Patent Application
20220192890
The present invention relates generally to tissue engineering for wound repair and regeneration methods, and more specifically to the use of a multi-solution system containing bioactive factors that, once combined, form a gel or expanding foam that forms a wound liner, a wound filler, or a scaffold or structure between elements to be joined or healed which supports regenerative tissue engineering.
Tissue wound healing involves a complex and intricate set of interrelated, systematic events. The dynamic nature of these cascading events can go awry based on any one of many aberrant processes which can result in failure of proper wound healing and lead to long-term, pathological problems. Failure of wounds to heal properly after trauma, surgery, or acute or chronic diseases affects millions of people every year, with chronic wounds costing patients tens of billions of dollars collectively.
Complex wounds involving tissue loss and/or damage to skin, cartilage, bone, muscle, nerves, or blood vessels often require extensive surgical correction and long-term treatment modalities to attempt to restore normal anatomical structure and function. Full recovery of anatomical homeostasis can be hindered by limitations of the tissue healing process and therapeutic treatments. Complex wounds are more likely to result in chronic non-healing wounds than anatomically simpler wounds, and chronic non-healing wounds have a direct effect on increased morbidity and mortality in patients. Chronic wounds are prone to infection, which may progress to sepsis and death. Even if they heal, the prolonged process can result in disfigurement, loss of function, extensive scarring, and other long term sequalae. Ultimately, lack of proper wound healing in patients can lead to systemic and chronic ailments that reduce tissue structure and function and lead to a decrease in patient quality of life. Wound dressings are often considered the standard of care for many wounds, both acute and chronic, and have evolved over the years to improve patient outcomes.
The prior art includes technologies and methodologies for use of a gelatinous or foam material inserted in or on a wound to promote tissue genesis and improve wound healing, with or without the application of a pressure gradient. Open-cell, reticulated porous foam inserts are commonly used with the application of pressure gradients (i.e. negative/vacuum pressure or positive pressure) as a means to accelerate wound closure and fluid egress for surgical site wound prep, traumatic and acute wounds, ulcerative or chronic wounds, and to improve efficacy of skin grafting procedures. Small cell or closed cell foams, usually used for re-epithelialization of wounds, have also been used with pressure gradients (usually negative pressure).
The use of a porous foam wound insert with a semipermeable adhesive film connected to a vacuum source is often termed negative pressure wound therapy (NPWT). NPWT has demonstrated clinical efficacy by its ability to promote blood flow, improve the removal of fluid and edema, stimulate mechanotransduction signaling and cellular proliferation, stabilize the wound reducing microshear and augment the overall healing process. Such NPWT benefits have improved outcomes for many patients, including those afflicted with chronic and non-healing wounds.
Solution-based systems previously have been used as therapeutic options for wound care. They work by forming a gelatinous dressing or hemostatic agent, such as hydrogel-based dressings or fibrin glue. Hydrogels work by fabricating a hydrated three-dimensional (3D) gel made with biological or polymer-based compounds within a highly saturated substrate. These are often greater than 90% water by weight and can be premade and applied to a wound as a dressing to provide a moist environment and promote wound healing. Hydrogels frequently contain extracellular matrix components such as collagen, fibrin, or hyaluronic acid and are often used in conjunction with another polymer or polysaccharide, such as polyethylene glycol or chitosan, respectively.
Fibrin glue was initially used in clinical practice as a hemostatic agent to seal wounds and prevent exsanguination. More recently fibrin-based glues have been investigated for their ability to deliver bioactive components or stem cells for tissue engineering applications to promote tissue genesis. Hydrogels can be used as standalone wound dressings. Both of these types of agents have demonstrated efficacy in promoting wound healing by stimulating extracellular matrix deposition and angiogenesis.
