Methods and compositions for wound healing
Inventors
Agarwal, Ankit • Pranami, Gaurav • Nelson, Tyler B. • O'Keefe, Anna M. • Abbott, Nicholas L. • Crawford, Eric
Assignees
Publication Number
US-11554194-B2
Publication Date
2023-01-17
Expiration Date
2037-07-28
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Abstract
The present invention relates to large scale manufacture of nanoscale microsheets for use in applications such as wound healing or modification of a biological or medical surface.
Core Innovation
The invention relates to methods and compositions for the large scale manufacture of nanoscale polymeric microsheets intended for applications such as wound healing and modification of biological or medical surfaces. These microsheets comprise nanometer to micrometer scale polymer layers deposited on flexible substrates with low surface energy surfaces, enabling them to be peeled as free-standing films. The invention provides continuous roll-to-roll processes to deposit these nanoscale polymer multilayers, which include alternating layers of positively and negatively charged polyelectrolytes, on substrates having a surface area greater than 0.52 square meters.
The primary problem addressed by the invention is the lack of previously described large-scale, efficient manufacturing methods for producing molecularly thin polymeric sheets containing bioactive agents. Prior approaches relied on small-scale batch production methods that are slow, inefficient in reagent use, and limited to producing microsheets with relatively small surface areas. The invention solves this problem by using flexible polymeric sheets with low surface energy surfaces and roll-to-roll coating processes, which allow for the generation of defect-free, molecularly thin polymeric sheets suitable for wound healing and biological surface modification at large scale.
Claims Coverage
The claims disclose a process for manufacturing nanoscale polymer multilayer articles involving flexible substrates with specific release coatings, coating methods, bioactive agent incorporation, and characteristics of the resulting microsheets. There are multiple inventive features outlining the materials, methods, and compositions employed.
Process for continuous roll-to-roll deposition of nanoscale polymer multilayers on flexible substrates
The process includes providing a flexible substrate with a release coated surface selected from specified coatings such as silicone, PDMS, fluorocarbon, polyacrylate, polystyrene, polystyreneacrylic, chromium sterate complex, or polyolefin. The process continuously deposits a nanoscale polymer multilayer (0.5 to 10000 nm thick) with alternating layers of at least one positively charged polyelectrolyte and one negatively charged polyelectrolyte while transferring the substrate between rolls, followed by peeling the nanoscale polymer layer associated with a second polymer layer to provide a free-standing microsheet with surface area greater than 0.1 square meters.
Selection of polyelectrolytes for polymer multilayers
At least one positively charged polyelectrolyte is selected from poly(allylamine hydrochloride), polyl-lysine, poly(ethylene imine), poly(histidine), poly(N,N-dimethyl aminoacrylate), poly(N,N,N-trimethylaminoacrylate chloride), poly(methyacrylamidopropyltrimethyl ammonium chloride), and chitosan. At least one negatively charged polyelectrolyte is selected from poly(acrylic acid), poly(styrenesulfonate), alginate, hyaluronic acid, heparin, heparan sulfate, chondroitin sulfate, dextran sulfate, poly(methacrylic acid), oxidized cellulose, carboxymethyl cellulose, polyaspartic acid, and polyglutamic acid.
Control of molecular weight and solution conditions of polyelectrolytes
The polyelectrolytes exhibit unimodal or multimodal molecular weight distributions within 1 to 10000 kDa and are provided in aqueous solutions at concentrations from 1 to 10000 mM based on polymer repeat unit. The pH of the solutions is adjusted so that polymers are at least 0.01% charged, and inorganic or organic salts may be included in concentrations from 1 to 10000 mM.
Incorporation of bioactive agents into nanoscale polymer layers
Bioactive agents including antimicrobial agents, antibiofilm agents, growth factors, hemostatic agents, bioactive peptides/polypeptides, analgesics, local anesthetics, opioids, opioid agonists/antagonists, anticoagulants, anti-inflammatory agents, and drug compounds are introduced into the nanoscale polymer layer to form a bioactive nanoscale polymer layer. The antimicrobial agents may include silver ions, salts, or nanoparticles; antibiofilm agents may include gallium ion, salts, nanoparticles, alloys of gallium, or alloys of gallium and silver.
Method for silver nanoparticle formation within polymer multilayers
Silver ions are introduced into the nanoscale polymer multilayer by immersion in silver nitrate solutions (concentrations 0.1 to 10000 mM for 1 to 3600 seconds) followed by in situ reduction of silver ions using reducing agents such as sodium borohydride (concentrations from 0.1 to 10000 mM for 1 to 3600 seconds) to form silver nanoparticles.
Use of second polymer layers to modulate bioactive agent release
The second polymer layer, which may include polyvinyl alcohol, polyacrylic acid, polyvinylpyrrolidone, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, hydroxyethyl cellulose, alginates, polyvinylacetate, polylactic acid, polylactic-co-glycolic acid, polyglycolic acid, or polyanhydrides, slows the release rate of bioactive agents from the nanoscale polymer layer by 1 to 1000 times. This layer may be ionically, physically, or chemically crosslinked, and have thickness from approximately 0.1 μm to 100 μm.
Loading concentrations and combinations of bioactive agents
Bioactive agents are loaded at concentrations approximately 0.01 to 1000 μg/cm2 in the nanoscale polymer layer and from 0.01 μg/cm2 to 10 mg/cm2 in the second polymer layer. Multiple bioactive agents may be included in the combined nanoscale and second polymer layers for enhanced therapeutic benefit.
Variety of flexible substrates and additives in second polymer layers
Flexible substrates can comprise polymer films from polyester, polyethylene terephthalate, polycarbonate, polyethylene variants, polyvinyl chloride, polyvinylidene chloride, polyvinylidene fluoride, nylon, polystyrene, acetate, polyurethane, ethylene vinyl acetate copolymer, cast polypropylene, uniaxially or biaxially oriented polypropylene films. Second polymer layers may include additives such as surfactants, emulsifiers, wetting agents, rheology modifiers, plasticizers, emollients, humectants, disintegrants, lubricants, binders, compatibilizing agents, antistatic agents, and fillers.
The claims collectively cover a novel continuous manufacturing process using flexible substrates with low surface energy release coatings for forming free-standing nanoscale polymer multilayers with incorporated bioactive agents. The inventive features include selection and processing of polyelectrolytes, methods for bioactive agent incorporation such as silver nanoparticle formation, use of second polymer layers to control release, and broad substrate and additive options for producing therapeutic microsheets suitable for applications like wound healing.
Stated Advantages
Enables large scale, continuous manufacturing of nanoscale polymeric microsheets, overcoming limitations of small-scale, batch processes.
Efficient use of reagents and scalable production of defect-free thin polymer layers with large surface areas.
Customization of bioactive agent incorporation and controlled release profiles via multilayer assembly and second polymer layers.
Facilitates production of free-standing, transferable polymeric films suitable for wound healing and biological surface modification.
Documented Applications
Use of nanoscale polymeric microsheets for wound healing applications, including promoting granulation tissue formation, epithelialization, and reducing infection risk.
Modification of biological or medical surfaces, such as wound dressings, biologic wound dressings, surgical meshes, and other medical devices.
Incorporation of bioactive agents such as antimicrobial agents (silver, gallium), analgesics, growth factors, and anti-inflammatory agents for targeted therapeutic delivery.
Modification of commercially available wound dressings and biologic wound dressings by application of polymer multilayer microsheets to improve healing outcomes.
Use in biocompatible films for controlled drug delivery to wounds, internal tissues, corneas, lenses, bones, tendons, and surgical mesh surfaces.
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