Wound healing and hyper-hydration - a counter intuitive model

Winters seminal work in the 1960s relating to providing an optimal level of moisture to aid wound healing (granulation and re-epithelialisation) has been the single most effective advance in wound care over many decades. As such the development of advanced wound dressings that manage the fluidic wound environment have provided significant benefits in terms of healing to both patient and clinician. Although moist wound healing provides the guiding management principle confusion may arise between what is deemed to be an adequate level of tissue hydration and the risk of developing maceration. In addition, the counter-intuitive model ‘hyper-hydration’ of tissue appears to frustrate the moist wound healing approach and advocate a course of intervention whereby tissue is hydrated beyond what is a normally acceptable therapeutic level. This paper discusses tissue hydration, the cause and effect of maceration and distinguishes these from hyper-hydration of tissue. The rationale is to provide the clinician with a knowledge base that allows optimisation of treatment and outcomes and explains the reasoning behind wound healing using hyper-hydration

Nano-Layered Microneedles for Transcutaneous Delivery of Polymer Nanoparticles and Plasmid DNA

Multilayer-coated microneedles achieve transcutaneous delivery of plasmid DNA to the viable epidermis. Cy3-labeled plasmid DNA encoding luciferase (yellow) is deposited on biodegradable microneedle arrays through multilayer self-assembly and then delivered to the skin by microneedle application to achieve colocalization with Langerhans dendritic cells (MHC II-GFP–green).United States. Dept. of Defense (DAAD19- 02-D-0002)United States. Dept. of Defense (W911NF-07-D-0004)Ragon Institute of MGH, MIT and HarvardNational Institutes of Health (U.S.) (NIH Biotechnology Training Program at MIT)Howard Hughes Medical Institute (Investigator

In vivo optical monitoring of transcutaneous delivery of calcium carbonate microcontainers

We have developed a method for delivery of biocompatible CaCO3 microcontainers (4.0 ± 0.8 µm) containing Fe3O4 nanoparticles (14 ± 5 nm) into skin in vivo using fractional laser microablation (FLMA) provided by a pulsed Er:YAG laser system. Six laboratory rats have been used for the microcontainer delivery and weekly monitoring implemented using an optical coherence tomography and a standard histological analysis. The use of FLMA allowed for delivery of the microcontainers to the depth about 300 μm and creation of a depot in dermis. On the seventh day we have observed the dissolving of the microcontainers and the release of nanoparticles into dermis

Role of transdermal potential difference during intophoretic drug delivery.

Potential differences have been measured during transdermal iontophoresis in order to establish the effect of voltage, as opposed to current, on cutaneous blood flow. It is known that, even in the absence of drugs, the iontophoresis current can sometimes produce increased blood flow. The role of voltage in this process is studied through single-ended measurements (between electrode and body) of the potential difference during iontophoresis with 100-/spl mu/A, 20-s current pulses through deionized water, saturated 20.4% NaCl solution, 1 % acetylcholine, and 1 % sodium nitroprusside. It is found that the voltage needed to deliver the current varied by orders of magnitudes less than the differences in the conductance of these different electrolytes, and it is concluded that, at least for the present current protocol, the voltage as such is not an important factor in increasing the blood flow

Composite Dissolving Microneedles for Coordinated Control of Antigen and Adjuvant Delivery Kinetics in Transcutaneous Vaccination

Transcutaneous administration has the potential to improve therapeutics delivery, providing an approach that is safer and more convenient than traditional alternatives, while offering the opportunity for improved therapeutic efficacy through sustained/controlled drug release. To this end, a microneedle materials platform is demonstrated for rapid implantation of controlled-release polymer depots into the cutaneous tissue. Arrays of microneedles composed of drug-loaded poly(lactide-co-glycolide) (PLGA) microparticles or solid PLGA tips are prepared with a supporting and rapidly water-soluble poly(acrylic acid) (PAA) matrix. Upon application of microneedle patches to the skin of mice, the microneedles perforate the stratum corneum and epidermis. Penetration of the outer skin layers is followed by rapid dissolution of the PAA binder on contact with the interstitial fluid of the epidermis, implanting the microparticles or solid polymer microneedles in the tissue, which are retained following patch removal. These polymer depots remain in the skin for weeks following application and sustain the release of encapsulated cargos for systemic delivery. To show the utility of this approach the ability of these composite microneedle arrays to deliver a subunit vaccine formulation is demonstrated. In comparison to traditional needle-based vaccination, microneedle delivery gives improved cellular immunity and equivalent generation of serum antibodies, suggesting the potential of this approach for vaccine delivery. However, the flexibility of this system should allow for improved therapeutic delivery in a variety of diverse contexts.Massachusetts Institute of Technology. Ragon Institute of MGH, MIT and HarvardNational Institutes of Health (U.S.) (Award AI095109)United States. Army Research Office (Contract W911NF-07-D-0004

