WO2025096885A1

WO2025096885A1 - Injectable delivery system and uses thereof

Info

Publication number: WO2025096885A1
Application number: PCT/US2024/054046
Authority: WO
Inventors: Cato T. Laurencin; Marc MERRIMAN; James H. Chapman; Seyyedmorteza ATTARI; Fateme HOSSEINI; Amir A. ABEDINI; Taraje WHITFIELD
Original assignee: University of Connecticut
Current assignee: University of Connecticut
Priority date: 2023-11-01
Filing date: 2024-11-01
Publication date: 2025-05-08
Anticipated expiration: 2026-05-01

Abstract

The present disclosure describes an injectable delivery system or device (also called a dual syringe system) and a method for injecting materials alone or in addition to bioactive and/or inert substances using the disclosed system or device.

Description

INJECTABLE DELIVERY SYSTEM AND USES THEREOF

RELATED APPLICATIONS

[0001] This application claims priority to U.S. Application No. 63/595,013, filed on

November 1, 2023, the contents of which are herein incorporated by reference.

GOVERNMENT SUPPORT

[0002] This invention was made with government support under AR079114 awarded by the National Institutes of Health, and 1332329 awarded by the National Science Foundation. The government has certain rights in the invention.

FIELD OF THE DISCLOSURE

[0003] The invention disclosed herein relates to an injectable delivery system and uses thereof, and particularly, to an injectable delivery system to inject implantable materials alone or in addition to bioactive and/or inert substances (such as patient-derived products, natural/synthetic polymer solutions, or hydrogels, etc.) or crystalloids (for example, normal saline) for use as an injectable therapy for biomedical applications.

BACKGROUND

[0004] At present, the predominant approach for implanting materials such as the amniotic membrane involves either open or arthroscopic surgery. Open surgery often has significant postoperative pain and extended recovery periods as it involves making large incisions while arthroscopic surgery is a less invasive surgical technique that uses smaller incisions and specific instruments to access and treat the interior of joints or other body cavities. There exists a demand for more advanced and less invasive approach for implanting materials, thereby offering patients a significantly less invasive and swifter path of recovery. SUMMARY

[0005] In an aspect, disclosed is an injectable delivery system or device as shown and described herein.

[0006] In an aspect, disclosed is a method for injecting implantable materials alone or in addition to bioactive and/or inert substances as shown and described herein.

[0007] In an aspect, disclosed is an injectable delivery system for delivering an implantable material into a tissue of a subject, the system comprising: (a) a first assembly comprising at least a first needle and a lumen into which an implantable material can be loaded for delivery into the tissue of the subject; and (b) a second assembly comprising at least a first plunger that is configured to slide bidirectionally within the lumen of the first needle to deliver the implantable material into the tissue of the subject when a user inserts the first needle into the tissue of the subject and applies an axial pressure to the at least the first plunger.

[0008] In some aspects, at least the first plunger comprises a wire, a rod, or a needle.

[0009] In other aspects, the first assembly comprises a first syringe comprising a first barrel having a first opening at one end and the first needle at an opposite end, wherein the first opening is configured to receive a second barrel of a second syringe into the first barrel of the first syringe, and the second assembly comprises a second syringe comprising a second barrel having a second opening at one end, and a piston and a second needle at an opposite end, wherein the second opening is configured to receive at least the first plunger, wherein the piston is configured to enable the second syringe barrel to slide bidirectionally within the first barrel of the first syringe, and wherein the second needle is configured to slide bidirectionally within the lumen of the first needle to deliver the implantable material into the tissue of a subject when at least the first plunger is pressed into the second opening of the second barrel of the second syringe.

[0010] In yet other aspects, the first assembly comprises a first syringe comprising a first barrel having a first opening at one end and the first needle at an opposite end, wherein the first opening is configured to receive the plunger of the second assembly, and the second assembly comprises: (i) a second syringe comprising a second barrel having the plunger slidably disposed inside the first opening of the first barrel and further comprising at least a second needle that is configured to slide bidirectionally within the lumen of the first needle to deliver the implantable material into a target tissue of a subject; and (ii) a syringe gun comprising: (1) a body comprising a syringe holder that holds the first assembly in place with at least the first plunger slidably disposed inside the first opening of the first barrel; and (2) a trigger, wherein the syringe gun is configured to cause at least the first plunger to slide bidirectionally inside the first barrel and the second needle to slide bidirectionally within the lumen of the first needle to deliver the implantable material into the tissue of the subject when a user inserts the first needle into the tissue of the subject and pulls the trigger.

[0011] In yet still other aspects, the first assembly comprises a first syringe comprising a first barrel having a second plunger at one end and the first needle at an opposite end; and the second assembly comprises: (i) a plurality of syringes positioned inside the first barrel of the first syringe, each of the plurality of syringes comprising at least a second syringe barrel comprising at least a second opening at one end and at least a third plunger at the opposite end; (ii) the at least the first plunger; and (iii) at least one tube connected to the second opening of the at least the second syringe barrel, wherein the first needle is configured to deliver the implantable material into the tissue of a subject when a user inserts the first needle into the tissue of the subject and the at least the second plunger is pressed, and wherein the plurality of syringes is configured deliver at least first fluid through the at least one tube and into the first lumen when the at least the third plunger is pressed by the user.

[0012] In further aspects, the first assembly comprises (i) at least a first needle and a lumen into which an implantable material can be loaded for delivery into the tissue of the subject; and (ii) a shell needle; and the second assembly comprises: (i) at least a first, second, third, and/or fourth syringe comprising at least a first, second, third and/or fourth fluid outlet at one end and at least a second, a third, fourth, and/or fifth plunger at the opposite end, and at least a second, third, fourth, and/or fifth barrel extending between the one end and the opposite end; (ii) an adapter connected to the at least the first, second, third and/or fourth fluid outlet configured to channel fluid flowing through the outlet into a shared lumen that is connected to the shell needle; and (iii) at least the first plunger is configured to slide bidirectionally within the shared lumen and the lumen of the first needle to deliver the implantable material into the tissue of the subject when a user inserts the first needle into the tissue of the subject and applies an axial pressure to at least the first plunger. [0013] In certain aspects, the implantable material comprises amnionic membrane (AM), an AM hydrogel or precursor thereof, or a pharmaceutical composition thereof.

[0014] In certain other aspects, the AM folded, rolled, or twisted; and/or the AM is lyophilized.

[0015] In yet certain other aspects, the first needle comprises a removable needle and the lumen of the first needle is preloaded with the implantable material before the first needle is connected to the opposite end of the first syringe.

[0016] In still other aspects, the second syringe comprises a solution preloaded inside the second barrel. In still other aspects, the first syringe comprises a solution preloaded inside the first barrel. In still other aspects, at least the second barrel of each of the plurality of syringes comprises a solution preloaded inside. In still other aspects, the at least the second, at least the third, at least the fourth, and/or at least the fifth barrel comprises a solution preloaded inside.

[0017] In some aspects, the first needle comprises a gauge ranging from about 10G to about 28G needle; or the lumen of the first needle comprises an inner diameter ranging from about 0.15 mm to about 2 mm.

[0018] In other aspects, at least second needle comprise a gauge ranging from about 12G to about 32 G; or the lumen of the at least the second needle comprises a diameter ranging from about 0.3 to about 1.8 mm.

[0019] In yet another aspect, disclosed is a kit for delivering an implantable material into a tissue of a subject, the kit comprising: (a) an injectable delivery system the present disclosure; and (b) instructions for delivering an implantable material into a tissue of a subject with the injectable delivery system.

[0020] In yet another aspect, disclosed is a method for delivering an implantable material into a target tissue of a subject, the method comprising: (a) inserting a tip of a first needle comprising a lumen with an implantable material loaded inside of it into a target tissue of a subject; and (b) depressing a plunger to cause it to slide bidirectionally within the lumen of the first needle, thereby delivering the implantable material into the target tissue of the subject.

[0021] In some aspects, the method further comprises, prior to inserting the tip of the first needle into the target tissue of the subject, loading the implantable material into the lumen of the first needle; and/or the implantable material comprises a section of amnion and loading comprises folding, rolling, or twisting the section of amnion inside the lumen.

[0022] In other aspects, the amnion is lyophilized before being loaded into the lumen of the first needle; the amnion is lyophilized after being loaded into the lumen of the first needle, and the method further comprises rehydrating the lyophilized amnion inside the lumen of the first needle; or the amnion is lyophilized inside of a tubular mold with an inner diameter that is equivalent to an inner diameter of the lumen of the first needle, and the method further comprises rehydrating the lyophilized amnion inside the lumen of the first needle.

[0023] In yet other aspects, rehydrating comprises depressing the plunger into the second barrel of the second syringe to cause a solution inside the second barrel to transfer into the lumen of the first needle into contact with the lyophilized amnion.

[0024] In yet another aspect, disclosed is a method for delivering an implantable material into a target tissue of a subject in need thereof, the method comprising: (a) obtaining a coaxial syringe assembly comprising an outer syringe and an inner syringe slidably disposed within an opening of a first barrel of the outer syringe, the outer syringe comprising a first needle comprising a first gauge comprising a lumen with a implantable material loaded inside, the inner syringe comprising a second barrel comprising a solution loaded inside and a second needle comprising a second gauge that enables the second needle to slide bidirectionally within the lumen of the first needle; and (b) positioning a tip of the first needle onto an outer surface of the subject’s skin or other lumen or tissue within the body at an injection site near the target tissue; and (c) depressing a plunger disposed within the second barrel of the inner syringe to cause the second needle to slidably move through the lumen of the first needle, thereby causing the needle to penetrate the subject’s skin or other lumen or tissue within the body and deliver the implantable material into the target tissue.

[0025] In some aspects, the method further comprises prior to depressing step (c), depressing a plunger disposed within the second barrel of the inner syringe to cause the solution loaded inside the second barrel of the inner syringe to enter through a second lumen of the second needle into the first lumen of the first needle, thereby causing the solution to contact the implantable material. [0026] In other aspects, the implantable material comprises decellularized amnion that is optionally lyophilized.

[0027] In yet another aspect, disclosed is a method for preparing to deliver an implantable material into a tissue of a subject, the method comprising: (a) connecting a first removable needle comprising a first lumen with an implantable material preloaded within it to a first end of a first barrel of an outer syringe of a coaxial syringe assembly comprising the outer syringe and an inner syringe slidably disposed within the outer syringe through a first opening at an opposite second end of the first barrel of the outer syringe; and (b) depressing a plunger into a second barrel of the inner syringe through a second opening of the second barrel proximal to the first opening at the opposite second end of the first barrel of the outer syringe to cause a solution contained within the second barrel of the inner syringe to flow through a second lumen of a second needle situated proximal to the first end of the first barrel into the first lumen of the first removable needle into contact with the implantable material inside the first lumen.

[0028] In some aspects, prior to connecting step (a), the method further comprises loading the implantable material into the first lumen of the first removable needle and/or loading the solution into the second barrel.

[0029] In yet another aspect, disclosed is a method for delivering an implantable material into a target tissue of a subject in need thereof, the method comprising: (a) obtaining a coaxial syringe assembly comprising an outer syringe and an inner syringe slidably disposed within an opening of a first barrel of the outer syringe, the outer syringe comprising a first needle comprising a first gauge comprising a lumen with a implantable material loaded inside, the inner syringe comprising a second barrel comprising a solution loaded inside and a second needle comprising a second gauge that enables the second needle to slide bidirectionally within the lumen of the first needle; (b) positioning a tip of the first needle onto an outer surface of the subject’s skin or other lumen or tissue within the body at an injection site near the target tissue; and (c) depressing a plunger disposed within the second barrel of the inner syringe to cause the second needle to slidably move through the lumen of the first needle, thereby causing the needle to penetrate the subject’s skin or other lumen or tissue within the body and deliver the implantable material into the target tissue. [0030] In some aspects, prior to depressing step (c), the method further comprises depressing a plunger disposed within the second barrel of the inner syringe to cause the solution loaded inside the second barrel of the inner syringe to enter through a second lumen of the second needle into the first lumen of the first needle, thereby causing the solution to contact the implantable material.

[0031] These and other aspects of the present invention are described in more detail below.

BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Having thus described the presently disclosed subject matter in general terms, reference will now be made to the accompanying Figures, which are not necessarily drawn to scale, and wherein:

[0033] Figure 1 shows an exemplary embodiment of an assembled delivery system of the present disclosure with all parts including, an outer or first syringe and an outer or first needle containing the amnion (the implantable material) at the tip of the outer needle while an inner or second syringe with a second or inner needle and a plunger. Note that the second needle acts like a plunger to push the amnion (the implantable material) through the first or outer needle.

