Local Drug Delivery System Research Articles

Development of Metronidazole-loaded In situ Thermosensitive Hydrogel for Periodontitis Treatment

Periodontal treatment focuses on the thorough removal of specific periodontal pathogens, mainly anaerobic Gram-negative bacteria, by mechanical scaling and root planning. In case the periodontal abscess is detected after treatment, a high dose of antimicrobial agents is commonly applied via oral administration. However, this approach increases the risk of antibiotic resistance and systemic side effects and decreases efficacy. To overcome the aforementioned issues, this study focused on the development of thermosensitive hydrogel to deliver the antibiotic drug metronidazole (MTZ) directly and locally to the oral infection site. The thermosensitive hydrogels were prepared by blending 28% w/v Pluronic F127 with various concentrations of methylcellulose (MC) and silk fibroin (SF). The gel properties, such as sol-gel transition time, viscosity, and gel strength, were investigated. The drug dissolution profiles, together with their theoretical models and gel dissolution characteristics, were also determined. All hydrogel formulations exhibited sol-gel transitions at 37°C within 1 min. An increase in MC content proportionally increased the viscosity but decreased the gel strength of the hydrogel. By contrast, the SF content did not significantly affect the viscosity but increased the gel strength of the hydrogel. The thermosensitive hydrogels also showed prolonged MTZ release characteristics for 10 days in phosphate-buffered saline (PBS) at pH 6.6, which followed the Higuchi diffusion model. Moreover, MTZ-thermosensitive hydrogel exhibited delayed dissolution in PBS at 37°C for more than 9 days. MTZ-thermosensitive hydrogels could be considered a prospective local oral drug delivery system to achieve efficient sustained release and improve the drug pharmacological properties in periodontitis treatment.

Vancomycin Loaded Alginate/Cockle Shell Powder Nanobiocomposite Bone Scaffold for Antibacterial and Drug Release Evaluation

Bacterial infection and biofilm formation is a major concern in orthopaedic implants and bone reconstructive surgery complications that may be addressed with localized drug delivery system. The potential use of a fabricated nanobiocomposite bone scaffold using alginate and nano cockle shell powder for drug release and antibacterial properties was investigated. Vancomycin loaded bone scaffolds were fabricated with 3 and 5 wt% vancomycin, respectively, while a non-drug loaded scaffold was used as controls. The mineralization of the scaffolds using simulated body fluid (SBF) as well as biofilm formation were evaluated using microscopic observations. Drug release study and antimicrobial activity of the eluent from each sampling period was tested for growth inhibition of Staphylococcus aureus and Staphylococcus epidermidis for a period of 21 days. Significant difference of cumulative amount of vancomycin eluted from scaffolds loaded with 5 wt% vancomycin compared to 3 wt% (p<0.05) were noted. Eluent from both groups showed inhibitory effect against bacterial strain tested for 21 days. The findings are further supported with histological observations of reduced biofilm formation by Staphylococcus epidermidis on surface of 5 wt% vancomycin loaded scaffolds compared to control scaffolds. Basic mineralization studies conducted showed no alteration in drug loaded scaffolds characteristics compared to control scaffolds. Findings from this study indicates antibacterial properties can be conferred to the fabricated bone scaffold with successful incorporation of vancomycin with potentials to be used for local drug delivery application.

Development and evaluation of a novel biodegradable implants with excellent inflammatory response suppression effect by hot-melt extrusion

PurposeDexamethasone (Dex) is a widely used drug for the treatment of inflammatory and autoimmune conditions, however, long-term systemic use of Dex is associated with serious adverse effects. The objective of the present study was to develop an implantable device to avoid side effects and realize a controlled release of Dex at the implant site. MethodsHydrophobic Dex was incorporated into biodegradable polyesters derived from PCL and Pluronic® L64 (PCL-Pluronic L64-PCL, PCLC) by hot-melt extrusion (HME) method to prepare Dex/PCLC implantable devices. Drug loading and encapsulation efficiency, a series of physicochemical properties, and in vivo features of the implants were studied. ResultsThe maximum value of the drug loading and encapsulation efficiency for the Dex/PCLC implants were up to 47% and 94%, respectively. Incorporation of Dex resulted in accelerated crystallization of PCLC, decreased the wettability, increased contact angles and viscosity, and accelerated Dex release rate and degradation rate from the implants in vivo. Moreover, Dex/PCLC implants showed excellent biocompatibility. Furthermore, the inflammatory response to the Dex/PCLC implants was less severe than that to the positive control group. ConclusionAll these results suggested that Dex/PCLC implants might be a safe and controlled local drug delivery system with excellent inflammatory response suppression effect.

