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WO2013166525A2 - Emballage pour la distribution de cellules vivantes - Google Patents

Emballage pour la distribution de cellules vivantes Download PDF

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Publication number
WO2013166525A2
WO2013166525A2 PCT/ZA2013/000019 ZA2013000019W WO2013166525A2 WO 2013166525 A2 WO2013166525 A2 WO 2013166525A2 ZA 2013000019 W ZA2013000019 W ZA 2013000019W WO 2013166525 A2 WO2013166525 A2 WO 2013166525A2
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WO
WIPO (PCT)
Prior art keywords
cells
sterile
package
stem cells
bag
Prior art date
Application number
PCT/ZA2013/000019
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English (en)
Inventor
Campbell MACFARLANE
Original Assignee
Macfarlane Campbell
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Macfarlane Campbell filed Critical Macfarlane Campbell
Publication of WO2013166525A2 publication Critical patent/WO2013166525A2/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M45/00—Means for pre-treatment of biological substances
    • C12M45/22—Means for packing or storing viable microorganisms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • nanofibres When spun nanofibres are extruded onto a suitable solid support, like spaghetti falling from a fork, they form a random nano-scaffold and an aerogel. The spaces between the fibres form the aerogel. When these spaces are exposed to medium containing SCs, a hydrogel is formed, and the stem cells occupy or populate the scaffold. The process is similar to that which happens on dunking a rusk or a biscotti biscuit into tea or coffee. When a natural or synthetic nano-scaffold is immersed in a suspension of stem cells, the stem cells infiltrate the scaffold and populate it with stem cells throughout its volume.
  • the spaces between the fibres are in the nanometer or low micrometer range and this makes the volume of the hydrogel within the nano-scaffold very large when compared to the size of the nano-scaffold.
  • the SCs are "anchored" to the scaffold.
  • the nano-scaffolds have a high volume-to-surface ratio this means that a relatively large number of cells can be retained within the hydrogel.
  • the populated scaffolds can be used to introduce stem cells to patients as a cardiac patch or as a dressing for an open wound.
  • the commercial collagen " «a «o"-scaffold or sponge used in the cardiac patch was 7 x 5cm 2 and less than 0,6cm thick, pore size 50-100 ⁇ , but it contained 5x10 5 mesenchymal stem cells (MSCs). After 90 minutes immersion in a suspension of MSCs the capture was 70%. A collagen membrane of 35 cm 2 and 2,4mm thick could contain 2xl0 6 (two million) MSCs after 90 minutes immersion. A measured rocking action using a laboratory shaker was used to ensure SCs in remained in suspension during the adsorption process. Our experience was that the medium and suspended stem cells were immediately absorbed into the scaffold. If the pore size was less, scaffolds could be manufactured which would accommodate many more stem cells per unit volume.
  • MSCs mesenchymal stem cells
  • a variety of synthetic nano-scaffolds of various densities, porosities, fluidities and surface-to-volume fibre ratios can be engineered from various nanomaterials using a variety of cross-links.
  • Biocompatible and biodegradable nanofibres can be engineered from 30-40 different polymers and these can be from 50-100 nanometres in diameter and have various active groups present.
  • the diameter of the spaces between the fibres can be from 20-200 micrometres. This results in either fluid or more solid gels, and this will influence clinical use and stem cell retention and release.
  • scaffolds materials such as natural fibrin scaffolds or sponge-like collagen or alginate scaffolds, polylacetate, poly (lactic co-glycolic acid) (PLGA) or poly ⁇ -caprolactone/gelatin, etc.
  • stem cells in a package in which the stem cells are stabilized within a solid nano-scaffold as a hydrogel, as they are in a sponge tissue patch or in some wound dressing. Immobilization would prevent cell damage from vibrations and collisions during cell distribution. As the cells are distributed in a thin liquid film and exist close to the liquid surface, gas exchange with the air and uptake of oxygen by the cells can occur. Carbon dioxide can diffuse out of the fluid and into the air by moving along equilibrating, diffusion concentration gradients of C0 2 .
  • the package would be constructed so that the stem cells would remain in an environment of 20% oxygen, 80% nitrogen and 0.04% carbon dioxide (air), and 28% humidity to stabilize volume. Temperature would be close to 37 degrees Celsius, pH close to 7,4 and the cell package would be shielded from damage due to excessive bending, crushing or other physical damage.
