Microcirculation and Pace Therapy

and Mariusz Mielniczuk²

(1)

Department of General Surgery, Oncologic Gastroenterologic Surgery and Plastic Surgery, Poznan University of Medical Sciences, Poznan, Poland

(2)

Department of Anesthesiology and Intensive Therapy, University Hospital no 1 in Bydgoszcz, Bydgoszcz, Poland

Abstract

Pulsed Acoustic Cellular Expression (PACE) is a novel technology utilizing Extracorporeal Shock Waves (ESW) in as a source of acoustic energy in a pulsed manner capable of delivering a cellular expression response. It has multiple indications in medicine but exact mechanism of PACE remains unknown. In our experiment in a large group of animals we checked influence of PACE on microcirculation in a well-known model of rats’ cremaster muscle. Results revealed that PACE therapy increases circulation in cremaster muscle and causes neovascularization and angiogenesis. It also has anti-inflammatory effect on the muscle. To achieve desired results PACE therapy has to be used periodically.

Keywords

PACEESWTMicrocirculationCremaster muscleAngiogenesisNeovascularizationIschemiaReperfusion

Abbreviations

CCL2

Chemokine (C-C motif) ligand 2

CCR2

Chemokine (C-C motif) receptor 2

CXCL5

Chemokine (C-X-C motif) ligand 5

eNOS

Endothelial nitric oxide synthase

ESW

Extracorporeal Shock Waves

ESWT

Extracorporeal Shock Wave Technology

I/R

Ischemia/Reperfusion

iNOS

Inducible nitric oxide synthase

PACE

Pulsed Acoustic Cellular Expression

RBC

Red Blood Cells

VEGF

Vascular endothelial growth factor

vWF

von Willebrand factor

Pulsed Acoustic Cellular Expression (PACE) is a novel technology utilizing Extracorporeal Shock Waves (ESW) in as a source of acoustic energy in a pulsed manner capable of delivering a cellular expression response. It is delivered by high voltage acoustic waves generated by an explosive evaporation of water. By focusing the acoustic waves with a semi-ellipsoid reflector, the waves can be transmitted to a specific tissue site [1].

Extracorporeal Shock Wave Technology (ESWT) was introduced for medical practice approximately 30 years ago for fragmentation of kidney stones [2, 3]. It has become gold standard for treatment of a significant amount of urinary calculi. It is also widely used in a number of orthopedic pathologies such as bone non-union and tendinopathies [4–6]. However, the energy of shock wave used in treatment of orthopedic disorders is significantly lower compared to the energy levels used in kidney stones treatment (approximately 10 %). Shock wave of low energy has also found application in cardiology where it may ameliorate myocardial ischemia in patients with severe coronary artery disease [7]. It was also found to improve healing after a partial thickness burns [8].

Recent experimental studies revealed that treatment utilizing ESWT has the potential to induce a neovascularization process and facilitate cell proliferation [9, 10]. It also has been shown to reduce necrosis and induce survival in an experimental skin flap model [11]. Despite numerous studies the exact mechanism of shock wave and its effect on tissue microcirculatory hemodynamics and neovascularization remains unknown. To better investigate the influence of PACE in wound healing and angiogenesis, a study was conducted aimed at assessing changes in rats’ cremaster muscle circulation after a short-acting (15 min and 24 h) and long-acting (3, 7 and 21 days) PACE conditioning followed by muscle flap harvesting. Because in many clinical situations such as free tissue transfer, replantation, organ transplantation, myocardial infarction, and stroke it is not only the initial ischemia [12], but ischemia-reperfusion (I/R) that contributes to tissue damage and difficulty with recovery, a separate part of the study involved investigation of a muscle flap after 5 h of ischemia followed by reperfusion before and after PACE application. Previous extensive experience regarding methods for assessment of microcirculatory hemodynamics in a cremaster muscle and leukocyte-endothelial interactions provided valuable tools for assessment of microcirculatory changes after surgical trauma, ischemia and reperfusion injury [13–16].

The study design involved in-vivo measurements of microcirculatory data-Vessel Diameters, Red Blood Cells (RBC) Velocity, Functional Capillary Density, leukocyte-endothelial interactions) with the use of immunostaining and real-time PCR quantification thus enabling detection of changes in microcirculation and expression of proangiogenic and proinflammatory genes.

There were nine study groups consisting of eight Lewis rats each:

Group 1 (n = 8) Non-ischemic controls. Animals did not receive any treatment before cremaster muscle dissection.

Group 2 (n = 8) 5 h Ischemia without conditioning. After cremaster muscle dissection the femoral and illiac vessels were clamped for 5 h to induce ischemia. After ischemia and 15 min of reperfusion microcirculatory recordings were taken for 2 h.

Group 3 (n = 8) Pre-ischemic (5 h) PACE conditioning. Before cremaster muscle dissection, 500 impulses of PACE (0.10 mJ/mm² energy flux density) were applied to the scrotum. Next, the cremaster muscle was dissected and placed on a tissue bath. Once microcirculatory hemodynamics were stabilized, the iliac and femoral vessels were clamped for 5 h to induce ischemia. After ischemia and 15 min of reperfusion standard microcirculatory recordings were taken for 2 h.

Group 4 (n = 8) Post-ischemic (5 h) PACE conditioning. Following dissection and before PACE application the femoral and illiac vessels were dissected and clamped for 5 h to induce ischemia. After 5 h of ischemia the clamps were released and after 15 min of reperfusion 500 impulses of PACE (0.10 mJ/mm² energy flux density) was applied to cremaster muscle, than cremaster muscle was prepared on a tissue bath for microcirculatory recordings, which were taken for 2 h.

Group 5: short-acting PACE conditioning (n = 8) received 500 impulses (0.10 mJ/mm² energy flux density) 15 min before cremaster surgical isolation.

Group 6: short-acting PACE conditioning (n = 8) received 500 impulses (0.10 mJ/mm² energy flux density) 24 h before cremaster surgical isolation.

Group 7: long-acting PACE conditioning (n = 8) received 500 impulses (0.10 mJ/mm² energy flux density) 3 days before cremaster surgical isolation.

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