Multiple Drug Delivery Research Articles

Biomimetic and temporal-controlled nanocarriers with ileum transporter targeting for achieving oral administration of chemotherapeutic drugs

BackgroundOral chemotherapy is preferred for patients with cancer owing to its multiple advantages, including convenience, better patient compliance, and improved safety. Nevertheless, various physical barriers exist in this route that hamper the development of oral chemotherapeutic formulations, including destruction of drugs in the gastrointestinal tract (GIT), low permeability in enterocytes, and short residence time in the intestine. To overcome these limitations, it is necessary to design an efficient oral drug delivery system with high efficacy and improved safety.ResultsHerein, we designed novel glycocholic acid (GCA)-functionalized double layer nanoparticles (GCA-NPs), which can act via an endogenous pathway and in a temporally controlled manner in the intestine, to enhance the oral bioavailability of hydrophobic chemotherapeutic drugs such as paclitaxel (PTX). GCA-NPs were composed of quercetin (Qu)-modified liposomes (QL) coated with GCA-chitosan oligosaccharide conjugate (GCOS). The GCA-NPs thus prepared showed prolonged intestinal retention time and good GIT stability due to the presence of chitosan oligosaccharide (COS) and enhanced active transportation via intestinal apical sodium-dependent bile acid transporter (ASBT) due to the presence of GCA. GCA-NPs also efficiently inhibited intestinal P-gp induced by Qu. PTX-loaded GCA-NPs (PTX@GCA-NPs) had a particle size of 84 nm and an entrapment efficiency of 98% with good stability. As a result, the oral bioavailability of PTX was increased 19-fold compared to that of oral Taxol® at the same dose. Oral PTX@GCA-NPs displayed superior antitumor efficacy and better safety than Taxol® when administered intravenously.ConclusionsOur novel drug delivery system showed remarkable efficacy in overcoming multiple limitations and is a promising carrier for oral delivery of multiple drugs, which addresses several challenges in oral delivery in the clinical context.Graphical

Three-Dimensional Printing of a Container Tablet: A New Paradigm for Multi-Drug-Containing Bioactive Self-Nanoemulsifying Drug-Delivery Systems (Bio-SNEDDSs).

This research demonstrates the use of fused deposition modeling (FDM) 3D printing to control the delivery of multiple drugs containing bioactive self-nano emulsifying drug-delivery systems (SNEDDSs). Around two-thirds of the new chemical entities being introduced in the market are associated with some inherent issues, such as poor solubility and high lipophilicity. SNEDDSs provide for an innovative and easy way to develop a delivery platform for such drugs. Combining this platform with FDM 3D printing would further aid in developing new strategies for delivering poorly soluble drugs and personalized drug-delivery systems with added therapeutic benefits. This study evaluates the performance of a 3D-printed container system containing curcumin (CUR)- and lansoprazole (LNS)-loaded SNEDDS. The SNEDDS showed 50% antioxidant activity (IC50) at concentrations of around 330.1 µg/mL and 393.3 µg/mL in the DPPH and ABTS radical scavenging assay, respectively. These SNEDDSs were loaded with no degradation and leakage from the 3D-printed container. We were able to delay the release of the SNEDDS from the hollow prints while controlling the print wall thickness to achieve lag phases of 30 min and 60 min before the release from the 0.4 mm and 1 mm wall thicknesses, respectively. Combining these two innovative drug-delivery strategies demonstrates a novel option for tackling the problems associated with multi-drug delivery and delivery of drugs susceptible to degradation in, i.e., gastric pH for targeting disease conditions throughout the gastrointestinal tract (GIT). It is also envisaged that such delivery systems reported herein can be an ideal solution to deliver many challenging molecules, such as biologics, orally or near the target site in the future, thus opening a new paradigm for multi-drug-delivery systems.

