In situ therapeutic production: methods and compositions

Abstract

This disclosure is directed to compositions of engineered cells that are incorporated into immunomodulatory substances that act as semi-permeable membranes. These compositions provide for sustained delivery of various biologic and therapeutic molecules, such as cytokines or monoclonal antibodies, for a range of diseases, including infectious diseases, cancer immunotherapy and auto-immune disorders.

Description

IN SITU THERAPEUTIC PRODUCTION: METHODS AND COMPOSITIONSCLAIM OF PRIORITY

[0001] This application claims priority to U.S. Application No. 63 / 509,396, filed on June 21, 2023. The entire contents of the foregoing application are incorporated by reference in their entirety.BACKGROUND

[0002] Biologic-based therapies have revolutionized various fields of medicine, including infectious disease, immunotherapy, and autoimmune disorders. However, challenges remain in achieving optimal delivery and sustained release of biologic products in a safe and effective manner.1The current invention addresses these challenges by utilizing an implantable biocompatible semi-permeable membrane for encapsulating genetically engineered cells that can produce biologies. One challenge of successfully implanting medical devices are host immune responses mounted against devices. Implanted biomaterials lead to foreign body responses, an immune-mediated reaction where inflammatory events lead to fibrosis, or collagenase depositions that wall off implants). This fibrotic response decreases implant functionality and ultimately leads to implant failure. Thus, there is a significant need for a system that is able to both deliver controlled therapeutic doses long-term and reduce foreign body response to such an implant.SUMMARY

[0003] This invention is directed towards biologic producing engineered cells encapsulated in a semi -permeable membrane, such as alginate capsules or alginate-laden devices, which provides an innovative solution for the controlled and sustained delivery of biologic products. The semi-permeable membrane can serve as a protective microenvironment, maintaining the viability and functionality of the enclosed cells, while enabling the controlled release of the produced biologies over extended timespans. Such encapsulated cells can be implanted at various sites (e.g., intraperitoneal cavity, subcutaneously) to provide localized administration to specific tissues or systemic delivery of biologies. Biologies can include a cytokine, anengineered protein, a secreted protein, an antibody, a nanobody, a diabody, a single-chain variable fragment, a hormone, an enzyme, or a peptide.

[0004] Furthermore, semi-permeable membranes can be modified to mitigate host immune response. Modifications can include, but are not limited to, conjugating small molecules with immune-evasive properties to membranes, incorporating immunomodulatory molecules into membrane matrices, or utilizing sentinel cells that produce immunomodulatory molecules to protect engineered cells. W ithout wishing to be bound by theory, a list of antibody-based therapeutics that are marketed or in late-stage clinical trials that can be produced in such a system is provided herein.

[0005] The use of the word "a" or "an" when used in conjunction with the term "comprising" in the claims and / or the specification can mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one." The word "about" means plus or minus 5% of the stated number.

[0006] Any method or composition described herein can be implemented with respect to any other method or composition described herein. Other objects, features and advantages of the instant disclosure will become apparent from the following detailed description. It can be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the disclosure, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.BRIEF DESCRIPTION OF THE DRAWINGS

[0007] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0008] The following drawings form part of the instant specification and are included to further demonstrate certain aspects of the instant disclosure. The disclosure can be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments described herein.

[0009] FIG. 1A-B: Example map of a protein expression vector. This vector can be for natalizumab, but light and heavy antibody chain sequences can be replaced by sequences forother biologies. The order of components in the lower panel is a representative example and the order of components can be swapped or the protein components can be swapped to produce other multidomain proteins

[0010] FIG. 2: Antibody Production Values in Polyclonal Population. Obtained using Abcam's Human IgG ELISA Kit (abl95215). Data was obtained by placing 1 0 K engineered cells into a 96-well plate, letting cells rest overnight, replacing the media, then harvesting the supernatant 24 hours later and performing an ELISA following Ab e am ’ s' s protocol.

[0011] FIG. 3: Data from ELISA verifying presence of full antibody. In order to verify that complete antibody was being produced an ELISA was also run that captures the Heavy chain of the antibody and detects via HRP-Conjugated antibody the Light Chain of the antibody.

[0012] FIG. 4: Data from ELISA verifying binding of correct antigen. In order to verify that the produced antibodies were binding correctly to the specified antigen, an example ELISA was run that used PD-1 bound to a 96 well plate to capture pembrolizumab (ab237652).

[0013] FIG. 5A-B: Device configurations (FIG. 5 A) and Workflow (FIG. 5B).

[0014] FIGS. 6A-B: Microchip schematic. Figure 6A) A schematic of the microchip polymer with a representative lattice structure. Figure 6B) The size of the microchip can be scalable, allowing a range of encapsulated cell volumes.

[0015] FIGS. 7A-C: Microchip Prototyping. Figure 7 A) The pore size of the microchip allows the containment of bulk encapsulated cell construct form factors, as well as capsules. Figure 7B). Quantified cell viability can be above 96% for bulk and capsule form factor devices. Figure 7C) Productivity data of therapeutic cells encapsulated in the microchip platform.

[0016] FIG. 8: Antibody Production Values in Monoclonal Cell Lines. Obtained using Abcam's Human IgG ELISA Kit (abl95215). Monoclonal lines were developed using limited dilution of polyclonal populations. Data was obtained by placing lOKengineered cells into a 96- well plate, letting cells rest overnight, replacing the media, and then harvesting the supernatant 24 hours later and performing an ELISA following Abcam’s protocol.

[0017] FIG. 9: In Vivo Antibody Productivity. Obtained using Abcam's Human IgGELISA Kit (abl95215). Various doses of encapsulated monoclonal cells (i.e., 63K, 126K, 252K, 504K cells) were implanted subcutaneously in NOD.Cg-Prkdcscid / J mice. In vivo antibody productivity was assessed by analyzing mouse sera acquired from saphenous blood draws on an ELISA following Abcam's protocol and normalized by mouse weight.

[0018] FIG. 10 is an illustration of an exemplary, single promoter plasmid map used to engineer a variety of therapeutic ARPE-19 cells.

[0019] FIG. 11 is a bar graph demonstrating production of a variety of biologies from engineered ARPE-19 cells.

[0020] FIGS. 12A-B are activity and neutralization assays demonstrating the production of a variety of biologies produced by engineered ARPE-19 cells that are functional and comparable to clinical grade controls. FIG. 12A is a bar graph showing a matrix metalloproteinase (MMP) assay with the relative fluorescence for MMP1 and MMP13. FIG. 12B is a bar graph showing the TZM.B1 HIV Neutralization Assay with IC50 (pg / mL) for 3BNC1 17 and PGT121 antibodies, where ARPE-19 produced antibody and control antibodies were compared.

[0021] FIG. 13 is a graph illustrating a dose escalation study in which therapeutics cells were encapsulated in an immunomodulatory biomaterial and implanted in mice. The data demonstrates that the IgG therapeutic dose can be modulated based on the number of cells, as is indicated by the differences in IgG levels across groups.

[0022] FIG. 14 is a graph illustrating long-term IgG titer in immunocompromised mice measured for over 7 months, contrasting two delivery methods: immunomodulatory biomaterial encapsulated cells, and a bolus injection of IgG, which represents traditional biologies administration. The results demonstrate that the immunomodulatory biomaterial encapsulated cells provide stable and durable IgG delivery over the long term, whereas the bolus injection shows a rapid decline in IgG levels.

[0023] FIG. 15 is a long-term IgG titer in B-cell deficient mice using various immunomodulatory biomaterials collected for over 6 months. Therapeutic IgG-producing cells encapsulated in various immunomodulatory biomaterials and implanted in B-cell deficient mice. These B-cell deficient mice exhibit a largely functional immune system,including a foreign body response but lack anti-drug antibodies (ADA). The graph demonstrates the efficacy of the antifibrotic biomaterials to deliver stable levels of biologies over the long-term while simultaneously mitigating fibrosis in an in vivo setting.

[0024] FIG. 16 is a graph showing IgG titer data from fully immunocompetent mice over a period of 6 months. The study compares three delivery methods: immunomodulatory biomaterial encapsulated cells, bolus IgG injection, and cells encapsulated in a biomaterial not modified with antifibrotic small molecules. The results demonstrate the differences in IgG levels over time across each method. The immunomodulatory biomaterial encapsulated cells show sustained and stable IgG delivery, significantly outperforming the bolus injection, which shows a rapid decline in IgG levels. The cells encapsulated in a non-modified biomaterial exhibit a gradual decline in IgG levels due to fibrosis. These results underscore the advantage of utilizing antifibrotic small molecule- modified biomaterials in maintaining long-term stable biologies delivery in fully immunocompetent mice.

[0025] FIGS. 17A-B demonstrate enhanced durability of therapeutic cells co-encapsulated with immunomodulatory, engineered cells, employing unmodified materials allowing for the attribution of antifibrotic effects to the immunomodulatory, engineered cells. FIG. 17A is a graph showing the change in IgG titer over time: unmodified, encapsulated cells show a decline, whereas immunomodulatory, engineered cells maintain higher IgG titers. FIG. 17B is a series of images of capsules before implantation and after explant. The top row shows unmodified capsules, and the bottom row shows immunomodulatory engineered-cell, co-encapsulated capsules. Coencapsulation of immunomodulatory, engineered cells results in demonstrably less fibrosis.

[0026] FIG. 18 is a graph showing the results of a dose escalation study wherein the dose was modulated to achieve an IgG titer by varying the density of encapsulated cells rather than increasing the volume or number of implanted devices.

[0027] FIG. 19 is a graph showing the retrieval of a minimally invasive device implanted subcutaneously with a trocar, wherein the retrieval occurred 1 month after implantation. The implantation device can be safely retrieved after implantation, allowing for termination or replacement of therapy as necessary.DESCRIPTION OF II I I S I RA I I VE EMBODIMENTS

[0028] Here the inventors report on a new platfonn technology for the long-term production of therapeutic biologies by encapsulated cells for in-patient delivery and production. This technology utilizes engineered cells that produce biologies such as 3BNC117, PGT121, pembrolizumab, ipilimumab, daratumumab, dulaglutide, blinatumomab, and others. These biologies can be used for disease areas such as oncology, cardiovascular health, metabolic disease, infectious disease, neurology, autoimmune disease, and others. Further, we report on the development of implantable micro capsules and macrodevices as carriers of these engineered cells as well as a therapeutic tissue device. These and other aspects of the disclosure are described in detail herein.

[0029] Engineered Cells

[0030] An engineered cell be derived from any mammalian organ or tissue, including the brain, nerves, ganglia, spine, eye, heart, liver, kidney, lung, spleen, bone, thymus, lymphatic system, skin, muscle, pancreas, stomach, intestine, blood, ovary, uterus, or testes. A cell can be derived from a donor (e.g., an allogeneic cell), derived from a subject (e.g., an autologous cell), or from another species (e.g., a xenogeneic cell). In an embodiment, a cell can be grown in cell culture, or prepared from an established cell culture line, or derived from a donor (e.g., a living donor or a cadaver). In an embodiment, a cell can be genetically engineered. In another embodiment, a cell is not genetically engineered. A cell can include a stem cell, such as a reprogrammed stem cell, or an induced pluripotent cell. Exemplary cells include mesenchymal stem cells (MSCs), fibroblasts (e.g., primary fibroblasts). HEK cells (e.g., HEK293T), Jurkat cells, HeLa cells, retinal pigment epithelial (RPE) cells, HUVEC cells, NIH3T3 cells, CHO-K1 cells, COS-1 cells, COS-7 cells, PC- 3 cells, HCT 116 cells, A549MCF-7 cells, HuH-7 cells, U-2 OS cells, HepG2 cells, Neuro-2a cells, and SF9 cells. In an embodiment, a cell for use in an implantable construct can comprise an RPE cell. A cell included in a device or capsule can produce or secrete a therapeutic agent. In an embodiment, a cell included in a device or capsule can produce or secrete a single type of therapeutic agent or a plurality of therapeutic agents. In an embodiment, a device or capsule can comprise a cell that is transduced or transfected with a nucleic acid (e.g., a vector) comprising an expressionsequence of a therapeutic agent. For example, a cell can be transduced or transfected with a lentivirus. A nucleic acid introduced into a cell (e.g., by transduction or transfection) can be incorporated into a nucleic acid delivery system, such as a plasmid, or can be delivered directly.

[0031] In an embodiment, a nucleic acid introduced into a cell (e.g., as part of a plasmid) can include a region to enhance expression of the therapeutic agent and / or to direct targeting or secretion, for example, a promoter sequence, an activator sequence, or a cellsignaling peptide, or a cell export peptide. Exemplary promoters include EF-la, CMV, Ube, hPGK, VMD2, and CAG. Exemplary activators include the TET1 catalytic domain, P300 core, VPR, rTETR, Cas9 (e.g., from 5. pyogenes or S. aureus), and Cpfl (e.g., from L. bacterium).

[0032] In some embodiments, the vector, e g., plasmid, encoding for the therapeutic agent can comprise one or more promoters, e.g., CAG or CMV. In some embodiments, the vector, e g., plasmid, can comprise a Kozak or IRES sequence for the transcription of nucleic acid sequences encoding for various proteins comprising a therapeutic agent, e.g., a biologic, e.g., an antibody comprising a heavy chain and a light chain. In some embodiments, the vector, e.g., plasmid can comprise one or more antibiotic resistance genes, e.g., resistance genes for puromycin, ampicillin, kanamycin, penicillin, inter alia. In some embodiments, the vector, e.g., plasmid can comprise a pUC origin sequence or ITR sequence orientated in the 5’ or 3’ direction. In some embodiments, the vector, e.g., plasmid can comprise a poly adenylation signal, e.g. BGH polyA.

[0033] In some embodiments, the order of components in the vector, e.g., plasmid, in the 5’ to 3’ direction can comprise the following for an IRES system: (i) CAG promoter; (ii) biologic light chain; (iii) IRES; and (iv) biologic heavy chain. In some embodiments, the order of components in the vector, e.g., plasmid, in the 5’ to 3’ direction can comprise the following for a P2A system: i) CAG promoter; (ii) biologic light chain; (iii) P2A ; and (iv) biologic heavy chain. In some embodiments, the order of components in the vector, e.g., plasmid, in the 5’ to 3’ direction can comprise the following for a dual promoter system: (i) a first promoter, e.g. CAG promoter; (ii) biologic light chain; (iii) a second promoter, e.g., hPGK; and (iv) biologic heavy chain.

[0034] In an embodiment, the vector, e.g., plasmid, encoding for the therapeuticagent, e.g., Natalizumab, can comprise a pUC origin sequence, a CAG promoter, a Kozak sequence, a sequence encoding for a first chain of a therapeutic agent, e.g., Natalizumab light chain, an IRES sequence, a sequence encoding for a first chain of a therapeutic agent, e.g., Natalizumab heavy chain, a CMV promoter, a puromycin resistance gene, PGH pA sequence, a 3’ ITR, and ampicillin resistance gene.

[0035] In another embodiment, the vector, e.g., plasmid, encoding for a therapeutic agent can comprise a 5’ ITR, a CAG promoter, a Kozak sequence, a nucleic acid sequence encoding for human IL- 10 (hILlO), a rBG pA signal sequence, a CMV promoter, a puromycin resistance gene, a BGH pA signal sequence, a 3’ ITR, and an ampicillin resistance gene.

[0036] The therapeutic agent can be a biologic, e.g., a monoclonal or polyclonal antibody. The therapeutic agent can comprise multiple protein subunits, e g., one or more heavy chains and one or more light chains. In some embodiments, the therapeutic agent can be selected from one or more of the following: Nemolizumab, Zanidatamab, Linvoseltamab, Axatilimab, Tarlatamab, Marstacimab, Garadacimab, Vilobelimab, Zolbetuximab, Odronextamab, Crovalimab, Camrelizumab, Serplulimab, Sugemalimab, Concizumab, Cosibelimab, Donanemab, Sintilimab, Narsoplimab, Pozelimab, Elranatamab, Rozanolixizumab, Talquetamab, Epcoritamab, Lebrikizumab, Glofitamab, Mirikizumab, Tislelizumab, Toripalimab, Retifanlimab, Lecanemab, Teplizumab, Ublituximab, Nirsevimab, Tremelimumab, Spesolimab, Teclistamab, Mosunetuzumab, Tixagevimab (Cilgavimab), Relatlimab, Tebentafusp, Faricimab, Sutimlimab,Sotrovimab, Regdanvimab, Casirivimab, Imdevimab, Tezepelumab, Amivantamab, Anifrolumab, Bimekizumab, Tralokinumab, Evinacumab, Aducanumab, Dostarlimab, Ansuvimab, Margetuximab, Naxitamab, Atoltivimab, Maftivimab, Tafasitamab, Satralizumab, Inebilizumab, Teprotumumab, Isatuximab, Eptinezumab, Crizanlizumab, Risankizumab, Romosozumab, Ravulizumab, Emapalumab, Cemiplimab, Fremanezumab, Moxetumomab pasudotox, Galcanezumab, Lanadelumab, Mogamulizumab, Erenumab, Tildrakizumab, Ibalizumab, Burosumab, Durvalumab, Emicizumab, Benralizumab, Ocrelizumab, Guselkumab, Sarilumab, Dupilumab, Avelumab, Brodalumab, Atezolizumab, Bezlotoxumab, Olaratumab, Reslizumab,Obiltoxaximab, Ixekizumab, Daratumumab, Elotuzumab, Necitumumab, Idarucizumab, Alirocumab, Mepolizumab, Evolocumab, Dinutuximab, Secukinumab, Nivolumab, Blinatumomab, Pembrolizumab, Ramucirumab, Vedolizumab, Siltuximab, Obinutuzumab, Raxibacumab, Pertuzumab, Belimumab, Ipilimumab, Denosumab, Tocilizumab, Ofatumumab, Canakinumab, Golimumab, Ustekinumab, Catumaxomab, Eculizumab, Ranibizumab, Panitumumab, Natalizumab, Bevacizumab, Cetuximab, Efalizumab, Efalizumab, Omalizumab, Tositumomab-1131, Ibritumomab tiuxetan, Adalimumab, Alemtuzumab, Trastuzumab, Infliximab, Palivizumab, Basiliximab, Daclizumab, Rituximab, Abciximab, and Muromonab-CD3 or a functional fragment thereof.

[0037] Table 2. Exemplary biologies and their amino acid sequences, if applicable.

[0038] The therapeutic agent can comprise an enzyme replacement therapy. In some embodiments, the enzyme replacement therapy can be selected from one or more of the following: Human recombinant AD AMTS 13, Alpha 1 -Proteinase inhibitor, Collagenase, Asparaginase, Anti-Inhibitor Coagulant Complex, tPa (Alteplase), Pegademase (bovine), Alglucerase (Imiglucerase), Factor IX, DNase, PANCRELIPASE (AMYLASE, LIPASE, PROTEASE), Sacrosidase, truncated (non-glycosylated)tPA (357 of 527aa), recombinant coagulation Factor Vila, tissue Plasminogen activator variant, Uricase (Aspergillus flavus). Antihemophilic factor, Laronidase, Agalsidase beta, Hyaluronidase (ovine), Hyaluronidase (bovine), Galsulfase, Hyaluronidase (Human), Idursulfase, Al glucosidase alfa, Thrombin (human), Thrombin (Bovine), Velaglucerase alfa, Pegloticase, asparaginase (Erwinia chrysanihem). Taliglucerase alfa, recombinant truncated form of human plasmin, Recombinant carboxypeptidase g2 (Glucarpidase), Coagulation Factor Xllla, Elosulfase alfa, Coagulation factor X, Asfotase Alfa, SEBELIPASE ALFA, CERLIPONASE ALFA, vestronidase alfa-vjbk, pegvaliase-pqpz, and algasidase alfa, or a functional fragment thereof.

