Nanoscale Particle Therapies for Wounds and Ulcers

Roberta Cortivo; Vincenzo Vindigni; Laura Iacobellis; Giovanni Abatangelo; Paolo Pinton; Barbara Zavan

Nanomedicine. 2010;5(4):641-656.

Conclusion & Future Perspective

Recently, tremendous progress has been made in discovering the cellular and molecular mechanisms underlying the wound healing process. An efficient and complete process of wound healing is critical for the general wellbeing of any patient. Traditional clinical treatments of wounds/ulcers are still relevant, but more overlap between novel highly technological approaches, incorporating knowledge on cellular and subcellular events occurring during the normal healing process, could markedly improve future therapeutic interventions.

Nanotechnology offers great opportunity in improving wound healing treatments. The nanometer scale opens the way for the development of novel materials for use in highly advanced medical technology. Future developments indeed depend on the identification of clinically relevant targets and on raising targeting efficiency of the multifunctional nanocarriers. As researchers develop the ever-expanding body of nanoparticles for use as drug- or gene-delivery vehicles, there is a growing need to understand how a given nanoparticle's physical and chemical properties affect biological activity and toxicity. Despite the many advantages given by their size (i.e., they can easily pass through the skin barrier), some unpredictable events could occur as well. For example, nanoparticles may interfere with some functions of proteins on the surface of cells, or be taken up into cells and bind to intracellular molecules.

Furthermore, as of today, there is no specific European, American or international standard on the toxicology and biocompatibility of nanoparticles. Thus, while these products are already in use, further research on these medical devices and development of standards on biocompatibility must be extended to the applied science of nanotechnology.

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Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.

Cite this: Nanoscale Particle Therapies for Wounds and Ulcers - Medscape - Jun 01, 2010.

Sidebar

Executive Summary

Inflammation

Skin damage
- Increasing life time of the fibrin clot: one of the first products of the hemostatic response is thrombin, which is responsible for the aggregation of blood platelets in the formation of the 'platelet plug' and for increasing vascular permeability, allowing cells and fluid to enter the wounded tissue. In human plasma, the half-life of thrombin is shorter than 15. In order to provide drugs with long-term protection it has been suggested that therapeutic drugs be conjugated to nanoparticles, thereby enhancing their effectiveness. In the Ziv-Polat laboratory, they have conjugated thrombin to maghemite (g-Fe₂ -O₃) nanoparticles (iron oxide nanoparticles) for the treatment of incisional wounds on rat skin.
- Bacterial infection and sepsis: the presence of bacteria in the healing bed exaggerates the tissue-damaging processes.
- Nanoparticles bearing antibiotics against methicillin-resistant Staphylococcus aureus ( MRSA): one of the most common human pathogens commonly found in skin abrasions and open wounds is represented by MRSA, an opportunistic microbe. Several nanoparticles bearing vancomycin or N -methylthiolated β-lactams against MRSA have been developed to this regard.
- Silver-based nanoparticles: silver shows multilevel antibacterial effects on cells that considerably reduce the chances of developing resistance. Jain et al. synthesized silver nanoparticles by a proprietary process that involves photoassisted reduction of Ag⁺ to metallic nanoparticles and their biostabilization. Using silver nanoparticles in an in vivo model, Tian et al. confirmed that silver promotes wound healing by decreasing inflammation through cytokine modulation.
- Nitric oxide (NO)-delivering nanoparticles: NO, a reactive free radical produced by inflammatory cells, possess broad-spectrum antibacterial properties against both Gram-positive and Gram-negative bacteria. Small molecules of NO donor based on several materials (e.g., silica) shows speed healing by killing bacteria and overcoming the general NO deficiency.
Gastrointestinal ulcers
- Bacterial infection: Helicobacter pylori is the major cause of gastrointestinal infection. In this view, Ramteke et al. prepared clarithromycin- and omeprazole-containing gliadin nanoparticles; polystyrene nanoparticles have been instead employed by Hasani et al. for a detailed analysis of their ability to adhere on the ulcerate tissue of the stomach. A complete study of drug release and attachment behavior of nanoparticles has been performed by Lin et al. in which pH-responsive chitosan/heparin nanoparticles for stomach-specific anti- H. pylori therapy have been developed and characterized.

Proliferation

Growth factors: the aim of growth factors is to attract cells into the wound and to promote cell migration into the wound area, stimulate the growth of epithelial cells and fibroblasts, start the formation of new blood vessels, and have a profound influence on the matrix formation and remodeling of the scars. One way of enhancing the in vivo efficacy of growth factors is to facilitate the sustained release of bioactive molecules by their incorporation into polymer nanocarriers. Hyaluronan/gelatin/poly( D , L -lactic-co-glycolic) acid (PLGA) nanoparticles embedded with different growth factors have been successfully applied on skin wounds.
Opioids: recently it has been showed that opioids enhance the wound healing process by improving keratinocyte migration. Wolf et al., using solid lipid nanoparticles and a dentritic core-multishell nanotransporter both embedded with several opioids, confirmed the influence of these drugs on keratinocyte migration and local tolerability.

Remodeling

The last step of normal acute wound healing is remodeling, during which the extracellular matrix components will be modified by the balanced mechanisms of proteolysis and new matrix secretion, and during which the wound becomes gradually less vascularized.
- Gene therapy: nonviral polymeric gene delivery systems offer increased protection from nuclease degradation, enhanced plasmid DNA uptake and controlled dosing to sustain the duration of plasmid DNA administration. Such gene-delivery systems can be formulated from biocompatible and biodegradable polymers, such as PLGA, polysaccharides and chitosan.
- Stem cells: stem cells hold great potential as cell-based therapies to promote vascularization and tissue regeneration. Nonviral, biodegradable polymeric nanoparticles were developed by Yang et al. to deliver the hVEGF gene to human mesenchymal stem cells and human embryonic stem cell-derived cells, confirming the engraftment of the graft tissue.

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