Biomimetic Polydopamine-Modified Silk Fibroin/Curcumin Nanofibrous Scaffolds for Chemo-photothermal Therapy of Bone Tumor.

The simultaneous therapy of tumor recurrence and bone defects resulting from surgical resection of osteosarcoma is still a challenge in the clinic. Combination therapy based on a localized drug-delivery system shows great promise in the treatment of osteosarcoma. Herein, bifunctional polydopamine (PDA)-modified curcumin (CM)-loaded silk fibroin (SF) composite (SF/CM-PDA) nanofibrous scaffolds, which combined photothermal therapy with chemotherapy to synergistically enhance osteosarcoma therapy, were prepared by PDA coating of the SF/CM nanofibrous scaffolds fabricated by supercritical carbon dioxide (SC-CO2) technology. The PDA coating improved hydrophilicity and mechanical strength of the SF/CM scaffolds. The SF/CM-PDA scaffolds present good photothermal conversion capacity and excellent photostability. The low pH and near-infrared (NIR) irradiation could effectively accelerate release of CM in the SF/CM-PDA scaffolds. The in vitro anticancer results indicated that the biocompatible SF/CM-PDA scaffolds had a long-term, stable, and superior anticancer effect compared to pure CM. Furthermore, the SF/CM-PDA scaffolds significantly increased the growth inhibition of osteosarcoma MG-63 cells under NIR irradiation (808 nm and 1.3 W/cm2). Besides, the SF/CM-PDA scaffolds could enhance osteoblast MC3T3-E1 cell proliferation in vitro when the mass ratio of CM was 0.05–0.5%. This work has therefore demonstrated that the bifunctional SF/CM-PDA scaffolds provide a competitive strategy for local osteosarcoma therapy and bone regeneration.

Synthesis and Characterization of New Biodegradable Injectable Thermosensitive Smart Hydrogels for 5-Fluorouracil Delivery.

In this paper, injectable, thermosensitive smart hydrogel local drug delivery systems (LDDSs) releasing the model antitumour drug 5-fluorouracil (5-FU) were developed. The systems were based on biodegradable triblock copolymers synthesized via ring opening polymerization (ROP) of ε-caprolactone (CL) in the presence of poly(ethylene glycol) (PEG) and zirconium(IV) acetylacetonate (Zr(acac)4), as co-initiator and catalyst, respectively. The structure, molecular weight (Mn) and molecular weight distribution (Đ) of the synthesized materials was studied in detail using nuclear magnetic resonance (NMR) and gel permeation chromatography (GPC) techniques; the optimal synthesis conditions were determined. The structure corresponded well to the theoretical assumptions. The produced hydrogels demonstrated a sharp sol–gel transition at temperature close to physiological value, forming a stable gel with good mechanical properties at 37 °C. The kinetics and mechanism of in vitro 5-FU release were characterized by zero order, first order, Higuchi and Korsmeyer–Peppas mathematical models. The obtained results indicate good release control; the kinetics were generally defined as first order according to the predominant diffusion mechanism; and the total drug release time was approximately 12 h. The copolymers were considered to be biodegradable and non-toxic; the resulting hydrogels appear to be promising as short-term LDDSs, potentially useful in antitumor therapy.

Gingipain-Responsive Thermosensitive Hydrogel Loaded with SDF-1 Facilitates In Situ Periodontal Tissue Regeneration.

