Device and system for delivering a therapeutic agent

Abstract

Devices, methods, and systems are provided for extravascular delivery of a pharmaceutical fluid formulation to a target site within a patient using metered infusion capabilities while maintaining positional stability.SOLUTION: The device 100 can be configured to deliver a discontinuous flow or bolus of fluid to the target site. The infusion device 100 may be engaged with a trocar 200 that is configured to have one or more stabilizing features on its shaft such that the trocar 200 provides a stable delivery mechanism for the infusion device 100. The trocar 200 is configured to receive therein an injection needle attached to the injection device 100, through which the injection device 100 can deliver fluid to a target tissue site.SELECTED DRAWING: Figure 7

Description

[Technical Field]

[0001] The present disclosure relates generally to devices, methods, and systems for delivering therapeutic agents, such as compounds, compositions, cells, or cellular products, such as exosomes. In a non-limiting example, the devices provided herein are configured for extravascular delivery of agents to a target location within a patient while maintaining positional stability and providing metered infusion capabilities. [Background technology]

[0002] Cell therapy is a therapeutic treatment in which cellular material is injected into a patient to treat a variety of different diseases, specifically targeting specific organs within the patient's body. In some cell therapies, cellular material can be extracted from the patient, processed for therapeutic benefit, and then reinjected into the patient at the treatment or delivery site. In certain cases, successful cell delivery requires that the injected cells also be viable, typically intact. Cell therapy delivery can be achieved in several different ways, including intravascular or extravascular delivery. Intravascular delivery involves cellular therapeutic agents being injected through the blood vessels. Targeting specific organs in this way is possible in a variety of ways. However, efficiency can be low, and the residence time of the therapeutic cellular material delivered to the organ(s) can be short due to the patient's body's natural flushing. Summary of the Invention

[0003] Provided herein are devices, methods, and systems for delivering therapeutic agents, such as compounds, compositions, cells, and cell products, among others. In certain embodiments, the devices and systems provided herein are configured for administering cellular therapeutic agents. In certain embodiments, the devices and systems provided herein include metered injection capabilities. In certain embodiments, the devices and systems provided herein are configured for extravascular delivery of therapeutic agents to a target location within a patient, such as the interior of an organ, while maintaining positional stability. For example, in one exemplary embodiment, a cellular therapy delivery device is provided that includes a body having an actuator, a fluid reservoir with fluid therein, and a fluid delivery mechanism. In certain embodiments, a detachable injection needle extends distally from the body, and the fluid delivery mechanism is configured to deliver a continuous flow or bolus of fluid through the injection needle. In certain embodiments, the organ is a kidney. In certain embodiments, the patient has cancer and the organ includes a tumor.

[0004] The device can have many variations. In certain embodiments, the fluid delivery mechanism can include an electromechanical system having a central processing unit and a pump. In certain embodiments, the device can also include a valve configured to translate proximally and distally parallel to the injection needle during device deployment and fluid delivery. In certain embodiments, the valve can be configured to translate distally and proximally approximately 2 cm. In certain embodiments, the device can include a fluid receiver configured to removably and replaceably receive a fluid reservoir. In certain embodiments, the fluid reservoir can include at least one cartridge containing a known dose of fluid. In certain embodiments, the fluid receiver can be configured to sterilely receive one or more cartridges (e.g., one, two, three, four, or five). In certain embodiments, the fluid receiver can be configured to serially receive multiple cartridges (e.g., the contents of one cartridge are used, the cartridge is removed, and one or more additional cartridges are inserted as needed to continue administration). In certain embodiments In certain embodiments, the fluid receiver can be configured to simultaneously receive multiple cartridges. In certain embodiments, the fluid can include therapeutic cells or cell products for the treatment of kidney disease. In certain embodiments, the fluid can include an anti-cancer drug for the treatment of cancer. In certain embodiments, the device can include a touch display that can be configured to control operation of the device. In certain embodiments, the display can be configured to set one or more parameters for delivering the fluid, including at least one of pressure and volume. In certain embodiments, the display can be configured to provide real-time fluid discharge information during delivery. In certain embodiments, the actuator can be one of a trigger, a plunger, a switch, or a button. In certain embodiments, the device can also include an engagement mechanism at the distal end of the body configured to removably engage with a trocar.

[0005] In one aspect, a trocar is provided that includes an elongate body having a proximal end and a distal end. In certain embodiments, the body has a head at its proximal end, an elongate shaft extending distally from the head, and a lumen extending from the proximal end to the distal end therethrough. In certain embodiments, a stabilizing means is provided on a distal portion of the elongate shaft and configured to stabilize the distal end of the elongate body against a tissue surface.

[0006] Trocars can have many variations. In certain embodiments, the stabilizing means can include one or more engaging components configured to deploy to releasably grasp a tissue surface upon actuation. In certain embodiments, the engaging components can include a plurality of feet. In certain embodiments, the feet can include microhooks. In certain embodiments, the engaging components can include at least one of an adhesive component, a suction component, and a clamping component. In certain embodiments, the trocar can include a removable stylet configured to extend through a lumen of the elongate body. In certain embodiments, the stylet is configured to actuate the engaging components upon removal. In certain embodiments, at least a portion of the elongate shaft can be configured to translate distally and proximally parallel to the longitudinal axis of the elongate shaft. In certain embodiments, at least a portion of the elongate shaft can be configured to translate distally and proximally approximately 2 cm.

[0007] In one aspect, a method of delivering a pharmaceutical fluid formulation to tissue is provided, comprising attaching an injection device to a trocar. In certain embodiments, the trocar has a lumen extending therethrough and a stylet disposed therein. In certain embodiments, the method also comprises connecting a fluid source to the injection device and advancing the injection device and trocar through an external tissue surface of a patient to penetrate an internal tissue target site. In certain embodiments, the method further comprises detaching the stylet from the trocar, disengaging the injection device from the trocar, and attaching an injection needle to the injection device. In certain embodiments, the method also comprises inserting the injection needle through the trocar and into the tissue target site and activating the injection device to deliver a continuous stream or bolus of fluid from the fluid source through the injection needle to the tissue target site. In certain embodiments, the pharmaceutical fluid formulation comprises, consists essentially of, or consists of a population of cells or products thereof and a fluid pharmaceutically acceptable carrier. In certain embodiments, the cellular therapy comprises stem cells, progenitor cells, primary cells, or cell lines. In certain embodiments, the tissue target site is the kidney. In certain embodiments, the patient has kidney disease. In certain embodiments, the kidney disease is chronic kidney disease. In certain embodiments, the cellular therapy comprises bioactive kidney cells. In certain embodiments, the cellular therapy agent comprises selected kidney cells. In certain embodiments, the cellular therapy agent comprises a liquid formulation comprising cells and a temperature-sensitive biomaterial. In certain embodiments, the cellular therapy agent is a Neo-Kidney Augment (NKA). In certain embodiments, the cells are in the form of spheroids or cell clusters. In certain embodiments, the pharmaceutical fluid formulation comprises a cell product, such as a vesicle, e.g., a microvesicle or an exosome. In certain embodiments, the pharmaceutical fluid formulation comprises a chemical compound. In certain embodiments, the pharmaceutical fluid formulation comprises an anti-cancer agent. In certain embodiments, the patient has cancer. In certain embodiments, the tissue target site is a tumor.

[0008] The method can be varied in numerous ways. For example, the method can further include deploying a stabilizing means at a distal portion of the trocar to stabilize the distal end of the trocar against the tissue target site prior to inserting the injection needle through the trocar. In certain embodiments, deployment of the stabilizing means can be activated by removal of the stylet. In certain embodiments, the method can also include retracting the injection needle during delivery of the fluid (e.g., a continuous stream or a bolus thereof). In certain embodiments, the method can further include stabilizing the injection device using a translation valve and stabilizing the trocar using a compression spring portion of the trocar during actuation of the injection device.

[0009] The present invention will be more fully understood from the following detailed description when read in conjunction with the accompanying drawings, in which: [Brief explanation of the drawings]

[0010] [Figure 1] FIG. 1 is a diagram of a patient in a prone position. [Figure 2] FIG. 1 is a diagram of a patient in a lateral position. [Figure 3]FIG. 1 details an exemplary process for using a commercially available device to treat a subject. [Figure 4A] FIG. 4 illustrates one embodiment of the use of a commercially available device to provide treatment to a patient according to the process of FIG. 3. [Figure 4B] FIG. 4 illustrates an embodiment of a commercially available device for providing treatment to a patient according to the process of FIG. 3. [Figure 4C] FIG. 4 illustrates an embodiment of a commercially available device for providing treatment to a patient according to the process of FIG. 3. [Figure 5] FIG. 1 is a side view of one embodiment of a trocar. [Figure 6] FIG. 1 is a side view of one embodiment of a cannula. [Figure 7] FIG. 1 is a side view of one embodiment of an injection device with a trocar attached and a stylet inserted therein. [Figure 8] FIG. 1 is a simplified diagram of a bolus fluid delivery profile. [Figure 9] FIG. 1 is a simplified diagram of a continuous fluid delivery profile. [Figure 10] FIG. 1 illustrates one embodiment of a cartridge. [Figure 11] FIG. 8 shows a side view of the trocar of FIG. 7. [Figure 12] FIG. 8 is a side view of the trocar of FIG. 7 in a deployed state. [Figure 13] FIG. 1 is a side view of one embodiment of a trocar inserted. [Figure 14] FIG. 14 is a side view of the trocar of FIG. 13 in a deployed state. [Figure 15] FIG. 14 is a side view of the trocar of FIG. 13 in a deployed state. [Figure 16A] FIG. 1 is a side view of one embodiment of a drywall anchor being deployed. [Figure 16B] FIG. 16B is a side view of the drywall anchor of FIG. 16A being deployed. [Figure 16C] FIG. 16C is a side view of the drywall anchor of FIG. 16B being deployed. [Figure 16D] FIG. 16D is a side view of the drywall anchor of FIG. 16C being deployed. [Figure 17] FIG. 1 is a view of the distal portion of one embodiment of a needle having surface features. [Figure 18A] FIG. 1 is a view of the distal tip of one embodiment of a stylet. [Figure 18B] FIG. 10 is a view of the distal tip of another embodiment of a stylet. [Figure 18C] FIG. 10 is a view of the distal tip of another embodiment of a stylet. [Figure 18D] FIG. 10 is a view of the distal tip of another embodiment of a stylet. [Figure 19] 1 is a simplified diagram of one embodiment of an injection needle. [Figure 20] FIG. 1 is a cutaway side view of the renal capsule. [Figure 21] FIG. 1 is a diagram showing how to find the optimal needle size. [Figure 22] FIG. 1 shows the distal end of a needle and a ruler. [Figure 23] FIG. 23 shows the distal end of the needle of FIG. 22 and a ruler, highlighting the placement of the holes in the distal end. [Figure 24] 10A-10C illustrate an exemplary method for holding a miniature syringe for better control. [Figure 25] 8A and 8B show simplified cross-sectional views of the placement of the trocar of FIG. 7 in the kidney. [Figure 26] 26 shows a simplified cross-sectional view of the placement of the trocar of FIG. 7 in the kidney of FIG. 25. [Figure 27A] FIG. 1 illustrates an embodiment for delivering multiple boluses of therapeutic agent to the kidney. [Figure 27B] FIG. 1 illustrates an embodiment for delivering multiple boluses of therapeutic agent to the kidney. [Figure 27C] FIG. 1 illustrates an embodiment for delivering multiple boluses of therapeutic agent to the kidney. [Figure 27D] FIG. 1 illustrates an embodiment for delivering multiple boluses of therapeutic agent to the kidney. [Figure 27E]FIG. 1 illustrates an embodiment for delivering multiple boluses of therapeutic agent to the kidney. [Figure 27F] FIG. 1 illustrates an embodiment for delivering multiple boluses of therapeutic agent to the kidney. DETAILED DESCRIPTION OF THE INVENTION

[0011] It should be understood that the above-referenced drawings are not necessarily to scale, but rather present somewhat simplified representations of various preferred features illustrating the underlying principles of the present disclosure. Specific design features of the present disclosure, including, for example, specific dimensions, orientations, locations, and shapes, are determined in part by the particular intended application and use environment.

[0012]

[0023] Hereinafter, embodiments of the present disclosure will be described in detail with reference to the accompanying drawings. Those skilled in the art will recognize that the described embodiments can be modified in various different ways, all without departing from the spirit or scope of the present disclosure. Furthermore, throughout this specification, like reference numerals refer to like elements.

[0013] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure. As used herein, the singular forms "a," "an," and "the" may be used interchangeably where the context is clear. The plural forms are intended to be included unless otherwise indicated. As used herein, the terms "comprises" and / or "comprises" specify the presence of stated features, integers, steps, operations, elements, and / or components, but will be further understood to not exclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items. Linking terms such as "coupled," "engaged," and the like indicate a physical relationship between two components, either directly connected to one another or indirectly connected through one or more intermediate components.

[0014] As used herein, the term "patient" or other similar terms is understood to include any subject (human or animal) to which the treatments disclosed herein can be administered. As used herein, the term "user" encompasses any entity capable of interacting with or controlling a device. A "user" may be a "patient," or the "user" and "patient" may be separate entities, as described herein. In certain embodiments, the subject is a living animal. In certain embodiments, the subject is a mammal, such as a dog, cat, horse, rabbit, zoo animal, cow, pig, sheep, goat, camel, mouse, rat, or guinea pig. In certain embodiments, the subject is a primate, such as a human, chimpanzee, orangutan, monkey, or baboon. In certain embodiments, the subject is a human. In certain embodiments, the subject is a patient who is experiencing or has experienced one or more signs, symptoms, or other indicators of kidney disease and is a candidate for treatment. Such subjects include, without limitation, newly diagnosed subjects, or subjects previously diagnosed and currently experiencing a recurrence or flare-up, or subjects at risk for kidney disease regardless of cause. In certain embodiments, the subject may or may not have previously been treated for kidney disease. In certain embodiments, the subject has diabetes. In certain embodiments, the subject has type I diabetes. In certain embodiments, the subject has type II diabetes. In certain embodiments, the subject has chronic kidney disease. In certain embodiments, the subject has a congenital anomaly of the kidney and / or urinary tract. In certain embodiments, the subject is a human with a congenital anomaly of the kidney and urinary tract. In certain embodiments, the subject is experiencing or has experienced one or more signs, symptoms, or other indicators of an organ-related disease, such as kidney disease, anemia, or erythropoietin (EPO) deficiency. In certain embodiments, the subject does not have diabetes. In certain embodiments, the subject does not have type I diabetes. In certain embodiments, the subject does not have type II diabetes. In certain embodiments, the subject does not have kidney disease. In certain embodiments, the subject has cancer. In certain embodiments, the cancer comprises a solid tumor.

