed that the 2,2-diphenyl-1-picrylhydrazyl (DPPH) absorbance of the neem and echinacea extract was highest at 50 micrograms.  Conclusion The combination of neem and echinacea extract-based gel possessed high antimicrobial and anti-inflammatory activity when compared with standard drugs, such as amoxicillin and diclofenac sodium. The antioxidant activity of the gel was equal to butylated hydroxytoluene (BHT), and also the gel has a low cytotoxic potential even at its higher concentrations. Hence, the gel can be used as a natural remedy with minimal side effects, making it a valuable alternative to chemical agents.

Enhancing pancreatic cancer immunotherapy: Leveraging localized delivery strategies through the use of implantable devices and scaffolds.

Pancreatic cancer (PC) remains the predominant type of upper gastrointestinal tract cancer, associated with heightened morbidity and a survival rate below 12%. While immunotherapy has brought about transformative changes in the standards of care for most solid tumors, its application in PC is hindered by the ''cold tumor'' microenvironment, marked by the presence of immunosuppressive cells. Modest response rates in PC are attributed, in part to, the fibrotic stroma that obstructs the delivery of systemic immunotherapy. Furthermore, the occurrence of immune-related adverse events (iRAEs) often necessitates the use of sub-therapeutic doses or treatment discontinuation. In the pursuit of innovative approaches to enhance the effectiveness of immunotherapy for PC, implantable drug delivery devices and scaffolds emerge as promising strategies. These technologies offer the potential for sustained drug delivery directly to the tumor site, overcoming stromal barriers, immunosuppression, T cell exclusion, immunotherapy resistance, optimizing drug dosage, and mitigating systemic toxicity. This review offers a comprehensive exploration of pancreatic ductal adenocarcinoma (PDAC), the most common and aggressive form of PC, accompanied by a critical analysis of the challenges the microenvironment presents to the development of successful combinational immunotherapy approaches. Despite efforts, these approaches have thus far fallen short in enhancing treatment outcomes for PDAC. The review will subsequently delve into the imperative need for refining delivery strategies, providing an examination of past and ongoing studies in the field of localized immunotherapy for PDAC. Addressing these issues will lay the groundwork for the development of effective new therapies, thereby enhancing treatment response, patient survival, and overall quality of life for individuals diagnosed with PDAC.

Programmable Release of Chemotherapeutics from Ferrocene-Based Injectable Hydrogels Slows Melanoma Growth.

Hydrogel-based injectable drug delivery systems provide temporally and spatially controlled drug release with reduced adverse effects on healthy tissues. Therefore, they represent a promising therapeutic option for unresectable solid tumor entities. In this study, a peptide-starPEG/hyaluronic acid-based physical hydrogel is modified with ferrocene to provide a programmable drug release orchestrated by matrix-drug interaction and local reactive oxygen species (ROS). The injectable ROS-responsive hydrogel (hiROSponse) exhibits adequate biocompatibility and biodegradability, which are important for clinical applications. HiROSponse is loaded with the two cytostatic drugs (hiROSponsedox/ptx) doxorubicin (dox) and paclitaxel (ptx). Dox is a hydrophilic compound and its release is mainly controlled by Fickian diffusion, while the hydrophobic interactions between ptx and ferrocene can control its release and thus be regulated by the oxidation of ferrocene to the more hydrophilic state of ferrocenium. In a syngeneic malignant melanoma-bearing mouse model, hiROSponsedox/ptx slows tumor growth without causing adverse side effects and doubles the relative survival probability. Programmable release is further demonstrated in a tumor model with a low physiological ROS level, where dox release, low dose local irradiation, and the resulting ROS-triggered ptx release lead to tumor growth inhibition and increased survival.

Injectable vancomycin-loaded silk fibroin/methylcellulose containing calcium phosphate-based in situ thermosensitive hydrogel for local treatment of osteomyelitis: Fabrication, characterization, and in vitro performance evaluation.