[0034] Figure 2 shows disassembled components the exemplary embodiment of the assembled delivery system shown in Figure 1, where 1 is an outer or first needle that includes the implantable material such as the tissue; 2 is the outer or first syringe that holds and handles the outer needle 1 including the implantable material such as tissue; 3 is an inner or second syringe with a second plunger/inner and a second or inner needle attached to it that moves inside of the outer syringe and injects the tissue through the outer needle 1; 4 is the plunger for the inner or second syringe that can be used to inject liquids using the inner or second syringe 3.

[0035] Figure 3 depicts the main elements of an exemplary delivery system of the present disclosure, including the inner or second syringe with the inner or second needle and the plunger (the second or inner syringe assembly) that can be used to inject any suitable liquid (Left), and the outer or first syringe that is connected to the outer or first needle containing the implantable materials (for example, amniotic membrane) (Right). [0036] Figure 4 illustrates different stages of injection using an exemplary embodiment of the injectable delivery system of the present disclosure, including (1) an exemplary implantable material (e.g., lyophilized amniotic membrane) is placed inside of the 18G needle (the outer or first needle) by folding the membrane; (2) a preferred liquid solution is injected by the second or inner syringe assembly (including the second syringe, the second needle and the plunger) into the outer needle to hydrate the lyophilized membrane; (3) the inner or second syringe, the inner or second needle, and the plunger (the second syringe assembly) is placed inside the outer or first syringe to inject the implantable material (e.g., amniotic membrane).

[0037] Figure 5 shows the loading of an exemplary implantable material (e.g., amnionic membrane) into an exemplary embodiment of an injectable delivery system of the present disclosure.

[0038] Figure 6 shows the capability of an exemplary implantable material (e.g., amnionic membrane) for absorbing bioactive or inert liquids (for example, autologous blood). [0039] Figure 7 illustrates different stages of using an exemplary embodiment of an injection system of the present disclosure for the delivery of an implantable material (e.g., amniotic membrane) into rabbit’s tendon.

[0040] Figure 8 shows a process of using an exemplary embodiment of a delivery system of the present disclosure to deliver an implantable material (e.g., amniotic membrane) into rabbit’s cartilage.

[0041] Figures 9A, 9B and 9C illustrate an exemplary embodiment of the present disclosure in which the implantable material (e.g., amnion) can be lyophilized in a twisted, rolled, or folded form inside a tubular mold. Figure 9A shows an amnion membrane which has lyophilized inside of a needle shaped mold. Figure 9B shows a user of the system inserting the amnion into the first needle and Figure 9C shows the amnion partially inserted into the lumen of the first needle.

[0042] Figure 10 shows an exemplary embodiment of an injectable delivery system of the present disclosure comprising a syringe gun.

[0043] Figure 11 shows an exemplary embodiment of an injectable delivery system of the present disclosure in which the second assembly comprises a plurality of syringes inside of the first barrel of the first syringe. [0044] Figures 12A and 12B show an exemplary embodiment of an injectable delivery system of the present disclosure in which the second assembly comprises a plurality of syringes

DETAILED DESCRIPTION

[0045] Before the disclosed processes and materials are described, it is to be understood that the aspects described herein are not limited to specific embodiments, or examples, and as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting.

[0046] In some aspects, the disclosure provides an injectable delivery system that can be used to inject implantable materials, such as an amniotic membrane alone or in addition to bioactive and/or inert reagents, for use as an injectable therapy for biomedical applications. In other aspects, the delivery system of the present disclosure reduces the risk of morbidity. In yet other aspects, the delivery system of the present disclosure reduces or eliminates the need for surgery (for example, using an injection rather than a surgical procedure to place the amniotic membrane). This can save time, and money, and reduce complications associated with surgery /anesthesia. In further aspect, the disclosure provides methods of using the injectable system of the present disclosure for delivery of implantable materials (e.g., amniotic membrane alone or in combination with any other substance).

[0047] In an aspect, disclosed is a device or a system including an outer or a first barrel such as a first or outer syringe with a first top end and a first bottom end; an outer or a first needle (that can be used to load a desired implatnable material); an inner or a second barrel such as a second or inner syringe with a second top end and a second bottom end; an inner or a second needle (this needle can be a pointed needle, a blunt needle, a hallow needle, or an unhallow needle); a plunger or piston for the second barrel; and an implantable material that is to be delivered to a subject. In an embodiment, the first top of the first barrel includes a first adapter to attach the first needle and the second top end of the second barrel includes a second adapter to attach the second needle. In an embodiment, the outer or first barrel such as the first or outer syringe with a first top end and a first bottom end; and the outer or first needle are together called as a first or outer barrel or syringe assembly. In an embodiment, the inner or a second barrel such as the second or inner syringe with a second top end and a second bottom end; the inner or a second needle; and the plunger or piston for the second barrel are together called as a second or inner barrel or syringe assembly.

[0048] In an embodiment, the implantable material that is to be delivered to the subject is preloaded in the outer or first needle. In an embodiment, the second needle is a blunt needle or an unhallow needle (a needle like a rod, with no void space) that can work as a plunger to inject the implantable material through the first or outer needle to a subject. In an embodiment, the second needle is a blunt needle. In an embodiment, the second needle is a pointed needle. In an embodiment, the second needle is a hallow needle. In an embodiment, the second needle is a unhallow needle. In an embodiment, the implantable material that is to be delivered to the subject is preloaded in the outer or first needle. In an embodiment, the system or device is an injectable delivery system or a dual syringe delivery system. In an embodiment, the desired implantable material can be loaded into a first or outer needle of a suitable size. In an embodiment, the subject is human.

[0049] In an embodiment, the disclosed system or device is an injectable delivery system or device (also called a dual syringe system), the system includes an outer or a first syringe including an outer or a first needle; an inner or a second syringe including an inner or a second needle and a plunger or piston for the second syringe; and an implantable material that is to be delivered. In an embodiment, the implantable material is preloaded in the outer or first needle. In an embodiment, the outer or first syringe with a first top end and a first bottom end; and the outer or first needle are together called as a first or outer syringe assembly. In an embodiment, the inner or a second syringe with a second top end and a second bottom end; the inner or a second needle; and the plunger or piston for the second syringe are together called as a second syringe assembly. In an embodiment the second syringe assembly operated inside the first syringe assembly. In an embodiment, the second needle is a blunt needle or an unhallow needle (a needle like a rod, with no void space) that can work as a plunger to inject the implantable material through the first or outer needle to a subject. In an embodiment, the second needle is a blunt needle. In an embodiment, the second needle is an unhallow needle. In an embodiment, the second needle is a pointed needle. In an embodiment, the second needle is a hallow needle. In an embodiment, the implantable material is delivered to a subject. In an embodiment, the subject is human.

[0050] In an embodiment, the system can be preloaded and employed to introduce the implantable materials including but not limited to membranes, for example, minimally manipulated amniotic membranes, along with a bioactive liquid or inert materials. In an embodiment, the implantable material can be a biological or biocompatible material. To achieve this, the target membrane can be placed into the needle, for example, the outer or first needle, and subsequently be pushed using any suitable object that can act like a plunger, for example, the inner or second needle. In an embodiment, the object that can act like a plunger is the inner or second needle. In an embodiment, membranes, such as an amniotic membrane, can be lyophilized within a needle of an outer syringe of the system and then rehydrated with a suitable liquid using an inner syringe of the system right before injection. In an embodiment, the device may use vacuum process to allow delivery of implantable materials with pressure differential. In an embodiment, the dual-syringe system may further be used to deliver any suitable implantable material and a bioactive and/or inert substance into the various joint spaces of a subject or into any cavity or tissue of the subject. In an embodiment, the subject is a mammal. In an embodiment, the subject is human.

[0051] In an embodiment, this system can be employed for the purpose of inserting specific implantable materials, which can be pre-loaded into a needle and subsequently injected into tissues using an object that can act like a plunger. In an embodiment, the implantable material is preloaded in the first or outer needle or in the first or outer syringe. In an embodiment, the object that can act like a plunger is the inner or second needle. In an embodiment, the inner or second needle is a blunt needle. The choice of needle and plunger size depends on the size of the materials to be implanted and can be readily determined by a person skilled in the art. Additionally, if needed, bioactive and/or inert solutions can be injected alongside the implantable materials using an inner or second syringe of the system.

[0052] In an embodiment, the device can be used to deliver preferred bioactive and/or inert fluids alongside an absorbent material, such as the minimally manipulated amniotic membrane. By employing this approach, the absorbent material can effectively retain the bioactive and/or inert liquid in the targeted location within the tissue. [0053] In an embodiment, depending on the size of the membrane or other kinds of implantable materials, the outer or first and inner or second needles with different sizes can be used. In an aspect, different sizes of inner and outer syringes can be used to inject different amounts of therapeutic or inert solutions. In an embodiment, the described delivering method can be used for tendonitis and tendinopathy as it is an injection and not a surgery. In certain embodiments, the described delivering method can be used for accelerating the regeneration of other soft tissues like cartilage, ligaments, tendons, skeletal muscle, and/or combination thereof. [0054] The injectable delivery system as described herein and the delivery method using the injectable delivery system as described herein are less invasive compared to some of the current methods that employ a 12G gauge cannula, which is notably invasive, particularly to a knee joint. The disclosed injectable delivery system utilizes 18G gauge needle which is minimally invasive. Also, the method using the injectable delivery system as described herein can inject the amnionic membrane along with other solutions (for example, saline or bioactive solutions).

[0055] Definitions

[0056] The following terms are used to describe the invention of the present disclosure. In instances where a term is not specifically defined herein, that term is given an art-recognized meaning by those of ordinary skill applying that term in context to its use in describing the present disclosure.

[0057] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For example, any nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics, and protein and nucleic acid chemistry and hybridization described herein are well known and commonly used in the art. In case of conflict, the present disclosure, including definitions, will control. Exemplary methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the embodiments and aspects described herein.

[0058] Compounds and materials are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. The following terms are used to describe the invention of the present disclosure. In instances where a term is not specifically defined herein, that term is given an art-recognized meaning by those of ordinary skill applying that term in context to its use in describing the present disclosure.

[0059] The use of the terms “a” and “an” and “the” and similar referents (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. By way of example, "an element" means one element or more than one element.

[0060] As used herein, the term “substantially” means to a great or significant extent, but not completely.

[0061] It should also be understood that, in certain methods described herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited unless the context indicates otherwise. Furthermore, the terms first, second, etc., as used herein are not meant to denote any particular ordering, but simply for convenience to denote a plurality of, for example, layers.

[0062] The terms “comprising”, “having”, “including”, and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to”) unless otherwise noted.

[0063] The terms “about” or “approximately,” as used herein, is inclusive of the stated value and means within an acceptable range of deviation for the particular value as determined by one of ordinary skill in the ail, considering the measurement in question and the error associated with measurement of the particular quantity (i.e., the limitations of the measurement system). For example, “about” can mean within one or more standard deviations, or within ± 10% or 5% of the stated value. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All ranges disclosed herein include both end points as discrete values as well as all integers and fractions specified within the range. For example, a range of 0.1-2.0 includes 0.1, 0.2, 0.3, 0.4 . . . 2.0. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.

The use of any and all examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any nonclaimed element as essential to the practice of the invention as used herein.

[0064] The phrase "and/or," as used herein in the specification and in the claims, should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with "and/or" should be construed in the same fashion, i.e., "one or more" of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the "and/or" clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to "A and/or B", when used in conjunction with open-ended language such as "comprising" can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0065] As used herein in the specification and in the claims, "or" should be understood to have the same meaning as "and/or" as defined above. For example, when separating items in a list, "or" or "and/or" shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or "exactly one of," or, when used in the claims, "consisting of," will refer to the inclusion of exactly one element of a number or list of elements. In general, the term "or" as used herein shall only be interpreted as indicating exclusive alternatives (i.e., "one or the other but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of."

[0066] As used herein in the specification and in the claims, the phrase "at least one," in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified. Thus, as a nonlimiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently "at least one of A and/or B") can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0067] The phrase "one or more," as used herein, means at least one, and thus includes individual components as well as mixtures/combinations of the listed components in any combination.

[0068] Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients and/or reaction conditions are to be understood as being modified in all instances by the term "about," meaning within 10% of the indicated number (e.g., "about 10%" means 9%- 11% and "about 2%" means 1.8%-2.2%).

