WO2024091534A1

WO2024091534A1 - Implantable encapsulated device with controlled perfusion that generates reprogrammed cells

Info

Publication number: WO2024091534A1
Application number: PCT/US2023/035855
Authority: WO
Inventors: Lindsey MUIR; Indika RAJAPAKSE; Christian Macedonia
Original assignee: The Regents Of The University Of Michigan
Priority date: 2022-10-25
Filing date: 2023-10-25
Publication date: 2024-05-02

Abstract

An implantable encapsulated device for implantation into a body includes a chamber encapsulated at least in part by a permeable membrane and including a supportive scaffold for holding one of patient and donor derived cells within the chamber, A perfusion system includes an input port and an output port in communication with a permeable passage within the chamber, wherein the input port is connected to a source of therapeutic fluid for delivery through the input port and the permeable passage to the one of patient and donor derived cells with the supportive scaffold.

Description

IMPLANTABLE ENCAPSULATED DEVICE WITH CONTROLLED PERFUSION THAT GENERATES REPROGRAMMED CELLS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63/419,070, filed October 25, 2022. The entire disclosure of the above application is incorporated herein by reference.

FIELD

[0002] The present disclosure relates to an implantable device for in vivo cell reprogramming.

BACKGROUND

[0003] Previous attempts have been made to transplant cells into a body by injection. However, these attempts have often resulted in a large loss of cells within days.

[0004] The October 28, 2013 Pub Med publication entitled “Transplantation of Human Islets Without Immunosuppression” by Ludwig et al. discloses an initial device design for pancreatic islet delivery. The device used a hydrophilic 0.4 pm porous polytetrafluoroethylene membrane for an outer covering and hydrophobically modified alginate for cells. https://pubmed.ncbi.nlm.nih.gov/24167261/.

[0005] The December 14, 2016 Pub Med Central publication entitled “Application of Semipermeable Membranes in Glucose Biosensing” by Kulkarni et al. discloses a review of glucose biosensing. Table 1 discloses controlled permeability membranes used in glucose biosensing. https://www.ncbi.nlm.nih.qov/Dmc/articles/PMC5192411/

[0006] The February 2, 2018 Pub Med publication entitled “Transplantation of macro-encapsulated human islets within the bioartificial pancreas |3Air to patients with type 1 diabetes mellitus” by Carlsson et al. discloses a clinical trial showing encapsulated device (Beta-Air) safety in context of beta cell delivery. Allogeneic islets were maintained several months in vivo. The study used alginate slabs loaded with >100k islets, implanted subcutaneously, used ports to refill oxygen and a device designed to provide 30h oxygen. https://Dubmed.ncbi.nlm.nih.qov/29288549/ (Cl i n i caltri als . qov:NCT02064309) . [0007] The January 30, 2018 Journal of the American College of Cardiology publication entitled “Transplantation of Human Embryonic Stem Cell-Derived Cardiovascular Progenitors for Severe Ischemic Left Ventricular Dysfunction” by Menasche et al. discloses implantation of a 20cm^A2 human fibrin patch containing cardiovascular progenitor cells. A "Kangaroo" procedure is described with fibrinogen/thrombin gel with cells from cardiovascular lineage derived from hESCs, implanted onto epicardium of cardiac infarct area, under pericardial sheet. https://www.sciencedirect.com/science/article/pii/S0735109717417281

[0008] The October 25, 2018 Diabetic Medicine publication entitled “Stem cell therapies for Type 1 diabetes: current status and proposed road map to guide successful clinical trials” by Senior et al. discloses a review of encapsulation requirements related to type 1 diabetes implantable devices. https://onlinelibrarv.wilev.eom/doi/Ddf/10.1111 /dme.13846

[0009] The July 14, 2020 PubMed Central publication entitled “A percutaneous catheter for in vivo hyperspectral imaging of cardiac tissue: Challenges, Solutions and Future Directions” by Armstrong et al. discloses a catheter for in vivo hyperspectral imaging of cardiac lesions and includes a discussion of low UV exposure to cardiac tissue and safety, and using tissue autofluorescence for increased imaging capabilities. httDs://www.ncbi.nlm.nih.qov/Dmc/articles/PMC7530025/

