Method for regulating lymphatic pathway of central nervous system

Abstract

In some embodiments described herein, implantable stents, compositions thereof, and methods for modulating lymphatic pathways within and near the central nervous system are provided. In accordance with some embodiments, the present invention modulates the lymphatic pathway, increases the flow and turnover of fluids within the central nervous system, in particular induces the formation of new lymphatic vessels, for the treatment, prevention or amelioration of symptoms of neurodegenerative diseases.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit and priority of U.S. Provisional Application No. 63 / 386,406, filed on December 7, 2022, the content of which is incorporated herein by reference in its entirety. Technical field

[0003] The present invention generally relates to procedures and devices for promoting increased cerebrospinal fluid turnover and flow in the central nervous system for the treatment of diseases (such as Alzheimer's disease, Parkinson's disease, and other neurological and psychiatric disorders). Specifically, the present invention relates to methods of implanting a biodegradable device that induces the formation of complementary lymphatic pathways and / or increases the capacity of the lymphatic system in the head and / or neck. Background art

[0004] Alzheimer's disease (AD) is the most common neurodegenerative disease and the most common cause of dementia in the elderly. Due to the increasingly aging population, the prevalence of AD dementia patients is expected to increase exponentially in the coming years. Dementia caused by AD is characterized by the accumulation of pathological β - amyloid (Aβ) and Tau proteins and leads to potential neurodegeneration. Impaired brain waste clearance increases this aggregation. Therefore, improving the clearance system is crucial for AD treatment [References 24, 25]. The present invention provides a treatment approach for Alzheimer's disease that stems from the understanding that plaques and tangles are consequences of the cause but only underlying mechanisms, where genetic and / or environmental factors disrupt the clearance of toxic factors in the brain.

[0005] Several neurodegenerative diseases are characterized by the intracellular or extracellular accumulation of protein aggregates and various metabolic debris [Reference 1]. In recent years, our understanding of how the lymphatic system is involved in this process in AD and other neurological disorders has undergone a sudden shift [References 2, 3]. After years of almost exclusive focus on the blood - brain barrier, researchers have found that brain lymphatic drainage is important for clearing β - amyloid, one of the neuropathological hallmarks of AD [References 4, 5].

[0006] Therefore, there is an urgent need for significant progress and treatment. Summary of the invention

[0007] The head and neck lymphatic system consists of lymph nodes and lymphatic vessels. A part of this lymphatic system receives cerebrospinal fluid (CSF) and / or interstitial fluid (ISF) from the central nervous system (CNS). We refer to this part as the CSF drainage (lymphatic) system. It is important for parenchymal waste clearance, brain homeostasis, and the regulation of immune and inflammatory processes in the brain. There are several lymph nodes in the CSF drainage system that are the first to receive CSF and / or ISF. These are the primary lymph nodes, namely the dcLN (deep cervical lymph nodes), which are involved in the immune response to CNS-derived antigens. The same CNS-derived antigens may cause cytotoxic immune reactions in other parts of the lymphatic system, such as in some of the scLN (superficial cervical lymph nodes) [Reference 26]. Therefore, it is important to detect and use the primary lymph nodes as the main recipients of CSF. The current invention described herein aims to reconstruct and repair the drainage lymphatic system of the head and neck to improve parenchymal waste clearance, brain homeostasis, and the regulation of immune and inflammatory processes in the brain.

[0008] The inventive therapeutic interventions proposed herein can reduce the risks and complications associated with AD and other neurological and psychiatric disorders such as Parkinson's disease, frontotemporal dementia, mild cognitive impairment, idiopathic dementia, vascular dementia, amyotrophic lateral sclerosis, and concussion injury.

[0009] In some embodiments, the present invention provides methods for treating neurological disorders and psychiatric conditions by increasing the turnover and / or flow of cerebrospinal fluid in the central nervous system. The treatment is based on the formation of complementary lymphatic pathways via directed lymphatic regeneration and / or increasing the capacity of the head and neck lymphatic system. In some embodiments herein, implantable scaffolds, their compositions, and methods for regulating lymphatic pathways within and near the central nervous system are presented. According to some embodiments, the lymphatic pathways are regulated, particularly the induction of the formation of new lymphatic vessels for treating, preventing, or improving the symptoms of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, frontotemporal dementia, mild cognitive impairment, idiopathic dementia, vascular dementia, amyotrophic lateral sclerosis, concussion injury, multiple sclerosis, and other neurological and psychiatric disorders.

