Local Drug Delivery System Research Articles

Preparation and Evaluation of Poloxamer/Carbopol In-Situ Gel Loaded with Quercetin: In-Vitro Drug Release and Cell Viability Study.

Periodontitis is a severe chronic inflammatory disease, whose traditional systemic antimicrobial therapy faces great limitations. In-situ gels provide an effective solution as an emerging local drug delivery system. In this study, the novel thermosensitive poloxamer/carbopol in-situ gels loaded with 20μmol/L quercetin for the treatment of periodontitis were prepared by cold method. Thirteen batches of in-situ gels based on two independent factors (X1: poloxamer 407 and X2: carbopol 934P) were designed and optimized by the statistical method of central composite design (CCD). The transparency, pH, injectability, viscosity, gelation temperature, gelation time, elasticity modulus, degradation rate and in-vitro drug release studies of the batches were evaluated, and the percentage of drug release in the first hour, the time required for 90% drug release, gelation temperature, and gelation time were selected as dependent variables. These two independent factors significantly affected the four dependent variables (p < 0.05). The optimization result displayed that the optimized concentration of poloxamer 407 was 20.84% (w/v), and carbopol 934P was 0.5% (w/v). The optimized formulation showed a clear appearance (++), acceptable injectability (Pass), viscosity(151,798mPas), gelation temperature (36°C), gelation time (213s), preferable cell viability and cell proliferation, conformed to first-order release kinetics, and had a significant antibacterial effect. The article demonstrates the great potential of the quercetin in-situ gel as an effective treatment for periodontitis.

Intranasal liposomal angiotensin-(1-7) administration reduces inflammation and viral load in the lungs during SARS-CoV-2 infection in K18-hACE2 transgenic mice.

To effectively reduce the health impact of coronavirus disease (COVID-19), it is essential to adopt comprehensive strategies to protect individuals from severe acute respiratory syndrome. In that sense, much effort has been devoted to the discovery and repurposing of effective antiviral and anti-inflammatory molecules. The endogenous peptide angiotensin-(1-7) [Ang-(1-7)] has been recently proposed as a promising anti-inflammatory agent to control respiratory infections. Liposomes also emerged as a safe and effective drug carrier system for local drug delivery to the lungs. In this context, the aim of this study was to develop a liposomal formulation of Ang-(1-7) [LAng (1-7)] and investigate its impact on animal survival as well as its antiviral and anti-inflammatory efficacies after intranasal administration in transgenic K18-hACE2 mice infected with SARS-CoV-2. The liposomal formulation was prepared by the ethanol injection method, exhibiting a mean diameter of 100 nm and a polydispersity index of 0.1. Following treatment of infected mice every 12 hours for 5 days, LAng (1-7) extended animal survival compared to the control groups that received either empty liposomes, free Ang-(1-7), or phosphate-buffered saline. Furthermore, the treatment with LAng (1-7) significantly decreased the viral load, as well as IL-6 and tumor necrosis factor levels in the lungs. Conventional treatment with remdesivir by parenteral route used as a positive control promoted similar effects, leading to improved survival rates and reduced viral load in the lungs without significant effects on IL-6 level. In conclusion, liposomal Ang-(1-7) emerges as a promising formulation to improve the treatment and decrease the severity of respiratory infections, such as COVID-19.

A pH-Responsive Ti-Based Local Drug Delivery System for Osteosarcoma Therapy.

Osteosarcoma is one of the major bone cancers, especially for youngsters. The current treatment usually requires systemic chemotherapy and the removal of bone tumors. Titanium (Ti)-based implants can be modified as local drug delivery (LDD) systems for controllable and localized chemotherapeutic drug release. In this work, a pH-responsive Ti-based LDD prototype was designed by introducing polydopamine (PDA) to release doxorubicin (DOX) around osteosarcoma cells with low pH. Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and a contact angle meter were applied for surface characterization. Both direct and indirect cell culture modes were performed for biocompatibility and biofunction assessments. The results indicate that the Ti-based LDD prototype exhibits significant pH-dependent DOX release. The cumulative release can reach up to approximately 40% at pH = 6.0 after 72 h, but only around 20% at pH = 7.4. The Ti-based LDD implant shows good biocompatibility with approximately 93% viability of MC3T3 cells after direct culture in vitro for 24 h. Both direct and indirect culture modes verify the good anti-osteosarcoma function of the LDD implant, which should be attributed to the pH-responsive release of DOX.