LIPID-POLYMER HYBRID NANOCARRIERS AS A NOVEL DRUG DELIVERY PLATFORM

The main aim of my review to discuss the most prominent nanocarrier, “Lipid-Polymer Hybrid Nanoparticle” (LPHNPs) that overcomes the limitation of lipid and polymeric nanoparticles. That consists of polymeric core and lipid outer layer. The polymeric core encapsulates both hydrophilic and hydrophobic drugs and lipid shell provides a coat that gives a barrier to prevent drug leakage and easily penetrate into the skin. The LPHNPs has significant application in drug delivery, drug targeting, cancer treatment, brain drug delivery, multiple drug delivery, delivery of diagnostic imaging agent and Small interfering Ribonucleic acid (siRNA). This session is based on literature information in which LPHNPs were prepared by Two-step and Single-step method. Most of the researcher use the Single-step method by emulsification solvent evaporation and Nanoprecipitation method that are easy to prepare LPHNPs. The Polylactic Glycolic acid (PLGA), Poly € caprolactone, Chitosan, Alginate, Dextron, Sodium Alginate, etc used as polymeric core and Stearic Acid, Palmitic Acid, Cetyl Alcohol, Behenol Alcohol, etc used as lipid core. All results were analyzed by us according to the literature and authors’ expertise. The drug release depends on diffusion processes, followed by erosion, then swelling of the matrix. The lipid shell provides a biocompatible shield that acts as the phospholipid bilayer of skin and easily penetrates into the skin. That also capable to deliver the multidrug and diagnostic imaging agent for the treatment of cancer. The Lipid-Polymer Hybrid Nanoparticles are the most prominent nanocarrier for drug delivery. That is capable to deliver both Hydrophilic and Lipophilic drugs and show high bioavailability.

Design, Physicochemical Characterization, and In Vitro Permeation of Innovative Resatorvid Topical Formulations for Targeted Skin Drug Delivery.

Nonmelanoma skin cancers (NMSCs) are the most common malignancies worldwide and affect more than 5 million people in the United States every year. NMSC is directly linked to the excessive exposure of the skin to solar ultraviolet (UV) rays. The toll-like receptor 4 (TLR4) antagonist, resatorvid (TAK-242), is a novel prototype chemo preventive agent that suppresses the production of inflammation mediators induced by UV exposure. This study aimed to design and develop TAK-242 into topical formulations using FDA-approved excipients, including DermaBaseTM, PENcreamTM, polyethylene glycol (PEG)-400, propylene glycol (PG), carbomer gel, hyaluronic acid (HA) gel, and Pluronic® F-127 poloxamer triblock copolymer gel for the prevention of skin cancer. The physicochemical properties of raw TAK-242, which influence the compatibility and solubility in the selected base materials, were confirmed using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), hot-stage microscopy (HSM), Raman spectroscopy, and attenuated total reflectance Fourier-transform infrared (ATR-FTIR) spectroscopic analysis. The permeation behavior of TAK-242 from the prepared formulations was determined using Strat-M® transdermal diffusion membranes, and 3D cultured primary human-derived epidermal keratinocytes (EpiDermTM). Despite TAK-242′s high molecular weight and hydrophobicity, it can permeate through reconstructed human epidermis from all formulations. The findings, reported for the first time in this study, emphasize the capabilities of the topical application of TAK-242 via these multiple innovative topical drug delivery formulation platforms.

Adsorption of Cisplatin Molecules in Nanoporous Inorganic Materials as Drug Delivery Vehicles

The use of nanoparticles as anticancer cargo systems for drug delivery is a promising modality, as they avoid the known toxicity of anticancer drugs on healthy cells by the delivery of multiple drugs to the target cells. Here, the adsorption behavior of cisplatin drug molecules in two different inorganic materials, silica and metallic gold, is investigated mathematically. The 6–12 Lennard-Jones potential, together with the continuum approximation, is adapted to calculate the molecular interatomic energies between molecules. For each material, the relation between the pore radius ℓ and the minimum energy is determined, and the results indicate that the minimum energy occurs when the radii are ℓ=5.3 and ℓ=4.7 Å for the silica and gold nanopores, respectively. The method is promising for applications in the design of novel nanocapsules for future targeted drug and gene delivery.

