Method and device for modulating lymphatic pathway of central nervous system

Abstract

In some embodiments herein, implantable scaffolds, their compositions, and methods for modulating lymphatic pathway in the central nervous system and in the vicinity of the central nervous system are presented. Modulating lymphatic pathway, increasing the flow and / or turnover of fluid in the central nervous system, and, in particular, inducing formation of new lymphatic vessels, in accordance with some embodiments, are used to treat, prevent, or ameliorate symptoms of neurodegenerative diseases.

Description

METHOD AND DEVICE FOR MODULATING LYMPHATIC PATHWAY OF CENTRAL NERVOUS SYSTEMCROSS-REFERENCE TO RELATED APPLICATION

[0001] The present application claims priority to United States Provisional Patent Application No. 63 / 668,890. titled 'Method and Device for Modulating Lymphatic Pathway of Central Nervous System,” and filed on July 9, 2024, the entirety of which is incorporated by reference herein.FIELD OF THE INVENTION

[0002] The invention relates to procedures and devices that facilitate the increase in flow or turnover of cerebrospinal fluid in the central nervous system for the purpose of treating Alzheimer's disease, Parkinson's disease, and other neurological and psychiatric disorders. In particular, the invention relates to a method of implanting a biodegradable scaffold that induces a formation of complementary' lymphatic pathways or / and increases a capacity of the collecting lymphatic system in the head and / or neck.BACKGROUND

[0003] Alzheimer’s disease (AD) is the most frequent neurodegenerative disorder and most common cause of dementia in the elderly. Due to the increasingly aging population, the prevalence of AD dementia patients is expected to grow exponentially in the upcoming years. Dementia due to AD is characterized by the accumulation of pathological Amyloid-Beta (A|3) and Tau proteins, with potential neurodegeneration as a result. This agglomeration is increased by impaired clearance of waste from the brain. Therefore, an improvement of the clearance system is crucial for AD treatment [24,25], This invention provides a therapeutic approach to treating Alzheimer's disease that emerged from the understanding that plaquesand tangles are causative but mere consequences of an underlying mechanism in which the clearance of toxic factors from the brain has been disrupted by genetic and / or environmental factors.

[0004] Several neurodegenerative diseases are characterized by intracellular or extracellular accumulation of protein aggregates and various metabolic debris [1]. In recent years, there has been a sudden shift in our understanding of how the lymphatic system may be involved in this process in AD and other neurological disorders [2, 3], After years of focusing almost exclusively on the blood-brain barrier, researchers found that brain lymphatic drainage is important for removing beta-amyloid, one of the neuropathological hallmarks of AD [4, 5],

[0005] Head and neck lymphatic system consists of lymph nodes and lymphatic vessels. A part of this lymphatic system receives CSF (cerebrospinal fluid) and / or ISF (interstitial fluid) from CNS (central nervous system). We call this part - CSF drainage (lymphatic) system. It is important for parenchymal waste clearance, brain homeostasis, and the regulation of immune and inflammatory processes within the brain. There are a few lymph nodes in the CSF drainage system that are first to receive the CSF and / or ISF. These are the principal lymph nodes, dcLNs - deep cervical lymph nodes, involved in the immune response to CNS-derived antigens. Same CNS-derived antigens may cause a cytotoxic immune response in some other part of lymphatic system, for example, in some scLNs (superficial cervical lymph nodes). Therefore, it is important to detect and use the principal lymph nodes as a primary recipient of CSF. The current invention aims at reconstruction and repair of the drainage of lymphatic system in head and neck to improve parenchymal waste clearance, brain homeostasis, and the regulation of immune and inflammatory processes within the brain. Special attention is given to the methods and systems that minimize the device implantation time and its invasiveness since the length of the surgery is an important riskfactor for AD patients

[0026] , The ultrasound guided needle biopsy is used as a basis for the new implantation procedure connecting deep cervical lymph nodes and meningeal lymphatics to functional superficial lymphatics.

[0006] The proposed therapeutic interventions may reduce risks and complications associated with AD as well as other neurological and psychiatric conditions, e.g., Parkinson's disease, frontal -temporal dementia, mild cognitive impairment, idiopathic dementia, vascular dementia, amyotrophic lateral sclerosis, and concussive brain injury.SUMMARY OF THE INVENTION

[0007] The invention provides a method and device to treat neurological disorders and psychiatric conditions by increasing flow or turnover of cerebrospinal fluid in the central nervous system. The treatment is based on a formation of complementary’ lymphatic pathways via directional lymphatic regeneration and / or increasing the capacity of the collecting lymphatic system of the head and neck. In some embodiments herein, implantable scaffolds, their compositions, and methods for modulating lymphatic pathway in the central nervous system and in the vicinity of the central nervous system are presented. Modulating lymphatic pathway and, in particular, inducing formation of new lymphatic vessels, in accordance with some embodiments, are used to treat, prevent, or ameliorate symptoms of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, frontal- temporal dementia, mild cognitive impairment, idiopathic dementia, vascular dementia, amyotrophic lateral sclerosis, concussive brain injury, multiple sclerosis, as well as other neurological and psychiatric disorders.