Transcutaneous delivery of anti-arthritic agents

There is a substantial clinical need for improved therapeutic systems for the treatment of arthritis. This thesis concerns the development of a novel medication that is applied to the skin directly overlying the areas affected. The system comprises the co-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), plus a non-steroidal anti-inflammatory (NSAID) drug. The source of EPA and DHA is fish oil which contains high proportions of these compounds and, although still largely considered a 'neutraceutical', its therapeutic value is supported by an ever increasing body of evidence, both scientific and anecdotal. The NSAID examined was ketoprofen, a widely used drug, found in a number of topical preparations. Synergistic action involving the two substances would be expected to provide a multi-faceted attack on the aetiology of arthritis. Ketoprofen and EPA/DHA were successfully delivered across full-thickness porcine ear skin in-vitro, although the presence of thickening agent retarded permeation of the latter. The successful delivery of these compounds into the joint capsule of a porcine forelimb was also demonstrated in-vitro. A novel transcutaneous delivery model was developed and used to provide preliminary data for the uptake of EPA into an ex-vivo cartilage ex-plant post transcutaneous permeation. The last three chapters can be considered collectively as an investigation into the unexpected phenomenon of enhancement of EPA/DHA by ketoprofen and two main hypotheses were tested firstly, the formation of a Jt-jc ketoprofen / EPA complex - the existence of which was strongly supported by the NMR/molecular modelling work of Chapter 8 secondly, the ketoprofen inhibition of epidermal enzymes active upon EPA, discussed in Chapters 7 and 9. In summary, the development of a novel dual-action, transcutaneous anti-arthritic formulation is possible and has been supported by this work. Furthermore, a hitherto unknown topical delivery mechanism has been elucidated.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Hydroelectrophoresis for Transdermal Administration of Verapamil or of Hyaluronic Acid in Peyronie's Disease: A Prospective, Open Label, Multicenter Study

Aim & Objective: To assess the efficacy of a new electromotive system for the transcutaneous delivery of verapamil or of hyaluronic acid to improve the symptoms of Peyronie' s disease (PD) in patients with a curvature deformity of < 30° at the beginning of therapy. Methods & Materials: Sixty-one PD patients were studied. Thirty were randomly assigned to receive verapamil 10 mg/session (Isoptin®, BGP Products, Rome-Italy), (Group 1, median age 56 years, range 49-62), and 31 were randomly assigned to receive hyaluronic acid 8 mg/session (Sinovial®, IBSA, Lodi-Italy) (Group 2, median age 58 years, range 51-56). There were ten sessions, 2 sessions/week for each drug. Each drug was transdermally administered using the hydroelectrophoresis technique and carried out using a Hydro4and apparatus (Swiss4Med SA, Morbio Inferiore, Switzerland). With respect to the efficacy of the drugs studied, the endpoints were: side effects, pain, erectile function, penile deviations and plaque area (cm2) before, and 3 and 6 months after drug administration. The differences were assessed using the Mann-Whitney Rank test (unmatched groups) or using the Wilcoxon Signed Rank test (matched groups). The differences between the groups in terms of side effects were assessed using the chi-square test. Results: No significant difference emerged among the baseline values of the two groups. Pain, erectile function, plaque area and penile deformity significantly improved in both groups after treatment, but a notably higher improvement occurred in the patients in whom hyaluronic acid was administered. Only a few negligible side effects occurred in the Group 1 patients treated with Verapamil, with no significant difference between the groups. Conclusion: Administration of both hyaluronic acid and verapamil using the Hydro4and apparatus is a safe and efficient method for PD therapy