Spinal cord injury target-immunotherapy with TNF-α autoregulated and feedback-controlled human umbilical cord mesenchymal stem cell derived exosomes remodelled by CRISPR/Cas9 plasmid

Human umbilical cord mesenchymal stem cell (hucMSC) derived exosomes (EXOs) have been investigated as a new treatment for spinal cord injury (SCI) because of their anti-inflammatory, anti-apoptotic, angiogenesis-promoting, and axonal regeneration properties. The CAQK peptide found in the brains of mice and humans after trauma has recently been found to specifically bind to the injured site after SCI. Thus, we developed a nanocarrier system called EXO-C@P based on hucMSC exosomes remodelled by the CRISPR/Cas9 plasmid to control inflammation and modified by the CAQK peptide. EXO-C@P was shown to effectively accumulate at the injury site and saturate the macrophages to significantly reduce the expression of inflammatory cytokines in a mouse model of SCI. Moreover, EXO-C@P treatment improved the performance of mice in behavioural assessments and upregulated soluble tumour necrosis factor receptor-1 (sTNFR1) in serum and at the trauma site after SCI surgery, but lowered the proportion of iNOS+ cells and the concentration of proinflammatory factors. In conclusion, EXO-C@P provides an effective alternative to multiple topical administration and drug delivery approaches for the treatment of SCI. Statement of significanceSCI is a serious disease characterised by a high incidence, high disability rate, and high medical costs, and has become a global medical problem. Several studies have shown that the inflammatory response is the critical inducer of secondary injury after SCI. The inflammatory cytokine TNF-α is considered to be one of the most significant therapeutic targets for autoimmune diseases. Antibodies targeting TNF-α and sTNFR1 are capable of neutralising free TNF-α. In this study, exosomes in the CRISPR/Cas9 system were used to establish stem cells with an autoregulated and feedback-controlled TNF-α response, with these cells secreting sTNFR1, which neutralised TNF-α and antagonised the inflammation stimulated by TNF-α. Moreover, the plasmid was combined with CAQK, which targeted the injury site and promoted the recovery of SCI function.

Ratiometric co-delivery of doxorubicin and paclitaxel prodrug by remote-loading liposomes for the treatment of triple-negative breast cancer.

Liposomal delivery system that concurrent delivery of multiple drugs can improve efficacy of cancer treatments, yet remain challenging because of differential properties, fairly low loading thresholds of many drugs, and drug burst release. Here, we report a ratiometrically designed liposomal nanoplatform with synergistic efficacy, utilizing remote loading to co-encapsulate ROS-sensitive paclitaxel prodrug (PSN) and doxorubicin (DOX). This novel dual-delivery liposomes possess high two-drug encapsulation efficacy and colloidal stability, resulting in synergistic cytotoxicity, extended blood circulation, favorable biodistribution, always maintain the ratiometrically synergistic drug ratio in vivo, and potent synergistic anticancer activity. Such a combination of PSN and DOX with synergistic effects encapsulated in a safe and effective dual-delivery liposomal nanomedicine may hold promise for the further clinical translation and provides a new strategy for high-efficient combination chemotherapy.

Polymeric Nanoparticles: A Holistic Approach to Combat Tuberculosis

The emergence of multidrug-resistant (MDR) and extremely drug resistant (XDR) forms of pulmonary tuberculosis (TB) remains a major health challenge in this advanced era of health science. The longer therapy and higher dose of anti-tubercular drugs (ATDs) increases the patient incompliance at its peak levels of intolerance as well as toxicity. In the recent decades, nanoparticulate drug delivery has emerged as an excellent venture for the effective treatment of cancer, infectious diseases, brain as well as TB. Currently, encapsulation and conjugation of therapeutics to polymeric nanoparticles (PNPs) is an attractive strategy to enhance the effectivity of chemotherapeutics and minimize the toxic effects associated with ATDs. Various characteristics of nanoparticles (NPs) such as high stability, high loading efficiency, and high carrying capacity gives preference to the NPs over other drug delivery systems. Multiple or dual drug delivery concept is continuously gaining attention as a strict and favourable requirement of anti-TB therapy. The ideal properties of NPs including controlled or sustained drug release from the matrix enhances drug bioavailability with dose reduction and also enhance compliance of TB patients. Natural and synthetic polymers are playing important role in curtailing the side effects of chemotherapeutics. This review extensively highlights the drug delivery approaches of ATDs and emphasized on the importance and application of PNPs to combat TB.

Calixarene-modified albumin for stoichiometric delivery of multiple drugs in combination-chemotherapy.

