Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Blood-Derived Products for Tissue Repair/Regeneration 2.0

Special Issue Editors
Special Issue Information
Published Papers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 72447

Share This Special Issue

Special Issue Editors

Dr. Isabel Andia

E-Mail Website
Guest Editor

Bioprinting Laboratory, Regenerative Therapies, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza Cruces 12, 48903 Barakaldo, Bizkaia, Spain
Interests: healing mechanisms; orthobiologics; sports injuries; regenerative medicine technologies; wound management
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Nicola Maffulli

E-Mail Website
Co-Guest Editor

1. Barts and The London School of Medicine and Dentistry, Mile End Hospital, Queen Mary University of London, 275 Bancroft Road, London E1 4DG, UK
2. School of Pharmacy and Bioengineering, Keele University Faculty of Medicine, Thornburrow Drive, Stoke on Trent ST4 7QB, UK
3. Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Fisciano, Italy
Interests: orthopaedic
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Blood-derived products, in particular platelet-rich plasma (PRP), have recently become the focus of intensive interest and discussion, in part because of the evolution of our understanding of platelet biology and the reinterpretation of some of their traditional roles in hemostasis and tissue repair. The biological effects of PRPs are largely attributed to the platelet secretome and plasma signaling proteins. Clinical data suggest that PRPs may exploit different regenerative mechanisms under diverse clinical conditions, including hemostasis, inflammation, angiogenesis, and tissue anabolism, among others. However, many potential molecular mechanisms acting simultaneously to promote tissue healing present a challenge to the identification of critical mechanisms behind PRP therapies.

A vast array of barriers, ranging from deficits in basic research to clinical differences in formulations and application procedures, challenge current efforts to set effective PRP protocols or interventions based on combination products (i.e., PRP + cell products) for optimized therapies in diverse medical fields.

This Special Issue will cover a selection of articles that inform and provide insights about PRP biology and PRPs’ (or other blood-derived products) and combination products’ (PRP and cell products, PRP and drugs, and PRP and biomaterials) clinical successes and failures.

Experimental papers, clinical studies, up-to date reviews, and commentaries are all welcome.

Dr. Isabel Andia
Prof. Dr. Nicola Maffulli
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (11 papers)

Download All Papers

Research

Jump to: Review

18 pages, 2839 KiB

Open AccessArticle

Fibrin-Plasma Rich in Growth Factors Membrane for the Treatment of a Rabbit Alkali-Burn Lesion

by Ronald M. Sánchez-Ávila, Natalia Vázquez, Manuel Chacón, Mairobi Persinal-Medina, Agustín Brea-Pastor, Silvia Berisa-Prado, Luis Fernández-Vega-Cueto, Eduardo Anitua, Álvaro Meana and Jesús Merayo-Lloves

Int. J. Mol. Sci. 2021, 22(11), 5564; https://doi.org/10.3390/ijms22115564 - 25 May 2021

Cited by 4 | Viewed by 2596

Abstract

The purpose of this work is to describe the use of Fibrin-Plasma Rich in Growth Factors (PRGF) membranes for the treatment of a rabbit alkali-burn lesion. For this purpose, an alkali-burn lesion was induced in 15 rabbits. A week later, clinical events were evaluated and rabbits were divided into five treatment groups: rabbits treated with medical treatment, with a fibrin-PRGF membrane cultured with autologous or heterologous rabbit Limbal Epithelial Progenitor Cells (LEPCs), with a fibrin-PRGF membrane in a Simple Limbal Epithelial Transplantation and with a fibrin-PRGF membrane without cultured LEPCs. After 40 days of follow-up, corneas were subjected to histochemical examination and immunostaining against corneal or conjunctival markers. Seven days after alkali-burn lesion, it was observed that rabbits showed opaque cornea, new blood vessels across the limbus penetrating the cornea and epithelial defects. At the end of the follow-up period, an improvement of the clinical parameters analyzed was observed in transplanted rabbits. However, only rabbits transplanted with cultured LEPCs were positive for corneal markers. Otherwise, rabbits in the other three groups showed positive staining against conjunctival markers. In conclusion, fibrin-PRGF membrane improved the chemically induced lesions. Nonetheless, only fibrin-PRGF membranes cultured with rabbit LEPCs were able to restore the corneal surface. Full article

(This article belongs to the Special Issue Blood-Derived Products for Tissue Repair/Regeneration 2.0)

► Show Figures

Figure 1

12 pages, 1698 KiB

Open AccessArticle

Cell-free Stem Cell-Derived Extract Formulation for Regenerative Medicine Applications

by Ashim Gupta, Craig Cady, Anne-Marie Fauser, Hugo C. Rodriguez, R. Justin Mistovich, Anish G. R. Potty and Nicola Maffulli

Int. J. Mol. Sci. 2020, 21(24), 9364; https://doi.org/10.3390/ijms21249364 - 9 Dec 2020

Cited by 27 | Viewed by 3931

Abstract

Stem cells for regenerative medicine purposes offer therapeutic benefits, but disadvantages are still ill defined. The benefit of stem cells may be attributed to their secretion of growth factors (GFs), cytokines (CKs), and extracellular vesicles (EVs), including exosomes. We present a novel cell-free stem cell-derived extract (CCM), formulated from human progenitor endothelial stem cells (hPESCs), characterized for biologically active factors using ELISA, nanoparticle tracking analysis and single particle interferometric reflectance imaging sensing. The effect on fibroblast proliferation and ability to induce stem cell migration was analyzed using Alamar Blue proliferation and Transwell migration assays, respectively. GFs including IGFBP 1, 2, 3, and 6, insulin, growth hormone, PDGF-AA, TGF-α, TGF-β1, VEGF, and the anti-inflammatory cytokine, IL-1RA were detected. Membrane enclosed particles within exosome size range and expressing exosome tetraspanins CD81 and CD9 were identified. CCM significantly increased cell proliferation and induced stem cell migration. Analysis of CCM revealed presence of GFs, CKs, and EVs, including exosomes. The presence of multiple factors including exosomes within one formulation, the ability to promote cell proliferation and induce stem cell migration may reduce inflammation and pain, and augment tissue repair. Full article

(This article belongs to the Special Issue Blood-Derived Products for Tissue Repair/Regeneration 2.0)

► Show Figures

Figure 1

16 pages, 3074 KiB

Open AccessArticle

Comparative Evaluation of the Clinical Efficacy of PRP-Therapy, Minoxidil, and Their Combination with Immunohistochemical Study of the Dynamics of Cell Proliferation in the Treatment of Men with Androgenetic Alopecia

by Elena E. Pakhomova and Irina O. Smirnova

Int. J. Mol. Sci. 2020, 21(18), 6516; https://doi.org/10.3390/ijms21186516 - 6 Sep 2020

Cited by 31 | Viewed by 6160

Abstract

Platelet-rich plasma (PRP) therapy has been considered as a promising treatment for androgenetic alopecia (AGA). The aim of the study was comparative evaluation of the clinical efficacy of PRP-therapy, minoxidil, and their combination in the treatment of men with AGA and to evaluate the effects of PRP on the proliferation of hair follicle (HF) cells in skin biopsy. Materials and Methods: The study involved 69 men who were divided into 3 groups who received PRP therapy, minoxidil, and their combination. The clinical efficacy of the therapy was evaluated by the dynamics of morphometric of hairs. To assess cell proliferation antibodies to β-catenin, CD34, Ki67, and to Dkk-1 were used. Results. PRP treatment was more effective than minoxidil therapy (p = 0.005). Complex therapy turned out to be more effective than minoxidil monotherapy (p < 0.0001) and PRP monotherapy (p = 0.007). After applying PRP the absolute and relative values of the β-catenin and CD34 expression area increased; an increase in Ki67+ index was also significant. Conclusions: PRP can be considered as a treatment option for AGA. Combined PRP and minoxidil use seems promising for the treatment of AGA. PRP increase in the proliferative activity of HF cells and improves hair morphology in patients with AGA. Full article

(This article belongs to the Special Issue Blood-Derived Products for Tissue Repair/Regeneration 2.0)

► Show Figures

Figure 1

19 pages, 5018 KiB

Open AccessArticle

Human Platelet Lysate Supports Efficient Expansion and Stability of Wharton’s Jelly Mesenchymal Stromal Cells via Active Uptake and Release of Soluble Regenerative Factors

by Mariana Cañas-Arboleda, Karl Beltrán, Carlos Medina, Bernardo Camacho and Gustavo Salguero

Int. J. Mol. Sci. 2020, 21(17), 6284; https://doi.org/10.3390/ijms21176284 - 31 Aug 2020

Cited by 11 | Viewed by 2875

Abstract

Manufacturing of mesenchymal stromal cell (MSC)-based therapies for regenerative medicine requires the use of suitable supply of growth factors that enhance proliferation, cell stability and potency during cell expansion. Human blood derivatives such as human platelet lysate (hPL) have emerged as a feasible alternative for cell growth supplement. Nevertheless, composition and functional characterization of hPL in the context of cell manufacturing is still under investigation, particularly regarding the content and function of pro-survival and pro-regenerative factors. We performed comparative analyses of hPL, human serum (hS) and fetal bovine serum (FBS) stability and potency to support Wharton’s jelly (WJ) MSC production. We demonstrated that hPL displayed low inter-batch variation and unique secretome profile that was not present in hS and FBS. Importantly, hPL-derived factors including PDGF family, EGF, TGF-alpha, angiogenin and RANTES were actively taken up by WJ-MSC to support efficient expansion. Moreover, hPL but not hS or FBS induced secretion of osteoprotegerin, HGF, IL-6 and GRO-alpha by WJ-MSC during the expansion phase. Thus, hPL is a suitable source of factors supporting viability, stability and potency of WJ-MSC and therefore constitutes an essential raw material that in combination with WJ-MSC introduces a great opportunity for the generation of potent regenerative medicine products. Full article

(This article belongs to the Special Issue Blood-Derived Products for Tissue Repair/Regeneration 2.0)

► Show Figures

Figure 1

24 pages, 5300 KiB

Open AccessArticle

Expansion of Human Limbal Epithelial Stem/Progenitor Cells Using Different Human Sera: A Multivariate Statistical Analysis

by Raquel Hernáez-Moya, Sheyla González, Arantza Urkaregi, Jose Ignacio Pijoan, Sophie X. Deng and Noelia Andollo

Int. J. Mol. Sci. 2020, 21(17), 6132; https://doi.org/10.3390/ijms21176132 - 25 Aug 2020

Cited by 5 | Viewed by 2940

Abstract

Transplantation of human cultured limbal epithelial stem/progenitor cells (LESCs) has demonstrated to restore the integrity and functionality of the corneal surface in about 76% of patients with limbal stem cell deficiency. However, there are different protocols for the expansion of LESCs, and many of them use xenogeneic products, being a risk for the patients’ health. We compared the culture of limbal explants on the denuded amniotic membrane in the culture medium—supplemental hormone epithelial medium (SHEM)—supplemented with FBS or two differently produced human sera. Cell morphology, cell size, cell growth rate, and the expression level of differentiation and putative stem cell markers were examined. Several bioactive molecules were quantified in the human sera. In a novel approach, we performed a multivariate statistical analysis of data to investigate the culture factors, such as differently expressed molecules of human sera that specifically influence the cell phenotype. Our results showed that limbal cells cultured with human sera grew faster and contained similar amounts of small-sized cells, higher expression of the protein p63α, and lower of cytokeratin K12 than FBS cultures, thus, maintaining the stem/progenitor phenotype of LESCs. Furthermore, the multivariate analysis provided much data to better understand the obtaining of different cell phenotypes as a consequence of the use of different culture methodologies or different culture components. Full article

(This article belongs to the Special Issue Blood-Derived Products for Tissue Repair/Regeneration 2.0)

► Show Figures

Figure 1

17 pages, 13515 KiB

Open AccessArticle

Endothelial Response Boosted by Platelet Lysate: The Involvement of Calcium Toolkit

by Simona Martinotti, Mauro Patrone, Valeria Balbo, Laura Mazzucco and Elia Ranzato

Int. J. Mol. Sci. 2020, 21(3), 808; https://doi.org/10.3390/ijms21030808 - 26 Jan 2020

Cited by 8 | Viewed by 2606

Abstract

Wound repair is a dynamic process during which crucial signaling pathways are regulated by growth factors and cytokines released by several kinds of cells directly involved in the healing process. However, the limited applications and heterogeneous clinical results of single growth factors in wound healing encouraged the use of a mixture of bioactive molecules such as platelet derivatives for best results in wound repair. An interesting platelet derivative, obtained from blood samples, is platelet lysate (PL), which has shown potential clinical application. PL is obtained from freezing and thawing of platelet-enriched blood samples. Intracellular calcium (Ca²⁺) signals play a central role in the control of endothelial cell survival, proliferation, motility, and differentiation. We investigated the role of Ca²⁺ signaling in the PL-driven endothelial healing process. In our experiments, the functional significance of Ca²⁺ signaling machinery was highlighted performing the scratch wound assay in presence of different inhibitors or specific RNAi. We also pointed out that the PL-induced generation of intracellular ROS (reactive oxygen species) via NOX4 (NADPH oxidase 4) is necessary for the activation of TRPM2 and the resulting Ca²⁺ entry from the extracellular space. This is the first report of the mechanism of wound repair in an endothelial cell model boosted by the PL-induced regulation of [Ca²⁺]_i. Full article

(This article belongs to the Special Issue Blood-Derived Products for Tissue Repair/Regeneration 2.0)

► Show Figures

Figure 1

14 pages, 1864 KiB

Open AccessArticle

Wound Dressing Selection Is Critical to Enhance Platelet-Rich Fibrin Activities in Wound Care

by Cristina Del Amo, Arantza Perez-Valle, Elena Perez-Zabala, Karmele Perez-del-Pecho, Ainara Larrazabal, Andima Basterretxea, Paola Bully and Isabel Andia

Int. J. Mol. Sci. 2020, 21(2), 624; https://doi.org/10.3390/ijms21020624 - 17 Jan 2020

Cited by 16 | Viewed by 8431

Abstract

The use of platelet-rich fibrin (PRF) is investigated in ulcer management because it provides a healing milieu rich in growth factors and cytokines. Although crucial, the relevance of secondary dressings is under-researched and no data support the use of any particular dressing in preference to another. We assessed the properties of different dressing categories, including alginates, hydrocolloids, foams, hydrofibers, films, meshes and gauzes, in terms of affinity for PRF, releasate management (retention/extrusion) and the kinetics of cytokine release as well as the influence of each combination product, [PRF + dressing], on dermal cell behaviour, aiming to provide useful information for choosing the most adequate dressing for each particular patient. Active dressings including alginates, hydrofibers, foams and hydrocolloids blend with PRF, creating a diverse combination of products with different performances. Alginate and hydrofiber showed the highest affinity but moderate retention of releasate, without interfering with cell functions. Instead, the foam sequestered the releasate and hindered the release of growth factors, thereby compromising cell activities. Film and mesh presented very poor releasate retention and performed similarly to PRF by itself. Affinity index and releasate management explained 79% of platelet-derived growth factor (PDGF-BB) concentration variability, p < 0.001. Cell proliferation depended on the ability of the combination product to retain/release supernatant, PDGF-BB concentration and cell adhesion R² = 0.91, p = 0.014. Full article

(This article belongs to the Special Issue Blood-Derived Products for Tissue Repair/Regeneration 2.0)

► Show Figures

Graphical abstract

Review

Jump to: Research

36 pages, 3368 KiB

Open AccessReview

Platelet-Rich Plasma: New Performance Understandings and Therapeutic Considerations in 2020

by Peter Everts, Kentaro Onishi, Prathap Jayaram, José Fábio Lana and Kenneth Mautner

Int. J. Mol. Sci. 2020, 21(20), 7794; https://doi.org/10.3390/ijms21207794 - 21 Oct 2020

Cited by 377 | Viewed by 28472

Abstract

Emerging autologous cellular therapies that utilize platelet-rich plasma (PRP) applications have the potential to play adjunctive roles in a variety of regenerative medicine treatment plans. There is a global unmet need for tissue repair strategies to treat musculoskeletal (MSK) and spinal disorders, osteoarthritis (OA), and patients with chronic complex and recalcitrant wounds. PRP therapy is based on the fact that platelet growth factors (PGFs) support the three phases of wound healing and repair cascade (inflammation, proliferation, remodeling). Many different PRP formulations have been evaluated, originating from human, in vitro, and animal studies. However, recommendations from in vitro and animal research often lead to different clinical outcomes because it is difficult to translate non-clinical study outcomes and methodology recommendations to human clinical treatment protocols. In recent years, progress has been made in understanding PRP technology and the concepts for bioformulation, and new research directives and new indications have been suggested. In this review, we will discuss recent developments regarding PRP preparation and composition regarding platelet dosing, leukocyte activities concerning innate and adaptive immunomodulation, serotonin (5-HT) effects, and pain killing. Furthermore, we discuss PRP mechanisms related to inflammation and angiogenesis in tissue repair and regenerative processes. Lastly, we will review the effect of certain drugs on PRP activity, and the combination of PRP and rehabilitation protocols. Full article

(This article belongs to the Special Issue Blood-Derived Products for Tissue Repair/Regeneration 2.0)

► Show Figures

Graphical abstract

18 pages, 874 KiB

Open AccessReview

Freeze-Drying of Platelet-Rich Plasma: The Quest for Standardization

by Isabel Andia, Arantza Perez-Valle, Cristina Del Amo and Nicola Maffulli

Int. J. Mol. Sci. 2020, 21(18), 6904; https://doi.org/10.3390/ijms21186904 - 20 Sep 2020

Cited by 39 | Viewed by 6093

Abstract

The complex biology of platelets and their involvement in tissue repair and inflammation have inspired the development of platelet-rich plasma (PRP) therapies for a broad array of medical needs. However, clinical advances are hampered by the fact that PRP products, doses and treatment protocols are far from being standardized. Freeze-drying PRP (FD-PRP) preserves platelet function, cytokine concentration and functionality, and has been proposed as a consistent method for product standardization and fabrication of an off-the-shelf product with improved stability and readiness for future uses. Here, we present the current state of experimental and clinical FD-PRP research in the different medical areas in which PRP has potential to meet prevailing medical needs. A systematic search, according to PRISMA (Preferred Reported Items for Systematic Reviews and Meta-Analyses) guidelines, showed that research is mostly focused on wound healing, i.e., developing combination products for ulcer management. Injectable hydrogels are investigated for lumbar fusion and knee conditions. In dentistry, combination products permit slow kinetics of growth factor release and functionalized membranes for guided bone regeneration. Full article

(This article belongs to the Special Issue Blood-Derived Products for Tissue Repair/Regeneration 2.0)

► Show Figures

Figure 1

14 pages, 1065 KiB

Open AccessReview

Biotech-Educated Platelets: Beyond Tissue Regeneration 2.0

by Sheila Siqueira Andrade, Alessandra Valéria de Sousa Faria, Manoel João Batista C. Girão, Gwenny M. Fuhler, Maikel P. Peppelenbosch and Carmen V. Ferreira-Halder

Int. J. Mol. Sci. 2020, 21(17), 6061; https://doi.org/10.3390/ijms21176061 - 23 Aug 2020

Cited by 1 | Viewed by 3085

Abstract

The increasing discoveries regarding the biology and functions of platelets in the last decade undoubtedly show that these cells are one of the most biotechnological human cells. This review summarizes new advances in platelet biology, functions, and new concepts of biotech-educated platelets that connect advanced biomimetic science to platelet-based additive manufacturing for tissue regeneration. As highly responsive and secretory cells, platelets could be explored to develop solutions that alter injured microenvironments through platelet-based synthetic biomaterials with instructive extracellular cues for morphogenesis in tissue engineering beyond tissue regeneration 2.0. Full article

(This article belongs to the Special Issue Blood-Derived Products for Tissue Repair/Regeneration 2.0)

► Show Figures

Figure 1

16 pages, 1045 KiB

Open AccessReview

Platelets and Defective N-Glycosylation

by Elmina Mammadova-Bach, Jaak Jaeken, Thomas Gudermann and Attila Braun

Int. J. Mol. Sci. 2020, 21(16), 5630; https://doi.org/10.3390/ijms21165630 - 6 Aug 2020

Cited by 26 | Viewed by 4458

Abstract

N-glycans are covalently linked to an asparagine residue in a simple acceptor sequence of proteins, called a sequon. This modification is important for protein folding, enhancing thermodynamic stability, and decreasing abnormal protein aggregation within the endoplasmic reticulum (ER), for the lifetime and for the subcellular localization of proteins besides other functions. Hypoglycosylation is the hallmark of a group of rare genetic diseases called congenital disorders of glycosylation (CDG). These diseases are due to defects in glycan synthesis, processing, and attachment to proteins and lipids, thereby modifying signaling functions and metabolic pathways. Defects in N-glycosylation and O-glycosylation constitute the largest CDG groups. Clotting and anticlotting factor defects as well as a tendency to thrombosis or bleeding have been described in CDG patients. However, N-glycosylation of platelet proteins has been poorly investigated in CDG. In this review, we highlight normal and deficient N-glycosylation of platelet-derived molecules and discuss the involvement of platelets in the congenital disorders of N-glycosylation. Full article

(This article belongs to the Special Issue Blood-Derived Products for Tissue Repair/Regeneration 2.0)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Blood-Derived Products for Tissue Repair/Regeneration 2.0

Share This Special Issue

Special Issue Editors

Special Issue Information

Published Papers (11 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI