Structure for intracorporeal spacer and method of use thereof

Abstract

In some aspects, the present disclosure relates to a hydrogel fixation structure comprising an anchoring element configured to anchor the structure to body tissue and a hydrogel retention element configured to retain a mass of hydrogel. Other aspects of the present disclosure include a kit comprising such a hydrogel fixation structure. Other aspects of the present disclosure relate to a method comprising the steps of: (a) delivering a structure comprising a hydrogel retention element into a subject comprising first and second tissues such that the hydrogel retention element can be disposed between the first and second tissues, and (b) delivering a hydrogel to the structure such that the hydrogel is loaded onto and / or into the hydrogel retention element and retained in place by the hydrogel retention element.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority under 35 U.S.C. §119 to U.S. Provisional Patent Application No. 61 / 987,449, filed on March 10, 2020, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure relates to anchoring structures and methods of in vivo spacing using the same. Background Art

[0004] Patients with locally advanced pancreatic cancer (LAPC) survive longest when they receive chemotherapy, surgical resection, and advanced external beam radiotherapy, particularly stereotactic body radiation therapy (SBRT). It is well known that increasing the dose of SBRT can prolong survival. Increasing current radiation dose levels, which are not limited by SBRT machines, may further prolong survival. However, there are other limitations. In this regard, due to the basic principles of radiation therapy, some radiation dose is delivered to tissues adjacent to a given treatment target tissue (e.g., a tumor). This unintended radiation dose to adjacent tissues, such as the gastrointestinal (GI) system (e.g., stomach, duodenum, intestines) in the case of pancreatic tumors, leads to toxic side effects, which range from vomiting and pain to ulcers and internal bleeding. Higher SBRT doses to the target pancreatic tissue result in higher doses to the GI tissue, which leads to increased side effects.

[0005] To reduce the incidence of toxic side effects, it is necessary to use bubbles (i.e., small clumps) of suitable hydrogel spacer material to reduce unintended doses to adjacent tissues. However, the inventors believe that two factors may limit the efficacy of this approach, particularly when used to separate the stomach from the pancreas. First, the hydrogel bubbles may reposition after injection, thereby losing their protective effect. For intense SBRT, patients typically undergo 5-30 treatments on separate days. Between the stomach and pancreas, there are some tissue features that differ along the entire length of the pancreas. In some places, it is connective tissue that attaches the two organ walls. In other places, it is a large connective tissue sac that extends further down into the abdomen. If patients receive hydrogel bubbles at the gastro-pancreatic interface, they may walk or otherwise move between SBRT sessions. This movement would therefore dislodge the stomach and pancreatic tissue that holds the bubbles in place, potentially forcing the bubbles to reposition further into the sac. Upon returning for further SBRT, the protective GI spacing would no longer be present, and toxic side effects would increase. In contrast, there is no pouch between the pancreas and the duodenum (i.e., the curved GI tube downstream of the stomach) to facilitate the repositioning of such bubbles, so injections in this area are not easily repositioned. Second, gastric tissue may fold between multiple small hydrogel bubbles along the direction of the pancreas, which will provide insufficient protection for the tissue. In contrast to the duodenum, where there is a small and relatively hard pancreatic head and duodenum interface, the gastric-pancreatic interface is much larger in area and the tissue is considered more flexible, making it more difficult to protect the stomach by positioning multiple clumps (bubbles) between the stomach and pancreas. When bubbles are injected into this gastric-pancreatic interface, the stomach and pancreas may compress around each bubble. Unless there are multiple bubbles covering the entire relevant interface (which may be prohibited due to the large area), it is likely that gastric tissue will sag between the bubbles and enter the higher radiation dose area.

[0006] The above-referenced and other problems may be addressed by the present disclosure, which relates to devices and methods that can be used to protect tissue, including gastrointestinal tissue, by separating such tissue from treatment target tissue using a hydrogel and a structure configured to hold the hydrogel in place. Summary of the Invention

[0007] In some aspects, the present disclosure relates to a hydrogel fixation structure comprising an anchoring element configured to anchor the structure to body tissue and a hydrogel retention element configured to retain a hydrogel mass.

[0008] In various embodiments that may be used in conjunction with the above aspects, the tissue anchoring element can be radiopaque.

[0009] In various embodiments that may be used in combination with the above aspects and embodiments, the tissue anchoring element may be bioabsorbable.

[0010] In various embodiments, which may be used in combination with any of the above aspects and embodiments, the tissue anchoring element can comprise an adhesive.

[0011] In various embodiments that may be used in combination with any of the above aspects and embodiments, the tissue anchoring element can include at least one filament. For example, the at least one filament can be selected from a biostable metal, a bioabsorbable metal, a biostable polymer, and a bioabsorbable polymer. Alternatively or additionally, the at least one filament can be in the form of at least one curved structure, for example, an arc or a spiral. Alternatively or additionally, the at least one filament can be in the form of at least one tine. Alternatively or additionally, the at least one filament can be a shape memory filament. For example, the at least one shape memory filament can deform under a load and can return to its original shape after the load is removed, or the at least one shape memory filament can return to its original shape when it is ejected from a compressed structure.

[0012] In various embodiments, which may be used in combination with any of the above aspects and embodiments, the hydrogel retention element can be radiopaque.

[0013] In various embodiments, which may be used in combination with any of the above aspects and embodiments, the hydrogel retention element may be bioresorbable.

[0014] In various embodiments that may be used in combination with any of the above aspects and embodiments, the hydrogel retention element can be a biostable metal, a bioabsorbable metal, a biostable polymer, or a bioabsorbable polymer.

[0015] In various embodiments, which may be used in combination with any of the above aspects and embodiments, the hydrogel retention element may comprise one or more filaments.

[0016] In various embodiments, which may be used in combination with any of the above aspects and embodiments, the hydrogel retention element may comprise one or more shape memory filaments.

[0017] In various embodiments that may be used in conjunction with any of the above aspects and embodiments, the hydrogel retention element can include an expandable stent. In some of these embodiments, at least a portion of the expandable stent can include an overall shape in the form of a spiral (including helical and tapered spirals), an ellipsoid, a cone, a disc-shaped structure, or a random structure. Alternatively or additionally, at least a portion of the expandable stent can include an overall shape having shape memory.

[0018] In various embodiments that may be used in combination with any of the above aspects and embodiments, the hydrogel retention element can include a mesh formed from at least one filament. For example, the mesh can be a closed mesh having an internal volume, and / or the mesh can have an overall disk shape.