Rationale: In combination chemotherapy, the molar ratio of drugs is a critical parameter that determines the synergistic effects. However, most co-delivery vectors are incapable of maintaining the optimal molar ratio of drugs throughout the delivery process. Herein, a calixarene-modified albumin (CaMA), which can co-deliver multiple drugs with precise control of the drug ratio, is presented.Methods: CaMA was prepared by chemically conjugating multiple sulfonate azocalix[4]arenes (SAC4A) onto the surface of bovine serum albumin (BSA). The precise drug loading and synchronous drug release were measured using fluorescence spectroscopy. Mouse tumor cell 4T1 and 4T1-bearing mice were used to evaluate the combined effects of mitomycin C (MMC) and doxorubicin (DOX) in vitro and in vivo.Results: With multiple hypoxia-responsive calixarenes conjugated onto a single albumin molecule, CaMA achieved precise drug loading and synchronous release of multiple drugs into the tumor microenvironment. This unique drug loading and release mechanism ensures that CaMA maintains the drug ratio from the initial drug loading to the release site, providing a solid foundation for multi-drug combination therapy with the goal of achieving predictable therapeutic outcomes in vivo. The delivery of the model drug combination MMC and DOX at a prescreened ratio via CaMA achieved significantly enhanced tumor suppression and reduced systemic toxicity.Conclusions: This stoichiometric delivery feature makes CaMA a powerful tool for the development of combination chemotherapy and personalized medications for cancer treatment.

Cascade-Responsive Hierarchical Nanosystems for Multisite Specific Drug Exposure and Boosted Chemoimmunotherapy.

The precise delivery of multiple drugs to their distinct destinations plays a significant role in safe and efficient combination therapy; however, it is highly challenging to simultaneously realize the targets and overcome the intricate biological hindrances using an all-in-one nanosystem. Herein, a cascade-responsive hierarchical nanosystem containing checkpoint inhibitor anti-PD-L1 antibody (αPD-L1) and paclitaxel (PTX) is developed for spatially programed delivery of multiple drugs and simultaneously overcoming biological pathway barriers. The hierarchical nanoparticles (MPH-NP@A) are composed of pH-sensitive hyaluronic acid-acetal-PTX prodrugs (HA-ace-PTX(SH)) chaperoned by αPD-L1 and metalloproteinase-9 (MMP-9)-responsive outer shells, which could be fast cleaved to release αPD-L1 in the tumor microenvironment (TME). The released αPD-L1 sequentially synergizes with PTX released in the cytoplasm for boosted chemoimmunotherapy due to direct killing of PTX and intensified immune responses through immunogenic cell death (ICD) as well as suppression of immune escape by blocking the PD-1/PD-L1 axis. The in vitro and in vivo studies demonstrate that MPH-NP@A evokes distinct ICD, enhanced cytotoxic T lymphocytes infiltration, as well as significant tumor inhibition, thus providing a promising therapeutic nano-platform for safe and efficient combination therapy.

Multiple Stimuli-Responsive MXene-Based Hydrogel as Intelligent Drug Delivery Carriers for Deep Chronic Wound Healing.

Chronic wound healing is an important and basic issue in medical and healthcare fields. Recently, stimuli-responsive hydrogel systems have emerged as promising drug delivery carriers for wound management. However, given to the limited therapeutic outcomes, new hydrogel systems for efficient wound treatment are urgently needed. Here, the development of a 2D MXene-based hydrogel system for highly efficient photo- and magnetic-responsive drug delivery oriented to deep chronic wounds repair is presented. The intelligent responsive MXene-based hydrogel drug delivery system is composed of MXene-wrapped magnetic colloids and poly(N-isopropyl acrylamide)-alginate dual-network hydrogels. It is demonstrated that the MXene-based hydrogel system exhibits multiple response capability and controllable drug delivery ability, which can reduce the toxic side effects of drugs and promote the wound healing process as well. Notably, the practical performance of the MXene-based hydrogel drug delivery system is demonstrated by applying it to the treatment of the full-thickness cutaneous wound and subcutaneous infected wound of the rat model, which indicates the great prospect in clinical wound healing and other related biomedical fields.

Locally Injectable Hydrogels for Tumor Immunotherapy.

