Three-Dimensional Printing Technologies for Drug Delivery Applications: Processes, Materials, and Effects.

Since the 1930s, new methods of drug delivery, such as implantable devices with drug release control, have been developed. However, manufacturing techniques require bulk due to high initial production costs. Three-dimensional (3D) printing, also known as additive manufacturing or rapid prototyping, allows the fabrication of personalized drug delivery that uses different materials and complex geometries with multiple release profiles, thereby eradicating high initial costs. Different studies have been developed showing the extensive potential of 3D printing for the pharmaceutical industry, and despite in-depth discussions that have been published, there is no comprehensive review of processes, materials, and effects in drug delivery applications thus far. This review aims to fill this gap by presenting the use of 3D printing technology for drug delivery, exposing the different variations of the technique according to the characteristics, material, and dosage form sought. There are seven main categories of 3D printing according to the standards jointly developed by International Organization for Standardization and American Society for Testing and Materials: material jetting, binder jetting, material extrusion, vat photopolymerization, powder bed fusion, sheet lamination, and directed energy deposition. There are different 3D fabrication processes used for drug delivery applications depending on the dosage form and material applied. In this context, polymers, glasses, and hydrogels represent the most frequent materials used. 3D printing allows different forms of drug dosage. Oral, topical, rectal and vaginal, parental and implantable are discussed in this paper, presenting the identification of the type of 3D printing technology, the active pharmaceutical ingredient, formulation, and pharmaceutical effect. The main aim of this paper is to offer insights to people from academy and industry who are interested in the advancement of drug delivery and in knowing the future directions in the development of 3D printing applications in this area.

Research Dynamics of Tissue Spheroids as Building Blocks: A Scientometric Analysis.

Tissue spheroids represent an innovative solution for tissue engineering and regenerative medicine. They constitute an in vitro three-dimensional cell culture model capable of mimicking the complex composition of a native tissue on a micro-scale; this model can function as a building block and be assembled into larger tissue constructs. Due to the potential tissue spheroids have for the evolution of the health industry, there is a need to assess the research dynamics of this field. Thus far, there have been no studies on their use as building blocks. To fill this gap, a study was performed to characterize the evolution of research where tissue spheroids were used as building blocks to generate tissue constructs. A scientometric analysis of the literature regarding tissue spheroid technologies was developed by quantification of bibliometric performance indicators. For this purpose, articles published during the period January 1, 2015 - December 31, 2021, from the Scopus database were organized and analyzed. The main subject areas, countries, cities, journals, institutions, and top-cited articles as well as the types of techniques, cells, culture time, and principal applications were identified. This research supports the definition and growth of research and development strategies for new technologies such as tissue spheroids.

Bioinks for 3D Bioprinting: A Scientometric Analysis of Two Decades of Progress.

This scientometric analysis of 393 original papers published from January 2000 to June 2019 describes the development and use of bioinks for 3D bioprinting. The main trends for bioink applications and the primary considerations guiding the selection and design of current bioink components (i.e., cell types, hydrogels, and additives) were reviewed. The cost, availability, practicality, and basic biological considerations (e.g., cytocompatibility and cell attachment) are the most popular parameters guiding bioink use and development. Today, extrusion bioprinting is the most widely used bioprinting technique. The most reported use of bioinks is the generic characterization of bioink formulations or bioprinting technologies (32%), followed by cartilage bioprinting applications (16%). Similarly, the cell-type choice is mostly generic, as cells are typically used as models to assess bioink formulations or new bioprinting methodologies rather than to fabricate specific tissues. The cell-binding motif arginine-glycine-aspartate is the most common bioink additive. Many articles reported the development of advanced functional bioinks for specific biomedical applications; however, most bioinks remain the basic compositions that meet the simple criteria: Manufacturability and essential biological performance. Alginate and gelatin methacryloyl are the most popular hydrogels that meet these criteria. Our analysis suggests that present-day bioinks still represent a stage of emergence of bioprinting technology.

Discovering the Latest Scientific Pathways on Tissue Spheroids: Opportunities to Innovate.

Tissue spheroids consist of a three-dimensional model of cells which is capable of imitating the complicated composition of healthy and unhealthy human tissue. Due to their unique properties, they can bring innovative solutions to tissue engineering and regenerative medicine, where they can be used as building blocks for the formation of organ and tissue models used in drug experimentation. Considering the rapid transformation of the health industry, it is crucial to assess the research dynamics of this field to support the development of innovative applications. In this research, a scientometric analysis was performed as part of a Competitive Technology Intelligence methodology, to determine the main applications of tissue spheroids. Papers from Scopus and Web of Science published between 2000 and 2019 were organized and analyzed. In total, 868 scientific publications were identified, and four main categories of application were determined. Main subject areas, countries, cities, authors, journals, and institutions were established. In addition, a cluster analysis was performed to determine networks of collaborations between institutions and authors. This article provides insights into the applications of cell aggregates and the research dynamics of this field, which can help in the decision-making process to incorporate emerging and innovative technologies in the health industry.

