**Table 1.**

*Comparison of treatment methods for bone injuries along with advantages and disadvantages.*

*Recent Advances, Challenges and Future Opportunities for the Use of 3D Bioprinting in Large… DOI: http://dx.doi.org/10.5772/intechopen.111495*

#### *4.1.2 Low-intensity pulsed ultrasonography*

Ultrasound treatment is a safe non-invasive method and it was started in the early 1930s for therapy applications [44]. For bone healing Low-Intensity pulsed ultrasonography, the ultrasound is applied every day at 1.5 MHz, with 1 kHz pulse and 30 mW/cm2 for 20 min time periods [45]. Both bone-forming osteoblasts and mechano-sensitive osteocyte cells can sense the applied ultrasound. Osteoblast accelerates bone formation while regulating inflammatory responses. On the other hand, osteocytes that consisted high percentage of bone cells can sense acoustic radiation force created by ultrasound which leads to biological signals and enhance bone formation [46]. However, some limitation was detected in Low-Intensity pulsed ultrasonography such as low effect on pain reduction, poor functional recovery, and poor capability to reduce recurrent fracture [44].

#### *4.1.3 Extracorporeal shock wave therapy*

Extracorporeal shock wave therapy is a non-invasive therapy technique and can be defined as a sequence of high-energy acoustic impulses with a different course that can produce pressure changes while it propagates [47]. This technique has some advantages such as being safe, non-invasive, easy, and can apply to most patients, however, some surgeons believed that it has no significant difference from a placebo [48]. While it was demonstrated that extracorporeal shock wave therapy can be involved in the activation of various biochemical signals that trigger neoangiogenesis, fibroblast proliferation, collagen synthesis, and finally tissue regeneration. On the other hand, the negative phase of the shocks can enhance cell membrane permeability and inhibit calcification deposits and reduce pain [49]. The involved cellular signaling pathways during extracorporeal shock wave therapy are focal adhesion kinase, Extracellular-signal-regulated kinase, Wnt/β-catenin, Protein kinase R-like endoplasmic reticulum kinase/activated transcription factor, ATP/P2X7, Brain-derived neurotrophic factor [50].

#### **4.2 Surgical techniques**

Ilizarov method is a simple, effective, common, minimally invasive external fixation technique based on applying compression or distraction forces to the bone defects due to osteogenesis induced by tension stress [51]. Although the Ilizarov method is an applicable technique, especially for large bone defects, in some cases it may be associated with dissatisfaction such as pin tract infection, unconnected bone, re-fracture, bone malformation and transform death reported [52, 53]. One of the other popular surgical methods especially in large bone defects is Masquelet induced membrane [54]. This procedure includes two main steps: first, the created cavity is carefully debridement then is filled with polymethyl methacrylate cement to produce a membrane and inhibit soft tissue formation. In the second step, the cement is removed and the iliac crest cancellous bone or RIA (Reamer-Irrigator-Aspirator) cancellous bone is used to fill the cavity [54, 55].
