Specifications:
Design
Goals, Tradeoffs and Constraints:
Mechanical
Properties: The personalized implant scaffold will be fabricated with a Young’s Modulus >= 2.86GPa and an
ultimate compressive strength (UCS) >=70MPa. Clinical studies have
shown that the ‘gold standard’ procedure for craniofacial reconstruction, the
autograft with bone sourced from parietal bone, has exhibited a Young’s modulus
ranges from approximately 0.9 to 15.54 GPa and an average UCS of 100MPa,,,,. Further studies indicate
that cranial implants experience additional degenerative forces: internal
pressure caused by tensile forces within the skull that range from 80-100kPa,
external pressures caused by impacts to the skull, and pressure applied by the
skin, which results in both shear and tensile forces. These mechanical
properties vary within the calvarial bone depending on several factors (eg.
loading speed, location within calvarium bone, skull thickness, age, etc.), but
human skulls rarely experience these instantaneous pressure changes of these
magnitudes. The scaffold should have the appropriate mechanical properties to
withstand these forces and pressures, but patients with the scaffold should
limit exposure to excessive external forces on the skull.
Currently, PMMA-based
cements (among other synthetic treatment options) have shown that pure
PMMA-based cements have a Young’s Modulus of around 2.86GPa and a UCS of
approximately 93.0MPa,. When we reached out to our stakeholders, Dr. Brooks advised our
team that the mechanical properties of the scaffold do not need to equal those
of autologous bone growth, but must display enough strength so that the
scaffold can withstand the surgical procedure for implantation and maintain the
structural integrity of filling the calvarial bone.
Porosity: The personalized implanted
scaffold will have an average porosity of 60-90%. Studies show that
porosity of 60-90% provides the optimal range for seeding the scaffold with
cells, drugs, growth factors, and other biologics. The pores must be
interconnected to develop and maintain a vascular system required for continued
bone development,,. We will optimize the ideal percent porosity
when we run mechanical testing due to the inverse relationship between porosity
and mechanical strength. No major “trade-offs” will be made, as we will,
ideally, pick the most porous material that is able to meet the minimal limit
of the defined mechanical strength properties. Additionally, the average pore
size for all pores within the generated scaffold will fall between 200 to 350µm
in diameter, and no pore will have a pore size of 150µm or smaller due to the
risks of improper seeding and release of pre-osteoblast cells. Small pores
allow the biologics and growth factors to seed initially in the scaffold, but
will allow also for vascularization and ossification within the pores to ensure
proper bone growth.
Reconstruction: Critical-sized cranial defects will be reconstructed into a 3D
CAD model from a stack of axial CT images. As previously stated, we will
initially limit the scope of the project to only the calvarium of the skull,
which incorporates two major bones: the parietal bone and the frontal bone.
Other bones do not clearly reflect the ovular shape of the skull in axial CT,
so reconstruction will require more advanced algorithms. With the
reconstruction itself, we will be able to take any patient’s 3D-CT stack and
produce a personalized output within a matter of minutes. Specifically, we will
develop the capacity to load in any stack of .DICOM files corresponding to
3D-CT images supplied by a radiologist. Individual slices will then be analyzed
from the stack, and with this data, an algorithm will be developed to identify
and trace the missing section of skull within a single slice. These
individually-corrected slices will then be compiled into a 3D stack and
exported as a CAD-compatible .STL file.
Reconstruction Accuracy: Within each cross-section, modeled data points will be plotted
along the peripherals of the skull geometry (inner and outer borders), with a
minimum accuracy of 90%. By outlining the skull with thousands of data
points, we will fit an ellipse, among other geometrical figures, to these data
points and estimate the skull geometry to this high accuracy for reliable
reconstruction. Although ellipses will likely not be used as the final
reconstruction geometry, these data points are fit through a least-squares
regression to minimize the distance from the borders of the skull to the
implant. Within a single cross-section, the plotted data will be scaled
to accurately resemble the true dimensions of the patient’s skull. Data
points within the CT-images will not be true dimensions of the patient’s skull,
so the algorithm will utilize a scale bar within the CT slices to ensure the
scaffold has the correct dimensions when printed.
3D Printing: When compiling the two-dimensional cross sections of the CT
slices, the third dimension in the superior direction of the axial plain will
have a slice thickness of <1.5mm. Although CT scans of the smallest
clinically feasible slice thickness of the skull, 0.625mm are ideal, studies
have shown that CT slice thickness <1.5mm showed no significant difference
in quantitative properties (eg. volume, surface area) of the skull. Images
acquired at a thickness greater than 1.5mm have demonstrated significantly
different reconstruction values, so they will be avoided for the purposes of
clinical feasibility. The average height of 3D-printed PLA is 400 µm, so we anticipate the resulting constructs
will fall within a standard deviation of 400 µm
due to the major limiting factor of low resolution of the CT scanner itself.
Constraints: For the scope of this project, the primary constraint is the
budget. Due to the pre-set budget of $600, the magnitude and selection of
technology, material, and testing are limited. Specifically, it is particularly
expensive to gain access to imaging modalities such as CT or MRI within the
School of Medicine and Singh Nanotechnology, to buy specific growth factors.
Secondly, there are significant time constraints for the entirety of the
project, as we will not be able to conduct many of the assays we hope to prove
feasibility. Ideally, the implant will go through the inchoate prototype stage
followed by the first round of dry evaluation and in-vitro testing.
However, the fast-approaching deadline limits the project to the prototyping
and, if even possible, simpler in-vitro testing. This rudimentary
testing will allow us to evaluate the proof-of-concept and feasibility;
however, the deadline inhibits the project from proceeding to advanced in-vitro,
ex-vivo, or in-vivo testing stage, where the majority of the
biological feasibility work would occur. Finally, limited meeting times between
group members and our advisors is a constraint that we face. We would like to
be able to brainstorm with our advisors and each other on a more frequent basis
than what scheduling has so-far allowed.
Regulatory Pathway: Our advisor has several years of experience dealing with United
States and European regulatory committees in the field of medical device
production, so we are confident that the physical biomaterials used in this
project would qualify for the 510(k) regulatory pathway within the FDA as a
Class-II medical device. So long as the material used is deemed “substantially
equivalent” to other clinically-approved products such as PMMA-based scaffolds,
then the PCL/Xerogel-based substance will likely be approved with various
biologics and drugs. As discussed previously, there exists a number of
implantable scaffolds for the application of craniofacial reconstruction,
although few are largely-composed of 3D-printed biological material. Thus,
there is a possibility that the overall treatment pathway will require
Pre-Market Approval (PMA) from the FDA due to the invasiveness during
implantation and potential direct human injury with its use. That is, the
scaffold itself would likely only required 510(k) approval due to similarities
with other devices currently available. However, the overall treatment pathway
which utilizes the scaffold will require PMA. Additionally, the FDA is
generally known to be wary of algorithm-based clinical treatment due to the
lack of human overview of the device. Therefore, in producing this device, it
is likely that large-scale randomized, controlled trials will need to be run in
comparing the efficacy of the proposed treatment pipeline compared to current
clinical standards.
[1] https://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm126054.pdf
[2]https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/ucm062592.pdf
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