[0039] The therapeutic agent can comprise a peptide or polypeptide therapeutic. In some embodiments, the peptide or polypeptide therapeutic can be selected from one or more of the following: Exenatide, Brolucizumab, Caplacizumab, Liraglutide, Lixisenatide, Albiglutide, Dulaglutide, Teduglutide, Pramlintide, Aviptadil, Carbetocin, Teriparatide, Abaloparatide, Plecanatide, Nesiritide, Angiotensin II, Lucinactant, Pasireotide, and Setmelanotide, or a functional fragment thereof.

[0040] The therapeutic agent can comprise a protein replacement therapy. In some embodiments, the protein replacement can be selected from one or more of the following: Eftrenonacog alfa (Fc-FIX), Albumin FIX, and FIX Alal48 isoform, or a functional fragment thereof.

[0041] This disclosure provides methods for evaluating the productivity,specificity, and / or activity of the therapeutic agent, e.g., biologic. In some embodiments, the method can comprise evaluating the productivity of the biologic, e.g., antibody, secreted from an engineered cell via an immunoassay known in the art, e.g., ELISA. In some embodiments, the method can comprise evaluating the specificity of the biologic, e.g., antibody, secreted from an engineered cell by evaluating the ability of the biologic, e.g., antibody, to bind to its target antigen. In some embodiments, the evaluating can be performed by an immunoassay known in the art, e.g., ELISA. In some embodiments, the method can comprise evaluating the activity of the biologic, e.g., antibody, secreted from an engineered cell. In some embodiments, evaluating the activity can comprise performing a matrix metalloproteinase (MMP) assay. In some embodiments, the evaluating the activity can comprise performing a neutralization assay, e g., an HIV neutralization assay.

[0042] The engineered cell can express and / or secrete one or more therapeutic agents upon introduction of a nucleic acid into the cell (e.g., by transfection with a vector, e.g., a plasmid, as described herein, or transduction. In some embodiments, the therapeutic agent can comprise a biologic, e.g. one or more antibodies as described herein. In some embodiments, the therapeutic agent can comprise an enzyme replacement therapy, e g., one or more enzyme replacement therapies as described herein. In some embodiments, the therapeutic agent can comprise a peptide or polypeptide therapeutic, e.g., one or more peptide or polypeptide therapeutics as described herein. In some embodiments, the engineered cell can produce or secrete a therapeutic agent, e.g., 3BNC117, PGT121, 3BNC117LS, L9LS, PB27, Axitilimab, Dulaglutide,Pembrolizumab, Exenatide, Leptin, IL10, CS43LS, Ipilimumab, or Natalizumab. In some embodiments, the production of the therapeutic agent is about 0.01, 0.02, 0.03, 0.04, 0.05, 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, 100 or more pg / cell / day. In some embodiments, the engineered cell can comprise an engineered ARPE-19 cell.

[0043] In some embodiments, the engineered cell can express or secrete a therapeutic agent, e.g., a biologic, e.g., an antibody comprising a heavy and a light chain. In some embodiments, an immunoassay , e.g., enzyme-linked immunosorbent assay (ELISA), is utilized to evaluate the production of the biologic and its components. Forexample, ELISA can be used to verify the production of a complete antibody, in which the heavy chain of the antibody is captured and detects the light chain of the antibody via HRP-conjugated antibody.

[0044] The engineered cell can express or secrete a biologic, e,g., an antibody derived from a monoclonal cell line. This disclosure provides methods for developing a monoclonal cell line using limited dilution of polyclonal populations. In some embodiments, the method can comprise: (i) disposing engineered cells, e.g., 10K engineered cells into an array, e.g., a 96-well plate; (ii) resting the engineered cells overnight; (iii) replacing the media; (iv) harvesting the supernatant 24 h after plating the engineered cells; (iv) performing an immunoassay, e.g., ELISA, such as Abeam’ s Human IgG ELISA Kit® (abl95215). In some embodiments, the antibody can comprise 3BNC117P1-D9, PGT121P1-E5, Pembrolizumab 11-2-2, or Ipilimumab. In some embodiments, the production of the antibody, e.g., 3BNC117P1-D9, PGT121P1-E5, Pembrolizumab 11-2-2, or Ipilimumab, can comprise about 5, 10, 15, 20, or 25 pg / cell / day. In some embodiments, the production of the antibody, e.g., 3BNC117P1-D9, PGT121P1-E5, Pembrolizumab 11-2-2, or Ipilimumab, can comprise about to about 25 pg / cell / day.

[0045] The engineered cell can express or secrete a biologic, e.g., an antibody, that correctly binds to its target antigen. In some embodiments, an immunoassay, e.g., ELISA, is utilized to verify the correct binding to its target antigen. In some embodiments, ELISA can be used with immobilized PD-1 to capture pembrolizumab (ab237652). In some embodiments, the production of pembrolizumab can comprise about 1.8 / pg / cell from pembrolizumab-producing ARPE-19 cells as evaluated via the method described herein.

[0046] The biologies produced by engineered cells are functional and comparable to clinical-grade controls. In some embodiments, the activity of the biologies can be evaluated by an MMP assay, e.g., by measuring the relative fluorescence of the biologies for MMP1 and MMP13. In some embodiments, the relative fluorescence can comprise about 50, 100, 150, 200, 250 relative fluorescence units (RFU) for MMP1 and MMP13 and is equal to or greater than RFU for control. In some embodiments, the engineered cells are ARPE-19 cells.

[0047] In some embodiments, the IC50 for biologies, e.g., antibodies, secretedfrom engineered cells is comparable to a clinical-grade control. In some embodiments, the IC50 for a 3BNC117 antibody secreted by engineered cell in an HIV neutralization antibody is comparable to a clinical grade control, e.g., about 0.02, 0.04, 0.06, 0.08, or 0.10 pg / mol. In some embodiments, the IC50 for a PGT121 antibody secreted by an engineered cell in an HIV neutralization antibody is comparable to a clinical grade control, e.g., about 0.02, 0.04, 0.06, 0.08, or 0.10 pg / mol.

[0048] A device or capsule described herein can comprise a cell or a plurality of cells. In the case of a plurality of cells, the concentration and total cell number can be varied depending on a number of factors, such as cell type, implantation location, and lifetime of the implantable construct. In an embodiment, the total number of cells included in an implantable construct is greater than about 2, 4, 6, 8, 10, 20, 30, 40, 50, 75, 100, 200, 250, 500, 750, 1000, 1500, 2000, 5000, 10000, or more. In an embodiment, the total number of cells included in an implantable construct is greater than about 1.0 x 102, 1.0 x 103, 1.0 x 104, 1.0 x IO3, 1.0 x 106, 1.0 x 107, 1.0 x 108, 1.0 x 109, 1.0 x 1010, or more. In an embodiment, the total number of cells included in an implantable construct is less than about than about 10000, 5000, 2500, 2000, 1500, 1000, 750, 500, 250, 200, 100, 75, 50, 40, 30, 20, 10, 8, 6, 4, 2, or less. In an embodiment, the total number of cells included in an implantable construct is less than about 1.0 x 1010, 1.0 x 109, 1.0 x 108, 1.0 x lO7, 1.0 x 106, 1.0 x 105, 1.0 x 104, 1.0 x 103, 1.0 x 102, or less. In an embodiment, a plurality of cells is present as an aggregate. In an embodiment, a plurality of cells is present as a cell dispersion.

[0049] Specific features of a cell contained within a device or capsule can be determined, e.g., prior to and / or after incorporation into the implantable construct. For example, cell viability, cell density, or cell expression level can be assessed. In an embodiment, cell viability, cell density, and cell expression level can be determined using standard techniques, such as cell microscopy, fluorescence microscopy, histology, or biochemical assay.

[0050] Capsules and Devices

[0051] The capsules / devices of this disclosure comprising an engineered cell have an inner housing chamber with which the cells are housed. This in turn can be surrounded by a biocompatible supporting structure / lattice or are disposed in a capsule formed from abiocompatible material. The following discussion of materials and methods for production relate to these capsules / devices

[0052] Alginates

[0053] The inventors can use the alginates to create protective coatings for cells contained in the devices and capsules according to this disclosure. They have identified immunomodulatory small molecules using combinatorial chemistry and high throughput screening (Vegas et al., 2016b) and validated the long-term effectiveness of these small molecules in the prevention of fibrosis and long-term cell survival in non-human primates. In some embodiments, the degradable zone can comprise a polymeric hydrogel, such as but not limited to chitosan, cellulose, hyaluronic acid, or alginate. In some embodiments, the alginate can comprise SLG20. In some embodiments, the SLG20 can comprise about 0. l%-3% SLG20.

[0054] One embodiment provides for the use of modified alginate polymers in the construction of cell containing devices. Modified alginate polymers can be of any molecular weight. The weight average molecular weight of the alginates is preferably between 1,000 and 1,000,000 Daltons, more preferably between 10,000 and 500,000 Daltons as determined by gel permeation chromatography.

[0055] Modified alginate polymers can contain any ratio of mannuronate monomers, guluronate monomers, and covalently modified monomers. In some embodiments, greater than 2.5%, 5%, 7.5%, 10%, 12%, 14%, 15%, 16%, 18%, 20%, 22%, 24%, 25%, 26%, 28%, 30%, 32.5%, 35%, 37.5%, 40%, 45%, 50%, 55%, or 60% of the monomers in the modified alginate polymer are covalently modified monomers. Greater than 10%, greater than 20%, or greater than 30% of the monomers in the modified alginate polymer are covalently modified monomers.

[0056] Modified alginate polymers can be produced incorporating covalently modified monomers possessing a range of different hydrogen bonding potentials, hydrophobicities / hydrophilicities, and charge states. The inclusion of covalently modified monomers into an alginate polymer alters the physiochemical properties of alginate polymer. Accordingly, the physiochemical properties of alginates can be tuned for applications by the selective incorporation of covalently modified monomers.

[0057] For example, the glass transition temperature (Tg), can be varied by theincorporation of covalently modified monomers. In some embodiments, the modified alginate polymer powder possess a Tg, as measured by differential scanning calorimetry (DSC), of greater than 50°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°c, 105°C, 110°c, 115°C, 120°c, 125°C, 130°C, 135°C, 140°C, 145°C, 150°C, 160°C, 175°C, 190°C, or 200°c.

[0058] The hydrophobicity / hydrophilicity of alginates can be varied by the incorporation of hydrophobic and / or hydrophilic covalently modified monomers. In embodiments, the modified alginate polymer contains one or more hydrophobic covalently modified monomers. The relative hydrophobicity / hydrophilicity of modified alginates can be quantitatively assessed by measuring the contact angle of a water droplet on a film of the modified alginate polymer using a goniometer. In some embodiments, the modified alginate has a contact angle of less than 90° (i.e., it is hydrophilic). In embodiments, the modified alginate has a contact angle of more than 90° (i.e., it is hydrophobic). In some embodiments, the modified alginate has a contact angle of more than 95°, 100°, 105°, 110°, 115°, or 120°.

[0059] In embodiments used for cell encapsulation, the modified alginate polymer can9 9 9 be ionically crosslinked by a polyvalent cation such as Ca +, Sr +, or Ba + to form hydrogels.

[0060] In some embodiments, the modified alginate polymer forms hydrogels such that the fluorescence intensity measured using the high throughput hydrogel formation assay described herein is greater than 10,000, 15,000, 20,000, 25,000, 30,000, 35,000, 40,000, 45,000, 50,000, or 55,000. In embodiments, the modified alginate polymer forms hydrogels such that the fluorescence intensity measured using the high throughput hydrogel formation assay described herein can be greater than 15,000. In embodiments, the modified alginate polymer forms hydrogels such that the fluorescence intensity measured using the high throughput hydrogel formation assay described herein is between 15,000 and 55,000, preferably between 20,000 and 55,000, more preferably between 25,000 and 55,000.

[0061] The porosity and surface area of modified alginates can be measured using BET analysis. Prior to BET analysis, solvent and volatile impurities are removed by prolonged heating of the modified alginate gel under vacuum. Subsequently, the hydrogel samples arecooled under vacuum, for example by liquid nitrogen, and analyzed by measuring the volume of gas (e.g., N2, Kr, CO2, or Ar gas) adsorbed to the hydrogel at specific pressures. Analysis of the physisorption of the gas at variable pressures can be used to characterize the total surface area and porosity of gels formed by the modified alginate polymers. A method of determining hydrogel porosity can comprise BET analysis.

[0062] In embodiments, the modified alginate forms a hydrogel with sufficient porosity to permit nutrients, waste, and the hormones and / or proteins secreted from encapsulated cells to diffuse freely into and out of the capsules, while simultaneously preventing the incursion of immune cells into the gel matrix. In some embodiments, the porosity of the hydrogel formed by the modified alginate polymer is increased by 5%, 10%, 15%, or 20% relative to the porosity of a hydrogel formed from the unmodified alginate polymer. In alternative embodiments, the porosity of the hydrogel formed by the modified alginate polymer is decreased by 5%, 10%, 15%, or 20% relative to the porosity of a hydrogel formed from the unmodified alginate polymer.

[0063] In embodiments used for cell encapsulation, the modified alginate is biocompatible. The biocompatibility of modified alginates can be quantitatively determined using the fluorescence-based in vivo biocompatibility assay described in Example 5. In this assay, cathepsin activity was measured using an in vivo fluorescence assay to quantify the foreign body response to the modified alginate.

[0064] In some embodiments, the modified alginate polymer can be biocompatible such that the fluorescence response normalized to unmodified alginate measured using the in vivo biocompatibility assay described herein is less than 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40%. In embodiments, the modified alginate polymer induces a lower foreign body response than unmodified alginate. This is indicated by fluorescence response normalized to unmodified alginate of less than 100%. In some embodiments, the modified alginate polymer can be biocompatible such that the fluorescence response normalized to unmodified alginate measured using the in vivo biocompatibility assay described herein can be less than 75%, more preferably less than 65%, and most preferably less than 50%.

[0065] The modified alginates can be chemically modified as described herein to anydensity of modifications. The density of modifications is the average number of modifications (that is, attached compounds) per a given weight, volume, or area of the surface of a capsule or product that includes the modified alginate. A density at or above a threshold density can provide a beneficial effect, such as lower foreign body response. In some embodiments, a high density is not required. Without being bound to any theory of operation, the chemical modifications can signal to, indicate to, or can be identified by, one or more immune system or other body components to result in a beneficial effect, such as a lower foreign body response. In some embodiments, a lower density of modifications can be effective for this purpose.

[0066] Useful densities include densities of at least, of less than, of about, or of 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20,25,30,35,40,45,50,55,60,65, 70, 75,80,85,90,95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190,200,210,220,230,240,250,260,270, 280, 290, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 550, 600, 650, 700, 750, 800, 850, 900, and 1000 modifications per square p r , per pg, or per cubic prp. All ranges defined by any pair of these densities are disclosed.

[0067] In some embodiments, the density of the modifications on a surface, surfaces, or portions of a surface(s) of a capsule or product that, when the product is administered to (e.g., implanted in the body of) a subject, can be in contact with fluid(s), cell(s), tissue(s), other component(s), or a combination thereof of the subject's body is greater than the density of the modifications on other surfaces of the product.

[0068] Density can also be expressed in terms of the concentration of the surface modifications as measured by X-ray photoelectron spectroscopy (XPS). XPS is a surfacesensitive quantitative spectroscopic technique that measures the elemental composition at the parts per thousand range of the elements that exist within a material.

[0069] XPS spectra are obtained by irradiating a material with a beam of X-rays while simultaneously measuring the kinetic energy and number of electrons that escape from the top 0 to 10 nm of the material being analyzed. By measuring elements present on the surface, the percentage of the elements that come from the surface modifications can be calculated. This can be accomplished by, for example, taking the percentage of nitrogen (and / or other elementsin the surface modifications) in the total elemental signal measured. Nitrogen is a useful indicator for the surface modification because many sub strated and materials forming the capsule or product contain little nitrogen. For convenience, the percent of the element(s) used to indicate the surface modifications can be stated as the percent surface modifications. Also, for convenience, the percent surface modifications can be referred to as the concentration of surface modifications.

[0070] Useful percent surface modifications include concentrations of about, less than or at 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, and 100 percent surface modifications. Ranges defined by any pair of these concentrations are also disclosed.

[0071] In one aspect, the alginates can be used to form a capsule. Capsules are particles having a mean diameter of about 150 pm to about 5 cm. The disclosed capsules can be formed of cross- linked hydrogel. Other than the encapsulated material, the capsules, for example, can be formed solely of cross-linked hydrogel, can have a cross-linked hydrogel core that is surrounded by one or more polymeric shells, can have one or more cross-linked hydrogel layers, can have a cross- linked hydrogel coating, or a combination thereof. The capsule can have any shape suitable for, for example, cell encapsulation. The capsule can contain one or more cells dispersed in the cross- linked hydrogel, thereby "encapsulating" the cells. Capsules can be formed of or include one or more of the disclosed modified alginates.

[0072] Capsules can have a mean diameter of about 150 pm to about 8 mm. Capsules can have any mean diameter from about 150 pm to about 5 cm. The capsules can have a mean diameter that is greater than 1 mm, such as a mean diameter of 1.5 mm or greater. In some embodiments, the capsules can be as large as about 8 mm in diameter. For example, the capsule can be in a size range of about 1 mm to 8 mm, 1 mm to 6 mm, 1 mm to 5 mm, 1 mm to 4 mm, 1 mm to 3 mm, 1 mm to 2 mm, 1 mm to 1.5 mm, 1.5 mm to 8 mm, 1.5 mm to 6 mm, 1.5 mm to 5 mm, 1.5 mm to 4 mm, 1.5 mm to 3 mm, or 1.5 mm to 2 mm.

[0073] The rate of molecules entering the capsule necessary for cell viability and the rate of therapeutic products and waste material exiting the capsule membrane can be selected by modulating capsule permeability. Capsule permeability can also be modified to limit entry of immune cells, antibodies, and cytokines into the capsule. As shown by the examples,known methods of forming hydrogel capsules can produce capsules the permeability of which limit entry of immune cells, antibodies, and cytokines into the capsule. Since different cell types have different metabolic requirements, the permeability of the membrane can be optimized based on the cell type encapsulated in the hydrogel. The diameter of the capsules is an important factor that influences both the immune response towards the cell capsules as well as the mass transport across the capsule membrane.

[0074] The growing recognition of the parameters driving fibrosis in vivo has been applied to the analysis of the performance of modified alginates. Intraperitoneal (IP) implantation of modified alginate capsules revealed that modified alginates can result in abnormally shaped capsules when crosslinked using conditions defined for unmodified alginates. These abnormally shaped capsules can complicate implementation and interpretation of modified alginate capsules implanted IP. In an effort to improve the capsule morphology, formulation methods for use with modified alginate microparticles were developed where modified alginates were blended with a small amount of high molecular weight alginate. Particles prepared from this mixture yielded particles with improved morphology and stability.

[0075] The unmodified alginate has a weight average molecular weight of about 50,000 Daltons to about 500,000 Daltons; however, unmodified alginates having molecular weights can also be used. In some embodiments, the weight average molecular weight is from about 50,000 to about 250,000 Daltons, more preferably from about 50,000 to about 150,000 Daltons. In some embodiments, the weight average molecular weight is about 100,000 Daltons.

[0076] In other embodiments, one or more additional hydrogel-forming polymers are used in combination with unmodified alginate or in place of unmodified alginate. Such polymers are known in the art. Examples include, but are not limited to, PEG, chitosan, dextran, hyaluronic acid, silk, fibrin, poly(vinyl alcohol) and poly(hydroxyl ethyl methacrylate).

