Performance and safety assessment of materials used in the medical devices destinated for pressure ulcer management.

Pressure ulcers are a significant health problem that affects a large population, especially the elderly and individuals with physical limitations. These injuries cause pain, are difficult to heal, and can be expensive to manage, leading to a negative impact on the quality of life of those affected. This scientific paper provides an overview of medical devices such as support surfaces, dressings, and topical agents for preventing and managing pressure ulcers. This review focuses on the importance of understanding the viscoelastic mechanical properties, water vapor transmission rate, and biocompatibility testing of medical devices, which can help define performance criteria needed to prevent and manage pressure ulcers effectively. The paper highlights the potential use of alginate, polyurethane, silicone, polyvinyl alcohol, and collagen as pressure relief and wound care solutions. Synthesizing this research can help medical device manufacturers make better decisions and improve the quality of care for patients with pressure ulcers.

Liquid chromatography with tandem mass spectrometry for the simultaneous identification and quantification of cardiovascular drugs applied to the detection of substandard and falsified drugs.

The counterfeiting of pharmaceuticals has been detected since about 1990 and has alarmingly continued to pick up steam. We have been recently involved in an evaluation program of some of the most commonly prescribed cardiovascular drugs in Africa, for analysing an important number of tablets or capsules obtained from different places in seven African countries. A reversed-phase high-performance liquid chromatography with tandem mass spectrometry method was developed and validated to simultaneously control the identity and the quantity of acenocoumarol, amlodipine, atenolol, captopril, furosemide, hydrochlorothiazide and simvastatin in tablets. Their separation was performed on a Kinetex® C(18) (100 mm × 2.1 mm inside diameter, 2.6 µm) column using a gradient elution of 20 mM ammonium formate buffer and acetonitrile (90:10 10:90 v/v) at a flow rate of 0.5 mL/min. The analytes were detected using electrospray ionisation tandem mass spectrometry in both positive and negative modes with multiple reaction monitoring. Tandem mass spectrometry fragmentation patterns of captopril, furosemide and acenocoumarol, up to now not detailed in the literature, were also studied to assist in the selection of the most relevant transitions towards the objectives. The developed method was validated as per International Conference on Harmonisation guidelines with respect to specificity, linearity, trueness, precision, limits of detection and quantification. It has been successfully applied to the control of oral forms of seven cardiovascular drugs collected in African countries.

Mechanical Performance and Cytotoxicity of an Alginate/Polyacrylamide Bipolymer Network Developed for Medical Applications.

Several hydrogels could be used as scaffolds for tissue engineering and a model of extracellular matrices for biological studies. However, the scope of alginate in medical applications is often severely limited by its mechanical behavior. In the present study, the modification of the mechanical properties of the alginate scaffold is obtained by its combination with polyacrylamide in order to obtain a multifunctional biomaterial. The advantage of this double polymer network is due to an improvement in the mechanical strength with regard to the alginate alone, and in particular, its Young's modulus values. The morphological study of this network was carried out by scanning electron microscopy (SEM). The swelling properties were also studied over several time intervals. In addition to mechanical property requirements, these polymers must meet several biosafety parameters as part of an overall risk management strategy. Our preliminary study illustrates that the mechanical property of this synthetic scaffold depends on the ratio of the two polymers (alginate, polyacrylamide) which allows us to choose the appropriate ratio to mimic replaceable body tissue and be used in various biological and medical uses, including 3D cell culture, tissue engineering, and protection against local shocks.

Evolution of the Chronic Venous Leg Ulcer Microenvironment and Its Impact on Medical Devices and Wound Care Therapies.

Studies have reported that the constituents of the wound microenvironment are likely to have critical roles in the degradation and fate of the polymeric matrix and the compounds dissolved in the wound dressing matrix. Thus, chronic wound assessment and the design of effective medical devices and drug products for wound care partly rely on an in-depth understanding of the wound microenvironment. The main aim of this review is to identify and discuss the different stages of chronic wound progression, focusing on the changes in the biochemical composition of the wound microenvironment, with particular attention given to venous leg ulcers (VLUs), as they are one of the most prevalent chronic wound aetiologies. The pathophysiology of venous ulcers is detailed, followed by a thorough review of what is known about the VLU microenvironment and its changes as a function of the evolution of the VLU. Simulating conditions for VLU are then discussed with the view of highlighting potentially relevant simulating media as a function of VLU evolution for a better assessment of biological safety, in particular medical devices intended to be in contact with these wounds.

