Pathophysiology to advanced intra-articular drug delivery strategies: Unravelling rheumatoid arthritis.

Rheumatoid arthritis (RA) is one of the most prevalent life-long autoimmune diseases with an unknown genesis. It primarily causes chronic inflammation, pain, and synovial joint-associated cartilage and bone degradation. Unfortunately, limited information is available regarding the etiology and pathogenesis of this chronic joint disorder. In the last few decades, an improved understanding of RA pathophysiology about key immune cells, antibodies, and cytokines has inspired the development of several anti-rheumatic drugs and biopharmaceuticals to act on RA-affected joints. However, life-long frequent systemic high doses of commercially available drugs are currently a limiting factor in the efficient management of RA. To address this issue, various single and double-barrier intra-articular drug delivery systems (IA-DDSs) such as nanocarriers, microparticles, hydrogels, and particles-hybrid hydrogel composite have been developed which can exclusively target the RA-affected joint cavity and release the precisely controlled therapeutic drug concentration for prolonged time whilst avoiding the systemic toxicity. This review provides a comprehensive overview of the pathogenesis of RA and discusses the rational design and development of biomaterials-based novel IA-DDs, ranging from conventional to advanced systems, for improved treatment of RA. Therefore, this review aims to unravel the pathophysiology of rheumatoid arthritis and explore cutting-edge IA-DD strategies exploiting biomaterials. It offers researchers a consolidated and up-to-date resource platform to analyze existing knowledge, identify research gaps, and contribute to the scientific literature.

Digitization in Skin Shade Matching for Maxillofacial Prostheses: A Systematic Review.

Color matching of maxillofacial prostheses for the restoration of maxillofacial defects is an important factor for esthetic results. Various methods have been introduced for the accurate and reliable color matching of prostheses with the skin color of patients. A systematic review was conducted to search the existing literature on color-matching digital techniques for maxillofacial prostheses. An electronic literature search was conducted in PubMed/Medline, Scopus, and Web of Science from January 2000 to December 2022 using Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Two independent reviewers conducted the search. Eight articles that fulfilled the inclusion criteria after a full-text evaluation were included in this review. Most of these studies were published in prosthodontics journals and conducted in various countries around the world. A computerized color formulation system was used in three studies; a non-contact spectroradiometer (PR 705; Photo Research Inc., Chatsworth, CA) with a Xenon arc lamp was used in two studies; a mobile phone colorimeter was used in one study; additive manufacturing of 3D facial skin with a spectrophotometer was used in one study; and a recently introduced computerized method known as e-skin (Spectromatch, Bath, UK) was used in two studies. Most of these methods were accurate in color matching, except for the additive manufacturing system, which showed less accuracy, but good repeatability. Owing to a lack of sufficient studies, no method can be labeled as the best method for color-matching maxillofacial prostheses. The latest computerized method, the e-skin, can be used to achieve better accuracy and good color matching. However, further studies are required to validate the use of e-skin for precise color matching.

Designing nanoformulation for the nose-to-brain delivery in Parkinson's disease: Advancements and barrier.

Parkinson's disease (PD), a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons, which results in the loss of motor activity. In the management of PD, the primary aim is to increase the dopamine content in the brain either by delivering the precursors of dopamine or by inhibiting the molecules responsible for dopamine degradation. Due to the low bioavailability, a higher dosage of drugs needs to be administered repeatedly for achieving the desired therapeutic effect. This repeated high dose not only increases the severe side effects but also produces tolerance in the body. Often, direct administration of drugs fails to ameliorate the symptoms as the unmodified drugs cannot cross the blood-brain barrier (BBB). Nanotherapeutic is at the forefront of the alternative treatment against the central nervous system (CNS) disorders due to the ability to circumvents the BBB. Here, all the available treatments for PD have been discussed with their limitation. The current trends of nanotherapeutics for PD have been explored. Suitability and formulation prospects for nasal delivery have been analyzed in detail to explore new research scope. The most effective approach is the nose-to-brain delivery for targeting drugs directly to the brain. This delivery bypasses the BBB and concentrates more drugs at the target site. Thus, developments of nose-to-brain delivery of nanoformulations explicit the new scope to manage PD better. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

Synthesis and characterization of an injectable microparticles integrated hydrogel composite biomaterial: In-vivo biocompatibility and inflammatory arthritis treatment.