[0077] In some embodiments, the alginate can compri s e-D-mannuronic acid (M) and a-L-guluronic acid (G) linked together. In some embodiments, alginate can comprise a high guluronic acid (G) alginate. In some embodiments, the alginate can comprise a high mannuronic acid (M) alginate. In some embodiments, the ratio of M:G is about 1. In someembodiments, the ratio of M:G is less than 1. In some embodiments, the ratio of M:G is greater than 1.

[0078] The particles prepared from a mixture of modified alginate and unmodified alginate produced more homogenous microparticle populations in terms of shape and size as evaluated by scanning electron microscopy (SEM). In some embodiments, the hydrogel capsules can have any suitable shape. Useful shapes include spheres, sphere-like shapes, spheroids, spheroid-like shapes, ellipsoids, ellipsoid-like shapes, stadiumoids, stadiumoid- like shapes, disks, disk-like shapes, cylinders, cylinder-like shapes, rods, rod-like shapes, cubes, cube-like shapes, cuboids, cuboid-like shapes, toruses, torus- like shapes, and flat and curved surfaces. Products, devices, and surfaces that have been or will be coated can have any of these shapes or any shape suitable for the product or device.

[0079] Spheres, spheroids, and ellipsoids are shapes with curved surfaces that can be defined by rotation of circles, ellipses, or a combination around each of the three perpendicular axes, a, b, and c. For a sphere, the three axes are the same length. For oblate spheroids (also referred to as oblate ellipsoids of rotation), the length of the axes are a= b > c. For prolate spheroids (also can be referred to as prolate ellipsoids of rotation), the length of the axes are a= b < c. For tri -axial ellipsoids (also referred to as scalene ellipsoids), the length of the axes are a> b > c. Stadiumoids are rotational shapes of stadiums. Cylinders are rotational shapes of rectangles rotated on the long axis. Disks are squashed cylinders where the diameter is greater than the height. Rods are elongated cylinders where the long axis is ten or more times the diameter.

[0080] "Sphere-like shape," "spheroid-like shape," "ellipsoid-like shape," "stadiumoid- like shape," "cylinder-like shape," "rod-like shape," "cube-like shape," "cuboidlike shape," and "torus- like shape" refers to an object having a surface that roughly forms a sphere, spheroid, ellipsoid, stadiumoid, cylinder, rod, cube, cuboid, or torus, respectively. Beyond a perfect or classical form of the shape, a sphere-like shape, spheroid-like shape, ellipsoid-like shape, stadiumoid-like shape, cylinder-like shape, rod- like shape, cube-like shape, cuboid-like shape, and torus-like shape can have waves and undulations.

[0081] A sphere-like shape can comprise an ellipsoid (for its averaged surface) with semi- principal axes within 10% of each other. The diameter of a sphere or sphere-likeshape is the average diameter, such as the average of the semi-principal axes. A spheroid-like shape can comprise an ellipsoid (for its averaged surface) with semi-principal axes within 100% of each other. The diameter of a spheroid or spheroid-like shape is the average diameter, such as the average of the semi-principal axes. An ellipsoid-like shape can comprise an ellipsoid (for its averaged surface) with semi-principal axes within 100% of each other. The diameter of an ellipsoid or ellipsoid-like shape is the average diameter, such as the average of the semi-principal axes. A stadiumoid-like shape can comprise a stadiumoid (for its averaged surface) with semi-principal axes of the ends within 20% of each other. The diameter of a stadiumoid or stadiumoid-like shape is the average diameter, such as the average of the semiprincipal axes. Alternatively, the size of a stadiumoid or stadiumoid-like shape can be given as the average of the long axis. A cylinder-like shape can comprise a cylinder (for its averaged surface) with semi- principal axes within 20% of each other. The diameter of a cylinder or cylinder-like shape is the average diameter, such as the average of the semi-principal axes.

[0082] Alternatively, the size of a cylinder or cylinder-like shape can be given as the average of the long axis. A rod-like shape can comprise a rod (for its averaged surface) with semi-principal axes within 10% of each other. The diameter of a rod or rod-like shape is the average diameter, such as the average of the semi-principal axes. Alternatively, the size of a rod or rod-like shape can be given as the average of the long axis. A cubelike shape can comprise a cube (for its averaged surface) with sides within 10% of each other. The diameter of a cube or cube-like shape is the average side length. A cuboid-like shape can comprise a cuboid (for its averaged surface) with matching sides within 10% of each other. The diameter of a cuboid or cuboid-like shape is the average side length.

[0083] A torus-like shape can comprise a torus (for its averaged surface) with semiprincipal axes within 10% of each other. The diameter of a torus or torus-like shape is the average diameter, such as the average of the semi-principal axes. Alternatively, the size of a torus or torus-like shape can be given as the diameter across the ring.

[0084] 'Flat side" refers to a contiguous area of more than 5% of a surface that has a curvature of 0. "Sharp angle" refers to a location on a surface across which the tangent to the surface changes by more than 10% over a distance of 2% or less of the circumference of the surface. Edges, comers, grooves, and ridges in a surface are forms of sharp angles.

[0085] Capsules can be made of biocompatible materials, have a diameter of at least 1 mm and less than 10 mm, has a spheroid-like shape, and have one or more of the additional characteristics: surface pores of the capsules greater than 0 nm and less than 10 pm; surface of the capsules neutral or hydrophilic; curvature of the surface of the capsules at least 0.2 and is not greater than 2 on points of the surface; and surface of the capsules lacking flat sides, sharp angles, grooves, or ridges. The capsules can elicit less of a fibrotic reaction after implantation than the same capsules lacking one or more of these characteristics that are present on the capsules. In some embodiments, the capsules are provided as a preparation and at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% of the capsules in the preparation have a shape characteristic described herein, e.g., have a spheroidlike shape, or have a curvature of the surface of at least 0.2 to 2.0 on points of the surface.

[0086] In some embodiments, the hydrogel capsules have a mean diameter that is greater than 1 mm, such as a mean diameter of 1.5 mm or greater. In some embodiments, the hydrogel capsules can be as large as 8 mm in diameter. For example, the hydrogel capsules is in a size range of 1 mm to 8 mm, 1 mm to 6 mm, 1 mm to 5 mm, 1 mm to 4 mm, 1 mm to 3 mm, 1 mm to 2 mm, 1 mm to 1.5 mm, 1.5 mm to 8 mm, 1.5 mm to 6 mm, 1.5 mm to 5 mm, 1.5 mm to 4 mm, 1.5 mm to 3 mm, 1.5 mm to 2 mm, 2 mm to 8 mm, 2 mm to 7 mm, 2 mm to6 mm, 2 mm to 5 mm, 2 mm to 4 mm, 2 mm to 3 mm, 2.5 mm to 8 mm, 2.5 mm to 7 mm, 2.5 mm to 6 mm, 2.5 mm to 5 mm, 2.5 mm to 4 mm, 2.5 mm to 3 mm, 3 mm to 8 mm, 3 mm to7 mm, 3 mm to 6 mm, 3 mm to 5 mm, 3 mm to 4 mm, 3.5 mm to 8 mm, 3.5 mm to 7 mm, 3.5 mm to 6 mm, 3.5 mm to 5 mm, 3.5 mm to 4 mm, 4 mm to 8 mm, 4 mm to 7 mm, 4 mm to 6 mm, 4 mm to 5 mm, 4.5 mm to 8 mm, 4.5 mm to 7 mm, 4.5 mm to 6 mm, 4.5 mm to 5 mm, 5 mm to 8 mm, 5 mm to 7 mm, 5 mm to 6 mm, 5.5 mm to 8 mm, 5.5 mmto 7 mm, 5.5 mm to 6 mm, 6mm to 8 mm, 6mm to7 mm, 6.5 mm to 8 mm, 6.5 mm to 7 mm, 7 mm to 8 mm, or 7.5 mm to 8 mm. In some embodiments, the capsule has a mean diameter or size between 1 mm to 8 mm. In some embodiments, the capsule has a mean diameter or size between 1 mm to 4 mm. In some embodiments, the capsule has a mean diameter or size between 1 mm to 2 mm. In some embodiments, the capsules are provided as a preparation and at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% of the hydrogel capsules in the preparation have a diameter in a size range described herein. Suitable alginatesand modified alginates are described in US20160030360A1, US20170239397 Al, WO2012167223, and WO2017075631, each of which is incorporated herein by reference.

[0087] 3D Printable Devices

[0088] The inventors can use 3D printing processes that can fabricate 3D materials. Indeed, with printing parameter optimization, the limit to what can be fabricated depends on what one can model. In addition, more complex designs that contain heterogenous properties in a single layer or in multiple layers can be fabricated. For instance, grayscale photomasks with predefined gradients can be incorporated to obtain a layer with varied stiffness or for controlled immobilization of biomolecules and cells while still using the same vat and solution. Additionally, utilization of fractal space-filling models to computationally grow vascular networks around and through pre-existing vascular networks or following the architecture of native tissues can be achieved by computer growth models for even more complex and physiologically relevant 3D models. These mathematical fractal, space-filling models can be derived from, for example, knot theory, the Hilbert curve, and the L-system. Such mathematical fractal space-filling models to predict idealized vascular networks include, but are not limited to knot theory, Plumber's Nightmare, Peano curve, Hilbert curve, Pythagoras tree, and Brownian tree models. As an example, the Plumber's Nightmare model essentially comprises two Vascular Ladder models that are connected to each other by straight vertical cylinders. Multiple Plumber's Nightmare models can be intercalated such that they are interpenetrating. The Vascular Ladder models are comprised of 1 inlet and 1 outlet with two horizontal cylinders that are connected by diagonal cylinders, resulting in interchannel junctions.

[0089] Photopolymerizable hydrogel materials such as poly(ethylene glycol) diacrylate (PEGDA) can be crosslinked using a photoinitiator system such as lithium acylphosphinate (LAP) (Fairbanks et al. 2009) which absorbs in the UV to visible light wavelength range. By adding, for example, low concentrations of carbon black (which can absorb light across UV- visible light spectrum), or low concentrations of tartrazine (which has a peak light absorption near 500 nm), the inventors can limit the depth of penetration of light. To quantify this process, the inventors developed a photorheology assay to monitor hydrogels polymerization and stiffness evolution as a function of light dosage and sample thickness. Indeed, the addition of additive materials, such as tartrazine, control the extent of gelation of thepre-polymerizationmixture by impacting the gelation kinetics and final gel rheological properties. Other materials include -ene modified natural and synthetic materials that can be photopolymerized such as alginate, silk, dextran, chondroitin sulfate, hyaluronic acid, cellulose, heparin, and poly (caprolactone) and multi-component versions of these. To achieve complex patterning of multilayered hydrogels, on the order of several centimeters, with high pattern fidelity, light exposure during the printing process is controlled so that the light projected onto the build platform interacts mainly with the layer that undergoes gelation for partial or complete gelation. Radical mediated photopolymerization of hydrogels utilizes a photoinitiator - a molecule sensitive to a wavelength range that, upon light absorption, the molecule decays and release free radicals which can catalyze hydrogel polymerization. To this end, it is imperative to quantify the wavelength sensitivity of the photoinitiator. High concentrations of photoinitiator will absorb more light and provide higher z- resolution by limiting penetration depth of the incident light. However, high photoinitiator concentrations disrupt the photopolymerization reaction (more free radicals have a higher chance of annihilating each other), and photoinitiators at high concentrations are cytotoxic. In addition, with high x-y resolution from the projector, a complication is that light shines through the z- direction of the previously printed layers, potentially limiting the ability to form complex overhang structures (such as found in vasculature), and also can cause phototoxicity to entrapped cells.

[0090] Thus, to achieve high resolution printing, this disclosure provides a photochemical means to provide, for the first time, high z-resolution in bioprinted tissues while maintaining high cell viability. To address the concerns outlined herein, the inventors have identified a general strategy whereby biocompatible materials or chemicals are added to the pre-polymerization solution to provide higher z-resolution. The additive material is selected based on three criteria: 1) ability to absorb light wavelengths which fully encompass the photosensitive wavelength range of the photoinitiator, 2) limited participation or limited inhibition of photopolymerization reactions, and 3) biocompatibility at concentrations of interest. This additive material can be referred to herein as a biocompatible, light-absorbing additive material suitable to control light penetration. Multiple molecules have been screened that absorb light, limiting the penetration depth of light into already formed layers. Suitablemolecules absorb in the same region as the photoinitiator used in the pre- polymerization solution. Examples of molecules that can control light penetration and therefore can be suitable for use as the biocompatible, light-absorbing additive material can include carbon black, yellow food coloring, tartrazine, nanoparticles, microparticles, gold nanoparticles, riboflavin, phenol red, Beta-carotene, curcumin, saffron, and turmeric. Proteins can also act as suitable biocompatible, light-absorbing additive materials provided that their peak absorption overlaps with the peak absorption of the photoinitiator and matched to the incident light source.

[0091] Other 3D printing methods include material jetting, material extrusion, light polymerization (such as DLP, SLA and CLIP), powder bed (including SLS, discussed herein), laminated object manufacturing, powder fed (DED, EHLA) and wire (EBF).

[0092] Selective laser sintering, or SLS, is an additive manufacturing (AM) technique that uses a laser as the power and heat source to sinter powdered material (e.g., nylon or polyamide), aiming the laser automatically at points in space defined by a 3D model, binding the material together to create a solid structure. It is similar to selective laser melting; the two are instantiations of the same concept but differ in technical details. SLS (as wen as the other mentioned AM techniques) is a relatively new technology that so far has mainly been used for rapid prototyping and for low-volume production of component parts.

[0093] Stereolithography (SLA or SL; also known as vat photopolymerisation, optical fabrication, photo-solidification, or resin printing) is a form of 3D printing technology used for creating models, prototypes, patterns, and production parts in a layer- by- layer fashion using photochemical processes by which light causes chemical monomers and oligomers to cross-link together to form polymers. Those polymers then make up the body of a three-dimensional solid. Stereolithography can be used to create prototypes for products in development medical models, and computer hardware, as well as in many other applications. While stereolithography is fast and can produce almost any design, it can be expensive.

[0094] The device comprising a plurality of engineered cells can be configured in any suitable shape. Suitable shapes include, spheres, sphere-like shapes, spheroids, spheroid-like shapes, ellipsoids, ellipsoid-like shapes, stadiumoids, stadiumoid-like shapes, disks, disk-like shapes, cylinders, cylinder-like shapes, rods-rod-like shapes, cubes, cube-like shapes,cuboids, cuboid-like shapes, toruses, torus-like shapes, and flat and curved surfaces, inter alia. In some embodiments, the device can be configured as a cylinder or cylinder-like shape comprising a plurality of engineered cells and a biocompatible structural material. In some embodiments, the device can be configured as a cylinder or cylinder-like shape comprising a plurality of engineered ARPE-19 cells and a biocompatible structural material comprising an alginate or modified alginate.

[0095] The device is further configured to release a therapeutic agent, e.g., a biologic or biomolecule, into the surrounding milieu. In some embodiments, the therapeutic agent can be immunomodulating.

[0096] In some embodiments, the device is configured to have an injection port.

[0097] The device can be configured as a bulk-core platform or a capsule-core platform. In some embodiments, the device is configured as a bulk-core platform, wherein the device core can comprise bulk encapsulated cells. In some embodiments, the capsule-core platform can comprise capsules (e.g., comprising engineered cells).

[0098] The cell viability of the bulk-core and capsule-core platforms is robust and comparable. In some embodiments, the cell viability of the bulk-core and capsule-core platform is about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more three days after injection into the device.

[0099] The production of therapeutic agents from engineered cells in the bulk-core and capsule-core platforms is also robust relative to capsules comprising engineered cells. In some embodiments, the production of the therapeutic agent is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 pg / cell / day or more for the capsule, capsule-core, and bulk-core platforms. In some embodiments, the production of the therapeutic agent is about 4 to 8 pg / cell / day for the capsule, capsule-core, and bulk-core platforms.[000100] The device can be configured as a cylinder or cylinder-like shape. In some embodiments, the diameter of the cylinder or cylinder-like shape is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mm or more. In some embodiments, the diameter of the cylinder or cylinder-like shape is between about 1 to 10, 1 to 9, 1 to 8, 1 to 7, Ito 6, or 1 to 5 mm. In some embodiments, the diameter of the cylinder or cylinder-like shape is between about 2 to 4 mm.[000101] In some embodiments, the length of the cylinder or cylinder-like shape is 10,15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 mm or more. In some embodiments, the length of the cylinder or cylinder-like shape is between about 10 to 100, 10 to 90, 10 to 80, 10 to 70, 10 to 60, 10 to 50, 10 to 40, 10 to 30, or 10 to 20 mm. In some embodiments, the length of the cylinder or cylinder-like shape is between about 10 to 55 mm. In some embodiments, the length of the cylinder or cylinder-like shape is 20 mm. In some embodiments, the length of the cylinder or cylinder-like shape is 55 mm.[000102] In some embodiments, the cylinder or cylinder-like shaped device has an injection port with a diameter of about 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mm. In some embodiments, the cylinder or cylinder-like shaped device has an injection port with a diameter of about 1 mm.[000103] In some embodiments, the cylinder or cylinder-like shape can have pores. The pores can assume any shape, e.g., circles, or polygons, e.g., triangles, squares, pentagons, hexagons, heptagons, octagons, nonagons, decagons and the like. In some embodiments, the shape of a pore is a hexagon, e.g., a regular hexagon. In some embodiments, a first length of the pore is about 0.1, 0.2, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5 mm or more. In some embodiments, the first length of the pore is between about 0.1 to 5, 0.1 to 4, 0.1 to 3, 0.1 to 2, 0.1 to 1, 0.1 to 0.5, 0.1 to 0.4, 0.1 to 0.3, or 0.1 to 0.2 mm. In some embodiments, the first length of the pore is between about 0.5 to 1.5 mm.[000104] In some embodiments, the distance between pores is 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 250, 300, 400, 500, 1000 gm or more. In some embodiments, the distance between pores is about 250 gm.[000105] This disclosure further provides methods for fabricating devices or capsules comprising a plurality of engineered cells. In some embodiments, the method can comprise the following steps: (i) genetically modifying cells to produce antibodies; validating antibody quality and quantifying antibody production via immunoassay; (iii) encapsulating cells in capsules or devices; and (iv) performing in vivo testing. In some embodiments, the method can comprise the following steps: (i) genetically modifying ARPE-19 cells to produce antibodies; validating antibody quality and quantifying antibody production via ELISA; (iii) encapsulating cells in a cylindrical or cylindrical-like shaped device comprising alginate or modified alginate; and (iv) performing in vivo testing.[000106] Methods of treatment[000107] Described herein are methods of treatment or uses of engineered cells for the preparation of a pharmaceutical composition (or medicament) for the treatment of tumors or a disease.[000108] In some embodiments, the disease is a proliferative disease. In an embodiment, the proliferative disease is cancer. A cancer can comprise an epithelial, mesenchymal, or hematological malignancy. A cancer includes primary malignant cells or tumors (e.g., those whose cells have not migrated to sites in the subject's body other than the site of the original malignancy or tumor) and secondary malignant cells or tumors (e.g., those arising from metastasis, the migration of malignant cells or tumor cells to secondary sites that are different from the site of the original tumor). In an embodiment, the cancer is a solid tumor (e.g., carcinoid, carcinoma or sarcoma), a soft tissue tumor (e.g., a heme malignancy), or a metastatic lesion, e.g., a metastatic lesion of any of the cancers disclosed herein. In an embodiment, the cancer can comprise a fibrotic or desmoplastic solid tumor. In some embodiments, the tumor can comprise a mesothelioma tumor.[000109] Exemplary cancers that can be treated by the methods provided for herein can include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. In an embodiment, the cancer affects a system of the body, e.g., the nervous system (e.g., peripheral nervous system (PNS) or central nervous system (CNS)), vascular system, skeletal system, respiratory system, endocrine system, lymph system, reproductive system, or gastrointestinal tract. In some embodiments, cancer affects a part of the body, e.g., blood, eye, brain, skin, lung, stomach, mouth, ear, leg, foot, hand, liver, heart, kidney, bone, pancreas, spleen, large intestine, small intestine, spinal cord, muscle, ovary, uterus, vagina, or penis. Non-limiting examples of such cancers can include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer or uterine carcinoma, salivary gland carcinoma, kidney or renalcancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.[000110] Other examples of cancers can include, but are not limited to: Acute Childhood Lymphoblastic Leukemia, Acute Lymphoblastic Leukemia, Acute Lymphocytic Leukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma, Adult (Primary) Hepatocellular Cancer, Adult (Primary) Liver Cancer, Adult Acute Lymphocytic Leukemia, Adult Acute Myeloid Leukemia, Adult Hodgkin's Disease, Adult Hodgkin's Lymphoma, Adult Lymphocytic Leukemia, Adult Non- Hodgkin's Lymphoma, Adult Primary Liver Cancer, Adult Soft Tissue Sarcoma, AIDS-Related Lymphoma, AIDS-Related Malignancies, Anal Cancer, Astrocytoma, Bile Duct Cancer, Bladder Cancer, Bone Cancer, Brain Stem Glioma, Brain Tumors, Breast Cancer, Cancer of the Renal Pelvis and Ureter, Central Nervous System (Primary) Lymphoma, Central Nervous System Lymphoma, Cerebellar Astrocytoma, Cerebral Astrocytoma, Cervical Cancer, Childhood (Primary) Hepatocellular Cancer, Childhood (Primary) Liver Cancer, Childhood Acute Lymphoblastic Leukemia, Childhood Acute Myeloid Leukemia, Childhood Brain Stem Glioma, Childhood Cerebellar Astrocytoma, Childhood Cerebral Astrocytoma, Childhood Extracranial Germ Cell Tumors, Childhood Hodgkin's Disease, Childhood Hodgkin's Lymphoma, Childhood Hypothalamic and Visual Pathway Glioma, Childhood Lymphoblastic Leukemia, Childhood Medulloblastoma, Childhood Non-Hodgkin's Lymphoma, Childhood Pineal and Supratentorial Primitive Neuroectodermal Tumors, Childhood Primary Liver Cancer, Childhood Rhabdomyosarcoma, Childhood Soft Tissue Sarcoma, Childhood Visual Pathway and Hypothalamic Glioma, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Colon Cancer, Cutaneous T-Cell Lymphoma, Endocrine Pancreas Islet Cell Carcinoma, Endometrial Cancer, Ependymoma, Epithelial Cancer, Esophageal Cancer, Ewing's Sarcoma and Related Tumors, Exocrine Pancreatic Cancer, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer, Female Breast Cancer, Gaucher's Disease, Gallbladder Cancer, Gastric Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Tumors, Germ Cell Tumors, Gestational Trophoblastic Tumor, Hairy Cell Leukemia, Head and Neck Cancer, Hepatocellular Cancer, Hodgkin's Disease, Hodgkin's Lymphoma, Hypergammaglobulinemia, Hypopharyngeal Cancer,Intestinal Cancers, Intraocular Melanoma, Islet Cell Carcinoma, Islet Cell Pancreatic Cancer, Kaposi's Sarcoma, Kidney Cancer, Laryngeal Cancer, Lip and Oral Cavity Cancer, Liver Cancer, Lung Cancer, Lymphoproliferative Disorders, Macroglobulinemia, Male Breast Cancer, Malignant Mesothelioma, Malignant Thymoma, Medulloblastoma, Melanoma, Mesothelioma, Metastatic Occult Primary Squamous Neck Cancer, Metastatic Primary Squamous Neck Cancer, Metastatic Squamous Neck Cancer, Multiple Myeloma, Multiple Myeloma / Plasma Cell Neoplasm, Myelodysplastic Syndrome, Myelogenous Leukemia, Myeloid Leukemia, Myeloproliferative Disorders, Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin's Lymphoma During Pregnancy, Nonmelanoma Skin Cancer, Non-Small Cell Lung Cancer, Occult Primary Metastatic Squamous Neck Cancer, Oropharyngeal Cancer, Osteo- / Malignant Fibrous Sarcoma, Osteosarcoma / Malignant Fibrous Histiocytoma, Osteosarcoma / Malignant Fibrous Histiocytoma of Bone, Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor, Ovarian Low Malignant Potential Tumor, Pancreatic Cancer, Paraproteinemias, Purpura, Parathyroid Cancer, Penile Cancer, Pheochromocytoma, Pituitary Tumor, Plasma Cell Neoplasm / Multiple Myeloma, Primary Central Nervous System Lymphoma, Primary Liver Cancer, Prostate Cancer, Rectal Cancer, Renal Cell Cancer, Renal Pelvis and Ureter Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoidosis Sarcomas, Sezary Syndrome, Skin Cancer, Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Neck Cancer, Stomach Cancer, Supratentorial Primitive Neuroectodermal and Pineal Tumors, T-Cell Lymphoma, Testicular Cancer, Thymoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Transitional Renal Pelvis and Ureter Cancer, Trophoblastic Tumors, Ureter and Renal Pelvis Cell Cancer, Urethral Cancer, Uterine Cancer, Uterine Sarcoma, Vaginal Cancer, Visual Pathway and Hypothalamic Glioma, Vulvar Cancer, Waldenstrom's Macroglobulinemia, Wilms' Tumor, and any other hyp erproliferative disease, besides neoplasia, located in an organ system listed herein.[000111] In some embodiments, the disease can comprise a pleural disease or condition. Examples of pleural diseases or conditions can include, but are not limited to: pleural cancer, pleural metastatic disease, pleurisy, lung infection, viral pneumonia, bacterial pneumonia, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, pleural thickening, pleuralpseudotumor, pleural plaque, extrapleural hematoma, Castleman disease, hemangioendothelioma, splenosis, paramalignang effusion, pleural effusion, pneumothorax, hemothorax, reactive pleuritis. In some embodiments, pleural cancer includes, but is not limited to lung cancer, metastases, mesothelioma, malignant mesothelioma, lymphoma, malignant fibrous tumor, sarcoma, askin tumor, extraskeletal osteosarcoma, malignant fibrous histiocytoma, solitary fibrous tumor, lipoma, mesothelial cyst, calcifying fibrous pseudotumor, primary effusion lymphoma.[000112] In some embodiments, the cancer can comprise mesothelioma. In some embodiments, the mesothelioma can comprise a pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, testicular mesothelioma, epithelioid mesothelioma, sarcomatoid mesothelioma, biphasic mesothelioma, small cell mesothelioma, deciduoid mesothelioma, cystic and papillary mesothelioma, desmoplastic mesothelioma, adenomatoid mesothelioma, heterologous mesothelioma, well-defined papillary cell mesothelioma, or any combination thereof. In some embodiments, the mesothelioma can comprise a pleural mesothelioma. In some embodiments, the mesothelioma can comprise a peritoneal mesothelioma. In some embodiments, the mesothelioma can comprise a pericardial mesothelioma. In some embodiments, the mesothelioma can comprise a testicular mesothelioma. In some embodiments, the mesothelioma can comprise a epithelioid mesothelioma. In some embodiments, the mesothelioma can comprise a sarcomatoid mesothelioma. In some embodiments, the mesothelioma can comprise a biphasic mesothelioma. In some embodiments, the mesothelioma can comprise a small cell mesothelioma. In some embodiments, the mesothelioma can comprise a deciduoid mesothelioma. In some embodiments, the mesothelioma can comprise a cystic and papillary mesothelioma. In some embodiments, the mesothelioma can comprise a desmoplastic mesothelioma. In some embodiments, the mesothelioma can comprise a adenomatoid mesothelioma. In some embodiments, the mesothelioma can comprise a heterologous mesothelioma. In some embodiments, the mesothelioma can comprise a well-defined papillary cell mesothelioma.[000113] In some embodiments, methods of treating a disease, in a subject, can comprise implanting, or delivering to, the subject a pharmaceutical composition comprising a populationof engineered cells comprising aheterologous oligonucleotide molecule encoding a polypeptide such as IL-1, IL-la, IL-1 , IL-IRA, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-12a, IL-12b, IL-13, IL-14, IL-15, IL-16, IL-17, G-CSF, GM-CSF, IL-20, IL-23, IFN-a, IFN- , IFN-y, CD 154, LT- , CD70, CD 153, CD 178, TRAIL, TNF-a, TNF- , SCF, M-CSF, MSP, 4-1BBL, LIF, OSM, or any combination thereof. In some embodiments, the native human cytokine can comprise IL-2.[000114] In some embodiments, methods of treating a disease, in a subject, can comprise implanting, or delivering to, the subject, such as to the pleural cavity, subcutaneous space, or IP space, of a pharmaceutical composition comprising a population of encapsulated cells comprising a heterologous oligonucleotide molecule encoding the native human IL-2 are provided. In some embodiments, the disease is as provided herein. In some embodiments, the disease can comprise a cancer. In some embodiments, the disease can comprise a pleural disease. In some embodiments, the pleural disease or condition can comprise pleural cancer, pleural metastatic disease, pleurisy, lung infection, viral pneumonia, bacterial pneumonia, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, pleural thickening, pleural pseudotumor, pleural plaque, extrapleural hematoma, Castleman disease, hemangioendothelioma, splenosis, paramalignang effusion, pleural effusion, pneumothorax, hemothorax, reactive pleuritis. In some embodiments, the pleural disease can comprise a pleural cancer. In some embodiments, the pleural cancer can comprise lung cancer, metastases, mesothelioma, malignant mesothelioma, lymphoma, malignant fibrous tumor, sarcoma, a skin tumor, extraskeletal osteosarcoma, malignant fibrous histiocytoma, solitary fibrous tumor, lipoma, mesothelial cyst, calcifying fibrous pseudotumor, primary effusion lymphoma.[000115] This disclosure provides methods of treating a disease in a subject via implanting into a subject a plurality of capsules comprising engineered cells. In some embodiments, the cells can be characterized as a monoclonal cell line. In some embodiments, the dose of encapsulated cells implanted into the subject can be modulated, e.g., the dose can be 10,000; 50,000; 100,000; 150,000; 200,000; 300,000; 400,000; 500,000; 750,000; 1,000,000 encapsuled cells or more. In some embodiments, the dose can be 63,000; 126,000; 252,000; or 504,000 cells. In some embodiments, the subject can comprise an animal. In some embodiments, thesubject can comprise a mammal. In some embodiments, the subject can comprise a rodent, e.g., a mouse, e.g., a NOD.Cg-Prkdcscid / J mouse. In some embodiments, the subject can comprise a human.[000116] This disclosure further provides methods of treating a disease in a subject, wherein the in vivo biologic productivity is evaluated, e.g., by a suitable immunoassay well- known in the art. In some embodiments, in vivo antibody productivity is assessed by analyzing sera acquired from a blood draw on an ELISA. In some embodiments, the in vivo antibody productivity is by analyzing mouse sera acquired from saphenous blood draws on an ELISA following a commercially available ELISA kit, e.g., Abcam's Human IgG ELISA Kit (abl95215) and normalizing by the mouse weight.[000117] In an aspect, this disclosure provides methods for modulating the therapeutic dose by varying the number of cells, e.g., 30,000; 60,000; 120,000; or 250,000 cells, implanted into a subject. For example, the therapeutic dose of IgG can vary be targeted to be 1, 5, 10, 25, 50, 100, or 1000 ng / mL in a subject over a period of time, e.g., 1, 2, 3, 5, 10, 15, 20, 25, 30, 35, 40 days or more. In some embodiments, the subject is an animal, e.g., a mammal, e.g., a rodent, e.g., a mouse. In some embodiments, the subject is a human. In some embodiments, the engineered cells can comprise ARPE-19 cells.[000118] In some embodiments, the dose can be modulated to achieve an IgG titer by varying the density of the engineered cells rather than increasing the volume or number of implanted capsules or devices. In some embodiments, the density of cells is modulated to achieve an IgG titer of about 10; 100; 1,000; 10,000 or more over a period of time, e.g., about 10, 20, 30, 40, 50 days or more. In some embodiments, the cell density is about 2.5e6, 10e6, or 40e6 cell / mL without increasing the volume or number of implanted capsules or devices. In some embodiments, the IgG titer is about 10 ng / mL over a period of about 48 days at a cell density of about 2.5e6 cells / mL. In some embodiments, the IgG titer is about 100 ng / mL over a period of about 48 days at a cell density of about 10e6 cells / mL. In some embodiments, the IgG titer is about 1,000 ng / mL over a period of about 48 days at a cell density of about 40e6 cells / mL.[000119] The methods of treating a disease as described herein are characterized by superior long-term delivery of the therapeutic agent, e.g., biologic, relative to conventional biologiesadministration, e.g., intravenous (bolus) administration, e.g., by injection. In some embodiments, the method as described herein can comprise implanting a plurality of encapsulated, engineered cells, wherein the cells can secrete a biologic, e.g., an antibody. In some embodiments, the biologic maintains a concentration, e.g., 100; 500; 1,000; 5000; 10,000; 50,000; 100,000 ng / mL in a subject over a period of time, e.g., 30, 60, 90, 120, 150, 180, 210, 240 days or more. In some embodiments, the biologic maintains an IgG concentration of about 1000 ng / mL over 210 days in mice. However, a bolus administration as is conventionally performed in the art will fail to maintain a concentration of interest for a time period of at least 30 days; on the contrary, the bolus administration will manifest a rapid decline in IgG levels. In some embodiments, the subject is an animal, e.g., a mammal, e.g., a rodent, e.g., a mouse. In some embodiments, the subject is a human. In some embodiments, the encapsulated engineered cells can comprise ARPE-19 cells. In another aspect, the methods of treating a disease by long-term delivery of a biologic, e.g., an antibody, entail modifying the capsule or device comprising the engineered cells with an immunomodulatory small molecule to delay, mitigate or prevent fibrosis. In some embodiments, the immunomodulatory small molecule, is a triazole or derivative thereof, e.g., Z4A10, Z1A3, Z2A19, Z1A14, Z1A17, Z1A34, Z4A43, B2A17, or Z1A16. In some embodiments, the immunomodulatory small molecule is Z4A10, Z1A3 orZ2A19. In some embodiments, the IgG concentration is about 100; 1,000; 10,000; or 100,000 ng / mL in a subject over a period of time, e.g., 50, 100, 150, or 200 days or more. In some embodiments, the subject is an animal, e.g., a mammal, e.g., a rodent, e.g., a mouse. In some embodiments, the subject is a human. In some embodiments, the encapsulated engineered cells are ARPE-19 cells. In some embodiments, the long-term IgG titer in B-cell deficient mice comprising implanted, immunomodulatory biomaterials encapsulated in Z4A10, Z1 A3 or Z2A19 is about 10,000 ng / mL in B-cell deficient mice.[000120] In some embodiments, capsules or devices modified with immunomodulatory biomaterials can be characterized by superior long-term delivery of biologies relative to bolus administration or encapsulated cells without modification with immunomodulatory materials. In some embodiments, implantation of a capsule modified with an immunomodulatory small molecule, e.g., a triazole or derivative thereof, e.g., Z4A10, Z1A3, Z2A19, Z1A14, Z1A17, Z1A34, Z4A43, B2A17, or Z1A16, can result in a sustained IgG titer of about 1; 10; 100;1,000; 10,000; 100,00 ng / mL in a subject over a period of time, e.g., about 30, 60, 90, 120, 150, 180 days or more and can maintain an IgG titer for a longer period time relative to a comparable dose administered by intravenous injection (bolus) or implantation of a capsule without modification with an immunomodulatory small molecule. In some embodiments, the subject is an animal, e.g., a mammal, e.g., a rodent, e.g., a mouse, e.g., an immunocompetent mouse. In some embodiments, the subject is a human. In some embodiments, the encapsulated engineered cells are ARPE-19 cells. In some embodiments, implantation of a capsule modified with Z4A10 maintains an IgG titer between about 100 to 1,000 ng / mL in an immunocompetent mouse over a period of 180 days or more, whereas IV bolus administration or implantation of an unmodified capsule fail to maintain a comparable IgG titer in an immunocompetent mouse.[000121] In another aspect, this disclosure provides methods of treating a disease comprising a sentinel cell, e.g., a cell that can produce an immune-modulating molecule, e.g., a cytokine, or a cell comprising an immune-modulating substance. An example of an immune-modulating substance is a steroid crystal. In some embodiments, the method of treating can comprise: (i) coencapsulating a therapeutic cell with an immunomodulatory, engineered cell (sentinel cell) into a capsule or device; (ii) implanting the capsule or device into a subject, in some embodiments, the capsule or device is further modified with an immunomodulatory small molecule, e.g., a triazole or derivative thereof, e.g., Z4A10, Z1A3, Z2A19, Z1A14, Z1A17, Z1A34, Z4A43, B2A17, or Z1A16. In some embodiments, the capsule or device is not further modified with an immunomodulatory small molecule. In some embodiments, the subject is an animal, e.g., a mammal, e.g., a rodent, e.g., a mouse. In some embodiments, the subject is a human. In some embodiments, the encapsulated engineered cells can comprise ARPE-19 cells. In some embodiments, capsules comprising cells that can produce an immune-modulating molecule and therapeutics cells, wherein the capsule is not further modified with a immunomodulatory small molecule, maintains an IgG titer of about 10; 100; 1,000; 10,000 ng / mL or more over a period of time, e.g., 20, 40, 60 days or more. In some embodiments, capsules comprising cells that can produce an immune-modulating molecule and therapeutics cells, wherein the capsule is not further modified with a immunomodulatory small molecule, maintains an IgG titer of about 1,000 ng / mL or a period of 60 days, whereas implantation of capsules comprising therapeutic cells only have a IgG titer that significantly decreases from about 1,000 ng / mL to about 5 ng / mL over the sameperiod of time.[000122] In some embodiments, the methods of treating a disease as described herein with capsules or devices comprising sentinel cells, e.g., capsules or devices co-encapsulated with immunomodulatory cells and therapeutic cell, result in reduced reduced fibrosis after explantation relative to “unmodified” capsules or devices only comprising therapeutic cells without any immunomodulatory activity. In some embodiments, the reduction is fibrosis is evaluated by microscopy, e.g., optical microscopy.[000123] This disclosure further provides methods for terminating treatment or replacing therapy. In some embodiments, the method of treating a disease further comprises retrieving the capsule or device. In some embodiments, the retrieving is performed after a prescribed period of time, e.g., 10, 20, 30, 40, 50, 60 days or more. In some embodiments, the retrieving is performed after an outcome, e.g., a therapeutic or diagnostic outcome, is achieved. In some embodiments, the IgG titer in a subject is about 500; 1,000; 1,500; 2,000; 2,500 ng / mL for a period of time before retrieval, e.g., 10, 20, 30, 40, 50, 60, days or more. In some embodiments, the IgG titer after retrieval decreases, e.g., from about 2,500 to 0; 2,000 to 0; 1,500 to 0; 1,000 to 0; or 500 to 0 ng / mL over a period of time, e.g., 10, 20, 30, 40, 50, 60, days or more. In some embodiments, the IgG titer is between about 1,500 to 2,000 ng / mL for a period of about 28 days before retrieval. In some embodiments, the capsules are retrieved 28 days after implantation and the IgG titer decreases from about 1,500 on day 28 to about 100 ng / mL on day 60.[000124] Accordingly, in some embodiments, methods of treating a cancer, in a subject, are provided. In some embodiments, the methods can comprise implanting in the intraperitoneal space of the subject a pharmaceutical composition comprising a plurality of a population of encapsulated cells (e.g., a capsule) as provided for herein to treat the tumor. In some embodiments, the cancer can comprise a pleural cancer. In some embodiments, the pleural cancer can comprise lung cancer, metastases, mesothelioma, malignant mesothelioma, lymphoma, malignant fibrous tumor, sarcoma, a skin tumor, extraskeletal osteosarcoma, malignant fibrous histiocytoma, solitary fibrous tumor, lipoma, mesothelial cyst, calcifying fibrous pseudotumor, primary effusion lymphoma. In some embodiments, the pleural cancer is mesothelioma.[000125] In some embodiments, the disease can comprise an infectious disease. Aninfectious disease can include diseases caused by bacteria, viruses, fungi, parasites, or other microbes. In one embodiment, the disease can comprise human immunodeficiency virus (HIV). In one embodiment, the disease can comprise swine influenza. In one embodiment, the disease is malaria. In some embodiments, the disease can comprise an autoimmune disease. An autoimmune disease can comprise a disease in which the body's own immune system mistakenly attacks its own healthy cells and tissues. In one embodiment, the disease can comprise multiple sclerosis. In one embodiment, the disease can comprise Crohn's disease. In one embodiment, the disease can comprise ulcerative colitis.[000126] Formulation and Administration[000127] This disclosure provides pharmaceutical compositions. Such compositions can comprise a prophylactically or therapeutically effective amount of a cell, and a pharmaceutically acceptable earner. In a specific embodiment, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other recognized pharmacopeia for use in animals, such as humans. The term "carrier" can refer to a diluent, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can comprise sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, such as for injectable solutions.[000128] Other suitable pharmaceutical excipients can include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. [000129] The composition can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical agents are described in "Remington'sPharmaceutical Sciences." Such compositions can contain a prophylactically or therapeutically effective amount of the agent, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation can suit the mode of administration, which can be oral, intravenous, intraarterial, intrabuccal, intranasal, nebulized, bronchial inhalation, intra- rectal, vaginal, topical or delivered by mechanical ventilation.[000130] Pharmaceutically acceptable salts can include the acid salts and those which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.EXAMPLES[000131] The following examples are included to demonstrate preferred embodiments. It can be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent techniques discovered by the inventor to function well in the practice of embodiments, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art can, in light of the instant disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.