Local Drug Delivery Methods Research Articles

Optimizing revision arthroplasty: the role of customized articulating spacers

Introduction The advancement of surgery is set against a backdrop of continuous development and surgical innovations have transformed the way clinical care is delivered. Revision surgery might be required to address complications of primary arthroplasty. The first stage of revision arthroplasty would involve removal of an implant and placement of an antibiotic-impregnated cement spacer to maintain the joint space and stability, prevent soft tissue retraction, provide local antibiotic release and preserve bone tissue for revision implantation at the final stage of revision. Custom-made articulating spacers are a promising tool for optimizing the first stage of revision arthroplasty.The objective was to summarize the current data and present comprehensive information about spacers used in two-stage revision arthroplasty including manufacturing techniques, physical and chemical properties, clinical applications, the possibility of customization within the first stage of revision arthroplasty, current and promising directions for research.Material and methods The original literature search was conducted on key resources including Scientific Electronic Library (www.elibrary.ru), the National Library of Medicine (www.pubmed.org), the Cochraine Library (www.cochranelibrary.com) between 2018 and 2023 using search words and phrases: total arthroplasty, complications, revision arthroplasty, articulating spacer, periprosthetic joint infection, additive manufacturing, 3D printing.Results A comparative analysis of factory supplied, home-made, dynamic and static spacer models showed that the choice of articulating spacers for revision arthroplasty of major joints is of great relevance. Advantages of factory-made spacers include standardized range of sizes, the reliability and availability for medical institutions. They are characterized by limited use in repair of severe bone defects.Discussion Custom-made articulating spacers enable specific tailoring to accommodate individual defects. Despite high expectations from custom-made spacers, development of optimal technologies for rapid prototyping is essential. Investments in research and development in this area have the potential to create innovative solutions that can significantly improve the results of revision arthroplasty.Conclusion The paper explores the importance of systemization of knowledge about spacers and the role of new research in improving the design and functionality. Progress in the field of materials science, additive technologies and a personalized approach to spacer manufacturing can expand possibilities of revision arthroplasty and the effectiveness. Personalized approaches and improved methods of local drug delivery that provide controlled release of antibiotics can improve the results of treatment of periprosthetic joint infections.

Novel Collagen Membrane Formulations with Irinotecan or Minocycline for Potential Application in Brain Cancer.

Our study explores the development of collagen membranes with integrated minocycline or irinotecan, targeting applications in tissue engineering and drug delivery systems. Type I collagen, extracted from bovine skin using advanced fibril-forming technology, was crosslinked with glutaraldehyde to create membranes. These membranes incorporated minocycline, an antibiotic, or irinotecan, a chemotherapeutic agent, in various concentrations. The membranes, varying in drug concentration, were studied by water absorption and enzymatic degradation tests, demonstrating a degree of permeability. We emphasize the advantages of local drug delivery for treating high-grade gliomas, highlighting the targeted approach's efficacy in reducing systemic adverse effects and enhancing drug bioavailability at the tumor site. The utilization of collagen membranes is proposed as a viable method for local drug delivery. Irinotecan's mechanism, a topoisomerase I inhibitor, and minocycline's broad antibacterial spectrum and inhibition of glial cell-induced membrane degradation are discussed. We critically examine the challenges posed by the systemic administration of chemotherapeutic agents, mainly due to the blood-brain barrier's restrictive nature, advocating for local delivery methods as a more effective alternative for glioblastoma treatment. These local delivery strategies, including collagen membranes, are posited as significant advancements in enhancing therapeutic outcomes for glioblastoma patients.