The conventional treatment of osteomyelitis with antibiotic-loaded nondegradable polymethylmethacrylate (ATB-PMMA) beads has certain limitations, including impeded bone reconstruction and the need for secondary surgery. To overcome this challenge, this study aimed to develop and characterize an injectable vancomycin-loaded silk fibroin/methylcellulose containing calcium phosphate-based in situ thermosensitive hydrogel (VC-SF/MC-CAPs). The VC-SF/MC-CAPs solution can be easily administered at room temperature with a low injectability force of ≤30 N and a high vancomycin (VC) content of ~96%. Additionally, at physiological temperature (37 °C), the solution could transform into a rigid hydrogel within 7 minutes. In vitro drug release performed under both physiological (pH 7.4) and infection conditions (pH 4.5) revealed a prolonged release pattern of VC-SF/MC-CAPs following the Peppas-Sahlin kinetic model. In addition, the released VC from VC-SF/MC-CAPs hydrogels exhibited antibacterial activity against Staphylococcus aureus for a period exceeding 35 days, as characterized by the disk diffusion assay. Furthermore, at pH 7.4, the VC-SF/MC-CAPs demonstrated >60% degradation within 35 days. Importantly, when exposed to physiological pH conditions, CAPs are transformed into bioactive hydroxyapatite, which benefits bone formation. Therefore, VC-SF/MC-CAPs showed significant potential as a local drug delivery system for treating osteomyelitis.

Clinical Efficacy of Scaling and Root Planing With Placental Extract Gel Under Magnification in Chronic Periodontitis Patients: A Split-Mouth Study.

Background Chronic localized periodontitis is a prevalent and persistent inflammatory condition in which there is the gradual degradation of the gingiva, periodontal ligament fibers, and alveolar bone loss. The objectives of periodontal therapy encompass not solely the elimination of local factors from the periodontal pocket but also the eradication of the dysbiotic microbial milieu to restore periodontal health. The present study aimed to compare the efficacy of scaling and root planing (SRP) with and without the placement of placental extract gel in the therapeutic management of chronic localized periodontitis under magnification. Materials and methods The present investigation encompassed 40 sites in 20 systemically healthy patients with chronic localized periodontitis. The allocation of the sites was done randomly, resulting in two distinct groups: group I (test site) and group II (control site). Group I was subjected to SRP, followed by the placement of placental extract gel, while group II solely received SRP. Clinical evaluations of pocket probing depth, plaque index, relative attachment level (RAL), gingival index (GI), and bleeding on probing (BoP) were performed at each site at baseline, six weeks, and three months. Results Placental extract gel as an accompaniment to SRP showed significant improvement in clinical parameters like pocket probing depth, RAL, GI, and BoP. Conclusion Placental extract gel may significantly act as a local drug delivery agent in the treatment of localized periodontal pockets.

Clinical and Biochemical Effects of Antioxidant Gel as a Local Drug Delivery Agent in Stage II Grade A Periodontitis Patients: A Prospective Clinical Study.

Background Periodontal tissue breakdown is mainly due to pathogenic bacteria and dysregulated immune response resulting in the production of reactive oxygen species/reactive nitrogen species (ROS/RNS) causing tissue degradation. Scaling and root planing (SRP) is usually done for the management of periodontitis. However, it has been reported that adjuncts like antibiotics, antiseptics, and antioxidants in the form of local drug delivery enhance the outcome of SRP. Aim The present clinical study aims to examine the efficacy of an antioxidant oral gel (Bluem®) as a local drug delivery agent adjunct to SRP in the management of stage II grade A periodontitis in terms of clinical and biochemical parameters. Materials and methods The prospective clinical study was conducted among 40 stage II grade A periodontitis patients. The participants were then divided into two groups: Group 1 (Control)-SRP alone (n=20) and Group 2 (Test)-antioxidant gel (Bluem®) with SRP (n=20). Clinical variables including plaque index (PI), gingival index (GI), probing depth (PD), and clinical attachment level (CAL) were recorded. Saliva (unstimulated) specimens were collected to measure total oxidant status (TOS), total antioxidant capacity (TAOC), and oxidative stress index (OSI). Specimen collection and assessment of clinical variables were done before intervention (baseline) and after three months. SPSS Software (Version 20.0, Armonk, NY, USA: IBM Corp) was used for statistical analysis. Intragroup and intergroup comparisons were done by paired t-test and independent t-test, respectively. A p-value <0.05 indicated that the result was statistically significant. Results On intragroup analysis, both the groups at three months revealed statistically significant improvement of PI, GI, PD, CAL, TOS, TAOC, and OSI (p<0.05) from baseline. Intergroup comparison in the third month showed a statistically significant improvement in favor of Group 2 in terms of all the clinical and biochemical parameters (p<0.05) except for PI (p>0.05). Conclusion The locally delivered antioxidant gel as an adjunct to SRP seems to be effective in reducing oxidative stress and improving the periodontal parameters among stage II grade A periodontitis patients.

