RU2839077C1 - Pharmaceutical formulation delivery device - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medical equipment, namely to a pharmaceutical formulation delivery device. Pharmaceutical fluid delivery device comprises a body, a removable injection needle and a trocar. Housing has an actuator, a fluid receiver and a fluid delivery mechanism. Removable injection needle extends distally from the body. Fluid delivery mechanism is configured to deliver boluses or a continuous flow of the fluid through the injection needle. Trocar comprises an elongated body having proximal and distal ends. Body has a head at its proximal end, an elongated shaft extending distally from the head, and a lumen extending from the proximal end to the distal end therethrough. Stabilizing mechanism on the distal portion of the elongated shaft is configured to stabilize the distal end of the elongated body relative to the tissue surface. Stabilizing mechanism comprises steps and shafts. Steps are arranged radially symmetrically around the elongated body. Each shaft is connected to the corresponding lower part of the steps at the first end and is connected to the elongated body by means of corresponding hinge points at the other end. Footrest and the shaft are movable from the recessed position along the elongated body to the stretched position, by rotation in the direction away from the elongated body by means of hinge points, when using a trocar. In the stretched position, the footrests grip the surface of the fabric with the possibility of disengagement.

EFFECT: use of the invention enables extravascular delivery of therapeutic agents to target locations within a patient while maintaining positional stability.

16 cl, 27 dwg

Description

Field of technology to which the invention relates

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

State of the art

[0002] Cell therapy is a therapeutic process in which cellular material is injected into a patient for a therapeutic effect to treat a variety of different diseases, in particular to target selected organs in the patient's body. In some cell therapies, the cellular material may be removed from a patient treated for a therapeutic effect and reinjected into the patient at the treatment or delivery site. In certain cases, for successful cell delivery, the injected cells typically must also be intact living cells. Delivery of cellular therapies can be accomplished in several different ways, such as through intravascular delivery or extravascular delivery. Intravascular delivery involves cellular therapy that is infused through a vascular access. Targeting specific organs for treatment through this process can be accomplished in a variety of ways. However, the efficiency may be low and the residence time of the therapeutic cellular material delivered to the organ(s) may be short due to the flushing that the patient's body naturally performs.

The essence of the invention

[0003] Disclosed herein are, among other things, devices, methods, and systems for delivering therapeutic agents, such as chemical compounds, compositions, cells, and cellular products. In particular embodiments, the devices and systems provided herein are configured to administer cellular therapy. In particular embodiments, the devices and systems provided herein include metered infusion capabilities. In particular embodiments, the devices and systems provided herein are configured to deliver a therapeutic agent extravascularly 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 housing having an actuator, a fluid reservoir with a fluid therein, and a fluid delivery mechanism. In particular embodiments, a removable injection needle extends distally from the housing, and the fluid delivery mechanism is configured to deliver a continuous stream or boluses of fluid through the injection needle. In particular embodiments, the organ is a kidney. In certain embodiments, the patient has cancer and the organ contains a tumor.

[0004] The device may have many variations. In particular embodiments, the fluid delivery mechanism may include an electromechanical system having a central processor and a pump. In particular embodiments, the device may also include a valve that is configured to move in space proximally and distally parallel to the injection needle during placement of the device and delivery of the fluid. In particular embodiments, the valve may be configured to move in space approximately 2 cm distally and proximally. In particular embodiments, the device may include a fluid receptacle configured to removably and replaceably receive a fluid reservoir. In particular embodiments, the fluid reservoir may include at least one cartridge that includes a known dosage of fluid. In particular embodiments, the fluid receptacle may be configured to receive one or more (e.g., 1, 2, 3, 4, or 5) cartridges aseptically. In particular embodiments, the fluid receptacle may be configured to receive multiple cartridges in series (e.g., the contents of one cartridge are used, the cartridge is removed, and then one or more additional cartridges are inserted as needed to continue dispensing). In particular embodiments, the fluid receptacle may be configured to receive multiple cartridges in parallel. In particular embodiments, the fluid may include therapeutic cells or cell products for treating a kidney disease. In particular embodiments, the fluid may include an anticancer agent for treating cancer. In particular embodiments, the device may include a touchscreen display that may be configured to control the operation of the device. In particular embodiments, the display may be configured to set one or more parameters for delivering the fluid, including at least one of pressure and volume. In particular embodiments, the display may be configured to provide real-time dispensing information of the fluid during delivery. In particular embodiments, the actuator may be one of a trigger, a plunger, a switch, or a button. In particular embodiments, the device may also include an engaging feature at the distal end of the housing configured to removably engage a trocar.

[0005] In an aspect, a trocar is provided that includes an elongated body with proximal and distal ends. In particular embodiments, the body has a head at the proximal end, an elongated shaft extending distally from the head, and a lumen extending from the proximal end to the distal end through it. In particular embodiments, a stabilization means is provided on the distal portion of the elongated shaft and is configured to stabilize the distal end of the elongated body relative to the tissue surface.

[0006] The trocar may have many variations. In particular embodiments, the stabilizing means may include one or more engaging components that are configured to open to releasably grasp a tissue surface upon actuation. In particular embodiments, the engaging components may include a plurality of legs. In particular embodiments, the legs may have microhooks. In particular embodiments, the engaging components may include at least one of an adhesive, a suction cup, and a clamp. In particular embodiments, the trocar may include a removable stylet configured to extend through a lumen of the elongated body. In particular embodiments, the stylet is configured to actuate the engaging components upon withdrawal. In particular embodiments, at least a portion of the elongated shaft may be configured to move in space distally and proximally parallel to the longitudinal axis of the elongated shaft. In particular embodiments, at least a portion of the elongated shaft may be configured to move in space approximately 2 cm distally and proximally.

[0007] In an aspect, a method of delivering a pharmaceutical composition based on a fluid into a tissue is provided, which includes connecting an injection device to a trocar. In particular embodiments, the trocar has a lumen therethrough and a stylet positioned therein. In particular embodiments, the method also includes connecting a source of fluid to the injection device and advancing the injection device and the trocar through the outer surface of the patient's tissue and ensuring penetration through the inner target site of the tissue. In particular embodiments, the method further includes removing the stylet from the trocar and disengaging the injection device and the trocar and connecting an injection needle to the injection device. In particular embodiments, the method also includes inserting the injection needle through the trocar into the target site of the tissue and actuating the injection device to deliver a continuous stream or boluses of fluid from the source of fluid through the injection needle and into the target site of the tissue. In specific embodiments, the pharmaceutical fluid formulation comprises, consists essentially of, or consists of a population of cells or a product thereof for a pharmaceutically acceptable fluid carrier. In specific embodiments, the cell therapy comprises stem cells, progenitor cells, primary cells, or a cell line. In specific embodiments, the target tissue site is the kidneys. In specific embodiments, the patient has a kidney disease. In specific embodiments, the kidney disease is a chronic kidney disease. In specific embodiments, the cell therapy comprises bioactive renal epithelial cells. In specific embodiments, the cell therapy comprises selected renal epithelial cells. In specific embodiments, the cell therapy comprises a liquid formulation comprising cells and a temperature-sensitive biomaterial. In specific embodiments, the cell therapy is non-renal augmentation (NKA). In specific embodiments, the cells are in the form of spheroids or cell clusters. In particular embodiments, the pharmaceutical fluid formulation comprises a cellular product, such as a vesicle, such as a microbubble or an exosome. In particular embodiments, the pharmaceutical fluid formulation comprises a chemical compound. In particular embodiments, the pharmaceutical fluid formulation comprises an anticancer agent. In particular embodiments, the patient has cancer. In particular embodiments, the target tissue site is a tumor.

[0008] The method can be varied in a variety of ways. For example, the method can further include, prior to inserting the injection needle through the trocar, deploying a stabilizing means on the distal portion of the trocar so as to stabilize the distal end of the trocar relative to the target tissue site. In particular embodiments, deploying the stabilizing means can be actuated by withdrawing the stylet. In particular embodiments, the method can also include retracting the injection needle during delivery of the fluid (e.g., its continuous flow or boluses). In particular embodiments, the method can further include, during actuation of the injection device, stabilizing the injection device using a spatially movable valve and stabilizing the trocar using a compressive spring section of the trocar.

Brief description of the drawings

[0009] The invention will be better understood from the following detailed description taken in conjunction with the accompanying drawings, in which:

[0010] Fig. 1 illustrates a view of the patient in a lying position;

[0011] Fig. 2 illustrates a view of the patient in a transverse position;

[0012] Fig. 3 illustrates a diagram detailing an exemplary process for using commercially available devices to treat a subject of interest;

[0013] Fig. 4A illustrates an embodiment of using commercially available devices to deliver treatment to a patient in accordance with the process of Fig. 3;

[0014] Fig. 4B and C illustrate embodiments of commercially available devices for delivering treatment to a patient in accordance with the process of Fig. 3;

[0015] Fig. 5 illustrates a side view of one embodiment of a trocar;

[0016] Fig. 6 illustrates a side view of one embodiment of a cannula;

[0017] Fig. 7 illustrates a side view of one embodiment of an injection device with a trocar attached thereto that has a stylet inserted;

[0018] Fig. 8 illustrates a simplified diagram of a bolus delivery profile of a fluid;

[0019] Fig. 9 illustrates a simplified diagram of a continuous fluid delivery profile;

[0020] Fig. 10 illustrates one embodiment of a cartridge;

[0021] Fig. 11 illustrates a side view of the trocar of Fig. 7;

[0022] Fig. 12 illustrates a side view of the deployable trocar of Fig. 7;

[0023] Fig. 13 illustrates a side view of an embodiment of an insertable trocar;

[0024] Fig. 14 illustrates a side view of the deployable trocar of Fig. 13;

[0025] Fig. 15 illustrates a side view of the deployable trocar of Fig. 13;

[0026] Fig. 16A illustrates a side view of one embodiment of a drop-down drywall anchor;

[0027] Fig. 16B illustrates a side view of the drop-down drywall anchor of Fig. 16A;

[0028] Fig. 16C illustrates a side view of the drop-down drywall anchor of Fig. 16B;

[0029] Fig. 16D illustrates a side view of the drop-down drywall anchor of Fig. 16C;

[0030] Fig. 17 illustrates a distal view of one embodiment of a needle with surface features;

[0031] Fig. 18A illustrates a view from the distal tip of one embodiment of a stylet;

[0032] Fig. 18B illustrates a view from the distal tip of another embodiment of a stylet;

[0033] Fig. 18C illustrates a view from the distal tip of another embodiment of a stylet;

[0034] Fig. 18D illustrates a view from the distal tip of another embodiment of a stylet;

[0035] Fig. 19 illustrates a simplified diagram of one embodiment of an injection needle;

[0036] Fig. 20 illustrates a side sectional view of the renal corpuscle capsule;

[0037] Fig. 21 illustrates a diagram related to identifying the optimal needle size;

[0038] Fig. 22 illustrates the distal end of an injection needle with a ruler;

[0039] Fig. 23 illustrates the distal end of the injection needle of Fig. 22 with a ruler clearly indicating the placement of the slot in the distal end;

[0040] Fig. 24 illustrates an exemplary method of holding a small syringe for improved control;

[0041] Fig. 25 illustrates a simplified cross-sectional view of the placement of the trocar of Fig. 7 in the kidney;

[0042] Fig. 26 illustrates a simplified cross-sectional view of the placement of the trocar of Fig. 7 in the kidney of Fig. 25;

[0043] Figs. 27A-F illustrate an embodiment of delivering multiple boluses of a therapeutic agent to the kidney.

[0044] It should be understood that the above drawings are not necessarily drawn to scale, but represent a somewhat simplified representation of various preferred features illustrating the basic principles of the disclosure. Specific design features of the present disclosure, including, for example, specific dimensions, orientations, locations, and shapes, should be determined in part by the specific intended application and environment of use.

Detailed description of the invention

[0045] Exemplary embodiments of the present disclosure are now described in detail with reference to the accompanying drawings. Those skilled in the art will appreciate that the described embodiments can be modified in various ways without departing from the spirit or scope of the present disclosure. Additionally, throughout the detailed description, like reference numerals indicate like elements.

[0046] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the disclosure. As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise. It should be further understood that the terms "comprises" and/or "comprising," as used in this detailed description, specify the presence of the recited features, integers, steps, operations, elements, or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, or groups thereof. As used herein, the term "and/or" includes any and all combinations of one or more of the associated recited elements. Linking terms such as "sleeved," "engaged," etc., denote a physical relationship between two components whereby the components are either directly connected to each other or indirectly connected through one or more intermediate components.

[0047] It should be understood that the term "patient" or other similar term, when used herein, encompasses any test subject (human or animal) to which the therapy disclosed herein can be performed. The term "user," when used herein, encompasses any object capable of interacting with or controlling the device. A "user" may also be a "patient," or the "user" and "patient" may be separate objects, as described herein. In particular embodiments, the test subject is a living animal. In particular embodiments, the test subject is a mammal, such as a dog, cat, horse, rabbit, zoo animal, cow, pig, sheep, goat, camel, mouse, rat, or guinea pig. In particular embodiments, the test subject is a primate, such as a human, chimpanzee, orangutan, monkey, or baboon. In particular embodiments, the test subject is a human. In specific embodiments, the test subject is a patient eligible for treatment who is experiencing or has experienced one or more signs, symptoms or other indicators of kidney disease. Such test subjects include, but are not limited to, test subjects who are being diagnosed for the first time or who have been previously diagnosed and are now experiencing a relapse or exacerbation or are at risk for kidney disease, regardless of the cause. In specific embodiments, the test subject may or may not have been previously treated for kidney disease. In specific embodiments, the test subject has diabetes. In specific embodiments, the test subject has type 1 diabetes. In specific embodiments, the test subject has type 2 diabetes. In specific embodiments, the test subject has chronic kidney disease. In specific embodiments, the test subject has a congenital anomaly of the kidney and/or urinary tract. In specific embodiments, the test subject is a human with congenital anomalies of the kidney and urinary tract. In specific embodiments, the test subject experiences 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 specific embodiments, the test subject does not have diabetes. In specific embodiments, the test subject does not have type 1 diabetes. In specific embodiments, the test subject does not have type 2 diabetes. In specific embodiments, the test subject does not have kidney disease. In specific embodiments, the test subject has cancer. In specific embodiments, the cancer comprises a solid tumor.

[0048] In one aspect, the devices, systems, and methods provided herein are useful for administering an anti-cancer agent or chemotherapy to a patient. In some embodiments, administering an anti-cancer agent comprises delivering the anti-cancer agent or chemotherapy to an internal tissue or organ of a subject under study. In some embodiments, the patient has a solid tumor. In some embodiments, the solid tumor is within, on, invades, or is part of an organ. In some embodiments, the internal tissue site or organ is a 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 some embodiments, the test subject has cancer. In some embodiments, the cancer is melanoma (e.g., metastatic melanoma that has spread to an internal location such as an organ), a neuroendocrine tumor, a carcinoma, or a sarcoma. In some 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 or metastatic breast cancer), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung carcinoma, squamous cell lung carcinoma, adenocarcinoma, large cell carcinoma lung, 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 (such as of the head, neck, or esophagus), or colorectal cancer. In some embodiments, the test subject has cancer of the thyroid gland, endocrine system, brain, breast, cervix, colon, head and neck, esophagus, liver, kidney, lung, non-small cell lung, melanoma, sarcoma, stomach, uterine medulloblastoma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumor, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, testicular cancer, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cancer, medullary thyroid cancer, medullary thyroid cancer, metastatic melanoma (e.g., melanoma that has spread (an internal location such as an organ), colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget's disease of the nipple, phyllodes tumor, lobular carcinoma, ductal carcinoma, pancreatic stellate cell carcinoma, hepatic stellate cell carcinoma, or prostate cancer. The term "sarcoma" generally refers to a tumor that is composed of a substance similar to embryonic connective tissue and is usually composed of tightly packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that can be treated with the device, system or method provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemeti's sarcoma, adipose sarcoma, liposarcoma, alveolar soft tissue sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor, 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 lymphoblastic sarcoma, immunoblastic T-cell sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymal sarcoma, parosteal sarcoma, reticulocyte sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectatic sarcoma. The term "melanoma" usually refers to a tumor arising from the melanocytic system of the skin and other organs. Melanomas that can be treated using the device, system, or method provided herein include, for example, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna type melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma. In some embodiments, the melanoma is metastatic melanoma, which has spread to an internal location (e.g., an organ or lymph node) in the patient. The term "carcinoma" refers to a malignant neoplasm composed of epithelial cells that tend to infiltrate surrounding tissues and cause metastasis. Exemplary carcinomas that can be treated using the device, system or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenal cortex carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basal cell carcinoma, basal squamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedone carcinoma, corpus carcinoma, carcinoma in cuirass, skin cancer, cylindrical carcinoma, cylindrical cell carcinoma, ductal carcinoma, ductal carcinoma, carcinoma of the dura mater, embryonal carcinoma, encephaloid carcinoma, epidermoid carcinoma, epithelial carcinoma of the adenoid, exophytic carcinoma, ex-ulcerative carcinoma, fibrous carcinoma, gelatiniform carcinoma, gelatinous carcinoma, giant cell carcinoma, giant cellular carcinoma, glandular carcinoma, granulosa cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher carcinoma, Kulchitsky carcinoma, large cell carcinoma, lenticular carcinoma, lenticular carcinoma, lipomatous carcinoma, lobular carcinoma, lymphoepithelial carcinoma, carcinoma medullary, medullary carcinoma, melanotic carcinoma, carcinoma of the palate, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellular, mucoepidermoid carcinoma, carcinoma mucosa, mucosal carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, forceps cell carcinoma, vesicular carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, solanoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, spongiform carcinoma, squamous cell carcinoma, squamous cell carcinoma, string carcinoma, telangiectatic carcinoma, telangiectotic carcinoma, transitional cell carcinoma, tubercular carcinoma, tubular carcinoma, tuberous carcinoma, warty carcinoma, or villous carcinoma.

[0049] An "anti-cancer agent" is a therapeutic agent used to treat or prevent cancer. In some embodiments, the anti-cancer agent may be a large molecule (e.g., a protein or other organic compound with a molecular weight of at least 2,000 daltons) or a small molecule (e.g., an organic compound with a molecular weight of less than 2,000 daltons). Examples of anti-cancer agents include antibodies, small molecules, and large molecules, or combinations thereof. In some embodiments, the anti-cancer agent comprises a cell, such as an immune cell. In some embodiments, the immune cell has been modified (e.g., genetically and/or by exposure to a tumor antigen) to attack or stimulate an immune response to tumor cells. In some 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 plasmacytoid dendritic cell). In some embodiments, the immune cell has been genetically modified, such as a chimeric antigen receptor (CAR) T cell. In some embodiments, the anti-cancer agent inhibits cell growth or proliferation. In some embodiments, the anti-cancer agent is a chemotherapeutic agent. In some embodiments, the anti-cancer agent is an agent described herein that is useful in methods for treating cancer. In some 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 U.S. for the treatment of cancer. Examples of anticancer agents include, but are not limited to, MEK inhibitors (e.g., MEK1, MEK2, or MEK1 and MEK2) (e.g., XL518, CI-1040, PD035901, selumetinib/AZD6244, GSK1120212/trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY 869766), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, thiourostemin, uraiomustin, nitrogen mustards (e.g. mechlorethamine, cyclophosphamide, chlorambucil, meifalan), ethyleneimine and methylmelamines (e.g. hexamethylmelamine, thiotepa), alkyl sulfonates (e.g. busulfan), nitrosoureas (e.g. carmustine, lomusitne, semustine, streptozocin), triazenes (decarbazine)), antimetabolites (e.g. 5-azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folate analogue (e.g. methotrexate) or pyrimidine analogues (e.g. fluorouracil, floxuridine, cytarabine), purine analogues (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-based drugs or platinum-containing agents (e.g. cisplatin, oxaloplatin, carboplatin), anthracenedione (e.g. mitoxantrone), substituted urea (e.g. hydroxyurea), methylhydrazine derivative (e.g. procarbazine), adrenocortical suppressant (e.g. mitotane, aminoglutethimide), epipodophyllotoxins (eg, etoposide), antibiotics (eg, daunorubicin, doxorubicin, bleomycin), enzymes (eg, L-asparaginase), mitogen-activated protein kinase signaling inhibitors (eg, U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, or wortmannin LY294002), Syk inhibitors, mTOR inhibitors, antibodies (eg, rituxan), gossifol, genasens, polyphenol E, chlorofusin, all-trans retinoic acid (ATRA), bryostatin, tumor necrosis factor-associated apoptosis-inducing ligand tumors (TRAIL), 5-aza-2'-deoxycytidine, all-trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec®), geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), 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 antagonists; altretamine; acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; D antagonist; G antagonist; antarelix; antidorsalizing morphogenetic protein-1; antiandrogen, prostate carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorines; benzoylstaurosporine; beta-lactam derivatives; beta-aletin; betalamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnaphid; bistraten A; bizelesin; breflat; bropirimine; budotitan; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canary pox IL-2; capecitabine; carboxamide-aminotriazole; carboxyamidotriazole; KaRest M3; CARN 700; cartilage origin inhibitor; carcelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomiphene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambecidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanethraquinones; cycloplatam; cypemycin; cytarabine oxphosphate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexiphosphamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemen; emifur; epirubicin; episteride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fudarabine; fluorodaunorucin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; halocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfame; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulatory peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplast; irsogladine; isobengazole; isohomogalicondrine 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 analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribin; lartothecan; lutetium texaphyrin; Lysof line; lytic peptides; maytansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; metrelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double-stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor - saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotropin; monophosphoryl lipid A + myobacterial cell wall sk; mopidamole; multidrug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agent; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestipe; naloxone + pentazocine; napavine; nafterpine; narthragrastim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nizamycin; nitric oxide modulators; nitroxide antioxidant; nitrulline; 06-benzylguanine; octreotide; oxycenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoyl rhizoxin; pamidronic acid; panaxytriol; panomifen; parabactin; pazelliptin; pegaspargase; peldesin; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perphosphamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; pyritrexime; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; sodium porfimer; porfiromycin; prednisolone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immunomodulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgae; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; polyoxyethylated pyridoxylated hemoglobin conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptin demethylated; rhenium etidronate Re 186; rhizoxin; ribozymes; RII retinamide; roglethimide; rohitukin; romertide; roquinimex; rubiginone B 1; ruboxil; safingol; sentopin; SarChNU; sarcophytol A; sargramostim; Sdi-1 mimetics; semustine; senescence inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single-chain antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spamycin D; spiromustin; splenentin; spongistatin 1; squalamine; stem cell inhibitor; stem cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradistu; suramin; swainsonine; synthetic glycosaminoglycans; thallimustine; tamoxifen methiodide; tavromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrilium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlordecaoxide; tetrazomine; taliblastine; thiocoralin; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinane; thyroid stimulating hormone; tin ethyl etiopurpurine; tirapazamine; titanocene dichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, gene therapy of red blood cells; velaresol; veramin; verdeny; verteporfin; vinorelbine; vinxaltine; vitamin; vorozole; zanoteron; zeniplatin; zilascorb; zinostatin stimulator; adriamycin; dactinomycin; bleomycin; vinblastine; cisplatin; acivicin; aclarubicin; acodazole hydrochloride; acronin; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepu; azotomycin; batimastat; benzodepu; bicalutamide; bisantrene hydrochloride; Bisnafide dimesylate; Biselesin; Bleomycin sulfate; Brequinar sodium; Bropirimine; Busulfan; Cactinomycin; Calusterone; Karacemid; Carbetimer; Carboplatin; Carmustine; Carubicin hydrochloride; Carcelesin; Cedefingol; Chlorambucil; Cirolemycin; Cladribine; Crisnatol mesylate; Cyclophosphamide; Cytarabine; Dacarbazine; Daunorubicin hydrochloride; Decitabine; Dexormaplatin; Desaguanine; Desaguanine mesylate; Diaziquone; Doxorubicin; Doxorubicin hydrochloride; Droloxifene; Droloxifene citrate; Dromostanolone propionate; Duazomycin; Edatrexate; Eflornithine hydrochloride; Elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flucitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; imifosine; interleukin II (including recombinant interleukin II or rIL ₂₎ , 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; Meturedepu; Mitindomide; Mitocarcin; Mitocromin; Mitogilline; Mitomalcin; Mitomycin; Mitospir; Mitotane; Mitoxantrone hydrochloride; Mycophenolic acid; Nocodazoles; Nogalamycin; Ormaplatin; Oxysuran; Pegaspargase; Peliomycin; Pentamustine; Peplomycin sulfate; Perphosphamide; Pipobroman; piposulfan; pyroxantrone hydrochloride; plicamycin; plomestan; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; roglethimide; safingol; safingol hydrochloride; semustine; simtrazen; sodium sparfosate; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepu; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; tricyribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulosole hydrochloride; uracil mustard; uredepu; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglicinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride, agents that arrest cells in the G2-M phases and/or modulate microtubule formation or stability (e.g., Taxol™ (i.e., paclitaxel), Taxotere™, compounds containing the taxane skeleton, erbulozole (i.e., R-55104), Dolastatin 10 (i.e., DLS-10 and NSC-376128), Mivobulin Isethionate (i.e., as CI-980), Vincristine, NSC-639829, Discodermolide (i.e., as NVP-XX-A-296), ABT-751 (Abbott, i.e., E-7010), Altorhirtins (e.g., Altorhirtin A and Altorhirtin C), Spongistatins (e.g., Spongistatin 1, spongistatin 2, spongistatin 3, spongistatin 4, spongistatin 5, spongistatin 6, spongistatin 7, spongistatin 8 and spongistatin 9), cemadotin hydrochloride (e.g. LU-103793 and NSC-D-669356), epothilones (e.g. epothilone A, epothilone B, epothilone C (i.e., deoxyepothilone A or dEpoA), epothilone D (i.e., KOS-862, dEpoB, and deoxyepothilone B), epothilone E, epothilone F, epothilone B N-oxide, epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (i.e., BMS-310705), 21-hydroxyepothilone D (i.e., deoxyepothilone F and dEpoF), 26-fluoroepothilone, auristatin PE (i.e., NSC-654663), soblidotin (i.e., TZT-1027), vincristine sulfate, cryptophycin 52 (i.e., LY-355703), vitilevamid, tubulysin A, canadensol, kentauridin (i.e., NSC-106969), oncocidin A1 (i.e., BTO-956 and DF E), fijianolide B, laulimali de, narcosine (also known as NSC-5366), nascapine, hemiasterlin, vanadocene acetylacetonate, monsatrol, linanocin (e.g., NSC-698666), eleutherobins (such as desmethyleleutherobin, desaethyleleutherobin, isoeleutherobin A, and Z-eleutherobin), caribeoside, caribeolin, halichondrin B, diazonamide A, taccalonolide A, diozostatin, (-)-phenylhistine (ieNSCL-96F037), myoseverin B, resveratrol sodium phosphate, steroids (eg, dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone (GnRH) agonists such as goserelin or leuprolide, adrenocorticosteroids (eg, prednisolone), progestins (eg, hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (eg, diethylstilbestrol, ethinyl estradiol), antiestrogens (e.g. tamoxifen), androgens (e.g. testosterone propionate, fluoxymesterone), antiandrogens (e.g. flutamide), immunostimulants (e.g. bacille Calmette-Guérin (BCG), levamisole, interleukin-2, alpha interferon, etc.), monoclonal antibodies (e.g. anti-CD20, anti-FER2, anti-CD52, anti-ULA-DR and anti-VEGF monoclonal antibodies), immunotoxins (e.g. anti-CD33-calicheamicin monoclonal antibody, anti-CD22-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g. anti-CD20 monoclonal antibody conjugated with U1ln, 90 Y or mI, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabraferfitib, EGFR inhibitor therapy or therapeutic agents (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/desmethyl erlotinib, AZD8931, AEE788, pelitinib/EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, hormonal therapy, etc.

[0050] The transitional term "comprising," which is synonymous with "including," "containing," or "characterized by," is inclusive or multivariate and does not exclude additional unrecited features, integers, steps, operations, elements, and/or components. In contrast, the transitional phrase "consisting of" excludes any features, integers, steps, operations, elements, and/or components that are not recited. The transitional phrase "consisting essentially of" limits the scope of a claim to the recited features, integers, steps, operations, elements, and/or components "and features, integers, steps, operations, elements, and/or components that do not substantially affect the basic and novel characteristic(s)" of the claimed invention.

[0051] 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 limited range.

[0052] The term "ambient temperature" means the temperature at which the compositions of the present disclosure are applied to the test subject. In general, ambient temperature is the temperature of a thermally controlled environment. Ambient temperature ranges from about 18°C to about 30°C. In particular embodiments, the 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.

[0053] A "fluid-based pharmaceutical formulation" is a pharmaceutical composition that is a liquid at the time it is delivered (i.e., administered) to a patient. In particular embodiments, the fluid-based pharmaceutical formulation comprises an active agent, such as a chemical compound, a cell, or a cellular product, and a pharmaceutically acceptable carrier. In particular embodiments, the pharmaceutically acceptable carrier is a temperature-sensitive biomaterial.

[0054] The devices, systems, and methods provided herein are generally useful for delivering fluid-based pharmaceutical formulations to tissue sites, such as organs (e.g., solid organs). In particular embodiments, the tissue site is a tumor (e.g., a solid or rigid tumor). In particular embodiments, the tissue site is an organ that contains cancer cells or a tumor. In particular embodiments, the tissue site contains tumor cells. In particular embodiments, the tissue site is a lymph node that contains tumor cells. However, in particular embodiments, the present subject matter is particularly useful for delivering bioactive renal epithelial cells (e.g., bioactive renal epithelial cells, such as selected renal epithelial cells) to the kidneys of patients with kidney disease.

[0055] The term "bioactive renal epithelial cells" or "BRCs," as used herein, refers to renal epithelial cells that have one or more of the following properties when applied to the kidney of a test subject: the ability to reduce (e.g., slow or stop) the worsening or progression of a chronic kidney disease or symptom thereof, the ability to improve renal function, the ability to affect (improve) renal homeostasis, and the ability to accelerate the healing, repair, and/or regeneration of renal tissue or the kidney. In particular embodiments, these cells may include functional tubular cells (e.g., based on improvements in creatinine excretion and protein deposition), glomerular cells (e.g., based on improvements in protein deposition), vascular cells, and other corticomedullary junction cells. In particular embodiments, the BRCs are obtained by isolating and stretching renal epithelial cells from kidney tissue. In particular embodiments, BRCs are obtained by isolating and expanding renal epithelial cells from kidney tissue using methods that select bioactive cells. In particular embodiments, BRCs have a regenerative effect on the kidney. In particular embodiments, BRCs comprise, consist essentially of, or consist of selected renal epithelial cells (SRCs). In particular embodiments, BRCs are SRCs.

[0056] In particular embodiments, the SRCs are cells obtained from the isolation and expansion of renal epithelial cells from a suitable renal tissue source, wherein the SRCs comprise a higher percentage of one or more cell types and lack or have a lower percentage of one or more other cell types, compared to the starting population of renal cells. In particular embodiments, the SRCs comprise an increased proportion of BRCs compared to the starting population of renal cells. In particular embodiments, the SRC population is an isolated population of renal cells supplemented with specific bioactive components and/or cell types and/or lacking specific inactive and/or unhelpful components or cell types for use in the treatment of kidney disease, i.e., in providing stabilization and/or improvement and/or regeneration of kidney function. The SRCs provide superior therapeutic and regenerative results compared to the starting population. In particular embodiments, the SRCs are obtained from renal cortical tissue of a patient via a kidney biopsy. In particular embodiments, the SRCs are selected (e.g., by fluorescence-activated cell sorting, or "FACS") based on their expression of one or more markers. In particular embodiments, the SRCs are depleted (e.g., by fluorescence-activated cell sorting, or "FACS") of one or more cell types based on the expression of one or more markers relative to the cell types. In particular embodiments, the SRCs are selected from a population of bioactive renal epithelial cells. In particular embodiments, the SRCs are selected by density gradient separation of stretched renal epithelial cells. In particular embodiments, the SRCs are selected by separation of stretched renal epithelial cells by centrifugation at a density limit, barrier, or interface, or by single-step discontinuous step gradient separation. In particular embodiments, the SRCs are selected by continuous or discontinuous density gradient separation of stretched renal epithelial cells that are cultured under hypoxic conditions. In particular embodiments, the SRCs are selected by density gradient separation of stretched renal epithelial cells that have been cultured under hypoxic conditions for at least about 8, 12, 16, 20, or 24 hours. In particular embodiments, the SRCs are selected by separation by centrifugation at a density limit, barrier, or interface of stretched renal epithelial cells that have been cultured under hypoxic conditions. In particular embodiments, the SRCs are selected by separation by centrifugation at a density limit, barrier, or interface (e.g., single-step discontinuous density gradient separation). In particular embodiments, the SRCs are composed primarily of tubular renal epithelial cells. In particular embodiments, other parenchymal (e.g., vascular) and stromal (e.g., collecting duct) cells may be present in the SRC. In particular embodiments, less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the cells in the SRC population are vascular cells. In particular embodiments, less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the cells in the SRC population are collecting duct cells. In particular embodiments, less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the cells in the SRC population are vascular or collecting duct cells.

[0057] The term "non-renal augmentation (NKA)" means a bioactive cellular formulation that is an injectable product consisting of autologous selected renal epithelial cells (SRCs) in a pre-fabricated biomaterial formulation containing a gelatin hydrogel.

[0058] The term "kidney disease" as used herein means disorders associated with any stage or degree of acute or chronic renal failure that results in the loss of the kidney's ability to perform its function of filtering blood and removing excess fluid, electrolytes, and waste from the blood. Kidney disease may also include endocrine dysfunctions such as anemia (deficiency of erythropoietin) and mineral imbalances (deficiency of vitamin D). Kidney disease may originate in the kidney or may be secondary to a variety of conditions including, but not limited to, heart failure, hypertension, diabetes, autoimmune disease, or liver disease. Kidney disease may be a condition of chronic renal failure that develops subsequent to acute kidney injury. For example, kidney injury due to ischemia and/or exposure to toxicants may cause acute renal failure; Incomplete recovery from acute kidney injury can lead to the development of chronic renal failure.

[0059] The term "spheroid" means an aggregate or node of cells cultured to provide three-dimensional growth, as opposed to growth as a monolayer. It should be noted that the term "spheroid" does not imply that the aggregate is a geometric sphere. In particular embodiments, the aggregate may be highly organized with a well-defined morphology, or the aggregate may be a disorganized mass. In particular embodiments, the spheroid may include one cell type or more than one cell type. In particular embodiments, the cells may be primary isolates or a continuous cell line, or a combination thereof. In particular embodiments, the spheroids (e.g., cell aggregates or organoids) are formed in a centrifuge tube. In particular embodiments, the spheroids (e.g., cell aggregates or organoids) are formed in a three-dimensional matrix.

[0060] With respect to kidney disease, and depending on the context, "treatment" means both therapeutic treatment and prophylactic or preventative measures for kidney disease, tubular transport cell deficiency, or glomerular filtration deficiency, wherein the goal is to reverse, prevent, or slow (reduce) the target disorder or symptom. Those in need of treatment include those who already have kidney disease, tubular transport cell deficiency, or glomerular filtration deficiency, as well as those susceptible to kidney disease, tubular transport cell deficiency, or glomerular filtration deficiency, or those in whom kidney disease, tubular transport cell deficiency, or glomerular filtration deficiency is to be prevented. In specific embodiments, treatment includes stabilizing and/or improving kidney function. With respect to cancer, treatment may include, for example, reduced tumor volume, reduced tumor growth rate, increased immune response to a tumor antigen, decreased cancer cell growth, decreased cancer cell proliferation, or decreased cancer cell survival (e.g., increased cell death, such as apoptosis or necrosis, of tumor cells).

[0061] Use of therapeutic agents

[0062] Extravascular delivery may involve direct injection of a fluid-based pharmaceutical formulation (e.g., a fluid-based pharmaceutical formulation containing therapeutic cells) into an organ, such as into the stroma of an organ, via one or more devices such as syringes, catheters, trocars, etc. "Extravascular injection" means delivery by injection outside of blood vessels. In extravascular delivery, the residence time of the therapeutic cells may be long. For example, the cleaning or washing process may rely on cleaning processes associated with local trauma and removal of edema at the delivery site. The efficiency of delivery may also be high. However, successful delivery of therapeutic cells or their products may be difficult. For example, extravasation of therapeutic cellular material through the entry slit of a delivery device may be difficult due to a variety of different issues. Extravasation may be considered as leakage (particularly unintentional leakage) of fluid from the injection target site. For example, natural movement of the delivery target due to patient movement (and thus movement of the target site), for example, through breathing, may result in an unsteady delivery target. Inaccurate delivery of therapeutic cell material may also be caused by trauma to the treatment site due to impact and cutting action by delivery instruments caused by movement during application. Additionally, delivery may be difficult due to how the infusion of therapeutic cells or their products occurs, for example, through a continuous flow with a dose rate into the target site.

[0063] For these and other reasons, improved devices, methods, and systems for delivering fluid-based pharmaceutical formulations (e.g., cell therapy) are needed. Provided herein are, among other things, improved devices, methods, and systems for delivering therapeutic compositions, such as compositions containing chemical compounds, cells, or cellular products.

[0064] In an aspect, the present document includes devices, methods, and systems for delivering cell therapy, for example, with metered infusion capabilities delivered extravascularly to target locations within a patient while maintaining positional stability. The use of cell therapy is a very popular and successful approach to treating a variety of different diseases. For example, extravascular delivery of cell therapy is successful in providing a long residence time of the therapeutic cell material at the treatment site and increased delivery efficiency. However, extravascular delivery leads to problems such as extravasation of the therapeutic cell material caused by factors such as patient movement (and thereby target site movement), treatment site trauma due to impact and cutting action by delivery instruments caused by patient movement, and infusion of therapeutic cell materials through a continuous flow in a metered manner into the treatment site. Thus, devices, methods and systems are provided that are designed to provide stability of delivery of a therapeutic agent (for example, cellular material, for example, cells or their product, such as exosomes), for example, by providing a physically stable delivery process and intermittent flows taking into account the dosage of the therapeutic cellular material.

[0065] In an aspect, included herein are devices, methods, and systems for delivering a fluid-based pharmaceutical composition (e.g., a cell therapy), such as with metered infusion capabilities, delivered extravascularly to target locations within a patient while maintaining positional stability. 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.

[0066] In particular embodiments, the injection device provided herein is configured to deliver a continuous flow of fluid to a target site. In particular embodiments, the injection device provided herein is configured to deliver an intermittent flow or bolus of fluid to a target site. An exemplary device provided herein may be configured to deliver intermittent flows or boluses of fluid, such as a fluid-based pharmaceutical formulation containing cells or cellular products, to a target site. A bolus may be considered one physical portion of a pharmaceutical composition (such as a fluid-based pharmaceutical formulation). In particular embodiments, a bolus is a portion of a pharmaceutical composition (such as a fluid-based pharmaceutical formulation) that is delivered as a single event. In specific embodiments, a bolus is a portion of a pharmaceutical composition (such as a fluid-based pharmaceutical formulation) that is delivered as part of multiple portions (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more portions) that are delivered one after the other, such as during administration of the pharmaceutical composition. In specific embodiments, a single bolus is delivered. In specific embodiments, the pharmaceutical composition is not delivered between multiple discrete boluses. In specific embodiments, a continuous flow of the pharmaceutical composition occurs. In specific embodiments, the delivery is continuous, but the amount of the pharmaceutical composition is pulsatile (i.e., the flow does not stop, but increases and decreases over time). In specific embodiments, the device provided herein is configured to be operated with one hand. In particular embodiments, the injection device may be engaged with an exemplary trocar, which is configured to have one or more stabilizing mechanisms on the shaft, so that the trocar provides a stable delivery mechanism to the injection device. In particular embodiments, the trocar is configured to receive an injection needle that is connected to the injection device, and the injection device can deliver a dose as a continuous flow of fluid through it to the target tissue site. In particular embodiments, the trocar is configured to receive an injection needle that is connected to the injection device, and the injection device can deliver fluid through it in bolus doses to the target tissue site. In specific embodiments, the devices, systems, and methods provided herein can be used in a variety of treatments, such as delivering a measured dosage of therapeutic cells or cellular products to a kidney (e.g., in a patient who has a kidney disease, such as chronic kidney disease) by directly delivering a fluid containing the therapeutic cells or cellular products to multiple extravascular injection sites in the renal parenchymal/stromal regions of the patient. In specific embodiments, the patient is positioned in a prone position or in a transverse position, as illustrated in Figs. 1 and 2. "Parenchyma" is the functional tissue of an organ, as opposed to connective and supportive tissue. "Stroma" is the supportive tissue of an epithelial organ, tumor, gonad, etc., consisting of connective tissues and blood vessels. In specific embodiments, the subject has an advanced stage of kidney failure. However, although the disclosure explains the treatment of the kidneys herein, the devices, systems, and methods can be used broadly. In particular embodiments, the devices, systems, and methods provided herein can be used in a variety of treatments, such as delivering a measured dosage of therapeutic cells or cell products to a tissue site that has cancer cells, such as a solid tumor. In particular embodiments, the tissue site is an organ that has or is suspected of having cancer cells (e.g., metastatic cancer cells or a tumor).

[0067] In particular embodiments, the devices, systems and methods provided herein are useful for percutaneous injection of fluid-based pharmaceutical formulations into a cancer cell or solid tumor containing an organ and/or directly into a tumor. In particular embodiments, it is important to distribute the formulation in the organ as widely as possible. In particular embodiments, distribution of the formulation in the organ or tumor is achieved by entering the organ or tumor at an angle that ensures deposition of the formulation in the organ or tumor as widely as possible. In particular embodiments, the organ or tumor is imaged in a longitudinal or transverse approach using ultrasound guidance or axial imaging based on computed tomography (CT), depending on the individual patient characteristics. In particular embodiments, the injection comprises multiple deposits as the injection needle is gradually withdrawn. In particular embodiments, the entire volume of the formulation can be deposited at one or more entry points. In specific embodiments, up to two entry points may be used to deposit the full volume of the therapeutic composition into the organ or tumor.

[0068] In particular embodiments, the devices, systems and methods provided herein are useful for percutaneous injection of fluid-based pharmaceutical formulations into the renal cortex of a kidney. In particular embodiments, it is important to distribute the formulation in the renal cortex as widely as possible. In particular embodiments, distribution of the formulation in the renal cortex is achieved by entering the renal cortex at an angle that ensures deposition of the formulation in the renal cortex as widely as possible. In particular embodiments, the kidney is imaged in a longitudinal or transverse approach using ultrasound guidance or axial CT imaging, depending on the individual patient characteristics. In particular embodiments, the injection comprises multiple deposits as the injection needle is gradually withdrawn. In particular embodiments, the entire volume of the formulation can be deposited at one or more entry points. In specific embodiments, up to two entry points may be used to deposit the full volume of the therapeutic composition into the kidney. In specific embodiments, the injection may be applied to one kidney, using one or more entry points, such as one or two entry points. In specific embodiments, the injection is performed in both kidneys, in each kidney, using one or more entry points, such as one or two entry points.

[0069] The devices and systems provided herein provide advantages over commercially available devices. Figs. 3 and 4 illustrate a process for performing cell therapy using standard components for a patient's kidney. For example, standard parts such as needles, trocars/hubs, luer locks, valves, tubing, 3 cc syringes, and 10 cc syringes can be stored as inventory at a location where the therapeutic cell material is processed. A kit can be prepared that contains the above elements in parallel assays, with a range of sizes for different needles and trocars/hubs. The range of gauge sizes for needles can include a range of lengths: 10 cm, 15 cm, and 20 cm. A 10 cc syringe, which can be used in a package that provides aseptic filling for cell therapy, can be filled with a dose. The syringe with the drug dose may then be shipped separately to the procedure site in temperature controlled packaging that maintains the therapy at approximately 4-8°C during transport. At the procedure site, a protocol may be implemented to warm the syringe, assemble the injection system, and organize and prepare supplies for the user. For example, the syringe may be heated to approximately 26-28°C for a controlled period of time, such as approximately 30 minutes. The user may then begin the procedure within an allocated window for the viability of the products, which may be approximately 1.5 hours. Fig. 4 illustrates a non-restrictive injection system as discussed above in which a 3 cc syringe is connected to a 10 cc syringe via a 3-way stopcock. The output from the stopcock is sent through a tubing system to a luer lock on the injection needle in a trocar/hub positioned inside the patient. The cell therapy may initially be transferred into a 3 cc syringe via a 10 cc plunger, and may then be injected into the patient's kidney with the control and ease of plunger movement provided by the smaller syringe. Injection of the cell therapy may be a complex task that may require a minimum of both hands by the lead user and often an additional hand to assist with the plunger manipulation while stabilizing the trocar, needle, and injection system. The devices and systems included herein provide advantages over the processes and components illustrated in Figs. 3 and 4, such as increased stability (and less damage) during delivery of the therapeutic agent, as well as more consistent delivery of the therapeutic agent (e.g., in amount and location).

[0070] Fig. 5 illustrates one non-limiting embodiment of a trocar 20 that may be used herein. As a non-limiting example, in its simplest form, a trocar may be approximately a pen-shaped instrument with at least a somewhat sharp triangular point at one end, often used within a hollow tube known as a cannula or sleeve, to create an opening in the body through which the sleeve can be inserted to provide an access port during surgery. In particular embodiments, the trocar is a pen-shaped instrument with two parts, a solid obturator/stylet with a sharp triangular point at one end within a hollow tube known as a cannula or sleeve (e.g., the trocar is used to create an opening in the body; the stylet can be removed, leaving the sleeve to provide a port for access to internal structures). The trocar 20, as illustrated in Fig. 5 may have a handle 22, an extended shaft 24, a shield 26 and a shield release 28. The lumen may extend through them. Fig. 6 illustrates one non-limiting cannula 30 that may be used herein. The cannula 30 has a handle 32 and a sleeve 34, and it may have a lumen extending through them. When a trocar, such as trocar 20, is placed inside a patient, the trocar is secured primarily at two points. The frictional grip of the trocar occurs in the through-passage in the skin, and similarly, a weaker interaction occurs in the trocar through the internal tissue, for example, the capsule of the kidney. The frictional grip in the internal tissue is weaker due to the small penetration depth of the trocar. However, stabilizing the depth of trocar penetration into tissue, such as the kidney, during the procedure may be advantageous to avoid tissue trauma and assist in smoother injection of therapeutic cell material, and detrimental movement of the dermal anchor point relative to the anchor point of internal tissues, such as the kidney, may occur.

[0071] Injection device

[0072] Fig. 7 illustrates one non-limiting example of an injection device 100 that may be configured to be operated with one hand with a removable trocar 200 that has a stylet 300 and that extends distally from the device 100 along a longitudinal axis L1 of the device 100. The injection device 100 has a housing 101, a handle 102, an actuator 104, a fluid receptacle 106, a display 108, and a trocar engagement mechanism 110. In particular embodiments, the display 108 is omitted. In particular embodiments, the device 100 is provided with a pump (not shown), one or more sensors configured to detect a plurality of conditions such as pressure, flow rate, temperature, etc. (not shown), a power source such as a battery (not shown), and/or a central processing unit (CPU) (not shown). In Fig. 7, the handle 102 extends from the casing 101 and has the shape of a pistol grip. However, a variety of handles, grips, controls, etc. may be used.

[0073] The actuator 104 is a trigger pawl that is configured to actuate the delivery of a fluid from the fluid receptacle 106 and through the valve 120 at the distal end of the injection device 100, explained in more detail below. Although the actuator 104 is illustrated as a trigger pawl, the actuator may have various forms, such as plungers, buttons, switches, electronic actuation means, CPU-driven means included in the display 108, etc. The actuator 104 is configured to be manually pressed toward the handle 102. In particular embodiments, as the actuator 104 is pressed, the actuator 104 may be configured to provide tactile feedback to the user. In particular embodiments, the haptic feedback may be physically generated from a manual pressing of the actuator 104, or it may be simulated. For example, the device 100 may have one or more haptic feedback mechanisms built into it that are configured to simulate a mechanical action of the actuator 104, which is actually electromechanical and controlled by a CPU. In particular embodiments, the pressing of the actuator 104 is configured to deliver fluid from the fluid receptacle 106 to the valve 120 in a pulsed delivery pattern that includes discrete boluses 122 of fluid delivery to the target site, as illustrated in Fig. 8, and it is configured to retract the injection needle from the target site during fluid delivery in order to provide space for distension for the delivered fluid. In particular embodiments, the discrete boluses 122 of fluid may be configured to not be in direct contact with each other, which allows preventing or reducing extravasation from the target tissue site. In particular embodiments, the device may alternatively be configured to deliver continuous streams 123 of fluid, as illustrated in Fig. 9, or to implement a combination thereof. In particular embodiments, the pulsed delivery pattern and the retraction of the needle may be created by an electromechanical system with a pumping mechanism in the device 100, which may be created by a pump and a CPU. However, the pumping and retraction mechanism may also be mechanical in nature, or the entire device 100 may be purely mechanical. In particular embodiments, the fluid may be drawn from a fluid reservoir engaged with a fluid receptacle 106.

[0074] In particular embodiments, as shown in Fig. 7, the fluid receptacle 106 is positioned on the upper surface of the device 100. However, it may be contained anywhere on the device 100. In particular embodiments, the fluid receptacle 106 is configured to receive a fluid from a fluid reservoir, such as the cartridge 130 shown in Fig. 10 or a syringe, and is configured to deliver the fluid to the valve 120 when the actuator 104 is actuated. In particular embodiments, the fluid receptacle 106 is configured to receive the cartridge 130, at least partially, and to pierce the cartridge 130 using an aseptic septum piercing element. However, the fluid receptacle 106 may alternatively be configured to receive one or more cartridges 130 in their entirety, to be connected to one or more fluid lines, etc. The fluid receptacle 106 may also alternatively have one or more valves, nozzles, engagements, etc. to be connected to the fluid reservoir(s). In particular embodiments, the fluid receptacle 106 may also have temperature control integrated into the housing 101 to control the temperature of the cartridge 130. In particular embodiments, the cartridge 130 comprises a hydrogel (e.g., a gelatin hydrogel) that is heated until the hydrogel melts into a liquid. In particular embodiments, the therapeutic agent (e.g., a cell population or a cell product, such as an exosome) is dispersed (e.g., uniformly) throughout the hydrogel and/or the fluid.

[0075] A fluid reservoir, such as a cartridge 130, is configured to deliver one or more fluids through the device 100 and to a target site upon actuation of the actuator 104. The cartridge 130, illustrated in Fig. 10, is a cartridge in the form of a glass tube with a rubber diaphragm interface that is configured to deliver a fluid when pierced by an aseptic septum piercing element of the fluid receptacle 106. In particular embodiments, the cartridge includes material characteristics that take into account the viscosity of the therapeutic agent (e.g., cell therapy), thereby preventing loss of the therapeutic agent adhering to the inner walls of the cartridge. In particular embodiments, the cartridge 130 can be assembled with the device 100 in a sterile field, and the aspiration line that enters the cartridge to connect with the fluid line through the device 100 can be configured to prevent fluid losses due to access in orientations in various uses of the cartridge 130, for example, if the cartridge 130 is inverted. The cartridge 130 can also be configured to be securely held by the device 100 in the receptacle 106 for the fluid. In particular embodiments, the reservoir for the fluid can be made of a variety of materials, such as polymers, rubber, etc., and can have a variety of shapes, such as bags, fluid lines, containers, etc., which can be connected to the reservoir for the fluid 106 by a variety of means, such as through ports, valves, etc. The cartridges 130 may also be configured to be removable and replaceable, such as after the fluid has been delivered thereto. In particular embodiments, the cartridges 130 may be provided in preselected doses and/or configurations such that users may use multiple cartridges 130 during a single treatment depending on the desired treatment. Alternatively, the device 100 may have an integrated fluid reservoir that is intended for a single use. In particular embodiments, the device 100 may also have one or more mechanisms for setting an individually adjustable dose from the cartridge 130, such as by using the display 108 (explained below). In particular embodiments, the cartridges 130 may have one or more computer chips that communicate with the device 100 upon insertion and provide detailed information regarding the contents of the cartridge 130, recommended doses, flow rates, timing, etc. The computer chips may be connected to the CPU of the device 100 via one or more means, such as via wired connections located in the fluid receiving device 106 and/or wirelessly.

[0076] In particular embodiments, the cartridge 130 may be configured to be coupled to the device 100 such that a minimal dead volume is formed upon coupling, and the cartridge 130 may be configured to be aseptically filled at the source of manufacture with a fluid as needed for the cell therapy and transported to the surgical site while maintaining a transport temperature of about 0°C to about 20°C, and more particularly about 2°C to about 8°C or about 4°C to about 8°C. In particular embodiments, the device 100 may be configured to receive the cartridge 130, which may have a reduced transport temperature, as detailed above, to warm the cartridge 130 to a temperature for delivery to the patient within a selectable period of time and maintain the cartridge 130 at a temperature that is acceptable for use for another selectable period of time and/or until the cartridge 130 is used. For example, the device 100 can be configured to receive a cartridge 130, the contents of which have a transport temperature of, for example, from about 4 °C to about 8 °C. The device 100 can then heat the cartridge 130 to a temperature for use inside a patient, for example, from about 20 °C to about 40 °C, and more specifically, from about 25 °C to about 37 °C, for a certain period of time, for example, for 15 minutes, for 30 minutes, or for 45 minutes. The device 100 can then be configured to maintain the temperature of the cartridge 130 approximately constant until the cartridge 130 is used, or for a fixed period of time, for example, for about 1.5 hours. In some non-limiting examples, the device 100 can be configured to indicate to the user if the cartridge 130 is not heated correctly and/or if the cartridge 130 is not used within an allocated window for sample viability. In particular embodiments, the device 100 may prevent the user from using the cartridge 130 if the device 100 determines that the viability of the samples is unacceptable, such as preventing the device 100 from being activated. The volume of the cartridge 130 may vary depending on the desired treatment. For example, the range of volumes used for cell therapy may be from about 1 ml to about 15 ml, or more specifically, from about 3 ml to about 8 ml. When used during kidney treatment, the volumes of the cartridges 130 used may depend on the kidney mass of the patients. Table 1 illustrates exemplary dosage volumes that may optionally be used herein in kidney treatment.

Table 1

Estimated kidney weight (g*KW _est ) * Dosage volume (ml) Median weight (g) Weight range (g) 100 95-108 3.0 117 109-125 3.5 133 126-141 4.0 150 142-158 2.5 167 159-175 5.0 183 176-191 5.5 200 192-208 6.0 217 209-225 6.5 233 226-241 7.0 250 242-258 7.5 --- >259 8.0

[0077] A pharmaceutical formulation based on a fluid may include a variety of therapeutic treatments, such as therapeutic cells and/or products thereof, such as exosomes), suspended in a liquid. For example, use in the kidney may use a fluid including therapeutic cells and a support hydrogel with a viscosity of, for example, about 1.05 to 1.35 cP. The viscosity of the fluid may introduce additional factors when using the components disclosed herein, such as an injection needle and a syringe with a barrel and plunger. For example, in order to initiate flow from a component, such as an injection needle, a force must be applied to the plunger of the syringe that is greater than the force required to maintain the flow once it has begun. Additionally, there may be an initial burst of fluid, such as therapeutic cells and a support hydrogel, from the needle that is beyond the manual control of the plunger of the syringe. Once flow has begun, removing the plunger force may not stop the flow of fluid. Hysteresis may occur in the buildup of pressure in the syringe barrel, and fluid outflow may only be stopped by retracting the plunger. Because of these considerations, users may operate with the ability to pulse the plunger used to provide better control of flow from the needle.

[0078] In particular embodiments, the viscous nature of the therapeutic agent (e.g., a cell therapy, e.g., a fluid-based pharmaceutical formulation containing cells) may tend to create a situation where a portion of the therapeutic agent is lost, i.e., the therapeutic agent (e.g., a portion thereof) adheres to the interior of the cartridge and cannot be removed through the normal process of the device. In particular embodiments, the interior surface of the cartridge is hydrophobic. In particular embodiments, the interior surface of the cartridge is superhydrophobic. In particular embodiments, the interior surface of the cartridge is hydrophobic or superhydrophobic to reduce wetting and adhesion of the therapeutic agent (e.g., a cell therapy) to the cartridge. In particular embodiments, the interior surface of the cartridge is hydrophobic or superhydrophobic to prevent wetting and adhesion of the therapeutic agent (e.g., a cell therapy) to the cartridge.

[0079] A variety of fluids may be used herein, such as the fluids described in U.S. Patent No. 8,318,484, issued November 27, 2012; International 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 entireties. The fluid receiving device 106 is therefore configured to operably connect the cartridge 130 to the valve 120 to ensure delivery of fluid through it.

[0080] In the exemplary device illustrated in Fig. 7, the valve 120 is positioned internally at the distal end of the device 100, at which the trocar 200 is connected to the device 100. In particular embodiments, the valve 120 is a luer connector that is configured to be connected to an injection needle for delivering a fluid through it. However, a plurality of valves configured to be connected to an injection needle can be used. In particular embodiments, the valve 120 is engaged with the housing 101 of the device 100 by means of a flexible assembly that is configured to move in space longitudinally distally and proximally along an axis L1 of the device 100, which is approximately parallel to the flow path for the fluid through the injection needle. In particular embodiments, the valve 120 can move in space distally and proximally up to about 5 cm (for example, up to about 1, 2, 3, 4 or 5 cm), and more particularly, up to about 2 cm. Thus, the valve 120 is configured to move in space distally and proximally when the device 100 is activated to dispense fluid through itself, providing a more stable delivery of fluid to the target delivery site and proximal retraction of the injection needle from the target site during delivery of the fluid.

[0081] In particular embodiments, a display 108, such as an input/output touch screen, is positioned at a proximal end of the device 100, for example, as shown in Fig. 7. In particular embodiments, the display 108 is configured to interact with the CPU to allow a user to control various functions and features on the device 100. For example, the display 108 may allow a user to set injection parameters, prime an injection needle, monitor various pressure levels and delivered fluids, resolve interlocks between components, provide real-time dosing information, etc. In an example, the display 108 is a touch screen with a plurality of input controls displayed thereon. However, the display 108 may alternatively and/or additionally have one or more physical buttons, controls, switches, dials, meters, toggle switches, etc. to control one or more functions of the device 100. The display 108 may also be positioned anywhere on the device 100, such as on top or to the sides of the device 100.

[0082] In particular embodiments of the device 100, the housing 101 may also have a lumen 140 for removing the stylet that extends along the axis L1, and it is configured to allow the stylet 300 to be removed through it after the trocar 200 has been placed (explained below). The lumen 140 may provide for manual removal of the stylet 300, for example, configured to allow the stylet 300 to be pulled proximally from the proximal end of the lumen 140 so as to provide manual grasping, or the lumen 140 may include one or more mechanical and/or electrical mechanisms to provide for removal of the stylet 300, for example, by using one or more gears, wheels, hooks, moving tracks, etc. In particular embodiments of the injection device, the penetration depths of the needle can be adjustablely set on the device itself.

[0083] The device 100 may have a variety of sizes as needed, for example, it may fit within a space with a width of about 300 mm, a depth of about 200 mm, and a height of about 100 mm, and more specifically, it may fit within a space with a width of about 205 mm, a depth of about 105 mm, and a height of about 70 mm. The device 100 may have a variety of weights and/or masses as needed. In particular embodiments, the device 100 may have a mass of less than about 2000 g, and more specifically, a mass of less than about 1400 g. The device 100 may be made of a variety of materials, such as metal, resin, etc., or a combination of materials. The device 100 may be configured to be disposable or may be configured to be a reusable device that requires repeated sterilization. In certain embodiments, the cell-contacting materials are configured to meet certain use requirements, such as ISO10993, to address issues such as the risk of leachable products and compatibility with sterilization (multiple cycles). Descriptions related to ISO10993 are provided in the Food and Drug Administration's Industry Guidance for Personnel (document issued: June 16, 2016), entitled: Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within the risk management process," Center for Device and Radiation Safety, U.S. Food and Drug Administration, Department of Health and Human Services (available at www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm348890.pdf), the contents of which are incorporated herein by reference in their entirety. The materials used for the device 100 may also be compliant with Class I/II device regulations, and the device 100 may optionally exclude the use of lubricants so as to avoid interfering with the viability of the therapeutic cell material. Descriptions related to Class I/II devices are provided in the Medical Devices document "Classify Your Medical Device", updated March 27, 2018, U.S. Food and Drug Administration (available at www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/ClassifyYourDevice/ucm2005371.htm), the contents of which are incorporated herein by reference in their entirety. In various embodiments, the device 100 may have an interlock to prevent accidental exposure of any cartridge 130 containing a dose of drug or therapeutic cell material. Additionally, in other non-limiting embodiments, it includes a dynamic injection system to assist in tissue penetration, such as a renal capsule, an interlocking system can be used to prevent accidental release when the device is not in the proper position relative to the tissue. In some embodiments, the device 100 may require a power source, and the power source can be rechargeable. For example, the device can include a charging interface, such as a USB interface. In certain embodiments, push-button interfaces are likely to comply with the 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, revision 1.1 2014-01, International Electrotechnical Commission, the contents of which are incorporated herein by reference in their entirety.

[0084] The device 100 may be coupled to the removable trocar 200 via an engagement mechanism 110, which may include a plurality of different friction-fit holes, latches, hooks, levers, etc.

[0085] Trocar with stylet

[0086] Fig. 11 illustrates one non-limiting example of a trocar (which, for example, may be removable with respect to the device provided herein). Trocar 200 is configured to be positioned within a patient and provide access to an area of internal tissue, such as an organ containing a kidney tumor or a tumor. Trocar 200 of Fig. 11 has an expanding head 202 and a hollow, elongated cylindrical shaft 204 extending distally therefrom. Head 202 is configured to be removably and replaceably attached to device 100 along axis L1 in engagement mechanism 110. A lumen extends through head 202 and elongated shaft 204, and it is configured to receive instruments, such as stylet 300 and injection needle, through itself. The extended shaft 204 has a tapered distal end 206 and a stabilizing mechanism 220 on the distal part. The shaft 204 has a compression spring section 208 and a solid section 210. The compression spring section 208 is designed with the ability to compress and stretch together with the patient's movement and interaction with the device 100. The spring section 208 therefore provides a translational movement in space proximally and distally along the axis L1, providing greater stationary interaction with the tissue, smoother delivery of the fluid to the target tissue area and proximal removal of the injection needle from the target area during the delivery of the fluid. In particular embodiments, the spring section 208 can provide a distal and proximal movement in space up to about 5 cm (for example, up to about 1, 2, 3, 4 or 5 cm), and more particularly, up to about 2 cm. The compression spring section 208 is illustrated in the middle part on the shaft 204. However, the compression spring section 208 can be positioned at different points along the shaft 204, for example, in a position proximal with respect to the midpoint of the shaft 204, or in a position distal with respect to the midpoint. The solid section 210 is positioned on the distal part of the shaft 204, and it has a stabilizing mechanism 220.

[0087] The stabilizing mechanism 220 is configured to help stabilize the trocar 200 relative to an internal portion of tissue within a patient when the trocar 200 is positioned through an external surface of tissue, such as the dermis of the patient. The stabilizing mechanism 220 is thereby configured to reversibly hold the trocar 200 in a fixed position relative to the tissue as instruments pass through the trocar 200. For example, when the trocar 200 is used during kidney treatment, the stabilizing mechanism 220 may be configured to reversibly lock the distal end 206 of the trocar 200 in position relative to the surface 250 of the kidney. The stabilizing mechanism 220 illustrated in FIG. 11 and 12 includes three footrests 222 on shafts 223, engaged with the shaft 204 at hinge points 224. In particular embodiments, the footrests 222 are arranged radially symmetrically about the shaft 204 and are configured to open to reversibly engage tissue in a target area. In particular embodiments, the footrests 222 are configured to move from a recessed position on the shaft 204, such as during insertion of the trocar 200 into a patient, to an extended position, such as during stabilization of the trocar 200 in use, by rotating in a direction away from the shaft 204 about the hinge points 224 to an engaged position, as illustrated in Fig. 12. In the recessed position, the feet 222 can be received in the recessed pockets 226 such that the feet 222 sit flush with the outer surface of the shaft 204. During deployment, the feet 222 can be configured to rotate in a direction away from the shaft 204 by 90-180 degrees, for example, by approximately 100 degrees, so as to engage with the fabric.

[0088] A plurality of rotary mechanisms may be included in the shaft 204 to cause rotation of the footrests 222, including gears, springs, electronic motors, shafts, electrically heated nitinol spacers, etc. For example, small cams (not shown) can be included in the shaft 204 at approximately the hinge points 224, which can be configured to engage one or more features on the stylet 300 when the stylet 300 is withdrawn, wherein this withdrawal can be configured to actuate the cams and cause rotation of the footrests 222. The stabilizing mechanism 220, in general, can have one or more deployment means that are actuated when the stylet 300 is withdrawn. In particular embodiments, the footrests 222 can have one or more engagement means, such as biomimetic microhooks configured to reversibly engage tissue upon initial surface contact. The microhooks can have a variety of sizes, such as from about 100 to 500 μm in scale. The trocar 200 is thereby secured in place without causing significant trauma until the user wants to remove the trocar 200, so that the legs 222 are disengaged. Many other engagement means are possible, such as biomimetic or other hooks, temporary adhesives, active suction, friction, spring compression force, a mechanism similar to a lamprey latch mechanism, etc. The engagement means may also be expendable and/or biodegradable. Although three legs 222 are illustrated, a plurality of legs may be provided. Additionally, the stabilizing mechanism 220 may have various alternative and/or additional embodiments other than the legs 222. For example, the stabilizing mechanism may include pinching mechanisms, hooks, various adhesives and glues, suction, friction fit, etc.

[0089] The trocar 200 may also have one or more additional or alternative engagement mechanisms for engaging tissue and further stabilizing the trocar 200 when deployed within a patient, such as at an entry point of the trocar 200 into the dermis of the patient. For example, the trocar 200, as illustrated, is configured to be frictionally engaged by the dermis of the patient when deployed. However, additional engagement mechanisms are possible, such as a reversibly collapsible stretchable member 500 that can be included in the shaft 602 of the trocar 600, similar to the trocar 200. In particular embodiments, as illustrated in FIG. 13-15, the stretch member 500 can operate similarly to a drywall anchor (for example, similarly to the exemplary drywall anchoring system as illustrated in Figs. 16A-16D, showing drilling a slot, driving in an exemplary drywall anchor, using a screwdriver to stretch the anchoring arms, and finally screwing the screw in place). The stretch member 500 is movable between a placement position, as illustrated in Fig. 13, in which the shaft 602 is inserted through the dermis 620 of the patient, to a stretched position, as illustrated in Fig. 14 and 15. The stretchable member 500 has one or more legs 502 that are hinged or bendable at an approximate midpoint 504 along the legs 502 (illustrated in Fig. 13 by a dotted line). In particular embodiments, one or more stretching mechanisms can be included in the shaft 602 and are configured to cause the legs 502 to stretch outward, such as a thread configured to retract the distal portion of the trocar 600 proximally after it is positioned within the dermis 620 such that the legs 502 stretch outward (as shown by the arrows in Fig. 13) with the ability to attach to the inner surface of the dermis 620 (as illustrated in Fig. 14 and 15). The stretchable element 500 is configured to change direction to the opposite position in the user's placement position when the user wants to remove the trocar 600 from the patient.

[0090] The exemplary trocar 200 is thus configured to be stabilized and/or secured at two points when the trocar 200 is positioned within a patient, at the surface of the internal target tissue (e.g., an organ such as a kidney or a solid tumor) and at an entry point through the tissue into the patient (e.g., in the dermis) using one or more of the mechanisms discussed above. The stabilization of the trocar 200 is configured to provide a stable depth of penetration into the tissue during deployment, which prevents or reduces tissue damage and reduces the loss of excess therapeutic cells or cellular products during injection due to shear of the instruments caused by shear of the tissue and movement of the patient, such as the natural movement of the organ and the breathing of the patient. In particular embodiments, one or more surface features may also be added to the outer distal surface of the shaft 204 of the trocar 200, such as bumps, grooves, notches, markings, etc., which are configured to provide better visualization of the location of the trocar 200, for example, according to ultrasound, and therefore more accurate placement within the patient. For illustration, exemplary echogenic surface features 272 are illustrated in a non-limiting embodiment of an ultrasonic biopsy needle in Fig. 17. "Echoic" may 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®. Trocar 200 can optionally be used with a cannula or trocar sleeve as desired, for example, with a trocar sleeve that has a weight of at least 20 g, and it can be of such a size and shape that it can penetrate a patient to a plurality of depths, for example, approximately 3-5 mm into a target internal tissue area, such as a kidney of the patient. Trocar 200 can have a plurality of lengths, for example, approximately 5-25 cm, more specifically, 10-20 cm, and even more specifically, approximately 15-20 cm. Spring section 208 can have a plurality of lengths, for example, approximately 5-10 cm.

[0091] The stylet 300 is configured to be received within the lumen of the trocar 200 along the axis L1 during advancement and placement of the trocar 200 within the patient. The stylet 300 has an elongated stylet shaft 302 with a distal tip 304. The shaft 302 is sized and shaped such that it is received in the trocar 200 and extends distally and proximally from the trocar 200. For example, the distal tip 304 may be configured to extend distally from a tapered distal end 206 of the trocar 200 such that the distal tip 304 can pierce tissue and the proximal end of the stylet 300 can extend proximally from the trocar 200 to remove the stylet 300. An exemplary distal tip 304 has a blunt-conical shape, as illustrated in Fig. 18A, but many other shapes may be used, such as pyramidal, as illustrated in Fig. 18B, pointed, as illustrated in Fig. 18C, and blunt, as illustrated in Fig. 18D. Although a variety of tips can be used, in particular embodiments, a blunt conical tip can be used effectively in kidney tissue because the blunt conical tip is configured to minimize trauma caused during the initial insertion of the trocar 200 with the stylet 300 into the target tissue site, such as the kidney. After the trocar 200 is positioned within the patient, the stylet 300 can be configured to be removed. The stylet 300 can be configured to be manually removed from the trocar 200 directly when the device 100 is not engaged with the trocar 200, or it can be configured to be removed from the trocar 200 through an optional lumen 140 for removing the device 100, manually, mechanically, electrically, or through some combination, as explained above. In particular embodiments, the stylet 300 may have one or more features configured to actuate the opening of the stabilizing mechanism 220 of the trocar 200 when the stylet 300 is removed from it. For example, the stylet 300 may have one or more features of gear teeth positioned in the direction of the distal tip 304, which are configured to actuate cams on the trocar 200 and cause rotation of the footrests 222.

[0092] Thus, in a non-limiting example, the trocar 200 (with or without a sleeve) may be configured to pierce the skin of a patient due to the action of the stylet 300. An exemplary target penetration depth of the trocar 200 and/or the sleeve into tissue, such as an organ (e.g., a kidney), may be approximately 2-6 mm, or more preferably approximately 3-5 mm, when the stylet 300 is withdrawn. When the stylet 300 is withdrawn, the trocar 200 (i.e., the trocar sleeve) may then be secured in place. The fixation of the trocar 200 (i.e. the trocar sleeve) can be carried out at least at two points, such as frictional grip in the passage for the dermis, etc., as a weaker interaction in the tissue into which the trocar 200 (i.e. the trocar sleeve) penetrates, for example, in the capsule of the kidney. The trocar (i.e. the trocar sleeve) 200 can be designed with the ability to stabilize at the depth of penetration into the tissue, for example, into an organ (e.g., into the kidney), during the procedure. However, the placement of the components penetrating the tissue can be dynamic due to potential shear of the tissue, for example, of the organ (e.g., the kidney) and according to the breathing cycle of the patient. Therefore, harmful movement of the dermal anchor point relative to the anchor point of the internal tissue, such as an organ (such as a kidney), may occur and as such may be minimized using the components provided herein, such as the stabilizing mechanism 220. Minimizing trauma to the tissue, such as an organ (such as a kidney), may also be beneficial to the overall success of any treatment. For example, trauma may occur when unintentional movement of the needle 400 occurs in the trocar 200, which ruptures the tissue, such as an organ (such as a kidney). Trauma may also occur during the initial insertion of the trocar 200 into the tissue, such as an organ (such as a kidney), such as if the distal tip 304 of the stylet 300 has any cutting action (such as a sharp point, as is caused by the pyramidal or conical designs discussed above). Thus, stabilization of the trocar 200 may help to reduce or eliminate tissue trauma by reducing or eliminating inadvertent movement of the needle 400, and the blunt conical tip may be used to puncture tissue, such as an organ (e.g., a kidney), and minimize trauma.

[0093] In certain embodiments, trauma can occur due to two sources: 1) there are stylet/needle tip morphologies that cause greater tissue damage, and 2) inadvertent movement of the trocar/needle during the procedure can rupture the kidney. In certain embodiments, of the stylet points shown in Figs. 18A-D, blunt-tapered ones are recommended to pierce the kidney and minimize trauma. In certain embodiments, the needle tip is blunt and non-cutting. The size-gauge of the needles can also contribute to trauma. In certain embodiments, smaller needles cause less severe trauma, but may be ineffective in piercing the fibrous capsule. In certain embodiments, larger needle sizes are easier to see with ultrasound, taking into account placement. Thus, in certain embodiments, in a design solution that includes a dynamic mode to pierce the capsule effectively with a small needle, the possibility of less serious injuries and a lower risk of failure to penetrate the capsule is ensured, but potential problems with visualization arise. In certain embodiments, significant differences between the sleeve and the needle can lead to bending of the small needle in the sleeve, and the device is designed to minimize bending of the needle in the sleeve.

[0094] Injection needle

[0095] Fig. 19 illustrates a non-limiting example of an injection needle 400 that is configured to engage with the device 100 and be inserted through the trocar 200 when the trocar 200 is in place within a patient. In particular embodiments, the needle 400 is configured to deliver a fluid-based pharmaceutical composition (e.g., compositions containing cells and/or a product thereof) to a target site of internal tissues, such as an organ (e.g., a kidney), from the device 100. The illustrated needle 400 has an engaging head 402 and an elongated shaft 404 with a lumen therethrough and a distal tip 406 thereon. The distal tip 406 has a slot to allow the fluid to flow distally from the needle 400. The engagement head 402 is configured to be removably and replaceably connected to the device 100 along the axis L1 in the engagement mechanism 110. When the head 402 is connected, it is configured to engage with the valve 120. When the device 100 is actuated, the head 402 and the lumen of the elongated shaft 404 are configured to create a flow path for the fluid for the fluid in the fluid reservoir connected to the receiving device 106 for the fluid from the fluid reservoir, through the valve 120, along the lumen of the shaft 404 and from the opening in the distal tip 406. The needle 400 is also configured to be retractable from its position in the target tissue as the fluid is delivered during actuation. The size, length, and gauge of a 400 injection needle can vary. For example, a 400 needle can range from approximately 25g to approximately 20g. The size-gauge of needles can contribute to tissue trauma, and larger size-gauges (which are smaller needles) can cause less severe trauma.

[0096] When considering the size of needles for use in treating an organ (e.g., a kidney), a balance may be sought between penetrating the renal corpuscle capsule and potential tissue trauma. As illustrated in Fig. 20, the renal corpuscle capsule is a tough fibrous layer that surrounds the kidney. Thus, a larger needle is more useful for penetrating the renal corpuscle capsule. However, a larger needle may cause more severe trauma to the kidney. Therefore, an optimal needle size may be sought that takes into account the competing factors, as illustrated in Fig. 21.

[0097] Although smaller needles may be less effective in puncturing tissue, the needle 400 used in combination with the trocar 200 and stylet 300 herein may be configured to provide both successful puncturing of tissue and placement of a smaller needle. A variety of different needles may be used herein. Table 2 illustrates additional exemplary needle gauge sizes that may optionally be used herein.

Table 2

Denomination Denomination Needle caliber OD (inches) OD (mm) OD range (inches) ID (inches) ID (mm) ID range (inches) Wall (inches) 20 0.036 0.91 0.0355-0.0360 0.024 0.6 0.0230-0.0245 0.006 20.5 0.0343 0.87 0.0340-0.0345 0.0265 0.67 0.0255-0.0275 0.004 21 0.032 0.82 0.0320-0.0325 0.02 0.51 0.0195-0.0210 0.006 21.5 0,0303 0.77 0.0300-0.0305 0.0238 0.6 0.0230-0.0245 0.0035 22 0.028 0.72 0.0280-0.0285 0,016 0.41 0.0155-0.0170 0.006 22s 0.028 0.718 0.0280-0.0285 0,007 0.168 0.0055-0.0077 0,011 22.5 0.0263 0.67 0.0260-0.0265 0,0203 0.52 0.0195-0.0210 0.003 23 0.025 0.64 0.0250-0.0255 0,013 0.34 0.0125-0.0140 0.006 23s 0.025 0.642 0.0250-0.0255 0,005 0.116 0.0040-0.0051 0.01 23.5 0.0233 0.59 0.0230-0.0235 0,0173 0.44 0.0165-0.0180 0.003 24 0.022 0.57 0.0220-0.0225 0,012 0.31 0.0115-0.0130 0.005 22.5 0,0213 0.54 0.0210-0.0215 0,0163 0.41 0.0155-0.0170 0.002 25 0.02 0.51 0.0200-0.0205 0.01 0.26 0.0095-0.0110 0.005 25s 0.02 0.515 0.0200-0.0205 0.006 0.153 0.0055-0.0065 0,007

[0098] In particular embodiments, the needle is an 18-30 gauge needle. In particular embodiments, the needle is less than 20 gauge. In particular embodiments, the needle is less than 21 gauge. In particular embodiments, the needle is less than 22 gauge. In particular embodiments, the needle is less than 23 gauge. In particular embodiments, the needle is less than 24 gauge. In particular embodiments, the needle is less than 25 gauge. In particular embodiments, the needle is less than 26 gauge. In particular embodiments, the needle is less than 27 gauge. In particular embodiments, the needle is less than 28 gauge. In particular embodiments, the needle is less than 29 gauge. In particular embodiments, the needle is approximately 20 gauge. In particular embodiments, the needle is less than 29 gauge. In particular embodiments, the needle is approximately 21 gauge. In particular embodiments, the needle is less than 29 gauge. In particular embodiments, the needle is approximately 22 gauge. In specific embodiments, the needle is less than 29 gauge. In specific embodiments, the needle is approximately 23 gauge. In specific embodiments, the needle is less than 29 gauge. In specific embodiments, the needle is approximately 24 gauge. In specific embodiments, the needle is less than 29 gauge. In specific embodiments, the needle is approximately 25 gauge. In specific embodiments, the needle is less than 29 gauge. In specific embodiments, the needle is approximately 26 gauge. In specific embodiments, the needle is less than 29 gauge. In specific embodiments, the needle is approximately 27 gauge. In specific embodiments, the needle is less than 29 gauge. In specific embodiments, the needle is approximately 28 gauge. In specific embodiments, the needle is less than 29 gauge. In specific embodiments, the needle is approximately 29 gauge.

[0099] In specific embodiments, the inner diameter of the needle is less than 0.84 mm. In specific embodiments, the inner diameter of the needle is less than 0.61 mm. In specific embodiments, the inner diameter of the needle is less than 0.51 mm. In specific embodiments, the inner diameter of the needle is less than 0.41 mm. In specific embodiments, the inner diameter of the needle is less than 0.33 mm. In specific embodiments, the inner diameter of the needle is less than 0.25 mm. In specific embodiments, the inner diameter of the needle is less than 0.20 mm. In specific embodiments, the inner diameter of the needle is less than 0.15 mm. In specific embodiments, the outer diameter of the needle is less than 1.27 mm. In specific embodiments, the outer diameter of the needle is less than 0.91 mm. In specific embodiments, the outer diameter of the needle is less than 0.81 mm. In specific embodiments, the outer diameter of the needle is less than 0.71 mm. In specific embodiments, the outer diameter of the needle is less than 0.64 mm. In specific embodiments, the outer diameter of the needle is less than 0.51 mm. In specific embodiments, the outer diameter of the needle is less than 0.41 mm. In specific embodiments, the outer diameter of the needle is less than 0.30 mm. In specific embodiments, the needle has one of the dimensions in the following table:

ID-size OD size Caliber inches mm inches mm 14 0,060 1.55 0.072 1.83 15 0.054 1.37 0.065 1.65 16 0.047 1.19 N/A N/A 18 0.033 0.84 0,050 1.27 20 0.023 0.61 0.036 0.91 21 0,020 0.51 0.032 0.81 22 0,016 0.41 0.028 0.71 23 0,013 0.33 0.025 0.64 25 0,010 0.25 0,020 0.51 27 0,008 0.20 0,016 0.41 30 0.006 0.15 0,012 0.30 32 0.004 0.10 0,009 0.23

[00100] The needle 400, for example, can be injected into an area of internal tissue that is at a relatively large distance from the device 100, such as at a distance of approximately 10 cm to 20 cm. In such an example, the trocar 200 can also mechanically support the needle 400 against twisting that may develop as a result of penetrating an area of internal tissue at a relatively large distance. In particular embodiments, the length of the needle 400 can be configured such that approximately 5 cm to approximately 6 cm of the distal portion of the needle 400 extends beyond the distalmost end of the trocar 200. For example, approximately 5.3 cm (e.g., approximately 5.5, 6, or 6.5 cm) of the needle 400 can be configured to extend distally beyond the distalmost end of the trocar 200, as illustrated in Fig. 22. The length can provide a sufficient depth of penetration of the needle 400 into the target tissue, for example, in an organ (for example, in a kidney), for deposition of therapeutic cells or cellular products. In particular embodiments of the injection device, the depths of penetration of the needle can be adjustable. In particular embodiments, with such a length, the slit in the distal tip 406 of the needle 400 can be positioned approximately 5.1 cm behind the most distal end of the trocar 200, as illustrated in Fig. 23. In particular embodiments, the slit of the needle is preferably located transversely approximately 0.2 cm from the tip of the needle, and the slit is located 5.1 cm behind the trocar for a length of 5.3 cm. In particular embodiments associated with an extension of approximately 6 cm, the slit is located approximately 5.8 cm behind the trocar. In certain embodiments, the transverse positioning of the exit slit has an advantage regarding the extrusion and placement of the therapeutic cell while ensuring that the needle is coreless. In certain embodiments, the slit may optionally be positioned transversely, which allows for an advantage regarding the extrusion and placement of therapeutic cells or cellular products in the target tissue area. In various examples, one or more surface features may also be added to the outer distal surface of the elongated shaft 404 of the needle 400, similar to the trocar 200, such as bumps, grooves, marks, etc., which are configured to provide better visualization of the location of the needle 400, for example, according to ultrasound, and therefore more accurate placement inside the patient. More than one needle 400 of varying sizes may also be used depending on the desired treatment. In some examples, the size-gauge of the needles may contribute to trauma. For example, larger gauge sizes (which are smaller needles) may cause less trauma, but may not be effective in penetrating tissue, such as a fibrous capsule. Therefore, this document provides components, such as the trocar 200, that can assist through dynamic mode and/or dynamic movement to penetrate tissue, such as a capsule, effectively with a small needle. This may result in less trauma and less risk of failure to penetrate tissue, such as a capsule.

[00101] In particular embodiments, the components herein may be designed in a manner that takes into account the needs of a user, such as a surgeon using the device. In use, all components herein, such as the movable surfaces, may preferably be comfortable and fit a wide range of male and/or female hand sizes. Anti-slip surfaces may optionally be integrated into one or more components discussed herein, such as providing surface features, surfaces and/or materials that interact well and prevent leakage in surgical gloves. In particular embodiments, the input interfaces may be easily visible and easily activated by gloved fingers. In particular embodiments, one or more interfaces may provide tactile feedback upon activation, and if any part of the injection process is mechanical, tactile feedback may be important for the successful use of the components disclosed herein, such as as a fluid, such as a therapeutic cell material, is injected into a tissue, such as a renal space. Users often prefer smaller syringes because smaller syringes require less force to infuse their contents, and smaller syringes are sometimes held in atypical hand positions for better control, as illustrated in the non-limiting example of Fig. 24. Thus, ergonomics and comfort of component fit may be taken into account herein. In particular embodiments, one or more instructions, instructions for use, manuals, videos, operating instructions, etc. may be provided and may be individually adapted to the needs of the end user (e.g., a surgeon). The instructions, etc. may be configured to be in accordance with and/or specified by the needs of the design process of the contract engineering organization.

[00102] The device 100, the trocar 200, and the 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 in the trocar 200. The cartridge 130 or other fluid reservoir can be engaged with the device 100 at this time or before the injection. The trocar 200 and the stylet 300 can then be maneuvered to penetrate through the outer surface of the tissue, such as through the dermis, and through the inner target site of the tissue, such as through an organ (e.g., a kidney) of the patient at a desired depth (as explained above). The stylet 300 can then be removed from the trocar 200 through the lumen 140 for removal. Removing the stylet 300 may lower the pawl to activate the stabilizing mechanism 220 on the trocar 200. As illustrated in Fig. 12, the legs 222 may open to grasp or engage tissue. The trocar 200 may be detached from the device 100, at which point during use, the trocar 200 should be supported through frictional engagement with the dermis and through the use of the stabilizing mechanism 220. In a non-limiting illustrative example, Fig. 25 illustrates a simplified diagram of a trocar 200 used for a kidney, in which the trocar 200 is subjected to frictional interaction with the dermis and is subjected to stabilization through the use of a stabilizing mechanism 220 relative to the renal cortex, which is the outer part of the kidney between the capsule of the renal corpuscle and the medulla of the kidney, which can vary in thickness depending on the patient. For example, the cortical thickness can be approximately 3-12 mm, and more specifically, approximately 3.2-11 mm with an average value of approximately 5.9 mm. The injection needle 400 can be engaged with the device 100. The needle 400 can then be inserted into the trocar 200 until the needle 400 penetrates the target tissue through an identical slit created by the stylet 300 at a desired depth (as explained above), and the actuator 104 on the device 100 can be actuated to deliver a fluid, such as therapeutic cells or cellular products, to the target site. The stabilizing mechanism 220 can work in combination with the compression spring section 208 of the trocar 200 and the flexible mounting of the valve 120 to absorb movement of the tissue site, such as an organ (for example, a kidney), relative to the holding and actuation, by the user, of the device 100. As the fluid is delivered, the needle 400 can be retracted from its penetrating position in the target tissue site. The trigger activates an electromechanical system that delivers pulses of therapeutic solution into the needle path as the needle is retracted. Multiple injections can be performed into an identical tissue area, such as an organ.

[00103] Alternatively, the trocar 200 and stylet 300 may be maneuvered into place within the patient without being attached to the device 100, and the stylet 300 may be removed to actuate the stabilizing mechanism 220 on the trocar 200. The needle 400 with the engaged device 100 may then be inserted into the trocar 200 to deliver fluid. The trocar 200 with the stylet 300 can also be positioned inside the patient when connected to the device 100, and then the device 100 can be disconnected from the trocar 200 to manually remove the stylet 300 before the needle 400 is connected and inserted into the trocar 200. If the trocar 200 has an additional engagement mechanism, such as a reversibly flattened expandable member 500, the injection device 100 can be connected to the trocar 200 with the stylet 300 in place in the trocar 200. The trocar 200 and the stylet 300 can then be maneuvered to penetrate the outer surface of the tissue and the inner target area of the tissue. After the stylet 300 is removed and the device 100 is disconnected, but before the needle 400 is inserted, the expandable member 500 can be deployed. However, this order may vary depending on the mechanism of use of various engaging mechanisms. When the device 100 is used specifically for treating the kidneys, the trocar 200, the stylet 300 and the needle 400 may be used, as explained above, to pierce the kidney capsule, an area of potentially fibrous tissue, and deliver a restricted volume into the kidney while withdrawing the needle 400 to provide space for distension for the delivered bolus of therapeutic cells or cellular products. As used herein and depending on the context, "fibrous" means or denotes the deposition of a fibrous extracellular matrix that is typically denser than the surrounding tissue. Dense fibrous tissue is often the result of a chronic disease state. In certain embodiments, fibrous tissue is the result of a chronic disease state. In certain embodiments, dense fibrous tissue is the result of a chronic disease state. In specific embodiments, fibrous tissue is present in an organ being treated (e.g., is the site of delivery of a composition delivered using) using a device, system, or method provided herein.

[00104] In particular embodiments, prior to use, the cartridge 130 may be heated to about 25-30 °C, and more particularly, to about 26-28 °C. In particular embodiments, prior to use, the cartridge 130 may be heated to about 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 or 37 °C. In particular embodiments, the heating may occur for a controlled period of time, such as for about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 minutes, or from about 15 to about 45 minutes. In particular embodiments, after the cartridge 130 is heated, the delivery of fluid therein may preferably occur within approximately 0.5, 1, 1.5, 2, or 2.5 hours to avoid ejection of the cartridge 130.

[00105] In certain embodiments, after the fluid is delivered and the injection needle 400 is removed from the target tissue site and the trocar 200, the plug 700 (for example, a hydrogel plug or a tampon, such as a Gelfoam® tampon) can be manually inserted into the trocar 200 and pushed and squeezed out of the distal end 206 of the trocar 200 to close the penetrating wound. The device 100 and the trocar 200 can be configured to accommodate the delivery of the plug. In particular embodiments, a tampon (such as a Gelfoam® tampon) that begins about 2 to about 4 mm by about 10 mm is compressed to allow insertion (e.g., manual insertion) into a trocar, and is pushed and squeezed out of the tip of the trocar to close a wound in the renal capsule. In particular embodiments, the tampon is a small piece of absorbent cotton wool or other soft material (e.g., a hydrogel). In particular embodiments, the tampon or plug is used to plug a wound or other opening in the body or organ. In particular embodiments, the device is configured to accommodate this terminal wound closure process. In a non-limiting illustrative example, FIG. 26 illustrates a simplified diagram of a trocar 200 used in a kidney, in which a plug 700 is "musket loaded" or placed into place manually through the trocar 200. The trocar 200 can then be removed from the patient. Thus, during the process disclosed herein, one or more components can assist in manual puncturing of tissue such as fibrous renal capsules, smooth controlled delivery of a fluid such as a therapeutic cell material, and positional stability of the trocar in the dynamic environment of the patient (which in turn provides stability during delivery of the therapeutic cell material while minimizing tissue trauma), which are complexities in other approaches but which one or more current components herein can be designed to cope with.

[00106] Although described with a focus on the kidney as a target tissue site and/or organ, the components herein may have broad application to a variety of organs and/or internal tissue sites and/or related therapies. As a non-limiting example, the components described herein are thereby pocket-sized injection components designed to deliver one or more injectable volumes (e.g., in a cell therapy) into one or more target tissue sites, such as the parenchymal and/or stromal portions of a diseased site, e.g., an organ (such as a kidney or a tumor site). In particular embodiments, the components may thereby pierce the outer surface of a tissue site, e.g., an organ site, such as the renal capsule, an area of potentially fibrous tissue in the kidney, and may deliver a restricted volume along the injection tract while withdrawing the injection needle to provide distension space for the delivered volume, e.g., a bolus of therapeutic cell material. In particular embodiments, multiple injections into an identical target site, such as an organ, may be possible. In particular embodiments, the components herein may have a means to stabilize themselves relative to the surface of the target tissue site, such as an organ, via a trocar opening, may receive pre-filled aseptic cartridges containing a volume, such as a solution with a therapeutic cell material, and may be ergonomic for the intended physician, such as a surgeon. In particular embodiments, the component herein may be intuitive and accommodate hypodermic needles within a specified range of sizes and may have the ability to set variable injected or dispensed volumes and penetration depths.

[00107] In particular embodiments, the injection device may consist of a single physical device that can receive therapeutic doses based on a cartridge. In particular embodiments, standard trocar/core/needle combinations may be included in the device from standard, individually packaged and sterilized stocks. In such examples, the target sizes may vary from various standard sizes, for example, hypodermic needles are in the range of about 25 grams minimum to about 20 grams maximum, and trocar/core combinations are at least about 20 g. In particular embodiments, the trocar/core size is from about 21 g to about 18 g. In particular embodiments, the test subject has a high body mass index (e.g., a BMI of at least about 35, 36, 37, 38, 39 or 40 kg/m ² ). BMI is an indicator of obesity, and high BMI is associated with severe obesity. In particular embodiments, a core size of about 20 g to about 18 g and a needle of about 21 g and a length of about 20 to about 30 (e.g., 25 cm) is used for patients with a high BMI. In particular embodiments, a device or system is provided herein that is useful for treating patients with normal and high BMI. In particular embodiments, an injection path of an injection needle into a target site, such as an organ, can be provided by pairing with a trocar. In particular embodiments, the trocar can serve to mechanically support the injection needle against twisting that may develop in some cases as a result of penetrating a target tissue, such as an organ, at a relatively large distance, such as about 5-25 cm, and more particularly about 10-20 cm from the injection device.

[00108] In particular embodiments of one or more components herein, the components may be labeled with ISO-compliant warning symbols in accordance with appropriate regulatory agency documentation (e.g., U.S. 21 C.F.R. § 801). In particular embodiments, the components herein may be considered safe for unguided access when the various housing and product trims are in place and secured, and the components herein may optionally be free of accessible sharp edges with a radius of less than about 0.5 mm, excluding the various components of the trocar, sleeve, and needle. In particular embodiments, the components may be free of an externally accessible electrical connection that allows for a supply of more than about 1.0 A at about 5.25 VDC. In particular embodiments, any materials, such as plastic and/or trim materials, may have a flammability rating of UL94 V-0 or better.

[00109] In particular embodiments, the components herein may be configured to be used in temperature-controlled indoor environments, such as in clinics and hospitals, and the components may be configured to meet performance requirements within the range of environmental conditions provided in Table 3:

Table 3

Parameter (units) Min. Max. Temperature (°C) 28 37 Relative humidity (%) 20 90 Ambient pressure (bar) 0.7 1.05 Light level (lux) 100 1000 Vibration (g RMS) 0 0,1

[00110] In particular embodiments, the components disclosed herein may be configured to operate normally after various sterilization processes (e.g., standard sterilization processes), such as through gamma radiation, ethylene oxide, E-beam, or gas. In particular embodiments including one or more plastics, the plastic may be configured to not become brittle through the sterilization process, and discoloration or change in color may be minimal. In particular embodiments herein that include one or more electromechanical components, sterilization processes that are compatible with electronic equipment may be used, which may include various steps and additional features, such as removing removable covers and/or surfaces that can be sterilized and aseptically contain the working elements of one or more components. Table 4 and Table 5 provide resin-based materials that are compatible with various types of sterilization.

Table 4

Compatibility of plastics with sterilization methods Polymer Abbreviation of the polymer name Autoclave Dry heat Ethylene oxide (Eto) Gamma irradiation Electron beam Biopolymers Poly(L-lactide) PLLA Satisfactorily Fine Fine Fine Fine Polylactic acid PLA Badly Satisfactorily Fine Fine Fine Polyhydroxybutyrate PHB Badly Badly Fine Satisfactorily Satisfactorily Polyglycolic acid PGA Fine Fine Fine Fine Fine Poly(lactic-co-glycolic) acid PLGA Badly Badly Fine Satisfactorily Satisfactorily Polycaprolactone PCL Satisfactorily Fine Fine Fine Fine Elastomers Silicones VMQ, PMQ, PVMQ Fine Fine Fine Fine Fine Urethane thermoplastic elastomer TPU Badly Satisfactorily Fine Fine Fine Copolyester thermoplastic elastomer TPC Badly Fine Fine Fine Fine Polyamide thermoplastic elastomer TPA Badly Badly Fine Fine Fine Styrene thermoplastic elastomer TPS Badly Badly Fine Fine Fine Olefin thermoplastic elastomer TPO Badly Satisfactorily Fine Fine Fine Fluoropolymers Polytetrafluoroethylene ¹ PTFE Satisfactorily Satisfactorily Fine Badly Badly Fluorinated ethylene propylene FEP Fine Fine Fine Satisfactorily Satisfactorily Perfluoroalkoxyl PFA Fine Fine Fine Fine Fine Ethylene chlorotrifluoroethylene ECTFE Fine Fine Fine Fine Fine Ethylene tetrafluoroethylene ETFE Fine Fine Fine Fine Fine Polyvinyl fluoride PVF Fine Fine Fine Fine Fine Polyvinylidene difluoride PVF2 Fine Fine Fine Fine Fine High temperature thermoplastics Polysulfones PSU Fine Fine Fine Fine Fine Polyphenylene sulfide P.P.S. Fine Fine Fine Fine Fine Liquid Crystal Polymer LCP Fine Fine Fine Fine Fine Polyetherimide PEI Satisfactorily Satisfactorily Fine Fine Fine Polyamidoimide PAI Satisfactorily Satisfactorily Fine Fine Fine Polyetheretherketone PEEK Fine Fine Fine Fine Fine ¹ Radiation-stable classes should be used for sterilization by irradiation.

Table 5

Compatibility of plastics with sterilization methods Polymer Abbreviation of the polymer name Autoclave Dry heat Ethylene oxide (Eto) Gamma irradiation Electron beam Polyamides Nylon 6, Nylon 66 PA6, PA66 Satisfactorily Satisfactorily Fine Satisfactorily Satisfactorily Aromatic compounds AP Fine Fine Fine Fine Fine Nylon 12, 6/12 PA12 Badly Badly Fine Satisfactorily Satisfactorily Polyesters Polybutylene terephthalate PBT Satisfactorily Satisfactorily Fine Fine Fine Polyethylene terephthalate PET Badly Badly Fine Fine Fine Copolyesters Badly Badly Fine Fine Fine Polyolefins High density polyethylene HOPE Badly Badly Fine Fine Fine Low density polyethylene LDPE Badly Badly Fine Fine Fine Ultra-high molecular weight polyethylene UHMWPE Badly Badly Fine Fine Fine Polypropylene ¹ P.P. Fine Satisfactorily Fine Satisfactorily Satisfactorily Polypropylene copolymers PPC Fine Satisfactorily Fine Satisfactorily Satisfactorily Cycloolefin copolymer COC Satisfactorily Satisfactorily Fine Fine Fine Plasticized polyvinyl chloride ^1.2 PVC Satisfactorily Satisfactorily Fine Fine Fine Unplasticized polyvinyl chloride ^1.2 PVC Badly Badly Fine Satisfactorily Satisfactorily Polystyrene/styrenes Polystyrene P.S. Badly Badly Fine Fine Fine Acrylonitrile-butadiene styrene copolymer (Abs) ABS Badly Badly Fine Fine Fine Styrene-acrylopitrile copolymer (San) SAN Badly Badly Fine Fine Fine Copolymer of acrylonitrile and styrene acrylate ASA Badly Badly Fine Fine Fine Copolymer of methacrylate, acrylonitrile and butadiene styrene MABS Badly Badly Fine Fine Fine Copolymer of styrene and butadiene SBC Badly Badly Fine Fine Fine Acrylic polymers ^1,2 PMMA Badly Badly Fine Fine Fine Polycarbonates ^1,2 PC Satisfactorily Satisfactorily Fine Fine Fine Heat-resistant polycarbonates PC Fine Fine Fine Fine Fine Polyurethanes PU, PUR Badly Badly Fine Fine Fine Acetals POM Fine Fine Fine Badly Badly ¹ Radiation-stable classes should be used for sterilization by irradiation.
² PVC, acrylic polymers and PC require corrective painting to compensate for discoloration.

[00111] In particular embodiments, one or more components herein that are packaged may be configured to operate normally when returned to an operating range of changing environmental conditions after an extended period of time. For example, Table 6 illustrates packaging with exposure to various ranges of changing environmental conditions for 72 hours of storage, after which the components operate normally:

Table 6

Parameter (units) Min. Max. Temperature (°C) 0 50 Relative humidity (%) 20 90 Ambient pressure (bar) 0.7 1.05

[00112] In particular embodiments that are packaged, the packaged components may be configured and packaged such that they do not suffer functional or visible cosmetic damage when shipped by commercial carriers. Additionally, various packaged embodiments of components herein may be configured and packaged such that they do not suffer functional or visible cosmetic damage when dropped from a height of approximately 1 meter.

[00113] Each component discussed above may be used independently of one another, used in whole together, or in any combination thereof. For example, the components may be provided independently or may be provided in various combinations, systems, and kits to end users. Various combinations of cartridges 130 and/or ranges of sizes and types of needles 400, trocars 200, and/or stylets 300 may also comprise the device 100. In particular embodiments, one or more components or all components together may be packaged and supplied as a fully assembled unit, ready for action by an end user after removal from the package. In particular embodiments, instructions for assembly and/or use may be provided with any of the components, for example, with the ability for an end user to assemble or configure one or more of them for operation in less than about 10 minutes.

[00114] Non-limiting examples of injectable formulations

[00115] The devices and systems provided herein may be configured to deliver various pharmaceutical fluid-based formulations. In particular embodiments, the fluid-based formulations comprise an active agent (such as a cell, a cell product, or a chemical compound) and a temperature-sensitive biomaterial. In particular embodiments, the temperature-sensitive biomaterial is a pharmaceutically acceptable carrier for the active agent. In particular embodiments, the formulation includes biomaterials having properties that create a favorable environment for the active agent, such as bioactive renal epithelial cells, to be applied to the subject under study.

[00116] In certain embodiments, the fluid-based composition is capable of converting into a hydrogel, such as the composition is a hydrogel that has a temperature greater than its melting point.

[00117] In particular embodiments, the devices and systems provided herein are configured to deliver a composition (e.g., NKA) that is heated to a temperature sufficient to melt or otherwise ensure that the composition is a liquid. In particular embodiments, the device is configured to heat the composition or maintain a temperature at which the composition is a liquid.

[00118] In certain embodiments, the temperature sensitivity of the composition can be varied by adjusting the percentage of biomaterial in the composition. For example, the percentage of gelatin in a solution can be adjusted to modulate the temperature sensitivity of the gelatin in the final composition (e.g., liquid, gel, beads, etc.).

[00119] In particular embodiments, the temperature-sensitive biomaterial may have (i) a substantially solid state at or below about 8°C and (ii) a substantially liquid state at or above ambient temperature. In particular embodiments, the ambient temperature is approximately room temperature.

[00120] In particular embodiments, the state of the temperature-sensitive biomaterial is a substantially solid state at a temperature of about 8°C or below. In particular 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 particular embodiments, the substantially solid state is in the form of a gel. In particular embodiments, the state of the temperature-sensitive biomaterial is a substantially liquid state at ambient temperature or above. In particular 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 particular embodiments, the ambient temperature is about room temperature.

[00121] In particular embodiments, the state of the temperature-sensitive biomaterial is a substantially solid state at a temperature of about ambient temperature or below. In particular embodiments, the ambient temperature is about room temperature. In particular 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.

[00122] In particular embodiments, the cell populations and the drugs to be delivered may be deposited, deposited, embedded, attached, seeded, suspended, or entrapped in the temperature-sensitive biomaterial. In particular embodiments, the cell populations may be assembled as three-dimensional cell aggregates or spheroids or three-dimensional tubular structures in the temperature-sensitive biomaterial.

[00123] In particular embodiments, the temperature-sensitive biomaterial has a transition state between the first state and the second state. In particular embodiments, the transition state is a solid-to-liquid transition between a temperature of about 8°C and about ambient temperature. In particular embodiments, the ambient temperature is about room temperature. In particular embodiments, the solid-to-liquid transition 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.

[00124] In particular embodiments, temperature-sensitive biomaterials have a specific viscosity at a given temperature, measured in centipoise (cP). In particular embodiments, the biomaterial has a viscosity at 25°C of from about 1 cP to about 5 cP, from about 1.1 cP to about 4.5 cP, from about 1.2 cP to about 4 cP, from about 1.3 cP to about 3.5 cP, from about 1.4 cP to about 3.5 cP, from about 1.5 cP to about 3 cP, from about 1.55 cP to about 2.5 cP, or from about 1.6 cP to about 2 cP. In particular embodiments, the biomaterial has a viscosity at 37°C of from 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 particular embodiments, the biomaterial is a gelatin solution. Gelatin is present at about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, or about 1% (w/v) in the solution. 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 at 25°C of about 1.6 cP to about 2 cP. In certain embodiments, the 0.75% (w/v) solution has a viscosity at 37°C of about 1.07 cP to about 1.08 cP. Gelatin solution can be provided in PBS, DMEM or other suitable solvent.

[00125] In specific embodiments, the fluid-based composition is gelatin. Gelatin is a non-toxic, biodegradable and water-soluble protein derived from collagen, which is the main component of the extracellular matrix (ECM) of mesenchymal tissues. Collagen is the main structural protein in the extracellular space in various connective tissues in animal bodies. As a major component of connective tissue, it is the most predominant protein in mammals, accounting for 25% to 35% of the protein content in the entire body. Depending on the degree of mineralization, collagen tissues can be rigid (bone), pliable (tendon), or have a gradient from rigid to pliable (cartilage). Collagen, in the form of elongated fibrils, is primarily found in fibrous tissues, such as tendons, ligaments and skin. It is also prevalent in corneas, cartilage, bone, blood vessels, the digestive tract, intervertebral discs, and the dentin in teeth. In muscle tissue, it serves as the main component of the endomysium. Collagen makes up one to two percent of muscle tissue and accounts for 6% of the weight of strong, sinewy muscles. Collagen occurs in many places throughout the body. However, more than 90% of the collagen in the human body is type I.

[00126] To date, 28 types of collagen have been identified and characterized. They can be divided into several groups according to the structure they form: Fibrillar (type I, II, III, v, XI). Non-fibrillar FACIT (fibril-associated collagens with interrupted triple helices) (type IX, XII, XIV, XVI, XIX). Short chain (type VIII, X). Basement membrane (type IV). Multiplexin (with several regions of interrupted triple helices) (type XV, XVIII). MACIT (membrane-associated collagens with interrupted triple helices) (type XIII, XVII). Other (type VI, VII). The five most common types are as follows: Type I: skin, tendon, vascular ligature, organs, bone (major component of the organic portion of bone). Type II: Cartilage (major collagen component of cartilage). Type III: Reticular (major component of reticular fibers), usually found with Type I. Type IV: Forms the basal lamina, the epithelial secretory layer of the basement membrane. Type V: Cell surfaces, hair, and placenta.

[00127] Gelatin retains information signals including the arginylglycylaspartic acid (RGD) sequence, which accelerates cell adhesion, proliferation, and stem cell differentiation. A characteristic property of gelatin is that it exhibits upper critical solution temperature (UCST) behavior. Above a certain threshold temperature, gelatin can dissolve in water by forming flexible random single coils. Upon cooling, hydrogen bonding and van der Waals interactions occur, leading to the formation of triple helices. These collagen-like triple helices act as transition zones and thereby initiate the sol-gel transition. Gelatin is widely used in pharmaceutical and medical applications.

[00128] In particular embodiments, the injectable cell formulation based on a fluid is based on porcine gelatin, which can be obtained from porcine skin and is commercially available, for example, from Nitta Gelatin NA Inc (NC, USA) or Gelita USA Inc. (IA, USA). The gelatin can be dissolved, for example, in Dulbecco's phosphate-buffered saline (DPBS) to form a thermosensitive hydrogel that can thicken and liquefy at various temperatures. In particular embodiments, the hydrogel used to prepare the injectable cell composition formulation is based on recombinant human or animal gelatin expressed and purified using techniques known to those skilled in the art. In particular embodiments, an expression vector comprising all or a portion of the cDNA for human collagen type I, alpha I, is expressed in the yeast Pichia pastoris. Other expression vector systems and organisms will be known to those skilled in the art. In particular embodiments, the gelatin hydrogel of the present disclosure is a liquid at and above room temperature (22-28°C) and (2-8°C) gels when cooled to refrigeration temperatures.

[00129] Those skilled in the art will appreciate additional features and advantages of the invention based on the embodiments described above. Accordingly, the invention should not be limited by what is specifically shown and described except as indicated by the appended claims. All publications and references cited herein are expressly incorporated herein in their entirety by reference.

Claims (25)

1. A fluid-based pharmaceutical composition delivery device comprising: - a housing having an actuator, a fluid receiving device and a fluid delivery mechanism; and - a removable injection needle extending distally from the body, - wherein the fluid delivery mechanism is configured to deliver boluses or a continuous flow of fluid through the injection needle; and trocar containing an elongated body having proximal and distal ends, the body having a head at its proximal end, an elongated shaft extending distally from the head, and a lumen extending from the proximal end to the distal end therethrough; and - a stabilizing mechanism on the distal portion of the elongated shaft, designed to stabilize the distal end of the elongated body relative to the tissue surface, wherein The stabilizing mechanism contains: footrests arranged radially symmetrically around the elongated body; and shafts, each of which is connected to the corresponding lower part of the footrests at the first end and connected to the elongated body by means of corresponding hinge points at the other end, wherein the footrest and the shaft are designed with the possibility of moving from a recessed position along the elongated body to an extended position, by rotation in the direction from the elongated body by means of hinge points, when using a trocar, wherein in the extended position the footrests grasp the surface of the tissue with the possibility of disengaging. 2. The device of claim 1, wherein (a) the fluid delivery mechanism comprises an electromechanical system having a central processor and a pump; or (b) the actuator is one of a trigger dog, a plunger, a switch, or a button. 3. The device according to claim 1, further comprising a valve configured to move in space proximally and distally parallel to the injection needle during placement of the device and delivery of the fluid. 4. The device according to claim 3, wherein the valve is designed with the ability to move in space by 2 cm distally and proximally. 5. The device according to claim 1, wherein the fluid receiving device is configured to removably and replaceably receive the fluid reservoir, and the fluid reservoir comprises at least one cartridge that includes a dosage of fluid. 6. The device according to claim 5, wherein the receiving device for the fluid medium is configured to receive cartridges in parallel. 7. The device of claim 1, wherein the fluid comprises therapeutic cells or their products for treating kidney disease. 8. The device according to item 1, additionally comprising a touch display configured to control the operation of the device. 9. The device of claim 8, wherein the display is configured to set one or more parameters for delivering 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 according to claim 1, further comprising an engaging element at the distal end of the housing, configured to removably engage the trocar. 12. The device according to claim 1, wherein the footrests have micro hooks on them. 13. The device of claim 1, wherein the footrests include at least one of an adhesive, a suction cup, and a clamp. 14. The device according to claim 1, additionally comprising a removable stylet, configured to pass through the lumen of the elongated body, wherein the stylet is configured to activate the stabilizing mechanism upon removal. 15. The device according to claim 1, wherein at least part of the elongated shaft is designed with the ability to move in space distally and proximally parallel to the longitudinal axis of the elongated shaft. 16. The device according to claim 15, wherein at least part of the elongated shaft is designed with the ability to move in space by 2 cm distally and proximally.