A human bone infection organ model for biomaterial research

Kuehling, Theodor; Schilling, Pia; Bernstein, Anke; Mayr, Hermann O.; Serr, Annerose; Wittmer, Annette; Bohner, Marc; Seidenstuecker, Michael

doi:10.1016/j.actbio.2022.03.020

Cited by 14 publications

(17 citation statements)

References 51 publications

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“…The release experiments from the ADA-GEL beads showed similar results in terms of the release of CLI to those we have published in the past [ 41 , 42 ]. However, the use of the ADA-GEL gel resulted in an increase in burst release compared to our previously published work.…”

Section: Discussionsupporting

confidence: 85%

“…The fact that the ADA-GEL gel structure was different from that of the pure alginate changed the burst release and the total release. Nevertheless, the application of the drug release system, in another part of the project, showed very good antimicrobial efficacy [ 42 ]. Sarker et al [ 43 ] also described in their work differences in the mechanical properties of the ADA-GEL gels compared to pure alginate gels.…”

Section: Discussionmentioning

confidence: 99%

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Gelatin Nanoparticles for Targeted Dual Drug Release out of Alginate-di-Aldehyde-Gelatin Gels

Schrade

Ritschl

Süss

et al. 2022

Gels

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The aim of the present work was to develop a dual staged drug release of an antibiotic (clindamycin) and a growth factor: bone morphogenetic protein-2 (BMP-2) from a biodegradable system consisting of hydrogel and gelatin nanoparticles (GNP). Two-step de-solvation allowed us to prepare GNPs (~100 nm) as drug carriers. Fluorescein isothiocyanate (FITC)-conjugated protein A was used as a model substance for BMP-2. A 28-day release experiment was performed to determine the release kinetics from GNP for both FITC-protein A and BMP-2, and for clindamycin (CLI) from the hydrogel. The size, structure, and overall morphology of GNP samples (empty, loaded with FITC-protein A and BMP-2) were examined using an environmental scanning electron microscope (ESEM). Cell culture assays (Live/dead; cell proliferation; cytotoxicity) were performed with MG-63 cells and BMP-2-loaded GNPs. Drug release experiments using clindamycin-loaded alginate-di-aldehyde (ADA) gelatin gels containing the drug-loaded GNPs were performed for 28 days. The resulting GNPs showed an empty size of 117 ± 29 nm, 176 ± 15 nm and 216 ± 36 nm when containing 2% FITC-protein A and 1% BMP-2, respectively. No negative effects of BMP-2-loaded GNPs on MG-63 cells were observed in live/dead staining. In the proliferation assay, an increase in cell proliferation was observed for both GNPs (GNP + BMP-2 and controls). The cytotoxicity assay continuously showed very low cytotoxicity for GNPs (empty; loaded). Clindamycin release showed a concentration of 25-fold higher than the minimum inhibitory concentration (MIC) against Staphylococcus aureus throughout the 28 day period. BMP-2 showed a reduced burst release and a steady release (~2 µg/mL) over a 28 day period.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Gelatin Nanoparticles for Targeted Dual Drug Release out of Alginate-di-Aldehyde-Gelatin Gels

Schrade

Ritschl

Süss

et al. 2022

Gels

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“…Tissue section‐based systems reported an initial lag phase regarding the bacterial count/activity – ranging from a few hours to some days, 31,32 attributed to an adjustment period in which bacterial cells modify the functionality in response to the altered environment 34 . In our model, an increased CFUs count was verified from day 1 onwards – growing exponentially with the lowest inoculum up to the 6th day and achieving a plateau from day 2 onwards with the higher inoculums.…”

Section: Discussionmentioning

confidence: 58%

“…Whether no external biomechanical stimuli were added to the system, the interactions of the cultured bone with the porous mesh of the culture insert further provided the contact stimuli required for the structured organotypic development of the bone, 27 and commonly found to be an issue within bone tissue ex vivo models. 17,27 Tissue section-based systems reported an initial lag phase regarding the bacterial count/activity -ranging from a few hours to some days, 31,32 attributed to an adjustment period in which bacterial cells modify the functionality in response to the altered environment. 34 In our model, an increased CFUs count was verified from day 1 onwardsgrowing exponentially with the lowest inoculum up to the 6th day and achieving a plateau from day 2 onwards with the higher inoculums.…”

