Innovative Drug Delivery Systems for Regenerative Medicine

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 23301

Special Issue Editor


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Guest Editor
1. Chemical and Interdisciplinarity, Synthesis, Analysis, Modelisation, CEISAM UMR CNRS 6230, University of Nantes, 44300 Nantes, France
2. Department of Elaboration and Evaluation of Drugs, Faculty of Pharmaceutical and Biological Sciences, University of Nantes, 44000 Nantes, France
Interests: regenerative medicine; tissue engineering; drug delivery; controlled release; biomaterial; nanotechnology; innovative design and processing; pre-clinical studies; clinical studies
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Special Issue Information

Dear Colleagues,

Regenerative medicine seeks to treat patients with dysfunctional tissue, and the development of innovative biomaterial-based technologies is the subject of intensive research addressing this issue. Regarding active compound delivery systems, the spatiotemporal control of the release profile represents a real challenge in terms of optimal activity, stability and safety and would offer personalized medicine. In response to these challenges, sophisticated delivery systems are emerging, and this Special Issue aims to review recent advances in this field.

Focusing on strategies for spatiotemporal control of drug delivery within scaffolds for tissue engineering, major mechanisms and critical factors affecting release profiles will be highlighted, as well as nanotechnologies and mathematical model contributions to these new therapeutic approaches.

This Special Issue aims to cover all the steps from bench to bedside, starting from basic principles underlaying the design of delivery vehicles up to regulatory frameworks governing clinical applications.

Dr. Elise Verron
Guest Editor

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Keywords

  • regenerative medicine
  • tissue engineering
  • drug delivery
  • controlled release
  • biomaterial
  • nanotechnology
  • innovative design and processing
  • pre-clinical studies
  • clinical studies

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Published Papers (11 papers)

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Editorial

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4 pages, 179 KiB  
Editorial
Innovative Drug Delivery Systems for Regenerative Medicine
by Elise Verron
Pharmaceutics 2024, 16(2), 295; https://doi.org/10.3390/pharmaceutics16020295 - 19 Feb 2024
Viewed by 920
Abstract
In the past two decades, research on drug delivery systems has achieved significant advances [...] Full article
(This article belongs to the Special Issue Innovative Drug Delivery Systems for Regenerative Medicine)

Research

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16 pages, 2864 KiB  
Article
Release of TGF-β3 from Surface-Modified PCL Fiber Mats Triggers a Dose-Dependent Chondrogenic Differentiation of Human Mesenchymal Stromal Cells
by Leonie Berten-Schunk, Yvonne Roger, Heike Bunjes and Andrea Hoffmann
Pharmaceutics 2023, 15(4), 1303; https://doi.org/10.3390/pharmaceutics15041303 - 21 Apr 2023
Cited by 3 | Viewed by 1585
Abstract
The design of implants for tissue transitions remains a major scientific challenge. This is due to gradients in characteristics that need to be restored. The rotator cuff in the shoulder, with its direct osteo-tendinous junction (enthesis), is a prime example of such a [...] Read more.
The design of implants for tissue transitions remains a major scientific challenge. This is due to gradients in characteristics that need to be restored. The rotator cuff in the shoulder, with its direct osteo-tendinous junction (enthesis), is a prime example of such a transition. Our approach towards an optimized implant for entheses is based on electrospun fiber mats of poly(ε-caprolactone) (PCL) as biodegradable scaffold material, loaded with biologically active factors. Chitosan/tripolyphosphate (CS/TPP) nanoparticles were used to load transforming growth factor-β3 (TGF-β3) with increasing loading concentrations for the regeneration of the cartilage zone within direct entheses. Release experiments were performed, and the concentration of TGF-β3 in the release medium was determined by ELISA. Chondrogenic differentiation of human mesenchymal stromal cells (MSCs) was analyzed in the presence of released TGF-β3. The amount of released TGF-β3 increased with the use of higher loading concentrations. This correlated with larger cell pellets and an increase in chondrogenic marker genes (SOX9, COL2A1, COMP). These data were further supported by an increase in the glycosaminoglycan (GAG)-to-DNA ratio of the cell pellets. The results demonstrate an increase in the total release of TGF-β3 by loading higher concentrations to the implant, which led to the desired biological effect. Full article
(This article belongs to the Special Issue Innovative Drug Delivery Systems for Regenerative Medicine)
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19 pages, 7441 KiB  
Article
Amorphous Pterostilbene Delivery Systems Preparation—Innovative Approach to Preparation Optimization
by Natalia Rosiak, Ewa Tykarska and Judyta Cielecka-Piontek
Pharmaceutics 2023, 15(4), 1231; https://doi.org/10.3390/pharmaceutics15041231 - 13 Apr 2023
Cited by 9 | Viewed by 1681
Abstract
The aim of our research was to improve the solubility and antioxidant activity of pterostilbene (PTR) by developing a novel amorphous solid dispersion (ASD) with Soluplus® (SOL). DSC analysis and mathematical models were used to select the three appropriate PTR and SOL [...] Read more.
The aim of our research was to improve the solubility and antioxidant activity of pterostilbene (PTR) by developing a novel amorphous solid dispersion (ASD) with Soluplus® (SOL). DSC analysis and mathematical models were used to select the three appropriate PTR and SOL weight ratios. The amorphization process was carried out by a low-cost and green approach involving dry milling. An XRPD analysis confirmed the full amorphization of systems in 1:2 and 1:5 weight ratios. One glass transition (Tg) observed in DSC thermograms confirmed the complete miscibility of the systems. The mathematical models indicated strong heteronuclear interactions. SEM micrographs suggest dispersed PTR within the SOL matrix and a lack of PTR crystallinity, and showed that after the amorphization process, PTR-SOL systems had a smaller particle size and larger surface area compared with PTR and SOL. An FT-IR analysis confirmed that hydrogen bonds were responsible for stabilizing the amorphous dispersion. HPLC studies showed no decomposition of PTR after the milling process. PTR’s apparent solubility and antioxidant activity after introduction into ASD increased compared to the pure compound. The amorphization process improved the apparent solubility by ~37-fold and ~28-fold for PTR-SOL, 1:2 and 1:5 w/w, respectively. The PTR-SOL 1:2 w/w system was preferred due to it having the best solubility and antioxidant activity (ABTS: IC50 of 56.389 ± 0.151 µg·mL−1 and CUPRAC: IC0.5 of 82.52 ± 0.88 µg·mL−1). Full article
(This article belongs to the Special Issue Innovative Drug Delivery Systems for Regenerative Medicine)
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24 pages, 7883 KiB  
Article
Development of L-Lysine-Loaded PLGA Microparticles as a Controlled Release System for Angiogenesis Enhancement
by Nunzia Gallo, Stefano Quarta, Marika Massaro, Maria Annunziata Carluccio, Amilcare Barca, Donato Cannoletta, Luisa Siculella, Luca Salvatore and Alessandro Sannino
Pharmaceutics 2023, 15(2), 479; https://doi.org/10.3390/pharmaceutics15020479 - 1 Feb 2023
Cited by 5 | Viewed by 1685
Abstract
Vascularization is a highly conserved and considerably complex and precise process that is finely driven by endogenous regulatory processes at the tissue and systemic levels. However, it can reveal itself to be slow and inadequate for tissue repair and regeneration consequent to severe [...] Read more.
Vascularization is a highly conserved and considerably complex and precise process that is finely driven by endogenous regulatory processes at the tissue and systemic levels. However, it can reveal itself to be slow and inadequate for tissue repair and regeneration consequent to severe lesions/damages. Several biomaterial-based strategies were developed to support and enhance vasculogenesis by supplying pro-angiogenic agents. Several approaches were adopted to develop effective drug delivery systems for the controlled release of a huge variety of compounds. In this work, a microparticulate system was chosen to be loaded with the essential amino acid L-lysine, a molecule that has recently gained interest due to its involvement in pro-angiogenic, pro-regenerative, and anti-inflammatory mechanisms. Poly (lactic-co-glycolic acid), the most widely used FDA-approved biodegradable synthetic polymer for the development of drug delivery systems, was chosen due to its versatility and ability to promote neovascularization and wound healing. This study dealt with the development and the effectiveness evaluation of a PLGA-based microparticulate system for the controlled release of L-lysine. Therefore, in order to maximize L-lysine encapsulation efficiency and tune its release kinetics, the microparticle synthesis protocol was optimized by varying some processing parameters. All developed formulations were characterized from a morphological and physicochemical point of view. The optimized formulation was further characterized via the evaluation of its preliminary biological efficacy in vitro. The cellular and molecular studies revealed that the L-lysine-loaded PLGA microparticles were non-toxic, biocompatible, and supported cell proliferation and angiogenesis well by stimulating the expression of pro-angiogenic genes such as metalloproteinase-9, focal adhesion kinases, and different growth factors. Thus, this work showed the potential of delivering L-lysine encapsulated in PLGA microparticles as a cost-effective promoter system for angiogenesis enhancement and rapid healing. Full article
(This article belongs to the Special Issue Innovative Drug Delivery Systems for Regenerative Medicine)
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38 pages, 15626 KiB  
Article
Silk-Elastin-like Polymers for Acute Intraparenchymal Treatment of the Traumatically Injured Spinal Cord: A First Systematic Experimental Approach
by Pau González, Carlos González-Fernández, Alfredo Maqueda, Virginia Pérez, Sara Escalera-Anzola, Ángel Rodríguez de Lope, Francisco Javier Arias, Alessandra Girotti and Francisco Javier Rodríguez
Pharmaceutics 2022, 14(12), 2713; https://doi.org/10.3390/pharmaceutics14122713 - 3 Dec 2022
Cited by 3 | Viewed by 1837
Abstract
Despite the promising potential of hydrogel-based therapeutic approaches for spinal cord injury (SCI), the need for new biomaterials to design effective strategies for SCI treatment and the outstanding properties of silk-elastin-like polymers (SELP), the potential use of SELPs in SCI is currently unknown. [...] Read more.
Despite the promising potential of hydrogel-based therapeutic approaches for spinal cord injury (SCI), the need for new biomaterials to design effective strategies for SCI treatment and the outstanding properties of silk-elastin-like polymers (SELP), the potential use of SELPs in SCI is currently unknown. In this context, we assessed the effects elicited by the in vivo acute intraparenchymal injection of an SELP named (EIS)2-RGD6 in a clinically relevant model of SCI. After optimization of the injection system, the distribution, structure, biodegradability, and cell infiltration capacity of (EIS)2-RGD6 were assessed. Finally, the effects exerted by the (EIS)2-RGD6 injection—in terms of motor function, myelin preservation, astroglial and microglia/macrophage reactivity, and fibrosis—were evaluated. We found that (EIS)2-RGD6 can be acutely injected in the lesioned spinal cord without inducing further damage, showing a widespread distribution covering all lesioned areas with a single injection and facilitating the formation of a slow-degrading porous scaffold at the lesion site that allows for the infiltration and/or proliferation of endogenous cells with no signs of collapse and without inducing further microglial and astroglial reactivity, as well as even reducing SCI-associated fibrosis. Altogether, these observations suggest that (EIS)2-RGD6—and, by extension, SELPs—could be promising polymers for the design of therapeutic strategies for SCI treatment. Full article
(This article belongs to the Special Issue Innovative Drug Delivery Systems for Regenerative Medicine)
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22 pages, 7044 KiB  
Article
Therapeutic Potential of Mesenchymal Stem Cells versus Omega n − 3 Polyunsaturated Fatty Acids on Gentamicin-Induced Cardiac Degeneration
by Fatma Y. Meligy, Hanan Sharaf El-Deen Mohammed, Tarek M. Mostafa, Mohamed M. Elfiky, Israa El-Sayed Mohamed Ashry, Ahmed M. Abd-Eldayem, Nermin I. Rizk, Dina Sabry, Eman S. H. Abd Allah and Salwa Fares Ahmed
Pharmaceutics 2022, 14(7), 1322; https://doi.org/10.3390/pharmaceutics14071322 - 22 Jun 2022
Cited by 5 | Viewed by 2258
Abstract
This study compared the cardioprotective action of mesenchymal stem cells (MSCs) and PUFAs in a rat model of gentamicin (GM)-induced cardiac degeneration. Male Wistar albino rats were randomized into four groups of eight rats each: group I (control group), group II (gentamicin-treated rats [...] Read more.
This study compared the cardioprotective action of mesenchymal stem cells (MSCs) and PUFAs in a rat model of gentamicin (GM)-induced cardiac degeneration. Male Wistar albino rats were randomized into four groups of eight rats each: group I (control group), group II (gentamicin-treated rats receiving gentamicin intraperitoneally (IP) at dose of 100 mg/kg/day for 10 consecutive days), group III (gentamicin and PUFA group receiving gentamicin IP at dose of 100 mg/kg/day for 10 consecutive days followed by PUFAs at a dose of 100 mg/kg/day for 4 weeks), and group IV (gentamicin and MSC group receiving gentamicin IP at dose of 100 mg/kg/day followed by a single dose of MSCs (1 × 106)/rat IP). Cardiac histopathology was evaluated via light and electron microscopy. Immunohistochemical detection of proliferating cell nuclear antigen (PCNA), caspase-3 (apoptosis), Bcl2, and Bax expression was performed. Moreover, cardiac malonaldehyde (MDA) content, catalase activity, and oxidative stress parameters were biochemically evaluated. Light and electron microscopy showed that both MSCs and PUFAs had ameliorative effects. Their actions were mediated by upregulating PCNA expression, downregulating caspase-3 expression, mitigating cardiac MDA content, catalase activity, and oxidative stress parameters. MSCs and PUFAs had ameliorative effects against gentamicin-induced cardiac degeneration, with MSCs showing higher efficacy compared to PUFAs. Full article
(This article belongs to the Special Issue Innovative Drug Delivery Systems for Regenerative Medicine)
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10 pages, 4857 KiB  
Article
Preparation and Drug Release Profile of Chitosan–Siloxane Hybrid Capsules Coated with Hydroxyapatite
by Yuki Shirosaki, Yasuyo Tsukatani, Kohei Okamoto, Satoshi Hayakawa and Akiyoshi Osaka
Pharmaceutics 2022, 14(5), 1111; https://doi.org/10.3390/pharmaceutics14051111 - 23 May 2022
Cited by 2 | Viewed by 1702
Abstract
Chitosan is a cationic polymer that forms polymerized membranes upon reaction with anionic polymers. Chitosan−carboxymethyl cellulose (CMC) capsules are drug delivery carrier candidates whose mechanical strength and permeability must be controlled to achieve sustained release. In this study, the capsules were prepared from [...] Read more.
Chitosan is a cationic polymer that forms polymerized membranes upon reaction with anionic polymers. Chitosan−carboxymethyl cellulose (CMC) capsules are drug delivery carrier candidates whose mechanical strength and permeability must be controlled to achieve sustained release. In this study, the capsules were prepared from chitosan−γ-glycidoxypropyltrimethoxysilane (GPTMS)−CMC. The mechanical stability of the capsules was improved by crosslinking the chitosan with GPTMS. The capsules were then coated with hydroxyapatite (HAp) by alternately soaking them in calcium chloride solution and disodium hydrogen phosphate solution to prevent rapid initial drug release. Cytochrome C (CC), as a model drug, was introduced into the capsules via two routes, impregnation and injection, and then the CC released from the capsules was examined. HAp was found to be deposited on the internal and external surfaces of the capsules. The amount of CC introduced, and the release rate were reduced by the HAp coating. The injection method was found to result in the greatest CC loading. Full article
(This article belongs to the Special Issue Innovative Drug Delivery Systems for Regenerative Medicine)
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Review

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16 pages, 2648 KiB  
Review
Long Non-Coding RNAs and Proliferative Retinal Diseases
by Anamika Sharma and Nikhlesh K. Singh
Pharmaceutics 2023, 15(5), 1454; https://doi.org/10.3390/pharmaceutics15051454 - 10 May 2023
Cited by 3 | Viewed by 1617
Abstract
Retinopathy refers to disorders that affect the retina of the eye, which are frequently caused by damage to the retina’s vascular system. This causes leakage, proliferation, or overgrowth of blood vessels through the retina, which can lead to retinal detachment or breakdown, resulting [...] Read more.
Retinopathy refers to disorders that affect the retina of the eye, which are frequently caused by damage to the retina’s vascular system. This causes leakage, proliferation, or overgrowth of blood vessels through the retina, which can lead to retinal detachment or breakdown, resulting in vision loss and, in rare cases, blindness. In recent years, high-throughput sequencing has significantly hastened the discovery of new long non-coding RNAs (lncRNAs) and their biological functions. LncRNAs are rapidly becoming recognized as critical regulators of several key biological processes. Current breakthroughs in bioinformatics have resulted in the identification of several lncRNAs that may have a role in retinal disorders. Nevertheless, mechanistic investigations have yet to reveal the relevance of these lncRNAs in retinal disorders. Using lncRNA transcripts for diagnostic and/or therapeutic purposes may aid in the development of appropriate treatment regimens and long-term benefits for patients, as traditional medicines and antibody therapy only provide temporary benefits that must be repeated. In contrast, gene-based therapies can provide tailored, long-term treatment solutions. Here, we will discuss how different lncRNAs affect different retinopathies, including age-related macular degeneration (AMD), diabetic retinopathy (DR), central retinal vein occlusion (CRVO), proliferative vitreoretinopathy (PVR), and retinopathy of prematurity (ROP), which can cause visual impairment and blindness, and how these retinopathies can be identified and treated using lncRNAs. Full article
(This article belongs to the Special Issue Innovative Drug Delivery Systems for Regenerative Medicine)
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23 pages, 710 KiB  
Review
Drug Delivery Systems in Regenerative Medicine: An Updated Review
by Alaa Mansour, Maya Romani, Anirudh Balakrishna Acharya, Betul Rahman, Elise Verron and Zahi Badran
Pharmaceutics 2023, 15(2), 695; https://doi.org/10.3390/pharmaceutics15020695 - 18 Feb 2023
Cited by 30 | Viewed by 4169
Abstract
Modern drug discovery methods led to evolving new agents with significant therapeutic potential. However, their properties, such as solubility and administration-related challenges, may hinder their benefits. Moreover, advances in biotechnology resulted in the development of a new generation of molecules with a short [...] Read more.
Modern drug discovery methods led to evolving new agents with significant therapeutic potential. However, their properties, such as solubility and administration-related challenges, may hinder their benefits. Moreover, advances in biotechnology resulted in the development of a new generation of molecules with a short half-life that necessitates frequent administration. In this context, controlled release systems are required to enhance treatment efficacy and improve patient compliance. Innovative drug delivery systems are promising tools that protect therapeutic proteins and peptides against proteolytic degradation where controlled delivery is achievable. The present review provides an overview of different approaches used for drug delivery. Full article
(This article belongs to the Special Issue Innovative Drug Delivery Systems for Regenerative Medicine)
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24 pages, 3619 KiB  
Review
Enhanced Corrosion Resistance and Local Therapy from Nano-Engineered Titanium Dental Implants
by Tianqi Guo, Jean-Claude Scimeca, Sašo Ivanovski, Elise Verron and Karan Gulati
Pharmaceutics 2023, 15(2), 315; https://doi.org/10.3390/pharmaceutics15020315 - 17 Jan 2023
Cited by 10 | Viewed by 2704
Abstract
Titanium is the ideal material for fabricating dental implants with favorable biocompatibility and biomechanics. However, the chemical corrosions arising from interaction with the surrounding tissues and fluids in oral cavity can challenge the integrity of Ti implants and leach Ti ions/nanoparticles, thereby causing [...] Read more.
Titanium is the ideal material for fabricating dental implants with favorable biocompatibility and biomechanics. However, the chemical corrosions arising from interaction with the surrounding tissues and fluids in oral cavity can challenge the integrity of Ti implants and leach Ti ions/nanoparticles, thereby causing cytotoxicity. Various nanoscale surface modifications have been performed to augment the chemical and electrochemical stability of Ti-based dental implants, and this review discusses and details these advances. For instance, depositing nanowires/nanoparticles via alkali-heat treatment and plasma spraying results in the fabrication of a nanostructured layer to reduce chemical corrosion. Further, refining the grain size to nanoscale could enhance Ti implants’ mechanical and chemical stability by alleviating the internal strain and establishing a uniform TiO2 layer. More recently, electrochemical anodization (EA) has emerged as a promising method to fabricate controlled TiO2 nanostructures on Ti dental implants. These anodized implants enhance Ti implants’ corrosion resistance and bioactivity. A particular focus of this review is to highlight critical advances in anodized Ti implants with nanotubes/nanopores for local drug delivery of potent therapeutics to augment osseo- and soft-tissue integration. This review aims to improve the understanding of novel nano-engineered Ti dental implant modifications, focusing on anodized nanostructures to fabricate the next generation of therapeutic and corrosion-resistant dental implants. The review explores the latest developments, clinical translation challenges, and future directions to assist in developing the next generation of dental implants that will survive long-term in the complex corrosive oral microenvironment. Full article
(This article belongs to the Special Issue Innovative Drug Delivery Systems for Regenerative Medicine)
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21 pages, 4496 KiB  
Review
Emerging Bioactive Agent Delivery-Based Regenerative Therapies for Lower Genitourinary Tissues
by Lin-Cui Da, Yan Sun, Yun-Hong Lin, Su-Zhu Chen, Gang-Xin Chen, Bei-Hong Zheng and Sheng-Rong Du
Pharmaceutics 2022, 14(8), 1718; https://doi.org/10.3390/pharmaceutics14081718 - 17 Aug 2022
Viewed by 1839
Abstract
Injury to lower genitourinary (GU) tissues, which may result in either infertility and/or organ dysfunctions, threatens the overall health of humans. Bioactive agent-based regenerative therapy is a promising therapeutic method. However, strategies for spatiotemporal delivery of bioactive agents with optimal stability, activity, and [...] Read more.
Injury to lower genitourinary (GU) tissues, which may result in either infertility and/or organ dysfunctions, threatens the overall health of humans. Bioactive agent-based regenerative therapy is a promising therapeutic method. However, strategies for spatiotemporal delivery of bioactive agents with optimal stability, activity, and tunable delivery for effective sustained disease management are still in need and present challenges. In this review, we present the advancements of the pivotal components in delivery systems, including biomedical innovations, system fabrication methods, and loading strategies, which may improve the performance of delivery systems for better regenerative effects. We also review the most recent developments in the application of these technologies, and the potential for delivery-based regenerative therapies to treat lower GU injuries. Recent progress suggests that the use of advanced strategies have not only made it possible to develop better and more diverse functionalities, but also more precise, and smarter bioactive agent delivery systems for regenerative therapy. Their application in lower GU injury treatment has achieved certain effects in both patients with lower genitourinary injuries and/or in model animals. The continuous evolution of biomaterials and therapeutic agents, advances in three-dimensional printing, as well as emerging techniques all show a promising future for the treatment of lower GU-related disorders and dysfunctions. Full article
(This article belongs to the Special Issue Innovative Drug Delivery Systems for Regenerative Medicine)
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