Biodegradable Poly(ester) Urethane Acrylate Resins for Digital Light Processing: From Polymer Synthesis to 3D Printed Tissue Engineering Constructs.

Digital light processing (DLP) is an accurate and fast additive manufacturing technique to produce a variety of products, from patient-customized biomedical implants to consumer goods. However, DLP's use in tissue engineering has been hampered due to a lack of biodegradable resin development. Herein, a library of biodegradable poly(esters) capped with urethane acrylate (with variations in molecular weight) is investigated as the basis for DLP printable resins for tissue engineering. The synthesized oligomers show good printability and are capable of creating complex structures with mechanical moduli close to those of medium-soft tissues (1-3 MPa). While fabricated films from different molecular weight resins show few differences in surface topology, wettability, and protein adsorption, the adhesion and metabolic activity of NCTC clone 929 (L929) cells and human dermal fibroblasts (HDFs) are significantly different. Resins from higher molecular weight oligomers provide greater cell adhesion and metabolic activity. Furthermore, these materials show compatibility in a subcutaneous in vivo pig model. These customizable, biodegradable, and biocompatible resins show the importance of molecular tuning and open up new possibilities for the creation of biocompatible constructs for tissue engineering.

Surface modifications to promote the osteoconductivity of ultra-high-molecular-weight-polyethylene fabrics for a novel biomimetic artificial disc prosthesis: An in vitro study.

A novel biomimetic artificial intervertebral disc (bioAID) for the cervical spine was developed, containing a hydrogel core representing the nucleus pulposus, an UHMWPE fiber jacket as annulus fibrosis, and titanium endplates with pins for mechanical fixation. Osseointegration of the UHMWPE fibers to adjacent bone structures is required to achieve proper biomimetic behavior and to provide long-term stability. Therefore, the aim of this study was to assess the osteoconductivity of several surface modifications of UHMWPE fabrics, 2D weft-knitted, using non-treated UHMWPE fibers (N), plasma treated UHMWPE fibers (PT), 10% hydroxy apatite (HA) loaded UHMWPE fibers (10%HA), plasma treated 10%HA UHMWPE fibers (PT-10%HA), 15%HA loaded UHMWPE fibers (15%HA) and plasma treated 15%HA UHMWPE fibers (PT-15%HA). Scanning electron microscopy (SEM) was used for surface characterization. Biological effects were assessed by evaluating initial cell attachment (SEM, DNA content), metabolic activity (PrestoBlue assay), proliferation, differentiation (alkaline phosphatase activity) and mineralization (energy dispersive x-ray, EDX analysis) using human bone marrow stromal cells. Plasma treated samples showed increased initial cell attachment, indicating the importance of hydrophilicity for cell attachment. However, incorporation only of HA or plasma treatment alone was not sufficient to result in upregulated alkaline phosphatase activity (ALP) activity. Combining HA loaded fibers with plasma treatment showed a combined effect, leading to increased cell attachment and upregulated ALP activity. Based on these results, combination of HA loaded UHMWPE fibers and plasma treatment provided the most promising fabric surface for facilitating bone ingrowth.

Supramolecular Biomaterials in the Netherlands.

Synthetically designed biomaterials strive to recapitulate and mimic the complex environment of natural systems. Using natural materials as a guide, the ability to create high-performance biomaterials that control cell fate, and support the next generation of cell- and tissue-based therapeutics, is starting to emerge. Supramolecular chemistry takes inspiration from the wealth of noncovalent interactions found in natural materials that are inherently complex, and using the skills of synthetic and polymer chemistry, recreates simple systems to imitate their features. Within the past decade, supramolecular biomaterials have shown utility in tissue engineering and the progress predicts a bright future. On this 30th anniversary of the Netherlands Biomaterials and Tissue Engineering society, we briefly recount the state of supramolecular biomaterials in the Dutch academic and industrial research and development context. This review provides the background, recent advances, industrial successes and challenges, as well as future directions of the field, as we see it. Throughout this work, we notice the intricate interplay between simplicity and complexity in creating more advanced solutions. We hope that the interplay and juxtaposition between these two forces can propel the field forward. Impact statement Supramolecular biomaterials based on noncovalent interactions hold the ability to rebuild some of the complexity of natural biomaterials in synthetic systems. While still in its infancy, the field is currently vigorously moving from fundamental experiments toward applications and products in the tissue engineering and regenerative medicine arena. Herein, we review the current state of the field in the Netherlands. While supramolecular biomaterials have incredible potential, systematic studies, balancing complexity and simplicity, efficient translation, and enhanced performance are all required for success of these strategies. As we move the field toward commercial solutions for clinical patients, we must also pay homage and remember the fundamental studies that allow these jumps in innovation.

