A doença arterial coronariana crônica apresenta alta prevalência e morbidade na população, manifestando-se como uma síndrome clínica caracterizada por sintomas álgicos tipicamente desencadeados ou agravados pelo esforço físico - a angina. Define-se a angina como refratária na presença de isquemia miocárdica documentada não passível de tratamento por meio de revascularização e não controlada a despeito do tratamento farmacológico máximo tolerado. O uso de terapia com ondas de choque extracorpóreas no tratamento da isquemia miocárdica tem sido proposto como uma alternativa promissora para o alívio dos sintomas anginosos e melhora da carga isquêmica por meio da promoção de vasodilatação e neoangiogênese. No presente estudo, avaliamos o efeito da terapia guiada com ondas de choque na reserva de fluxo miocárdico, obtida pela ecocardiografia de perfusão miocárdica em tempo real (EPMTR), em pacientes com angina refratária. Determinamos, também, as implicações da terapia com ondas de choque nas variáveis clínicas por meio da avaliação da classe funcional de angina pelo escore da Canadian Cardiovascular Society (CCS), capacidade funcional pelo escore de insuficiência cardíaca da New York Heart Association (NYHA) e qualidade de vida pelo Seattle Angina Questionnaire (SAQ), assim como nas variáveis ecocardiográficas. Foram estudados 15 pacientes com angina refratária procedentes do Ambulatório de Angina Refratária do Instituto do Coração (InCor, HC-FMUSP), os quais foram submetidos a 9 sessões de terapia com ondas de choque, ao longo de 9 semanas, e acompanhados por um período de 6 meses após a conclusão do tratamento. A dinâmica das microbolhas no miocárdio foi quantificada pela EPMTR utilizando programas computacionais específicos, tanto em repouso como durante o estresse pelo dipiridamol (0,84 mg/Kg). A reserva de volume miocárdico normatizada (Anor), a reserva de velocidade de repreenchimento de microbolhas no miocárdio (?) e a reserva de fluxo miocárdico (Anor x ?) foram obtidas pela relação entre os parâmetros de fluxo durante a hiperemia e o repouso, antes e 6 meses após o tratamento com ondas de choque. Nos 15 pacientes incluídos no estudo, avaliamos 32 segmentos com isquemia miocárdica submetidos à terapia, 31 segmentos com isquemia miocárdica não submetidos à terapia e 60 segmentos não isquêmicos. Os pesquisadores que realizaram as quantificações da EPMTR não tinham conhecimento dos dados clínicos no momento da análise de perfusão. A média etária da amostra foi de 61,5 (± 12,8) anos com predomínio do sexo masculino (67%), sendo que 93% deles apresentavam doença multiarterial. Após 6 meses da conclusão da terapia com ondas de choque, foi observada uma melhora da classe de angina (CCS) de 3,20 ± 0,56 para 1,93 ± 0,70 (p = 0,0001) e de insuficiência cardíaca (NYHA) de 2,8 ± 0,56 para 2,33 ± 0,81 (p = 0,048), resultados que foram concordantes com os achados do SAQ, o qual evidenciou melhora significativa da pontuação em todas as categorias (análise global com incremento da pontuação média de 42,33 ± 13,0 para 71,16 ± 14,3; p = 0,0001). Houve uma variação da fração de ejeção do ventrículo esquerdo de 50,30 ± 13,1% para 53,20 ± 10,6% (p = 0,049) na ausência de alterações no diâmetro diastólico final (de 53,80 ± 6,61 mm para 53,53 ± 7,05 mm; p = 0,81), no volume diastólico final (de 134,67 ± 34,33 mL para 146,13 ± 59,45 mL; p = 0,29) ou na função diastólica. A análise da perfusão miocárdica pela EPMTR evidenciou um aumento significativo da reserva de fluxo miocárdico (Anor x ?) de 1,33 ± 0,22 para 1,74 ± 0,29 (p = 0,0001) e também da reserva Anor de 1,02 ± 0,21 para 1,24 ± 0,33 (p = 0,004) nos segmentos isquêmicos submetidos à terapia com ondas de choque, mas não da reserva beta (de 1,33 ± 0,24 para 1,47 ± 0,35; p = 0,055). Não houve alterações significativas na perfusão miocárdica nos segmentos isquêmicos não tratados ou nos segmentos não isquêmicos. A análise global demonstrou uma melhora na reserva de fluxo miocárdico (de 1,78 ± 0,54 para 1,89 ± 0,49; p = 0,017) e na reserva beta (de 1,63 ± 0,43 para 1,70 ± 0,40; p = 0,039). Não foram registrados eventos cardiovasculares maiores durante o período de acompanhamento. Concluímos