Beyond hype: unveiling the Real challenges in clinical translation of 3D printed bone scaffolds and the fresh prospects of bioprinted organoids

Abstract

Bone defects pose significant challenges in healthcare, with over 2 million bone repair surgeries performed globally each year. As a burgeoning force in the field of bone tissue engineering, 3D printing offers novel solutions to traditional bone transplantation procedures. However, current 3D-printed bone scaffolds still face three critical challenges in material selection, printing methods, cellular self-organization and co-culture, significantly impeding their clinical application. In this comprehensive review, we delve into the performance criteria that ideal bone scaffolds should possess, with a particular focus on the three core challenges faced by 3D printing technology during clinical translation. We summarize the latest advancements in non-traditional materials and advanced printing techniques, emphasizing the importance of integrating organ-like technologies with bioprinting. This combined approach enables more precise simulation of natural tissue structure and function. Our aim in writing this review is to propose effective strategies to address these challenges and promote the clinical translation of 3D-printed scaffolds for bone defect treatment.

Keywords: Bone scaffolds; Clinical translation; Organoids; Printing materials; Printing methods.

Fig. 1

Diagram illustrating the challenges and current status for the clinical translation of 3D-printed bone scaffolds in bone tissue engineering

Fig. 2

Effectiveness of materials for printing stents in BTE. (A) Magnesium coating enhances osseointegration [84]. (a) Surface morphologies and elements of porous PEEK scaffolds in different groups examined by SEM and EDS. (a) Surface morphology and elements of porous PEEK scaffolds examined by SEM and EDS. (b, c) 3D reconstructed images of internal vessels and bone ingrowth in scaffolds determined by micro-CT. (Copyright 2023, Elsevier) (B) Functionalized silk-hydroxyapatite scaffolds for enhanced bone regeneration [85]. (a, b) Micro-CT of a 3D printed cube and anatomical structures. (c, d) SEM of a 3D-printed construct and immunofluorescent staining of osteopontin (OPN). (Copyright 2021, Elsevier) (C) 3D-printed PLGA/BP scaffold stimulates bone regeneration by modulating macrophage M2 polarization [86]. (a) Schematic of PLGA/BP scaffolds and proposed mechanism. (b, c) CLSM images of hBMSC cells and RAW264.7 cells on the scaffolds. (Copyright 2023, Advanced Science)

Fig. 3

Important fabrication techniques for bone-tissue-engineering materials. (A) Vat Photopolymerization. (B)ME. (C)BJ. (D)PBF.

Fig. 4

The long-term outcomes of a two-week osteogenic and ligamentous differentiation in hBFP-MSCs cultured on bioprinted sEV scaffolds were assessed. (a) Osteogenic assay showed increased ALP staining, indicating more ALP-positive cells after 2 weeks on bioprinted GelMA/hPDLCs-sEV scaffolds. (b) Alizarin Red staining and (c) its quantification demonstrated enhanced osteogenic differentiation on bioprinted sEV constructs. (d) Toluidine blue staining showed ligamentous differentiation of hBFP-MSCs on bioprinted sEV constructs after 2 weeks. (Copyright 2024, Biomaterials Advances)

Fig. 5

Bioprinted organoid for repairing bone defects in BTE. (A) Assembly of osteo-callus organoids into bone-like tissue [192]. New bone formation 4 weeks after implantation with (a) H&E and (b) Masson staining. (Copyright 2022, Elsevier). (B) The organoid promotes long bone healing [193]. In vivo implantation of (a) Hematoxylin and eosin (H&E), (b) Safranin O, (c) Masson’s Trichrome (M’s T), and (d) hOCN. (Copyright 2019, Advanced Science)