IN VIVO APPLICATION OF LOCAL DRUG DELIVERY SYSTEMS AGAINST MEDULLOBLASTOMA GROUP 3 AND ATYPICAL/TERATOID/RHABOID TUMOURS

Abstract AIMS Local drug delivery systems (LDDSs) applied during neurosurgery offer a means of overcoming poor blood brain barrier (BBB) permeability and have been extensively investigated for the treatment of adult gliomas, but to the best of our knowledge, not for the treatment of paediatric cerebellar tumours. Here we report the applicability of an LDDS against medulloblastoma group 3 (MB3) and atypical teratoid/rhaboid tumours (AT/RT), both of which are associated with poor prognoses. METHOD We prepared and characterised an injectable and biodegradable poly(ethyleneglycol)-poly(caprolactone)- poly(ethyleneglycol) (PECE) hydrogel, which has been investigated with an array of therapeutic agents against numerous cancer types. Here, we loaded the PECE hydrogel with chemotherapeutics previously identified as being effective against primary MB3 and AT/RT in vitro, but which do not cross the BBB in vivo, namely CHIR99021, ribavirin and PG545. Biocompatibility and cytotoxicity of drug loaded hydrogels was assessed in vitro. LDDSs safety and efficacy was evaluated using patient derived MB3 and AT/RT intracranial xenograft surgical resection models. RESULTS The hydrogel was both biocompatible and effected cytotoxicity following drug release. In vivo efficacy experiments against MB3 indicated a comparable median survival in treatment arms receiving radiotherapy or CHIR99021 and PG545 loaded LDDS. However, combined radiotherapy and LDDS conferred a significant survival enhancement, including long-term survivors. Against AT/RT, the median survival of arms receiving radiotherapy was comparable to that of the CHIR99021 and ribavirin loaded LDDS, with long-term survivors observed only in the latter arm. CONCLUSION The application of LDDSs against cerebellar brain tumours offers a promising novel therapeutic alternative. For MB3, the combination of radiotherapy and a LDDS significantly enhances survival compared to radiotherapy alone. For AT/RT, the comparable survival of the LDDS and radiotherapy alone is encouraging and indicates the possibility of circumventing radiation-induced adverse effects for young children impacted by this disease.

Enzyme-responsive microgel with controlled drug release, lubrication and adhesion capability for osteoarthritis attenuation

The treatment of osteoarthritis (OA) remains challenging due to the narrow therapeutic window and rapid clearance of therapeutic agents, even with intra-articular administration, resulting in a low treatment index. Recent advancements in local drug delivery systems have yet to overcome the issues of uncontrolled burst release and short retention time, leading to suboptimal OA treatment outcome. Herein, we developed a methacrylate-crosslinking hyaluronic acid (HA) microgel (abbreviated as CXB-HA-CBP) that covalently conjugates the anti-inflammatory drug celecoxib (CXB) via a metalloproteinase-2 (MMP-2)-responsive peptide linker (GGPLGLAGGC) and a collagen II binding peptide (WYRGRLC). The GGPLGLAGGC linker is specifically cleaved by the overexpressed MMP-2 enzyme within the OA joint, enabling the sustained and on-demand release of CXB entity. The synergistic action of CXB and HA effectively inhibited macrophage activation and reduced the production of pro-inflammatory cytokines, protecting chondrocytes from damage. Furthermore, the collagen II peptide introduced on the microgel surface enabled a cartilage-binding function to form an artificial lubrication microgel layer on the cartilage surface to reduce cartilage wear. The CXB-HA-CBP microgel showed an extended retention time of up to 18 days in the affected joint, leading to an effective OA treatment in rats. This sophistically designed microgel, characterized by the prolonged retention time, sustained drug delivery, and enhanced lubrication, presents a promising biomedicine for OA treatment. Statement of SignificanceA new methacrylate-crosslinking hyaluronic acid (HA) microgel, covalently conjugated with the celecoxib (CXB)-GGPLGLAGGC and the collagen II binding peptide (CBP, peptide sequence: WYRGRLC), was developed. The overexpressed MMP-2 in OA joint cleaved the GGPLGLAGGC linker to trigger the CXB moiety release. Besides, the CBP on the surface of microgels enabled a cartilage-attaching ability, resulting in a prolonged retention time and an improved lubrication property in joint. This advanced drug-loading microgel remarkably reduced macrophage activation and pro-inflammation cytokine production, while protecting the chondrocytes via a dual action of CXB and HA. This study demonstrated that the enzyme-responsive drug-loading microgel could serve as an platform to efficiently attenuate osteoarthritis.