[0019] In various embodiments, which may be used in combination with any of the above aspects and embodiments, the hydrogel retention element further comprises a retained hydrogel.

[0020] Other aspects of the present disclosure relate to kits comprising (a) the hydrogel immobilization structure of any one of the above aspects and embodiments; and (b) a hydrogel or one or more raw fluids that can be cross-linked to form a hydrogel.

[0021] In various embodiments that may be used in conjunction with the above-described additional aspects, the hydrogel for the kit can include one or more monomers selected from ethylene oxide, N-vinyl pyrrolidone, hydroxyethyl acrylate, hydroxyethyl methacrylate, PEG methyl ether acrylate, and PEG methyl ether methacrylate.

[0022] In various embodiments that may be used in conjunction with the additional aspects described above, the kit can include (a) a first raw fluid comprising a reactive multi-arm polymer comprising a plurality of hydrophilic polymer arms, at least a portion of the hydrophilic polymer arms comprising one or more reactive end groups; and (b) a second raw fluid comprising a polyfunctional compound comprising functional groups that react with the reactive end groups of the reactive multi-arm polymer.

[0023] Other aspects of the present disclosure relate to methods comprising the steps of: (a) delivering a structure comprising a hydrogel retention element into a subject comprising first and second tissues such that the hydrogel retention element can be positioned between the first tissue and the second tissue; and (b) delivering a hydrogel to the structure such that the hydrogel is loaded onto and / or into the hydrogel retention element and is held in place by the hydrogel retention element and such that the hydrogel is positioned between the first tissue and the second tissue, thereby separating the first tissue from the second tissue.

[0024] In various embodiments, which may be used in combination with the other aspects described above, the structure includes an anchoring element anchorable to at least one of the first and second tissues.

[0025] In various embodiments, which may be used in combination with the other aspects and embodiments described above, the hydrogel retention element may be a closed mesh, and the mesh may be filled with hydrogel.

[0026] In various embodiments, which may be used in combination with any of the other aspects and embodiments described above, the hydrogel retention element can comprise a scaffold.

[0027] In various embodiments, which may be used in combination with any of the other aspects and embodiments above, the hydrogel can be a bioresorbable or biostable hydrogel.

[0028] In various embodiments that may be used in combination with any of the above further aspects and embodiments, the hydrogel can be delivered as a preformed hydrogel, or the hydrogel can be formed from one or more fluids that are cross-linked in the presence of a hydrogel retention element.

[0029] In various embodiments, which may be used in combination with any of the other aspects and embodiments described above, the hydrogel can be applied in the form of a fluid containing a dispersion of hydrogel particles that can be retained by a hydrogel retention element.

[0030] In various embodiments that may be used in combination with any of the other aspects and embodiments above, the hydrogel can comprise one or more monomers selected from ethylene oxide, N-vinyl pyrrolidone, hydroxyethyl acrylate, hydroxyethyl methacrylate, PEG methyl ether acrylate, and PEG methyl ether methacrylate.

[0031] In various embodiments that can be used in combination with any of the other aspects and embodiments described above, the hydrogel can comprise a cross-linked product of the following substances: (a) a reactive multi-arm polymer comprising a plurality of hydrophilic polymer arms, at least a portion of the hydrophilic polymer arms comprising one or more reactive end groups; and (b) a polyfunctional compound comprising a functional group that reacts with the reactive end groups of the reactive multi-arm polymer. In some of these embodiments, the reactive end groups can be electrophilic groups, and the functional groups can be nucleophilic groups. In some of these embodiments, the reactive end groups can be selected from N-hydroxysuccinimide esters, imidazole esters, imidazole carboxylates, and benzotriazole esters, and the functional groups can be selected from amine groups and thiol groups. In some of these embodiments, the hydrophilic polymer arms of the reactive multi-arm polymer further comprise hydrolyzable ester groups.

[0032] In various embodiments, which may be used in combination with any of the other aspects and embodiments described above, the structure and hydrogel can be delivered through a hollow needle.

[0033] In various embodiments, which may be used in combination with any of the other aspects and embodiments described above, a probe may be used to push the structure, the hydrogel, or both through the needle.

[0034] In various embodiments, which may be used in combination with any of the other aspects and embodiments described above, an endoscopic delivery structure and a hydrogel can be used.

[0035] In various embodiments that may be used in combination with any of the other aspects and embodiments above, the method can further include delivering a treatment to the subject such that a first tissue receives more treatment than a second tissue. For example, the treatment can be selected from radiation therapy, proton-based therapy, ultrasound therapy, ablation therapy, and any other or future energy delivery procedures. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figures 1A-1BSchematic diagrams of two hydrogel fixing structures according to two embodiments of the present disclosure.

[0037] Figures 2A-2D For use according to the embodiment of the present disclosure Figure 1B Schematic diagram of the structural approach.

[0038] Figures 3A-3D For use according to the embodiment of the present disclosure Figure 1A Schematic diagram of the structural approach.

[0039] Figure 4A Schematic diagram of a hydrogel immobilization structure in an unloaded configuration according to an embodiment of the present disclosure.

[0040] Figure 4B According to the embodiment of the present disclosure Figure 4A Schematic diagram of a hydrogel fixed structure being loaded into a delivery needle.

[0041] Figure 5A is a schematic diagram of a hydrogel immobilization structure in an unloaded configuration according to an embodiment of the present invention.

[0042] Figure 5B According to the embodiment of the present disclosure Figure 5A Schematic diagram of a hydrogel fixed structure being loaded into a delivery needle.

[0043] Figure 6A Schematic diagram of a hydrogel immobilization structure in an unloaded configuration according to an embodiment of the present disclosure.

[0044] Figure 6B According to the embodiment of the present disclosure Figure 6A Schematic diagram of a hydrogel fixed structure being loaded into a delivery needle.

[0045] Figure 7A Schematic diagram of a hydrogel immobilization structure in an unloaded configuration according to an embodiment of the present disclosure.

[0046] Figure 7B According to the embodiment of the present disclosure Figure 7A Schematic diagram of a hydrogel fixed structure being loaded into a delivery needle.

[0047] Figure 8A Schematic diagram of a hydrogel immobilization structure in an unloaded configuration according to an embodiment of the present disclosure.

[0048] Figure 8B According to the embodiment of the present disclosure Figure 8A Schematic diagram of a hydrogel fixed structure being loaded into a delivery needle.