Delivery of Topical Drugs to the Olfactory Cleft

Olfactory dysfunction affects approximately 20% of the population globally, with incidence increasing over the age of 60. The pathophysiology is complex, not yet fully understood, and depends on many factors, including the underlying cause. Despite this, the present literature on olfaction is limited due to significant heterogeneity in methodological approaches. This has resulted in limited effective treatments available for olfactory dysfunction. Medications for olfactory dysfunction can be administered locally (directly to the olfactory epithelium) or systemically (orally or intravenously). Currently, there are various methods for local drug delivery to the olfactory epithelium (nasal drops, nasal sprays, atomisers, pressured meter-dosed inhalers, rinses, and exhalation delivery systems). The aims of this review are to summarise the different methods of drug delivery to the olfactory cleft, evaluate the current literature to assess which method is the most effective in delivering drugs to the olfactory epithelium, and review the medications currently available to treat olfactory dysfunction topically. Going forward, further research is required to better establish effective methods of drug delivery to the olfactory epithelium to treat smell disorders.

Dental Cones: A Novel Stratagem for Dental Drug Delivery

Dental Cones are little pills that are used after tooth extraction to reduce bleeding and halt the formation of germs. They should be made to dissolve or erode during a 20–40-minute period in the presence of a modest volume of serum or fluid. To determine if the local administration into the periodontal pocket could help in boosting medication concentration and reducing systemic adverse effects. d-PTFE membranes, painkillers, mouthwash, sutures, and CT scanners are some of the techniques employed in dental extraction and biomaterial insertion procedures. For this study, 39 Articles in total were included and examined. By having antibacterial, anti-inflammatory, and antioxidant properties, local drug delivery methods can aid in the management of periodontitis.

Comparative Evaluation of Tetracycline Hydrochloride Fiber and Simvastatin Gel as an Adjunct to Scaling and Root Planing in Periodontitis Patients.

Inflammation of oral soft tissues, caused by periodontal disease, results in the loss of attachment to supporting therapy and is a severe threat to dental health. Although there are a number of therapeutic options available, mechanical debridement continues to be the gold standard. Scaling and root planing is the gold standard therapy for periodontitis, but this research aims to examine the efficacy of tetracycline fibers and simvastatin gel as local drug delivery methods. We evaluated 60 sites, splitting them into three groups: 20 sites received just scaling and root planing; 20 sites received scaling and root planing plus simvastatin gel; and 20 sites received scaling and root planing plus tetracycline fibers. Clinical indicators such as the gingival index, the modified sulcular bleeding index, and the probing depth were measured at the start of the study, after one week, after one month, after three months, and after six months. After six months, the simvastatin group reduced the gingival index and modified sulcular bleeding index more than the tetracycline group, whereas the tetracycline group reduced probing depth more than the simvastatin group.

Drug-loaded mucoadhesive microneedle patch for the treatment of oral submucous fibrosis.

Oral submucous fibrosis is a chronic, inflammatory and potentially malignant oral disease. Local delivery of triamcinolone to lesion site is a commonly used therapy. The existing methods for local drug delivery include topical administration and submucosal injection. However, in the wet and dynamic oral microenvironment, these methods have drawbacks such as limited drug delivery efficiency and injection pain. Therefore, it is urgently needed to develop an alternative local drug delivery system with high efficiency and painlessness. Inspired by the structure of band-aid, this study proposed a novel double-layered mucoadhesive microneedle patch for transmucosal drug delivery. The patch consisted of a mucoadhesive silk fibroin/tannic acid top-layer and a silk fibroin microneedle under-layer. When applying the annealing condition for the medium content of β-sheets of silk fibroin, the microneedles in under-layer displayed both superior morphology and mechanical property. The mechanical strength of per needle (0.071N) was sufficient to penetrate the oral mucosa. Sequentially, the gelation efficiency of silk fibroin and tannic acid in top-layer was maximized as the weight ratio of tannic acid to silk fibroin reached 5:1. Moreover, in vitro results demonstrated the double-layered patch possessed undetectable cytotoxicity. The sustained release of triamcinolone was observed from the double-layered patch for at least 7days. Furthermore, compared with other commercial buccal patches, the double-layered patch exhibited an enhanced wet adhesion strength of 37.74kPa. In addition, ex vivo mucosal tissue penetration experiment confirmed that the double-layered patch could reach the lamina propria, ensuring effective drug delivery to the lesion site of oral submucous fibrosis. These results illustrate the promising potential of the drug-loaded mucoadhesive microneedle patch for the treatment of oral submucous fibrosis.

