as) United States
`a2) Patent Application Publication (10) Pub. No.: US 2003/0100824 Al
` Warrenetal. (43) Pub. Date: May29, 2003
`
`
`
`00:
`US 20030100824A 1
`
`(54) ARCHITECTURE TOOL AND METHODS OF
`USE
`
`Related U.S. Application Data
`
`(76)
`
`Inventors: William L. Warren, Stillwater, OK
`(US); Robert L. Parkhill, Stillwater,
`OK (US); Robert L. Stewart,
`Stillwater, OK (US); Anatoly M.
`Kachurin, Stillwater, OK (US); Robert
`M. Taylor, Perkins, OK (US); Brian H.
`Hargrave, Stillwater, OK (US);
`Kenneth H. Church,Stillwater, OK
`(US); Michael N. Nguyen, Stillwater,
`OK (US); Mark L. Kargel, Stillwater,
`OK (US); Mark W. Simpkins,
`Stillwater, OK (US)
`
`Correspondence Address:
`NEEDLE & ROSENBERG PC
`127 PEACHTREE STREET NE
`ATLANTA, GA 30303-1811 (US)
`:
`
`(21) Appl. No.:
`
`10/227,146
`
`(22)
`
`Filed:
`
`Aug. 23, 2002
`
`(60)
`
`Provisional application No. 60/314,344, filed on Aug.
`23, 2001. Provisional application No. 60/337,378,
`filed on Dec. 4, 2001. Provisional application No.
`60/337,383, filed on Dec. 4, 2001. Provisional appli-
`cation No. 60/340,706, filed on Dec. 11, 2001.
`
`Publication Classification
`
`(SL)
`(52)
`
`Tmt, Ca ececccccccccccsseesseseeeessesserseesseeseseneees AGIB 5/05
`ERSWG,
`sccccwesanewniccncumauniiiadianwn 600/407
`
`(57)
`
`ABSTRACT
`
`The invention provides an apparatus and methods for depos-
`iting materials on a substrate, and for performing other
`selected functions, such as material destruction and removal,
`temperature control, imaging, detection, therapy and posi-
`tional and locational control. In various embodiments, the
`apparatus and methods are suitable for use in a tabletop
`setting, in vitro or in vivo.
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`Patent Application Publication May 29,2003 Sheet 18 of 30
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`Patent Application Publication May 29,2003 Sheet 19 of 30)
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`Patent Application Publication May 29,2003 Sheet 20 of 30
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`Patent Application Publication May 29,2003 Sheet 21 of 30
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`Patent Application Publication May 29,2003 Sheet 22 of 30
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`Patent Application Publication May 29,2003 Sheet 23 of 30
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`Patent Application Publication May 29,2003 Sheet 24 of 30
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`Patent Application Publication May 29,2003 Sheet 25 of 30
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`Patent Application Publication May 29,2003 Sheet 26 of 30
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`Patent Application Publication May 29,2003 Sheet 27 of 30
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`Patent Application Publication May 29,2003 Sheet 30 of 30
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`US 2003/0100824 Al
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`May29, 2003
`
`ARCHITECTURE TOOL AND METHODS OF USE
`
`STATEMENT OF FEDERALLY SPONSORED
`RESEARCH
`
`[0001] This invention was made with government support
`under Grant No. NBCHCOLOO19 awarded by the Defense
`Advancement Research Projects Agency. The United States
`government may have certain rights in the invention.
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`[0002] This application claims benefit of priority from
`U.S. Provisional Application Serial No. 60/314,344, filed
`Aug. 23, 2001, and U.S. Provisional Application Serial No.
`60/337,378,
`filed Dec. 4, 2001, which applications are
`hereby incorporated by reference in their entirety.
`
`FIELD OF THE INVENTION
`
`physiochemical treatments. Surface is italicized above to
`illustrate that while this technology is highly successful for
`such applications as cell-based assays for drug discovery
`and planar biosensor arrays,
`it does not satisfy the 3D
`requirements for metabolic and tissue engineering.
`[0008] Existing tissue and organ losses are treated by
`transplantation of an organ from a donor, through surgical
`reconstruction, or by the use of a mechanical-type substitute.
`Mostpotential recipients die waiting for available transplant
`organs. Those fortunate enough to receive a donor organ are
`relegated to a lifetime of immunosuppression therapy. The
`option of surgical reconstruction, although usually involving
`the patient’s own tissues, again is not appropriate for many
`situations andis associated with significant morbidity. The
`burden to the patient and the health-care delivery system due
`to the extensive surgery often required and the high number
`of repeat procedures is no longer inline with the objectives
`of modern treatment preferences. Mechanical devices, such
`as kidney dialysis machines, provide a therapeutic value but
`represent a mere life-sustaining function for now andin the
`future.
`
`[0003] This invention relates generally to tools and meth-
`ods for depositing materials accurately on a selected sub-
`strate, or for performing a variety of other tasks, including
`[0009] Thus, a need exists to recreate the 3D relations
`material removal,
`imaging, and detection. The invention
`among cells and bioactive substances that are necessary to
`may be applied in the medical and biological fields, but is
`normal tissue morphogenesis and organ functions through a
`also applicable in many other environments and_fields,
`tool that introduces the new constructs with minimal trauma
`including the manufacture of a broad range of devices.
`to the host. A need exists for a tool that combines additive
`and subtractive processes in one integrated embodiment. For
`biological and/or medical applications, this is especially true
`if the tool can be integrated with minimally invasive surgery
`(MIS) techniques. A need also exists for technologies that
`enable such a tool and its use, including pumping systems,
`material delivery and mixing systems, position control sys-
`lems, material dispensing systems, material destruction and
`removal systems, material
`temperature control systems,
`imaging and detection systems, and therapeutic systems.
`
`BACKGROUND OFTHE INVENTION
`
`[0004] Because of the importance of three-dimensional
`(3D) structure (microenvironment) to the cell function, a
`goal
`in metabolic and tissue engineering is to control the
`spatial arrangement of cells to mimic the 3D ordering of
`cells in native tissues. To date, many efforts towardthis goal
`have focused on two-dimensional (2D) patterns using pho-
`tolithography or microcontact printing ofa single cell type.
`The 2D cell patterns provide two types of micrometer-scale
`regions, one in which the cells adhere, while the other has
`low cell adhesion, The design intentis for the cells to adhere
`selectively to the patterned regions of high adhesion.
`[0005] The aforementioned lithographic process is some-
`what successful for one cell type; however, culturing more
`than one cell type requires differential adhesion between the
`two cell types. The lithographic processfalls short of the true
`3D mark required to create the proper microenvironment for
`cell growth.
`
`to include transplantation,
`[0006] Current approaches,
`transfusion ofcells into a preformed implantable biocom-
`patible matrix, or 2D in vitro culturing of tissues, require
`both expensive and timely custom fabrication and tremen-
`dously invasive surgeries.
`[0007] Arecent review article by Jung et al. articulates the
`importance of topographical and physiochemical modifica-
`tion—the microenvironment—of the material surface to
`enable patterning ofliving cells. See D. R. Jung, R. Kapur,
`‘T. Adams, K. A. Giuliano, M. Mrksich, H. G, Craighead, and
`D. L. Taylor, Critical Reviews in Biotechnology 2001, 21,
`111, which is expressly incorporated herein in its entirety by
`this reference, The article provides several examples of the
`precise control of the architecture of multiple cells via
`precise engineering of the material surface (cell patterning).
`It is shown that selective phenotypic and genotypic control
`of living tissues is provided by surface topographic and
`
`32
`
`SUMMARY OF THE INVENTION
`
`[0010] As described herein, in one embodiment, the inven-
`tion includes a direct-write patterning system suitable for
`either
`fine-pattern microdispensing and/or
`fine-focused
`laser-beam writing over flat or conformal surfaces. One
`illustrative use of the invention is for dispensing uniform
`lines of viscous solutions, suspensions, sols, or pastes to
`create exact replicas of stored patterns. Materials thal may
`be deposited according to the invention include, but are not
`limited to, dielectric pastes and/or inks, semiconducting
`pastes, conducting pastes, polymers, hydrogels, cells,
`growth factors, nutrients, and extracellular matrix materials.
`In another embodiment, the invention provides integrated
`tool technologies for the direct-write deposition and laser
`micromachining of a wide variety of such materials and
`provides the capability for concurrent detection and imaging
`methods during additive and subtractive processes.
`
`[0011] The direct-write technologies may be usedto con-
`struct purely inorganic materials, purely organic materials,
`biological materials
`and/or
`any combination thereof.
`Throughout
`this specification,
`the direct-write deposition
`technology in general terms will be referred to as “direct-
`write deposition technology” (DWDT).
`
`[0012] The DWDTtechnology includes embodiments in
`which the apparatus of the invention is sized and shaped to
`enable use ofthe tool, for example, in MIS or other in vivo
`
`32
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`US 2003/0100824 Al
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`May29, 2003
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`description and the following detailed description are exem-
`plary and explanatory only and are not restrictive of the
`invention, as claimed.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`procedures as shown in FIG, 1. As set forth in further detail
`below,the tool in such embodiments may be a suitably small
`and maneuverable device to allow its use in endoscopic
`procedures, and may thus comprise an endoscopic device.
`
`and maneuverable
`small
`such
`[0013] Alternatively,
`embodiments may be utilized for applications, including
`organic and inorganic applications, in a “tabletop” setting
`(FIGS. 2A-2F). In another aspect, alternative embodiments
`of the invention include a larger, less maneuverable tabletop
`version of the tool
`in which constituent materials may be
`dispensed through multiple, discrete dispensing heads.
`Tabletop embodiments may also be utilized to perform all of
`the same biological, lissue-engineering, and medical-pro-
`cess applications using the same constituent printing mate-
`rials as the in vivo embodiments described herein. Thus,all
`embodiments disclosed herein for application in vivo may
`suitably be adapted for in vitro use and for tabletop settings.
`Similarly, embodiments disclosed herein for in vitro use or
`in tabletop settings may also be used or adapted for use in
`vivo. The described embodiments are not to be viewed as
`limited to either in vivo or in vitro usage.
`[0014] For biological, medical, bioengineering, and tis-
`sue-engineering embodiments of the DWDT, the apparatus
`may be referred to herein as the “human architecture tool”
`(HAT). The in vitro and/or
`in vivo HAT technology
`deseribedherein can allow the user to “print” biocompatible
`scaffolds, cells, growth factors,
`therapeutics, enzymes,
`extracellular matrix (ECM) proteins, andthe like inside the
`human body using a microscale dispensing orifice (¢.g., a
`dispenser or stylus) compatible with MIS medical practices.
`The HAT technologyis able to remove any unwanted tissue
`or substrate without trauma to surrounding structures using,
`a novel fiber-delivered ultrashort-pulse (USP) laser system
`in the same MIS-compatible tool.
`[0015]
`In various embodiments, the DWDTmay be used
`to perform biological, medical, bioengineering, bioelec-
`tronic, and lissue-engineering procedures, but it also may be
`used for non-medical applications, such as fabricating intri-
`cate electronic devices, including but not limited to, resis-
`tors, varistors, capacitors, varactors, interconnects, transis-
`tors, diodes, metal-semiconductor rectifiers, antennas, fuel
`cells, and batteries, for applications such as microelectro-
`mechanical systems (MEMS), embeddedbatteries, polymer
`light-emitting diodes, surface acoustic wave devices, sen-
`sors (€.g.,
`temperature, pressure, gas, humidity), decorative
`patterning, solar cells, transmission electron micrographic
`(TEM) sample extraction, three-dimensional (3D) metrol-
`ogy, via filling, interconnect patterning, thin-film head trim-
`ming, trimming andrepair, lenses, waveguides, on a variely
`of conformal surfaces.
`
`In various embodiments, the HAT may be used for
`[0016]
`applications including a broad variety of regenerative medi-
`cine and tissue engineering techniques, which include but
`are not
`limited to, building customized body parts on
`demand, in real time.
`
`[0017] Additional advantages of the invention will be set
`forth in part
`in the description which follows, and in part
`may be learned from the description, or may be learned by
`practice of the invention. The advantages of the invention
`will be realized and attained by means ofthe elements and
`combinations particularly pointed out
`in the appended
`claims. It is to be understood that both the foregoing general
`
`33
`
` [0037]
`
`[0018] FIG, 1 is a perspective view of an embodiment of
`the invention for tabletop use.
`
`FIGS. 2A-2F are a series of perspective views of
`[0019]
`embodiments of the invention for in vivouse.
`
`[0020] FIG. 3 is a perspective view of a cart carrying
`support components of the invention.
`
`[0021] FIG. 4 is a perspective view of an embodiment of
`the invention for in vivo use.
`
`[0022] FIG. 5 is a perspective view of another embodi-
`ment of the invention for in vivo use.
`
`[0023] FIGS. 6A and 6B are cross sectional side views of
`the embodiment of FIG, 5 showing extension and retraction
`of the material dispenser.
`
`FIG. 7 is a perspective view of an embodiment of
`[0024]
`the embodiment of FIG. 5 with components stripped away
`to show certain internal structures.
`
`[0025] FIG. 8 is a graph of damage threshold versus
`pulsewidth for one embodiment of a laser source for the
`invention.
`
`[0026] FIGS. 9A and 9B are views of a grating coupled
`surface emitting laser diode according to the invention.
`
`FIGS. 10A-10C are views of an embodiment of a
`[0027]
`temperature controller of the invention.
`
`FIGS. 1LA-11D are sequential operational views of
`[0028]
`an embodiment of the material dispenser of the invention.
`
`[0029] FIGS. 12A and 12B are views of an embodiment
`of the material dispenser of the invention.
`
`FIGS. 13A-13Care sequential operational views of
`[0030]
`an embodiment of the material dispenser of the invention.
`
`[0031] FIG. 14 is a perspective view of an embodiment of
`an insertion bundle for use the material dispenser of the
`invention.
`
`FIGS. 15A-15D are sequential operational views of
`[0032]
`an embodiment of the material dispenser of the invention.
`
`[0033] FIG. 16 is a side view ofa feed channel for use in
`an embodimentof the material dispenser of the invention.
`
`[0034] FIGS. 17A and 17B are views of an embodiment
`of an insertion bundle for use with the embodiments of the
`material dispenser of the invention.
`
`[0035] FIG. 18 is a schematicillustration of an exemplary
`system for dispensing materials using feedback to control
`the position of a dispenser according to one embodiment.
`
`[0036] FIGS. 19, 20A and 20B are views of various
`elements of exemplary dispensing systems in detail.
`
`IG. 21 is an exemplary graph of vibration AA vs.
`Af before and after contact between a vibrating element and
`another surface;
`
`33
`
`

`

`US 2003/0100824 Al
`
`May29, 2003
`
`[0038] FIG, 22 is a schematic illustration of an exemplary
`system for dispensing materials using feedback to control
`the position of a substrate of an alternative embodiment.
`[0039] FIG, 22A is a flow chart of an exemplary method
`of controlling the position of the elements ofa dispensing
`system.
`
`FIGS. 23A-23C are separate views of an exem-
`[0040]
`plary embodiment ofthe invention having a plurality of
`material dispensers,
`[0041] FIG, 24 illustrates views of white blood cells
`deposited on a substrate using an embodiment of the inven-
`lion.
`
`[0042] FIG. 25 illustrates two embodiments of an augur
`serew mixer for use with the embodiments of the material
`dispenser of the invention.
`
`[0043] FIG. 26 schematically illustrates an embodiment
`of a branch-and-recombine mixer for use in the embodi-
`ments of the material dispenser of the invention.
`[0044] FIGS. 27A is a top plan view ofa helix channel
`mixer for use with the embodiments of the material dis-
`penser ofthe invention.
`
`[0045] FIG, 27Bis a cross-sectional elevation view ofthe
`helix channel mixer of FIG. 27A.
`
`[0046] FIGS. 28A and 28Bare views of an embodiment
`of a mixing chamber for use in an embodiment of the
`material dispenser of the invention.
`
`FIGS. 29A-29C are separate views of a rotating
`[0047]
`needle valve embodiment of the material dispenser of the
`invention.
`
`[0048] FIG. 30 illustrates a four-stream mixer for use in
`an embodiment of the material dispenser of the invention.
`
`[0049] FIGS.31A and 31B illustrate the mixing effects of
`a pulsed flow in the embodiments of the material dispenser
`of the invention.
`
`[0050] FIGS. 32A and 32B are schematic views of a
`rotating needle valve embodiment of the material dispenser
`according to the invention.
`
`[0051] FIG. 33 is a flow chart of an exemplary method of
`providing feedback to a mixing system for use with the
`embodiments of the material dispenser of the invention.
`
`[0052] FIGS. 34A and 34B are views of an embodiment
`of the apparatus stabilizer according to the invention.
`[0053] FIG. 35 is a schematicillustration of a devices and
`methods for performing optical coherence tomography of
`the invention.
`
`[0054] FIG. 36 is a schematic illustration of devices and
`methods for controlling and synchronizing the position of
`the material dispenser and the position of the valve within
`the material dispenser of the invention.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`is more particularly
`invention
`present
`[0055] The
`described in the following examples that are intended as
`illustrative only since numerous modifications and varia-
`tions therein may be apparent to those skilled in the art. As
`
`34
`
`ae
`used in the specification and in the claims, “a,”“an,” and
`“the” can mean one or more, depending upon the context in
`which it is used. Several aspects of the present invention are
`now described with reference to the figures, in which like
`numbers indicate like parts throughout the figures.
`
`[0056] For convenience, abbreviations and symbols used
`throughout this specification are set forth in the following
`Tables 1 and 2.
`
`TABLE 1
`ABBREVIATIONS
`
`2D, 3D
`AF
`BCGF
`CAD
`CAM
`ecb
`CFD
`CMU
`CRT
`CSF
`cT
`CTGF
`cw
`DNA
`DPIV
`DPM
`DWDT
`ECGF
`ECM
`EF
`EGF
`ENT
`Epo
`YAG
`E-SEM
`ETC
`fe
`FD
`FGF
`FIB
`FSR
`FITR
`FTL
`FWHM
`GCSEI
`HAT
`HBEGP
`HGF
`HGFL.
`HMG
`ID
`LEN
`IGE
`IGPBP
`IL
`INGAP
`IR
`KGF
`LASIK
`LED
`LEPT
`LGF
`LIF
`lomo
`LP
`LYIBP
`MEMS
`MIS
`MRI
`mRNA
`MST
`MTC
`NA
`
`N Dimensions, -Dimensional
`Autofluorescence
`B-Cell Growth Factor
`Computer Aided Design
`Computer Aided Manufacturing
`Charge-Coupled Device
`Computational Fluid Dynamics
`Camegie Mellon University
`Cathode Ray Tube
`Colony Stimulating Factor
`Computerized Tomography
`Connective Tissue Growth Factor
`Continuous Wave (Laser)
`Deoxyribonucleic Acid
`Digital Particle Image Velocimetry
`Distributed Parameter Model
`Direct-Write Deposition Technology
`Endothelial Cell Growth Factor
`Extracellular Matrix
`Exogenous Fluorescence
`Endothelial Growth Factor
`Endogenoas Natural Tissue
`Erythropoietin
`Yttrium Aluminum Garnet
`Environmental SEM
`Engineered Tissue Construct
`Focal Number
`Finite-Dimensional
`Fibroblast Growth Factor
`Focused Lon Beam
`Femtosecond Regime (10-"—10-"* s)
`Fourier-Transform Infrared Spectroscopy
`Follow-the-Leader (Motion)
`Full Width at Half Maximum
`Grating-Coupled Surface-Emitting Laser
`Human Architecture Too!