TiO2 nanotubes with customized diameters for local drug delivery systems.

In this study, we evaluated the drug release behavior of diameter customized TiO2 nanotube layers fabricated by anodization with various applied voltage sequences: conventional constant applied potentials of 20 V (45 nm) and 60 V (80 nm), a 20/60 V stepped potential (50 nm [two-diameter]), and a 20-60 V swept potential (49 nm [full-tapered]) (values in parentheses indicate the inner tube diameter at the top part of nanotube layers). The structures of the 50 nm (two-diameter) and 49 nm (full-tapered) samples had smaller inner diameters at the top part of nanotube layers than that of the 80 nm sample, while the outer diameters at the bottom part of nanotube layers were almost the same size as the 80 nm sample. The 80 nm sample, which had the largest nanotube diameter and length, exhibited the greatest burst release, followed by the 50 nm (two-diameter), 49 nm (full-tapered), and 45 nm samples. The initial burst released drug amounts and release rates from the 50 nm (two-diameter) and 49 nm (full-tapered) samples were significantly suppressed by the smaller tube top. On the other hand, the largest proportion of the slow released drug amount to the total released drug amount was observed for the 50 nm (two-diameter) sample. Thus, 50 nm (two-diameter) achieved suppressed initial burst release and large storage capacity. Therefore, this study has, for the first time, applied TiO2 nanotube layers with modulated diameters (two-diameter and full-tapered) to the realization of a localized drug delivery system (LDDS) with customized drug release properties.

Sustained delivery of celecoxib from nanoparticles embedded in hydrogel injected into the biopsy cavity to prevent biopsy-induced breast cancer metastasis.

PURPOSE: We have previously reported that protracted Cyclooxygenase-2 (COX-2) activity in bone marrow-derived cells (BMDCs) infiltrating into biopsy wounds adjacent to the biopsy cavity of breast tumors in mice promotes M2-shift of macrophages and pro-metastatic changes in cancer cells, effects which were suppressed by oral administration of COX-2 inhibitors. Thus, local control of COX-2 activity in the biopsy wound may mitigate biopsy-induced pro-metastatic changes. METHODS: A combinatorial delivery system-thermosensitive biodegradable poly(lactic acid) hydrogel (PLA-gel) incorporating celecoxib-encapsulated poly(lactic-co-glycolic acid) nanoparticles (Cx-NP/PLA-gel)-was injected into the biopsy cavity of Py230 murine breast tumors to achieve local control of COX-2 activity in the wound stroma. RESULTS: A single intra-biopsy cavity injection of PLA-gel loaded with rhodamine-encapsulated nanoparticles (NPs) showed sustained local delivery of rhodamine preferentially to infiltrating BMDCs with minimal to no rhodamine uptake by the reticuloendothelial organs in mice. Moreover, significant reductions in M2-like macrophage density, cancer cell epithelial-to-mesenchymal transition, and blood vessel density were observed in response to a single intra-biopsy cavity injection of Cx-NP/PLA-gel compared to PLA-gel loaded with NPs containing no payload. Accordingly, intra-biopsy cavity injection of Cx-NP/PLA-gel led to significantly fewer metastatic cells in the lungs than control-treated mice. CONCLUSION: This study provides evidence for the feasibility of sustained, local delivery of payload preferential to BMDCs in the wound stroma adjacent to the biopsy cavity using a combinatorial delivery system to reduce localized inflammation and effectively mitigate breast cancer cell dissemination.

Mucosa-penetrating liposomes for esophageal local drug delivery.

Local drug delivery to the esophagus is hampered by rapid transit time and poor permeability of the mucosa. If some strategies aimed to improve the residence time have been proposed, non-invasive approaches to increase the drug penetration in the mucosa have not been described so far. Herein, we designed mucosa-penetrating liposomes to favor the penetration and retention of curcumin (CURC) in the esophagus. A novel mucosa penetrating peptide (MPP), SLENKGP, was selected by Phage Display and conjugated to pegylated liposomes at different PEG and MPP's surface densities. Pegylation assured a long residence time of liposomes (at least 30 min) in the esophagus in vivo, but it did not favor the penetration of CURC in the mucosa. MPP-decorated liposomes instead delivered a significant higher amount of CURC in the mucosa compared to naked pegylated liposomes. Confocal microscopy studies showed that naked pegylated liposomes remain confined in the superficial layers of the mucosa whereas MPP-decorated liposomes penetrate the whole epithelium. In vitro, MPP reduced the interaction of PEG with mucin, meanwhile favoring the paracellular penetration of liposomes across epithelial cell multilayers. In conclusion, pegylated liposomes represent a valid approach to target the esophagus and the surface functionalization with MPP enhances their penetration in the mucosa.

Comparative Evaluation of L-PRF and Ofloxacin Incorporated L-PRF as an Adjunctive to SRP-A Split-Mouth Randomized Clinical Trial.

Aim and Objectives: To compare and evaluate the clinical efficacy of "ofloxacin incorporated L-PRF" and "L-PRF alone" when used as an adjuvant to non-surgical periodontal therapy. Materials and Methods: A split-mouth study was conducted in 50 patients diagnosed as chronic periodontitis with pocket depth ≥6 with at least one site in each quadrant. All patients underwent scaling and root planning. Test site received with ofloxacin incorporated L-PRF and control site received L-PRF alone. Clinical parameters pocket depth (PD), plaque index (PI), and gingival bleeding index (GBI) were recorded at baseline and 1 month after scaling and root planning. Results: In total, 100 sites were treated (50 test group and 50 control group) with no uneventful healing effects. Statistically significant decreases in PD (P = .0001 for both test and control groups), PI (P = .001), GBI (P = .001 for both groups), between pre-treatment and 1 month post-treatment were noted in both test and control groups. For intergroup comparisons, there was a statistically significant difference in all clinical indices (P > .005). Conclusion: Use of L-PRF with ofloxacin as an adjuvant to non-surgical periodontal therapy showed better improvements in clinical parameters.

Preparation and Characterization of Ferulic Acid Hydrogel and Its Application as a Local Drug Delivery Agent in Periodontitis.

Introduction Periodontitis, a persistent inflammatory condition, impacts the tissues supporting teeth. Beyond mechanically eradicating the biofilm, additional host-modulating agents can aid in the treatment of periodontitis. Among these, gels are a very popular choice for use in the field of dentistry as these systems boast high biocompatibility and bioadhesiveness. These qualities make them easily administered and fabricated. They are typically placed into the periodontal site via wide-port needle syringes. Many investigations have demonstrated that hydrogels possess the ability for controlled drug release and aid in periodontal wound healing. Hence, this study aimed to develop a ferulic acid hydrogel and assess its effectiveness for managing periodontitis. Materials and methods Ferulic acid hydrogel was prepared followed by haemolysis assay and biocompatibility assay. After the in vitro analysis, a clinical trial was conducted: 20 patients were divided into Group A (comprising patients in whom scaling and root planing (SRP) was done) and Group B (comprising patients in whom SRP along with hydrogel application was done). Each patient's pocket depth (PD), clinical attachment loss (CAL), gingival index (GI), and plaque index (PI) were recorded at baseline and at three months. Intergroup and intragroup comparisons of the parameters were made. Results Ferulic acid hydrogels exhibit a minimal ratio of red blood cell destruction, indicating their low haemolytic activity. Beyond 94 hours, ferulic acid hydrogel demonstrates minimal toxicity towards human fibroblasts, suggesting it has good biocompatibility. When clinical parameters were compared after three months of treatment with SRP alone, significant reductions were observed in all parameters. However, when hydrogel application was done along with SRP, greater reduction was seen in terms of all clinical parameters indicating the efficacy of the ferulic acid hydrogel as an adjunct.  Conclusion Ferulic acid has distinct haemolytic activity as well as good biocompatibility. Its use also led to a considerable reduction in all clinical parameters, necessitating its role as a local drug delivery agent in the treatment of periodontitis.