Disclosing Main authors and Organisations collaborations in bioprinting through network maps analysis.

BACKGROUND: Scientific activity for 3D bioprinting has increased over the past years focusing mainly on fully functional biological constructs to overcome issues related to organ transplants. This research performs a scientometric analysis on bioprinting based on a competitive technology intelligence (CTI) cycle, which assesses scientific documents to establish the publication rate of science and technology in terms of institutions, patents or journals. Although analyses of publications can be observed in the literature, the identification of the most influential authors and affiliations has not been addressed. This study involves the analysis of authors and affiliations, and their interactions in a global framework. We use network collaboration maps and Betweenness Centrality (BC) to identify of the most prominent actors in bioprinting, enhancing the CTI analysis. RESULTS: 2088 documents were retrieved from Scopus database from 2007 to 2017, disclosing an exponential growth with an average publication increase of 17.5% per year. A threshold of five articles with ten or more cites was established for authors, while the same number of articles but cited five or more times was set for affiliations. The author with more publications was Atala A. (36 papers and a BC = 370.9), followed by Khademhosseini A. (30 documents and a BC = 2104.7), and Mironov (30 documents and BC = 2754.9). In addition, a small correlation was observed between the number of collaborations and the number of publications. Furthermore, 1760 institutions with a median of 10 publications were found, but only 20 within the established threshold. 30% of the 20 institutions had an external collaboration, and institutions located in and close to the life science cluster in Massachusetts showed a strong cooperation. The institution with more publications was the Harvard Medical School, 61 publications, followed by the Brigham and Women's hospital, 46 papers, and the Massachusetts Institute of Technology with 37 documents. CONCLUSIONS: Network map analysis and BC allowed the identification of the most influential authors working on bioprinting and the collaboration between institutions was found limited. This analysis of authors and affiliations and their collaborations offer valuable information for the identification of potential associations for bioprinting researches and stakeholders.

Revealing emerging science and technology research for dentistry applications of 3D bioprinting.

Science and technology (S&T) on three-dimensional (3D) bioprinting is growing at an increasingly accelerated pace; one major challenge represents how to develop new solutions for frequent oral diseases such as periodontal problems and loss of alveolar bone. 3D bioprinting is expected to revolutionize the health industry in the upcoming years. In dentistry, this technology can become a significant contributor. This study applies a Competitive Technology Intelligence methodology to uncover the main S&T drivers in this domain. Looking at a 6-year period from 2012 to 2018 an analysis of scientific and technology production was made. Three principal S& T drivers were identified: Scaffolds development, analysis of natural and synthetic materials, and the study of scaffold characteristics. Innovative hybrid and multiphasic scaffolds are being developed to regenerate periodontal tissue and alveolar bone by combining them with stem cells from the pulp or periodontal ligament. To improve scaffolds performance, biodegradable synthetic polymers are often used in combination with bioceramics. The characteristics of scaffolds such as fiber orientation, porosity, and geometry, were also investigated. This research contributes to people interested in bringing innovative solutions to the health industry, particularly by applying state-of-the-art technologies such as 3D bioprinting, in this case for dental tissues and dental bone diseases.

Discovering new 3D bioprinting applications: Analyzing the case of optical tissue phantoms.

Optical tissue phantoms enable to mimic the optical properties of biological tissues for biomedical device calibration, new equipment validation, and clinical training for the detection, and treatment of diseases. Unfortunately, current methods for their development present some problems, such as a lack of repeatability in their optical properties. Where the use of three-dimensional (3D) printing or 3D bioprinting could address these issues. This paper aims to evaluate the use of this technology in the development of optical tissue phantoms. A competitive technology intelligence methodology was applied by analyzing Scopus, Web of Science, and patents from January 1, 2000, to July 31, 2018. The main trends regarding methods, materials, and uses, as well as predominant countries, institutions, and journals, were determined. The results revealed that, while 3D printing is already employed (in total, 108 scientific papers and 18 patent families were identified), 3D bioprinting is not yet applied for optical tissue phantoms. Nevertheless, it is expected to have significant growth. This research gives biomedical scientists a new window of opportunity for exploring the use of 3D bioprinting in a new area that may support testing of new equipment and development of techniques for the diagnosis and treatment of diseases.

Analysis of the knowledge landscape of three-dimensional bioprinting in Latin America.

Bioprinting, the printing of living cells using polymeric matrixes (mainly hydrogels), has attracted great attention among science and technology circles. North America has been one of the sources of bioprinting-related technology in recent years. As a natural consequence of geography, high-quality research in the area of bioprinting has started to permeate Latin America. Here, we describe and analyze the knowledge landscape of bioprinting in Latin America using a competitive technology intelligence methodology. Our analysis provides relevant information, such as the scientific publication trends in Latin America and the scientific networks among research groups in Latin America and the world.

A bibliometric method for assessing technological maturity: the case of additive manufacturing.

While novel technologies have tremendous competitive potential, they also involve certain risks. Maturity assessment analyzes how well a technological development can fulfill an expected task. The technology readiness level (TRL) has been considered to be one of the most promising approaches for addressing technological maturity. Nonetheless, its assessment requires opinions of the experts, which is costly and implies the risk of personal bias. To fill this gap, this paper presents a Bibliometric Method for Assessing Technological Maturity (BIMATEM). It is a repeatable framework that assesses maturity quantitatively. Our method is based on the assumption that each technology life cycle stage can be matched to technology records contained in scientific literature, patents, and news databases. The scientific papers and patent records of mature technologies display a logistic growth behavior, while news records follow a hype-type behavior. BIMATEM determines the maturity level by curve fitting technology records to these behaviors. To test our approach, BIMATEM was applied to additive manufacturing (AM) technologies. Our results revealed that material extrusion, material jetting, powder bed fusion and vat photopolymerization are the most mature AM technologies with TRL between 6 and 7, followed by directed energy deposition with TRL between 4 and 5, and binder jetting and sheet lamination, the least mature, with TRL between 1 and 2. BIMATEM can be used by competitive technology intelligence professionals, policymakers, and further decision makers whose main interests include assessing the risk of implementing new technologies. Future research can focus on testing the method with regard to altmetrics.

Uncovering 3D bioprinting research trends: A keyword network mapping analysis.

A scientometric analysis as part of a Competitive Technology Intelligence methodology was used to determine the main research efforts in 3D bioprinting. Papers from Scopus and Web of Science (WoS) published between 2000 and 2017 were analysed. A network map of the most frequently occurring keywords in these articles was created, and their average publication year (APY) was determined. The analysis focused on the most relevant keywords that occurred at least five times. A total of 1,759 keywords were obtained, and a co-occurrence analysis was developed for APYs with more keywords: 2011-2016. The results indicated that Polylactic Acid (PLA) is the material used most often. Applications mainly focused on bone tissue engineering and regeneration. The most frequently used technique was inkjet printing, and the main cell sources were Mesenchymal Stem Cells (MSC). From a general perspective, 'Treatment' and 'Bioink' were the most frequent keywords. The former was mainly related to cancer, regenerative medicine, and MSC and the latter, to multicellular spheroid deposition and the use of hydrogels like GelMA (gelatin methacryloyl). This analysis provides insights to stakeholders involved in 3D bioprinting research and development who need to keep abreast of scientific progress in the field.

Scientometric and patentometric analyses to determine the knowledge landscape in innovative technologies: The case of 3D bioprinting.

This research proposes an innovative data model to determine the landscape of emerging technologies. It is based on a competitive technology intelligence methodology that incorporates the assessment of scientific publications and patent analysis production, and is further supported by experts' feedback. It enables the definition of the growth rate of scientific and technological output in terms of the top countries, institutions and journals producing knowledge within the field as well as the identification of main areas of research and development by analyzing the International Patent Classification codes including keyword clusterization and co-occurrence of patent assignees and patent codes. This model was applied to the evolving domain of 3D bioprinting. Scientific documents from the Scopus and Web of Science databases, along with patents from 27 authorities and 140 countries, were retrieved. In total, 4782 scientific publications and 706 patents were identified from 2000 to mid-2016. The number of scientific documents published and patents in the last five years showed an annual average growth of 20% and 40%, respectively. Results indicate that the most prolific nations and institutions publishing on 3D bioprinting are the USA and China, including the Massachusetts Institute of Technology (USA), Nanyang Technological University (Singapore) and Tsinghua University (China), respectively. Biomaterials and Biofabrication are the predominant journals. The most prolific patenting countries are China and the USA; while Organovo Holdings Inc. (USA) and Tsinghua University (China) are the institutions leading. International Patent Classification codes reveal that most 3D bioprinting inventions intended for medical purposes apply porous or cellular materials or biologically active materials. Knowledge clusters and expert drivers indicate that there is a research focus on tissue engineering including the fabrication of organs, bioinks and new 3D bioprinting systems. Our model offers a guide to researchers to understand the knowledge production of pioneering technologies, in this case 3D bioprinting.