Thermosensitive multivesicular liposomal hydrogel: a potential platform for loco-regional drug delivery in the treatment of osteomyelitis caused by antibiotic-resistant biofilm-forming bacteria.

Biofilm-mediated osteomyelitis presents significant therapeutic challenges. Given the limitations of existing osteomyelitis treatment approaches, there is a distinct need to develop a localized drug delivery system that is biocompatible, biodegradable, and capable of controlled antibiotic release. Multivesicular liposomes (MVLs), characterized by their non-concentric vesicular structure, distinct composition, and enhanced stability, serve as the system for a robust sustained-release drug delivery platform. In this study, various hydrogel formulations composed of poloxamer 407 and other hydrogels, incorporating vancomycin hydrochloride (VAN HL)-loaded MVLs (VAN HL-MVLs), were prepared and evaluated. The optimized VAN HL-MVL sol-gel system, consisting of poloxamer 407 and hyaluronic acid, successfully maintained drug release for up to 3 weeks and exhibited shear-thinning behavior at 37°C. While complete drug release from MVLs alone took place in 312 h, the hydrogel formulation extended this release to 504 h. The released drug effectively inhibited the Staphylococcus aureus biofilms growth within 24 h and methicillin-resistant S. aureus biofilms within 72 h. It also eradicated preformed biofilms of S. aureus and methicillin-resistant S. aureus in 96 and 120 h, respectively. This injectable in situ gel system incorporating VAN HL-MVLs holds potential as an alternative to undergoing multiple surgeries for osteomyelitis treatment and warrants further studies.

Hydrogels as a Potential Biomaterial for Multimodal Therapeutic Applications.

Hydrogels, composed of hydrophilic polymer networks, have emerged as versatile materials in biomedical applications due to their high water content, biocompatibility, and tunable properties. They mimic natural tissue environments, enhancing cell viability and function. Hydrogels' tunable physical properties allow for tailored antibacterial biomaterial, wound dressings, cancer treatment, and tissue engineering scaffolds. Their ability to respond to physiological stimuli enables the controlled release of therapeutics, while their porous structure supports nutrient diffusion and waste removal, fostering tissue regeneration and repair. In wound healing, hydrogels provide a moist environment, promote cell migration, and deliver bioactive agents and antibiotics, enhancing the healing process. For cancer therapy, they offer localized drug delivery systems that target tumors, minimizing systemic toxicity and improving therapeutic efficacy. Ocular therapy benefits from hydrogels' capacity to form contact lenses and drug delivery systems that maintain prolonged contact with the eye surface, improving treatment outcomes for various eye diseases. In mucosal delivery, hydrogels facilitate the administration of therapeutics across mucosal barriers, ensuring sustained release and the improved bioavailability of drugs. Tissue regeneration sees hydrogels as scaffolds that mimic the extracellular matrix, supporting cell growth and differentiation for repairing damaged tissues. Similarly, in bone regeneration, hydrogels loaded with growth factors and stem cells promote osteogenesis and accelerate bone healing. This article highlights some of the recent advances in the use of hydrogels for various biomedical applications, driven by their ability to be engineered for specific therapeutic needs and their interactive properties with biological tissues.

Oral Patch/Film for Drug Delivery-Current Status and Future Prospects.

In recent years, there has been extensive research into drug delivery systems aimed at enhancing drug utilization while minimizing drug toxicities. Among these systems, oral patches/films have garnered significant attention due to their convenience, noninvasive administration, ability to bypass hepatic first-pass metabolism, thereby enhancing drug bioavailability, and their potential to ensure good compliance, particularly among special patient populations. In this review, from the perspective of the anatomical characteristics of the oral cavity and the advantages and difficulties of oral drug delivery, we illustrate the design ideas, manufacturing techniques, research methodologies, and the essential attributes of an ideal oral patch/film. Furthermore, the applications of oral patches/films in both localized and systemic drug delivery were discussed. Finally, we offer insights into the future prospects of the oral patch/film, aiming to provide valuable reference for the advancement of oral localized drug delivery systems.

