Previous literature in this field lacks specificity; therefore, a scoping study methodology was chosen to correctly identify information gaps and precisely illustrate future research needs. The scoping review system creates a map of the published literature to explore the methodological and empirical differences in various knowledge areas.

Table 2 lists the articles included in this review. All reviewed studies contributed to understanding the complexity of applying cartilage bioprinting in humans. Table 3 summarizes the authors’ contributions regarding the first research question. This grouping allowed us to identify the approach according to the lines of research. The articles included in the group of in vivo studies emphasized the applied aspects of technology development, such as the elements that constituted the process (eg, bioink and its composition, replicability and cell viability, and the bioprinter), as well as bioprinting intervention strategies that included the use of a Biopen (ie, a manual bioprinter) with preclinical results in large animals. This is the strategy closest to human experimentation, according to the authors who used it.

Questions that arise from the studies cover a wide range of possibilities. Key elements for clinical translation included scalability and lesion characteristics, such as different lesion geometries and measurements. Insights from surgical application studies included problems specific to orthopedic, plastic, and otorhinolaryngology surgery. To progress toward human application, each surgical strategy must overcome these application-specific challenges. In addition, Boushell et al [23] opened debate on the scaffold versus cellular approaches. Li et al’s [27] translational study provided specific reading aimed at clinical professionals to establish synergies with basic research. Its goal was to reach surgical professionals not directly involved in the research.

Table 4 details the technical improvements identified in the studies that were necessary to continue progressing toward human application. In general, they involve two concepts: cellular sources and biomaterials, including scaffolds and hydrogels. Onofrillo [33], Apelgren et al [31], and Leberfinger [24] prioritized the need to develop protocols for obtaining cells; they also recognized that, despite variable sources, all cells must maintain chondrogenic capacity, not cause morbidity at the donor site, expand easily in the culture without losing phenotype, and support the mechanical load in the joint case. Di Bella et al [34], You et al [35], and Wu et al [25] presented disparate technical aspects that should be improved, since they followed different research paths. However, they all identified necessary biomaterial and scaffolding improvements, although the types of recommended improvements did not coincide.

The surgical application studies focused on certain surgical approaches and identified specific technical improvements needed to obtain better results; improvements included an algorithm to ensure that the nasal implant is not degraded or subjected to excessive long-term pressure [29]; a process to guarantee the characteristics of the skin of the ear in plastic surgery [31]; and in otorhinolaryngology, the use of a membrane trachea coating and image processing to optimize surgical results [36].

Table 5 reflects those aspects that were identified as recurrent among the different groups. An elaborate synthesis of the elements shared across the studies was completed. Analyzing these recurring elements allowed us to understand the group positions and identify the main shared aspects.

Table 6 reflects the lines that suggest prioritizing diverse groups. These were derived from the specific research studies, and therefore there was no shared opinion. At a general level, however, more research on manufacturing strategies to establish the role of scaffolding and accelerate integration of native and newly formed cartilage is required. Finally, when the technology is available to humans, the results obtained from bioprinted cartilage should be compared to the traditional gold standard.

In recent years, there has been an increase in the annual publication of articles on cartilage bioprinting, contributing to the knowledge and management of this process. The methodology adopted in this review allowed us to analyze 13 articles and present systematically summarized data. No clinical trials in humans have been identified to date. Tests with large animals presented some challenges and suggested possible strategies [37]. In this context, the reviewed articles provided polyhedral visions to the problem and proposed lines of research to progress toward human application. Identifying four groups based on research characteristics allowed us to establish synergies, understand confluences across studies, and highlight specific problems that surfaced as well as potential problems that may emerge as the field advances.

The Biopen [33,34] is the technique most likely to be applied in humans in the short term. The Biopen arose out of a collaboration between researchers at the University of Wollongong-based Australian Research Council Centre of Excellence for Electromaterials Science and orthopedic surgeons at St. Vincent’s Hospital in Melbourne. The Biopen technique is based on a small bioprinter that is easy to handle and is loaded with biological inks composed of stem cells inside a biopolymer, which in turn is protected by a second layer of hydrogel. The exchange of injectors allows different cells to be deposited at different concentrations on the surface to be repaired and, thus, recreates the zonal anatomy of native cartilage. It is then solidified by an ultraviolet light embedded in the pen. It is an attractive proposition for surgeons since its use does not require a long learning curve. The Biopen allows precise positioning of cells and biomaterials, rapid placement at the defect site, and minimal manipulation by the surgeon. Other authors advocate the predesign rather than in situ design of the implant: Yi et al [29], Apelgren et al [31], Li et al [36], Kaye et al [32], and Boushell et al [23]. These five studies focus on surgical applications in plastic surgery, otorhinolaryngology, and orthopedics.

