Table 1.

Bone and cartilage: mechanical force applications, from tissue rescue to metabolic remodeling

Aim/findings	Biomechanical stimulus	Vitro/vivo	Cell/tissue type	Observed effect	Reference
Treating skeletal conditions such as osteoporosis	Daily, long-term (1 year), 20-min bursts of very-low-magnitude, high-frequency vibration	vivo	Hind limbs of adult sheep	Significantly increased (by 34.2%) density of the trabecular bone in the proximal femur, compared to controls	Rubin et al.102
Clinical intervention in conditions plagued by bone loss (long-term space flight, bed rest, or immobilization caused by paralysis)	10 min/day, for 28 days, extremely low-magnitude (<10 microstrain), high-frequency mechanical signals	vivo	adult female rats	Restored anabolic bone cell activity inhibited by disuse	Rubin et al.103
Setting the basis for nonpharmacologic prevention of obesity and its sequelae	15 weeks of brief, daily exposure to high-frequency mechanical signals, induced at a magnitude well below that which would arise during walking	vivo	C57BL/6J mice	Inhibited adipogenesis by 27%; reduced key risk factors in the onset of type II diabetes, non-esterified free fatty acid (by 43%) and triglyceride content (by 39%), in the liver	Rubin et al.105
	Over 9 weeks, same LMS	vivo	C3H.B6-6T congenic mouse strain with accelerated age-related changes in body composition	Suppressed fat production by 22%
	6 weeks of LMS	vivo	irradiated mice receiving BM transplants from heterozygous GFP+ mice	Reduced commitment of MSC differentiation into adipocytes by 19%
Mechanical signals can act in vivo at the stem cell level to operate major developmental metabolic switches	Brief daily exposure to LMS (0.2gat 90 Hz, 15 min/day, 5 days/week)	vivo	murine model of diet-induced obesity	Restored bone structure and B cells to the levels detected in control mice fed a regular diet	Chan et al.106
Mechanical loading regulates MSC differentiation through inhibition of GSK3β, which in turn regulates multiple downstream effectors	Mechanical load (3600 cycles/day, 2% strain)	vitro	murine BM-MSCs cultured under strong adipogenic conditions	Inactivation of GSK3β in a Wnt-independent fashion, leading to the activation of both b-catenin and NFATc1 signaling, thus limiting MSC adipogenesis and promoting osteoblastic differentiation	Sen et al.107
Major role of cytoskeletal dynamics in cellular response to mechanical stimulation	MSCs were subjected to vibration frequencies (100 Hz and 30 Hz) and acceleration magnitudes (0.15 g, 1 g, and 2 g) that induced fluid shear stress ranging from 0.04 Pa to 5 Pa	vitro	AD-hMSCs	Vibration-induced increase in the osteogenic commitment and proliferation of MSCs does not depend on fluid shear; the mechanically driven osteogenic commitment of undifferentiated MSCs was influenced by the level of cytoskeletal remodeling	Uzer et al.108
MSCs respond to dynamical physical environment not only with “outside-in” signaling primed by HMS, but even through matrix independent “inside-inside” signaling conducted by LMS through the LINC complex	LMS: vibrations applied to MSCs at peak magnitudes of 0.7gat 90 Hz for 20 min (two 20 min bouts separated by 2 h rest). HMS: uniform 2% biaxial strain delivered at 10 cycles per min for 20 min	vitro	murine BM-MSCs	While HMS suppressed MSC Adipogenesis through FAK/mTORC2 signaling generated at focal adhesions, LMS suppressed MSC adipogenesis despite virtual absence of substrate strain (<0.001%); this response occurred through mechanical coupling of the cytoskeleton and the cell nucleus	Uzer et al.109
Gene and protein expression of BMPs is implicated in the bone healing action exerted by ESW	ESW treatment using 500 impulses at 0.16 mJ/mm2	vivo	Rats with a 5-mm segmental femoral defect	Intensive MSC aggregation, hypertrophic chondrogenesis, and endochondral/intramembrane ossification, resulting in the healing of segmental defect; ESW promoted BMP-2, BMP-3, BMP-4, and BMP-7 mRNA expression in callus (tissue-rescuing pattern)	Wang et al.110
SW-promoted bone healing is associated with significant increases in serum NO level and osteogenic growth factors	6000 impulses of SW at 28 kV in a single session	clinical trial	Patients affected by long bone non-unions	At 6 months radiographically confirmed bony union in 78.6% of treated patients; in these patients after 1 month of treatment higher serum levels of NO, TGF-beta1, VEGF and BMP-2 were measured	Wang et al.111
ESWT strategy is feasible, well tolerated, and suitable to be evaluated in a Phase III trial for acute traumatic wounds	Debridement, outpatient ESWT (100–1000 shocks/cm2 at 0.1 mJ/mm2, according to wound size, every 1 to 2 weeks over mean 3 treatments), and moist dressings	clinical trial	Patients with complicated, non-healing, acute and chronic soft-tissue wounds	Feasibility and safety of ESWT for acute and chronic soft-tissue wounds	Schaden et al.112
Application of a single defocused ESWT immediately after skin graft harvest can accelerate donor site epithelialization	Standard topical therapy and antiseptic gel to graft donor sites with or without defocused ESWT (100 impulses/cm2 at 0.1 mJ/mm2) applied once to the donor site, immediately after skin harvest	clinical trial	Patients with acute traumatic wounds and burns requiring skin grafting	Mean times to complete graft donor site epithelialization for patients who did and did not undergo ESWT were 13.9 ± 2.0 days and 16.7 ± 2.0 days, respectively (p = 0.0001)	Ottomann et al.113

BM: bone marrow, MSCs: mesenchymal stem cells, AD-hMSCs: adipose derived human MSCs, HMS: high magnitude strain, LMS: low magnitude mechanical signals, BMPs: bone morphogenetic proteins, ESW: extracorporeal shock waves, SW: shock wave, ESWT: extracorporeal shock wave therapy.