Existing local drug delivery systems for periodontitis suffer from poor antibacterial effect and unsatisfied periodontal regeneration. In this study, a smart gingipain-responsive hydrogel (PEGPD@SDF-1) was synthesized as an environmentally sensitive carrier for on-demand drug delivery. The PEGPD@SDF-1 hydrogel was synthesized from polyethylene glycol diacrylate (PEG-DA) based scaffolds, dithiothreitol (DTT), and a novel designed functional peptide module (FPM) via Michael-type addition reaction, and the hydrogel was further loaded with stromal cell derived factor-1 (SDF-1). The FPM exhibiting a structure of anchor peptide-short antimicrobial peptide (SAMP)-anchor peptide could be cleaved by gingipain specifically, and the SAMP was released out of the hydrogel for antibacterial effect in response to gingipain. The hydrogel properties were characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), swelling ratio analysis, degradation evaluation, and release curve description of the SAMP and SDF-1. Results in vitro indicated the PEGPD@SDF-1 hydrogel exhibited preferable biocompatibility and could promote the proliferation, migration, and osteogenic differentiation of periodontal ligament stem cells (PDLSCs). Antibacterial testing demonstrated that the PEGPD@SDF-1 hydrogel released the SAMP stressfully in response to gingipain stimulation, thereby strongly inhibiting the growth of Porphyromonas gingivalis. Furthermore, the study in vivo indicated that the PEGPD@SDF-1 hydrogel inhibited P. gingivalis reproduction, created a low-inflammatory environment, facilitated the recruitment of CD90+/CD34- stromal cells, and induced osteogenesis. Taken together, these results suggest that the gingipain-responsive PEGPD@SDF-1 hydrogel could facilitate in situ periodontal tissue regeneration and is a promising candidate for the on-demand local drug delivery system for periodontitis.

Drug transport kinetics of intravascular triggered drug delivery systems

Intravascular triggered drug delivery systems (IV-DDS) for local drug delivery include various stimuli-responsive nanoparticles that release the associated agent in response to internal (e.g., pH, enzymes) or external stimuli (e.g., temperature, light, ultrasound, electromagnetic fields, X-rays). We developed a computational model to simulate IV-DDS drug delivery, for which we quantified all model parameters in vivo in rodent tumors. The model was validated via quantitative intravital microscopy studies with unencapsulated fluorescent dye, and with two formulations of temperature-sensitive liposomes (slow, and fast release) encapsulating a fluorescent dye as example IV-DDS. Tumor intra- and extravascular dye concentration dynamics were extracted from the intravital microscopy data by quantitative image processing, and were compared to computer model results. Via this computer model we explain IV-DDS delivery kinetics and identify parameters of IV-DDS, of drug, and of target tissue for optimal delivery. Two parameter ratios were identified that exclusively dictate how much drug can be delivered with IV-DDS, indicating the importance of IV-DDS with fast drug release (~sec) and choice of a drug with rapid tissue uptake (i.e., high first-pass extraction fraction). The computational model thus enables engineering of improved future IV-DDS based on tissue parameters that can be quantified by imaging.

Hydrogel-By-Design: Smart Delivery System for Cancer Immunotherapy.

Immunotherapy has emerged as a promising strategy for cancer treatment, in which durable immune responses were generated in patients with malignant tumors. In the past decade, biomaterials have played vital roles as smart drug delivery systems for cancer immunotherapy to achieve both enhanced therapeutic benefits and reduced side effects. Hydrogels as one of the most biocompatible and versatile biomaterials have been widely applied in localized drug delivery systems due to their unique properties, such as loadable, implantable, injectable, degradable and stimulus responsible. Herein, we have briefly summarized the recent advances on hydrogel-by-design delivery systems including the design of hydrogels and their applications for delivering of immunomodulatory molecules (e.g., cytokine, adjuvant, checkpoint inhibitor, antigen), immune cells and environmental regulatory substances in cancer immunotherapy. We have also discussed the challenges and future perspectives of hydrogels in the development of cancer immunotherapy for precision medicine at the end.

Anti-Inflammatory Effect of Very High Dose Local Vessel Wall Statin Administration: Poly(L,L-Lactide) Biodegradable Microspheres with Simvastatin for Drug Delivery System (DDS).

