WO2024215516A2 - Dispositifs et méthodes de traitement d'œdème - Google Patents

Dispositifs et méthodes de traitement d'œdème Download PDF

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Publication number
WO2024215516A2
WO2024215516A2 PCT/US2024/022684 US2024022684W WO2024215516A2 WO 2024215516 A2 WO2024215516 A2 WO 2024215516A2 US 2024022684 W US2024022684 W US 2024022684W WO 2024215516 A2 WO2024215516 A2 WO 2024215516A2
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Prior art keywords
mammal body
capillary channel
capillary
extracellular fluid
edema
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PCT/US2024/022684
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WO2024215516A3 (fr
Inventor
Michael V. Paukshto
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Fibralign Corp
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Fibralign Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M27/00—Drainage appliance for wounds or the like, i.e. wound drains, implanted drains
    • A61M27/002—Implant devices for drainage of body fluids from one part of the body to another
    • A61M27/006—Cerebrospinal drainage; Accessories therefor, e.g. valves

Definitions

  • the present disclosure related generally to devices and methods for treatment of edema. More specifically, the present disclosure relates to devices and methods using electric stimulation applied along implanted scaffolds to enhance lymphatic regeneration and repair.
  • ES stimulates molecular and cellular processes including secretion of trophic factors, enhancement of wound healing, stimulation of lymphangiogenesis and reduction of fibrosis, which benefit resolution of lymphedema [12].
  • Treatment with low-intensity and extremely low frequency electric fields, supplementary to manual lymphatic drainage, can significantly enhance pain alleviation and swelling reduction in patients with secondary lymphedema compared with manual lymphatic drainage alone [13], though a similar treatment in another
  • Electro-osmotic flow may occur through small-channel structures such as gap junctions, capillaries, cells, cell membranes, and across a heterogenous tissue.
  • electrokinetic flow is a relevant transport mechanism in even the smallest lymphatic and blood vessels [22], In the context of myocardium, edema formation is viewed in part as a disturbed electrical environment generating a potential gradient.
  • This environment includes the negatively charged intraluminal layer (glycocalyx) which controls the permeability of the capillary wall and, in turn, the fluid balance and pressure conditions in the interstitium [23-25],
  • Glycocalyx negatively charged intraluminal layer
  • An externally applied weak electric current together with an electrical field normalizes the electrical environment, which results in increasing lymphatic flow by supporting the electrokinetically induced transport of electro-osmosis and electrophoresis and may also influence the charge of the glycocalyx [26], This view is in line with earlier studies of ES effect on interstitial flow and edema reduction, where the authors
  • SUBSTITUTE SHEET (RULE 26) proposed that low electrical current displaces the negatively charged plasma proteins found in the interstitium of the traumatized areas [27], They hypothesized that this increased mobility should accelerate protein uptake by the lymphatic capillaries, which facilitates lymphatic flow, as an established mechanism for extracellular fluid uptake. Further, an effective displacement of the proteins into the lymphatic capillaries may depend on the stimulus waveform or the total amount of current passed through the interstitial spaces, and the unidirectional current flow is desired for edema reduction, through direct nonexcitatory effects on charged particles at the cellular level [28],
  • lymphatic system is arranged in lymphosomes, each of them drains or collects the lymph from a specific body area/part [30], with no or minimum flow occurring across the borders of lymphosome. Removal of major lymph nodes in one lymphosome may induce spontaneous rerouting of regenerated lymphatics toward an adjacent lymphosome [31,32],
  • BioBridgeTM Collagen Matrix developed by Fibralign Corp [32-34] has an open structure composed of aligned collagen fibrils which allows the cells to attach throughout the scaffold and guides their migration along the fibrils.
  • BioBridge (see Figure 1) mimics the nanotopography of the native extracellular matrix and determines the organization of the cells (e.g. alignment) and their phenotype, promoting new vessel formation. This device bridges the gaps between the existing lymphatics.