[0008] In some embodiments herein, scaffolds are implanted under the guidance of imaging methods, in particular, by ultrasound. MR1, and x-ray CT. In some embodiments, scaffolds connected to a device for anchoring to a targeted soft tissue are disclosed makingpossible a minimally invasive implantation into a deep lymph node or into its vicinity. The device for anchoring of the scaffold to a soft tissue is a barb or anchor connected to the scaffold, and for example can be made from biodegradable materials including polymers, for example, from biodegradable homopolymer and an aliphatic polyester selected from the group consisting of lactic acid, lactide, glycolic acid, glycolide, caprolactone, dioxanone, trimethylcarbonate, and co-polymers and blends thereof. Also, it can comprise shape-memory alloys, biodegradable metals and non-biodegradable biocompatible metals.BRIEF DESCRIPTION OF THE FIGURES

[0009] FIG. 1 is a schematic diagram illustrating a thread-like scaffold (101) with a device for anchoring to a soft tissue in accordance with embodiments of the present invention (102), where A - side view with spring anchor inserted into scaffold and C - related cross view; B - side view with spring anchor loaded into the tubes.

[0010] FIG. 2 is a schematic diagram of the thread-like scaffold with device for anchoring to a soft tissue, in an initial configuration in accordance with embodiments of the present invention.

[0011] FIG. 3 is a schematic diagram of the thread-like scaffold (101 ) with the device for anchoring to a soft tissue ( 102), in a configuration after the release of the spring anchor ( 104) in accordance with embodiments of the present invention.

[0012] FIG. 4 illustrates step 1 of a scaffold implantation procedure which can be done under the guidance of ultrasound or MRI or CT according to embodiments of the method of the present invention.

[0013] FIG. 5 illustrates Step 2 of the scaffold implantation procedure according to embodiments of the present invention.

[0014] FIG. 6 illustrates Step 3 of the scaffold implantation procedure using the scaffold with the device for anchoring inserted through the guiding tube into the deep lymph node, according to embodiments of the present invention.

[0015] FIG. 7 illustrates Step 4 of the scaffold implantation procedure where the spring anchor is released into the deep lymph node in accordance with embodiments of the present invention.

[0016] FIG. 8 illustrates Step 5 of the scaffold implantation procedure wherein the guiding tube is removed in accordance with embodiments of the present invention.

[0017] FIG. 9 illustrates Step 6 of the scaffold implantation procedure wherein the external part of the scaffold implanted subcutaneously through the opening to reach the superficial lymph node in accordance with embodiments of the present invention.

[0018] FIG. 10 is a cross-sectional view of the thread-like scaffold with the device for anchoring to a soft tissue in accordance with embodiments of the present invention.

[0019] FIG. 11 is a schematic diagram of routes for drainage of CSF and ISF with implanted thread-like scaffolds as illustrated in Example 1 and Example 2.

[0020] FIG. 12 is a schematic diagram of routes for drainage of CSF and ISF with implanted (superficial) lymph node (vascularized lymph node transfer (VLNT) procedure) and thread-like scaffolds with an anchor and as illustrated in Example 3.

[0021] FIG. 13 is a schematic diagram of routes for drainage of CSF and ISF with implanted lymph node (VLNT procedure) and thread-like scaffolds and as illustrated in Example 4.

[0022] FIG. 14 is a schematic diagram of the routes for drainage of CSF and ISF with implanted thread-like scaffold having an anchor to connect impaired deep cervical lymph node, that supposed to drain CSF, to a healthy superficial cervical lymph node.

[0023] FIG. 15 is a schematic diagram of routes for drainage of CSF and ISF with implanted thread-like scaffolds and lymphaticovenous anastomosis (LVA) in the neck region connecting superficial cervical lymph node with a vein.