que a EPMTR foi capaz de identificar melhora da reserva de fluxo miocárdico nos segmentos submetidos à terapia com ondas de choque, possivelmente devido à neoproliferação vascular. Os resultados sugerem que a terapia com ondas de choque em pacientes com angina refratária é segura e tem o potencial de melhorar a isquemia miocárdica nos segmentos isquêmicos tratados, com impacto nos sintomas e na qualidade de vida / Chronic coronary artery disease shows high prevalence and morbidity levels in general population. In the clinical scenario, it is usually characterized by pain symptoms typically triggered or aggravated by physical effort - the angina. Refractory angina is defined as a documented and uncontrolled myocardial ischemia, untreatable by revascularization, despite maximum tolerated drug therapy. The use of extracorporeal cardiac shock wave therapy to treat myocardial ischemia has been suggested as a promising alternative to relieve angina symptoms and improve the ischemic load by promoting vasodilation and neoangiogenic phenomena. In the present study, we evaluated the effect of guided shock wave therapy on myocardial flow reserve, determined by real-time myocardial perfusion echocardiography (RTMPE), in patients with refractory angina. We also evaluated the implications of shock wave therapy in clinical variables by assessing the Canadian Cardiovascular Society (CCS) grading of angina pectoris, New York Heart Association (NYHA) functional classification and quality of life by the Seattle Angina Questionnaire (SAQ), as well as echocardiographic variables. Fifteen patients with refractory angina, from the refractory angina outpatient clinic of the Instituto do Coração (InCor, HC-FMUSP), were studied. Each patient underwent 9 shock wave therapy sessions over the course of 9 weeks and was followed for 6 months once the treatment was concluded. Using specific software, myocardial microbubble dynamics was quantified by RTMPE at rest as well as in stress by dipyridamole (0.84 mg/Kg). Normalized myocardial blood (Anor) reserve, myocardium microbubbles replenishment rate (?) reserve and myocardial flow reserve (Anor x ?) were obtained by the ratio of flow parameters during hyperemia and rest, before and 6 months after treatment. In the 15 patients included in the study, we evaluated 32 segments with myocardial ischemia submitted to therapy, 31 segments with myocardial ischemia not submitted to therapy and 60 non-ischemic segments. Researchers were blinded to all clinical data at the time of the perfusion analysis. Patients had mean age of 61.5 (± 12.8) years old, were predominantly men (67%), and 93% presented multiarterial disease. Six months after the completion of shock wave therapy, an improvement in CCS grading of angina pectoris was observed from 3.20 ± 0.56 to 1.93 ± 0.70 (p = 0.0001) and in NYHA functional classification (from 2.80 ± 0.56 to 2.33 ± 0.81; p = 0.048), results consistent with those found by SAQ, which evidenced a significant score improvement in all categories (global analysis with average score increased from 42.33 ± 13.0 to 71.16 ± 14.3; p = 0.0001). There was a variation in the left ventricular ejection fraction (from 50.3 ± 13.1% to 53.20 ± 10.6%; p = 0.049) in the absence of changes in end-diastolic diameter (from 53.80 ± 6.61 mm to 53.53 ± 7.05 mm; p = 0.81), the end-diastolic volume (from 134.67 ± 34.33 mL to 146.13 ± 59.45 mL; p = 0.29) or the diastolic function. Myocardial perfusion analysis by RTMPE evidenced a relevant increase in myocardial flow reserve (Anor x ?) from 1.33 ± 0.22 to 1.74 ± 0.29; p = 0.0001, as well as in the Anor reserve from 1.02 ± 0.21 to 1.24 ± 0.33 (p = 0.004) in ischemic segments submitted to shock wave therapy, but not in ? reserve (from 1.33 ± 0.24 to 1.47 ± 0.35; p = 0.055). There was no significant myocardial perfusion alteration in untreated ischemic segments or non-ischemic segments. Global analysis showed an improvement in myocardial flow reserve (from 1.78 ± 0.54 to 1.89 ± 0.49; p = 0.017) and ? reserve (1.63 ± 0.43 to 1.70 ± 0.40; p = 0.039). No major cardiac events were registered during the follow-up period. We concluded that RTMPE was able to identify an increase in myocardial flow reserve in the segments submitted to shock wave therapy, possibly due to vascular neoproliferation. Results suggest that shock wave therapy on patients with refractory angina is safe, with the potential to improve myocardial ischemia on treated ischemic segments, and positively affect symptoms and quality of life

