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Drug Delivery and Scaffolding in the Era of 3D-Printing and Microfluidic Techniques: Challenges and Opportunities

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Materials Science".

Deadline for manuscript submissions: closed (15 August 2020) | Viewed by 38298

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Dr. Ida Genta

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Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy
Interests: drug delivery; polymer nanoparticles; microspheres; biodegradable polymers; thermosensitive hydrogel; 3D bioprinting; tissue regeneration
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Prof. Dr. Bice Conti

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Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy
Interests: tissue engineering; nanomedicine; drug delivery; nanocarriers; electrospinning
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

In the era of precision medicine the development of new diagnostic and therapeutic approaches is being reached through the development of even more sophisticated pharmaceutical systems. In combination with the explosion of biomolecule discoveries and the knowledge of physiological and pathological pathways, pharmaceutical system applications have extended to the selective delivery of drugs and genetic materials (i.e. selective nanocarriers, manipulated with multifunctionality, also exploitable for theranostic purposes, and polymeric scaffolds used to tune drug or biomolecule delivery) and to cell delivery (i.e. polymeric scaffolds where the scaffold material and structure, cells and bioactive molecules interact for tissue engineering or regenerative medicine). To date, there has been a discrepancy between the amount of research devoted to the topic and its translation to patients due to the fact that pharmaceutical systems are often quite sophisticated in their design, difficult both to reliably and reproducibly manufacture and to characterize from a pharmaceutical and toxicological viewpoint.

Confident in the utility of new technological approaches in helping the clinical translation of innovative drug delivery systems, this Special Issue is aimed at highlighting the impact and challenges of the most recent technology in the development of more cost-effective as well as patient-friendly drug delivery systems.

Suggested topic are: 3D-printing, 3D-bio-printing, electrospinning, injection molding, and combinations thereof for scaffold development or for formulative development; microfluidics techniques for nanocarrier preparation; continuous manufacturing of pharmaceuticals; and regulatory approaches to innovative technologies.

Prof. Dr. Ida Genta
Prof. Dr. Bice Conti
Guest Editors

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Keywords

3D printing
3D bio-printing
electrospinning
microfluidics
injection molding
continuous manufacturing
regulatory approaches to innovative technologies in pharmaceutical field

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Published Papers (8 papers)

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Research

11 pages, 2635 KiB

Open AccessArticle

A Novel 3D Bioprinter Using Direct-Volumetric Drop-On-Demand Technology for Fabricating Micro-Tissues and Drug-Delivery

by Brian E. Grottkau, Zhixin Hui and Yonggang Pang

Int. J. Mol. Sci. 2020, 21(10), 3482; https://doi.org/10.3390/ijms21103482 - 14 May 2020

Cited by 25 | Viewed by 4152

Abstract

Drop-on-demand (DOD) 3D bioprinting technologies currently hold the greatest promise for generating functional tissues for clinical use and for drug development. However, existing DOD 3D bioprinting technologies have three main limitations: (1) droplet volume inconsistency; (2) the ability to print only bioinks with low cell concentrations and low viscosity; and (3) problems with cell viability when dispensed under high pressure. We report our success developing a novel direct-volumetric DOD (DVDOD) 3D bioprinting technology that overcomes each of these limitations. DVDOD can produce droplets of bioink from <10 nL in volume using a direct-volumetric mechanism with <± 5% volumetric percent accuracy in an accurate spatially controlled manner. DVDOD has the capability of dispensing bioinks with high concentrations of cells and/or high viscosity biomaterials in either low- or high-throughput modes. The cells are subjected to a low pressure during the bioprinting process for a very short period of time that does not negatively impact cell viability. We demonstrated the functions of the bioprinter in two distinct manners: (1) by using a high-throughput drug-delivery model; and (2) by bioprinting micro-tissues using a variety of different cell types, including functional micro-tissues of bone, cancer, and induced pluripotent stem cells. Our DVDOD technology demonstrates a promising platform for generating many types of tissues and drug-delivery models. Full article

(This article belongs to the Special Issue Drug Delivery and Scaffolding in the Era of 3D-Printing and Microfluidic Techniques: Challenges and Opportunities)

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21 pages, 8376 KiB

Open AccessArticle

Injection Molded Capsules for Colon Delivery Combining Time-Controlled and Enzyme-Triggered Approaches

by Federica Casati, Alice Melocchi, Saliha Moutaharrik, Marco Uboldi, Anastasia Foppoli, Alessandra Maroni, Lucia Zema, Christel Neut, Florence Siepmann, Juergen Siepmann and Andrea Gazzaniga

Int. J. Mol. Sci. 2020, 21(6), 1917; https://doi.org/10.3390/ijms21061917 - 11 Mar 2020

Cited by 21 | Viewed by 3424

Abstract

A new type of colon targeting system is presented, combining time-controlled and enzyme-triggered approaches. Empty capsule shells were prepared by injection molding of blends of a high-amylose starch and hydroxypropyl methylcellulose (HPMC) of different chain lengths. The dissolution/erosion of the HPMC network assures a time-controlled drug release, i.e., drug release starts upon sufficient shell swelling/dissolution/erosion. In addition, the presence of high-amylose starch ensures enzyme-triggered drug release. Once the colon is reached, the local highly concentrated bacterial enzymes effectively degrade this polysaccharide, resulting in accelerated drug release. Importantly, the concentration of bacterial enzymes is much lower in the upper gastrointestinal tract, thus enabling site-specific drug delivery. The proposed capsules were filled with acetaminophen and exposed to several aqueous media, simulating the contents of the gastrointestinal tract using different experimental setups. Importantly, drug release was pulsatile and occurred much faster in the presence of fecal samples from patients. The respective lag times were reduced and the release rates increased once the drug started to be released. It can be expected that variations in the device design (e.g., polymer blend ratio, capsule shell geometry and thickness) allow for a large variety of possible colon targeting release profiles. Full article

(This article belongs to the Special Issue Drug Delivery and Scaffolding in the Era of 3D-Printing and Microfluidic Techniques: Challenges and Opportunities)

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15 pages, 4580 KiB

Open AccessArticle

Fabrication of Three-Dimensional Composite Scaffold for Simultaneous Alveolar Bone Regeneration in Dental Implant Installation

by Hun-Jin Jeong, So-Jung Gwak, Kyoung Duck Seo, SaYa Lee, Jeong-Ho Yun, Young-Sam Cho and Seung-Jae Lee

Int. J. Mol. Sci. 2020, 21(5), 1863; https://doi.org/10.3390/ijms21051863 - 9 Mar 2020

Cited by 28 | Viewed by 7092

Abstract

Dental implant surgeries involve the insertion of implant fixtures into alveolar bones to replace missing teeth. When the availability of alveolar bone at the surgical site is insufficient, bone graft particles are filled in the insertion site for successful bone reconstruction. Bone graft particles induce bone regeneration over several months at the insertion site. Subsequently, implant fixtures can be inserted at the recipient site. Thus, conventional dental implant surgery is performed in several steps, which in turn increases the treatment period and cost involved. Therefore, to reduce surgical time and minimize treatment costs, a novel hybrid scaffold filled with bone graft particles that could be combined with implant fixtures is proposed. This scaffold is composed of a three-dimensionally (3D) printed polycaprolactone (PCL) frame and osteoconductive ceramic materials such as hydroxyapatite (HA) and β-tricalcium phosphate (β-TCP). Herein, we analyzed the porosity, internal microstructure, and hydrophilicity of the hybrid scaffold. Additionally, Saos-2 cells were used to assess cell viability and proliferation. Two types of control scaffolds were used (a 3D printed PCL frame and a hybrid scaffold without HA/β-TCP particles) for comparison, and the fabricated hybrid scaffold was verified to retain osteoconductive ceramic particles without losses. Moreover, the fabricated hybrid scaffold had high porosity and excellent microstructural interconnectivity. The in vitro Saos-2 cell experiments revealed superior cell proliferation and alkaline phosphatase assay results for the hybrid scaffold than the control scaffold. Hence, the proposed hybrid scaffold is a promising candidate for minimizing cost and duration of dental implant surgery. Full article

(This article belongs to the Special Issue Drug Delivery and Scaffolding in the Era of 3D-Printing and Microfluidic Techniques: Challenges and Opportunities)

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18 pages, 6438 KiB

Open AccessArticle

Tissue Engineered Esophageal Patch by Mesenchymal Stromal Cells: Optimization of Electrospun Patch Engineering

by Silvia Pisani, Stefania Croce, Enrica Chiesa, Rossella Dorati, Elisa Lenta, Ida Genta, Giovanna Bruni, Simone Mauramati, Alberto Benazzo, Lorenzo Cobianchi, Patrizia Morbini, Laura Caliogna, Marco Benazzo, Maria Antonietta Avanzini and Bice Conti

Int. J. Mol. Sci. 2020, 21(5), 1764; https://doi.org/10.3390/ijms21051764 - 4 Mar 2020

Cited by 18 | Viewed by 3140

Abstract

Aim of work was to locate a simple, reproducible protocol for uniform seeding and optimal cellularization of biodegradable patch minimizing the risk of structural damages of patch and its contamination in long-term culture. Two seeding procedures are exploited, namely static seeding procedures on biodegradable and biocompatible patches incubated as free floating (floating conditions) or supported by CellCrown^TM insert (fixed conditions) and engineered by porcine bone marrow MSCs (p-MSCs). Scaffold prototypes having specific structural features with regard to pore size, pore orientation, porosity, and pore distribution were produced using two different techniques, such as temperature-induced precipitation method and electrospinning technology. The investigation on different prototypes allowed achieving several implementations in terms of cell distribution uniformity, seeding efficiency, and cellularization timing. The cell seeding protocol in stating conditions demonstrated to be the most suitable method, as these conditions successfully improved the cellularization of polymeric patches. Furthermore, the investigation provided interesting information on patches’ stability in physiological simulating experimental conditions. Considering the in vitro results, it can be stated that the in vitro protocol proposed for patches cellularization is suitable to achieve homogeneous and complete cellularizations of patch. Moreover, the protocol turned out to be simple, repeatable, and reproducible. Full article

(This article belongs to the Special Issue Drug Delivery and Scaffolding in the Era of 3D-Printing and Microfluidic Techniques: Challenges and Opportunities)

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20 pages, 4236 KiB

Open AccessArticle

Dexamethasone Loaded Liposomes by Thin-Film Hydration and Microfluidic Procedures: Formulation Challenges

by MD Al-Amin, Federica Bellato, Francesca Mastrotto, Mariangela Garofalo, Alessio Malfanti, Stefano Salmaso and Paolo Caliceti

Int. J. Mol. Sci. 2020, 21(5), 1611; https://doi.org/10.3390/ijms21051611 - 26 Feb 2020

Cited by 56 | Viewed by 8545

Abstract

Liposomes have been one of the most exploited drug delivery systems in recent decades. However, their large-scale production with low batch-to-batch differences is a challenge for industry, which ultimately delays the clinical translation of new products. We have investigated the effects of formulation parameters on the colloidal and biopharmaceutical properties of liposomes generated with a thin-film hydration approach and microfluidic procedure. Dexamethasone hemisuccinate was remotely loaded into liposomes using a calcium acetate gradient. The liposomes produced by microfluidic techniques showed a unilamellar structure, while the liposomes produced by thin-film hydration were multilamellar. Under the same remote loading conditions, a higher loading capacity and efficiency were observed for the liposomes obtained by microfluidics, with low batch-to-batch differences. Both formulations released the drug for almost one month with the liposomes prepared by microfluidics showing a slightly higher drug release in the first two days. This behavior was ascribed to the different structure of the two liposome formulations. In vitro studies showed that both formulations are non-toxic, associate to human Adult Retinal Pigment Epithelial cell line-19 (ARPE-19) cells, and efficiently reduce inflammation, with the liposomes obtained by the microfluidic technique slightly outperforming. The results demonstrated that the microfluidic technique offers advantages to generate liposomal formulations for drug-controlled release with an enhanced biopharmaceutical profile and with scalability. Full article

(This article belongs to the Special Issue Drug Delivery and Scaffolding in the Era of 3D-Printing and Microfluidic Techniques: Challenges and Opportunities)

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16 pages, 6371 KiB

Open AccessArticle

Numerical Study of Bubble Breakup in Fractal Tree-Shaped Microchannels

by Chengbin Zhang, Xuan Zhang, Qianwen Li and Liangyu Wu

Int. J. Mol. Sci. 2019, 20(21), 5516; https://doi.org/10.3390/ijms20215516 - 5 Nov 2019

