# Advances in Three Dimensional Bioprinting for Wound Healing: A Comprehensive Review
## 3 Overview of Wound Pathophysiology and Wound Healing Process
### Scaffold-Based Bioink  
With the help of 3D bioprinting technology, a scaffold-based bioink can be used to create biomimetic and functional tissue constructs. Considering their strong mechanical properties and ability to function with various biomaterials [75], which is a remarkable advantage of scaffold-based bioink, it is a promising technology with the potential to make significant contributions to tissue engineering and regenerative medicine. The notable disadvantage of scaffold-based bioink is the initial cell density and the possibility of tissue self-assembly. Currently, hydrogels are in the field of interest for wound dressings due to their superior water uptake and swelling properties, biocompatibility, and biodegradability. Hydrogels are a class of cross-linked polymeric substances capable of absorbing and retaining large amounts of water. In the field of tissue engineering, hydrogels can be divided into two groups--naturally derived hydrogels and synthetically derived hydrogels. While synthetic polymers have been extensively used in the development of hydrogels, there is increasing interest in the use of natural polymers, also known as biopolymers, due to their advantages in terms of biocompatibility and biodegradability. Natural hydrops (such as collagen and gelatin, composed of proteins) and polysaccharide-based hydrogels (including agarose and ALG) have been synthesized using natural polymers. On the other hand, synthetic hydrogels such as polyethylene glycol (PEG) are lacking biological features inherent in their structure, but possess suitable structures to obtain biological functions [76]. Hydrogels have numerous applications in biofabrication and tissue engineering, most of which relate to drug delivery [77], contact lenses [78] and wound dressings [79]. Some hydrogels can mimic the natural tissue environment, possessing several key properties of natural ECM components [80] that enable cell encapsulation in a highly aqueous, mechanically robust 3D environment, without sacrificing biocompatibility. The scaffold-free approach employs fundamental units such as cell sheets, spheroids, or tissue strands, composed of cells and an extracellular matrix, to construct 3D tissue structures. This methodology relies on the inherent capability of these building blocks to interlace, effectively minimizing the significance of cell proliferation and migration. Consequently, this leads to a substantial reduction in the requisite time for tissue formation. A notable advantage of the scaffold-free approach is its capacity to address the intricate architectural complexity of complex tissues and organs. This achievement is realized through the controlled assembly of heterogeneous building blocks encompassing diverse cell types. Nonetheless, this approach also encompasses certain limitations. Firstly, the individual structural units exhibit relatively modest mechanical properties, potentially rendering cells susceptible to damage during manipulation. Secondly, an immobilization period is imperative for the initial fusion of building blocks and the accumulation of ECM [75; 81]. In conclusion, the scaffold-free approach holds promising prospects in the field of tissue engineering. Nevertheless, the constraints inherent to this approach, such as the modest mechanical attributes of individual structural units and the potential for cell damage during manipulation, underscore the need for further investigation and research. * Tissue Spheroids  
Tissue spheroids are a type of scaffold-free bioink material consisting of clusters of spherically arranged cells ranging from 200 to 400 \(\upmu\)m in diameter, which closely mimic the structure and function of the various types of tissue found in the human body. Tissue spheroids are widely used in tissue engineering research for modeling different diseases, and for drug testing purposes [82; 83; 84; 85].