(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(10) International Publication Number
`
`WO 2018/132515 A1
`
`h a
`
`WIPOI PCT
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`
`19 July 2018 (19.07.2018)
`
`(51)
`
`International Patent Classification:
`
`A613 5/15 (2006.01)
`
`(21)
`
`International Application Number:
`
`PCT/US2018/013223
`
`(22)
`
`International Filing Date:
`
`10 January 2018 (10.01.2018)
`
`(25)
`
`(26)
`
`(30)
`
`(71)
`
`(72)
`
`Filing Language:
`
`Publication Language:
`
`English
`
`English
`
`Priority Data:
`62/444,764
`62/468,906
`
`10 January 2017 (10.01.2017)
`08 March 2017 (08.03.2017)
`
`US
`US
`
`Applicant: DRAWBRIDGE HEALTH, INC. [US/US];
`2882 Sand Hill Road, Suite 240, Menlo Park, California
`94025 (US).
`
`Inventors: BEYERLEIN, Dagmar; 74 Mountain Spring
`Avenue, San Francisco, California 941 14 (US). DREXEL,
`
`(74)
`
`(81)
`
`Masao; 149 Kittoe Drive, Unit B, Mountain View, Califor—
`nia 94043 (US). JORDAN, Brett L.; 1325 Indiana Street,
`#107, San Francisco, California 94107 (US). JACKSON,
`Alicia; 2882 Sand Hill Road, Suite 240, Menlo Park, Cali—
`fornia 94025 (US). JUNEAU, Kara; 214 Durand Way, Pa-
`10 Alto, California 90304 (US).
`
`Agent: AU, Hin; WILSON SONSINI GOODRICH &
`ROSATI, 650 Page Mill Road, Palo Alto, California 94304
`(US).
`
`Designated States (unless otherwise indicated, for every
`kind ufnational protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN,
`HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP,
`KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME,
`MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ,
`OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA,
`
`(54) Title: DEVICES, SYSTEMS, AND METI IODS FOR SAMPLE COLLECTION
`
`100
`
`\
`
`’152
`
`170
`
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`166. 167
`
` 192
`
`102
`
`114,115 FlG. 1A
`
`110
`
`(57) Abstract: Disclosed herein are devices, apparatus, systems, methods and kits for collecting and storing a fluid sample from a
`subject. A device for collecting the fluid sample can include a housing comprising a recess having an opening, a vacuum chamber in
`the housing and in fluidic communication with the recess, and one or more piercing elements that are extendable through the opening
`to penetrate skin of the subject. The vacuum chamber can be configured for having a vacuum that draws the skin into the recess. The
`recess can be configured having a size or shape that enables an increased volume of the fluid sample to be accumulated in the skin
`drawn into the recess.
`
`[Continued on nextpage]
`
`
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`WO 2018/132515 A1 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
`
`SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN,
`TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ,
`UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,
`MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM,
`TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
`KM, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`— with international search report (Art. 21 (3))
`— before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments (Rule 48.2(h))
`
`

`

`WO 2018/132515
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`PCT/U82018/013223
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`DEVICES, SYSTEMS, AND NIETHODS FOR SAMPLE COLLECTION
`
`CROSS-REFERENCE TO RELATED APPLICATIONS
`
`[0001]
`
`This application claims the benefit of US. provisional patent application number
`
`62/444,764, filed January 10, 2017, and US. provisional patent application number 62/468,906,
`
`filed March 08, 2017, both of which are herein incorporated by reference in their entirety.
`
`BACKGROUND
`
`[0002]
`
`Body fluid collection, for example collection of blood samples for performing
`
`diagnostic tests, can be used to assess and inform the health of individuals. Early detection and
`
`reliable diagnosis can play a central role in making effective therapeutic decisions for treatment
`
`of diseases or managing certain physiological conditions. Detection can involve identification of
`
`disease-specific biomarkers in human body fluids that can indicate irregularities in cellular
`
`regulatory functions, pathological responses, or intervention to therapeutic drugs.