[0069] All percentages and ratios are calculated by weight unless otherwise indicated. All percentages are calculated based on the total composition unless otherwise indicated. Generally, unless otherwise expressly stated herein, "weight" or "amount" as used herein with respect to the percent amount of an ingredient refers to the amount of the raw material comprising the ingredient, wherein the raw material may be described herein to comprise less than and up to 100% activity of the ingredient. Therefore, weight percent of an active in a composition is represented as the amount of raw material containing the active that is used and may or may not reflect the final percentage of the active, wherein the final percentage of the active is dependent on the weight percent of active in the raw material.

[0070] All ranges and amounts given herein are intended to include subranges and amounts using any disclosed point as an end point. Thus, a range of "1% to 10%, such as 2% to 8%, such as 3% to 5%," is intended to encompass ranges of "1% to 8%," "1% to 5%," "2% to 10%, " and so on. All numbers, amounts, ranges, etc., are intended to be modified by the term "about," whether or not so expressly stated. Similarly, a range given of "about 1% to 10%" is intended to have the term "about" modifying both the 1% and the 10% endpoints. Further, it is understood that when an amount of a component is given, it is intended to signify the amount of the active material unless otherwise specifically stated.

[0071] As used herein, the term “administering” means the actual physical introduction of a composition into or onto (as appropriate) a subject, a host, or cell. Any and all methods of introducing the composition into the subject, host or cell are contemplated according to the invention; the method is not dependent on any particular means of introduction and is not to be so construed. Means of introduction are well-known to those skilled in the art, and also are exemplified herein. “Providing” means giving, administering, selling, distributing, transferring (for profit or not), manufacturing, compounding, or dispensing.

[0072] As used herein, “amniotic membrane (AM)” refers to the innermost layer of the placenta consisting of a thick basement membrane and an avascular stromal matrix. AM contains collagens (types I, III, IV, V and VI), fibronectin, laminin, proteoglycans and hyaluronan. AM has the potential to suppress the expression of potent pro-inflammatory cytokines, such as IL-lct and IL-Ib, and decrease matrix metalloproteinase (MMF) levels through expression of natural MMP inhibitors present in the membrane. AM may be from any suitable source, including but not limited to human placenta or any animal tissue source.

[0073] As used herein, “AM hydrogel” refers to a gel constructed from a network of AM polymers in a suitable aqueous medium, such as any neutral buffer, including but not limited to phosphate buffered saline (PBS). The AM hydrogels are capable of gelation at physiological pH and temperature and thus can form a gel upon injection to a subject, such as at a joint. The AM hydrogels or precursors thereof can be used, for example, in cell delivery and for tissue regeneration in a minimally invasive and cost-effective manner. In one non-limiting example, amnion hydrogel along with stem cells can reduce inflammation and slow down cartilage degradation in osteoarthritis patients (human or animal) and thus can have therapeutic potential. [0074] As used herein, a “precursor of the AM hydrogel” is decellularized amnionic membrane or powder (or any embodiment or combination of embodiments disclosed herein) prior to gelation at physiological pH and temperature. The precursors therefore can be, for example, injected to a site in a subject at which it is desired for the hydrogel to form.

[0075] As used herein, “decellularized” means removal of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or all cells present in the AM starting material. In one embodiment, the AM hydrogels of the disclosure include no detectable cells other than those exogenously added, as described below. The hydrogels or non-powder precursors thereof further include at least a minimum content of an aqueous medium, such as water or any neutral buffer including but not limited to PBS. In some embodiments, the AM hydrogel or non-powder precursor comprises at least 50% by weight, at least 55%, or at least 60% by weight of an aqueous medium based upon the total weight of the hydrogel or non -powder precursor (e.g., with a maximum of 80% by weight). In particular, the aqueous medium can comprise about 50% to about 80%, about 55% to about 75%, or about 60% to about 70% by weight of the hydrogel based on the total weight of the hydrogel or non-powder precursor.

[0076] In one embodiment, no detectable exogenous polymer is present in the AM hydrogel or precursor thereof. As used herein, "‘exogenous” polymer means a polymer not present in the amnionic membrane used to prepare the AM hydrogel or precursor thereof.

[0077] The AM may be enzymatically solubilized prior to hydrogel or precursor formation. In this embodiment, any suitable enzyme may be used to solubilize tire AM, including but not limited to pepsin or any other protease.

[0078] The AM may be present in the hydrogel or precursor thereof at any suitable concentration. In some embodiments, the AM is present at between about 1 mg/ml and about 15 mg/ml, about 1 mg/ml and about 14 mg/ml, about 1 mg/ml and about 13 mg/ml, about 1 mg/ml and about 12 mg/ml, about 1 mg/ml and about 11 mg/ml, about 1 mg/ml and about 10 mg/ml, about 1 mg/ml and about 9 mg/ml, about 1 mg/ml and about 8 mg/ml, about 2 mg/ml and about 15 mg/ml, about 2 mg/ml and about 14 mg/ml, about 2 mg/ml and about 13 mg/ml, about 2 mg/ml and about 12 mg/ml, about 2 mg/ml and about 11 mg/ml, about 2 mg/ml and about 10 mg/ml, about 2 mg/ml and about 9 mg/ml, or about 2 mg/ml and about 8 mg/ml in the hydrogel. In a specific embodiment, the AM is present at between about 2 mg/ml and about 8 mg/ml in the hydrogel.

[0079] Any suitable buffer may be used to dilute the AM to a desired concentration in the resulting hydrogel or precursor thereof. In non-limiting embodiments, the buffer may comprise physiological saline, phosphate-buffered saline, with or without serum albumin (such as bovine serum albumin (BSA)). [0080] The AM hydrogel may be of any shape or dimensions as deemed appropriate for an intended use. In various embodiments, the hydrogel or precursor thereof can be used in a range of volumes, including but not limited to a range of between about 50 pL and about 50 ml. In some embodiments, the AM may be mixed with different polymers including but not limited to hyaluronan, chitosan, alginate, collagen, dextran, pectin, carrageenan, polylysine, gelatin and/or agarose. In one embodiment, no detectable exogenous polymer is present in the AM hydrogel or precursor thereof. In another embodiment, the AM hydrogel has a swelling ratio of between about 5% and about 15%. The swelling ratio is a measure of the gel (and not the solution) before and after adding buffer, such as PBS. The ability of AM hydrogels to swell helps govern the diffusion of oxygen and nutrient required for cell growth in the AM hydrogel.

[0081] In various embodiments, the hydrogel has a storage modulus of between about 100 Pa to about 10,000 Pa, about 100 Pa to about 9,000 Pa, about 100 Pa to about 8,000 Pa, about 100 Pa to about 7,000 Pa, about 100 Pa to about 6,000 Pa, about 100 Pa to about 5,000 Pa, about 100 Pa to about 4,000 Pa, about 100 Pa to about 3,000 Pa, or about 100 Pa to about 2,000 Pa.

[0082] In another embodiment, tire hydrogel has shear- thinning properties. As used herein, “shear thinning” refers to decrease in the complex viscosity with increase in shear rate. The shear thinning property of the AM hydrogels facilitate easy delivery through, for example, a syringe or catheter.

[0083] As disclosed herein, the AM hydrogels can be used, for example, in cell delivery and for tissue regeneration m a minimally invasive and cost-effective manner. Thus, in another embodiment, hydrogels may further comprise biological cells within the hydrogel. Any suitable biological cells may be used in the hydrogels of the disclosure. In one embodiment, the biological cells comprise stem cells. The stem cells may be of any suitable type, including but not limited to human or animal adult stem cells, embryonic stem cells and induced pluripotent stem cells. In one embodiment, the stem cells comprise mesenchymal stem cells or adipose- derived stem cells. In all embodiments, the cells may be from human sources (for use in human applications, for example) or from animal sources (for use in veterinary applications, for example). The cells may be naturally occurring or may be engineered in any suitable way as appropriate for an intended use. The biological cells in the hydrogel may be ail of one type, or combinations of cell types as suitable for an intended use.

[0084] Any suitable concentration of biological cells may be present in the hydrogel as suitable for an intended use. In various embodiments, the biological cells arc present at a concentration of between about 1 x 10⁵ cells/ml and about 1 x 10⁸ cells/ml, and about 1 x 10⁵ cells/ml and about 1 x 10⁷ cells/ml.

[0085] As used herein, “implantable material” encompasses solid, semi-solid, and liquid materials that can be injected into a target tissue to support, repair, replace, or enhance biological structures. Implantable materials may include, but are not limited to, polymers, hydrogels, ceramics, biologically derived substances, and other formulations designed to be compatible with bodily tissues. Exemplary implantable materials include, AM, AM hydrogels, or precursors thereof. The “implantable material” may change its phase of matter prior to, during, or after injection into a target tissue.

[0086] As used herein, “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0087] As used herein, the term “solution” refers to any aqueous or non-aqueous liquid preparation, formulation, or composition that is applied, administered, or otherwise utilized in connection with implantation of a material (e.g., AM for tissue repair, healing, or regeneration, etc.) using a delivery system of the present disclosure. The term “solution” encompasses solutions for hydrating or preserving the implantable material (e.g., AM), preparing the injection site, reducing inflammation, promoting tissue regeneration, preventing infection, or enhancing the tissue adhesion of the implantable material (e.g., AM).

[0088] Examples of solutions within the scope of this definition include, but are not limited to saline solutions (e.g., PBS) or other isotonic preparations used for cleaning or hydrating the AM or injection site, antibiotic solutions, such as those containing gentamicin, bacitracin, or neomycin, which may be employed to reduce the risk of bacterial contamination or infection, antiseptic solutions, including but not limited to povidone-iodine or chlorhexidine, for sterilizing the injection site and minimizing microbial load, thrombin solutions, fibrin, or other biological adhesives that promote hemostasis and secure placement of the AM, growth factorcontaining solutions, such as platelet-rich plasma (PRP) or recombinant growth factors (e.g., epidermal growth factor), which are intended to enhance tissue regeneration and accelerate healing, corticosteroid solutions, such as dexamethasone or hydrocortisone, or other antiinflammatory preparations, designed to modulate the immune response and reduce inflammation at the graft site, hyaluronic acid (HA) solutions or similar hydrating agents that promote healing and minimizing scar formation, balanced electrolyte solutions (e.g., Buffered lactated Ringer’s solution), collagen-based solutions or other structural protein preparations that support tissue integrity and promote the integration of the graft with the surrounding tissue, local anesthetic or non-steroidal anti-inflammatory drug (NSAID) solutions, which may be administered to provide pain relief and control local inflammation during or after the procedure. Preferred exemplary solutions of the present disclosure include, without limitation, a crystalloid solution or other selected from the group consisting of hypotonic saline (0-0.9%), normal saline (0.9%), hypertonic saline (>0.9%), sterile water, deionized water, dextrose, dcxtrosc/salinc solution, blood product-derived solution (including but not limited to platelet-rich plasma [PRP]), fat- derived injectable solution(including but not limited to lipid emulsions), Langert’s solution, lactated Langers solution, bicarbonate solution, analgesic solution, or any combination of these solutions in varying ratios and concentrations. It is to be understood that the agents mentioned in the above exemplary solutions are also referred to herein as bioactive agents. The term “bioactive agents” also encompasses any other agent that would be desirable to implant into a target tissue, for example, during delivery of an AM, AM hydrogel or precursor, or pharmaceutical composition thereof. The term “solution” as used herein may encompass any combination of the above-mentioned substances and may further include other pharmacologically active agents (e.g., bioactive agents), excipients, stabilizers, or carriers known to those skilled in the art for enhancing the therapeutic efficacy, stability, or delivery of the solution in injection procedures.

[0089] The term “subject” or “patient” is used herein to refer to an animal, such as a mammal, including a primate (such as a human, a non-human primate, e.g., a monkey, and a chimpanzee), a non-primate (such as a cow, a pig, a camel, a llama, a horse, a goat, a rabbit, a sheep, a hamster, a guinea pig, a cat, a dog, a rat, a mouse, and a whale), a bird (e.g., a duck or a goose), and a shark. In an embodiment, the subject or patient is a human subject or a human patient, such as a human being treated or assessed for a disease, disorder or condition, a human at risk for a disease, disorder or condition, a human having a disease, disorder or condition, and/or human being treated for a disease, disorder or condition as described herein. In one embodiment, the subject is about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years of age. In another embodiment, the subject is about 5-10, 10-15, 15-20, 20-25, 25-30, 30-35, 35-40, 40-45, 45-50, 50-55, 55-60, 60-65, 65- 70, 70-75, 75-80, 80-85, 85-90, 90-95, or 95-100 years of age. Values and ranges intermediate to the above recited ranges are also intended to be part of this invention. In addition, ranges of values using a combination of any of the above-recited values as upper and/or lower limits are intended to be included. As used herein, a subject is “in need of treatment” if such subject would benefit biologically, medically, or in quality of life from such treatment. A subject in need of treatment does not necessarily present symptoms, particular in the case of preventative or prophylaxis treatments.