Evaluation of Clinical Efficacy of 1.2% Rosuvastatin Hydrogel as an Adjunct to Scaling and Root Planing in Generalized Chronic Periodontitis.

Background Periodontitis, characterized by chronic inflammation and tissue destruction, remains a significant public health concern. Conventional treatment like scaling and root planing (SRP) is effective but often augmented with adjunctive therapies to improve outcomes. Local drug delivery (LDD) systems containing pharmacological agents offer targeted treatment with reduced systemic side effects. Rosuvastatin (RSV), known for its anti-inflammatory and tissue regenerative properties, has shown promise in periodontal therapy. This prospective clinical trial assessed the effectiveness of 1.2% RSV hydrogel as an adjunct to SRP in managing generalized chronic periodontitis. Methods Thirty patients were grouped into Group A (SRP alone) and Group B (SRP + 1.2% RSV hydrogel). Clinical measurements, such as the modified sulcular bleeding index (mSBI), probing pocket depth (PPD), and clinical attachment level (CAL), were documented both at the beginning of the study and after three months. Statistical analysis was performed using SPSS software. A p-value of less than 0.05 was considered statistically significant. Results Participants in Group B showed significant improvements in mSBI (from 2.34 ± 0.59 to 1.01 ± 0.29), PPD (from 7.36 ± 1.12 mm to 4.63 ± 0.88 mm), and CAL (from 8.56 ± 1.22 mm to 5.90 ± 1.24 mm) compared to Group A at the three-month follow-up. The mean values of these parameters decreased significantly in both groups from baseline to three months. However, the reductions were more substantial in Group B, indicating the beneficial effect of RSV hydrogel adjunctive therapy. Conclusion The study demonstrates the efficacy of 1.2% RSV hydrogel employed as a localized drug in enhancing the outcomes of SRP for generalized chronic periodontitis. The adjunctive use of RSV hydrogel led to noteworthy enhancements in clinical parameters, highlighting its potential in periodontal therapy.

Intracoronary adenosine compared with adrenaline and verapamil in the treatment of no-reflow phenomenon following primary PCI in STEMI patients.

BACKGROUND: no-reflow can complicate up to 25% of pPCI and is associated with significant morbidity and mortality. We aimed to compare the outcomes of intracoronary epinephrine and verapamil with intracoronary adenosine in the treatment of no-reflow after primary percutaneous coronary intervention (pPCI). METHODS: 108 STEMI patients had no-reflow during pPCI were assigned into four groups. Group 1, in which epinephrine and verapamil were injected through a well-cannulated guiding catheter. Group 2, in which same drugs were injected in the distal coronary bed through a microcatheter or perfusion catheter. Group 3, in which adenosine was injected through a guiding catheter. Group 4, in which adenosine was injected in distal coronary bed. Primary end point was the achievement of TIMI III flow and MBG II or III. Secondary end point was major adverse cardiovascular and cerebrovascular events (MACCEs) during hospital stay. RESULTS: The study groups did not differ in their baseline characteristics. Primary end point was achieved in 15 (27.8%) patients in the guide-delivery arm compared with 34 (63%) patients in the local-delivery arm, p < 0.01. However, the primary end point did not differ between the epinephrine/verapamil group and the adenosine group (27 (50%) vs 22 (40.7%), p = 0.334). The secondary end points were similar between the study groups. CONCLUSION: Local delivery of epinephrine, verapamil and adenosine in the distal coronary bed is more effective in achieving TIMI III flow with MBG II or III compared with their guide-delivery in patients who suffered no-reflow during pPCI. There was no difference between epinephrine/verapamil Vs. adenosine.

Efficacy of Locally Delivered Aloe Vera Hydrogel in Patients With Chronic Periodontitis: A Prospective Clinical Study.

