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

2. 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.

3. 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

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

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

6. Case Report October 2000: ESWT + plaster cast (8weeks)
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 (8weeks)

7. Case Report
6 months after ESWT

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

9. 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.

10. Influence – Number of Impulses
Healed
Failure
< 3.000
253
183 (72%)
70 (28%)
> 3000 < 4.000
224
177 (79%)
47 (21%)
> < 6.000 40
26 (65%)
14 (35%)
> < 8.000 37
23 (62%)
14 (38%)
> 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

11. Osteointegrity depending on energy
M. Mayer (2002)
Fracture in trabecular bone
Fracture in cortical bone * 6 6 * 5 5 4 4
Animal [n]
Animal [n] 3 3 2 2 1 1
0,35
0,5
0,9
1,2
0,35
0,5
0,9
1,2
EFD [mJ/mm2]
EFD [mJ/mm2]
* = p<0,05 vs. ESWT
* = p<0,05 vs. ESWT

12. 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

13. 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 mJ/mm2) to the Achilles tendon near the insertion of the heel bone.
The left limbs (control side) received sham treatment.
Wang (Taiwan)

14. 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
(Neo-vessel)
(10 X)
(H-E stain)
(40 X)
Wang (Taiwan)

15. Results of Neo-Vessels
# Neo-Vessels Control Shockwave P-value-1
(N=50) (N=50)
0-week (N = 10)
Mean±SD 22 ± 3 24 ±
1-week (N = 10)
Mean±SD 24 ± 4 26 ±
P-value
4-week (N = 10)
Mean±SD 22 ± 5 42 ±
P-value
8-week (N = 10)
Mean±SD 24 ± 5 40 ±
P-value
12-week (N = 10)
Mean±SD 25 ± 6 42 ±
P-value
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. (40x).
Wang (Taiwan)

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

17. 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)

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

19. 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 F. S. Wang et al J Bone Joint Surg {Br} 2002;84-B:

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

21. Biological Responses – Stem Cells

22. Mechanotransduction
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

23. Direct mechanotransduction
Jaalouk, Nature Rev 2009

24. Indirect mechanotransduction
Wang, Tytell, Ingber Nature Rev 2009

25. Biological Effects of Shock Waves
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

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