[0024] FIG. 16(a) - (e) show Nanofibrillar thread-like collagen scaffold: a) the macroscopic view; b) the aligned nanofibrillar collagen structure of the scaffold; c) the surface of the scaffold; d) the cross-section of the scaffold with multilumen structure; e) the surface of the lumens with indicated aligned nanofibrillar collagen structure, useful for carry ing out the present invention. This scaffold can induce and direct lymphatic regeneration therefore it can be used in the procedures presented here.DETAILED DESCRIPTION

[0025] Herein we use several terms including: brain clearance system which includes meningeal lymphatic vessels and the glymphatic system; directional lymphatic regeneration which means a formation of lymphatic vessel along a specific direction, for example, along the gradient of VEGF-C growth factor or along the capillary flow induced by the scaffold; circulatory system which includes the blood circulatory system and lymphatic system; head and neck circulatory system; head and neck lymphatic system; nucleic acid, for example, modified mRNA like HGF-mRNA or VEGFC-mRNA; VLNT - Vascularized Lymph Node Transfer which is a transplantation of autologous functional lymph node with microanastomosis to vasculature in the recipient bed to maintain their blood supply; LVA - LymphaticoV enous Anastomosis which is a reconstructive surgical procedure to redirect lymphatic fluid into the venous system; CSF turnover which is defined as CSF production divided by its distribution volume; thread-hke scaffold is the scaffold having a shape of thread or suture.

[0026] Disclosed herein, in certain embodiments, is a biocompatible scaffold which is made from: collagen, fibronectin, fibrin, laminin, elastin, hyaluronic acid, chitosan, silk, peptides, block copolymers, lactide and glycolide polymers, caprolactone polymers, hydroxybutyric acids, polyanhydrides and polyesters, polyphosphates, porous silicon, polyphosphoesters, poly(ethylene glycol) (PEG) and poly(ethylene oxide) (PEO) including PEG and PEO with different end functionalities, as well as bifunctional cross-linkers and crosslinking agents, or the combinations of the above materials. In another embodiments, the biodegradable and biocompatible scaffold is an aligned nanofibrillar biopolymer, for example, biopolymer composed of aligned nanofibrillar collagen type I or type III. One example of biocompatible biodegradable thread-like scaffold is the aligned nanofibrillar collagen scaffold (BioBridge™) presented in FIG. 16. This scaffold is used for lymphedema treatment and prevention. It demonstrated the ability to induce directional lymphatic regeneration and create a complementary lymphatic pathway in animal models and in human [17,18,20-23], One end of the thread-like scaffold can be further connected with an anchor or barb or glue to hold the end in a targeted soft tissue after its implantation and therefore dramatically simplify the delivery of the scaffold to a deep lymphatics. Then the second end of the thread-like scaffold can be directed to a functional superficial lymphatics by using a standard methods of subcutaneous implantation (suture passers or similar devices).

[0027] Disclosed herein, some embodiments include a method of increasing flow and / or turnover of fluid in the central nervous system of a subject. In one embodiment, the method comprises biocompatible scaffold implanted into the head of a subject wherein the scaffold supports a flow of cerebrospinal and extracellular fluid into the lymphatic system of the subject and induces a formation of a complementary lymphatic pathway from the head to at least one lymph node of the head or neck of the subject, thereby increasing fluid flow in the central nervous system of the subject. In another embodiment, the method comprises thescaffolds supporting a flow of cerebrospinal and extracellular fluid into the lymphatic system of the subject and induces a formation of a complementary7lymphatic pathway from the meningeal lymphatics to at least one lymph nodes of the head or neck of the subject, thereby- increasing fluid flow and / or turnover in the central nervous system of the subject.

[0028] In one embodiment, the scaffold is a thread-like biodegradable scaffold or a set of thread-like biodegradable scaffolds. In one embodiment, the thread-like scaffold comprises a bundle of threads, or multi-filaments, or fibers, or fibrils made from biodegradable materials such that the bundle supports a capillary- flow of cerebrospinal and / or extracellular fluid in the bundle direction. In another embodiment, the thread-like scaffold has a multi-lumen or multichannel structure such that the thread-like scaffold enabling a flow of cerebrospinal and extracellular fluid in the thread-like scaffold direction.

[0029] In several embodiments, the thread-like scaffold comprises biodegradable materials selected from the group consisting of collagen, fibronectin, fibrin, laminin, elastin, hyaluronic acid, chitosan, silk, peptides, block copolymers, lactide and glycolide polymers, caprolactone polymers, hydroxybuty ric acids, polyanhydrides and polyesters, polyphosphates, porous silicon, polyphosphoesters, poly(ethylene glycol) (PEG) and polyethylene oxide) (PEO) including PEG and PEG with different end functionalities, as well as bifunctional cross-linkers and crosslinking agents, or the combinations of the above materials.

[0030] In several embodiments, thread-like scaffolds comprising a growth factor or cells or immunotherapeutic drug, which may include human VEGFC / D, or fibroblast growth factor, or hepatocyte growth factor, or platelet-derived growth factor, or insulin-like growth factor, or other lymphangiogenesis promoting growth factors.

