Wound healing device

Abstract

A plasma coating device for treating a wound comprises a plasma chamber having: one or more electrodes, a gas supply inlet, a plasma outlet exposed to ambient pressure, and an ignition system operatively connected to the electrodes for providing a non-thermal equilibrium plasma within the plasma chamber. An aerosol delivery system is operable to introduce a bioresorbable material as an aerosol into the plasma, to produce a coating on the wound surface.

Claims

1. A method for treating a patient, the method comprising: generating a non-thermal equilibrium plasma at a frequency between 100 kHz and 500 kHz via an electrode housed in a plasma chamber with a wall opposite an outlet exposed to ambient pressure, wherein the electrode extends through a first lumen parallel to a second lumen, wherein the wall defines an opening of the first lumen adjacent to an opening of the second lumen; introducing an aerosol comprising a bioresorbable material through the opening of the second lumen into the plasma chamber and the non-thermal equilibrium plasma through the distal opening of the second lumen; and contacting tissue of the patient with reactive species emanating from the plasma and with the aerosol downstream of the outlet to form a coating on the tissue, wherein the coating is bioresorbable.

2. The method of claim 1, wherein a distal tip of the electrode is proximate the wall of the plasma chamber opposite the outlet.

3. The method of claim 1, wherein the plasma is pulsed.

4. The method of claim 1, wherein the tissue is part of a wound, and contacting the tissue with the plasma sterilizes and coagulates the wound.

5. The method of claim 1, wherein the aerosol is generated from a liquid by a nebulizer, the bioresorbable material being dissolved or dispersed in the liquid.

6. The method of claim 1, wherein the bioresorbable material comprises a protein, a nucleic acid, a lipid, a drug, a polysaccharide, a biopolymer, a biodegradable polymer, a cell, or a combination thereof.

7. The method of claim 1, wherein the bioresorbable material comprises collagen, fibrin, fibronectin, chitin, hyaluronan, chitosan, alginate, cellulose, or a combination thereof.

8. The method of claim 1, wherein the bioresorbable material comprises blood plasma or a blood platelet.

9. The method of claim 1, wherein the bioresorbable material in the coating is biologically active.

10. The method of claim 1, wherein the bioresorbable material comprises: a. a biopolymer, a biodegradable polymer, a protein, or a combination thereof; and b. an antimicrobial, an analgesic, a vasoconstrictor, or a combination thereof.

11. A method for treating a patient, the method comprising: generating a non-thermal equilibrium plasma at a frequency between 100 kHz and 500 kHz via an electrode housed in a plasma chamber with a wall opposite an outlet exposed to ambient pressure, the wall defining a first opening containing a distal tip of the electrode and a second opening adjacent to the first opening, wherein the electrode extends through a first lumen parallel to a second lumen, the first lumen terminating at the first opening and the second lumen terminating at the second opening; introducing an aerosol comprising a bioresorbable material through the second opening into the plasma chamber and the non-thermal equilibrium plasma, such that the bioresorbable material contacts the non-thermal plasma within the plasma chamber and exits the plasma chamber with the non-thermal equilibrium plasma; and forming a coating comprising the bioresorbable material on tissue of the patient by directly contacting the tissue with the plasma and the aerosol downstream of the plasma chamber, wherein the tissue is part of a wound, wherein the coating is bioresorbable, and wherein the bioresorbable material in the coating is biologically-active.

12. The method of claim 11, wherein the coating seals the wound.

13. The method of claim 11, wherein the bioresorbable material in the coating is cross-linked.

14. The method of claim 11, wherein the plasma is pulsed.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) Embodiments of the invention will now be described, by way of example, with reference to the accompanying drawing, in which:

(2) FIG. 1 is a schematic view of a plasma device in accordance with an embodiment of the present invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

(3) Referring now to FIG. 1, there is shown a schematic view of a plasma device according to an embodiment of the invention. The device includes a plasma chamber 1 including a metal electrode 6 to which a high voltage power supply/ignition system 2 is operatively connected. The chamber 1 further includes a gas inlet port 3 through which a supply of gas, for example, helium, argon or nitrogen or mixtures thereof is fed in operation of the device and which in combination with the ignition system causes a plasma to be struck and to stream from an outlet 8 of the plasma chamber. In the illustrated embodiment, a liquid delivery system 4 is operatively connected to an inlet of the plasma chamber and an internal nebuliser 5 causes the supplied liquid to be sprayed 7 into the chamber 1 as an aerosol. In alternative embodiments, not shown, an external nebuliser feeds the aerosol to a region outside the plasma chamber where it interacts with the reactive species emanating from the outlet 8 of the plasma chamber before coating a wound over which the plasma device is being passed.

(4) In embodiments of the present invention, the plasma device initially sterilises and coagulates the wound. Then, by providing an aerosol from the supply 4 containing a bioresorbable material which may also contain an active agent, and introducing that aerosol into a plasma chamber 1, or into the reactive species that exist downstream of the plasma chamber 1, the device produces a coating on the wound. If required, the sterilisation, coagulation and coating deposition can occur simultaneously. Deposition of such a coating enables the continuous interaction of the pro-healing materials with the wound and provides for enhanced wound healing. Furthermore, the coating seals the wound and limits the opportunity for further bacteria to infect the wound site.

