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WO2018031654A1 - Dispositifs et procédés de récolte des segments de microvaisseau dérivés de graisse - Google Patents

Dispositifs et procédés de récolte des segments de microvaisseau dérivés de graisse Download PDF

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Publication number
WO2018031654A1
WO2018031654A1 PCT/US2017/046094 US2017046094W WO2018031654A1 WO 2018031654 A1 WO2018031654 A1 WO 2018031654A1 US 2017046094 W US2017046094 W US 2017046094W WO 2018031654 A1 WO2018031654 A1 WO 2018031654A1
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WIPO (PCT)
Prior art keywords
vessel
tissue
fdmss
centrifuge
mincing
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Ceased
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PCT/US2017/046094
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English (en)
Inventor
Christopher Rathbone
Brian Barnes
Samantha REILLY
Patrick Patterson
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Arteriocyte Inc
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Arteriocyte Inc
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Publication of WO2018031654A1 publication Critical patent/WO2018031654A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • C12M47/00—Means for after-treatment of the produced biomass or of the fermentation or metabolic products, e.g. storage of biomass
    • C12M47/04—Cell isolation or sorting
    • 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
    • C12M45/02—Means for pre-treatment of biological substances by mechanical forces; Stirring; Trituration; Comminuting
    • 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
    • C12M45/05—Means for pre-treatment of biological substances by centrifugation
    • 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
    • C12M45/09—Means for pre-treatment of biological substances by enzymatic treatment

