Instruments and methods for the subcutaneous deposition of a soft implantable

Abstract

The present disclosure provides instruments and methods related to implanting a soft implantable such as a hydrogel. In particular, the present disclosure provides novel instruments and methods for implanting soft implantable with minimal to no direct physical interaction between the operator of the instrument and the implantable.

Description

Atty. Docket No. UM-43679.601INSTRUMENTS AND METHODS FOR THE SUBCUTANEOUS DEPOSITION OF A SOFT IMPLANTABLE PRIORITYCLAIM

[0001] This application claims benefit of US Provisional Application No.63 / 699,958, filedSeptember 27, 2024, which is hereby incorporated by reference in its entirety.GOVERNMENT SUPPORT

[0002] This invention was made with government support under HD104173 awarded by theNational Institutes of Health. The government has certain rights in the invention.FIELD

[0003] The present disclosure provides instruments and methods related to implanting atherapeutic in a subject. As a specific non-limiting example, the present disclosure provides novel instruments and methods for treating and / or preventing Premature ovarian insufficiency (POI).BACKGROUND

[0004] Soft implantable therapeutics are an emerging technology in the medical field. Softmaterials like hydrogels are loaded with therapeutics and implanted in subcutaneous tissue for extended release. Due in part to the size and fragility of the hydrogels, their need to maintain hydration, and a lack of dedicated instrumentation, current protocols require insertion of the hydrogel by a trained surgeon under surgical conditions, greatly increasing cost and patient anxiety. Accordingly, instruments and methods that simplify implantation of a hydrogel or similarly fragile implantable medical device such that implantation could be performed by a general practitioner or equivalently qualified personnel in a clinical setting are in demand.

[0005] An example of a condition that can be treated with implantable hydrogels inpremature ovarian insufficiency (POI). POI is an accelerated truncation of ovarian physiology and occurs, chronologically, well in advance of the timeline destined for the typical female. POI affects female cancer survivors, particularly those treated with cytotoxic therapies during childhood. POI leads to sterility and other health complications due to estrogen deficiency (e.g., premature osteopenia, muscle wasting, and cardiovascular disease). Treatment of female cancer survivors with POI with a soft implantable designed to release suitable therapeutics can prevent sterility and other health issues due to estrogen deficiency and eliminate the need for immunosuppressive therapy.1Atty. Docket No. UM-43679.601SUMMARY

[0006] Provided herein are instruments and methods related to implanting a therapeutic ina subject. In some embodiments, the instrument is a trocar medical device designed specifically for the placement of a soft implantable in a subject. In some embodiments the soft medical device is or includes a therapeutic. In some non-limiting embodiments the therapeutic treats and / or prevents Premature ovarian insufficiency (POI).

[0007] In an embodiment, the present disclosure provides an instrument comprising an outercannula configured to be inserted inside a pocket formed in a subject’s tissue so as to maintain a desired size and depth of the pocket; and a plunger configured to be reversibly received by the outer cannula wherein movement of outer cannula and plunger relative to each other releases and deposits a soft implantable at known depth and location inside the pocket. In some embodiments the instrument may further comprise a needle piece configured to be reversibly received by the outer cannula and, which, when located within the outer cannula, is configured to create the pocket in the subject’s tissue. In some embodiments the cannula or plunger comprises a compartment for storage of the soft implantable. In some embodiments the compartment maintains the soft implantable in a particular condition, e.g. a hydrated state. In some embodiments the compartment is sealed in a first operative state and unsealed in a second operative state. In some embodiments the compartment is liquid impermeable.

[0008] In some embodiments the instrument is preloaded with the soft implantable prior touse. In some embodiments the soft implantable, whether or not preloaded in the instrument is between 5mm and 20mm in at least two dimensions and the outer cannula is sized to maintain the pocket at a size and shape that is large enough to receive the soft implantable. In some embodiments the soft implantable is or comprises a hydrogel.

[0009] In another embodiment, the present disclosure provides an instrument comprisingone or more of (1) a first piece comprising a handle, a slider, a slider locking mechanism, and a first lip; (2) a second piece comprising a second lip, a peg, a needle nose, and a first lock; (3) a third piece comprising a second lock and a track; (4) and a fourth piece comprising a door and a compartment; wherein the instrument is configured to deposit a soft implantable to a subject in need thereof. In some embodiments the compartment is configured to contain the implantable. In some embodiments the fourth piece is configured to removably couple with the third piece. In some embodiments the second piece is configured to accept, by insertion, the removably coupled fourth piece and third piece. In some embodiments, the needle nose is configured to open upon pushing the removably coupled fourth piece and third piece distally.2Atty. Docket No. UM-43679.601

[0010] In some embodiments, the instrument includes a locking system configured to limitthe movement of the various pieces with respect to each other when the pieces are seated in a particular configuration. In some embodiments the particular configuration is a configuration that delivers the soft implant to a desired location in a subject’s subcutaneous tissue.

[0011] In some embodiments the instrument comprises a compartment for a soft implant.In some embodiments the compartment comprises a door, which may slide or be hinged and which may open upon pushing an element of the instrument. In some embodiments upon pushing the element and opening the door, the soft implant is deposited in the subject’s subcutaneous tissue.

[0012] In some embodiments the soft implantable is a composition comprising a degradableinner core comprising a biological material and a non-degradable outer shell encapsulating the degradable inner core and comprising a thermosensitive gelatin microgel. In some embodiments the soft implantable comprises a therapeutic housing, which may be, for example, configured to contain an immunoisolation device. In some embodiments the therapeutic housing is capable of dissolving in the tissue of a subject.

[0013] According to various embodiments, the present disclosure provides methods ofdepositing a soft implant into a subject by inserting any of the herein disclosed instruments into a tissue of a subject and releasing the implant. In some embodiments, the method comprises depositing a soft implant inside of a subject’s tissue by: forming a pocket in the subject’s tissue; inserting any of the instruments disclosed herein into the pocket; moving two or more pieces of the instrument relative to one another to deposit the soft implant or therapeutic inside the pocket and removing the instrument. In some embodiments the soft implant is preloaded inside of the instrument. In some embodiments the operator of the instrument does not directly interact with the implantable at any time during the procedure. In some embodiments the implant is maintained under at least one particular condition (e.g., a hydrated state) while loaded inside the instrument.BRIEFDESCRIPTIONOFTHEDRAWINGS

[0014] FIG. 1 is a view illustrating the main components of a first instrument according toat least one embodiment of the present disclosure.

[0015] FIG.2 is a view illustrating the main components of a second instrument accordingto at least one embodiment of the present disclosure.

[0016] FIG.3 is a view illustrating the main components of a third instrument according toat least one embodiment of the present disclosure.3Atty. Docket No. UM-43679.601

[0017] FIG. 4 is a view illustrating the main components of a therapeutic housing (i.e., ahydrogel holding puck) according to at least one embodiment of the present disclosure.

[0018] FIG. 5 is a view illustrating the main components of a fourth instrument accordingto at least one embodiment of the present disclosure.

[0019] FIG. 6 is a view illustrating the main components of a fifth instrument according toat least one embodiment of the present disclosure.

[0020] FIGS. 7A-7F are views illustrating the main components of a sixth instrumentaccording to at least one embodiment of the present disclosure. FIG.7A is a view illustrating various components of the sixth instrument. FIG. 7B is another view illustrating various components of the sixth instrument. FIG.7C is a view illustrating various components of the sixth instrument. FIG.7D is a view illustrating an exemplary outer cannula component with a sliding mechanism. FIG 7E is a view of an exemplary needle piece according to an embodiment. FIG. 7F is another view of an exemplary needle piece according to an embodiment. FIG.7G is a view of an exemplary needle tip according to an embodiment. FIG.7H is a view of an exemplary inner cannula having a locking mechanism according to an embodiment. FIG.7I is a view of an exemplary

[0021] FIGS. 8A-8K are views illustrating the main components of a seventh instrumentaccording to at least one embodiment of the present disclosure. FIG.8A shows the three main components of the instrument. FIGS.8B, 8C, 8D, and 8E show operation of the instrument as it is used to deposit a soft implantable inside the subcutaneous tissue of a subject. FIG.8F shows a configuration wherein a needle piece having an angle guard for controlling the depth and angle of insertion is removably housed within an outer cannula piece. FIG. 8G shows another embodiment of a needle piece that does not include the angular guard. FIG.8H shows an embodiment wherein the needle piece includes an ergonomic grip. FIGS.8I, 8J, and 8K show an embodiment wherein the plunger piece includes a lock and pin transport lock and depth / plunging indicators.

[0022] FIGS. 9A – 9 are views illustrating the main components of an eighth instrumentaccording to at least one embodiment of the present disclosure. FIG.9A shows the assembled plunger and cannula assembly. FIG.9B is a close up of the locking mechanism of FIG.9A. FIG.9C is a close up of the indicator window of FIG.9A. FIG.9D shows the plunger piece. FIG.9E shows the canula assembly.

[0023] FIG.10 shows a cannula according to an embodiment including a flared portion thatprevents the cannula from being inserted too far into a pocket.4Atty. Docket No. UM-43679.601DETAILED DESCRIPTION

[0024] Provided herein are instruments and methods related to implanting a therapeutic. Insome embodiments, the instrument is a trocar medical device designed specifically for the placement of a soft implantable (e.g. a hydrogel or similarly fragile substance) in a subject. In some embodiments the soft implantable is or includes a therapeutic. In some non-limiting embodiments the therapeutic treats and / or prevents Premature ovarian insufficiency (POI).

[0025] Section headings as used in this section and the entire disclosure herein are merelyfor organizational purposes and are not intended to be limiting.1. Definitions

[0026] Although any methods and materials similar or equivalent to those described hereincan be used in the practice or testing of embodiments described herein, some preferred methods, instruments, devices, and materials are described herein. However, before the present materials and methods are described, it is to be understood that this invention is not limited to the particular instruments, methodologies, or protocols herein described, as these may vary in accordance with routine experimentation and optimization. It is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only and is not intended to limit the scope of the embodiments described herein.