[0010] For example, in one embodiment, a method for increasing the fluid flow within the central nervous system of a subject in need thereof is provided, the method comprising: implanting a biocompatible scaffold into the head or neck of the subject, wherein the scaffold induces directed lymphatic regeneration and the formation of complementary lymphatic pathways, thereby resulting in additional inflow of cerebrospinal fluid and / or extracellular fluid from the central nervous system into the circulatory system of the subject. In some embodiments, the range of the additional flow is an increase of about 1% to 10% of the flow rate of cerebrospinal fluid and / or extracellular fluid from the central nervous system into the circulatory system of the subject.

[0011] In another example, a method for increasing cerebrospinal fluid (CSF) turnover in a subject in need thereof is provided. The method includes implanting a biocompatible scaffold into the head or neck of the subject, wherein the scaffold induces directional lymphangiogenesis, resulting in a 1% to 10% increase in CSF turnover in the subject. In some embodiments, the increase is more than a 3% increase in CSF turnover in the subject. Clinical data demonstrate that tracer clearance in the ventricles of elderly individuals is on average more than 3% slower than that of healthy control groups [Reference 27], indicating a corresponding reduction in CSF turnover.

[0012] In some embodiments, the scaffold is configured to support the flow of CSF and / or extracellular fluid of the subject and induce the formation of complementary lymphatic pathways from the dura mater of the subject to the head and neck circulatory system, thereby increasing the fluid flow in the central nervous system of the subject. The scaffold may consist of a linear biodegradable scaffold or a group of linear biodegradable scaffolds. In some embodiments, the scaffold is an injectable scaffold. In some embodiments, the linear scaffold comprises a bundle of threads, or multiple strands, or fibers, or fibrils made of a biodegradable material, such that the bundle supports capillary flow of CSF and extracellular fluid along the bundle in the direction of the bundle. Additionally, the linear scaffold may comprise a multi-lumen or multi-channel structure such that the linear scaffold is capable of allowing CSF and extracellular fluid to flow along the direction of the linear scaffold. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Embodiments of the present invention are illustrated by way of example and not limitation in the figures, in which like references denote like elements and in which:

[0014] Figure 1 is a schematic diagram of a CSF and / or ISF drainage path with an implanted linear scaffold (labeled BB) according to some embodiments. Option 1 - Implant the linear scaffold subcutaneously in the head of the subject such that the first end of the linear scaffold points towards the functional lymph of the "head and neck lymphatic system" and the second end of the linear scaffold passes through the skull and enters the dura mater near the meningeal lymphatics. Option 2 - Implant the linear scaffold such that the first end of the linear scaffold is inserted near the ventral / lower edge of the brain surface near the functional lymph and the second end of the linear scaffold extends downward to the functional cervical lymph nodes.

[0015] Figure 2 is a schematic diagram of a CSF and / or ISF drainage path with an implanted lymph node (VLNT procedure or advanced lymphatic tissue flap [Reference 16]) and a linear scaffold (labeled BB) according to some embodiments. The scaffold is implanted to enhance the metastatic lymph node and improve its integration with the lymphatic system. In the example shown, the scaffold bridges the metastatic lymph node with the deep cervical lymph node having viable afferent lymphatic channels and unhealthy efferent lymphatic channels.

[0016] Figure 3Schematic diagram of a CSF and / or ISF drainage pathway with an implanted lymph node (VLNT procedure or advanced lymphatic tissue flap) and a linear scaffold (labeled BB) according to some embodiments. The scaffold is implanted to enhance the metastatic lymph node and improve its integration with the lymphatic system. The scaffold is implanted to connect the lymph near the ventral / lower edge of the brain surface to the implanted lymph node and to connect the implanted lymph node to healthy lymph nodes in the subject's neck.

[0017] Figure 4 Schematic diagram illustrating a CSF and / or ISF drainage pathway according to some embodiments, in which a linear scaffold (labeled BB) and an LVA are implanted in the neck region, which connect healthy lymphatic vessels extending from the ventral / lower boundary of the brain to the vein. The scaffold is implanted to enhance the flow of lymphatic fluid from the meningeal lymph to the LVA region.

[0018] Figure 5 Schematic diagram of a CSF and / or ISF drainage pathway according to some embodiments, in which a linear scaffold (labeled BB) and an LVA are implanted in the neck region, which connect healthy lymphatic vessels extending from the ventral / lower boundary of the brain to the vein. The scaffold is implanted to connect deep cervical lymph nodes with degenerated efferent lymphatic vessels and the LVA region that enhances CNS antigen surveillance.