[0090] As used here, the terms “treatment” and “treating” mean: (i) inhibiting the progression of the disorder; (ii) prophylactic use for example, preventing or limiting development of a disorder an individual who may be predisposed or otherwise at risk to the disorder but does not yet experience or display the pathology or symptomatology of the disorder; (iii) inhibiting the disorder; for example, inhibiting a disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disorder; and/or (iv) ameliorating the referenced disorder, for example, ameliorating a disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disorder (i.e., reversing or improving the pathology and/or symptomatology) such as decreasing the severity of the disorder. [0091] All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention as used herein. Unless defined otherwise, technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art of this disclosure. [0092] Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group.

[0093] All compounds are understood to include all possible isotopes of atoms occurring in the compounds. Isotopes include those atoms having the same atomic number but different mass numbers and encompass heavy isotopes and radioactive isotopes. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 11C, 13C, and 14C. Accordingly, the compounds disclosed herein may include heavy or radioactive isotopes in the structure of the compounds or as substituents attached thereto. Examples of useful heavy or radioactive isotopes include 18F, 15N, 180, 76Br, 1251 and 1311.

[0094] A significant change is any detectable change that is statistically significant in a standard parametric test of statistical significance such as Student’s t-test, where p < 0.05.

[0095] All statements herein reciting principles, aspects, and embodiments of the disclosure, as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents as well as equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure.

[0096] Various other components may be included and called upon for providing for aspects of the teachings herein. For example, additional materials, combinations of materials and/or omission of materials may be used to provide for added embodiments that are within the scope of the teachings herein. Adequacy of any particular element for practice of the teachings herein is to be judged from the perspective of a designer, manufacturer, seller, user, system operator or other similarly interested party, and such limitations are to be perceived according to the standards of the interested party. [0097] In the disclosure hereof any element expressed as a means for performing a specified function is intended to encompass any way of performing that function including, for example, a) a combination of circuit elements and associated hardware which perform that function or b) software in any form, including, therefore, firmware, microcode or the like as set forth herein, combined with appropriate circuitry for executing that software to perform the function. Applicants thus regard any means which can provide those functionalities as equivalent to those shown herein. No functional language used in claims appended herein is to be construed as invoking 35 U.S.C. § 112(f) interpretations as “means-plus-function” language unless specifically expressed as such by use of the words “means for” or “steps for” within the respective claim.

[0098] When introducing elements of the present invention or the embodiment(s) thereof, the articles “a,” “an,” and “the” arc intended to mean that there are one or more of the elements. Similarly, the adjective “another,” when used to introduce an element, is intended to mean one or more elements. The terms “including” and “having” arc intended to be inclusive such that there may be additional elements other than the listed elements. The term “exemplary” is not intended to be construed as a superlative example but merely one of many possible examples.

Injectable Delivery Systems

[0099] Aspects of the present disclosure relate to injectable delivery systems for delivering an implantable material into a subject.

[0100] In an aspect, the present disclosure provides an injectable delivery system for delivering an implantable material into a tissue of a subject, the system comprising: (a) a first assembly comprising at least a first needle and a lumen into which an implantable material can be loaded for delivery into the tissue of the subject; and (b) a second assembly comprising at least a first plunger that is configured to slide bidirectionally within the lumen of the first needle to deliver the implantable material into the tissue of the subject when a user inserts the first needle into the tissue of the subject and applies an axial pressure to the at least the first plunger. [0101] In some aspects, at least the first plunger comprises a wire, a rod, or a needle. In an embodiment, the at least the first plunger comprises a wire having a diameter that is less than the diameter of the lumen of the at least the first needle. In another embodiment, the at least the first plunger comprises a rod having a diameter that is less than the diameter of the lumen of the at least the first needle. In yet an embodiment, the at least the first plunger comprises at least a second needle having a diameter that is less than the diameter of the lumen of the at least the first needle.

[0102] In some aspects, the first assembly comprises a first syringe comprising a first barrel having a first opening at one end and the first needle at an opposite end, wherein the first opening is configured to receive a second barrel of a second syringe into the first barrel of the first syringe, and the second assembly comprises a second syringe comprising a second barrel having a second opening at one end, and a piston and a second needle at an opposite end, wherein the second opening is configured to receive at least the first plunger, wherein the piston is configured to enable the second syringe barrel to slide bidirectionally within the first barrel of the first syringe, and wherein the second needle is configured to slide bidirectionally within the lumen of the first needle to deliver the implantable material into the tissue of a subject when at least the first plunger is pressed into the second opening of the second barrel of the second syringe.

[0103] In another aspect, the injectable delivery system comprises (a) the first assembly comprises a first syringe comprising a first barrel having a first opening at one end and the first needle at an opposite end, wherein the first opening is configured to receive the plunger of the second assembly, and (b) a second assembly comprising: (i) a second syringe comprising a second barrel having the plunger slidably disposed inside the first opening of the first barrel and further comprising at least a second needle that is configured to slide bidirectionally within the lumen of the first needle to deliver the implantable material into a target tissue of a subject; and (ii) a syringe gun comprising: (1) a body comprising a syringe holder that holds the first assembly in place with at least the first plunger slidably disposed inside the first opening of the first barrel; and (2) a trigger, wherein the syringe gun is configured to cause at least the first plunger to slide bidirectionally inside the first barrel and the second needle to slide bidirectionally within the lumen of the first needle to deliver the implantable material into the tissue of the subject when a user inserts the first needle into the tissue of the subject and pulls the trigger.

[0104] In yet another aspect, the injectable delivery system comprises a first assembly comprising a first syringe comprising a first barrel having a second plunger at one end and the first needle at an opposite end; and a second assembly comprising (i) a plurality of syringes positioned inside the first barrel of the first syringe, each of the plurality of syringes comprising at least a second syringe barrel comprising at least a second opening at one end and at least a third plunger at the opposite end; (ii) the at least the first plunger; and (iii) at least one tube connected to the second opening of the at least the second syringe barrel, wherein the first needle is configured to deliver the implantable material into the tissue of a subject when a user inserts the first needle into the tissue of the subject and the at least the second plunger is pressed, and wherein the plurality of syringes is configured deliver at least first fluid through the at least one tube and into the first lumen when the at least the third plunger is pressed by the user.

[0105] In a further aspect, the injectable delivery system comprises a first assembly comprising at least a first needle and a lumen into which an implantable material can be loaded for delivery into the tissue of the subject (a) the first assembly comprising: (i) at least a first needle and a lumen into which an implantable material can be loaded for delivery into the tissue of the subject; and (ii) a shell needle; and (b) the second assembly comprising: (i) at least a first, second, third, and/or fourth syringe comprising at least a first, second, third and/or fourth fluid outlet at one end and at least a second, a third, fourth, and/or fifth plunger at the opposite end, and at least a second, third, fourth, and/or fifth barrel extending between the one end and the opposite end; (ii) an adapter connected to the at least the first, second, third and/or fourth fluid outlet configured to channel fluid flowing through the outlet into a shared lumen that is connected to the shell needle; and (iii) at least the first plunger is configured to slide bidirectionally within the shared lumen and the lumen of the first needle to deliver the implantable material into the tissue of the subject when a user inserts the first needle into the tissue of the subject and applies an axial pressure to at least the first plunger.

[0106] The injectable delivery systems of the present disclosure can be used to deliver any desired implantable material. In some aspects, the implantable material comprises an AM, hydrogel, or precursor thereof. In other aspects, the implantable material comprises a folded section of decellularized amnion. In yet other aspects, the implantable material comprises a decellularized and enzymatically solubilized AM hydrogel. In some instances, such a hydrogel can be preparing by (a) decellularizing amniotic membrane by application of a strong base, including but not limited to NaOH, to produce decellularized AM; (b) enzymatically solubilizing the decellularized AM to produce a decellularized and enzymatically solubilized amnionic AM; (c) diluting the decellularized and enzymatically solubilized amnionic AM to a desired concentration and pH in buffer to produce a decellularized and enzymatically solubilized amnionic AM solution; and (d) heating the decellularized and enzymatically solubilized amnionic AM solution to form a decellularized and enzymatically solubilized amnionic AM hydrogel.

[01071 The AM can be from any suitable source as noted above, such as human or animal placenta. The step of decellularizing amniotic membrane by application of the strong base may comprise the use of any suitable concentration of strong base, such as about 0.1M to about 0.5M strong base. In various non-limiting embodiments, the strong base may comprise one or more of lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), rubidium hydroxide (RbOH), cesium hydroxide (CsOH), calcium hydroxide (Ca(OH)2), strontium hydroxide (Sr(OH) ), barium hydroxide (Ba(OH)2)), or any combination thereof. In one embodiment, the strong base is NaOH. This step can be carried under any suitable conditions, including but not limited to carrying out at about room temperature. In one embodiment, the step of enzymatically solubilizing comprises contacting decellularized AM with pepsin or other suitable protease under conditions and for a time suitable to promote enzymatic solubilization of the decellularized AM.

[0108] In one embodiment, the method further comprises lyophilizing the decellularized AM prior to step (b). The step of heating may comprise heating the decell ularized and enzymatically solubilized amnionic AM at between about 20°C and about 40°C, between about 20°C and about 37°C, between about 25°C and about 40°C, between about 25°C and about 37°C, or about 37°C for a time sufficient to form the hydrogel. In one embodiment, the heating step comprises heating at about 37 °C.

[0109] In various embodiments, the AM is diluted to be present in the hydrogel and/or the decellularized and enzymatically solubilized amnionic AM solution at between about 1 mg/ml and about 15 mg/ml, about 1 mg/ml and about 14 mg/ml, about 1 mg/ml and about 13 mg/ml, about 1 mg/ml and about 12 mg/ml, about 1 mg/ml and about 11 mg/ml, about 1 mg/ml and about 10 mg/ml, about 1 mg/ml and about 9 mg/ml, about 1 mg/ml and about 8 mg/ml, about 2 mg/ml and about 15 mg/ml, about 2 mg/ml and about 14 mg/ml, about 2 mg/ml and about 13 mg/ml, about 2 mg/ml and about 12 mg/ml, about 2 mg/ml and about 11 mg/ml, about 2 mg/ml and about 10 mg/ml, about 2 mg/ml and about 9 mg/ml, or about 2 mg/ml and about 8 mg/ml. [0110] In another embodiment, the methods further comprise adding biological cells to the decellularized and enzymatically solubilized amnionic AM prior to step (d). In one embodiment, the decellularized and enzymatically solubilized amnionic AM solution is maintained on ice and cells are added prior to the heating step. Any suitable cells may be added, as disclosed above. In one embodiment, the biological cells comprise stem cells, including but not limited to human or animal adult stem cells, embryonic stem cells and induced pluripotent stem cells. In another embodiment, the stem cells comprise mesenchymal stem cells or adipose- derived stem cells. In a further embodiment, the biological cells are added at a concentration of between about 1 x 10⁵ cells/ml and about 1 x 10⁸ cells/ml, and about 1 x 10⁵ cells/ml and about 1 x 10⁷ cells/ml of the decellularized and enzymatically solubilized amnionic AM solution.

[0111] Before use, the implantable material can be loaded into the lumen of the first needle. In some instances, the implantable material is loaded into the lumen of the first needle when the injectable delivery system is in its assembled configuration. In other instances, the implantable material is loaded into the lumen of the first needle when the injectable delivery system is in its disassembled configuration.

[0112] In some aspects, the first needle comprises a removable needle. In some embodiments, the lumen of the removable needle is preloaded with the implantable material before the needle is removably connected to the end of the first syringe opposite the barrel opening. In other embodiments, the removable needle is connected to the first syringe barrel before loading the implantable material into lumen of the first needle.

[0113] In yet other aspects, the AM is lyophilized. In some embodiments, the AM is lyophilized before being loaded into the lumen of the first removable needle. In other embodiments, the amnion is lyophilized after being loaded into the lumen of the first needle. In yet still other aspects, the amnion is lyophilized in a tubular mold. In some embodiments, the amnion is lyophilized in a twisted form inside a tubular mold. In other embodiments, the amnion is lyophilized in a rolled form inside a tubular mold. In other embodiments, the amnion is lyophilized in a folded form inside a tubular mold. [0114] In some aspects, the second syringe or inner syringe can be loaded with a solution. In some aspects, the second syringe comprises a solution preloaded inside the second barrel.

[0115] The skilled artisan will appreciate that any desirable solution can be loaded into the syringe. In some embodiments, the solution comprises a saline solution (e.g., PBS) or other isotonic preparation. In other embodiments, the solution comprises an antibiotic solution. In yet other embodiments, the solution comprises an antiseptic solution. In still other embodiments, the solution comprises thrombin, fibrin, or other biological adhesives that promote hemostasis and secure placement of the AM. In still other embodiments, the solution comprises a growth factor, such as platelet-rich plasma (PRP) or recombinant growth factors (e.g., epidermal growth factor). In further embodiments, the solution comprises a corticosteroid solution designed to modulate the immune response and reduce inflammation at the injection site. In even further embodiments, the solution comprises a hyaluronic acid (HA) solution or similar agent that promotes healing and minimizing scar formation. In still even further embodiments, the solution comprises a balanced electrolyte solutions (e.g., Buffered lactated Ringer’s solution). In other embodiments, the solution comprises a collagen-based solutions or other structural protein preparations that supports tissue integrity and promote the integration of the AM with the surrounding tissue. In some other embodiments, the solution comprises a local anesthetic or non-steroidal anti-inflammatory drug (NSAID). The disclosure contemplates solutions comprising combinations of the above.

[0116] The skilled artisan will appreciate that a variety of syringe sizes can be used for the first and second needle. The skilled artisan will also appreciate that the size of the second needle depends on the size of the first needle, for instance, the second needle should be smaller than the first needle so that it can slide within the lumen of the first needle and function like a plunger to deliver the implantable material into a target tissue injection site.

[0117] In some aspects, the first needle comprises a gauge of from about 10G to about 28 needle, from about 12G to 26G, from about 14G to about 24G. In other aspects, the first needle comprises a gauge from about 13G, about 14G, about 15G, about 16G, about 17G, about 18G, about 19G, about 20G, about 21G, about 22G, about 23G, about 24G, about 25G, about 26G, or about 27 G. [0118] In yet other aspects, the lumen of the first needle comprises an inner diameter ranging from about 0.15 mm to about 2 mm, from about 0.16 mm to about 1.9 mm, from about 0.17 mm to about 1.8 mm, from about 0.18 mm to about 1.7 mm, from about 0.19 to about 1.6 mm, from about 0.20 to about 1.5 mm, from about 0.21 to about 1.4, or from about 0.22 to about 1.3. In still other aspects, the lumen of the first needle comprises an inner diameter of about 0.15mm, about 0.20mm, about 0.25mm, about 0.30mm, about 0.35mm, about 0.40mm, about

0.45mm, about 0.50mm, about 0.55mm, about 0.60mm, about 0.65mm, about 0.70mm, about

0.75mm, about 0.80mm, about 0.85mm, about 0.90mm, about 0.95mm, about 1.00mm, about

1.05mm, about 1.10mm, about 1.15mm, about 1.20mm, about 1.25mm, about 1.30mm, about

1.35mm, about 1.40mm, about 1.45mm, about 1.50mm, about 1.55mm, about 1.60mm, about

1.65mm, about 1.70mm, about 1.75mm, about 1.80mm, about 1.85mm, about 1.90mm, about

1.95mm.

[0119] The present disclosure contemplates a wide variety of sizes for the first barrel of the first syringe. In some aspects, the volume of the first barrel of the first syringe ranges from about 0.1ml to about 450ml, about 0.2 ml to about 440 ml, about 0.3 ml to about 430 ml, about 0.4 ml to about 420 ml, about 0.5 ml to about 410 ml, about 0.6 ml to about 400 ml, about 0.7 ml to about 390 ml, about 0.8 ml to about 380 ml, about 0.9 ml to about 370 ml, about 1.0 ml to about 360 ml, about 1.1 ml to about 350 ml, about 1.5 ml to about 340 ml, about 2.0 ml to about 330 ml, about 2.5 ml to about 320 ml, about 3.0 ml to about 310 ml, about 3.5 ml to about 300 ml, about 4.0 ml to about 290 ml, about 4.5 ml to about 280 ml, about 5.0 ml to about 270 ml, about 5.5 ml to about 260 ml, about 6.0 ml to about 250 ml, about 6.5 ml to about 240 ml, about 7.0 ml to about 230 ml, about 7.5 ml to about 220 ml, about 8.0 ml to about 210 ml, about 8.5 ml to about 200 ml, about 9.0 ml to about 190 ml, about 9.5 ml to about 180 ml, or from about 10.0 ml to about 170 ml. In other aspects, the volume of the first barrel of the first syringe is 80 ml, about 90 ml, about 100 ml, about 110 ml, about 120 ml, about 130 ml, about 140 ml, about 150 ml, about 160 ml, about 170 ml, about 180 ml, about 190 ml, about 200 ml, about 210 ml, about 220 ml, about 230 ml, about 240 ml, about 250 ml, about 260 ml, about 270 ml, about 280 ml, about 290 ml, about 300 ml, about 310 ml, about 320 ml, about 330 ml, about 340 ml, about 350 ml, about 360 ml, about 370 ml, about 380 ml, about 390 ml, about 400 ml, about 410 ml, about 420 ml, about 430 ml, or about 440 ml. [0120] In some aspects, the at least the second needle comprises a gauge of from about 12G to about 32G needle, from about 14G to 30G, from about 16G to about 28G. In other aspects, the first needle comprises a gauge from about 13G, about 14G, about 15G, about 16G, about 17G, about 18G, about 19G, about 20G, about 21G, about 22G, about 23G, about 24G, about 25G, about 26G, about 27G, about 28G, about 29G, about 30G, or about 31G.

[0121] In yet other aspects, the lumen of the at least the second needle comprises an inner diameter ranging from about 0.30 mm to about 1.8 mm, from about 0.32 mm to about 1.7 mm, from about 0.34 mm to about 1.6 mm, from about 0.36 mm to about 1.5mm, from about 0.37 to about 1.4 mm, or from about 0.38 to about 1.3 mm. In still other aspects, the lumen of the at least the second needle comprises an inner diameter of about 0.30mm, about 0.35mm, about 0.40mm, about 0.45mm, about 0.50mm, about 0.55mm, about 0.60mm, about 0.65mm, about 0.70mm, about 0.75mm, about 0.80mm, about 0.85mm, about 0.90mm, about 0.95mm, about 1.00mm, about 1.05mm, about 1.10mm, about 1.15mm, about 1.20mm, about 1.25mm, about 1.30mm, about 1.35mm, about 1.40mm, about 1.45mm, about 1.50mm, about 1.55mm, about 1.60mm, about 1.65mm, about 1.70mm, or about 1.75mm.

[0122] The present disclosure contemplates a wide variety of sizes for the second barrel of the second syringe. In some aspects, the volume of the first barrel of the first syringe ranges from about 0.5 ml to about 400 ml, about 0.6 ml to about 390 ml, about 0.7 ml to about 380 ml, about 0.8 ml to about 370 ml, about 0.9 ml to about 360 ml, about 1.0 ml to about 350 ml, about 1.1 ml to about 340 ml, about 1.2 ml to about 330 ml, about 1.3 ml to about 320 ml, about 1.4 ml to about 310 ml, about 2.0 ml to about 310 ml, about 2.5 ml to about 300 ml, about 3.0 ml to about 290 ml, about 3.5 ml to about 280 ml, about 4.0 ml to about 270 ml, about 4.5 ml to about 260 ml, about 5.0 ml to about 250 ml, about 5.5 ml to about 240 ml, about 6.0 ml to about 230 ml, about 6.5 ml to about 220 ml, about 7.0 ml to about 210 ml, about 7.5 ml to about 200 ml, about 8.0 ml to about 190 ml, about 8.5 ml to about 180 ml, about 9.0 ml to about 170 ml, about 9.5 ml to about 160 ml, or from about 10.0 ml to about 170 ml. In other aspects, the volume of the second barrel of the second syringe is 80 ml, about 90 ml, about 100 ml, about 110 ml, about 120 ml, about 130 ml, about 140 ml, about 150 ml, about 160 ml, about 170 ml, about 180 ml, about 190 ml, about 200 ml, about 210 ml, about 220 ml, about 230 ml, about 240 ml, about 250 ml, about 260 ml, about 270 ml, about 280 ml, about 290 ml, about 300 ml, about 310 ml, about 320 ml, about 330 ml, about 340 ml, about 350 ml, about 360 ml, about 370 ml, about 380 ml, about 390 ml.

[0123] The skilled artisan will appreciate that in aspects of the injectable delivery system in which the second assembly comprises a plurality of syringes (e.g., at least a second, at least a third, a least a fourth, and/or a least a fifth syringe), the syringes and accompanying needles (if present), can have similar dimensions to the dimensions described above for the first and/or second syringes, barrels, and needles. The skilled artisan will also appreciate that the dimensions can be varied depending on the particular clinical setting and/or procedure in which the injectable delivery system is intended to be used.

Methods

[0124] Aspects of the present disclosure relate to kits for using a delivery system of the present disclosure and implementing a method of the disclosure.

[0125] In an aspect, the disclosure provides a method for delivering an implantable material into a tissue of a subject, the method comprising inserting a tip of a first needle into a target tissue site of a subject and depressing a plunger to cause a second needle to slide within a lumen of the first needle, thereby delivering the implantable material into the tissue of the subject. In some aspects, the method includes the step of, prior to inserting the tip of the first needle into the target tissue of the subject, loading the implantable material into the lumen of the first needle.

[0126] In some embodiments, the implantable material comprises a section of amnion and loading comprises folding the section of amnion inside the lumen. In some embodiments, the implantable material comprises a AM, a AM hydrogel, or a precursor thereof, or a pharmaceutical composition thereof.

[0127] In some aspects, the AM is lyophilized before being loaded into the lumen of the first needle. In other aspects, the AM is lyophilized after being loaded into the lumen of the first needle, and the method further comprises rehydrating the lyophilized AM inside the lumen of the first needle.

[0128] In yet still other aspects, the amnion is lyophilized in a tubular mold before being loaded into the lumen of the first needle. In some embodiments, the amnion is lyophilized in a twisted form inside a tubular mold before being loaded into the lumen of the first needle. In other embodiments, the amnion is lyophilized in a rolled form inside a tubular mold before being inserted into the lumen of the first needle. In other embodiments, the amnion is lyophilized in a folded form inside a tubular mold before being inserted into the lumen of the first needle.

[0129] In some embodiments, the first needle comprises a removable needle. In some aspects, the method includes the step of, prior to inserting the tip of the first removable needle into the target tissue of the subject, loading the implantable material into the lumen of the first removable needle. In yet other aspects, the AM is lyophilized before being loaded into the lumen of the first removable needle. In other aspects, the AM is lyophilized after being loaded into the lumen of the first removable needle, and the method further comprises rehydrating the lyophilized amnion inside the lumen of the removable needle.

[0130] In certain aspects, rehydrating comprises depressing the plunger into the second barrel of the second syringe to cause a solution inside the second barrel to transfer into the lumen of the first needle into contact with the lyophilized AM. In other aspects, rehydrating comprises depressing the plunger into the second barrel of the second syringe to cause a solution inside the second barrel to transfer into the lumen of the first removable needle into contact with the lyophilized AM.

[0131] In yet another aspect, the present disclosure provides a method for preparing to deliver an implantable material into a tissue of a subject, the method comprising: (a) connecting a first removable needle comprising a first lumen with an implantable material preloaded within it to a first end of a first barrel of an outer syringe of a coaxial syringe assembly comprising the outer syringe and an inner syringe slidably disposed within the outer syringe through a first opening at an opposite second end of the first barrel of the outer syringe; and (b) depressing a plunger into a second barrel of the inner syringe through a second opening of the second barrel proximal to the first opening at the opposite second end of the first barrel of the outer syringe to cause a solution contained within the second barrel of the inner syringe to flow through a second lumen of a second needle situated proximal to the first end of the first barrel into the first lumen of the first removable needle into contact with the implantable material inside the first lumen. In some embodiments, the method comprises, prior to connecting step (a) loading the implantable material into the first lumen of the first removable needle and/or loading the solution into the second barrel. [0132] In yet an additional aspect, the disclosure provides a method for delivering an implantable material into a target tissue of a subject in need thereof, the method comprising: (a) obtaining a coaxial syringe assembly comprising an outer syringe and an inner syringe slidably disposed within an opening of a first barrel of the outer syringe, the outer syringe comprising a first needle comprising a first gauge comprising a lumen with an implantable material loaded inside, the inner syringe comprising a second barrel comprising a solution loaded inside and a second needle comprising a second gauge that enables the second needle to slide bidirectionally within the lumen of the first needle; and (b) positioning a tip of the needle onto an outer surface of the subject’s skin at an injection site near the target tissue; and (c) depressing a plunger disposed within the second barrel of the inner syringe to cause the second needle to slidably move through the lumen of the first needle, thereby causing the needle to penetrate the subject’s skin and deliver the implantable material into the target tissue. In some embodiments, the method comprises, prior to depressing step (c), depressing a plunger disposed within the second barrel of the inner syringe to cause the solution loaded inside the second barrel of the inner syringe to enter through a second lumen of the second needle into the first lumen of the first needle, thereby causing the solution to contact the implantable material. In some embodiments, the needle comprises a removable needle.