[0027] Unless otherwise defined, all technical and scientific terms used herein have thesame meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. However, in case of conflict, the present specification, including definitions, will control. Accordingly, in the context of the embodiments described herein, the following definitions apply.

[0028] As used herein, the term “and / or” includes any and all combinations of listed items,including any of the listed items individually. For example, “A, B, and / or C” encompasses A, B, C, AB, AC, BC, and ABC, each of which is to be considered separately described by the statement “A, B, and / or C.”

[0029] The phrase “in one embodiment” as used herein does not necessarily refer to thesame embodiment, though it may. Furthermore, the phrase “in another embodiment” as used herein does not necessarily refer to a different embodiment, although it may. Thus, as described below, various embodiments of the invention may be readily combined, without departing from the scope or spirit of the invention.

[0030] In addition, as used herein, the term “or” is an inclusive “or” operator and isequivalent to the term “and / or” unless the context clearly dictates otherwise. The term “based5Atty. Docket No. UM-43679.601on” is not exclusive and allows for being based on additional factors not described unless the context clearly dictates otherwise. In addition, throughout the specification, the meaning of “a”, “an”, and “the” include plural references. The meaning of “in” includes “in” and “on.”

[0031] As used herein, a “soft implantable” is a soft, biomaterial matrix that is suitable forimplantation into a biological subject. Exemplary characteristics of soft implantables include, but are not limited to, presence of a viscoelastic, hydrophilic polymer network, containing at least 50% water, tunable mesh size or porosity, elastic modulus on the order of kPa (10^0-10^2kPa. See e.g., Czerner et al., Determination of Elastic Modulus of Gelatin Gels by Indentation Experiments, Procedia Materials Science, Volume 8, 2015, Pages 287-296, ISSN 2211-8128; and US10918673B2.

[0032] As used herein, the term “polymer” means any compound that is made up of two ormore monomeric units covalently bonded to each other, where the monomeric units may be the same or different, such that the polymer may be a homopolymer or a heteropolymer. Representative polymers include polyamides (e.g., such as polypeptides), poly-N-substituted glycines (polypeptoids), polysaccharides, polyethylene glycol (PEG), plastics, polynucleotides (e.g., nucleic acids), and the like, where the polymers may be naturally occurring, non-naturally occurring, or synthetic.

[0033] As used herein, the term “poly(ethylene glycol)”, abbreviated “PEG”, refers to asynthetic polymer of ethylene glycol. PEG is water-soluble and can be modified with various functional groups that allow one to tailor its chemistry, physical, and biological properties.

[0034] As used herein, the abbreviation “PEGG+”, refers to a mixture of PEG and gelatin(e.g., biopolymer prepared by thermal denaturalization of collagen (e.g., a heterogeneous mixture of proteins and peptides derived from collagen, trace impurities extracted from raw materials, and chemicals added intentionally or unintentionally during the manufacturing process)) porogens (e.g., inorganic porogens (e.g., ammonium carbonate, calcium carbonate, ammonium bicarbonate and ammonium chloride, etc.) and organic porogens (e.g., sawdust, shell powder, starch, polystyrene, water-soluble polymers such as Poly ethylene glycol (PEG), Polyvinyl pyrrolidone (PVP), Polyvinylalcohol (PVA), Polymethaacrylate (PMA),Polyacrylicacid (PAA), etc.)). Gelatin obtained from collagen can be acidic or basicdepending on the method of extraction. Gelatin can be extracted from the skin, bones, cartilage, and other connective tissue rich in collagen from animals (e.g., pigs, cows, fish,chicken, etc.). Gelatin undergoes thermoreversible crosslinking at cool temperatures (e.g.,below 35oC) and solubilization at body temperature (e.g., above 35oC).6Atty. Docket No. UM-43679.601

[0035] As used herein, the term “polypeptides” includes proteins and fragments thereof(e.g., peptides). In some embodiments, polypeptides are disclosed as amino acid residue (or monomer) sequences. Those sequences are written left to right in the direction from the amino to the carboxy terminus. In accordance with standard nomenclature, amino acid residue sequences are denominated using either a three letter code or a single letter code as indicated as follows: Alanine (Ala, A), Arginine (Arg, R), Asparagine (Asn, N), Aspartic Acid (Asp, D), Cysteine (Cys, C), Glutamine (Gln, Q), Glutamic Acid (Glu, E), Glycine (Gly, G), Histidine (His, H), Isoleucine (Ile, I), Leucine (Leu, L), Lysine (Lys, K), Methionine (Met, M), Phenylalanine (Phe, F), Proline (Pro, P), Serine (Ser, S), Threonine (Thr, T), Tryptophan (Trp, W), Tyrosine (Tyr, Y), and Valine (Val, V). In addition, a polypeptide can include non-standard and / or non-naturally occurring amino acids or post-translationally modified amino acids such as hydroxylated amino acids, as well as other amino acids that may be found in phosphorylated proteins in organisms such as, but not limited to, animals, plants, insects, protists, fungi, bacteria, algae, single-cell organisms, and the like. The non-standard amino acids include, but are not limited to, selenocysteine, selenomethionine, pyrrolysine, gamma-aminobutyric acid, carnitine, ornithine, citrulline, homocysteine, hydroxyproline, hydroxylysine, sarcosine, and the like. The non-naturally occurring amino acids include, but are not limited to, trans-3-methylproline, 2,4-methanoproline, cis-4-hydroxyproline, trans-4-hydroxyproline, N-methylglycine or other N-substituted glycines, beta-amino acids, allo-threonine, methylthreonine, hydroxyethylcysteine, hydroxyethylhomocysteine, nitro-glutamine, homoglutamine, pipecolic acid, thiazolidine carboxylic acid, dehydroproline, 3- and 4-methylproline, 3,3-dimethylproline, tert-leucine, norvaline, 2-azaphenylalanine, 3-azaphenylalanine, 4-azaphenylalanine, and 4-fluorophenylalanine.

[0036] The term “attached” or the phrases “interacts with” and “associated with” refers toa stable physical, biological, biochemical, and / or chemical association. In general, association can be chemical bonding (e.g., covalently or ionically), a biological interaction, a biochemical interaction, and in some instances a physical interaction. The association can be a covalent bond, a non-covalent bond, an ionic bond, a metal ion chelation interaction, as well as moieties being linked through interactions such as, but not limited to, hydrophobic interactions, hydrophilic interactions such as hydrogel bonding, charge-charge interactions, π-stacking interactions, combinations thereof, and like interactions.

[0037] The term “cancer”, as used herein, shall be given its ordinary meaning, as a generalterm for diseases in which abnormal cells divide without control and form cancer or7Atty. Docket No. UM-43679.601neoplastic cells, tissues, or tumors. The term cancer can include cancer cells and / or precancerous cells. In particular, and in the context of the embodiments of the present disclosure, cancer refers to ovarian cancer and cancers of the female reproductive organs and system. Cancer cells can invade nearby tissues and can spread through the bloodstream and lymphatic system to other parts of the body. There are several main types of cancer, for example, carcinoma is cancer that begins in the skin or in tissues that line or cover internal organs. Sarcoma is cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. Leukemia is cancer that starts in blood-forming tissue such as the bone marrow and causes large numbers of abnormal blood cells to be produced and enter the bloodstream. Lymphoma is cancer that begins in the cells of the immune system.

[0038] When normal cells lose their ability to behave as a specified, controlled, andcoordinated unit, a tumor may be formed. Generally, a solid tumor is an abnormal mass of tissue that usually does not contain cysts or liquid areas (although some brain tumors do have cysts and central necrotic areas filled with liquid). A single tumor may even have different populations of cells within it, with differing processes that have gone awry. Solid tumors may be benign (not cancerous) or malignant (cancerous). Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) generally do not form solid tumors.

[0039] Representative cancers include, but are not limited to, bladder cancer, breastcancer, colorectal cancer, endometrial cancer, head and neck cancer, leukemia, lung cancer, lymphoma, melanoma, non-small-cell lung cancer, ovarian cancer, prostate cancer, testicular cancer, uterine cancer, cervical cancer, thyroid cancer, gastric cancer, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma, glioblastoma, ependymoma, Ewing’s sarcoma family of tumors, germ cell tumor, extracranial cancer, Hodgkin’s disease, leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, liver cancer, medulloblastoma, neuroblastoma, brain tumors generally, non-Hodgkin’s lymphoma, osteosarcoma, malignant fibrous histiocytoma of bone, retinoblastoma, rhabdomyosarcoma, soft tissue sarcomas generally, supratentorial primitive neuroectodermal and pineal tumors, visual pathway and hypothalamic glioma, Wilms’s tumor, acute lymphocytic leukemia, adult acute myeloid leukemia, adult non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, chronic myeloid leukemia, esophageal cancer, hairy cell leukemia, kidney cancer, multiple myeloma, oral cancer, pancreatic cancer, primary central nervous system lymphoma, skin cancer, small-cell lung cancer, among others.8Atty. Docket No. UM-43679.601

[0040] A tumor can be classified as malignant or benign. In both cases, there is anabnormal aggregation and proliferation of cells. In the case of a malignant tumor, these cells behave more aggressively, acquiring properties of increased invasiveness. Ultimately, the tumor cells may even gain the ability to break away from the microscopic environment in which they originated, spread to another area of the body (with a very different environment, not normally conducive to their growth), and continue their rapid growth and division in this new location. This is called metastasis. Once malignant cells have metastasized, achieving a cure is more difficult. Benign tumors have less of a tendency to invade and are less likely to metastasize.

[0041] As used herein, the term “hydrogel” refers to a substance formed when an organicpolymer (natural or synthetic) is cross-linked via covalent, ionic, or hydrogen bonds to create a three-dimensional open-lattice structure that entraps water molecules to form a gel. As used herein, the term “biocompatible hydrogel” refers to a polymer that forms a gel that is not toxic to living cells and allows sufficient diffusion of oxygen and nutrients to entrapped cells to maintain viability.

