Repurposing biodegradable tissue engineering scaffolds for localized chemotherapeutic delivery

Cyphert, Erika L.; Bil, Monika; Recum, Horst A. von; Święszkowski, Wojciech

doi:10.1002/jbm.a.36889

Cited by 9 publications

(9 citation statements)

References 36 publications

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“…RIF release quickly reached a plateau from the microparticles, yet the β-CD disk continued to sustain RIF release until day 30. With the β-cyclodextrin disks utilized in this study, the molecular weight and hydrophobicity of the drugs were found to correlate more closely with loading efficiency (Pearson correlation coefficients of r = −0.761 and r = −0.555, respectively [40]) than the affinity measurements (correlation coefficient of r = −0.390). Binding affinity correlated more with drug release rate from cyclodextrin-based polymers (r = −0.283) than molecular weight with release rate (r = −0.145), while solubility maintained a larger effect on the release half-life (r = −0.490).…”

Section: Drug-polymer Characteristics Juxtaposed With Release Datamentioning

confidence: 84%

Affinity Effects on the Release of Non-Conventional Antifibrotics from Polymer Depots

2020

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For many chronic fibrotic conditions, there is a need for local, sustained antifibrotic drug delivery. A recent trend in the pharmaceutical industry is the repurposing of approved drugs. This paper investigates drugs that are classically used for anthelmintic activity (pyrvinium pamoate (PYR)), inhibition of adrenal steroidgenesis (metyrapone (MTP)), bactericidal effect (rifampicin (RIF), and treating iron/aluminum toxicity (deferoxamine mesylate (DFOA)), but are also under investigation for their potential positive effect in wound healing. In this role, they have not previously been tested in a localized delivery system suitable for obtaining the release for the weeks-to-months timecourse needed for wound resolution. Herein, two cyclodextrin-based polymer systems, disks and microparticles, are demonstrated to provide the long-term release of all four tested non-conventional wound-healing drugs for up to 30 days. Higher drug affinity binding, as determined from PyRx binding simulations and surface plasmon resonance in vitro, corresponded with extended release amounts, while drug molecular weight and solubility correlated with the improved drug loading efficiency of cyclodextrin polymers. These results, combined, demonstrate that leveraging affinity interactions, in combination with drug choice, can extend the sustained release of drugs with an alternative, complimentary action to resolve wound-healing and reduce fibrotic processes. 126To first predict the relative binding affinities of the chosen drugs for the β-CD versus dextran 127 (chemically similar control without inclusion complex), a molecular docking program was utilized 128 (PyRx with Autodock Vina software [28,35]). The β-CD monomer, dextran, and drug molecule 129 structure files were downloaded from online databases as specified in the methods section (Figure 130 1A). DFOA, RIF, MTP, and PYR were individually simulated to determine minimal binding energy 131 configurations with either β-CD or dextran as the target host macromolecule. The results were 132 converted to dissociation constants for each simulated pair. 133 134 Figure 1. (A) Molecular structures of rifampicin (RIF), metyrapone (MTP), pyrvinium (PYR), and 135 deferoxamine (DFOA) represented in 3D with JMOL software showing relative size and potential 136 binding conformations for the β-CD inclusion complex formation. (B) PyRx simulations were 137 performed to predict the binding affinity of drugs with β-CD versus dextran as a chemically similar, 138 but non-inclusion-forming, control, as dextran lacks the binding cavity of β-CD. 139The lowest KD (highest binding affinity) was predicted for RIF and β-CD (0.04 mM), while the 140 KD for MTP and PYR β-CD complexes were more than twice as large at 0.098 and 0.104 mM, 141 respectively ( Figure 1B). DFOA resulted in the highest KD out of all the β-CD simulations at 1.463 142 mM. When the drugs were simulated with dextran, the KD values were higher. The combination of 143 RIF and dextran demonstrated a KD of 1.776 mM, followed by PYR-dextran (4.770 m...

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Section: Drug-polymer Characteristics Juxtaposed With Release Datamentioning

confidence: 84%

Affinity Effects on the Release of Non-Conventional Antifibrotics from Polymer Depots

2020

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“…In previous in vivo experiments, differences were demonstrated in the IM characteristics with regards to TNFα, VEGF and BMP expression between coated and non-coated BAG-S53P4 scaffolds without any obvious deleterious effects (Björkenheim et al, 2017;Björkenheim et al, 2019). The rationale behind the rapid degradation profile of the utilised PLGAminimum of 14 d (Cyphert et al, 2020) -was to allow the BAG-S53P4 to interact with the surroundings as early as possible to hinder the formation of a fibrotic capsule. These findings were hypothesised to be due to a stronger initial inflammatory reaction of PLGAcoated scaffolds compared to uncoated BAG-S53P4 scaffolds alone, leading to a formation of a biologically more active IM.…”

Section: Discussionmentioning

confidence: 99%

“…Designated BAG scaffolds were dip coated with an acid-terminated PLGA called PDLG5002A at a 50 : 50 ratio between DL-lactide and glycolide (Corbion, Gorinchem, the Netherlands). The theoretical minimum degradation time of the utilised PLGA is 14 d (Cyphert et al, 2020). After coating, the BAG-S53P4-PLGA scaffolds were dried in air and vacuum.…”

