Rapid prototyping tecnique in rigenerative medicine

Vincenzo Guarino, PhD
Researcher at Institute of Composite and Biomedical Materials (IMCB) National Research Council of Italy
Mail: vguarino@unina.it or vincenzo.guarino@cnr.it
Address: Viale Kennedy, 54 - Mostra d'Oltremare Pad. 20 - 80125 Napoli NA Campania
Fax.: (0039) 081 2425932
Rapid prototyping
technique in rigenerative
medicine

Researcher at Institute of Composite and Biomedical Materials (IMCB)
National Research Council of Italy
INTRODUCTION

DEFINITION
Rapid Prototype is a common name for a group
of techniques that can generate a physical
model directly from computer-aided design
data.
It is an additive process in which each part is
constructed in a layer-by-layer manner.
Wai-Yee Yeong, Chee-Kai Chua, Kah-Fai Leong, Margam Chandrasekaran, Rapid prototyping
in tissue engineering: challenges and potential, Trends in Biotechnology, Volume 22, Issue 12,
December 2004, Pages 643-652

Basic Principles of Rapid Prototyping
• 3d model generated
• Sliced
• Each slice manufactured and layers are fused together
• A voxel (volumetric pixel or, more correctly, Volumetric Picture Element) is a volume
element, representing a value on a regular grid in three dimensional space. This is
analogous to a pixel, which represents 2D image data in a bitmap (which is
sometimes referred to as a pixmap).

D. T. Pham, S. S. Dimov, Rapid manufacturing, Springer-Verlag, 2001, ISBN:1-85233-
360-X, page 6
Rapid Prototyping by Industry Sectors

Tissue Regeneration
IUPAC definition
Use of a combination of cells, engineering
and materials methods, and suitable biochemical
and physico-chemical factors to improve or replace
biological functions.
The textbook of pharmaceutical medicine Griffin, J P (John Parry). 6th ed.

Why study the rapid prototype in tissue regeneration ?

Result
Why study the rapid prototype in tissue regeneration ? ……

Analysis of the
technique

HISTORY
Rapid prototyping is quite a recent invention. The first
machine of rapid prototyping hit the markets in the
late 1980s, with the enormous growth in Computer
Aided Design and Manufacturing (CAD/CAM)
technologies when almost unambiguous solid models
with knitted information of edges and surfaces could
define a product and also manufacture it by CNC
machining.
Pandey, Pulak M. "RAPID PROTOTYPING TECHNOLOGIES, APPLICATIONS AND PART DEPOSITION
PLANNING."
HISTORY……

Pandey, Pulak M. "RAPID PROTOTYPING TECHNOLOGIES, APPLICATIONS AND PART DEPOSITION
PLANNING."
Milestones ….
HISTORY……

Different rapid prototyping (RP) technologies applied in
tissue engineering
Different rapid prototyping (RP) technologies applied in tissue engineering …

In a typical melt–dissolution deposition system, each layer is created by extrusion of a
strand of material through an orifice while it moves across the plane of the layer
crosssection. The material cools, solidifying itself and fixing to the previous layer.
Successive layer formation, one atop another, forms a complex 3D solid object. Porosity in
the horizontal XY plane is created by controlling the spacing between adjacent filaments
The vertical Z gap is formed by depositing the subsequent layer of filaments at an angle
with respect to the previous layer. Repetitive pattern drawing will produce a porous
structure ready to be used as a scaffold. A representative system using melt–dissolution
deposition is FDM. This method spins off several new systems that operate under similar
principles.
Melt – dissolution deposition technique

Build Volume: 8" x 8" x 10"
Materials: ABS, Casting Wax
Build Step Size: 0.007",
0.010", 0.013"
Up to 4x faster than the FDM
2000
Fused Deposition Modeling
Melt – dissolution deposition technique …

In particle-bonding techniques, particles are selectively bonded in a thin layer of powder material. The thin 2D layers
are bonded one upon another to form a complex 3D solid object. During fabrication, the object is supported by and
embedded in unprocessed powder. Therefore, this technique enables the fabrication of through channels and
overhanging features. After completion of all layers, the object is removed from the bed of unbonded powder. The
powder utilized can be a pure powder or surface-coated powder, depending on the application of the scaffold. It is
possible to use a single one-component powder or a mixture of different powders, blended together. These
techniques are capable of producing a porous structure with controllable macroporosity as well as microporosity.
The microporosity arises from the space between the individual granules of powder. These techniques offer control
over pore architecture by manipulating the region of bonding. However, the pore size is limited by the powder size of
the stock material. Larger pores can be generated by mixing porogen into the powder bed before the bonding
process. The powder-based materials provide a rough surface to the scaffold. It has been suggested that
topographical cues might have a significant effect upon cellular behavior. As a cell attaches to the scaffold, stretch
receptors are activated. Receptors on the scaffold surface might be subjected to varying degrees of deformation,
leading to activation of cell signal transduction pathways. Therefore, scaffolds fabricated via a particle-bonding
technique might be more advantageous in the context of cell attachment.
Particle-bonding techniques