Aqueous dispersions of oxygen nanobubbles for potential application in inhalation therapy

Inhalation is a non-invasive method of local drug delivery to the respiratory system. This study analyzed the potential use of aqueous dispersion of oxygen nanobubbles (ADON) as a drug carrier with the additional function of oxygen supplementation to diseased lungs. The suitability of the membrane-based method of ADON preparation and, next, the stability of ADON properties during storage and after aerosolization in nebulizers of various designs (jet, ultrasonic, and two vibrating mesh devices) was investigated. The increased oxygen content in the aerosol generated in two mesh nebulizers suggests that the proposed concept may be helpful in the oxygen supplementation during drug delivery by aerosol inhalation without using an additional oxygen source. This application can increase the overall effectiveness of lung disease treatment and pulmonary rehabilitation.

Convection-Enhanced Delivery In Silico Study for Brain Cancer Treatment.

Brain cancer therapy remains a formidable challenge in oncology. Convection-enhanced delivery (CED) is an innovative and promising local drug delivery method for the treatment of brain cancer, overcoming the challenges of the systemic delivery of drugs to the brain. To improve our understanding about CED efficacy and drug transport, we present an in silico methodology for brain cancer CED treatment simulation. To achieve this, a three-dimensional finite element formulation is utilized which employs a brain model representation from clinical imaging data and is used to predict the drug deposition in CED regimes. The model encompasses biofluid dynamics and the transport of drugs in the brain parenchyma. Drug distribution is studied under various patho-physiological conditions of the tumor, in terms of tumor vessel wall pore size and tumor tissue hydraulic conductivity as well as for drugs of various sizes, spanning from small molecules to nanoparticles. Through a parametric study, our contribution reports the impact of the size of the vascular wall pores and that of the therapeutic agent on drug distribution during and after CED. The in silico findings provide useful insights of the spatio-temporal distribution and average drug concentration in the tumor towards an effective treatment of brain cancer.

Local Drug Delivery Strategies for Glioblastoma Treatment.

Glioblastoma multiforme (GBM) is a brain tumor notorious for its malignancy. The key reason for the limited efficacy of standard treatment is the high recurrence rate of GBM, even after surgical resection. Hence, intensive postsurgical chemical therapies, such as the systemic delivery of various drugs and/or drug combinations, are typically followed after surgery. However, overcoming the blood-brain barrier by systemic administration to efficiently deliver drugs to the brain tumor remains a daunting goal. Therefore, various local drug delivery methods showing potential for improved therapeutic efficacy have been proposed. In particular, the recent application of electronic devices for the controlled delivery of chemotherapy drugs to GBM tissue has attracted attention. We herein review the recent progress of local drug delivery strategies, including electronics-assisted strategies, at the research and commercial level. We also present a brief discussion of the unsolved challenges and future research direction of localized chemotherapy methods for GBM.

Modulating surface charge of dexamethasone non-spherical microcrystals for improved inner ear delivery

It is important to achieve precise surface charge manipulation of non-spherical drug microcrystals using facile and time-efficient methods for local drug delivery. In this study, silk-coated dexamethasone (DEX) non-spherical microcrystals were synthesized by precipitation technique followed by alternate deposition of poly(allylamine hydrochloride) (PAH) (or PAH-coated Fe3O4) and silk fibroin (SF) via layer-by-layer assembly. EDC and glutaraldehyde were employed to manipulate positive or negative charge of particles by simple chemical cross-linking reactions, respectively. In vivo assessment was carried out by intratympanic (IT) injection of DEX non-spherical microcrystals in guinea pigs. In vivo pharmacokinetic results demonstrate that negatively charged DEX microcrystals appeared to improve outcomes of inner ear delivery in comparison to positively-charged counterparts. This is partly because of the adhesive features of the SF. The present study may provide new ideas to construct surface charge-tunable drug delivery vehicles that are capable of crossing biological barriers, especially for inner ear delivery due to the simple and practical strategy.