Definitions

  • the present disclosure relates to devices and methods for harvesting microvascular fragments (MVFs) or fat derived microvessel segments (FDMSs) that may be used to improve tissue perfusion.
  • MVFs microvascular fragments
  • FDMSs fat derived microvessel segments
  • harvested FDMSs can be used to improve tissue perfusion in areas where compromised blood flow leads to impaired healing.
  • One application of FDMSs could be for the treatment of foot ulcers, such as diabetic foot ulcers (DFUs).
  • DFUs diabetic foot ulcers
  • FDMSs are obtained by mincing, digesting, washing, and filtering tissue.
  • T2D type 2 diabetes
  • T1 D type 1 diabetes
  • T1 D type 1 diabetes
  • T1 D is normally detected in childhood, lasts a lifetime, and must be tightly controlled by insulin administration.
  • T1 D is less prevalent, affecting approximately 3 million Americans, more than 79,000 children were diagnosed worldwide in 2013, and the incidence of T1 D has risen by a startling 23% between 2001 and 2009 for persons under the age of 20.
  • the array of complications associated with diabetes which includes premature cardiovascular mortality, neuropathy, nephropathy, retinopathy and impaired wound healing, requires significant attention in order to improve the impaired qualities of life and shortened lifespans of patients with diabetes, consequentially reducing the enormous societal economic burden.
  • DFUs diabetic foot ulcers
  • Persons with diabetes have a 15% to 25% chance of developing a DFU during their lifetime, and a 50% to 70% recurrence rate over the ensuing 5 years.
  • a significant amount of healthcare resources is spent on the management of DFUs, including emergency room visits, antibacterial medications, amputations, and a multitude of other therapies directed at chronic, non-healing wounds.
  • Various estimates indicate that the cost of DFU treatment consumes 25 to 50% of the total cost of all diabetes treatment.
  • Microvascular fragments (MVFs) orfat derived microvessel segments (FDMSs) are a heterogenous mixture of arterioles, capillaries, and venules isolated from adipose tissue that have been shown to support tissue perfusion in a number of regenerative medicine/tissue engineering applications. Since FDMSs are delivered as intact microvessels, they circumvent the need for angiogenic ingrowth from the host tissue. Several studies have demonstrated the benefits of FDMSs for improving tissue perfusion. FDMSs bypass some of the challenges of delayed/impaired vascular ingrowth because they already consist of intact microvessels that do not require de novo development to be effective.
  • FDMSs have since been recognized and explored, having been used as a means to support tissue perfusion for cardiac and skin tissues and aiding islet implant survival. More recently, it has been demonstrated that FDMSs can be effectively used to improve tissue perfusion in large volumetric muscle loss defects.
  • Others have attempted to create vascular networks that can be implanted for immediate vascularization. However, in keeping with the theme of simplicity, it is important to point out that these other prevascularization strategies rely on the in vitro creation of microvessels that use several types of cells derived from a variety of sources for vascular development (e.g., fibroblasts, mesenchymal stem cells, human umbilical cord vascular endothelial cells) prior to their implantation in vivo.
  • sources for vascular development e.g., fibroblasts, mesenchymal stem cells, human umbilical cord vascular endothelial cells
  • HUVECs human umbilical cord vascular endothelial cells
  • human foreskin fibroblast cells human foreskin fibroblast cells
  • immortalized C2 skeletal muscle cells were used to create a preformed vasculature for implantation into an abdominal muscle defect.
  • HUVECs were co-cultured with mesenchymal stem cells (MSCs) prior to implantation into a subcutaneous defect.
  • MSCs mesenchymal stem cells
  • FDMSs fat derived microvessel segments
  • FDMSs are a source of stem cells
  • the large number of trophic factors secreted by the vessels and associated stem cells are another benefit of using FDMSs.
  • FDMSs in addition to other cells that comprise microvessels (e.g., endothelial cells), may act as sources of bioactive factors that provide a regenerative stimulus in the surrounding tissue.
  • FDMSs are not completely broken down, therefore, there is no need for de novo vessel growth and reorganization, potentially translating into greatly accelerated and improved healing.
  • FDMSs may be an effective means to improve tissue perfusion to facilitate rapid healing for tissue wounds like DFUs, thereby enabling patients to resume normal daily activities and reduce the risk of amputation.
  • the fact that freshly isolated autologous FDMSs can be utilized supports the idea that they can be rapidly translated to the clinic, thereby affecting a large number of patients suffering from DFUs.
  • FDMSs to date the clinical potential has not been realized.
  • the present disclosure relates to devices, systems, and apparatuses for the simple production of fat derived microvessel segments (FDMSs) from appropriate tissue.
  • FDMSs fat derived microvessel segments
  • a rapid, point-of-care device capable of isolating FDMSs would provide clinicians with a means to improve perfusion within DFUs.
  • the successful development of an automated device capable of isolating FDMSs also has the potential to drastically shift the current paradigms regarding the approach used to treat chronic wounds.
  • the introduction of this new methodology to the wound healing market is a major shift from the current approaches to treat wounds.
  • the apparatuses include systems for performing three different functions, and also include a centrifuge for separation of tissues from each other. Sample tissue is loaded into the apparatus and processed through it to obtain FDMSs.
  • the apparatus includes components for mincing of tissue, digestion of tissue, centrifugation and washing, and filtration / separation of FDMSs from the other tissue. One or more of these functions can be performed in a common vessel, as further discussed herein.