[0019] Figure 6 Schematic diagram showing a CSF and / or ISF drainage pathway according to some embodiments, in which a linear scaffold (labeled BB) and an LVA are implanted in the neck region. The scaffold is implanted to connect deep cervical lymph nodes with degenerated efferent lymphatic vessels and the LVA region that enhances CNS antigen surveillance, and to enhance the flow of lymphatic fluid from the meningeal lymph to the LVA region.

[0020] Figures 7a - 7e illustrate the linear scaffold BioBridge in various embodiments of the present invention TM : a) Macroscopic view; b) Nanofiber collagen structure of the scaffold arrangement; c) Scaffold surface; d) Cross-section of the scaffold with a multi-lumen structure; e) Lumen surface, showing the nanofiber collagen structure of the arrangement. Detailed embodiments

[0021] Here we define several terms used throughout the specification, including: the brain clearance system (including meningeal lymphatics and the glymphatic system); directed lymphangiogenesis (meaning the formation of lymphatic vessels along a specific direction, such as along the VEGF-C growth factor gradient); the circulatory system (including the blood circulatory system and the lymphatic system); the head and neck circulatory system; the head and neck lymphatic system; nucleic acids (such as modified mRNA, e.g., HGF-mRNA or VEGFC-mRNA); VLNT (vascularized lymph node transfer, which is the transplantation of autologous functional lymph nodes into the vasculature of the recipient bed via microanastomosis to maintain their blood supply); LVA (lymphaticovenular anastomosis, which is a reconstructive surgical procedure to redirect lymphatic fluid into the venous system); CSF turnover (which is defined as the CSF production rate divided by its distribution volume); a linear scaffold (a scaffold having a wire or suture shape); an injectable scaffold (a scaffold that can be formed from a solution or gel after injection, e.g., a microsphere suspension mixed with human VEGFC / D, or fibroblast growth factor, or hepatocyte growth factor, or platelet-derived growth factor, or insulin-like growth factor).

[0022] In certain embodiments, disclosed herein is a biocompatible scaffold made of one or more of the following materials: collagen, fibronectin, fibrin, laminin, elastin, hyaluronic acid, chitosan, silk, peptides, block copolymers, lactide and glycolide polymers, caprolactone polymers, hydroxybutyric acid, polyanhydrides and polyesters, polyphosphates, porous silicon, polyphosphoesters, polyethylene glycol (PEG) and poly(ethylene oxide) (PEO), including PEG and PEO with different end functional groups, and bifunctional crosslinking agents and crosslinking substances, or combinations of the above materials. In another embodiment, the biodegradable and biocompatible scaffold is composed of aligned nanofiber biopolymers, such as a biopolymer composed of aligned type I or type III nanofiber collagen. An example of a biocompatible biodegradable linear scaffold is the aligned nanofiber collagen scaffold shown in FIG. 7 (BioBridge TM ). This scaffold is used for the treatment and prevention of lymphedema. It has been shown to have the ability to induce directed lymphangiogenesis and create complementary lymphatic pathways in animal models and humans [References 17, 18, 20 - 23].

[0023] Some embodiments disclosed herein include methods for increasing fluid flow and / or turnover within the central nervous system of a subject. In one embodiment, the method includes implanting a biocompatible scaffold into the head of the subject, wherein the scaffold supports the inflow of cerebrospinal fluid and / or extracellular fluid into the lymphatic system of the subject and induces the formation of complementary lymphatic pathways from the head of the subject to at least one lymph node in the head or neck, thereby increasing fluid flow in the central nervous system of the subject. In another embodiment, the method includes a scaffold that supports the inflow of cerebrospinal fluid and extracellular fluid into the lymphatic system of the subject and induces the formation of complementary lymphatic pathways from the meningeal lymphatics to at least one lymph node in the head or neck of the subject, thereby increasing fluid flow and / or turnover in the central nervous system of the subject.

[0024] In one embodiment, the scaffold is a linear biodegradable scaffold or a group of linear biodegradable scaffolds. In another embodiment, the scaffold is an injectable scaffold. In one embodiment, the linear scaffold comprises a bundle of threads made of a biodegradable material, or multiple strands, or fibers, or fibrils, such that the bundle supports capillary flow of cerebrospinal fluid and / or extracellular fluid along the direction of the bundle. In another embodiment, the linear scaffold has a multi-lumen or multi-channel structure such that the linear scaffold can enable the flow of cerebrospinal fluid and / or extracellular fluid along the direction of the linear scaffold.