  • the environment of the stem cells must adhere closely to these parameters if the stem cells are to survive. Many cells survive in oxygen levels of less than 10% and this oxygen tension more accurately reflects oxygen tensions in the tissues. With 20% oxygen or air there is a large margin- of-error in terms of cell survival, nevertheless too many growing cells in a small container can quickly become anoxic and die.
  • fetal calf serum would be added and the inner bag would be sterilised before the populated nano-scaffold was placed inside.
  • the suspension media would contain streptomycin (100 ⁇ g/ml) and penicillin (lOOU/ml).
  • streptomycin 100 ⁇ g/ml
  • penicillin lOOU/ml
  • the culture of the stem cells on scaffolds as discussed is an example of a sterile, "adherent" 3-D maintenance tissue culture and such would be the condition of the live cells during transport. If necessary the cells could be maintained in a standard culture medium, like Dulbecco's modified Eagle's medium (DMEM). Of course many variations in culture medium and additions are possible.
  • DMEM Dulbecco's modified Eagle's medium
  • a temperature sensitive strip could be incorporated onto the outside surface of the inner bag. This could be maximum/minimum temperature or a continuous, digital storage of temperature throughout transport.
  • SCs stem cells
  • other than autologous progenitor stem cells can be used for engraftment or re-population of damaged or diseased tissues. Distribution of these other allogeneic stem cells could be done using the distribution packages described in this patent application.
  • Suitable SCs include but are not limited to: unfractionated adipose derived SCs, modified embryonic stem cells, genetically modified adult stem cells, induced pluripotent adult stem cells, endometrial SCs , parthenogenetic SCs, Wharton's jelly or placental SCs, modified, fractionated or expanded embryonic SCs, stem cell lines or pluripotent adult stem cells like MIAMI cells, spore-like cells, blastomere-like adult stem cells or very small embryonic-like stem cells.
  • the packages could be used to distribute commercially produced mesenchymal stem cells (MSCs), such as those produced by Osiris or Mesoblast.
  • MSCs could naturally deliver anti-inflammatory cytokines, chemokines or exosomes to sites of inflammation, such as in rheumatoid arthritis, or they could be used to encapsulate biologicals for site specific delivery and reduced side-effects in diseases like cancer. They could be used to deliver appropriate treg immune cells in autoimune diseases. It will be apparent that this technology has many uses in transporting living cells and it is to be expected that further applications will arise in the future.
  • progenitor SCs In young patients sufficient endogenous, progenitor SCs exist for re-population. In older patients with reduced amounts of progenitor stem cells, some of the above SCs, like embryonic or MIAMI SCs, could be used for re- population and mesenchymal stem cells (MSCs) could be used as a co-transplant.
  • MSCs mesenchymal stem cells
  • the co-transplant would facilitate acceptance of the implant through immune modulatory actions on Treg cells and encourage re- population with endogenous progenitor SCs (young patients) or allogeneic SCs (older patients).
  • the different types of stem cell could be transported in similar, separate packages to the site of need.
  • MSCs Mesenchymal stem cells
  • MHC Class II or HLA-DR surface antigens are to some extent immune na ' ive due to low or absent levels of MHC Class II or HLA-DR surface antigens. This may allow them to be used in an allogeneic, off-the-shelf basis and to be stored without full tissue typing. They may be useful for formation of a public, allogeneic stem cell bank and for universal donation.
  • the distribution package discussed in this patent application, together with universal donation will greatly reduce transplant costs. Normally tissue matched cells are transported in liquid nitrogen using a dry shipment container, and this requires large, heavy and expensive containers, large volumes of liquefied nitrogen and is expensive and dangerous as evaporation occurs at the low pressures which may be experienced in aircraft.
  • the containers are very expensive (approximately R50,000 for container and R1,000- Rl 0,000 for distribution) and they have to be transported back from the delivery destination, which increases costs further.
  • the small pore size of nano-scaffolds used in the transport package described here would provide a fast and safe distribution option of millions of SCs by air or courier, which could make stem cell therapies available at time and place of need e.g. war zones, emergency and elective surgery, game farm injuries, etc.
  • These "packages” would be used to distribute allogeneic stem cells to the point-of-need by airmail rather than by surface transport in liquid nitrogen. This would enable de-centralised use in rural Africa and other third world countries, and global export to sites of need. Distribution would be cheaper, safer and faster than currently used methods.