Polymeric hydrogels and microparticles have been widely used for localized drug delivery applications for the treatment of arthritis. Nonetheless, owing to initial burst drug release, non-specific biodistribution and low retention time at the target site in body, these polymeric drug delivery systems have been found with low in-vivo performance. Hence, the above limitations need to be resolved by designing a smart novel drug delivery system which is the current need in biomedicine. Herein, a novel localized injectable thermoresponsive microparticles embedded hydrogel composite drug delivery system has been developed for the treatment of inflammatory arthritis. In the current study, methotrexate (MTX) loaded alginate microparticles (MTX-Microparticles) are embedded into thermoreversible hydrogel matrix (MTX-MPs-H) prepared by physical blending of sodium hyaluronate and methylcellulose (SHMC). Microparticles-hydrogel composite system exhibited appropriate in-vitro thermoreversibility (sol at 4 °C and gel at 37 °C), biocompatibility (>80 %), hemocompatibility, and controlled drug release profile. The in-vivo biocompatibility studies for 10 days revealed that composite system is non-toxic in nature. The developed MTX-MPs-H composite drug delivery system effectively decreased the swelling/ inflammation of the arthritis affected paw in wistar rats in comparison to only alginate microparticles and pure MTX up to 30 days.

Chitosan-polycaprolactone blend sponges for management of chronic osteomyelitis: A preliminary characterization and in vitro evaluation.

Blending two polymers is an effective technique to obtain a novel material with desirable properties. Chitosan (CH) has limited applications in tissue engineering owing to its poor mechanical strength in a wet state. Polycaprolactone (PCL) has low toxicity with good mechanical strength and controlled release properties, but lack cell recognition signals. Thus, the blending of CH and PCL (CH/PCL) polymers would provide a better biomaterial required for the management of chronic osteomyelitis (OM) after surgical debridement possessing superior physicomechanical and controlled release properties. Herein, blend sponges using different ratios of CH and PCL, i.e., 100%CH/00%PCL, 75%CH/25%PCL, 50%CH/50%PCL and 25%CH/75%PCL were prepared, which are denoted as 100CH/00PCL, 75CH/25PCL, 50CH/50PCL and 25CH/75PCL, respectively. These blend sponges were characterized using FTIR, XRD, DSC, SEM, and contact angle. The results revealed that CH and PCL polymers were well dispersed in a blend at a molecular level without any chemical interactions. Blend sponges were loaded with ciprofloxacin hydrochloride (CIP) and ibuprofen. Further, in vitro efficacy of drug-loaded blend sponges was evaluated for drug release, antibacterial potential, and anti-inflammatory activity. Amongst four blend sponges, the 75CH/25PCL sponge demonstrated the controlled release of ibuprofen and an ideal release profile of CIP along with potential antibacterial as well as anti-inflammatory activity over the study period. Thus, it can be concluded that the 75CH/25PCL sponge is a promising candidate for the management of chronic OM after surgical debridement.

Chitosan sponges as a sustained release carrier system for the prophylaxis of orthopedic implant-associated infections.

The present investigation aims to study the chitosan sponge as a carrier matrix for the sustained antibiotic release system for the prophylaxis of orthopedic implant-associated infections (OIAIs). We have prepared sponges of three broad-spectrum antibiotics, namely vancomycin, ciprofloxacin and cefuroxime possessing different physicochemical properties. The blank, vancomycin, ciprofloxacin and cefuroxime loaded chitosan sponges were denoted as Blank-CH, CH-VAN, CH-CIP, and CH-CEF sponges. Chitosan sponges were assessed for morphology, drug-release, antibacterial potential, and preclinical evaluation using a rat subcutaneous implantation model. The results revealed that the physicochemical properties of the drug incorporated into the chitosan matrix play an important role in the morphology, degradation and drug release profile. Due to the highly hydrophilic properties of vancomycin, the CH-VAN sponge showed the highest swelling and fastest degradation profile. The CH-VAN sponge demonstrated the short-term release in contrast with the CH-CEF and CH-CIP sponges, which showed sustained release along with sustainable antibacterial activity. The preclinical evaluation proved that the CH-CIP and CH-CEF sponges were biodegradable, non-toxic and biocompatible. Further, the CH-CIP and CH-CEF sponges were able to maintain minimum plasma concentration with higher local tissue antibiotic concentration. Therefore, the CH-CIP and CH-CEF sponges could be promising candidates for the long-term prophylaxis of OIAIs.

