Biological Principles Mechanotransduction W Schaden Trauma Center Meidling

Biological Principles - Mechanotransduction W. Schaden Trauma Center Meidling / Vienna Ludwig Boltzmann Institute for Experimental and Clinical Traumatology www. shockwavetherapy-vienna. at

For almost 40 years shockwaves are used successfully in urology practically without side effects. Just the mechanical properties of shockwaves were of interest. For use in all other medical disciplines the biological effects are most important. The absence of dangerous long term effects (malignant degeneration of treated soft tissues, etc. ) is the only important message.

Effects on Bone Tissue In control X-rays performed one year after disintegration of ureter and bladder concrements, Haupt (1986, Bochum) observed a thickening of the iliac bone where the shockwaves passed through. kidney swollen ureter iliac crest where the SW travels through stone in ureter bladder

Effects on Bone Tissue In the beginning everybody focused on the mechanical forces….

ESWT – Mechanical Model Hypothesis: Provocation of micro lesions in the tissue initiates and stimulates tissue repair/regeneration processes.

Case Report 58 years old, male, TKR June 96, supracondylar fract. March 2000 => double plate, cemented KR; May 2000 dislocation => re-plating; July 2000 dislocation => long stem revision TKR, cerclage; October 2000 fracture of the stem, persistent non-union October 2000: ESWT + plaster cast (8 weeks)

Case Report 6 months after ESWT

ESWT – Mechanical Model …was not able to explain such phenomena…. .

ESWT – Mechanical Model First doubts on this mechanical model came up when Schaden et al. (2001) could show, that less number of pulses (= less total amount of energy) is more efficient in the treatment of non-unions. Maier et al. (2002, Munich) proved most efficient osteostimulation in rat femura at energy levels without any mechanical destruction.

Influence – Number of Impulses Pulses Number Healed Failure < 3. 000 253 183 (72%) 70 (28%) > 3000 < 4. 000 224 177 (79%) 47 (21%) > 4. 000 < 6. 000 40 26 (65%) 14 (35%) > 6. 000 < 8. 000 37 23 (62%) 14 (38%) > 8. 000 - 12. 000 93 65 (70%) 28 (30%) total 647 477 (73%) 173 (27%) Numbers are shown for long bones and scaphoid Schaden et al. , 2001, Clin Orthop

Osteointegrity depending on energy M. Mayer (2002) Fracture in trabecular bone * 5 5 4 4 3 2 1 0 0 0 3 2 1 0 0, 35 * 6 Animal [n] 6 Fracture in cortical bone 0, 5 0, 9 EFD [m. J/mm 2] * = p<0, 05 vs. ESWT 1, 2 0 0 0, 35 0, 9 EFD [m. J/mm 2] * = p<0, 05 vs. ESWT 1, 2

From Mechanical Model to Bioresponse § Lower amounts of pulses more effective (Schaden) § Osteogenesis without mechanical destruction (Maier) Hypothesis: SW treatment causes biological responses without damaging / destroying tissue

Biological Response of Shock Wave in Tendon Materials and Methods: 50 New Zealand white rabbits, 12 months old, body weight ranging from 2. 5 to 3. 5 Kg were used in this study. The right limbs (study side) received 500 impulses of shock wave treatment at 14 KV (equivalent to 0. 18 m. J/mm 2) to the Achilles tendon near the insertion of the heel bone. The left limbs (control side) received sham treatment. Wang (Taiwan)

Biological Response of Shock Waves in Tendon Materials and Methods: Biopsies of the Achilles tendon-bone unit were performed in both the study and control limbs in 0, 1, 4, 8 and 12 weeks with 10 rabbits at each time period. The neo-vessels were examined microscopically with H-E stain. Tendon Bone (10 X) (H-E stain) (Neo-vessel) (40 X) Wang (Taiwan)

Results of Neo-Vessels # Neo-Vessels Control (N=50) Shockwave (N=50) P-value-1 0 -week (N = 10) Mean±SD 22 ± 3 24 ± 4 0. 93 1 -week (N = 10) Mean±SD 24 ± 4 26 ± 5 0. 95 P-value-2 0. 86 0. 92 4 -week (N = 10) Mean±SD 22 ± 5 42 ± 4 0. 024 P-value-2 0. 71 0. 0017 8 -week (N = 10) Mean±SD 24 ± 5 40 ± 5 0. 021 P-value-2 0. 81 0. 0025 12 -week (N = 10) Mean±SD 25 ± 6 42 ± 4 0. 017 P-value-2 0. 92 0. 0082 P-value-1: Comparison of control with shock wave therapy; P-value-2: Comparison of 0 -week with 1 -, 4 -, 8 - and 12 - week. Mann-Whitney test. (40 x). Wang (Taiwan)

Results of e. NOS Expression Microscopic Features of e. NOS Expression: Bone Tendon (Control) Bone Tendon (Shock Wave) ESWT promotes the expression of e. NOS signal transduction. The effects of shock waves appear to be time-dependent. Wang (Taiwan)

Results of VEGF Expression Microscopic Features of VEGF Expression: --●-- Control --○-- Shock Wave (Control ) (Shock Wave) ESWT promotes VEGF induction for angiogenesis. The effects of shock waves appear to be time-dependent. Wang (Taiwan)

Results of PCNA Expression Microscopic Features of PCNA Expression: Bone (Bone) ---● --- Control --○-- Shock Wave Tendon (Control) Bone Tendon (Shock Wave) ESWT promotes cell proliferation at the tendon-bone junction. The effects of shock waves appears to be time-dependent. Wang (Taiwan)

Biological Responses – Stem Cells Regeneration by increased cell differentiation Differentiation of bone-marrow mesenchymal cells by the induction of osteogenic growth factors such as transforming growth factor beta 1 (TGF- 1) Extracorporeal shock wave promotes growth and differentiation of bone-marrow stromal cells towards osteoprogenitors associated with induction of TGF- 1 F. S. Wang et al. J Bone Joint Surg {Br} 2002; 84 -B: 457 -61.

Biological Responses – Stem Cells Recruitment of i. v. administered EPC to ischemic adductor muscle is significantly enhanced after SW pre-conditioning Red – EPC Green – v. WF White – laminin Blue - nuclei Aicher et al. , 2006, Circulation

Biological Responses – Stem Cells

Mechanotransduction describes the cellular processes that translate mechanical stimuli into biochemical signals, thus enabling cells to adapt to their physical surroundings. Jaalouk and Lammerding Nature, 2009 Acute fuctional response Tissue plasticity including structural und functional adaptation Target are active and passive structures Muscle Endothelium Connective tissue Epithelia

Direct mechanotransduction Jaalouk, Nature Rev 2009

Indirect mechanotransduction Wang, Tytell, Ingber Nature Rev 2009

Biological Effects of Shock Waves o o o o o Permeability change of cell membrane Stimulation of mitochondria, ATP release Dilution of substance p Reduction of non-myelinited nerve fibers Anti-inflammatory effect Angio- and vasculogenesis Promotion of NO (nitric oxide) Promotion of growth factors (VEGF, BMP´s, OP´s, etc. ) Mobilization, migration homing and differentiation of stem cells

Message to be taken home: Ø shockwaves do not damage tissue Ø shockwaves stimulate biological regeneration via mechanotransduction