  • the concept of an artificial conduit to drain lymphatic fluid through capillary action was introduced previously using silk sutures [42], Teflon multifilament material [43], and silicone tubing [44], These studies validate the concept of creating an artificial channel for the acute relief from lymphedema.
  • Embodiments of the present disclosure provide a novel treatment where electric stimulation (ES) is applied along implanted scaffolds which further enhances lymphatic regeneration and repair.
  • ES electric stimulation
  • SUBSTITUTE SHEET (RULE 26) bridging an area of lymphatic obstruction with implanted thread-like scaffolds providing microcapillary channels between the healthy lymph draining areas or between the impaired lymphatic drainage area and healthy area in adjacent lymphosome and (2) enhancing the drainage of accumulated interstitial fluid or CSF electrokinetically by applied low current alone the microcapillary channels.
  • a biocompatible implant for a transfer of an extracellular fluid from one part of a mammal body to other part of the mammal body, the biocompatible implant comprising: a membrane having at least one capillary channel, where the at least one capillary channel has a positively or negatively charged internal surface.
  • a biocompatible implant for transfer of an extracellular fluid from one part of a mammal body to other part of the mammal body comprising: at least one capillary channel, and wherein a first end of the capillary channel is placed into one part of the mammal body and a second end of the capillary channel is placed into other part of the mammal body wherein the channel induces a flow of the extracellular fluid to transfer the extracellular fluid from one part of a mammal body to other part of the mammal body.
  • embodiments of the present disclosure further provide a system for transferring an extracellular fluid from one part of a mammal body to other part of the mammal body, the system comprising: a biocompatible implant as described above; and an electric field generator configured to generate an electric field along the biocompatible implant.
  • FIGs. 1A - IE are photographs illustrating examples of implantable and biodegradable scaffolds with multi-lumen microchannels that enable a capillary flow of extracellular fluid or CSF, according to some embodiments of the present disclosure
  • FIGs. 2A - 2C are photographs illustrating examples of implantable and biodegradable scaffolds with multi-lumen microchannels that enable a capillary flow of extracellular fluid or CSF, according to some embodiments of the present disclosure
  • FIGs. 3A - 3B are photograph showing a folded membrane which may be used to form the scaffolds, according to some embodiments of the present disclosure
  • FIG. 4 is a photograph showing capillary flow induced by the scaffolds according to the present disclosure
  • FIG. 5 is a schematic diagram showing a scaffold with negatively charged coating according to embodiments of the present disclosure
  • FIG. 6 presents a simple experiment demonstrated electro-osmotic flow through the multilumen fibrillar collagen scaffold (BioBridge) with the modified surface with zeta potential 20 mV.
  • FIGs. 7A - 7B are schematic diagrams illustrating treatment methods with implanted scaffolds according to embodiments of the present disclosure.
  • FIG. 8A - 8B are a schematic diagram illustrating electro-osmotic flow generation in a rat lymphedema model to transfer the interstitial fluid from the edema area to a health lymphosome;
  • FIG. 9 and FIG. 10 are schematic representations of a biocompatible scaffold implanted to connect the dura layer and/or meningeal lymphatics with the superficial lymphatic system, and showing that the flow can be enhanced by electro-osmotic pumping, with placing one electrode in the dura layer and a second electrode under the head skin, according to embodiments of the present disclosure;
  • FIG. 11 is a schematic diagram presenting an alternative approach to direct CSF flow from meningeal lymphatics to the superficial cervical lymph node.
  • FIG. 12 is a cross-sectional view of a biocompatible implant according to embodiments of the present disclosure, which may be utilized in-vitro or in-vivo for nanotransfection.
  • Edema is a condition characterized by an excess of watery fluid collecting in the cavities or tissues of the body.
  • lymphedema is a common complication in cancer survivors, as well as patients who undergo pelvic dissections or radiation therapy, such as treatment for breast cancer and other cancers.
  • Other types of edemas include, but are not limited to, postoperative edema, myocardial edema, or wound edema.
  • Some neurological disorders are also characterized by an abnormal accumulation of cerebrospinal fluid (CSF) within the brain or reduced drainage of CSF to the lymphatic system.