Atherosclerosis involves an ongoing inflammatory response of the vascular endothelium and vessel wall of the aorta and vein. The pleiotropic effects of statins have been well described in many in vitro and in vivo studies, but these effects are difficult to achieve in clinical practice due to the low bioavailability of statins and their first-pass metabolism in the liver. The aim of this study was to test a vessel wall local drug delivery system (DDS) using PLA microstructures loaded with simvastatin. Wistar rats were fed high cholesterol chow as a model. The rat vessels were chemically injured by repeated injections of perivascular paclitaxel and 5-fluorouracil. The vessels were then cultured and treated by the injection of several concentrations of poly(L,L-lactide) microparticles loaded with the high local HMG-CoA inhibitor simvastatin (0.58 mg/kg) concentration (SVPLA). Histopathological examinations of the harvested vessels and vital organs after 24 h, 7 days and 4 weeks were performed. Microcirculation in mice as an additional test was performed to demonstrate the safety of this approach. A single dose of SVPLA microspheres with an average diameter of 6.4 μm and a drug concentration equal to 8.1% of particles limited the inflammatory reaction of the endothelium and vessel wall and had no influence on microcirculation in vivo or in vitro. A potent pleiotropic (anti-inflammatory) effect of simvastatin after local SVPLA administration was observed. Moreover, significant concentrations of free simvastatin were observed in the vessel wall (compared to the maximum serum level). In addition, it appeared that simvastatin, once locally administered as SVPLA particles, exerted potent pleiotropic effects on chemically injured vessels and presented anti-inflammatory action. Presumably, this effect was due to the high local concentrations of simvastatin. No local or systemic side effects were observed. This approach could be useful for local simvastatin DDSs when high, local drug concentrations are difficult to obtain, or systemic side effects are present.

Efficacy of Xanthan-Based Chlorhexidine Gel on the Levels of Interleukin-1β in Chronic Periodontitis: An Interventional Study.

ABSTRACTAims and Objectives:Xanthan-based chlorhexidine gel (Chlosite®) is a local drug delivery system that exposes the sub-gingival bacteria to the effects of chlorhexidine (CHX) for a prolonged time. Hence, the study aimed at evaluating the clinical efficacy of the subgingival application of Chlosite gel as an adjunctive to mechanical scaling and root planing (SRP) and at evaluating the salivary interleukin (IL)-1β level to substantiate the clinical efficacy of xanthan-based CHX gel.Materials and Methods:A total number of 40 patients with chronic periodontitis in the age group of 30–50 years were enrolled in this interventional study. The patients were assigned to group A, in which only SRP was done, and group B, in which SRP along with the subgingival application of Chlosite gel was done. Periodontal parameters and salivary IL-1β level were evaluated, and the data obtained were statistically analyzed by using paired and unpaired “t” tests.Results:The results obtained showed a statistically significant reduction in the mean gingival index (GI), probing pocket depth (PPD), clinical attachment level (CAL), and salivary IL-1β values in both the groups from baseline to 30 days. There was a statistically significant reduction in GI, in group B when compared with group A, after the treatment. Salivary IL-1β value in group B was slightly lower when compared with group A after the treatment, but it was not statistically significant.Conclusions:The xanthan-based CHX gel is therapeutically effective when used as an adjunct to SRP. The study also indicated that salivary IL-1β can be used as a reliable biomarker.

Facile preparation of chitosan-dopamine-inulin aldehyde hydrogel for drug delivery application

Chitosan-based hydrogels are a suitable and versatile system for the design of localized and controlled drug delivery systems. In the current study, a hydrogel based on chitosan (CS), Dopamine (DA), and Inulin aldehyde (IA) was fabricated without the further use of catalyst or initiators. The effect of the IA contents as a crosslinking agent on the properties of the prepared hydrogel was studied. The crosslinking reaction between CS and IA was verified by Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). Various characteristics of the CS/DA/IA hydrogels were further assessed utilizing swelling experiment, in vitro drug release, in vitro cytotoxicity assay. The drug-loaded hydrogels represented the sustained release of Indomethacin according to the in vitro drug release test in acidic (pH = 4), basic (pH = 10) medium as well as physiological condition (pH = 7). Finally, the CS/DA/IA hydrogels exhibited appropriate cytocompatibility against the L-929 fibroblast cell line according to the direct contact MTT assay.

Role of Polymeric Local Drug Delivery in Multimodal Treatment of Malignant Glioma: A Review.