Hydrogel-based local delivery systems provide a good delivery platform for cancer immunotherapy. Injectable hydrogels can directly deliver antitumor drugs to the tumor site to reduce systemic toxicity and achieve low-dose amplification immunotherapy. Therefore, it may overcome the problems of low drug utilization rate and the systemic side effects in cancer immunotherapy through systemic immune drugs, and it provides simple operation and little invasion at the same time. This study aimed to review the research progress of injectable hydrogels in tumor immunotherapy in recent years. Moreover, the local delivery of multiple drugs using injectable hydrogels in tumors is introduced to achieve single immunotherapy, combined chemo-immunotherapy, combined radio-immunotherapy, and photo-immunotherapy. Finally, the application of hydrogels in tumor immunotherapy is summarized, and the challenges and prospects for injectable hydrogels in tumor immunotherapy are proposed.

Advanced Nanoengineering Approach for Target-Specific, Spatiotemporal, and Ratiometric Delivery of Gemcitabine-Cisplatin Combination for Improved Therapeutic Outcome in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an intractable malignancy with a dismal survival rate. Recent combination therapies have had a major impact on the improvement of PDAC prognosis. Nevertheless, clinically used combination regimens such as FOLFIRINOX and gemcitabine (Gem)/nab-paclitaxel still face major challenges due to lack of the safe and ratiometric delivery of multiple drugs. Here, a rationally designed mesoporous silica nanoparticle (MSN)-based platform is reported for the target-specific, spatiotemporal, ratiometric, and safe co-delivery of Gem and cisplatin (cisPt). It is shown that systemic administration of the nanoparticles results in synergistic therapeutic outcome in a syngeneic and clinically relevant genetically engineered PDAC mouse model that has rarely been used for the therapeutic evaluation of nanomedicine. This synergism is associated with a strategic engineering approach, in which nanoparticles provide redox-responsive controlled delivery and in situ differential release of Gem/cisPt drugs with the goal of overcoming resistance to Pt-based drugs. The platform is also rendered with additional tumor-specificity via a novel tumor-associated mucin1 (tMUC1)-specific antibody, TAB004. Overall, the platform suppresses tumor growth and eliminates the off-target toxicities of a highly toxic chemotherapy combination.

Anisotropic and Amphiphilic Mesoporous Core-Shell Silica Microparticles Provide Chemically Selective Environments for Simultaneous Delivery of Curcumin and Quercetin.

Porous silica materials are often used for drug delivery. However, systems for simultaneous delivery of multiple drugs are scarce. Here we show that anisotropic and amphiphilic dumbbell core-shell silica microparticles with chemically selective environments can entrap and release two drugs simultaneously. The dumbbells consist of a large dense lobe and a smaller hollow hemisphere. Electron microscopy images show that the shells of both parts have mesoporous channels. In a simple etching process, the properly adjusted stirring speed and the application of ammonium fluoride as etching agent determine the shape and the surface anisotropy of the particles. The surface of the dense lobe and the small hemisphere differ in their zeta potentials consistent with differences in dye and drug entrapment. Confocal Raman microscopy and spectroscopy show that the two polyphenols curcumin (Cur) and quercetin (QT) accumulate in different compartments of the particles. The overall drug entrapment efficiency of Cur plus QT is high for the amphiphilic particles but differs widely between Cur and QT compared to controls of core-shell silica microspheres and uniformly charged dumbbell microparticles. Furthermore, Cur and QT loaded microparticles show different cancer cell inhibitory activities. The highest activity is detected for the dual drug loaded amphiphilic microparticles in comparison to the controls. In the long term, amphiphilic particles may open up new strategies for drug delivery.