[0049] Figure 9A Schematic diagram of a hydrogel immobilization structure in an unloaded configuration according to an embodiment of the present disclosure.

[0050] Figure 9B According to the embodiment of the present disclosure Figure 9A Schematic diagram of a hydrogel fixed structure being loaded into a delivery needle.

[0051] Figure 10A Schematic diagram of a hydrogel immobilization structure in an unloaded configuration according to an embodiment of the present disclosure.

[0052] Figure 10B According to the embodiment of the present disclosure Figure 10A Schematic diagram of a hydrogel fixed structure being loaded into a delivery needle.

[0053] Figure 11A Schematic diagram of a hydrogel immobilization structure in an unloaded configuration according to an embodiment of the present disclosure.

[0054] Figure 11B According to the embodiment of the present disclosure Figure 11A Schematic diagram of a hydrogel fixed structure being loaded into a delivery needle.

[0055] Figure 12A Schematic diagram of a hydrogel immobilization structure in an unloaded configuration according to an embodiment of the present disclosure.

[0056] Figure 12B According to the embodiment of the present disclosure Figure 12A Schematic diagram of a hydrogel fixed structure being loaded into a delivery needle.

[0057] Figure 13 Schematic diagram of a hydrogel-filled hydrogel retention element positioned between the stomach and pancreas according to an embodiment of the present disclosure.

[0058] Figure 14 Schematic diagram of a hydrogel-filled hydrogel fixation structure anchored to the pancreas or stomach according to an embodiment of the present disclosure.

[0059] Figure 15 Schematic diagram of a hydrogel-filled hydrogel fixation structure anchored to the pancreas or stomach according to an embodiment of the present disclosure.

[0060] Figure 16 Schematic diagram of a method for providing a hydrogel-filled hydrogel retention element between the stomach and pancreas according to an embodiment of the present disclosure. DETAILED DESCRIPTION

[0061] In various embodiments, for example, to address the issue of repositioning, a structure with tissue anchoring and hydrogel retention capabilities can be delivered to the pancreas-stomach interface prior to injection of the hydrogel bubbles. The anchoring elements of the structure will adhere to the walls of the pancreatic tissue, stomach, or both to resist movement between, for example, energy delivery procedures (e.g., SBRT, EBRT, intensity modulated radiation therapy, stereotactic radiation therapy, proton-based radiation therapy, etc.). After anchoring the structure, a hydrogel material can be injected into / onto the hydrogel retention element, and the material can engulf the support elements of the structure and lock itself to the support elements of the structure. In this way, the hydrogel can be attached to the structure, and the structure can be attached to the tissue, making the hydrogel resistant to repositioning, which allows it to continue to protect adjacent tissues during treatment.

[0062] It is noteworthy that, instead of protecting pancreatic management of gastrointestinal tissue, the various hydrogel fixation structures described herein can be used in many tissues to improve management of many systems. Furthermore, while the present disclosure emphasizes the use of hydrogel fixation structures to improve SBRT therapy, such structures can also be used for other and future localized therapies. For example, various minimally invasive ablation techniques can benefit from the use of such structures, including, for example, microwave ablation, radiofrequency ablation, irreversible electroporation ablation, cryoablation-based ablation, ultrasound ablation, or any other technique associated with dose leakage to adjacent tissues.

[0063] Figure 1A and Figure 1B Two embodiments of a hydrogel fixation structure 110 according to the present disclosure are schematically illustrated, each having an anchoring element 110a and a hydrogel retaining support element 110b.

[0064] As discussed in more detail below, materials that may be used to form the hydrogel fixation structure 110 include metals, polymers, and combinations thereof.

[0065] The materials that can be used to form the hydrogel fixation structure 110 described herein, including the anchoring element 110a, the hydrogel retaining support element 110b, and the hollow hydrogel retaining element 110b described further below, can be bioabsorbable. Alternatively or additionally, the material that can be used to form such a hydrogel fixation structure 110 can be radiopaque. For example, the hydrogel fixation structure 110 can be formed using a metal that is itself radiopaque, or the hydrogel fixation structure 110 can be primarily formed of a non-radiopaque material (e.g., a non-iodinated polymer) and a radiopaque material, and the radiopaque material can be mixed with the non-radiopaque material or coated on all or part of the non-radiopaque material. In this regard, currently, some pancreatic disease patients receive radiopaque fiducial markers injected into pancreatic tissue to improve treatment, such as external beam radiation therapy (EBRT) or stereotactic body radiation therapy (SBRT). Such markers can be seen on imaging, which allows the operator to adjust the treatment plan to better locate the disease and better prevent toxic side effects. The hydrogel fixation structure 110 described herein can have radiopaque properties to replace such markers or improve the performance of such markers.

[0066] Now combine Figures 2A-2D and Figures 3A-3D Schematic diagram depicting deployment in a patient Figure 1A and Figure 1B The hydrogel fixed structure 110 and the typical process of the related hydrogel.

[0067] First, the patient can undergo a minimally invasive gastrointestinal endoscopy as needed. After preparation, the clinician performing the procedure navigates an endoscope (e.g., an echoendoscope or other suitable endoscope) to a portion of the wall of the stomach 210 adjacent to the tumor treatment area of the pancreas 220. The clinician then pushes the hydrogel fixation structure 110 into the needle 120 of an injection needle catheter or other device such as an aspiration catheter, with the anchoring element 110a facing the distal tip of the needle 120. (Alternatively, the hydrogel fixation structure 110 can be pre-loaded into the needle 120, for example, prepared by the clinician before surgery or loaded by a third party (e.g., a manufacturer) before clinical processing.) The gauge of the needle is variable and can be, for example, an 18-gauge needle or a 22-gauge needle, among other possible gauges.

[0068] This process compresses the hydrogel fixation structure 110 circumferentially, causing the structure 110 to temporarily deform under load (e.g., similar to various capture devices that can then spring outward into tissue). If desired, the clinician can push the needle 120 through a small piece of wax to force the wax into the lumen of the needle 120, thereby locking the hydrogel fixation structure 110 in place, as is common in fiducial marker delivery. The clinician then advances the needle 120 of the injection needle catheter through the working channel and to the end of the echoendoscope (not shown), at which point the tip of the needle 120 is advanced through the wall of the stomach 210, through any additional connective tissue (not shown), through the pancreatic-gastric space 230, and into the wall of the pancreas 220, as shown. Figure 2A and 3A shown.