[000132] Example 1[000133] Biologic Therapeutic Production. ARPE-19 or other engineerable cell chassis are genetically modified to continuously produce protein-based therapeutics using custom designed vectors described herein. In the described iteration the constructs are transfected into cells using a lipid-based transfection method with a PiggyBac transposase for genomic integration however cells can also be engineered using other methods such as polymer- based transfection or viral transduction. Antibodies are very amenable to the plug and play nature of the described platform due to several large constant regions making up the bulk of the proteinand small hypervariable domains that can be changed to confer binding affinity to a specific antigen of interest. The platform can also be used for any protein based therapeutic including cytokines such as interleukin-2, interleukin- 12, interleukin- 10, interferon gamma or metabolic regulators such as glucagon-like-peptide-1 or gastric-inhibitory-polypeptide.[000134] Table 1. Representative antibody-based therapeutics and their functions[000135] For biologies containing multiple components such as antibodies or heterodimeric proteins like interleukin-12, vectors in one embodiment can be designed using 1) an IRES system, 2) a P2A self-cleaving peptide system, or 3) a dual promoter system. Protein expression from these systems is driven uing a promoter, which in some iterations is CAG, and a Kozak sequence followed by a protein encoding region such as light or heavy chain antibody sequences. For expression of multiple proteins or protein subunits this can be followed by IRES, P2A, or another promoter and the second coding region which in the representative example of an antibody can be the remaining light or heavy chain sequence. Similar vectors without the IRES, P2A or second promoter can be used to produce individual protein-based therapeutics with a single protein domain.[000136] Vectors can also contain a selectable marker such as resistance to anantibiotic like puromycin separately or in combination with a visible marker such as green fluorescent protein.[000137] In some iterations this selection marker can be driven under a separate promoter such as CMV. Vectors also can contain components to increase expression levels or integrate the vector into the genome of the engineered cell such as BGH p A, 3' and 5' ITR sequences (see plasmid map provided herein).[000138] Encapsulation Methods. In one embodiment cells can be encapsulated in an alginate-based hydrogel. Modified alginates were initially dissolved at 3-5% w / v in 0.8% saline and then blended with 3% w / v SLG100 (also dissolved in 0.8% saline) at a volume ratio of 70% modified alginate to 30% SLG100. Alginate solutions were sterilized by filtration through a 0.2-pm filter.[000139] Immediately before encapsulation, the cultured cells were centrifuged at 250G for 5 minutes and washed with Ca-free Krebs buffer (4.7 mM KC1, 25 mM HEPES, 1.2 mM KH2PO4, 1.2 mM MgSO4 7H2O, 135 mM NaCl). After washing, cells were centrifuged again and supernatants were aspirated. The cell pellet was then resuspended in alginate solution at the cell density of l~5xl06cells per 0.5 mL alginate solution. Alginate capsules were made using an electro-spraying machine (Pump 11 Pico Plus, Harvard Apparatus, MA, USA). 18G blunt-tipped needle was attached to a 1-mL Luer-lock syringe containing the alginate solution, clipped to a syringe pump oriented vertically over a 150 mL of crosslinking solution bath (20mM BaC12, 250mM D- Mannitol, 25mM HEPES with 0.01 v / v % tween 20). A voltage generator was attached to the needle tip and grounded to the crosslinking bath. The settings of the syringe pump were 5 mL / hr flow rate. Cell density per capsule was maintained by adjusting a voltage between 5.5 and 7 kV. After the capsules were formed in the crosslinking bath, they were then collected and washed three times with HEPES buffer (25 mM HEPES (Gibco, Life Technologies, California, USA), 1.2 mM MgC12x6H2O, 4.7 mM KC1, 132 mM NaCl). Capsules were washed three times with cell culture medium and cultured overnight in a 37°C incubator for transplantation. Capsules can be also made in micrometer size. Modified alginates were dissolved at 3~5% w / v in 0.8% saline and blended with 3% w / v SLG 100 at 70:30 ratio. SLG20 were dissolved at 1.4% w / v in 0.8 saline. Formulated alginate solutions were used to make 300-400 pm size capsules. Encapsulation procedures were thesame with 1.5 mm size capsules, except that a 30G needle was used for microcapsules with a 200 pL / min flow rate.[000140] Microcapsule Design. In one embodiment the cells can be encapsulated in capsules of biocompatible material such as alginate. These capsules can range in size from micrometer to millimeter scale. Capsules containing the engineered cells can then be implanted or injected at the site of therapeutic interest.[000141] Retrievable Device Design. In one iteration of this design the cells are encapsulated in a retrievable device for delivering therapeutic cells to a target site in a patient. The device can comprise a structure that can be 3D printed or otherwise fabricated that provides mechanical stability and allows for insertion. This insertion can be done using a non-invasive procedure with a device like a trocar. The device further comprises an internal compartment that contains encapsulated therapeutic cells. The encapsulating material acts as an immune- isolating barrier while allowing for the controlled release of bioactive molecules and diffusion of oxygen and nutrients. The device can also contain other materials such as a membrane or other chemical modifications to modulate the immune response to the device or to modulate availability of bioactive molecules.[000142] The following describes fabrication of one iteration of the device which uses a method of 3D printing for fabrication and a trocar for implantation of the long-acting retrievable device. The method can comprise the following steps:1. Providing a biocompatible material that can be 3D printed into a lattice support structure, such as biocompatible resin (Formlabs Biomed Clear), polycaprolactone (PCL), polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), nylon, polycarbonate (PC) or Teflon.2. Designing a 3D model of the device using computer-aided design (CAD) software, comprising an outer lattice support structure and an inner compartment for housing the therapeutic cells. a. In one embodiment, the device has a diameter of 4 mm to fit the trocar insertion and a scalable length to accommodate a volume of cells (Fig 6A & 6B).3. 3D printing the device using a suitable technique, such as fused deposition modeling(FDM), stereolithography (SLA), or selective laser sintering (-).4. Post processing of the 3D printed device, including washing, curing, and sterilization steps. a. In situations where the device is SLA 3D printed from biocompatible resin, it is washed with IP A, acetone, and then water to remove uncured resin and toxic byproducts. b. Then the device is cured via exposure to a UV light source. c. Last, it is sterilized by autoclaving or ETO sterilization.5. Loading the therapeutic cells into the inner compartment of the device, encapsulated inside of an immune-isolating hydrogel that protects them from immune rejection and provides a suitable microenvironment for their survival and function. a. In situations where the cells are encapsulated in alginate hydrogels: b. Cells are washed in a calcium free buffer three times. c. Homogenously mixed and encapsulated into the alginate. d. Loaded into the internal device compartment via the top injection port. e. Submerged in crosslinker solution for 20 minutes to solidify the alginate. f. Washed in HEPES buffer three times to remove excess crosslinking solution. g. And stored in relevant cell culture media until ready for implantation.6. Inserting the device into the patient using a non-invasive Trocar.7. Retrieving the device when needed.[000143] Microchip Prototyping. Variations of the retrievable microchip device will be comprised of different approaches for encapsulating cells within the internal compartment of the lattice support structure. In this example we describe a bulk-core encapsulation format and a capsule-core encapsulation format (Figure 7A). The bulk-core encapsulation format is created by injecting a solution of alginate or other cell encapsulating material and therapeuticcells, then crosslinking or otherwise solidifying the encapsulating material, thus filling the entire internal compartment with encapsulated cells. The capsule-core format entails filling the internal compartment with previously crosslinked spherical capsules of a sufficiently large diameter to remain entrapped within the internal compartment. Figure 7A shows images of bulk and capsule-core format microchip devices filled with a crosslinked alginate hydrogel- stained pink for easy visualization. The internal compartment of the bulk core device was loaded with 160ul of alginate whereas the capsule-core device was loaded with 1.5mm diameter capsules. Figure 7B and Figure 7C demonstrate that both microchip form factors are cytocompatible and support therapeutically relevant densities of cells. The internal compartment of each form factor was loaded with bulk alginate or alginate capsules encapsulating 10e6 3BNC 117 ARPE cells per milliliter and cultured for three days. After three days the number of living cells was calculated indicating greater than 96% viability for both conditions. In addition, the productivity of cells within each condition was compared with stand-alone capsules and cells grown on a standard 2D culture plate. ELISA results indicate that therapeutic cells encapsulated in the microchip device equally as (or more) productive as previous standards (Figure 7D).[000144] Immunomodulation. Long-term survival and function of encapsulated cells represents a key technical challenge due to attack from the host immune response. To achieve this, the microchip device and encapsulating matrix is modified with antifibrotic small molecules (Table 2), immune modulating sentinel cells engineered to secrete cytokines such as IL- 12 or IL- 10, or long-acting drug formulations for local immune suppression, such as Triamcinolone Hexacetonide, Dexamethasone, or GW2580.[000145] Table 2. A list of immunomodulatory small molecules for alginate and device modification.[000146] Generic strategies for the synthesis and characterization of alginate Amide coupling reactions were performed using one equivalent of UP-VLVG alginate and one equivalent of amine linkers (10 different amine linkers) in the presence of a coupling agent of 0.5 equivalent of 4-(4,6- Dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride resulting in 10 distinct amine linker conjugated alginate polymers compounds listed in Table 2. These linker-modified alginate derivatives were purified by dialysis for three days (in saline and water) using a 10-12 kDa dialysis membrane followed by lyophilization, the starting alginates. In the following step, one equivalent of alkynes was conjugated with the appropriately modified alginates by copper-catalyzed click reactions. Triazole-containing alginate derivatives were generated from the synthesis. Table 2 provided herein lists our top performing small molecules that can be coupled to alginate.[000147] Example 2[000148] Plasmid Design The example set forth herein describes the design of vectors, e g., plasmids, encoding for biologies. The vectors, e.g., plasmids, can comprise one or morepromoters, e.g., a CAG or CMV. The plasmids can also comprise Kozak or IRES sequences to allow for the transcription of multiple nucleic acid sequences encoding for various protein components of a larger protein, e g., an antibody comprising one or more heavy chains and / or one or more light chain chains. The vector, e.g., plasmid, also can comprise one or more antibiotic resistance genes for selection such as puromycin, ampicillin, kanamycin, penicillin, and the like. The vector, e.g., plasmid, can also be designed to have stary sequence oriented in the 5’ or 3’ direction, e.g., a pUC origin sequence or an ITR sequence. Finally, the vector, e.g., plasmid, can also contain a polyadenylation signal, e.g., a BGH polyA.[000149] The order of the components in the vector, e.g., plasmid, in the 5’ to 3’ direction can be of a certain order for various promoter systems as shown in FIG. IB. The order of components in the vector, e.g., plasmid, in the 5’ to 3’ direction was designed to be the following for an IRES system: (i) CAG promoter; (ii) biologic light chain; (iii) IRES; and (iv) biologic heavy chain. For a P2A system, the order of components in the 5’ to 3’ direction can be: i) CAG promoter; (ii) biologic light chain; (iii) P2A ; and (iv) biologic heavy chain. Finally for a dual promoter system, the order of components can be the following: (i) a first promoter, e.g. CAG promoter; (ii) biologic light chain; (iii) a second promoter, e.g., hPGK; and (iv) biologic heavy chain.[000150] An exemplary plasmid design encoding for Natalizumab can comprise a pUC origin sequence, a CAG promoter, a Kozak sequence, a sequence encoding for the Natalizumab light chain, an IRES sequence, a sequence encoding for the Natalizumab heavy chain, a CMV promoter, a puromycin resistance gene, PGH pA sequence, a 3’ ITR, and an ampicillin resistance gene, as illustrated in FIG. 1A.[000151] Another exemplary plasmid design encoding for a biologic as depicted in FIG. 10 can comprise a 5’ ITR, a CAG promoter, a Kozak sequence, a nucleic acid sequence encoding for human IL- 10 (hILlO), a rBG pA signal sequence, a CMV promoter, a puromycin resistance gene, a BGH pA signal sequence, a 3’ ITR, and an ampicillin resistance gene.[000152] Example 3[000153] Verification of Biologic Productivity[000154] The example set forth herein describes methods for assessing the productivity ofbiologies form engineered cells employing ELISA. Briefly, ARPE-19 cells were engineered to express 3BNC117, PGT121, 3BNC117LS, L9LS, PB27, Axitilimab, Dulaglutide, Pembrolizumab, Exenatide, Leptin, IL 10, CS43LS, Ipilimumab, or Natalizumab by following a transfection protocol known in the art. Engineered ARPE-19 cells were encapsulated in SLG alginate capsules as previously described herein. Biologic production was evaluated by ELISA following instructions from a commercially available kit (e.g., Abeam Human IgG ELISA Kit® (abl95215)). The productivity of the aforementioned antibodies secreted by the encapsulated engineered cells was measured to be about 0.1 to about 10 pg / cell / day via ELISA as shown in FIGS. 2 and 11.[000155] Immunological methods were further utilized to assess the expression of the heavy chain and light chain components of 3BNC117 antibody. As illustrated in FIG. 3, ELISA was used to verify the productivity of 3BNC117 heavy chain and light chain at time points Tl, T2, T3, T4, and T5 is between about 1 to 5 pg / cell / day.[000156] Example 4[000157] Verification of Antibody Antigenicity[000158] The example set forth herein describes experiments to verify the correct binding of antibody to its target antigen. Briefly, ARPE-19 cells were engineered to expressPembrolizumab by following a transfection protocol known in the art. Engineered ARPE- 19 cells were encapsulated in SLG alginate capsules as previously described herein. PD- 1 was immobilized on 96-well plates in order to capture Pembrolizumab (ab237652), and antigenicity was assessed by ELISA. As demonstrated in FIG. 4, Pembrolizumab-producing ARPE-19 cells produce about 1.8 pg / cell / day relative to no production in the Ipilimumab Control and non-engineered ARPE-19 cells.[000159] Example 5[000160] Biologic Activity and Neutralization Assays[000161] The example set forth herein describes experiments to evaluate the functionality of biologies secreted by encapsulated, engineered cells. In short, ARPE-19 cells were engineered to express biologies by following a transfection protocol known in the art. Engineered ARPE-19 cells were encapsulated in SLG alginate capsules as previously described herein. A matrix metalloproteinase (MMP) assay was carried out to measure MMP1 andMMP13 activity. As demonstrated in FIG. 12A, the relative fluorescence is about 170 RFU for MMP1 and about 220 RFU for MMP13, whereas the Control had a relative fluorescence of about 120 RFU.[000162] The IC50 secreted from encapsulated, engineered cells was also measured an comparable to clinical-grade controls in an TZM.B1 HIV neutralization assay. As shown in FIG. 12B, the IC50 for a 3BNC117 antibody secreted by engineered cell was measured to be about 0.08 pg / ml in an HIV neutralization antibody and comparable to a clinical grade control. In some embodiments, the IC50 for a PGT121 antibody secreted by an engineered cell was measured to be about 0.05 pg / ml in an HIV neutralization antibody is comparable to a clinical grade control.[000163] Example 6[000164] Capsule and Device Design and Configuration[000165] The example set forth herein describes the design and configuration of capsules and devices. Briefly, devices and capsules were fabricated according to the following general steps: (i) genetically modifying ARPE-19 cells to produce antibodies; (ii) validating antibody quality and quantifying antibody production; (iii) encapsulating ARPE-19 cells in capsules or devices; and (iv) performing in vivo testing, as described in FIG. 5B.[000166] The devices were fabricated in a variety of shapes, including cylinders and cylinderlike shapes as shown in FIG. 6A. The devices were comprised of a biocompatible structural material and a plurality of engineered cells that can secrete an immunomodulatory therapeutic as illustrated in FIG. 5A.The diameter of the cylindrical devices had diameters of about 2-4 mm and lengths of between about 10-55 mm. The devices were also fabricated with injection ports of approximately 1 mm in diameter. Further, the cylindrical devices had a number of hexagonal pores measuring approximately 0.5-1.5 mm with about 250 pm between each pore. The pores allowed for the transport of the therapeutic from the device to the surrounding milieu. Fabricated devices with lengths of 20 mm and 55 mm, respectively, are shown relative to a U.S. quarter is shown in FIG. 6B[000167] Devices were configured as both a bulk-core platform configuration and a capsulecore platform configuration as shown in FIG. 7A. The bulk-core platform was configured such that the device core comprised bulk encapsulated cells. The capsule-core plastform was configuredsuch that the core of the device comprised capsules.[000168] The cell viability of the bulk-core and capsule-core platforms was determined to be robust and comparable between platforms. The 3-day cell viability of both the bulk-core and capsule-core platforms was measured to be over 90% as shown in FIG. 7B. A further study was carried out to validate the productivity of the platforms relative to capsules. As demonstrated in FIG. 7C, both the capsule-core and bulk-core platforms had biologic productivities of about 5 pg / cell / day, which is compared to TCP and capsules.[000169] Example 7[000170] In Vivo Productivity of Monoclonal Cell Lines[000171] The example set forth herein describes methods to evaluate in vivo antibody productivity of encapsulated monoclonal cells. Briefly, monoclonal ARPE-19 cell lines were developed by following techniques known in the art and encapsulated in capsules or devices. Various doses of encapsulated monoclonal ARPE-19 cell lines (63,000; 126,000; 252,000; and 504,000) were implanted subcutaneously in NOD.Cg-Prkdcscid / J mice. In vivo antibody productivity was assessed by analyzing mouse sera acquired from saphenous blood draws on an ELISA following Abcam's protocol and normalized by mouse weight. As described in FIG. 9, NSG Mouse Blood Ab concentration plateaus at about 150 ng / mL.[000172] Example 8[000173] Dose Escalation[000174] The example set forth herein describes methods for modulating the therapeutic number of cells to achieve an IgG titer in a subject. Alternatively, the example further provides methods for achieved an IgG titer by varying the density of the engineered cells rather than increasing the volume or number of implanted capsules or devices.[000175] First, in order to achieve an IgG titer, the number of cells was varied in the subject. 30,000; 60,000; 120,000; and 250,000 ARPE-19 cells were dosed into mice. IgG titer was measured every 5 to 10 days for 1 month. Dosing a number of cells yielded a higher IgG titer as evidenced in FIG. 13. The 250,000 cells had a relatively constant IgG titer of about 100 ng / mL, whereas the 63,000-cell dose had a relatively constant IgG titer of about 5 ng / mL over the 1 -month time period.[000176] Second, the density of the engineered cells was modulated rather than varying thevolume or number of implanted capsules or devices as follows: Capsules and / or devices comprising 2.5e6, 10e6, and 40e6 ARPE-19 cells / mL cell densities were implanted in mice and the IgG titer was measured for 48 days. As illustrated in FIG. 18, the highest cell density (40e6 cells / L) capsules or devices achieved a more robust IgG titer of about 100 to 100 ng / mL relative to the lowest cell density capsules or devices of about 1-20 ng / mL over the measurement period.[000177] Example 9[000178] Long-term Delivery of Biologies from Capsules and Devices[000179] The example set forth herein demonstrates superior long-term delivery of biologies from capsules and devices as described herein relative to alternative administration routes. Briefly, encapsulated engineered cells were implanted in various subjects and the long-term IgG titer was assessed. First, encapsulated engineered cells modified with an immunomodulatory biomaterial were implanted in immunocompromised mice and the IgG titer was measured for over 7 months and compared against a conventional IV bolus at the same dosage. As demonstrated in FIG. 14, the IgG titer remained relatively stable at about 1,000 ng / mL over 7 months, whereas the IgG titer of the IV bolus was characterized by an initial peak and then a steep drop in IgG concentration in less than 30 days.[000180] Second, the long-term IgG titer was evaluated in B-cell deficient mice using various immunomodulatory biomaterials collected for over 6 months. Therapeutic IgG- producing cells encapsulated in various immunomodulatory biomaterials and implanted in B- cell deficient mice. These B-cell deficient mice exhibit a largely functional immune system, including a foreign body response but lack anti-drug antibodies (ADA). As shown in FIG. 15, the long-term IgG titer of encapsulated, engineered ARPE-9 cells with the immunomodulatory small molecules Z4A10, Z 1 A3, and Z2A19 was relatively stable between about 1,000 to about 10,000 ng / mL during the measurement period of over 6 months. The graph demonstrates the efficacy of the antifibrotic biomaterials to deliver stable levels of biologies over the long-term while simultaneously mitigating fibrosis in an in vivo setting.[000181] Finally, the long-term IgG titer was assessed in fully immunocompetent mice over a period of six months. Immunomodulatory biomaterial encapsulated cells, bolus IgG injection, and cells encapsulated in a biomaterial not modified with antifibrotic small molecules were evaluated. As shown in FIG. 16, capsules modified with the antifibrotic, immunomodulatory smallmolecule Z4A10 had a relatively stable IgG titer of between about 100 to about 1000 ng / mL over 6 months. However, the IV bolus with the same dosage was characterized by an initial peak and a rapid decrease in the IgG concentration within 30 days. Likewise, the unmodified capsule was superior to the capsule, but failed to maintain a measurable IgG titer after approximately 100 days due to fibrosis. The results demonstrate the differences in IgG levels over time across each method. The immunomodulatory biomaterial encapsulated cells show sustained and stable IgG delivery, significantly outperforming the bolus injection, which shows a rapid decline in IgG levels. The cells encapsulated in a non-modified biomaterial exhibit a gradual decline in IgG levels due to fibrosis. These results underscore the advantage of utilizing antifibrotic small molecule-modified biomaterials in maintaining long-term stable biologies delivery in fully immunocompetent mice.[000182] Example 10[000183] Enhanced Durability and Robustness of Sentinel Cells[000184] The example set forth herein demonstrates enhanced durability of therapeutic cells co-encapsulated with immunomodulatory engineered cells, employing unmodified materials, in which the full spectrum of antifibrotic effects is derived from the immunomodulatory, engineered cells, , i.e. “sentinel cells.” Sentinel cells are cells that can produce an immune-modulating molecule, e.g., a cytokine, or a cell comprising an immune-modulating substance. An example of an immune-modulating substance is a steroid crystal. Briefly, sentinel cells were fabricated according to the following method: (i) co-encapsulating a therapeutic cell with an immunomodulatory, engineered cell (sentinel cell) into a capsule or device; (ii) implanting the capsule or device into a subject. The capsule or device can be further modified with an immunomodulatory small molecule, e.g., a triazole or derivative thereof, e.g., Z4A10, Z1A3, Z2A19, Z1A14, Z1A17, Z1A34, Z4A43, B2A17, or Z1A16. Alternatively, the capsule or device is unmodified.[000185] First, the IgG titer over unmodified, encapsulated, engineered cells and sentinel cells were evaluated in mice over of a period of 60 days. As demonstrated in FIG. 17A, unmodified, encapsulated cells show a decline from about 1000 ng / mL to 0, whereas immunomodulatory, engineered cells maintain higher IgG titers of about 1000 ng / mL over the 60- day period.[000186] The unmodified, encapsulated engineered cells and sentinel cells weresubsequently investigated for fibrosis. 60 days after implantation, both the unmodified, encapsulated engineered cells and sentinel cells were explanted and viewed by optical microscopy for the presence of any fibrosis. As depicted in FIG. 17B, the bottom row of sentinel cells have significantly less fibrosis relative to the unmodified, encapsulated engineered cells as contrasted with microscopy images of the same capsules pre-implantation. The data therefore indicates that co-encapsulation of immunomodulatory, engineered cells results in demonstrably less fibrosis.[000187] Example 11[000188] Capsule and Device Retrieval for Terminating Treatment or Replacing Therapy[000189] The example set forth herein describes the retrieval of a minimally invasive device implanted subcutaneously with a trocar, wherein the retrieval occurred 1 month after implantation. As described in FIG. 19, the IgG titer is relatively stable at between about 1,500 to 2,000 ng / mL for the first 28 days after implantation. On day 28 post-implantation, the minimally-invasive device is explanted and the IgG gradually decreases to near 0 in the next 30 days. These data indicate that the implantation device can be safely retrieved after implantation, allowing for termination or replacement therapy as necessary.[000190] Compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the instant disclosure. While the compositions and methods of this disclosure have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations can be applied to the compositions and methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the disclosure. More specifically, it will be apparent that certain agents which are both chemically and physiologically related can be substituted for the agents described herein while the same or similar results can be achieved. Similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the disclosure as defined by the appended claims.[000191] References[000192] The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference.1. Mitragotri, S., Burke, P. & Langer, R. Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. Nat Rev Drug Discov 13, 655- 672 (2014). / / doi.org / 10.1038 / nrd4363