  • a neatly fitting round sponge of collagen, alginate, cellulose or other scaffolding material can be added in a sterile processing cabinet and the petri dish can be immediately closed using autoclave tape. The sponge absorbs the medium and the suspended cells immediately.
  • the petri dish can now be inserted into the breathable inner polyethylene bag (l 50mmX180mm), and inserted into a bubble wrap/foil laminated outer bag ( 181 mmX273mm) (see diagram).
  • the inner bag would be made of biaxially orientated polypropylene (35 ⁇ /40 ⁇ BOPP), -which allows gas exchange but very limited water vapour exchange across the membrane.
  • a larger bubble wrap-foil laminate is used as the outer bag and gas exchange takes place between the cells in the inner bag and the air trapped in the large bubbles on the inner side of the much larger outer bag.
  • the outer bag uses larger bubbles which have a slow leakage of the entrapped air.
  • the air trapped in fhe large fhe bubbles of the outer laminate acts as a,
  • the holes in the inner bag which is made from biaxially orientated polypropylene (BOPP), allow gas exchange with the stem cells in the scaffold but as no laser perforations are used, there is no leakage of water vapour.
  • BOPP biaxially orientated polypropylene
  • BOPP polypropylene
  • the sponge or scaffold containing the stem cells could be natural or synthetic.
  • Natural sponges could be protein (collagen, fibrin or silk fibroin) or carbohydrate (agarose, alginate, hyaluronan, cellulose or chitosan), and synthetic sponges could be poly (lactate-co-glycolic acid (PLGA), poly LI poly DL lactic acid (PLLA/PLDLA) or poly-(ethylene glycol) (PEG).
  • PLGA lactate-co-glycolic acid
  • PLLA/PLDLA poly LI poly DL lactic acid
  • PEG poly-(ethylene glycol)
  • collagen sponges are very expensive and the cellulose sponge offers the lowest cost and a scaffold from which stem cells can be recovered without use of enzymes.
  • the alginate sponge is biodegradable and biocompatible. It has been tested in small animals for cytotoxicity, allergic reactivity and sensitization and has received an ISO 10993 accreditation in Taiwan. It is certified as a medical wound dressing and has been in clinical use in a fibrous form for many years. We will use an alginate rather than a cellulose or collagen scaffold. This patent is for the transport bags and not for the alginate scaffolds which are produced by a company in Taiwan.
  • the alginate sponge has an additional advantage.
  • the scaffold itself can be degraded with tri-sodium citrate which complexes the calcium ions which cross-link the alginate polymers and this dissolves the scaffold. This releases the cells into the medium with a very small chance of damaging surface antigens on the cells.
  • the cell suspension can be centrifuged for 4 minutes at 3000g and the stem cells collected, then washed with sterile PBS and concentrated. After checking for bacterial and viral contamination the cells may be filtered through a 700 ⁇ nylon mesh. The recovery of cells from the scaffold is therefore clean, simple and effective.
  • This patent application is for the complete package.
  • the alginate scaffold and the polystyrene petri dish would be received as certified, gamma irradiated (30kGy) sterile product.
  • the sponge would be removed in a sterile HEPA-filtered laminar flow cabinet, inserted into the petri dish and the dish would be placed in a gamma sterilized (25 kGy) BOPP bag and heat sealed.
  • the inner bag would be added to the outer bag which would be sealed and sent to the cell supplier or wholesale client.
  • the cells would be added to the sponge by the client in a laminar HEPA filtered cabinet and the package would be re-assembled. It would be posted it to the end-user or retail client at the point-of-need or point-of-care.
  • the cells transported could be iPS stem cells, genetically modified stem cells or embryonic stem cells. It could also include cells expanded in a commercial incubator or stem cell lines from for example the ATCC.
  • the transport package could be useful in stem cell banking at a distance, when cells are harvested in one country and stored in another.
  • the stem cells could be collected from bone marrow, cord blood, cord tissue, adipose tissue, etc., immediately processed then incorporated into the transport bags for transport to the distant storage site.
  • the transport package would be useful for distribution of clinically useful sponges infiltrated with allogeneic or immune naive stem cells. Possibly the company using the transport bags may wish to incorporate immune nai've, culturally expanded, immune nai ' ve stem cells into dressings for open wounds.
  • the dressings would be a complete package transported in the transport bags and the end user would simply aseptically remove the dressing , place it on the open wound and cover with gauze and a light bandage.
  • Populated scaffolds or small decellularised organs (like valves for urinary bladders) for transplant could be transported in the bags.