[0069] Once the tip of the needle 120 is properly positioned in the wall of the pancreas 220, an intra-needle probe (not shown) can be used to slowly push the hydrogel fixation structure 110 (and wax, if present) out of the tip of the needle 120. As the hydrogel fixation structure 110 exits the tip of the needle 120, the anchoring elements 110a deploy and adhere to the wall of the pancreas 220, while the hydrogel retaining scaffold elements 110b of the hydrogel fixation structure 110 remain positioned in the pancreatic-gastric space 230, as shown. Figure 2B and 3B shown.

[0070] The spacer hydrogel 130 is then injected using a suitable device (in the illustrated embodiment, the same device 120 used to deliver the hydrogel-retaining stent element 110b). For example, the clinician may slightly retract the tip of the needle 120, such as Figure 2B and 3B As shown, and loaded with a spacer hydrogel 130, as Figure 2C and 3C As shown, a spacer hydrogel 130 is then injected from the needle 120 at the needle tip location in the pancreatic-gastric space 230. During injection, hydrogel bubbles 130b will form and entangle with the hydrogel retaining scaffold element 110b of the hydrogel fixation structure 110, thereby locking the hydrogel bubbles 130b to the hydrogel retaining scaffold element 110b, which in turn is locked to the pancreatic wall via the anchoring element 110a. In certain embodiments, described in more detail below, the hydrogel can be an in situ formed hydrogel formed from one or more fluids that crosslink upon injection, further securing the hydrogel bubbles 130b to the hydrogel retaining scaffold element 110b. This process can be repeated until the clinician determines that sufficient bubbles 230b have been placed for adequate tissue protection.

[0071] While endoscopic delivery is described, it should be understood that the present disclosure is not limited to such delivery, as the hydrogel fixation structure 110 may be delivered by other delivery techniques, such as by open surgery, laparoscopic, intravascular, or percutaneous delivery, among other possibilities.

[0072] If the hydrogel fixation structure 110 and / or the hydrogel 130b itself is formed using a radiopaque material, the patient may be repeatedly imaged as needed to ensure that the hydrogel fixation structure 110 remains in place (eg, to ensure the patient is protected during multiple ablation procedures).

[0073] In the case where the hydrogel fixed structure 110 and the hydrogel bubbles 130b are formed using bioabsorbable materials, the hydrogel bubbles 130b and the hydrogel fixed structure 110 will be absorbed into the body after the process is completed.

[0074] Various embodiments related to the various anchoring elements 110a of the hydrogel fixation structure 110 of the present disclosure will now be described.

[0075] Now refer to Figure 4A , a hydrogel fixation structure 110 according to the present disclosure is shown in an unloaded configuration (i.e., an unconstrained configuration, e.g., after deployment from a constrained configuration within a needle 120) that includes an anchoring element 110a and a hydrogel retention support element 110b. The hydrogel retention support element 110b is generally shown as a shaded circle / oval and can correspond to a variety of designs, including the following in Figures 7A-7B , 8A-8B, 9A-9B, 10A-10B, 11A-11B, and 12A-12B, etc. The anchoring element 110a in the illustrated embodiment includes a plurality of tines having shape memory properties that can be used to secure the device to the pancreatic wall and other tissue structures. Although a plurality of tines that are curved backwards are shown, other designs are clearly possible. Figure 4B Shown in a restrained pre-deployment state when loaded into needle 120 Figure 4A When loaded into the needle 120, the tines will be manipulated backwards on each bend so that the tines extend and the tine tips 110t are closest to the needle opening 120t. After deployment, the tines will enter the tissue and at least partially recover to their memorized position. Figure 4A The curved shape of the ligament to secure itself to the tissue.

[0076] Figure 5A FIG. 1 is a schematic diagram of a hydrogel fixing structure 110 according to another embodiment of the present disclosure, which is shown in an unloaded (ie, unconstrained) configuration. The hydrogel fixing structure 110 includes an anchoring element 110a and a hydrogel retaining support element 110b. Figures 4A-4BLikewise, the hydrogel retaining stent element 110b is generally shown as a shaded circle / oval. The anchoring element 110a in the illustrated embodiment comprises a helical thread having shape memory properties that can be used to secure the structure 110 to the pancreatic wall and other tissue locations. Figure 5A The single helix design can also be used in a multi-helix design. Figure 5B Shown in a restrained pre-deployment state when loaded into needle 120 Figure 5A When loaded into the needle 120, the helix can be stretched to reduce the overall radius, with the tip 110t of the helix closest to the needle opening 120t. After expansion, the helix will return to its original helical shape, which can be screwed into the tissue.

[0077] Figure 6A FIG. 1 is a schematic diagram of a hydrogel fixing structure 110 according to another embodiment of the present disclosure, which is shown in an unloaded (ie, unconstrained) configuration. The hydrogel fixing structure 110 includes an anchoring element 110a and a hydrogel retaining support element 110b. Figures 4A-4B Likewise, the hydrogel retention scaffold element 110b is generally illustrated by the shaded circle / oval. The anchor element 110a in the illustrated embodiment comprises a volume of tissue adhesive material. Figure 6B Shown in a restrained pre-deployment state when loaded into needle 120 Figure 6A The device is a device in which the anchoring element 110a is positioned closest to the needle opening 120t. Depending on the unconstrained width of the volume of the tissue adhesive material and the diameter of the lumen of the needle 120, when loaded into the needle 120, the tissue adhesive material can be stretched to reduce its total width so that it fits within the lumen of the needle 120. After deployment, the tissue adhesive material contacts the tissue and attaches itself to the tissue. In addition, when stretched to fit the lumen of the needle 120, the volume of the tissue adhesive material can return to its original shape, depending on the shape memory degree of the material. In certain embodiments, a tissue adhesive material that is activated by contact with the tissue can be selected to help prevent the adhesive from inadvertently attaching to anything (e.g., the inside of the delivery mechanism) before the expected deployment. Specific examples of adhesive materials include, for example, fibrin glue, cyanoacrylate glue, and gelatin-resorcinol-formaldehyde / glutaraldehyde glue. Such materials are bioabsorbable and approved for clinical use, for example as surgical glue. Alternative tissue adhesive materials include biomimetic tissue adhesives.

[0078] Embodiments related to various hydrogel-retaining scaffold elements 110b of the hydrogel fixation structure 110 of the present disclosure will now be described.