[0010] The June 24, 2021 Frontiers publication entitled “Optimized Protocol for Subcutaneous Implantation of Encapsulated Cells Device and Evaluation of Biocompatibility” by Audouard et al. describes implantation of wireless-powered cellbased devices in mice. The publication also provides a discussion of other papers using enclosed/semi-permeable devices that contain cells. Used for delivery of therapeutic molecules. https://www.frontiersin.org/articles/10.3389/fbioe.2021 ,620967/full

[0011] The December 2, 2021 Cell publication entitled “Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes” By Ramzy et al. discloses hESC-derived beta cells in an implanted device. https://doi.Org/10.1016/i.stem.2021 .10.003

[0012] The December 2, 2021 Cell Reports Medicine publication entitled “Insulin expression and C-peptide in type 1 diabetes subjects implanted with stem cell-derived pancreatic endoderm cells in an encapsulation device” by Shapiro et al. discloses hESC-derived beta cells in an implanted device. httos://doi.orq/10.1016/i.xcrm.2O21 .100466

[0013] The January 19, 2021 Nature Communications publication entitled “Concomitant control of mechanical properties and degradation in resorbable elastomer-like materials using stereochemistry and stoichiometry for soft tissue engineering” by Wandel et al. disclose control of degradation of resorbable elastomerlike materials. Varying ratio of cis-trans double bonds in backbone (stoichiometry of succinate incorporation) offers control over degradation rate. Material is highly hydrophobic, subject to surface erosion. https://www.nature.com/articles/s41467-020-20610-5

[0014] The May 15, 2022 Science Direct publication entitled “3D printed hydrogel for articular cartilage regeneration” by Yang et al. discloses a summary of state of art for 3D printed hydrogels for articular cartilage regeneration. https://www.sciencedirect.com/science/article/pii/S13598368220024387via%3Dihub

SUMMARY

[0015] This section provides a general summary of the disclosure, and is not a comprehensive disclosure of its full scope or all of its features.

[0016] An implantable device for cell reprogramming in vivo in an encapsulated environment is built for real-time adjustable infusions of cell reprogramming factors and for monitoring reprogrammed cells and tissues. The device is optionally self-contained or has a transcutaneous connection to a control module. The device includes cells and reprogramming substrates, supportive scaffolding, and a perfusion system surrounded by a membrane with controlled permeability, as well as input and output access ports connecting to a control module with the capability to monitor and nurture the bioconstructs.

[0017] According to an aspect of the present disclosure, an implantable encapsulated device for implantation into a body includes a chamber encapsulated at least in part by a permeable membrane and including a supportive scaffold for holding one of patient and donor derived cells within the chamber, A perfusion system includes an input port and an output port in communication with a permeable passage within the chamber, wherein the input port is connected to a source of therapeutic fluid for delivery through the input port and the permeable passage to the one of patient and donor derived cells with the supportive scaffold.

[0018] According to a further aspect, the source of therapeutic material includes a pump.

[0019] According to a further aspect, a monitoring device is connected to the output port for monitoring material received from the output port.

[0020] According to a further aspect, the permeable membrane includes at least one layer of at least one of cellulose acetate, polypyrrole, perfluorosulfonic acid polymer, polyurethane, polytetrafluoroethylene, chitosan and poly(2-hydroxyethyl methacrylate).

[0021] According to a further aspect, the scaffolding includes at least one of elastin, collagen, fibronectin, fibrinogen and thrombin.

[0022] Further areas of applicability will become apparent from the description provided herein. The description and specific examples in this summary are intended for purposes of illustration only and are not intended to limit the scope of the present disclosure.

BRIEF DESCRIPTION OF DRAWINGS

[0023] The drawings described herein are for illustrative purposes only of selected embodiments and not all possible implementations, and are not intended to limit the scope of the present disclosure.