Surface and mechanical properties of polyurethane central venous catheters after repeated contact with chemotherapy excipient solutions.

This article investigates the impact of the interactions between polyurethane central venous catheters and solutions containing excipients used in cisplatin and paclitaxel formulations. Changes to the properties of catheters and the leaching of catheter additives into the infused solutions were studied while these solutions were infused cyclically for several months. Chemotherapy treatment was mimicked in vitro in compliance with hospital practices. The treatment cycle was repeated 10 times, using solutions containing only the excipients. After 10 treatment cycles, no physical or chemical degradation of the catheter was observed. Mechanical performances were stable, but surface modifications occurred, causing the surface to become more hydrophobic. A loss in polyurethane antioxidant amount was observed in part due to a leaching phenomenon.

Impact of lock solutions on the mechanical performance of polyurethane central venous catheters: A comparative study.

The impact of ethanol locks on the mechanical performances of central venous catheters was compared to that of aqueous-based locks. Several mechanical tests were performed to evaluate catheter behavior: kinking radius measurements, burst pressure, and tensile tests. Different polyurethanes were studied to assess the impact of radio-opaque charge and polymer chemical composition on catheter behavior. The results were correlated to swelling measurements and calorimetric measurements. In particular, ethanol locks have a higher impact on long contact time than aqueous-based locks: stresses and strains at break were lower, and kinking radii were higher. However, for all catheters, the mechanical performances remain much higher than the normative requirements.

Unequal Behaviour between Hydrolysable Functions of Nirmatrelvir under Stress Conditions: Structural and Theoretical Approaches in Support of Preformulation Studies.

Nirmatrelvir is an antiviral drug approved for the treatment of COVID-19. The available dosage form consists of tablets marketed under the brand name PAXLOVID®. Although knowledge of nirmatrelvir's intrinsic stability may be useful for any potential development of other pharmaceutical forms, no data regarding this matter is available to date. Preliminary forced degradation studies have shown that the molecule is stable under oxidative and photolytic conditions, while hydrolytic conditions, both acidic and basic, have proven deleterious. Indeed, the molecule presents a priori several functions that can undergo hydrolysis, i.e., three amide moieties and a nitrile function. However, considering the degradation products formed under forced conditions and which were detected and identified by LC-UV-HRMSn, the hydrolysis process leading to their formation is selective since it involved only 2 of the 4 hydrolysable functions of the molecule. Ab initio studies based on density functional theory (DFT) have helped better understand these reactivity differences in aqueous media. Some hydrolyzable functions of nirmatrelvir differ from others in terms of electrostatic potential and Fukui functions, and this seems to correlate with the forced degradation outcomes.

Identification of the Major Degradation Pathways of Selumetinib.

Selumetinib is administered orally in capsule form and is indicated for the treatment of neurofibromatosis. To facilitate dosage adjustments, liquid preparations, such as solutions or suspensions, are to be developed. This led, first, to determine the stability profile of soluble or dispersed selumetinib and, secondly, to look for ways to stabilize the active substance. The degradation kinetics of selumetinib as a function of stress conditions were determined and compared. The degradation products were detected and identified by LC-HRMSn. In solution, selumetinib is sensitive to oxidation and degrades by photooxidation. In both cases, the side chain represented by the oxoamide group is concerned, leading to the formation of an amide derivative for the first case and an ester derivative for the second. The identification of such degradation mechanisms allowed us to study, in a targeted way, processes aiming at stabilizing the active molecule.

Polymorphic transformation of anhydrous caffeine under compression and grinding: a re-evaluation.