BACKGROUND: Various herbal and natural products have been used for multiple purposes in medicine due to recent interest and advancements in the field of alternative medicine. For the past few millennia, aloe vera has been used as medicine. Its anti-inflammatory and antibacterial properties have been proven to reduce periodontal disease. AIM: In patients with generalised chronic periodontitis, this study examined the impact of aloe vera hydrogel in conjunction with scaling and root planing (SRP). METHODS: Sixty patients with generalised chronic periodontitis were enrolled in this study and split into two groups: Group 1 (control) - SRP alone (n=30) and Group 2 (test) - Aloe vera hydrogel with SRP (n=30). Clinical parameters related to periodontal disease, such as plaque index (PI), clinical attachment level (CAL), and probing depth (PD) were measured at baseline and three months after the procedure, and the results were compared using Statistical Product and Service Solutions (SPSS, version 23.0; IBM SPSS Statistics for Windows, Armonk, NY) software. A p-value of <0.05 indicated that the result was statistically significant. RESULTS: When comparing both groups' third-month periodontal clinical parameters to the baseline, there was a significant improvement (p<0.05). In the third month, the test group showed better improvement in PD and CAL than the control group (p<0.05). CONCLUSION: The combination of SRP and aloe vera hydrogel greatly improved periodontal clinical parameters. However, studies with long-term follow-up assessing the efficacy of other modes of delivering aloe vera and also its effect on microbiological and immunological parameters are warranted in the future to substantiate these findings.

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.

Advances in local drug delivery technologies for improved rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by an inflammatory microenvironment and cartilage erosion within the joint cavity. Currently, antirheumatic agents yield significant outcomes in RA treatment. However, their systemic administration is limited by inadequate drug retention in lesion areas and non-specific tissue distribution, reducing efficacy and increasing risks such as infection due to systemic immunosuppression. Development in local drug delivery technologies, such as nanostructure-based and scaffold-assisted delivery platforms, facilitate enhanced drug accumulation at the target site, controlled drug release, extended duration of the drug action, reduced both dosage and administration frequency, and ultimately improve therapeutic outcomes with minimized damage to healthy tissues. In this review, we introduced pathogenesis and clinically used therapeutic agents for RA, comprehensively summarized locally administered nanostructure-based and scaffold-assisted drug delivery systems, aiming at improving the therapeutic efficiency of RA by alleviating the inflammatory response, preventing bone erosion and promoting cartilage regeneration. In addition, the challenges and future prospects of local delivery for clinical translation in RA are discussed.

Sound Exposure Promotes Intratympanic Drug Delivery to the Inner Ear.

OBJECTIVE: To investigate the impact of sound exposure, with the resultant windows vibration on perilymphatic concentrations following intratympanic (IT) dexamethasone and gentamicin in an animal model. STUDY DESIGN: Animal model blinded study. SETTING: Animal facility of a tertiary medical center. METHODS: Bilateral IT dexamethasone or gentamicin was applied to 15 tested rats. Following injections, each rat was exposed for 3 minutes to free field 30 dB sound pressure level (SPL), 512 vHz noise, with 1 external auditory canal plugged (contralateral control). Following noise exposure, perilymph was obtained from both ears. Drug concentrations were measured using ultrahigh-performance liquid chromatography-mass spectrometer. RESULTS: For dexamethasone, the average (±SD) perilymphatic steroidal concentration was 0.417 µg/mL (±0.549) in the control ears versus 0.487 µg/mL (±0.636) in the sound-exposed ears (P = .008). The average (±SD) gentamicin perilymphatic concentration was 8.628 µg/mL (±2.549) in the sound-exposed ears, compared to 4.930 µg/mL (±0.668) in the contralateral control (nonsound exposed) ears. Sound exposure promoted steroidal and gentamicin diffusion to the inner ear by an averaged (±SD) factor of 1.431 and 1.730 (±0.291 and 0.339), respectively. CONCLUSION: Low-intensity noise (30 dB SPL) was found to enhance dexamethasone phosphate and gentamicin diffusion to the inner ear (by an averaged factor of ∼1.4 and 1.7, respectively) in a murine model.

Enhanced immunomodulation and periodontal regeneration efficacy of subgingivally delivered progranulin-loaded hydrogel as an adjunct to non-surgical treatment for Class II furcation involvement in dogs.