[0133] In another aspect, the disclosure provides methods for treating a disorder, comprising administering to a subject in need thereof an amount effective to treat the disorder of the AM hydrogel, precursor thereof, or pharmaceutical composition thereof, wherein administering comprises injecting the AM hydrogel, precursor or pharmaceutical composition thereof into a tissue of a subject using an injectable delivery system of the present disclosure. The AM hydrogels are capable of gelation at physiological pH and temperature and thus can form a gel upon injection to a subject, such as at a joint. The AM hydrogels or precursors thereof can be used, for example, in cell delivery and for tissue regeneration in a minimally invasive and cost-effective manner. The methods may comprise the treatment of any disorder that can suitably be treated using the AM hydrogel, precursor thereof, or pharmaceutical composition. In various embodiments, the disorder may be selected from the group consisting of an inflammatory disease, inflammatory and degenerative conditions of the soft tissues and joints, a musculoskeletal tissue order, a skin tissue disorder including but not limited to bums, wounds, and ulcers; and an eye disorder including but not limited to a corneal defect. In other embodiments, the disorder comprises an inflammatory and/or degenerative condition of the soft tissues or joints including but not limited to plantar fasciitis, Achilles tendinosis, joint tendinitis, tennis/golfer’s elbow, ligament damage, arthritis including but not limited to osteoarthritis and rheumatoid arthritis, rotator cuff inflammation and/or degeneration, and discogenic pain in one embodiment, the disorder comprises osteoarthritis.

Compositions

[0134] Aspects of the present disclosure relate to pharmaceutical compositions comprising a AM hydrogel or precursor thereof delivery using an injectable delivery system of the present disclosure. In an aspect, the disclosure provides a pharmaceutical composition comprising the AM hydrogel or precursor thereof and a pharmaceutically acceptable carrier. Any suitable pharmaceutically acceptable earner may be used as appropriate for an intended use, including but not limited to physiological buffer. The pharmaceutical composition may be formulated for any suitable route of administration, including topical, spray, drop, and by injection. When formulated for injection, the composition, such as a composition comprising AM hydrogel precursor, may be present with an injection device, including but not limited to a syringe, or a catheter. In a preferred embodiment, the pharmaceutical composition is loaded into the tip of a first needle of an injectable delivery system of the present disclosure and delivered into a tissue of a subject in need thereof using the injectable delivery system.

[0135] The pharmaceutical compositions may comprise any other therapeutic component as deemed appropriate for an intended use, including but not limited to other cell types, secretomes, nano/micro particles, proteins and peptides, small molecular weight drugs, growth factors etc.

Kits

[0136] Aspects of the present disclosure relate to kits for using a delivery system of the present disclosure and implementing a method of the disclosure.

[0137] In an aspect, the disclosure provides a kit for delivering an implantable material into a tissue of a subject, the kit comprising: (a) an injectable delivery system of the present disclosure; and instructions for delivering an implantable material into a tissue of a subject with the injectable delivery system. [0138] In some aspects, the injectable delivery system of the kit comprises system components in a disassembled configuration. In other aspects, the injectable delivery system of the kit comprises system components in an assembled configuration.

[0139] In yet other aspects, the kit includes a bioactive agent. In yet additional aspects, the kit includes a solution described herein. In some embodiments, the bioactive agent and/or the solution are pre-loaded in the second barrel of the second syringe.

[0140] The kit can include instructions for performing a method of the disclosure.

[0141] In certain aspects, the kit includes instructions for loading an implantable material into the first needle. In other aspects, the kit includes instructions for loading an AM, AM hydrogel, hydrogel precursor, or pharmaceutical composition thereof into the first needle. In some embodiments, the instructions are for pre-loading the AM, AM hydrogel, hydrogel precursor, or pharmaceutical composition thereof. In other embodiments, the instructions arc for loading the AM, AM hydrogel, hydrogel precursor, or pharmaceutical composition thereof into the first needle when the injection system is in an assembled configuration.

[0142] In some aspects, the kit includes instructions for extracting a section of AM. In other aspects, the kit includes instructions for preparing to deliver the AM, AM hydrogel, hydrogel precursor, or pharmaceutical composition thereof into a subject in need thereof. In yet other aspects, the kit includes a tubular mold (e.g., a metallic or plastic tubular mold) with the same dimensions as the first needle and instructions for lyophilizing the implantable material (e.g., amnion) in the tubular mold. In some embodiments, the instructions instruct the user to lyophilize the implantable material (e.g., amnion) in a twisted form inside a tubular mold. In other embodiments, the instructions instruct a user to lyophilize the implantable material (e.g., amnion) in a rolled form inside a tubular mold. In other embodiments, the instructions instruct a user to lyophilize the implantable material (e.g., amnion) in a folded form inside a tubular mold. [0143] In still other aspects, the kit includes instructions for using the delivery system to treat a disorder using the injection delivery system.

[0144] The present disclosure is illustrated and further described in more detail with reference to the following non-limiting examples. Section headings as used in this section and the entire disclosure herein are merely for organizational purposes and are not intended to be limiting. EXAMPLES

Example 1 - Preparation for injectable delivery system

[0145] This example describes how an exemplary implantable material was prepared for delivery using an exemplary embodiment of an injectable delivery system of the present disclosure. A precise section of decellularized amnion sheet was carefully extracted from the whole amnion tissue. Once the desired patch of tissue was successfully separated, it was placed into the tip of a first needle. Then through the entering point within the body of the syringe, the solution can be injected into the needle and the amnion can be hydrated in a liquid before injection. This enables the amnion to absorb the biologically active components enhancing the regeneration process. Moreover, the injectable amnion is now swollen and can exhibit good mechanical properties as a graft.

Example 2 - Injection of amnion tissue patch

[0146] This example illustrates how an exemplary delivery system of the present disclosure was used to inject an exemplary implantable material. The sheet of amnion tissue was inserted into a syringe filled with normal saline and injected using needles of different gauges. When the tissue sheet suspended in normal saline was pushed through a hypodermic needle using a plunger, it successfully passed through the needle tip and entered the tissue. Measurements taken before and after the injection process revealed that the amnion tissue patch remained unchanged in shape and size, indicating its injectability without structural deformations.

[0147] After fabrication, an exemplary delivery system of the present disclosure was used to inject an amnion membrane into the tissues of a cadaver rabbit. Using this device amnion membrane was successfully inserted into the tissues. Compared to other amnion membrane delivery devices, the injection device disclosed herein is less invasive and the membrane could be delivered easily without any need of surgical procedure.

Example 3 - Principle of operation of an exemplary embodiment of an injectable delivery system of the present disclosure

[0148] This example explains the operational principles of an exemplary embodiment of an injectable delivery system of the present disclosure, for example, in an assembled configuration. As shown in the enlarged view of Figure 1, an injectable delivery system (1) of the present disclosure includes a first assembly (2) comprising at least a first needle (10) and a lumen (13) into which an implantable material (15) (e.g., AM) can be loaded for delivery into the tissue of the subject; and (b) a second assembly (20) comprising at least a first plunger (22) that is configured to slide bidirectionally within the lumen of the first needle to deliver the implantable material into the tissue of the subject when a user inserts the first needle into the tissue of the subject and applies an axial pressure to the at least the first plunger. In the enlarged view of Figure 1 , at least the first plunger is shown as a rod, but the at least the first plunger can also be a needle from at least a second syringe that is part of the second assembly. As is also shown in Figure 1, in an assembled configuration, the inner syringe moves like a piston or a plunger within the outer or first syringe in such a way that the inner or second needle connected to the inner or second syringe moves withing the first or outer needle like a plunger and pushes the membrane that is inside of the first or outer needle.

Example 4 -Operational principles of an exemplary embodiment of an injectable delivery system of the present disclosure in a disassembled configuration.

[0149] This example explains the operational principles of an exemplary embodiment of an injectable delivery system of the present disclosure in a disassembled configuration. As shown in Figure 2, 1 is an outer or first needle that includes the implantable material such as the tissue; 2 is the outer or first syringe that holds and handles the outer needle 1 including the implantable material such as tissue; 3 is an inner or second syringe with a second or inner needle attached to it that moves inside of the outer syringe and injects the tissue through the outer needle 1 ; and 4 is the plunger/piston for the inner or second syringe that can be used to inject liquids using the inner or second syringe 3. Figure 3 shows basic components of an exemplary embodiment of a delivery system of the present disclosure, including the inner or second syringe with the inner or second needle and the plunger (the second or inner syringe assembly) that can be used to inject any suitable liquid (Left), and the outer or first syringe that is connected to the outer or first needle containing the implantable materials (for example, amniotic membrane) (Right).

Example 5 - Stages of using an exemplary injectable delivery system of the present disclosure to inject an implantable material [0150] Figure 4 describes exemplary stages of injection using an exemplary embodiment of an injectable delivery system of the present disclosure. To inject an implantable material (e.g., lyophilized amniotic membrane), which has been preloaded into the first or outer needle, the first step is to rehydrate the membrane with the preferred liquid that can be injected by the second or inner syringe. The second or inner syringe, the second or inner needle and the plunger of the second or inner syringe (together called as the second or inner syringe assembly) operates through the first or outer syringe and the first or outer needle (together called as a first or outer syringe assembly) as shown in Figure 4 ( 1 )-(3). The preferred liquid can be administered using the second syringe assembly. Note that the second (inner) needle which is connected to the second (inner) syringe acts as a plunger inside the first or outer needle and moves inside the outer needle to push the implantable material.

Example 6 - Loading and lyophilizing an exemplary implantable material

[0151] This example illustrates the process of loading and lyophilizing an exemplary implantable material (e.g., amnionic membrane) into an exemplary embodiment of an injectable delivery system of the present disclosure. As shown in Figure 5, the implantable material (e.g., amnionic membrane) can be loaded into an injectable delivery system of the present disclosure by (a) pulling the amniotic membrane through the first or outer needle to load it, and (b) after loading, lyophilizing the membrane inside the first or outer needle.

Example 7 - Absorptive properties of exemplary implantable materials

[0152] This example demonstrates the absorptive properties of an exemplary implantable material (e.g., amniotic membrane) that can be injected using an exemplary delivery system of the present disclosure. As shown in Figure 6, the amnionic membrane is capable of absorption of bioactive liquids/solutions.

Example 8 - Exemplary embodiment of an injectable delivery system of the present disclosure

[0153] This is an example demonstrating an exemplary embodiment of an injectable delivery system of the present disclosure, for example, an animal model of injecting an implantable material. For example, Figure 7 and Figure 8 show a method for injecting amniotic membrane into rabbit’s tendon and cartilage respectively. As shown in figure 7, after loading the first or outer needle with the implantable material (e.g., membrane), the second syringe assembly can be used to inject the folded amniotic membrane into the rabbit’s tendon. As shown in Figure 8, the first or outer needle, preloaded with the implantable material (e.g., membrane), was connected to the first or outer syringe (together called as the first or outer syringe assembly), then the second or inner syringe assembly (including the second or inner syringe, the second or inner needle and the plunger) was loaded with a liquid (e.g., normal saline) to aid the injection of the membrane into rabbit’s cartilage.

[0154] Example 9 - Lyophilization inside a tubular mold

[0155] This is an example demonstrating an exemplary embodiment of the present disclosure in which the implantable material (e.g., amnion) can be lyophilized in a twisted, rolled, or folded form inside a tubular mold. Figure 9A shows an amnion membrane which has lyophilized inside of a needle shaped mold. The mold used in this experiment was a metallic tube with the same dimensions as the first needle used in the system to inject the implantable material, ensuring a precise fit for the insertion. After lyophilization, the implantable material (e.g., amnion) is removed from the mold and inserted into a first needle for deployment. Figure 9B shows a user of the system inserting the amnion into the first needle and Figure 9C shows the amnion partially inserted into the lumen of the first needle. Though metal was used for the tubular mold in this example, the skilled artisan will appreciate that the mold could also be made from other materials, such as plastic, for manufacturing flexibility.