Path planning of surgical needle: A new adaptive intelligent particle swarm optimization method

Percutaneous puncture interventional therapy is an important method for pathological examination, local anesthesia, and local drug delivery in modern clinics. Due to the existence of complex obstacles such as nerves, arteries, bones and so on in the puncture path, it is a challenging work to design the optimal path for surgical needle. In this paper, we propose a new path planning method based on the adaptive intelligent particle swarm optimization (PSO) algorithm with parameter adjustment mechanism. First, force and motion analysis are carried out on the bevel-tip flexible needle after piercing into human tissues, the motion model of the needle and the spatial transformation model of puncture route in three-dimensional space are obtained, respectively. Then, a multi-objective function is established, which includes puncture path length function, puncture error function and collision detection function. Finally, the optimal puncture path is obtained based on the adaptive intelligent PSO algorithm. The simulation results show that the newly proposed path planning method has higher efficiency, better adaptability to complex environments and higher accuracy than other path planning methods in literature.

Strontium ranelate-laden near-infrared photothermal-inspired methylcellulose hydrogel for arthritis treatment

Rheumatoid arthritis (RA) is of foremost concern among long-term autoimmune disorders, as it leads to inflammation, exudates, chondral degeneration, and painful joints. Because RA severity often fluctuates over time, a local drug delivery method that titrates release of therapeutics to arthritis bioactivity should represent a promising paradigm of RA therapy. Given the local nature of RA chronic illnesses, polysaccharide-drug delivering systems have the promise to augment therapeutic outcomes by offering controlled release of bioactive materials, diminishing the required frequency of administration, and preserving therapeutic levels in affected pathological regions. Herein, an intra-articular photothermal-laden injectable methylcellulose (MC) polymeric hydrogel carrier incorporating strontium ranelate (SrR) and sodium chloride was investigated to resolve these issues. Physicochemical and cellular characteristics of the MC carrier system were thoroughly evaluated. The slow release of SrR, enhancement of the material mechanical strength, and the potential of the non-invasive near-infrared photothermal gel to improve blood circulation and suppress inflammation in a mini-surgical model of RA were examined. Biocompatibility and suppression of intracellular ROS-induced inflammation were observed. This multifunctional photothermal MC hydrogel carrier is anticipated to be an alternative approach for future orthopedic disease treatment.

Molecular Screening Strategy to Identify a Non-invasive Delivery Mechanism for the Treatment of Middle Ear Disorders.

Middle ear ailments include a broad range of pathological conditions. Otitis media is the leading middle ear disease of childhood, which incurs significant health care resources in developed countries and, in developing countries, causes significant mortality and morbidity. Recurrent and chronic infections of the middle ear lead to the prolonged presence of inflammatory factors and cellular infiltrates resulting in temporary hearing loss. However, long-term alteration of the middle ear space can pose the risk of permanent damage to the delicate ear structures and cause tissue remodeling. While the etiopathogenesis of middle ear diseases is multifactorial, targeting the biological mechanisms and molecular networks that drive disease development is critical. Yet, a pivotal step in realizing the potential of molecular therapies is the development of methods for local drug delivery, since systemic application risks side effects. Utilizing bacteriophage display in the rat, we discovered rare peptides that are able to transit the intact tympanic membrane from the external canal to the middle ear cavity by an active process. An in vitro assay demonstrated that transport occurs across the tympanic membranes of humans and that the peptides cross the membrane independent of phage. Transport of phage, which is ~900 nm in length, suggests that these peptides could non-invasively deliver drug packages or gene therapy vectors into the middle ear.