Microneedle patch capable of dual drug release for drug delivery to brain tumors.

Primary brain tumors are mostly managed using surgical resection procedures. Nevertheless, in certain cases, a thin layer of tumors may remain outside of the resection process due to the possibility of permanent injury; these residual tumors expose patients to the risk of tumor recurrence. This study has introduced the use of microneedle patches implanted after surgery with a dual-release mechanism for the administration of doxorubicin. The proposed patches possess the capability to administer drugs directly to the residual tumors and initiate chemotherapy immediately following surgical procedures. Three-dimensional simulation of drug delivery to residual tumors in the brain has been performed based on a finite element method. The impact of four important parameters on drug delivery has been investigated, involving the fraction of drug released in the burst phase, the density of microneedles on the patch, the length of microneedles, and the microvascular density of the tumor. The simulation findings indicate that lowering the fraction of drug released in the initial burst phase reduces the maximum average concentration, but the sustained release that continues for a longer period, increasing the bioavailability of free drug. However, the area under curve (AUC) for different release rates remains unchanged due to the fact that an identical dose of drug is supplied in each instance. By increasing the density of microneedles on the patch, concentration accumulation is provided over an extensive region of tumor, which in turn induces more cancer cell death. A comparative analysis of various lengths reveals that longer microneedles facilitate profound penetration into the tumor layers and present better therapeutic response due to extensive area of the tumor which is exposure to chemotherapeutic drugs. Furthermore, high microvascular density, as a characteristic of the tumor microenvironment, is shown to have a significant impact on the blood microvessels drainage of drugs and consequently lower therapeutic response outcome. Our approach offers a computational framework for creating localized drug delivery systems and addressing the challenges related to residual brain tumors.

Antibacterial Activity of Cissus quadrangularis (Veldt Grape) Against Porphyromonas gingivalis, a Keystone Pathogen in Periodontal Disease: An In Vitro Study.

Porphyromonas gingivalis, a keystone pathogen and one of the primary pathogens responsible for periodontitis, leads to a chronic inflammatory condition that destroys the periodontal tissues and ultimately results in tooth loss. While conventional non-surgical therapy combined with antibiotics and local drug delivery systems are commonly used to treat periodontitis, certain medicinal herbs have also demonstrated efficacy in its prevention. Cissus quadrangularis L. (CQ), a perennial plant from the Vitaceae family, is widely recognized and used as a medicinal herb in many tropical countries, predominantly in India, Sri Lanka, Thailand, Java, West Africa, and the Philippines. The aim of the study was to determine the antibacterial activity of CQ against the periodontal keystone pathogen P. gingivalis. Aqueous and ethanolic extracts of CQ were prepared using a Soxhlet extractor. The antibacterial effectiveness of these extracts against the periodontal pathogen P. gingivalis was evaluated at different concentrations, and the minimal inhibitory concentration (MIC) was determined using broth microdilution. The ethanolic extract of CQ mixed with 10% dimethyl sulfoxide (DMSO) showed higher inhibition compared to the aqueous extract of CQ against P. gingivalis. Our study revealed the potent inhibitory effects of CQ against P. gingivalis. Both aqueous and ethanolic extracts displayed MIC values of 500 µg/mL. Notably, the ethanolic extract of CQ, dissolved in 10% DMSO, demonstrated superior efficacy with a lower IC50 value of 194.36 µg/mL. These findings indicate promising potential for CQ in the management of periodontal disease.

Local delivery of carboplatin-loaded hydrogel and calcium carbonate enables two-stage drug release for limited-dose radiation to eliminate mouse malignant glioma

Postoperative radiotherapy remains the gold standard for malignant glioma treatment. Clinical limitations, including tumor growth between surgery and radiotherapy and the emergence of radioresistance, reduce treatment effectiveness and result in local disease progression. This study aimed to develop a local drug delivery system to inhibit tumor growth before radiotherapy and enhance the subsequent anticancer effects of limited-dose radiotherapy.We developed a compound of carboplatin-loaded hydrogel (CPH) incorporated with carboplatin-loaded calcium carbonate (CPCC) to enable two-stage (peritumoral and intracellular) release of carboplatin to initially inhibit tumor growth and to synergize with limited-dose radiation (10 Gy in a single fraction) to eliminate malignant glioma (ALTS1C1 cells) in a C57BL/6 mouse subcutaneous tumor model.The doses of carboplatin in CPH and CPCC treatments were 150 μL (carboplatin concentration of 5 mg/mL) and 15 mg (carboplatin concentration of 4.1 μg/mg), respectively. Mice receiving the combination of CPH-CPCC treatment and limited-dose radiation exhibited significantly reduced tumor growth volume compared to those receiving double-dose radiation alone. Furthermore, combining CPH-CPCC treatment with limited-dose radiation resulted in significantly longer progression-free survival than combining CPH treatment with limited-dose radiation.Local CPH-CPCC delivery synergized effectively with limited-dose radiation to eliminate mouse glioma, offering a promising solution for overcoming clinical limitations.