The characteristics of these approaches make it difficult to use on-site technologies, while the preoperative design of the implants is necessary. In Kaye et al’s study [32], tracheal substitution started from a decellularized extracellular matrix trachea and subsequently seeded cells. Currently, in situ application of the technique appears to be restricted to joint injuries, despite being in a more advanced state of research. The image-mediated design, with algorithms such as those proposed by Yi et al [29], allows an implant, as similar as possible, while allowing for preoperative assessment of pressure and skin growth effects in plastic surgery implants. For Li et al [36] and Yi et al [29], the use of images is a line that must be exploited to ensure functional transplants with preservation capacity in both nasal and orthopedic applications. The Biopen technique would make it possible to ignore image studies, which contain a certain margin of error. This is evident in both Li et al’s [36] and Yi et al’s [29] studies, where they recommended technical improvements for obtaining and processing previous images to guarantee the implant design and facilitate optimal implantation.

Both impression approaches face a series of challenges, including maintenance of the implant form, cell viability, and mechanical resistance. The interface between the implant and adjoining native tissues also needs to be addressed. Form maintenance encompasses different strategies, such as the use of desacralized structures, as described by Kaye et al [32] with tracheal implants.

Scaffolds can contribute rigidity and mechanical resistance to the implant. In scaffolding, a structure with synthetic biopolymers provides mechanical support to maintain shape and load, while hydrogel provides a biological environment for regeneration of bioprinted cartilage [5]. Boushell et al [23] advocated the use of scaffolds insofar as they require a lower cellular concentration and facilitate the mechanical properties of the implant, which seems to adopt better mechanical-functional behaviors. On the other hand, Biopen techniques do not require a classic scaffold; however, they should guarantee both peri- and postoperative safety, functionality, and nondegradation of the construct, while scaffolds must ensure lateral integration of the implant. There is debate about the usefulness of scaffolds in orthopedic surgery. To date, lateral integration of the implant has not been confirmed with enough clarity.

Implant integration and fixation are aspects that can affect all the analyzed proposals. Correct integration and fixation of the neocartilage requires geometric measures of the osteochondral lesion’s total volume. Resistance to implanted cartilage degradation should be guaranteed in the long term, whether or not scaffolding is used. Wu et al [25] proposed semiconfined compression as an excellent way to mimic the native mechanical environment in future studies, facilitating research on how mechanical stimuli regulate cell activities in bioprinted constructs.

The risk of inflammation or the contraction or deformation of the implanted tissue, either with or without a scaffold, affecting the end result should not be overlooked. Kaye et al’s [32] work highlighted this difficulty in tracheal surgery; Yi et al [29] advocated greater precision in the algorithm to ensure that there is no modification of the postoperative nasal implant related to external causes. Postoperative cellular viability, such as maintaining cellular replication over time, must be analyzed by methods such as those proposed by Apelgren et al [30]. To date, the Biopen technique has not provided long-term viability results in large animals.

The hydrogels used must respond to a variety of biological needs, ensuring balanced mechanical properties, electrical conductivity, degradation rate, biocompatibility, and chondro-inducing properties [27]. Specific equilibria can be found in the speed of printing and the maintenance of cell viability [36]. In plastic surgery and otorhinolaryngology, they must also allow the correct irrigation of the tissue to avoid situations of hypoxia. The combination of biomaterials, such as alginate/hydroxyapatite [35] or a cross-linked gelatin methacrylate/hyaluronic methacrylate [33], should be considered a critical component for regeneration of the osteochondral interface in orthopedic surgery.

The cellular source of the implants is the last element of debate. There are two issues: cellular origin and cell treatment. The cells can be obtained from adult tissue-derived stem cells (ie, fat cells, bone marrow, and others), mesenchymal stem cells, autologous chondrocytes, and induced pluripotent cells. Researchers used two types of cells in the reviewed works: mesenchymal stem cells and stem cells derived from adipocytes. Cells extracted from the patient encounter extraction problems, but the chondrogenic capacity facilitates cellular processing and regulatory requirements, which are much higher with stem cells. Standardizing all steps in the process (eg, cell differentiation, the composition of the hydrogels, and the speed of printing) is necessary to enable translation to humans [27].

Although approaches differ depending on the study type and the application, a series of gaps and challenges were identified that were shared across studies, although there are differences in the ease of resolution, functional technique, and surgical strategies:

One limitation is the heterogeneity of the selected articles. Evaluating the methodological quality of the included studies was not within the scope of this review, which aimed to identify and synthesize the key concepts in cartilage bioprinting research. There may be additional relevant works that were not identified by the search strategy used in this review.

This concise review presented the evolving technology of cartilage bioprinting and its main components, with a particular focus on clinical translation. This work contributes a summary and update of current research in this area, which can be made available to clinicians to facilitate a better understanding of this new technology.

Human applications for bioprinted cartilage are likely to emerge in the near future. Advanced research on bioprinted cartilage can become a spearhead for adapting the technology to bioprint other types of tissue. On-site printing strategies and predesigned models can adapt to different situations. In addition, as imaging technology advances, processing implants and identifying the predictive capacity of implant behavior will allow better results. Regulation of the technology across different countries and cost-effectiveness of the technique will also need to be addressed in future studies.