Cefuroxime conjugated chitosan hydrogel for treatment of wound infections.

Hydrogels are excellent drug delivery systems for the treatment of chronic wound infections. However, the problem of high burst release still remains a challenge that needs to be tackled. In terms of antibiotic release from the hydrogels, as the drug payload depletes it could act as a substrate for bacterial seeding which can create a life-threatening condition. Therefore, to provide the sustained effect of an antibiotic at the localized site via hydrogel matrix, we prepared a chitosan (CS) hydrogel system in which cefuroxime (CEF) is covalently conjugated with chitosan polymer via an ester linkage. To prepare the cefuroxime conjugated chitosan hydrogel, the formulations were optimized using different concentrations of cefuroxime, 0% (CS/CEF_0), 5% (CS/CEF_5), 10% (CS/CEF_10) and 20% (CS/CEF_20) w/w of chitosan. Fourier Transform Infra-red Spectroscopy (FTIR) confirmed the conjugation of cefuroxime and chitosan. The drug release studies showed that the release of cefuroxime was higher in the phosphate buffer (pH 7.4) with esterase enzyme and alkaline medium (pH 10) compared to phosphate buffer (pH 7.4) alone. Hemolysis assay was performed to demonstrate the hemocompatibility of the prepared hydrogel samples. The cell viability study using the L929 fibroblast and MG63 osteosarcoma cell lines revealed that synthesized hydrogel is biocompatible. Furthermore, a potent antibacterial activity for the extended time period proved the biological efficacy of a hydrolyzed cefuroxime. Thus, CS/CEF_5, CS/CEF_10, and CS/CEF_20 hydrogels have a promising future in the treatment of chronic wound infections.

Chitosan nanoparticles and povidone iodine containing alginate gel for prevention and treatment of orthopedic implant associated infections.

Orthopedic Implant associated infections (OIAIs) are the most serious complications in the orthopedic surgery. Such complications are of major concern unless encountered during initial stages of contamination due to the bacterial biofilm formation. Thus, our aim is to eradicate bacteria at the early stages of infection. Herein, we develop a vancomycin-loaded chitosan nanoparticles (CNPs) and povidone-iodine (PI) containing in situ alginate (CNPs-PI-Alg) gel for antibacterial and antibiofilm activity, respectively. The CNPs were synthesized by ionic gelation method and the processing parameters were optimized to attain nanoparticles of 200-250 nm size and 37.13 ±â€¯3.18 mV charge. A PI-loaded in situ alginate (PI-Alg) gel served as a carrier wherein, the CNPs were incorporated to attain sustained release of an antibacterial agent. The CNPs-PI-Alg gel showed more stability and mechanical properties compared to the Blank-Alg gel. The CNPs-PI-Alg gel exhibited sustained release of vancomycin and PI over a period of 10-15 days. The hemolysis and cytocompatibility studies demonstrated the safety and biocompatibility of CNPs-PI-Alg gel. Furthermore, significant antibacterial and antibiofilm effect against Staphylococcus aureus showed that the CNPs-PI-Alg in situ gel has a potential for the prevention of OIAIs.

Dual-purpose Injectable Doxorubicin Conjugated Alginate Gel Containing Polycaprolactone Microparticles for Anti-Cancer and Anti-Inflammatory Therapy.