[0079] Figure 7AFIG. 1 is a schematic diagram of a hydrogel fixation structure 110 according to an embodiment of the present disclosure, shown in an unloaded (i.e., unconstrained) configuration. The hydrogel fixation structure 110 includes an anchoring element 110a and a hydrogel retaining support element 110b. The anchoring element 110a is generally shown as a shaded triangle and can correspond to a variety of designs, including those described above. Figures 4A-4B 、 Figures 5A-5B 、 Figures 6A-6B Those designs described in et al. Figure 7A The hydrogel retaining stent element 110b in the illustrated embodiment comprises a coil frame, more specifically a helical frame, which has shape memory properties and can be used to fix the hydrogel material that is subsequently injected. Figure 7A The single helix design is typical, and a variety of other coil designs are also available.

[0080] Figure 7B Shown in a restrained pre-deployment state when loaded into needle 120 Figure 7A The device of claim 1, wherein anchoring element 110a is positioned closest to needle opening 120t. When loaded into needle 120, the spiral can be stretched to reduce the overall radius so as to fit within the lumen of needle 120. Upon deployment, the spiral frame will return to its original shape and can be at least partially positioned in the space between the patient's pancreas and gastrointestinal system (or any other tissue that is desired to be separated). The hydrogel material can then be injected near (e.g., into, onto, or around) the stent element 110b to maintain the position of the hydrogel relative to the pancreas (or other anchoring tissue).

[0081] Figure 8A FIG. 1 is a schematic diagram of a hydrogel fixing structure 110 according to another embodiment of the present disclosure, which includes an anchoring element 110a and a hydrogel retaining support element 110b and is shown in an unloaded (ie, unconstrained) configuration. Figures 7A-7B , the anchoring element 110a is generally shown as a shaded triangle. The hydrogel retaining stent element 110b in the illustrated embodiment comprises a spherical frame having shape memory properties. Figure 8A In addition to the spherical design shown, a variety of other designs may be used, including spherical designs other than the vertically supported embodiment shown, and shapes other than spheres, such as oblate spheroids and prolate spheroids. Figure 8B Shown in a restrained pre-deployment state when loaded into needle 120 Figure 8A1. The present invention provides a device in which the anchoring element 110a is positioned closest to the needle opening 120t. When loaded into the needle 120, the spherical frame can be elongated to reduce the overall radius so that it fits within the lumen of the needle 120. Upon deployment, the spherical frame will return to its original shape and can be positioned at least partially in the space between the patient's pancreas and gastrointestinal system (or any other tissue that is desired to be separated). The hydrogel material can then be injected into the space near the support element 110b to maintain the position of the hydrogel relative to the pancreas (or other anchoring tissue).

[0082] Figure 9A FIG2 is a schematic diagram of a hydrogel fixation structure 110 according to another embodiment of the present disclosure, which includes an anchoring element 110a and a hydrogel retaining support element 110b, and is shown in an unloaded (i.e., unconstrained) configuration. As described above, the anchoring element 110a is generally shown as a shaded triangle. The hydrogel retaining support element 110b in the illustrated embodiment includes a tapered frame having shape memory properties. Figure 9A In addition to the particular design of FIG, a variety of other designs may be employed, including tapered designs in addition to the vertically supported embodiment shown. Figure 9B Shown in a restrained pre-deployment state when loaded into needle 120 Figure 9A 120t. When loaded into the needle 120, the tapered frame can be elongated to reduce the overall radius so that it fits within the lumen of the needle 120. Upon deployment, the tapered frame will return to its original shape and can be positioned at least partially in the space between the patient's pancreas and gastrointestinal system (or any other tissue that is desired to be separated). The hydrogel material can then be injected into the space near the stent element 110b to maintain the position of the hydrogel relative to the pancreas (or other anchoring tissue).

[0083] Figure 10A FIG1 is a schematic diagram of a hydrogel fixing structure 110 according to another embodiment of the present disclosure, which includes an anchoring element 110a and a hydrogel retaining support element 110b, and is shown in an unloaded (i.e., unconstrained) configuration. As described above, the anchoring element 110a is generally shown as a shaded triangle. The hydrogel retaining support element 110b in the illustrated embodiment includes an umbrella-shaped frame having shape memory properties. Figure 10A In addition to the particular design of FIG, a variety of other designs may be employed, including umbrella-shaped designs other than those based on a disc-shaped expandable portion as shown. Figure 10B Shown in a restrained pre-deployment state when loaded into needle 120 Figure 10A1. The present invention provides a device in which the anchoring element 110a is positioned closest to the needle opening 120t. When loaded into the needle 120, the umbrella-shaped frame can be stretched and compressed to reduce the overall radius so that it fits within the lumen of the needle 120 as shown. When deployed, the umbrella-shaped frame will return to its original shape and can be positioned at least partially in the space between the patient's pancreas and gastrointestinal system (or any other tissue that is desired to be separated). The hydrogel material can then be injected into the space near the support element 110b to maintain the position of the hydrogel relative to the pancreas (or other anchoring tissue).

[0084] Figure 11A FIG2 is a schematic diagram of a hydrogel fixation structure 110 according to another embodiment of the present disclosure, which includes an anchoring element 110a and a hydrogel retaining support element 110b, and is shown in an unloaded (i.e., unconstrained) configuration. As described above, the anchoring element 110a is generally shown as a shaded triangle. The hydrogel retaining support element 110b in the illustrated embodiment includes a mesh frame having shape memory properties. Figure 11A In addition to the specific design of , a variety of other designs may be employed, including mesh designs other than those based on integrally tapered expandable sections as shown. Figure 11B Shown in a restrained pre-deployment state when loaded into needle 120 Figure 11A 1. The present invention provides a device in which the anchoring element 110a is positioned closest to the needle opening 120t. When loaded into the needle 120, the mesh frame can be stretched and compressed to reduce the overall radius so that it fits within the lumen of the needle 120 as shown. Upon deployment, the mesh frame will return to its original shape and can be positioned at least partially in the space between the patient's pancreas and gastrointestinal system (or any other tissue that is desired to be separated). The hydrogel material can then be injected into the space near the support element 110b to maintain the position of the hydrogel relative to the pancreas (or other anchoring tissue).