Polymorphic transformations that may occur during mechanical treatment are of great interest for the production of pharmaceutical solids. Anhydrous caffeine is a well-known example of such transformations but a careful reading of the already existing literature shows that published results are contradictory. In this study, both forms of caffeine, form I and form II, respectively metastable and stable at ambient pressure and temperature, were submitted to compression in an instrumented alternative press and to grinding, and were studied before and after treatment by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). Compression experiments showed no changes of form II during compression, whereas form I was partially transformed into form II. Nevertheless, this transformation did not happen immediately. Form II appeared after a kinetically slow transformation and was clearly detectable only after a few days, fact that was never mentioned by previous authors. Same phenomenon was observed after the grinding of form I but also after an extensive grinding of form II. DSC and XRPD measurements indicated that polymorphic transformation did not happen directly, but that a new intermediate form was obtained after mechanical treatment, which slowly turned into form II within a few days.

Ruxolitinib photodegradation mechanisms by theoretical and experimental chemistry.

Ruxolitinib is a Janus Kinase inhibitor currently approved for the treatment of myelofibrosis. It is also a promising drug for the treatment of skin and infectious diseases. In terms of pharmaceutical stability, although ruxolitinib has been established as being sensitive to light, no data on photodegradation processes are available to date, while these may be useful for quality risk management and any potential development of other pharmaceutical forms for other routes of administration. One way to partially fill this gap was to carry out a study that combines a consistent determination of the most sensitive sites of the molecule to photolysis through theoretical calculations based on functional density, with the identification of the main photodegradation products obtained after forced degradation. This integrated approach has shown converging results describing the mechanisms based on photo-oxidation that can lead to the opening of the pyrrole ring. Having access to the structure of the degradation products and intermediates then made it possible to carry out an in silico evaluation of their potential mutagenicity and it appears that some of them feature alert structures.

EBT3 Gafchromic® film as a new substrate for in vitro evaluation of sun protection factor.

There exist different methods for the determination of sun protection factor (SPF) values for sunscreens. We aimed to develop a new in vitro method using EBT3 Gafchromic® film as a substrate. The colour of EBT3 Gafchromic® film changes when exposed to UV light. Films were covered by sunscreen preparations of different SPF values ranging from 0 to 50. Uncovered and covered films were exposed to different solar light energies and their colour change was compared. Absorbance spectra of films was measured at 633 nm using a UV-VIS spectrophotometer apparatus. The colour of the film darkens when ultraviolet energy increases, which means that absorbance increases with exposure time. However, when films are covered by sunscreens, the colour change is less visible and the absorbance significantly decreases with increasing SPF value. There is a linear correlation between the absorbance of EBT3 Gafchromic® film and SPF value of sunscreens covering the film. Statistical analysis demonstrated that the SPF value of a sunscreen can be predicted using EBT3 Gafchromic® film as a substrate. This is the first report of an in vitro method based on colour change of a substrate which takes into consideration exposure time, and relates more closely to conditions of real-life. Based on these parameters, this is a reliable in vitro method for SPF testing.

Intrinsic stability of the antiviral drug umifenovir by stress testing and DFT studies.

Umifenovir is an antiviral drug approved in China and Russia for the treatment of influenza. The available dosage form consists of capsules marketed under the brand name Arbidol®. Due to its broad spectrum, umifenovir may also be used in other viral contexts, alone or combined with other antiviral drugs. Although knowledge of umifenovir intrinsic stability may be useful for any potential development of other pharmaceutical forms for other routes of administration and for quality risk management, no data regarding this matter is available to date. In this study, the exploration of the molecule's behaviour under hydrolytic, oxidative and photolytic conditions was carried out experimentally and supported by density functional theory (DFT) studies. It comes out that umifenovir is sensitive to these stress conditions giving rise to 6 structurally characterized degradation products. The one-electron oxidation process produced on the sulphur atom is probably the main cause of umifenovir degradation with reference to the structures of the degradation products formed and the DFT data.

A multiscale approach to assess the complex surface of polyurethane catheters and the effects of a new plasma decontamination treatment on the surface properties.