[0025] In several embodiments, the linear scaffold and the injectable scaffold comprise a biodegradable material selected from the following: collagen, fibronectin, fibrin, laminin, elastin, hyaluronic acid, chitosan, silk, peptides, block copolymers, lactide and glycolide polymers, caprolactone polymers, hydroxybutyric acid, polyanhydrides and polyesters, polyphosphates, porous silicon, polyphosphoesters, polyethylene glycol (PEG) and poly(ethylene oxide) (PEO), including PEG and PEO with different end functional groups, as well as bifunctional crosslinking agents and crosslinking substances, or combinations of the above materials.

[0026] In several embodiments, the injectable scaffold and the linear scaffold comprise growth factors or cells or immunotherapeutic agents, 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 growth factors that promote lymphangiogenesis.

[0027] In several embodiments, the injectable and linear scaffolds comprise nucleic acids or cells that promote lymphangiogenesis. Specifically, the nucleic acid is a modified messenger RNA that promotes lymphangiogenesis, such as VEGFC / D-mRNA or FGF-mRNA or HGF-mRNA or PDGF-mRNA or IGF-mRNA or a combination thereof. The cells that promote lymphangiogenesis are, for example, autologous or allogeneic endothelial cells or endothelial progenitor cells.

[0028] In various embodiments, the device and program can be used to treat neurological and psychiatric disorders associated with disrupted cerebrospinal fluid (CSF) flow and drainage, including Alzheimer's disease, Parkinson's disease, frontotemporal dementia, mild cognitive impairment, idiopathic dementia, vascular dementia, concussion injury, stroke, traumatic brain injury, multiple sclerosis, and other neurological and psychiatric disorders.

[0029] In various embodiments, the program is performed in conjunction with an imaging method to identify healthy and pathological lymph nodes and lymphatic vessels of the CSF / ISF drainage lymphatic system, identify meningeal lymphatic vessels, and target the openings in the jugular foramen and cribriform plate. Preferred imaging methods are high-frequency ultrasound (20 MHz - 70 MHz) and contrast-enhanced MRI.

[0030] Examples

[0031] Patients with neurological or psychiatric disorders (e.g., AD) are examined by a high-frequency ultrasound system (20 - 70 MHz) and / or other diagnostic systems (e.g., MRI) that can identify CSF lymphatic drainage problems and specifically determine healthy and diseased lymph nodes and lymphatic vessels in the head and neck [References 6, 7]. Depending on the CSF drainage problem, the patient can be treated by implanting a biodegradable scaffold that supports directional lymphatic regeneration, as Figure 1-6 shown.

[0032] Example 1.

[0033] A linear scaffold is implanted subcutaneously in the head of the subject such that the first end of the linear scaffold points to the functional lymphatic vessels of the "head and neck lymphatic system", and the second end of the linear scaffold passes through the skull into the dura mater near the meningeal lymphatic vessels, see Figure 1 . For example, the scaffold is made of an aligned nanofiber biopolymer containing aligned nanofibers of type I collagen. The scaffold can also contain growth factors (e.g., VEGFC) or nucleic acids (e.g., HGF-mRNA) or cells (e.g., endothelial cells or endothelial progenitor cells) that promote lymphangiogenesis, as shown in [References 8 - 15]. The gradient of the VEGFC growth factor will further enhance directional regeneration. Sustained release of HGF-modified messenger RNA (HGF-mRNA) and delivered endothelial cells will accelerate lymphatic regeneration and form complementary lymphatic pathways through the skull prior to bone regeneration.

[0034] Example 2.

[0035] A linear scaffold is implanted such that the first end of the linear scaffold is inserted into the cribriform plate or the jugular foramen, and the second end of the linear scaffold extends to the functional cervical lymph nodes, see Figure 1 . Both ends of the scaffold are sutured to the soft tissue. The guided delivery of the scaffold is performed under high-frequency ultrasound guidance.

[0036] Example 3.