[0031] In several embodiments, the thread-like scaffolds comprising nucleic acid or cells promoting lymphangiogenesis. In particular, nucleic acid is a modified messenger RNApromoting lymphangiogenesis, for example, VEGFC / D-mRNA or FGF-mRNA or HGF- mRNA or PDGF-mRNA or IGF-mRNA or their combinations. The cells promoting lymphangiogenesis are, for example, autologous or allogeneic endothelial or endothelial progenitor cells.

[0032] In various embodiments, the device and procedure can be used to treat neurological and psychiatric diseases associated with disruptions of cerebrospinal fluid flow and drainage, including Alzheimer's disease, Parkinson's disease, frontal-temporal dementia, mild cognitive impairment, idiopathic dementia, vascular dementia, concussive brain injury, stroke, post-traumatic brain injury, multiple sclerosis, as well as other neurological and psychiatric disorders.

[0033] In various embodiments, the procedure is performed in conjunction with imaging methods to identify healthy and pathological lymph nodes and lymphatic vessels of the CSF / ISF draining lymphatic system, identify meningeal lymphatic, and target jugular foramen and apertures in the cribriform plate.

[0034] In some embodiments, the scaffold delivery is guided by ultrasound and, in particular, high- and ultra-high frequency ultrasound. The scaffold itself can be fdled with microbubble contrast agent to increase visibility of the scaffold by ultrasound. The microbubble contrast agent can be also delivered to CSF to provide selective visibility of the principal lymph nodes involved into the CSF clearance. The high frequency ultrasound and / or contrast enhanced MRI are also used to determine impaired lymphatics involved into the CSF clearance.

[0035] Turing to the figures, FIG. 1 A - 1C show a schematic diagram of the thread-like scaffold 101 configured for anchoring to a soft tissue. FIG. 1 A is a side view showing a spring anchor inserted into scaffold and FIG 1C - related cross view; FIG. IB - side view with spring anchor loaded into the tubes. The thread-like scaffold 101 includes device 102 foranchoring to a soft tissue, some parts of this device can be removed after the implantation (for example, part 103 and 105). A preloaded scaffold 101 having a first tube 103 and a spring anchor 104 is inserted into scaffold, - second tube 105 (piston) to push the spring anchor with scaffold out of first tube. The spring anchor 104 is a biocompatible wire show n in relaxed state in the schematic A (cross section view' C) and in the strained state loaded into the tube 103 in the schematic B. The spring anchor 104 is designed to be connected with the thread-like scaffold 101. The second tube 105 (or piston or plunger) is designed to push the spring anchor 104 with the end of the scaffold 101 out of first tube 103.

[0036] In FIG. 2 the thread-like scaffold with the device for anchoring the scaffold to a soft tissue is shown in an initial configuration. The scaffold 101 together w ith the spring anchor 104 is loaded into the rigid plastic tube 103. The second tube 105 or piston or plunger is inserted into the first tube, and it is used for releasing the spring anchor 104 together with the tip (proximal end) of the scaffold into a targeted area in a soft tissue.

[0037] In FIG. 3 the thread-like scaffold 101 with the device for anchoring the scaffold to a soft tissue is shown in the configuration after the release of the spring anchor 104. The spring anchor 104 together with the tip of the scaffold 101 is pushed out by the piston 105 (second tube) from the first tube 1 3. Now both tubes can be freely removed from the scaffold in the direction opposite to the proximal end of scaffold connected with the spring anchor.

[0038] Figures 4 - 9 illustrate method steps in accordance with embodiments of the present invention. In FIG. 4, Step 1 of the scaffold implantation procedure is shown which can be done under the guidance of ultrasound or MRI or CT. Specifically shown in FIG. 4: 106 - sharp indenter, 107 - guiding tube, 108 - deep lymph node or another soft tissue target, 109 - superficial lymph node. The trocar (guiding tube) 107 with a sharp insert (indenter) 106 is similar to the needle biopsy device and its implantation procedure can be conducted underthe guidance of ultrasound. Here, the targeted soft tissue is the deep (cervical) lymph node 108. Superficial lymph node 109 is presented as a reference.

[0039] In FIG. 5 Step 2 of the scaffold implantation procedure is show n. Once the trocar (guiding tube) 107 has reached the targeted area of the soft tissue (deep lymph node) 108, the indenter 106 can be removed.

[0040] In FIG. 6 Step 3 of the scaffold implantation procedure is show n where the scaffold with the device for anchoring is inserted through the guiding tube into the deep lymph node. Specifically shown in FIG. 6: 107 - guiding tube, 108 - deep lymph node, 109 - superficial lymph node, 110 - scaffold with the device for anchoring to a soft tissue (which includes the parts 101 and 102). The scaffold with the device for anchoring 110 is inserted through the guiding tube 107 into the deep lymph node 108

[0041] In FIG. 7 Step 4 of the scaffold implantation procedure is shown where the spring anchor is released into the deep lymph node. Specifically shown in FIG. 7 : 104 - spring anchor inserted into scaffold, 107 - guiding tube, 108 - deep lymph node, 109 - superficial lymph node, 110 - scaffold with the device for anchoring scaffold to a soft tissue (which includes the parts 101 and 102). The spring anchor 104 is released into the deep lymph node 108 together with the scaffold tip (the first (proximal) end of the scaffold).