[0042] As used herein, the term “biocompatible” generally refers to a material and anymetabolites or degradation products thereof that are generally non-toxic to the recipient and do not cause any significant adverse effects to the subject.

[0043] As used herein, phosphate buffered saline, abbreviated “PBS”, and Dulbecco’sphosphate buffered saline, abbreviated “DPBS,” are buffered saline used in biological studies. PBS and DPBS are used in research involving cells. The ion concentration and osmolarity of PBS and DPBS are isotonic, that is, compatible with the human body. In some embodiments, these buffers provide and preserve a stable pH of 7.2-7.6. There is no significant difference between PBS and DPBS. Both of them contain sodium phosphate, sodium chloride, and, when required, potassium phosphate and potassium chloride. In some embodiments, preparations of PBS or DPBS may or may not contain calcium and magnesium. PBS and DPBS have numerous applications because they are not noxious to cells. Both PBS and DPBS can be used to rinse instruments or containers contaminated with cells. Also, both of them can be used in diluting substances.

[0044] As used herein, the terms “degradable” and “biodegradable” generally refer to amaterial that degrades or erodes by hydrolysis or enzymatic action under physiologic conditions to smaller units or chemical species that are capable of being metabolized, eliminated, or excreted by the subject.9Atty. Docket No. UM-43679.601

[0045] As used herein, the “degradation rate” refers to a rate relating the number ofsmaller units or chemical species that are produced by biodegradation or degradation of a material as a function of time.

[0046] As used herein, the “degradation time” refers to the time required to produce athreshold number of smaller units or chemical species by biodegradation or degradation of a material and is a function of polymer composition and morphology.

[0047] As used herein, the term “non-degradable” refers to a material that is not“degradable” or that is substantially or effectively less degradable than a degradable material (e.g., has a substantially or effectively lower degradation rate or a substantially or effectively longer degradation time).

[0048] As used herein, the term “mammalian cell” refers to any cell derived from amammalian subject suitable for transplantation into the same or a different subject. The cell may be syngeneic, xenogeneic, autologous, or allogeneic. The cell can be a primary cell obtained directly from a mammalian subject. The cell may also be a cell derived from the culture and expansion of a cell obtained from a subject. For example, the cell may be a stem cell. Immortalized cells are also included within this definition. In some embodiments, the cell has been genetically engineered to express a recombinant protein and / or nucleic acid.

[0049] As used herein, the term “transplant” refers to the transfer of a cell, tissue, or organto a subject from another source. The term is not limited to a particular mode of transfer. Encapsulated cells may be transplanted by any suitable method, such as by injection or surgical implantation.

[0050] As used herein, the term “autologous” refers to a transplanted biological substancetaken from the same individual.

[0051] As used herein, the term “xenogeneic” refers to a transplanted biological substancetaken from a different species. As used herein, the term “xenogeneic transplantation” refers to the transplantation of living cells, tissues, or organs from one species to another. Such cells, tissues, or organs are called “xenografts” or “xenotransplants”. Both allotransplantation (e.g., a same-species transplant) and xenotransplantation can cause rejection of the graft because the immune system of the host recognizes the transplant as foreign (e.g., as “non-self”). In addition to rejection, disease transmission (“xenozoonosis”) and permanent alteration to the host genetic code are causes for concern. Accordingly, the use of an immunoisolation device provides a technology to prevent, eliminate, and / or minimize rejection of a graft and / or to prevent, eliminate, and / or minimize the risk of disease transmission.10Atty. Docket No. UM-43679.601

[0052] As used herein, the term “allogeneic” refers to a transplanted biological substancetaken from a different individual of the same species. Accordingly, as used herein, the term “allogeneic transplantation” or “allotransplantation” refers to the transplantation (e.g., of a cell, tissue, or organ) to a recipient from a genetically non-identical donor of the same species. The transplant is called an allograft, allogeneic transplant, or homograft. Most human tissue and organ transplants are allografts because humans genetically differ from each other. Similarly, transplantation of a tissue between different strains of mice is termed an allogeneic transplantation. An immune response against an allograft, termed rejection, will arise in healthy individuals without immune suppression.

[0053] As used herein, the term “isogeneic transplantation” or “syngraft” is a graftbetween genetically identical individuals, typically between identical twins or between animals of a single highly inbred strain. This type of graft typically does not provoke the immune system and does not cause rejection.

[0054] As used herein, the term “endocrine system” refers to the collection of cells andtissues of an organism that secrete hormones directly into the blood to control physiological and behavioral activities of the organism. The endocrine system comprises a series of glands that produce molecules called hormones. A number of glands that signal to each other in a sequence are usually referred to as an axis, for example, the hypothalamic-pituitary-gonadal (HPG) axis that in a female connects the glands involved in regulating the ovarian function. Reproductive endocrine function is mediated by sex hormones, such as estradiol and progesterone. Besides the effect of the sex hormones on the reproductive organ, they have other functions, such as metabolism, fat storage, blood vessel and skin maintenance, protein synthesis, prevention of bone resorption, and muscle degeneration.

[0055] As used herein, the term “endogenous” as it relates to an organism or biologicalsystem refers to a substance, molecule, etc. produced or synthesized within the organism or biological system.

[0056] As used herein, the term “endogenous hormones” as it relates to an organism orbiological system refers to hormones produced or synthesized within the organism or biological system. For example, in females estradiol is produced in special structures called ovarian follicles. Follicles produce estradiol in response to other hormones that regulate ovarian function.

[0057] As used herein, the terms “epiphyses” and “epiphyseal growth plate” refer tofeatures of a bone. Bone is a living tissue comprising a protein (collagen) matrix upon which calcium salts are deposited. A growing bone is described by the ends, or epiphyses, and the11Atty. Docket No. UM-43679.601shaft. The portion of each epiphysis in contact with the shaft is a plate of actively proliferating cartilage (connective tissue composed of collagen and other fibrous proteins) called the epiphyseal growth plate. Linear growth of the shaft can continue as long as the epiphyseal growth plates exist but cease when the growth plates are converted to bone as a result of hormonal influences at puberty. This is known as epiphyseal closure and occurs at different times in different bones.

[0058] As used herein, the term “estrogen” refers to a class of steroid hormones secretedby the ovaries. For example, estradiol is a predominant estrogen in the plasma. Estradiol is produced and secreted from ovaries and it plays a key role in puberty, providing a hormonal milieu for physical and psychosocial development. Estradiol is responsible for the development of the female appearance, bone growth, and brain development. Simultaneously, increases in estradiol levels during puberty stimulate other growth hormones that lead to the pubertal growth spurt. The hypothalamus, pituitary gland, and the ovary interact along the “HPG axis”. The pulsatile release of Gonadotropin Releasing Hormone (GnRH) from the hypothalamus stimulates the secretion of Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) from the pituitary gland in the brain. FSH directly stimulates granulosa cells in the growing follicles to secrete estradiol. LH stimulates theca cells in the follicle to produce precursors of estradiol to increase its production. HPG axis is a loop that is tightly regulated by the secreted hormones.

[0059] As used herein, the term “exogenous” as it relates to an organism or biologicalsystem refers to a substance, molecule, etc. originating from outside an organism or biological system.

[0060] As used herein, the term “exogenous hormone” as it relates to an organism orbiological system refers to a hormone originating from outside the organism or biological system. Exogenous estrogen is a synthetic analog of the estradiol and can mimic the function of endogenous estradiol.

[0061] As used herein, the term “follicle” or “ovarian follicle” refers to the functional unitof the ovary. It contains a germ cell that is future to develop into an egg, surrounded by multiple layers of supportive cells, called granulosa cells. In the ovaries, granulosa cells synthesize and secrete estradiol in response to the hormones that control the ovarian function. Theca cells build the outside layer of the follicle. Theca cells produce androgens, which are the precursors for estradiol produced by granulosa cells.12Atty. Docket No. UM-43679.601

[0062] As used herein, the term “follicular stimulating hormone”, abbreviated “FSH”,refers to a hormone that is secreted from the pituitary gland as a result of hypothalamus stimulation. FSH acts on ovaries and stimulates estradiol secretion and follicle growth.

[0063] As used herein, the term “folliculogenesis” refers to a process that describes thematuration of the ovarian follicle, a densely packed shell of somatic cells that surround a germ cell. Folliculogenesis describes the progression of small immature follicles to a mature follicle ready for ovulation. Hormones secreted from hypothalamus (GnRH) and pituitary gland (FSH and LH) regulate the process of follicle development. In response to hormonal stimulation follicles produce estradiol and progesterone that regulate the hormone production in the brain in a series of positive and negative feedback mechanisms. The levels of all hormones in the HPG axis cyclically fluctuate.

[0064] As used herein, the term “gamete” refers to a cell that fuses with another cellduring fertilization in organisms that reproduce sexually. In a female, the gamete is as “egg”.

[0065] As used herein, the term “germ cell” refers to a cell that gives rise to a femalegamete (egg) or a male gamete (sperm).

[0066] As used herein, the term “hormone” refers to a substance released from endocrinetissue into the bloodstream where it travels to a target tissue to generate a response.Hormones regulate various human functions, including metabolism, growth and development, tissue function, sleep, and mood. The term hormone as used herein also encompasses natural or synthetic molecules having the same or similar bioactive properties as a hormone released by endocrine tissue; and encompasses derivatives of natural and synthetic hormones and natural and synthetic molecules having the same or similar bioactive properties as a hormone released by endocrine tissue.

[0067] As used herein, the term “gonadotropin releasing hormone”, abbreviated “GnRH”,is the first hormone in the axis between hypothalamus, pituitary gland, and ovary. GnRH stimulates the secretion of the hormones from the pituitary gland (FSH and LH), which in turn control the ovarian function.

[0068] In some embodiments, the term “immunoisolation device” refers to a compositioncomprising a degradable inner core comprising a biological material and a non-degradable outer shell encapsulating the degradable inner core and comprising a thermosensitive gelatin microgel.

