Needleless or Noninvasive Delivery Technology.

Injections of drugs or vaccines have become an indispensable part of living systems. Introduction to injections begins from the vaccination regimen at the neonatal stage and continues throughout the life span of an individual. Conventionally, injections are administered using hypodermic needles and syringes. These usually inject the liquid in the muscle, thus making intramuscular injections the most common form of administration. Although hypodermic syringes have been a clinician's tool in global vaccination efforts, they also have a set of undesirable characteristics. Pathogen transmission in case of HIV and HBV is one of the deadliest disadvantages of the needle-based injection system. Generation of plastic wastes in clinics, needlestick injury, and most importantly, pain associated with needle-based injections are a few more reasons of concern. In light of these issues, developing needle-free injection systems has excited researchers across the globe since the 1950s. Significant advancement has been reported in this field and various needle-free injection systems have been developed and are in clinical practice. This article briefly describes the history of needle-free injection systems and provides a detailed account of a few well-known methods of needle-less injections available.

Shockwave Therapy Efficiently Cures Multispecies Chronic Periodontitis in a Humanized Rat Model.

Biofilms are ubiquitous in nature and are invariably associated with health and diseases of all living beings. Periodontal diseases & dental caries are the most prevalent conditions in which biofilm has established as a primary causative factor. Managing poly-microbial biofilm is the mainstay of periodontal therapy. Plethora of antimicrobials have been used till date to combat biofilm, but the emergence of antibiotic tolerance and resistance in biofilms is a major cause of concern. Apart from use of antimicrobials, various anti-biofilm strategies have evolved which include the use of mechanical, and chemical means to disrupt biofilms. However, none of these approaches have led to desired or optimal biofilm control and hence search for novel approach continues. Shockwaves are used in medical practice for various therapeutic purposes and in local drug delivery, gene therapy, wound healing & regeneration. With this background, a study was designed with an attempt to explore the possibility of using the shockwave for their effect on multispecies oral biofilm development from subgingival plaque samples obtained from chronic periodontitis patients. Plaque samples from 25 patients were used to derive multispecies biofilm which were used to check the efficacy of shockwaves and antibacterial efficacy of four clinically relevant antimicrobials. Biofilms were analyzed by scanning electron microscope; atomic force microscope and their biomass was quantitated by crystal violet staining. Further, a humanized rat model of periodontitis was developed. Patient derived plaque was used to establish periodontitis in healthy rats. The model was validated by performing colony forming unit (CFU) analysis of the infected tissue. The animals were subjected to low intensity shockwaves using a hand-held shockwave generator at the site of infection. Shockwave treatment was done with or without antimicrobial application. The animals were monitored for clearance of infection and for mortality. The results show that shockwave treatment in combination with antimicrobials is significantly effective in clearing a multispecies biofilm. This also brings out the possibility of application of shockwaves in the management of oral biofilms either alone or in combination with established antimicrobial agents. With further research, safety profile validation and clinical trials, shockwaves can be an effective, novel approach in management of biofilm associated periodontal disease.

Stimulation of angiogenesis using single-pulse low-pressure shock wave treatment.

Endothelial cells respond to mechanical stimuli such as stretch. This property can be exploited with caution to induce angiogenesis which will have immense potential to treat pathological conditions associated with insufficient angiogenesis. The primary aim of this study is to test if low-pressure shock waves can be used to induce angiogenesis. Using a simple diaphragm-based shock tube, we demonstrate that a single pulse of low pressure (0.4 bar) shock wave is enough to induce proliferation in bovine aortic endothelial cells and human pulmonary microvascular endothelial cells. We show that this is associated with enhanced Ca++ influx and phosphorylation of phosphatidylinositol-3-kinase (PI3K) which is normally observed when endothelial cells are exposed to stretch. We also demonstrate the pro-angiogenic effect of shock waves of single pulse (per dose) using murine back punch wound model. Shock wave treated mice showed enhanced wound-induced angiogenesis as reflected by increased vascular area and vessel length. They also showed accelerated wound closure compared to control mice. Overall, our study shows that just a single pulse/shot (per dose) of shock waves can be used to induce angiogenesis. Importantly, we demonstrate this effect using a pulse of low-pressure shock waves (0.4 bar, in vitro and 0.15 bar, in vivo). KEY MESSAGES: Low-pressure single-pulse shock waves can induce endothelial cell migration and proliferation. This effect is endothelial cell specific. These shock waves enhance wound-induced angiogenesis in vivo. These shock waves can also accelerate wound healing in vivo.