Pharmacokinetics and efficacy of a ketorolac-loaded ocular coil in New Zealand white rabbits.

Eye drops are considered standard practice for the delivery of ocular drugs. However, low patient compliance and low drug levels compromise its effectiveness. Our group developed a ketorolac-loaded ocular coil for sustained drug delivery up to 28 days. The aim of this study was to gain insight into the pharmacokinetics and efficacy of the ocular coil. The pharmacokinetics of the ketorolac-loaded ocular coil versus eye drops were tested in New Zealand White rabbits by repetitive sampling for 28 days. Efficacy of the ocular coil was also tested in New Zealand White rabbits. Ocular inflammation was induced where after the ocular coil was inserted, or eye drops, or no treatment was provided. The total protein concentration and cytokine levels were measured in tears, aqueous humor, and plasma at 4 h, 8 h, 24 h, 4 d, 7 d, 14 d, 21 d, and 28 d. Four h after inserting the ocular coil in the eye, ketorolac levels in aqueous humor and plasma were higher in the ocular coil group than in the eye drop group. Ketorolac released from the ocular coil could be detected up to 28 d in tears, up to 4 d in aqueous humor and up to 24 h in plasma. After inducing inflammation, both the ocular coil and eye drops were able to suppress prostaglandin E2, TNFα and IL-6 levels in aqueous humor and plasma as compared to the group that received no treatment. To conclude, the ocular coil facilitated a sustained release of the drug and showed similar therapeutic benefit in suppressing post-operative inflammation as eye drops.

Design of the ocular coil, a new device for non-invasive drug delivery.

Eye drops and ointments are the most prescribed methods for ocular drug delivery. However, due to low drug bioavailability, rapid drug elimination, and low patient compliance there is a need for improved ophthalmic drug delivery systems. This study provides insights into the design of a new drug delivery device that consists of an ocular coil filled with ketorolac loaded PMMA microspheres. Nine different ocular coils were created, ranging in wire diameter and coiled outer diameter. Based on its microsphere holding capacity and flexibility, one type of ocular coil was selected and used for further experiments. No escape of microspheres was observed after bending the ocular coil at curvature which reflect the in vivo situation in human upon positioning in the lower conjunctival sac. Shape behavior and tissue contact were investigated by computed tomography imaging after inserting the ocular coil in the lower conjunctival fornix of a human cadaver. Thanks to its high flexibility, the ocular coil bends along the circumference of the eye. Because of its location deep in the fornix, it appears unlikely that in vivo, the ocular coil will interfere with eye movements. In vitro drug release experiments demonstrate the potential of the ocular coil as sustained drug delivery device for the eye. We developed PMMA microspheres with a 26.5 ± 0.3 wt% ketorolac encapsulation efficiency. After 28 days, 69.9% ± 5.6% of the loaded ketorolac was released from the ocular coil when tested in an in vitro lacrimal system. In the first three days high released dose (48.7% ± 5.4%) was observed, followed by a more gradually release of ketorolac. Hence, the ocular coil seems a promising carrier for ophthalmic drugs delivery in the early postoperative time period.

Safety and Comfort of an Innovative Drug Delivery Device in Healthy Subjects.

Purpose: The aim of this study was to investigate safety and comfort of two versions of a placebo-microsphere filled ocular coil (straight and curved) in healthy subjects. Methods: The study was a single-center intervention study. One ocular coil was placed in the inferior conjunctival fornix for the intended duration of 28 days. Forty-two healthy adult subjects were included. At baseline, 30 minutes, 8 hours, 24 hours, 48 hours, 7 days, 14 days, 21 days, and 28 days after insertion, examinations were performed, including slit lamp evaluation to score ocular redness, intraocular pressure measurement, visual acuity, tear secretion test, and questionnaires. Results: The straight and curved ocular coils had a median retention time of 5 days and 12 days, respectively. After 48 hours, 57% and 81% subjects retained the straight and curved ocular coil, respectively. Four (19%) subjects with the straight coil and six (29%) with the curved coil completed the entire study period. Minor changes in ocular hyperemia were observed in both groups. On day 7, the straight coil was more comfortable than the curved coil with a visual analogue scale (VAS) score of 77 ± 21 compared to 94 ± 11 (P = 0.028), respectively. No other ocular adverse events were observed. Conclusions: Comfort and safety of the straight and curved ocular coil are high. Because the retention time is too short for long-term sustained drug release, the use in the perioperative or immediate postoperative period could prove to be more valuable. Translational Relevance: The ocular coil is a noninvasive, comfortable and safe short-term drug delivery device.

Poly(caprolactone-co-trimethylenecarbonate) urethane acrylate resins for digital light processing of bioresorbable tissue engineering implants.

To exploit the usability of Digital Light Processing (DLP) in regenerative medicine, biodegradable, mechanically customizable and well-defined polyester urethane acrylate resins were synthesized based on poly(caprolactone-co-trimethlenecarbonate). By controlling the monomer ratio, the resultant fabricated constructs showed tunable mechanical properties, degradation and attached hMSC morphologies.

Polypeptide Polymer Brushes by Light-Induced Surface Polymerization of Amino Acid N-Carboxyanhydrides.

Silicon wafers are decorated with photoamine generator 4,5-dimethoxy-2-nitrobenzyl 3-(triethoxysilyl)propyl carbamate. UV-irradiation in the presence of benzyl-l-glutamate N-carboxyanhydride is carried out, resulting in the release of the surface-bound primary amines, making them viable N-carboxyanhydride (NCA) polymerization initiators. Successful polypeptide grafting is confirmed by water contact angle measurements as well as by ellipsometry, revealing a poly(benzyl-l-glutamate) (PBLG) layer of ≈3 nm. X-ray photoelectron spectroscopy confirms the presence of amide groups in the grafted PBLG while time-of-flight secondary ion mass spectroscopy provides additional evidence for the presence of PBLG on the surface. Evaluation of negative control samples confirms successful UV surface grafting. The approach is thus established as a viable general method for light exposure directable polypeptide functionalization of silicon surfaces.

Exploring Tyrosine-Triazolinedione (TAD) Reactions for the Selective Conjugation and Cross-Linking of N-Carboxyanhydride (NCA) Derived Synthetic Copolypeptides.

Highly efficient functionalization and cross-linking of polypeptides is achieved via tyrosine-triazolinedione (TAD) conjugation chemistry. The feasibility of the reaction is demonstrated by the reaction of 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) with tyrosine containing block copolymer poly(ethylene glycol)-Tyr4 as well as a statistical copolymer of tyrosine and lysine (poly(Lys40 -st-Tyr10 )) prepared form N-carboxyanhydride polymerization. Selective reaction of PTAD with the tyrosine units is obtained and verified by size exclusion chromatography and NMR spectroscopy. Moreover, two monofunctional and two difunctional TAD molecules are synthesized. It is found that their stability in the aqueous reaction media significantly varied. Under optimized reaction conditions selective functionalization and cross-linking, yielding polypeptide hydrogels, can be achieved. TAD-mediated conjugation can offer an interesting addition in the toolbox of selective (click-like) polypeptide conjugation methodologies as it does not require functional non-natural amino acids.