[0069] In some embodiments, the term “therapeutic” refers to a substance (i.e., a chemical,a biological, a cell (i.e., an implanted cell), and / or a tissue (i.e., an implanted tissue)) used in13Atty. Docket No. UM-43679.601the diagnosis, treatment, or prevention of disease in a subject and / or for restoring, correcting, or modifying organic functions in a subject.

[0070] As used herein, the term “immunoisolation” or “immune isolation” refers to astrategy used to protect a therapeutic (i.e., implanted cells and / or tissue) from being rejected by a donor. By providing a barrier around the therapeutic, an immunoisolation device allows the passage of nutrients and oxygen into the device to support the survival of implanted cells or tissue and prevents the passage of immune cells and antibodies into the device, thus eliminating or minimizing rejection of the implanted cells or tissue by the host immune system. Immunoisolation of a therapeutic (i.e., an implanted cell and / or an implanted tissue) allows foreign grafts to survive for extended, often indefinite intervals.

[0071] As used herein, the term “in vitro” refers to an environment outside a livingorganism. In science this term refers to experiments performed in an artificial or synthetic environment.

[0072] As used herein, the term “in vivo” refers to within a living organism. In sciencethis term refers to experiments performed in an animal model or in humans.

[0073] As used herein, the term “luteinizing hormone”, abbreviated “LH” refers to ahormone that is secreted from the pituitary gland as a result of hypothalamus stimulation. LH acts on theca cells in the follicles to stimulate the production of the precursors of estradiol.

[0074] As used herein, the term “primordial follicles” refers to immature and undevelopedstage of the follicles. These follicles contain one germ cell, which is surrounded by several somatic cells. The primordial follicles constitute the majority of the ovarian reserve at any age.

[0075] As used herein, the term “thrombosis” refers to the formation of a blood clot(“thrombus”) inside a blood vessel, obstructing the flow of blood through the circulatory system. When a thrombus is significantly large enough to reduce the blood flow to a tissue, oxygen deprivation can occur and metabolic products can accumulate. A larger thrombus causing a much greater obstruction to the blood flow may result in anoxia, the complete deprivation of oxygen and tissue death.

[0076] As used herein, the term “biological communication” refers to the ability of abiological component to communicate with another biological component, e.g., by exchange of communicating substances such as metabolites, catabolites, proteins, nucleic acids, small molecules (e.g., hormones), lipids, etc. with the biological component. A first biological component in biological communication with a second biological component is exposed to communicating substances produced and / or secreted by the second biological component. As14Atty. Docket No. UM-43679.601used herein, a “biological component” is not limited by size or scale and thus may be a molecule, biological structure, organelle, cell, tissue, organ, system, or organism.

[0077] The terms “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof,as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures.

[0078] For the recitation of numeric ranges herein, each intervening number there betweenwith the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.

[0079] As used herein, the term “approximately” and “about” is intended to encompassnormal statistical variation as would be understood by those of ordinary skill in the art as appropriate to the relevant context. In certain embodiments, the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

[0080] “Correlated to” as used herein refers to compared to.

[0081] As used herein, the term “subject” and “patient” as used herein interchangeablyrefers to any vertebrate, including, but not limited to, a mammal (e.g., cow, pig, camel, llama, horse, goat, rabbit, sheep, hamsters, guinea pig, cat, dog, rat, and mouse, a non-human primate (e.g., a monkey, such as a cynomolgus or rhesus monkey, chimpanzee, macaque, etc.) and a human). In some embodiments, the subject may be a human or a non-human. In one embodiment, the subject is a human. The subject or patient may be undergoing various forms of treatment. For veterinary applications, a wide variety of subjects is suitable, e.g., livestock such as cattle, sheep, goats, cows, swine, and the like; poultry such as chickens, ducks, geese, turkeys, and the like; and domesticated animals particularly pets such as dogs and cats. For diagnostic or research applications, a wide variety of mammals will be suitable subjects, including rodents (e.g., mice, rats, hamsters), rabbits, primates, and swine such as inbred pigs and the like.

[0082] In some embodiments, the terms “administration of” and “administering” acomposition refer to providing a composition of the present disclosure to a subject in need of treatment (e.g., hormonal treatment). A composition of the present disclosure may be administered by parenteral (e.g., subcutaneous injection or implant) and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic15Atty. Docket No. UM-43679.601pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.

[0083] As used herein, the term “treat,” “treating” or “treatment” are each usedinterchangeably herein to describe reversing, alleviating, or inhibiting the progress of a disease and / or injury, or one or more symptoms of such disease, to which such term applies. Depending on the condition of the subject, the term also refers to preventing a disease, and includes preventing the onset of a disease, or preventing the symptoms associated with a disease (e.g., viral infection). A treatment may be either performed in an acute or chronic way. The term also refers to reducing the severity of a disease or symptoms associated with such disease prior to affliction with the disease. Such prevention or reduction of the severity of a disease prior to affliction refers to administration of a treatment to a subject that is not at the time of administration afflicted with the disease. “Preventing” also refers to preventing the recurrence of a disease or of one or more symptoms associated with such disease.

[0084] In some embodiments, “treatment,” covers any treatment of a disease, disorder, orcondition in a subject and includes: (a) reducing the risk of occurrence of a disease, disorder, or condition in a subject determined to be predisposed to the disease, disorder, or condition, but not yet diagnosed as having the disease, disorder, or condition; (b) impeding the development of a disease, disorder, or condition; (c) relieving a disease, disorder, or condition (e.g., causing regression of the disease, disorder, or condition and / or relieving one or more symptoms of the disease, disorder, or condition); (d) ameliorating, reducing, or reversing one or more symptoms of a disease, disorder, or condition and / or ameliorating, reducing, or reversing one or more symptoms resulting from a treatment for the disease, disorder, or condition; and (e) providing or restoring normal (or near normal, adequate, sufficient, essentially normal, and / or effectively normal) or improved biological processes in a subject, e.g., a subject who has impaired or damaged biological processes due to a disease, disorder, or condition and / or from treatment of a disease, disorder, or condition. “Treatment” is also meant to encompass providing a pharmacologic effect in a normal subject or in a subject in the absence of a disease, disorder, or condition. For example, “treatment” encompasses providing for improved, enhanced, or desirable effects in the subject (e.g., reduction of tumor load, reduction of symptoms, improved or normal growth and development, extension of a period of a patient’s apparent, functional health, etc.).

[0085] As used herein, the terms “prophylactically treat” or “prophylactically treating”refers to completely or partially preventing a disease or symptom thereof and / or may be16Atty. Docket No. UM-43679.601therapeutic in terms of a partial or complete cure for a disease and / or adverse effect attributable to the disease.

[0086] In some embodiments, the term “symptoms are reduced” refers to a reduction inmagnitude (e.g., intensity, severity, etc.) and / or frequency of one or more symptoms of a particular disease, disorder or condition. For purposes of clarity, a delay in the onset of a particular symptom is considered one form of reducing the frequency of that symptom.

[0087] In some embodiments, the term pen-like mechanism and / or “pen-like” refer to, forexample, a pen mechanism that employs a push button plunger (e.g., a shaft) that rotates a rachet which alternately engages and disengages from spaced apart teeth on the inner wall of the pen (e.g., a mechanism illustrated in Patent Number 3,120,837 dated February 11, 1964).

[0088] In some embodiments, the term “structured to [verb]” means that the identifiedelement or assembly has a structure that is shaped, sized, disposed, coupled, and / or configured to perform the identified verb. For example, a member that is “structured to move” is movably coupled to another element and includes elements that cause the member to move or the member is otherwise configured to move in response to other elements or assemblies. As such, as used herein, “structured to [verb]” recites structure and not function. Further, as used herein, “structured to [verb]” means that the identified element or assembly is intended to, and is designed to, perform the identified verb.

[0089] In some embodiments, the term “associated” means that the elements are part of thesame assembly and / or operate together or act upon / with each other in some manner. For example, an automobile has four tires and four hub caps. While all the elements are coupled as part of the automobile, it is understood that each hubcap is “associated” with a specific tire.

[0090] In some embodiments, the term “coupled” refers to two or more components that aresecured, by any suitable means, together. Accordingly, in some embodiments, the statement that two or more parts or components are “coupled” shall mean that the parts are joined or operate together either directly or indirectly, e.g., through one or more intermediate parts or components.

[0091] In some embodiments, the term “directly coupled” means that two elements aredirectly in contact with each other. As used herein, “fixedly coupled” or “fixed” means that two components are coupled so as to move as one while maintaining a constant orientation relative to each other. Accordingly, when two elements are coupled, all portions of those elements are coupled. A description, however, of a specific portion of a first element being coupled to a second element, e.g., an axle first end being coupled to a first wheel, means that the specific portion of the first element is disposed closer to the second element than the other17Atty. Docket No. UM-43679.601portions thereof. Further, an object resting on another object held in place only by gravity is not “coupled” to the lower object unless the upper object is otherwise maintained substantially in place. That is, for example, a book on a table is not coupled thereto, but a book glued to a table is coupled thereto.

[0092] In some embodiments, the term “removably coupled” or “temporarily coupled”means that one component is coupled with another component in an essentially temporary manner. That is, the two components are coupled in such a way that the joining or separation of the components is easy and does not damage the components. Accordingly, “removably coupled” components may be readily uncoupled and recoupled without damage to the components.

[0093] In some embodiments, the term “operatively coupled” means that a number ofelements or assemblies, each of which is movable between a first position and a second position, or a first configuration and a second configuration, are coupled so that as the first element moves from one position / configuration to the other, the second element moves between positions / configurations as well. It is noted that a first element may be “operatively coupled” to another without the opposite being true.

[0094] In some embodiments, the term “rotatably coupled” refers to two or morecomponents that are coupled in a manner such that at least one of the components is rotatable with respect to the other.

[0095] In some embodiments, the term “translatably coupled” refers to two or morecomponents that are coupled in a manner such that at least one of the components is translatable with respect to the other.