Closed-wound injuries under intact skin, or internal injuries, include bone fractures and soft tissue ruptures and tears. Conventional therapeutic approaches include reduction, splinting and casting. In cases where aligning fractured bone segments and maintaining reduction are difficult, care providers have employed open reduction and internal fixation (ORIF) procedures. Through an incision, hardware can be applied to or inserted into bony segments to achieve alignment and firm fixation. These include metals in the form of screws, plates (with or without compression), rods, and bone segment replacements or prosthetics, as in the case of fixation of a hip fracture with a new prosthetic femoral head, and these materials include plastics and absorbable materials. However, this form of tissue repair can require surgery, which can further damage tissue. Repairing damaged soft tissue and bone can necessitate the permanent placement of fixation devices, such as screws, anchors and plates, that remain in the body.
Though these prior wound treatments have demonstrated clinical efficacy for many patients, several limitations still remain with NPWT and reticulated open-cell foam (ROCF) dressings. The limitations of NWPT include tissue enmeshing in the ROCF and the lack of ability to effectively tailor a custom foam insert for different shapes and sizes of wounds.
Tissue enmeshing presents a problem with current open-cell foam inserts used for negative pressure therapy because these foams must be removed every 1-3 days, and newly forming tissue grows into the reticulated porous foam, resulting in removal of this tissue during dressing changes. This tissue ingrowth is often attached to, or anchored with, newly formed tissue within the wound bed as well, resulting in removal of newly formed, healthy tissue and irritation of the wound site. This mechanical irritation often results in some form of an inflammatory response. Persistent inflammation is a known cause of chronic non-healing wounds. Thus, repetitive removal of dressings with enmeshed tissue can potentially lead to persistent irritation of a wound site and cause a delay in proper healing, as well as pain and discomfort for the patient.
Additionally, tissue enmeshing can provide seed points for bacteria to adhere to and propagate within a wound bed, and constant dressing changing increases the opportunity for introducing new bacteria, since, by definition, an open wound cannot be sterile. Therefore, minimizing the amount of tissue ingrowth into foam and decreasing the number of dressing changes required would offer a new way to handle dressings in open wounds, remedy some of the undesirable factors associated with prior art systems, and improve overall wound healing.
The lack of customization of foam inserts for wounds is also a major obstacle. Current technology requires one to hand cut preformed porous, open-cell foam blocks into a desired shape and then insert the cut foam into a wound. This makes it very difficult to mimic the shape, contour, and size of many wounds, especially wounds over joint articulations, complex bone architecture of the face, and complex wound shapes associated with traumatic wounds. Additionally, the range of materials approved for fabricating foam inserts for wound treatment is limited. Conforming foam materials to irregularly-shaped wounds can be time-consuming and challenging.
Surface contact with the wound is inherently desired to optimize the function of these dressings, and wounds with irregular sides, undermining, tunneling, and clefting make manual preparation of inserts technically difficult. Creating the complex shape of a wound by utilizing small blocks or pieces of the foam material, either provided by the manufacturer or manually fashioned on site, has been utilized and has dramatically increased the number of overlooked and retained foreign bodies in these wounds.
Wounds have various depths, tissues, and environments. Therefore, it would be highly beneficial to be able to easily modify the foam inserts used for these wounds to maximize the clinical efficacy of negative pressure wound systems and wound dressings in general.
Currently, gelatinous wound dressings are used as a dressing to fill, cover, and/or seal a wound. Though effective in what they are currently used for, gelatinous wound dressings can be modified and used in a different manner as a wound liner and/or foam insert during pressure gradient therapy. Current gels generally are not mechanically robust enough to withstand pressure gradient therapy and often must be used with an additional dressing to secure the gel dressing in place. Moreover, currently utilized, pre-formed gel dressings are flat and difficult to use in complex, deep, irregular wounds.
Gel pastes, on the other hand, can be difficult to apply as thin films on wound walls. Hydrogel dressings are highly saturated with water such that the wound can become overhydrated. Fibrin glue and other wound sealants are typically not used as dressings, but some wound dressings incorporate fibrin and other extracellular matrix compounds to enhance the wound healing process. When used as a sealant to bind tissue, they tend to trap exudative and edematous fluids and thus impair wound healing. Therefore, though these gelatinous wound therapies have been shown to promote vital wound healing processes, they still lack in their ability to maintain dimensional stability on their own and help promote fluid egress from the wound site.
Treatment of closed wound injuries could be improved if the need for open surgical correction and fixation could be reduced. What is desired is a pourable material to be utilized in situations having separated bone and tissues, not by open incision as described above, but by injection as a glue-like or binding agent that can provide structural support and dimensional stability to the injury, while also serving as a temporary or permanent scaffold for cells to migrate within and proliferate to form new tissue.
Such an approach to fixation would have several beneficial advantages. Experience with prosthetic joint replacements shows that reticular or trabecular formation of material with specific pore sizes allows for bone tissue ingrowth into prosthetics and firmer fixation to bone. Since injectable material can be formed into a foam or mesh liner in situ and made reticular, it could firmly become attached to respective bone fragments by ingrowth. Further, since a needle or tubing can be used to insert the foam or mesh material, such wound site access can also be used to add negative pressure to the system once the material is hardened in situ.
This adjunct therapy would speed the movement of tissue and osteoblast ingrowth into trabecular pattern prosthetics and across the bone fracture junction, thereby speeding healing strength and decreasing healing time. This approach would have the added benefit of potentially eliminating the need for open surgery, which can prolong healing and result in increased scar tissue formation. Such an approach would still need external fixators, a splint, or a cast for a prescribed amount of time for the bone to knit and gain strength. The advantage of negative pressure through a needle or catheter in this approach though is that callus-inducing hematoma can be drained and ingrowth can be induced into the trabecular structure of the injected foam. In theory, this could mean that patients would not need external splints, casts or fixators for as long.
Heretofore there has not been available a customizable, multi-solution system or method for wound treatment to prevent tissue enmeshing and to promote tissue genesis with the advantages and features of the present invention, including inter-tissue gels and/or foams with a modifiable porous fraction and inclusion of bioactive compounds, that can be poured, sprayed, injected or spread into a wound site with the ability to be utilized with or without a pressure gradient system.
The present invention discloses an improved wound treatment dressing and method. The present approach circumvents the previously mentioned limitations of current gelatinous dressings and foam or mesh inserts utilized in wound care, with or without pressure gradient therapy. The present invention covers customizable and premade sets of multi-solution systems that form an amorphous gel or foam wound liner or an amorphous, expandable foam wound insert that can be poured, sprayed, injected, or spread to fill a wound bed for specific tissue applications. This approach allows for fabrication of a tailored, multi-solution set of systems with bioactive synthetic and natural compounds, including factors to promote tissue growth, cell migration, and proliferation; to improve the dimensional stability of gel or foam liners or wound inserts; and to augment porous fractions.
The porous fraction of the liners and inserts can either be closed-cell, with discontinuity of pores, or open-cell, with continuous pores. For example, various functional considerations may be factors in optimizing the closed-cell and open-cell pore sizes. Moreover, the invention is scalable to adapt to various applications. The pore sizes of the continuous pores of the open-cell foam tend to affect fluid transfer and flow functional parameters. Still further, the open-cell or closed-cell character of the foam can change over the course of a treatment procedure. For example, continuous pores in an open-cell configuration can close as healing occurs or when subject to negative pressure, resulting in a partially or fully-closed configuration.
In terms of physiologic tissue response, the pore size is a significant variable in determining whether the epithelial cells will be able to migrate beneath the material unimpeded or if the epithelial cells will be disrupted and unable to migrate because the granulation has enmeshed into the open pores. Even if the enmeshing is only one pore deep, epithelial cell migration can be compromised. The open or closed cell characteristics can affect the ability of a dressing to collapse and “firm-up” under negative pressure. Moisture evaporation rates and the ability to handle exudate are additional physiological functional criteria, which are affected by the foam materials and configurations, including open and closed cells, and pore sizes.
The pore sizes can be manipulated, and the connectivity of the pores can be altered to modulate the ability for fluid to pass through a wound liner. Small-cell systems decrease tissue enmeshing while still allowing the transport of fluid through the system. Systems with larger, open-cell configurations allow for both tissue ingrowth and fluid transport, while also being highly compactable or compressible to accommodate decreases in wound area under vacuum or negative pressure. In some embodiments, a sacrificial component is incorporated to augment the porous fraction of the liner and/or inserts. The ability to fine-tune pore size and porosity in a foam insert allows better control over complex and variable tissue responses. This is because the modulation of pore size and bulk porosity can have an overall effect on the compactability or compressibility of the foam insert. The compactability or compressibility will directly correlate to the contraction and deformability of the wounded tissue and therefore the degree of physicochemical and mechanotransduction response occurring within the damaged tissue.
The degree of swelling within the hydrogel and the subsequent pore size can be controlled to achieve optimum healing outcomes. For example, the composition of the hydrogel and the application of a rinsing solution can alter swelling and foam porosity factors, with corresponding effects on tissue responses and re-epitheliazation.
Additionally, the ability to have a variety of solutions with different premade compounds provides the capacity of tailoring gel or foam wound liners and/or foam inserts to specific wound applications. The use of a multi-solution system permits the ability for the curation rate of the wound liner and inserts to be modified to adjust for mode of application (i.e., pour, spray, inject, or spread) and for binding to another gel or foam liner(s) and/or insert(s), if desired. The wound liners can be used in conjunction with preformed foam inserts commonly used with pressure gradient therapy, with other wound dressings, or with the aforementioned expanding foam solution by using two different multi-solution systems. The expanding foam insert solutions can be used alone, with or without pressure gradient therapy, or with other wound dressings, including preformed foam inserts as a vacuum core and adhesive, semi-permeable dressings.
The use of a multi-solution system permits the user to pour, spray, inject, or spread amorphous solutions into a wound site where the solutions undergo a chemical reaction and cure to form a gel or foam that conforms to the shape and size of the wound and may or may not expand to fill the voided space within the wound. The expanding open-cell foam insert can be compacted or compressed under vacuum and decrease the wound area, and if used in conjunction with a closed-cell wound liner, tissue enmeshing will be limited. This overall approach eliminates the need to cut inserts by hand while permitting the customizability of solutions and reduction of tissue enmeshing from using a closed-cell wound liner system. The use of a solution-based system permits the manufacturer and the user to create additional solution systems for either liners or wound inserts and bind them together instead of using premade gels or foams that are made in generic shapes and sizes. Incorporation of sacrificial porogens, including solutes, gases, salts, and particles, can alter the porous fraction of the final wound liner and/or foam inserts. Specific combinations shown to be effective for particular wounds can be provided.
The drawings constitute a part of this specification and include exemplary embodiments of the present invention illustrating various objects and features thereof.
As required, detailed aspects of the present invention are disclosed herein, however, it is to be understood that the disclosed aspects are merely exemplary of the invention, which may be embodied in various forms. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art how to variously employ the present invention in virtually any appropriately detailed structure.
Certain terminology will be used in the following description for convenience in reference only and will not be limiting. For example, up, down, front, back, right, and left refer to the invention as orientated in the view being referred to. The words “inwardly” and “outwardly” refer to directions toward and away from, respectively, the geometric center of the aspect being described and designated parts thereof. Forwardly and rearwardly are generally in reference to the direction of travel, if appropriate. Additionally, anatomical terms are given their usual meanings. For example, proximal means closer to the trunk of the body, and distal means further from the trunk of the body. Said terminology will include the words specifically mentioned, derivatives thereof and words of similar meaning.
As described herein, the term foam shall be defined as any liquid or solid material having pockets of gas within the liquid or solid material, including both open-cell and closed-cell pockets. The term foam shall be interpreted broadly enough to include materials of any thickness, including thin materials such as meshes. Furthermore, the terms cure and curing shall be defined as the process of hardening a material, including but not limited to cross-linking of biological and/or synthetic components. A curing agent shall mean a substance or factor applied to a material to initiate curing of that material.
The present invention discloses an improved system and method for wound treatment. In an exemplary embodiment, a curable, amorphous wound dressing is applied to a wound in a liquid or semi-liquid state, which dressing forms to the shape of the wound cavity and cures within the wound. Preferably, the wound dressing forms into a foam material. Embodiments include both open-cell and closed-cell dressings, and the wound dressing material components can be configured for being poured, sprayed, injected, or spread into a wound. The wound dressing can include pores which are sized for physiologic effect, i.e., large, granulation-enmeshing or small, non-enmeshing pores. Additionally, the dressing may be hydrophobic or hydrophilic.
Without limitation on the generality of useful materials for forming a wound dressing 12 according to the present invention, the foam liner 8 and the filler 10 can be gel and/or foam, which can comprise premade, tailored solutions. Such solutions can include first and second compounds, which are the components of the gel and/or foam liner. A third, additional compound can comprise, for example, a sacrificial porogen (e.g., bioactive factors, curing agent or adhesion protein). The third compound can be added to either the first or second compound, or it can be added separately and allowed to mix within the wound 2 bed upon application with the first and second compounds.
The third compound can consist of a mixture of multiple solutions or be separated into multiple distinct solutions. Utilizing an application system such as a dual syringe (or other modality), the first and second compounds can be kept separate until application to the wound 2. Alternatively, they can be mixed together in a single chamber and then applied, depending on the compounds used and the method of curation.
Upon application of the multi-compound to the wound 2, the solution mixture will disperse throughout the wound 2 and cure to form a wound liner layer 8. The wound liner 8 can be used as its own modality or with other wound dressings and therapies, such as the foam filler 10.
The foam wound dressing material can be configured to cure via a chemical curing agent, a photo-initiator curing agent, water moisture, or change in temperature. Different embodiments of the wound dressing material may be made up of a polyurethane ester, a polyurethane ether, a polyethylene glycol, a polyvinyl alcohol, a polylactic acid, a polyester, a polycaprolactone (PCL), a silicone-based derivative or a polysaccharide. Furthermore, the foam wound dressing may be formed by covalent bonds, ionic bonds, or hydrogen bonds.
The wound dressing of the present invention may be used with additional wound dressing and/or wound therapies, as desired. The dressing may further be covered with an adhesive dressing covering. Additionally, negative pressure or positive pressure may be applied to the wound and dressing. In some embodiments, the wound dressing is configured for compacting or compressing under negative pressure, while in other embodiments, the wound dressing is configured to hold its structure under negative pressure. As the wound heals, the wound dressing of the present invention can be configured for removal from the wound or the dressing material may be configured for being resorbed in the wound.
In embodiments incorporating a sacrificial component, a sacrificial solution may be dissolved into the wound dressing compound. Alternatively, a sacrificial solution can be dissolved into a solution and then added to the wound dressing compound system. Moreover, in other embodiments, the sacrificial solution is dissolved into a solution and added into the wound simultaneously with the residual foam component system. The sacrificial component may also be removed by the application of negative pressure or vacuum after its dissolution, or the sacrificial component may be dissolved into the wound site and taken up by the surrounding tissue.
In some embodiments of the present invention, the porous fraction of the foam insert can be modified by modulating molecular characteristics of the sacrificial porogen, including but not limited to modification of the molecular weight or size of the porogen. The porous fraction of the foam insert can alternatively be modified by modulating molecular characteristics of the residual foam component, including but not limited to modification of the molecular weight or size of the residual compound or modification of the relative concentration of the residual foam compound. In additional embodiments, the porous fraction of the foam is created by using gas as a porogen. The gas porogen may be dissolved, mixed or incorporated into the multi-solution system before application and allowed to dissolve, permeate or evaporate out of the foam upon application to the wound or the gas may be applied to the wound site promoting the formation of bubbles within the residual polymer foam as it cures. In some embodiments, the sacrificial porogen may be resorbed or dissolved within the wound environment or degraded and removed by enzymatic activity. In other embodiments, the sacrificial porogen is dissolved within the wound environment after a change in temperature or after application of a solvent over the foam material. The solvent may be aqueous-based, an acid, or a base and may or may not contain an enzyme.
In a preferred embodiment, the sacrificial porogen is a natural occurring biological compound, including but not limited a protein, polysaccharide, nucleic acid, or salt. Protein sacrificial porogens include but are not limited to collagen, gelatin, silk fibroin, and fibrin. Polysaccharide sacrificial porogens include but are not limited to dextran, xanthan gum, pectin, hyaluronic acid, carrageenan, guar gum, and cellulose. Polymer sacrificial porogens may also be used, including but not limited to polyethylene oxide, polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylic acid, polyacrylamides, polyphosphate, and hydroxypropyl methacrylamide.
A smaller, preformed foam material may further be used as a core element in conjunction with the multi-solution system of the present invention. This core foam insert may become a vacuum core under negative pressure.
In an exemplary embodiment, a synthetic polymer foam is utilized, preferably a polyurethane fabricated by mixing isocyanate and polyols, but alternative polymer foam materials may be used. A sacrificial porogen including natural and/or synthetic compounds that dissolve in water, such as polyethylene glycol or gelatin, or a gas contained within a solution is mixed with the foam material. In some embodiments, the sacrificial compound can also dissolve into the wound site naturally. Biological sacrificial components may include fibrin, collagen, and/or hyaluronic acid. Soluble bioactive factors utilized may include growth factors and/or exosomes. In an exemplary embodiment, a crosslinking or curing agent is applied to the foam material to cure the foam within the wound. The crosslinking or curing agent may be a natural enzyme or factor such as factor XIII or calcium, water, natural enzyme, biological agent, chemical agent, temperature change or a particular spectrum of light such as UV light.
In some embodiments, an amorphous gel liner is utilized either in conjunction with the foam dressing or standalone. The liner may be poured, sprayed, injected, or spread into the wound. In a preferred embodiment, the liner is a closed-cell material used in conjunction with an open-cell foam material superficial to or positioned closer to the surface than the liner. A liner may also be used alone with negative pressure therapy. In preferred embodiments, a closed-cell liner is made up of bioactive compounds or extracellular matrix (ECM), such as but not limited to fibrin, collagen, or hyaluronic acid. The liner may or may not need to be removed from the wound site during the wound healing process. Similarly, the foam dressing material also may or may not need to be removed from the wound site.
In an exemplary embodiment of a pourable foam dressing material, isocyanate is mixed with polyol and a sacrificial porogen of polyethylene glycol or gelatin to form the foam material. In an exemplary embodiment of a pourable gel liner material, a fibrinogen-based first solution containing factor XIII and bioactive growth compounds is mixed with a thrombin-based second solution containing calcium chloride and ECM compounds to form the liner material. The liner material may optionally further include a sacrificial porogen (if desired) and/or synthetic or natural polymer (to enhance structural stability of the final gel material).
The following is a non-limiting listing of additional exemplary embodiments of the present invention:
It is to be understood that the invention can be embodied in various forms and is not to be limited to the examples specifically discussed above. The range of components and configurations which can be utilized in the practice of the present invention is virtually unlimited.
This application claims priority in U.S. Provisional Patent Application No. 63/127,364 Filed Dec. 18, 2020, which is incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 63127364 | Dec 2020 | US |
