Abstract
Many chronic wounds exhibit high matrix metalloproteinase (MMP) activity that impedes the normal wound healing process. Intradermal delivery (IDD) of sub-antimicrobial concentrations of doxycycline, as an MMP inhibitor, could target early stages of chronic wound development and inhibit further wound progression. To deliver doxycycline intradermally, the skin barrier must be disrupted. Microneedle rollers offer a minimally invasive technique to penetrate the skin by creating multiple microchannels that act as temporary conduits for drugs to diffuse through. In this study, an innovative and facile approach for delivery of doxycycline across Strat-MTM membrane was investigated using microneedle rollers. The quantity and rate of doxycycline diffusing through the micropores directly correlated with increasing microneedle lengths (250, 500 and 750 μm). Treatment of Strat-MTM with microneedle rollers resulted in a reduction in fibroblast-mediated collagen gel contraction and MMP activity compared with untreated Strat-MTM. Our results show that treatment of an epidermal mimetic with microneedle rollers provides sufficient permeabilization for doxycycline diffusion and inhibition of MMP activity. We conclude that microneedle rollers are a promising, clinically ready tool suitable for delivery of doxycycline intradermally to treat chronic wounds.
Highlights
Doxycycline hyclate is a tetracycline compound that is used as a broad-spectrum antibiotic in the treatment of a wide variety of bacterial infections including Chlamydia trachomatis and gonorrhea (Sloan & Scheinfeld, 2008; Kogawa & Salgado, 2012)
At sub-antimicrobial doses, doxycycline is a broad-spectrum inhibitor of matrix metalloproteinases (MMPs), endogenous enzymes that play an essential role in normal wound healing (Manning et al, 2003)
The recently launched Strat-MTM membrane was used to asses both (i) doxycycline permeation using a Franz diffusion cell system to establish fundamental permeation data under infinite dose conditions and (ii) the biological activity of the diffused drug using a three-dimensional cell-enriched collagen matrix that provided an indication of doxycycline-mediated inhibition of MMP activity
Summary
Doxycycline hyclate is a tetracycline compound that is used as a broad-spectrum antibiotic in the treatment of a wide variety of bacterial infections including Chlamydia trachomatis and gonorrhea (Sloan & Scheinfeld, 2008; Kogawa & Salgado, 2012). At sub-antimicrobial doses, doxycycline is a broad-spectrum inhibitor of matrix metalloproteinases (MMPs), endogenous enzymes that play an essential role in normal wound healing (Manning et al, 2003). Doxycycline has been experimentally shown to reduce tissue degradation (Bildt et al, 2009; Li et al, 2013) and its activity as an MMP inhibitor makes it attractive as a potential treatment for chronic wounds (Naidoo et al, 2009; Stechmiller et al, 2010). Doxycycline’s inhibitory activity extends to TNFa-converting enzyme (TACE), a molecule that causes release of tumor necrosis factor-alpha (TNFa), which is an important inflammatory mediator known to impair wound healing (Stechmiller et al, 2010)
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