Malignant gliomas (MGs) are the most common and devastating primary brain tumor. At present, surgical interventions, radiotherapy, and chemotherapy are only marginally effective in prolonging the life expectancy of patients with MGs. Inherent heterogeneity, aggressive invasion and infiltration, intact physical barriers, and the numerous mechanisms underlying chemotherapy and radiotherapy resistance contribute to the poor prognosis for patients with MGs. Various studies have investigated methods to overcome these obstacles in MG treatment. In this review, we address difficulties in MG treatment and focus on promising polymeric local drug delivery systems. In contrast to most local delivery systems, which are directly implanted into the residual cavity after intratumoral injection or the surgical removal of a tumor, some rapidly developing and promising nanotechnological methods—including surface-decorated nanoparticles, magnetic nanoparticles, and focused ultrasound assist transport—are administered through (systemic) intravascular injection. We also discuss further synergistic and multimodal strategies for heightening therapeutic efficacy. Finally, we outline the challenges and therapeutic potential of these polymeric drug delivery systems.

EMBR-31. DEVELOPMENT OF INJECTABLE POLYSACCHARIDE HYDROGEL TO ENHANCE DRUG PENETRATION IN PEDIATRIC BRAIN TUMORS

Improving unacceptable low response rates and reducing acute and long-term morbidities remain significant challenges in pediatric neuro-oncology. Chemotherapy is an effective primary or adjuvant treatment for pediatric disease, but current administration approaches hinder the pharmacological activity exerted by chemotherapy treatments. Barriers in the route of drug administration and in the tumor microenvironment limit anticancer drugs from penetrating tissue efficiently and reaching all cancer cells. Strategies have been proposed to overcome these barriers with hope of leading to sustained and elongated drug exposure in solid tumors. However, few methods have been explored to design drug delivery systems to circumvent these barriers with potential to enhance drug penetration and reduce adverse systemic side effects in treating pediatric brain tumors. In this study, we validate an injectable polysaccharide hydrogel capable of releasing drugs locally at tumor site, sustaining drug concentration, and eliciting tumor response. We synthesized a hydrogel with dimethyl sulfoxide (DMSO) incorporating amylopectin, a polysaccharide found in starch, loaded with doxorubicin. We determined the structure of doxorubicin is not altered when released from the hydrogel through characterization of drug-loaded and unloaded hydrogels, suggesting drug is encapsulated in the hydrogel network and is able to maintain structure to induce mechanism of action. We tested sustained release of drug and therapeutic efficacy in vitro with DAOY, a medulloblastoma cell line. Our approach demonstrates that local drug delivery presents potential to enhance drug penetration in pediatric brain tumors by sustaining drug concentration at tumor site for an extended period of time. Local drug delivery systems have been investigated for decades but few have been investigated for treatment of pediatric brain tumors. For researchers, physicians, and clinicians, this research can lead to a greater effort to improve current outcomes of conventional drug treatment and provide an opportunity to address current challenges in pediatric oncology.

Nanogels as a Versatile Drug Delivery System for Brain Cancer.

Chemotherapy and radiation remain as mainstays in the treatment of a variety of cancers globally, yet some therapies exhibit limited specificity and result in harsh side effects in patients. Brain tissue differs from other tissue due to restrictions from the blood–brain barrier, thus systemic treatment options are limited. The focus of this review is on nanogels as local and systemic drug delivery systems in the treatment of brain cancer. Nanogels are a unique local or systemic drug delivery system that is tailorable and consists of a three-dimensional polymeric network formed via physical or chemical assembly. For example, thermosensitive nanogels show promise in their ability to incorporate therapeutic agents in nano-structured matrices, be applied in the forms of sprays or sols to the area from which a tumor has been removed, form adhesive gels to fill the cavity and deliver treatment locally. Their usage does come with complications, such as handling, storage, chemical stability, and degradation. Despite these limitations, the current ongoing development of nanogels allows patient-centered treatment that can be considered as a promising tool for the management of brain cancer.

Preparation and Optimization of Vancomycin hydrochloride Encapsulated Multivesicular Liposomes for Sustained Locoregional Delivery