AIM: To evaluate the effect of subgingival delivery of progranulin (PGRN)/gelatin methacryloyl (GelMA) complex as an adjunct to scaling and root planing (SRP) on an experimental periodontitis dog model with Class II furcation involvement (FI). MATERIALS AND METHODS: A Class II FI model was established, and the defects were divided into four treatment groups: (a) no treatment (control); (b) SRP; (c) SRP + GelMA; (d) SRP + PGRN/GelMA. Eight weeks after treatment, periodontal parameters were recorded, gingival crevicular fluid and gingival tissue were collected for ELISA and RT-qPCR, respectively, and mandibular tissue blocks were collected for micro computed tomography (micro-CT) scanning and hematoxylin and eosin (H&E) staining. RESULTS: The SRP + PGRN/GelMA group showed significant improvement in all periodontal parameters compared with those in the other groups. The expression of markers related to M1 macrophage and Th17 cell significantly decreased, and the expression of markers related to M2 macrophage and Treg cell significantly increased in the SRP + PGRN/GelMA group compared with those in the other groups. The volume, quality and area of new bone and the length of new cementum in the root furcation defects of the PGRN/GelMA group were significantly increased compared to those in the other groups. CONCLUSIONS: Subgingival delivery of the PGRN/GelMA complex could be a promising non-surgical adjunctive therapy for anti-inflammation, immunomodulation and periodontal regeneration.

Exploring the vast potentials and probable limitations of novel and nanostructured implantable drug delivery systems for cancer treatment.

Conventional cancer chemotherapy regimens, albeit successful to some extent, suffer from some significant drawbacks, such as high-dose requirements, limited bioavailability, low therapeutic indices, emergence of multiple drug resistance, off-target distribution, and adverse effects. The main goal of developing implantable drug delivery systems (IDDS) is to address these challenges and maintain anti-cancer drugs directly at the intended sites of therapeutic action while minimizing inevitable side effects. IDDS possess numerous advantages over conventional drug delivery, including controlled drug release patterns, one-time drug administration, as well as loading and stabilizing poorly water-soluble chemotherapy drugs. Here, we summarized conventional and novel (three-dimensional (3D) printing and microfluidic) preparation techniques of different IDDS, including nanofibers, films, hydrogels, wafers, sponges, and osmotic pumps. These systems could be designed with high biocompatibility and biodegradability features using a wide variety of natural and synthetic polymers. We also reviewed the published data on these systems in cancer therapy with a particular focus on their release behavior. Various release profiles could be attained in IDDS, which enable predictable, adjustable, and sustained drug releases. Furthermore, multi-step or stimuli-responsive drug release could be obtained in these systems. The studies mentioned in this article have proven the effectiveness of IDDS for treating different cancer types with high prevalence, including breast cancer, and aggressive cancer types, such as glioblastoma and liver cancer. Additionally, the challenges in applying IDDS for efficacious cancer therapy and their potential future developments are also discussed. Considering the high potential of IDDS for further advancements, such as programmable release and degradation features, further clinical trials are needed to ensure their efficiency. The overall goal of this review is to expand our understanding of the behavior of commonly investigated IDDS and to identify the barriers that should be addressed in the pursuit of more efficient therapies for cancer. See also the graphical abstract(Fig. 1).

Lauric acid-based thermosensitive delivery system for the treatment of head and neck squamous cell carcinoma.

Traditional treatments for head and neck squamous cell carcinoma (HNSCC) such as surgery, radiation therapy, and chemotherapy, often have severe side effects. Local delivery of chemotherapeutic agents can be a promising approach to minimise systemic toxicity and improve efficacy. Lauric acid (LA), was explored as a novel injectable thermosensitive drug reservoir as a depot for sustained release of anticancer drugs to treat HNSCC. LA was characterised in terms of melting temperature and gelation time. The efficacy of LA-based drug formulations was tested in vitro in a HNSCC cell line and in vivo in a mouse model of HNSCC. LA was modified to have a melting point of 38.5 °C and a gelation time of 40 s at 37.5 °C, rendering it suitable for injection at body temperature. LA- based doxorubicin (DOXO) formulation showed slow release with a maximum of 18% release after 3 days. The in vitro study showed that LA enhanced the cytotoxic effect of DOXO. LA combined with DOXO prevented tumour progression and LA alone significantly reduced the original tumour volume compared to the untreated control group. These findings confirmed that LA can function as practical carrier for the local delivery of chemotherapeutics and provides a safe and simple strategy for the delivery of hydrophobic anticancer drugs and warrant further testing in clinical trials.