(5) The term wound can be taken to encompass all forms of damage to the skin or body including burns, cuts, tears, piercings, contusions, abrasions, lacerations, punctures, gun shots or other forms of injury to the body. It may also encompass infections or chronic wounds such as ulcers.

(6) The invention described herein allows the introduction of bioresorbable material including: proteins such as collagen, fibrin or fibronecin; biopolymers such as hyaluronan, chitosan, alginates and cellulose; and also biodegradable synthetic polymers such as PLGA which do not form using the same vinyl polymerisation reactions favoured by conventional plasma reactions onto a wound site. The plasma may cross-link these materials to produce a dry coating, but the degree of cross-linking is limited and is not sufficient to alter the functionality of the deposited material.

(7) Embodiments of the present invention employ non-thermal plasma devices where the plasma operates close to room temperature thus allowing the processing of temperature sensitive materials, without imposing a damaging thermal burden onto the material. Nonetheless, the hot electrons of the plasma create, through high-energy collisions, a rich source of radicals and excited species with a high chemical potential energy capable of chemical and physical reactivity. Non-thermal equilibrium plasmas can be created at ambient pressure and have been reviewed extensively by Roth (Roth J. R., Industrial Plasma Engineering, Volume 2 Applications to Non-thermal Plasma Processing, Institute of Physics Publishing, 2001, pages 37-73). Such plasmas include dielectric barrier discharges. Another non-thermal equilibrium plasma is the Atmospheric pressure glow discharge (APGD) as described by Okazaki et al (J. Phys. D: Appl. Phys., 26, 889-892 (1993)). These APGD plasmas have been described extensively by Roth as One Atmosphere Uniform Glow Discharge Plasmas (OUAGDP) and are found to operate from 0.5 to 40 kHz. Corona plasma devices can also operate in non-thermal equilibrium mode. Various plasma jets are also capable of operating in a cold or non-thermal equilibrium mode.

(8) Embodiments of the present invention employ plasma devices operating at frequencies above 100 kHz, which is beyond the sensory threshold of a patient's nervous system. For optimum control, the plasma is operated below 500 kHz and may be pulsed on and off in a controlled fashion to minimise the energy delivered to the aerosol and patient. This enables controlled plasma reactions that preserve precursor functionality and do not damage or fragment sensitive active species.

(9) Alternatively, the plasma can be contained between two electrodes, with a grounded electrode separating the person or object to be treated from the plasma, such that no significant voltage is applied to any object or person placed downstream of the device. This can be accomplished using a plasma device such as described by Ladwig et al (Surface & Coatings Technology 201 (2007) 6460-6464). Use of such a plasma device would allow the plasma to operate at frequencies below 100 kHz.

(10) The plasma parameters (electrode design, frequency, voltage, gas composition, etc.) can be chosen to control the plasma process and ensure that the plasma operates in a non-thermal manner to produce a low-temperature plasma, which does not adversely affect temperature sensitive materials which are being deposited.

(11) Furthermore, the precursor can be introduced downstream of the plasma chamber outlet to minimise damage to the coating forming materials. This allows coatings containing materials sensitive to temperature, ions, free radicals and other active species present in the plasma to be deposited where they would otherwise be damaged if introduced directly into the plasma chamber.

(12) Various active compounds can be incorporated into the coating produced by this device. These can include anti-cancer drugs, anti-inflammatory drugs, immuno-suppressants, antibiotics, antimicrobials, heparin, a functional protein, a regulatory protein, structural proteins, oligo-peptides, antigenic peptides, nucleic acids, immunogens, glycosaminoglycans and combinations thereof.

(13) Other active compounds include polypeptides, polyglycans, hormones, lipids, interferons, cartilage, therapeutic biologic agents both cellular and synthetically derived, autologous, homologous and allographic and zenographic biologic agents, autologous or homologous, recombinant and synthetic derived blood cells and products containing antimicrobiallantibiotic agents, bacteriostatic agents, stem cells, stromal cells; fibroblast derived Human Dermal Collagen, matrix proteins, growth factors and cytokines, fibronectin, cells found in loose connective tissue such as endothelial cells, cells found in adipose tissue, macrophages/monocytes, adipocytes, pericytes, reticular cells found in bone marrow stroma and cultured autologous keratinocytes.

(14) In a preferred application, the wound is coated with a layer of either coagulated blood or blood extracts. The coating is produced by nebulising a supply of blood, or blood constituents, into the plasma chamber or into the species exiting from the plasma chamber. This offers a route to producing thin films, which are highly biocompatible and already contain the necessary factors (fibrin, cytokines, etc.) necessary to seal the wound and to induce wound healing.

(15) Nonetheless, the nature of the deposited layer may be varied dependent on factors including: the underlying cause of the wound, the characteristics of the wound, the stage of wound healing, the particular patient needs and risk factors, availability of autologous materials.