[0042] In FIG. 8 Step 5 of the scaffold implantation procedure is shown where the guiding tube 107 is removed. Specifically shown in FIG. 8: 101 - thread-like scaffold, 108 — deep cervical lymph node, 109 - superficial cervical lymph node, 1 11 - area on the skin where the scaffold was introduced. The first tube 103, second tube 105 and the guiding tube 107 are removed w hile the scaffold 101 holds by the spring anchor 104 in the vicinity of the deep cervical lymph node 108.

[0043] In FIG. 9 Step 6 of the scaffold implantation procedure is shown where the external part of the scaffold implanted subcutaneously through the opening 111 to reach thesuperficial lymph node 109. The subcutaneous implantation is a standard procedure used for implantation of thread-like scaffold. The distal part of the scaffold 101 located outside the tissue is implanted subcutaneously by a standard suture passer to bring the second end of the scaffold 101 into vicinity of the superficial lymph node 109.

[0044] FIG. 10 shows a cross-sectional view of the thread-like scaffold with the device for anchoring to a soft tissue (see also Figs. 2 and 3). In some embodiments, the scaffold 101 has an approximate cross-section size in the range from 0. 1 mm to 1 mm. The spring anchor 104 connected to the scaffold tip is inserted in a compressed state with the scaffold into the first tube 103. The second tube (piston or plunger) 105 is presented separately but it should be inserted into the first tube 103 before the scaffold implantation. The internal diameter of the second tube 105 is slightly bigger than the diameter of the thread-like scaffold 101. The internal diameter of the first tube 103 in Fig. 10 is 1.8 mm and internal diameter 1.4 mm. The internal diameter of the second tube 105 in Fig. 10 is 1.3 mm and internal diameter 1.1 mm; the spring anchor 104 thickness is about 0.2 mm.

[0045] FIG. 11 shows a schematic diagram of routes for drainage of CSF and ISF with implanted thread-like scaffolds 101 in Examples 1 and 2. In Example 1 - the thread-like scaffold 101 implanted under the skin of the subject head such that the first end of the threadlike scaffold is directed to the functional lymphatics of the ‘'head and neck lymphatic system” and the second end of the thread-like scaffold with the anchor connected with the scaffold 104 goes through the skull into the dura mater 120 in the proximity of the meningeal lymphatics. In Example 2 - the thread-like scaffold 101 implanted such that the first end of the thread-like scaffold with the anchor 104 is inserted into the dura mater 120 located in the bottom of the skull or into the cribnform plate and the second end of the thread-like scaffold goes into a functional superficial cervical lymph node 109.

[0046] FIG. 12 shows a schematic diagram of routes for drainage of CSF and ISF with implanted (superficial) lymph node (vascularized lymph node transfer (VLNT) procedure) and thread-like scaffolds 101 with an anchor 104 in Example 3. The scaffolds implanted to augment the transferred lymph node 109 and improve its integration into lymphatic system. In the presented example the scaffold is bridging the transferred lymph node 109 with a deep cervical lymph node 108 which has a viable afferent lymphatic channel.

[0047] FIG. 13 shows a schematic diagram of routes for drainage of CSF and ISF with implanted lymph node (VLNT procedure) and thread-like scaffolds 101 in Example 4. The scaffolds implanted to augment the transferred lymph node 109 and improve its integration into lymphatic system. The scaffold 101 with an anchor 104 is implanted to connect the lymphatic of cribriform plate and / or meningeal lymphatics with the implanted lymph node 109 and an additional scaffold is implanted to connect the lymph node 109 with a healthy lymphatics in the cervical area.

[0048] FIG. 14 show s a schematic diagram of routes for drainage of CSF and ISF with implanted thread-like scaffold 101 having an anchor 104 to connect impaired deep cervical lymph node 108, that is supposed to drain CSF, to a healthy superficial cervical lymph node 109. The goal of this procedure is to improve the cerebrospinal fluid transport by influencing the '‘extracranial part” of the lymphatic system serving CNS. We consider this as a minimally invasive surgical procedure in the cervical area.