[0096] In some embodiments, the term “temporarily disposed” means that a first element orassembly is resting on a second element or assembly in a manner that allows the first element / assembly to be moved without having to decouple or otherwise manipulate the first element. For example, a book simply resting on a table, e.g., the book is not glued or fastened to the table, is “temporarily disposed” on the table.

[0097] In some embodiments, the term “correspond” indicates that two structuralcomponents are sized and shaped to be similar to each other and may be coupled with a minimum amount of friction. Thus, an opening which “corresponds” to a member is sized slightly larger than the member so that the member may pass through the opening with a minimum amount of friction. This definition is modified if the two components are to fit “snugly” together. In that situation, the difference between the size of the components is even smaller whereby the amount of friction increases. If the element defining the opening and / or18Atty. Docket No. UM-43679.601the component inserted into the opening are made from a deformable or compressible material, the opening may even be slightly smaller than the component being inserted into the opening. With regard to surfaces, shapes, and lines, two, or more, “corresponding” surfaces, shapes, or lines have generally the same size, shape, and contours.

[0098] In some embodiments, the term a “path of travel” or “path,” when used in associationwith an element that moves, includes the space an element moves through when in motion. As such, any element that moves inherently has a “path of travel” or “path.”

[0099] In some embodiments, the statement that two or more parts or components “engage”one another shall mean that the elements exert a force or bias against one another either directly or through one or more intermediate elements or components. Further, as used herein with regard to moving parts, a moving part may “engage” another element during the motion from one position to another and / or may “engage” another element once in the described position. Thus, it is understood that the statements, “when element A moves to element A first position, element A engages element B,” and “when element A is in element A first position, element A engages element B” are equivalent statements and mean that element A either engages element B while moving to element A first position and / or element A either engages element B while in element A first position.

[0100] In some embodiments, the term “operatively engage” means “engage and move.”That is, “operatively engage” when used in relation to a first component that is structured to move a movable or rotatable second component means that the first component applies a force sufficient to cause the second component to move. For example, a screwdriver may be placed into contact with a screw. When no force is applied to the screwdriver, the screwdriver is merely “coupled” to the screw. If an axial force is applied to the screwdriver, the screwdriver is pressed against the screw and “engages” the screw. However, when a rotational force is applied to the screwdriver, the screwdriver “operatively engages” the screw and causes the screw to rotate. Further, with electronic components, “operatively engage” means that one component controls another component by a control signal or current.

[0101] In some embodiments, the term “number” shall mean one or an integer greater thanone (e.g., a plurality).

[0102] In some embodiments, in the phrase “[x] moves between its first position and secondposition,” or, “[y] is structured to move [x] between its first position and second position,” “[x]” is the name of an element or assembly. Further, when [x] is an element or assembly that moves between a number of positions, the pronoun “its” means “[x],” i.e., the named element or assembly that precedes the pronoun “its.”19Atty. Docket No. UM-43679.601

[0103] In some embodiments, the term a “radial side / surface” for a circular or cylindricalbody is a side / surface that extends about, or encircles, the center thereof or a height line passing through the center thereof. As used herein, an “axial side / surface” for a circular or cylindrical body is a side that extends in a plane extending generally perpendicular to a height line passing through the center. That is, generally, for a cylindrical soup can, the “radial side / surface” is the generally circular sidewall and the “axial side(s) / surface(s)” are the top and bottom of the soup can.

[0104] In some embodiments, the term “unitary” means a component is created as a singlepiece or unit. That is, a component that includes pieces that are created separately and then coupled together as a unit is not a “unitary” component or body.

[0105] In some embodiments, the term a “coupling assembly” includes two or morecouplings or coupling components. The components of a coupling or coupling assembly are generally not part of the same element or other component. As such, the components of a “coupling assembly” may not be described at the same time in the following description.

[0106] In some embodiments, the term a “coupling” or “coupling component(s)” is one ormore component(s) of a coupling assembly. That is, a coupling assembly includes at least two components that are structured to be coupled together. It is understood that the components of a coupling assembly are compatible with each other. For example, in a coupling assembly, if one coupling component is a snap socket, the other coupling component is a snap plug, or, if one coupling component is a bolt, then the other coupling component is a nut.

[0107] In some embodiments, the term a “planar body” or “planar member” is a generallythin element including opposed, wide, generally flat surfaces as well as a thinner edge surface extending between the wide flat surfaces. The edge surface may include generally flat portions, e.g. as on a rectangular planar member, or be curved, as on a disk, or have any other shape.2. Instruments

[0108] According to various embodiments, the disclosure provides instruments for theparenteral insertion of soft implantable into a subject. In an embodiment, the instruments are particularly designed to accommodate soft implantable such as hydrogels and the like which a) require hydration maintenance, b) typically have an increased degree of fragility as compared to common solid or hard inserts (e.g., birth control hormone inserts such as those sold under the Nexplanon® trademark by Organon & Co (Jersey City, New Jersey, USA)), and c) are generally larger in size than typical solid or hard inserts. Embodiments of the present disclosure are described with reference to the figures.20Atty. Docket No. UM-43679.601

[0109] Embodiments of the present disclosure include a first instrument described hereinwith reference to FIG.1. In some embodiments, the first instrument is structured similar to a pen-like mechanism. In some embodiments, the first instrument is hollow. In some embodiments, the first instrument includes spaced apart teeth associated with the inner wall of the first instrument (e.g., a locking mechanism 111). In some embodiments, the first instrument has an opening at one end and a needle tip 113 on the other end. In some embodiments, the needle tip is structured to open and close (compare with FIG.1, inset showing needle tip 113 in closed position). In some embodiments, a shaft 110 corresponds to the opening in the first instrument. In some embodiments, the shaft 110 is sized slightly smaller than the hollow of the first instrument so that the shaft 110 passes distally through the opening with a minimum amount of friction. In some embodiments, the needle tip 113 is associated with the shaft 110. In some embodiments, the shaft 110 moves distally from the opening to meet the needle tip 113. In some embodiments, when the shaft 110 meets the needle tip 113, the shaft 110 engages the needle tip 113 from a first position (e.g., a closed position) to a second position (e.g., an open position). In some embodiments, when the shaft 110 meets the needle tip 113, the locking mechanism 111 engages and the shaft 110 stops moving distally.

[0110] Embodiments of the present disclosure include a second instrument described hereinwith reference to FIG. 2. In some embodiments, a first piece 210 (e.g., a cannula piece) is hollow. In some embodiments, the first piece 210 is approximately 6 cm. In some embodiments, the first piece 210 includes spaced apart teeth 212 associated with the inner wall of the first piece (e.g., a first part of a locking mechanism). In some embodiments, the first piece 210 has an opening at one end 211 (e.g., an opening for an insertion piece) and a needle tip 213 on the other end. In some embodiments, the needle tip 213 is shaped like a cone and is structured to open and close. In some embodiments, a second piece 220 (e.g., a shaft (e.g., an insertion piece)) is hollow. In some embodiments, the second piece 220 corresponds to the opening 211 in the first piece 210. In some embodiments, the second piece 220 is sized slightly smaller in diameter than the hollow of the first piece 210 so that the second piece 220 passes distally through the opening 211 with a minimum amount of friction. In some embodiments, the second piece 220 is longer (e.g., approximately 6 + x cm) than the first piece. In some embodiments, the second piece 220 includes spaced apart teeth 222 associated with the outer wall of the second piece 220 (e.g., a second part of the locking mechanism). In some embodiments, the second piece 220 includes a button 221 at one end, and a needle tip 226 on the other end. In some embodiments, the second piece 220 includes a sliding door 224 (e.g., asliding door to load a therapeutic) located directly above the needle tip 226. In some21Atty. Docket No. UM-43679.601embodiments, the needle tip 223 is shaped like a cone and is structured to open and close. In some embodiments, the button 221 is used to open the needle tip 223. In some embodiments, the second piece 220 includes a compartment 224 located distally from the button 221. In some embodiments, the compartment 224 is configured to house a therapeutic. In some embodiments, access to the interior of the compartment is by way of the sliding door 225. In some embodiments, the sliding door 225 is configured to open. In some embodiments, atherapeutic (not shown) is capable of being placed in the compartment 224. In someembodiments, a rod 226 is located within the hollow of the second piece 220. In some embodiments, the rod 226 is solid. In some embodiments, the button 221 is associated with the rod 226. In some embodiments, the rod 226 is configured to move distally from the button 221 to meet the needle tip 223. In some embodiments, the button 221, when pressed, is configured to push the rod 223 distally, which then moves into the compartment 224 and pushes the therapeutic, which pushes open needle tip 223 and releases the therapeutic out of the second piece 220.

[0111] Embodiments of the present disclosure include a third instrument described herein,with reference to FIG.3. In some embodiments, a first piece 310 (e.g., a cannula) is hollow. In some embodiments, the first piece 310 is approximately 6 cm. In some embodiments, the first piece 310 includes spaced apart teeth 312 associated with the inner wall of the first piece 310 (e.g., a first part of a locking mechanism). In some embodiments, the first piece 310 has an opening at one end 311 (e.g., an opening for an insertion piece). In some embodiments, a second piece 320 (e.g., a needle piece) is solid (e.g., solid metal). In some embodiments, the second piece 320 is longer (e.g., approximately 6 + x cm) than the first piece 310. In some embodiments, the second piece 310 includes a needle tip 322 (e.g., a solid metal needle tip) on one end. In some embodiments, the needle tip 322 is shaped like a cone. In some embodiments, a third piece 330 (e.g., a shaft (e.g., an insertion piece)) is hollow. In some embodiments, the third piece 330 corresponds to the opening 311 in the first piece 310. In some embodiments, the third piece 330 is sized slightly smaller in diameter than the hollow of the first piece 310 so that the third piece 330 passes distally through the opening 311 with a minimum amount of friction. In some embodiments, the third piece 330 is longer (e.g., approximately 6 + x cm) than the first piece 310. In some embodiments, the third piece 330 includes a first set of spaced apart teeth 332 and a second set of spaced apart teeth 333, wherein both the first set 332 and the second set 333 are associated with the outer wall of the third piece 330 (e.g., together, a locking mechanism). In some embodiments, the third piece 330 includes a button 331 at one end. In some embodiments, the third piece 330 includes a compartment 334 located distally22Atty. Docket No. UM-43679.601from the button 331. In some embodiments, the compartment 334 is configured to house a therapeutic 339. In some embodiments, the compartment 334 includes a sliding door 335 (e.g., a sliding door to load a therapeutic) located distally from the button 331. In some embodiments, the sliding door 335 is configured to open. In some embodiments, a therapeutic 339 is capable of being placed in the compartment 334. In some embodiments, the compartment 334 includesa trap door 337. In some embodiments, the trap door 337 is configured to open. In someembodiments, the button 331 is used to open the trap door 337 of the compartment 334. In some embodiments, a rod 338 is located within the hollow of the third piece 330. In some embodiments, the rod 338 is solid. In some embodiments, the button 331 is associated with the rod 333. In some embodiments, the rod 338 is configured to move distally from the button 321 to meet the compartment 334. In some embodiments, the button 331, when pressed, is configured to push the rod 338 distally, which then pushes on the compartment 334, which then pushes the therapeutic 339, which pushes open the trap door 337, which is attached to the third piece 330 by a hinge 336.

[0112] Embodiments of the present disclosure include a therapeutic and a therapeutichousing (e.g., a hydrogel holding puck) described herein, with reference to FIG.4. In some embodiments, the therapeutic housing 410 (e.g., a puck) has an opening on its top end 411. In some embodiments, the therapeutic housing 410 is configured to receive and / or house a therapeutic 420 (e.g., a hydrogel). In some embodiments, the therapeutic housing 410 is biocompatible and biodegradable. In some embodiments, the therapeutic housing 410 is capable of dissolving in the tissue of a subject over a period of time.

[0113] Embodiments of the present disclosure include a fourth instrument described herein,with reference to FIG.5. In some embodiments, the fourth instrument 510 includes an inner shell. In some embodiments, the fourth instrument 510 is coupled to the inner shell. In some embodiments, the fourth instrument 510 has a button 511 on one end and a needle tip 518 on the other end. In some embodiments, the button 511 is operatively connected to the inner shell. In some embodiments, the button 511 has stoppers 516 located distally from the needle tip 518. In some embodiments, the needle tip 518 has an opening mechanism 515. In some embodiments, the inner shell has a compartment 513 to house a therapeutic 512 and therapeutic housing (e.g., a hydrogel and puck). In some embodiments, the compartment has a sliding door 514 (e.g., a sliding door to load a therapeutic). In some embodiments, the compartment is located distally from the button 511.

[0114] Embodiments of the present disclosure include instruments comprising a fifthinstrument described herein, with reference to FIG.6. In some embodiments, a first piece 61023Atty. Docket No. UM-43679.601(e.g., cannula and needle piece) is hollow. In some embodiments, the first piece 610 has an opening 611 at one end. In some embodiments, the opening is configured to accept the insertion of a therapeutic 614 and therapeutic housing 615 (e.g., a hydrogel and puck). In some embodiments, the first piece 610 includes a needle tip 613 on one end. In some embodiments, the needle tip 613 is shaped like a cone. In some embodiments, the needle tip 613 includes anopening mechanism 612. In some embodiments, the needle tip 613 opens in response to atraditional trocar mechanism. In some embodiments, a second piece 620 (e.g., a solid insertion piece) is included. In some embodiments, the second piece 620 is configured to push therapeutic 614 and therapeutic housing 615 through the first piece 610, which opens the needle tip 612 and releases the therapeutic and therapeutic housing.

[0115] Embodiments of the present disclosure include a sixth instrument described herein,with reference to FIGS. 7A-7F. In some embodiments, the placement of the variouscomponents of the sixth instrument are as depicted in FIGS.7A-7F. In some embodiments, the various components of the sixth instrument include a fifth piece 750 (e.g., compartment (e.g., therapeutic compartment)), a fourth piece 740 (e.g., a button piece (e.g., to open a hinge trap door and release hydrogel)), a third piece 730 (e.g., an inner cannula), a second piece 720 (e.g., a needle piece (e.g., a retractable needle)), and a first piece 710 (e.g., an outer cannula).(FIG. 7C) In some embodiments, the first piece 710 is approximately 4cm, 5cm, 6 cm, 7cm,8cm, 9cm, 10cm, 11cm, or 12cm in length. In some embodiments, the first piece 710 includes a handle 711 (e.g., an ergonomic handle). In some embodiments, the handle 711 is located toward the upper end B of the first piece 710. In some embodiments, a first lip 713 (FIG.7D) is located toward the lower end A of the first piece 710. In some embodiments, a slider 712 and a slider locking mechanism 712a (FIG.7D, inset) are located on the exterior wall of the first piece 710. In some embodiments, the second piece 720 includes a second lip 721 e.g., lip to prevent needle from going past outer cannula), a peg 722 (e.g., a peg that locks into slider), a first lock 725 (e.g., a lock for inner compartment during insertion), and a needle nose 723 (e.g., a sharp spear-shaped needle piece). (FIGS.7E, 7F, 7G)) In some embodiments, the third piece 730 includes a track 732 (e.g., a track for the compartment to slide along) and a second lock 731 (e.g., a lock to connect with needle piece during insertion). (FIG. 7H) In some embodiments, the third piece 730 includes a door 741 (e.g., a hinge door) to release a therapeutic (e.g., an immunoisolation device) (FIG. 7I) and a compartment 742 (e.g., a compartment to hold a therapeutic (e.g., an immunoisolation device)). (FIG.7J)

[0116] Embodiments of the present disclosure include a seventh instrument 801 describedherein, with reference to FIGS. 8A-8K. In some embodiments, the placement and use of the24Atty. Docket No. UM-43679.601various components of the seventh instrument are as depicted in FIGS. 8A-8K. In some embodiments, the various components of the seventh instrument include a first piece 810 (e.g. outer canula), second piece 820 (e.g., a needle piece), and a third piece 830 (e.g., plunger piece). (FIG.8A). In some embodiments, the first piece 810 is approximately 4cm, 5cm, 6 cm, 7cm, 8cm, 9cm, 10cm, 11cm, or 12cm in length. In some embodiments, the first piece 810 optionally includes a handle 811 (e.g., an ergonomic handle, various configurations of which are shown in FIGS. 8A-8I, with FIGS 8J and 8K showing a needle piece without a handle). In some embodiments, the handle 811 is located toward the upper (distal) end B of the first piece 810. In some embodiments, the second piece 820 includes a handle 821 (e.g., an ergonomic handle) (FIG.8H), an angle guard 822 (e.g., an element that creates a subcutaneous track and controls the depth and angle of insertion of the needle) (FIG.8F), a needle nose 823 (e.g., a sharp spear-shaped needle piece) and a needle shaft 824 (FIG.8A). FIG.8G shows a version of second piece 820 that does not include an angle guard, seated within first piece 810. Needle piece 820 is sized to be removably received by first piece 810. In some embodiments, the third piece 830 includes a lip 831 and / or handle 832 (e.g., an ergonomic handle). In some embodiments, third piece 830 includes a series of pin holes 833 (e.g., for transport lock) (FIG.8I) and / or plunging indicators 835 (e.g., to indicate depth of insertion of the device) (FIG. 8K). In some embodiments, pin holes 833 are configured to receivably communicate with one or more locking pin(s) 834 (FIG.8I).

[0117] Turning to FIGS. 8B-8E, exemplary operation of the seventh instrument is shown.In this embodiment, a portion of second piece 820 is inserted into first piece 810 to create a pocket forming instrument 840 wherein the outer canula acts as a sleeve for needle shaft 824. The pocket forming instrument 840 is then inserted a desired depth and length into subcutaneous tissue 802 to form a pocket of a desired size at a desired depth (FIG.8B). The second piece 820 is then removed, leaving first piece 810 inside the tissue to maintain the pocket 803. While the first piece maintains pocket 803, implant 804 is seated inside first piece 810 (FIG.8C). The proximal end E of third piece 830 is then inserted into the first piece (FIG.8D). The first piece is then retracted while third piece 830 maintains the position of implant 804 such that implant 804 is deposited inside pocket 803 (FIG.8E). The entire instrument is then removed, leaving the implant placed in the pocket. The pocket can then be closed using standard medical techniques (i.e. suturing). As described in various embodiments above, third piece 830 may include a compartment configured to removably receive the implant. In this case, implant 804 is seated within first piece 820 by inserting third piece 810 into first piece 810. As described above, the compartment may be temporarily sealable so as to retain, for25Atty. Docket No. UM-43679.601example, liquid, inside the compartment in order to keep the implant hydrated during the insertion process.

[0118] Embodiments of the present disclosure include an eighth instrument 901 describedherein, with reference to FIGS. 9A-9E. In some embodiments, the placement and use of thevarious components of the eighth instrument are as depicted in FIGS. 9A-9E. In some embodiments, the various components of the eighth instrument include a first piece 910 (e.g. outer cannula, and a second piece 930 (e.g., plunger piece). Notably, in this particular embodiment, a needle piece is not included (though, of course as with any of the embodiments described herein one could be). In the case where a needle piece is not included, the incision and pocket may be formed, for example, using standard surgical instruments and techniques, for example the incision may be made with a scalpel, and the pocket may be formed with forceps. In some embodiments plunger piece 930 is a solid piece with an ovular cross section. In some embodiments cannula piece 910 is a hollow piece with an ovular cross section that the plunger piece can fit in concentrically. In some embodiments plunger piece 930 includes one or more locking pegs 940, which are received by peg holes 941 in cannula 910 (FIG.9B). This peg and hole locking mechanism prevents plunger 930 from being inserted further than desired into cannula 910, thus ensuring proper placement of the implant. In some embodiments, plunger piece 930 includes a visible indicator 950. When plunger piece 930 is fully seated within cannula 910 and locking pegs 940 are engaged in peg holes 941, visible indicator 950 can be seen through indicator window 951 (FIG.9C) indicating to the user that the desired depth has been reached and the plunger piece has been properly inserted and locked. Visible indicator 950 may be, for example, a colored “dot” or any other suitable element that can be seen through window 951. While not shown in the depicted embodiment, in some cases the indicator may comprise one or more elements (sound, light, tactile sensation etc.) which may require electronic elements and thus such elements are also contemplated as part of the present disclosure.