(16) Thus, different depositions can be used depending on whether wound healing is at the haemostasis, inflammation, proliferation/granulation or maturation/remodelling phase. Examples of materials for the various phases of wound healing include:

(17) 1. Fresh trauma/burns: Sealicontain wound with a temporary resorbable material containing appropriate active agents including, for example, antimicrobials, analgesics, vasoconstrictors in order to contain the wound while minimising dehydration/shock, pain, blood loss, risk of infection/contamination, further tissue loss, etc and initiating haemostasis.

(18) 2. Haemostasis stage: A resorbable material such as blood plasma or platelets including active agent(s) such as, vasoconstrictors, adenosine diphosphate (ADP), thrombin, fibrinogen/fibrin, cytokines (PDGF), chemotactic factors, chemocines or coagulation factors.

(19) 3. Inflammation stage: A resorbable material such as blood plasma including, for example, neutrophils, monocytes, phagocytes, mast cells, proteolytic enzymes, leukocytes.

(20) 4. Proliferation/granulation stage: A resorbable material including for: a. Granulationmacrophages. Fibroblastic Growth Factor (FGF), Epidermal Growth Factor (EGF), transforming growth factor beta (TGF-beta), Extra cellular matrix (ECM), fibroblasts, myofibroblasts b. Contracturefibroblasts, collagen, endothelial cells, keratinocytes, angiocytes, neurocytes, c. Epithelisationgrowth factors, fibrin, collagen, and fibronectin

(21) 5. Maturation/remodeling: Type I collagen.

(22) 6. Enhanced/accelerated wound healing or for large wound and burn injuries or chronic non-healing ulcers: Cytokines and growth factors

(23) Other applications including cornea regeneration using cytokines following abrasion or cataract treatment.

(24) All variants may also provide the following: A moisture retaining occlusive barrier and high humidity at the wound surface; Gaseous exchange; Thermal insulation; and Protection against secondary infection

Examples

(25) 1. Deposition of Blood Plasma Coating

(26) A biocompatible coating was deposited on to a glass slide using a non-thermal plasma discharge and blood plasma as the precursor. The plasma discharge was created by applying an alternating voltage to a corona needle electrode assembly within a dielectric housing. The voltage was applied at a frequency of 100 kHz from a Redline G2000 high voltage power supply. Helium was used as a ballast gas at a flow rate of 14 litres/minute. (It will be appreciated that other gases including argon or nitrogen or mixtures thereof could also be used.) The blood plasma extract was nebulised into the plasma using a Burgener pneumatic nebuliser (Burgener Research, Canada) at a flow rate of 51 microlitres/min. The input power was applied using a 45% duty cycle (ratio of time on to time off) and a selected input power on the power supply of 107 V. This corresponded to an actual applied voltage of 12.7 kV (pk-pk) applied to the electrodes. The substrate was a glass slide placed approximately 5 mm downstream of the plasma exit.

(27) The blood plasma was sprayed through the plasma and landed upon the glass slide, where it coagulated instantly to form a coating. After deposition, the coating was inspected at a magnification of 40 times and the viable cell numbers were counted. Prior to being exposed to the electrical discharge, cell viability was estimated to be 90%. After undergoing nebulisation and plasma coagulation, over 70% of the cells were still deemed viable, indicating that biological materials have been successfully deposited intact and capable of participating in a biological healing process.

(28) 2. Deposition of a Biopolymer (Chitosan)

(29) Chitson is known to have antimicrobial properties and is also a common scaffold material used in regenerative medicine. Water-soluble chitosan was dissolved in deionised water to give a concentration of 20 mg/ml. This liquid was introduced at 50 L/min into the equipment described in Example 1 and coatings were deposited onto glass slides. Coatings were deposited at a power input setting of 170V and 150 kHz and for times of 45 seconds, 1 minute and 3 minutes. In each case, a clear coating was detected on the surface of the glass slide. This coating was not removed by wiping with a tissue, indicating that the coating was dry, cured and adherent.

(30) 3. Deposition of a Protein Solution (Collagen) at Low Frequency

(31) Collagen is a known aid in wound healing process and is a key component of skin. A plasma device comprising a needle corona electrode powered by a 100 W Plasma Technics Inc power supply operating at c. 20 kHz was provided. Helium was introduced to the system at a rate of 8 litres/minute. An acidified solution of collagen (3.8 mgiml) was nebulised into the resultant discharge at a flow rate of 50 L/min and coatings were deposited onto glass slides for 1-2 minutes. All deposits were found to be coherent, dry and adhered well to the substrate, indicating that a cured coating had been formed.

(32) 4. Deposition of a Protein Solution (Collagen) at High Frequency

(33) A solution of collagen (1 mg/ml) was introduced into the equipment described in Example 1. The plasma was operated at 115V input power, 148 kHz and a duty cycle of 44%. Helium was introduced at a rate of 5 litres/min. The collagen solution was introduced at a rate of 50 pLimin and a coating was deposited onto polished Si wafers for either one minute or two minutes. Ellipsometry detected a coating with a thickness of 50 nm for the one minute sample and 140 nm for the two minute sample, confirming that a coating had been deposited.