[0024] FIG. 1 is a schematic view of an implantable device for cell reprogramming in vivo according to the principles of the present disclosure;

[0025] FIG, 2 is a schematic view of an array of implantable devices for cell reprogramming in vivo according to the principles of the present disclosure;

[0026] FIG. 3 is a schematic view of a matrix of implantable devices having a common input port according to the principles of the present disclosure;

[0027] FIG. 4 is a schematic view of a radial design of an implantable device for cell reprogramming in vivo;

[0028] FIG. 5 is an alternative design of an implantable device for cell reprogramming vivo; and

[0029] FIG. 6 is a schematic view of an example implantable device that is capable of releasing microcapsules from the implantable device directly into the body and/or removal of microcapsules from the implantable device without removing the implantable device from the body.

[0030] Corresponding reference numerals indicate corresponding parts throughout the several views of the drawings.

DETAILED DESCRIPTION

[0031] Example embodiments will now be described more fully with reference to the accompanying drawings.

[0032] With reference to FIG. 1 , an implantable device 10 is shown for cell reprogramming in vivo in an encapsulated environment. The implantable device 10 includes a chamber 12 with a semi-permeable membrane enclosure 14. The membrane enclosure 14 has a controlled permeability. An input port 16 and an output port 18 are provided in communication with the enclosed chamber 12 for real-time adjustable infusions of cell reprogramming factors and for monitoring reprogrammed cells and tissues. The input port 16 and the output port 18 are connected to a permeable region 19 within the chamber 12. The permeable region 19 allows the infusion of the cell reprogramming factors and withdrawal of material for monitoring of the cells. The chamber 12 of the implantable device includes cells for reprogramming and a supportive scaffolding 20 to support the attachment of the cells. The implantable device 10 is optionally self-contained or has a transcutaneous connection to a control module 22. The input and output access ports 16, 18 can be connected to the control module 22 with the capability to monitor and nurture the bio-constructs.

[0033] The implantable device 10 can be used for reprogramming patient or donor derived cells, for example from dermis, adipose, or blood. The support scaffolding may include extracellular matrix proteins and molecules such as elastin, collagen (e.g., II), fibronectin, fibrinogen, and/or thrombin. Key properties include optimized elasticity and structure modeled on the desired tissue (e.g., cartilage) for maintaining a physiological mechanical load on cells.

[0034] A major property of the encapsulating membrane 14 is controlled permeability that enables nutrient and oxygen perfusion at the target implantation site but is cell impermeable. The encapsulation membrane 14 may include one or more layers of size or charge selective materials such as cellulose acetate, polypyrrole, perfluorosulfonic acid polymer (nation), polyurethane, polytetrafluorethylene, chitosan, or poly(2-hydroxyethyl methacrylate). [0035] A single perfusion unit within the device consists of an input port 16 connected to an output port 18 via fenestrated or controlled permeability membrane/tubing 19 that extends across a specific distance (d) through an assembly of cells and scaffolding 20, with pump-mediated flow through of therapeutic reprogramming factors and isotonic oxygenated nutrient medium. The tubing 16, 18 can be composed of biologically inert, kink-free catheters of polypropylene, polyethylene, or like material. Continuous flow enables collection of out-flow, which can be monitored for markers of the desired conditions, for example with analysis of oxygen, metabolites, or biomarkers of cell health and identity. Inputs are tailored based on outflow to control cell viability and cell identity via reprogramming factors.

[0036] As shown in FIGS. 2-5, multiple units 10 may be constructed that have the same or independent input ports 16, or the same or independent output ports 18 to enable tailoring of input based on output of single units or groups of units. In the case of more than one perfusion unit as shown in FIG 4, inputs/outputs 16, 18 are enclosed in parallel to minimize surface area at the incision site. An external pump unit 22 may include or have couplings to multiple input ports 16 and a microfluidic device 24 can be connected to the output ports 18for collection of outflow, diverting to sampling or waste collection containers as needed. This microfluidic device may have a programmable control element for automated parameter adjustments to cells based on outflow analysis as well as effluent sampling and data outputs to additional computing platforms via a wireless protocol.