Section: Discussionmentioning

confidence: 99%

“…Preliminary ex vivo infection models were conducted with the bacterial colonization of devitalized bovine 31 and fresh human tissue sections of trabecular bone, 32 showcasing the feasibility of a bone infection organ model. However, the use of tissue sections may significantly hamper the experimental reproducibility, given the large diversity of the macro‐ and micro‐structural arrangements within the tissue, further failing to model the cortical/trabecular arrangement 31,33 .…”

Section: Discussionmentioning

confidence: 99%

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Integrative tissue, cellular and molecular responsiveness of an innovative ex vivo model of the Staphylococcus aureus‐mediated bone infection

Mariano,

Grenho,

Fernandes

et al. 2023

The FASEB Journal

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Osteomyelitis is a pathological condition of the bone, frequently associated with the presence of infectious agents – namely Staphylococcus aureus – that induce inflammation and tissue destruction. Recent advances in the understanding of its pathophysiology and the identification of innovative therapeutic approaches were gathered from experimental in vitro and in vivo systems. However, cell culture models offer limited representativeness of the cellular functionality and the cell–cell and cell‐matrix interactions, further failing to mimic the three‐dimensional tissue organization; and animal models allow for limited mechanistic assessment given the complex nature of systemic and paracrine regulatory systems and are endorsed with ethical constraints. Accordingly, this study aims at the establishment and assessment of a new ex vivo bone infection model, upon the organotypic culture of embryonic chicken femurs colonized with S. aureus, highlighting the model responsiveness at the molecular, cellular, and tissue levels. Upon infection with distinct bacterial inoculums, data reported an initial exponential bacterial growth, followed by diminished metabolic activity. At the tissue level, evidence of S. aureus‐mediated tissue destruction was attained and demonstrated through distinct methodologies, conjoined with decreased osteoblastic/osteogenic and increased osteoclastic/osteoclastogenic functionalities—representative of the osteomyelitis clinical course. Overall, the establishment and characterization of an innovative bone tissue infection model that is simple, reproducible, easily manipulated, cost‐effective, and simulates many features of human osteomyelitis, further allowing the maintenance of the bone tissue's three‐dimensional morphology and cellular arrangement, was achieved. Model responsiveness was further demonstrated, showcasing the capability to improve the research pipeline in bone tissue infection‐related research.

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Composite material consisting of microporous beta-TCP ceramic and alginate-dialdehyde-gelatin for controlled dual release of clindamycin and bone morphogenetic protein 2

Ritschl

Schilling

Wittmer

et al. 2023

J Mater Sci: Mater Med

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The aim of this study was to produce a composite of microporous β-TCP filled with alginate-gelatin crosslinked hydrogel, clindamycin and bone morphogenetic protein (BMP-2) to prolong the drug-release behaviour for up to 28 days. The most promising alginate-di-aldehyde(ADA)-gelatin gel for drug release from microcapsules was used to fill microporous β-TCP ceramics under directional flow in a special loading chamber. Dual release of clindamycin and BMP-2 was measured on days 1, 2, 3, 6, 9, 14, 21 and 28 by high performance liquid chromatography (HPLC) and enzyme-linked immunosorbent assay (ELISA). After release, the microbial efficacy of the clindamycin was checked and the biocompatibility of the composite was tested in cell culture. Clindamycin and the model substance FITC-protein A were released from microcapsules over 28 days. The clindamycin burst release was 43 ± 1%. For the loaded ceramics, a clindamycin release above the minimal inhibitory concentration (MIC) until day 9 and a burst release of 90.56 ± 2.96% were detected. BMP-2 was released from the loaded ceramics in low concentrations over 28 days. The release of active substances from β-TCP and hydrogel have already been extensively studied. Directional flow loading is a special procedure in which the ceramic could act as a stabilizer in the bone and, as a biodegradable system, enables a single-stage surgical procedure. Whether ADA-gelatin gel is suitable for this procedure as a more biodegradable alternative to pure alginate or whether a dual release is possible in this composite has not yet been investigated. Graphical Abstract

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A human bone infection organ model for biomaterial research

Cited by 14 publications

References 51 publications

Gelatin Nanoparticles for Targeted Dual Drug Release out of Alginate-di-Aldehyde-Gelatin Gels

Gelatin Nanoparticles for Targeted Dual Drug Release out of Alginate-di-Aldehyde-Gelatin Gels

Integrative tissue, cellular and molecular responsiveness of an innovative ex vivo model of the Staphylococcus aureus‐mediated bone infection

Composite material consisting of microporous beta-TCP ceramic and alginate-dialdehyde-gelatin for controlled dual release of clindamycin and bone morphogenetic protein 2

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