3-dimensional printinge
Particle-bonding techniques…

Indirect RP fabrication methods
RP systems can also be utilized to produce a sacrificial mould to fabricate tissue
engineering scaffolds. These multistep methods usually involve casting of material in a
mould and then removing or sacrificing the mould to obtain the final scaffold. Such
techniques enable the user to control both the external and the internal morphology of
the final construct. In addition, indirect methods also require less raw scaffold material
while increasing the range of materials that can be used and making it possible to use
composite blends that might require conflicting processing parameters. The original
properties of the biomaterial are well conserved because no heating process is imposed on
the scaffold material.

Droplet deposition
Indirect RP fabrication methods…

Rapid Prototyping Systems
All RP techniques employ the basic five-step process
1. Create a CAD model of the design
2. Convert the CAD model to STL format (stereolithography)
3. Slice the STL file into thin cross-sectional layers
4. Construct the model one layer atop another
5. Clean and finish the model

• First, the object to be built is modeled using a Computer-Aided Design (CAD) software
package.
• Solid modelers, such as Pro/ENGINEER, tend to represent 3-D objects more accurately
than wire-frame modelers such as AutoCAD, and will therefore yield better results.
• This process is identical for all of the RP build techniques.
Create a CAD model of the design
Rapid Prototyping Systems …

• To establish consistency, the STL (stereolithography, the first RP technique) format has
been adopted as the standard of the rapid prototyping industry.
• The second step, therefore, is to convert the CAD file into STL format. This format
represents a three-dimensional surface as an assembly of planar triangles
• STL files use planar elements, they cannot represent curved surfaces exactly. Increasing
the number of triangles improves the approximation
Convert the CAD model to STL format (stereolithography)

• In the third step, a pre-processing program prepares the STL file to be built.
• The pre-processing software slices the STL model into a number of layers from 0.01
mm to 0.7 mm thick, depending on the build technique.
• The program may also generate an auxiliary structure to support the model during
the build. Supports are useful for delicate features such as overhangs, internal
cavities, and thin-walled sections.
Slice the STL file into thin cross-sectional layers

• The fourth step is the actual construction of the part.
• RP machines build one layer at a time from polymers, paper, or powdered metal.
• Most machines are fairly autonomous, needing little human intervention.
Layer by Layer Construction

• The final step is post-processing. This involves removing the prototype from the
machine and detaching any supports.
• Some photosensitive materials need to be fully cured before use
• Prototypes may also require minor cleaning and surface treatment.
• Sanding, sealing, and/or painting the model will improve its appearance and
durability.
Clean and Finish

Pandey, Pulak M. "RAPID PROTOTYPING
TECHNOLOGIES, APPLICATIONS AND PART
DEPOSITION PLANNING."

Materials For Rapid Prototyping
Materials covered:
• Thermoplastics (FDM, SLS)
• Thermosets (SLA)
• Powder based composites (3D printing)
• Metals (EBM, SLS)
• Sealant tapes (LOM

Machine Cost Response Time Material Application
Fused Deposition
Modeler 1600 (FDM)
$10/hr 2 weeks
ABS or Casting
Wax
Strong Parts
Casting Patterns
Laminated Object
Manufacturing (LOM)
$18/hr 1 week Paper (wood-like)
Larger Parts
Concept Models
Sanders Model Maker 2
(Jet)
$3.30/hr 5 weeks Wax Casting Pattern
Selective Laser
Sintering 2000 (SLS)
$44/hr 1 week
Polycarbonate
TrueForm
SandForm
light: 100%; margin:
0">Casting Patterns
Concept Models
Stereolithography 250
(SLA)
$33/hr 2 weeks
Epoxy Resin
(Translucent)
Thin walls
Durable Models
Z402 3-D Modeller
(Jet)
$27.50/hr 1 week Starch/Wax Concept Models
Cost

Biomimetic approach to
tissue engineering

Biomimetic approach to tissue engineering
In living organisms, tissue development is
orchestrated by numerous regulatory factors,
dynamically interacting at multiple levels, in space
and time. Recent developments in the field of
tissue engineering are aimed at designing a new
generation of tissue-engineering systems with an
in vivo like, but fully controllable cell environment.
Such a ‘biomimetic’ environment, as a result of
biology and engineering interacting at multiple
levels, should be suitable to direct the cells to
differentiate at the right time, in the right place
and into the right phenotype and eventually to
assemble functional tissues by using biologically
derived design requirements.

Bioactivity of RP-fabricated scaffolds
The interaction of cells with the scaffold is governed by the structural and chemical
signaling molecules that have a decisive role for cell adhesion and the further behavior of
cells after initial contact.
Current strategies to control the proliferation and other behaviors of cells on advanced
biospecific materials involve patterning the material surfaces with adhesive molecules or
by incorporating a controlled release of biomolecules, such as natural growth factors,
hormones, enzymes or synthetic cell cycle regulators.
Some RP systems that have excluded high-temperature operation, such as MDM and
bioplotter, offer the opportunity of incorporating the biomolecule during the building
cycle. However, further information, such as the type of biomolecule, the optimal
concentration and spatial control of these biomolecules, is needed to produce the most
favorable scaffold.

Cell seeding and vascularization
One significant challenge in the scaffold-based approach in tissue engineering is to
distribute a high density of cells efficiently and uniformly throughout the scaffold volume.
RP systems present great flexibility in scaffold design and development. RP-fabricated
scaffolds can be designed to have interconnected flow channels to fit into the operation of
the bioreactor, as displayed by the work of Sakai et al.
The RP fabrication method offers the flexibility and capability to couple the design and
development of a bioactive scaffold with the advances of cell-seeding technologies, to
enhance the success of scaffold-based tissue engineering.

New development: automation and direct organ
fabrication
Automated design, development and characterization:
RP has the potential of automating the design and fabrication of patient-specific scaffolds.
In the work of Cheah et al., computer-aided design (CAD) data manipulation techniques
were utilized to develop a program algorithm that can be used to design scaffold internal
architectures from a selection of open-celled polyhedral shapes. The automated scaffold
assembly algorithm can be interfaced with various RP technologies, to achieve automated
production of scaffolds.

Boland et al. developed a cell printer to implement the technology.
The device is capable of printing single cells, cell aggregates and the
supportive thermoreversible gel that serves as ‘printing paper’.
These authors demonstrated the feasibility of this technique by
printing a tubular collagen gel with bovine aortal endothelial cells.
Organ printing
New development: automation and direct organ fabrication …

Laser printing of cells
A laser-based printer, termed matrix-assisted pulsed
laser evaporation direct write (MAPLE DW), was used to
deposit micron-scale patterns of pluripotent embryonic
carcinoma cells onto thin layers of hydrogel. A cell
viability of 95% was reported.

Valerie and Sangeeta adapted photolithographic
techniques from the silicon chip industry. The process
starts with filling a Teflon base with a thin layer of polymer
solution loaded with cells. UV light is shone through a
patterned template atop the thin film, curing the exposed
polymer that sets with cells inside. Complex 3D structures,
containing regions of different cells, can be built by using
different templates and adding layers atop each other.
Photopatterning of hydrogels

Tan and Desai reported a layer-by-layer microfluidic method to
build a 3D heterogeneous multiplayer tissue-like structure
inside microchannels. This approach extends the 2D cell
patterning technique into the vertical axis, involving
immobilization of a cell–matrix assembly, cell–matrix
contraction and pressure-driven microfluidic delivery
processes.
Microfluidics technology

The Future? Self-replication
RepRap achieved self-replication at 14:00 hours UTC on 29 May 2008 at Bath University in the UK. The machine
that did it - RepRap Version 1.0 “Darwin” - can be built now - see the Make RepRap Darwin link there or on the
left, and for ways to get the bits and pieces you need, see the Obtaining Parts link.

RP technologies hold great potential in the context of scaffold fabrication. This technology
enables the tissue engineer to have full control over the design, fabrication and modeling
of the scaffold being constructed, providing a systematic learning channel for investigating
cell–matrix interactions. Additionally, indirect RP methods, coupled with conventional
pore-forming techniques, further expand the range of materials that can be used in tissue
engineering. Inspired by the additive nature of layered manufacturing, the layer-by-layer
fabrication method underlines the future development of tissue engineering.
The Future? Self-replication …

Rapid prototyping tecnique in rigenerative medicine

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