A Comparative Study Between Preoperative Subconjunctival Bevacizumab Injection And Postoperative Topical Application In Prevention Of Recurrence After Excision Of Primary Pterygium In Egyptian Patients

Abstract Purpose to compare between recurrence incidence after primary pterygium excision when using preoperative subconjunctival injection of Bevacizumab (Avastin) and using it as a postoperative eye drops. Methods thirty two eyes of thirty patients (two patients had bilateral pterygium) with primary pterygia were clinically examined, classified into 3 groups and operated by simple excision with bare sclera technique. Group 1 included 10 patients received Bevacizumab (Avastin) in the form of eye drops (10 mg/ml) 3 times daily for 6 days postoperative. Group 2 included 10 patients received preoperative Bevacizumab in the form of subconjunctival injection (1.25 mg/0.05ml) single dose 1 week preoperative. Group 3 included 10 patients (12 eyes) 2 patients with bilateral Pterygium didn’t receive any form of Bevacizumab. Postoperative follow up was done clinically and by serial photography at 1 week, 1 month, 3 months and 6 months searching for signs of recurrence and/or complications. Results The results showed different grades of recurrence in 18 eyes of 32.True recurrence was seen in 7 patients of 18 (1 patient in group 1, 2 in group 2 and 4 in group3).Recurrence grades in group 1and 2 who used the Bevacizumab (20%grade II, 50% grade III, and 30% grade IV). Recurrence could be predicted by 100% depending on fibrovascular tissue appearing in the surgical bed at 3 months postoperative (P value 0.038).Preoperative fleshy pterygium has high statistical significance in realation to recurrence(P value = 0.006).Patient’s sex, residence and occupation had no statistically significant value in the process of recurrence (P value > 0.05). Patients with recurrent Pterygia (in group 1&2) had statistically significant changes in the corneal K- readings at 3 months and 6 months.No significant difference in the limbal or central corneal thickness in the operated eye and the other eye (Pvalue > 0.05). Conclusion Bevacizumab (Avastin) is a well tolerated drug with multiple drug delivery methods.The eye drops give better results than the subconjunctival injection.Appearance of fibrovascular tissue in the surgical bed at 3 months predict the recurrence by 100%. Preoperative fleshy pterygia will mostly recur again whatever Bevacizumab form was used .The corneal thickness by anterior segment OCT has no role in prediction or detection of early pterygium recurrence.

Theoretical Formulation Strategies towards Neutralizing Inter-individual Variability Associated with Tacrolimus Immunosuppressant Therapy: A Case Study on Nextgeneration Personalized Medicine.

Individualizing drug therapy and attaining maximum benefits of a drug devoid of adverse reactions is the benefit of personalized medicine. One of the important factors contributing to inter-individual variability is genetic polymorphism. As of now, dose titration is the only followed golden standard for implementing personalized medicine. Converting the genotypic data into an optimized dose has become easier now due to technology development. However, for many drugs, finding an individualized dose may not be successful, which further leads to a trial and error approach. These dose titration strategies are generally followed at the clinical level, and so industrial involvement and further standardizations are not feasible. On the other side, technologically driven pharmaceutical industries have multiple smart drug delivery systems which are underutilized towards personalized medicine. Transdisciplinary research with drug delivery science can additionally support the personalization by converting the traditional concept of "dose titration towards personalization" with novel "dose-cum-dosage form modification towards next-generation personalized medicine"; the latter approach is useful to overcome gene-based inter-individual variability by either blocking, to downregulate, or bypassing the biological protein generated by the polymorphic gene. This article elaborates an advanced approach to implementing personalized medicine with the support of novel drug delivery systems. As a case study, we further reviewed the genetic polymorphisms associated with tacrolimus and customized novel drug delivery systems to overcome these challenges factored towards personalized medicine for better clinical outcomes, thereby paving a new strategy for implementing personalized medicine for all other drug candidates.

Oral delivery of natural active small molecules by polymeric nanoparticles for the treatment of inflammatory bowel diseases.

The incidence of inflammatory bowel disease (IBD) is rapidly rising throughout the world. Although tremendous efforts have been made, limited therapeutics are available for IBD management. Natural active small molecules (NASMs), which are a gift of nature to humanity, have been widely used in the prevention and alleviation of IBD; they have numerous advantageous features, including excellent biocompatibility, pharmacological activity, and mass production potential. Oral route is the most common and acceptable approach for drug administration, but the clinical application of NASMs in IBD treatment via oral route has been seriously restricted by their inherent limitations such as high hydrophobicity, instability, and poor bioavailability. With the development of nanotechnology, polymeric nanoparticles (NPs) have provided a promising platform that can efficiently encapsulate versatile NASMs, overcome multiple drug delivery barriers, and orally deliver the loaded NASMs to targeted tissues or cells while enhancing their stability and bioavailability. Thus, NPs can enhance the preventive and therapeutic effects of NASMs against IBD. Herein, we summarize the recent knowledge about polymeric matrix-based carriers, targeting ligands for drug delivery, and NASMs. We also discuss the current challenges and future developmental directions.