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.

X-ray Opaque Polymer Drug-Eluting Beads Loaded with Iodized Oil: Preparation and In Vitro and In Vivo Evaluations.

Drug-eluting microspheres are commonly used as a local drug delivery system for interventional therapy. However, current drug-eluting microspheres have poor X-ray visibility, which can hinder tracking and postembolization evaluation. In the current study, X-ray-visible poly(acrylic acid) drug-eluting beads loaded with iodized oil (IO-PAA-DEBs) ranging from 100-300 μm were prepared and evaluated both in vitro and in vivo. Iodized oil served as the radiopaque agent, and X-ray and computed tomography scanning confirmed that the microspheres exhibited excellent X-ray-visible properties. The drug-loading capacities of bleomycin hydrochloride, doxorubicin hydrochloride, and oxaliplatin were also investigated. IO-PAA-DEBs exhibited sustained drug release properties, accompanied by a cumulative drug release rate that reached approximately 60% after 120 h. In vitro and in vivo experiments revealed that IO-PAA-DEBs had good biocompatibility. Collectively, these results demonstrated that IO-PAA-DEBs could facilitate transarterial embolization and sustained drug delivery.

Fabrication and Characterization of Electrospun Ocimum sanctum and Curcumin-Loaded Nanofiber Membrane for the Management of Periodontal Disease: An In Vitro Study.

Background Periodontal disease is a chronic inflammatory condition that gradually deteriorates the supportive tissues of teeth, eventually leading to tooth loss. Mechanical debridement stands as the gold standard method for treating periodontitis. However, antimicrobial therapy is recommended for optimal results when used alongside mechanical debridement. Numerous studies have investigated local drug delivery as an adjunct to mechanical debridement of affected tooth surfaces. Ocimum sanctum exhibits anti-inflammatory, antioxidant, and antimicrobial properties. Similarly, curcumin, as documented in the literature, demonstrates a broad spectrum of anti-inflammatory and antimicrobial effects. Electrospinning has demonstrated itself to be a highly effective method for fabricating drug-loaded fibers. Electrospun nanofibers containing Ocimum sanctum and curcumin are expected to exhibit greater efficacy due to their increased surface area, facilitating the dispersion of larger quantities of drugs, and their ability to control drug release when employed as a local drug delivery system. This study aims to fabricate and characterize the properties of nanofiber membranes loaded with Ocimum sanctum and curcumin using the electrospinning technique. Methods About 50 mg each of Ocimum sanctum and curcumin were blended with 15% polyvinyl alcohol and 2% chitosan polymer in a 4:1 ratio and left to stir overnight. A 10 mL syringe was filled with this solution, and an 18 G blunt-end needle charged at 15.9 kV was used for extrusion. Continuous fibers were collected onto a collector plate positioned 12 cm from the center of the needle tip, at a flow rate of 0.005 mL/min. The morphology of the fabricated membrane was assessed through scanning electron microscopy (SEM), the strength of the material was assessed through tensile strength analysis using INSTRON, an Electropuls E3000 Universal Testing Machine(INSTRON, Norwood, MA), and the drug release pattern was analyzed using Jasco V-730 UV-visible spectrophotometer(Jasco, Easton, MD). Results The morphology of this nanofiber showed a random distribution of fibers with no bead formation. The average diameter of the membrane was 383±102 nm, and the tensile strength of this material was 1.87 MPa. The drug release pattern showed an initial burst release of Ocimum sanctum, followed by a controlled release in subsequent hours. However, curcumin showed very little drug release because of its solubility. Conclusion In summary, the Ocimum sanctum and curcumin-loaded nanofibers exhibited robust tensile strength, a controlled drug release profile, and uniform drug distribution within the nanofiber membrane. Consequently, it can be concluded that curcumin nanofibers and electrospun Ocimum sanctum serve as valuable agents for local drug delivery in the treatment of periodontitis.