Claims

WHAT IS CLAIMED IS:

1. A device or capsule for implantation into a subject comprising an engineered cell that secretes:(i) a first heterologous biologic; and / or (ii) a first endogenous biologic, wherein each of (i) and(ii) are secreted at a level greater than found in an analogous non-engineered cell in the subject, and wherein the cells are secrete (i) and / or (ii) for greater than 24 hours.

2. The device or capsule of claim 1, where the biologic is selected from the group consisting of a cytokine, an engineered protein, a secreted protein, an antibody, a nanobody, a diabody, a single- chain variable fragment, a hormone, an enzyme, or a peptide.

3. The device or capsule of claim 1 or 2, wherein the biologic is selected from Nemolizumab,Zanidatamab, Linvoseltamab, Axatilimab, Tarlatamab, Marstacimab, Garadacimab, Vilobelimab, Zolbetuximab, Odronextamab, Crovalimab, Camrelizumab, Serplulimab, Sugemalimab, Concizumab, Cosibelimab, Donanemab, Sintilimab, Narsoplimab, Pozelimab, Elranatamab, Rozanolixizumab, Talquetamab, Epcoritamab, Lebrikizumab, Glofitamab, Mirikizumab, Tislelizumab, Toripalimab, Retifanlimab, Lecanemab, Teplizumab, Ublituximab, Nirsevimab, Tremelimumab, Spesolimab, Teclistamab, Mosunetuzumab, Tixagevimab (Cilgavimab), Relatlimab, Tebentafusp, Faricimab, Sutimlimab, Sotrovimab, Regdanvimab, Casirivimab, Imdevimab, Tezepelumab, Amivantamab, Anifrolumab, Bimekizumab, Tralokinumab, Evinacumab, Aducanumab, Dostarlimab, Ansuvimab, Margetuximab, Naxitamab, Atoltivimab, Maftivimab, Tafasitamab, Satralizumab,Inebilizumab, Teprotumumab, Isatuximab, Eptinezumab, Crizanlizumab, Risankizumab, Romosozumab, Ravulizumab, Emapalumab, Cemiplimab, Fremanezumab, Moxetumomab pasudotox, Galcanezumab, Lanadelumab, Mogamulizumab, Erenumab, Tildrakizumab, Ibalizumab, Burosumab, Durvalumab, Emicizumab, Benralizumab, Ocrelizumab, Guselkumab, Sarilumab, Dupilumab, Avelumab, Brodalumab, Atezolizumab, Bezlotoxumab, Olaratumab, Reslizumab, Obiltoxaximab, Ixekizumab, Daratumumab, Elotuzumab, Necitumumab, Idarucizumab, Alirocumab, Mepolizumab, Evolocumab, Dinutuximab, Secukinumab, Nivolumab, Blinatumomab, Pembrolizumab, Ramucirumab, Vedolizumab, Siltuximab, Obinutuzumab, Raxibacumab, Pertuzumab, Belimumab, Ipilimumab, Denosumab, Tocilizumab, Ofatumumab, Canakinumab, Golimumab, Ustekinumab, Catumaxomab, Eculizumab, Ranibizumab, Panitumumab, Natalizumab, Bevacizumab,Cetuximab, Efalizumab, Efalizumab, Omalizumab, Tositumomab-1131, Ibritumomab tiuxetan, Adalimumab, Alemtuzumab, Trastuzumab, Infliximab, Palivizumab, Basiliximab, Daclizumab, Rituximab, Abciximab, and Muromonab-CD3 or a functional fragment thereof.

4. The device or capsule of claim 1 or 2, wherein the biologic is an enzyme replacement therapy selected from Human recombinant ADAMTS13, Alpha 1 -Proteinase inhibitor, Collagenase, Asparaginase, Anti-Inhibitor Coagulant Complex, tPa (Alteplase), Pegademase (bovine), Alglucerase (Imiglucerase), Factor IX, DNase, Pancrelipase (Amylase, Lipase, Protease), Sacrosidase, truncated (non-glycosylated)tPA (357 of 527aa), recombinant coagulation Factor Vila, tissue Plasminogen activator variant, Uricase (Aspergillus flavus), Antihemophilic factor, Laronidase, Agalsidase beta, Hyaluronidase (ovine), Hyaluronidase (bovine), Galsulfase, Hyaluronidase (Human), Idursulfase, Alglucosidase alfa, Thrombin (human), Thrombin (Bovine), Velaglucerase alfa, Pegloticase, asparaginase (Erwinia chrysanthem), Taliglucerase alfa, recombinant truncated form of human plasmin, Recombinant carboxypeptidase g2 (Glucarpidase), Coagulation Factor Xllla, Elosulfase alfa, Coagulation factor X, Asfotase Alfa, Sebelipase alfa, Cerliponase alfa, vestronidase alfa-vjbk, pegvaliase- pqpz, and algasidase alfa, or a functional fragment thereof.

5. The device or capsule of claim 1 or 2, wherein the biologic is a peptide or polypeptide therapeutic selected from Exenatide, Brolucizumab, Caplacizumab, Liraglutide, Lixisenatide, Albiglutide, Dulaglutide, Teduglutide, Pramlintide, Aviptadil, Carbetocin, Teriparatide, Abaloparatide, Plecanatide, Nesiritide, Angiotensin II, Lucinactant, Pasireotide, and Setmelanotide, or a functional fragment thereof.

6. The device or capsule of any of the preceding claims, wherein the biologic is selected from any one of SEQ ID NOs: 1-348.

7. The device or capsule of any one of the preceding claims, wherein the biologic selected from any listed in Table 1 or 2.

8. The device or capsule of any of the preceding claims, wherein the biologic is selected from Muromonab- CD3, Efalizumab Tositumomab-1131, Daclizumab, Olaratumab, Abciximab, Rituximab, Basiliximab, Palivizumab, Infliximab, Trastuzumab, Adalimumab, Ibritumomab tiuxetan, Omalizumab, Cetuximab, Bevacizumab, Natalizumab, Panitumumab, Ranibizumab, Eculizumab, Certolizumab pegol, Ustekinumab, Canakinumab, Golimumab, Ofatumumab,Tocilizumab, Denosumab, Belimumab, Ipilimumab, Brentuximab vedotin, Pertuzumab, Ado- trastuzumab emtansine, Raxibacumab, Obinutuzumab, Siltuximab, Ramucirumab, Vedolizumab, Nivolumab, Pembrolizumab, Blinatumomab, Alemtuzumab, Evolocumab, Idarucizumab, Necitumumab, Dinutuximab, Secukinumab, Mepolizumab, Alirocumab, Daratumumab, Elotuzumab, Ixekizumab, Reslizumab, Bezlotoxumab, Atezolizumab, Obiltoxaximab, Brodalumab, Dupilumab, Inotuzumab ozogamicin, Guselkumab, Sarilumab, Avelumab, Emicizumab, Ocrelizumab, Benralizumab, Durvalumab, Gemtuzumab ozogamicin, Erenumab, erenumab- aooe, Galcanezumab, galcanezumab-gnlm, Burosumab, burosumab-twza, Lanadelumab, lanadelumab-flyo, Mogamulizumab, mogamulizumab-kpkc, Tildrakizumab; tildrakizumab-asmn, Fremanezumab, fremanezumab-vfrm, Ravulizumab, ravulizumab-cwvz, Cemiplimab, cemiplimab-rwlc, Ibalizumab, ibalizumab- uiyk, Emapalumab, emapalumab-lzsg, Moxetumomab pasudotox, moxetumomab, pasudotox-tdfk, Caplacizumab, caplacizumab-yhdp, Risankizumab, risankizumab-rzaa, Polatuzumab vedotin, polatuzumab vedotin-piiq, Romosozumab, romosozumab-aqqg, Brolucizumab, brolucizumab- dbll, Crizanlizumab; crizanlizumab-tmca, Enfortumab vedotin, enfortumab vedotin-ejfv, [fam- ]trastuzumab deruxtecan, fam- trastuzumab, deruxtecan-nxki, Isatuximab, isatuximab- irfc, Belantamab mafodotin, belantamab mafodotin- blmf, Sacituzumab govitecan; sacituzumab govitecan- hziy, Tafasitamab, tafasitamab-cxix, Satralizumab, satralizumab-mwge, Eptinezumab, eptinezumab-jjmr, Inebilizumab, inebilizumab-cdon, Teprotumumab, teprotumumab-trbw, Evinacumab, Dostarlimab, dostarlimab-gxly, Amivantamab, amivantamab-vmjw Tralokinumab, tralokinumab-ldrm, Anifrolumab, anifrolumab- fniaLoncastuximab tesirine, loncastuximab tesirine- Ipyl, Atoltivimab,maftivimab, odesivimab-ebgn, Naxitamab-gqgk, Margetuximab-cmkb, Ansuvimab-zykl, Aducanumab, aducanumab-avwa, Tisotumab vedotin, tisotumab vedotin-tftv, Tezepelumab, tezepelumab- ekko, Faricimab, faricimab- svoa, Sutimlimab, sutimlimab- jome, Spesolimab, Teplizumab, teplizumab- mzwv, Ublituximab, Tebentafusp, tebentafusp-tebn, Relatlimab, Mosunetuzumab, Teclistamab, Tremelimumab, Mirvetuximab soravtansine, mirvetuximab, soravtansine-gynx, Lecanemab, Retifanlimab, retifanlimab-Dlwr, Epcoritamab, Zolbetuximab, Ziltivekimab, Zilovertamab vedotin, Zilovertamab, Zanidatamab, Zamerovimab +mazorelvimab, Zalifrelimab, Xeligekimab, Vunakizumab, Vobramitamab duocarmazine, Vilobelimab, Vibostolimab, Upifitamab rilsodotin, Tusamitamab ravtansine,Trastuzumab rezetecan, Tozorakimab, Tosatoxumab, Tiragolumab, Telisotuzumab vedotin, Tebotelimab, Tarlatamab, Tarcocimab tedromer, Suvratoxumab, Suciraslimab, Solanezumab, Sibeprenlimab, Setrusumab, Semzuvolimab, Sasanlimab, Sabatolimab, Rulonilimab, Rosopatamab (177Lu- DOTA), Rocatinlimab, Retlirafusp alfa, Recaticimab, Quavonlimab, Pozelimab, Pivekimab sunirine, Patritumab deruxtecan, Paridiprubart, Pamrevlumab, Otilimab, Oregovomab, Ongericimab, Onfekafusp alfa, Oleclumab, Odronextamab, Ociperlimab, Nofazinlimab, Nipocalimab, Navicixizumab, Nadunolimab, Monalizumab, Mecbotamab vedotin, Marstacimab, Magrolimab, Litifilimab, Linvoseltamab, Ligelizumab, Latozinemab, Izalontamab, Ivuxolimab, Ivonescimab, Itepekimablparomlimab (anti-PD-1), Tuvonralimab (anti- CTLA-4), Inclacumab, Imsidolimab, lanalumab, Glenzocimab, Gefurulimab, Garetosmab, Garadacimab, Gantenerumab, Futuximab+modotuximab, Finotonlimab, Fianlimab, Felzartamab, Favezelimab, Erfonrilimab, Emactuzumab, Elranatamab, Ebronucimab, Ebdarokimab, Domvanalimab, Divozilimab, Depemokimab, Datopotamab deruxtecan, Dapirolizumab pegol, Dafsolimab setaritox +grisnilimab setaritox, Coprelotamab, Cobolimab, Clesrovimab, Clazakizumab, Cetrelimab, Cendakimab, Camidanlumab tesirine, Brazikumab, Birtamimab, Bintrafusp alfa, Bentracimab, Bemarituzumab, Batoclimab, Atisnolerbart, bremzalerbart,, umesolerbart, Apitegromab, Apamistamab-lodine (1311), Anselamimab, Anbenitamab, Adebrelimab, and Abelacimab.

9. The device or capsule of claim 1 or 2, wherein said cell secretes at least a second biologic.

10. The device or capsule of any one of claims 1-3 encapsulated in a semi-permeable membrane.

11. The device or capsule of any one of the preceding claims, wherein the device or capsule comprises an inner housing chamber which is surrounded by a biocompatible material, e.g., a biocompatible supporting structure / lattice.

12. The device or capsule of claim 5, comprising a plurality of engineered cells.

13. The device or capsule of any of the preceding claims, wherein the capsule is a sphere, a spherelike shape, a spheroid, a spheroid-like shape, an ellipsoid, an ellipsoid-like shape, a stadiumoid, , a stadiumoid-like shape, a disk, a disk-like shape, a cylinder, a cylinder-like shape, a rod, a rod-like shape, a cube, a cube-like shape, a cuboid, a cuboid-like shape, a torus, a torus- like shape, a flat surface, and a curved surface.