Methods of Topical Administration of Drugs and Biological Active Substances for Dental Implants-A Narrative Review.

Dental implants are, nowadays, established surgical devices for the restoration of lost teeth. Considered as an alternative for traditional prosthetic appliances, dental implants surpass them in reliability and patient feedback. Local drug delivery around the implants promotes osseointegration and reduces peri-implantitis. However, there are currently no methods of a multiple, precise topical administration of drugs to the implant area. Engineering coatings on the implants, drug application on carriers during implantation, or gingival pockets do not meet all requirements of dental surgeons. Therefore, there is a need to create porous implants and other medical devices that will allow a multiple drug delivery at a controlled dose and release profile without traumatic treatment. Due to the growing demand for the use of biologically active agents to support dental implant treatment at its various stages (implant placement, long-term use of dental superstructures, treatment of the peri-implant conditions) and due to the proven effectiveness of the topical application of pharmacological biologically active agents to the implant area, the authors would like to present a review and show the methods and devices that can be used by clinicians for local drug administration to facilitate dental implant treatment. Our review concludes that there is a need for research in the field of inventions such as new medical devices or implants with gradient solid–porous structures. These devices, in the future, will enable to perform repeatable, controllable, atraumatic, and repeatable injections of active factors that may affect the improvement of osteointegration and the longer survival of implants, as well as the treatment of peri-implantitis.

Bimodal neural probe for highly co-localized chemical and electrical monitoring of neural activities in vivo

Investigation of the chemical and electrical signals of cells in vivo is critical for studying functional connectivity and brain diseases. Most previous studies have observed either the electrical signals or the chemical signals of cells because recording electrical signals and neurochemicals are done by fundamentally different methods. Herein, we present a bimodal MEMS neural probe that is monolithically integrated with an array of microelectrodes for recording electrical activity, microfluidic channels for sampling extracellular fluid, and a microfluidic interface chip for multiple drug delivery and sample isolation from the localized region at the cellular level. In this work, we successfully demonstrated the functionality of our probe by monitoring and modulating bimodal (electrical and chemical) neural activities through the delivery of chemicals in a co-localized brain region in vivo. We expect our bimodal probe to provide opportunities for a variety of in-depth studies of brain functions as well as for the investigation of neural circuits related to brain diseases.

Differentiating Co-Delivery of Bisphosphonate and Simvastatin by Self-Healing Hyaluronan Hydrogel Formed by Orthogonal "Clicks": An In-Vitro Assessment.

Due to its unique properties resembling living tissues, hydrogels are attractive carriers for the localized and targeted delivery of various drugs. Drug release kinetics from hydrogels are commonly controlled by network properties and the drug-network interactions. However, and simultaneously, the programmable delivery of multiple drugs with opposing properties (hydrophilicity, molecular weight, etc.) from hydrogels with determined network properties is still challenging. Herein, we describe the preparation of injectable self-healing hyaluronic acid (HA) hydrogels that release hydrophobic simvastatin and hydrophilic aminobisphosphonate (BP) drugs independently in response to acidic and thiol-containing microenvironments, respectively. We apply a prodrug strategy to BP by conjugating it to HA via a self-immolative disulfide linker that is stable in the blood plasma and is cleavable in the cytoplasm. Moreover, we utilize HA-linked BP ligands to reversibly bind Ca2+ ions and form coordination hydrogels. Hydrazone coupling of hydrophobic ligands to HA permits the encapsulation of simvastatin molecules in the resulting amphiphilic HA derivative and the subsequent acid-triggered release of the drug. The conjugation of BP and hydrophobic ligands to HA enables preparation of both bulk self-healing hydrogels and nanogels. Moreover, the developed hydrogel system is shown to be multi-responsive by applying orthogonally cleavable linkers. The presented hydrogel is a potential candidate for the combination treatment of osteoporosis and bone cancers as well as for bone tissue regeneration since it can deliver bone anabolic and anti-catabolic agents in response to bone diseases microenvironments.