TiO2 nanotubes with customized diameters for local drug delivery systems

AbstractIn 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.

Efficacy of Locally Delivered Herbal Chip Containing (8% Mimusops elengi) as an Adjunct to Scaling and Root Planing in Chronic Periodontitis: A Randomised Split-mouth Clinical Study

Introduction: Conventional mechanical debridement does not remove all pathogenic bacteria from the subgingival environment. To overcome these limitations, local drug delivery systems enhance the curative effect by combining with drugs, which promote bone and tissue regeneration. Thus, this study aims to evaluate the efficacy of locally delivered herbal chips containing (8% Mimusops elengi) as an adjunct to scaling and root planing (SRP) and compared to SRP alone for the treatment of chronic periodontitis. Materials and Methods: A randomised split-mouth clinical study was conducted among chronic periodontitis patients undergoing periodontal therapy. Thirty subjects with 60 sites were divided into test and control groups. The control sites were treated with SRP alone, whereas the test sites were treated with SRP followed by placement of an 8% M. elengi herbal chip within the pockets. Patients were recalled on the 21st and 45th day, and clinical parameters were measured. Results: An inter-group comparison of all the clinical parameters between the control and test sides was statistically analysed. At all periods of the study, the mean difference was observed to be highly significant (P &lt; 0.001). Conclusion: The 8% M. elengi chip is effective as an adjunct to non-surgical periodontal therapy in chronic periodontitis probing depth. Further clinical studies are needed to evaluate the long-term efficacy of M. elengi.

SURG-02. INTRAOPERATIVE APPLICATION OF A POLYMER-BASED HYDROGEL AGAINST MEDULLOBLASTOMA GROUP 3 AND ATYPICAL TERATOID/RHABDOID TUMOURS

Abstract BACKGROUND Local drug delivery systems (LDDSs) applied during neurosurgery offer a means of overcoming poor blood brain barrier (BBB) permeability and have been extensively investigated for the treatment of adult gliomas. To the best of our knowledge, they have not been investigated for the treatment of paediatric cerebellar tumours, including medulloblastoma group 3 (MB3) and atypical teratoid/rhabdoid tumours (ATRT), both of which are associated with poor prognoses. METHODS We prepared and characterised an injectable and biodegradable poly(ethyleneglycol)-poly(caprolactone)-poly(ethyleneglycol) (PECE) hydrogel, which has been investigated broadly throughout the literature with an array of therapeutic agents against numerous cancer types. Here, we loaded the PECE hydrogel with chemotherapeutics previously identified as being effective against primary MB3 and ATRT in vitro, but which do not cross the BBB in vivo, namely CHIR99021, ribavirin and PG545. Biocompatibility and cytotoxicity of drug loaded hydrogels was assessed in vitro. LDDSs safety and efficacy was evaluated using patient derived MB3 and ATRT intracranial xenograft resection models. RESULTS The hydrogel was both biocompatible and effected cytotoxicity following drug release. In vivo efficacy experiments against MB3 indicated a comparable median survival in treatment arms receiving radiotherapy or CHIR99021 and PG545 loaded LDDS. However, combined radiotherapy and LDDS conferred a significant survival enhancement including long-term survivors. Against ATRT, the median survival of arms receiving radiotherapy was comparable to that of the CHIR99021 and ribavirin loaded LDDS, with long-term survivors observed only in the latter arm. CONCLUSIONS The application of LDDSs against cerebellar brain tumours offers a promising novel therapeutic alternative. For MB3, the combination of radiotherapy and a LDDS significantly enhances survival compared to radiotherapy alone. For ATRT, the comparable survival of the LDDS and radiotherapy alone is encouraging and indicates the possibility of circumventing radiation-induced adverse effects for young children impacted by this disease.