Polyurethane catheters made of Pellethane 2363-80AE® were treated with a low temperature plasma developed for the decontamination of reusable polymer devices in hospitals. We investigated the modifications of the polymer surface by studying the topographic modifications, the chemical modifications, and their consequences on the wettability and bacterial adhesion. This study showed that plasma treatment modified the topography and grafted oxygen and nitrogen species onto the surface, resulting in an increase in the surface polarity. This effect could be correlated to the number of nitrogen atoms interacting with the surface. Moreover, this study demonstrated the significance of multiscale heterogeneities, and the complexity of industrial medical devices made from polymers. Their surface can be heterogeneous, and they contain additives that can migrate and change the surface composition.

Physical and chemical stability of a generic etoposide formulation as an alternative to etoposide phosphate.

The generic Mylan® etoposide (ETP) has been investigated as an alternative for Etopophos®, in part due to a global shortage of the latter. The generic alternative is different both in its formulation and in its very limited stability (6 h at 25 °C against 4 days for Etopophos®) once reconstituted in ready-to-use chloride or glucose solutions. Its intrinsic stability has been thoroughly studied under various conditions. Two degradation products resulting from hydrolysis were characterized by LC-HR-MSn and supported by density functional theory calculations of the frontier molecular orbitals energies, molecular electrostatic potential mapping, and Mulliken charge analysis. Chemical degradation increases with temperature and can be fitted to a zero order kinetic model with a half-life of 119 days and a kinetic constant of 0.0028 mM day-1. Precipitation was only observed in solutions at 5 °C and -20 °C indicating that at these temperatures the reconstituted solutions are thermodynamically metastable. In conclusion, ETP at concentrations of 0.68 and 1 mM prepared and stored at 25 °C under good manufacturing practices remained unchanged over a period of 21 days irrespective of the nature of the solvents or the type of container.

Post hoc study to investigate the potential causes of poor quality of cardiovascular medicines collected in sub-Saharan countries.

OBJECTIVES: The incidence of cardiovascular diseases is increasing and there is a growing need to provide access to quality cardio drugs in Africa. In the SEVEN study, we analysed 1530 cardiovascular drug samples randomly collected from 10 African countries. By that time, of the seven drugs products analysed, only those containing amlodipine and captopril had very low assay values with active substance contents that could be less than 75% of those expected. In this article we investigate complementary aspects of the amlodipine and captopril samples so to explain the previously observed low assays for these two drugs. DESIGN: Post hoc analysis of the captopril and amlodipine drugs samples and their packages collected in the context of the SEVEN study. SETTING: 10 countries were concerned: Benin, Burkina Faso, Congo, Democratic Republic of the Congo, Guinea, Côte d'Ivoire, Mauritania, Niger, Senegal and Togo. PARTICIPANTS: Local scientists and hospital practitioners collected the drug samples in the 10 African countries. OUTCOME MEASURES: The drug amount and the relative amounts of drug impurities, as well as the main compounds of the drugs packaging, were analysed. RESULTS: Identification of the blister packaging of the samples led to separate both amlodipine and captopril drug samples in two groups. Mann Whitney's bilateral test showed a significant difference (p<0.0001) between the median value of the captopril dosage when tablets are packaged in blisters providing higher protection to humidity (n=105) as opposed to the tablets packaged in blisters providing lower humidity protection (n=130). CONCLUSION: Based on these results, particular attention should be paid to the materials and types of packaging used in order to minimise the lack of control over the exposures and drug circuits present in these different countries.

Impact of simulated biological aging on physicochemical and biocompatibility properties of cyclic olefin copolymers.

