Review of alginate-based hydrogel bioprinting for application in tissue engineering

The application of three-dimensional (3D) printing in medicine has increased rapidly in the last few years. Various new commercial 3D printers and 3D bioprinters are introduced into the current market. 3D printing scientific community has witnessed a rapid growth in the application of 3D printing for various medical needs. There has been a research advancement in 4D printing with a widened scope of 3D bioprinting. The growing demand for 3D printing and its use for commercial and industrial purposes in medical technology have facilitated the need for introduction of new international standards and regulations. The need for organ replacement has generated curiosity and competition among researchers to race for organ 3D printing, which can be identified with increased publications and patents that are filed in recent years. Hence, there is a need to update the readers with the latest information. The second edition of this chapter updates the contents of first section to fourth section with current information and some modified pictorial representations. New section describes the relevance of the new chapters added to this edition and updates the readers with insights on advancement of 3D printing in the last decade. Briefly, this chapter introduces the reader with a brief history of 3D printing in medical technology, components of 3D printing, 3D bioprinting, organ 3D bioprinting, advantages of 3D printing with current challenges and commercially available 3D printers in the current market. New sections introduced in this edition detail about the ASTM and ISO standards that are used for 3D printing in medicine, the regulatory framework with current challenges, ethical and social concerns with the current 3D printing scientific community, and the importance of intellectual property in safeguarding the interests of the innovators.

Advanced micro- and nanofabrication technologies for tissue engineering

Over recent decades, many attempts have been made to produce biomimetic products with desired properties for bioengineering applications. Electrospinning has attracted widespread attention in tissue engineering because it can produce micro/nanoscale fibrous products to imitate natural ECM in a simple and low-cost way. Nevertheless, the inability of these methods to accurately control the three-dimensional (3D) structure has posed a major challenge in generating complex tissues. 3D bioprinting technology has developed as a potential solution by delivering extraordinary flexibility in placing cells and biotic materials in a well-organized mode in three dimensions. The application of 3D printing in medicine can offer many benefits, such as increased cooperation; cost efficiency; the personalization and specialization of medical constructs, tools, and drugs; the customization of design and fabrication and enhanced productivity. In this chapter, we review general principles, concepts, and the application of 3D bioprinting. We first discuss several general methods of bioprinting with an emphasis on hybrid systems, which involve both 3D printing and electrospinning and their relevant advantages and disadvantages. Lastly, we summarize the challenges surrounding the future improvement of bioprinting technologies and also some indications of potential markets.

Personalized medicine and precision medicine are easier to conceptualize than define, and implementation can be even more challenging. 3D printing has intersected medicine to enable both. Personalized medicine is now delivered by “clinical modelers”, impassioned investigators are caretakers who model disease with 3D printing to define pathology, plan intervention, and treat patients. Creating, manipulating, and printing Standard Tessellation Language (STL) files is challenging; generating a hand-held model from a CT scan is harder than it has to be. Several diagnostic post-processing steps applied to the CT volume (collectively termed “3D visualization”) must be repeated to generate an STL file that is then 3D printed. Multiple software packages are typically required before the STL file is electronically placed on a separate build-tray software platform. In 5 years or less, the inefficiency of medical modeling will be a historical footnote. Current 3D printing publications are disparate. My group’s summary of the literature (submitted for publication in October 2014) attempted a comprehensive survey of the field stratified by organ section [1]. I personally apologize if your article was not included. However, those papers we did find and include spanned over 50 different journals. 3D Printing in Medicine is designed to provide a common platform peer-review platform. This forum is long overdue. The journal also addressed another missing piece: STL files are invited for submission and can be downloaded for free consumption by our readership. Those engaged in 3D printing are talented, and their creativity should be rewarded with development opportunities. 3D Printing in Medicine invites not only clinical studies, but also “concept papers” that will motivate and connect physicians, industry, engineers, and scientists in general. These papers will benefit from peer review and serve as a platform for funding that will drive further innovations. The journal will also address the question, “What defines a model that is clinically useful?” There are no 3D