Evaluation of polyesteramide (PEA) and polyester (PLGA) microspheres as intravitreal drug delivery systems in albino rats.

PURPOSE: To study the suitability of injectable microspheres based on poly(ester amide) (PEA) or poly lactic-co-glycolic acid (PLGA) as potential vehicles for intravitreal drug delivery in rat eyes. Dexamethasone-loaded PEA microspheres (PEA + DEX) were also evaluated. METHODS: Forty male Sprague Dawley rats were divided into four groups that received different intravitreally injected microspheres: PEA group (n = 12); PLGA group (n = 12); PEA + DEX group (n = 8); and control group (no injection, n = 8). Electroretinography (ERG), fundus autofluorescence (FAF), and spectral domain optical coherence tomography (sdOCT) were performed at baseline, weeks 1 and 2, and months 1, 2, and 3 after intravitreal injection. Eyes were histologically examined using light microscopy and transmission electron microscopy at the end of the in vivo study. RESULTS: There were no statistically significant changes in ERG among the groups. Abnormal FAF pattern and abnormal deposits in OCT were observed after injection but almost completely disappeared between week 2 and month 3 in all injected groups. GFAP staining showed that Müller glia cell activation was most pronounced in PLGA-injected eyes. Increased cell death was not observed by TUNEL staining at month 1. In electron microscopy at month 3, the remnants of microparticles were found in the retinal cells of all injected groups, and loss of plasma membrane was seen in the PLGA group. CONCLUSIONS: Although morphological changes such as mild glial activation and material remnants were observed histologically 1 month and 3 months after injection in all injected groups, minor cell damage was noted only in the PLGA group at 3 months after injection. No evidence of functional abnormality relative to untreated eyes could be detected by ERG 3 months after injection in all groups. Changes observed in in vivo imaging such as OCT and FAF disappeared after 3 months in almost all cases.

Reductively degradable α-amino acid-based poly(ester amide)-graft-galactose copolymers: facile synthesis, self-assembly, and hepatoma-targeting doxorubicin delivery.

Novel reductively degradable α-amino acid-based poly(ester amide)-graft-galactose (SSPEA-Gal) copolymers were designed and developed to form smart nano-vehicles for active hepatoma-targeting doxorubicin (DOX) delivery. SSPEA-Gal copolymers were readily synthesized via solution polycondensation reaction of di-p-toluenesulfonic acid salts of bis-l-phenylalanine 2,2-thiodiethanol diester and bis-vinyl sulfone functionalized cysteine hexanediol diester with dinitrophenyl ester of adipic acid, followed by conjugating with thiol-functionalized galactose (Gal-SH) via the Michael addition reaction. SSPEA-Gal formed unimodal nanoparticles (PDI = 0.10 - 0.12) in water, in which average particle sizes decreased from 138 to 91 nm with increasing Gal contents from 31.6 wt% to 42.5 wt%. Notably, in vitro drug release studies showed that over 80% DOX was released from SSPEA-Gal nanoparticles within 12 h under an intracellular mimicking reductive conditions, while low DOX release (<20%) was observed for reduction-insensitive PEA-Gal nanoparticles under otherwise the same conditions and SSPEA-Gal nanoparticles under non-reductive conditions. Notably, SSPEA-Gal nanoparticles exhibited high specificity to asialoglycoprotein receptor (ASGP-R)-overexpressing HepG2 cells. MTT assays using HepG2 cells showed that DOX-loaded SSPEA-Gal had a low half maximal inhibitory concentration (IC50) of 1.37 µg mL(-1), approaching that of free DOX. Flow cytometry and confocal laser scanning microscopy studies confirmed the efficient uptake of DOX-loaded SSPEA-Gal nanoparticles by HepG2 cells as well as fast intracellular DOX release. Importantly, SSPEA-Gal and PEA-Gal nanoparticles were non-cytotoxic to HepG2 and MCF-7 cells up to a tested concentration of 1.0 mg mL(-1). These tumor-targeting and reduction-responsive degradable nanoparticles have appeared as an interesting multi-functional platform for advanced drug delivery.

