WO2023146209A1 - Smart print bed for tissue construction under biomimetic control - Google Patents

Smart print bed for tissue construction under biomimetic control Download PDF

Info

Publication number
WO2023146209A1
WO2023146209A1 PCT/KR2023/000915 KR2023000915W WO2023146209A1 WO 2023146209 A1 WO2023146209 A1 WO 2023146209A1 KR 2023000915 W KR2023000915 W KR 2023000915W WO 2023146209 A1 WO2023146209 A1 WO 2023146209A1
Authority
WO
WIPO (PCT)
Prior art keywords
scaffold
smart
bed
tissue
print bed
Prior art date
Application number
PCT/KR2023/000915
Other languages
French (fr)
Korean (ko)
Inventor
오석중
손카리아산지브
Original Assignee
주식회사 에코월드팜
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 주식회사 에코월드팜 filed Critical 주식회사 에코월드팜
Publication of WO2023146209A1 publication Critical patent/WO2023146209A1/en

Links

Images

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B06—GENERATING OR TRANSMITTING MECHANICAL VIBRATIONS IN GENERAL
    • B06B—METHODS OR APPARATUS FOR GENERATING OR TRANSMITTING MECHANICAL VIBRATIONS OF INFRASONIC, SONIC, OR ULTRASONIC FREQUENCY, e.g. FOR PERFORMING MECHANICAL WORK IN GENERAL
    • B06B1/00—Methods or apparatus for generating mechanical vibrations of infrasonic, sonic, or ultrasonic frequency
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C64/00—Additive manufacturing, i.e. manufacturing of three-dimensional [3D] objects by additive deposition, additive agglomeration or additive layering, e.g. by 3D printing, stereolithography or selective laser sintering
    • B29C64/20—Apparatus for additive manufacturing; Details thereof or accessories therefor
    • B29C64/245—Platforms or substrates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C64/00—Additive manufacturing, i.e. manufacturing of three-dimensional [3D] objects by additive deposition, additive agglomeration or additive layering, e.g. by 3D printing, stereolithography or selective laser sintering
    • B29C64/30—Auxiliary operations or equipment
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y10/00—Processes of additive manufacturing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y30/00—Apparatus for additive manufacturing; Details thereof or accessories therefor
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y40/00—Auxiliary operations or equipment, e.g. for material handling
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y70/00—Materials specially adapted for additive manufacturing
    • 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
    • C12M1/00—Apparatus for enzymology or microbiology
    • C12M1/12—Apparatus for enzymology or microbiology with sterilisation, filtration or dialysis means
    • 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
    • C12M1/00—Apparatus for enzymology or microbiology
    • C12M1/42—Apparatus for the treatment of microorganisms or enzymes with electrical or wave energy, e.g. magnetism, sonic waves