[0049] FIG. 15 is a schematic diagram of routes for drainage of CSF and ISF with implanted thread-like scaffolds 101 and lymphaticovenous anastomosis (LVA) in the neck region connecting superficial cervical lymph node 109 with a vein 121. The scaffold 101 having an anchor 104 is implanted to connect a deep cervical lymph node 108 with superficial lymph node 109 enhancing CNS antigen surveillance and improving the cerebrospinal fluid transport. The LVA is conducted by using either efferent vessel of thesuperficial cervical lymph node 109 or vein 121 is directly connected to the superficial cervical lymph node 109. Thus, lymphatic fluid can flow from meningeal lymphatics to the deep lymphatic 108, then via implanted scaffold to the superficial lymph node 109 and further to the vein 121. LVA procedure using a cervical superficial lymph node is easier than the same procedure for a deep cervical lymph node. Thus, the scaffold helps to simplify and speed up the surgical procedure.

[0050] FIGs. 16 (a) - (e) show Nanofibrillar thread-like collagen scaffold that may be used in the present invention. Specifically shown is: a) the macroscopic view; b) the aligned nanofibrillar collagen structure of the scaffold; c) the surface of the scaffold; d) the crosssection of the scaffold with multilumen structure; e) the surface of the lumens with indicated aligned nanofibrillar collagen structure. This scaffold can induce and direct lymphatic regeneration therefore it can be used in the procedures presented here.EXAMPLES

[0051] A patient with neurological or psychiatric disorder (for example, AD) is examined by high frequency ultrasound system (18 - 70 MHz) and / or other diagnostic system (for example, MRI) [6,7] that can identify problems with lymphatic drainage of CSF and, specifically, determine the healthy and diseased lymph nodes and lymph vessels in head and neck. Depending on the CSF drainage problems the patient can be treated by implanting biodegradable scaffold supporting directional lymphatic regeneration as depicted in FIGS. 11-15. The following examples are presented for illustration purposes only and are not meant to limit the embodiments and present disclosure in any way.Example 1.

[0052] Thread-like scaffold is implanted under the skin of the subject head such that the first end of the thread-like scaffold is directed to the functional lymphatics of the “head and neck lymphatic system” and the second end of the thread-like scaffold goes through the skull into the dura mater in the proximity7of the meningeal ly mphatics, see FIG 11. For example, the scaffold is made from aligned nanofibrillar biopolymer comprising aligned nanofibrillar collagen ty pe I. The scaffold can also comprise a grow th factor (for example, VEGFC) or a nucleic acid (for example, HGF-mRNA) or cells promoting lymphangiogenesis (for example, endothelial or endothelial progenitor cells) as demonstrated in [8-15], The gradient of VEGFC growth factor will further enhance directional regeneration. The sustain release of HGF modified messenger RNA (HGF-mRNA) and delivered endothelial cells will speed up lymphatic regeneration and form a complementary lymphatic pathway through the scull before the bone regeneration.Example 2.

[0053] The thread-like scaffold is implanted such that the first end of the thread-like scaffold is inserted into cribriform plate or into jugular foramen in the proximity of the meningeal lymphatics and the second end of the thread-like scaffold goes into a functional cervical lymph node, see FIG 11. The ends of the scaffold are sutured to the soft tissue. The guided delivery7of the scaffold is conducted under the guidance of the high frequency ultrasound.Example 3.

[0054] The scaffolds are implanted to augment the transferred lymph node and improve its integration into lymphatic system, see FIG 12. In this example first scaffold is bridging thetransferred lymph node with a deep cervical lymph node which has a viable afferent and may have unhealthy efferent lymphatic channel, and second scaffold is connected transferred lymph node with a healthy lymphatics to induce a formation of new efferent lymphatic vessel. The healthy autologous lymph node can be transferred from groin or some another suitable donor place. A supraclavicular lymph node flap can be used as a propeller lymphatic tissue flap

[0016] , A supraclavicular lymph node flap is frequently used for lymphedema treatment without complications in the donor site. The scaffold connection between two lymph nodes in cervical area has been tested in mouse model and formation of new lymphatic channels between deep cervical lymph node and superficial cervical lymph node has been demonstrated in two months after the implantation of aligned nanofibrillar collagen scaffold (BioBridge™).Example 4.

[0055] The scaffolds implanted to augment the transferred lymph node and improve its integration into lymphatic system, see FIG 13. The first set of scaffolds is implanted to connect the lymphatics of cribriform plate and / or meningeal lymphatics with the transferred lymph node and the second set of scaffolds is implanted to connect transferred lymph node with a healthy lymphatics below transferred lymph node to induce a formation of new efferent lymphatic vessels.Example 5.

[0056] The thread-like scaffold is implanted in the neck region connecting deep cervical lymph node draining CSF with a healthy superficial cervical lymph node as presented in FIG. 14. The scaffold is implanted to enhance the flow of lymph fluid from meningeal lymphatic to the superficial lymph node (for example, supraclavicular lymph node). There is clinicalevidence [17,18] that the implanted aligned nanofibrillar collagen scaffold (BioBridge™) induces and directs a formation of new lymphatic vessels, which may connect deep cervical and superficial lymph nodes and enhance CSF drainage.Example 6.