14. The capsule of any of the preceding claims, where the capsule is a sphere.

15. The device of any of the preceding claims, wherein the device is a sphere, a sphere-like shape, a spheroid, a spheroid-like shape, an ellipsoid, an ellipsoid-like shape, a stadiumoid, , a stadiumoid-like shape, a disk, a disk-like shape, a cylinder, a cylinder-like shape, a rod, a rodlike shape, a cube, a cube-like shape, a cuboid, a cuboid-like shape, a torus, a torus- like shape, a flat surface, and a curved surface.

16. The device of any of the preceding claims, wherein the device is a cylinder.

17. The device of any of the preceding claims, wherein the length of the device is between about 10 mm to about 55 mm.

18. The device of any of the preceding claims, wherein the diameter of the device is between about 2 mm to about 4 mm.

19. The device of any of the preceding claims, wherein the device comprises a plurality of pores.

20. The device of any of the preceding claims, wherein the plurality of pores has a length of about 0.5 mm to about 1.5 mm.

21. The device of any of the preceding claims, wherein distance between the pores is about 250 pm.

22. The device of any of the preceding claims, wherein the device further comprises an injection port.

23. The device of any of the preceding claims, wherein the device is configured as a bulk-core platform, the bulk-core platform comprising a plurality of engineered cells in the interior of the device.

24. The device of any of the preceding claims, wherein the device is configured as a capsule-core platform, the capsule-core platform comprising a plurality of capsules comprising a plurality of engineered cells as described in claim 1, the capsules disposed in the interior of the device.

25. The device of any of the preceding claims, wherein the device retrieves from a subject after delivery.

26. The device of any of the preceding claims, wherein the device produces an IgG titer of a biologic post-delivery which is detectable in sera of the subject for at least 1, 2, 3, 4, 5, 6 months or more.

27. The device of any of the preceding claims, wherein the device is further modified with animmunomodulatory small molecule for preventing fibrosis.

28. The device of any of the preceding claims, wherein the immunomodulatory small molecule is selected from Z4A10, Z1A3, Z2A19, Z1A14, Z1A17, Z1A34, Z4A43, B2A17, and Z1A16.

29. The device of any of the preceding claims, wherein the device produces an IgG titer of the biologic in the subject post-implantation upon modification with immunomodulatory small molecules which is detectable in sera of the subject for a longer period of time relative to an intravenous bolus or a device that has not been modified with an immunomodulatory small molecule.

30. The device of any of the preceding claims, wherein the device secretes the biologic for preventing or treating cancer.

31. The device of any one of the preceding claims, wherein the device secretes the biologic for preventing or treating a pleural disease or condition.

32. The device of any of the preceding claims, wherein the pleural disease or condition is selected from: pleural cancer, pleural metastatic disease, pleurisy, lung infection, viral pneumonia, bacterial pneumonia, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, pleural thickening, pleural pseudotumor, pleural plaque, extrapleural hematoma, Castleman disease, hemangioendothelioma, splenosis, paramalignang effusion, pleural effusion, pneumothorax, hemothorax, reactive pleuritis, lung cancer, metastases, mesothelioma, malignant mesothelioma, lymphoma, malignant fibrous tumor, sarcoma, a skin tumor, extraskeletal osteosarcoma, malignant fibrous histiocytoma, solitary fibrous tumor, lipoma, mesothelial cyst, calcifying fibrous pseudotumor, primary effusion lymphoma.

33. The device of any of the preceding claims, wherein the device secretes the biologic for 1 day, 1 week, 1 month, 2 months, 3 months, 4 months, 5 month, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 1 year upon delivery of the device or capsule into the subj ect.

34. The device of any one of the preceding claims, wherein the device secretes a biologic for 1 day upon delivery of the device or capsule into the subject.

35. The device of any one of the preceding claims, wherein the device secretes the biologic for 1 month upon delivery of the device or capsule into the subject.

36. The device of any one of the preceding claims, wherein the device secretes the biologic for 3months upon delivery of the device or capsule into the subject.

37. The device of any one of the preceding claims, wherein the device secretes the biologic for 6 months upon delivery of the device or capsule into the subject.

38. The device of any one of the preceding claims, wherein the biologic secretes the biologic for 9 months upon delivery of the device or capsule into the subject.

39. The device of any one of the preceding claims, wherein the device secretes the biologic for 6 months upon delivery of the device or capsule into the subject.

40. The method of any one of the preceding claims, wherein the biologic is secreted for 1 year upon delivery of the device or capsule into the subject.

41. The device or capsule of claim 6, wherein the plurality of engineered cells secrete the same biologic.

42. The device or capsule of claim 6, wherein the plurality of engineered cells secrete different biologies.

43. The device or capsule of any one of claims 5-8, wherein the device or capsule comprises an immune modifying functionality.

44. The device or capsule of claim 9, wherein the immune modifying functionality comprises a sentinel cell producing an immune-modulating molecule or comprises an immune-modulating substance (e.g., steroid crystals), such as inside the semi-permeable membrane or device.

45. A method of treating a disease in a subject in need thereof, the method comprising: (i) transfecting a cell with a vector encoding for a biologic, thereby producing an engineered cell as described in claim 1; (ii) encapsulating a plurality of the engineered cells in a device; (iii) delivering the device comprising the plurality of engineered cells to the subject, thereby treating a disease in a subject in need thereof.

46. The method of claim 45, wherein the device comprises a capsule, e.g., a plurality of capsules.

47. The method of claim 45, wherein the device is a capsule, e.g., a plurality of capsules.

48. The method of claim 45, comprising delivering the device orally, intravenously, intraarterially, intrabuccally, intranasally, via nebulization, via bronchial inhalation, intrarectally, vaginally, topically, or via mechanical ventilation, via implantation, or a combination thereof.

49. The method of claim 45, wherein (iii) the delivering comprises implanting the devicesubcutaneously.

50. The method of any one of the preceding claims, wherein (iii) the delivering comprises implanting the device in the intraperitoneal space.

51. The method of any one of the preceding claims, wherein the engineered cell secretes a biologic selected from Nemolizumab, Zanidatamab, Linvoseltamab, Axatilimab, Tarlatamab, Marstacimab, Garadacimab, Vilobelimab, Zolbetuximab, Odronextamab, Crovalimab, Camrelizumab, Serplulimab, Sugemalimab, Concizumab, Cosibelimab, Donanemab, Sintilimab, Narsoplimab, Pozelimab, Elranatamab, Rozanolixizumab, Talquetamab, Epcoritamab, Lebrikizumab, Glofitamab, Mirikizumab, Tislelizumab, Toripalimab, Retifanlimab, Lecanemab, Teplizumab, Ublituximab, Nirsevimab, Tremelimumab, Spesolimab, Teclistamab, Mosunetuzumab, Tixagevimab (Cilgavimab), Relatlimab, Tebentafusp, Faricimab, Sutimlimab, Sotrovimab, Regdanvimab, Casirivimab, Imdevimab, Tezepelumab, Amivantamab, Anifrolumab, Bimekizumab, Tralokinumab, Evinacumab, Aducanumab, Dostarlimab, Ansuvimab, Margetuximab, Naxitamab, Atoltivimab, Maftivimab, Tafasitamab, Satralizumab, Inebilizumab, Teprotumumab, Isatuximab, Eptinezumab, Crizanlizumab, Risankizumab, Romosozumab, Ravulizumab, Emapalumab, Cemiplimab, Fremanezumab, Moxetumomab pasudotox, Galcanezumab, Lanadelumab, Mogamulizumab, Erenumab, Tildrakizumab, Ibalizumab, Burosumab, Durvalumab, Emicizumab, Benralizumab, Ocrelizumab, Guselkumab, Sarilumab, Dupilumab, Avelumab, Brodalumab, Atezolizumab, Bezlotoxumab, Olaratumab, Reslizumab, Obiltoxaximab, Ixekizumab, Daratumumab, Elotuzumab, Necitumumab, Idarucizumab, Alirocumab, Mepolizumab, Evolocumab, Dinutuximab, Secukinumab, Nivolumab, Blinatumomab, Pembrolizumab, Ramucirumab, Vedolizumab, Siltuximab, Obinutuzumab, Raxibacumab, Pertuzumab, Belimumab, Ipilimumab, Denosumab, Tocilizumab, Ofatumumab, Canakinumab, Golimumab, Ustekinumab, Catumaxomab, Eculizumab, Ranibizumab, Panitumumab, Natalizumab, Bevacizumab, Cetuximab, Efalizumab, Efalizumab, Omalizumab, Tositumomab-1131, Ibritumomab tiuxetan, Adalimumab, Alemtuzumab, Trastuzumab, Infliximab, Palivizumab, Basiliximab, Daclizumab, Rituximab, Abciximab, and Muromonab-CD3 or a functional fragment thereof.

52. The method of any one of the preceding claims, wherein the biologic is an enzyme replacementtherapy selected from Human recombinant AD AMTS 13, Alpha 1 -Proteinase inhibitor, Collagenase, Asparaginase, Anti -Inhibitor Coagulant Complex, tPa (Alteplase), Pegademase (bovine), Alglucerase (Imiglucerase), Factor IX, DNase, Pancrelipase (Amylase, Lipase, Protease), Sacrosidase, truncated (non-glycosylated)tPA (357 of 527aa), recombinant coagulation Factor Vila, tissue Plasminogen activator variant, Uricase (Aspergillus flavus), Antihemophilic factor, Laronidase, Agalsidase beta, Hyaluronidase (ovine), Hyaluronidase (bovine), Galsulfase, Hyaluronidase (Human), Idursulfase, Alglucosidase alfa, Thrombin (human), Thrombin (Bovine), Velaglucerase alfa, Pegloticase, asparaginase (Erwinia chrysanthem), Taliglucerase alfa, recombinant truncated form of human plasmin, Recombinant carboxypeptidase g2 (Glucarpidase), Coagulation Factor Xllla, Elosulfase alfa, Coagulation factor X, Asfotase Alfa, Sebelipase alfa, Cerliponase alfa, vestronidase alfa-vjbk, pegvaliase- pqpz, and algasidase alfa, or a functional fragment thereof.

53. The method of any one of the preceding claims, wherein the biologic is a peptide or polypeptide therapeutic selected from Exenatide, Brolucizumab, Caplacizumab, Liraglutide, Lixisenatide, Albiglutide, Dulaglutide, Teduglutide, Pramlintide, Aviptadil, Carbetocin, Teriparatide, Abaloparatide, Plecanatide, Nesiritide, Angiotensin II, Lucinactant, Pasireotide, and Setmelanotide, or a functional fragment thereof.

54. The method of any one of the preceding claims, wherein the biologic is selected from any one or more of SEQ ID NOs: 1-348.

55. The method of any one of the preceding claims, wherein the biologic selected from any listed in Table 1 or 2.

56. The method of any of the preceding claims, wherein the biologic is selected from Muromonab- CD3, Efalizumab Tositumomab-1131, Daclizumab, Olaratumab, Abciximab, Rituximab, Basiliximab, Palivizumab, Infliximab, Trastuzumab, Adalimumab, Ibritumomab tiuxetan, Omalizumab, Cetuximab, Bevacizumab, Natalizumab, Panitumumab, Ranibizumab, Eculizumab, Certolizumab pegol, Ustekinumab, Canakinumab, Golimumab, Ofatumumab, Tocilizumab, Denosumab, Belimumab, Ipilimumab, Brentuximab vedotin, Pertuzumab, Ado- trastuzumab emtansine, Raxibacumab, Obinutuzumab, Siltuximab, Ramucirumab, Vedolizumab, Nivolumab, Pembrolizumab, Blinatumomab, Alemtuzumab, Evolocumab, Idarucizumab, Necitumumab, Dinutuximab, Secukinumab, Mepolizumab, Alirocumab,Daratumumab, Elotuzumab, Ixekizumab, Reslizumab, Bezlotoxumab, Atezolizumab, Obiltoxaximab, Brodalumab, Dupilumab, Inotuzumab ozogamicin, Guselkumab, Sarilumab, Avelumab, Emicizumab, Ocrelizumab, Benralizumab, Durvalumab, Gemtuzumab ozogamicin, Erenumab, erenumab- aooe, Galcanezumab, galcanezumab-gnlm, Burosumab, burosumab-twza, Lanadelumab, lanadelumab-flyo, Mogamulizumab, mogamulizumab-kpkc, Tildrakizumab; tildrakizumab-asmn, Fremanezumab, fremanezumab-vfrm, Ravulizumab, ravulizumab-cwvz, Cemiplimab, cemiplimab-rwlc, Ibalizumab, ibalizumab- uiyk, Emapalumab, emapalumab-lzsg, Moxetumomab pasudotox, moxetumomab, pasudotox-tdfk, Caplacizumab, caplacizumab-yhdp, Risankizumab, risankizumab-rzaa, Polatuzumab vedotin, polatuzumab vedotin-piiq, Romosozumab, romosozumab-aqqg, Brolucizumab, brolucizumab- dbll, Crizanlizumab; crizanlizumab-tmca, Enfortumab vedotin, enfortumab vedotin-ejfv, [fam- ]trastuzumab deruxtecan, fam- trastuzumab, deruxtecan-nxki, Isatuximab, isatuximab- irfc, Belantamab mafodotin, belantamab mafodotin- blmf, Sacituzumab govitecan; sacituzumab govitecan- hziy, Tafasitamab, tafasitamab-cxix, Satralizumab, satralizumab-mwge, Eptinezumab, eptinezumab-jjmr, Inebilizumab, inebilizumab-cdon, Teprotumumab, teprotumumab-trbw, Evinacumab, Dostarlimab, dostarlimab-gxly, Amivantamab, amivantamab-vmjw Tralokinumab, tralokinumab-ldrm, Anifrolumab, anifrolumab- fniaLoncastuximab tesirine, loncastuximab tesirine- Ipyl, Atoltivimab,maftivimab, odesivimab-ebgn, Naxitamab-gqgk, Margetuximab-cmkb, Ansuvimab-zykl, Aducanumab, aducanumab-avwa, Tisotumab vedotin, tisotumab vedotin-tftv, Tezepelumab, tezepelumab- ekko, Faricimab, faricimab- svoa, Sutimlimab, sutimlimab- jome, Spesolimab, Teplizumab, teplizumab- mzwv, Ublituximab, Tebentafusp, tebentafusp-tebn, Relatlimab, Mosunetuzumab, Teclistamab, Tremelimumab, Mirvetuximab soravtansine, mirvetuximab, soravtansine-gynx, Lecanemab, Retifanlimab, retifanlimab-Dlwr, Epcoritamab, Zolbetuximab, Ziltivekimab, Zilovertamab vedotin, Zilovertamab, Zanidatamab, Zamerovimab +mazorelvimab, Zalifrelimab, Xeligekimab, Vunakizumab, Vobramitamab duocarmazine, Vilobelimab, Vibostolimab, Upifitamab rilsodotin, Tusamitamab ravtansine, Trastuzumab rezetecan, Tozorakimab, Tosatoxumab, Tiragolumab, Telisotuzumab vedotin, Tebotelimab, Tarlatamab, Tarcocimab tedromer, Suvratoxumab, Suciraslimab, Solanezumab, Sibeprenlimab, Setrusumab, Semzuvolimab, Sasanlimab, Sabatolimab, Rulonilimab, Rosopatamab (177Lu- DOTA), Rocatinlimab, Retlirafusp alfa, Recaticimab, Quavonlimab,Pozelimab, Pivekimab sunirine, Patritumab deruxtecan, Paridiprubart, Pamrevlumab, Otilimab, Oregovomab, Ongericimab, Onfekafusp alfa, Oleclumab, Odronextamab, Ociperlimab, Nofazinlimab, Nipocalimab, Navicixizumab, Nadunolimab, Monalizumab, Mecbotamab vedotin, Marstacimab, Magrolimab, Litifilimab, Linvoseltamab, Ligelizumab, Latozinemab, Izalontamab, Ivuxolimab, Ivonescimab, Itepekimablparomlimab (anti-PD-1), Tuvonralimab (anti- CTLA-4), Inclacumab, Imsidolimab, lanalumab, Glenzocimab, Gefurulimab, Garetosmab, Garadacimab, Gantenerumab, Futuximab+modotuxima b, Finotonlimab, Fianlimab, Felzartamab, Favezelimab, Erfonrilimab, Emactuzumab, Elranatamab, Ebronucimab, Ebdarokimab, Domvanalimab, Divozilimab, Depemokimab, Datopotamab deruxtecan, Dapirolizumab pegol, Dafsolimab setaritox +grisnilimab setaritox, Coprelotamab, Cobolimab, Clesrovimab, Clazakizumab, Cetrelimab, Cendakimab, Camidanlumab tesirine, Brazikumab, Birtamimab, Bintrafusp alfa, Bentracimab, Bemarituzumab, Batoclimab, Atisnolerbart, bremzalerbart,, umesolerbart, Apitegromab, Apamistamab-lodine (1311), Anselamimab, Anbenitamab, Adebrelimab, and Abelacimab, or a functional fragment thereof.

57. The method of any of the preceding claims, wherein the capsule is a sphere, a sphere-like shape, a spheroid, a spheroid-like shape, an ellipsoid, an ellipsoid-like shape, a stadiumoid, , a stadium oid-like shape, a disk, a disk-like shape, a cylinder, a cylinder-like shape, a rod, a rod-like shape, a cube, a cube-like shape, a cuboid, a cuboid-like shape, a torus, a torus- like shape, a flat surface, and a curved surface.

58. The method of any of the preceding claims, where the capsule is a sphere.

59. The method of any of the preceding claims, wherein the device is a sphere, a sphere-like shape, a spheroid, a spheroid-like shape, an ellipsoid, an ellipsoid-like shape, a stadiumoid, a stadiumoid-like shape, a disk, a disk-like shape, a cylinder, a cylinder-like shape, a rod, a rodlike shape, a cube, a cube-like shape, a cuboid, a cuboid-like shape, a torus, a torus- like shape, a flat surface, and a curved surface.

60. The method of any of the preceding claims, wherein the device is a cylinder.

61. The method of any one of the preceding claims, wherein the length of the device is between about 10 mm to about 55 mm.

62. The method of any one of the preceding claims, wherein the diameter of the device is betweenabout 2 mm to about 4 mm.

63. The method of any one of the preceding claims, wherein the device comprises a plurality of pores.

64. The method of any one of the preceding claims, wherein the plurality of pores has a length of about 0.5 mm to about 1.5 mm.

65. The method of any one of the preceding claims, wherein distance between the pores is about 250 pm.

66. The method of any one of the preceding claims, wherein the device further comprises an injection port.

67. The method of any one of the preceding claims, wherein the device is configured as a bulkcore platform, the bulk-core platform comprising a plurality of engineered cells in the interior of the device.

68. The method of any one of the preceding claims, wherein the device is configured as a capsulecore platform, the capsule-core platform comprising a plurality of capsules comprising a plurality of engineered cells as described in claim 1, the capsules disposed in the interior of the device.

69. The method of any one of the preceding claims, the method further comprising: (iv) retrieving the device after a period of time post-delivery, thereby terminating treatment or replacing therapy.

70. The method of claim 69, wherein retrieving the device is for terminating treatment.

71. The method of claim 69, wherein retrieving the device is for replacing a first device with a second device so as to extend the period of treatment in a subject in need thereof.

72. The method of any one of the preceding claims, wherein IgG titer of a biologic post-delivery of a device is detectable in sera of the subject for at least 1, 2, 3, 4, 5, 6 months or more.

73. The method of any one of the preceding claims, wherein the device is further modified with an immunomodulatory small molecule for preventing fibrosis.

74. The method of any one of the preceding claims, wherein the immunomodulatory small molecule is selected from Z4A10, Z1A3, Z2A19, Z1A14, Z1A17, Z1A34, Z4A43, B2A17, and ZlA16.