`
`[0003]
`
`Many individuals, however, may not relish the process of having blood drawn from
`
`their bodies, possibly due to association with pain, cuts, bleeding, sharp objects, sight of blood,
`
`fear of infections, etc. Typically, venous blood collection of a subject is performed at external
`
`facilities such as hospitals, skilled nursing facilities, and outpatient environments such as
`
`primary care physician (PCP) & specialty hospital clinics, surgery centers, occupational health
`
`clinics, or physician offices. The blood collection process can be tedious and time consuming
`
`for individuals who have to visit those facilities for blood draw, and for healthcare personnel
`
`who can have to attend to multiple patient encounters within a single day.
`
`[0004]
`
`Thus, a need exists for improved devices and methods that enable blood collection to
`
`be performed easily and conveniently by users, and that can decrease users’ reliance on
`
`traditional healthcare facilities for blood draw.
`
`SUMMARY
`
`[0005]
`
`The present disclosure addresses at least the above needs. Various embodiments of
`
`the present disclosure address the demand for devices and methods, that enable individuals to
`
`easily, conveniently, and reliably collect and store blood samples outside of traditional
`
`healthcare facilities, for example in their own homes, in remote locations, while traveling, etc.
`
`Individuals who have minimal to no medical training can use the disclosed devices and methods
`
`to efficiently collect and store blood on their own or with the help of others, without the need for
`
`trained healthcare personnel. The embodiments described herein can obviate the need for
`
`individuals to schedule, or make special or frequent trips to healthcare facilities for blood sample
`
`collection, which helps to free up the individuals’ time and reduce patient load on healthcare
`
`resources. Nonetheless, it should be appreciated that the disclosed devices and methods are also
`
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`WO 2018/132515
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`suitable for use by healthcare or non-healthcare personnel in a variety of environments or
`
`applications, for example in personalized point-of—care (POC), Emergency Medical Services
`
`(EMS), ambulatory care, hospitals, clinics, emergency rooms, patient examination rooms, acute
`
`care patient rooms, field environments, nurse’s offices in educational settings, occupational
`
`health clinics, surgery or operation rooms, etc.
`
`[0006]
`
`Blood samples collected using the devices and methods described herein can be
`
`analyzed to determine a person’s physiological state, for detecting diseases and also for
`
`monitoring the health conditions of the user.
`
`In some instances, individuals can rapidly evaluate
`
`their physiological status since blood samples can be quickly collected using the devices and
`
`methods described herein, and either (1) analyzed on the spot using for example immunoassays
`
`or (2) shipped promptly to a testing facility. The reduced lead-time for blood collection, analysis
`
`and quantification can be beneficial to many users, especially users who have certain
`
`physiological conditions/diseases that require constant and frequent blood sample
`
`collection/monitoring. Taking diabetes as an example, hemoglobin Alc (HbAlc) can make up
`
`60% of all glycohemoglobins and can be used for monitoring glycemic control. The amount of
`
`HbAlc, as a percentage of total hemoglobin, can reflect the average blood glucose concentration
`
`in a patient’s blood over the preceding 120 days. Generally it is recommended that diabetic
`
`patients test their HbAlc levels every three to six months. The glycemic recommendation for
`
`non-pregnant adults with diabetes can be <7.0%, while HbAlc levels of 28% can indicate that
`
`medical action can be required to control diabetic complications, including cognitive impairment
`
`and hypoglycemic vulnerability.
`
`[0007]
`
`The various embodiments described herein are capable of drawing blood at increased
`
`flowrates and higher sample volumes beginning from time of skin incision, compared to
`
`traditional non-venous blood collection devices and method. The disclosed devices and methods
`
`can be used to collect blood samples of predefined volumes, for example through the use of
`
`custom matrices for sample collection, and absorbent pads for holding and metering out excess
`
`blood. Additionally, the blood collection devices and methods described herein are minimally
`
`invasive and permit lower levels of pain (or perception of pain) in a subject, which can help to
`
`improve the overall blood collection experience for the subject.
`
`[0008]
`
`In some aspects, a handheld user-activable device or method disclosed herein can be
`
`configured or capable of collecting at least 150 uL of blood from a subject in less than 3 minutes
`
`beginning from time of incision or penetration of a skin portion of the subject.
`
`[0009]
`
`In some aspects, a device for collecting fluid sample from a subject is provided. The
`
`device can comprise a recess and a pre-evacuated vacuum chamber located within the device.