We study the effect of simulated biological aging on the properties of cyclic olefin copolymers and particularly their biocompatibility. Already reported as biocompatible polymers according to ISO/EN 10993 guidelines, COC are good candidates for medical devices. The influence of two major additives (antioxidants and lubricants) was investigated and comparison with non-aging COC was done. Four in vitro simulated biological conditions were tested: 2 extreme pH (1 and 9) to simulate digestive tract environment; THP-1-derived macrophages contact and pro-oxidant medium with hypochlorite solution simulating the oxidative attack during the foreign body reaction. After one month of incubation with the different media at 37 °C, surface topography was studied by atomic force microscopy (AFM) and IR spectroscopy. Extracts of incubated media were also analysed in chromatography to investigate potential degradation products. Cytotoxicity (MTT and LDH) of the materials was evaluated using cell culture methods with L929 fibroblasts. Oxidative stress (ROS and SOD analysis) and two inflammatory biomarkers (Il-6 and TNF-α secretion) were explored on THP-1-derived macrophages in direct contact with aged COC. Surface topography of COC was modified by aging conditions with an influence of antioxidant presence and under some conditions. HPLC analysis realized on freeze-dried solutions issued from the different incubations showed the presence of traces of low molecular weight compounds issued from polyphenolic antioxidant and from COC degradation. GC-MS analysis carried out directly on the different incubated COC, showed no detectable leachable molecules. No cytotoxicity has been observed with the different aged COC. However, results show that the pH environment had an influence on the cytotoxicity tests with a protecting effect of antioxidant presence; and pro-oxidant incubating conditions decreased cellular viability on COC. pH 1 and pH 9 conditions also induced an increase of ROS production which was partially reduced for COC containing an antioxidant or a lubricant. Il-6 production was globally more important for aged COC compared with basal condition and particularly for oxidative simulated environment. Those results indicate that physiological factors like pH or oxidant conditions have an impact on surface topography and on COC interaction with the biological environment but without compromising their biocompatibility. Antioxidant or lubricant presence could modulate these variations pointing out the necessity of a thoroughly investigation for biocompatibility assessment of COC as a component of implantable devices. COCs show a good biocompatibility even after accelerated aging under extreme biological conditions.

The crucial role of macromolecular engineering, drug encapsulation and dilution on the thermoresponsiveness of UCST diblock copolymer nanoparticles used for hyperthermia.

Poly(acrylamide-co-acrylonitrile) (P(AAm-co-AN)), an upper critical solution temperature (UCST)-type copolymer in water, was synthesized by reversible addition fragmentation chain transfer (RAFT) copolymerization and used as a macro-RAFT agent for the polymerization of oligo(ethylene glycol) methyl ether methacrylate (OEGMA) to yield amphiphilic diblock P(AAm-co-AN)-b-POEGMA copolymer. A series of copolymers with different AN content was obtained allowing to finely tune the UCST behavior (cloud point (Tt-UCST) from 35 to 78 °C). Addition of the POEGMA block did not modify the Tt-UCST regardless its Mn but provided a lower critical solution temperature behavior at high temperature. Nanoparticles were then formulated by the nanoprecipitation technique revealing that copolymers with higher Tt-UCST yield smaller, better-defined nanoparticles. Eventually, doxorubicin (Dox) was encapsulated into nanoparticles made from the copolymer having a Tt-UCST close to mild hyperthermia (~43 °C). Surprisingly, Dox encapsulation increased Tt-UCST and gave smaller nanoparticles as opposed to their unloaded counterparts. The dilution of the suspension also led to a decrease of Tt-UCST. No obvious hyperthermia effect was observed on the cytotoxicity of Dox-loaded nanoparticles. Our study highlighted the influence of macromolecular engineering, drug encapsulation and nanoparticle dilution on UCST behavior, important features often overlooked despite their crucial impact in the development of thermosensitive nanoscale drug delivery systems.

Electrospun Poly(ε-caprolactone) Fiber Scaffolds Functionalized by the Covalent Grafting of a Bioactive Polymer: Surface Characterization and Influence on in Vitro Biological Response.

The purpose of this study is to present the poly(caprolactone) (PCL) functionalization by the covalent grafting of poly(sodium styrene sulfonate) on electrospun scaffolds using the "grafting from" technique and evaluate the effect of the coating and surface wettability on the biological response. The "grafting from" technique required energy (thermal or UV) to induce the decomposition of the PCL (hydro)peroxides and generate radicals able to initiate the polymerization of NaSS. In addition, UV irradiation was used to initiate the radical polymerization of NaSS directly from the surface (UV direct "grafting from"). The interest of these two techniques is their easiness, the reduction of the number of process steps, and its applicability to the industry. The selected parameters allow controlling the grafting rate (i.e., degree of functionalization). The aim of the study was to compare two covalent grafting in terms of surface functionalization and hydrophilicity and their effect on the in vitro biological responses of fibroblasts. The achieved results showed the influence of the sulfonate functional groups on the cell response. In addition, outcomes highlighted that the UV direct "grafting from" method allows to moderate the amount of sulfonate groups and the surface hydrophilicity presents a considerable interest for covalently immobilizing bioactive polymers onto electrospun scaffolds designed for tissue engineering applications using efficient post-electrospinning chemical modification.

