Publications by authors named "M Croes"

22 Publications

Use of Therapeutic Pathogen Recognition Receptor Ligands for Osteo-Immunomodulation.

Materials (Basel) 2021 Feb 27;14(5). Epub 2021 Feb 27.

Department of Orthopedics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.

Therapeutic pathogen recognition receptor (PRR) ligands are reaching clinical practice following their ability to skew the immune response in a specific direction. We investigated the effects of various therapeutic PRR ligands on bone cell differentiation and inflammation. Following stimulation, alkaline phosphatase (ALP) activity (Day 10), osteocalcin, osteonectin expression (Day 14), and calcium deposition (Day 21) were quantified in bone marrow-derived human mesenchymal stem cells (hMSCs). The osteoclastogenic response was determined by measuring tartrate-resistant acid phosphate (TRAP) activity in human monocytes. TNF-α, IL-6, IL-8, and IL-10 expressions were measured by enzyme-linked immunosorbent assay as an indicator of the ligands' inflammatory properties. We found that nucleic acid-based ligands Poly(I:C) and CpG ODN C increased early ALP activity in hMSCs by 4-fold without affecting osteoclast formation. These ligands did not enhance expression of the other, late osteogenic markers. MPLA, Curdlan, and Pam3CSK4 did not affect osteogenic differentiation, but inhibited TRAP activity in monocytes, which was associated with increased expression of all measured cytokines. Nucleic acid-based ligands are identified as the most promising osteo-immunomodulators, as they favor early osteogenic differentiation without inducing an exaggerated immune-cell mediated response or interfering in osteoclastogenesis and thus can be potentially harnessed for multifunctional coatings for bone biomaterials.
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http://dx.doi.org/10.3390/ma14051119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957819PMC
February 2021

Combating Implant Infections: Shifting Focus from Bacteria to Host.

Adv Mater 2020 Oct 11;32(43):e2002962. Epub 2020 Sep 11.

Department of Orthopedics, University Medical Center Utrecht, Utrecht, 3508GA, The Netherlands.

The widespread use of biomaterials to support or replace body parts is increasingly threatened by the risk of implant-associated infections. In the quest for finding novel anti-infective biomaterials, there generally has been a one-sided focus on biomaterials with direct antibacterial properties, which leads to excessive use of antibacterial agents, compromised host responses, and unpredictable effectiveness in vivo. This review sheds light on how host immunomodulation, rather than only targeting bacteria, can endow biomaterials with improved anti-infective properties. How antibacterial surface treatments are at risk to be undermined by biomaterial features that dysregulate the protection normally provided by critical immune cell subsets, namely, neutrophils and macrophages, is discussed. Accordingly, how the precise modification of biomaterial surface biophysical cues, or the incorporation of immunomodulatory drug delivery systems, can render biomaterials with the necessary immune-compatible and immune-protective properties to potentiate the host defense mechanisms is reviewed. Within this context, the protective role of host defense peptides, metallic particles, quorum sensing inhibitors, and therapeutic adjuvants is discussed. The highlighted immunomodulatory strategies may lay a foundation to develop anti-infective biomaterials, while mitigating the increasing threat of antibacterial drug resistance.
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http://dx.doi.org/10.1002/adma.202002962DOI Listing
October 2020

Bactericidal coating to prevent early and delayed implant-related infections.

J Control Release 2020 10 21;326:38-52. Epub 2020 Jun 21.

Department of Orthopedics, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address:

The occurrence of an implant-associated infection (IAI) with the formation of a persisting bacterial biofilm remains a major risk following orthopedic biomaterial implantation. Yet, progress in the fabrication of tunable and durable implant coatings with sufficient bactericidal activity to prevent IAI has been limited. Here, an electrospun composite coating was optimized for the combinatorial and sustained delivery of antibiotics. Antibiotics-laden poly(ε-caprolactone) (PCL) and poly`1q`(lactic-co glycolic acid) (PLGA) nanofibers were electrospun onto lattice structured titanium (Ti) implants. In order to achieve tunable and independent delivery of vancomycin (Van) and rifampicin (Rif), we investigated the influence of the specific drug-polymer interaction and the nanofiber coating composition on the drug release profile and durability of the polymer-Ti interface. We found that a bi-layered nanofiber structure, produced by electrospinning of an inner layer of [PCL/Van] and an outer layer of [PLGA/Rif], yielded the optimal combinatorial drug release profile. This resulted in markedly enhanced bactericidal activity against planktonic and adherent Staphylococcus aureus for 6 weeks as compared to single drug delivery. Moreover, after 6 weeks, synergistic bacterial killing was observed as a result of sustained Van and Rif release. The application of a nanofiber-filled lattice structure successfully prevented the delamination of the multi-layer coating after press-fit cadaveric bone implantation. This new lattice design, in conjunction with the multi-layer nanofiber structure, can be applied to develop tunable and durable coatings for various metallic implantable devices. This is particularly appealing to tune the release of multiple antimicrobial agents over a period of weeks to prevent early and delayed onset IAI.
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http://dx.doi.org/10.1016/j.jconrel.2020.06.014DOI Listing
October 2020

A multifaceted biomimetic interface to improve the longevity of orthopedic implants.