  • CSF cerebrospinal fluid
  • Electroosmotic flow is the motion of liquid induced by an applied potential across a porous material, or capillary channel, or membrane, or microchannel, or any other fluid holding scaffold.
  • Lymphosome is a particular region of the body where lymphatic vessels connect to the same subgroup of regional lymph nodes.
  • the inventive approach includes (see Fig. 7 or Fig. 9): (1) bridging an area of lymphatic obstruction with implanted thread-like scaffolds providing microcapillary channels between the healthy lymph draining areas or between the impaired lymphatic drainage area and healthy area in adjacent
  • SUBSTITUTE SHEET (RULE 26) lymphosome and (2) enhancing the drainage of accumulated interstitial fluid or CSF electrokinetically by applied low current alone the microcapillary channels.
  • edema can be treated, at least in part, using a scaffold with capillary channels facilitating a flow of extracellular fluid or CSF away from the cavities or tissues.
  • Figures 1 and 2 illustrates examples of the implantable and biodegradable scaffolds with multi-lumen microchannels that enable a capillary flow of extracellular fluid or CSF.
  • the scaffolds are made by a folded membrane like one that presented, for example, in Figure 3.
  • the fibrils/fibers are aligned in a same direction as the direction of the microchannels, see, for example, the scaffold presented in the Figure 1.
  • the scaffolds can be made of any suitable, biocompatible material including, but not limited to, collagen, fibronectin, fibrin, laminin, elastin, hyaluronic acid, chitosan, silk, silicone, peptides, biodegradable block copolymers, lactide and glycolide polymers, caprolactone polymers, hydroxybutyric acids, polyanhydrides and polyesters, polyphosphazenes, polyphosphoesters, polyethylene glycol) (PEG), polyethylene oxide) (PEG), PEG or PEG with different end-functionalities and, optionally, bifunctional crosslinkers and crosslinking agents, or the like or any combination thereof
  • Figure 4 illustrates one example in which a scaffold made by a folded collagen membrane was vertically dipped into an aqueous solution of methylene blue (0.1% w/v).
  • the capillarity of the scaffold caused the solution to rise along the membrane.
  • the capillary flow rates were variable between the samples of the scaffolds ranging from 0.5cm/min to 2.2cm/min. No difference was observed in an incubation chamber with variable relative humidity.
  • the surface of the capillary channels or any other suitable portion of a scaffold surface can be charged or modified such
  • SUBSTITUTE SHEET (RULE 26) that the resulting surface forms an electric double layer in the fluid.
  • Applying a potential across such capillary channels or the scaffold can result in electroosmotic flow of fluid (see, for example, Figure 5) along the capi 11 ary channels or through the scaffold (such as, for example, a porous material, capillary tube, membrane, microchannel, or any other fluid holding conduit.)
  • This electroosmotic flow can be used to remove fluid from cavities or tissues of the body to treat an edema.
  • the electric charge is constrained to a two- dimensional surface, such as, for example, along the interior surface of capi 11 ary channels.
  • the surface charge density can be measured in coulombs per square meter (Om-2) to describe the charge distribution on the surface.
  • the membrane or capillary channel has a positively charged internal surface. In at least some embodiments, the membrane or capillary channel has a negatively charged internal surface.
  • the membrane or capillary channels can be treated with heparin to produce a negatively charged internal surface.
  • Heparin is a glycosaminoglycan with a relatively high negative charge density due to abundant sulfate groups.
  • heparin binds to various proteins and grow th factors via electrostatic interactions. Heparin may also bind to specific heparin-binding sites. Immobilization of heparin on collagen matrices produces a material which has been used to stimulate endothelial cell proliferation.
  • the negatively charged surface can form a diffuse double layer with counterions present in the tissue fluid, and when placed under electric field, stimulate the flow of fluid across/through the membrane or capillary channels.