Novel biodegradable polyesteramide microspheres for controlled drug delivery in Ophthalmology.

Most of the posterior segment diseases are chronic and multifactorial and require long-term intraocular medication. Conventional treatments of these pathologies consist of successive intraocular injections, which are associated with adverse effects. Successful therapy requires the development of new drug delivery systems able to release the active substance for a long term with a single administration. The present work involves the description of a new generation of microspheres based on poly(ester amide)s (PEA), which are novel polymers with improved biodegradability, processability and good thermal and mechanical properties. We report on the preparation of the PEA polymer, PEA microspheres (PEA Ms) and their characterization. PEA Ms (~15µm) were loaded with a lipophilic drug (dexamethasone) (181.0±2.4µg DX/mg Ms). The in vitro release profile of the drug showed a constant delivery for at least 90days. Based on the data from a performed in vitro release study, a kinetic ocular model to predict in vivo drug concentrations in a rabbit vitreous was built. According to the pharmacokinetic simulations, intravitreal injection of dexamethasone loaded PEA microspheres would provide release of the drug in rabbit eyes up to 3months. Cytotoxicity studies in macrophages and retinal pigment epithelial cells revealed a good in vitro tolerance of the microsystems. After sterilization, PEA Ms were administered in vivo by subtenon and intravitreal injections in male Sprague-Dawley rats and the location of the microspheres in rat eyes was monitored. We conclude that PEA Ms provide an alternative delivery system for controlling the delivery of drugs to the eye, allowing a novel generation of microsphere design.

Enzymatically and reductively degradable α-amino acid-based poly(ester amide)s: synthesis, cell compatibility, and intracellular anticancer drug delivery.

A novel and versatile family of enzymatically and reductively degradable α-amino acid-based poly(ester amide)s (SS-PEAs) were developed from solution polycondensation of disulfide-containing di-p-toluenesulfonic acid salts of bis-l-phenylalanine diesters (SS-Phe-2TsOH) with di-p-nitrophenyl adipate (NA) in N,N-dimethylformamide (DMF). SS-PEAs with Mn ranging from 16.6 to 23.6 kg/mol were obtained, depending on NA/SS-Phe-2TsOH molar ratios. The chemical structures of SS-PEAs were confirmed by (1)H NMR and FTIR spectra. Thermal analyses showed that the obtained SS-PEAs were amorphous with a glass transition temperature (Tg) in the range of 35.2-39.5 °C. The in vitro degradation studies of SS-PEA films revealed that SS-PEAs underwent surface erosion in the presence of 0.1 mg/mL α-chymotrypsin and bulk degradation under a reductive environment containing 10 mM dithiothreitol (DTT). The preliminary cell culture studies displayed that SS-PEA films could well support adhesion and proliferation of L929 fibroblast cells, indicating that SS-PEAs have excellent cell compatibility. The nanoparticles prepared from SS-PEA with PVA as a surfactant had an average size of 167 nm in phosphate buffer (PB, 10 mM, pH 7.4). SS-PEA nanoparticles while stable under physiological environment undergo rapid disintegration under an enzymatic or reductive condition. The in vitro drug release studies showed that DOX release was accelerated in the presence of 0.1 mg/mL α-chymotrypsin or 10 mM DTT. Confocal microscopy observation displayed that SS-PEA nanoparticles effectively transported DOX into both drug-sensitive and -resistant MCF-7 cells. MTT assays revealed that DOX-loaded SS-PEA nanoparticles had a high antitumor activity approaching that of free DOX in drug-sensitive MCF-7 cells, while more than 10 times higher than free DOX in drug-resistant MCF-7/ADR cells. These enzymatically and reductively degradable α-amino acid-based poly(ester amide)s have provided an appealing platform for biomedical technology in particular controlled drug delivery applications.