[0037] Implanted scaffolds are used to enhance metastatic lymph nodes and improve their integration with the lymphatic system, see Figure 2 . In this example, the first scaffold bridges the metastatic lymph node with deep cervical lymph nodes having viable afferent lymphatic vessels and unhealthy efferent lymphatic vessels, and the second scaffold connects the metastatic lymph node to healthy lymphatics to induce the formation of new efferent lymphatic vessels. Healthy autologous lymph nodes can be transferred from the groin or other suitable donor sites. Supraclavicular lymph node flaps can be used as advancing lymphoid tissue flaps [Reference 16]. Supraclavicular lymph node flaps are commonly used in the treatment of lymphedema without complications at the donor site. The connection of scaffolds between two lymph nodes in the neck region has been tested in a mouse model, and it has been demonstrated that new lymphatic channels are formed between deep cervical lymph nodes and superficial cervical lymph nodes two months after implantation of aligned nanofiber collagen scaffolds (BioBridge TM ).

[0038] Example 4.

[0039] Implanted scaffolds are used to enhance metastatic lymph nodes and improve their integration with the lymphatic system, see Figure 3 . The first scaffold is implanted to connect the cribriform plate lymphatic vessels with the metastatic lymph node, and the second scaffold is implanted to connect the metastatic lymph node with healthy lymphatics below the metastatic lymph node to induce the formation of new efferent lymphatic vessels.

[0040] Example 5.

[0041] Figure 4 Shown are implanted linear scaffolds and LVA in the neck region, which connect healthy lymphatic vessels extending from meningeal lymphatics with veins. Implanted scaffolds are used to enhance the flow of lymphatic fluid from meningeal lymphatics to the LVA region. There is clinical evidence [17, 18] that implantation of aligned nanofiber collagen scaffolds (BioBridge TM ) near the LVA induces the formation of new lymphatic vessels in patients with upper and lower limb lymphedema.

[0042] Example 6.

[0043] Figure 5 Shown are implanted linear scaffolds and LVA in the neck region, which connect healthy lymphatic vessels extending from meningeal lymphatics with veins. Implanted scaffolds are used to connect deep cervical lymph nodes with degenerated efferent lymphatic vessels and the LVA region, induce the formation of new efferent lymphatic vessels and enhance CNS antigen surveillance.

[0044] Example 7.

[0045] Figure 6Shows implanted linear scaffolds and LVA in the neck region, which connect healthy lymphatic vessels to veins. A first scaffold is implanted to connect deep cervical lymph nodes with degenerated efferent lymphatic vessels and the LVA region, inducing the formation of new efferent lymphatic vessels and enhancing CNS antigen surveillance. A second scaffold is implanted to connect meningeal lymphatic vessels to the region near the LVA, inducing the formation of new lymphatic vessels from meningeal lymph flow to the vicinity of the LVA and enhancing CSF flow.

[0046] Example 8.

[0047] Human recombinant VEGF-C was reconstituted in 4 mM HCl and mixed with a purified porcine type I collagen solution (3 mg / ml, dissolved in 4 mM HCl). Collagen microspheres (CMS) filled with VEGF-C (20 ng VEGF-C per mg of collagen) with a particle size of 1 - 2 microns were prepared using a spray drying system. The VEGF-C release of this material was tested in vitro by ELISA, and the VEGF-C bioactivity was tested in EC cultures. The ratio of VEGF-C to collagen was selected based on the dose delivered in vivo in a mouse AD model [Reference 19]. A suspension of CMS in PBS solution with a collagen concentration of 40 mg / ml was injectable into the dura mater through a 30G needle to form an injectable scaffold that could provide sustained release of VEGF-C to increase meningeal lymphatic vessel capacity and flow in the CNS.

[0048] It should be understood that the terms "the present invention" or "invention" as used herein should not be construed to mean that there is only one invention having a single fundamental element or group of elements. Similarly, it should also be understood that the terms "the present invention" or "invention" encompass several independent innovations, each of which may be regarded as a separate invention. Although the present invention has been described in detail in connection with the preferred embodiments and their accompanying drawings, it will be apparent to those skilled in the art that various adjustments and modifications can be made to the embodiments of the present invention without departing from the spirit and scope of the present invention. Therefore, it should be understood that the detailed description and drawings set forth above are not intended to limit the scope of the present invention, which should be inferred only from the following claims and their legally equivalent proper interpretations.