In modern conditions, the possibilities of using 3D printing in medicine are expanding, and it occupies about 11% of the global additive manufacturing market. At the Kirov Military Medical Academy and the ERA Military Innovation Technopolis, 3D printing is used for training, preoperative planning, the creation of splints, the manufacture of non-invasive functional products, and the creation of COVID-19 prevention aids.
 In order to determine the prospects for development, foreign experience in the use of 3D printing in medicine has been studied over the past 5 years.
 It is established that a register of clinical data on 3D printing is being created for training, 3D models are being printed to simulate tissue resistance during surgery. With the help of preoperative planning, Siamese twins are separated, doctors are trained in surgical operations on 3D models of elastic resin feet, cardiological models are used to predict the risk of complications during transcatheter implantation of an artificial aortic valve, as well as rehearsals of operations with congenital heart anomalies. Individual implants are manufactured for the lumbar and cervical spine, replacement of the damaged area of the chest and rib, finger phalanges, hip and knee replacements. As auxiliary products, individual surgical instruments for operations with low trauma, orthopedic insoles, elastic stents for the urethra and mesh stents of the trachea are created. New materials made of polyamide (PA11), polyesteresterketone, titanium alloys, absorbable polymer and biocompatible resin are offered for 3D printing. There are new 3D printing software and updates of existing ones. Personalized braces and aligners are printed in dentistry. With the help of 3D printing, individual multi-layered polytablets, smart tablets that release medicinal substances on command from a smartphone, childrens chewing tablets are created. For research purposes, the following devices have been printed: simulating cardiac tissue with sensors to track the effects of drugs and toxins; predicting the individual response of the biopsy tumor material to treatment; diagnosing some infectious diseases using a smartphone and a silicon microfluidic chip.
 The use of 3D printing in medicine individualizes and improves the quality of medical care.

Current and emerging applications of 3D printing in medicine

3D printing for biomedical applications seems to be a technology that is developing in a wavelike manner. Not long after the first attempts for computer-aided design and manufacturing (CAD/CAM) were made in fields such as mechanical engineering and design, researchers also tried to apply these new possibilities in medicine. Only a few years later, the first patient-specific implants, for example, for the treatment of skull defects, became available. While in the very beginning subtractive technologies such as computerized numeric controlled milling were still used, soon new options for additive manufacturing (AM) started to take off [1]. For biomedical applications, laser-based methods such as selective laser sintering (SLS) or 3D powder printing were mostly used, both of which were mostly limited in the beginning to metals and ceramic materials, respectively. A very important step therefore was the development of fused deposition modeling (FDM) as the first extrusion-based AM technology using polymeric materials. For biomedical applications, manufacturing of porous 3D scaffolds with defined outer and inner morphology and their utilization in tissue engineering was investigated in detail, using FDM of poly(lactic acid) or polycaprolactone. These polymers were also among the first biodegradable materials successfully applied in AM. Probably because of the limitations concerning the applicable materials (most early AM machines could only be operated with a few different materials) and the high price of the devices, even at the beginning of the 21st century only a few groups further investigated AM technologies for medical applications. But the situation has changed dramatically since a variety of cheaper 3D printers have become available, of which many can handle different types of materials, offering the necessary flexibility for new developments. In addition, the breakthrough concerning integration of living cells in the printing process (‘bioprinting’) was achieved using ink-jet as well as extrusion-based technologies, opening up the possibility to directly generate artificial tissues. We have therefore seen a strong increase of publications in the field of 3D printing in medicine in the last couple of years, coming from researchers from all over the world, accompanied by new conferences, solely focused on this topic. Nevertheless, we are still at the beginning of a huge and strong development and nobody knows what will become possible in the future. In my opinion, the following directions are those with the strongest driving force at the moment:

Biomaterial-based 3D bioprinting strategy for orthopedic tissue engineering.

The burden of musculoskeletal diseases in the United States.

Chapter 1 - 3D Printing in Medicine: Current Challenges and Potential Applications

Dramatic news headlines imply that the use of additive manufacturing/3D printing in medicine is a brand new way to save and improve lives. The truth is, it’s not so new. Twenty years ago anatomical models were beginning to be used for planning complicated surgeries. In 2000, hearing aid cases were being 3D-printed and within a few years became industry standard. Medical applications have been a leader in taking 3D printing technology far beyond a product development tool. The combination of using medical imaging data to create patient-matched devices and the ability to manufacture structures difficult to produce with traditional technologies is compelling to an industry always looking for ways to innovate. Surgical uses of 3D printing-centric therapies have a long history beginning with anatomical modeling for bony reconstructive surgery planning[8]. By practicing on a tactile model before surgery surgeons were more prepared and patients received better care. Patient matched implants were a natural extension of this work, leading to truly personalized implants that fit one unique individual[10]. Virtual planning of surgery and guidance using 3D printed, personalized instruments have been applied to many areas of surgery including total joint replacement and craniomaxillofacial reconstruction with great success[9,11]. Further study of the use of models for planning heart and solid organ surgery has lead to increased use in these areas[14]. Finally, hospital-based 3D printing is now of great interest and many institutions are pursuing adding this specialty within individual radiology departments[12,13]. Despite these successful areas of application, widespread use has been fairly slow. Working toward increasing the use of 3D printing in medicine, industry professionals, clinicians, technology developers, and researchers[1] are working together to first identify the challenges and then develop tools and resources to address these challenges.