Introduction: Osteomyelitis is a destructive inflammatory condition of the bone that is usually caused by a wide range of microorganisms especially Staphylococcus aureus. Considering the downsides of systemic antibiotic therapies as well as conventional local drug delivery systems such as using polymethylmethacrylate, this study aimed to develop, characterize and optimize vancomycin hydrochloride loaded multivesicular liposomes (MVLs) as a proper therapeutic option for the treatment of osteomyelitis. Methods and Results: A 23 full factorial design technique was applied to determine the effects of three variables (lipid to drug ratio, triolein content and cholesterol to phospholipid ratio) on the encapsulation efficiency and release profile of vancomycin hydrochloride loaded MVLs to optimize the final formulation. Further characterization was performed on the optimized formula by evaluating the morphology, size and storage stability. The average drug encapsulation efficiency and the mean diameter of the optimized formulation was 54.7 ± 0.3% and 9.019 ± 0.26 µm, respectively with a span value of 0.188. Additionally, the spherical and multivesicular nature of MVLs was visible using optical microscopy (x400). The optimized formula showed an in vitro sustained release characteristic with proper stability and insignificant change in size, morphology and EE% for 30 days at 4°C. Conclusion: This study suggests that vancomycin hydrochloride loaded MVLs might have the potential to be used in the treatment of chronic osteomyelitis as a biocompatible drug carrier with a high antibiotic entrapment capacity as well as controlled drug release.

Research progress of nanomaterials in osteomyelitis treatment

To review the related studies on the application of nanomaterials in the treatment of osteomyelitis, and to provide new ideas for the research and clinical treatment of osteomyelitis. The literature about the treatment of osteomyelitis with nanomaterials at home and abroad in recent years was reviewed and analyzed. At present, surgical treatment and antibiotic application are the main treatment options for osteomyelitis. But there are many defects such as antibiotic resistance, residual bone defect, and low effective concentration of local drugs. The application of nanomaterials can make up for the above defects. In recent years, nanomaterials play an important role in the treatment of osteomyelitis by filling bone defects, establishing local drug delivery system, and self-antibacterial properties. It will provide a new idea and an important research direction for the treatment of osteomyelitis to fully study the related characteristics of nanomaterials and select beneficial materials to make drug delivery system or substitute drugs.

Injectable hydroxypropyl chitin hydrogels embedded with carboxymethyl chitin microspheres prepared via a solvent-free process for drug delivery

Microspheres and injectable hydrogels derived from natural biopolymers have been extensively investigated as controlled local drug delivery systems. In this study, we prepared carboxymethyl chitin microspheres (CMCH-Ms) with a diameter of 10-100 μm through physical crosslinking by increasing temperature in an aqueous two-phase system without using organic solvents, surfactants and crosslinking agents. The stable microspheres keeping spherical shape with porous microstructure in different pH environments were embeded in thermosensitive hydroxypropyl chitin (HPCH) hydrogels. The morphology, gelation rate, swelling, rheological and mechanical properties, in vitro degradation and cytotoxicity, drug loading and drug release of the CMCH-Ms/HPCH gel scaffolds were examined. In vitro degradation and cytotoxicity test indicated that CMCH-Ms/HPCH gel scaffolds were biodegradable and non-cytotoxic. Moreover, no organic solvent was used in the preparation and drug loading process of CMCH-Ms/HPCH gel scaffold. Importantly, less burst drug release and long-term sustained-release from the CMCH-Ms/HPCH composite hydrogel was observed than those from only CMCH-Ms or HPCH hydrogel. Thus, the composite CMCH-Ms/HPCH hydrogel exhibited great potential application for loading different drugs and sustained drug release in controlled local drug delivery systems.

TiO₂-Chitosan Hybrid Materials for Drug Delivery Applications: Conjugation Reaction with a Model Drug and Evaluation of the Functional Properties.

The combination of TiO₂ and chitosan is known to allow the achievement of implantable devices which combines the mechanical properties of TiO₂, with the presence of chitosan, which ensures antibacterial properties combined with an in-situ drug-delivery of biomolecules physisorbed and/or covalently linked to chitosan. In this study, 5-aminofluorescein (5-AF), a derivative of fluorescein containing a primary amino group, has been used as model molecule to simulate a drug. This dye is characterized by low cost and low toxicity, and due to its high molar absorptivity it can easily be detected by means of absorption and emission spectroscopies. The combination of 5-AF and maleic anhydride (MA) with TiO₂-chitosan materials has generated a range of novel hybrid materials tailored to applications in localized stimuli-responsive drug delivery systems. Maleic anhydride has been used as pH sensitive spacer for the covalent functionalization of the TiO₂-chitosan hybrid with MA as linker molecule. This functionalization allowed to obtain a pH-sensitive hybrid material. The efficiency of the functionalization has been verified by means of different physico-chemical characterization techniques. The behaviour of the functionalized materials is related to different parameters, among which the ratio between physisorbed/coordinated and chemisorbed 5-AF and the matrix degradation. Moreover, delivery tests in simulated body solutions at different pH have been performed showing a pH-sensitive drug delivery behaviour and indicating that the release of 5-AF is favoured at basic pH.