Syfte Syftet med föreliggande studie var att försöka klargöra om stötvågsbehandling har någon effekt på smärta och handgreppstyrka hos patienter med lateral epikondylalgia. Frågeställningar 1. Har stötvågsbehandling någon effekt på smärta hos patienter med lateral epikondylalgia, i så fall vilken? 2. Har stötvågsbehandling någon effekt på handgreppsstyrka hos patienter med lateral epikondylalgia, i så fall vilken? Metod Sökning av litteratur utfördes i PubMed, Cochrane, Cinahl och PEDro. Detta resulterade i 14 artiklar, som granskades och bedömdes enligt PEDro Scale. Poängbedömningen utifrån PEDro Scale omsattes till Statens Beredning för medicinsk Utrednings (SBU) mall för bevisvärde. Utifrån artiklarnas sammantagna bevisvärde bestämdes evidensnivån enligt SBU:s fyra nivåer. Resultat Enligt GRADE-systemet förelåg det ett starkt vetenskapligt belägg för att stötvågsbehandling har en smärtlindrande effekt vid lateral epikondylalgia. Studier av likartad vetenskaplig kvalitet påvisar motsägande resultat avseende om stötvågsbehandling är bättre än placebo, kortison eller tenotomi. Detta innebär att det vetenskapliga underlaget är otillräckligt och att mer forskning behövs. Enligt GRADE-systemet förelåg det ett starkt vetenskapligt belägg för att stötvågsbehandling leder till förbättrad handgreppsstyrka vid lateral epikondylalgia. Vidare förelåg det ett starkt vetenskapligt belägg för att stötvågsbehandling inte är bättre än någon annan behandling gällande ökning av handgreppsstyrka vid lateral epikondylalgia. Slutsats Stötvågsbehandling har en smärtlindrande effekt hos patienter med lateral epikondylalgia. Det finns dock ingen evidens för att stötvågsbehandling är bättre ur smärthänseende än någon annan behandling såsom placebo, kortison eller tenotomi. Stötvågsbehandling leder till förbättrad handgreppsstyrka men är inte bättre än placebo, kortison eller tenotomi på att öka handgreppsstyrkan hos patienter med lateral epikondylalgia. / Aim The aim of the present study was to try to find out whether shock wave therapy has any effect on pain and grip strength in patients with lateral epicondylitis. Objectives 1. Does shock wave therapy reduce pain in patients with lateral epicondylitis? 2. Does shock wave therapy improve grip strength in patients with lateral epicondylitis? Method A literature review was performed in the databases PubMed, Cochrane, Cinahl and PEDro. Fourteen articles were found and critically reviewed. These articles were scored according to the PEDro scale and the scores were translated into a scale of evidence by the Statens Beredning för medicinsk Utredning (SBU) and the level of evidence was determined based on the four different grades presented by the SBU. Results According to the GRADE-system there was a strong scientific evidence for a reduction of pain using shock wave therapy in patients with lateral epicondylitis. Contradictory results whether shock wave therapy was better than placebo, corticosteoroid injection or tenotomy have been reported in studies of similar scientific quality. This means that more research is needed in this field. According to the GRADE-system there was a strong scientific evidence for an improvement of grip strength using shock wave therapy. Furthermore, there was a strong scientific evidence for that shock wave is not better than any other therapy in terms of improving grip strength in patients with lateral epicondylitis. Conclusion Shock wave therapy reduces pain in patients with lateral epicondylitis. There is, however, no evidence for shock wave therapy to be superior to any other treatment such as placebo, corticosteoroid injection or tenotomy. Shock wave therapy improves grip strenght but is not better than placebo, corticoidsteroid injection or tenotomy in increasing grip strength in patients with lateral epicondylitis.