[0037] With reference to FIG 6, an example implantable device 110 is shown including multiple chambers 112 within a permeable enclosure 114. Each chamber 112 can be connected to a common or individual input ports 1 16 and a common or individual output ports 118. Each chamber 112 can include cells or microcapsules 119 therein. Each chamber 112 can include a first permeable membrane 120 that is exposed to the tissue 122 and a second permeable membrane 122 that covers the outlet ports 118. The first and second membranes 120, 122 allow fluids to permeate therethrough so that body fluids can pass into the chambers 112 from the tissue T and so that fluids within the chambers 112 can pass through the output ports 118 for analysis. The first permeable membrane 120 can also be designed to be dissolvable by a first enzyme and the second permeable membrane 122 can be designed to be dissolvable by a different second enzyme. Accordingly, by the introduction of the first or the second enzyme, the chambers 112 are capable of releasing cells or microcapsules 119 from the implantable device directly into the body and/or removal of cells or microcapsules from the implantable device through the output port 118 without removing the implantable device 110 from the tissue T.

[0038] The microcapsules can include 3D bio-print cells and matrices that can be produced from collagen and have a diameter of less than or equal to 200 pm for containing body cells. A predetermined number of the microcapsules containing selected cells can be contained within each chamber 12/112 either in a suspension or a loose capsule matrix.

[0039] The present disclosure provides a system and method of gentle in vivo privileged cell re-programing by combining the reprogramming and transplanting process for improved cell survival. The implantable device 10/110 can be utilized for gradually tolerating therapeutic cells to the in vivo environment. The implantable device 10/110 reduces transplant/engraftment stress on the cells due to shear stress of fluidic delivery and adapt the tissue cells to oxygen tension verses atmospheric. The implantable device 10/110 is also clinical trial supportive by providing an easy test response with input and output control and easy removal. The implantable device 10/110 allows cell tissue to be tolerant to implanted cells pre-vascularization. The implantable device 10/110 allows for the selection of an implant site (peritoneal, fat, muscle, sub-cutaneous, etc.) that best pre-conditions the cells as needed. The implantable device 10/110 also allows for the selection of reprogrammed cells that tolerate the in vivo environment. The implantable device 10/110 also allows the addition of cells to the chambers 12 on the fly. The scaffolding provides structural support for the implanted cells until engraftment is achieved. The implantable device 10/110 allows for monitoring of the reprogramming and survival of the cells via units that can be extracted without damage.

[0040] The general use of the implantable devices 10/110 can leave the cells encapsulated for the production of therapeutic molecules or hormones that can be extracted or delivered directly to the body. The implantable device 10/110 can be removed and the reprogrammed cells can be reimplanted where needed. The host of the implantable device can be different that the patient receiving the reprogrammed cells. A break-away application can enable removal of capsules and controlled release of cells by units with units being released to the tissue and adjacent units collected for analysis. Specific uses may include solid tissue (muscle, skin) regeneration and production of blood and red blood cells. [0041] The cells and scaffolding 20 are assembled by (1 ) unpatterned construction, where a matrix is constructed first and cells are seeded into the matrix, or where matrix and cells are intermixed and allowed to form natural patterns via migration and cell-cell interaction or (2) patterned construction, where a matrix is given initial patterning via 3D printing, or where matrix and cells are given initial patterning via 3D bioprinting. Cells and scaffolding 20 are constructed around perfusion units with a maximum distance y between a perfusion unit and an outer encapsulating membrane. y is determined empirically for each target cell type based on the maximum y that has less than 10% deviation from baseline cell viability under fixed perfusion conditions and is within the physical constraints of the target implantation site. Perfusion units with cells will be assembled in three dimensions to a size compatible with the target implantation site and subject to limitations on transcutaneous access port incision size. Access ports may be maintained via a single incision site, or using more than one incision/access port site if the device size or shape generates higher clinical risk with increased internal components vs. externalizing the components via dividing into more than one access port.

[0042] The applications for the implantable encapsulated device 10 of the present disclosure can include cartilage/articular cartilage repair in tissue reconstruction, for example in joint injury or osteoarthritis. Additional applications can include maturation of glucose sensing, insulin producing reprogrammed cells and incubation and reprogramming of cell cultures (donor or autologous) for the purposes of cell based treatments of cancers, metabolic disorders, wound healing, or any other cell based therapy requiring high viability of target cells with minimal ex vivo manipulation.