Shear stress preconditioning and microbubble flow pattern modulate ultrasound-assisted plasma membrane permeabilization

The recent and exciting success of anti-inflammatory therapies for ischemic heart disease (e.g. atherosclerosis) is hindered by the lack of site-specific and targeted therapeutic deposition. Microbubble-mediated focused ultrasound, which uses circulating, lipid-encapsulated intravascular microbubbles to locally enhance endothelial permeability, offers an exciting approach. Atherosclerotic plaques preferentially develop in regions with disturbed blood flow, and microbubble-endothelial cell membrane interactions under such flow conditions are not well understood. Here, using an acoustically-coupled microscopy system, endothelial cells were sonicated (1 MHz, 20 cycle bursts, 1 ms PRI, 4 s duration, 300 kPa peak-negative pressure) under perfusion with Definity™ bubbles to examine microbubble-mediated endothelial permeabilization under a range of physiological conditions. Endothelial preconditioning under prolonged shear influenced physiology and the secretome, inducing increased expression of pro-angiogenesis analytes, decreasing levels of pro-inflammatory ones, and increasing the susceptibility of ultrasound therapy. Ultrasound treatment efficiency was positively correlated with concentrations of pro-angiogenic cytokines (e.g. VEGF-A, EGF, FGF-2), and negatively correlated with pro-inflammatory chemokines (e.g. MCP-1, GCP-2, SDF-1). Furthermore, ultrasound therapy under non-reversing pulsatile flow (∼4–8 dyne/cm2, 0.5–1 Hz) increased permeabilization up to 2.4-fold compared to shear-matched laminar flow, yet treatment under reversing oscillatory flow resulted in more heterogeneous modulation. This study provides insight into the role of vascular physiology, including endothelial biology, into the design of a localized ultrasound drug delivery system for ischemic heart disease.

Poloxamer 407 modified collagen/β-tricalcium phosphate scaffold for localized delivery of alendronate.

Systemic administration of alendronate is associated with various adverse reactions in clinical settings. To mitigate these side effects, poloxamer 407 (P-407) modified with cellulose was chosen to encapsulate alendronate. This drug-loaded system was then incorporated into a collagen/β-tricalcium phosphate (β-TCP) scaffold to create a localized drug delivery system. Nuclear magnetic resonance spectrum and rheological studies revealed hydrogen bonding between P-407 and cellulose as well as a competitive interaction with water that contributed to the delayed release of alendronate (ALN). Analysis of the degradation kinetics of P-407 and release kinetics of ALN indicated zero-order kinetics for the former and Fickian or quasi-Fickian diffusion for the latter. The addition of cellulose, particularly carboxymethyl cellulose (CMC), inhibited the degradation of P-407 and prolonged the release of ALN. The scaffold's structure increased the contact area of P-407 with the PBS buffer, thereby, influencing the release rate of ALN. Finally, biocompatibility testing demonstrated that the drug delivery system exhibited favorable cytocompatibility and hemocompatibility. Collectively, these findings suggest that the drug delivery system holds promise for implantation and bone healing applications.

Local delivery of methotrexate/glycyrrhizin-loaded hyaluronic acid nanofiber for the management of oral cancer

The challenges in treating oral cancer include the limited effectiveness and systemic side effects of conventional chemotherapy and radiation therapy. Hyaluronic acid (HA) based Glycyrrhizin (GL) and Methotrexate (MT) loaded localized delivery systems, specifically nanofiber (NF) based platforms, were developed to address these challenges. The electrospinning method was used for the successful fabrication of a homogenous NF membrane and characterized for morphology, drug entrapment efficiency, tensile strength, and ex-vivo mucoadhesive study. Also, it was evaluated for in-vitro drug release profile, ex-vivo drug permeability, in-vitro anti-inflammatory, apoptosis assay by MTT and flow, and against specific cell lines in order to determine their potential for therapeutic use. Superior tensile breaking force (50 g), mucoadhesive strength of 153 gm/cm2, drug permeability, and releasing properties of designed NF, making them perfect requirements for oral cavity delivery. The anticancer potential of MT in the MTT assay and flow cytometry analysis was significantly increased in oral epidermal carcinoma cell (KB cell) for drug-loaded NF with 63.97 ± 1.99 % apoptosis, at 24 h. With these incorporated, GL with MT in NF had an anti-inflammatory potential, also demonstrated in-vitro and in-vivo. In the Ehrlich Ascites Carcinoma (EAC) induced mice model, the optimal formulation’s shows better potential for tumor regression when comparing the developed NF formulation to the drugs. Experimental results show that by lowering mucositis-related inflammation and enhancing the effectiveness of oral cancer treatment, a developed nanofiber-based local drug delivery system offers a feasible strategy for managing oral cancer.