`
`The recess can be configured to maintain contact with at least 5.0 cm2 ofa skin surface area of
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`the subject under vacuum pressure, prior to and as the fluid sample is being collected from the
`
`skin of the subject.
`
`[0010]
`
`In some aspects, a device for collecting fluid sample from a subject can comprise: a
`
`housing comprising a recess having an opening; a vacuum chamber in the housing in fluidic
`
`communication with the recess; and one or more piercing elements that are extendable through
`
`the opening to penetrate skin of the subject. The vacuum chamber can be configured for having
`
`a vacuum that draws the skin into the recess, and the recess can be configured having a size or
`
`shape that enables an increased volume of the fluid sample to be accumulated in the skin drawn
`
`into the recess.
`
`[0011]
`
`In some aspects, a method for collecting a fluid sample from a subject can comprise:
`
`providing a device having a housing, said housing configured to support a vacuum chamber and
`
`a piercing module, the housing comprising a recess having an opening, placing the recess of the
`
`housing adjacent to skin of the subj ect; activating the vacuum in the vacuum chamber to draw
`
`the skin into the recess; accumulating an increased volume of the fluid sample in the skin drawn
`
`into the recess, wherein the recess is configured having a size or shape that enables the increased
`
`volume of the fluid sample to be accumulated; extending one or more piercing elements through
`
`the opening to penetrate the skin, and maintaining the device adjacent to the skin for a sufficient
`
`amount of time to draw the fluid sample into the device,
`
`[0012]
`
`In some embodiments, the fluid sample can comprise blood from the subject. The
`
`recess can serve as a suction cavity for drawing the skin and increasing capillary pressure
`
`differential. The increased volume of the fluid sample can depend on a volume and/or surface
`
`area of the skin that is drawn into the recess.
`
`In some cases, the volume of the skin enclosed by
`
`the recess can range from about 0.4 cm3 to about 4.0 cm3. The surface area of the skin in contact
`
`with the recess can range from about 3 .2 cm2 to about 7.2 cm2. The increased volume of the
`
`fluid sample can depend on a pressure of the vacuum in the vacuum chamber. The pressure of
`
`the vacuum in the vacuum chamber can range from about -4psi g to about -l 5psi g. The increased
`
`volume of the fluid sample in the skin drawn into the recess can be at least about 50 [LL prior to
`
`the penetration of the skin.
`
`In some cases, the increased volume of the fluid sample in the skin
`
`drawn into the recess, an increased capillary pressure, and with aid of the vacuum, can permit the
`
`fluid sample to be drawn from the skin and collected at an average flowrate of at least 30uL/min.
`
`In some cases, the fluid sample can be collected at an average flowrate of at least 100 uL/min.
`
`In
`
`some cases, the fluid sample can be collected at an average flowrate of at least ISOuL/min.
`
`In
`
`some cases, the average flowrate can be sustained at least until about 150-3 OOuL of the fluid
`
`sample has been collected. The size and/or shape of the recess can be configured to permit the
`
`skin to substantially conform to the recess. A gap between the skin and the recess can be
`
`-3-
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`WO 2018/132515
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`negligible when the skin is drawn into the recess. A surface of the recess can be substantially in
`
`contact with the skin drawn into the recess.
`
`In some cases, a size of the recess can be at least two
`
`times a size of the opening within the recess.
`
`In some cases, the size of the opening within the
`
`recess can range from about 1.5mm to about 6mm, and the size of the recess at its outermost
`
`periphery can range from about 10mm to about 60mm. A surface area of the recess can be
`
`substantially greater than an area of the opening.
`
`In some cases, the surface area of the recess
`
`can be at least ten times the area of the opening. In some cases, the surface area of the recess can
`
`range from about 75mm2 to about 2900mm2, and the area of the opening can range from about
`
`1.5mm2 to about 3Omm2. In some cases, an area of the skin directly under the opening can be at
`
`least 1.5 times smaller than a total area of the skin drawn into the recess. In some cases, the area
`
`of the skin directly under the opening can be at least 5 times smaller than the total area of the
`
`skin drawn into the recess.
`
`[0013]
`
`In some embodiments, the recess can comprise a concave cavity.
`
`In some cases, the
`
`concave cavity can have a volume ranging from about 1.0 cm3 to about 5.0 cm3. The recess can
`
`be in the shape of a spherical cap.
`
`In some cases, a base diameter of the spherical cap can range
`
`from about 10mm to about 60mm, and a height of the spherical cap can range from about 3mm
`
`to about 30 mm. The spherical cap can be a hemisphere. The opening can be at an apex of the
`
`spherical-capped recess.
`
`In some embodiments, the recess can comprise one or more fillets
`
`configured to improve vacuum suction to the skin and reduce vacuum leak. The one or more
`
`fillets can extend continuously along a periphery of the recess. The one or more fillets of the
`
`recess can be configured to be in contact with the skin when the skin is drawn into the recess.
`
`[0014]
`
`In some embodiments, a vacuum pressure of at least about —1 psig can be provided in
`
`order to draw the skin into and completely fill the recess.
`
`In some cases, the skin can be drawn
`
`into the recess by the vacuum and can completely fill the recess in less than 1 second.
`
`In some
`
`cases, the skin can be drawn into the recess by the vacuum and can completely fill the recess in
`
`no more than 5 seconds.
`
`[0015]
`
`In some embodiments, (l) the size or shape of the recess or (2) a pressure of the
`
`vacuum can be configured to achieve a minimum capillary pressure in the skin drawn into the
`
`recess.
`
`In some cases, (1) the size or shape of the recess or (2) a pressure of the vacuum can be
`
`configured to achieve a minimum tension in the skin drawn into the recess. The device can be
`
`supported and held in place on the skin of the subject with the aid of an adhesive. The device
`
`can be supported and held in place on the skin of the subject with the aid of the vacuum. The
`
`device can be supported and held in place on the skin of the subject primarily with the aid of the
`
`vacuum. The device can be configured for use on an upper portion of the subj ect’s arm. The
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`PCT/U82018/013223
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`device can be configured to remain in its position on the subj ect’s arm independent of any
`
`movement or changes in orientation of the subj ect’s arm.
`
`[0016]
`
`In some embodiments, the device can be capable of collecting 250uL of fluid sample
`
`from the subject in less than 1 minute 45 seconds.
`
`In some cases, the device can be capable of
`
`collecting at least l75uL to 300uL of fluid sample from the subject in less than 3 minutes.
`
`In
`
`some cases, the device can be capable of collecting at least ZOOuL of fluid sample from the
`
`subject in less than 5 minutes. The device can be configured to collect the fluid sample at a rate
`
`that is dependent on the size or shape of the recess and/or vacuum pressure. The recess can be
`
`configured having a size and shape that enables an increased volume of the fluid sample to be
`
`accumulated in the skin drawn into the recess. The recess can be configured having a size and
`
`shape that enables the increased volume of the fluid sample to be accumulated. In some cases,
`
`(1) the size and shape of the recess and (2) a pressure of the vacuum can be configured to
`
`achieve a minimum capillary pressure in the skin drawn into the recess.
`
`In some cases, (1) the
`
`size and shape of the recess and (2) a pressure of the vacuum can be configured to achieve a
`
`minimum tension in the skin drawn into the recess. The device can be configured to collect the
`
`fluid sample at a rate that is dependent on the size and shape of the recess.
`
`[0017]
`
`In some other aspects, a device for collecting a fluid sample from a subject is
`
`provided. The device can comprise: a housing comprising a piercing activator configured to
`
`activate one or more skin piercing elements, and a vacuum activator separate from the piercing
`
`activator and configured to activate an evacuated vacuum chamber prior to the activation of the
`
`one or more piercing elements by the piercing activator.
`
`[0018]
`
`In some aspects, a method for collecting a fluid sample from a subject can comprise:
`
`placing a device packaged with an evacuated vacuum chamber and one or more piercing
`
`elements on skin area of the subj ect; activating the evacuated vacuum chamber to effectuate
`
`vacuum pressure on the skin area; piercing the skin area after vacuum activation; and
`
`maintaining the vacuum pressure during and after penetrating the skin area of the subject, in
`
`order to draw the fluid sample from the skin into device.
`
`[0019]
`
`In some embodiments, the piercing activator and the vacuum activator can be two
`
`separate components. The vacuum activator can comprise a first input interface on the housing,
`
`and the piercing activator can comprise a second input interface on the housing.
`
`In some cases,
`
`at least one of the first input interface or the second input interface can comprise a button.
`
`In
`
`some alternative cases, the vacuum activator can comprise a first input interface and the piercing
`
`activator can comprise a second input interface, and at least one of the first input interface or the
`
`second input interface can be remote from the housing.
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`[0020]
`
`In some embodiments, the piercing activator can be configured to activate the one or
`
`more piercing elements after the skin is drawn into the recess. The piercing activator can be
`
`configured to activate the one or more piercing elements after the skin is drawn into the recess by
`
`the vacuum for a predetermined length of time. In some cases, the predetermined length of time
`
`can range from about 1 second to about 60 seconds.
`
`In some embodiments, the housing can
`
`comprise the pre—evacuated vacuum chamber, and the vacuum activator can be configured to
`
`activate the vacuum in the pre-evacuated vacuum chamber.
`
`In some cases, the piercing activator
`
`can be configured to activate the one or more piercing elements only after the vacuum has been
`
`activated.
`
`In some cases, the piercing activator can be locked and incapable of activating the one
`
`or more piercing elements prior to activation of the vacuum. The piercing activator can
`
`comprise a locking mechanism coupled to the vacuum activator. The locking mechanism can be
`
`configured such that the piercing activator is initially in a locked state. The vacuum activator
`
`can serve as a key for unlocking the piercing activator, and the piercing activator can be
`
`simultaneously unlocked when the vacuum activator is activated. The vacuum activator can be
`
`configured to activate the vacuum by establishing fiuidic communication to the pre-evacuated
`
`vacuum chamber. For example, the vacuum activator can be configured to pierce a foil seal or
`
`open a valve to establish the fiuidic communication to the pre-evacuated vacuum chamber.
`
`[0021]
`
`In some embodiments, the vacuum activator can be located on the housing such that
`
`the vacuum activator is configured to be pressed in a first direction, and the piercing activator
`
`can be located on the housing such that the piercing activator is configured to be pressed in a
`
`second direction.
`
`In some cases, the first direction and the second direction can be substantially
`
`the same. Alternatively, the first direction and the second direction can be substantially
`
`different. In some cases, the first direction and the second direction can be substantially parallel
`
`to each other.
`
`In some cases, at least one of the first direction or the second direction does not
`
`extend toward the skin of the subject. For example, the second direction does not extend toward
`
`the skin of the subject.
`
`In some cases, at least one of the first direction or the second direction
`
`can extend substantially parallel to the skin of the subj ect, In some cases, the first direction and
`
`the second direction can both extend substantially parallel to the skin of the subject.
`
`In some
`
`cases, at least one of the first direction or the second direction can extend in a direction of
`
`gravitational force.
`
`In some cases, the first direction and the second direction can both extend in
`
`the direction of gravitational force.
`
`In some embodiments, the piercing activator and the vacuum
`
`activator can be located on a same side of the housing, and can be ergonomically accessible by
`
`the subject when the device is mounted onto an arm of the subject. For example, the piercing
`
`activator can be located on a cover of the housing, and the vacuum activator can be located on a
`
`base of the housing where the vacuum chamber is located. Alternatively, the piercing activator
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`and the vacuum activator can be located on different sides of the housing, and can be
`
`ergonomically accessible by the subject when the device is mounted onto an arm of the subject.
`
`[0022]
`
`In some further aspects, a method for collecting a fluid sample from a subject is
`
`provided. The method can comprise: with aid of a fluid acquisition device: piercing skin of the
`
`subject and delivering the fluid sample from the subject to a matrix disposed within a deposition
`
`chamber of the fluid acquisition device, wherein the delivery of the fluid sample is assisted or
`
`enhanced using (1) gravitational force, (2) vacuum force, (3) a pressure difference between
`
`capillary pressure and internal pressure of the device, and (4) wicking behavior of the fluid
`
`sample along the matrix,
`
`[0023]
`
`In some aspects, a device for collecting a fluid sample from skin of a subject and
`
`delivering it to a deposition chamber is provided, wherein fluid flow from the skin to a matrix in
`
`the deposition chamber can be preferably enhanced by (1) gravitational force, (2) vacuum force,
`
`(3) a pressure differential between capillary pressure and internal pressure of the device, and (4)
`
`wicking behavior of the fluid sample along the matrix.
