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International Journal of Bioprinting Progress in bioprinted ear reconstruction

Study Aim of study Study Animal Study focus 3D printing Components Printed Printed Cell nature/type Notable post- Assessment Findings Limitations and suggested
setting model (if technique shape material printing of success/ improvements
any) modifications integration
• At 12 months, the reconstructed auricle • Multiple additional
presented high stiffness and low flexibility, surgical steps
whereas at 24 months, an obvious incorporated:
improvement in inflexibility with more • Tissue expanded
distinct structures were achieved. preoperatively for 3
• Among the total five cases, four cases showed months (psychosocial
obvious cartilage formation after 6 months impact)
post-implantation (one case was lost to • Split-thickness skin
follow-up). graft from groin was
• MRI conformed a significant portion of PCL required
has degraded (complete degradation of PCL • Scar revision
in vivo normally requires 2–4 years). Biopsied surgeries were
samples revealed formation of mature in vivo required at 6 and 18
cartilage at 6 months and 18 months post- months
operatively.
Abbreviations: ACM, ; ACMMA, methacrylate-modified acellular cartilage matrix; ASCs, adipose-derived stem cells; AuCPCs, auricular cartilage pro-
genitor cells; CAD, computer-aided design; CAM, computer-aided manufacturing; CPS, cell-printed structure; CSHS, cell-seeded hybrid scaffold; CSS,
cell-seeded scaffold; CT, computed tomography; DLP, digital light processing; DMEM, Dulbecco’s Modified Eagle Medium; ECM, extracellular matrix;
FDM, fused deposition modeling; GAG, glycosaminoglycan; GelMA, gelatin methacrylate; H&E, hematoxylin and eosin staining; HA, hyaluronic acid;
HAMA, hyaluronic acid methacrylate; MRI, magnetic resonance imaging; MSCs, mesenchymal stem cells; PBS, phosphate-buffered saline; PCL, poly-
caprolactone; PEG, polyethylene glycol; PEO, poly(ethylene oxide); PGA, polyglycolic acid; PGLA, poly(lactic-co-glycolic acid); PLA, polylactic acid; PPU,
perforated polyurethane; PRP, platelet-rich plasma; PU, polyurethane; SEM, scanning electron microscopy; SLS, selective laser sintering; UV, ultraviolet.

scarring, and intrinsic contractile forces as the scaffold et al. (2021) found that the implantation of a bioscaffold can
matures . Therefore, a fine balance must be struck be performed in under 25 min, as the surgical techniques
[10]
[4]
between creating an auricle that is strong enough to involved are theoretically much simpler .
maintain its shape and yet pliable enough to mimic true Additionally, regulatory approval is essential for 3D
elastic cartilage and not cause ulceration, which happens bioprinting applications in auricular reconstruction.
when the mechanical stiffness of the skin is low in relation In the United States, personalized 3D-printed medical
to the construct . This means that the structure needs to devices are regulated under the medical device category or
[33]
either be synthetic with perfect mechanical properties and with custom device exemptions. The United States Food
completely inert and free from biodegradation or that it and Drug Administration (FDA) provides guidelines for
needs to be partially biological and, over time, integrate 3D-printed materials to ensure product quality, efficacy,
into the patient’s body. Several of the studies in this and classification for regulations. In the European Union,
review attempted to solve this conundrum by combining the regulation of 3D-printed medical devices has evolved.
bioinks and multiple materials or through specific post- Previously, 3D-printed medical device products followed
printing modifications. However, all studies agree on the legislation like AIMDD 90/385/EE, MDD 93/42/EEC,
necessity of longer-term in vivo research. This is crucial and IVDMDD 98/79/EC, with medical devices classified
to verify that the bioprinted constructs will maintain their based on patient contact duration, degree of invasiveness,
form and functionality over time, without issues such as and implantation/contact location in the human body [34,35] .
[29]
deformation or collapse . However, the current regulation, known as the Medical
Since more than 1 in 500 people is affected by an external Device Regulation (MDR 2017/745), has replaced these
ear deformity per year, large-scale production would directives, providing a more comprehensive and stringent
be desirable. However, currently available bioprinting framework for the approval and post-market surveillance
technologies are not ready for mass production, and of medical devices . Moreover, 3D-bioprinted tissues
[36]
concerns have been raised that the costs associated with cell do not directly fall into existing regulatory categories.
harvest and expansion prior to construct fabrication are They are considered “bio-objects,” which fall in between
currently prohibitive to routine clinical use . Arguably, this the existing categories of living and non-living matter,
[34]
cost could be offset in saved operating time, not to mention thus requiring new regulations/laws for clinical trials
the reduced morbidity (and thus cost) associated with not and commercialization. In this context, the European
needing to perform rib cartilage grafting. In fact, Brennan Regulation No. 1394/2007 and Directive 2001/83/EC,

Volume 9 Issue 6 (2023) 303 https://doi.org/10.36922/ijb.0898