`Heparin Binding Epidermal Growth Factor
`Hepatocyte Growth Factor
`Hepatocyte Growth Factor-Like
`High-Mobility Group Protein
`Infinite-Dimensional
`Interferon
`Insulin-Like Growth Factor
`IGF Binding Protein
`Interleukin
`Pancreatic Beta Cell Growth Factor
`Infrared (Radiation)
`Keratinocyte Growth Factor
`Laser In Situ Keratomileusis
`Light-Emitting Diode
`Low-Energy Photon Therapy
`Laplacian-Gaussian Filter
`Laser-Induced Fluorescence
`Locally Monotonic
`Long Pulse (Laser)
`Latent Transforming Growth Factor Beta Binding Protein
`Microelectromechanical Systems
`Minimally Invasive Surgery
`Magnetic Resonance [maging
`Messenger RNA
`Macrophage-Stimulating
`Model Tissue Construct
`Numerical Aperture
`
`34
`
`

`

`US 2003/0100824 Al
`
`May29, 2003
`
`TABLE 1-continued
`ABBREVIATIONS
`
`NGF
`Nerve Growth Factor
`NLO
`Nonlinear Optics, -Optical
`NSR
`Nanosecond Regime (10°-°-107" s)
`OocT
`Optical Coherence Tomography
`OM
`Optical Micrograph
`osu
`OklahomaState University
`PBF
`Photonic Bandgap Fiber (Material)
`pc
`Personal Computer
`PCR
`Polymerase Chain Reaction
`PDGF
`Platelet-Derived Growth Factor
`PEG
`Poly(ethylene glycol)
`PGFL
`Placental Growth Factor-Like
`PPE
`Poly(propylene fumarate)
`PSR
`Picosecond Regime (107'°-107"" s)
`R&D
`Research & Development
`RNA
`Ribonucleic Acid
`S/N
`Signal to Noise Ratio
`SEM
`Scanning Electron Micrograph
`SCDGF
`Spinal Cord-Derived Growth Factor
`SCGF
`Stem Cell Growth Factor
`SRS
`Stimulated Raman Scattering
`TDGF
`Teratocarcinoma-Derived Growth Factor
`TEM
`Transmission Electron Micrograph
`TGF
`Transforming Growth Factor
`TNF
`Tumor Necrosis Factor
`TSL
`Titanium-Doped Sapphire Laser
`TV
`Television
`UA
`University of Arizona
`USP
`Ultrashort Pulse (Laser)
`uv
`Ultraviolet (Radiation)
`VEGF
`Vascular Endothelial Growth Factor
`VGR
`Vegetal Related Growth Factor
`WBC
`White Blood Cell
`
`
`[0057]
`
`TABLE 2
`
`
`SYMBOLS
`
`
`a
`A
`d
`E,
`f
`f,
`EF
`Fiction
`Funmage
`u
`L
`n
`p
`Pivg
`Pas
`Pan
`Pocok
`Pin
`QO
`r
`Re
`R,
`t
`u
`U
`w
`XV, 2
`Z
`A
`A
`he
`
`Areal Density (m~*)
`Amplitude or Magnitude
`Diameter (m)
`Energy, Pulse (J)
`Frequency (Hz)
`Frequency, Resonance (Hz)
`Fluence or Energy Density (J/m*)
`Fluence, Ablation Threshold (J/m*)
`Fuence, Damage Threshold (J/m*)
`Irradiance or Power Density (W/m?)
`Nozzle Design Parameter (m)
`Refractive Index
`Pressure (Pa)
`Power, Average (W)
`Power, Input (W)
`Power, Output (W)
`Power, Peak (W)
`Power, Threshold (W)
`Quality Factor
`Radius (m)
`Reynolds Number (—)
`Repetition Rate, Pulse (Hz)
`Time or Period (s)
`Velocity, Fluid (m/s)
`Flow Rate, Fluid (L/s)
`Spot Size (m)
`Cartesian Coordinates (m)
`Impedance (£2)
`Difference Operator
`Wavelength (m)
`Wavelength, Fluorescence (m)
`
`TABLE 2-continued
`
`
`SYMBOLS
`
`
`Viscosity, Dynamic (Pa s)
`H
`Density (kg/m*)
`p
`Duration, Fluorescence Decay (s)
`Tr
`Duration, Pulse (s)
`Tp
`Shear Stress (Pa)
`ty
`
`Tecwall Shear Stress, Wall (Pa)
`
`[0058] The invention includes embodiments of a tool for
`in vitro or in vivo use in biological, tissue-engineering, and
`medical processes. A DWDT embodiment ofthe invention
`for in vitro use is illustrated in FIG. 1. Embodiments for in
`vivo use may be sized and shapedto enable use of the tool
`in MIS procedures as shown in FIGS. 2A-F. As set forth in
`further detail below, the tool in its in vivo embodiments may
`be a suitably small and maneuverable device to allow its use
`in endoscopic procedures. Alternatively, such small and
`maneuverable embodiments may be utilized for in vitro
`applications in a tabletop setting (FTG. 1). In other alterna-
`tive embodiments intended for in vitro use, a larger, less
`maneuverable tabletop version ofthe tool is contemplated in
`which constituent materials may be dispensed through mul-
`tiple, discrete dispensing heads. Tabletop embodiments may
`also be utilized to perform all of the same biological,
`lissue-engineering, and medical-process applications using
`the same constituent printing materials as the in vivo
`embodiments described herein. Thus, all embodiments dis-
`closedherein for application in vivo may suitably be adapted
`for in vitro use and fortabletop settings. Similarly, embodi-
`ments disclosed herein for in vitro application may also be
`used or adapted for use in vivo. The described embodiments
`are not to be viewedas limited to either in vivo or in vitro
`usage.
`
`DWDTand HATspecifically for tabletop processes
`[0059]
`or in vivo and in vitro medical processes are unique in at
`least four aspects: First, in some embodiments, the DWDT/
`HAT may include an imaging device 500, a detector 600,
`and a location control device 800 that permits navigation
`among internal cavities, and structural elements such as
`bones, muscles, tendons, mucosal layers, nerve channels, as
`well as arteries and veins, within the body. Additionally, an
`optional material remover 300 allows the disposal oftissue
`or fluids removed or cut from the target area, and an optional
`temperature controller 400 enables the user to heat or cool
`materials dispensed through the tool or elements within the
`tool
`itself. An optional apparatus stabilizer 900 allows
`positional control of the tool with respect to the target area.
`The optional detector 600 permits visualization through
`various spectroscopies including laser-induced fluorescence
`(LIF), time-resolved LIF, infrared (IR), Raman scattering,
`ultrasound, optical coherence tomography (OCT); and/or
`terahertz imaging interrogation to distinguish healthy and
`diseased tissues; and an optional
`therapeutic emitter 700
`enabling therapies such as
`low-energy photon therapy
`(LEPT). Furthermore, prior generated imaging processes
`such aS magnetic resonance imaging (MRI) or thin-film
`histology may be used in concourse with the HAT.
`
`[0060] Second, the DWDT/HAT has the ability to add
`desirable and/or subtract unwanted tissues and materials in
`a seamless and facile fashion.
`In one embodiment,
`the
`
`35
`
`

`

`US 2003/0100824 Al
`
`May29, 2003
`
`apparatus may perform subtractive processes using a mate-
`rial destroyer 200, which in one embodiment comprises a
`USP-laser-based system that replaces the cutting tools in a
`traditional orthoscopic tool. The laser system may be
`equipped with USP or long-pulse (LP) capability, combina-
`tions thereof, or a pulse duration (t,) within the LP-USP
`cusp region (1-300ps). This permits the apparatus to trim,
`to shape, and to removetissue in the damaged or construc-
`lion region in either a thermal or an athermal manner, with
`the athermal process not damaging such surrounding mate-
`rials as tissue.
`
`in some embodiments the DWDT/HAT
`[0061] Third,
`combines the fabrication and assembly processes. For
`example,DWDT/HATmay include a material dispenser 100
`that facilitates the fabrication and assembly of biocompat-
`ible scaffolds, cells, nutrients, growth factors, ECM proteins,
`therapeutics, and other biological, organic, or
`inorganic
`components as desired to form various components, such as
`3D engineered tissue constructs (ETC).
`[0062] Fourth, the DWDT/HATallowsthe processes to be
`performed both outside and within the body.
`
`In some embodiments, the HATdevice for in vivo
`[0063]
`use is similar in visual appearance to existing MIS devices.
`HATcan image, add, and subtract, in vivo, a wide range of
`materials with reproducible precision. The precise 3D in
`vivo direct deposition of cells, bioactive factors, and sup-
`portive 3D scaffolding using the miniaturized dispensing,
`nozzle deposition system may help harness the potential of
`modern biology to deliver therapeutic regenerative medi-
`cine. The ability to precisely and selectively add,
`in real
`lime, supportive 3D matrices, bioactive factors, and cells
`that differentiate and grow brings about a new-to-the-world
`advance to the metabolic- and tissue-engineering commu-
`nities. It also enables medical procedures intendedtorepair,
`replace, rebuild, and/or reactivate tissue with minimized
`trauma to the human and/or animal body. The HATdevice
`and methods enable the precise in vivo placement and
`microenvironment control of cells with high proliferative
`capacities and specified differentiation.
`
`[0064] A goal of molecular medicine is to channel multi-
`potent human cells with high proliferative capacities into
`specified differentiation programs within the body. This goal
`may be achieved by leveraging the biological knowledge of
`the importance of three-dimensionality and cell microenvi-
`ronment to achieve normal tissue morphogenesis, vascular-
`ization, and organ functions, A multitude of thera