Orientador: William Dias Belangero / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-28T23:43:39Z (GMT). No. of bitstreams: 1 Faria_LidiaDornelasde_M.pdf: 3066212 bytes, checksum: 6cb5506682740e2fcb2de4b1694998a3 (MD5) Previous issue date: 2015 / Resumo: A Terapia por ondas de choque (TOC) é uma alternativa não invasiva utilizada como método de indução a formação óssea que consiste em pulsos sonoros de alta energia transmitidas de modo focal a um tecido específico. Artigos demonstram aumento de vascularização, que ativação de proteínas como BMP (bone morphogenic protein) e Erk (extracellular signal-regulated kinase) induzindo diferenciação osteogênica após sua utilização no tecido ósseo. O presente estudo visou avaliar os níveis das proteínas Erk e Akt (akutely transforming), envolvidas na cascata protéica responsiva a deformação celular gerada por estímulo mecânico e consequente transformação em estímulo bioquímico induzindo a osteogênese. Os animais selecionados para o estudo foram anestesiados e divididos em dois diferentes grupos, onde no dia 1, o primeiro grupo foi submetido a TOC em sessão única de 500 impulsos gerados por aparelho eletrohidráulico a 0,12mJ/mm²na tíbia intacta e o segundo não recebeu TOC. Na sequência, os animais foram divididos em 3 subgrupos para cada tempo de segmento de 7, 14 e 21 dias A determinação dos níveis das proteínas propostas foi realizada por meio de immunoblotting. A fosforilação das proteínas Erk e Akt dos tecidos ósseos das tíbias extraídas dos ratos aumentou nos grupos submetidos a TOC após 7, 14 e se manteve elevado até o 21° dia quando comparado ao controle / Abstract: Extracorporeal shock wave therapy (ESWT) is a non-invasive alternative used as a method for inducing bone formation that consists of high-energy acoustic pulses transmitted in a focal way to a specific tissue. Studies show increase in vascularization which activate proteins such as BMP and Erk inducing osteogenic differentiation after its use in the bone tissue. The present study aimed at evaluating the levels of Erk and AKT proteins involved in the protein cascade responsive to cell deformation in biochemical stimulus inducing osteogenesis. The animals selected for the study were under anesthesia and divided in two different groups where on day 1 the first group was submitted to ESWT in one 500 pulse-session generated by an electrohydraulic device at 0,12mJ/mm² in intact tibia and fibula and the second did not receive ESWT. Then the animals were divided into 3 sub-groups, one for each segment times of 7, 14 and 21 days. Immunoblotting analysis was performed to determine the levels of the proposed proteins. The Erk and Akt protein phosphorylation of the bone tissues of extracted tibia from the animals increased in the groups submitted to ESWT and kept elevated until the 21st day when compared to the control group / Mestrado / Fisiopatologia Cirúrgica / Mestra em Ciências

A doença arterial coronariana crônica apresenta alta prevalência e morbidade na população, manifestando-se como uma síndrome clínica caracterizada por sintomas álgicos tipicamente desencadeados ou agravados pelo esforço físico - a angina. Define-se a angina como refratária na presença de isquemia miocárdica documentada não passível de tratamento por meio de revascularização e não controlada a despeito do tratamento farmacológico máximo tolerado. O uso de terapia com ondas de choque extracorpóreas no tratamento da isquemia miocárdica tem sido proposto como uma alternativa promissora para o alívio dos sintomas anginosos e melhora da carga isquêmica por meio da promoção de vasodilatação e neoangiogênese. No presente estudo, avaliamos o efeito da terapia guiada com ondas de choque na reserva de fluxo miocárdico, obtida pela ecocardiografia de perfusão miocárdica em tempo real (EPMTR), em pacientes com angina refratária. Determinamos, também, as implicações da terapia com ondas de choque nas variáveis clínicas por meio da avaliação da classe funcional de angina pelo escore da Canadian Cardiovascular Society (CCS), capacidade funcional pelo escore de insuficiência cardíaca da New York Heart Association (NYHA) e qualidade de vida pelo Seattle Angina Questionnaire (SAQ), assim como nas variáveis ecocardiográficas. Foram estudados 15 pacientes com angina refratária procedentes do Ambulatório de Angina Refratária do Instituto do Coração (InCor, HC-FMUSP), os quais foram submetidos a 9 sessões de terapia com ondas de choque, ao longo de 9 semanas, e acompanhados por um período de 6 meses após a conclusão do tratamento. A dinâmica das microbolhas no miocárdio foi quantificada pela EPMTR utilizando programas computacionais específicos, tanto em repouso como durante o estresse pelo dipiridamol (0,84 mg/Kg). A reserva de volume miocárdico normatizada (Anor), a reserva de velocidade de repreenchimento de microbolhas no miocárdio (?) e a reserva de fluxo miocárdico (Anor x ?) foram obtidas pela relação entre os parâmetros de fluxo durante a hiperemia e o repouso, antes e 6 meses após o tratamento com ondas de choque. Nos 15 pacientes incluídos no estudo, avaliamos 32 segmentos com isquemia miocárdica submetidos à terapia, 31 segmentos com isquemia miocárdica não submetidos à terapia e 60 segmentos não isquêmicos. Os pesquisadores que realizaram as quantificações da EPMTR não tinham conhecimento dos dados clínicos no momento da análise de perfusão. A média etária da amostra foi de 61,5 (± 12,8) anos com predomínio do sexo masculino (67%), sendo que 93% deles apresentavam doença multiarterial. Após 6 meses da conclusão da terapia com ondas de choque, foi observada uma melhora da classe de angina (CCS) de 3,20 ± 0,56 para 1,93 ± 0,70 (p = 0,0001) e de insuficiência cardíaca (NYHA) de 2,8 ± 0,56 para 2,33 ± 0,81 (p = 0,048), resultados que foram concordantes com os achados do SAQ, o qual evidenciou melhora significativa da pontuação em todas as categorias (análise global com incremento da pontuação média de 42,33 ± 13,0 para 71,16 ± 14,3; p = 0,0001). Houve uma variação da fração de ejeção do ventrículo esquerdo de 50,30 ± 13,1% para 53,20 ± 10,6% (p = 0,049) na ausência de alterações no diâmetro diastólico final (de 53,80 ± 6,61 mm para 53,53 ± 7,05 mm; p = 0,81), no volume diastólico final (de 134,67 ± 34,33 mL para 146,13 ± 59,45 mL; p = 0,29) ou na função diastólica. A análise da perfusão miocárdica pela EPMTR evidenciou um aumento significativo da reserva de fluxo miocárdico (Anor x ?) de 1,33 ± 0,22 para 1,74 ± 0,29 (p = 0,0001) e também da reserva Anor de 1,02 ± 0,21 para 1,24 ± 0,33 (p = 0,004) nos segmentos isquêmicos submetidos à terapia com ondas de choque, mas não da reserva beta (de 1,33 ± 0,24 para 1,47 ± 0,35; p = 0,055). Não houve alterações significativas na perfusão miocárdica nos segmentos isquêmicos não tratados ou nos segmentos não isquêmicos. A análise global demonstrou uma melhora na reserva de fluxo miocárdico (de 1,78 ± 0,54 para 1,89 ± 0,49; p = 0,017) e na reserva beta (de 1,63 ± 0,43 para 1,70 ± 0,40; p = 0,039). Não foram registrados eventos cardiovasculares maiores durante o período de acompanhamento. Concluímos que a EPMTR foi capaz de identificar melhora da reserva de fluxo miocárdico nos segmentos submetidos à terapia com ondas de choque, possivelmente devido à neoproliferação vascular. Os resultados sugerem que a terapia com ondas de choque em pacientes com angina refratária é segura e tem o potencial de melhorar a isquemia miocárdica nos segmentos isquêmicos tratados, com impacto nos sintomas e na qualidade de vida / Chronic coronary artery disease shows high prevalence and morbidity levels in general population. In the clinical scenario, it is usually characterized by pain symptoms typically triggered or aggravated by physical effort - the angina. Refractory angina is defined as a documented and uncontrolled myocardial ischemia, untreatable by revascularization, despite maximum tolerated drug therapy. The use of extracorporeal cardiac shock wave therapy to treat myocardial ischemia has been suggested as a promising alternative to relieve angina symptoms and improve the ischemic load by promoting vasodilation and neoangiogenic phenomena. In the present study, we evaluated the effect of guided shock wave therapy on myocardial flow reserve, determined by real-time myocardial perfusion echocardiography (RTMPE), in patients with refractory angina. We also evaluated the implications of shock wave therapy in clinical variables by assessing the Canadian Cardiovascular Society (CCS) grading of angina pectoris, New York Heart Association (NYHA) functional classification and quality of life by the Seattle Angina Questionnaire (SAQ), as well as echocardiographic variables. Fifteen patients with refractory angina, from the refractory angina outpatient clinic of the Instituto do Coração (InCor, HC-FMUSP), were studied. Each patient underwent 9 shock wave therapy sessions over the course of 9 weeks and was followed for 6 months once the treatment was concluded. Using specific software, myocardial microbubble dynamics was quantified by RTMPE at rest as well as in stress by dipyridamole (0.84 mg/Kg). Normalized myocardial blood (Anor) reserve, myocardium microbubbles replenishment rate (?) reserve and myocardial flow reserve (Anor x ?) were obtained by the ratio of flow parameters