[0043] The foregoing description of the embodiments has been provided for purposes of illustration and description. It is not intended to be exhaustive or to limit the disclosure. Individual elements or features of a particular embodiment are generally not limited to that particular embodiment, but, where applicable, are interchangeable and can be used in a selected embodiment, even if not specifically shown or described. The same may also be varied in many ways. Such variations are not to be regarded as a departure from the disclosure, and all such modifications are intended to be included within the scope of the disclosure.

Claims

CLAIMS What is claimed is:

1. An implantable encapsulated device for implantation into a body, comprising: a chamber encapsulated at least in part by a permeable membrane and including a supportive scaffold for holding one of patient and donor derived cells within the chamber; and a perfusion system including an input port and an output port in communication with a permeable passage within the chamber, wherein the input port is connected to a source of therapeutic fluid for delivery through the input port and the permeable passage to the one of patient and donor derived cells with the supportive scaffold.

2. The implantable encapsulated device according to claim 1 , wherein the source of therapeutic material includes a pump.

3. The implantable encapsulated device according to claim 1 , further comprising a monitoring device connected to the output port for monitoring material received from the output port.

4. The implantable encapsulated device according to claim 1 , wherein the permeable membrane includes at least one layer of at least one of cellulose acetate, polypyrrole, perfluorosulfonic acid polymer, polyurethane, polytetrafluoroethylene, chitosan and poly(2-hydroxyethyl methacrylate).

5. The implantable encapsulated device according to claim 1 , wherein the scaffolding includes at least one of elastin, collagen, fibronectin, fibrinogen and thrombin.

6. An implantable encapsulated device for implantation into a body, comprising: a plurality of chambers each encapsulated at least in part by a permeable membrane and each including a supportive scaffold for holding one of patient and donor derived cells within the chamber; and a perfusion system including an input port and an output port in communication with a permeable passage within each of the chambers, wherein each input port is connected to a source of therapeutic fluid for delivery through the input port and the permeable passage to the one of patient and donor derived cells with the supportive scaffold.

7. The implantable encapsulated device according to claim 6, wherein the source of therapeutic material includes a pump.

8. The implantable encapsulated device according to claim 6, further comprising a monitoring device connected to the output ports for monitoring material received from the output ports.

9. The implantable encapsulated device according to claim 6, wherein the permeable membrane includes at least one layer of at least one of cellulose acetate, polypyrrole, perfluorosulfonic acid polymer, polyurethane, polytetrafluoroethylene, chitosan and poly(2-hydroxyethyl methacrylate).

10. The implantable encapsulated device according to claim 6, wherein the scaffolding in each chamber includes at least one of elastin, collagen, fibronectin, fibrinogen and thrombin.

11 . The implantable encapsulated device according to claim 6, wherein the input port of each chamber is attached to a common source of therapeutic fluid.

12. An implantable encapsulated device for implantation into a body, comprising: a chamber encapsulated at least in part by a first permeable membrane for holding one of patient and donor derived cells within the chamber; and a perfusion system including an input port and an output port each in communication with the chamber, wherein the input port is connected to a source of therapeutic fluid for delivery through the input port and the first permeable membrane is dissolvable with exposure to a first enzyme.

13. The implantable encapsulated device according to claim 12, wherein the output port includes a second permeable membrane that is dissolvable with exposure to a second enzyme.

14. The implantable encapsulated device according to claim 12, wherein the source of therapeutic material includes a pump.

15. The implantable encapsulated device according to claim 12, further comprising a monitoring device connected to the output port for monitoring material received from the output port.

16. The implantable encapsulated device according to claim 12, wherein the first permeable membrane includes at least one layer of at least one of cellulose acetate, polypyrrole, perfluorosulfonic acid polymer, polyurethane, polytetrafluoroethylene, chitosan and poly(2-hydroxyethyl methacrylate).

17. The implantable encapsulated device according to claim 12, wherein the scaffolding includes at least one of elastin, collagen, fibronectin, fibrinogen and thrombin.