  • Any other suitable, biocompatible surface modification can be applied to the membrane or capillary channels to provide a positively or negatively charged surface. Such surface modification can include, but is not limited to, binding charged or chargeable
  • SUBSTITUTE SHEET (RULE 26) molecules or substituents to the surface, adding charged or chargeable substituents to the surface, radicalizing the surface, remove some charged or chargeable substituents of the surface, or the like or any combination thereof.
  • the native amino groups and carboxylic acid groups of collagen can be modified to change the ratio of positive and negative charges on the collagen fibrils at a given pH. It is also possible to remove the native amino groups of collagen by treatment with nitrous acid using a deamination reaction. In this case the net result will be more negative charges from the native carboxylic groups.
  • This method provides the control of the surface Zeta potential in the range from -5 mV to -20 mV at the neutral pH.
  • the resulting collagen material supports cell viability and proliferation [1],
  • an electrical field is applied externally or internally to produce directional flow of interstitial fluid or CSF through the membrane or capillary' channels.
  • the direction of the flow depends on the direction of the electric field and the charge (negative or positive) of the surface of the membrane or capillary channels.
  • Any suitable electrical field generator can be used to apply the electrical field.
  • the surface of a collagen scaffold with capillary microchannels or collagen membrane can be modified with heparin to obtain a scaffold with capillary properties and negatively charged surface.
  • the negatively charged scaffold will form a diffuse double layer with counterions present in the tissue fluid, and when placed under electric field, stimulate the flow of fluid across the scaffold.
  • the aim at the flow rates at least 0.1-2 um/s (physiological range for interstitial flow [4]) and not to exceed 13 um/s (shown to damage the cells [5, 6]) we can use the range of electric fields
  • SUBSTITUTE SHEET (RULE 26) between 100 mV/mm and 1000 mV/mm [1], considering that higher voltages (2800 mV/mm for 5 min [7, 8]) may reduce cell viability.
  • electrical stimulation can reinforce the treatment of lymphedema progression and complications.
  • the membrane may support lymphangiogenesis in the alignment direction and restore the lymphatic pathways that have been disrupted during the cancer surgery by bridging across damaged lymphatic tissue and providing support needed to effectuate lymphatic repair, and guide and restore the lymphatic function.
  • the application of electric field along the membrane directs the flow of interstitial fluid to regions with healthy lymphatic tissues.
  • the membrane is implanted to bridge an area of lymphatic obstruction.
  • a patch lead is placed on the skin near the midline and a coil lead is implanted subcutaneously parallel to the patch lead.
  • electrical stimulation is conducted after the membrane implantation to treat an edema.
  • the inventor herein provides a novel treatment when ES applied along the implanted scaffolds further enhances lymphatic regeneration and repair.
  • the proposed approach includes (see Fig. 7 and Fig. 8): (1) bridging an area of lymphatic obstruction with implanted thread-like scaffolds providing microcapillary channels between the healthy lymph draining areas or between the impaired lymphatic drainage area and healthy area in adjacent lymphosome and (2) enhancing the drainage of accumulated interstitial fluid or CSF electrokinetically by applied low current alone the microcapillary channels.
  • the implanted scaffold When applied across the border of impaired lymphatic drainage toward a healthy lymphatics area, the implanted scaffold facilitates the interstitial flow or CSF flow in the direction of healthy lymphatics, reduces fluid accumulation, and enhances lymphatic
  • SUBSTITUTE SHEET (RULE 26) regeneration in the affected area An additional ES helps to enhance the interstitial flow or CSF flow toward the healthy lymphatic bed such that the resulting treatment eliminates lymph accumulation or increases CSF drainage and facilitates lymphatic repair.
  • Methods of electric current application One of the methods of electrical stimulation described in the paragraph 1 above can be used in combination with the threadlike scaffold to induce electrokinetic flow and/or lymphatic repair and regeneration.
  • a current can be induced by the electrodes applied to the skin such that at least a part of the scaffold is located between the electrodes (see, Figure 8).
  • the electrodes with or without electrical generator (or battery) can be implanted such that at least a part of the scaffold is located between the electrodes (see, Figure 8).