Technological advancements have made 3D printing more accessible and affordable for both individuals and institutions. Despite significant efforts by the International Medical Device Regulators Forum to standardize 3D printing regulations for medical use, challenges remain. We conducted a survey to gather insights from physician end-users on their opinions regarding the regulation of 3D printing in medicine. Additionally, since FDA guidance is often adopted internationally, this survey aimed to capture the demographics of physician end-users globally and provide a snapshot of the current use of 3D printing in clinical practice and research. After developing and validating a 26-question survey, we emailed it to the corresponding authors of all PubMed-indexed publications on 3D printing in medicine. Participants received an introductory email explaining the survey's purpose and an invitation to participate. Only responses from participants who declared themselves to be physicians were accepted. The survey was open for responses from April 5th to May 3rd, 2022, with weekly reminders sent until the response period closed. Responses with at least 80% survey completion were accepted for analysis. Out of 951 surveys sent, we received 114 responses (11.9%) with an average completion rate of 89%. Most respondents were from Europe (35.5%) and North America (30.9%), followed by Australia and New Zealand (9.1%). The majority were affiliated with academic institutions (83.9%) and were primarily surgeons (49.1%). The most common application of 3D printing was surgical planning (74.1%), followed by medical education (61.6%). Nearly 50% of respondents used open-source segmentation software without FDA approval. Most had access to an onsite printer (82.2%) and specially trained staff to assist with segmentation (53.4%). The integration of 3D printing technologies into clinical practice will continue to grow. This paper presents the largest survey of physicians practicing 3D printing to date. Given the underrepresentation of this key demographic within regulatory bodies, the opinions and positions of physician respondents reported here should be considered in the development and application of new guidelines and regulations in the field.

Three-dimensional (3D) bioprinting is a process that allows for the rapid prototyping of complex structures by depositing layer-by-layer materials using computer-aided design, which is an accelerating innovation in a variety of fields such as automobiles, medicine, manufacturing, aerospace, art, education, marine, robotics, and so on. Metals, polymers, ceramics, glass, and composites are used in 3D bioprinting. Compared with other materials, polymers have benefits such as cheap cost, flexibility, and tailorable properties that may be engineered prior to polymer production. This study endorses an insight into the 3D bioprinting of polymers for biomedical applications such as bionics and tissue engineering. A concise outline of several 3D bioprinting processes for polymers has been presented, as well as a compendium of notable polymers and their 3D bioprinting features. Because polymer-based 3D-printed components are weaker than metal, ceramic, and glass parts, the mechanical qualities of 3D-bioprinted polymeric products may be enhanced by reinforcing materials such as fibers, particles, or even nanoparticles. Various polymer reinforcements such as fibers, particles, and nanoparticles for 3D-bioprinted components are addressed, and subsequently, the application of these polymers in biomedical applications is explored, culminating with a future perspective. Tissues, bones, tracheal splints, heart tissues, and cartilaginous tissues have all been identified as possible 3D bioprinting milestones.

Application of three-dimensional (3D) bioprinting in anti-cancer therapy

Technical developments in medical imaging techniques have led to significant improvements in the diagnostic performance of less-invasive imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI), nuclear medicine and ultrasound. Quantitative analysis of these imaging modalities allows for detection and diagnosis of various diseases with high accuracy (1-10). Despite promising results available in the literature, traditional two-dimensional (2D) and three-dimensional (3D) visualization tools are still limited to a 2D screen, which affect realistic visualization of anatomical structures and pathologies of 3D datasets, and this is particularly apparent when dealing with complex pathologies. This has created potential opportunities for the use of 3D printing technique in medical applications. 3D printing has shown increasing applications in the medical field over the last decades with reports covering different areas which range from its original applications in orthopedics to cardiovascular disease and tumor imaging (11-15). In 2016, the Special Interest Group (SIG) on 3D printing was established by the Radiological Society of North America (RSNA) to provide guidelines, recommendations and training sessions for the appropriate use of 3D printing in medical applications with the aim of providing better healthcare service to patients (16,17). There is a growing body of evidence in the literature to show how 3D-printed models assist clinicians to better manage patients with improved clinical outcomes. This editorial mainly focuses on the rapidly expanding applications of 3D printing in medicine, in particular in congenital heart disease (CHD), vascular disease and tumors. Furthermore, an emerging area of using 3D-printed models to develop optimal CT scanning protocols is also discussed, with future research directions highlighted.