[0015] In one aspect, the devices, systems, and methods provided herein are useful for administering an anti-cancer or chemotherapeutic agent to a patient. In certain embodiments, administering the anti-cancer agent includes delivering the anti-cancer or chemotherapeutic agent to an internal tissue site or organ of the subject. In certain embodiments, the patient has a solid tumor. In certain embodiments, the solid tumor is within, on, invading, or part of an organ. In certain embodiments, the internal tissue site or organ is the kidney, lung, heart, spleen, stomach, pancreas, bladder, brain, small intestine, colon, rectum, appendix, ovary, uterus, esophagus, liver, gallbladder, thyroid, parathyroid, adrenal gland, breast, lymph node, muscle, spinal cord, testicle, prostate, pharynx, larynx, bone, or trachea. In certain embodiments, the subject has cancer. In certain embodiments, the cancer is melanoma (e.g., metastatic melanoma that has spread to an internal site such as an organ), neuroendocrine tumor, carcinoma, or sarcoma. In certain embodiments, the patient has sarcoma, bladder cancer, bone cancer, brain tumor, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g., triple negative, estrogen receptor (ER) positive, ER negative, chemotherapy resistant, herceptin resistant, HER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobular carcinoma, primary breast cancer, or metastatic breast cancer), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, or sarcoma), glioblastoma multiforme, glioma, melanoma, prostate cancer, castration-resistant prostate cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., of the head, neck, or esophagus), or colorectal cancer. In certain embodiments, the subject is diagnosed with cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, esophagus, liver, kidney, lung, non-small cell lung, melanoma, sarcoma, stomach, and uterus, medulloblastoma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytopenia, primary macroglobulinemia, primary brain tumor, malignant pancreatic insulinoma, malignant carcinoid, urinary bladder cancer, testicular cancer, thyroid cancer, esophageal cancer, urinary system cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, medullary thyroid carcinoma, medullary thyroid carcinoma, metastatic melanoma, The term "sarcoma" generally refers to tumors composed of a substance like embryonic connective tissue, and generally consists of dense cells embedded in a fibrous or homogeneous substance. Sarcomas that may be treated using the devices, systems, or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma, and thyroid cancer. sarcoma), liposarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, green sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemia sarcoma, malignant mesenchymal sarcoma, parosteal osteosarcoma, reticulosarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or telangiectatic sarcoma. The term "melanoma" refers to tumors arising from the melanocytic system of the skin and other organs. Melanomas that may be treated using the devices, systems, or methods provided herein include, for example, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, and erythroderma. melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma. In certain embodiments, the melanoma is metastatic melanoma that has spread to an internal site (such as an organ or lymph node) of the patient. The term "carcinoma" refers to a malignant neoplasm composed of epithelial cells that tend to infiltrate surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated using the devices, systems, or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, tufted carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma of the adrenal cortex, alveolar carcinoma, alveolar epithelial carcinoma, basal cell carcinoma, carcinoma basocellulare, basoid carcinoma, basosquamous carcinoma, and basaloid carcinoma. Basosquamous cell carcinoma, bronchoalveolar carcinoma, bronchiolar carcinoma, tracheal Follicular carcinoma, cerebriform carcinoma, cholangiocarcinoma, choriocarcinoma, mucinous carcinoma comedo carcinoma, uterine body carcinoma, cribriform carcinoma, carcinoma en cuirasse, skin carcinoma , cylindrical carcinoma, columnar cell carcinoma, ductal carcinoma, ductal carcinoma, carcinoma dura carcinoma durum, embryonal carcinoma, encephalomyocarcinoma, epidermoid carcinoma, adenoid epithelial carcinoma, exophytic carcinoma, ulcerative carcinoma, fibrocarcinoma, gelatiniforni carcinoma, colloid adenocarcinoma, giant cell carcinoma, carcinoma gigantocellulare, adenocarcinoma, granulosa cell carcinoma, hair matrix carcinoma, hematoid carcinoma, Hepatocellular carcinoma, Hürthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, childhood embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma Carcinoma, intraepithelial carcinoma, Krompecher carcinoma , Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lobular carcinoma, lymphoepithelial carcinoma, medullary carcinoma, medullary carcinoma medullary carcinoma, melanoma, molle carcinoma, mucinous carcinoma, mucinous secreting carcinoma, carcinoma mucocellulare, mucoepidermoid carcinoma, mucinous carcinoma Carcinoma (carcinoma mucosum), mucinous carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, Ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, Included are squamous cell carcinoma, plutaceous carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, carcinoma sarcomatoides, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, solanoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, spinous cell carcinoma, string carcinoma, telangiectasia carcinoma, telangiectasia-like carcinoma, transitional cell carcinoma, nodular carcinoma, tubular carcinoma, nodular carcinoma, verrucous carcinoma, or choriocarcinoma.

[0016] An "anti-cancer agent" is a therapeutic agent used in the treatment or prevention of cancer. In certain embodiments, the anti-cancer agent can be a macromolecule (e.g., a protein or other organic compound having a molecular weight of at least 2000 daltons) or a small molecule (e.g., an organic compound having a molecular weight of less than 2000 daltons). Exemplary anti-cancer agents include antibodies, small molecules, and macromolecules, or combinations thereof. In certain embodiments, the anti-cancer agent comprises a cell, such as an immune cell. In certain embodiments, the immune cell has been modified (e.g., genetically and / or via exposure to tumor antigens) to attack tumor cells or promote an immune response against tumor cells. In certain embodiments, the immune cell is a T cell (such as a CD4 T cell, a CD8 T cell, or a combination thereof) or a dendritic cell (such as a plasmacytic dendritic cell). In certain embodiments, the immune cell is genetically modified, such as a chimeric antigen receptor (CAR) T cell. In certain embodiments, the anti-cancer agent inhibits cell growth or proliferation. In certain embodiments, the anti-cancer agent is a chemotherapeutic agent. In certain embodiments, the anti-cancer agent is an agent identified herein as having utility in methods for treating cancer. In certain embodiments, the anti-cancer agent is an agent approved by the U.S. Food and Drug Administration (FDA) or a similar regulatory agency in a country other than the United States to treat cancer. Examples of anti-cancer agents include, but are not limited to, MEK (e.g., MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g., XL518, CI-1040, PD035901, selumetinib / AZD6244, GSK1120212 / trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY869766). , alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, chlorambucil, uramustine), ethyleneimines and methylmelamines (e.g., hexamethylmelamine, thiotepa), alkylsulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine,lomustine, semustine, streptozocin), triazenes (decarbazine)), antimetabolites (e.g., 5-azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxuridine, cytarabine), purine analogs (e.g., mercaptopurine , thioguanine, pentostatin, etc.), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate, teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin, , daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum compounds or platinum-containing agents (e.g., cisplatin, oxaloplatin, carboplatin), anthracenediones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenocortical suppressants (e.g., mitotane, aminoglutethimide), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), inhibitors of mitogen-activated protein kinase signaling (e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002, Syk inhibitors, mTOR inhibitors, antibodies (e.g., Rituxan), gossypol, genasense, polyphenol E, chlorofusin, all-trans retinoic acid (ATRA), , bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all-trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec®), geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-A AG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, PD184352, 20-epi-1,25-dihydroxyvitamin D3, 5-ethynyluracil, abiraterone, aclarubicin, acylfulvene, adecipenol, adozelesin, aldesleukin, ALL-TK antagonist, altretamine, ambamustine, amidox, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, andrographolide, angiogenesis inhibitor, antagonist D, antagonist G, antarelix, anti-dorsalizing morphogenetic protein-1, for prostate cancer Antiandrogens, antiestrogens, antineoplastons, antisense oligonucleotides, aphidicolin glycinate, apoptosis gene modulators, apoptosis regulators, apurinic acid, ara-CDP-DL-PTBA, arginine deaminase, asulacrine, atamestane, atlimustine, axinastatin 1, axinastatin 2, axinastatin 3, azasetron, azatoxin, azatyrosine, baccatin III derivatives, balanol, bachimasu Tat, BCR / ABL antagonists, benzochlorins, benzoylstaurosporine, beta-lactam derivatives, beta-arretin, beta-lactamycin B, betulinic acid, bFGF inhibitors, bicalutamide, bisantrene, bisazilidinyl spermine, bisnafide, bisstraten A, bizelesin, breflate, bropirimine, budotitanium, buthionine sulfoximine, calcipotriol, calphostin C, camptothecin derivatives, canarypox, IL-2, capecitabine, carboxamide Aminotriazole, carboxyamidotriazole, CaRest M3, CARN700, cartilage-derived inhibitor, carzelesin, casein kinase inhibitor (ICOS), castanospermine, cecropin B, cetrorelix, chlorin, chloroquine oxalin sulfonamide, cicaprost, cisporphyrin, cladribine, clomiphene analogs, clotrimazole, colismycin A, colismycin B, combretastatin A4, combretastatin analogs, conagenin, crambescidin 816 816), crisnatol, cryptophycin 8, cryptophycin A derivative, curacin A, cyclopentanethraquinone, cycloplatam, sipemycin, cytarabine ocphosphate, cytolytic factor, cytostatin, dacliximab, decitabine, dehydrodemnin B, deslorelin, dexamethasone, dexphosphamide, dexrazoxane, dexverapamil, diazicon, didemnin B, didox, diazepam Tilnorspermine, dihydro-5-azacytidine, 9-dioxamycin, diphenylspiromustine, docosanol, dolasetron, doxifluridine, droloxifene, dronabinol, duocarmycin SA, ebselen, ecomustine, edelfosine, edrecolomab, eflornithine, elemene, emiteflu, epirubicin, epristeride, estramustine analogues, estrogen agonists, estro Genitourinary antagonists, etanidazole, etoposide phosphate, exemestane, fadrozole, fazarabine, fenretinide, filgrastim, finasteride, flavopiridol, flezelastine, fluasterone, fludarabine, fluorodaunorunicin hydrochloride, forfenimex, formestane, fostriecin, fotemustine, gadolinium texaphyrin, gallium nitrate, gallocitabine, ganirelix, gelatinase inhibitors, gemcitabine, glutathione inhibitors, hepsulfam, heregulin, hexamethylene bisacetamide, hypericin, ibandronate, idarubicin, idoxifene, idramantone, ilmofosine, ilomastat, imidazoacridone, imiquimod, immunostimulatory peptides, insulin-like growth factor-1 receptor inhibitors, interferon agonists,Interferon, interleukin, iobenguane, iodosorubicin, 4-ipomeanol, ilopract, irsogladine, isobengazole, isohomohalichondrin B, itasetron, jasplakinolide, kahalalide F, lamellarin N triacetate, lanreotide, leinamycin, lenograstim, lentinan sulfate, leptolstatin, letrozole, leukemia inhibitory factor, leukocyte alpha interferon, leuprolide + estrogen + progesterone, leuprorelin, levamisole, liarozole, linear polyamine analogues, lipophilic disaccharide peptides, lipophilic, Platinum compounds, risoclinamide 7, lobaplatin, lombricine, lometrexol, lonidamine, losoxantrone, lovastatin, loxoribine, lurtotecan, lutetium texaphyrin, lisofylline, lytic peptides, maytansine, mannostatin A, marimastat, massoprocol, maspin, matrilysin inhibitors, matrix metalloproteinase inhibitors, menogaril, mervalone, meterelin, methioninase, metoclopramide, MIF inhibitors, mifepristone, miltefosine, mirimostim, mismatched double-stranded RNA, mitoguazone, mitractol ol, mitomycin analogues, mitonafide, mitotoxin fibroblast growth factor-saporin, mitoxantrone, mofalotene, molgramostim, monoclonal antibodies, human chorionic gonadotrophin, monophosphoryl lipid A + myobacterial cell wall sk, mopidamol, multidrug resistance gene inhibitors, multitumor suppressor 1-based therapeutic agents, mustard anticancer drugs, mycaperoxide B, mycobacterial cell wall extract, myriaporone, N-acetyldinaline, N-substituted benzamides, nafarelin, nagrestip, naloxone + pentazocine, napavine, naf Terpin, nartograstim, nedaplatin, nemorubicin, neridronic acid, neutral endopeptidase, nilutamide, nisamycin, nitric oxide modulators, nitric oxide antioxidants, nitrulline, 06-benzylguanine, octreotide, oxenon, oligonucleotides, onapristone, ondansetron, oracin, oral cytokine inducers, ormaplatin, osateron, oxaliplatin, oxaunomycin, palauamine, palmitoylrhizoxin, pamidronate, panaxytriol, panomyphen, parabactin, pazelliptin, pegaspargase, perdecin, pentosan polysulfate sodium sodium, pentostatin, pentrazole, perflubron, perfosfamide, perillyl alcohol, phenazinomycin, phenyl acetate, phosphatase inhibitors, picibanil, pilocarpine hydrochloride, pirarubicin, piritrexim, prasetin A, prasetin B, plasminogen activator inhibitors, platinum complexes, platinum compounds, platinum triamine complexes, porfimer sodium, porfiromycin, prednisone, propyl bis-acridone, prostaglandin J2, proteasome inhibitors, protein A system immunomodulators, protein kinase C inhibitors, protein kinase C inhibitors, microalgae, protein tyrosine phosphatases enzyme inhibitors, purine nucleoside phosphorylase inhibitors, purpurin, pyrazoloacridine, pyridoxylated hemoglobin polyoxyethylene conjugates, raf antagonists, raltitrexed, ramosetron, ras farnesyl protein transferase inhibitors, ras inhibitors, ras-GAP inhibitors, reterliptin demethylation, rhenium Re186 etidronate, rhizoxin, ribozyme, RII retinamide, rogletimide, rohitukin, romurtide, roquinimex, rubiginone B1, ruboxil, safingol, saintpin, SarCNU, sarcophytol A, sargramostin, Sdi 1 mimetic, semustine, senescence derived inhibitor 1, sense oligonucleotide, signal transduction inhibitor, signal transduction modulator, single chain antigen binding protein, sizofuran, sobuzoxane, sodium borocaptate, Sodium phenylacetate, sorberol, somatomedin-binding protein, sonermin, sparfosic acid, spicamycin D, spiromustine, splenopentin, spongistatin 1, squalamine, stem cell inhibitors, stem cell division inhibitors, stipiamid, stromelysin inhibitors, sulfinosine, superactive vasoactive intestinal peptide antagonists, suradista, suramin, swainsonine, synthetic glycosaminoglycans, ta Limustine, tamoxifen methiodide, tauromustine, tazarotene, tecogalan sodium, tegafur, tellapyrylium, telomerase inhibitors, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, tetrazomine, thaliblastine, thiocoraline, thrombopoietin, thrombopoietin mimetics, thymalfasin, thymopoietin receptor agonist, thymotrin, thyroid-stimulating hormone, tin ethyl etiopurpurin, tirapazamine, titanocene dichloride, topsentin, toremifene, totipotent stem cell factor, tranexamin Translation inhibitors, tretinoin, triacetyluridine, triciribine, trimetrexate, triptorelin, tropisetron, turosteride, tyrosine kinase inhibitors, tyrphostin, UBC inhibitors, ubenimex, urogenital sinus-derived growth inhibitory factor, urokinase receptor antagonists, vapreotide, Variolin B, vector systems for red blood cell gene therapy, veraresol, veramine, verudin, verteporfin, vinorelbine, vinxartin, vitaxin, vorozole, zanoterone, zeniplatin, zilascorb, zinostatin stimalamer, adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin, aclarubicin, acodazole hydrochloride, acronine, adzelesin, aldesleukin, altretamine, ambomycin, amethanthrone acetate, aminoglutethimide, amsacrine, anastrozole, Anthramycin, asparaginase, asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, visnafide dimesylate, bizercin, bleomycin sulfate, brequinar sodium, bropirimine, busulfan, cactinomycin, calsterone, caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedefingol, chlorambucil, ciloremycin, cladribine, crisnatol mesylate, cyclophosphamide, cytara vin, dacarbazine, daunorubicin hydrochloride, decitabine, dexorumaplatin, dezaguanine, dezaguanine mesylate, diaziconazole, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin, edatrexate, eflornithine hydrochloride, elsamitrucin, enloplatin, enpromate, epipropizine, epirubicin hydrochloride, elbrozole, esorubicin hydrochloride, estramustine, estramustine phosphate sodium, etanidazole, etoposide, etoposide cidophosphate, etoprine, fadrozole hydrochloride, fazarabine, fenretinide, floxuridine, fludarabine phosphate, fluorouracil, fluorocitabine, fosquidone, fostriecin sodium, gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, iimofosine, interleukin II (including recombinant interleukin II, or rIL2), interferon alpha-2a, interferon alpha-2b, interferon alpha-nl,Interferon alpha-n3, interferon beta-la, interferon gamma-lb, iproplatin, irinotecan hydrochloride, lanreotide acetate, letrozole, leuprolide acetate, liarozole hydrochloride, lometrexol sodium, lomustine, losoxantrone hydrochloride, masoprocol, maytansine, mechlorethamine hydrochloride, megestrol acetate, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate, methotrexate sodium, metoprine, meturedepa, mitindomide, mitocalcin, mitochromin, mitogillin, mitomarcine, mitomycin, mitospel, mitotane, mitoxantrone hydrochloride, mycophenolate, nocodazole, nogalamycin, ormaplatin, oxisuran, pegaspargase, periomycin, pentamstine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, promestane, porfima sodium, porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, ribopurine, rogletimide, safingol, safingol hydrochloride, semustine, simtrazene, sparfosate sodium, sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin, streptonigrin, streptozocin, sulofenur, tallysomycin, tecogalan sodium, tegafur, teloxan Thoron hydrochloride, temoporfin, teniposide, teloxylon, testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin, tirapazamine, toremifene citrate, trestrone acetate, triciribine phosphate, trimetrexate, trimetrexate glucuronate, triptorelin, tubrozole hydrochloride, uracil mustard, uredepa, vapreotide, verteporfin, vinblastine sulfate, vincristine sulfate, vindesine sulfate, vinnepi sulfate, vincristine, vinglisinate sulfate, vinleurosine sulfate, vinorelbine tartrate, vinrocidine sulfate, vinzolidine sulfate, vorozole, zeniplatin, zinostatin, zorubicin hydrochloride, agents that arrest cells in the G2-M phase and / or agents that modulate the formation or stability of microtubules (e.g., Taxol® (i.e., paclitaxel), Taxotere®, compounds containing a taxane skeleton, elbrozole (i.e., R-55104), dolastatin 10 (i.e., DLS-10 and NSC-376128), mibobulin isethionate (i.e., as CI-980), vincristine, NSC-639829, discodermolide (i.e., as NVP-XX-A-296), ABT-751 (A bbott, i.e., E-7010), Altorhyrtins (e.g., Altrirthin A and Altrirthin C), Spongestants (e.g., Spongestant 1, Spongestant 2, Spongestant 3, Spongestant 4, Spongestant 5, Spongestant 6, Spongestant 7, Spongestant 8, and Spongestant 9), Cemadotin Hydrochloride (e.g., LU-103793 and NSC-D-669356), Epothilones (e.g., Epothilone A, Epothilone B, Epothilone C (i.e., Desoxyepothilone A or dEpoA), Epothilone D (i.e., KOS-862, dEpoB, and Desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide, epothilone A N-oxide, 16-aza-epithilone B, 21-aminoepothilone B (i.e., BMS-310705), 21-hydroxyepothilone D (i.e., desoxyepothilone F and dEpoF), 26-fluoroepothilone, auristatin PE (i.e., NSC-654663), soblidotin (i.e., TZT-1027), vincristine sulfate, cryptophycin 52 (i.e., LY-355703), bitilebamide, tublysin A, canadensol, centaureydin (i.e., NSC-106969), oncocidin A (i.e., BTO-956 and DFE), physidianolide B, lorimalide, narcosine (also known as NSC-5366), nascapine, hemiasterin, vanadocene acetylacetonate, Monsatrol, inanocine (i.e., NSC-698666), eleutherobins (desmethyleutherobin, desaethyleutherobin, isoeutherobin A, Z-eutherobin, etc.), carybeoside, carybeolin, halichondrin B, diazonamide A, taccalonolide A, diozostatin, (-)-phenylahistin (i.e., NSCL-96F03 7), myoseverin B, resberastatin sodium phosphate, steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as goserelin or leuprolide, adrenocortical hormones (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinylestradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), immunostimulants (e.g., bacille-calmette-guerin (BCG), levamisole, interleukin-2, α-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-FLER2, anti-CD52, anti-ULA-DR, anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., anti-CD20 monoclonal antibody conjugate with Ulln, 90Y, or mI, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin , irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR) targeted therapy or treatment (e.g., gefitinib (Iressa®), erlotinib (Tarceva®), cetuximab (Erbitux®), lapatinib (Tykerb®), panitumumab (Vectibix®), vandetanib (Caprelsa®), afatinib / BIBW2992, CI-1033 / canertinib, neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib / PF299804, OSI-420 / desmethylerlotinib, AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, and hormonal therapy Examples include agents.

[0017] "including," "containing," or "characterized by" The transitional phrase "comprising," which is synonymous with "comprising," is inclusive or open-ended and does not exclude additional, unrecited features, integers, steps, operations, elements, and / or components. In contrast, the transitional phrase "consisting of" includes all of the specified features, integers, steps, operations, elements, and / or components. The transitional phrase "consisting essentially of" limits the scope of a claim to the specified features, integers, steps, operations, elements, and / or components and those "that do not materially affect the basic and novel characteristic(s)" of the claimed invention.

[0018] As used herein, the term "about" in the context of a numerical value or range means ±10% of the stated or claimed numerical value or range, unless the context requires a more specific range.

[0019] The term "ambient temperature" refers to the temperature at which a formulation of the present disclosure is administered to a subject. Generally, ambient temperature is the temperature of a temperature-controlled environment. Ambient temperature ranges from about 18°C ​​to about 30°C. In certain embodiments, ambient temperature is about 18°C, about 19°C, about 20°C, about 21°C, about 22°C, about 23°C, about 24°C, about 25°C, about 26°C, about 27°C, about 28°C, about 29°C, or about 30°C.

[0020] A "pharmaceutical fluid formulation" is a pharmaceutical composition that is liquid at the time it is delivered (i.e., administered) to a patient. In certain embodiments, a pharmaceutical fluid formulation includes an active agent, such as a compound, cells, or cell product, and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutically acceptable carrier is a temperature-sensitive biomaterial.

[0021] The devices, systems, and methods provided herein are generally useful for delivering pharmaceutical fluid formulations to a tissue site, such as an organ (e.g., a solid organ). In certain embodiments, the tissue site is a tumor (e.g., a solid or hard tumor). In certain embodiments, the tissue site is an organ containing cancer cells or a tumor. In certain embodiments, the tissue site contains tumor cells. In certain embodiments, the tissue site is a lymph node containing tumor cells. However, in certain embodiments, the present subject matter is particularly useful for delivering bioactive renal cells (such as bioactive renal cells, e.g., selected renal cells) to the kidney of a patient with kidney disease.

[0022] As used herein, the term "bioactive renal cells" or "BRCs" refers to renal cells that, when administered to a subject's kidney, have one or more of the following properties: the ability to reduce (e.g., slow or stop) the deterioration or progression of chronic kidney disease or its symptoms; the ability to enhance renal function; the ability to affect (improve) renal homeostasis; the ability to promote healing, repair, and / or regeneration of renal tissue or the kidney. In certain embodiments, these cells include functional tubular cells (e.g., due to improved creatinine excretion and protein retention), glomerular cells (e.g., due to improved protein retention), vascular cells, and cells of the corticomedullary junction, among others. In certain embodiments, the BRCs are obtained by isolating and expanding renal cells from kidney tissue. In certain embodiments, the BRCs are obtained by isolating and expanding renal cells from kidney tissue using a method for selecting bioactive cells. In certain embodiments, the BRCs have a regenerative effect on the kidney. In certain embodiments, the BRCs comprise, consist essentially of, or consist of selected renal cells (SRCs). In certain embodiments, the BRCs are SRCs.

[0023] In certain embodiments, SRCs are cells obtained by isolating and expanding renal cells from a suitable renal tissue source, and the SRCs are enriched in one or more cell types and lack or are deficient in one or more other cell types compared to the starting renal cell population. In certain embodiments, the SRCs comprise an increased proportion of BRCs compared to the starting renal cell population. In certain embodiments, the SRC population is an isolated renal cell population enriched in certain bioactive components and / or cell types and / or depleted in certain inactive and / or undesirable components or cell types for use in the treatment of kidney disease, i.e., to stabilize and / or improve and / or regenerate kidney function. SRCs provide superior therapeutic and regenerative outcomes compared to the starting population. In certain embodiments, the SRCs are obtained from a patient's renal cortical tissue via kidney biopsy. In certain embodiments, the SRCs are selected based on the expression of one or more markers (e.g., by fluorescence-activated cell sorting, or "FACS"). In certain embodiments, SRCs are depleted of one or more cell types (e.g., by fluorescence-activated cell sorting or "FACS") based on the expression of one or more markers for the cell type. In certain embodiments, SRCs are selected from a population of bioactive renal cells. In certain embodiments, SRCs are selected by density gradient separation of expanded renal cells. In certain embodiments, SRCs are selected by separation of expanded renal cells by centrifugation across a density boundary, density barrier, or density interface, or by single step discontinuous step gradient separation. In certain embodiments, SRCs are selected by continuous or discontinuous density gradient separation of expanded renal cells cultured under hypoxic conditions. In certain embodiments, SRCs are selected by density gradient separation of expanded renal cells cultured under hypoxic conditions for at least about 8 hours, 12 hours, 16 hours, 20 hours, or 24 hours.In certain embodiments, SRCs are selected by centrifugal separation across a density boundary, density barrier, or density interface of expanded renal cells cultured under hypoxic conditions. In certain embodiments, SRCs are selected by centrifuging expanded renal cells cultured under hypoxic conditions for at least about 8 hours, 12 hours, 16 hours, 20 hours, or 24 hours across a density boundary, density barrier, or density interface (e.g., single-stage discontinuous density gradient separation). In certain embodiments, SRCs are primarily composed of renal tubular cells. In certain embodiments, other parenchymal (e.g., vascular) and interstitial (e.g., collecting duct) cells can be present in SRCs. In certain embodiments, less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the cells in a population of SRCs are vascular cells. In certain embodiments, less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the cells in a population of SRCs are collecting duct cells. In certain embodiments, less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the cells in a population of SRCs are vascular cells or collecting duct cells.

[0024] The term "Neo Kidney Augment (NKA)" refers to an injectable bioactive cell preparation consisting of autologous selected kidney cells (SRCs) encapsulated in a biomaterial composed of a gelatin-based hydrogel.

[0025] As used herein, the term "kidney disease" refers to the kidneys that filter blood and remove excess fluid from the blood. It refers to disorders associated with any stage or degree of acute or chronic renal failure resulting from the loss of the kidney's ability to remove electrolytes and waste products. Kidney disease can also include endocrine dysfunction, such as anemia (erythropoietin deficiency) and mineral imbalance (vitamin D deficiency). Kidney disease can originate in the kidney or be secondary to a variety of diseases, including, but not limited to, heart failure, hypertension, diabetes, autoimmune disease, or liver disease. Kidney disease can also be a state of chronic renal failure that develops after acute kidney injury. For example, kidney damage due to ischemia and / or exposure to toxic substances can cause acute renal failure. Incomplete recovery after acute kidney failure can lead to the development of chronic kidney failure.

[0026] The term "spheroid" refers to an aggregate or collection of cells cultured to allow three-dimensional growth, as opposed to monolayer growth. Note that the term "spheroid" does not imply that the aggregate is a geometric sphere. In certain embodiments, the aggregate may be highly organized as a well-defined shape, or the aggregate may be an unorganized mass. In certain embodiments, the spheroid may comprise a single cell type or two or more cell types. In certain embodiments, the cells may be primary isolates, permanent cell lines, or a combination of the two. In certain embodiments, the spheroids (e.g., cell aggregates or organoids) are formed in a spinner flask. In certain embodiments, the spheroids (e.g., cell aggregates or organoids) are formed in a three-dimensional matrix.

[0027] With respect to kidney disease, depending on the context, "treatment" refers to both treatment and prophylactic measures for kidney disease, renal tubular transport disorders, or glomerular filtration disorders, with the goal of reversing, preventing, or slowing (alleviating) the targeted disorder or symptoms. Those in need of treatment include those who already have kidney disease, renal tubular transport disorders, or glomerular filtration disorders, as well as those prone to kidney disease, renal tubular transport disorders, or glomerular filtration disorders, or those seeking to prevent kidney disease, renal tubular transport disorders, or glomerular filtration disorders. In certain embodiments, treatment includes stabilizing and / or improving renal function. With respect to cancer, treatment can include, for example, reducing tumor volume, reducing tumor growth rate, increasing immune responses to tumor antigens, reducing cancer cell growth, reducing cancer cell proliferation, or reducing cancer cell survival (e.g., increasing tumor cell death, such as apoptosis or necrosis).

[0028] Administration of therapeutic drugs Extravascular delivery can involve injecting a medicinal fluid formulation (e.g., a medicinal fluid formulation containing therapeutic cells) directly into an organ, such as the interstitium of an organ, via one or more devices, such as a syringe, catheter, trocar, etc. "Extravascular injection" means delivery by injection outside of a blood vessel. Extravascular delivery can provide a longer residence time for the therapeutic cells. For example, a clearing or flushing process can be relied upon to remove local trauma and edema at the delivery site. Delivery efficiency can also be high. However, successful delivery of therapeutic cells or their products can be difficult. For example, extravasation of therapeutic cell material through the inlet holes of the delivery device can be a problem caused by a variety of different issues. Extravasation can be considered the leakage (especially unintentional leakage) of fluid from the target injection site. Natural movement of the delivery target, for example, due to patient movement (and therefore movement of the target site), such as breathing, can cause instability of the delivery target. Trauma to the treatment site from impacts and cuts by the delivery instrument caused by movement during administration can also cause inaccurate delivery of therapeutic cellular material. Additionally, delivery can be difficult due to how the therapeutic cells or their products are injected, such as by a continuous flow of administration to the target site.

[0029] For these and other reasons, there is a need for improved devices, methods, and systems for delivering pharmaceutical fluid formulations (such as cellular therapeutics). Provided herein are improved devices, methods, and systems for delivering therapeutic compositions, such as compositions containing compounds, cells, or cell products, among others.

[0030] In one aspect, the present disclosure includes devices, methods, and systems for extravascular delivery of cellular therapeutic agents to a target location within a patient while maintaining positional stability, e.g., using metered injection capabilities. The use of cellular therapeutic agents is a very common and successful method for treating a variety of different diseases. For example, extravascular delivery of cellular therapeutic agents has been successful in increasing the residence time of therapeutic cellular materials at the treatment site and improving delivery efficiency. However, extravascular delivery presents challenges, such as patient movement (and thus movement of the target site), trauma to the treatment site due to impacts and cuts by the delivery device caused by patient movement, and extravasation of therapeutic cellular materials caused by continuous administration flow of therapeutic cellular materials to the treatment site. Therefore, provided are devices, methods, and systems configured to stabilize delivery of therapeutic agents (cellular materials, e.g., cells or their products, such as exosomes) by, e.g., providing a physically stable delivery process and a discontinuous administration flow of therapeutic cellular materials.

[0031] In one aspect, included herein are devices, methods, and systems for extravascular delivery of medicinal fluid formulations (e.g., cellular therapeutics) to a target location within a patient while maintaining positional stability, for example, using metered injection capabilities. The devices, systems, and methods provided herein can be used to treat a variety of different diseases, including, but not limited to, kidney disease and cancer.

[0032] In certain embodiments, the infusion devices provided herein are configured to deliver a continuous flow of fluid to a target site. In certain embodiments, the infusion devices provided herein are configured to deliver a discontinuous flow or bolus of fluid to a target site. Exemplary devices provided herein can be configured to deliver a discontinuous flow or bolus of fluid, such as a pharmaceutical fluid formulation containing cells or cell products, to a target site. A bolus can be considered a single physical portion of a pharmaceutical composition (such as a pharmaceutical fluid formulation). In certain embodiments, a bolus is a portion of a pharmaceutical composition (such as a pharmaceutical fluid formulation) that is delivered as a single event. In certain embodiments, a bolus is a portion of a pharmaceutical composition (such as a pharmaceutical fluid formulation) that is delivered as part of multiple portions (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more portions) delivered one after the other during administration of the pharmaceutical composition. In certain embodiments, a single bolus is delivered. In certain embodiments, no pharmaceutical composition is delivered between multiple discrete boluses. In certain embodiments, there is a continuous flow of the pharmaceutical composition. In certain embodiments, the delivery is continuous, but the amount of pharmaceutical composition is pulsed (i.e., the flow does not stop, but increases and decreases over time). In certain embodiments, the devices provided herein are configured for one-handed operation. In certain embodiments, the present injection devices can be engaged with exemplary trocars configured with one or more stabilizing features on the shaft, such that the trocar provides a stable delivery mechanism for the injection device. In certain embodiments, the trocar is configured to receive a needle attached to the injection device therein, and the injection device can deliver a dose to the target tissue site as a continuous flow of fluid through the needle. In certain embodiments, the trocar is configured to receive a needle attached to the injection device therein, and the injection device can deliver fluid to the target tissue site through the needle in bolus doses.In certain embodiments, the devices, systems, and methods provided herein administer therapeutic cells or cell products to multiple extravascular infusion sites within the renal parenchymal / interstitial compartment of a patient. The present disclosure describes kidney treatments, but the devices, systems, and methods can be used in a variety of treatments, such as administering therapeutic cells or cell products to a tissue site containing cancerous cells, such as a solid tumor, by directly delivering a fluid containing the therapeutic cells or cell products to the kidney (e.g., in a patient with kidney disease, such as chronic kidney disease). In certain embodiments, the patient is positioned in a prone or lateral decubitus position, as shown in FIGS. 1 and 2 . "Parenchyma" refers to the functional tissue of an organ, as distinguished from connective and supportive tissue. "Stroma" refers to the supportive tissue, such as epithelial organs, tumors, and gonads, consisting of connective tissue and blood vessels. In certain embodiments, the subject has late-stage failure. However, while this disclosure describes kidney treatments, the devices, systems, and methods can be used broadly. In certain embodiments, the devices, systems, and methods provided herein can be used in a variety of treatments, such as administering therapeutic cells or cell products to a tissue site containing cancerous cells, such as a solid tumor. In certain embodiments, the tissue site is an organ containing or suspected of containing cancerous cells (e.g., metastatic cancer cells or tumors).

[0033] In certain embodiments, the devices, systems, and methods provided herein are useful for percutaneously injecting a pharmaceutical fluid formulation into an organ containing cancer cells or solid tumors and / or directly into the tumor. In certain embodiments, it is important to distribute the formulation as widely as possible within the organ. In certain embodiments, distribution of the formulation within the organ or tumor is achieved by entering the organ or tumor at an angle that allows for as wide a deposition of the formulation as possible within the organ or tumor. In certain embodiments, the organ or tumor is imaged in a longitudinal or transverse approach using ultrasound guidance or axial computed tomography (CT) imaging, depending on the characteristics of the individual patient. In certain embodiments, the injection includes multiple depositions as the needle is gradually withdrawn. In certain embodiments, the entire amount of the formulation can be deposited at a single or multiple entry points. In certain embodiments, up to two entry points can be used to deposit the entire amount of the therapeutic formulation into the organ or tumor.

[0034] In certain embodiments, the devices, systems, and methods provided herein are useful for percutaneously injecting a pharmaceutical fluid formulation into the renal cortex of the kidney. In certain embodiments, it is important to distribute the formulation as widely as possible throughout the renal cortex. In certain embodiments, distributing the formulation throughout the renal cortex is achieved by entering the renal cortex at an angle that allows for as wide a deposition of the formulation as possible throughout the renal cortex. In certain embodiments, the kidney is imaged in a longitudinal or transverse approach using ultrasound guidance or axial CT imaging, depending on the characteristics of the individual patient. In certain embodiments, the injection includes multiple depositions as the needle is gradually withdrawn. In certain embodiments, the entire amount of the formulation can be deposited at a single or multiple entry points. In certain embodiments, up to two entry points can be used to deposit the entire amount of the therapeutic formulation into the kidney. In certain embodiments, the injection can be administered into a single kidney using more than one entry point, for example, one or two entry points. In certain embodiments, the injection is into both kidneys, using more than one entry point in each kidney, for example, one or two entry points.

[0035] The devices and systems provided herein offer advantages over commercially available devices. Figures 3 and 4 outline a process for administering cell therapy to a patient's kidney using commercially available components. For example, commercially available components such as needles, trocars / sleeves, luer fittings, stopcocks, tubing, 3 cc syringes, and 10 cc syringes can be stocked at the location where the therapeutic cell material is processed. A range of needle and trocar / sleeve sizes can be provided, and kits containing the above items can be prepared. Needle gauge sizes can be available in lengths of 10 cm, 15 cm, and 20 cm. Pre-filled 10 cc syringes can be packaged and used to aseptically fill the cell therapy. The filled syringes can be stored at approximately 4°C to 8°C during shipping. The cellular therapy can be transported separately to the treatment site in a temperature-controlled package that maintains the temperature at 26°C. At the treatment site, protocols can be implemented to warm the syringe, assemble the injection system, and organize and prepare the equipment for the user. For example, the syringe can be warmed to approximately 26°C-28°C over a controlled period of time, such as approximately 30 minutes. The user can then begin treatment within the allotted time for product viability (which may be approximately 1.5 hours). Figure 4 illustrates a non-limiting injection system, as described above, in which a 3cc syringe is connected to a 10cc syringe via a three-way stopcock. The output from the stopcock is routed via tubing to a Luer connection on the injection needle within a trocar / sleeve attached to the patient. The cellular therapy can be first transferred through the 10cc plunger into the 3cc syringe, and then injected into the patient's kidney, with the smaller syringe controlling and facilitating plunger movement. Injecting a cellular therapy can be a challenging task, requiring at least two hands of the lead user, and often a second hand as an assistant, to operate the plunger while stabilizing the trocar, needle, and injection system. The devices and systems included herein offer advantages over the processes and components shown in Figures 3 and 4, including increased stability (and reduced damage) during delivery of the therapeutic agent, and more consistent delivery (e.g., amount and location) of the therapeutic agent.

[0036] FIG. 5 illustrates one non-limiting embodiment of a trocar 20 that can be used herein. By way of non-limiting example, in its simplest form, a trocar can be a generally pen-shaped instrument with at least a somewhat sharp triangular point on one end, often used inside a hollow tube known as a cannula or sleeve to create an opening into the body through which a sleeve can be passed to provide an access port during surgery. In certain embodiments, the trocar is a two-part pen-shaped instrument with a solid obturator / stylet with a sharp triangular point on one end inside a hollow tube known as a cannula or sleeve (e.g., the trocar is used to create an opening into the body, and the stylet can be removed, leaving the sleeve behind, to provide an access port to an internal structure). The trocar 20 illustrated in FIG. 5 can have a handle 22, an elongated shaft 24, a shield 26, and a shield release 28. It can have a lumen extending therethrough. FIG. 6 illustrates one non-limiting example of a cannula 30 that can be used herein. The cannula 30 has a handle 32 and a sleeve 34 and may have a lumen extending therethrough. When a trocar, such as trocar 20, is placed in a patient, fixation of the trocar is achieved primarily in two locations. Frictional grip of the trocar occurs at the skin penetration point, and a similar, weaker interaction occurs on the trocar with internal tissue, such as the kidney capsule. Due to the shallow penetration depth of the trocar, frictional grip in internal tissue is relatively weak. However, stabilizing the trocar's penetration depth into tissue, such as the kidney, during a procedure can be beneficial to avoid tissue trauma and aid in smoother injection of therapeutic cellular material, which can result in adverse migration of the dermal anchor point relative to the internal tissue anchor point, such as the kidney.

[0037] injection device FIG. 7 illustrates one non-limiting example of an injection device 100 that can be configured for one-handed operation using a detachable trocar 200 having a stylet 300 therein and extending distally from the device 100 along a longitudinal axis L1 of the device 100. The injection device 100 includes a housing 101, a handle 102, an actuator 104, a fluid receiving portion 106, a display 108, and a trocar engagement mechanism 110. In certain embodiments, the display 108 is omitted. In certain embodiments, the device 100 includes a pump (not shown), one or more sensors (not shown) configured to detect various conditions such as pressure, flow rate, temperature, etc., a power source (not shown), such as a battery, and / or a central processing unit (CPU) (not shown). In FIG. 7, the handle 10 2 extends from the housing 101 and is in the shape of a pistol grip, however, a variety of handles, grips, controls, etc. can be used.

[0038] The actuator 104 is a trigger configured to actuate the delivery of fluid from the fluid receiving portion 106 through a valve 120 at the distal end of the injection device 100, which is described in more detail below. While the actuator 104 is shown as a trigger, the actuator can have a variety of forms, such as a plunger, a button, a switch, electronic actuation, a means activated by a CPU, or integrated into the display 108. The actuator 104 is configured to be manually depressed toward the handle 102. In certain embodiments, the actuator 104 can be configured to provide tactile feedback to the user when the actuator 104 is depressed. In certain embodiments, the tactile feedback can be physically generated from manually depressing the actuator 104 or can be simulated. For example, the device 100 can incorporate one or more tactile feedback mechanisms configured to simulate the mechanical action of an actuator 104 that is electromechanical in nature and controlled by a CPU. In certain embodiments, depression of the actuator 104 is configured to deliver fluid from the fluid receiving portion 106 through the valve 120 in a pulsed delivery pattern that includes delivering discrete boluses 122 of fluid to the target site, as shown in FIG. 8, and to retract the injection needle from the target site during fluid delivery to allow expanded space for the delivered fluid. In certain embodiments, the discrete boluses 122 of fluid can be configured to avoid direct contact with each other, thereby preventing or reducing extravasation from the target tissue site. In certain embodiments, the device can alternatively be configured to deliver a continuous stream 123 of fluid, as shown in FIG. 9, and / or a combination of the two. In certain embodiments, the pulsed delivery pattern and needle retraction can be achieved by an electromechanical system having a pump mechanism within the device 100, which can be achieved by the pump and CPU.However, the pump and retraction mechanism may be mechanical in nature, or the entire device 100 may be purely mechanical. In certain embodiments, fluid may be drawn from a fluid reservoir engaged with the fluid receiver 106.

[0039] In certain embodiments, the fluid receiving portion 106 is located on the top surface of the device 100, as shown in FIG. 7. However, the fluid receiving portion 106 can be incorporated anywhere on the device 100. In certain embodiments, the fluid receiving portion 106 is configured to receive fluid from a fluid reservoir, such as a cartridge 130 or syringe, as shown in FIG. 10, and is configured to deliver fluid to the valve 120 upon actuation of the actuator 104. In certain embodiments, the fluid receiving portion 106 is configured to at least partially receive the cartridge 130 and pierce the cartridge 130 using an aseptic septum-piercing element therein. However, the fluid receiving portion 106 can alternatively be configured to fully receive one or more cartridges 130 and connect to one or more fluid lines, etc. Alternatively, the fluid receiving portion 106 can have one or more valves, connectors, engagement portions, etc. for connecting to a fluid reservoir(s). In certain embodiments, the fluid receiving portion 106 can also have a temperature control integrated into the housing 101 for controlling the temperature of the cartridge 130. In certain embodiments, the cartridge 130 contains a hydrogel (e.g., a gelatin-based hydrogel) that is heated until it melts and becomes a liquid. In certain embodiments, a therapeutic agent (e.g., a cell population or a cellular product such as exosomes) is dispersed (e.g., uniformly) throughout the hydrogel and / or fluid.

[0040] A fluid reservoir, such as cartridge 130, is configured to deliver one or more fluids to a target site through device 100 upon actuation of actuator 104. The cartridge 130 shown in FIG. 10 is a glass vial cartridge with a rubber diaphragm interface configured to deliver fluid when pierced by a sterile septum-piercing element in fluid receiving portion 106. In certain embodiments, the cartridge has material properties that account for the viscosity of a therapeutic agent (e.g., a cellular therapy agent) and thus prevent the therapeutic agent from adhering to the interior walls of the cartridge and being lost. In certain embodiments, cartridge 130 can be assembled with device 100 in a sterile environment, and a suction path into the cartridge that connects to a fluid path through device 100 can be configured to prevent fluid loss due to access in various orientations of cartridge 130, such as when cartridge 130 is inverted. Additionally, cartridge 130 can be configured to be securely held by device 100 within fluid receiving portion 106. In certain embodiments, the fluid reservoirs can be made from a variety of materials, such as polymers, rubbers, etc., and can have a variety of forms, such as pouches, fluid lines, containers, etc., that can be connected to the fluid reservoir 106 in a variety of ways, such as via ports, valves, etc. The cartridge 130 can be configured to be removable and replaceable, for example, after delivering the fluid therein. In certain embodiments, the cartridge 130 can be provided in preselected doses and / or configurations, allowing a user to use multiple cartridges 130 during a single treatment depending on the desired treatment. Alternatively, the device 100 can have a built-in fluid reservoir intended for single use. In certain embodiments, the device 100 can also have one or more mechanisms for setting a customized dose from the cartridge 130, such as through the use of the display 108 (described below). In certain embodiments, the cartridge 130 can have one or more computer chips that interface with the device 100 upon insertion and provide details regarding the contents of the cartridge 130, recommended dose, flow rate, timing, etc. The computer chips can interface with the CPU of the device 100 through one or more means, such as via a wired connection disposed in the fluid receiving portion 106 and / or wirelessly.

[0041] In certain embodiments, cartridge 130 can be configured to couple with device 100 to minimize dead volume upon connection, and cartridge 130 can be configured to be sterile filled with fluid at a manufacturing site as needed for the cellular therapy and transported to an operating room while maintaining a transport temperature of about 0°C to about 20°C, more specifically about 2°C to about 8°C, or about 4°C to about 8°C. In certain embodiments, device 100 can be configured to receive cartridge 130, which may have a reduced transport temperature, as detailed above, warm cartridge 130 to a temperature for delivery to a patient within a selectable time period, and maintain cartridge 130 at an acceptable temperature for use for another selectable time period and / or until cartridge 130 is used. For example, device 100 can be configured to accept cartridge 130 whose contents are at a transport temperature, such as about 4°C to about 8°C. The device 100 can then warm the cartridge 130 to a temperature for use on a patient, such as about 20°C to about 40°C, more specifically about 25°C to about 37°C, within a certain time period, such as within 15 minutes, 30 minutes, or 45 minutes. The device 100 can then be configured to maintain the temperature of the cartridge 130 substantially constant until the cartridge 130 is used or for a certain period of time, such as about 1.5 hours. In some non-limiting examples, the device 100 can be configured to notify the user if the cartridge 130 is heated incorrectly and / or if the cartridge 130 is not used within the allotted time frame for sample viability. In certain embodiments, the device 100 can prevent the user from using the cartridge 130, such as by preventing operation of the device 100, if the device 100 determines that the sample viability is unacceptable. The device 100 can also be configured to notify the user if the cartridge 130 is heated incorrectly and / or if the cartridge 130 is not used within the allotted time frame for sample viability. In certain embodiments, the device 100 can prevent the user from using the cartridge 130, such as by preventing operation of the device 100, if the device 100 determines that the sample viability is unacceptable. The volume can vary depending on the desired treatment. For example, volumes used for cell therapy can range from about 1 ml to about 15 ml, more specifically from about 3 ml to about 8 ml. For use in renal therapy, the volume of the cartridge 130 used can depend on the mass of the patient's kidney. Table 1 shows exemplary dosages that can optionally be used herein when treating the kidney.

[0042] [Table 1]

[0043] Pharmaceutical fluid formulations can include various therapeutic treatments, such as therapeutic cells and / or their products, such as exosomes, suspended in a liquid. For example, for renal applications, a fluid containing therapeutic cells and a support hydrogel, e.g., having a viscosity of approximately 1.05 cP to 1.35 cP, can be utilized. Fluid viscosity can pose additional considerations when using components disclosed herein, such as needles and syringes with barrels and plungers. For example, initiating flow from a component such as a needle requires applying a greater force to the syringe plunger than is required to maintain flow once it has begun. Furthermore, the initial extrusion of fluid, such as therapeutic cells and a support hydrogel, from the needle can be so severe that the syringe plunger cannot be manually controlled. Once flow has begun, removing the plunger force may not stop the fluid flow. Hysteresis may exist in the pressure buildup within the syringe barrel, and the fluid can only be stopped by pulling back on the plunger. For this reason, users may pulse the plunger during use to maintain better control of the flow from the needle.

[0044] In certain embodiments, the viscosity of the therapeutic agent (such as a cellular therapy agent, e.g., a pharmaceutical fluid formulation containing cells) may tend to result in a situation where some of the therapeutic agent is lost, i.e., the therapeutic agent (e.g., a portion thereof) adheres to the inside of the cartridge and cannot be removed through normal processes of the device. In certain embodiments, the inner surface of the cartridge is hydrophobic. In certain embodiments, the inner surface of the cartridge is superhydrophobic. In certain embodiments, the inner surface of the cartridge is hydrophobic or superhydrophobic to reduce wetting and adhesion of the therapeutic agent (e.g., cellular therapy agent) to the cartridge. In certain embodiments, the inner surface of the cartridge is hydrophobic or superhydrophobic to reduce wetting and adhesion of the therapeutic agent (e.g., cellular therapy agent) to the cartridge. To prevent adhesion, the inner surface of the cartridge is hydrophobic or superhydrophobic.

[0045] Various fluids may be used herein, such as those described in U.S. Patent No. 8,318,484, issued November 27, 2012, PCT Publication No. WO 2011 / 143499, published November 17, 2011, U.S. Patent No. 9,724,367, issued August 8, 2017, U.S. Patent Application Publication No. 2017 / 0281684, published October 5, 2017, and U.S. Patent Application Publication No. 2016 / 0101133, published April 14, 2016, all of which are incorporated herein by reference in their entirety. Thus, fluid receiver 106 is configured to fluidly connect cartridge 130 with valve 120 so that fluid can be delivered through valve 120.

[0046] In the exemplary device shown in FIG. 7 , valve 120 is located within device 100 at the distal end where trocar 200 connects to device 100. In certain embodiments, valve 120 is a luer hub configured to connect to an injection needle so that fluid can be delivered therethrough. However, various valves configured to connect to an injection needle can be used. In certain embodiments, valve 120 engages housing 101 of device 100 via a flexible attachment configured for distal and proximal longitudinal translation along axis L1 of device 100, which is generally parallel to the fluid flow path through the injection needle. In certain embodiments, valve 120 can translate distally and proximally up to about 5 cm (e.g., up to about 1 cm, 2 cm, 3 cm, 4 cm, or 5 cm), more specifically up to about 2 cm. The valve 120 is therefore configured to translate distally and proximally upon actuation of the device 100 to expel fluid therethrough, allowing for more stable delivery of fluid to the target delivery site and for the proximal retraction of the injection needle from the target site during fluid delivery.

[0047] In certain embodiments, a display 108, such as an I / O touchscreen, is located at the proximal end of the device 100, as shown in FIG. 7 . In certain embodiments, the display 108 is configured to interact with the CPU to allow a user to control various functions and features of the device 100. For example, the display 108 may allow a user to set injection parameters, prime the needle, monitor various pressure levels and delivered fluids, release interlocks between components, provide real-time administration information, etc. In one example, the display 108 is a touchscreen with multiple input controls displayed on it. However, the display 108 may alternatively and / or additionally include one or more physical buttons, controls, switches, dials, gauges, toggles, etc. for controlling one or more of the functions of the device 100. The display 108 may also be located anywhere on the device 100, such as on the top or side of the device 100.

[0048] In certain embodiments of the device 100, the housing 101 may also include a stylet removal lumen 140 extending along the axis L1 and configured to allow removal of the stylet 300 therethrough following placement of the trocar 200 (described below). The lumen 140 may allow for manual removal of the stylet 300, e.g., the stylet 300 may be configured to extend proximally from the proximal end of the lumen 140 for manual grasping, or the lumen 140 may incorporate one or more mechanical and / or electrical mechanisms to provide for removal of the stylet 300, e.g., by using one or more gears, wheels, hooks, moving tracks, etc. In certain embodiments of the injection device, the needle penetration depth may be variably set on the device itself.

[0049] The device 100 can have various sizes as needed, for example, it can fit into a space about 300 mm wide by about 200 mm deep by about 100 mm high, and more specifically, it can fit into a space about 205 mm wide by about 105 mm deep by about 70 mm high. The device 100 can have various weights and / or masses as needed. In certain embodiments, the device 100 can have a mass less than about 2000 g, more specifically, a mass less than about 1400 g. The device 100 can be fabricated from various materials, such as metal, resin, or combinations of materials. The device 100 can be configured for single use or can be configured to be a reusable device that requires resterilization. In certain embodiments, the materials that contact the cells are configured to meet certain usage requirements, such as ISO 10993, to address issues such as the risk of leachables and compatibility with sterilization (over multiple cycles). For information related to ISO10993, see Use of International Standard ISO 10993-1, "Biological evaluation of medical "Devices - Part 1: Evaluation and testing within a risk management process," US Department of Health and Human Services Food and Drug Administration Center for Devices and Radiological Health (available at www.fda.gov / downloads / medicaldevices / deviceregulationandguidance / guidancedocuments / ucm348890.pdf) The Guidance for Industry and Food and Drug Administration Staff (Issue Date: June 16, 2016), the entire contents of which are incorporated herein by reference. Materials used in the device 100 can also comply with regulations for Class I / II devices, and the device 100 can optionally be lubricant-free to avoid affecting the viability of the therapeutic cellular material. A description of Class I / II devices is provided in the Medical Devices "Classify Your Medical Device" US Food & Drug Administration, updated March 27, 2018 (available at www.fda.gov / MedicalDevices / DeviceRegulationandGuidance / Overview / ClassifyYourDevice / ucm2005371.htm), the entire contents of which are incorporated herein by reference. In various embodiments, the device 100 can have an interlock to prevent accidental deployment of any loaded cartridge 130 or therapeutic cellular material. Additionally, in other non-limiting embodiments incorporating a dynamic injection system to assist in penetration of tissue, such as the kidney capsule, an interlock system can be used to prevent accidental triggering when the device is not in the proper position relative to the tissue. In some embodiments, device 100 can require a power source, which can be rechargeable. For example, the device can incorporate a charging interface, such as a USB interface. In certain embodiments, the button interface will likely need to comply with usability standards set forth in IEC 62366.See, for example, International Electrotechnical Commission (2014), "Application of usability engineering to medical devices, International IEC Standard 62366 edition 1.1 2014-01. International Electrotechnical Commission," the entire contents of which are incorporated herein by reference.

[0050] The device 100 can be coupled to the detachable trocar 200 via an engagement mechanism 110 which can include a variety of different friction fit openings, snaps, hooks, levers, and the like.

[0051] Trocar with stylet FIG. 11 illustrates one non-limiting example of a trocar (which may be detachable from the devices provided herein, for example). The trocar 200 is configured to be placed within a patient to provide access to an internal tissue site, such as an organ or tumor, including a kidney tumor. The trocar 200 of FIG. 11 has a flared head 202 and a hollow, elongated, cylindrical shaft 204 extending distally therefrom. The head 202 is configured to be removably and replaceably attached to the device 100 along axis L1 at the engagement mechanism 110. A lumen extends through the head 202 and the elongated shaft 204. The lumen is configured to receive instruments such as a stylet 300 and an injection needle therethrough. The elongate shaft 204 has a tapered distal end 206 and a stabilizing mechanism 220 at its distal end. The shaft 204 has a compression spring portion 208 and a solid portion 210. The compression spring portion 208 is configured to compress and expand with patient movement and interaction with the device 100. The spring portion 208 therefore allows for proximal and distal translational movement along the axis L1, allowing for more stationary interaction with tissue, smoother delivery of fluid to the target tissue site, and proximal needle retraction from the target site during fluid delivery. In certain embodiments, the spring portion 208 can allow for distal and proximal translation of up to about 5 cm (e.g., up to about 1 cm, 2 cm, 3 cm, 4 cm, or 5 cm), more specifically up to about 2 cm. The compression spring section 208 is shown at a mid-portion of the shaft 204. However, the compression spring section 208 may be located at various points along the shaft 204, such as before or further from the mid-point of the shaft 204. A solid section 210 is located at a distal portion of the shaft 204 and has a stabilizing feature 220 thereon.

[0052] The stabilizing mechanism 220 is configured to help stabilize the trocar 200 against an internal tissue site within a patient when the trocar 200 is positioned through an external tissue surface, such as the patient's dermis. Thus, the stabilizing mechanism 220 is configured to reversibly maintain the trocar 200 in a fixed position relative to tissue as instruments are passed through the trocar 200. For example, when the trocar 200 is used during a kidney procedure, the stabilizing mechanism 220 can be configured to reversibly fix the distal end 206 of the trocar 200 in position relative to the surface 250 of the kidney. The stabilizing mechanism 220 shown in FIGS. 11 and 12 includes three feet 222 on a shaft 223 that engage with the shaft 204 at hinge points 224. In certain embodiments, the feet 222 are radially symmetrically positioned around the shaft 204 and are configured to deploy at the target site to reversibly engage tissue. In certain embodiments, the feet 222 are configured to move from a stowed position on the shaft 204, e.g., during insertion of the trocar 200 into a patient, to an extended position, e.g., during stabilization of the trocar 200 during use, by rotating about the hinge point 224 away from the shaft 204 to an engaged position, as shown in FIG. 12 . In the stowed position, the feet 222 can be received within the receiving pocket 226 such that the feet 222 are flush with the outer surface of the shaft 204. The feet 222 can be configured to rotate between 90 and 180 degrees, e.g., approximately 100 degrees, away from the shaft 204 to engage tissue upon deployment.

[0053] Various rotation mechanisms can be incorporated into the shaft 204 to cause rotation of the foot 222, including gears, springs, electric motors, shafts, electrically heated nitinol posts, etc. For example, a small cam (not shown) can be incorporated into the shaft 204 near the hinge point 224 that can be configured to engage one or more features on the stylet 300 upon removal of the stylet 300, such that removal of the stylet 300 activates the cam, causing rotation of the foot 222. The stabilization mechanism 220 can generally include one or more deployment means that are activated upon removal of the stylet 300. In certain embodiments, the foot 222 can include one or more engagement means, such as, for example, biomimetic microhooks configured to reversibly engage tissue upon initial surface contact. The microhooks can have a variety of sizes, for example, on the scale of approximately 100 μm to 500 μm. In this way, the trocar 200 is secured in place without causing significant trauma until the user attempts to remove the trocar 200 and releases the feet 222. A variety of other engagement means are possible, such as biomimetic or other hooks, temporary adhesives, active suction, friction, spring force, mechanisms similar to the lamprey latching mechanism, etc. The engagement means may be sacrificial and / or biocompatible. The stabilizing mechanism 220 may be removable. Although three feet 222 are shown, multiple feet may be provided. Additionally, the stabilizing mechanism 220 may have various alternative and / or additional embodiments other than the feet 222. For example, the stabilizing mechanism may include a clamping mechanism, hooks, various adhesives and cohesives, suction, a friction fit, etc.

[0054] The trocar 200 may also have one or more additional or alternative engagement features to engage tissue and further stabilize the trocar 200 when placed in a patient, such as the entry point of the trocar 200 in the patient's dermis. For example, the illustrated trocar 200 is configured to be frictionally gripped by the patient's dermis when placed. However, additional engagement features are possible, such as a reversibly collapsible expander element 500 that may be incorporated into the shaft 602 of a trocar 600 similar to the trocar 200. In certain embodiments shown in FIGS. 13-15, the expander element 500 may operate similarly to a drywall anchor (e.g., an exemplary drywall anchor system shown in FIGS. 16A-16D, which schematically illustrate drilling a hole, driving an exemplary drywall anchor, expanding the anchor arms using a driver, and finally screwing a screw into place). The expander element 500 is configured to move between a deployed position, shown in FIG. 13 , in which the shaft 602 is inserted through the patient's dermis 620, and an expanded position, shown in FIGS. 14 and 15 . The expander element 500 has one or more legs 502 that are hinged or bendable at approximately a midpoint 504 along the legs 502 (shown in dashed lines in FIG. 13 ). In certain embodiments, one or more expander mechanisms can be incorporated into the shaft 602 that are configured to expand the legs 502 outward, for example, threading that is configured to retract a distal portion of the trocar 600 proximally after the trocar 600 is positioned within the dermis 620, such that the legs 502 expand outward (as indicated by the arrows in FIG. 13 ) and secure against the inner surface of the dermis 620 (as shown in FIGS. 14 and 15 ). ) The expansion element 500 is configured to be returned to the deployed position by the user when the user wishes to remove the trocar 600 from the patient.

[0055] Thus, the exemplary trocar 200 is configured to be stabilized and / or anchored using one or more of the mechanisms described above at two points when the trocar 200 is placed within a patient: at the surface of the internal target tissue (e.g., an organ such as the kidney or a solid tumor) and at an entry point through the tissue into the patient (e.g., within the dermis). The stabilization of the trocar 200 is configured to allow a consistent penetration depth into the tissue during deployment, thereby preventing or reducing tissue damage and reducing the loss of excess therapeutic cells or cell products during injection from a displaced instrument caused by tissue displacement and patient movement (e.g., natural organ movement and patient breathing). In certain embodiments, one or more surface features, such as protrusions, grooves, holes, markings, or the like, can be added to the distal outer surface of the shaft 204 of the trocar 200, configured to better visualize the position of the trocar 200, such as under ultrasound, and thus provide more accurate placement within the patient. For illustrative purposes, the non-limiting embodiment of an ultrasound biopsy needle in FIG. 17 shows an exemplary echogenic surface feature 272. Echogenicity can be considered to mean having the property of being visible under ultrasound imaging. As a non-limiting example, the illustrated needle is a Cook Medical EchoTip®. The trocar 200 can optionally be used with a desired cannula or trocar sleeve, such as a trocar sleeve measuring at least about 20 g, and can be sized and shaped to penetrate the patient to various depths, such as about 3 mm to 5 mm, within an internal target tissue site, such as the patient's kidney. The trocar 200 can have various lengths, such as about 5 cm to 25 cm, more specifically about 10 cm to 20 cm, and even more specifically about 15 cm to 20 cm. The spring portion 208 can have various lengths, such as about 5 cm to 10 cm.

[0056] The stylet 300 is configured to be received within the lumen of the trocar 200 along axis L1 during advancement and placement of the trocar 200 within a patient. The stylet 300 has an elongate stylet shaft 302 having a distal tip 304. The shaft 302 is sized and shaped to be received within the trocar 200 and extend both distally and proximally from the trocar 200. For example, the distal tip 304 can be configured to extend distally from the tapered distal end 206 of the trocar 200 so that the distal tip 304 can penetrate tissue, and the proximal end of the stylet 300 can extend proximally from the trocar 200 to remove the stylet 300. The exemplary distal tip 304 has a blunt conical shape as shown in FIG. 18A , although various other shapes can be used, such as a pyramidal shape as shown in FIG. 18B , a pointed conical shape as shown in FIG. 18C , and a blunt shape as shown in FIG. 18D . While various tips can be used, in certain embodiments, a blunt conical tip is configured to minimize trauma during initial insertion of the trocar 200 with the stylet 300 into a target tissue site, such as a kidney, and therefore can be effectively used in renal tissue. The stylet 300 can be configured to be removed after the trocar 200 is placed within the patient. The stylet 300 can be configured to be manually removed directly from the trocar 200 when the device 100 is not engaged with the trocar 200, or it can be configured to be removed from the trocar 200 via the optional removal lumen 140 of the device 100 manually, mechanically, electrically, or some combination, as described above. In certain embodiments, the stylet 300 can have one or more features configured to actuate the deployment of the stabilizing mechanism 220 of the trocar 200 when the stylet 300 is removed from the trocar 200 .For example, the stylet 300 can have one or more gear-tooth features disposed toward the distal tip 304 that are configured to activate a cam in the trocar 200 to cause rotation of the foot 222. do.

[0057] Thus, in a non-limiting example, the trocar 200 (with or without a sleeve) can be configured to penetrate the patient's skin by the action of the stylet 300. An exemplary target penetration depth of the trocar 200 and / or sleeve into tissue, such as an organ (e.g., a kidney), can be approximately 2 mm to 6 mm, more preferably approximately 3 mm to 5 mm, when the stylet 300 is removed. Once the stylet 300 is removed, the trocar 200 (i.e., the trocar sleeve) can be secured in place. Securement of the trocar 200 (i.e., the trocar sleeve) can be achieved in at least two places: through a frictional grip at the dermal penetration site and through a similar, weaker interaction in the tissue (e.g., the kidney capsule) through which the trocar (i.e., the trocar sleeve) 200 penetrates. The trocar (i.e., the trocar sleeve) 200 can be configured to be stabilized at its penetration depth into tissue, such as an organ (e.g., a kidney), during a procedure. However, the placement of tissue-penetrating components can be dynamic due to the shifting of tissue, such as organs (e.g., kidneys), and the patient's respiratory cycle. Therefore, adverse movement of the dermal anchor points relative to the anchor points of internal tissue, such as organs (e.g., kidneys), can occur, and thus, movement can be minimized using components provided herein, such as the stabilization mechanism 220. Minimizing trauma to tissue, such as organs (e.g., kidneys), can be beneficial to the overall success of any treatment. For example, trauma can occur when there is unintended movement of the needle 400 within the trocar 200, causing lacerations in the tissue, such as organs (e.g., kidneys). Trauma can also occur, for example, when the distal tip 304 of the stylet 300 has some cutting action (such as the sharp point that occurs in the pyramidal or pointed cone designs described above). Therefore, stabilizing the trocar 200 reduces or eliminates unintended movement of the needle 400, thereby reducing or eliminating trauma to the tissue. is useful for expelling, and a blunt conical tip can be used to penetrate tissue such as organs (e.g., kidneys) to minimize trauma.

[0058] In certain embodiments, trauma can occur from two sources: 1) the stylet / needle tip configuration is prone to tissue damage; or 2) unintended movement of the trocar / needle during the procedure can cause lacerations to the kidney. In certain embodiments, of the stylet tips shown in FIGS. 18A-18D , a blunt cone shape is recommended to penetrate the kidney and minimize trauma. In certain embodiments, the needle tip is blunt and non-cutting. The gauge size of the needle also has a significant impact on trauma. In certain embodiments, smaller needles cause less trauma but may be less effective at penetrating the fibrous capsule. In certain embodiments, larger needle sizes are more easily visualized by ultrasound to confirm placement. Thus, in certain embodiments, design solutions that include a dynamic mode to effectively penetrate the capsule with smaller needles result in less trauma and a lower risk of capsule penetration failure, but may present visualization challenges. In certain embodiments, a large difference between the sleeve and the needle can cause a small needle to bend within the sleeve, and the device is configured to minimize bending of the needle within the sleeve.

[0059] syringe needle 19 shows a non-limiting example of an injection needle 400 configured to engage with and be inserted through the device 100 when the trocar 200 is in place within a patient. In certain embodiments, the needle 400 is configured to deliver a medicinal fluid formulation (such as a formulation including cells and / or products thereof) from the device 100 to a targeted internal tissue site, such as an organ (e.g., a kidney). The illustrated needle 400 has an engagement head 402 and an elongated shaft 404 having a lumen therethrough and a distal tip 406. The distal tip 406 has a bore that allows fluid to flow distally from the needle 400. The engagement head 402 is configured to be removably and replaceably attached to the device 100 along axis L1 at the engagement mechanism 110. The head 402 is configured to engage with the valve 120 once attached. The lumen of the head 402 and the elongate shaft 404 are configured to provide a fluid flow path for fluid in a fluid reservoir connected to the fluid receiving portion 106, from the fluid reservoir through the valve 120, along the lumen of the shaft 404, and out the opening in the distal tip 406 upon actuation of the device 100. Furthermore, the needle 400 is configured to retract from its position within the target tissue when fluid is delivered thereto upon actuation. The size, length, and gauge of the injection needle 400 are variable. For example, the needle 400 can be approximately 25 g to approximately 20 g. The gauge size of the needle has a significant effect on trauma to the tissue site, with larger gauge sizes (smaller needles) causing less trauma.

[0060] When considering the size of a needle to be applied to treat an organ (e.g., a kidney), a balance must be struck between penetration of the renal capsule and potential trauma to the tissue. As shown in Figure 20, the renal capsule is a tough, fibrous layer that surrounds the kidney. Therefore, larger needles are more useful for penetrating the renal capsule. However, larger needles may cause more trauma to the kidney. Therefore, the optimal needle size can be determined by considering these opposing factors, as shown in Figure 21.

[0061] Smaller needles may be less effective at penetrating tissue, but the needles 400 used with the trocars 200 and stylets 300 herein can be configured to allow for both successful tissue penetration and placement of smaller needles. A variety of different needles may be used herein. Table 2 shows additional exemplary needle gauge sizes that may optionally be used herein. is doing.

[0062] [Table 2]

[0063] In certain embodiments, the needle is an 18-30 gauge needle. In certain embodiments, the needle is smaller than 20 gauge. In certain embodiments, the needle is smaller than 21 gauge. In certain embodiments, the needle is smaller than 22 gauge. In certain embodiments, the needle is smaller than 23 gauge. In certain embodiments, the needle is smaller than 24 gauge. In certain embodiments, the needle is smaller than 25 gauge. In certain embodiments, the needle is smaller than 26 gauge. In certain embodiments, the needle is smaller than 27 gauge. In certain embodiments, the needle is smaller than 28 gauge. In certain embodiments, the needle is smaller than 29 gauge. In certain embodiments, the needle is about 20 gauge. In certain embodiments, the needle is smaller than 29 gauge. In certain embodiments, the needle is about 21 gauge. In certain embodiments, the needle is smaller than 29 gauge. In certain embodiments, the needle is about 22 gauge. In certain embodiments, the needle is smaller than 29 gauge. In certain embodiments, the needle is about 23 gauge. In certain embodiments, the needle is smaller than 29 gauge. In certain embodiments, the needle is about 24 gauge. In certain embodiments, the needle is smaller than 29 gauge. In certain embodiments, the needle is about 25 gauge. In certain embodiments, the needle is smaller than 29 gauge. In certain embodiments, the needle is about 26 gauge. In certain embodiments, the needle is smaller than 29 gauge. In certain embodiments, the needle is about 27 gauge. In certain embodiments, the needle is smaller than 29 gauge. In certain embodiments, the needle is about 28 gauge. In certain embodiments, the needle is smaller than 29 gauge. In certain embodiments, the needle is about 29 gauge.

[0064] In certain embodiments, the inner diameter of the needle is less than 0.84 mm. In certain embodiments, the inner diameter of the needle is less than 0.61 mm. In certain embodiments, the inner diameter of the needle is less than 0.51 mm. In certain embodiments, the inner diameter of the needle is less than 0.41 mm. In certain embodiments, the inner diameter of the needle is less than 0.33 mm. In certain embodiments, the inner diameter of the needle is less than 0.25 mm. In certain embodiments, In certain embodiments, the inner diameter of the needle is less than 0.20 mm. In certain embodiments, the inner diameter of the needle is less than 0.15 mm. In certain embodiments, the outer diameter of the needle is less than 1.27 mm. In certain embodiments, the outer diameter of the needle is less than 0.91 mm. In certain embodiments, the outer diameter of the needle is less than 0.81 mm. In certain embodiments, the outer diameter of the needle is less than 0.71 mm. In certain embodiments, the outer diameter of the needle is less than 0.64 mm. In certain embodiments, the outer diameter of the needle is less than 0.51 mm. In certain embodiments, the outer diameter of the needle is less than 0.41 mm. In certain embodiments, the outer diameter of the needle is less than 0.30 mm. In certain embodiments, the needle has one of the sizes in the following table.

[0065] [Table 3]

[0066] The needle 400 can inject into an internal tissue site that is a relatively long distance from the device 100, such as, for example, a distance of about 10 cm to 20 cm. In such instances, the trocar 200 can also mechanically support the needle 400 against kinking that may occur as a result of penetrating a relatively large distance into the internal tissue site. In certain embodiments, the length of the needle 400 can be configured such that about 5 cm to about 6 cm of the distal portion of the needle 400 extends beyond the distal-most end of the trocar 200. For example, as shown in FIG. 22, about 5.3 cm (e.g., about 5.5 cm, 6 cm, or 6.5 cm) of the needle 400 can be configured to extend distally beyond the distal-most end of the trocar 200. This length can allow sufficient penetration depth of the needle 400 into a target tissue, such as an organ (e.g., a kidney), for deposition of therapeutic cells or cell products. In certain embodiments of the injection device, the needle penetration depth can be variably configured. In certain embodiments, at such lengths, the hole in the distal tip 406 of the needle 400 can be positioned approximately 5.1 cm past the distal-most end of the trocar 200, as shown in FIG. 23 . In certain embodiments, the needle hole is preferably positioned approximately 0.2 cm lateral from the needle tip, with the hole positioned 5.1 cm past the trocar at a length of 5.3 cm. In certain embodiments, the hole is positioned approximately 5.8 cm past the trocar at a length of approximately 6 cm. In certain embodiments, the lateral positioning of the exit hole has a beneficial effect on the extrusion and placement of the cellular therapy while ensuring that the needle is non-coring. In certain embodiments, the hole can optionally be positioned laterally, which can have a beneficial effect on the extrusion and placement of the therapeutic cells or cell product at the target tissue site. In various examples, one or more surface features, such as protrusions, grooves, markings, etc., may be added to the distal outer surface of the elongate shaft 404 of the needle 400, as well as the trocar 200, configured to better visualize the position of the needle 400, such as under ultrasound, and therefore provide for more accurate placement within the patient. Two or more needles 400 of different sizes may also be used. In some instances, the gauge size of the needle may have a significant effect on trauma. For example, a larger gauge size (a smaller needle) may cause less trauma, but may be less effective at penetrating tissue such as a fibrous capsule. Accordingly, provided herein are components such as trocars 200 that can assist through dynamic modes and / or dynamic motions to effectively penetrate tissue such as a capsule with smaller needles. This may result in less trauma and a lower risk of failure to penetrate tissue such as a capsule.

[0067] In certain embodiments, the components herein can be designed in a manner that accommodates the needs of the user, such as a surgeon, who will be utilizing the device. In use, all of the components herein, such as moving surfaces, are preferably easy to hold and A wide range of male and / or female hand sizes can be accommodated. One or more of the components described herein can optionally incorporate a non-slip surface, for example, by providing surface features, surfaces, and / or materials that interact well with surgical gloves to prevent slippage. In certain embodiments, the input interfaces can be easily displayed and activated using gloved fingers. In certain embodiments, one or more of the interfaces can provide tactile feedback when activated, and if any part of the injection process is mechanical, the tactile feedback can be used to indicate, for example, when a fluid, such as a therapeutic cellular material, is being injected into tissue, such as a renal space. The proper use of the components disclosed herein can be important when used in conjunction with a syringe. Users often prefer smaller syringes because they require less force to inject their contents and may be held in a particular hand position for better control, as shown by way of a non-limiting example in FIG. 24 . Thus, the ergonomics and fit of the components herein can be considered. In certain embodiments, one or more instructions, instructions, guides, videos, operating manuals, etc. can be provided and can be tailored to the needs of the end user (e.g., surgeon). The instructions, etc. can be configured according to and / or as defined by the needs of the contract engineering organization's design process.

[0068] The device 100, trocar 200, and needle 400 can be used in a variety of different ways. For example, the injection device 100 can be attached to the trocar 200 with the stylet 300 in place within the trocar 200. A cartridge 130 or other fluid reservoir can be engaged with the device 100 at this point or prior to injection. The trocar 200 and stylet 300 can then be manipulated to penetrate an outer tissue surface, such as the patient's dermis, and an inner tissue target site, such as an organ (e.g., a kidney), at a desired depth (as described above). The stylet 300 can then be removed from the trocar 200 through the removal lumen 140. Removal of the stylet 300 can trigger activation of the stabilizing mechanism 220 of the trocar 200. As shown in FIG. 12 , the feet 222 can deploy to grasp or engage tissue. The trocar 200 can be detached from the device 100, and at this point in use, the trocar 200 is supported through frictional interaction with the dermis and through the use of the stabilizing mechanism 220. In a non-limiting illustrative example, FIG. 25 shows a simplified diagram of the trocar 200 being used on a kidney, with the trocar 200 undergoing frictional interaction with the dermis and stabilizing action against the kidney's cortex (the outer portion of the kidney between the renal capsule and the renal medulla, which can vary in thickness from patient to patient) through the use of the stabilizing mechanism 220. For example, the cortex may have a thickness of approximately 3 mm to 12 mm, more specifically approximately 3.2 mm to 11 mm, with an average thickness of approximately 5.9 mm. An injection needle 400 can then be engaged with the device 100. The needle 400 can then be inserted into the trocar 200 until it penetrates the target tissue through the same hole created by the stylet 300 (as described above) at the desired depth, and the actuator 104 of the device 100 can be actuated to initiate the infusion of therapeutic cells, cell products, or the like. The fluid can be delivered to a target site. The stabilizing mechanism 220, in cooperation with the compression spring portion 208 of the trocar 200 and the flexible mounting portion of the valve 120, can absorb movement of a tissue site, such as an organ (e.g., a kidney), relative to the user's holding and actuation of the device 100. When fluid is to be delivered, the needle 400 can be retracted from a penetration position within the target tissue site. A trigger lever activates an electromechanical system that delivers pulses of therapeutic solution into the needle lumen as the needle is retracted. Multiple injections into the same tissue site, such as an organ, can be performed.

[0069] Alternatively, the trocar 200 and stylet 300 can be advanced to a predetermined location within a patient without being attached to the device 100, the stylet 300 can be removed, and the stabilizing mechanism 220 of the trocar 200 can be activated. The needle 400, engaged with the device 100, can then be inserted into the trocar 200 for fluid delivery. The trocar 200 with the stylet 300 attached can also be placed within a patient while attached to the device 100, after which the device 100 can be removed from the trocar 200, the stylet 300 manually removed, and the needle 400 can then be attached and inserted into the trocar 200. If the trocar 200 has an additional engagement mechanism, such as a reversibly collapsible dilator element 500, the injection device 100 can be attached to the trocar 200 with the stylet 300 in place within the trocar 200. The trocar 200 and stylet 300 can then be manipulated to penetrate an outer tissue surface and an inner tissue target site. After removing the stylet 300 and disconnecting the device 100, but before inserting the needle 400, the expansion element 500 can be deployed. However, this order can vary depending on the mechanism of use of different engagement mechanisms. When the device 100 is used specifically to treat the kidney, the trocar 200, stylet 300, and needle 400 can be used as described above to penetrate the kidney's capsule, potentially an area of ​​fibrous tissue, to deliver a predetermined volume to the kidney and allow expansion space for the delivery bolus of therapeutic cells or cell products while simultaneously withdrawing the needle 400. As used herein, depending on the context, "fibrotic" means or refers to the deposition of a fibrous extracellular matrix, which is typically denser than the surrounding tissue. Densely fibrotic tissue is often the result of a chronic disease state. In certain embodiments, fibrotic tissue is the result of a chronic disease state. In certain embodiments, densely fibrotic tissue is the result of a chronic disease state. In certain embodiments, the fibrous tissue is present in an organ that is being treated with a device, system, or method provided herein (e.g., that is the delivery site of a composition delivered using the device, system, or method).

[0070] In certain embodiments, prior to use, cartridge 130 can be warmed to about 25° C. to 30° C., more specifically, about 26° C. to 28° C. In certain embodiments, prior to use, cartridge 130 can be warmed to about 25° C., 26° C., 27° C., 28° C., 29° C., 30° C., 31° C., 32° C., 33° C., 34° C., 35° C., 36° C., or 37° C. In certain embodiments, warming can occur over a controlled period of time, such as about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes, or over a period of about 15 to about 45 minutes. In certain embodiments, once the cartridge 130 is warmed, delivery of the fluid therein can occur preferably within about 0.5 hours, 1 hour, 1.5 hours, 2 hours, or 2.5 hours to avoid discarding the cartridge 130.

[0071] In certain embodiments, after fluid delivery and withdrawal of the injection needle 400 from the target tissue site and trocar 200, a plug 700 (such as a hydrogel plug or pledget, e.g., a Gelfoam® pledget) can be manually inserted into the trocar 200 and pushed down to exit the distal end 206 of the trocar 200, sealing the penetration wound. The device 100 and trocar 200 can be configured to accommodate the delivery of a plug. In certain embodiments, a pledget (such as a Gelfoam® pledget), starting at about 2 mm to about 4 mm by about 10 mm, is compressed for insertion (e.g., manual insertion) into the trocar and pushed down and out the tip of the trocar to seal the wound in the kidney capsule. In certain embodiments, the pledget is a small piece of absorbent cotton or other soft material (such as a hydrogel). In certain embodiments, the pledget or plug is used to plug a wound or other opening in the body or organ. In certain embodiments, the device is configured to accommodate this distal wound sealing process. In a non-limiting illustrative example, FIG. 26 shows a simplified diagram of a trocar 200 being used on a kidney, with a plug 700 being "musket loaded" or manually placed into place through the trocar 200. The trocar 200 can then be removed from the patient. Thus, throughout the processes disclosed herein, one or more components can assist in manually penetrating tissue such as the fibrous kidney capsule, smoothly and controlled delivery of fluids such as therapeutic cellular material, and positionally stabilizing the trocar in the dynamic environment of the patient (thus providing stability to the delivery of therapeutic cellular material while minimizing tissue trauma), which would otherwise present challenges that one or more of the components shown herein can be configured to address.

[0072] While the description focuses on the kidney as a target tissue site and / or target organ, the components herein may be broadly applicable to numerous organs and / or internal tissue sites and / or their respective treatments. As a non-limiting example, the components described herein are components of a handheld injection device designed to deliver one or more injection volumes (e.g., cellular therapeutic agents) to one or more target tissue sites, such as the parenchymal and / or interstitial compartments of a diseased site, such as an organ (e.g., a kidney or tumor site). Thus, in certain embodiments, the components herein can penetrate the exterior surface of a tissue site, such as an organ site like the kidney capsule, potentially an area of ​​fibrous tissue within the kidney, and deliver a predetermined volume along an injection path while simultaneously withdrawing the needle to allow expansion space for a delivered volume, such as a bolus of therapeutic cellular material. In certain embodiments, multiple injections into the same target site, such as an organ, may be possible. In certain embodiments, the components herein may have a means for stabilizing themselves against the surface of a target tissue site, such as an organ, through trocar deployment, be able to accept a pre-filled sterile cartridge containing a volume, such as a therapeutic cellular material solution, and be ergonomic for the intended operator, such as a surgeon. In certain embodiments, the components herein are intuitive, can accept hypodermic needles within a specified size range, and can have the ability to set variable injection or delivery volumes and penetration depths.

[0073] In certain embodiments, the injection device can consist of a single physical device capable of accepting cartridge-based therapeutic doses. In certain embodiments, a standard trocar / sleeve / needle combination can be incorporated into the device from commercially available, individually packaged, and sterile supplies. In such instances, subject sizes can be interchangeable from a variety of standard sizes, e.g., hypodermic needles ranging from a minimum of about 25 g to a maximum of about 20 g, with trocar / sleeve combinations of at least about 20 g. In certain embodiments, the trocar / sleeve size is from about 21 g to about 18 g. In certain embodiments, the subject has a high body mass index (e.g., at least about 35 kg / m 2 , 36 kg / m 2 , 37 kg / m 2 , 38 kg / m 2 , 39 kg / m 2 , or 40 kg / m 2 The BMI is an indicator of obesity, with a higher BMI being associated with higher obesity. In certain embodiments, for patients with a high BMI, a sleeve size of about 20 g to about 18 g and a needle of about 21 g and about 20 cm to about 30 cm (e.g., 25 cm) in length is used. In certain embodiments, provided herein are devices or systems useful for treating both patients with a normal BMI and patients with a high BMI. In certain embodiments, the injection path for the injection needle to the target site, such as an organ, can be provided in combination with a trocar, which can serve to mechanically support the injection needle against kinking that may occur as a result of penetrating into the target tissue, such as an organ, at a relatively large distance, such as about 5 cm to 25 cm, more particularly about 10 cm to 20 cm, from the injection device.

[0074] In certain embodiments of one or more of the components herein, the components may be labeled with ISO-compliant safety labels in accordance with appropriate regulatory agency documents (e.g., 21 CFR Part 801). In certain embodiments, the components herein may be labeled with various housings and product skins in place. When in place and secured, they can be considered safe against uncontrolled access, and components herein, with the exception of various trocar, sleeve, and needle components, can optionally have no externally accessible sharp edges having a radius of less than about 0.5 mm. In certain embodiments, components can have no externally accessible electrical connections capable of supplying greater than about 1.0 A at about 5.25 VDC. In certain embodiments, any materials, such as plastics, and / or finishes can have a flammability rating of UL94 V-0 or higher.

[0075] In certain embodiments, the components herein may be configured for use in temperature-controlled indoor environments such as clinics and hospitals, and the components may be configured to meet performance requirements over a range of environmental conditions, as shown in Table 3.

[0076] [Table 4]

[0077] In certain embodiments, components disclosed herein can be configured to function normally after various sterilization processes (e.g., standard sterilization processes), such as those using gamma radiation, ethylene oxide, electron beam, or gas. In certain embodiments incorporating one or more plastics, the plastic can be configured to resist embrittlement through the sterilization process and minimize discoloration or color change. In certain embodiments herein incorporating one or more electromechanical components, a sterilization process compatible with electronics can be used, which can incorporate various steps and additional features, such as removing removable skins and / or surfaces that can be sterilized to aseptically contain the working elements of one or more components. Tables 4 and 5 present resin materials compatible with various types of sterilization.

[0078] [Table 5] TIFF2026001158000007.tif26170

[0079] [Table 6] TIFF2026001158000009.tif45170

[0080] In certain embodiments, one or more packaged components herein can be configured to operate normally when returned to the operating environmental range after an extended period of time. For example, Table 6 shows how components will operate normally after the package has been exposed to various environmental conditions during a 72-hour storage period.

[0081] [Table 7]

[0082] In certain packaged embodiments, the packaged components can be configured and packaged to withstand functional or visible cosmetic damage when shipped by commercial carriers. Additionally, various packaged embodiments of the components herein can be configured and packaged to withstand functional or visible cosmetic damage when dropped from a height of approximately one meter.

[0083] Each of the components described above can be used independently of one another, fully integrated together, or in any combination thereof. For example, components can be provided to an end user independently or in various combinations, systems, and kits. Various combinations of cartridges 130 and / or a range of sizes and types of needles 400, trocars 200, and / or stylets 300 can also be provided with device 100. In certain embodiments, one or more components or all components can be packaged and shipped as a fully assembled unit that can be immediately operated by an end user upon removal from the package. In certain embodiments, assembly and / or use instructions can be provided with any component, for example, instructions that enable an end user to assemble or configure and operate one or more in less than about 10 minutes.

[0084] Non-limiting examples of injectable formulations The devices and systems provided herein can be configured to deliver different pharmaceutical fluid formulations. In certain embodiments, the fluid formulation includes an active agent (such as cells, cell products, or compounds) and a temperature-sensitive biomaterial. In certain embodiments, the temperature-sensitive biomaterial is a pharmaceutically acceptable carrier for the active agent. In certain embodiments, the formulation incorporates a biomaterial with properties that create a favorable environment for an active agent, such as bioactive renal cells, administered to a subject.

[0085] In certain embodiments, the fluid formulation can be a hydrogel, eg, the formulation is a hydrogel above its melting temperature.

[0086] In certain embodiments, the devices and systems provided herein are configured to deliver a formulation (such as an NKA) that has been heated to a temperature sufficient to melt or otherwise ensure that the composition is liquid. In certain embodiments, the device is configured to warm the formulation or maintain a temperature at which the formulation is liquid.

[0087] In certain embodiments, the temperature sensitivity of the formulation can be altered by adjusting the percentage of biomaterial in the formulation, for example, adjusting the percentage of gelatin in the solution to adjust the temperature sensitivity of the gelatin in the final formulation (e.g., liquid, gel, beads, etc.).

[0088] In certain embodiments, the temperature-sensitive biomaterial can be (i) substantially solid at or below about 8° C. and (ii) substantially liquid at or above ambient temperature. In certain embodiments, ambient temperature is about room temperature.

[0089] In certain embodiments, the temperature-sensitive biomaterial is in a substantially solid state at temperatures of about 8°C or less. In certain embodiments, the substantially solid state is maintained at about 1°C, about 2°C, about 3°C, about 4°C, about 5°C, about 6°C, about 7°C, or about 8°C. In certain embodiments, the substantially solid state has the form of a gel. In certain embodiments, the temperature-sensitive biomaterial is in a substantially liquid state at ambient temperatures or above. In certain embodiments, the substantially liquid state is maintained at about 25°C, about 25.5°C, about 26°C, about 26.5°C, about 27°C, about 27.5°C, about 28°C, about 28.5°C, about 29°C, about 29.5°C, about 30°C, about 31°C, about 32°C, about 33°C, about 34°C, about 35°C, about 36°C, or about 37°C. In certain embodiments, the ambient temperature is about room temperature.

[0090] In certain embodiments, the temperature-sensitive biomaterial is in a substantially solid state at or below ambient temperature. In certain embodiments, ambient temperature is about room temperature. In certain embodiments, the substantially solid state is maintained at about 17°C, about 16°C, about 15°C, about 14°C, about 13°C, about 12°C, about 11°C, about 10°C, about 9°C, about 8°C, about 7°C, about 6°C, about 5°C, about 4°C, about 3°C, about 2°C, or about 1°C.

[0091] In certain embodiments, the delivered cell populations and preparations may be coated with, deposited on, embedded in, attached to, seeded into, suspended in, or contained within a temperature-sensitive biomaterial. In certain embodiments, the cell populations may be organized as three-dimensional cell aggregates or spheroids or three-dimensional tubular structures within the temperature-sensitive biomaterial.

[0092] In certain embodiments, the temperature-sensitive biomaterial has a transition state between a first state and a second state. In certain embodiments, the transition state is a solid-to-liquid transition state between a temperature of about 8°C and about ambient temperature. In certain embodiments, ambient temperature is about room temperature. In certain embodiments, the solid-to-liquid transition state occurs at one or more of about 8°C, about 9°C, about 10°C, about 11°C, about 12°C, about 13°C, about 14°C, about 15°C, about 16°C, about 17°C, and about 18°C.

[0093] In certain embodiments, the temperature-sensitive biomaterial has a certain viscosity, measured in centipoise (cP), at a given temperature. In certain embodiments, the biomaterial has a viscosity at 25° C. of about 1 cP to about 5 cP, about 1.1 cP to about 4.5 cP, about 1.2 cP to about 4 cP, about 1.3 cP to about 3.5 cP, about 1.4 cP to about 3.5 cP, about 1.5 cP to about 3 cP, about 1.55 cP to about 2.5 cP, or about 1.6 cP to about 2 cP. In certain embodiments, the biomaterial has a viscosity at 37° C. of about 1.0 cP to about 1.15 cP. The viscosity at 37° C. can be about 1.0 cP, about 1.01 cP, about 1.02 cP, about 1.03 cP, about 1.04 cP, about 1.05 cP, about 1.06 cP, about 1.07 cP, about 1.08 cP, about 1.09 cP, about 1.10 cP, about 1.11 cP, about 1.12 cP, about 1.13 cP, about 1.14 cP, or about 1.15 cP. In certain embodiments, the biomaterial is a gelatin solution. The gelatin is present in the solution at about 0.5% (w / v), about 0.55% (w / v), about 0.6% (w / v), about 0.65% (w / v), about 0.7% (w / v), about 0.75% (w / v), about 0.8% (w / v), about 0.85% (w / v), about 0.9% (w / v), about 0.95% (w / v), or about 1% (w / v). In one example, the biomaterial is a 0.75% (w / v) gelatin solution in PBS. In certain embodiments, the 0.75% (w / v) solution has a viscosity of about 1.6 cP to about 2 cP at 25°C. In certain embodiments, the 0.75% (w / v) solution has a viscosity of about 1.07 cP to about 1.08 cP at 37°C. The gelatin solution may be provided in PBS, DMEM, or another suitable solvent.

[0094] In certain embodiments, the fluid formulation is gelatin-based. Gelatin is a non-toxic, biodegradable, water-soluble protein derived from collagen, a major component of the extracellular matrix (ECM) of mesenchymal tissues. Collagen is the major structural protein in the extracellular space of various connective tissues in animals. As the main component of connective tissue, collagen is the most abundant protein in mammals, accounting for 25% to 35% of the total body protein content. Depending on the degree of mineralization, collagen tissues can be hard (bone), flexible (tendon), or have a hard-to-flexible gradient (cartilage). Collagen is elongated and fibril-like and is found primarily in fibrous tissues such as tendons, ligaments, and skin. It is also abundant in the cornea, cartilage, bone, blood vessels, intestine, intervertebral discs, and tooth dentin. In muscle tissue, collagen serves as the main component of the endomysium. Collagen accounts for 1% to 2% of muscle tissue and 6% of the weight of muscles with strong tendons. Collagen is found in various places in the body, but more than 90% of the collagen present in the human body is type I.

[0095] To date, 28 types of collagen have been identified and described. These can be divided into several groups based on the structure they form: fibril-forming (types I, II, III, V, and XI), non-fibril-forming FACIT (Fibril Associated Collagens with Interrupted Triple Helices) (I). types X, XII, XIV, XVI, and XIX), short chains (types VIII and X), basement membrane (type IV), multiplexins (multiple triple helix domains with interruptions) (types XV and XVIII), MACITs (membrane associated collagens with interrupted triple helices) (types XIII and XVII), and others (types VI and VII). The five most common types are: Type I: skin, tendons, vascular nodules, organs, and bone (the main component of the organic part of bone); Type II: cartilage (the main collagen component of cartilage); Type III: reticular (the main component of reticular fibers) (along with Type I), Type IV: basal layer, forming the epithelium-secreted layer of the basement membrane; and Type V: cell surfaces, hair, and placenta.

[0096] Gelatin is an arginine-glycine-asparagine derivative that promotes cell adhesion, proliferation, and stem cell differentiation. It carries information signals containing the RGD sequence. A distinctive property of gelatin is that it exhibits upper critical solution temperature (UCST). Above a certain temperature threshold, gelatin forms a flexible, random single coil and can dissolve in water. Upon cooling, hydrogen bonding and van der Waals interactions occur, forming a triple helix. This collagen-like triple helix acts as a junction, inducing the sol-gel transition. Gelatin is widely used in pharmaceutical and medical applications.

[0097] In certain embodiments, the fluid injectable cell preparation is based on porcine gelatin, which may be sourced from pig skin and is commercially available, for example, from Nitta Gelatin NA Inc. (NC, USA) or Gelita USA Inc. (IA, USA). Gelatin may be dissolved, for example, in Dulbecco's phosphate buffered saline (DPBS) to form a thermoresponsive hydrogel that can gel and liquefy at different temperatures. In certain embodiments, the hydrogel used to formulate the injectable cell composition is based on recombinant human or animal gelatin expressed and purified using methodology known to those skilled in the art. In certain embodiments, an expression vector containing all or part of the cDNA for type I, alpha I human collagen is transformed into the yeast Pichia pastoris (Pichia pastoris). Other expression vector systems and organisms are known to those skilled in the art. In certain embodiments, the gelatin-based hydrogels of the present disclosure are liquid at or above room temperature (22°C to 28°C) and gel when cooled to refrigeration temperatures (2°C to 8°C).

[0098] Those skilled in the art will appreciate further features and advantages of the present invention based on the above-described embodiments. Accordingly, the invention is not to be limited by what has been particularly shown and described, except as indicated by the appended claims. All publications and references cited herein are expressly incorporated herein by reference in their entirety.

Claims

1. a body having an actuator, a fluid receiving portion, and a fluid delivery mechanism; a removable injection needle extending distally from the body; Equipped with The medicinal fluid formulation delivery device, wherein the fluid delivery mechanism is configured to deliver a bolus or a continuous flow of the fluid through the injection needle.

2. The device of claim 1 , wherein the fluid delivery mechanism comprises an electromechanical system having a central processing unit and a pump.

3. 10. The device of claim 1, further comprising a valve configured to translate proximally and distally parallel to the injection needle during deployment of the device and delivery of the fluid.

4. 4. The device of claim 3, wherein the valve is configured to translate distally and proximally approximately 2 cm.

5. 10. The device of claim 1, wherein the fluid receiving portion is configured to removably and replaceably receive a fluid reservoir, the fluid reservoir including at least one cartridge containing a known dosage of fluid.

6. The device of claim 5 , wherein the fluid receiver is configured to simultaneously receive multiple cartridges.

7. The device of claim 1 , wherein the fluid comprises therapeutic cells or products thereof for the treatment of kidney disease.

8. The device of claim 1 , further comprising a touch display configured to control operation of the device.

9. The device of claim 8 , wherein the display is configured to set one or more parameters for the delivery of the fluid, including at least one of pressure and volume.

10. The device of claim 8 , wherein the display is configured to provide real-time dispensing information of the fluid during delivery.

11. The device of claim 1 , wherein the actuator is one of a trigger, a plunger, a switch, or a button.

12. The device of claim 1 , further comprising an engagement mechanism at a distal end of the body configured to releasably engage a trocar.

13. an elongate body having a proximal end and a distal end, the elongate body having a head at the proximal end, an elongate shaft extending distally from the head, and an inner lumen extending therethrough from the proximal end to the distal end; a stabilizing means at a distal portion of the elongate shaft configured to stabilize the distal end of the elongate body against a tissue surface; and A trocar comprising:

14. The trocar of claim 13 , wherein the stabilizing means includes one or more engaging components configured to deploy upon actuation to releasably grasp the tissue surface.

15. The trocar of claim 14 , wherein the engagement component includes a plurality of feet.

16. The trocar of claim 16 , wherein the feet have microhooks.

17. The trocar of claim 14 , wherein the engaging component comprises at least one of an adhesive element, a suction element, and a clamping element.

18. The trocar of claim 14, further comprising a removable stylet configured to extend through the lumen of the elongate body, the stylet configured to actuate the engaging component upon removal.

19. The trocar of claim 13 , wherein at least a portion of the elongate shaft is configured for distal and proximal translation parallel to a longitudinal axis of the elongate shaft.

20. 20. The trocar of claim 19, wherein the at least a portion of the elongate shaft is configured to translate distally and proximally by approximately 2 cm.

21. 1. A method of delivering a medicinal fluid formulation to a tissue, comprising: Attaching the injection device to a trocar, the trocar having a lumen therethrough and a stylet disposed therein; connecting a fluid source to the injection device; advancing the injection device and trocar through an outer tissue surface of a patient and penetrating an inner tissue target site; removing the stylet from the trocar to disengage the injection device from the trocar; attaching a needle to the injection device; inserting the injection needle through the trocar into the tissue target site; activating the injection device to deliver a continuous flow or bolus of fluid from the fluid source through the injection needle to the tissue target site; A method comprising:

22. 22. The method of claim 21, further comprising deploying a stabilizing means in a distal portion of the trocar to stabilize the distal end of the trocar against the tissue target site prior to inserting the injection needle through the trocar.

23. 23. The method of claim 22, wherein deployment of the stabilizing means is actuated by removal of the stylet.

24. 22. The method of claim 21, further comprising retracting the needle during delivery of the fluid.

25. 22. The method of claim 21, further comprising stabilizing the injection device using a translation valve and stabilizing the trocar using a compression spring portion of the trocar during actuation of the injection device.

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