[0049] References

[0050] 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: 25523424

[0051] 2. Chachaj A, 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: 35410605

[0052] 3. Maloveská M, Humeník F, Vikartovská Z, et al. Brain fluid channels for metabolite removal. Physiol Res 2022; 71(2): 199-208. http: / / dx.doi.org / 10.33549 / physiolres.934802 PMID: 35344669

[0053] 4. Pappolla M, Sambamurti K, Vidal R, Pacheco-Quinto J, Poeggeler B, Matsubara E. Evidence for lymphatic Aβ clearance in Alzheimer’s transgenic mice. Neurobiol Dis 2014; 71: 215-9. http: / / dx.doi.org / 10.1016 / j.nbd.2014.07.012 PMID: 25102344

[0054] 5. Pappolla MA, Matsubara E, Vidal R, et al. Melatonin treatment enhances Aβ lymphatic clearance in a transgenic mouse model of amyloidosis. Curr Alzheimer Res 2018;15(7):637-42. http: / / dx.doi.org / 10.2174 / 1567205015666180411092551 PMID:29637859

[0055] 6. Bianchi A, Visconti G, Hayashi A, Santoro A, Longo V, Salgarello M. Ultra-Highfrequency ultrasound imaging of lymphatic channels correlates with their histological features: A step forward in lymphatic surgery. J Plast Reconstr Aesthet Surg. 2020 Sep;73(9):1622-1629.

[0056] 7. Carare RO, Aldea R, Agarwal N, Bacskai BJ, Bechman I, Boche D, Bu G, Bulters D, Clemens A. Clearance of interstitial fluid (ISF) and CSF (CLIC) group - part of Vascular Professional Interest Area (PIA): Cerebrovascular disease and the failure of elimination of Amyloid-β from the brain and retina with age and Alzheimer's disease - Opportunities for Therapy. Alzheimers Dement(Amst). 2020;12(1):e12053.

[0057] 8. Hadamitzky C, Zaitseva TS, Bazalova-Carter M, Paukshto MV, Hou L, Strassberg Z, Ferguson J, Matsuura Y, Dash R, Yang PC, Kretchetov S, Vogt PM, Rockson SG, Cooke JP, Huang NF. Aligned nanofibrillar collagen scaffolds–Guiding lymphangiogenesis for treatment of acquired lymphedema. Biomaterials 2016, 102, 259–267.

[0058] 9. Christiana Raymond-Pope, Tatiana Zaitseva, Eduard Yakubov, Daniel Hoffman, Benjamin Corona, Michael Paukshto, Sarah Greising. Optimizing growth factor mRNA delivery in a bioengineered aligned scaffold to treat volumetric muscle loss. 2022 Military Health System Research Symposium. Poster. 2022. https: / / news.cehd.umn.edu / raymond-pope-presents-at-the-2022-military-health-system-research-symposium /

[0059] 10. Zaitseva TS, Yang G, Dionyssiou D, Zamani M, Sawamura S, Yakubov E, Ferguson J, Hallett RL, Fleischmann D, Paukshto MV, Huang NF. Delivery of hepatocyte growth factor mRNA from nanofibrillar scaffolds in a pig model of peripheral arterial disease. Regen Med. 2020 06;15(6):1761-1773.

[0060] 11. Hu C, Zaitseva TS, Alcazar C, Tabada P, Sawamura S, Yang G, Borrelli MR, Wan DC, Nguyen DH, Paukshto MV, Huang NF. Delivery of Human Stromal VascularFractionCells on Nanofibrillar Scaffolds for Treatment of Peripheral ArterialDisease. FrontBioeng Biotechnol. 2020;8:689.

[0061] 12. Zaitseva TS, Alcazar C, Zamani M, Hou L, Sawamura S, Yakubov E, HopkinsM, Woo YJ, Paukshto MV, Huang NF. Aligned Nanofibrillar Scaffolds for ControlledDelivery ofModified mRNA. Tissue Eng Part A. 2019 01;25(1 - 2):121 - 130.

[0062] 13. Ngan F. Huang, Tatiana Zaitseva, Cynthia Alcazar, Maedeh Zamani, EduardYakubov, Greg King, Michael Paukshto. Delivery of Modified mRNA-LoadedAlignedNanofibrillar Scaffolds for Treatment of Traumatic MuscleInjury. Society forBiomaterials 2018 Annual Meeting. Poster.

[0063] 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.

[0064] 15. Huang NF, Okogbaa J, Lee JC, Jha A, Zaitseva TS, Paukshto MV, Sun JS, Punjya N, Fuller GG, Cooke JP. The modulation of endothelial cell morphology, function, and survival using anisotropic nanofibrillar collagen scaffolds. Biomaterials. 2013.34:4038-4047.