Pancreatic cancer stem cell proliferation is strongly inhibited by diethyldithiocarbamate-copper complex loaded into hyaluronic acid decorated liposomes.

BACKGROUND: Pancreatic cancer stem cells (CSCs) are responsible for resistance to standard therapy, metastatic potential, and disease relapse following treatments. The current therapy for pancreatic ductal adenocarcinoma (PDAC) preferentially targets the more differentiated cancer cell population, leaving CSCs as a cell source for tumor mass formation and recurrence. For this reason, there is an urgent need to improve current therapies and develop novel CSC-targeted therapeutic approaches. METHODS: Hyaluronic acid (HA) decorated liposomes, containing diethyldithiocarbamate­copper (Cu(DDC)2), able to target the specific CSC marker CD44 receptor were prepared by ion gradient technique and fully characterized. Their antiproliferative effect was evaluated on pancreatic CSCs derived from PDAC cell lines or patients. To clarify the mechanism of action of Cu(DDC)2 liposomes, ROS level neutralization assay in the presence of N-acetyl-L-cysteine was performed. RESULTS: Liposomes showed high encapsulation efficiency and Cryo-TEM analysis revealed the presence of Cu(DDC)2 crystals in the aqueous core of liposomes. In vitro test on pancreatic CSCs derived from PDAC cell lines or patients showed high ROS mediated anticancer activity of HA decorated liposomes. The sphere formation capability of CSCs obtained from patients was drastically reduced by liposomal formulations containing Cu(DDC)2. CONCLUSIONS: The obtained results show that the encapsulation of Cu(DDC)2 complex in HA decorated liposomes strongly increases its anti-proliferative activity on pancreatic CSCs. GENERAL SIGNIFICANCE: This paper describes for the first time the use of HA decorated liposomes containing Cu(DDC)2 against pancreatic CSCs and opens the way to the development of nanomedicine based CSC-targeted therapeutic approaches.

Biocompatibility of polymer-based biomaterials and medical devices - regulations, in vitro screening and risk-management.

Biomaterials play an increasing role in modern health care systems. Biocompatibility poses a significant challenge for manufacturers of medical devices and contemporary intelligent drug delivery technologies from materials development to market approval. Despite a highly regulated environment, biocompatibility evaluation of biomaterials for medical devices is a complex task related to various factors that include mainly chemical nature and physical properties of the material, the contact tissue and duration of contact. Although international standards, such as ISO 10993-1, are generally employed to prove regulatory compliance needed for market clearance or for initiating clinical investigations, they may not offer sufficient guidance, or risk-management perspective when it comes to choosing materials or appropriate in vitro biocompatibility screening methods when developing medical devices. The global normative approach towards the biocompatibility evaluation of medical devices is presented in this review, with a focus on in vitro studies. Indeed, a risk-management approach towards the judicial choice of in vitro tests throughout the development and production of medical devices and drug delivery systems will facilitate rapid regulatory approval, avoid unnecessary animal studies, and ultimately reduce risks for patients. A detailed overview towards the construction of a comprehensive biological evaluation plan is described herein, with a focus on polymer-based materials used in medical applications. Polymeric materials offer a broad spectrum of applications in the manufacturing of medical devices. They are extensively employed within both conventional and innovative drug delivery systems with superior attributes supporting robust, extended use capacity, capable of meeting specific requirement such as adhesion, drug release, and more. Various methods of biocompatibility assessment are detailed within, with an emphasis on scientific analysis. This review may be of interest to those involved in the design, manufacturing and in vitro testing of medical devices and innovative drug delivery technologies, specifically with respect to a risk-management approach towards the biocompatibility assessment of polymer-based devices.