`
`[0024]
`
`In some embodiments, the device can comprise an enclosure for holding one or more
`
`piercing elements, and the enclosure can be in fluidic communication with the deposition
`
`chamber. The deposition chamber and the enclosure can be initially at ambient pressure, prior to
`
`activation of a vacuum from a pre-evacuated vacuum chamber located onboard the device.
`
`In
`
`some cases, the deposition chamber, the vacuum chamber, and the enclosure can be configured
`
`to equalize to an internal pressure that is less than the ambient pressure after the vacuum has
`
`been activated. The internal pressure can be higher than the initial evacuated vacuum pressure of
`
`the vacuum chamber.
`
`In some cases, the internal pressure can be about —5.5 psig, and the sealed
`
`vacuum pressure can be about —12 psig. The internal pressure can be configured to draw the skin
`
`into a recess of the housing. The internal pressure can be configured to draw blood from
`
`capillary beds to the skin that is being drawn into the recess. A pressure differential can be
`
`created between capillary pressure and the internal pressure when the skin is penetrated by one
`
`or more piercing elements of the device. The internal pressure can increase as the fluid sample is
`
`drawn from the skin towards the deposition chamber and the enclosure.
`
`In some cases, the
`
`internal pressure in the enclosure can increase more rapidly compared to a collective internal
`
`pressure of the deposition chamber and the vacuum chamber. The internal pressure in the
`
`enclosure can increase substantially more than the collective internal pressure of the deposition
`
`chamber and the vacuum chamber. The substantially increased internal pressure of the enclosure
`
`can inhibit the flow of the fluid sample into the enclosure. The substantially increased internal
`
`pressure of the enclosure can result in preferential flow of the fluid sample towards the
`
`deposition chamber instead of towards the enclosure. The substantially increased internal
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`pressure of the enclosure can cause the flow of the fluid sample into the enclosure to slow or
`
`stop, while the fluid sample can continue to flow towards the deposition chamber under the
`
`influence of the pressure differential. In some cases, ( 1) a volume of the enclosure and (2) a
`
`collective volume of the deposition chamber and the vacuum chamber, can be configured such
`
`that minimal amounts of the fluid sample flows towards and into the enclosure.
`
`In some cases, a
`
`ratio of the volume of the enclosure to the collective volume of the deposition chamber and the
`
`vacuum chamber can range from about 1:5 to about 1:15.
`
`In some cases, the one or more
`
`piercing elements can be configured to penetrate the skin to generate cuts, and the pressure
`
`differential can enable deeper cuts and the cuts to be held open under tension. The pressure
`
`differential can be configured to increase the size of the cuts to enable a higher flowrate and
`
`volume of the fluid sample to be collected from the skin.
`
`[0025]
`
`In some further aspects, a device for penetrating skin of a subject is provided. The
`
`device can comprise: one or more piercing elements supported by a piercing holder movable by
`
`two or more spring elements; a deployment spring positioned to deploy the one or more piercing
`
`elements through an opening in the device; and a retraction spring positioned to retract the one or
`
`more piercing elements back into the device, wherein a length of the one or more piercing
`
`elements is less than about 20 mm, and the depth of penetration of the one or more piercing
`
`elements is about 2 mm.
`
`In some cases, the length of the one or more piercing elements is about
`
`12.7mm.
`
`[0026]
`
`In some aspects, a method for penetrating skin of a subject can comprise providing
`
`the aforementioned device, drawing the skin of the subject into a recess of the device; activating
`
`the deployment spring and deploying the one or more piercing elements through the opening in
`
`the device; penetrating the skin of the subject using the one or more piercing elements; and using
`
`the retraction spring to retract the one or more spring elements back into the device.
`
`[0027]
`
`In some embodiments, two or more piercing elements can be supported by a holder
`
`in a random configuration. In some cases, the two or more piercing elements can have random
`
`orientations relative to each other. The two or more piercing elements can comprise beveled
`
`edges that are randomly oriented relative to each other. The beveled edges of the two or more
`
`piercing elements can be non-symmetrical to each other. The beveled edges of the two or more
`
`piercing elements can be at an acute or oblique angle relative to each other.
`
`[0028]
`
`In some cases, two or more piercing elements can be supported by a holder in a
`
`predefined configuration. The two or more piercing elements can have predefined orientations
`
`relative to each other. The two or more piercing elements can comprise beveled edges that are
`
`oriented relative to each other in a predefined manner. The beveled edges of the two or more
`
`piercing elements can be symmetrical to each other.
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`[0029]
`
`In some embodiments, the piercing elements can comprise two or more lancets.
`
`Optionally, the piercing elements can comprise needles and/or microneedles.
`
`In some cases, two
`
`or more lancets can have a same bevel angle. Alternatively, two or more lancets can have
`
`different bevel angles. In some cases, the bevel angle(s) can range from about 10 degrees to
`
`about 60 degrees.
`
`In some cases, the two or more lancets can comprise beveled faces having a
`
`same bevel length. Alternatively, the two or more lancets can comprise beveled faces having
`
`different bevel lengths. In some cases, the bevel length(s) can range from about 2mm to about
`
`10mm.
`
`[0030]
`
`In some embodiments, two or more piercing elements can be configured to generate
`
`cuts on the skin that extend in different directions along the skin and that are non-parallel to each
`
`other.
`
`[0031]
`
`In some embodiments, the deployment spring can be configured to move and cause
`
`the piercing elements to penetrate the skin of the subject at speeds ranging from about 0.5 m/s to
`
`about 2.0 m/s. The deployment spring can be configured to move and cause the piercing
`
`elements to penetrate the skin of the subject with a force ranging from about 1.3 N to about 24.0
`
`N. A spring-force of the retraction spring can be less than a spring-force of the deployment
`
`spring.
`
`In some cases, the deployment spring can have a spring-rate of about 2625 N/m, and the
`
`retraction spring can have a spring-rate of about 175 N/m. The deployment spring can be
`
`configured to cause the one or more piercing elements to penetrate the skin to depths ranging
`
`from about 0.5mm to about 3mm. The retraction spring can be configured to retract the piercing
`
`elements from the skin of the subject at speeds ranging from about 0.1 m/s to about 1.0 m/s.
`
`[0032]
`
`In some embodiments, the device can further comprise: a vacuum activator
`
`configured to activate a vacuum for drawing the skin into a recess of the device.
`
`In some cases,
`
`a piercing activator can be configured to activate the deployment spring only after the vacuum
`
`activator is activated.
`
`[0033]
`
`In some further aspects, a device for monitoring fluid sample collection from a
`
`subject is provided, The device can comprise: a housing comprising a cartridge chamber; a
`
`cartridge operably coupled to the cartridge chamber, components for penetrating skin of the
`
`subject and drawing the fluid sample from the skin into the cartridge, and a flow meter on the
`
`housing that enables the subject or a user to monitor a progress of the fluid sample collection in
`
`real—time as the fluid sample is collected into the cartridge.
`
`[0034]
`
`In some aspects, a method for monitoring fluid sample collection from a subject can
`
`comprise: providing (1) a housing comprising a cartridge chamber, (2) a cartridge operably
`
`coupled to the cartridge chamber, (3) components for penetrating skin of the subject and drawing
`
`the fluid sample from the skin into the cartridge, and (4) a flow meter on the housing; and
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`monitoring, with aid of the flow meter, a progress of the fluid sample collection in real-time as
`
`the fluid sample is collected into the cartridge.
`
`[0035]
`
`In some embodiments, the flow meter can be provided on a lid covering a base of the
`
`housing. The flow meter is not obscured by a cover of the housing. The flow meter can be in
`
`proximity to the cartridge chamber. The flow meter can be substantially aligned with a cartridge
`
`located within the cartridge chamber.
`
`In some embodiments, the flow meter can comprise a
`
`plurality of windows disposed parallel to a longitudinal axis of the cartridge. The plurality o