Corrigendum: Successful treatment of biofilm infections using shock waves combined with antibiotic therapy.

This corrects the article DOI: 10.1038/srep17440.

Insights into the mechanism of a novel shockwave-assisted needle-free drug delivery device driven by in situ-generated oxyhydrogen mixture which provides efficient protection against mycobacterial infections.

BACKGROUND: Needle-free, painless and localized drug delivery has been a coveted technology in the area of biomedical research. We present an innovative way of trans-dermal vaccine delivery using a miniature detonation-driven shock tube device. This device utilizes~2.5 bar of in situ generated oxyhydrogen mixture to produce a strong shockwave that accelerates liquid jets to velocities of about 94 m/s. METHOD: Oxyhydrogen driven shock tube was optimized for efficiently delivering vaccines in the intradermal region in vivo. Efficiency of vaccination was evaluated by pathogen challenge and host immune response. Expression levels of molecular markers were checked by qRT-PCR. RESULTS: High efficiency vaccination was achieved using the device. Post pathogen challenge with Mycobacterium tuberculosis, 100% survival was observed in vaccinated animals. Immune response to vaccination was significantly higher in the animals vaccinated using the device as compared to conventional route of vaccination. CONCLUSION: A novel device was developed and optimized for intra dermal vaccine delivery in murine model. Conventional as well in-house developed vaccine strains were used to test the system. It was found that the vaccine delivery and immune response was at par with the conventional routes of vaccination. Thus, the device reported can be used for delivering live attenuated vaccines in the future.

Mechanism of transformation in Mycobacteria using a novel shockwave assisted technique driven by in-situ generated oxyhydrogen.

We present a novel method for shockwave-assisted bacterial transformation using a miniature oxyhydrogen detonation-driven shock tube. We have obtained transformation efficiencies of about 1.28 × 106, 1.7 × 106, 5 × 106, 1 × 105, 1 × 105 and 2 × 105 transformants/µg of DNA for Escherichia coli, Salmonella Typhimurum, Pseudomonas aeruginosa, Mycobacterium smegmatis, Mycobacterium tuberculosis (Mtb) and Helicobacter pylori respectively using this method which are significantly higher than those obtained using conventional methods. Mtb is the most difficult bacteria to be transformed and hence their genetic modification is hampered due to their poor transformation efficiency. Experimental results show that longer steady time duration of the shockwave results in higher transformation efficiencies. Measurements of Young's modulus and rigidity of cell wall give a good understanding of the transformation mechanism and these results have been validated computationally. We describe the development of a novel shockwave device for efficient bacterial transformation in complex bacteria along with experimental evidence for understanding the transformation mechanism.

Successful treatment of biofilm infections using shock waves combined with antibiotic therapy.

Many bacteria secrete a highly hydrated framework of extracellular polymer matrix on suitable substrates and embed within the matrix to form a biofilm. Bacterial biofilms are observed on many medical devices, endocarditis, periodontitis and lung infections in cystic fibrosis patients. Bacteria in biofilm are protected from antibiotics and >1,000 times of the minimum inhibitory concentration may be required to treat biofilm infections. Here, we demonstrated that shock waves could be used to remove Salmonella, Pseudomonas and Staphylococcus biofilms in urinary catheters. The studies were extended to a Pseudomonas chronic pneumonia lung infection and Staphylococcus skin suture infection model in mice. The biofilm infections in mice, treated with shock waves became susceptible to antibiotics, unlike untreated biofilms. Mice exposed to shock waves responded to ciprofloxacin treatment, while ciprofloxacin alone was ineffective in treating the infection. These results demonstrate for the first time that, shock waves, combined with antibiotic treatment can be used to treat biofilm infection on medical devices as well as in situ infections.