Section: Methodsmentioning

confidence: 99%

“…To study the indirect immunomodulatory effect of BAGs, BAG-S53P4 and BAG-S53P4-PLGA scaffolds were introduced to the wells on day 6 of macrophage culturing, thereby allowing the scaffolds to interact with cells for 24 h. On day 7, culture media were further supplemented with 100 ng/mL LPS (Sigma-Aldrich) for either 6 or 24 h. At both timepoints, cell lysates and media samples were obtained as described above. LPS concentration was chosen based on a previous investigation (Day and Boccaccini, 2005). All stimulations were performed in duplicate wells, with appropriate controls included.…”

Section: Macrophage Stimulation With Scaffoldsmentioning

confidence: 99%

“…Concentrations of the cytokines TNFα, IL-1β, IL-6 and IL-1Ra were analysed from 24 h macrophage culture media using sandwich ELISA (DuoSet kits, R&D Systems, Minneapolis, MN), according to the manufacturer's instructions. The pro-inflammatory cytokines TNFα, IL-1β, and IL-6 are central for www.ecmjournal.org R Björkenheim et al BAG immunomodulatory and osteogenic properties initiating the fracture repair (bone regeneration) cascade (Einhorn et al, 1995;Gerstenfeld et al, 2003;Lange et al, 2010). The initial inflammatory response to these factors includes recruitment of inflammatory and other cells necessary for bone regeneration and promotion of angiogenesis (Barnes et al, 1999).…”

Section: Elisamentioning

confidence: 99%

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Sintered S53P4 bioactive glass scaffolds have anti-inflammatory properties and stimulate osteogenesis in vitro

Björkenheim

Jämsen²,

Eriksson³

et al. 2021

eCM

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Bioactive glasses (BAG) are used as bone-graft substitutes in orthopaedic surgery. A specific BAG scaffold was developed by sintering BAG-S53P4 granules. It is hypothesised that this scaffold can be used as a bone substitute to fill bone defects and induce a bioactive membrane (IM) around the defect site. Beyond providing the scaffold increased mechanical strength, that the initial inflammatory reaction and subsequent IM formation can be enhanced by coating the scaffolds with poly(DL-lactide-co-glycolide) (PLGA) is also hypothesised. To study the immunomodulatory effects, BAG-S53P4 (± PLGA) scaffolds were placed on monolayers of primary human macrophage cultures and the production of various pro- and anti-inflammatory cytokines was assessed using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and ELISA. To study the osteogenic effects, BAG-S53P4 (± PLGA) scaffolds were cultured with rabbit mesenchymal stem cells and osteogenic differentiation was evaluated by RT-qPCR and matrix mineralisation assays. The scaffold ion release was quantified and the BAG surface reactivity visualised. Furthermore, the pH of culture media was measured. BAG-S53P4 scaffolds had both anti-inflammatory and osteogenic properties that were likely attributable to alkalinisation of the media and ion release from the scaffold. pH change, ion release, and immunomodulatory properties of the scaffold could be modulated by the PLGA coating. Contrary to the hypothesis, the coating functioned by attenuating the BAG surface reactions and subsequent anti-inflammatory properties, rather than inducing an elevated inflammatory response compared to BAG-S53P4 alone. These results further validated the use of BAG-S53P4 (± PLGA) scaffolds as bone substitutes and indicate that scaffold properties can be tailored to a specific clinical need.

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Scale and structure dependent solute diffusivity within microporous tissue engineering scaffolds

Offeddu

Mohee

Cameron

2020

J Mater Sci: Mater Med

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Diffusion of nutrients to cells cultured within three-dimensional scaffolds is fundamental for cell survival during development of the tissue construct, when no vasculature is present to aid transport. Significant efforts have been made to characterize the effect of structure on solute diffusivity in nanoporous hydrogels, yet a similar thorough characterization has not been attempted for microporous scaffolds. Here, we make use of freeze-dried collagen scaffolds, possessing pore sizes in the range 150–250 μm and isotropic or aligned morphology, to study the diffusivity of fluorescent dextran molecules. Fluorescence recovery after photobleaching is used to measure the self diffusivity of the solutes within single pores, while Fickian diffusion over scales larger than the pore size is studied by assessing the solute concentration profile within the materials over time. We show that, not only do the morphological parameters of the scaffolds significantly affect the diffusivity of the solutes, but also that the assessment of such diffusivity depends on the length scale of diffusion of the molecules under investigation, with the resulting diffusion coefficients being differently affected by the scaffold structure. The results provided can guide the design of scaffolds with tailored diffusivity and nutrient concentration profiles.

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Repurposing biodegradable tissue engineering scaffolds for localized chemotherapeutic delivery

Cited by 9 publications

References 36 publications

Affinity Effects on the Release of Non-Conventional Antifibrotics from Polymer Depots

Affinity Effects on the Release of Non-Conventional Antifibrotics from Polymer Depots

Sintered S53P4 bioactive glass scaffolds have anti-inflammatory properties and stimulate osteogenesis in vitro

Scale and structure dependent solute diffusivity within microporous tissue engineering scaffolds

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