[0057] The LVA reconstruction in the neck region connecting a superficial lymphatic vessel or a superficial lymph node to a low pressure vein become a promising treatment procedure ameliorating symptoms of some neurodegenerative diseases. In order to enhance the outcome of this procedure a thread-like scaffold can be implanted to connect a deep cervical lymph node with the superficial lymph node inducing a formation of a new efferent lymphatic vessel and enhancing CNS antigen surv eillance, see FIG. 15.

[0058] It will be appreciated that the term “present invention” as used herein should not be construed to mean that only a single invention having a single essential element or group of elements is presented. Similarly, it will also be appreciated that the term "present invention" encompasses a number of separate innovations, which can each be considered separate inventions. Although the present invention has been described in detail with regards to embodiments and drawings thereof, it should be apparent to those skilled in the art that various adaptations and modifications of embodiments of the present invention may be accomplished without departing from the spirit and the scope of the invention. Accordingly, it is to be understood that the detailed description and the accompanying drawings as set forth hereinabove are not intended to limit the breadth of the present invention, which should be inferred only from the following claims and their appropriately construed legal equivalents.REFERENCES:1. Baranello R, Bharani K, Padmaraju V, et al. Amyloid-beta protein clearance and degradation (ABCD) pathways and their role in Alzheimer's disease. Curr Alzheimer Res 2015; 12(1): 32-46. http: / / dx.doi.org / 10.2174 / 1567205012666141218140953 PMID: 25523424mar2. Chachaj A, Gasiorowski K, Szuba A, Sieradzki A, Leszek J. Lymphatic system in the brain clearance mechanisms - new therapeutic perspectives for Alzheimer’s disease. Curr Neuropharmacol 2022; http: / / dx.doi.org / 10.2174 / 1570159X20666220411091332 PMID: 354106053. Maloveska M. Humenik F. Vikartovska Z, et al. Brain fluid channels for metabolite removal. 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Eduard Yakubov. Greg King, Michael Paukshto. Delivery7of Modified mRNA-Loaded Aligned NanofibrillarScaffolds for Treatment of Traumatic Muscle Injury. Society for Biomaterials 2018 Annual Meeting. Poster.14. Nakayama KH, Hong G. Lee JC, Patel J, Edwards B, Zaitseva TS, Paukshto MV, Dai H, Cooke JP, Woo YJ, Huang NF. Aligned-Braided Nanofibrillar Scaffold with Endothelial Cells Enhances Arteriogenesis. ACS Nano. 2015 Jul 28;9(7):6900-8.15. Huang NF, Okogbaa J, Lee JC, Jha A, Zaitseva TS, Paukshto MV, Sun JS, PunjyaN, Fuller GG, Cooke JP. The modulation of endothelial cell morphology, function, and survival using anisotropic nanofibrillar collagen scaffolds. Biomaterials. 2013. 34:4038-4047.16. Dimitrios Dionyssiou, Dung Nguyen, Anastasios Topalis, Peter Deptula, Michael Paukshto, Tatiana Zaitseva, Efterpi Demiri. Aggeliki Cheva. Stanley Rockson. Treating rat lymphedema with a propeller lymphatic tissue flap combined with nanofibrillar collagen scaffolds. 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Claims

CLAIMSThe claimed invention is:

1. A method of improving cerebrospinal fluid transport by repairing cervical lymphatics serving the central nervous system of a subject in need thereof, the method comprising: implanting a biocompatible scaffold, having a device for anchoring the scaffold to a soft tissue, into the subject’s head or neck wherein the scaffold induces a directional lymphatic regeneration and formation of a complementary' lymphatic pathway, thereby resulting in an additional flow of cerebrospinal and / or extracellular fluid from the central nervous system into the circulatory system of the subject.

2. A method of increasing turnover of cerebrospinal fluid of a subject in need thereof, the method comprising: implanting a biocompatible scaffold, having a device for anchoring the scaffold to a soft tissue, into the subject head or neck wherein the scaffold induces a directional lymphangiogenesis, thereby resulting in an increase in turnover of the subject’s cerebrospinal fluid.

3. The method of claim 1 or claim 2, wherein said subject has Alzheimer's Disease or Parkinson’s disease or stroke or post-traumatic brain injury or some other relevant neurological disorder or condition depending on the brain clearance system.

4. A method of claim 1 or claim 2, wherein the scaffold supports a flow of lymph fluid or cerebrospinal fluid or extracellular fluid of the subject and induces a formation of acomplementary' lymphatic pathway in the subject head or neck, thereby increasing fluid flow or turnover in the central nervous system of the subject.