Definitions

  • the present invention relates to a smart printed bed for tissue construction with biomimetic control.
  • the present invention : 1. By introducing a state-of-the-art bioprinting platform, it is planned to accelerate the development of fully functional replacement tissues and organs for clinical grade products, and 2. 4D printed bed design function. is uniquely compatible with and controllable with the dynamics of a smart bio-responsive scaffold environment that induces the combination of multi-cells and multi-cell types, and 3. This technology converts intracellular nanoscale factors to the extracellular matrix (ECM). Synchronizing components will influence organizational growth. This represents a major step towards the 'next generation' of smart (4D) bioprinters that are not currently on the market.
  • ECM extracellular matrix
  • Matrices provide essential biophysical signals, such as mechanical, electrical, and force generated from superficial adhesion, for transition signals generated for directional and morphological growth of tissues at cell-cell and cell-scaffold interfaces. This is a very important and unmet technology in the field of bioprinting technology.
  • the application of stretching to the scaffold allows physical manipulation of scaffold cell interactions, and the application of vibration to the scaffold to determine the orientation of biological fibers and their potential to align biological fibers to trigger mechanotransduction at the scaffold cell interface. It is necessary to obtain meta materials that minutely imitate various tissue configurations by applying sonic waves to the scaffold to provide strain-induced stress generated from mechanical force to the scaffold.
  • Patent Publication No. 10-2020-0112894 (published on October 05, 2020) "Adjustable print bed for 3D printing"
  • Patent Publication No. 10-2020-0112894 "Adjustable Print Bed for 3D Printing” applies stretching to the scaffold to physically manipulate scaffold-cell interactions, and applies vibration to the scaffold to change the orientation of biological fibers. It has the potential to align biological fibers to determine and induce mechanotransduction at the scaffold cell interface, but not to provide the scaffold with strain-induced stress generated from mechanical forces by applying acoustic waves to the scaffold.
  • the present invention has been devised to solve the above problems, by applying stretching to the scaffold to physically manipulate scaffold cell interactions, by applying vibration to the scaffold to determine the direction of biological fibers, and mechanical transmission at the scaffold cell interface
  • a smart printed bed for tissue construction with biomimetic control to provide the scaffold with strain-induced stress generated from mechanical force by applying sound waves to the scaffold. Its purpose is to provide
  • each part of the edge of the scaffold 20 is fixed in a pulled state, so that the scaffold 20 is stretched based on a single axis or two or more axes It is characterized in that it includes a plurality of fixing means (12) so that the scaffold (20) is stretched in a direction based on a single axis or two or more axes.
  • a frequency converter (30) controlling the frequency and intensity of vibration of the plurality of vibration motors (32);
  • a plurality of sound wave converters 40 installed at each part of the lower part of the printed bed 10 to apply sound waves of each frequency to the scaffold 20 at a set intensity so that each strain induced stress is provided to the scaffold 20 It is characterized in that it further comprises.
  • Stretchable scaffolds that can be transformed from static to dynamic or dynamic to static provide a unique environment for simulating extracellular matrix (ECM), especially for natural piezoelectric materials such as collagen.
  • ECM extracellular matrix
  • Dynamic scaffolds are essential for cell alignment during growth and differentiation phases.
  • the scaffold 20 fibers may be aligned perpendicular or parallel to the direction of stretching. Stretching cycles and parameters can be programmed to facilitate cell alignment and tissue regeneration during the bioprinting process.
  • Biologically aligned nanofibers have been demonstrated to significantly improve the growth structure and function of cells. Currently, no such bioprinting cell scaffold technology exists.
  • the vibrational waves generated by the vibrating printing bed have the potential to align the biological fibers to determine their orientation and trigger mechanotransduction effects at the scaffold cell interface.
  • smart intelligent scaffolds can enhance the heightening and functioning of various cell types.
  • alignment of materials such as piezoelectric fibers is difficult. Therefore, it is possible to find a non-invasive and biocompatible method using vibration waves.
  • Elastomeric hydrogels composed of fibers have the ability to stretch or slide. Alignment and orientation can be triggered by vibrational waves surrounding the scaffold. The direction and degree of alignment is determined by the magnitude and frequency of the interacting waves.
  • the present invention utilizes a cell-based material to receive intracellular signals from the outside through sound vibrations and transmit sound waves absorbed in the cell surface area between cells. It visually shows various patterns that occur through sound waves.
  • This approach has the potential to uniquely tailor cells to specific cell types due to the variety of cells responding to different sound waves.
  • cells respond to specific natural vibration frequencies, imbalances in printing tissues, which are in an imperfect state, can be better corrected by using cells related to cell signals generated by a given sound wave and size.
  • the morphological coupling of tissue originates from signal transmission through mechanical conversion of nanometers through bioelectricity generated from the piezoelectric effect. This technology requires an input of external energy to enable programming of the print bed material.
  • FIG. 1 is a diagram showing two embodiments of a smart printed bed for tissue composition with biomimetic control according to the present invention.
  • FIG. 2 is a view showing each example in which a scaffold is stretched in a smart printing bed for tissue construction by biomimetic control according to FIG. 1 .
  • FIG. 3 is a block diagram showing an embodiment of a vibrating device installed in a smart printing bed for tissue composition with biomimetic control according to the present invention.
  • FIG. 4 is a view showing an embodiment of a vibrating printing bed schematically designed to transmit vibrational waves along two axes by controlling the frequency and intensity.
  • FIG. 5 is a view showing an embodiment of components of a vibrating print bed.
  • FIG. 6 is a block diagram showing an embodiment of a sound wave transducer installed in a smart printing bed for tissue composition with biomimetic control according to the present invention.
  • FIG. 7 is a view showing an example in which a plurality of sound wave converters according to FIG. 6 are installed in a print bed.
  • the present invention designs and implements a smart interactive printing bed for a new innovative bio-printer capable of generating different external but controllable energy waves to induce the growth of cells using a bioreactive scaffold through the energy waves. are proposing
  • the present invention has its significance in enhancing tissue structure and function that can replace bioengineered tissue implants. This is important to reduce loss of tissue performance.
  • the present invention uses the principle of cell response to an environment changed by an external force at a cell scaffold interface.
  • the new innovative eco-bioprinting system is a smart printed bed system that utilizes programmable materials as smart materials developed by (1) a 3D printing process or (2) a synthesis process.
  • This technology requires an input of external energy that affects the programmability of the print bed material.
  • the present invention induces deformation of the smart material by utilizing 1. Scaffolding with a stretching mode 2. Vibration 3. Sound waves as external energy.
  • FIG. 1 is a view showing two embodiments of a smart printing bed for tissue construction with biomimetic control according to the present invention, and is composed of a printing bed 10, a fixing means 12 and a scaffold 20.
  • FIG. 2 is a view showing each example in which a scaffold 20 is stretched in a smart printing bed for tissue construction by biomimetic control according to FIG. 1 .
  • FIG. 3 is a block diagram showing an embodiment of a vibrating device installed in a smart printing bed for tissue composition with biomimetic control according to the present invention, and is composed of a frequency converter 30 and a vibrating motor 32.
  • FIG. 4 is a view showing an embodiment of a vibrating printing bed 10 schematically designed to transmit vibrational waves along two axes by controlling the frequency and intensity.
  • FIG. 5 is a view showing an embodiment of the components of the vibratory printing bed 10.
  • FIG. 6 is a block diagram showing an embodiment of a sound wave transducer 40 installed in a smart printing bed for tissue composition with biomimetic control according to the present invention.
  • FIG. 7 is a view showing an example in which a plurality of sound wave converters according to FIG. 6 are installed in a print bed, and is composed of a print bed 10 and a plurality of sound wave converters 40 .
  • the printing bed 10 allows the scaffold 20 seated on the upper surface to be printed for tissue composition by biomimetic control.
  • the plurality of fixing means 12 are installed inside the edge of the upper surface of the print bed 10, respectively, and fix each part of the edge of the scaffold 20 in a pulled state so that the scaffold 20 has a single axis or two or more An axial stretch is applied so that the scaffold 20 is stretched in a single axis or two or more axis directions.
  • the fixing means 12 includes screws.
  • the print bed design supports 'static' or continuous 'cyclic' stretch modes for scaffolds with variable frequency (stretching period) and strength.
  • the scaffold can be converted from a 'relaxed' state to a 'stretched' state to change the physical alignment, orientation and intrinsic properties of the natural fiber materials constituting the scaffold.
  • Current cell sorting techniques rely on exposing cells to magnetic particles that respond to high electric fields to sort the cells.
  • the present invention uses a (a) single-axis, (b) two-axis, and (c) multi-axis approach as shown in FIG. 2 using a stretchable print bed 10 to stretch the stretchable scaffold 20 and set
  • a plurality of vibration motors 32 as shown in FIG. 3 vibrate while attached to each part of the lower end of the print bed 10 so that vibration is applied to the scaffold 20 to determine the direction of the biological fibers and at the scaffold cell interface. It has the potential to align biological fibers to trigger mechanotransduction.
  • the frequency converter 30 controls the frequency and intensity of vibration of the plurality of vibration motors 32 .
  • the frequency converter 30 is preferably installed at the bottom of the print bed 10 .
  • the frequency converter 30 may be designed to transmit vibration waves along two axes as shown in FIG. 4 by controlling the frequency and intensity of vibration of the plurality of vibration motors 32 .
  • the printed bed 10 can create a controlled mechanical strain along the interfaced scaffold 20 .
  • the transmission of vibrational energy waves from mechanical vibrations can be easily absorbed through the scaffold 20, and can strengthen or soften the scaffold 20 to increase compatibility with soft or hard elastomeric scaffolds.
  • FIG. 5 is a view showing an embodiment of the components of the vibrating print bed 10, (1) a frequency converter 30, (2) a vibrating motor 32 are all attached to (3) a printing platform to generate a vibrating print bed form (10).
  • the frequency converter 30 adjusts the vibrational energy of the vibration motor 32 by allowing controllable access to the voltage and frequency of the vibration motor 32 .
  • the vibration motor 32 may be attached to points 1, 2, 3, and 4 of the bottom of the print bed 10 .
  • a circuit program embedded in a microcontroller mounted within the plurality of vibration motors 32 allows for acceleration, deceleration, or intermittent vibration that can be set within a time range of a few seconds to a few minutes in a periodic and repetitive pattern. Enables precise control of units.
  • the operating voltage for oscillation can be set in the range of 2.5 to 3.8V.
  • a plurality of sound wave converters 40 as shown in FIGS. 6 and 7 are installed in each part of the lower part of the print bed 10 and apply sound waves of each frequency to the scaffold 20 at a set intensity to induce each deformation in the scaffold 20 Stress is provided.
  • deformation-induced stress generated from mechanical force can be applied to scaffolding or physical manipulation to accompany complex deformation by stretching.
  • the transmission of mechanical force induces a voltage that is converted into electrical activity (current flow) through a piezoelectric sensitive biocomponent.
  • any energy source capable of causing mechanical deformation may be applied as an external energy source for the programmable material embedded in the print bed 10 .
  • Cells respond differently to low and high frequencies. Cells and molecules within them can be oriented in the direction of sound waves along the crystal structure.
  • the present invention relies on local resonances located in the vicinity of cells after extrusion.
  • a plurality of sound wave transducers 40 are used to transmit energy through air to generate mechanical vibrations on the cell surface.
  • a plurality of sound wave transducers 40 are disposed at each part of the lower part of the print bed 10 so that the sound waves are distributed right below the scaffold 20 .
  • the generated wavelengths can be delivered continuously or in pulses or single bursts, depending on the nature of the cell, and can vary from low-frequency infrared acoustic waves to very high-frequency ultrasound.
  • the propagation of broad-frequency acoustic waves at the scaffold-cell interface enables triggering of various mechanisms that assist cell-cell interactions in biological materials.
  • Acoustic waves applied to the print bed 10 are designed to operate in conventional ultrasonic waves ( ⁇ MHz) ranging from a medium frequency range of 10 KHz to 1 MHz and a high frequency range of 10 MHz to 1 GHz.
  • Frequencies in the much lower range, from 40 Hz to hundreds of Hz, can exert much less force on the cell surface.
  • a higher range of frequencies can be applied to lipid cell membranes and the biological changes that occur within them.
  • the ultra-thin plate design helps to transmit these high-frequency vibrations easily.
  • the vibration function can be set to operate during printing or between cell bioprinting under certain conditions.
  • a barrier to cell patterning beyond the centimeter scale is the lack of cell-cell lineages and spheroid formation, the 3D cell aggregates in which cell signaling allows the matrix to evolve.
  • the cell's sound wave patterning is used to control the amplitude and sound image to improve the flexibility of the particle motion, leading the cells to grow into large-scale assemblies along the sound trajectory that promotes sphere formation.
  • the present invention applies stretching to the scaffold 20 to physically manipulate scaffold cell interactions, applies vibration to the scaffold 20 to determine the direction of biological fibers, and induces mechanical transmission at the scaffold cell interface. Since it has the potential to align biological fibers to the scaffold, and by applying sound waves to the scaffold 20 to provide the scaffold with strain-induced stress generated from mechanical force, metamaterials that mimic various tissue configurations are obtained There are advantages to doing it.

Landscapes

  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Materials Engineering (AREA)
  • Health & Medical Sciences (AREA)
  • Manufacturing & Machinery (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Biotechnology (AREA)
  • Mechanical Engineering (AREA)
  • Genetics & Genomics (AREA)
  • Optics & Photonics (AREA)
  • Microbiology (AREA)
  • Sustainable Development (AREA)
  • Biomedical Technology (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Medicinal Chemistry (AREA)
  • Prostheses (AREA)
  • Cell Biology (AREA)
  • Immunology (AREA)

Abstract

According to the present invention, a smart interactive print bed for a new innovative bio-printer capable of generating different external but controllable energy waves is designed and implemented to induce the growth of cells using a bio-reaction scaffold and the energy waves. The present invention has the significance of enhancing the construction and function of tissue that can replace tissue implants made through bioengineering. These benefits are important to reduce the loss of tissue performance. The invention uses the principle of cellular response to an environment that changes due to external force at a cellular scaffold interface. Here, the new innovative eco-bio-printing system is a smart print bed system utilizing a programmable material as a smart material developed by (1) a 3D printing process or (2) a synthesis process. This technique requires the input of external energy affecting the programmability of the print bed material. The present invention induces deformation of the smart material by utilizing, as the external energy, 1. the scaffold to which stretching mode has been applied, 2. oscillation, 3. sound waves.

Description

생체모방 제어로 조직구성을 위한 스마트 인쇄 베드Smart printed bed for tissue construction with biomimetic control
본 발명은 생체모방 제어로 조직구성을 위한 스마트 인쇄 베드에 관한 것이다.The present invention relates to a smart printed bed for tissue construction with biomimetic control.
현재 3차원 세포 구조의 조립을 위해 적층 제조를 이용한 조직 공학은 의료용 장기 임플란트에 상당한 가능성을 가지고 있다. 그러나 연골과 뼈와 같은 세포 간 물질의 임상 적용을 위한 현재 바이오 프린팅 기술의 한계는 유도된 조립(guided assembly)과 다차원 조직의 성숙에 의존한다. 이러한 한계는 현재의 바이오 프린팅 기술 플랫폼은 체내 의료 애플리케이션에 기능적으로 유용한 생체 조직 아키텍처를 인쇄할 수 있는 기능에서 설계에 의해 제약을 받는다.Currently, tissue engineering using additive manufacturing for the assembly of three-dimensional cellular structures holds significant promise for medical long-term implants. However, a limitation of current bioprinting techniques for clinical application of intercellular materials such as cartilage and bone is their dependence on guided assembly and maturation of multidimensional tissues. This limitation is that current bioprinting technology platforms are constrained by design in their ability to print functionally useful biotissue architectures for in vivo medical applications.
이러한 제약을 극복하기 위하여 본 발명은: 1. 최첨단 바이오 프린팅 플랫폼을 도입해 임상등급(clinical grade) 제품을 완전하게 기능을 다하는 대체 조직과 장기로서의 개발을 앞당길 예정이며 2. 4차원 인쇄 배드 디자인 기능은 멀티 셀 및 멀티 셀 유형의 조합을 유도하는 스마트 바이오 리스펀시브 비계 환경의 역학과 고유하게 호환되고 제어될 수 있으며, 그리고 3. 이 기술은 세포 내 나노스케일 인자를 세포 외 기질(ECM)의 구성요소에 동기화 함으로써 조직 성장에 영향을 미칠 것이다. 이는 현재 시중에 아직 나오지 않은 스마트(4D) 바이오 프린터의 '차세대'로 나아가는데 큰 진보를 의미한다.In order to overcome these limitations, the present invention: 1. By introducing a state-of-the-art bioprinting platform, it is planned to accelerate the development of fully functional replacement tissues and organs for clinical grade products, and 2. 4D printed bed design function. is uniquely compatible with and controllable with the dynamics of a smart bio-responsive scaffold environment that induces the combination of multi-cells and multi-cell types, and 3. This technology converts intracellular nanoscale factors to the extracellular matrix (ECM). Synchronizing components will influence organizational growth. This represents a major step towards the 'next generation' of smart (4D) bioprinters that are not currently on the market.
집단 세포 간 통신은 생물학적 정보의 흐름에 매우 중요하며 세포 구조가 셀 별 프로세스로부터 생물학적 기능을 정의하는 3차원 형태로 올바르게 만들어 지도록 보장한다. 아무런 기능이 없는 미성숙 세포는 기능성 세포로 특화되기 위하여 다양한 방법으로 생물학적 기능을 읽는다. 세포 경로를 제어하는 것은 결코 사소한 것이 아니며 조직 재생 실패의 주요 원인이다. 성장 및 억제 요인, 단백질, 효소 펩타이드, 복합당류, 당단백질 및 기타 중요한 성분을 포함하는 기질 네트워크의 '올바른' 구성을 보장하기 위한 신호 전달. 3D 바이오 프린팅은 셀 성장에 대한 방향의 레이어링을 제공 할 수 있지만, 현재의 바이오 프린팅 기술은 (1) 인쇄 가능한 바이오잉크 형태로 기질의 구성 (2) 모양과 (3) 역학을 모방할 만큼 충분히 발전되지 않았다. 기질은 세포-세포 및 세포-비계 인터페이스에서 조직의 방향적, 형태학적 성장을 위해 발생되는 전이 신호를 위해 기계적, 전기적, 표면적 접착에서 생성된 힘과 같은 필수 생물물리학적 신호를 제공한다. 이는 매우 중요하며, 아직 바이오 프린팅 기술 분야에서 충족되지 못한 기술이다.Collective cell-to-cell communication is critical to the flow of biological information and ensures that cellular structures are built correctly from cell-by-cell processes to three-dimensional shapes that define biological functions. Immature cells without any function read biological functions in various ways to specialize into functional cells. Controlling cellular pathways is by no means trivial and is a major cause of tissue regeneration failure. Signal transduction to ensure the 'correct' organization of the substrate network, including growth and inhibitory factors, proteins, enzyme peptides, complex sugars, glycoproteins and other important components. 3D bioprinting can provide directional layering for cell growth, but current bioprinting technologies are advanced enough to mimic (1) the construction of substrates in the form of printable bioinks (2) their shapes and (3) their mechanics. It didn't work. Matrices provide essential biophysical signals, such as mechanical, electrical, and force generated from superficial adhesion, for transition signals generated for directional and morphological growth of tissues at cell-cell and cell-scaffold interfaces. This is a very important and unmet technology in the field of bioprinting technology.
따라서 비계에 스트레칭을 가하여 비계 세포 상호작용을 물리적으로 조작할 수 있도록 하고, 비계에 진동을 가하여 생물학적 섬유의 방향을 결정하고 비계 세포 인터페이스에서 기계 전달을 유발하기 위해 생물학적 섬유를 정렬할 수 있는 잠재력을 가지고 있도록 하며, 비계에 음파(Sonic wave)를 가하여 기계적인 힘에서 발생하는 변형 유도 응력을 비계에 제공하도록 함으로써 다양한 조직구성을 미세하게 모방한 메타 물질(meta materials)을 획득하도록 할 필요가 있다.Therefore, the application of stretching to the scaffold allows physical manipulation of scaffold cell interactions, and the application of vibration to the scaffold to determine the orientation of biological fibers and their potential to align biological fibers to trigger mechanotransduction at the scaffold cell interface. It is necessary to obtain meta materials that minutely imitate various tissue configurations by applying sonic waves to the scaffold to provide strain-induced stress generated from mechanical force to the scaffold.
이와 관련된 선행기술문헌 정보 : 공개특허공보 제10-2020-0112894호(공개일자 2020년10월05일) "3D 인쇄를 위한 조정가능한 프린트 베드"Prior art literature information related to this: Patent Publication No. 10-2020-0112894 (published on October 05, 2020) "Adjustable print bed for 3D printing"
이와 같은 선행기술문헌에 따른 "3D 인쇄를 위한 조정가능한 프린트 베드"는 지지 재료에 대한 필요성을 감소시킴으로써 물체의 3D 스캐닝 및 인쇄를 용이하게 하도록 한다.This prior art “adjustable print bed for 3D printing” facilitates 3D scanning and printing of objects by reducing the need for support materials.
그러나, 공개특허공보 제10-2020-0112894호 "3D 인쇄를 위한 조정가능한 프린트 베드"는 비계에 스트레칭을 가하여 비계 세포 상호작용을 물리적으로 조작할 수 있도록 하고, 비계에 진동을 가하여 생물학적 섬유의 방향을 결정하고 비계 세포 인터페이스에서 기계 전달을 유발하기 위해 생물학적 섬유를 정렬할 수 있는 잠재력을 가지고 있도록 하며, 비계에 음파를 가하여 기계적인 힘에서 발생하는 변형 유도 응력을 비계에 제공하도록 하지는 못한다.However, Patent Publication No. 10-2020-0112894 "Adjustable Print Bed for 3D Printing" applies stretching to the scaffold to physically manipulate scaffold-cell interactions, and applies vibration to the scaffold to change the orientation of biological fibers. It has the potential to align biological fibers to determine and induce mechanotransduction at the scaffold cell interface, but not to provide the scaffold with strain-induced stress generated from mechanical forces by applying acoustic waves to the scaffold.
본 발명은 전술한 과제를 해결하기 위하여 안출한 것으로, 비계에 스트레칭을 가하여 비계 세포 상호작용을 물리적으로 조작할 수 있도록 하고, 비계에 진동을 가하여 생물학적 섬유의 방향을 결정하고 비계 세포 인터페이스에서 기계 전달을 유발하기 위해 생물학적 섬유를 정렬할 수 있는 잠재력을 가지고 있도록 하며, 비계에 음파를 가하여 기계적인 힘에서 발생하는 변형 유도 응력을 비계에 제공하도록 하기 위한 생체모방 제어로 조직구성을 위한 스마트 인쇄 베드를 제공하는데 그 목적이 있다.The present invention has been devised to solve the above problems, by applying stretching to the scaffold to physically manipulate scaffold cell interactions, by applying vibration to the scaffold to determine the direction of biological fibers, and mechanical transmission at the scaffold cell interface A smart printed bed for tissue construction with biomimetic control to provide the scaffold with strain-induced stress generated from mechanical force by applying sound waves to the scaffold. Its purpose is to provide
이와 같은 목적을 달성하기 위하여,To achieve this purpose,
본 발명의 일 형태에 따르면,According to one aspect of the present invention,
상면에 안착된 비계(20)에 생체모방 제어로 조직구성을 위한 인쇄가 진행되도록 하는 인쇄 베드(10)로서,As a printing bed 10 that allows printing for tissue composition to proceed with biomimetic control on the scaffold 20 seated on the upper surface,
상기 인쇄 베드(10)의 상면의 가장자리 내측에 각기 설치되어 상기 비계(20)의 가장자리의 각 부분을 당긴 상태로 고정시켜 상기 비계(20)에 단일 축 또는 2개 이상의 축에 의거하는 스트레칭이 가해지도록 해서 상기 비계(20)가 단일 축 또는 2개 이상의 축에 의거하는 방향으로 늘어나도록 하는 복수의 고정 수단(12)을 포함하는 것을 특징으로 한다.It is installed inside the edge of the upper surface of the print bed 10, and each part of the edge of the scaffold 20 is fixed in a pulled state, so that the scaffold 20 is stretched based on a single axis or two or more axes It is characterized in that it includes a plurality of fixing means (12) so that the scaffold (20) is stretched in a direction based on a single axis or two or more axes.
상기 인쇄 베드(10)의 하단의 각 부분에 부착된 상태에서 진동하여 상기 비계(20)에 진동이 가해지도록 해서 생물학적 섬유의 방향을 결정하고 비계 세포 인터페이스에서 기계 전달을 유발하기 위해 생물학적 섬유를 정렬할 수 있는 잠재력을 가지고 있도록 하는 복수의 진동 모터(32); 및Vibrating while attached to each part of the lower end of the printing bed 10 so that the scaffold 20 is vibrated to determine the direction of the biological fibers and align the biological fibers to cause mechanical transmission at the scaffold cell interface A plurality of vibration motors 32 that have the potential to do; and
상기 복수의 진동 모터(32)의 진동수와 진동세기를 제어하는 주파수 변환기(30);a frequency converter (30) controlling the frequency and intensity of vibration of the plurality of vibration motors (32);
를 더 포함하는 것을 특징으로 한다.It is characterized in that it further comprises.
상기 인쇄 베드(10)의 하부의 각 부분에 설치되어 상기 비계(20)에 각 주파수의 음파를 설정된 강도로 가하여 상기 비계(20)에 각 변형 유도 응력이 제공되도록 하는 복수의 음파 변환기(40)를 더 포함하는 것을 특징으로 한다.A plurality of sound wave converters 40 installed at each part of the lower part of the printed bed 10 to apply sound waves of each frequency to the scaffold 20 at a set intensity so that each strain induced stress is provided to the scaffold 20 It is characterized in that it further comprises.
정적 상태에서 동적 상태로 혹은 동적 상태에서 정적 상태로 변환될 수 있는 신축성 비계는 특히 콜라겐과 같은 자연 압전 물질에 대해 Extracellular Matric(ECM: 세포외 매트릭)을 시뮬레이션 하기 위한 고유의 환경을 제공한다. 동적 비계는 성장과 분화 단계에서 세포의 정렬에 필수 적이다. 비계(20) 섬유는 늘어나는 방향에 대해 수직으로 또는 평행하게 정렬 될 수 있다. 스트레칭 사이클과 파라미터는 바이오 프린팅 과정 동안 세포 정렬과 조직 재생이 원활하게 될 수 있도록 프로그래밍 될 수 있다. 생물학적으로 정렬된 나노섬유는 세포의 성장 구조와 기능을 크게 향상시키는 것으로 입증 되었다. 현재 이러한 바이오 프린팅 세포 비계 기술은 존재하지 않는다.Stretchable scaffolds that can be transformed from static to dynamic or dynamic to static provide a unique environment for simulating extracellular matrix (ECM), especially for natural piezoelectric materials such as collagen. Dynamic scaffolds are essential for cell alignment during growth and differentiation phases. The scaffold 20 fibers may be aligned perpendicular or parallel to the direction of stretching. Stretching cycles and parameters can be programmed to facilitate cell alignment and tissue regeneration during the bioprinting process. Biologically aligned nanofibers have been demonstrated to significantly improve the growth structure and function of cells. Currently, no such bioprinting cell scaffold technology exists.
진동하는 인쇄 베드에서 생성되는 진동파는 생물학적 섬유의 방향을 결정하고 비계 세포 인터페이스에서 기계 전달 효과를 유발하기 위해 생물학적 섬유를 정렬할 수 있는 잠재력을 가지고 있다. 제어된 기계적 응력의 조건에서, 스마트 지능형 비계는 다양한 세포 유형의 고조와 기능을 향상 시킬 수 있다. 그러나, 압전섬유와 같은 물질의 정렬은 어렵다. 따라서, 진동파를 이용하여 비침입적이고 생체적으로 적합한 방법을 찾을 수 있다. 섬유로 구성된 탄성중합체 하이드로겔은 늘어나거나 미끄러지는 능력이 있다. 정렬과 방향은 비계를 둘러싼 진동파에 의해 촉발될 수 있다. 정렬의 방향과 정도는 상호작용하는 파동의 크기와 빈도에 의해 결정된다.The vibrational waves generated by the vibrating printing bed have the potential to align the biological fibers to determine their orientation and trigger mechanotransduction effects at the scaffold cell interface. Under conditions of controlled mechanical stress, smart intelligent scaffolds can enhance the heightening and functioning of various cell types. However, alignment of materials such as piezoelectric fibers is difficult. Therefore, it is possible to find a non-invasive and biocompatible method using vibration waves. Elastomeric hydrogels composed of fibers have the ability to stretch or slide. Alignment and orientation can be triggered by vibrational waves surrounding the scaffold. The direction and degree of alignment is determined by the magnitude and frequency of the interacting waves.
세포-세포 및 세포-비계 인터페이스에서 기계적 변형을 유도하기 위한 비침해적 접근법으로 음파를 이용하는 방법이 있다. 본 발명은 세포기반 소재를 활용하여 음진동을 통해 세포 내 신호를 외부에서 수신하고 세포 표면 영역에서 흡수된 음파를 전달해 세포 간 전달한다. 음파를 통해 발생하는 다양한 패턴을 시각적으로 보여준다. 이 접근법은 다양한 음파에 따라 반응하는 다양한 세포들로 인하여 특정 세포 유형에 맞게 고유하게 세포를 변형할 수 있는 잠재적 능력을 가지고 있다. 세포가 특정 자연 진동 주파수에 반응하는 경우, 주어진 음파와 크기에 의해 생성된 세포 신호와 관련된 세포를 이용하여 불완전한 상태인 인쇄 조직(printing tissues)의 불균형을 더 잘 교정할 수 있다. 조직의 형태학적 결합은 압전 효과에서 발생하는 생체전기를 통한 나노미터 단위의 기계적인 변환을 통한 신호 전달에서 비롯된다. 이 기술은 인쇄 베드 재료의 프로그래밍을 가능하게 하는 외부 에너지의 입력을 필요로 한다.There is a method using sound waves as a non-invasive approach to induce mechanical deformation at cell-cell and cell-scaffold interfaces. The present invention utilizes a cell-based material to receive intracellular signals from the outside through sound vibrations and transmit sound waves absorbed in the cell surface area between cells. It visually shows various patterns that occur through sound waves. This approach has the potential to uniquely tailor cells to specific cell types due to the variety of cells responding to different sound waves. When cells respond to specific natural vibration frequencies, imbalances in printing tissues, which are in an imperfect state, can be better corrected by using cells related to cell signals generated by a given sound wave and size. The morphological coupling of tissue originates from signal transmission through mechanical conversion of nanometers through bioelectricity generated from the piezoelectric effect. This technology requires an input of external energy to enable programming of the print bed material.
도 1은 본 발명에 따른 생체모방 제어로 조직구성을 위한 스마트 인쇄 베드의 두 실시 예를 나타낸 도면이다.1 is a diagram showing two embodiments of a smart printed bed for tissue composition with biomimetic control according to the present invention.
도 2는 도 1에 따른 생체모방 제어로 조직구성을 위한 스마트 인쇄 베드에서 비계가 늘어나는 각 예를 나타낸 도면이다.FIG. 2 is a view showing each example in which a scaffold is stretched in a smart printing bed for tissue construction by biomimetic control according to FIG. 1 .
도 3은 본 발명에 따른 생체모방 제어로 조직구성을 위한 스마트 인쇄 베드에 설치되는 진동 장치의 일 실시 예를 나타낸 블록도이다.3 is a block diagram showing an embodiment of a vibrating device installed in a smart printing bed for tissue composition with biomimetic control according to the present invention.
도 4는 진동수와 세기의 제어로 진동파를 2개의 축을 따라 전달하도록 설계된 것을 도식화 한 진동 인쇄 베드의 일 실시 예를 나타낸 도면이다.4 is a view showing an embodiment of a vibrating printing bed schematically designed to transmit vibrational waves along two axes by controlling the frequency and intensity.
도 5는 진동 인쇄 베드의 구성 요소의 일 실시 예를 나타낸 도면이다.5 is a view showing an embodiment of components of a vibrating print bed.
도 6은 본 발명에 따른 생체모방 제어로 조직구성을 위한 스마트 인쇄 베드에 설치되는 음파 변환기의 일 실시 예를 나타낸 블록도이다.6 is a block diagram showing an embodiment of a sound wave transducer installed in a smart printing bed for tissue composition with biomimetic control according to the present invention.
도 7은 도 6에 따른 복수의 음파 변환기가 인쇄 베드에 설치되는 예를 나타낸 도면이다.FIG. 7 is a view showing an example in which a plurality of sound wave converters according to FIG. 6 are installed in a print bed.
본 발명은 서로 다른 외부적인 하지만 제어 가능한 에너지파를 생성할 수 있는 새로운 혁신 바이오 프린터를 위한 스마트 인터랙티브 인쇄 베드를 설계하고 구현하여 그 에너지파를 통해 생체 반응 비계를 사용하는 세포의 성장을 유도할 것을 제안하고 있다. 본 발명은 생체 공학적으로 만들어진 조직 임플란트를 대체 할 수 있는 조직 구조와 기능을 강화함에 그 의의가 있다. 이것은 조직 성능의 손실을 줄이기 위해 중요하다.The present invention designs and implements a smart interactive printing bed for a new innovative bio-printer capable of generating different external but controllable energy waves to induce the growth of cells using a bioreactive scaffold through the energy waves. are proposing The present invention has its significance in enhancing tissue structure and function that can replace bioengineered tissue implants. This is important to reduce loss of tissue performance.
본 발명은 세포 비계 인터페이스에서 외부의 힘에 의해 변화하는 환경에 대한 세포 반응의 원리를 사용한다. 여기서, 새로운 혁신적인 에코 바이오 프린팅 시스템은 (1) 3D 프린팅 공정 또는 (2) 합성 공정에 의해 개발된 스마트 재료로 프로그래밍 가능한 물질을 활용하는 스마트 인쇄 베드 시스템이다. 이 기술은 인쇄 베드 재료의 프로그래밍 가능성에 영향을 미치는 외부 에너지의 입력을 필요로 한다. 본 발명은 그 외부 에너지로써, 1. 스트레칭 모드가 적용된 비계 2. 진동 3. 음파를 활용하여 스마트 재료의 변형을 유도한다.The present invention uses the principle of cell response to an environment changed by an external force at a cell scaffold interface. Here, the new innovative eco-bioprinting system is a smart printed bed system that utilizes programmable materials as smart materials developed by (1) a 3D printing process or (2) a synthesis process. This technology requires an input of external energy that affects the programmability of the print bed material. The present invention induces deformation of the smart material by utilizing 1. Scaffolding with a stretching mode 2. Vibration 3. Sound waves as external energy.
이하, 첨부된 도면을 참조하여 본 발명에 따른 실시 예를 상세히 설명하면 다음과 같다.Hereinafter, embodiments according to the present invention will be described in detail with reference to the accompanying drawings.
도 1은 본 발명에 따른 생체모방 제어로 조직구성을 위한 스마트 인쇄 베드의 두 실시 예를 나타낸 도면으로, 인쇄 베드(10), 고정 수단(12) 및 비계(20)로 구성된다.1 is a view showing two embodiments of a smart printing bed for tissue construction with biomimetic control according to the present invention, and is composed of a printing bed 10, a fixing means 12 and a scaffold 20.
이와 같은 본 발명을 도 2 내지 도 7을 참조하여 상세히 보면 다음과 같다.The present invention will be described in detail with reference to FIGS. 2 to 7 .
도 2는 도 1에 따른 생체모방 제어로 조직구성을 위한 스마트 인쇄 베드에서 비계(20)가 늘어나는 각 예를 나타낸 도면이다.FIG. 2 is a view showing each example in which a scaffold 20 is stretched in a smart printing bed for tissue construction by biomimetic control according to FIG. 1 .
도 3은 본 발명에 따른 생체모방 제어로 조직구성을 위한 스마트 인쇄 베드에 설치되는 진동 장치의 일 실시 예를 나타낸 블록도로, 주파수 변환기(30) 및 진동 모터(32)로 구성된다.3 is a block diagram showing an embodiment of a vibrating device installed in a smart printing bed for tissue composition with biomimetic control according to the present invention, and is composed of a frequency converter 30 and a vibrating motor 32.
도 4는 진동수와 세기의 제어로 진동파를 2개의 축을 따라 전달하도록 설계된 것을 도식화 한 진동 인쇄 베드(10)의 일 실시 예를 나타낸 도면이다.4 is a view showing an embodiment of a vibrating printing bed 10 schematically designed to transmit vibrational waves along two axes by controlling the frequency and intensity.
도 5는 진동 인쇄 베드(10)의 구성 요소의 일 실시 예를 나타낸 도면이다.5 is a view showing an embodiment of the components of the vibratory printing bed 10.
도 6은 본 발명에 따른 생체모방 제어로 조직구성을 위한 스마트 인쇄 베드에 설치되는 음파 변환기(40)의 일 실시 예를 나타낸 블록도이다.6 is a block diagram showing an embodiment of a sound wave transducer 40 installed in a smart printing bed for tissue composition with biomimetic control according to the present invention.
도 7은 도 6에 따른 복수의 음파 변환기가 인쇄 베드에 설치되는 예를 나타낸 도면으로, 인쇄 베드(10) 및 복수의 음파 변환기(40)로 구성된다.FIG. 7 is a view showing an example in which a plurality of sound wave converters according to FIG. 6 are installed in a print bed, and is composed of a print bed 10 and a plurality of sound wave converters 40 .
도 1 내지 도 7에 있어서, 인쇄 베드(10)는 상면에 안착된 비계(20)에 생체모방 제어로 조직구성을 위한 인쇄가 진행되도록 한다.1 to 7, the printing bed 10 allows the scaffold 20 seated on the upper surface to be printed for tissue composition by biomimetic control.
즉, 복수의 고정 수단(12)은 인쇄 베드(10)의 상면의 가장자리 내측에 각기 설치되어 비계(20)의 가장자리의 각 부분을 당긴 상태로 고정시켜 비계(20)에 단일 축 또는 2개 이상의 축에 의거하는 스트레칭이 가해지도록 해서 비계(20)가 단일 축 또는 2개 이상의 축에 의거하는 방향으로 늘어나도록 한다. 고정 수단(12)은 나사못을 포함한다.That is, the plurality of fixing means 12 are installed inside the edge of the upper surface of the print bed 10, respectively, and fix each part of the edge of the scaffold 20 in a pulled state so that the scaffold 20 has a single axis or two or more An axial stretch is applied so that the scaffold 20 is stretched in a single axis or two or more axis directions. The fixing means 12 includes screws.
인쇄 베드 디자인은 가변 주파수(스트레칭 주기)와 강도를 가진 비계에 대하여 '정적' 또는 연속적 '순환' 스트레치 모드를 지원한다. 비계는 '릴렉스'된 상태에서 '늘어난' 상태로 전환되어 비계를 구성하는 천연 섬유 물질의 물리적 정렬, 방향 및 고유 특성을 변화시킬 수 있다. 현재 세포 정렬기술은 세포를 정렬하기 위해 높은 전기장에 반응하는 자기 입자에 셀을 노출시키는 방법에 의존한다. 본 발명은 스트레칭이 가능한 인쇄 베드(10)를 사용하여 도 2와 같이 (a) 단일 축, (b) 2개의 축 및 (c) 다중축 접근법을 사용하여 스트레칭이 가능한 비계(20)를 늘리고 방향을 설정한다.The print bed design supports 'static' or continuous 'cyclic' stretch modes for scaffolds with variable frequency (stretching period) and strength. The scaffold can be converted from a 'relaxed' state to a 'stretched' state to change the physical alignment, orientation and intrinsic properties of the natural fiber materials constituting the scaffold. Current cell sorting techniques rely on exposing cells to magnetic particles that respond to high electric fields to sort the cells. The present invention uses a (a) single-axis, (b) two-axis, and (c) multi-axis approach as shown in FIG. 2 using a stretchable print bed 10 to stretch the stretchable scaffold 20 and set
도 3과 같은 복수의 진동 모터(32)는 인쇄 베드(10)의 하단의 각 부분에 부착된 상태에서 진동하여 비계(20)에 진동이 가해지도록 해서 생물학적 섬유의 방향을 결정하고 비계 세포 인터페이스에서 기계 전달을 유발하기 위해 생물학적 섬유를 정렬할 수 있는 잠재력을 가지고 있도록 한다.A plurality of vibration motors 32 as shown in FIG. 3 vibrate while attached to each part of the lower end of the print bed 10 so that vibration is applied to the scaffold 20 to determine the direction of the biological fibers and at the scaffold cell interface. It has the potential to align biological fibers to trigger mechanotransduction.
주파수 변환기(30)는 복수의 진동 모터(32)의 진동수와 진동세기를 제어한다. 이때 주파수 변환기(30)는 인쇄 베드(10)의 하단에 설치되는 것이 바람직하다.The frequency converter 30 controls the frequency and intensity of vibration of the plurality of vibration motors 32 . At this time, the frequency converter 30 is preferably installed at the bottom of the print bed 10 .
주파수 변환기(30)가 복수의 진동 모터(32)의 진동수와 진동세기를 제어하여 도 4와 같이 진동파를 2개의 축을 따라 전달하도록 설계할 수 있다. 이와 같은 설계를 통해 인쇄 베드(10)는 인터페이스된 비계(20)를 따라 제어된 기계적 변형률을 만들어 낼 수 있다. 기계적 진동으로부터의 진동 에너지파의 전달은 비계(20)를 통해 쉽게 흡수될 수 있으며, 비계(20)를 강화하거나 부드럽게 하여 부드럽거나 단단한 탄성중합체 비계와의 호환성을 높일 수 있다.The frequency converter 30 may be designed to transmit vibration waves along two axes as shown in FIG. 4 by controlling the frequency and intensity of vibration of the plurality of vibration motors 32 . Through this design, the printed bed 10 can create a controlled mechanical strain along the interfaced scaffold 20 . The transmission of vibrational energy waves from mechanical vibrations can be easily absorbed through the scaffold 20, and can strengthen or soften the scaffold 20 to increase compatibility with soft or hard elastomeric scaffolds.
도 5는 진동 인쇄 베드(10)의 구성 요소의 일 실시 예를 나타낸 도면으로, (1) 주파수 변환기(30) (2) 진동 모터(32)는 모두 (3)인쇄 플랫폼에 부착되어 진동 인쇄 베드(10)를 형성한다. 주파수 변환기(30)는 진동 모터(32)의 전압 및 주파수에 대하여 제어 가능한 접근을 허용하여 진동 모터(32)의 진동 에너지를 조절한다. 진동 모터(32)는 인쇄 베드(10) 하단 1, 2, 3, 및 4 지점에 부착될 수 있다. 복수의 진동 모터(32) 내에 장착되어 있는 마이크로 컨트롤러에 내장된 회로 프로그램은 주기적이고 반복적인 패턴으로 몇 초에서 몇 분까지의 시간 범위 내에서 설정될 수 있는 가속, 감속 또는 간헐적 진동을 허용하며 마이크로 단위의 정밀한 제어를 가능케 한다. 진동을 위한 작동 전압은 2.5~3.8V 범위로 설정할 수 있다.5 is a view showing an embodiment of the components of the vibrating print bed 10, (1) a frequency converter 30, (2) a vibrating motor 32 are all attached to (3) a printing platform to generate a vibrating print bed form (10). The frequency converter 30 adjusts the vibrational energy of the vibration motor 32 by allowing controllable access to the voltage and frequency of the vibration motor 32 . The vibration motor 32 may be attached to points 1, 2, 3, and 4 of the bottom of the print bed 10 . A circuit program embedded in a microcontroller mounted within the plurality of vibration motors 32 allows for acceleration, deceleration, or intermittent vibration that can be set within a time range of a few seconds to a few minutes in a periodic and repetitive pattern. Enables precise control of units. The operating voltage for oscillation can be set in the range of 2.5 to 3.8V.
도 6 및 도 7과 같은 복수의 음파 변환기(40)는 인쇄 베드(10)의 하부의 각 부분에 설치되어 비계(20)에 각 주파수의 음파를 설정된 강도로 가하여 비계(20)에 각 변형 유도 응력이 제공되도록 한다.A plurality of sound wave converters 40 as shown in FIGS. 6 and 7 are installed in each part of the lower part of the print bed 10 and apply sound waves of each frequency to the scaffold 20 at a set intensity to induce each deformation in the scaffold 20 Stress is provided.
세포 표면의 음파에 의해 유발된 응력은 세포 고유의 변화를 일으키는 전류 신호를 생성한다.Stress induced by sound waves on the cell surface creates current signals that cause cell-specific changes.
음파를 사용하여 기계적인 힘에서 발생하는 변형 유도 응력을 비계나 물리적 조작에 가하여 스트레칭에 의한 복합적 변형을 수반하도록 할 수 있다. 기계적 힘의 전달은 압전에 민감한 생체 성분을 통해 전기적 활동(전류 흐름)으로 변환되는 전압을 유도한다. 그러나 인쇄 베드(10)에 내장된 프로그래밍 가능한 재료에 대한 외부 에너지원은 기계적 변형을 유발할 수 있는 어떠한 에너지원 이라도 적용될 수 있다.By using sound waves, deformation-induced stress generated from mechanical force can be applied to scaffolding or physical manipulation to accompany complex deformation by stretching. The transmission of mechanical force induces a voltage that is converted into electrical activity (current flow) through a piezoelectric sensitive biocomponent. However, any energy source capable of causing mechanical deformation may be applied as an external energy source for the programmable material embedded in the print bed 10 .
세포는 낮은 주파수와 높은 주파수에 따라 다르게 반응한다. 세포와 그 안에 있는 분자들은 결정 구조를 따라 음파 방향으로 방향을 잡을 수 있다.Cells respond differently to low and high frequencies. Cells and molecules within them can be oriented in the direction of sound waves along the crystal structure.
본 발명은 압출 후 세포 근방에 위치한 로컬 공명에 의존한다. 복수의 음파 변환기(40)는 공기를 통해 에너지를 전달하여 세포 표면에 기계적 진동을 발생시키는데 사용된다. 복수의 음파 변환기(40)는 비계(20) 바로 아래에 음파가 분산되도록 인쇄 베드(10)의 하부의 각 부분에 배치된다. 생성된 파장은 세포의 특성에 따라 연속적이거나 펄스 또는 싱글 버스트(burst)로 전달될 수 있으며 저주파 적외선 음파부터 매우 높은 주파수의 초음파에 이르기까지 변경될 수 있다.The present invention relies on local resonances located in the vicinity of cells after extrusion. A plurality of sound wave transducers 40 are used to transmit energy through air to generate mechanical vibrations on the cell surface. A plurality of sound wave transducers 40 are disposed at each part of the lower part of the print bed 10 so that the sound waves are distributed right below the scaffold 20 . The generated wavelengths can be delivered continuously or in pulses or single bursts, depending on the nature of the cell, and can vary from low-frequency infrared acoustic waves to very high-frequency ultrasound.
비계-세포 인터페이스에서 광범위한 주파수의 음파 전달은 생물학적 물질들의 세포-세포간 상호작용을 도와주는 다양한 메커니즘을 촉발할 수 있게 한다.The propagation of broad-frequency acoustic waves at the scaffold-cell interface enables triggering of various mechanisms that assist cell-cell interactions in biological materials.
인쇄 베드(10)에 가해지는 음파는 일반적으로 10KHz - 1MHz의 중간 주파수 범위와 10MHz - 1GHz의 높은 주파수 영역에 이르는 기존의 초음파(≤MHz)에서 작동하도록 설계된다. 이보다 훨씬 더 낮은 범위의 40Hz에서 수백Hz까지의 주파수는 세포 표면에 훨씬 더 적은 힘을 가할 수 있다. 더 높은 범위의 주파수는 지질 세포막과 그 안에 일어나는 생물학적 변화에 적용될 수 있다. 초박형 판 디자인은 이러한 고주파 진동을 용이하게 전달하는데 도움이 된다. 진동 기능은 인쇄 중 또는 일정한 조건에서의 세포 바이오 프린팅 사이에 작동하도록 설정할 수 있다. 센티미터 단위 이상의 세포 패턴화에 대한 장벽은 세포-세포 계통과 세포 신호가 기질이 진화할 수 있도록 하는 3D 세포 집합체인 구형 형성(spheroid formation)의 부족이다. 본 발명에서는 세포의 음파 패턴화를 이용하여 진폭과 음상을 제어해서 입자 움직임의 유연성을 개선하여 구형 형성을 촉진하는 소리 궤적을 따라 세포를 대규모 조립체로 성장하도록 유도한다.Acoustic waves applied to the print bed 10 are designed to operate in conventional ultrasonic waves (≤ MHz) ranging from a medium frequency range of 10 KHz to 1 MHz and a high frequency range of 10 MHz to 1 GHz. Frequencies in the much lower range, from 40 Hz to hundreds of Hz, can exert much less force on the cell surface. A higher range of frequencies can be applied to lipid cell membranes and the biological changes that occur within them. The ultra-thin plate design helps to transmit these high-frequency vibrations easily. The vibration function can be set to operate during printing or between cell bioprinting under certain conditions. A barrier to cell patterning beyond the centimeter scale is the lack of cell-cell lineages and spheroid formation, the 3D cell aggregates in which cell signaling allows the matrix to evolve. In the present invention, the cell's sound wave patterning is used to control the amplitude and sound image to improve the flexibility of the particle motion, leading the cells to grow into large-scale assemblies along the sound trajectory that promotes sphere formation.
이와 같은 본 발명은 비계(20)에 스트레칭을 가하여 비계 세포 상호작용을 물리적으로 조작할 수 있도록 하고, 비계(20)에 진동을 가하여 생물학적 섬유의 방향을 결정하고 비계 세포 인터페이스에서 기계 전달을 유발하기 위해 생물학적 섬유를 정렬할 수 있는 잠재력을 가지고 있도록 하며, 비계(20)에 음파를 가하여 기계적인 힘에서 발생하는 변형 유도 응력을 비계에 제공하도록 하기 때문에 다양한 조직구성을 미세하게 모방한 메타 물질을 획득하게 되는 장점이 있다.As such, the present invention applies stretching to the scaffold 20 to physically manipulate scaffold cell interactions, applies vibration to the scaffold 20 to determine the direction of biological fibers, and induces mechanical transmission at the scaffold cell interface. Since it has the potential to align biological fibers to the scaffold, and by applying sound waves to the scaffold 20 to provide the scaffold with strain-induced stress generated from mechanical force, metamaterials that mimic various tissue configurations are obtained There are advantages to doing it.
이상에서 본 발명에 대한 기술사상을 첨부도면과 함께 서술하였지만 이는 본 발명의 바람직한 실시 예를 예시적으로 설명한 것이지 본 발명을 한정하는 것은 아니다. 또한, 이 기술분야의 통상의 지식을 가진 자라면 누구나 본 발명의 기술사상의 범주를 이탈하지 않는 범위 내에서 다양한 변형 및 모방이 가능함은 명백한 사실이다.Although the technical idea of the present invention has been described above with the accompanying drawings, this is an illustrative example of a preferred embodiment of the present invention, but does not limit the present invention. In addition, it is obvious that various modifications and imitations can be made by anyone skilled in the art within the scope of the technical idea of the present invention.
<부호의 설명><Description of codes>
10 : 인쇄 베드10: print bed
12 : 고정 수단12: fixing means
20 : 비계20: scaffolding
30 : 주파수 변환기30: frequency converter
32 : 진동 모터32: vibration motor
40 : 음파 변환기40: sound wave converter