[0065] 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. J Reconstr Microsurg. 2023 Jul 05.

[0066] 17. Nguyen D, Zaitseva TS, Zhou A, Rochlin D, Sue G, Deptula P, Tabada P, Wan D, Loening A, Paukshto M, Dionyssiou D. Lymphatic regeneration after implantation of aligned nanofibrillar collagen scaffolds: Preliminary preclinical and clinical results. J Surg Oncol. 2022 Feb;125(2):113 - 122.

[0067] 18. Nguyen DH, Zhou A, Posternak V, Rochlin DH. Nanofibrillar Collagen Scaffold Enhances Edema Reduction and Formation of New Lymphatic Collectors after Lymphedema Surgery. Plast Reconstr Surg. 2021 Dec 1;148(6):1382 - 1393.

[0068] 19. Da Mesquita S, Louveau A, Vaccari A, Smirnov I, Cornelison RC, Kingsmore KM, Contarino C, Onengut - Gumuscu S, Farber E, Raper D, Viar KE, Powell RD, Baker W, Dabhi N, Bai R, Cao R, Hu S, Rich SS, Munson JM, Lopes MB, Overall CC, Acton ST, Kipnis J. Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease. Nature. 2018 08;560(7717):185 - 191.

[0069] 20. Bianchi LMG, Irmici G, Cè M, D'Ascoli E, Della Pepa G, Di Vita F, Casati O, Soresina M, Menozzi A, Khenkina N, Cellina M. Diagnosis and Treatment of Post-Prostatectomy Lymphedema: What's New?Curr Oncol. 2023 Apr 25;30(5):4512-4526.

[0070] 21. Inchauste SM, Nguyen DH, and Ming-Huei Cheng. Animal Study and Cadaver Dissection of Lymphedema. In book: Principle of Lymphatic System. Elsevier, 2022.

[0071] 22. Chin-Yu Yang, Ines E. Tinhofer, Dung Nguyen, Ming-Huei Cheng. Enhancing lymphangiogenesis and lymphatic drainage to vascularized lymph nodes with nanofibrillar collagen scaffolds. J Surg Oncol. 2022;1-7.

[0072] 23. Deptula P, Zhou A, Posternak V, He H, Nguyen D. Multimodality Approach to Lymphedema Surgery Achieves and Maintains Normal Limb Volumes: A Treatment Algorithm to Optimize Outcomes. J Clin Med. 2022 Jan 25;11(3):598.

[0073] 24. Attier-Zmudka J, Sérot JM, Valluy J, Saffarini M, Macaret AS, Diouf M, Dao S, Douadi Y, Malinowski KP, Balédent O. Decreased Cerebrospinal Fluid Flow Is Associated With Cognitive Deficit in Elderly Patients. Front Aging Neurosci. 2019;11:87.

[0074] 25. Loureiro-Campos E, Pinto L, Mendanha A. CSF circulation regulates depression: do not disturb the flow!Mol Psychiatry. 2021 12;26(12):7072 - 7073.

[0075] 26. Noé FM, Marchi N. Central nervous system lymphatic unit, immunity, and epilepsy: Is there a link?Epilepsia Open. 2019 Mar;4(1):30 - 39.

[0076] 27. Kelly L, Brown C, Michalik D, Hawkes CA, Aldea R, Agarwal N, Salib R, Alzetani A, Ethell DW, Counts SE, de Leon M, Fossati S, Koronyo-Hamaoui M, Piazza F, Rich SA, Wolters FJ, Snyder H, Ismail O, Elahi F, Proulx ST, Verma A, Wunderlich H, Haack M, Dodart JC, Mazer N, Carare RO. Clearance of interstitial fluid (ISF) and CSF (CLIC) group - part of Vascular Professional Interest Area (PIA), updates in 2022 - 2023. Cerebrovascular disease and the failure of elimination of Amyloid-β from the brain and retina with age and Alzheimer's disease: Opportunities for therapy. Alzheimers Dement. 2023 Oct 28.

Claims

1. A method for increasing the fluid flow within the central nervous system of a subject in need, the method comprising: A biocompatible scaffold is implanted into the head or neck of the subject, wherein the scaffold induces directed lymphatic regeneration and the formation of complementary lymphatic pathways, thereby causing an additional influx of cerebrospinal fluid and / or extracellular fluid from the central nervous system into the circulatory system of the subject.