  • a company could incorporate their commercially produced stem cells into biodegradable sponges like alginate and use this to distribute their biological product. They could also be used to transport bone marrow stem cells to the site of need.
  • Other stem cell types could be IPS stem cells, genetically modified stem cells or embryonic stem cells.
  • the transport packages would be constructed as follows (Figure 1): A bubble wrap filled with air would be laminated with thick aluminium foil and this laminate would be made into bags of various sizes. The bubble layer would be inside the bag and the aluminium laminate would be outside. This is the outer bag.
  • the nano- scaffold would be placed inside a cell culture polystyrene petri dish to protect the stem cells and scaffold from physical damage. The petri dish would be loosely-sealed with sterilizing tape and placed inside the
  • the polypropylene inner bag and this would be placed inside the outer foil laminated bag.
  • the inner BOPP bag would preserve cell sterility and buffer volume (osmolarity), and the outer bag would preserve oxygen content and temperature of the stem cells in the bag.
  • the cells would be in suspension culture and only small amounts of carbon dioxide would be produced. This would diffuse out of the inner bag and oxygen would flow across the BOPP membrane into the inner bag.
  • the stem cells would be suspended in basic medium without fetal calf serum and the medium would maintain the pH of the stem cells.
  • the outer commercially available jiffy type bag would be sealed and posted or transported to the site of need.
  • the polyethylene bubbles have a nylon barrier inserted into the polyethylene to reduce gas leakage and encourage cushioning and insulation.
  • Nano-scaffolds could be made from various materials but two commercial collagen scaffolds, pangen 2 from Urgolab, UK, which has a CE mark, and pelnac from Gunze Ltd. Co., Tokyo are available. These scaffolds are biocompatible and suitable for adherence of stem cells. They have been used in patients to treat cardiac disease and open wounds respectively. They are biodegradable and have no adverse effect on patients. They are however very expensive. We would use an alginate scaffold from Taiwan.
  • aluminium foils are available as are several bubble wraps and jiffy bags.
  • An aluminium-bubble wrap laminate with aluminium on both sides and the bubbles sandwiched between them is also available from several companies, it is known as a cushion shield bag and is used to transport electronic printed circuit boards to protect them from static and physical damage. The purpose and design is different from the outer bag for which this patent application is made.
  • the inner wrap which would be made from BOPP polypropylene and this allows gas exchange across the membrane. Carbon dioxide crosses at a faster rate than oxygen.
  • the outer bag the size of the bubbles, the pressure of the air in the bubbles, the thickness of the polyethylene, and the configuration of the bubbles on the sheet would all be selected to optimize the rate and amount of air released from the bubbles.
  • the aluminium laminate would be of sufficient thickness to ensure robust use and appropriate temperature buffering. Heat insulation through radiation and reduced absorption of heat would be realized by the reflective outer laminate of the outer bag.
  • the air bubbles on the inside face of the laminate outer bubble bag would assist in temperature control through limiting heat convection.
  • the inner bag containing the nano-scaffold would be placed in the outer bag and sent to the distribution or wholesale client. Before insertion into the inner bag the nano-scaffold and stem cells would be placed into the cassette or petri dish and the inner bag would be sealed or welded closed. After insertion of the nano- scaffold with the entrapped cells, the aluminium bag would be sealed by heat welding or an adhesive strip. On the outside of the inner bag could be a digital strip thermometer connected to a temperature probe inside the inner bag. This strip could contain a micro-chip to continuously monitor temperature during transit. Similar probes could monitor and record pH and oxygen saturation. Each of these would be sealed and deactivated until ready for use and they would record a change in colour at a pre-set threshold change in temperature, pH or oxygen tension.
  • the inner bags and the petri dishes could be of various sizes to accommodate different quantities of stem cells, although a one-size-fits-all would still be a low cost option. In order to minimize air loss from the bubbles the bags would then be at 4 degrees centigrade until sent to clients.
  • the inner bag On arrival at the stem cell production or storage unit, the inner bag would be removed from the outer bag in a laminar flow cabinet in a HEPA-filtered laboratory with a cGMP clean room. The inner bag would be opened and the petri dish and the nano-scaffold removed. The required stem cell suspension would be added. The stem cells would have been trypsinsed and washed several times before final suspension in culture medium. The stem cells number and viability would be known. They would have been checked for the presence of pathogenic organisms. They may also have been analysed by a flow cytometer to enumerate different types of stem cells, like CD34+ haemopoietic stem cells.
  • the cells may also have been tissue typed or immune naive status may have been assessed by measuring the absence of MHC Class II antigens on the cell surface.
  • the cell suspension would be left for 30 minutes to allow the sponge to absorb the stem cells.
  • the lid of the petri dish would be placed onto the base and taped on with sterilizing tape.
  • the populated scaffold would be placed back into the inner bag, now at room temperature and this would be welded closed using a simple bench top tool heat sealing tool (a 350 watt Impulse Sealer).
  • the inner bag would be place in an addressed laminated outer bag with appropriate regulatory labels, and this would be sealed and posted to the treating facility or retail client.
  • stem cells were harvested and processed in real time at the bedside, they may be used for autologous transplant in real time at the harvesting site. If the harvesting site is distant from the banking or storage site such that transport of whole blood with a subsequent delay in processing of longer than 36 hours happens, this is not advised as there can be a significant loss in stem cell viability (up to 25% in 36 hours). If the stem cells were processed at the whole blood collection site or a local cell culture laboratory with a cGTP facility, and absorbed onto a scaffold, they could be sent by airmail at reasonable cost to the banking site without significant loss of cell viability. This would allow a single company to have collection and distribution sites in different countries. The stem cells would be processed before being transported.
  • stem cells When the stem cells arrive in the transit bag at the site of need or treating facility, they would be removed from the transport scaffold in a stem cell station in a catheterization laboratory, usually adjacent to the operating theatre, which will be completely sterile with a HEPA filtered air cabinet. That is a small sterile stem cell workstation would be present which would meet cGTP requirements.
  • the isolated stem cells could be used directly as a wound dressing, or they could be recovered from the scaffold and , now in suspension, could be directly injected into tissues either in PBS or in a nascent fibrin gel.
  • the stem cells could be expanded through in vitro culture before injection into patients, and for example be selected for adherent cells, generally taken to be mesenchymal or CFTJ-F stem cells.
  • CD antigens may be determined and more specific stem cells populations may be isolated. They could be used for in vitro drug discovery or toxicity testing, If this is done final viability and stem cell numbers have to be determined again before use.
  • the stem cell platform required for this would meet international cGMP standards.
  • the scaffolds, stem cell cassette or petri dish, outer bag, other reagents and transport buffer and media are all commercially available in many countries.
  • a double wrapping, like use of an inner and outer bag, is required to comply with International Air Transport Association (IATA) and International Civil Aviation Organisation (ICAO) requirements for transport of medical or biological specimens.
  • IATA International Air Transport Association
  • IAO International Civil Aviation Organisation
  • a CE Mark can be obtained for the assembled device and that it will obtain 51 OK endorsement from the FDA and eventually ISO 9001/17025 and ISO 10993 accreditation of the production or assembly facility.
  • the monitoring of temperature, pH and oxygen levels during transit and digital recording of these real-time results with later print-out will enable compliance with ISO cell and tissue handling requirements and allow continuous QC and QA monitoring and audit of the transit process.

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  • Health & Medical Sciences (AREA)
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  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
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  • Wood Science & Technology (AREA)
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PCT/ZA2013/000019 2012-04-17 2013-03-15 Emballage pour la distribution de cellules vivantes WO2013166525A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ZA201202779 2012-04-17
ZA2012/02779 2012-04-17

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WO2013166525A2 true WO2013166525A2 (fr) 2013-11-07

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3153572A4 (fr) * 2014-06-09 2018-01-17 Seiichi Yokoo Récipient fermé de culture pour cellules dépendantes d'un support
CN110184174A (zh) * 2019-07-12 2019-08-30 贵州省人民医院 一种多用途细胞及微粒筛选针结构
US20220330542A1 (en) * 2017-01-27 2022-10-20 Stratatech Corporation Tissue container systems

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3153572A4 (fr) * 2014-06-09 2018-01-17 Seiichi Yokoo Récipient fermé de culture pour cellules dépendantes d'un support
US11078455B2 (en) * 2014-06-09 2021-08-03 Seiichi YOKOO Closed culture vessel for adherent cells
US20220330542A1 (en) * 2017-01-27 2022-10-20 Stratatech Corporation Tissue container systems
CN110184174A (zh) * 2019-07-12 2019-08-30 贵州省人民医院 一种多用途细胞及微粒筛选针结构

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