BACKGROUND: In situ gel formulations have been widely reported as a carrier for sustained release delivery systems due to certain advantages such as targeted drug delivery, minimal invasiveness and potent therapeutic activity. OBJECTIVE: Herein, in situ gel system for sustained release of doxorubicin and ibuprofen for anti-cancer and anti-inflammatory activity is reported. METHOD: Doxorubicin-conjugated alginate (dox-alg) gel was prepared using EDC-NHS chemistry and loaded with ibuprofen encapsulated polycaprolactone (PCL) microparticles (dox-alg composite). PCL microparticles were prepared by a solvent evaporation method (size 50 - 100µm). The gel was characterized using SEM, FTIR, XRD and TGA analysis. RESULTS: Dox-alg composite gel showed good syringeability and gel formation properties. Burst release was observed for both drugs within 24 h followed by sustained release till day 21. Doxorubicin released from composite showed considerable cytotoxic effect. Cell uptake was confirmed by confocal microscopy using MDA-MB-231 cells. Anti-inflammatory activity of ibuprofen released from composite gel was compared with the free drug. An injection of dox-alg composite gel in the tissue would fill the void created after tumor removal surgery, prevent the resuscitation of remnant cancerous cells and reduce inflammation. CONCLUSION: Thus, the dox-alg composite gel could be a potential agent for the dual anti-cancer and anti-inflammatory therapy.

Nanobiotechnology Perspectives on Prevention and Treatment of Ortho-paedic Implant Associated Infection.

Implants are an inevitable part of orthopaedic surgery. However, implant associated infection remains a major challenge for orthopaedic surgeons and researchers. This review focuses on current options available for prevention of implant associated infection, their drawbacks and future promising applications of nanotechnology-based approaches. Nanobiotechnology has shown remarkable progress in recent years especially in biomaterials, diagnostics, and drug delivery system. Although several applications of nanobiotechnology in orthopaedics have been described, few have elaborated their role in the prevention of implant related infection in orthopaedics. Novel "smart" drug delivery systems that release antibiotics locally in response to stimuli such as pH, temperature, enzymes or antigens; implant surface modification on a nanoscale to inhibit bacterial adhesion and propagation at the surgical site and biological approaches such as gene therapy to neutralize bacterial virulence and biomolecules to inhibit the quorum sensing adhesion of bacteria and disruption of biofilms can be used effectively to prevent orthopaedic implant related bacterial infection.

Clinical characteristics of patients with community-acquired complicated intra-abdominal infections: a prospective, multicentre, observational study.

In this prospective, observational, multicentre study using data from five countries (Columbia, The Philippines, Portugal, Taiwan and Thailand), the clinical impact of extended-spectrum ß-lactamase (ESBL)-producing organisms on hospitalised patients with community-acquired complicated intra-abdominal infections (CA-cIAIs) was compared with that of non-ESBL-producing organisms during the period April 2010 to December 2011. Adult patients (aged ≥18 years) requiring surgery or percutaneous drainage were enrolled and were followed during the first hospitalisation course. An unadjusted statistical comparison of risk factors for ESBL-positive and ESBL-negative patients was performed. Multivariate regression analyses were performed to assess whether length of stay (LOS) in hospital, clinical cure rate and some important clinical characteristics were associated with ESBL positivity. During the study period, a total of 105 adult patients from five countries were enrolled, of whom 17 (16.2%) had CA-cIAI due to ESBL-positive organisms and 88 (83.8%) had CA-cIAI due to ESBL-negative organisms. Escherichia coli was isolated in 73.3% of all samples. Infections were cured in 8 (47.1%) of the patients with CA-cIAI due to ESBL-positive organisms and in 59 (67.0%) of the patients with CA-cIAI due to ESBL-negative organisms (P=0.285). The median LOS was 11.6 days for patients with infections due to ESBL-negative organisms and 17.6 days for patients with infections due to ESBL-positive organisms (P=0.011). Multivariate logistic regression analysis revealed that pre-existing co-morbidities, but not ESBL positivity, were adversely associated with clinical cure of CA-cIAIs. In contrast, duration of hospitalisation was longer for patients with CA-cIAI due to ESBL-positive organisms.