Claims (2)

  1. 상면에 안착된 비계(20)에 생체모방 제어로 조직구성을 위한 인쇄가 진행되도록 하는 인쇄 베드(10)로서,As a printing bed 10 that allows printing for tissue composition to proceed with biomimetic control on the scaffold 20 seated on the upper surface,
    상기 인쇄 베드(10)의 상면의 가장자리 내측에 각기 설치되어 상기 비계(20)의 가장자리의 각 부분을 당긴 상태로 고정시켜 상기 비계(20)에 단일 축 또는 2개 이상의 축에 의거하는 스트레칭이 가해지도록 해서 상기 비계(20)가 단일 축 또는 2개 이상의 축에 의거하는 방향으로 늘어나도록 하는 복수의 고정 수단(12); 및It is installed inside the edge of the upper surface of the print bed 10, and each part of the edge of the scaffold 20 is fixed in a pulled state, so that the scaffold 20 is stretched based on a single axis or two or more axes a plurality of fixing means (12) for extending the scaffold (20) in a direction based on a single axis or two or more axes; and
    상기 인쇄 베드(10)의 하부의 각 부분에 설치되어 상기 비계(20)에 각 주파수의 음파를 설정된 강도로 가하여 상기 비계(20)에 각 변형 유도 응력이 제공되도록 하는 복수의 음파 변환기(40);A plurality of sound wave converters 40 installed at each part of the lower part of the printed bed 10 to apply sound waves of each frequency to the scaffold 20 at a set intensity so that each strain induced stress is provided to the scaffold 20 ;
    를 포함하는 것을 특징으로 하는 생체모방 제어로 조직구성을 위한 스마트 인쇄 베드.Smart printing bed for tissue composition with biomimetic control, characterized in that it comprises a.
  2. 청구항 1에 있어서,The method of claim 1,
    상기 인쇄 베드(10)의 하단의 각 부분에 부착된 상태에서 진동하여 상기 비계(20)에 진동이 가해지도록 해서 생물학적 섬유의 방향을 결정하고 비계 세포 인터페이스에서 기계 전달을 유발하기 위해 생물학적 섬유를 정렬할 수 있는 잠재력을 가지고 있도록 하는 복수의 진동 모터(32); 및Vibrating while attached to each part of the lower end of the printing bed 10 so that the scaffold 20 is vibrated to determine the direction of the biological fibers and align the biological fibers to cause mechanical transmission at the scaffold cell interface A plurality of vibration motors 32 that have the potential to do; and
    상기 복수의 진동 모터(32)의 진동수와 진동세기를 제어하는 주파수 변환기(30);a frequency converter (30) controlling the frequency and intensity of vibration of the plurality of vibration motors (32);
    를 더 포함하는 것을 특징으로 하는 생체모방 제어로 조직구성을 위한 스마트 인쇄 베드.Smart printing bed for tissue construction with biomimetic control, characterized in that it further comprises.
PCT/KR2023/000915 2022-01-25 2023-01-19 Smart print bed for tissue construction under biomimetic control WO2023146209A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020220010703A KR102442915B1 (en) 2022-01-25 2022-01-25 Smart print bed for tissue constructs under biomimetic control
KR10-2022-0010703 2022-01-25

