Due to high costs of biological approaches and the difficulties in their controllable delivery, biophysical modalities have been tested and widely applied in clinical settings, such as mechanical stimulation, electrical stimulation, pulsed electrical magnetic fields (PEMFs), and LIPUS (at 100-200 bursts, 1.5-2 MhZ, 30 mW/cm
2 ) that have been evaluated intensively for their potential for enhancing fracture healing or soft tissue repair; the underlying mechanisms for promoting healing are associated chemical and biological responses due to the mechanical stimulations that are in favor of osteogenesis and angiogenesis[
124‐
127]. Clinically, surgical reattachment of tendon to bone is often followed by a longer period of immobilization. Immobilization-induced problems to musculoskeletal tissues are well known in orthopaedic sports medicine and therefore postoperative rehabilitation programs are highly appreciated. As early motion or direct mechanical stimulation, e.g. tension or cyclic loading via external force onto the healing tissue may impair its healing [
127‐
129], using non-contact 'biomechanical stimulations' would be beneficial for augmentation in early healing phase. LIPUS is such a form of mechanical stimulations, i.e. a noninvasive form of mechanical energy transmitted transcutaneously as high frequency acoustical pressure waves in biologic tissues and thus provides a direct mechanical effect on endochondral ossification, osteoblasts proliferation to produce bone by modulating various biosynthesis processes, including angiogenesis[
35,
130,
131]. LIPUS has been documented as a non-invasive mean for accelerating fracture healing, delayed union, non-union, and soft tissue repair process [
43,
79,
126,
130,
131] as well as promotion of bone mineralization and its remodeling during distraction osteogenesis[
132]. The authors of this review paper pioneered in the experimental work for potential clinical indication of LIPUS for accelerating TBI repair and confirmed that LIPUS was generally capable of promoting maturation of inhomogenous tissues, as evidenced with increase in the matrix hardness of the healing tissues at TBI, including new bone, regenerated fibrocartilage and tendon tissues [
43], especially with significant augmentation in new bone formation and its remodeling[
78]. Similar to soft tissue healing [
133], more profound treatment effects were demonstrated in the early healing phase in our series of LIPUS investigation for accelerating TBI repair[
42]. Our recent microarray study demonstrated that over 100 genes were related to the underlying molecular mechanism of LIPUS that LIPUS regulated the transient expression of numerous critical genes, especially the cytoskeleton genes in osteoblastic cells[
134]. These in vitro results provided further understanding about the role of LIPUS in the regulation of osteoblastic activity potentially involved in osteogensis in TBI repair[
134]. A new and interesting finding of this study was up-regulation of genes associated with cell apoptosis, such as BCL2-associated × protein (BAX), suggesting LIPUS accelerated tissue remodeling by activating apoptotic genes and osteogenesis. Our preclinical findings are appreciated by clinicians and patients. The impact of the research findings of LIPUS for TBI repair can be seen from a personal communication with American LIPUS scientists (Dr. Neil Pounder, Smith & Nephew, personal communication) "American surgeons prescribe LIPUS for many patients now, even if FDA only allows the application on non-unions and tibial fresh simple fracture. The surgeons prescribe on other sites at their own risk. One prescription is on Achilles tendon junction healing. But the patients need to claim insurance, where your paper is the key evidence for them to claim the insurance". This is a big contribution to the improvement of patient care. However, not all patients may benefit from such findings. Delayed TBI healing was observed in some patients even after treatment with LIPUS during postoperative examinations in our orthopaedic clinics[
135]. For the management of delayed healing in patients with TBI surgery, we tested if extracorporeal shockwave (ESW), which is often used for the treatment of delayed union or non-union [
127], would be able to promote TBI repair using a recently established delayed TBI healing model in rabbits[
37]. Our findings showed that ESW was able to treat delayed TBI injury by triggering osteogenesis, regeneration of fibrocartilage zone, and remodeling in the delayed TBI animal model[
136]. Our preclinical data published in the American Journal of Sports Medicine in February issue of 2008 attracted media's great attention and was reported in
Reuters Health in New York of USA, with hope of attracting potential clinical applications of ESW in the management of this difficult delayed TBI injury.