Transcutaneous delivery of anti-breast cancer agents

Breast cancer is the most common female malignancy in the western world. Currently, tamoxifen remains the gold standard anti-hormone for ER+ breast cancer. However de novo resistance to tamoxifen is a huge clinical problem. What is more, as many as 50% of initial responders develop acquired resistance to tamoxifen and relapse. Aberrant growth factor signalling has been linked to the resistant phenotype, in particular EGFR and IGF-IR signalling and often gives a more aggressive disease type and poorer patient outlook. There is a substantial clinical need for new anti-breast cancer therapeutics that target the resistant phenotype or prevent this from occurring. One hypothesis is to combine both anti-hormonal therapies with anti-EGFR therapies, in hope of preventing resistant growth. Many downstream pathways of EGFR have been targeted to develop novel therapeutics against however, these compounds are almost certain to give severe adverse reactions, furthermore a complex tablet regime or IV injections have a negative effect on patient compliance. A novel transcutaneous delivery system would give a more patient friendly alternative, with patients re-applying a patch or cream once a day, with rapid termination of dosing in the event of adverse event This would also go some way to prevent endometrial complications associated with tamoxifen use. The in vitro simultaneous delivery of 4-hydroxytamoxifen and signal transduction inhibitors LY294002 and PD98059 along with EPA determined that all compounds were capable of permeating porcine skin and nipple. Masses able to permeate were 5.14 0.93,6.97 0.99, 5.06 0.93 and 1121.6 143 &mu;gcm2 across skin respectively and 21.14 2.75,18.2 2.55,25.1 6.89 and 3081.2 252.7 &mu;gcm2 across porcine nipple. These compounds were formulated with 2.5% v/v DMSO and ethanol and 4% w/v Cab-o-sil. Fish oil was shown to be a skin friendly vehicle. Ki-67 assays confirmed that incubation with fish oil maintained skin viability and H &amp; E staining confirmed no obvious histological effects. Growth Studies were performed on MCF-7 and TamR cells and showed that the combination of these compounds was able to reduce cell growth to 4.04 0.15 and 2.47 1.4 % of control growth when incubated at 25 &mu;M PD98059 &mu;M LY294002 x 107M 4-hydroytamoxifen and 1 &mu;LmL-1 fish oil. This combination of compounds, without 4-hydroxytamoxifen, was able to reduce the migratory capacity of TamR cells (P = < 0.005). Results confirmed that the simultaneous transcutaneous delivery of multiple anti-breast cancer agents is possible and that these show promising anti- tumorogenic actions post skin.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Implantable and transcutaneous photobiomodulation promote neuroregeneration and recovery of lost function after spinal cord injury

Spinal cord injury (SCI) is a cause of profound and irreversible damage, with no effective therapy to promote functional recovery. Photobiomodulation (PBM) may provide a viable therapeutic approach using red or near-infrared light to promote recovery after SCI by mitigating neuroinflammation and preventing neuronal apoptosis. Our current study aimed to optimize PBM dose regimens and develop and validate the efficacy of an invasive PBM delivery paradigm for SCI. Dose optimization studies were performed using a serum withdrawal model of injury in cultures of primary adult rat dorsal root ganglion neurons (DRGN). Implantable and transcutaneous PBM delivery protocols were developed and validated using cadaveric modeling. The efficacy of PBM in promoting recovery after SCI in vivo was studied in a dorsal column crush injury model of SCI in adult rats. Optimal neuroprotection in vitro was achieved between 4 and 22 mW/cm2. 11 mW/cm2 for 1 min per day (0.66 J/cm2) increased cell viability by 45% over 5 days (p &lt;0.0001), increasing neurite outgrowth by 25% (p &lt; 0.01). A method for invasive application of PBM was developed using a diffusion-tipped optogenetics fiber optic. Delivery methods for PBM were developed and validated for both invasive (iPBM) and noninvasive (transcutaneous) (tcPBM) application. iPBM and tcPBM (24 mW/cm2 at spinal cord, 1 min per day (1.44 J/cm2) up to 7 days) increased activation of regeneration-associated protein at 3 days after SCI, increasing GAP43+ axons in DRGN from 18.0% (control) to 41.4% ± 10.5 (iPBM) and 45.8% ± 3.4 (tcPBM) (p &lt; 0.05). This corresponded to significant improvements at 6 weeks post-injury in functional locomotor and sensory function recovery (p &lt; 0.01), axonal regeneration (p &lt; 0.01), and reduced lesion size (p &lt; 0.01). Our results demonstrated that PBM achieved a significant therapeutic benefit after SCI, either using iPBM or tcPBM application and can potentially be developed for clinical use in SCI patients