A porous collagen-based hydrogel and implantation method for corneal stromal regeneration and sustained local drug delivery

Biomaterials designed to replace the diseased cornea could be used to treat corneal blindness where human donor tissue is in short supply, but challenges are the integration of biomaterials with host tissue and cells, avoiding a rapid material degradation and maintaining corneal transparency. Additionally, implantation surgery often triggers an aggressive wound healing response that can lead to corneal thinning and opacity. Here, we report a collagen-based hydrogel with transparency and mechanical properties suitable for replacing a substantial portion of a damaged or diseased corneal stroma. The porous hydrogel permitted migration and population by host cells while maintaining transparency and thickness six months after surgical implantation in an in vivo model of human corneal surgery. With a novel hybrid surgical implantation technique inspired by LASIK refractive surgery, rapid wound healing occurred around implants to maintain biomaterial integrity, transparency and function. Host stromal cell repopulation and regeneration of host epithelium and nerves were observed, as necessary steps towards corneal regeneration. Finally, as a proof-of-principle, the hydrogel loaded with a neuroregenerative drug achieved sustained slow-release drug delivery in vitro. The proposed hydrogel and novel implantation technique together represent a therapeutic approach with translational potential for replacing and regenerating diseased corneal stromal tissue.

Dextran methacrylate hydrogel microneedles loaded with doxorubicin and trametinib for continuous transdermal administration of melanoma

Microneedles (MNs) technology has many advantages and is an ideal local transdermal drug delivery method. Here we synthesized photocrosslinkable dextran methacrylate (DexMA), and its degree of substitution is 5 % higher than the previous method. We used DexMA hydrogel for the first time to develop a new type of MNs for continuous transdermal administration. The prepared hydrogel MNs can successfully penetrate the epidermal layer and achieve sustained drug release. Doxorubicin (DOX) and trametinib (Tra) are anticancer drugs approved by FDA. Besides, Tra can also reverse P-gp-mediated multidrug resistance (MDR) to effectively block the efflux of DOX by P-gp. We used MNs to simultaneously load Tra and DOX, and achieved synergy in a B16 cell xenograft nude mouse model. The DexMA hydrogel MNs developed in this study can be used to enhance the transdermal delivery of small molecule drugs and reduce systemic toxicity and side effects.

Rifampicin-eluting biodegradable PLGA coatings can significantly inhibit in vitro biofilm formation for 10 weeks

Biofilm infection is a challenging complication of implanted medical devices due to difficulties in delivering a concentrated dose of antimicrobial to the infection site. To prevent biofilm pathogenesis, a local drug-delivery method, such as drug-eluting technology using biodegradable polymers to coat implantable devices, may be favourable. Implantable medical-grade polyester was coated in formulations of Poly(lactic-co-glycolic acid) and rifampicin (50:50, 60:40) and placed in PBS (37°C; 120rpm). To characterise release, media was collected periodically over 10 weeks and analysed (UV-spectrophotometry; 334nm). To examine biofilm inhibition, material was removed and submerged in Staphylococcus aureus and Escherichia coli suspensions (37°C; 24hrs) to stimulate biofilm formation. Biofilms were recovered using agitation/sonication, and enumerated. Release data revealed that both formulations had an initial burst-release phase during the first 24 hours, releasing 92% (50:50) and 88% (60:40) of their respective rifampicin loads. For both formulations, this was followed by slow-release for the remainder of the examined time, reaching 98.9% (50:50) and 97.9% release (60:40). Despite a small fraction of loaded rifampicin remaining, the formulations were able to significantly inhibit S. aureus biofilm formation (up to 99%) for 10 weeks, and E. coli biofilm formation (up to 57%) for 6 weeks. Drug-eluting polymer technology has already seen success in medical devices, such as coronary stents, to prevent restenosis. Here it has been indicated that this technology has potential in the field of infection prevention, by demonstrating the ability to inhibit in vitro biofilm formation to a significant degree for up to 10 weeks.

New method for local drug delivery using resorbable base material in periodontal therapy.