Characterization of Gentamicin Impregnated Collagen Scaffolds: In Vitro Elution, Cytocompatibility, and In Vivo Tissue Interface

Infection is a common complication in orthopedic surgery, and it is often challenging to prevent or eliminate bacterial infection. Treatment is complicated by biofilm formation, insufficient antibiotic penetration, and systemic side effects associated with prolonged antibiotic administration. The desire to eliminate bacterial infection while minimizing side effects has inspired the creation of local drug delivery systems for local antibiotic delivery. Challenges accompanying the use of local drug delivery devices include: foreign body reaction, bacterial colonization on the device, and the risk of prolonged subtherapeutic antibiotic release that could promote antimicrobial resistance (AMR). This study aimed to evaluate the antibiotic elution profile and cytocompatibility, in vitro, and the effect of local delivery of high dose gentamicin on the tissue-scaffold interface, in vivo, with a commercially available collagen matrix (Fibro Gide, Geistlich) selected as the drug delivery vehicle. Our hypothesis was that the gentamicin impregnated scaffolds would be cytocompatible, would elute gentamicin with an initial burst release, and that the gentamicin impregnated scaffolds would negatively impact the tissue-scaffold interface in vivo. Cytocompatibility testing was performed using 3T3-E1 murine pre-osteoblast cells, cultured in standard media and media spiked with increasing doses of gentamicin (50mg/mL and 100mg/mL). Results of cell proliferation assays, calcein AM staining, and histology of the in vitro scaffolds indicated that the gentamicin impregnated scaffolds were cytocompatible. In vitro gentamicin elution was characterized by an initial burst release of antibiotic followed by gradual, sustained low-concentration release. In vivo assessment of tissue-scaffold interfaces was performed using a rat mandible defect model. Surgical defects were created unilaterally in the mandible of 12 rats and scaffolds were placed within the defect (n=6, 40mg/kg gentamicin; n=6, native scaffold). Rectal culture swabs were collected throughout the study to evaluate for the development of AMR. Histopathology of the tissue-scaffold interface was performed on mandible defects harvested 28 days after implantation. AMR to gentamicin was not detected at any timepoint. Histopathology results showed no significant difference in tissue integration between the native and gentamicin impregnated groups. Based on the results of this study, the collagen matrix was cytocompatible, capable of eluting gentamicin for a period of 14 days, and local delivery of a high dose of gentamicin did not significantly alter the tissue-scaffold interface. This collagen matrix represents a promising device for utilization in local drug delivery. This model and drug delivery platform may be used for future studies to evaluate various drugs and their effects on infection, AMR, and tissue-scaffold integration.

Mesoporous Silica-Bioglass Composite Pellets as Bone Drug Delivery System with Mineralization Potential.

For decades, local bone drug delivery systems have been investigated in terms of their application in regenerative medicine. Among them, inorganic polymers based on amorphous silica have been widely explored. In this work, we combined two types of amorphous silica: bioglass and doxycycline-loaded mesoporous silica MCM-41 into the form of spherical granules (pellets) as a bifunctional bone drug delivery system. Both types of silica were obtained in a sol-gel method. The drug adsorption onto the MCM-41 was performed via adsorption from concentrated doxycycline hydrochloride solution. Pellets were obtained on a laboratory scale using the wet granulation-extrusion-spheronization method and investigated in terms of physical properties, drug release, antimicrobial activity against Staphylococcus aureus, mineralization properties in simulated body fluid, and cytotoxicity towards human osteoblasts. The obtained pellets were characterized by satisfactory mechanical properties which eliminated the risk of pellets cracking during further investigations. The biphasic drug release from pellets was observed: burst stage (44% of adsorbed drug released within the first day) followed by prolonged release with zero-order kinetics (estimated time of complete drug release was 19 days) with maintained antimicrobial activity. The progressive biomimetic apatite formation on the surface of the pellets was observed. No cytotoxic effect of pellets towards human osteoblasts was noticed.