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3D Printing and Biomaterials for Biological and Medical Application: Recent Advances

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

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 18625

Special Issue Editors


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Guest Editor
Department Translational Medicine, University of Ferrara, 44121 Ferrara, Italy
Interests: tissue engineering; regenerative medicine; 3D printing; stem cells; exosomes; biomaterials
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Institute of Polymers, Composites and Biomaterials, National Research Council, 80125 Naples, Italy
Interests: biomaterials; 3D printing; multifunctional scaffolds; biomimetic design
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Department of Neurosciences, Dentistry Section, University of Padova, 35122 Padova, Italy
Interests: dentistry; 3D printing; tissue regeneration
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In the past decade, 3D printing has emerged as a versatile technology platform for the rapid manufacturing for application on medicine. 3D printing is advantageous in terms of design freedom, automation, production speed, great accuracy, customization, and limited waste generation. By reducing the complexity of manufacturing system, designers can produce entire systems using fewer subcomponents with more complex geometries. Moreover, 3D printing has the potential to approach zero-waste manufacturing by maximizing material utilization. This novel production method enables the efficient creation and modification of physical models for validation purposes during the production process. Any design errors can be identified in advance, and the resulting changes can be introduced in the early stages of product development, eliminating the need for expensive corrections at later stages of the process. In addition, 3D printing is less wasteful in terms of both construction materials and replacement tools.

Although the direct costs of production with new methods and materials are usually higher, the flexibility offered by 3D printing substantially lowers the total cost. 3D printing is overtaking traditional machining and casting techniques for designing and manufacturing various biomedical devices. The benefits of 3D printing include not only the customization of medical products, equipment, and drugs but also increased productivity, specificity, and cost-effectiveness.

In the biomedical field, 3D printing technologies are applied in:

  1. the creation of personalized prosthetics, implants, and anatomical models;
  2. the reconstruction of organs and tissues;
  3. the manufacturing of medical instruments.

Moreover, 3D printing can be harnessed for pharmaceutical research on the dosage forms, production, and delivery of drugs and for innovative medical device manufacturing. Commercially available 3D-printed medical devices include implants (e.g., cranial plates or hip joints), external prostheses (e.g., hands), and instrumentations (e.g., guides to assist with proper surgical placement of a device).

Dr. Barbara Zavan
Dr. Alfredo Ronca
Dr. Stefano Sivolella
Guest Editors

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Keywords

  • 3D printing
  • biomaterials
  • tissue engineering
  • regenerative medicine
  • bioprinting
  • bio-ink
  • cell-laden hydrogels
  • chemically modified polymers
  • cells
  • exosomes

Published Papers (7 papers)