[0156] Example 10 - syringe gun

[0157] This example demonstrates an exemplary embodiment in which the implantable material (e.g., amnion) can be injected using a syringe gun, as shown in Figure 10. This would be useful in clinical settings where the implantable material (e.g., amnion) and the first needle are long, making an ordinary injection difficult. The syringe gun provides simplicity and precision in delivering an implantable material in those settings, enhancing usability in procedures where traditional injections are impractical due to size constrains. As shown in Figure 10, the injectable delivery system (1) includes (a) the first assembly (2) comprising a first syringe (4) comprising a first barrel (6) having a first opening (8) at one end and the first needle (10) at an opposite end, wherein the first opening is configured to receive the plunger of the second assembly, and (b) a second assembly (20) comprising (i) at least the first plunger (22) slidably disposed inside the first opening of the first barrel; and (ii) a syringe gun (30) comprising a body (32) comprising a syringe holder (34) that holds the first assembly in place with at least the first plunger slidably disposed inside the first opening of the first barrel; and a trigger (36), wherein the syringe gun is configured to cause at least the first plunger to slide bidirectionally inside the first barrel and deliver the implantable material into the tissue of the subject when a user inserts the first needle into the tissue of the subject and pulls the trigger. Though not shown, the second assembly (20) can also include a second syringe with a second syringe barrel inside the first syringe barrel and the at least the first plunger (22) comprises at least a second needle of the second syringe configured to slide bidirectionally inside the lumen of the first needle (10). In such configuration, upon pressing the trigger (36), at least the first plunger causes at least the second needle of the second syringe to deliver the implantable material inside the lumen of the first needle into a target tissue of a subject. When the second barrel is preloaded with a solution (e.g., containing a bioactive agent) in such configuration, pressing the trigger (36) also causes the solution to be delivered with the implantable material. [0158] Example 11 - injectable delivery system for delivering implantable material and multiple additional materials

[0159] This example demonstrates an exemplary embodiment of the injectable delivery system in which multiple syringes are inside and move inside first barrel of the first syringe and are connected to at least the first plunger. The multiple smaller syringe assemblies can each contain a different material (e.g., solution, bioactive agent, etc.). The smaller syringes can each be connected to at least the first plunger through a lumen, enabling coordinated movement. During or after the pushing of the implantable material (e.g., amnion), the multiple material can also be injected. This setup allows for the simultaneous or sequential delivery of multiple substances, offering flexibility in treatment protocols. This embodiment of the system is designed to streamline the process by combining the injection of the implantable material with the controlled release of various solutions and/or bioactive agents. As shown in Figure 11, the injectable delivery system (1) comprises (a) a first assembly (2) comprising a first syringe (4) comprising a first barrel (6) having a second plunger (24) at one end and the first needle (not shown) at an opposite end (11); and (b) a second assembly (20) comprising (i) a plurality of syringes (40) positioned inside the first barrel of the first syringe, each of the plurality of syringes comprising at least a second syringe barrel (42) comprising at least a second opening (44) at one end and at least a third plunger (46) at the opposite end; (ii) the at least the first plunger (22); and (iii) at least one tube (48) connected to the second opening of the at least the second syringe barrel, wherein the first needle is configured to deliver the implantable material into the tissue of a subject when a user inserts the first needle into the tissue of the subject and the at least the second plunger is pressed, and wherein the plurality of syringes is configured deliver at least first fluid through the at least one tube and into the first lumen when the at least the third plunger is pressed by the user. Note that the in this embodiment, the second plunger (24) helps the second assembly (smaller syringes connected to the first plunger) moves and push solid material out. At the same time, it presses at least the third plunger (46) to release fluids inside to be injected through the at least one tube into at least the first plunger and ultimately out of the lumen of the first needle and into the target tissue. Though illustrated with 3 syringes inside the first barrel of the first syringe, the plurality of syringes could be at least 2, at least 3, at least 4 or at least 5 syringes, depending on the number of different substances desirable for use in an application.

[0160] Example 12 - injectable delivery system for delivering implantable material and multiple additional materials

[0161] This example demonstrates an exemplary embodiment of an injectable delivery system of the present disclosure where multiple syringes are connected to a single outer shell needle. A core needle, positioned within the shell needle, is filled with an implantable material, such as amnion. Inside the first needle, at least the first plunger is designed to push the implantable material out during the injection process. In this setup, first needle serves as a core needle, into which a plunger is slidably disposed to push the implantable material. The shell needle houses the core needle, and the shell needle is connected to a shared lumen linked to other syringes containing different fluids. During operation, the plungers for both the implantable material and fluid syringes can be pushed simultaneously. As a result, the implantable material is pushed out of the core needle, while the fluids, mixed in the shared lumen, are released from the shell needle. This allows us to inject the solid material and fluids together. This system allows for the simultaneous administration of the implantable material (e.g., amnion) and a solution mixture (e.g., containing one or more bioactive agents), optimizing the treatment process. The design enhances precision and efficiency in complex medical procedures, offering a controlled release of both components in one action.

[0162] As shown in Figures 12A and 12B, the injectable delivery system (1) comprises (a) a first assembly (2) comprising (i) at least a first needle (10) and a lumen (13) into which an implantable material (15) can be loaded for delivery into the tissue of a subject; and (ii) a shell needle (17); and (b) a second assembly (20) comprising: (i) at least a first (50), second (60), third (70), and/or fourth (80) syringe comprising at least a first (52), second (62), third (72) and/or fourth (82) fluid outlet at one end and at least a second (54), a third (64), fourth (74), and/or fifth (84) plunger at the opposite end, and at least a second (56), third (66), fourth (76), and/or fifth (86) barrel extending between the one end and the opposite end; (ii) an adapter (90) connected to the at least the first, second, third and/or fourth fluid outlet configured to channel fluid flowing through the outlet into a shared lumen (19) that is connected to at least the shell needle; and (iii) at least the first plunger (22) is configured to slide bidirectionally within the shared lumen and the lumen of the first needle to deliver the implantable material into the tissue of the subject when a user inserts the first needle into the tissue of the subject and applies an axial pressure to at least the first plunger.

[0163] While the invention has been described with reference to an exemplary embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims. Any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0164] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims. [0165] For reasons of completeness, various aspects of the disclosure are set out in the following numbered clauses:

[0166] Clause 1. An injectable delivery system for delivering an implantable material into a tissue of a subject, the system comprising: (a) a first assembly comprising at least a first needle and a lumen into which an implantable material can be loaded for delivery into the tissue of the subject; and (b) a second assembly comprising at least a first plunger that is configured to slide bidirectionally within the lumen of the first needle to deliver the implantable material into the tissue of the subject when a user inserts the first needle into the tissue of the subject and applies an axial pressure to the at least the first plunger

[0167] Clause 2. The injectable delivery system of clause 1, wherein at least the first plunger comprises a wire, a rod, or a needle.

[0168] Clause 3. The injectable delivery system of clause 1, wherein: (a) the first assembly comprises a first syringe comprising a first barrel having a first opening at one end and the first needle at an opposite end, wherein the first opening is configured to receive a second barrel of a second syringe into the first barrel of the first syringe, and (b) the second assembly comprises a second syringe comprising a second barrel having a second opening at one end, and a piston and a second needle at an opposite end, wherein the second opening is configured to receive at least the first plunger, wherein the piston is configured to enable the second syringe barrel to slide bidirectionally within the first barrel of the first syringe, and wherein the second needle is configured to slide bidirectionally within the lumen of the first needle to deliver the implantable material into the tissue of a subject when at least the first plunger is pressed into the second opening of the second barrel of the second syringe.

[0169] Clause 4. The injectable delivery system of clause 1, wherein: (a) the first assembly comprises a first syringe comprising a first barrel having a first opening at one end and the first needle at an opposite end, wherein the first opening is configured to receive the plunger of the second assembly, and (b) the second assembly comprises: (i) a second syringe comprising a second barrel having the plunger slidably disposed inside the first opening of the first barrel and further comprising at least a second needle that is configured to slide bidirectionally within the lumen of the first needle to deliver the implantable material into a target tissue of a subject; and (ii) a syringe gun comprising: (1) a body comprising a syringe holder that holds the first assembly in place with at least the first plunger slidably disposed inside the first opening of the first barrel; and (2) a trigger, wherein the syringe gun is configured to cause at least the first plunger to slide bidirectionally inside the first barrel and the second needle to slide bidirectionally within the lumen of the first needle to deliver the implantable material into the tissue of the subject when a user inserts the first needle into the tissue of the subject and pulls the trigger.

[0170] Clause 5. The injectable delivery system of clause 1, wherein: (a) the first assembly comprises a first syringe comprising a first barrel having a second plunger at one end and the first needle at an opposite end; and (b) the second assembly comprises: (i) a plurality of syringes positioned inside the first barrel of the first syringe, each of the plurality of syringes comprising at least a second syringe barrel comprising at least a second opening at one end and at least a third plunger at the opposite end; (ii) the at least the first plunger; and (iii) at least one tube connected to the second opening of the at least the second syringe barrel, wherein the first needle is configured to deliver the implantable material into the tissue of a subject when a user inserts the first needle into the tissue of the subject and the at least the second plunger is pressed, and wherein the plurality of syringes is configured deliver at least first fluid through the at least one tube and into the first lumen when the at least the third plunger is pressed by the user.

[0171] Clause 6. The injectable delivery system of clause 1, wherein: (a) the first assembly comprises at least a first needle and a lumen into which an implantable material can be loaded for delivery into the tissue of the subject; and (b) the second assembly comprising: (i) at least a first, second, third, and/or fourth syringe comprising at least a first, second, third and/or fourth fluid outlet at one end and at least a second, a third, fourth, and/or fifth plunger at the opposite end, and at least a second, third, fourth, and/or fifth barrel extending between the one end and the opposite end; (ii) an adapter connected to the at least the first, second, third and/or fourth fluid outlet configured to channel fluid flowing through the outlet into a shared lumen that is connected to at least the first needle; and (iii) at least the first plunger is configured to slide bidirectionally within the shared lumen and the lumen of the first needle to deliver the implantable material into the tissue of the subject when a user inserts the first needle into the tissue of the subject and applies an axial pressure to at least the first plunger.

[0172] Clause 7. The injectable delivery system of any one of clauses 1-6, wherein the first needle comprises a removable needle and the lumen of the first needle is preloaded with the implantable material before the first needle is connected to the opposite end of the first syringe. [0173] Clause 8. The injectable delivery system of clause 3, wherein the second syringe comprises a solution preloaded inside the second barrel, or the system of clause 4, wherein the first syringe comprises a solution preloaded inside the first barrel, or the system of clause 5, wherein at least the second barrel of each of the plurality of syringes comprises a solution preloaded inside, or the system of clause 6, wherein the at least the second, at least the third, at least the fourth, and/or at least the fifth barrel comprises a solution preloaded inside.

[0174] Clause 9. The injectable delivery system of any one of clauses 1 and 3-8, wherein: (i) the first needle comprises a gauge ranging from about 10G to about 28G needle; or (ii) the lumen of the first needle comprises an inner diameter ranging from about 0.15 mm to about 2 mm.

[0175] Clause 10. The injectable delivery system of any one of clauses 1 and 3-9, wherein a volume of the first barrel of the first syringe ranges from about 0.1ml to about 450ml. [0176] Clause 11. The injectable delivery system of any one of clauses 3-10, wherein: (i) at least second needle comprise a gauge ranging from about 12G to about 32 G; (ii) the lumen of the at least the second needle comprises a diameter ranging from about 0.3 to about 1.8 mm.

[0177] Clause 12. The injectable delivery system of any one of clauses 3-11, wherein a volume of the second syringe barrel ranges from about 0.5 ml to about 400 ml.

[0178] Clause 13. The injectable delivery system of any one of clauses 1-12, wherein the implantable material comprises amnionic membrane (AM), an AM hydrogel or precursor thereof, or a pharmaceutical composition thereof.

[0179] Clause 14. The injectable delivery system of clause 13, wherein: (i) the AM folded, rolled, or twisted; and/or (ii) the AM is lyophilized.

[0180] Clause 15. A kit for delivering an implantable material into a tissue of a subject, the kit comprising: (a) the injectable delivery system of any one of clauses 1-14; and (b) instructions for delivering an implantable material into a tissue of a subject with the injectable delivery system.

[0181] Clause 16. A method for delivering an implantable material into a target tissue of a subject, the method comprising: (a) inserting a tip of a first needle comprising a lumen with an implantable material loaded inside of it into a target tissue of a subject; and (b) depressing a plunger to cause it to slide bidirectionally within the lumen of the first needle, thereby delivering the implantable material into the target tissue of the subject.

[0182] Clause 17. The method of clause 16, further comprising, prior to inserting the tip of the first needle into the target tissue of the subject, loading the implantable material into the lumen of the first needle.

[0183] Clause 18. The method of clause 17, wherein the implantable material comprises a section of amnion and loading comprises folding, rolling, or twisting the section of amnion inside the lumen.

[0184] Clause 19. The method of clause 18, wherein: (i) the amnion is lyophilized before being loaded into the lumen of the first needle; (ii) the amnion is lyophilized after being loaded into the lumen of the first needle, and the method further comprises rehydrating the lyophilized amnion inside the lumen of the first needle; or (iii) the amnion is lyophilized inside of a tubular mold with an inner diameter that is equivalent to an inner diameter of the lumen of the first needle, and the method further comprises rehydrating the lyophilized amnion inside the lumen of the first needle.

[0185] Clause 20. The method of clause 19, wherein rehydrating comprises depressing the plunger into the second barrel of the second syringe to cause a solution inside the second barrel to transfer into the lumen of the first needle into contact with the lyophilized amnion. [0186] Clause 21. A method for preparing to deliver an implantable material into a tissue of a subject, the method comprising: (a) connecting a first removable needle comprising a first lumen with an implantable material preloaded within it to a first end of a first barrel of an outer syringe of a coaxial syringe assembly comprising the outer syringe and an inner syringe slidably disposed within the outer syringe through a first opening at an opposite second end of the first barrel of the outer syringe; and (b) depressing a plunger into a second barrel of the inner syringe through a second opening of the second barrel proximal to the first opening at the opposite second end of the first barrel of the outer syringe to cause a solution contained within the second barrel of the inner syringe to flow through a second lumen of a second needle situated proximal to the first end of the first barrel into the first lumen of the first removable needle into contact with the implantable material inside the first lumen.

[0187] Clause 22. The method of clause 21, further comprising prior to connecting step

(a) loading the implantable material into the first lumen of the first removable needle and/or loading the solution into the second barrel.

[0188] Clause 23. A method for delivering an implantable material into a target tissue of a subject in need thereof, the method comprising: (a) obtaining a coaxial syringe assembly comprising an outer syringe and an inner syringe slidably disposed within an opening of a first barrel of the outer syringe, the outer syringe comprising a first needle comprising a first gauge comprising a lumen with a implantable material loaded inside, the inner syringe comprising a second barrel comprising a solution loaded inside and a second needle comprising a second gauge that enables the second needle to slide bidirectionally within the lumen of the first needle;

(b) positioning a tip of the first needle onto an outer surface of the subject’s skin or other lumen or tissue within the body at an injection site near the target tissue; and (c) depressing a plunger disposed within the second barrel of the inner syringe to cause the second needle to slidably move through the lumen of the first needle, thereby causing the needle to penetrate the subject’s skin or other lumen or tissue within the body and deliver the implantable material into the target tissue.

[0189] Clause 24. The method of clause 23, further comprising prior to depressing step (c), depressing a plunger disposed within the second barrel of the inner syringe to cause the solution loaded inside the second barrel of the inner syringe to enter through a second lumen of the second needle into the first lumen of the first needle, thereby causing the solution to contact the implantable material.

[0190] Clause 25. The method of clause 23 or 24, wherein the implantable material comprises decellularized amnion that is optionally lyophilized.

[0191] Clause 26. The system, kit, or method of any one of the preceding clauses, wherein the first needle comprises a removable needle.

Claims

CLAIMS What is claimed is:

1. An injectable delivery system for delivering an implantable material into a tissue of a subject, the system comprising:

(a) a first assembly comprising at least a first needle and a lumen into which an implantable material can be loaded for delivery into the tissue of the subject; and

(b) a second assembly comprising at least a first plunger that is configured to slide bidirectionally within the lumen of the first needle to deliver the implantable material into the tissue of the subject when a user inserts the first needle into the tissue of the subject and applies an axial pressure to the at least the first plunger.

2. The injectable delivery system of claim 1, wherein at least the first plunger comprises a wire, a rod, or a needle.

3. The injectable delivery system of claim 1, wherein:

(a) the first assembly comprises a first syringe comprising a first barrel having a first opening at one end and the first needle at an opposite end, wherein the first opening is configured to receive a second barrel of a second syringe into the first barrel of the first syringe, and

(b) the second assembly comprises a second syringe comprising a second barrel having a second opening at one end, and a piston and a second needle at an opposite end, wherein the second opening is configured to receive at least the first plunger, wherein the piston is configured to enable the second syringe barrel to slide bidirectionally within the first barrel of the first syringe, and wherein the second needle is configured to slide bidirectionally within the lumen of the first needle to deliver the implantable material into the tissue of a subject when at least the first plunger is pressed into the second opening of the second barrel of the second syringe.

4. The injectable delivery system of claim 1, wherein:

(a) the first assembly comprises a first syringe comprising a first barrel having a first opening at one end and the first needle at an opposite end, wherein the first opening is configured to receive the plunger of the second assembly, and (b) the second assembly comprises:

(i) a second syringe comprising a second barrel having the plunger slidably disposed inside the first opening of the first barrel and further comprising at least a second needle that is configured to slide bidirectionally within the lumen of the first needle to deliver the implantable material into a target tissue of a subject; and

(ii) a syringe gun comprising:

(1) a body comprising a syringe holder that holds the first assembly in place with at least the first plunger slidably disposed inside the first opening of the first barrel; and

(2) a trigger, wherein the syringe gun is configured to cause at least the first plunger to slide bidirectionally inside the first barrel and the second needle to slide bidirectionally within the lumen of the first needle to deliver the implantable material into the tissue of the subject when a user inserts the first needle into the tissue of the subject and pulls the trigger.

5. The injectable delivery system of claim 1, wherein:

(a) the first assembly comprises a first syringe comprising a first barrel having a second plunger at one end and the first needle at an opposite end; and

(b) the second assembly comprises:

(i) a plurality of syringes positioned inside the first barrel of the first syringe, each of the plurality of syringes comprising at least a second syringe barrel comprising at least a second opening at one end and at least a third plunger at the opposite end;

(ii) the at least the first plunger; and

(iii) at least one tube connected to the second opening of the at least the second syringe barrel, wherein the first needle is configured to deliver the implantable material into the tissue of a subject when a user inserts the first needle into the tissue of the subject and the at least the second plunger is pressed, and wherein the plurality of syringes is configured deliver at least first fluid through the at least one tube and into the first lumen when the at least the third plunger is pressed by the user.

6. The injectable delivery system of claim 1, wherein: (a) the first assembly comprises at least a first needle and a lumen into which an implantable material can be loaded for delivery into the tissue of the subject; and

(b) the second assembly comprising:

(i) at least a first, second, third, and/or fourth syringe comprising at least a first, second, third and/or fourth fluid outlet at one end and at least a second, a third, fourth, and/or fifth plunger at the opposite end, and at least a second, third, fourth, and/or fifth barrel extending between the one end and the opposite end;

(ii) an adapter connected to the at least the first, second, third and/or fourth fluid outlet configured to channel fluid flowing through the outlet into a shared lumen that is connected to at least the first needle; and

(iii) at least the first plunger is configured to slide bidirectionally within the shared lumen and the lumen of the first needle to deliver the implantable material into the tissue of the subject when a user inserts the first needle into the tissue of the subject and applies an axial pressure to at least the first plunger.

7. The injectable delivery system of any one of claims 1-6, wherein the first needle comprises a removable needle and the lumen of the first needle is preloaded with the implantable material before the first needle is connected to the opposite end of the first syringe.

8. The injectable delivery system of claim 3, wherein the second syringe comprises a solution preloaded inside the second barrel, or the system of claim 4, wherein the first syringe comprises a solution preloaded inside the first barrel, or the system of claim 5, wherein at least the second barrel of each of the plurality of syringes comprises a solution preloaded inside, or the system of claim 6, wherein the at least the second, at least the third, at least the fourth, and/or at least the fifth barrel comprises a solution preloaded inside.

9. The injectable delivery system of any one of claims 1 and 3-8, wherein:

(i) the first needle comprises a gauge ranging from about 10G to about 28G needle; or

(ii) the lumen of the first needle comprises an inner diameter ranging from about 0.15 mm to about 2 mm.

10. The injectable delivery system of any one of claims 1 and 3-9, wherein a volume of the first barrel of the first syringe ranges from about 0.1ml to about 450ml.

11. The injectable delivery system of any one of claims 3-10, wherein: (i) at least second needle comprise a gauge ranging from about 12G to about 32 G; (ii) the lumen of the at least the second needle comprises a diameter ranging from about 0.3 to about 1.8 mm.

12. The injectable delivery system of any one of claims 3-11, wherein a volume of the second syringe barrel ranges from about 0.5 ml to about 400 ml.

13. The injectable delivery system of any one of claims 1-12, wherein the implantable material comprises amnionic membrane (AM), an AM hydrogel or precursor thereof, or a pharmaceutical composition thereof.

14. The injectable delivery system of claim 13, wherein: (i) the AM folded, rolled, or twisted; and/or (ii) the AM is lyophilized.

15. A kit for delivering an implantable material into a tissue of a subject, the kit comprising: (a) the injectable delivery system of any one of claims 1-14; and

(b) instructions for delivering an implantable material into a tissue of a subject with the injectable delivery system.

16. A method for delivering an implantable material into a target tissue of a subject, the method comprising:

(a) inserting a tip of a first needle comprising a lumen with an implantable material loaded inside of it into a target tissue of a subject; and

(b) depressing a plunger to cause it to slide bidirectionally within the lumen of the first needle, thereby delivering the implantable material into the target tissue of the subject.

17. The method of claim 16, further comprising, prior to inserting the tip of the first needle into the target tissue of the subject, loading the implantable material into the lumen of the first needle.

18. The method of claim 17, wherein the implantable material comprises a section of amnion and loading comprises folding, rolling, or twisting the section of amnion inside the lumen.

19. The method of claim 18, wherein:

(i) the amnion is lyophilized before being loaded into the lumen of the first needle;

(ii) the amnion is lyophilized after being loaded into the lumen of the first needle, and the method further comprises rehydrating the lyophilized amnion inside the lumen of the first needle; or

(iii) the amnion is lyophilized inside of a tubular mold with an inner diameter that is equivalent to an inner diameter of the lumen of the first needle, and the method further comprises rehydrating the lyophilized amnion inside the lumen of the first needle.

20. The method of claim 19, wherein rehydrating comprises depressing the plunger into the second barrel of the second syringe to cause a solution inside the second barrel to transfer into the lumen of the first needle into contact with the lyophilized amnion.

21. A method for preparing to deliver an implantable material into a tissue of a subject, the method comprising:

(a) connecting a first removable needle comprising a first lumen with an implantable material preloaded within it to a first end of a first barrel of an outer syringe of a coaxial syringe assembly comprising the outer syringe and an inner syringe slidably disposed within the outer syringe through a first opening at an opposite second end of the first barrel of the outer syringe; and

(b) depressing a plunger into a second barrel of the inner syringe through a second opening of the second barrel proximal to the first opening at the opposite second end of the first barrel of the outer syringe to cause a solution contained within the second barrel of the inner syringe to flow through a second lumen of a second needle situated proximal to the first end of the first barrel into the first lumen of the first removable needle into contact with the implantable material inside the first lumen.

22. The method of claim 21, further comprising prior to connecting step (a) loading the implantable material into the first lumen of the first removable needle and/or loading the solution into the second barrel.

23. A method for delivering an implantable material into a target tissue of a subject in need thereof, the method comprising:

(a) obtaining a coaxial syringe assembly comprising an outer syringe and an inner syringe slidably disposed within an opening of a first barrel of the outer syringe, the outer syringe comprising a first needle comprising a first gauge comprising a lumen with a implantable material loaded inside, the inner syringe comprising a second barrel comprising a solution loaded inside and a second needle comprising a second gauge that enables the second needle to slide bidirectionally within the lumen of the first needle;

(b) positioning a tip of the first needle onto an outer surface of the subject’s skin or other lumen or tissue within the body at an injection site near the target tissue; and

(c) depressing a plunger disposed within the second barrel of the inner syringe to cause the second needle to slidably move through the lumen of the first needle, thereby causing the needle to penetrate the subject’s skin or other lumen or tissue within the body and deliver the implantable material into the target tissue.

24. The method of claim 23, further comprising prior to depressing step (c), depressing a plunger disposed within the second barrel of the inner syringe to cause the solution loaded inside the second barrel of the inner syringe to enter through a second lumen of the second needle into the first lumen of the first needle, thereby causing the solution to contact the implantable material.

25. The method of claim 23 or 24, wherein the implantable material comprises decellularized amnion that is optionally lyophilized.

26. The system, kit, or method of any one of the preceding claims, wherein the first needle comprises a removable needle.