Acta Biomater 2020 07 25;110:266-279. Epub 2020 Apr 25.

Department of Orthopedics, University Medical Center Utrecht, Utrecht 3508GA, the Netherlands.

The rise of additive manufacturing has provided a paradigm shift in the fabrication of precise, patient-specific implants that replicate the physical properties of native bone. However, eliciting an optimal biological response from such materials for rapid bone integration remains a challenge. Here we propose for the first time a one-step ion-assisted plasma polymerization process to create bio-functional 3D printed titanium (Ti) implants that offer rapid bone integration. Using selective laser melting, porous Ti implants with enhanced bone-mimicking mechanical properties were fabricated. The implants were functionalized uniformly with a highly reactive, radical-rich polymeric coating generated using a unique combination of plasma polymerization and plasma immersion ion implantation. We demonstrated the performance of such activated Ti implants with a focus on the coating's homogeneity, stability, and biological functionality. It was shown that the optimized coating was highly robust and possessed superb physico-chemical stability in a corrosive physiological solution. The plasma activated coating was cytocompatible and non-immunogenic; and through its high reactivity, it allowed for easy, one-step covalent immobilization of functional biomolecules in the absence of solvents or chemicals. The activated Ti implants bio-functionalized with bone morphogenetic protein 2 (BMP-2) showed a reduced protein desorption and a more sustained osteoblast response both in vitro and in vivo compared to implants modified through conventional physisorption of BMP-2. The versatile new approach presented here will enable the development of bio-functionalized additively manufactured implants that are patient-specific and offer improved integration with host tissue. STATEMENT OF SIGNIFICANCE: Additive manufacturing has revolutionized the fabrication of patient-specific orthopedic implants. Although such 3D printed implants can show desirable mechanical and mass transport properties, they often require surface bio-functionalities to enable control over the biological response. Surface covalent immobilization of bioactive molecules is a viable approach to achieve this. Here we report the development of additively manufactured titanium implants that precisely replicate the physical properties of native bone and are bio-functionalized in a simple, reagent-free step. Our results show that covalent attachment of bone-related growth factors through ion-assisted plasma polymerized interlayers circumvents their desorption in physiological solution and significantly improves the bone induction by the implants both in vitro and in vivo.
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http://dx.doi.org/10.1016/j.actbio.2020.04.020DOI Listing
July 2020

Impact of atrial programmed electrical stimulation techniques on unipolar electrogram morphology.

J Cardiovasc Electrophysiol 2020 04 25;31(4):943-951. Epub 2020 Feb 25.

Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands.

Introduction: Intra-atrial conduction abnormalities are associated with the development of atrial fibrillation (AF) and cause morphological changes of the unipolar atrial electrogram (U-AEGM). This study examined the impact of different atrial programmed electrical stimulation (APES) protocols on U-AEGM morphology to identify the most optimal APES protocol provoking conduction abnormalities.

Methods: APES techniques (14 protocols) were applied in 30 patients referred for an electrophysiology study, consisting of fixed rate, extra, and decremental stimuli at different frequencies. U-AEGM morphologies including width, amplitude, and fractionation for patients without (control group) and with a history of AF (AF group) were examined during APES. In addition, sinus rhythm (SR) U-AEGMs preceding different APES protocols were compared to evaluate the morphology stability over time.

Results: U-AEGM morphologies during SR before the APES protocols were comparable (all P > .396). Atrial refractoriness was longer in the AF group compared to the control group (298 ± 48 vs 255 ± 33 ms; P ≤ .020), but did not differ between AF patients with and without amiodarone therapy (278 ± 48 vs 311 ± 40 ms; P ≥ .126). Compared to the initial SR morphology, U-AEGM width, amplitude, and fractionation changed significantly during the 14 different APES protocols, particularly in the AF group. In both groups, U-AEGM changes in morphology were most pronounced during fixed-rate stimulation with extra stimuli (8S1-S2 = 400-250 ms).

Conclusion: APES results in significant changes in U-AEGM morphology, including width, amplitude, and fractionation. The impact of APES differed between APES sequence and between patients with and without AF. These findings suggest that APES could be useful to identify AF-related conduction abnormalities in the individual patient.
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http://dx.doi.org/10.1111/jce.14394DOI Listing
April 2020