Cited by 5 | Viewed by 3091

Abstract

Hydrodynamic behaviors of bubble stream flow in fractal tree-shaped microchannels is investigated numerically based on a two-dimensional volume of fluid (VOF) method. Bubble breakup is examined in each level of bifurcation and the transition of breakup regimes is discussed in particular. The pressure variations at the center of different levels of bifurcations are analyzed in an effort to gain further insight into the underlying mechanism of bubble breakup affected by multi-levels of bifurcations in tree-shaped microchannel. The results indicate that due to the structure of the fractal tree-shaped microchannel, both lengths of bubbles and local capillary numbers decrease along the microchannel under a constant inlet capillary number. Hence the transition from the obstructed breakup and obstructed-tunnel combined breakup to coalescence breakup is observed when the bubbles are flowing into a higher level of bifurcations. Compared with the breakup of the bubbles in the higher level of bifurcations, the behaviors of bubbles show stronger periodicity in the lower level of bifurcations. Perturbations grow and magnify along the flow direction and the flow field becomes more chaotic at higher level of bifurcations. Besides, the feedback from the unequal downstream pressure to the upstream lower level of bifurcations affects the bubble breakup and enhances the upstream asymmetrical behaviors. Full article

(This article belongs to the Special Issue Drug Delivery and Scaffolding in the Era of 3D-Printing and Microfluidic Techniques: Challenges and Opportunities)

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19 pages, 6072 KiB

Open AccessArticle

3D Printing PLA/Gingival Stem Cells/ EVs Upregulate miR-2861 and -210 during Osteoangiogenesis Commitment

by Jacopo Pizzicannella, Francesca Diomede, Agnese Gugliandolo, Luigi Chiricosta, Placido Bramanti, Ilaria Merciaro, Tiziana Orsini, Emanuela Mazzon and Oriana Trubiani

Int. J. Mol. Sci. 2019, 20(13), 3256; https://doi.org/10.3390/ijms20133256 - 2 Jul 2019

Cited by 84 | Viewed by 4951

Abstract

Bone tissue regeneration strategies require approaches that provide an osteogenic and angiogenic microenvironment able to drive the bone growth. Recently, the development of 3D printing biomaterials, including poly(lactide) (3D-PLA), enriched with mesenchymal stem cells (MSCs) and/or their derivatives, such as extracellular vesicles (EVs) has been achieving promising results. In this study, in vitro results showed an increased expression of osteogenic and angiogenic markers, as RUNX2, VEGFA, OPN and COL1A1 in the living construct 3D-PLA/human Gingival MSCs (hGMSCs)/EVs. Considering that EVs carry and transfer proteins, mRNA and microRNA into target cells, we evaluated miR-2861 and miR-210 expression related to osteoangiogenesis commitment. Histological examination of rats implanted with 3D-PLA/hGMSCs/EVs evidenced the activation of bone regeneration and of the vascularization process, confirmed also by MicroCT. In synthesis, an upregulation of miR-2861 and -210 other than RUNX2, VEGFA, OPN and COL1A1 was evident in cells cultured in the presence of the biomaterial and EVs. Then, these results evidenced that EVs may enhance bone regeneration in calvaria defects, in association with an enhanced vascularization offering a novel regulatory system in the osteoangiogenesis evolution. The application of new strategies to improve biomaterial engraftment is of great interest in the regenerative medicine and can represent a way to promote bone regeneration. Full article

(This article belongs to the Special Issue Drug Delivery and Scaffolding in the Era of 3D-Printing and Microfluidic Techniques: Challenges and Opportunities)

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14 pages, 4405 KiB

Open AccessArticle

Improvement of the Firocoxib Dissolution Performance Using Electrospun Fibers Obtained from Different Polymer/Surfactant Associations

by Lauretta Maggi, Valeria Friuli, Enrica Chiesa, Silvia Pisani, Mirena Sakaj, Paolo Celestini and Giovanna Bruni

Int. J. Mol. Sci. 2019, 20(12), 3084; https://doi.org/10.3390/ijms20123084 - 24 Jun 2019

Cited by 12 | Viewed by 3230

Abstract

An electrospinning process was optimized to produce fibers of micrometric size with different combinations of polymeric and surfactant materials to promote the dissolution rate of an insoluble drug: firocoxib. Scanning Electron Microscopy (SEM) showed that only some combinations of the proposed carrier systems allowed the production of suitable fibers and further fine optimization of the technique is also needed to load the drug. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) suggest that the drug is in an amorphous state in the final product. Drug amorphization, the fine dispersion of the active in the carriers, and the large surface area exposed to water interaction obtained through the electrospinning process can explain the remarkable improvement in the dissolution performance of firocoxib from the final product developed. Full article

(This article belongs to the Special Issue Drug Delivery and Scaffolding in the Era of 3D-Printing and Microfluidic Techniques: Challenges and Opportunities)

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