A new method for local drug delivery to the subgingival plaque was developed using hydroxypropylcellulose (HPC) as a base material. Using this material prepared in the form of strips containing antimicrobial drugs, the clinical and microbiological effects by this method on the human periodontal disease were studied. Before the clinical trials, the rate of the drug release from the strips was studied. Both drugs used in this study (CH: chlorhexidine and TC: tetracycline) were released almost within 2 hours from the strips in vitro. In the gingival crevicular fluid, however, it was found that the TC was maintained for 24 hours after the local delivery. Five patients who had deep pockets contralaterally were selected. The CH-containing HPC strips (5%) were applied in one pocket of each patient and the placebo strips were applied in other pocket on day 0, 2 and 4. Plaque Index, Gingival Index, probing depth and the presence or absence of bleeding on probing were recorded on day 0, 2, 4 and 6. Marked reduction of bleeding on probing was found in the pockets applied the CH-containing HPC strips. There was a significant reduction in the proportion of Bacteroides asaccharolyticus in these pockets (p less than 0.01).

Iontophoresis in lateral epicondylitis: a randomized, double-blind clinical trial

Lateral epicondylitis (LE) is a painful condition typically caused by excessive use of tendons, resulting in tendinopathy, inflammation, pain, and sensitivity changes in the lateral elbow. Iontophoresis is a noninvasive method of systemic and local drug delivery by means of a current. The study aimed to evaluate the effects of iontophoresis in patients with LE. We performed a randomized, double-blind clinical trial. Twenty-four patients with LE, randomized into an iontophoresis group and a galvanic current group. The iontophoresis group received a solution of dexamethasone (4 mg/mL) and gel lidocaine-applied on the negative electrode by means of a continuous current at 5 mA for 15 minutes-and the positive electrode received a base gel solution. Patients in the galvanic current group received the same protocolbut using a base gel solution on both electrodes. Both groups showed a significant improvement in pain on exertion and rest; increased handgrip strength in elbow extension and flexion; and improved function, as evaluated by the Patient-Rated Tennis Elbow Evaluation scale (P < .05). Iontophoresis showed superior results compared with galvanic current in pain on exertion and rest and in the function of individuals with tennis elbow. Iontophoresis proved to be an effective technique in reducing pain and improving strength and function in individuals with LE (tennis elbow).

Modern Possibilities of Organ-Preserving Treatment in Children with Intraocular Retinoblastoma

Retinoblastoma is one of highly curable diseases; today the total 5-year survival rate in patients with retinoblastoma exceeds 95%. The article summarizes the current world experience on treatment of patients with intraocular retinoblastoma. The treating skills of intraocular malignant tumor in children are a balance between the patient’s life and the preservation of an eye and its visual functions. The complex and challenging task is the treatment of common intraocular retinoblastoma groups «C», «D», «E» when the large size or localization of the tumor does not allow performing the local (focal) destruction of the tumor. As a rule, in such cases neoadjuvant chemotherapy (CT) is performed at the first stage in order to reduce the size of the tumor for further focal therapy. However, the analysed data on the effectiveness of neoadjuvant CT in combination with focal or radiotherapy demonstrated the limited possibilities of the proposed therapy. Local drug delivery in cancer therapy became a real breakthrough in the organ-preserving treatment of children with large intraocular retinoblastoma. The most widely used current methods of local drug delivery are intravitreal (IVitC) and selective intra-arterial chemotherapy (SIAC) as monotherapy or in combination with neoadjuvant CT and focal therapy which significantly increased the percentage of preserved eyes without radiotherapy administration or damage to the patient survival. The review discusses the different IVitC and SIAC techniques, chemotherapy schemes, dosages of chemotherapy, immediate and long-term complications of treatment.

Selected Medicines Used in Iontophoresis.

Iontophoresis is a non-invasive method of systemic and local drug delivery using an electric field. Iontophoresis enables diffusion of the selected drug via skin, mucosa, enamel, dentin, and other tissues. The amount of delivered therapeutic molecules is about 10–2000 times greater than conventional forms of delivery. Among other fields, this method is used in dentistry, ophthalmology, otorhinolaryngology, and dermatology. According to related literature, the most important drugs studied or administered by iontophoresis are: Local anesthetics, opioids, steroids, non-steroidal anti-inflammatory drugs, antibacterial drugs, antifungal drugs, antiviral drugs, anticancer drugs, fluorides, and vitamins. The present review covers current available data regarding the selected medicines used in iontophoresis. Furthermore, indications and conditions of iontophoresis application are reviewed.