Publications (1)

Publication Number Publication Date
WO2023146209A1 true WO2023146209A1 (en) 2023-08-03

Family

ID=83281628

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2023/000915 WO2023146209A1 (en) 2022-01-25 2023-01-19 Smart print bed for tissue construction under biomimetic control

Country Status (2)

Country Link
KR (1) KR102442915B1 (en)
WO (1) WO2023146209A1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102442915B1 (en) * 2022-01-25 2022-09-15 주식회사 에코월드팜 Smart print bed for tissue constructs under biomimetic control

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20010043159A (en) * 1998-04-29 2001-05-25 캐롤린 에이. 베이츠 Receptor sheet for inkjet printing having an embossed surface
JP2005532853A (en) * 2002-07-16 2005-11-04 バイオジェンティス、インコーポレーテッド Fabrication method of artificial tissue
JP4116057B2 (en) * 2004-06-17 2008-07-09 研 中田 Biomechanical stimulus loading device
KR20090041802A (en) * 2007-10-24 2009-04-29 한국기계연구원 Bio-plotter with vibration structure
KR20150125350A (en) * 2014-04-30 2015-11-09 재단법인대구경북과학기술원 Cell stimulation system
KR101700344B1 (en) * 2015-09-23 2017-02-01 원광대학교산학협력단 Film type safety bed for head of 3D printer
KR20200053665A (en) * 2018-10-31 2020-05-19 계명대학교 산학협력단 Device and method for manufacturing multi-layer bio-scaffold using 3D printing
KR102442915B1 (en) * 2022-01-25 2022-09-15 주식회사 에코월드팜 Smart print bed for tissue constructs under biomimetic control

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20010043159A (en) * 1998-04-29 2001-05-25 캐롤린 에이. 베이츠 Receptor sheet for inkjet printing having an embossed surface
JP2005532853A (en) * 2002-07-16 2005-11-04 バイオジェンティス、インコーポレーテッド Fabrication method of artificial tissue
JP4116057B2 (en) * 2004-06-17 2008-07-09 研 中田 Biomechanical stimulus loading device
KR20090041802A (en) * 2007-10-24 2009-04-29 한국기계연구원 Bio-plotter with vibration structure
KR20150125350A (en) * 2014-04-30 2015-11-09 재단법인대구경북과학기술원 Cell stimulation system
KR101700344B1 (en) * 2015-09-23 2017-02-01 원광대학교산학협력단 Film type safety bed for head of 3D printer
KR20200053665A (en) * 2018-10-31 2020-05-19 계명대학교 산학협력단 Device and method for manufacturing multi-layer bio-scaffold using 3D printing
KR102442915B1 (en) * 2022-01-25 2022-09-15 주식회사 에코월드팜 Smart print bed for tissue constructs under biomimetic control

Also Published As

Publication number Publication date
KR102442915B1 (en) 2022-09-15

Similar Documents

Publication Publication Date Title
WO2023146209A1 (en) Smart print bed for tissue construction under biomimetic control
Butler et al. The impact of biomechanics in tissue engineering and regenerative medicine
Delaine-Smith et al. Preclinical models for in vitro mechanical loading of bone-derived cells
CN112899158A (en) Micro-processing gas matching layer modulation body ultrasonic cell assembling and arranging device, preparation method and application
Cowin Mechanosensory mechanisms in bone
EP3896149A1 (en) Modular magnetically driven bioreactor for cellular cultures and biomedical applications
Kim et al. Actuation-augmented biohybrid robot by hyaluronic acid-modified Au nanoparticles in muscle bundles to evaluate drug effects
Javaheri et al. Preclinical models for in vitro mechanical loading of bone-derived cells.
KR102243546B1 (en) Artificial tissue for transplantation therapy, drug screening, Manufacturing method thereof, and Manufacturing apparatus therefor
Trzewik et al. Evaluation of lateral mechanical tension in thin-film tissue constructs
Khan et al. Biomimetic Approaches in Cardiac Tissue Engineering: Replicating the Native Heart Microenvironment
US20130230907A1 (en) High-throughput sensorized bioreactor for applying hydrodynamic pressure and shear stress stimuli on cell cultures
Wang et al. Pneumatic Non-Equibiaxial Cell Stretching Device With Live-Cell Imaging
Stottlemire et al. Remote-controlled 3D porous magnetic interface toward high-throughput dynamic 3D cell culture
KR20130082341A (en) Bioreactor using sonic vibration
Zhang et al. Research Article A Manta Ray-Inspired Biosyncretic Robot with Stable Controllability by Dynamic Electric Stimulation
Neal et al. Co-fabrication of live skeletal muscles as actuators in a millimeter scale mechanical system
CN206114880U (en) Biological elasticity imaging system of shear wave excitation system and magnetic resonance
CN115386568B (en) Cell regulation and control method, cell regulation and control device and cell mechanical property measurement method
Farahani et al. Emerging biomaterials and technologies to control stem cell fate and patterning in engineered 3D tissues and organoids
WO2024177483A1 (en) Array-type focused ultrasound transducer and medical ultrasonic device
WO2013035971A1 (en) Ultrasonic generator and ultrasonic vibrator
Young-Bok Abraham et al. The development, use, and challenges of electromechanical tissue stimulation systems
Lee et al. Mechanical Conditioning
CN101092595A (en) Experimental apparatus for loading cell through digital controlled mechanical strain

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23747251

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE