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A special issue of Materials (ISSN 1996-1944). This special issue belongs to the section "Biomaterials".

Deadline for manuscript submissions: closed (15 February 2019) | Viewed by 100063

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Prof. Dr. Jose M.F. Ferreira

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Department of Materials and Ceramics Engineering, CICECO, University of Aveiro, 3810-193 Aveiro, Portugal
Interests: synthesis of powders by different techniques; structural (oxide- and non-oxide-based) ceramics; functional (piezoelectric, ferroelectric, magnetic, etc.) materials; development of materials for optical and energy related applications; development and processing of materials for applications in biomedicine, especially in dentistry, orthopedics and tissue engineering

Special Issue Information

Dear Colleagues,

Research efforts are often driven by real needs for new or better materials, processes or systems that do not satisfactorily fulfil expected/desired roles or functions. The discovery of bioactive glasses (BGs) in the late 1960s, intended to replace inert metal and plastic implants that were not well tolerated by the body, represents a remarkable milestone in the field of synthetic and resorbable bone grafts. This discovery has inspired many other investigations, aiming at further exploring the in vitro and in vivo performances of BGs and other inorganic bioactive materials based on calcium phosphates and or inorganic/organic composites by suitably mixing the inorganic components with biopolymer matrices aiming at better mimicking the mechanical behavior and properties of bone tissues. However, successful tissue engineering strategies typically involve a combination of cells and bioactive factors with an implantable porous biomaterial construct to provide an environment conducive to cell differentiation and proliferation. Several processing techniques might be used to generate the 3D porous structure. Printing methods have recently gained tremendous importance, being increasingly applied to inorganic, polymeric and composite acellular materials. However, some of the most exciting developments in the last years are related to: (i) the bioprinting of cellularized constructs from hydrogels to engineer heterogeneously cellular 3D environments that lead to tissues that can mimic specific organ functions; and (ii) multifunctional devices that include in situ drug release and antibacterial activity. Contributions to this Special Issue on the abovementioned topics, but not limited to them, will be welcome.

Prof. Dr. Jose M.F. Ferreira
Guest Editor

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Keywords

bioactive bone graft materials
osteoinduction of hMSC
porous constructs
additive manufacturing techniques
bioprinting

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Published Papers (12 papers)

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Research

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11 pages, 2064 KiB

Open AccessArticle

Cuttlefish Bone-Derived Biphasic Calcium Phosphate Scaffolds Coated with Sol-Gel Derived Bioactive Glass

by Ana S. Neto, Daniela Brazete and José M.F. Ferreira

Materials 2019, 12(17), 2711; https://doi.org/10.3390/ma12172711 - 24 Aug 2019

Cited by 11 | Viewed by 3487

Abstract

The combination of calcium phosphates with bioactive glasses (BG) has received an increased interest in the field of bone tissue engineering. In the present work, biphasic calcium phosphates (BCP) obtained by hydrothermal transformation of cuttlefish bone (CB) were coated with a Sr-, Mg- and Zn-doped sol-gel derived BG. The scaffolds were characterized by X-ray diffraction, Fourier transform infrared spectroscopy and scanning electron microscopy. The initial CB structure was maintained after hydrothermal transformation (HT) and the scaffold functionalization did not jeopardize the internal structure. The results of the in-vitro bioactivity after immersing the BG coated scaffolds in simulated body fluid (SBF) for 15 days showed the formation of apatite on the surface of the scaffolds. Overall, the functionalized CB derived BCP scaffolds revealed promising properties, but further assessment of the in-vitro biological properties is needed before being considered for their use in bone tissue engineering applications. Full article

(This article belongs to the Special Issue Scaffold Materials for Tissue Engineering)

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12 pages, 3133 KiB

Open AccessFeature PaperArticle

Bone Tissue Engineering in a Perfusion Bioreactor Using Dexamethasone-Loaded Peptide Hydrogel

by Marina Panek, Maja Antunović, Lidija Pribolšan, Alan Ivković, Marijan Gotić, Andreja Vukasović, Katarina Caput Mihalić, Maja Pušić, Tanja Jurkin and Inga Marijanović

Materials 2019, 12(6), 919; https://doi.org/10.3390/ma12060919 - 19 Mar 2019

Cited by 33 | Viewed by 5521

Abstract

The main goal of this study was the formation of bone tissue using dexamethasone (DEX)-loaded [COCH₃]-RADARADARADARADA-[CONH₂] (RADA 16-I) scaffold that has the ability to release optimal DEX concentration under perfusion force. Bone-marrow samples were collected from three patients during a hip arthroplasty. Human mesenchymal stem cells (hMSCs) were isolated and propagated in vitro in order to be seeded on scaffolds made of DEX-loaded RADA 16-I hydrogel in a perfusion bioreactor. DEX concentrations were as follows: 4 × 10⁻³, 4 × 10⁻⁴ and 4 × 10⁻⁵ M. After 21 days in a perfusion bioreactor, tissue was analyzed by scanning electron microscopy (SEM) and histology. Markers of osteogenic differentiation were quantified by real-time polymerase chain reaction (RT-PCR) and immunocytochemistry. Minerals were quantified and detected by the von Kossa method. In addition, DEX release from the scaffold in a perfusion bioreactor was assessed. The osteoblast differentiation was confirmed by the expression analysis of osteoblast-related genes (alkaline phosphatase (ALP), collagen I (COL1A1) and osteocalcin (OC). The hematoxylin/eosin staining confirmed the presence of cells and connective tissue, while SEM revealed morphological characteristics of cells, extracellular matrix and minerals—three main components of mature bone tissue. Immunocytochemical detection of collagen I is in concordance with given results, supporting the conclusion that scaffold with DEX concentration of 4 × 10⁻⁴ M has the optimal engineered tissue morphology. The best-engineered bone tissue is produced on scaffold loaded with 4 × 10⁻⁴ M DEX with a perfusion rate of 0.1 mL/min for 21 days. Differentiation of hMSCs on DEX-loaded RADA 16-I scaffold under perfusion force has a high potential for application in regenerative orthopedics. Full article

(This article belongs to the Special Issue Scaffold Materials for Tissue Engineering)

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18 pages, 3176 KiB

Open AccessArticle

Efficient Fabrication of Polycaprolactone Scaffolds for Printing Hybrid Tissue-Engineered Constructs

by Enrique Sodupe Ortega, Andres Sanz-Garcia, Alpha Pernia-Espinoza and Carmen Escobedo-Lucea

Materials 2019, 12(4), 613; https://doi.org/10.3390/ma12040613 - 18 Feb 2019

Cited by 26 | Viewed by 4896

Abstract

Hybrid constructs represent substantial progress in tissue engineering (TE) towards producing implants of a clinically relevant size that recapitulate the structure and multicellular complexity of the native tissue. They are created by interlacing printed scaffolds, sacrificial materials, and cell-laden hydrogels. A suitable biomaterial is a polycaprolactone (PCL); however, due to the higher viscosity of this biopolymer, three-dimensional (3D) printing of PCL is slow, so reducing PCL print times remains a challenge. We investigated parameters, such as nozzle shape and size, carriage speed, and print temperature, to find a tradeoff that speeds up the creation of hybrid constructs of controlled porosity. We performed experiments with conical, cylindrical, and cylindrical shortened nozzles and numerical simulations to infer a more comprehensive understanding of PCL flow rate. We found that conical nozzles are advised as they exhibited the highest shear rate, which increased the flow rate. When working at a low carriage speed, conical nozzles of a small diameter tended to form-flatten filaments and became highly inefficient. However, raising the carriage speed revealed shortcomings because passing specific values created filaments with a heterogeneous diameter. Small nozzles produced scaffolds with thin strands but at long building times. Using large nozzles and a high carriage speed is recommended. Overall, we demonstrated that hybrid constructs with a clinically relevant size could be much more feasible to print when reaching a tradeoff between temperature, nozzle diameter, and speed. Full article

(This article belongs to the Special Issue Scaffold Materials for Tissue Engineering)

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12 pages, 4577 KiB

Open AccessArticle

Chitosan/Poly(vinylpyrrolidone) Matrices Obtained by Gamma-Irradiation for Skin Scaffolds: Characterization and Preliminary Cell Response Studies

by Maria Helena Casimiro, Susana R. Gomes, Gabriela Rodrigues, João Paulo Leal and Luís M. Ferreira

Materials 2018, 11(12), 2535; https://doi.org/10.3390/ma11122535 - 13 Dec 2018

Cited by 25 | Viewed by 4252

Abstract

Several studies have shown that chitosan possesses characteristics favorable for promoting dermal regeneration and accelerated wound healing. In this work we have reported the work that has been done on the development and characterization of biocompatible and biodegradable chitosan based matrices to be used as skin scaffolds. Poly(vinylpyrrrolidone) (PVP) was used as copolymer and a two steps methodology of freeze-drying and gamma irradiation was used to obtain the porous matrices. The influence of PVP content, synthesis procedure and absorbed radiation dose on matrices’ physical, chemical and structural properties was evaluated by ATR-FTIR, TGA, SEM, contact angle measurements and degradation behavior. The in vitro cellular viability and proliferation of HFFF2 fibroblast cell line was analyzed as a measure of matrices’ biocompatibility and ability to assist skin regeneration. Results show that over the studied range values, gamma-radiation dose, copolymer concentration and synthesis procedure can be used to tailor the matrices’ morphology in terms of porosity and surface roughness. Early results from biological assays evidence the biocompatibility of the prepared chitosan/PVP matrices since cells adhered to the surface of all matrices (chitosan/PVP (5%) γ-irradiated at 10 kGy presents the higher cellular viability). These features show that the resultant matrices could be a potential suitable scaffold for skin tissue regeneration. Full article

(This article belongs to the Special Issue Scaffold Materials for Tissue Engineering)

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14 pages, 3460 KiB

Open AccessArticle

Assessment of Migration of Human MSCs through Fibrin Hydrogels as a Tool for Formulation Optimisation

by Nasseem Salam, Sotiria Toumpaniari, Piergiorgio Gentile, Ana Marina Ferreira, Kenneth Dalgarno and Simon Partridge

Materials 2018, 11(9), 1781; https://doi.org/10.3390/ma11091781 - 19 Sep 2018

Cited by 23 | Viewed by 6619

Abstract

Control of cell migration is fundamental to the performance of materials for cell delivery, as for cells to provide any therapeutic effect, they must migrate out from the delivery material. Here the influence of fibrinogen concentration on the migration of encapsulated human mesenchymal stem cells (hMSCs) from a cell spheroid through fibrin hydrogels is tracked over time. Fibrin was chosen as a model material as it is routinely employed as a haemostatic agent and more recently has been applied as a localised delivery vehicle for potential therapeutic cell populations. The hydrogels consisted of 5 U/mL thrombin and between 5 and 50 mg/mL fibrinogen. Microstructural and viscoelastic properties of different compositions were evaluated using SEM and rheometry. Increasing the fibrinogen concentration resulted in a visibly denser matrix with smaller pores and higher stiffness. hMSCs dispersed within the fibrin gels maintained cell viability post-encapsulation, however, the migration of cells from an encapsulated spheroid revealed that denser fibrin matrices inhibit cell migration. This study provides the first quantitative study on the influence of fibrinogen concentration on 3D hMSC migration within fibrin gels, which can be used to guide material selection for scaffold design in tissue engineering and for the clinical application of fibrin sealants. Full article

(This article belongs to the Special Issue Scaffold Materials for Tissue Engineering)

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16 pages, 4647 KiB

Open AccessArticle

Demineralized Bone Matrix Coating Si-Ca-P Ceramic Does Not Improve the Osseointegration of the Scaffold

by Andrés Parrilla-Almansa, Nuria García-Carrillo, Patricia Ros-Tárraga, Carlos M. Martínez, Francisco Martínez-Martínez, Luis Meseguer-Olmo and Piedad N. De Aza

Materials 2018, 11(9), 1580; https://doi.org/10.3390/ma11091580 - 1 Sep 2018

Cited by 18 | Viewed by 4066

Abstract

The aim of this study was to manufacture and evaluate the effect of a biphasic calcium silicophosphate (CSP) scaffold ceramic, coated with a natural demineralized bone matrix (DBM), to evaluate the efficiency of this novel ceramic material in bone regeneration. The DBM-coated CSP ceramic was made by coating a CSP scaffold with gel DBM, produced by the partial sintering of different-sized porous granules. These scaffolds were used to reconstruct defects in rabbit tibiae, where CSP scaffolds acted as the control material. Micro-CT and histological analyses were performed to evaluate new bone formation at 1, 3, and 5 months post-surgery. The present research results showed a correlation among the data obtained by micro-CT and the histomorphological results, the gradual disintegration of the biomaterial, and the presence of free scaffold fragments dispersed inside the medullary cavity occupied by hematopoietic bone marrow over the 5-month study period. No difference was found between the DBM-coated and uncoated implants. The new bone tissue inside the implants increased with implantation time. Slightly less new bone formation was observed in the DBM-coated samples, but it was not statistically significant. Both the DBM-coated and the CSP scaffolds gave excellent bone tissue responses and good osteoconductivity. Full article

(This article belongs to the Special Issue Scaffold Materials for Tissue Engineering)

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2318 KiB

Open AccessArticle

3D Printed Structures Filled with Carbon Fibers and Functionalized with Mesenchymal Stem Cell Conditioned Media as In Vitro Cell Niches for Promoting Chondrogenesis

by Josefa Predestinación García-Ruíz and Andrés Díaz Lantada

Materials 2018, 11(1), 23; https://doi.org/10.3390/ma11010023 - 24 Dec 2017

Cited by 19 | Viewed by 6475

Abstract

In this study, we present a novel approach towards the straightforward, rapid, and low-cost development of biomimetic composite scaffolds for tissue engineering strategies. The system is based on the additive manufacture of a computer-designed lattice structure or framework, into which carbon fibers are subsequently knitted or incorporated. The 3D-printed lattice structure acts as support and the knitted carbon fibers perform as driving elements for promoting cell colonization of the three-dimensional construct. A human mesenchymal stem cell (h-MSC) conditioned medium (CM) is also used for improving the scaffold’s response and promoting cell adhesion, proliferation, and viability. Cell culture results—in which scaffolds become buried in collagen type II—provide relevant information regarding the viability of the composite scaffolds used and the prospective applications of the proposed approach. In fact, the advanced composite scaffold developed, together with the conditioned medium functionalization, constitutes a biomimetic stem cell niche with clear potential, not just for tendon and ligament repair, but also for cartilage and endochondral bone formation and regeneration strategies. Full article

(This article belongs to the Special Issue Scaffold Materials for Tissue Engineering)

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Review

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42 pages, 5127 KiB

Open AccessReview

Scaffolding Strategies for Tissue Engineering and Regenerative Medicine Applications

by Sandra Pina, Viviana P. Ribeiro, Catarina F. Marques, F. Raquel Maia, Tiago H. Silva, Rui L. Reis and J. Miguel Oliveira

Materials 2019, 12(11), 1824; https://doi.org/10.3390/ma12111824 - 5 Jun 2019

Cited by 360 | Viewed by 16624

Abstract

During the past two decades, tissue engineering and the regenerative medicine field have invested in the regeneration and reconstruction of pathologically altered tissues, such as cartilage, bone, skin, heart valves, nerves and tendons, and many others. The 3D structured scaffolds and hydrogels alone or combined with bioactive molecules or genes and cells are able to guide the development of functional engineered tissues, and provide mechanical support during in vivo implantation. Naturally derived and synthetic polymers, bioresorbable inorganic materials, and respective hybrids, and decellularized tissue have been considered as scaffolding biomaterials, owing to their boosted structural, mechanical, and biological properties. A diversity of biomaterials, current treatment strategies, and emergent technologies used for 3D scaffolds and hydrogel processing, and the tissue-specific considerations for scaffolding for Tissue engineering (TE) purposes are herein highlighted and discussed in depth. The newest procedures focusing on the 3D behavior and multi-cellular interactions of native tissues for further use for in vitro model processing are also outlined. Completed and ongoing preclinical research trials for TE applications using scaffolds and hydrogels, challenges, and future prospects of research in the regenerative medicine field are also presented. Full article

(This article belongs to the Special Issue Scaffold Materials for Tissue Engineering)

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54 pages, 2454 KiB

Open AccessReview

Bioactive Glasses and Glass-Ceramics for Healthcare Applications in Bone Regeneration and Tissue Engineering

by Hugo R. Fernandes, Anuraag Gaddam, Avito Rebelo, Daniela Brazete, George E. Stan and José M. F. Ferreira

Materials 2018, 11(12), 2530; https://doi.org/10.3390/ma11122530 - 12 Dec 2018

Cited by 258 | Viewed by 12994

Abstract

The discovery of bioactive glasses (BGs) in the late 1960s by Larry Hench et al. was driven by the need for implant materials with an ability to bond to living tissues, which were intended to replace inert metal and plastic implants that were not well tolerated by the body. Among a number of tested compositions, the one that later became designated by the well-known trademark of 45S5 Bioglass^® excelled in its ability to bond to bone and soft tissues. Bonding to living tissues was mediated through the formation of an interfacial bone-like hydroxyapatite layer when the bioglass was put in contact with biological fluids in vivo. This feature represented a remarkable milestone, and has inspired many other investigations aiming at further exploring the in vitro and in vivo performances of this and other related BG compositions. This paradigmatic example of a target-oriented research is certainly one of the most valuable contributions that one can learn from Larry Hench. Such a goal-oriented approach needs to be continuously stimulated, aiming at finding out better performing materials to overcome the limitations of the existing ones, including the 45S5 Bioglass^®. Its well-known that its main limitations include: (i) the high pH environment that is created by its high sodium content could turn it cytotoxic; (ii) and the poor sintering ability makes the fabrication of porous three-dimensional (3D) scaffolds difficult. All of these relevant features strongly depend on a number of interrelated factors that need to be well compromised. The selected chemical composition strongly determines the glass structure, the biocompatibility, the degradation rate, and the ease of processing (scaffolds fabrication and sintering). This manuscript presents a first general appraisal of the scientific output in the interrelated areas of bioactive glasses and glass-ceramics, scaffolds, implant coatings, and tissue engineering. Then, it gives an overview of the critical issues that need to be considered when developing bioactive glasses for healthcare applications. The aim is to provide knowledge-based tools towards guiding young researchers in the design of new bioactive glass compositions, taking into account the desired functional properties. Full article

(This article belongs to the Special Issue Scaffold Materials for Tissue Engineering)

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62 pages, 2022 KiB

Open AccessFeature PaperReview

Cationic Substitutions in Hydroxyapatite: Current Status of the Derived Biofunctional Effects and Their In Vitro Interrogation Methods

by Teddy Tite, Adrian-Claudiu Popa, Liliana Marinela Balescu, Iuliana Maria Bogdan, Iuliana Pasuk, José M. F. Ferreira and George E. Stan