Controlled block copolymer micelle formation for encapsulation of hydrophobic ingredients.

We report on the formation of polymeric micelles in water using triblock copolymers with a polyethylene glycol middle block and various hydrophobic outer blocks prepared with the precipitation method. We form micelles in a reproducible manner with a narrow size distribution. This suggests that during the formation of the micelles the system had time to form micelles under close-to-thermodynamic control. This may explain why it is possible to use an equilibrium self-consistent field theory to predict the hydrodynamic size and the loading capacity of the micelles in accordance with experimental finding. Yet, the micelles are structurally quenched as concluded from the observation of size stability in time. We demonstrate that our approach enables to prepare rather hydrophobic block copolymer micelles with tunable size and loading.

α-Amino acid containing degradable polymers as functional biomaterials: rational design, synthetic pathway, and biomedical applications.

Currently, biomedical engineering is rapidly expanding, especially in the areas of drug delivery, gene transfer, tissue engineering, and regenerative medicine. A prerequisite for further development is the design and synthesis of novel multifunctional biomaterials that are biocompatible and biologically active, are biodegradable with a controlled degradation rate, and have tunable mechanical properties. In the past decades, different types of α-amino acid-containing degradable polymers have been actively developed with the aim to obtain biomimicking functional biomaterials. The use of α-amino acids as building units for degradable polymers may offer several advantages: (i) imparting chemical functionality, such as hydroxyl, amine, carboxyl, and thiol groups, which not only results in improved hydrophilicity and possible interactions with proteins and genes, but also facilitates further modification with bioactive molecules (e.g., drugs or biological cues); (ii) possibly improving materials biological properties, including cell-materials interactions (e.g., cell adhesion, migration) and degradability; (iii) enhancing thermal and mechanical properties; and (iv) providing metabolizable building units/blocks. In this paper, recent developments in the field of α-amino acid-containing degradable polymers are reviewed. First, synthetic approaches to prepare α-amino acid-containing degradable polymers will be discussed. Subsequently, the biomedical applications of these polymers in areas such as drug delivery, gene delivery and tissue engineering will be reviewed. Finally, the future perspectives of α-amino acid-containing degradable polymers will be evaluated.

Epicardial application of an amiodarone-releasing hydrogel to suppress atrial tachyarrhythmias.

BACKGROUND: Amiodarone is currently the most effective antiarrhythmic drug for sinus rhythm maintenance. However, due to serious extracardiac adverse effects, prophylactic amiodarone therapy is only appropriate for patients at high risk for postoperative atrial fibrillation (AF). We hypothesized that epicardial application of an amiodarone-releasing hydrogel would produce therapeutic myocardial drug concentrations, while systemic levels would remain low. METHODS: Goats were fitted with right atrial epicardial patch electrodes. A poly(ethylene glycol)-based hydrogel with amiodarone (1mg/kg bw) (n=10) or without drug (n=6) was applied to the right atrial epicardium. Atrial effective refractory period (AERP), conduction time and atrial response to burst pacing (rapid atrial response, RAR) were assessed up to 28days in awake goats. Myocardial, plasma and extracardiac tissue amiodarone concentrations were analysed by high-performance liquid chromatography. RESULTS: The amiodarone-loaded hydrogel produced therapeutic drug concentrations in the right atrium up to 21days after application. In this period, AERP and conduction time were prolonged, while RAR inducibility was reduced (P<0.05) compared to animals treated with drug-free hydrogel. Mean amiodarone concentrations in the right atrium were 1 order of magnitude higher than in other heart chambers and 2 orders of magnitude higher than in extracardiac tissues. Plasma amiodarone levels remained below the detection limit (<10ng/mL) during the 28-day follow-up. CONCLUSIONS: Epicardial application of an amiodarone-releasing hydrogel reduces atrial vulnerability to tachyarrhythmias up to 3weeks, while extracardiac drug levels remain low. Therefore, amiodarone-releasing hydrogel could be applied during cardiac surgery to prevent postoperative AF at minimal risk for extracardiac adverse side effects.

Atrium-targeted drug delivery through an amiodarone-eluting bilayered patch.

OBJECTIVE: Clinical studies have demonstrated the efficacy of oral and intravenous amiodarone therapy to prevent postoperative atrial fibrillation. However, because of significant extracardiac side effects, only high-risk patients are eligible for prophylactic amiodarone therapy. This study addressed the hypothesis that atrium-specific drug delivery through an amiodarone-eluting epicardial patch reduces vulnerability to atrial tachyarrhythmias, whereas ventricular and plasma drug concentrations are minimized. METHODS: Right atrial epicardiums of goats were fitted with electrodes and a bilayered patch (poly[ethylene glycol]-based matrix and poly[lactide-co-caprolactone] backing layer) loaded with amiodarone (10 mg per patch, n = 10) or without drug (n = 6). Electrophysiologic parameters (atrial effective refractory period, conduction time, and rapid atrial response to burst pacing) and amiodarone levels in plasma and tissue were measured during 1 month's follow-up. RESULTS: Epicardial application of amiodarone-eluting patches produced persistently higher drug concentrations in the right atrium than in the left atrium, ventricles, and extracardiac tissues by 2 to 4 orders of magnitude. Atrial effective refractory period and conduction time increased, whereas rapid atrial response inducibility decreased significantly (P < .05) during the 1-month follow-up compared with that seen in animals treated with drug-free patches. Amiodarone concentrations in plasma remained undetectably low (<10 ng/mL). CONCLUSIONS: Atrium-specific drug delivery through an amiodarone-eluting patch produces therapeutic atrial drug concentrations, whereas ventricular and systemic drug levels are minimized. This study demonstrates that sustained targeted drug delivery to a specific heart chamber is feasible and might reduce the risk for ventricular and extracardiac adverse effects. Epicardial application of amiodarone-eluting patches is a promising strategy to prevent postoperative atrial fibrillation.

The relationship between the antimicrobial effect of catheter coatings containing silver nanoparticles and the coagulation of contacting blood.

It is well known that surface coatings for medical devices can be made antimicrobial through introduction of silver nanoparticles. By virtue of their extremely large surface-to-volume ratio, the silver particles serve as a depot for sustained release of silver ions, despite the fact that silver is not readily oxidized. Antimicrobial coatings are especially important in connection with indwelling catheters with a high risk of bacterial line infections, such as central venous catheters (CVCs). This study specifically addressed the question what the impact of silver nanoparticles (exposed at the coating's surface) and/or the release of silver ions would be on coagulation of contacting blood. Studies, performed in vitro with fresh platelet-rich blood plasma (PRP) from 5 different healthy volunteer donors, clearly pointed out that: (i) the presence of silver nanoparticles correlates with accelerated thrombin formation upon contact of the coating with PRP; (ii) platelet activation is stronger as a result from the contact with silver nanoparticle-containing coatings as compared to other coatings which are devoid of silver. A series of titration experiments, in which the potential effect of silver ions is mimicked, revealed that the observed activation of blood platelets can be best explained through a collision mechanism. The results suggest that platelets that collide with silver, exposed at the surface, become activated without adhering to the surface. These new results point, rather unexpectedly, at a double effect of the silver nanoparticles in the coating: a strong antimicrobial effect occurs simultaneously with acceleration of the coagulation of contacting blood. This new information is, evidently, most relevant for the development of improved surface coatings for indwelling catheters (such as CVCs) which should combine antimicrobial features and close-to-zero thrombogenicity.

The evolving functionalities of coating.

Coatings that mediate the interface between biological tissue and implant are arguably some of the most critical material components that affect the performance of a medical device. Developments in coatings for catheters and stents are reviewed here and include biodegradable and cell signalling coatings that are currently in clinical trials.