Biomaterial-Based Additive Manufactured Composite/Scaffolds for Tissue Engineering and Regenerative Medicine: A Comprehensive Review

Abstract

Additive manufacturing (AM), also referred to as three-dimensional printing/printed (3DP), has emerged as a transformative approach in the current design and manufacturing of various biomaterials for the restoration of damaged tissues inside the body. This advancement has greatly aided the development of customized biomedical devices including implants, prosthetics, and orthotics that are specific to the patients. In tissue engineering (TE), AM enables the fabrication of complex structures that promote desirable cellular responses in the regeneration of tissues. Since the choice of biomaterials plays a vital role in scaffold performance as well as cellular responses, meticulous material selection is essential in optimizing the functionality of scaffolds. These scaffolds often possess certain characteristics such as biodegradability, biocompatibility, biomimicry, and porous structure. To this end, polymers such as chitosan, collagen, alginate, hyaluronic acid, polyglycolic acid, polylactic acid, and polycaprolactone have been extensively investigated in the fabrication of tissue-engineered scaffolds. Furthermore, combinations of biomaterials are also utilized to further enhance the scaffolds' performance and functionality. This review discusses the principle of AM and explores recent advancements in AM technologies in the development of TE and regenerative medicine. In addition, the applications of 3DP, polymer-based scaffolds will be highlighted.

Keywords: 3D printing; additive manufacturing; biomaterials; regenerative medicine; scaffold; tissue engineering.

Figure 1

Illustration showing laser-assisted sintering process. The upward arrow indicates the upward movement of the reservoir platform, while the downward arrow indicates the lowering of the building platform. Reproduced with permission from [43] under CCBY.

Figure 2

Schematic illustration of digital light processing 3DP. Prepared using BioRender Version 201.

Figure 3

Schematic illustration of stereolithography 3DP. Reproduced with permission from [49] under CCBY 4.0.

Figure 4

Schematic illustration of extrusion-based 3DP. Microelements V1, V2, V3, and V4 are synthetic biomaterials. Reproduced with permission from [54] under CCBY 4.0.

Figure 5

Schematic illustration of thermal (a) and piezoelectric (b) inkjet printing. Reproduced with permission from [49] under CCBY 4.0.

Figure 6

Schematic illustration of fusion deposition modeling-based 3DP. Reproduced with permission from [49] under CCBY 4.0.

Figure 7

Various 3DP techniques and their applications in TE, emphasizing the utilization of various biomaterials, including metals, polymers, ceramics, and bioinks, to fabricate functional tissues such as heart, skin, cartilage, and bone.

Figure 8

The cranial implant for human use comprises interconnected calcium phosphate tiles supported by a titanium frame, including fixation arms to anchor it to the native skull bone. This design ensures structural stability and bio-integration (A). Post-operative CT scans showing the BioCer implant (B). The gross image of the retrieved BioCer scaffold after 21 months of implantation, highlighting its complete integration with the surrounding bone tissue (C). Microscopic views of the BioCer implant. Top—peripheral view; middle—central view; bottom—transitional view (D). Areas with resorption of the BioCer, revealing a typical bone-remodeling pattern, with osteoclast-like cells (OCL) (white arrow) concomitant with an osteoblast (Ob) seam (black arrow), new bone (NB), and BVs (E). Reproduced with permission from [132] under CCBY.

Figure 9

(A) Schematic illustration of the fabrication process for 3D hydrogel constructs and a photograph of 3D hydrogel constructs for vascular and bone formation. (B) Schematic diagram of vascular construct. (C) Real image of vascular construct. Reproduced with permission from [136] under CCBY.

Figure 10

Schematic of pre-vascularized stem cell patch. (A) Illustration of 3D cell printing system, and (B) macroscopic view of the printer. (C) Illustration of pre-vascularized stem cell patch including multiple cell-laden bioinks and supporting PCL polymer. (D) Fabricated patch including the two types of cell-laden bioink and PCL supporting layer. (E) Optical image of the implanted patch. Reproduced with permission from [160] under CCBY.

Figure 11

(A) Manufacturing strategy using sacrificial 3DP to create hollow channel after post-encapsulation with a gelatin–fibrin ECM hydrogel. (B) Proximal tubule-like cell fully epithelialized after post-seeding and culturing with proximal tubule epithelial cells. (C) A phase contrast image of a mature 3DP construct taken at 6 weeks. (D) 3D rendering of a partial tubule showing the apical side, which highlights the primary cilia (red), and an image of the PT highlighting the presence of Na/K ATPase in green. (E) Image of the 3DP, highlighting the presence of (Aquaporin 1) AQP1 in yellow. (F) Image highlighting actin in red and showing AQP1 in yellow. Reproduced with permission from [162] under CCBY.

Figure 12

Diagram illustrating 3DP method for self-healing elastomeric liver models (A) and self-healing behavior (B). Demonstration of a healed sample being deformed (C). Reproduced with permission from [163] under CCBY.

Figure 13

Three-dimensional design of bicuspid valve (i-A). Flow characterization of 3D-printed bicuspid valve [168] (i-B). Image representing particle size velocimetry (i-C). Mathematical space-filling curves to entangled vessel topologies (ii-A,B), showing magnified regions in (ii-C). Measurement of oxygen capacity (ii-D) (* is the oxygen delivery values). Architectural design of an alveolar model topology (iii-A). Elaboration of a lung-mimetic design through generative growth of the airway, offset growth of opposing inlet and outlet vascular networks, and population of branch tips with a distal lung subunit (iii-B). Three-dimensional printed distal lung subunit showing major parts (airduct, air sac) (iii-C). Measurement of ventilation (iii-D). Reproduced with permission from [167] under CCBY.