[0085] Figure 12A FIG2 is a schematic diagram of a hydrogel fixation structure 110 according to another embodiment of the present disclosure, which includes an anchoring element 110a and a hydrogel retaining support element 110b, and is shown in an unloaded (i.e., unconstrained) configuration. As described above, the anchoring element 110a is generally shown as a shaded triangle. The hydrogel retaining support element 110b in the illustrated embodiment includes a helical frame having shape memory properties. Figure 12A In addition to the specific design of , a variety of other designs may be used, including spiral designs other than those based on an overall conical spiral design as shown, including helical spirals. Figure 12B Shown in a restrained pre-deployment state when loaded into needle 120 Figure 12A1. The device of claim 1, wherein anchoring element 110a is positioned closest to needle opening 120t. When loaded into needle 120, the helical frame can be stretched and compressed to reduce the overall radius so as to fit within the lumen of needle 120 as shown. Upon deployment, the helical frame will return to its original shape and can be positioned at least partially in the space between the patient's pancreas and gastrointestinal system (or any other tissue desired to be separated). The hydrogel material can then be injected into the space near stent element 110b to maintain the position of the hydrogel relative to the pancreas (or other anchoring tissue).

[0086] The dimensions of the hydrogel-retaining scaffold elements 110b of the present disclosure can vary widely, with typical unloaded dimensions ranging from 0.2 to 5 cm in height and 0.2 to 5 cm in width.

[0087] It should be noted that although various hydrogel fixation structures 110 described herein include a single anchoring element 110a, other embodiments may include two or more anchoring elements 110a. Additionally, although various hydrogel fixation structures 110 described herein include a single hydrogel retention support element 110b, other embodiments may include two or more hydrogel retention support elements 110b.

[0088] Various embodiments are also provided herein that employ a hydrogel fixation structure comprising a hollow hydrogel retention element that can provide a large, continuous mass of hydrogel to ensure consistent spacing between adjacent tissues, such as the stomach and pancreas. In various embodiments, such a hydrogel fixation structure can further comprise one or more anchoring elements that help hold the hollow hydrogel retention element in place.

[0089] As with the hydrogel retention stent elements described above, the hollow hydrogel retention elements described herein and any anchoring elements associated with the hollow hydrogel retention elements can be bioabsorbable, radiopaque, or both.

[0090] Figure 13 One embodiment is schematically illustrated, showing a hollow hydrogel retention element 110b comprising a continuous mass of hydrogel, wherein the hydrogel retention element 110b and the hydrogel therein can resist pressure exerted by the stomach 210 and pancreas 220 against each other. In the illustrated embodiment, the hollow hydrogel retention element 110b can be in the form of a hollow mesh. In certain embodiments, an expandable mesh can be provided that applies tension to the hydrogel to resist deformation of the hydrogel due to any pressure exerted on the hydrogel by the stomach 210 and pancreas 220, thereby ensuring spacing.

[0091] In these embodiments, when the mesh and hydrogel expand together, the mesh and hydrogel can form a monolithic disc-shaped hydrogel-fixing structure. Preferably, as the mesh is filled with hydrogel, the thickness of the disc expands while limiting radial expansion. The mesh selected is advantageously sufficiently dense so that any injected hydrogel does not leak through gaps in the mesh as the mesh expands. This parameter will depend on the properties of the specific hydrogel selected.

[0092] As described above, to prevent the mesh-hydrogel system from migrating within the abdomen, the mesh-hydrogel system can be anchored to the stomach, pancreas, or both. Several possible anchoring embodiments are discussed below.

[0093] For example, reference Figure 16 , a biocompatible adhesive 110a can be applied to the hollow hydrogel retaining element 110b before deployment, which is then delivered and attached to the surface of the target tissue, such as the pancreas 220 and / or stomach 210, after which the hollow hydrogel retaining element 110b is filled with hydrogel.

[0094] In, for example Figure 4A 、 4B In other embodiments shown, adhesive 110a can be delivered to the tissue prior to delivery of the hollow hydrogel retention element 110b. For example, where the hollow hydrogel retention element 110b is a mesh, pre-delivery of adhesive 110a can prevent the mesh from self-adhesion or tangling. The adhesive can be delivered via the same device used to deliver the mesh to the target site.

[0095] In other embodiments, one or more tines 110a (eg, spikes) may be employed that cover one or more filaments of the mesh 110b and penetrate into the tissue of the pancreas 220 or stomach 210, as in Figure 15 For example, one or more tines 110a can be used to anchor the mesh 110b to the pancreas 220 proximal to a tumor in the pancreas, where spacing is critical. Like the mesh 110b, the tines 110a can be bioabsorbable, radiopaque, or both.

[0096] The dimensions of the hollow hydrogel retention elements of the present disclosure, including the mesh, will vary depending on the site of implantation. In the case where the hollow hydrogel retention element is used to separate a tumor from the stomach, the dimensions of the expanded hollow hydrogel retention element can range from, for example, 0.5 to 5 cm in height, typically 1 to 3 cm in height, and having a width of approximately 1 to 5 times the height, among other possibilities.

[0097] Now combine Figure 16 Schematic diagram depicting the typical process of deploying the mesh-hydrogel system in a patient.

[0098] First, the patient can be prepared for a gentle, minimally invasive gastroendoscopy procedure, as needed. After preparation, the clinician performing the procedure navigates an echoendoscope (not shown) to a portion of the wall of the stomach 210 adjacent to the tumor treatment area of the pancreas 220. The clinician then passes a needle 120 through the working channel of the echoendoscope, through the stomach wall, and possibly through additional connective tissue.

[0099] The clinician then uses a probe (not shown) to push the mesh 110b through the needle 120 and into the desired space 230 between the stomach 210 and pancreas 220. If a tine anchoring approach is used, one or more tines will be advanced through the needle 120 via a probe and delivered over the mesh 110b and into the pancreas 220 to lock the mesh 110b in place.

[0100] The clinician can then load the needle 120 with the hydrogel 130. The clinician then advances the hydrogel 130 through the needle 120 and injects the hydrogel 130 into the pancreatic-gastric space 230. During the injection, a volume of the hydrogel 130 will form and expand within the previously placed mesh 110b.

[0101] In some embodiments, upon delivery, the mesh is at least partially filled with hydrogel 130 to provide the mesh shape. Additional hydrogel can then be added to fill the mesh 110b with hydrogel 130. In some embodiments, the needle 120 can be angled and positioned proximal to the tumor so that the mesh-hydrogel system expands toward the tumor.

[0102] As described above, the hydrogel fixation structures 110 described herein, including the anchoring elements 110a, the hydrogel retention stent elements 110b, and the hollow hydrogel retention elements 110b described herein, can be formed using a material that is inherently radiopaque, or the hydrogel fixation structures 110 can be primarily formed of a non-radiopaque material (e.g., a non-iodinated polymer) and a radiopaque material, which can be mixed with or coated on all or a portion of the non-radiopaque material forming the hydrogel fixation structure 110. Also as described above, all or a portion of the hydrogel fixation structures 110 described herein can be formed of a bioabsorbable material, making them temporary.

[0103] Such temporary hydrogel fixation structure 110 can be designed to maintain sufficient shape and function until a given treatment regimen is completed. In addition, if the structure is matched with the bioabsorbable hydrogel 130, both the hydrogel fixation structure 110 and the hydrogel 130 can be decomposed without leaving behind (or leaving behind minimal) material.

[0104] Various materials used in conjunction with the present disclosure will now be described.

[0105] The materials of the tines and hydrogel-retaining stent elements described herein include various shape memory metals, including nickel-titanium alloys or other polycrystalline or lightweight alloys, such as copper-based, iron-based, cobalt-based, nickel-based, titanium-based, magnesium-based, and aluminum-based alloys. The materials of the tines and hydrogel-retaining stent elements described herein further include magnesium-based metals having shape memory. For example, see Daniel J. Hoh, M.D., et al., “Shape Memory Alloys: Metallurgy, Biocompatibility, and Biomechanics for Neurosurgical Applications,” Operative Neurosurgery, Vol. 64, No. 5, May 1, 2009, pp. 199-214, and Yukiko Ogawa et al., “A lightweight shape-memory magnesium alloy,” Science, Vol. 353, No. 6297, July 22, 2016, pp. 368-370. Materials for hydrogel-retaining stent elements also include shape-memory polymers. In this regard, there are various bioresorbable shape memory polymers, including those based on poly(propylene carbonate) (PPC), poly(ε-caprolactone) (PCL), oligo(ε-caprolactone) (OCL), polyurethane, poly(lactide-co-glycolide) (PLGA), and poly(ethylene glycol) (PEG).

[0106] To improve performance (e.g., improved adhesion, improved biocompatibility, improved safety, improved spacing efficacy, provision of additional therapeutic agents, etc.), the hydrogel fixation structure 110 described herein can have various coatings. For example, to improve adhesion between the hydrogel and the hydrogel retention element 110b of the hydrogel fixation structure 110 described herein, the hydrogel retention element 110b can be coated with a polymer comprising one or more monomers corresponding to the one or more monomers of the hydrogel. For example, if the hydrogel comprises ethylene oxide, the hydrogel retention element 110b can be coated with a polymer comprising ethylene oxide (e.g., PEO); if the hydrogel comprises N-vinyl pyrrolidone, the hydrogel retention element 110b can be coated with a polymer comprising N-vinyl pyrrolidone; if the hydrogel comprises hydroxyethyl acrylate, the hydrogel retention element 110b can be coated with a polymer comprising hydroxyethyl acrylate; if the hydrogel comprises hydroxyethyl methacrylate, the hydrogel retention element 110b can be coated with a polymer comprising hydroxyethyl methacrylate, and so on. Alternatively or additionally, the hydrogel fixation structure 110 described herein may also have a coating, such as a conventional coating, a stealth coating, a drug eluting coating, etc. For examples of coatings that enhance biocompatibility, see, for example, OF Bertrand et al., “Biocompatibility aspects of new stent technology,” J. Am. Coll. Cardiol., 32(3) (1998), pp. 562-571 and P. Mandracci et al., “Surface treatments and functional coatings for biocompatibility improvement and bacterial adhesion reduction in dental implantology,” Coatings, 6(1) (2016), pp. 1-22.

[0107] As used herein, hydrogel materials include biostable and bioerodible hydrogels, as well as hydrogels that may be preformed or in situ formed, which may be formed from one or more fluids that cross-link upon injection.

[0108] In certain embodiments, the hydrogel material may include a cross-linked product of (a) a reactive multi-arm polymer and (b) a multifunctional compound, wherein the reactive multi-arm polymer includes a core region and multiple hydrophilic polymer arms including one or more reactive end groups, and the multifunctional compound includes functional groups that react with the reactive end groups of the reactive multi-arm polymer.

[0109] The hydrophilic polymer arms can be formed from one or more hydrophilic monomers, examples of which can be selected from ethylene oxide, N-vinyl pyrrolidone, hydroxyethyl acrylate, hydroxyethyl methacrylate, PEG methyl ether acrylate, and PEG methyl ether methacrylate. In some embodiments, the hydrophilic polymer arms can include hydrolyzable ester groups.

[0110] In some embodiments, the reactive end group can be an electrophilic group, and the functional group can be a nucleophilic group. In some embodiments, the reactive end group can be selected from N-hydroxysuccinimide esters, imidazole esters, imidazole carboxylates, and benzotriazole esters, and the functional group can be selected from amine groups and thiol groups.

[0111] In some embodiments, the reactive multi-arm polymer can include a core region and a plurality of hydrophilic polymer arms comprising polyethylene oxide and succinimide ester groups linked to the hydrophilic polymer arms through a hydrolyzable ester.

[0112] In some embodiments, the core region includes the residue of a polyol for forming the polymer arm. Exemplary polyols can be selected from, for example, linear, branched and cyclic aliphatic polyols including linear, branched and cyclic polyhydroxyalkanes, linear, branched and cyclic polyhydroxy ethers including polyhydroxy polyethers, linear, branched and cyclic polyhydroxy alkyl ethers including polyhydroxy alkyl polyethers, linear, branched and cyclic sugars and sugar alcohols such as glycerol, mannitol, sorbitol, inositol, xylitol, chelidonol, threitol, arabitol, erythritol, adibitol, galactitol, fucose, ribose, arabinose, xylose, lyxose, rhamnose, galactose, glucose, fructose, Sorbitol, mannose, pyranose, altrose, talose, tagatose, pyranoside, sucrose, lactose and maltose, oligomers of linear, branched and cyclic sugars and sugar alcohols (defined herein as having a range of 2-10 units including dimers, trimers, tetramers, pentamers, hexamers, heptamers, octamers, nonamers and decamers), polymers of linear, branched and cyclic sugars and sugar alcohols (defined herein as having 11 or more units) include the aforementioned sugars and sugar alcohols, starch, amylose, dextrin, cyclodextrin, as well as polyhydroxy crown ethers and polyhydroxy alkyl crown ethers. In certain beneficial embodiments, the polyol is an oligomer of a sugar alcohol such as glycerol, mannitol, sorbitol, inositol, xylitol or erythritol. In certain beneficial embodiments, the polyol may contain three or more hydroxyl groups, for example, in some cases, between four and twelve hydroxyl groups.