during hyperemia and rest, before and 6 months after treatment. In the 15 patients included in the study, we evaluated 32 segments with myocardial ischemia submitted to therapy, 31 segments with myocardial ischemia not submitted to therapy and 60 non-ischemic segments. Researchers were blinded to all clinical data at the time of the perfusion analysis. Patients had mean age of 61.5 (± 12.8) years old, were predominantly men (67%), and 93% presented multiarterial disease. Six months after the completion of shock wave therapy, an improvement in CCS grading of angina pectoris was observed from 3.20 ± 0.56 to 1.93 ± 0.70 (p = 0.0001) and in NYHA functional classification (from 2.80 ± 0.56 to 2.33 ± 0.81; p = 0.048), results consistent with those found by SAQ, which evidenced a significant score improvement in all categories (global analysis with average score increased from 42.33 ± 13.0 to 71.16 ± 14.3; p = 0.0001). There was a variation in the left ventricular ejection fraction (from 50.3 ± 13.1% to 53.20 ± 10.6%; p = 0.049) in the absence of changes in end-diastolic diameter (from 53.80 ± 6.61 mm to 53.53 ± 7.05 mm; p = 0.81), the end-diastolic volume (from 134.67 ± 34.33 mL to 146.13 ± 59.45 mL; p = 0.29) or the diastolic function. Myocardial perfusion analysis by RTMPE evidenced a relevant increase in myocardial flow reserve (Anor x ?) from 1.33 ± 0.22 to 1.74 ± 0.29; p = 0.0001, as well as in the Anor reserve from 1.02 ± 0.21 to 1.24 ± 0.33 (p = 0.004) in ischemic segments submitted to shock wave therapy, but not in ? reserve (from 1.33 ± 0.24 to 1.47 ± 0.35; p = 0.055). There was no significant myocardial perfusion alteration in untreated ischemic segments or non-ischemic segments. Global analysis showed an improvement in myocardial flow reserve (from 1.78 ± 0.54 to 1.89 ± 0.49; p = 0.017) and ? reserve (1.63 ± 0.43 to 1.70 ± 0.40; p = 0.039). No major cardiac events were registered during the follow-up period. We concluded that RTMPE was able to identify an increase in myocardial flow reserve in the segments submitted to shock wave therapy, possibly due to vascular neoproliferation. Results suggest that shock wave therapy on patients with refractory angina is safe, with the potential to improve myocardial ischemia on treated ischemic segments, and positively affect symptoms and quality of life

Chapter–I Introduction Shock waves appear in nature whenever the different elements in a fluid approach one another with a velocity larger than the local speed of sound. Shock waves are essentially non-linear waves that propagate at supersonic speeds. Such disturbances occur in steady transonic or supersonic flows, during explosions, earthquakes, tsunamis, lightening strokes and contact surfaces in laboratory devices. Any sudden release of energy (within few μs) will invariably result in the formation of shock wave since it is one of the efficient mechanisms of energy dissipation observed in nature. The dissipation of mechanical, nuclear, chemical, and electrical energy in a limited space will result in the formation of a shock wave. However, it is possible to generate micro-shock waves in laboratory using different methods including controlled explosions. One of the unique features of shock wave propagation in any medium (solid, liquid or gases) is their ability to instantaneously enhance pressure and temperature of the medium. Shock waves have been successfully used for disintegrating kidney stones, non-invasive angiogenic therapy and osteoporosis treatment. In this study, we have generated a novel method to produce micro-shock waves using micro-explosions. Different biological applications were developed by further exploring the physical properties of shock waves. Chapter – II Bacterial transformation using micro-shock waves In bacteria, uptake of DNA occurs naturally by transformation, transduction and conjugation. The most widely used methods for artificial bacterial transformation are procedures based on CaCl2 treatment and electroporation. In this chapter, controlled micro-shock waves were harnessed to develop a unique bacterial transformation method. The conditions have been optimized for the maximum transformation efficiency in E. coli. The highest transformation efficiency achieved (1 × 10-5 transformants per cell) was at least 10 times greater than the previously reported ultrasound mediated transformation (1 × 10-6 transformants per cell). This method has also been successfully employed for the efficient and reproducible transformation of Pseudomonas aeruginosa and Salmonella Typhimurium. This novel method of transformation has been shown to be as efficient as electroporation