2. A method for increasing cerebrospinal fluid turnover in a subject in need thereof, the method comprising: A biocompatible scaffold is implanted into the head or neck of the subject, wherein the scaffold induces directed lymphangiogenesis, thereby resulting in an increase in cerebrospinal fluid turnover in the subject.

3. The method of claim 1 or claim 2, wherein the subject has Alzheimer's disease or Parkinson's disease or stroke or traumatic brain injury or other related neurological diseases affected by the brain clearance system.

4. The method of claim 1, wherein the scaffold supports the flow of cerebrospinal fluid and / or extracellular fluid of the subject and induces the formation of complementary lymphatic pathways from the dura mater to the head and neck circulatory system of the subject, thereby increasing the fluid flow in the central nervous system of the subject.

5. The method of claim 1 or claim 2, wherein the scaffold consists of a linear biodegradable scaffold or a group of said linear biodegradable scaffolds.

6. The method of claim 1 or claim 2, wherein the scaffold is an injectable scaffold.

7. The method of claim 5, wherein the linear scaffold comprises a bundle of threads made of a biodegradable material, or multiple strands of filaments, or fibers, or fibrils, such that the bundle supports capillary flow of cerebrospinal fluid and / or extracellular fluid along the bundle in the direction of the bundle.

8. The method of claim 5, wherein the linear scaffold has a multi-lumen or multi-channel structure, such that the linear scaffold can enable the flow of cerebrospinal fluid and / or extracellular fluid along the direction of the linear scaffold.

9. The method of claim 5, wherein the linear scaffold comprises a biodegradable material selected from the following: collagen, fibronectin, fibrin, laminin, elastin, hyaluronic acid, chitosan, silk, peptides, block copolymers, lactide and glycolide polymers, caprolactone polymers, hydroxybutyric acid, polyanhydrides and polyesters, polyphosphates, porous silicon, polyphosphoesters, polyethylene glycol (PEG) and polyethylene oxide (PEO), including PEG and PEO with different terminal functional groups, as well as bifunctional crosslinking agents and crosslinking substances, or combinations of the above materials.

10. The method of claim 5, wherein the linear scaffold comprises aligned nanofiber biopolymers.

11. The method of claim 1 or claim 2, wherein the scaffold comprises a growth factor that promotes lymphangiogenesis.

12. The method of claim 1 or claim 2, wherein the scaffold comprises a nucleic acid that promotes lymphangiogenesis.

13. The method of claim 1 or claim 2, wherein the scaffold comprises cells that repair lymphatics.

14. The method of claim 13, wherein the cells are autologous or allogeneic endothelial cells or endothelial progenitor cells.

15. The method of claim 2, wherein the scaffold is implanted into the dura mater to increase meningeal lymphatic capacity and enhance cerebrospinal fluid turnover.

16. The method of claim 4, wherein the linear stent is implanted subcutaneously in the head of the subject such that a first end of the linear stent remains near functional lymphatics of the head and neck lymphatic system, and a second end of the linear stent passes through the skull into the dura mater near meningeal lymphatics.

17. The method of claim 6, wherein the injectable stent comprises a biodegradable material 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 acid, polyanhydrides and polyesters, polyphosphates, porous silicon, polyphosphoesters, polyethylene glycol (PEG) and poly(ethylene oxide) (PEO), including PEG and PEO with different end functional groups, and bifunctional crosslinkers and crosslinking substances, or combinations of the foregoing materials.

18. The method of claim 6, wherein the injectable stent comprises collagen microspheres containing a growth factor or nucleic acid or cell that promotes lymphangiogenesis.

19. The method of claim 11 or claim 18, wherein the growth factor is human VEGFC / D, or fibroblast growth factor, or hepatocyte growth factor, or platelet-derived growth factor, or insulin-like growth factor, or other growth factor that promotes lymphangiogenesis.

20. The method of claim 1, wherein increasing fluid flow within the central nervous system of the subject is combined with immunotherapy or other methods of removing central nervous system waste and preventing infection.

21. The method of claim 2, wherein increasing cerebrospinal fluid turnover within the central nervous system of the subject is combined with immunotherapy or other methods of removing central nervous system waste and preventing infection.

22. The method of claim 1 or claim 2, wherein implantation of the biocompatible stent is performed in conjunction with an imaging method to identify healthy and pathologic lymph nodes and lymphatics of the CSF / ISF drainage lymphatic system, and / or to identify meningeal lymphatics, and / or to identify and target the openings in the jugular foramen and cribriform plate.

Images