[0113] In some embodiments, the polyfunctional compound may include multiple amine functional groups. Specific examples of polyfunctional amines that can be used as polyfunctional compounds include trilysine, ethylenetriamine, diethylenetriamine, hexamethylenetriamine, di(heptamethylene)triamine, di(trimethylene)triamine, di(hexamethylene)triamine, triethylenetetramine, tripropylenetetramine, tetraethylenepentamine, hexamethyleneheptamine, pentaethylenehexamine, dimethyloctylamine, and dimethyldecylamine, as well as amines available from Fluntsman Corporation. Polyetheramine, etc.

[0114] The hydrogel materials used herein include polyethylene glycol (PEG) based hydrogels, such as A long-lasting bioresorbable, injectable hydrogel based on multi-arm PEG, which has been used to create or maintain a space between the prostate and the rectum to reduce the side effects of off-target radiation therapy, and Hydrogel, a bioerodible, injectable synthetic hydrogel composed primarily of water and iodinated cross-linked polyethylene glycol (PEG). See “Augmenix Announces Positive Three-year SpaceOAR Clinical Trial Results” in Imaging Technology News, October 27, 2016, and “Augmenix Receives FDA Clearance to Market its TracelT” in BusinessWire, January 28, 2013. TM Tissue Marker (Augmenix received FDA approval to market its TracelT TM tissue markers).

[0115] In some embodiments, recently developed hydrogels with tissue-adhesive properties can be used, which can eliminate the need for a separate anchoring mechanism. See, for example, Lu Han et al., "Tough, self-healable and tissue-adhesive hydrogel with tunable multifunctionality," Nature, NPG Asia Mater 9, e372 (2017) doi: 10.1038 / am.2017.33. In embodiments where the hydrogel retaining element is a mesh, such a hydrogel can be loaded directly into the mesh without the need for an additional anchoring step.

[0116] Mesh materials useful in the present disclosure include various mesh materials that can be woven into strands (thereby forming a mesh) and are sufficiently strong to overcome the forces exerted on the mesh by the outward expansion of the hydrogel. Specific materials include biostable and bioabsorbable mesh materials, which can be selected from, for example, polypropylene, polyethylene terephthalate, polytetrafluoroethylene, and poly(lactic acid), among others, including various other materials known for use in surgical mesh applications.

[0117] Adhesives used in the present disclosure include fibrin glue, gelatin-resorcinol-formaldehyde / glutaraldehyde adhesives, and various surgical adhesives, including octyl-cyanoacrylate adhesives and other adhesives that can solidify and maintain under moist conditions, solidify quickly, and are bioabsorbable over a long period of time. See, for example, Vrushali Bhagat and Matthew L. Becker, "Degradable Adhesives for Surgery and Tissue Engineering," Biomacromolecules, 2017, 18, 10, 3009-3039.

[0118] In addition to the various embodiments described herein, variations, modifications, and other implementations of the present disclosure may occur to those of ordinary skill in the art.

Claims

1. A hydrogel fixation structure comprising a tissue anchoring element and a hydrogel retention element, wherein the tissue anchoring element is configured to anchor the hydrogel fixation structure to the wall of the pancreas, the hydrogel retention element being configured to receive and retain an injected hydrogel mass after the hydrogel fixation structure is anchored to the wall of the pancreas, wherein the tissue anchoring element comprises at least one filament in the form of at least one tine and is configured to secure the tissue anchoring element to the wall of the pancreas, and wherein The hydrogel retention element includes one or more shape memory filaments and is configured to reside in the space between the walls of the stomach and pancreas.

2. The hydrogel fixed structure according to claim 1, wherein: The tissue anchoring element is radiopaque, bioabsorbable, or both radiopaque and bioabsorbable.

3. The hydrogel fixed structure according to claim 1, wherein: An injectable hydrogel mass is an in situ formed hydrogel mass formed from one or more fluids that cross-link upon injection.

4. The hydrogel fixed structure according to claim 1, wherein: The tissue anchoring element includes a plurality of filaments in the form of a plurality of curved tines.

5. The hydrogel fixed structure according to claim 1, wherein: The at least one filament is in the form of at least one curved structure.

6. The hydrogel fixed structure according to claim 1, wherein: The at least one filament is a shape memory filament.

7. The hydrogel fixed structure according to claim 1, wherein: The hydrogel retention element is radiopaque, the hydrogel retention element is bioabsorbable, or the hydrogel retention element is both radiopaque and bioabsorbable.

8. The hydrogel fixed structure according to claim 1, wherein: The hydrogel retaining element includes one or more shape memory filaments.

9. The hydrogel fixed structure according to claim 1, wherein: The hydrogel retention element is configured to be loaded into the needle in a constrained pre-deployment state and to return to an original unconstrained state when deployed from the needle.

10. The hydrogel fixed structure according to claim 9, wherein: The original unconstrained state is in the form of a sphere.

11. The hydrogel fixed structure according to claim 9, wherein: The original unconstrained state is in the form of a cone, a spiral or a tapered helix.

12. The hydrogel fixed structure according to claim 1, wherein: The hydrogel retention element is bioabsorbable, and wherein the tissue anchoring element is bioabsorbable.

13. A kit comprising (a) the hydrogel immobilization structure according to any one of claims 1 to 12, and (b) a hydrogel or one or more precursor fluids that are cross-linked to form a hydrogel.

14. The kit of claim 13, comprising a hydrogel comprising one or more monomers selected from the group consisting of ethylene oxide, N-vinyl pyrrolidone, hydroxyethyl acrylate, hydroxyethyl methacrylate, PEG methyl ether acrylate, and PEG methyl ether methacrylate.

15. The kit according to claim 13, comprising (a) a first raw fluid, the first raw fluid comprising a reactive multi-arm polymer, the reactive multi-arm polymer comprising a plurality of hydrophilic polymer arms, at least a portion of the hydrophilic polymer arms comprising one or more reactive end groups; and (b) a second raw fluid, the second raw fluid comprising a polyfunctional compound, the polyfunctional compound comprising functional groups that react with the reactive end groups of the reactive multi-arm polymer.

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