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Research

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15 pages, 4702 KiB  
Article
Dual-Action Effect of Gallium and Silver Providing Osseointegration and Antibacterial Properties to Calcium Titanate Coatings on Porous Titanium Implants
by Alejandra Rodríguez-Contreras, Diego Torres, David Piñera-Avellaneda, Lluís Pérez-Palou, Mònica Ortiz-Hernández, María Pau Ginebra, José Antonio Calero, José María Manero and Elisa Rupérez
Int. J. Mol. Sci. 2023, 24(10), 8762; https://doi.org/10.3390/ijms24108762 - 15 May 2023
Cited by 3 | Viewed by 1818
Abstract
Previously, functional coatings on 3D-printed titanium implants were developed to improve their biointegration by separately incorporating Ga and Ag on the biomaterial surface. Now, a thermochemical treatment modification is proposed to study the effect of their simultaneous incorporation. Different concentrations of AgNO3 [...] Read more.
Previously, functional coatings on 3D-printed titanium implants were developed to improve their biointegration by separately incorporating Ga and Ag on the biomaterial surface. Now, a thermochemical treatment modification is proposed to study the effect of their simultaneous incorporation. Different concentrations of AgNO3 and Ga(NO3)3 are evaluated, and the obtained surfaces are completely characterized. Ion release, cytotoxicity, and bioactivity studies complement the characterization. The provided antibacterial effect of the surfaces is analyzed, and cell response is assessed by the study of SaOS-2 cell adhesion, proliferation, and differentiation. The Ti surface doping is confirmed by the formation of Ga-containing Ca titanates and nanoparticles of metallic Ag within the titanate coating. The surfaces generated with all combinations of AgNO3 and Ga(NO3)3 concentrations show bioactivity. The bacterial assay confirms a strong bactericidal impact achieved by the effect of both Ga and Ag present on the surface, especially for Pseudomonas aeruginosa, one of the main pathogens involved in orthopedic implant failures. SaOS-2 cells adhere and proliferate on the Ga/Ag-doped Ti surfaces, and the presence of gallium favors cell differentiation. The dual effect of both metallic agents doping the titanium surface provides bioactivity while protecting the biomaterial from the most frequent pathogens in implantology. Full article
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17 pages, 2784 KiB  
Article
Applied Compressive Strain Governs Hyaline-like Cartilage versus Fibrocartilage-like ECM Produced within Hydrogel Constructs
by Hamed Alizadeh Sardroud, Xiongbiao Chen and B. Frank Eames
Int. J. Mol. Sci. 2023, 24(8), 7410; https://doi.org/10.3390/ijms24087410 - 18 Apr 2023
Cited by 5 | Viewed by 1564
Abstract
The goal of cartilage tissue engineering (CTE) is to regenerate new hyaline cartilage in joints and treat osteoarthritis (OA) using cell-impregnated hydrogel constructs. However, the production of an extracellular matrix (ECM) made of fibrocartilage is a potential outcome within hydrogel constructs when in [...] Read more.
The goal of cartilage tissue engineering (CTE) is to regenerate new hyaline cartilage in joints and treat osteoarthritis (OA) using cell-impregnated hydrogel constructs. However, the production of an extracellular matrix (ECM) made of fibrocartilage is a potential outcome within hydrogel constructs when in vivo. Unfortunately, this fibrocartilage ECM has inferior biological and mechanical properties when compared to native hyaline cartilage. It was hypothesized that compressive forces stimulate fibrocartilage development by increasing production of collagen type 1 (Col1), an ECM protein found in fibrocartilage. To test the hypothesis, 3-dimensional (3D)-bioprinted hydrogel constructs were fabricated from alginate hydrogel impregnated with ATDC5 cells (a chondrogenic cell line). A bioreactor was used to simulate different in vivo joint movements by varying the magnitude of compressive strains and compare them with a control group that was not loaded. Chondrogenic differentiation of the cells in loaded and unloaded conditions was confirmed by deposition of cartilage specific molecules including glycosaminoglycans (GAGs) and collagen type 2 (Col2). By performing biochemical assays, the production of GAGs and total collagen was also confirmed, and their contents were quantitated in unloaded and loaded conditions. Furthermore, Col1 vs. Col2 depositions were assessed at different compressive strains, and hyaline-like cartilage vs. fibrocartilage-like ECM production was analyzed to investigate how applied compressive strain affects the type of cartilage formed. These assessments showed that fibrocartilage-like ECM production tended to reduce with increasing compressive strain, though its production peaked at a higher compressive strain. According to these results, the magnitude of applied compressive strain governs the production of hyaline-like cartilage vs. fibrocartilage-like ECM and a high compressive strain stimulates fibrocartilage-like ECM formation rather than hyaline cartilage, which needs to be addressed by CTE approaches. Full article
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22 pages, 4285 KiB  
Article
Influence of Scaffold Microarchitecture on Angiogenesis and Regulation of Cell Differentiation during the Early Phase of Bone Healing: A Transcriptomics and Histological Analysis
by Julien Guerrero, Ekaterina Maevskaia, Chafik Ghayor, Indranil Bhattacharya and Franz E. Weber
Int. J. Mol. Sci. 2023, 24(6), 6000; https://doi.org/10.3390/ijms24066000 - 22 Mar 2023
Cited by 3 | Viewed by 1723
Abstract
The early phase of bone healing is a complex and poorly understood process. With additive manufacturing, we can generate a specific and customizable library of bone substitutes to explore this phase. In this study, we produced tricalcium phosphate-based scaffolds with microarchitectures composed of [...] Read more.
The early phase of bone healing is a complex and poorly understood process. With additive manufacturing, we can generate a specific and customizable library of bone substitutes to explore this phase. In this study, we produced tricalcium phosphate-based scaffolds with microarchitectures composed of filaments of 0.50 mm in diameter, named Fil050G, and 1.25 mm named Fil125G, respectively. The implants were removed after only 10 days in vivo followed by RNA sequencing (RNAseq) and histological analysis. RNAseq results revealed upregulation of adaptive immune response, regulation of cell adhesion, and cell migration-related genes in both of our two constructs. However, significant overexpression of genes linked to angiogenesis, regulation of cell differentiation, ossification, and bone development was observed solely in Fil050G scaffolds. Moreover, quantitative immunohistochemistry of structures positive for laminin revealed a significantly higher number of blood vessels in Fil050G samples. Furthermore, µCT detected a higher amount of mineralized tissue in Fil050G samples suggesting a superior osteoconductive potential. Hence, different filament diameters and distances in bone substitutes significantly influence angiogenesis and regulation of cell differentiation involved in the early phase of bone regeneration, which precedes osteoconductivity and bony bridging seen in later phases and as consequence, impacts the overall clinical outcome. Full article
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24 pages, 11875 KiB  
Article
Osteoregenerative Potential of 3D-Printed Poly ε-Caprolactone Tissue Scaffolds In Vitro Using Minimally Manipulative Expansion of Primary Human Bone Marrow Stem Cells
by Logan M. Lawrence, Roozbeh (Ross) Salary, Virginia Miller, Anisha Valluri, Krista L. Denning, Shannon Case-Perry, Karim Abdelgaber, Shannon Smith, Pier Paolo Claudio and James B. Day
Int. J. Mol. Sci. 2023, 24(5), 4940; https://doi.org/10.3390/ijms24054940 - 3 Mar 2023
Cited by 6 | Viewed by 2162
Abstract
The repair of orthopedic and maxillofacial defects in modern medicine currently relies heavily on the use of autograft, allograft, void fillers, or other structural material composites. This study examines the in vitro osteo regenerative potential of polycaprolactone (PCL) tissue scaffolding, fabricated via a [...] Read more.
The repair of orthopedic and maxillofacial defects in modern medicine currently relies heavily on the use of autograft, allograft, void fillers, or other structural material composites. This study examines the in vitro osteo regenerative potential of polycaprolactone (PCL) tissue scaffolding, fabricated via a three-dimensional (3D) additive manufacturing technology, i.e., a pneumatic micro extrusion (PME) process. The objectives of this study were: (i) To examine the innate osteoinductive and osteoconductive potential of 3D-printed PCL tissue scaffolding and (ii) To perform a direct in vitro comparison of 3D-printed PCL scaffolding with allograft Allowash® cancellous bone cubes with regards to cell-scaffold interactions and biocompatibility with three primary human bone marrow (hBM) stem cell lines. This study specifically examined cell survival, cell integration, intra-scaffold cell proliferation, and differentiation of progenitor cells to investigate the potential of 3D-printed PCL scaffolds as an alternative to allograft bone material for the repair of orthopedic injuries. We found that mechanically robust PCL bone scaffolds can be fabricated via the PME process and the resulting material did not elicit detectable cytotoxicity. When the widely used osteogenic model SAOS-2 was cultured in PCL extract medium, no detectable effect was observed on cell viability or proliferation with multiple test groups showing viability ranges of 92.2% to 100% relative to a control group with a standard deviation of ±10%. In addition, we found that the honeycomb infill pattern of the 3D-printed PCL scaffold allowed for superior mesenchymal stem-cell integration, proliferation, and biomass increase. When healthy and active primary hBM cell lines, having documented in vitro growth rates with doubling times of 23.9, 24.67, and 30.94 h, were cultured directly into 3D-printed PCL scaffolds, impressive biomass increase values were observed. It was found that the PCL scaffolding material allowed for biomass increase values of 17.17%, 17.14%, and 18.18%, compared to values of 4.29% for allograph material cultured under identical parameters. It was also found that the honeycomb scaffold infill pattern was superior to the cubic and rectangular matrix structures, and provided a superior microenvironment for osteogenic and hematopoietic progenitor cell activity and auto-differentiation of primary hBM stem cells. Histological and immunohistochemical studies performed in this work confirmed the regenerative potential of PCL matrices in the orthopedic setting by displaying the integration, self-organization, and auto-differentiation of hBM progenitor cells within the matrix. Differentiation products including mineralization, self-organizing “proto-osteon” structures, and in vitro erythropoiesis were observed in conjunction with the documented expression of expected bone marrow differentiative markers including CD-99 (>70%), CD-71 (>60%), and CD-61 (>5%). All of the studies were conducted without the addition of any exogenous chemical or hormonal stimulation and exclusively utilized the abiotic and inert material polycaprolactone; setting this work apart from the vast majority of contemporary investigations into synthetic bone scaffold fabrication In summary, this study demonstrates the unique clinical potential of 3D-printed PCL scaffolds for stem cell expansion and incorporation into advanced microstructures created via PME manufacturing to generate a physiologically inert temporary bony defect graft with significant autograft features for enhanced end-stage healing. Full article
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16 pages, 4344 KiB  
Article
Gamma Irradiation Processing on 3D PCL Devices—A Preliminary Biocompatibility Assessment
by Fernando Guedes, Mariana V. Branquinho, Sara Biscaia, Rui D. Alvites, Ana C. Sousa, Bruna Lopes, Patrícia Sousa, Alexandra Rêma, Irina Amorim, Fátima Faria, Tatiana M. Patrício, Nuno Alves, António Bugalho and Ana C. Maurício
Int. J. Mol. Sci. 2022, 23(24), 15916; https://doi.org/10.3390/ijms232415916 - 14 Dec 2022
Cited by 2 | Viewed by 1722
Abstract
Additive manufacturing or 3D printing applying polycaprolactone (PCL)-based medical devices represents an important branch of tissue engineering, where the sterilization method is a key process for further safe application in vitro and in vivo. In this study, the authors intend to access the [...] Read more.
Additive manufacturing or 3D printing applying polycaprolactone (PCL)-based medical devices represents an important branch of tissue engineering, where the sterilization method is a key process for further safe application in vitro and in vivo. In this study, the authors intend to access the most suitable gamma radiation conditions to sterilize PCL-based scaffolds in a preliminary biocompatibility assessment, envisioning future studies for airway obstruction conditions. Three radiation levels were considered, 25 kGy, 35 kGy and 45 kGy, and evaluated as regards their cyto- and biocompatibility. All three groups presented biocompatible properties, indicating an adequate sterility condition. As for the cytocompatibility analysis, devices sterilized with 35 kGy and 45 kGy showed better results, with the 45 kGy showing overall improved outcomes. This study allowed the selection of the most suitable sterilization condition for PCL-based scaffolds, aiming at immediate future assays, by applying 3D-customized printing techniques to specific airway obstruction lesions of the trachea. Full article
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Review

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25 pages, 3787 KiB  
Review
Bioprinting Technologies and Bioinks for Vascular Model Establishment
by Zhiyuan Kong and Xiaohong Wang
Int. J. Mol. Sci. 2023, 24(1), 891; https://doi.org/10.3390/ijms24010891 - 3 Jan 2023
Cited by 13 | Viewed by 5041
Abstract
Clinically, large diameter artery defects (diameter larger than 6 mm) can be substituted by unbiodegradable polymers, such as polytetrafluoroethylene. There are many problems in the construction of small diameter blood vessels (diameter between 1 and 3 mm) and microvessels (diameter less than 1 [...] Read more.
Clinically, large diameter artery defects (diameter larger than 6 mm) can be substituted by unbiodegradable polymers, such as polytetrafluoroethylene. There are many problems in the construction of small diameter blood vessels (diameter between 1 and 3 mm) and microvessels (diameter less than 1 mm), especially in the establishment of complex vascular models with multi-scale branched networks. Throughout history, the vascularization strategies have been divided into three major groups, including self-generated capillaries from implantation, pre-constructed vascular channels, and three-dimensional (3D) printed cell-laden hydrogels. The first group is based on the spontaneous angiogenesis behaviour of cells in the host tissues, which also lays the foundation of capillary angiogenesis in tissue engineering scaffolds. The second group is to vascularize the polymeric vessels (or scaffolds) with endothelial cells. It is hoped that the pre-constructed vessels can be connected with the vascular networks of host tissues with rapid blood perfusion. With the development of bioprinting technologies, various fabrication methods have been achieved to build hierarchical vascular networks with high-precision 3D control. In this review, the latest advances in 3D bioprinting of vascularized tissues/organs are discussed, including new printing techniques and researches on bioinks for promoting angiogenesis, especially coaxial printing, freeform reversible embedded in suspended hydrogel printing, and acoustic assisted printing technologies, and freeform reversible embedded in suspended hydrogel (flash) technology. Full article
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22 pages, 1633 KiB  
Review
Four-Dimensional Printing and Shape Memory Materials in Bone Tissue Engineering
by Xinwei Zhang, Yixin Yang, Zhen Yang, Rui Ma, Maierhaba Aimaijiang, Jing Xu, Yidi Zhang and Yanmin Zhou
Int. J. Mol. Sci. 2023, 24(1), 814; https://doi.org/10.3390/ijms24010814 - 3 Jan 2023
Cited by 15 | Viewed by 3913
Abstract
The repair of severe bone defects is still a formidable clinical challenge, requiring the implantation of bone grafts or bone substitute materials. The development of three-dimensional (3D) bioprinting has received considerable attention in bone tissue engineering over the past decade. However, 3D printing [...] Read more.
The repair of severe bone defects is still a formidable clinical challenge, requiring the implantation of bone grafts or bone substitute materials. The development of three-dimensional (3D) bioprinting has received considerable attention in bone tissue engineering over the past decade. However, 3D printing has a limitation. It only takes into account the original form of the printed scaffold, which is inanimate and static, and is not suitable for dynamic organisms. With the emergence of stimuli-responsive materials, four-dimensional (4D) printing has become the next-generation solution for biological tissue engineering. It combines the concept of time with three-dimensional printing. Over time, 4D-printed scaffolds change their appearance or function in response to environmental stimuli (physical, chemical, and biological). In conclusion, 4D printing is the change of the fourth dimension (time) in 3D printing, which provides unprecedented potential for bone tissue repair. In this review, we will discuss the latest research on shape memory materials and 4D printing in bone tissue repair. Full article
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