5. A method of claim 1 or claim 2, wherein the scaffold is a thread-like biodegradable scaffold or a set of thread-like biodegradable scaffolds.

6. A method of claim 5, wherein the thread-like scaffold comprises a bundle of threads, or multi-filaments, or fibers, or fibrils made from biodegradable materials such that the bundle supports a capillary' flow of lymph fluid or cerebrospinal fluid or extracellular fluid along the bundle, in the bundle direction.

7. A method of claim 5, wherein the thread-like scaffold has a multi-lumen or a multichannel structure such that the thread-like scaffold enabling a flow of lymphatic fluid or cerebrospinal fluid or extracellular fluid in the thread-like scaffold direction.

8. A method of claim 5, wherein the thread-like scaffold comprising biodegradable materials selected from the group consisting of collagen, fibronectin, fibrin, laminin, elastin, hyaluronic acid, chitosan, silk, peptides, block copolymers, lactide and glycolide polymers, caprolactone polymers, hydroxybutyric acids, polyanhydrides and polyesters, polyphosphates, porous silicon, polyphosphoesters, poly(ethylene glycol) (PEG) and polyethylene oxide) (PEG) including PEG and PEG with different end functionalities, as well as bifunctional cross-linkers and crosslinking agents, or the combinations of the above materials.

9. A method of claim 5. wherein the thread-like scaffold comprising aligned nanofibrillar biopolymer.

10. A method according to claim 1 or claim 2 wherein said device comprising an anchor or a barb or a glue to hold the scaffold at a targeted area of the soft tissue after the scaffold implantation.

11. A method of claim 1 or claim 2, wherein the scaffold comprises a growth factor promoting or inducing lymphangiogenesis.

12. A method of claim 11, wherein the growth factor is the human VEGFC / D, or fibroblast growth factor, or hepatocyte growth factor, or platelet-derived growth factor, or insulin-like growth factor, or other lymphangiogenesis promoting growth factor.

13. A method of claim 1 or claim 2, wherein the scaffold comprises anucleic acid promoting or inducing lymphangiogenesis or cerebrospinal fluid production.

14. A method of claim 1 or claim 2, wherein the scaffold comprising cells that promoting or inducing lymphangiogenesis.

15. A method of claim 14, wherein the cells are autologous or allogeneic endothelial or endothelial progenitor cells.

16. A method of claim 1 or claim 2, wherein the scaffold is implanted into the dura mater to increase the capacity of meningeal lymphatics and enhance the flow or turnover of cerebrospinal and / or extracellular fluid.

17. A method of claim 1 or claim 2, wherein the thread-like scaffold is implanted under the skin of the subject head such that the first end of the thread-like scaffold is kept in the proximity of the functional lymphatics of the head and neck lymphatic system and the second end of the thread-like scaffold goes through the skull into the dura mater in the proximity of the meningeal lymphatics.

18. A method of claim 1, wherein the increasing flow of fluid in the central nervous system of the subject is combined with immunotherapy or other methods removing waste from central nervous system and protecting from infection.

19. A method of claim 2, wherein the increasing turnover of cerebrospinal fluid in the central nervous system of the subj ect is combined with immunotherapy or other methods removing waste from central nervous system and protecting from infection.

20. A method of claim 1 or claim 2, wherein the implantation of biocompatible scaffold is performed in conjunction with imaging methods to identify healthy and pathological lymph nodes and lymphatic vessels of the CSF / ISF draining lymphatic system and / or to identify meningeal lymphatic and / or to identify and target jugular foramen and apertures in the cribriform plate.2121. A method of claim 20, wherein the implantation of biocompatible scaffold is performed under the guidance of ultrasound imaging.

22. A method of claim 21, wherein the implantation of biocompatible scaffold is performed under the guidance of high frequency ultrasound.

23. A method of claim 21, wherein the biocompatible scaffold has a porous structure which is filled with microbubble contrast agent to enhance the guidance by ultrasound imaging.

24. A method of claim 10 and claim 20, wherein the device for anchoring scaffold to a soft tissue has a positive or negative contrast enhancing visibility of the scaffold with respect to the targeted area of the soft tissue.

25. A method of claim 24, w herein the targeted area of the soft tissue is a lymphatic vessel or a lymph node or a meningeal lymphatic vessel.

26. A method of claim 10, w h erein the anchor or the barb are made from biodegradable material.

27. A method of claim 26, wherein the anchor or the barb comprise at least one of a biodegradable homopolymer and an aliphatic polyester selected from the group consisting of lactic acid, lactide, glycolic acid, glycolide, caprolactone, dioxanone, trimethylcarbonate, and co-polymers and blends thereof.22

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