with the added advantage of better recovery of cells, economical (40 times cheaper than commercial electroporator) and growth-phase independent transformation. Chapter – III Needle-less vaccine delivery using micro-shock waves Utilizing the instantaneous mechanical impulse generated behind the micro-shock wave during controlled explosion, a novel non-intrusive needleless vaccine delivery system has been developed. It is well established, that antigens in the epidermis are efficiently presented by resident Langerhans cells, eliciting the requisite immune response, making them a good target for vaccine delivery. Unfortunately, needle free devices for epidermal delivery have inherent problems from the perspective of patient safety and comfort. The penetration depth of less than 100 µm in the skin can elicit higher immune response without any pain. Here the efficient utilization of the device for micro-shock wave mediated vaccination was demonstrated. Salmonella enterica serovar Typhimurium vaccine strain pmrG-HM-D (DV-STM-07) was delivered using our device in the murine salmonellosis model and the effectiveness of the delivery system for vaccination was compared with other routes of vaccination. The device mediated vaccination elicits better protection as well as IgG response even in lower vaccine dose (ten-fold lesser), compare to other routes of vaccination. Chapter – IV In vitro and in vivo biofilm disruption using shock waves Many of the bacteria secrete highly hydrated framework of extracellular polymer matrix on encountering suitable substrates and get embedded within the matrix to form biofilm. Bacterial colonization in biofilm form is observed in most of the medical devices as well as during infections. Since these bacteria are protected by the polymeric matrix, antibiotic concentration of more than 1000 times of the MIC is required to treat these infections. Active research is being undertaken to develop antibacterial coated medical implants to prevent the formation of biofilm. Here, a novel strategy to treat biofilm colonization in medical devices and infectious conditions by employing shock waves was developed. Micro-shock waves assisted disintegration of Salmonella, Pseudomonas and Staphylococcus biofilm in urinary catheters was demonstrated. The biofilm treated with micro-shock waves became susceptible to antibiotics, whereas the untreated was resistant. Apart from medical devices, the study was extended to Pseudomonas lung infection model in mice. Mice exposed to shock waves responded well to ciprofloxacin while ciprofloxacin alone could not rescue the mice from infection. All the mice survived when antibiotic treatment was provided along with shock wave exposure. These results clearly demonstrate that shock waves can be used along with antibiotic treatment to tackle chronic conditions resulting from biofilm formation in medical devices as well as biological infections. Chapter – V Shock wave responsive drug delivery system for therapeutic application Different systems have been used for more efficient drug delivery as well as targeted delivery. Responsive drug delivery systems have also been developed where different stimuli (pH, temperature, ultrasound etc.) are used to trigger the drug release. In this study, a novel drug delivery system which responds to shock waves was developed. Spermidine and dextran sulfate was used to develop the microcapsules using layer by layer method. Ciprofloxacin was loaded in the capsules and we have used shock waves to release the drug. Only 10% of the drug was released in 24 h at pH 7.4, whereas 20% of the drug was released immediately after the particles were exposed to shock waves. Almost 90% of the drug release was observed when the particles were exposed to shock waves 5 times. Since shock waves can be used to induce angiogenesis and wound healing, Staphylococcus aureus skin infection model was used to show the effectiveness of the delivery system. The results show that shock wave can be used to trigger the drug release and can be used to treat the wound effectively. A brief summary of the studies that does not directly deal with the biological applications of shock waves are included in the Appendix. Different drug delivery systems were developed to check their effect in Salmonella infection as well as cancer. It was shown for the first time that silver nanoparticles interact with serum proteins and hence the antimicrobial properties are affected. In a nutshell, the potential of shock waves was harnessed to develop novel experimental tools/technologies that transcend the traditional boundaries of basic science and engineering.