  • apparatuses for obtaining fat derived microvessel segments comprising: a first component comprising a paddle blender in a first vessel; a second component fluidly connected to the first component and comprising a second vessel; a centrifuge fluidly connected to the second component; and a third component fluidly connected to the centrifuge and comprising an upper-size filter and a lower-size filter placed within a third vessel.
  • FDMSs fat derived microvessel segments
  • the first vessel may have at least one opening for loading sample tissue.
  • a bag containing the sample tissue can be loaded into the first vessel.
  • the second vessel may also include an enzymatic inlet for introducing enzymes.
  • the centrifuge may have a wash/rinse outlet through which fluid can exit.
  • the third vessel may have an outlet through which FDMSs are collected.
  • FDMSs fat derived microvessel segments
  • the mincing vessel receives sample tissue and minces the sample tissue.
  • the digestion vessel receives enzymes and the sample tissue to make digested tissue.
  • the washing centrifuge washes the sample tissue.
  • the sample tissue passes through filters in the filtration vessel to separate the washed tissue into tissue of improper size, and tissue of a desired size (i.e. the microvascular fragments).
  • the mincing vessel may comprise a paddle blender, an opening for loading sample tissue, and an outlet through which minced tissue exits the mincing vessel.
  • the filtration vessel may comprise an inlet, an upper size filter and a lower size filter through which tissue is passed, a waste outlet for removal of tissue of improper size, and an FDMS outlet for collecting FDMSs of a desired size.
  • the digestion vessel may comprise an inlet for receiving tissue, an enzymatic inlet, and an outlet.
  • the washing centrifuge may comprise an inlet for receiving tissue, a wash/rinse inlet for introducing fluid into the washing centrifuge, a wash/rinse outlet through which the fluid can exit the washing centrifuge, and an outlet.
  • the mincing vessel and the digestion vessel are a common vessel in which the mincing and digesting occur.
  • the sample tissue can subsequently pass from the common vessel to the centrifuge, and subsequently to the filtration vessel.
  • the mincing vessel and the filtration vessel are a common vessel in which the mincing and filtering occur.
  • the sample tissue then passes from the common vessel to the digestion vessel, and subsequently to the centrifuge.
  • the mincing vessel, the digestion vessel, and the filtration vessel are a common vessel.
  • the sample tissue subsequently passes from the common vessel to the centrifuge.
  • FDMSs fat derived microvessel segments
  • the sample tissue may be loaded into a sterile bag which is loaded into the apparatus.
  • the apparatus may include a paddle blender, a digestion tank, a centrifuge, and a filtration tank for processing the sample tissue.
  • the paddle blender compresses and minces sample tissue to create tissue fragments. Enzymes are used to digest the tissue fragments. About 1 mg to about 5 mg of enzymes can be used per ml_ of sample tissue. The enzymes may digest the tissue fragments for a period of from about 5 minutes to about 15 minutes.
  • the digested tissue fragments may be centrifuged at a force of about 100 g's to about 600 g's.
  • the digested tissue fragments may be centrifuged for a period of from about 1 minute to about 10 minutes.
  • the digested tissue fragments may be filtered through a first filter and a second filter to obtain fragments of a desired size.
  • the first filter may be an upper size filter that, for example, has a size of 400 micrometers.
  • the second filter may be a lower size filter that, for example, has a size of 40 micrometers.
  • FIG. 1 is a schematic diagram of a first exemplary embodiment of the present disclosure.
  • Sample tissue is loaded into a mincing tank and processed/passed through a digestion tank, a washing centrifuge, and a filtration tank, from which FDMSs are extracted.
  • FIG. 2 is a schematic diagram of a second exemplary embodiment of the present disclosure. Mincing and digestion first occur in a common vessel, followed by centrifugation and filtration.
  • FIG. 3 is a schematic diagram of a third exemplary embodiment of the present disclosure. Mincing and filtration take place first in a common vessel, followed by digestion in a second component and subsequent centrifugation.
  • FIG. 4 is a schematic diagram of a fourth exemplary embodiment, in which mincing, digestion and filtration occur in a common vessel followed by centrifugation.
  • the term “comprising” may include the embodiments “consisting of” and “consisting essentially of.”
  • the terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients/steps and permit the presence of other ingredients/steps.
  • compositions or processes as “consisting of” and “consisting essentially of” the enumerated ingredients/steps, which allows the presence of only the named ingredients/steps, along with any impurities that might result therefrom, and excludes other ingredients/steps.
  • FDMS fat derived microvessel segments. This term is generally used herein to refer to segments obtained from sample tissue containing vascular parts such as blood vessels.
  • the present disclosure relates to devices and apparatuses that take as input large biological tissue samples and output minimally manipulated FDMSs that can be used for clinical treatment of conditions such as diabetic foot ulcers (DFUs).
  • the apparatuses perform four different functions, which are (a) tissue mincing; (b) tissue digestion; (c) centrifugation and washing of the digested tissue; and (d) filtration to separate FDMSs from the other tissue fragments.
  • a first exemplary embodiment is shown in the schematic diagram of FIG. 1.
  • tissue may include adipose tissue or lipoaspirate. This tissue is generally relatively large compared to the desired size for the FDMSs.
  • Sample tissue is loaded into a first component 110.
  • the first component may include a paddle blender within a first vessel.
  • the blender minces the sample tissue into smaller pieces.
  • the minced tissue is then passed to the second component 120, which may include a second vessel. Enzymes are added to the second vessel to digest the minced tissue.
  • the enzymes may be added through an enzymatic inlet that is separate from the inlet through which the minced tissue enters the second component.
  • the digested tissue then passes from the second component to the centrifuge 130 where it is rinsed and washed.
  • the washed and digested tissue then passes to the third component 140, where filtering of the tissue occurs to obtain the desired FDMSs of the desired size.
  • the third component may include a third vessel that uses an upper-size filter and a lower-size filter to obtain the desired FDMSs.
  • the first component may include a paddle blender within a first vessel, an opening, for accessing the first vessel, and an outlet for the minced tissue to exit.
  • This component may also be referred to as a mincing vessel.
  • the tissue sample to be processed can be added loose, or in a bag, through the opening.
  • the bag can be clamped into position.
  • Paddle blenders use paddles to crush and knead, compressing the tissue sample and alternately press on the outer surface of the bag, thereby kneading the bag's contents to achieve a grinding action that minces the tissue sample into minced tissue.
  • the minced tissue fragments then travel out of the first vessel through the first component outlet, which is fluidly connected to an inlet of the second component.
  • the second component is generally contemplated to include a second component inlet, a second vessel, and a second component outlet.
  • the second component may also have an enzymatic inlet which is separate from the second component inlet.
  • Minced tissue fragments enter the second vessel through the second component inlet.
  • Enzymes are then added to the minced tissue fragments to digest the tissue.
  • Such enzymes may include collagenase, trypsin, elastase, and protease type XIV. It is contemplated the amount of enzyme used may range from about 0.01 mg to about 5 mg of enzyme per milliliter (ml_) of sample tissue.
  • the tissue is digested for a period of about 1 minute to about 15 minutes. This allows the microvessel architecture of the tissue to remain intact. Following digestion, the tissue fragments may pass through the second component outlet and into the washing centrifuge, these two components being fluidly connected to each other. This component may also be referred to as a digestion tank.
  • the centrifuge may include a centrifuge inlet and a centrifuge outlet.
  • the centrifuge may further comprise a wash/rinse inlet and a wash/rinse outlet, through which the water or another aqueous rinse solution may be added to the centrifuge separately from the minced / digested tissue fragments.
  • the digested tissue is mixed with a wash/rinse solution, then centrifuged, and the supernatant removed.
  • the centrifuge may be operated at a speed sufficient to create a force of about 100 gravities (g's) to about 600 g's, including a speed of about 300 g's to about 600 g's. Each round of centrifugation may occur for a period of about 1 minute to about 10 minutes, including from about 1 minute to about 5 minutes. This wash/rinse cycle can be repeated as many times as needed. Following centrifugation, the washed tissue fragments may pass through the centrifuge outlet into the third component. After centrifugation, the tissue fragments may be in the form of a pellet. [0052] The third component may also be referred to as a filtration tank.
  • the third component may include a third component inlet, an upper size filter and a lower size filter within a third vessel, and a third component outlet.
  • the third component may further include a suspension liquid inlet, through which liquid (for example phosphate buffered saline) may be added to re-suspend the tissue fragments if desired.
  • the washed tissue fragments then may enter the third component through the third component inlet.
  • the tissue fragments are filtered through an upper-size filter and a lower-size filter to separate the tissue fragments into undesired tissue (i.e. of improper size) and the desired fat derived microvessel segments (FDMSs).
  • FDMSs fat derived microvessel segments
  • the upper-size filter is between 200 micrometers (pm) and 600 micrometers. In specific embodiments, the upper-size filter is 400 micrometers. In particular embodiments, the lower-size filter is between 20 micrometers and 80 micrometers. In specific embodiments, the lower-size filter is 40 micrometers.
  • the FDMSs may be obtained from the third vessel through the third component outlet. It is particularly contemplated that the FDMSs can be removed from the third vessel by a syringe.
  • the desired physical form of the FDMSs can depend on the application. For example, if it is intended that the FDMSs be injected, they can be suspended in a liquid. If the FDMSs are to be applied topically, they may be in a gel formulation. The FDMSs can be combined with other ingredients to form the liquid or gel, either in the third vessel or after being removed therefrom, as desired.
  • FIG. 2 is an example of one such embodiment, in which mincing and digestion happen in a common vessel 210, followed by centrifugation 220 and filtration 230.
  • FIG. 3 is an example of another embodiment, in which mincing and filtration take place in a common vessel 310, followed by digestion 320 and centrifugation 330.
  • FIG. 4 is an example of a third embodiment, in which mincing, digestion and filtration occur in a common vessel 410, followed by centrifugation 420.
  • the order of the process steps can be varied. Generally, smaller tissue fragments must first be made, so the mincing occurs first. Digestion or filtration can occur next, depending on the extent of the mincing. The centrifugation / washing then occurs. Filtration can also occur last. As a result, FDMSs are obtained. Desirably, the apparatus will be of a size sufficiently small / portable for clinical use.
  • FDMSs generally contain arterioles; capillaries; venules; endothelial cells; stem cells; smooth muscle cells; and pericytes.
  • arterioles and venules should make up the majority of the FDMS extract, potentially as high as 90% or more of the extract, with capillaries being the next most common ingredient.
  • the washing and digestion procedure has reduced the amount of adipocytes, collagenase, red blood cells, white blood cells, and other stem progenitors to a minimal amount in the FDMSs.
  • FDMS functionality is defined by the ability to undergo spontaneous angiogenesis. This can be tested in vitro by suspending the FDMSs in a collagen hydrogel and evaluating their ability to form sprouts.

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  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
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Abstract

La présente invention concerne un appareil permettant d'obtenir des fragments microvasculaires (FMV) ou des segments de microvaisseaux dérivés de graisse (SMVG). Les échantillons de tissus sont chargés dans un appareil à liaison fluidique, dans lequel ils sont hachés à l'aide d'un mélangeur à palettes, digérés par des enzymes, lavés et filtrés, ce qui permet d'obtenir des SMVG avec une manipulation minimale. L'invention concerne également des procédés de traitement d'échantillons de tissu pour obtenir des SMVG.
PCT/US2017/046094 2016-08-09 2017-08-09 Dispositifs et procédés de récolte des segments de microvaisseau dérivés de graisse Ceased WO2018031654A1 (fr)

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US62/372,409 2016-08-09

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020210415A1 (fr) * 2019-04-10 2020-10-15 Advanced Solutions Life Sciences, Llc Systèmes et méthodes pour isoler des microvaisseaux à partir de tissu adipeux
RU2793525C1 (ru) * 2022-09-12 2023-04-04 Федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр глазных болезней имени Гельмгольца" Министерства здравоохранения Российской Федерации (ФГБУ "НМИЦ ГБ им. Гельмгольца" Минздрава России) Способ хирургического лечения дефектов роговицы при лимбально-клеточной недостаточности

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WO2005012480A2 (fr) * 2003-06-25 2005-02-10 Macropore Biosurgery Inc. Systemes et techniques de separation et de concentration de cellules regeneratives prelevees sur des tissus
WO2013030761A1 (fr) * 2011-08-29 2013-03-07 Stempeutics Research Private Limited Système pour isoler des cellules de fraction stroma-vasculaire (svf) de tissu adipeux et son procédé

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Title
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M PILIA ET AL: "Transplantation and perfusion of microvascular fragments in a rodent model of volumetric muscle loss injury", EUROPEAN CELLS AND MATERIALS, vol. 28, 14 July 2014 (2014-07-14), pages 11 - 24, XP055420505, DOI: 10.22203/eCM.v028a02 *
RHOADS R P ET AL: "Satellite cells isolated from aged or dystrophic muscle exhibit a reduced capacity to promote angiogenesisin vitro", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 440, no. 3, 23 September 2013 (2013-09-23), pages 399 - 404, XP028759435, ISSN: 0006-291X, DOI: 10.1016/J.BBRC.2013.09.085 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020210415A1 (fr) * 2019-04-10 2020-10-15 Advanced Solutions Life Sciences, Llc Systèmes et méthodes pour isoler des microvaisseaux à partir de tissu adipeux
RU2793525C1 (ru) * 2022-09-12 2023-04-04 Федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр глазных болезней имени Гельмгольца" Министерства здравоохранения Российской Федерации (ФГБУ "НМИЦ ГБ им. Гельмгольца" Минздрава России) Способ хирургического лечения дефектов роговицы при лимбально-клеточной недостаточности

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