[0119] In some embodiments such as, but not limited to, the embodiment shown withrespect to FIGS.9A-9E, the various instruments described above may be used or provided without a needle piece. In this case, the initial incision and pocket formation may be performed using, for example, a scalpel and forceps.

[0120] In any of the embodiments, as illustrated in FIG. 10, a cannula 1030 (or any of thecannula designs shown or described herein may include a flared portion 1038 which prevents the cannula from being inserted too far into the pocket.26Atty. Docket No. UM-43679.601

[0121] In some embodiments the width of the various instruments described above issuitable for or even determined by the width of the implantable. In some embodiments the size and / or shape of the compartment configured to removably receive the implant is suitable for or even determined by the size and / or shape of the implantable.

[0122] While various embodiments are described above as having or optionally havingergonomic handles, it will be understood that any handles described herein may or may not be ergonomic in design and that in many, if not all, embodiments, any handles are entirely optional.

[0123] The various components of the instruments may be formed from the same ordifferent materials. For example, some or all of the components may be formed from plastic. Some or all of the components may be formed from one or more surgical grade metals (e.g., steel). Some or all of the components may be disposable (that is suitable for only a single use.) Some or all of the components may be reusable. Some or all of the reusable components may be able to withstand sterilization conditions (e.g., extreme temperatures, extreme pressures, vacuum).3. Implantables

[0124] Embodiments of the present disclosure also include soft implantables with or withouttherapeutic effect. Soft implantables include, but are not limited to, various hydrogels and other similarly fragile implantable devices, including, for example, synthetic tissue, sensors (i.e sensors on, in, or incorporating a soft implantable substrate), organoids, nanofiber meshes, responsive elastomers, and the like. In general, an implantable may take any suitable form including as a puck, pellet(s), disc, amorphous gel, etc. One of the advantages of the presently described instrument is the ability to maintain the implantable in a solution and thus the implantable may require hydration or maintenance in a particular solution including, but not limited to water, saline, actual, synthetic or mimetic biological fluids, or the like.

[0125] According to a specific embodiment, the soft implantable is an immuno-isolatingovarian restoration hydrogel such as that described in Brunette, Margaret A., Hadrian M. Kinnear, Prianka H. Hashim, Colleen L. Flanagan, James R. Day, Marilia Cascalho, Vasantha Padmanabhan, and Ariella Shikanov. "Human ovarian follicles xenografted in immunoisolating capsules survive long term implantation in mice." Frontiers in Endocrinology 13 (2022): 886678. Day, James R., Anu David, Alexa L. Cichon, Tanay Kulkarni, Marilia Cascalho, and Ariella Shikanov. "Immunoisolating poly (ethylene glycol) based capsules support ovarian tissue survival to restore endocrine function." Journal of biomedical materials27Atty. Docket No. UM-43679.601research Part A 106, no.5 (2018): 1381-1389. Day, James Ronald, Anu David, Mayara Garcia de Mattos Barbosa, Margaret Ann Brunette, Marilia Cascalho, and Ariella Shikanov. "Encapsulation of ovarian allograft precludes immune rejection and promotes restoration of endocrine function in immune-competent ovariectomized mice." Scientific reports 9, no. 1 (2019): 16614. Day, J. R., Flanagan, C. L., David, A., Hartigan-O’Connor, D. J., Garcia de Mattos Barbosa, M., Martinez, M. L., Lee, C., Barnes, J., Farkash, E., Zelinski, M., Tarantal, A., Cascalho, M., & Shikanov, A. (2023). Encapsulated Allografts Preclude Host Sensitization and Promote Ovarian Endocrine Function in Ovariectomized Young Rhesus Monkeys and Sensitized Mice. Bioengineering, 10(5), 550. See also, Clegg JR, Adebowale K, Zhao Z, Mitragotri S. Hydrogels in the clinic: An update. Bioeng Transl Med. 2024 May 16;9(6):e10680. doi: 10.1002 / btm2.10680. PMID: 39545079; PMCID: PMC11558196.

[0126] In some embodiments the implant is between 1 mm and 20 mm, between 1 mm and5 mm between 5 mm and 15 mm, or between 10 mm and 15 mm, in at least one dimension. In some embodiments the implant is between 1 mm and 20 mmm between 1 mm and 5 mm, between 5 mm and 15 mm, or between 10 mm and 15 mm, in at least two dimensions. In some embodiments, the implant is between 1 mm and 20 mm, between 1 mm and 5 mm, between 8 mm and 15 mm, or between 10 mm and 15 mm, in three dimensions.

[0127] In some embodiments, implantable is or comprises a composition comprising adegradable inner core comprising a biological material and a non-degradable outer shell encapsulating the degradable inner core and comprising a thermosensitive gelatin microgel. In some embodiments implantable comprises a therapeutic housing. In some embodiments the therapeutic housing comprises an opening on its top end and is configured to contain an immunoisolation device. In some embodiments the therapeutic housing is capable of dissolving in the tissue of a subject.4. Pre-loaded “Ready to use” instrument

[0128] In some embodiments, the instrument is provided to the operator with a pre-loadedimplantable such that the operator of the instrument does not need to directly contact the implantable. According to various embodiments, the pre-loaded implantable may, for example, be selected from any of the above-mentioned hydrogels. In this embodiment, if needed or desired, the instrument may be designed as described with respect to many of the embodiments disclosed above, to include a reversibly sealable compartment that maintains the implant / therapeutic under one or more desired conditions. For example, the reversibly sealable28Atty. Docket No. UM-43679.601compartment may contain a particular solution to maintain the implant in a hydrated state, at a particular pH level, at a particular salinity level, to deliver any necessary or desired nutrients.

[0129] In some embodiments, the instrument may be delivered to the operator in a sterilestate, for example, inside of sterile packaging, so that the instrument can be applied to / used on the subject without any additional sterilization or pre-insertion maintenance / procedures.

[0130] In some embodiments, the instrument itself or the packaging therefore may includemarkings of other indicators identifying a size, shape, and / or content of the implantable and / or instrument.5. Methods

[0131] Embodiments of the present disclosure also include methods comprising injecting atherapeutic into a subject, wherein injecting comprises (a) inserting a first instrument described herein, with reference to FIG.1, into the tissue (e.g., subcutaneous tissue) of a subject (e.g., a human subject); (b) placing a therapeutic (e.g., a hydrogel 112 and its hydrating solution) through the opening of the first instrument and into the interior hollow chamber of the first instrument; (c) inserting the shaft 110 through the opening of the first instrument and into the interior hollow chamber of the first instrument; (d) pushing (e.g., pushing by an outside force) the shaft 110 distally from the opening to meet the needle tip 113; (e) further pushing (e.g., pushing by an outside force) the shaft 110 distally from the opening until the shaft 110 engages the needle tip 113 from a first position (e.g., a closed position) to a second position (e.g., an open position); further pushing (e.g., pushing by an outside force) the shaft 110 distally from the opening until the therapeutic (e.g., a hydrogel 112 and its hydrating solution) is ejected from the hollow of the first; and further pushing (e.g., pushing by an outside force) the shaft 110 distally from the opening until the locking mechanism 111 engages and the shaft 110 stops moving distally.

[0132] Embodiments of the present disclosure also include methods comprising injecting atherapeutic into a subject, wherein injecting comprises inserting a second instrument described herein, with reference to FIG.2, into the tissue of a subject, by (a) inserting the first piece 210 is into the tissue (e.g., subcutaneous tissue) of a subject; (b) inserting the second piece 220 into the first piece 210; (c) pressing the button 221 to push the rod 223 distally until the rod 223 enters a compartment 225 which is configured to house, and does house, a therapeutic); (d) pushing the therapeutic and engaging the needle tip 226 from a first position (e.g., a closed position) to a second position (e.g., an open position); (e) engaging the first part 212 and the second part 222 of the locking mechanism to stop moving the rod 223 distally; (f) releasing the29Atty. Docket No. UM-43679.601therapeutic into the tissue of the subject; and (g) removing the first piece 210 and the second piece 220 from the tissue of the subject.

[0133] Embodiments of the present disclosure also include methods comprising injecting atherapeutic into a subject, wherein injecting comprises inserting a third instrument described herein with reference to FIG.3 into the tissue of a subject wherein injecting comprises inserting the third instrument described herein with reference to FIG.3 into the tissue of a subject, by any one or more of the methods described herein.

[0134] Embodiments of the present disclosure also include methods comprising injecting atherapeutic and a therapeutic housing, with reference to FIG.4, into a subject, wherein injecting comprises inserting any one or more of the instruments described herein, with reference to FIG.1, FIG.2, FIG.3, FIG.5, FIG.6, and / or FIG.7 into the tissue of a subject, by any one or more of the methods described herein.

[0135] Embodiments of the present disclosure also include methods comprising injecting atherapeutic into a subject, wherein injecting comprises inserting a fourth instrument described herein, with reference to FIG.5, by (a) inserting a therapeutic 512 and a therapeutic housing 513 into a compartment 513 of an inner shell of a first piece 610; (b) inserting the first piece 610 into a tissue (e.g., subcutaneous tissue) of a subject; (c) pushing a button 511 on one end of the first piece 610 to engage to opening mechanism 515; (d) releasing the therapeutic 512 and a therapeutic housing 513 into the tissue of the subject.

[0136] Embodiments of the present disclosure also include methods comprising injecting atherapeutic into a subject, wherein injecting comprises inserting a fifth instrument described herein, with reference to FIG.6, into the tissue of a subject, by (a) inserting the first piece 610 is into the tissue (e.g., subcutaneous tissue) of a subject; (b) inserting a therapeutic and therapeutic housing 611 into the first piece 610; (c) inserting the second piece 620 into the first piece 210; (d) pushing the second piece 620 distally until the second piece 620 reaches the therapeutic and therapeutic housing 611; (e) further pushing the second piece 620 distally until the therapeutic and therapeutic reach the needle tip 613; (f) further pushing the second piece 620 distally until the therapeutic and therapeutic engage the needle tip 613 from a first position (e.g., a closed position) to a second position (e.g., an open position); (g) further pushing the second piece 620 distally until the therapeutic and therapeutic are released from the first piece 610 and enter the tissue of a subject; and (g) removing the first piece 610 and the second piece 620 from the tissue of the subject.

[0137] Embodiments of the present disclosure also include methods comprising injecting atherapeutic into a subject, wherein injecting includes inserting a sixth instrument described30Atty. Docket No. UM-43679.601herein, with reference to FIGS.7A-7G, by (a) inserting a therapeutic into a compartment 742 of a fourth piece 740 (e.g., a button rod); (b) removably coupling the fourth piece 740 (e.g., a button rod) with a third piece 730 (e.g., an inner cannula); (c) inserting the removably coupled fourth piece 740 (e.g., a button rod) and third piece 730 (e.g., an inner cannula) into a secondpiece 720 (e.g., a needle piece) until a first lock 725 and a second lock 731 are removablycoupled; (d) pushing the removably coupled fourth piece 740 (e.g., a button rod) and third piece 730 (e.g., an inner cannula) distally until a needle nose 723 opens; (e) pushing the fourth piece 740 (e.g., a button rod) distally until a door 741 (e.g., a trap door) opens; (f) releasing the therapeutic into the tissue of the subject; (g) pulling proximally on the slider 712 until the second piece 720 (e.g., a needle piece) is retracted from the tissue of the subject. In some embodiments, injecting further includes inserting a therapeutic into a therapeutic housing prior to inserting a therapeutic into a compartment 742 of a fourth piece 740 (e.g., a button rod).

[0138] Embodiments of the present disclosure also include methods comprising injecting atherapeutic into a subject, wherein injecting includes inserting a seventh instrument described herein, with reference to FIGS.8A-8K, by (a) inserting a portion of second piece 820 into first piece 810 to create a pocket forming instrument 840 wherein the outer canula acts as a sleeve for needle shaft 824; (b) inserting the pocket forming instrument 840 a desired depth and length into subcutaneous tissue 802 to form a pocket 803 of a desired size at a desired depth (FIG.8B); (c) removing the second piece 820 while leaving first piece 810 inside the tissue to maintain pocket 803; (d) seating the therapeutic inside first piece 810; (e) depositing the therapeutic inside the pocket by retracting the first piece 810 while third piece 830 maintains the position of implant 804; and (f) removing the entire instrument.

[0139] In some embodiments, the various instruments described above may be used withouta needle piece. In this case, the initial incision and pocket formation may be performed using, for example, a scalpel and forceps. The outer cannula (with or without the soft implant preloaded inside, depending on the particular embodiment) is then inserted into the pocket. A plunger (or similar piece) (again with or without the soft implanted preloaded inside depending on the particular embodiment) is then inserted into the outer cannula and the plunger and outer canula moved with respect to one another such that the soft implant is deposited inside the pocket. In some embodiments the soft implant is loaded into the device (cannula, plunger, etc., based on the embodiment) by the operator, for example, during the insertion procedure. Alternatively in some embodiments the soft implant is pre-loaded into the device such that it is never directly handled by the operator.31Atty. Docket No. UM-43679.601

[0140] In some embodiments the method is performed in a non-surgical setting, (i.e., in aclinic, doctor’s office, in the field, etc.) and / or by a non-surgeon (i.e., general practitioner, nurse practitioner, field medic, or other non-surgically trained personnel.)32

Claims

Atty. Docket No. UM-43679.601CLAIMSWhat is claimed is:

1. An instrument comprising an outer cannula configured to be inserted inside a pocket formed in a subject’s tissue so as to maintain a desired size and depth of the pocket; and a plunger configured to be reversibly received by the outer cannula wherein movement of outer cannula and plunger relative to each other releases and deposits a soft implantable at known depth and location inside the pocket.

2. The instrument of claim 1 further comprising a needle piece configured to be reversibly received by the outer cannula and, which, when located within the outer cannula, is configured to create the pocket in the subject’s tissue.

3. The instrument of claims 1 or 2 wherein the cannula or plunger comprises a compartment for storage of the soft implantable.

4. The instrument of claim 3 wherein the compartment maintains the soft implantable in a particular condition.

5. The instrument of claim 4 wherein the particular condition is a hydrated state.

6. The instrument of claim 5 wherein the compartment is sealed in a first operative state and unsealed in a second operative state.

7. The instrument of claim 4 wherein when sealed, the compartment is liquid impermeable.

8. The instrument of claims 1-7 wherein the instrument is preloaded with the soft implantable prior to use.

9. The instrument of claim 1-8 wherein the soft implantable is between 5mm and 20mm in at least two dimensions and the outer cannula is sized to maintain the pocket at a size and shape that is large enough to receive the soft implantable.

10. The instrument of claims 1-9 wherein the soft implantable is or comprises a hydrogel.

11. An instrument comprising (1) a first piece comprising a handle, a slider, a slider locking mechanism, and a first lip; (2) a second piece comprising a second lip, a peg, a needle nose, and a first lock; (3) a third piece comprising a second lock and a track; (4) and a fourth piece comprising a door and a compartment; wherein the instrument is configured to deposit a soft implantable to a subject in need thereof.33Atty. Docket No. UM-43679.60112. The instrument of claim 11, wherein the compartment is configured to contain the soft implantable.

13. The instrument of claim 11 or 12, wherein the fourth piece is configured to removably couple with the third piece.

14. The instrument of any one of claims 11-13, wherein, the second piece is configured to accept, by insertion, the removably coupled fourth piece and third piece.

15. The instrument of any one of claims 11-14, wherein, a first lock and a second lock are configured to removably couple with each other and a needle nose is exposed and is configured to upon insertion of the removably coupled fourth piece and third piece into the second piece.

16. The instrument of any one of claims 11-15, wherein the needle nose is configured to open upon pushing the removably coupled fourth piece and third piece distally.

17. The instrument of any one of claims 3-7 or 11-16, wherein the compartment comprises a door.

18. The instrument of claim 17, wherein the door is hinged.

19. The instrument of claim 18, wherein the door opens upon pushing an element of the instrument.

20. The instrument of claim 19, wherein, upon pushing the element and opening the door, the implant is deposited in the subject’s subcutaneous tissue.

21. The instrument of any one of claims 11-15, wherein the second piece is configured to retract upon pulling proximally on the slider.

22. The instrument of any one of claims 3-7 or 11-21, wherein the compartment further comprises a sliding door.

23. The instrument of any one of claims 1-22, wherein the soft implantable is a composition comprising a degradable inner core comprising a biological material and a non-degradable outer shell encapsulating the degradable inner core and comprising a thermosensitive gelatin microgel.

24. The instrument of claim 23, wherein the soft implantable further comprises a therapeutic housing.34Atty. Docket No. UM-43679.60125. The instrument of claim 24, wherein the therapeutic housing comprises an opening on its top end and is configured to contain an immunoisolation device.

26. The instrument of claim 25, wherein the therapeutic housing is capable of dissolving in the tissue of a subject.

27. A method comprising depositing a soft implant into a subject by inserting the instrument of any one of claims 1-26 into a tissue of a subject and releasing the implant.

28. A method comprising depositing a soft implant inside of a subject’s tissue comprising forming a pocket in the subject’s tissue; inserting the instrument of any one of claims 1-26 into the pocket; moving two or more pieces of the instrument relative to one another to deposit the soft implant or therapeutic inside the pocket and removing the instrument.

29. The method of claim 28 wherein the soft implant is preloaded inside of the instrument.

30. The method of claim 29 wherein the operator of the instrument does not directly interact with the soft implant at any time during the procedure.

31. The method of claims 28-30 wherein the soft implant is maintained under at least one particular condition while loaded inside the instrument.

32. The method of claim 31 wherein the particular condition is a hydrated state.

33. A method comprising providing a therapeutic to a subject in need thereof by inserting the instrument of any one of claims 11-26 into a tissue of a subject by (a) inserting atherapeutic into a compartment of a fourth piece; (b) removably coupling the fourth piecewith a third piece; (c) inserting the removably coupled fourth piece and third piece into asecond piece until a first lock and a second lock are removably coupled and the needle nose isclosed and exposed; (d) pushing the removably coupled fourth piece and third piece distallyuntil a needle nose opens; (e) pushing the fourth piece distally until a door opens; (f)releasing the therapeutic into the tissue of the subject; (g) pulling proximally on the slideruntil the second piece is retracted from the tissue of the subject.

34. The method of claims 27-33 wherein the soft implan or therapeutic is or comprises a hydrogel.

35. The method of claim 34 wherein the hydrogel is or comprises a therapeutic.35Atty. Docket No. UM-43679.60136. The method of claim 35, wherein the therapeutic is a composition comprising a degradable inner core comprising a biological material and a non-degradable outer shell encapsulating the degradable inner core and comprising a thermosensitive gelatin microgel.

37. The method of claim 33, further comprising inserting the therapeutic into a therapeutic housing prior to inserting the therapeutic into a compartment of a fourth piece.

38. The method of claim 20, wherein the therapeutic housing comprises an opening on its top end and is configured to contain the therapeutic.

39. The method of claim 21, wherein the therapeutic housing is capable of dissolving in the tissue of the subject.

40. Use of the instrument of any one of claims 1-39 to provide a therapeutic to a subject in need thereof.36

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