Advanced Therapy Medicinal Products for Eye Diseases: Goals and Challenges

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

Deadline for manuscript submissions: closed (1 July 2021) | Viewed by 44815

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Special Issue Editors

1. School of Medicine, University of Valladolid, Ramón y Cajal 7, 47001 Valladolid, Spain
2. Instituto Universitario de Oftalmobiología Aplicada (IOBA), Universidad de Valladolid, Paseo de Belén 17, 47011 Valladolid, Spain
3. Centro de Investigación Biomédica en Red Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto de Salud Carlos III, Valladolid, Spain
Interests: advanced therapy; biomaterials; cell culture; conjunctiva; cornea; drug delivery; inflammation; nanomedicine; ocular surface
Instituto Universitario de Oftalmobiología Aplicada (IOBA), Universidad de Valladolid, Paseo de Belén 17, 47011 Valladolid, Spain
Interests: advanced therapy; cell culture; conjunctiva; cornea; dry eye disease; inflammation; in vitro models; ocular surface

Special Issue Information

Dear Colleagues,

The concept of advanced therapy medicinal products (ATMPs) encompasses novel kinds of medicines for human use that are based on genes, cells or tissues. These intend to offer not only regeneration but complete functional recovery of diseased tissues and organs using different strategies. Gene therapy, cell therapy and tissue engineering are the main areas in which promising advanced therapies are emerging. The eye is a very complex organ whose main structures, the cornea and the retina, play a pivotal role in maintaining normal vision, as severe alterations in these tissues can lead to blindness. Ocular tissues are starting to benefit from ATMPs by fighting against the enormous complexity and devastating potential of many ocular diseases. However, developments arising from this field of work face important challenges related to vectors to deliver drugs and genetic material to target tissues, suitable biomaterials to prepare cell scaffolds and cell stemness, among others—not to mention the complicated legislation around ATMPs, the complexity in production and quality control and the absence of standardized protocols.

The purpose of this Special Issue is to serve as an overview of the current progress in the application of cell and gene therapies as well as tissue engineering to restore functionality in diseased ocular structures and the challenges linked to reaching patients.

This Special Issue will cover the following topics but is not limited to them:

  • ATMPs legislation and major challenges in ophthalmology;
  • Pharmacology-related issues with ATMPs for the eye;
  • In vitro, ex vivo and in vivo models to test ATMPs;
  • Gene therapy for corneal and retinal diseases;
  • Stem cell therapy in the eye: ocular surface diseases, glaucoma, retinal degeneration;
  • Eye tissue banking and other sources of human ocular tissues for regenerative medicine;
  • Biomaterials for ophthalmic applications;
  • Tissue engineering for ocular tissues.

Research scientists and clinicians working in any of these fields or related ones are invited to contribute to this Special Issue by submitting original research articles, review articles or expert opinions.

Prof. Dr. Yolanda Diebold
Dr. Laura García-Posadas
Guest Editors

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Keywords

  • advanced therapy
  • biomaterial
  • cell therapy
  • cornea
  • drug delivery
  • eye
  • gene delivery
  • gene therapy
  • retina
  • scaffold
  • tissue engineering

Published Papers (11 papers)

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Editorial

Jump to: Research, Review

3 pages, 191 KiB  
Editorial
Advanced Therapy Medicinal Products for Eye Diseases: Goals and Challenges
by Yolanda Diebold and Laura García-Posadas
Pharmaceutics 2021, 13(11), 1819; https://doi.org/10.3390/pharmaceutics13111819 - 01 Nov 2021
Viewed by 1209
Abstract
Advanced therapy medicinal products (ATMPs) are a novel class of medicines with enormous potential to improve treatments for a wide range of diseases, including those affecting eye structures [...] Full article

Research

Jump to: Editorial, Review

18 pages, 7495 KiB  
Article
Generation of a Biomimetic Substitute of the Corneal Limbus Using Decellularized Scaffolds
by David Sánchez-Porras, Manuel Caro-Magdaleno, Carmen González-Gallardo, Óscar Darío García-García, Ingrid Garzón, Víctor Carriel, Fernando Campos and Miguel Alaminos
Pharmaceutics 2021, 13(10), 1718; https://doi.org/10.3390/pharmaceutics13101718 - 17 Oct 2021
Cited by 9 | Viewed by 2403
Abstract
Patients with severe limbal damage and limbal stem cell deficiency are a therapeutic challenge. We evaluated four decellularization protocols applied to the full-thickness and half-thickness porcine limbus, and we used two cell types to recellularize the decellularized limbi. The results demonstrated that all [...] Read more.
Patients with severe limbal damage and limbal stem cell deficiency are a therapeutic challenge. We evaluated four decellularization protocols applied to the full-thickness and half-thickness porcine limbus, and we used two cell types to recellularize the decellularized limbi. The results demonstrated that all protocols achieved efficient decellularization. However, the method that best preserved the transparency and composition of the limbus extracellular matrix was the use of 0.1% SDS applied to the half-thickness limbus. Recellularization with the limbal epithelial cell line SIRC and human adipose-derived mesenchymal stem cells (hADSCs) was able to generate a stratified epithelium able to express the limbal markers p63, pancytokeratin, and crystallin Z from day 7 in the case of SIRC and after 14–21 days of induction when hADSCs were used. Laminin and collagen IV expression was detected at the basal lamina of both cell types at days 14 and 21 of follow-up. Compared with control native limbi, tissues recellularized with SIRC showed adequate picrosirius red and alcian blue staining intensity, whereas limbi containing hADSCs showed normal collagen staining intensity. These preliminary results suggested that the limbal substitutes generated in this work share important similarities with the native limbus and could be potentially useful in the future. Full article
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16 pages, 3232 KiB  
Article
Optimization of Collagen Chemical Crosslinking to Restore Biocompatibility of Tissue-Engineered Scaffolds
by Mohammad Mirazul Islam, Dina B. AbuSamra, Alexandru Chivu, Pablo Argüeso, Claes H. Dohlman, Hirak K. Patra, James Chodosh and Miguel González-Andrades
Pharmaceutics 2021, 13(6), 832; https://doi.org/10.3390/pharmaceutics13060832 - 03 Jun 2021
Cited by 29 | Viewed by 6580
Abstract
Collagen scaffolds, one of the most used biomaterials in corneal tissue engineering, are frequently crosslinked to improve mechanical properties, enzyme tolerance, and thermal stability. Crosslinkers such as 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) are compatible with tissues but provide low crosslinking density and reduced mechanical [...] Read more.
Collagen scaffolds, one of the most used biomaterials in corneal tissue engineering, are frequently crosslinked to improve mechanical properties, enzyme tolerance, and thermal stability. Crosslinkers such as 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) are compatible with tissues but provide low crosslinking density and reduced mechanical properties. Conversely, crosslinkers such as glutaraldehyde (GTA) can generate mechanically more robust scaffolds; however, they can also induce greater toxicity. Herein, we evaluated the effectivity of double-crosslinking with both EDC and GTA together with the capability of sodium metabisulfite (SM) and sodium borohydride (SB) to neutralize the toxicity and restore biocompatibility after crosslinking. The EDC-crosslinked collagen scaffolds were treated with different concentrations of GTA. To neutralize the free unreacted aldehyde groups, scaffolds were treated with SM or SB. The chemistry involved in these reactions together with the mechanical and functional properties of the collagen scaffolds was evaluated. The viability of the cells grown on the scaffolds was studied using different corneal cell types. The effect of each type of scaffold treatment on human monocyte differentiation was evaluated. One-way ANOVA was used for statistical analysis. The addition of GTA as a double-crosslinking agent significantly improved the mechanical properties and enzymatic stability of the EDC crosslinked collagen scaffold. GTA decreased cell biocompatibility but this effect was reversed by treatment with SB or SM. These agents did not affect the mechanical properties, enzymatic stability, or transparency of the double-crosslinked scaffold. Contact of monocytes with the different scaffolds did not trigger their differentiation into activated macrophages. Our results demonstrate that GTA improves the mechanical properties of EDC crosslinked scaffolds in a dose-dependent manner, and that subsequent treatment with SB or SM partially restores biocompatibility. This novel manufacturing approach would facilitate the translation of collagen-based artificial corneas to the clinical setting. Full article
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19 pages, 12997 KiB  
Article
Material Characterisation and Stratification of Conjunctival Epithelial Cells on Electrospun Poly(ε-Caprolactone) Fibres Loaded with Decellularised Tissue Matrices
by Lucy A. Bosworth, Kyle G. Doherty, James D. Hsuan, Samuel P. Cray, Raechelle A. D’Sa, Catalina Pineda Molina, Stephen F. Badylak and Rachel L. Williams
Pharmaceutics 2021, 13(3), 318; https://doi.org/10.3390/pharmaceutics13030318 - 28 Feb 2021
Cited by 14 | Viewed by 3155
Abstract
The conjunctiva, an under-researched yet incredibly important tissue, plays key roles in providing protection to the eye and maintaining homeostasis of its ocular surface. Multiple diseases can impair conjunctival function leading to severe consequences that require surgical intervention. Small conjunctival defects can be [...] Read more.
The conjunctiva, an under-researched yet incredibly important tissue, plays key roles in providing protection to the eye and maintaining homeostasis of its ocular surface. Multiple diseases can impair conjunctival function leading to severe consequences that require surgical intervention. Small conjunctival defects can be repaired relatively easily, but larger defects rely on tissue grafts which generally do not provide adequate healing. A tissue engineering approach involving a biomaterial substrate capable of supporting a stratified epithelium with embedded, mucin-secreting goblet cells offers a potential solution. As a first step, this study aimed to induce stratification of human conjunctival epithelial cells cultured on electrospun scaffolds composed from poly(ε-caprolactone) (PCL) and decellularised tissue matrix (small intestinal submucosa (SIS) or urinary bladder matrix (UBM)) and held at the air/liquid interface. Stratification, up to 5 cell layers, occurred more frequently on scaffolds containing PCL + UBM. Incorporation of these decellularised tissue matrices also impacted material properties, with significant changes occurring to their fibre diameter, tensile properties, and chemical composition throughout the scaffold structure compared to PCL alone. These matrix containing scaffolds warrant further long-term investigation as a potential advanced therapy medicinal product for conjunctiva repair and regeneration. Full article
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12 pages, 2454 KiB  
Article
MPC Polymer Promotes Recovery from Dry Eye via Stabilization of the Ocular Surface
by Noriaki Nagai, Shunsuke Sakurai, Ryotaro Seiriki, Misa Minami, Mizuki Yamaguchi, Saori Deguchi and Eiji Harata
Pharmaceutics 2021, 13(2), 168; https://doi.org/10.3390/pharmaceutics13020168 - 27 Jan 2021
Cited by 3 | Viewed by 2632
Abstract
The polymer that includes 2-methacryloyloxy ethyl phosphorylcholine (MPC) is well-known as an effectively hydrating multifunction agent. In this study, we prepared an MPC polymer (MPCP) using radical polymerization with co-monomers—MPC/Stearyl Methacrylate/N,N-dimethylacrylamide—and evaluated the MPCP’s usefulness for dry eye treatment [...] Read more.
The polymer that includes 2-methacryloyloxy ethyl phosphorylcholine (MPC) is well-known as an effectively hydrating multifunction agent. In this study, we prepared an MPC polymer (MPCP) using radical polymerization with co-monomers—MPC/Stearyl Methacrylate/N,N-dimethylacrylamide—and evaluated the MPCP’s usefulness for dry eye treatment using a rabbit model treated with N-acetylcysteine. The MPCP particle size was 50–250 nm, and the form was similar to that of micelles. The MPCP viscosity (approximately 0.95 mPa·s) was 1.17-fold that of purified water, and a decrease in the transepithelial electrical resistance value (corneal damage) was not observed in the immortalized human corneal epithelial cell line HCE-T cell (HCE-T cell layer). The MPCP enhanced the water maintenance on the cornea, and the instillation of MPCP increased the lacrimal fluid volume and prolonged the tear film breakup time without an increase in total mucin contents in the lacrimal fluid of the normal rabbits. The therapeutic potential of the MPCP for dry eye was evaluated using an N-acetylcysteine-treated rabbit model, and, in our investigation, we found that MPCP enhanced the volume of lacrimal fluid and promoted an improvement in the tear film breakup levels. These findings regarding the creation and characteristics of a novel MPCP will provide relevant information for designing further studies to develop a treatment for dry eyes. Full article
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Review

Jump to: Editorial, Research

34 pages, 2157 KiB  
Review
Goals and Challenges of Stem Cell-Based Therapy for Corneal Blindness Due to Limbal Deficiency
by Margarita Calonge, Teresa Nieto-Miguel, Ana de la Mata, Sara Galindo, José M. Herreras and Marina López-Paniagua
Pharmaceutics 2021, 13(9), 1483; https://doi.org/10.3390/pharmaceutics13091483 - 16 Sep 2021
Cited by 14 | Viewed by 6064
Abstract
Corneal failure is a highly prevalent cause of blindness. One special cause of corneal failure occurs due to malfunction or destruction of the limbal stem cell niche, upon which the superficial cornea depends for homeostatic maintenance and wound healing. Failure of the limbal [...] Read more.
Corneal failure is a highly prevalent cause of blindness. One special cause of corneal failure occurs due to malfunction or destruction of the limbal stem cell niche, upon which the superficial cornea depends for homeostatic maintenance and wound healing. Failure of the limbal niche is referred to as limbal stem cell deficiency. As the corneal epithelial stem cell niche is easily accessible, limbal stem cell-based therapy and regenerative medicine applied to the ocular surface are among the most highly advanced forms of this novel approach to disease therapy. However, the challenges are still great, including the development of cell-based products and understanding how they work in the patient’s eye. Advances are being made at the molecular, cellular, and tissue levels to alter disease processes and to reduce or eliminate blindness. Efforts must be coordinated from the most basic research to the most clinically oriented projects so that cell-based therapies can become an integrated part of the therapeutic armamentarium to fight corneal blindness. We undoubtedly are progressing along the right path because cell-based therapy for eye diseases is one of the most successful examples of global regenerative medicine. Full article
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13 pages, 662 KiB  
Review
Is the Conjunctiva a Potential Target for Advanced Therapy Medicinal Products?
by Yolanda Diebold and Laura García-Posadas
Pharmaceutics 2021, 13(8), 1140; https://doi.org/10.3390/pharmaceutics13081140 - 26 Jul 2021
Cited by 8 | Viewed by 3737
Abstract
The conjunctiva is a complex ocular tissue that provides mechanical, sensory, and immune protection for the ocular surface. It is affected by many diseases through different pathological mechanisms. If a disease is not treated and conjunctival function is not fully restored, the whole [...] Read more.
The conjunctiva is a complex ocular tissue that provides mechanical, sensory, and immune protection for the ocular surface. It is affected by many diseases through different pathological mechanisms. If a disease is not treated and conjunctival function is not fully restored, the whole ocular surface and, therefore, sight is at risk. Different therapeutic approaches have been proposed, but there are still unsolved conjunctival alterations that require more sophisticated therapeutic options. Advanced therapy medicinal products (ATMPs) comprise a wide range of products that includes cell therapy, tissue engineering, and gene therapy. To the best of our knowledge, there is no commercialized ATMP specifically for conjunctival treatment yet. However, the conjunctiva can be a potential target for ATMPs for different reasons. In this review, we provide an overview of the advances in experimental phases of potential ATMPs that primarily target the conjunctiva. Important advances have been achieved through the techniques of cell therapy and tissue engineering, whereas the use of gene therapy in the conjunctiva is still marginal. Undoubtedly, future research in this field will lead to achieving commercially available ATMPs for the conjunctiva, which may provide better treatments for patients. Full article
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25 pages, 586 KiB  
Review
Cell Replacement Therapy for Retinal and Optic Nerve Diseases: Cell Sources, Clinical Trials and Challenges
by Rosa M. Coco-Martin, Salvador Pastor-Idoate and Jose Carlos Pastor
Pharmaceutics 2021, 13(6), 865; https://doi.org/10.3390/pharmaceutics13060865 - 11 Jun 2021
Cited by 14 | Viewed by 4066
Abstract
The aim of this review was to provide an update on the potential of cell therapies to restore or replace damaged and/or lost cells in retinal degenerative and optic nerve diseases, describing the available cell sources and the challenges involved in such treatments [...] Read more.
The aim of this review was to provide an update on the potential of cell therapies to restore or replace damaged and/or lost cells in retinal degenerative and optic nerve diseases, describing the available cell sources and the challenges involved in such treatments when these techniques are applied in real clinical practice. Sources include human fetal retinal stem cells, allogenic cadaveric human cells, adult hippocampal neural stem cells, human CNS stem cells, ciliary pigmented epithelial cells, limbal stem cells, retinal progenitor cells (RPCs), human pluripotent stem cells (PSCs) (including both human embryonic stem cells (ESCs) and human induced pluripotent stem cells (iPSCs)) and mesenchymal stem cells (MSCs). Of these, RPCs, PSCs and MSCs have already entered early-stage clinical trials since they can all differentiate into RPE, photoreceptors or ganglion cells, and have demonstrated safety, while showing some indicators of efficacy. Stem/progenitor cell therapies for retinal diseases still have some drawbacks, such as the inhibition of proliferation and/or differentiation in vitro (with the exception of RPE) and the limited long-term survival and functioning of grafts in vivo. Some other issues remain to be solved concerning the clinical translation of cell-based therapy, including (1) the ability to enrich for specific retinal subtypes; (2) cell survival; (3) cell delivery, which may need to incorporate a scaffold to induce correct cell polarization, which increases the size of the retinotomy in surgery and, therefore, the chance of severe complications; (4) the need to induce a localized retinal detachment to perform the subretinal placement of the transplanted cell; (5) the evaluation of the risk of tumor formation caused by the undifferentiated stem cells and prolific progenitor cells. Despite these challenges, stem/progenitor cells represent the most promising strategy for retinal and optic nerve disease treatment in the near future, and therapeutics assisted by gene techniques, neuroprotective compounds and artificial devices can be applied to fulfil clinical needs. Full article
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18 pages, 1722 KiB  
Review
Advanced Therapy Medicinal Products for the Eye: Definitions and Regulatory Framework
by Marina López-Paniagua, Ana de la Mata, Sara Galindo, Francisco Blázquez, Margarita Calonge and Teresa Nieto-Miguel
Pharmaceutics 2021, 13(3), 347; https://doi.org/10.3390/pharmaceutics13030347 - 06 Mar 2021
Cited by 12 | Viewed by 3903
Abstract
Advanced therapy medicinal products (ATMPs) are a group of innovative and complex biological products for human use that comprises somatic cell therapy medicinal products, tissue engineered products, gene therapy medicinal products, and the so-called combined ATMPs that consist of one of the previous [...] Read more.
Advanced therapy medicinal products (ATMPs) are a group of innovative and complex biological products for human use that comprises somatic cell therapy medicinal products, tissue engineered products, gene therapy medicinal products, and the so-called combined ATMPs that consist of one of the previous three categories combined with one or more medical devices. During the last few years, the development of ATMPs for the treatment of eye diseases has become a fast-growing field as it offers the potential to find novel therapeutic approaches for treating pathologies that today have no cure or are just subjected to symptomatic treatments. Therefore, it is important for all professionals working in this field to be familiar with the regulatory principles associated with these types of innovative products. In this review, we outline the legal framework that regulates the development of ATMPs in the European Union and other international jurisdictions, and the criteria that each type of ATMP must meet to be classified as such. To illustrate each legal definition, ATMPs that have already completed the research and development stages and that are currently used for the treatment of eye diseases are presented as examples. Full article
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24 pages, 2008 KiB  
Review
Significance of Crosslinking Approaches in the Development of Next Generation Hydrogels for Corneal Tissue Engineering
by Promita Bhattacharjee and Mark Ahearne
Pharmaceutics 2021, 13(3), 319; https://doi.org/10.3390/pharmaceutics13030319 - 28 Feb 2021
Cited by 28 | Viewed by 4606
Abstract
Medical conditions such as trachoma, keratoconus and Fuchs endothelial dystrophy can damage the cornea, leading to visual deterioration and blindness and necessitating a cornea transplant. Due to the shortage of donor corneas, hydrogels have been investigated as potential corneal replacements. A key factor [...] Read more.
Medical conditions such as trachoma, keratoconus and Fuchs endothelial dystrophy can damage the cornea, leading to visual deterioration and blindness and necessitating a cornea transplant. Due to the shortage of donor corneas, hydrogels have been investigated as potential corneal replacements. A key factor that influences the physical and biochemical properties of these hydrogels is how they are crosslinked. In this paper, an overview is provided of different crosslinking techniques and crosslinking chemical additives that have been applied to hydrogels for the purposes of corneal tissue engineering, drug delivery or corneal repair. Factors that influence the success of a crosslinker are considered that include material composition, dosage, fabrication method, immunogenicity and toxicity. Different crosslinking techniques that have been used to develop injectable hydrogels for corneal regeneration are summarized. The limitations and future prospects of crosslinking strategies for use in corneal tissue engineering are discussed. It is demonstrated that the choice of crosslinking technique has a significant influence on the biocompatibility, mechanical properties and chemical structure of hydrogels that may be suitable for corneal tissue engineering and regenerative applications. Full article
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28 pages, 3455 KiB  
Review
Current Insights into 3D Bioprinting: An Advanced Approach for Eye Tissue Regeneration
by Sandra Ruiz-Alonso, Ilia Villate-Beitia, Idoia Gallego, Markel Lafuente-Merchan, Gustavo Puras, Laura Saenz-del-Burgo and José Luis Pedraz
Pharmaceutics 2021, 13(3), 308; https://doi.org/10.3390/pharmaceutics13030308 - 26 Feb 2021
Cited by 28 | Viewed by 4986
Abstract
Three-dimensional (3D) printing is a game changer technology that holds great promise for a wide variety of biomedical applications, including ophthalmology. Through this emerging technique, specific eye tissues can be custom-fabricated in a flexible and automated way, incorporating different cell types and biomaterials [...] Read more.
Three-dimensional (3D) printing is a game changer technology that holds great promise for a wide variety of biomedical applications, including ophthalmology. Through this emerging technique, specific eye tissues can be custom-fabricated in a flexible and automated way, incorporating different cell types and biomaterials in precise anatomical 3D geometries. However, and despite the great progress and possibilities generated in recent years, there are still challenges to overcome that jeopardize its clinical application in regular practice. The main goal of this review is to provide an in-depth understanding of the current status and implementation of 3D bioprinting technology in the ophthalmology field in order to manufacture relevant tissues such as cornea, retina and conjunctiva. Special attention is paid to the description of the most commonly employed bioprinting methods, and the most relevant eye tissue engineering studies performed by 3D bioprinting technology at preclinical level. In addition, other relevant issues related to use of 3D bioprinting for ocular drug delivery, as well as both ethical and regulatory aspects, are analyzed. Through this review, we aim to raise awareness among the research community and report recent advances and future directions in order to apply this advanced therapy in the eye tissue regeneration field. Full article
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