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Biocomposites with Bacteriophages

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Bacteriophages Containing Drug Sustained/Controlled Release Type Polymeric Composites – New Effective Preparations for the Treatment of Infected Wounds and Cavites

Tech Area / Field

  • CHE-POL/Polymer Chemistry/Chemistry
  • BIO-MIB/Microbiology/Biotechnology
  • MED-OTH/Other/Medicine

Status
8 Project completed

Registration date
27.12.1999

Completion date
01.04.2005

Senior Project Manager
Zalouzhny A A

Leading Institute
Georgian Technical University / Research Center for Medical Polymers and Biomaterials, Georgia, Tbilisi

Collaborators

  • Cornell University, USA, NY, Ithaca\nUniversity of Maryland / School of Medicine, USA, MD, Baltimore

Project summary

The aim of the project is to create the technology for obtaining a new generation of biocomposite materials based on original biodegradeble poly(ester amide)s as a matrix, and using bacteriophages as an bactericidal substance, acting in drug sustained/controlled release fashion, capable to promote tissue regeneration, having an accelerated wound healing potential, and effective against emerging bacterial pathogens resistant to “standard” antibiotic therapy.

Biocomposites, acting in drug sustained/controlled release fashion, turned out especially efficacious for healing infected wounds and cavities. Film materials (so called “Artificial skin”), prepared from these biocomposites, possess high therapeutic effect which consists of:


— Polymer material acts as a protector from external action and bacterial invasion, as well as prevents warmth and moisture loss that would happen because of uncontrolled evaporation from injured surface, especially at superficial damages of skin;
— High and constant local concentration (at low integral doses) of active substances and rather deep penetration into surrounding tissues;

Apart from high curing effect, application of biocomposite “artificial skin” in many cases does not require stationary regime enabling patient to maintain active mode of life, reduces healing terms of the wound and minimizes quantity of dressing changes. All of these factors cut down necessary expenses for treatment, i.e. result in considerable economical effect.

The important thing for proper and effective functioning of biocomposites is selection of polymer matrix. Based on published material we can consider that the best matrix for creating biocomposites, acting in drug sustained/controlled release fashion is biodegradable (more accurately, bioerodable) polymers. Such polymers tend to be exposed to the erosion with controllable and permanent rate and release of active substances into surrounding tissues is ensured. The absence of toxic fragments of polymers is also important to mention.

Scientific team, headed by Prof. R.Katsarava has more than 20 years research expertise and experience in the chemical synthesis and study of new macromolecular systems composed of naturally occurring a-amino acids and by other non-toxic building blocks. It was revealed by this team, that these polymers practically are ideal for the matrix for obtaining biocomposites, acting in drug sustained/controlled release fashion.

The main task during treatment of infected wounds is to suppress local bacterial flora. Utilizing biocomposite materials, this can be achieved by introducing in the biocomposition structure bactericidal substances, mostly antibiotics. Though, in the case of pathogenic microorganisms, which are sensitive to antibiotics, antibiotics penetrate very poorly into such wounds, making eradication of infection extremely difficult. Problem is aggravated when wounds are infected by one or more generation of new, antibiotic-resistant bacteria. That’s why, recently, in biocomposites such bactericidal substances as silver sulfadiazine, furagin and chlorhexydin are utilized. All of them are enough toxic and in some cases characterized by contra-indications (such as diabetes, liver and kidney diseases - in case when organism is sensitive towards indicated substances) and their utilization somehow limited. That’s why the authors of the project give preference to the bactericides of natural origin – highly specific, so called “kind” viruses – bacteriophages.

For the first time, lysis of microorganisms, occasioned by the viruses were discovered at the beginning of our century. Phages have high capacity for specific bacterial strains, a characteristic, which requires that therapy be carefully targeted (i.e., there is no analogy to the broad-spectrum antibiotics which can “kill anything”). Therefore, phage therapy can be used to lyse specific pathogens without disturbing normal bacterial flora.

Phages, have been convincingly reported by different authors, to be effective in treating skin infections caused by Pseudomonas, Staphylococcus, Klebsiella, Proteus, E. coli and so on. Reported success rates ranged from 75 to 100%, depending on the pathogen. Bacteriophages are produced in different vehicles: liquid preparations (i.e. water solutions) aerosols and creams.

The authors of the present project were the first to obtain bacteriophages as drug devices in the form of polymer biocomposites. A base composition was produced and patented in Georgia as “PhageDerm”. Diversified modifications of “PhageDerm”have been recommended for clinical trials carried out successfully in Georgia for treatment of infected surface or poorly vascularized wounds and gum diseases. At present clinical trial of this material is ongoing in gynecology.

Notwithstanding the achieved success the created products are not optimal since they contain such admixtures as gelatin, saccharose, components of bacterial lysis as well (created during rising of bacteriophages on the expedient bacterio target), which causes immune reactions. At the first stage of creating biocomposites, this was done deliberately because it was impossible to obtain dry, powder like phage preparation necessary for producing biocomposites and show their effectiveness.

The present project is supposed to create biocomposites, free from above mentioned analogical admixtures, on the bases of purification of bacteriophages. Purification works will be conducted together with the U.S. team (University of Maryland), headed by Prof. Glann Morris. This is an area in which the mentioned team has extensive experience. Recently, US staff has been intensively working on the problems on phagotherapy. Prof. G. Morris group has concluded an agreement with the Research Center for Medical Polymers and Biomaterials on cooperation in creating bacteriophage-containing biocomposites, strictly complying with demands of FDA.

The main task of the Georgian team is to elaborate new technology of receiving bacteriophage-containing biocomposites, by application of purified phages. To achieve this goal it is necessary to solve the following tasks:


— Synthesis and selection of biodegraded PEA's with optimal mechanical and biomechanical features;
— Elaboration of the technology of creating biocomposites on the bases of purified bacteriophages, using ultrasonic dispergation;
— Refinement of method of film casting and with solvent recuperation;
— Making perforated large-scale films with the dimensions (to 20-30 cm2) and manufacturing of perforator for this purpose;
— To study in experiments In vitro kinetics of releasing bacteriophages from biocomposites;
— Study the issues related to sterilization and packing of the produced preparations;
— Carry out clinical trials of the preparations, for treatment of surface wounds and ulcers of different etiology in dentistry and gynecology;
— Preparation of biocomposite preparation "IntenstiPhage" for clinical trials.


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The International Science and Technology Center (ISTC) is an intergovernmental organization connecting scientists from Kazakhstan, Armenia, Tajikistan, Kyrgyzstan, and Georgia with their peers and research organizations in the EU, Japan, Republic of Korea, Norway and the United States.

 

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