Mduduzi Nkosinathi Sithole

Biomaterials are either cross-linked ionically, chemically, or physically, or they can be functionalized with amino acids to overcome inherent biocompatibility and stability limitations. Hydrogels for scaffold fabrication have been effectively utilized to promote tissue integration and cellular processes for soft tissue regeneration. Despite significant progress, poor remodeling limitations persist, hence the need for cross-linkers with dynamic adaptability, native tissue mimicry, and controllable degradation. The aim of this review is to highlight cysteine’s capability and potential to cross-link biomaterials using thiol chemistry while discussing the different cross-linking strategies to aid in the fabrication of robust hydrogel inks and bioinks. Furthermore, cysteine’s limitations and research scarcity in soft tissue scaffolds are highlighted for its chemical significance and potential role. The review examines cysteine’s thiol reactions, including disulfide bonds, thiol–ene, thiol–yne, and Michael additions, and cross-linking ability, with a specialized focus on adipose tissue regeneration. The fabrication methods reviewed include 3D bioprinting, electrospinning, films, and nanostructured scaffolds, with a primary focus on 3D bioprinting of hydrogel scaffolds. Cysteine cross-linking enhances the scaffolds’ stability, printability, biocompatibility, degradability, and biological performance of scaffolds with an 85% increase in Young’s modulus. Cysteine adequately enhances the mechanical properties and degradation rates of adipose tissue scaffolds. This review addresses the underexplored use of cysteine cross-linking in soft tissue scaffolds, beyond its common bone tissue applications.

The physicochemical properties of polymeric hydrogels render them attractive for the development of 3D printed prototypes for tissue engineering in regenerative medicine. Significant effort has been made to design hydrogels with desirable attributes that facilitate 3D printability. In addition, there is significant interest in exploring stimuli-responsive hydrogels to support automated 3D printing into more structurally organised prototypes such as customizable bio-scaffolds for regenerative medicine applications. Synthesizing stimuli-responsive hydrogels is dependent on the type of design and modulation of various polymeric materials to open novel opportunities for applications in biomedicine and bio-engineering. In this review, the salient advances made in the design of stimuli-responsive polymeric hydrogels for 3D printing in tissue engineering are discussed with a specific focus on the different methods of manipulation to develop 3D printed stimuli-responsive polymeric hydrogels. Polymeric functionalisation, nano-enabling and crosslinking are amongst the most common manipulative attributes that affect the assembly and structure of 3D printed bio-scaffolds and their stimuli- responsiveness. The review also provides a concise incursion into the various applications of stimuli to enhance the automated production of structurally organized 3D printed medical prototypes.

This research aimed to substantiate the potential practicality of utilizing a matrix-like platform, a novel 3D-printed biomaterial scaffold, to enhance and guide host cells’ growth for bone tissue regeneration. The 3D biomaterial scaffold was successfully printed using a 3D Bioplotter^® (EnvisionTEC, GmBH) and characterized. Osteoblast-like MG63 cells were utilized to culture the novel printed scaffold over a period of 1, 3, and 7 days. Cell adhesion and surface morphology were examined using scanning electron microscopy (SEM) and optical microscopy, while cell viability was determined using MTS assay and cell proliferation was evaluated using a Leica microsystem (Leica MZ10 F). The 3D-printed biomaterial scaffold exhibited essential biomineral trace elements that are significant for biological bone (e.g., Ca-P) and were confirmed through energy-dispersive X-ray (EDX) analysis. The microscopy analyses revealed that the osteoblast-like MG63 cells were attached to the printed scaffold surface. The viability of cultured cells on the control and printed scaffold increased over time (p < 0.05); however, on respective days (1, 3, and 7 days), the viability of cultured cells between the two groups was not significantly different (p > 0.05). The protein (human BMP-7, also known as growth factor) was successfully attached to the surface of the 3D-printed biomaterial scaffold as an initiator of osteogenesis in the site of the induced bone defect. An in vivo study was conducted to substantiate if the novel printed scaffold properties were engineered adequately to mimic the bone regeneration cascade using an induced rabbit critical-sized nasal bone defect. The novel printed scaffold provided a potential pro-regenerative platform, rich in mechanical, topographical, and biological cues to guide and activate host cells toward functional regeneration. The histological studies revealed that there was progress in new bone formation, especially at week 8 of the study, in all induced bone defects. In conclusion, the protein (human BMP-7)-embedded scaffolds showed higher regenerative bone formation potential (week 8 complete) compared to the scaffolds without protein (e.g., growth factor; BMP-7) and the control (empty defect). At 8 weeks postimplantation, protein (BMP-7) significantly promoted osteogenesis as compared to other groups. The scaffold underwent gradual degradation and replacement by new bones at 8 weeks in most defects.

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