  • at least one of the electrodes can be inserted into the skin.
  • the electrodes can generate a DC current or AC current (biphasic or monophasic).
  • Multiple electrodes can be used for the treatment including a belt electrode.
  • a wireless magnetic field stimulation can be used as an alternative.
  • Electro-osmotic membrane can be also applied for in-vivo or in-vitro nanotransfection.
  • Figure 12 shows a electro-osmotic biocompatible device according to the present disclosure.
  • the biocompatible device may be used in-vitro or in- vivo for nanotransfection.
  • the device generally includes an electro-osmotic pump coupled with biocompatible scaffold.
  • the electrostatic pump (porous layer/membrane sandwiched between conductive layers) may be comprised of a porous glass frit sandwiched between conductive coatings.
  • the conductive layers are comprised of metal nanowires, such as but not
  • SUBSTITUTE SHEET (RULE 26) limited to platinum nanowires (PtNWs).
  • PtNWs platinum nanowires
  • the layer of the membrane with conductive coating is covered by the patterned collagen layer treated with laminin, fibronectin, or other bioactive material to stimulate cell adhesion on the top of the layer.
  • This structure is used as bottom of a cell culture dish and is coupled with the reservoir that may contain any suitable solution, such as for example a plasmid/mRNA solution.
  • An additional electrode can be attached to the top of the culture dish. After the suitable cells are plated on the botom of the culture dish, an electrical field can be applied between the electrodes to induce nanotransfection through the plated cells and introduce the required plasmids or mRNAs.
  • the electrical impulse is generated by an electrical generator (not shown) which is used to apply potential to the top electrode and to the botom (PtNWs) conductive layer (electroporation).
  • the electro-osmotic flow can be initiated by an application of electrical potential between the two coatings sandwiched the porous membrane/layer.
  • the electro-osmotic flow can coincide with the electroporation.
  • Electro-kinetically modulated peristaltic transport of multilayered power-law fluid in an axisymmetric tube Eur Phys J Plus 2020; 135348. Verbrugge FH, Bertrand PB, Willems E, Gielen E, Mullens W, Giri S, Tang WHW, Raman SV, Verhaert D. Global myocardial oedema in advanced decompensated heart failure. Eur Heart J Cardiovasc Imaging 2017;18(7):787-794. Davis KL, Laine GA, Geissler HJ, Mehlhom U, Brennan M, Allen SJ. Effects of myocardial edema on the development of myocardial interstitial fibrosis. Microcirculation 2000;7(4):269-280.

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Abstract

Les présents modes de réalisation concernent des dispositifs et des méthodes de traitement de l'œdème. Dans certains modes de réalisation, l'invention concerne des dispositifs et des méthodes faisant appel à une stimulation électrique appliquée le long d'échafaudages implantés pour améliorer la régénération et la réparation lymphatiques. Un dispositif peut être constitué d'un implant biocompatible pour un transfert d'un fluide extracellulaire d'une partie d'un corps de mammifère à une autre partie du corps de mammifère, l'implant biocompatible peut comprendre une membrane ayant au moins un canal capillaire, le ou les canaux capillaires ayant une surface interne chargée positivement ou négativement.
PCT/US2024/022684 2023-04-10 2024-04-02 Dispositifs et méthodes de traitement d'œdème Ceased WO2024215516A2 (fr)

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* Cited by examiner, † Cited by third party
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US8475531B1 (en) * 2009-04-21 2013-07-02 Scott A. Maxson Anchored multi-phasic osteochondral construct
WO2013103423A2 (fr) * 2011-10-11 2013-07-11 Fibralign Corporation Greffe destinée à la régénération vasculaire et lymphatique et procédés de guidage d'ensemble de cellules endothéliales
WO2015054654A1 (fr) * 2013-10-10 2015-04-16 Fibralign Corporation Méthode et dispositif de traitement du lymphœdème
US20240149035A1 (en) * 2021-03-01 2024-05-09 Fibralign Corporation Conductive Biocompatible Scaffold For Electroporation

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