75. The method of any one of the preceding claims, wherein IgG titer of a biologic in a subject post-delivery with a device modified with immunomodulatory small molecules is detectable in sera of the subject for a longer period of time relative to an intravenous bolus or a device that has not been modified with an immunomodulatory small molecule.

76. The method of any one of the preceding claims, wherein the disease is cancer.

77. The method of any one of the preceding claims, wherein the disease is a pleural disease or condition.

78. The method of any one of the preceding claims, wherein the pleural disease or condition is selected from: pleural cancer, pleural metastatic disease, pleurisy, lung infection, viral pneumonia, bacterial pneumonia, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, pleural thickening, pleural pseudotumor, pleural plaque, extrapleural hematoma, Castleman disease, hemangioendothelioma, splenosis, paramalignang effusion, pleural effusion, pneumothorax, hemothorax, reactive pleuritis, lung cancer, metastases, mesothelioma, malignant mesothelioma, lymphoma, malignant fibrous tumor, sarcoma, a skin tumor, extraskeletal osteosarcoma, malignant fibrous histiocytoma, solitary fibrous tumor, lipoma, mesothelial cyst, calcifying fibrous pseudotumor, primary effusion lymphoma.

79. The method of any one of the preceding claims, wherein the biologic is secreted for 1 day, 1 week, 1 month, 2 months, 3 months, 4 months, 5 month, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 1 year upon delivery of the device or capsule into the subject.

80. The method of any one of the preceding claims, wherein the biologic is secreted for 1 day upon delivery of the device or capsule into the subject.

81. The method of any one of the preceding claims, wherein the biologic is secreted for 1 month upon delivery of the device or capsule into the subject.

82. The method of any one of the preceding claims, wherein the biologic is secreted for 3 months upon delivery of the device or capsule into the subject.

83. The method of any one of the preceding claims, wherein the biologic is secreted for 6 months upon delivery of the device or capsule into the subject.

84. The method of any one of the preceding claims, wherein the biologic is secreted for 9 months upon delivery of the device or capsule into the subject.

85. The method of any one of the preceding claims, wherein the biologic is secreted for 6 months upon delivery of the device or capsule into the subject.

86. The method of any one of the preceding claims, wherein the biologic is secreted for 1 year upon delivery of the device or capsule into the subject.

87. A method of treating a disease in a subject in need thereof, the method comprising: (i) transfecting a cell with a vector encoding for biologic thereby producing an engineered cell as described in claim 1; (ii) co-encapsulating the engineered cell and a sentinel cell as described in claim 44 into a device; (iii) delivering the device into a subject, thereby treating a disease in a subject in need thereof.

88. The method of claim 87, wherein the device comprises a capsule, e.g., a plurality of capsules.

89. The method of claim 87, wherein the device is a capsule, e.g., a plurality of capsules.

90. The method of claim 87, comprising delivering the device orally, intravenously, intraarterially, intrabuccally, intranasally, via nebulization, via bronchial inhalation, intrarectally, vaginally, topically, or via mechanical ventilation, via implantation, or a combination thereof.

91. The method of claim 87, wherein (iii) wherein the delivering comprises implanting the device subcutaneously.

92. The method of any one of the preceding claims, wherein (iii) the delivering comprises implanting the device in the intraperitoneal space of the subject.

93. The method of any one of the preceding claims, wherein the engineered cell secretes a biologic selected from Nemolizumab, Zanidatamab, Linvoseltamab, Axatilimab, Tarlatamab, Marstacimab, Garadacimab, Vilobelimab, Zolbetuximab, Odronextamab, Crovalimab, Camrelizumab, Serplulimab, Sugemalimab, Concizumab, Cosibelimab, Donanemab, Sintilimab, Narsoplimab, Pozelimab, Elranatamab, Rozanolixizumab, Talquetamab, Epcoritamab, Lebrikizumab, Glofitamab, Mirikizumab, Tislelizumab, Toripalimab, Retifanlimab, Lecanemab, Teplizumab, Ublituximab, Nirsevimab, Tremelimumab, Spesolimab, Teclistamab, Mosunetuzumab, Tixagevimab (Cilgavimab), Relatlimab, Tebentafusp, Faricimab, Sutimlimab, Sotrovimab, Regdanvimab, Casirivimab, Imdevimab, Tezepelumab, Amivantamab, Anifrolumab, Bimekizumab, Tralokinumab, Evinacumab, Aducanumab, Dostarlimab, Ansuvimab, Margetuximab, Naxitamab, Atoltivimab, Maftivimab, Tafasitamab, Satralizumab, Inebilizumab, Teprotumumab, Isatuximab,Eptinezumab, Crizanlizumab, Risankizumab, Romosozumab, Ravulizumab, Emapalumab, Cemiplimab, Fremanezumab, Moxetumomab pasudotox, Galcanezumab, Lanadelumab, Mogamulizumab, Erenumab, Tildrakizumab, Ibalizumab, Burosumab, Durvalumab, Emicizumab, Benralizumab, Ocrelizumab, Guselkumab, Sarilumab, Dupilumab, Avelumab, Brodalumab, Atezolizumab, Bezlotoxumab, Olaratumab, Reslizumab, Obiltoxaximab, Ixekizumab, Daratumumab, Elotuzumab, Necitumumab, Idarucizumab, Alirocumab, Mepolizumab, Evolocumab, Dinutuximab, Secukinumab, Nivolumab, Blinatumomab, Pembrolizumab, Ramucirumab, Vedolizumab, Siltuximab, Obinutuzumab, Raxibacumab, Pertuzumab, Belimumab, Ipilimumab, Denosumab, Tocilizumab, Ofatumumab, Canakinumab, Golimumab, Ustekinumab, Catumaxomab, Eculizumab, Ranibizumab, Panitumumab, Natalizumab, Bevacizumab, Cetuximab, Efalizumab, Efalizumab, Omalizumab, Tositumomab-1131, Ibritumomab tiuxetan, Adalimumab, Alemtuzumab, Trastuzumab, Infliximab, Palivizumab, Basiliximab, Daclizumab, Rituximab, Abciximab, and Muromonab-CD3 or a functional fragment thereof.

94. The method of any one of the preceding claims, wherein the biologic is an enzyme replacement therapy selected from Human recombinant AD AMTS 13, Alpha 1 -Proteinase inhibitor, Collagenase, Asparaginase, Anti-Inhibitor Coagulant Complex, tPa (Alteplase), Pegademase (bovine), Alglucerase (Imiglucerase), Factor IX, DNase, Pancrelipase (Amylase, Lipase, Protease), Sacrosidase, truncated (non-glycosylated)tPA (357 of 527aa), recombinant coagulation Factor Vila, tissue Plasminogen activator variant, Uricase (Aspergillus flavus), Antihemophilic factor, Laronidase, Agalsidase beta, Hyaluronidase (ovine), Hyaluronidase (bovine), Galsulfase, Hyaluronidase (Human), Idursulfase, Alglucosidase alfa, Thrombin (human), Thrombin (Bovine), Velaglucerase alfa, Pegloticase, asparaginase (Erwinia chrysanthem), Taliglucerase alfa, recombinant truncated form of human plasmin, Recombinant carboxypeptidase g2 (Glucarpidase), Coagulation Factor Xllla, Elosulfase alfa, Coagulation factor X, Asfotase Alfa, Sebelipase alfa, Cerliponase alfa, vestronidase alfa-vjbk, pegvaliase- pqpz, and algasidase alfa, or a functional fragment thereof.

95. The method of any one of the preceding claims, wherein the biologic is a peptide or polypeptide therapeutic selected from Exenatide, Brolucizumab, Caplacizumab, Liraglutide, Lixisenatide, Albiglutide, Dulaglutide, Teduglutide, Pramlintide, Aviptadil, Carbetocin, Teriparatide,Abaloparatide, Plecanatide, Nesiritide, Angiotensin II, Lucinactant, Pasireotide, and Setmelanotide, or a functional fragment thereof.

96. The method of any one of the preceding claims, wherein the biologic is selected from any one or more of SEQ ID NOs: 1-348.

97. The method of any one of the preceding claims, wherein the biologic selected from any listed in Table 1 or 2.

98. The method of any of the preceding claims, wherein the biologic is selected from Muromonab- CD3, Efalizumab Tositumomab-1131, Daclizumab, Olaratumab, Abciximab, Rituximab, Basiliximab, Palivizumab, Infliximab, Trastuzumab, Adalimumab, Ibritumomab tiuxetan, Omalizumab, Cetuximab, Bevacizumab, Natalizumab, Panitumumab, Ranibizumab, Eculizumab, Certolizumab pegol, Ustekinumab, Canakinumab, Golimumab, Ofatumumab, Tocilizumab, Denosumab, Belimumab, Ipilimumab, Brentuximab vedotin, Pertuzumab, Ado- trastuzumab emtansine, Raxibacumab, Obinutuzumab, Siltuximab, Ramucirumab, Vedolizumab, Nivolumab, Pembrolizumab, Blinatumomab, Alemtuzumab, Evolocumab, Idarucizumab, Necitumumab, Dinutuximab, Secukinumab, Mepolizumab, Alirocumab, Daratumumab, Elotuzumab, Ixekizumab, Reslizumab, Bezlotoxumab, Atezolizumab, Obiltoxaximab, Brodalumab, Dupilumab, Inotuzumab ozogamicin, Guselkumab, Sarilumab, Avelumab, Emicizumab, Ocrelizumab, Benralizumab, Durvalumab, Gemtuzumab ozogamicin, Erenumab, erenumab- aooe, Galcanezumab, galcanezumab-gnlm, Burosumab, burosumab-twza, Lanadelumab, lanadelumab-flyo, Mogamulizumab, mogamulizumab-kpkc, Tildrakizumab; tildrakizumab-asmn, Fremanezumab, fremanezumab-vfrm, Ravulizumab, ravulizumab-cwvz, Cemiplimab, cemiplimab-rwlc, Ibalizumab, ibalizumab- uiyk, Emapalumab, emapalumab-lzsg, Moxetumomab pasudotox, moxetumomab, pasudotox-tdfk, Caplacizumab, caplacizumab-yhdp, Risankizumab, risankizumab-rzaa, Polatuzumab vedotin, polatuzumab vedotin-piiq, Romosozumab, romosozumab-aqqg, Brolucizumab, brolucizumab- dbll, Crizanlizumab; crizanlizumab-tmca, Enfortumab vedotin, enfortumab vedotin-ejfv, [fam- ]trastuzumab deruxtecan, fam- trastuzumab, deruxtecan-nxki, Isatuximab, isatuximab- irfc, Belantamab mafodotin, belantamab mafodotin- blmf, Sacituzumab govitecan; sacituzumab govitecan- hziy, Tafasitamab, tafasitamab-cxix, Satralizumab, satralizumab-mwge, Eptinezumab, eptinezumab-jjmr, Inebilizumab, inebilizumab-cdon, Teprotumumab,teprotumumab-trbw, Evinacumab, Dostarlimab, dostarlimab-gxly, Amivantamab, amivantamab-vmjw Tralokinumab, tralokinumab-ldrm, Anifrolumab, anifrolumab- fniaLoncastuximab tesirine, loncastuximab tesirine- Ipyl, Atoltivimab,maftivimab, odesivimab-ebgn, Naxitamab-gqgk, Margetuximab-cmkb, Ansuvimab-zykl, Aducanumab, aducanumab-avwa, Tisotumab vedotin, tisotumab vedotin-tftv, Tezepelumab, tezepelumab- ekko, Faricimab, faricimab- svoa, Sutimlimab, sutimlimab- jome, Spesolimab, Teplizumab, teplizumab- mzwv, Ublituximab, Tebentafusp, tebentafusp-tebn, Relatlimab, Mosunetuzumab, Teclistamab, Tremelimumab, Mirvetuximab soravtansine, mirvetuximab, soravtansine-gynx, Lecanemab, Retifanlimab, retifanlimab-Dlwr, Epcoritamab, Zolbetuximab, Ziltivekimab, Zilovertamab vedotin, Zilovertamab, Zanidatamab, Zamerovimab +mazorelvimab, Zalifrelimab, Xeligekimab, Vunakizumab, Vobramitamab duocarmazine, Vilobelimab, Vibostolimab, Upifitamab rilsodotin, Tusamitamab ravtansine, Trastuzumab rezetecan, Tozorakimab, Tosatoxumab, Tiragolumab, Telisotuzumab vedotin, Tebotelimab, Tarlatamab, Tarcocimab tedromer, Suvratoxumab, Suciraslimab, Solanezumab, Sibeprenlimab, Setrusumab, Semzuvolimab, Sasanlimab, Sabatolimab, Rulonilimab, Rosopatamab (177Lu- DOTA), Rocatinlimab, Retlirafusp alfa, Recaticimab, Quavonlimab, Pozelimab, Pivekimab sunirine, Patritumab deruxtecan, Paridiprubart, Pamrevlumab, Otilimab, Oregovomab, Ongericimab, Onfekafusp alfa, Oleclumab, Odronextamab, Ociperlimab, Nofazinlimab, Nipocalimab, Navicixizumab, Nadunolimab, Monalizumab, Mecbotamab vedotin, Marstacimab, Magrolimab, Litifilimab, Linvoseltamab, Ligelizumab, Latozinemab, Izalontamab, Ivuxolimab, Ivonescimab, Itepekimablparomlimab (anti-PD-1), Tuvonralimab (anti- CTLA-4), Inclacumab, Imsidolimab, lanalumab, Glenzocimab, Gefurulimab, Garetosmab, Garadacimab, Gantenerumab, Futuximab+modotuxima b, Finotonlimab, Fianlimab, Felzartamab, Favezelimab, Erfonrilimab, Emactuzumab, Elranatamab, Ebronucimab, Ebdarokimab, Domvanalimab, Divozilimab, Depemokimab, Datopotamab deruxtecan, Dapirolizumab pegol, Dafsolimab setaritox +grisnilimab setaritox, Coprelotamab, Cobolimab, Clesrovimab, Clazakizumab, Cetrelimab, Cendakimab, Camidanlumab tesirine, Brazikumab, Birtamimab, Bintrafusp alfa, Bentracimab, Bemarituzumab, Batoclimab, Atisnolerbart, bremzalerbart,, umesolerbart, Apitegromab, Apamistamab-lodine (1311), Anselamimab, Anbenitamab, Adebrelimab, and Abelacimab, or a functional fragment thereof.

99. The method of any of the preceding claims, wherein the capsule is a sphere, a sphere-like shape, a spheroid, a spheroid-like shape, an ellipsoid, an ellipsoid-like shape, a stadiumoid, a stadiumoid-like shape, a disk, a disk-like shape, a cylinder, a cylinder-like shape, a rod, a rodlike shape, a cube, a cube-like shape, a cuboid, a cuboid-like shape, a torus, a torus- like shape, a flat surface, and a curved surface.

100. The method of any of the preceding claims, where the capsule is a sphere.

101. The method of any of the preceding claims, wherein the device is a sphere, a sphere-like shape, a spheroid, a spheroid-like shape, an ellipsoid, an ellipsoid-like shape, a stadiumoid, , a stadiumoid-like shape, a disk, a disk-like shape, a cylinder, a cylinder-like shape, a rod, a rod-like shape, a cube, a cube-like shape, a cuboid, a cuboid-like shape, a torus, a torus- like shape, a flat surface, and a curved surface.

102. The method of any of the preceding claims, wherein the device is cylindrical in shape.

103. The method of any one of the preceding claims, wherein the length of the device is between about 10 mm to about 55 mm.

104. The method of any one of the preceding claims, wherein the diameter of the device is between about 2 mm to about 4 mm.

105. The method of any one of the preceding claims, wherein the device comprises a plurality of pores.

106. The method of any one of the preceding claims, wherein the plurality of pores has a length of about 0.5 mm to about 1 .5 mm.

107. The method of any of the preceding claims, wherein distance between the pores is about 250 pm.

108. The method of any one of the preceding claims, wherein the device further comprises an injection port.

109. The method of any one of the preceding claims, wherein the device is configured as a bulkcore platform, the bulk-core platform comprising a plurality of engineered cells in the interior of the device.

110. The method of any one of the preceding claims, wherein the device is configured as a capsule-core platform, the capsule-core platform comprising a plurality of capsules comprisinga plurality of engineered cells as described in claim 1, the capsules disposed in the interior of the device.

111. The method of any one of the preceding claims, the method further comprising: (iv) retrieving the device after a period of time post-delivery, thereby terminating treatment or replacing therapy.

112. The method of claim 111, wherein retrieving the device is for terminating treatment.

113. The method of claim 111, wherein retrieving the device is for replacing a first device with a second device so as to extend the period of treatment in a subject in need thereof.

114. The method of any one of the preceding claims, wherein IgG titer of a biologic in a subject post-implantation of a device is detectable in sera of the subject for at least 1, 2, 3, 4, 5, 6 months or more.

115. The method of any one of the preceding claims, wherein the device is further modified with an immunomodulatory small molecule for preventing fibrosis.

116. The method of any one of the preceding claims, wherein the immunomodulatory small molecule is selected from Z4A10, Z1A3, Z2A19, Z1A14, Z1A17, Z1A34, Z4A43, B2A17, and Z1A16.

117. The method of any one of the preceding claims, wherein IgG titer of a biologic in a subject post-delivery with a device modified with immunomodulatory small molecules is detectable in sera of the subject for longer period of time relative to an intravenous bolus or a device that has not been modified with an immunomodulatory small molecule.

118. The method of any one of the preceding claims, wherein the disease is cancer.

119. The method of any one of the preceding claims, wherein the disease a pleural disease or condition.

120. The method of any one of the preceding claims, wherein the pleural disease or condition is selected from: pleural cancer, pleural metastatic disease, pleurisy, lung infection, viral pneumonia, bacterial pneumonia, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, pleural thickening, pleural pseudotumor, pleural plaque, extrapleural hematoma, Castleman disease, hemangioendothelioma, splenosis, paramalignang effusion, pleural effusion, pneumothorax, hemothorax, reactive pleuritis, lung cancer, metastases,mesothelioma, malignant mesothelioma, lymphoma, malignant fibrous tumor, sarcoma, a skin tumor, extraskeletal osteosarcoma, malignant fibrous histiocytoma, solitary fibrous tumor, lipoma, mesothelial cyst, calcifying fibrous pseudotumor, primary effusion lymphoma.

121. The method any one of the preceding claims, wherein the sentinel cell secretes a cytokine or a chemokine.

122. The method of any one of the preceding claims, wherein the sentinel cell secretes a cytokine selected from one or of: IL-1, IL-la, IL-1 , IL-IRA, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-12a, IL-12b, IL-13, IL-14, IL-15, IL-16, IL-17, IL-20, IL-23, IFN-a, IFN- , IFN-y, and TNF-a.

123. The method of any one of the preceding claims, wherein the biologic is secreted for 1 day, 1 week, 1 month, 2 months, 3 months, 4 months, 5 month, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 1 year upon delivery of the device into the subject.

124. The method of any one of the preceding claims, wherein the biologic is secreted for 1 day upon delivery of the device or capsule into the subject.

125. The method of any one of the preceding claims, wherein the biologic is secreted for 1 month upon delivery of the device or capsule into the subject.

126. The method of any one of the preceding claims, wherein the biologic is secreted for 3 months upon delivery of the device or capsule into the subject.

127. The method of any one of the preceding claims, wherein the biologic is secreted for 6 months upon delivery of the device or capsule into the subject.

128. The method of any one of the preceding claims, wherein the biologic is secreted for 9 months upon delivery of the device or capsule into the subject.

129. The method of any one of the preceding claims, wherein the biologic is secreted for 6 months upon delivery of the device or capsule into the subject130. The method of any one of the preceding claims, wherein the biologic is secreted for 1 year upon delivery of the device or capsule into the subject.

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