Materials 2018, 11(11), 2081; https://doi.org/10.3390/ma11112081 - 24 Oct 2018

Cited by 220 | Viewed by 10936

Abstract

High-performance bioceramics are required for preventing failure and prolonging the life-time of bone grafting scaffolds and osseous implants. The proper identification and development of materials with extended functionalities addressing socio-economic needs and health problems constitute important and critical steps at the heart of clinical research. Recent findings in the realm of ion-substituted hydroxyapatite (HA) could pave the road towards significant developments in biomedicine, with an emphasis on a new generation of orthopaedic and dentistry applications, since such bioceramics are able to mimic the structural, compositional and mechanical properties of the bone mineral phase. In fact, the fascinating ability of the HA crystalline lattice to allow for the substitution of calcium ions with a plethora of cationic species has been widely explored in the recent period, with consequent modifications of its physical and chemical features, as well as its functional mechanical and in vitro and in vivo biological performance. A comprehensive inventory of the progresses achieved so far is both opportune and of paramount importance, in order to not only gather and summarize information, but to also allow fellow researchers to compare with ease and filter the best solutions for the cation substitution of HA-based materials and enable the development of multi-functional biomedical designs. The review surveys preparation and synthesis methods, pinpoints all the explored cation dopants, and discloses the full application range of substituted HA. Special attention is dedicated to the antimicrobial efficiency spectrum and cytotoxic trade-off concentration values for various cell lines, highlighting new prophylactic routes for the prevention of implant failure. Importantly, the current in vitro biological tests (widely employed to unveil the biological performance of HA-based materials), and their ability to mimic the in vivo biological interactions, are also critically assessed. Future perspectives are discussed, and a series of recommendations are underlined. Full article

(This article belongs to the Special Issue Scaffold Materials for Tissue Engineering)

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43 pages, 13257 KiB

Open AccessReview

Biofabrication of Electrospun Scaffolds for the Regeneration of Tendons and Ligaments

by Alberto Sensini and Luca Cristofolini

Materials 2018, 11(10), 1963; https://doi.org/10.3390/ma11101963 - 12 Oct 2018

Cited by 105 | Viewed by 13131

Abstract

Tendon and ligament tissue regeneration and replacement are complex since scaffolds need to guarantee an adequate hierarchical structured morphology, and non-linear mechanical properties. Moreover, to guide the cells’ proliferation and tissue re-growth, scaffolds must provide a fibrous texture mimicking the typical of the arrangement of the collagen in the extracellular matrix of these tissues. Among the different techniques to produce scaffolds, electrospinning is one of the most promising, thanks to its ability to produce fibers of nanometric size. This manuscript aims to provide an overview to researchers approaching the field of repair and regeneration of tendons and ligaments. To clarify the general requirements of electrospun scaffolds, the first part of this manuscript presents a general overview concerning tendons’ and ligaments’ structure and mechanical properties. The different types of polymers, blends and particles most frequently used for tendon and ligament tissue engineering are summarized. Furthermore, the focus of the review is on describing the different possible electrospinning setups and processes to obtain different nanofibrous structures, such as mats, bundles, yarns and more complex hierarchical assemblies. Finally, an overview concerning how these technologies are exploited to produce electrospun scaffolds for tendon and ligament tissue applications is reported together with the main findings and outcomes. Full article

(This article belongs to the Special Issue Scaffold Materials for Tissue Engineering)

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40 pages, 1876 KiB

Open AccessReview

Synthetic and Marine-Derived Porous Scaffolds for Bone Tissue Engineering

by Ana S. Neto and José M. F. Ferreira

Materials 2018, 11(9), 1702; https://doi.org/10.3390/ma11091702 - 13 Sep 2018

Cited by 72 | Viewed by 8377

Abstract

Bone is a vascularized and connective tissue. The cortical bone is the main part responsible for the support and protection of the remaining systems and organs of the body. The trabecular spongy bone serves as the storage of ions and bone marrow. As a dynamic tissue, bone is in a constant remodelling process to adapt to the mechanical demands and to repair small lesions that may occur. Nevertheless, due to the increased incidence of bone disorders, the need for bone grafts has been growing over the past decades and the development of an ideal bone graft with optimal properties remains a clinical challenge. This review addresses the bone properties (morphology, composition, and their repair and regeneration capacity) and puts the focus on the potential strategies for developing bone repair and regeneration materials. It describes the requirements for designing a suitable scaffold material, types of materials (polymers, ceramics, and composites), and techniques to obtain the porous structures (additive manufacturing techniques like robocasting or derived from marine skeletons) for bone tissue engineering applications. Overall, the main objective of this review is to gather the knowledge on the materials and methods used for the production of scaffolds for bone tissue engineering and to highlight the potential of natural porous structures such as marine skeletons as promising alternative bone graft substitute materials without any further mineralogical changes, or after partial or total transformation into calcium phosphate. Full article

(This article belongs to the Special Issue Scaffold Materials for Tissue Engineering)

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