Nanotechnology Orthopedics

1. Nanotechnology in
Orthopedics

2. • Nanotechnology is the study, production and controlled manipulation
of materials with a grain size < 100 nm.

3. • In 1959, Richard Feynman first introduced the concept of
nanotechnology, describing “a field in which little has been done, but
in which an enormous amount can be done in principle”

4. • The distinction between nanotechnology and microtechnology is
unclear and definitions often overlap. The International Metric
System of Units defines the prefix nano as 1 × 10−9 meters.

6. • Nanotechnology encompasses a broad range of technologies with a
diverse range of applications. It can be defined as the science and
engineering involved in the design, synthesis, characterization, and
application of materials and devices; the smallest functional
organization being at least one dimension on the nanoscale.

7. • Nanophase materials are composed of matter with a grain size much
smaller than that of their conventional counterparts, but with the
same basic atomic structure.
• There are two fundamental characteristics that distinguish one from
the other.
• The first is that the behaviour of nanophase materials is explained by
quantum, rather than classical, mechanics. Particles with a grain size <
100 nm behave in a markedly different way from larger particles in
terms of melting point, conductivity, combustibility and reactivity.
• The second is the concept that as grain size decreases, surface area
increases for a given volume.

8. • The impact of nanotechnology in medicine is growing, the leading
application being drug discovery and drug delivery in the
pharmaceutical field: for example, nanoscale polymer capsules
designed to break down and release drugs at controlled rates, and
target-specific diagnostic nanoparticle pharmaceuticals for use in
medical imaging.

9. Uses
• Implants : Spine and Trauma
• Implant material: Arthroplasty
• Tissue regeneration
• Diagnostic applications
• Therapeutic applications - drug delivery
• Therapeutic applications - anti-cancerous materials
• Bone Cement
• Sports Medicine: Chondrogenesis, Tendon healing
• Orthopedic infections

10. • Orthopaedic implant surfaces are smooth at the nanoscale, or have
constituent micron particle sizes. These do not provide a biologically
inspiring topography as bone has numerous nanometer features
because of nanostructured entities.
• Hydroxyapatite (HA) is between 2 and 5 nm wide and 50 nm long,
whereas Type 1 collagen is a triple helix approximately 300 nm long.
• Some prostheses are designed to promote bone ingrowth and
encourage initial cellular interactions to achieve success
Nanomaterials for Implants

11. • Mature bone has an inorganic mineral size of roughly 50 nm × 25 nm
× 4 nm, which represents a coarse surface in nanometric terms.
• In contrast, modern orthopaedic implant surfaces are smooth at the
nanometric level.
• Smooth surfaces preferentially induce the growth of fibrous tissue
rather than bone, whereas a nanotextured surface may enhance the
function of osteoblasts and reduce that of fibroblasts.
• This differential cellular activity is seen on nanotextured
hydroxyapatitecoated surfaces, as well as on many other
nanostructured surfaces, and is thought to be a direct result of their
decreased grain size.
• In addition to the favourable properties of nanophase
hydroxyapatite, nano-engineered titanium and cobalt–chromium–
molybdenum (CoCrMo) encourage osteoblast adhesion more than
their conventional counterparts.

12. • Nanotechnology can be used to achieve nanostructured implant
materials with the aim of providing a more proactive biointegratable
material.

13. • As much as three times more calcium deposition has been displayed
by osteoblasts cultured on nanostructured titanium compared with
microstructured (conventional) titanium
• Nanostructured materials that match natural bone have unique
surface properties, possessing a greater surface area to manipulate
protein interaction to promote osteoblast function.

14. • Helical rosette nanotubes (HRN) are a new class of self-assembled
organic tubes featuring the complementary hydrogen bonding arrays
of guanine and cytosine.
• These tubular assemblies can allow predefined chemical and physical
properties; for example, the attachment of growth factors or specific
bone recognition peptide sequences that promote bone cell
adhesion.
• In conjunction with the nanosurface roughness afforded by HRN,
arginine and lysine side chains are believed to contribute to the cell
adhesion observed on HRN-coated titanium.
• Another approach involves fabrication of a thin n-HA coating on
titanium using the sol-gel technique and a dip-coating method. The
particle size ranged from 25 to 100 nm depending on the technique

15. • The benefits of nanostructured ceramics, such as nanostructured
diamond, HA, and metalloceramic coatings, have been explored.
• These nanostructured ceramics are tougher and stronger than coarser-
grained ceramics.
• The wear rate of conventional implant components, such as ultrahigh
molecular weight polyethylene (UHMWPE), can be considerably lower
when articulated against ceramic materials such as zirconia than for
metallic materials.
• However, the common drawbacks to ceramic devices are brittleness and
geometric limitations. A goal is to develop coatings that can reduce
friction and wear in joint replacement components.
• Nanostructured ceramics have the potential to provide these demands,
allowing access to new levels of material properties and implant
characteristics. Additional studies are needed to confirm their long-term
safety, biocompatibility, and performance

16. • The understanding of the health effects of nanoscopic wear debris is
also limited.
• Early research on bearing surfaces showed that > 90% of polyethylene
wear debris is < 1000 nm in diameter; the particle size generally being
approximately 500 nm.
• When various immune cells are exposed to nanoscopic ultra-high
molecular weight polyethylene wear debris in vitro, several important
patterns arise.
• Macrophages are unable to phagocytose debris < 200 nm in size. On
the other hand, dendritic cells, which are policing cells critical to the
immune response, are capable of initiating a potent immune
response to polyethylene wear debris as small as 50 nm. When
dendritic cells encounter polyethylene wear on this scale, they
release the inflammatory cytokines IL1-β and IL6. These cytokines
may then activate the osteoclastic cells responsible for osteolysis.

17. • When challenged with wear debris, three general cellular responses
have been described, depending on particulate size. Particles
<150 nm are pinocytosed, particles 150 nm to 10 μm are
phagocytosed, and particles >20 μm induce multinucleated giant cell
formation, with some overlap

18. • The use of ultra-high molecular weight polyethylene (UHMWPE)
implants has been limited in the field of arthroplasty due to concern
for potential fracture. However, due to its favorable biocompatibility
properties and wear resistance, there has been increased interest in
improving the mechanical strength of UHMWPE through
nanotechnology.

19. • The addition of carbon nanotubes to this material to create a novel
composite has demonstrated translational success and may
eventually have utility as an acetabular lining or tibial component.
• Altering an implant’s surface nanostructure has the potential to
increase resistance to static and dynamic fatigue, improve
functionality, and increase implant survivorship

20. Spinal Implants
• Nanotechnology may potentially facilitate spinal fusion and avoid the
cost and potential complications associated with recombinant human
bone morphogenetic protein (rhBMP).
• Surface modifications to titanium spinal implants through the
addition of nanoparticles such as titanium oxide and zirconia have
shown promise in promoting increased bone formation and
decreased resorption compared to conventional smooth implants.
• Additionally, cervical cages enhanced with silicone nitride
nanoparticles have demonstrated multiple biomechanical advantages
over standard PEEK (poly-ether-ether-ketone.

21. • In 2014, the FDA approved the first interbody fusion device to feature
nanotechnology .
• The nanoLOCK™ by Titan Spine technology has been shown to induce
a greater amount of osteogenic and angiogenic growth factors
compared to conventional titanium PEEK cages

22. • Use of rhBMP-2 is commonly associated with side effects due to
supraphysiologic dosing.
• Nanotechnology efforts are underway to address these limitations.
• One particular strategy uses nanofiber structures known as
Peptide amphiphile (PA) molecules to mimic extracellular filaments
and induce cellular regeneration. Studies found that the use of PA
nanofibers in the form of a gel scaffold showed overall superior fusion
rates while allowing for reduction of therapeutic doses of BMP-2 by up
to 10-fold

23. Nanobiomaterials for Grafts
• There is high demand for bone graft because of the increase in
orthopaedic surgery resulting from advances in surgical practice and
an aging population
• The nanocomposition of these materials emulates the natural bone’s
hierarchic organization, to initiate the growth of an apatite (calcium
phosphate) layer, and to allow for the cellular and tissue response of
bone remodeling.
• The materials also have the potential to provide analogous
mechanical properties to bone, adaptable for different applications

24. • A bone graft or biomaterial should not only replace the missing bone,
but also should be intrinsically osteoinductive by acting as a scaffold
for guided bone growth.
• It is an essential requirement for an artificial biomaterial to form a
biologically active apatite layer to bond to living bone. The graft also
should provide a framework to support new blood vessels and soft
tissue in forming a bridge between existing bone

25. • Novel materials have been developed using biomimetic processes to form
nano-sized bone-like HA crystals.
• For example, one process described the deposition of nano-sized bone-like
apatite onto fine synthetic polymer fibers fabricated into a three-
dimensional structure similar to collagen fibers in bone.
• Another composite used n-HA with polyamide (poly hexamethylene
adipamide), producing n-HA crystals 5 to 26.7 nm in diameter and 30 to 84
nm long. The n-HA content in the composition reached 60%, almost equal
to natural bone.
• The Young’s modulus of the n-HA/PA matched well with natural bone,
which can help eliminate stress shielding associated with the mismatch of
mechanical properties between graft and bone

26. • In addition to bioactive materials, biodegradable properties in bone grafts
also are desirable.
• Biodegradable n-HA/collagen composites have been prepared by the
precipitation of HA from an aqueous solution onto collagen.
• The low crystallinity, carbonate substitution, and nanometer size of the
minerals in the composite were thought central to rapid turnover of the
bone substitute surface.
• When implanted in a marrow cavity, solution mediated dissolution and
giant cell-mediated resorption occurred at the bone-substitute interface, in
addition to new bone formation. This process of degradation and
consequent bone formation is reminiscent of the known natural process of
bone remodeling

27. • Nanofibrous scaffolds fabricated by electrospinning biodegradable
poly(lactic acid) (PLA) mixed with single-wall carbon nanotubes
showed favorable and promising biologic responses

28. • Nanocrystalline hydroxyapatite (HA) paste has been used as a filler of
bone defects, with encouraging results.
• A series of fractures of the distal radius showed this to be an
acceptable substitute for bone graft in metaphyseal defects.
• A further series by the same group showed similarly encouraging
results when it was used to treat metaphyseal defects in fractures of
the tibial plateau.

29. Cement
• Nanotechnology-based antibiotic carriers such as lipid nanoparticles silica
and clay nanotubes added to common cement material such as polymethyl
methacrylate (PMMA) may enhance drug delivery and allow for timed
release.
• Other types of non-antibiotic based nanotechnology cement additives such
as chitosan, silver, and dendrimer are also under investigation for their anti-
microbial properties .
• Additionally, PMMA is well-known for eliciting an autoimmune response that
can potentially lead to implant failure through fibrous encapsulation and
inflammation .Studies have found that the addition of nanostructured
additives to PMMA demonstrated increased osseointegration and
osteoblast activity

30. Nanotools
• Enhanced surgical blades and tools are being produced by novel
micronanofabrication techniques, providing microfeatures with highly
desirable surface finishes and tolerances.
• These material properties at the nanoscale allow for lower
penetration force, finer dissections, and cleaner cuts leading to more
rapid healing.
• The combination of desirable mechanical properties, good
formability, and enhanced corrosion and wear properties has been
made possible by nanotechnology.

31. • The cutting quality of a blade can be improved by the sharpness of
the cutting edge and the nanoscale surface roughness of the blade
using fabrication techniques such as plasma sharpening process and
focused ion beam milling.
• The plasma sharpening process has produced diamond-coated
carbide blades that have low surface roughness values (20–40 nm),
therefore minimizing frictional effects.
• Materials containing quasi-crystals measuring 1 to 10 nm prevent
dislocations and act as reinforcement. Quasi-crystals have a structure
between crystalline and amorphous which form during a heat
treatment and strengthen into a tough matrix, hence providing
desirable material properties. It has been suggested these materials
containing quasi-crystals are suitable for a range of medical tools
including bone drills.

32. • Traditional surgical tool material such as stainless steel and nickel-
cobalt–based alloys possess good corrosion properties, however they
do not provide adequate hardness and wear resistance.
• For example, suture needles require a material that combines
hardness and toughness: hardness because the point must be
sharpened and toughness so that the needle will not break during
surgery. Ultrahigh strength in the material allows the needles to be
very thin, minimizing tissue damage.This combination of corrosion
and wear protection can be provided by coatings as much as 2 mm
with combined amorphous and nonophase structures.

33. • A detonation gun thermal spray process was used to deposit the
nanoamorphous coatings of two compositions: Fe-Cr-P-C and W-C-
Co.
• These nanoamorphous coatings have been reported to provide
enhanced corrosion and wear properties for medical instruments.46
In addition to these hardness and wear resistance characteristics, the
coatings have a unique grain structure, and have been evaluated for
their high-friction gripping surfaces to enhance blade control.4

34. Nanotherapeutics
• The greatest short-term impact of nanotechnology is most likely
patient therapy, particularly cancer treatment.
• Promising discoveries have been reported using nanotechnology for
cancer diagnosis and treatment, moving rapidly from the laboratory
to clinical trials.

35. • A continual challenge in medicine is to deliver therapeutic agents to
specific body components without harming healthy tissue.
• Specific delivery of chemotherapeutic agents to tumor sites would
avoid the nonspecific effects of chemotherapy on vulnerable and
essential cells such as bone marrow cells.
• Nanoparticles or nanospheres have the potential to provide targeted
and controlled drug delivery which can result in reduced unwanted
side effects, improved patient compliance, and lower dose levels.

36. • Several approaches to harnessing nanotechnology in cancer
treatment have been explored.
• Dendrimers are a novel class of three-dimensional nanoscale, core-
shell structures with physical and chemical properties that may be
precisely controlled and developed into targeted cancer therapeutics.
• Colloidal dispersions of iron oxide nanoparticles into tumors is
another potential treatment using an external magnetic field which
causes the tissue to heat up and the cancer cells die and liquidize.
• Nanocapsules may be used to deliver antisense oligonucleotides
(AON) effective against junction oncogenes, inhibiting tumor growth.

37. • A nanochannel delivery system implanted near a tumor can provide
local, sustained release of antitumor compounds, thus avoiding
toxicity.
• One proposed device was designed to deliver the desired therapeutic
agent by zero-order kinetics to unresectable tumors.31 Most of these
examples illustrate a generic approach to cancer treatment; although
not so specified, they possess technologies that could be adapted and
used to treat bone diseases.

38. • Current bone-targeted therapies include radiation and
bisphosphonates (osteoclast-inhibiting agents), however these
treatments do not show an increase in survival.
• Enzyme pro-drug gene therapy is an emerging and promising method
for delivering site-specific chemotherapy.
• If this treatment proves successful in directly killing cancer cells,
nanotechnology could provide the missing link, allowing specific
delivery of the therapeutic enzyme to tumor cells.
• The obstacle of gene expression may be overcome using
nanofabricated surfaces as a barrier layer, allowing the target-specific
release of drug molecules but preventing the entry of macrophages.

39. • Nanotechnology has the potential to improve early cancer detection and
facilitate personalization of cancer therapy.
• The ultimate in personalized management of cancer would be
developments in preventive medicine.
• For example, nanodevices could be implanted to circulate freely and
detect cancer at the earliest stage.
• A polymerized nanoparticle system could enable placement of targeting
properties on the surface of the particles in addition to loading the
particles with different contrast and therapeutic agents.
• Alphanubeta3-targeted paramagnetic nanoparticles have been used for
noninvasive detection of very small regions of angiogenesis associated with
nascent tumors.

40. Arthritis
• Although arthritis may be treated by injecting antiinflammatory agents into the joint,
colloidal steroid microcrystals found in the treatment rapidly disappear from the synovial
cavity.
• The clinical problem known as crystal induced pain may depend on the size and
biocompatibility of the microparticles introduced into joint tissue.
• An ideal intraarticular delivery system should possess a prolonged release mechanism,
and the use of nano-sized particles may eliminate the problem of crystal-induced pain.
• A water-soluble corticosteroid (betamethasone sodium phosphate[BSP]) encapsulated
into nanospheres with a biodegradable polymer DL-lactide/glycolide copolymer (PLGA)
seemingly prolonged antiinflammatory action in joint disease.
• In that report the nanospheres, with a mean diameter ranging from 300 nm to 490 nm,
were administered directly into the joint of arthritic rabbits.
• The PLGA particulate system provided prolonged local antiinflammatory action, and was
biocompatible as reflected by histologic results.
• This area of research is encouraging, however progress is required before such
technologies can be used clinically.

41. Wound Dressing
• Postoperative patient recovery may be improved by applying
nanotechnology to wound dressings.
• Some pharmaceutical companies are using formulations or
dispersions containing components at the nanoscale.
• For example, colloidal silver is used in antimicrobial formulations of
dressings.
• A nanofibrous polyurethane membrane prepared by electrospinning
has characteristics desirable for an effective wound dressing.
• The wound dressings have controlled evaporative water loss and
excellent oxygen permeability.
• The dressings also promote fluid drainage, therefore decreasing build-
up under the covering to prevent wound desiccation.

42. • It has been proposed the dressings can inhibit exogenous
microorganism invasion because of its ultrafine nanoporous structure.
• Other polymer nanofibrous membrane dressings are able to
integrate pharmaceutical properties such as antiseptics into the
nanofibrous substrate.
• These properties are of particular interest in orthopaedics because of
widespread risk of postoperative infections.

43. Complications
• Nanomaterials, because of their small size, possess very high surface-to-
volume ratios, which make them more reactive and potentially more toxic
than larger materials.
• The effect of nanoparticulates on human health are not well understood,
and it is questionable whether exposure occurs through manufacturing of
nanophase materials or through implantation of nanophase materials.
• Nanoparticles may become loose through degradation of implanted
materials through oxidation and/or hydrolysis that accelerates exposure.
• The preliminary effects of nanoparticulate wear debris on cell viability have
been reported and suggest nanometer titanium and carbon nanotubes
decrease the overall cell survival rate. However, studies on nanophase
materials are just beginning, and many issues regarding health applications
must be answered.

44. • Recent research in oncology has shown selenium to be a powerful
potentiator of chemotherapeutic agents.
• When manufactured on the nanometric scale and applied to titanium
orthopaedic implants, nanophase selenium appears to inhibit the
growth of malignant osteoblasts at the implant– tissue interface.
• Similarly, nanophase HA causes in vitro inhibition and apoptosis of
osteosarcoma cells.37

45. • Nanophase silver is proving a significant source of interest for
orthopaedic traumatologists.
• Silver has been used on wounds for centuries as an antibacterial
agent. Over the past decade, nanophase silver dressings have reached
the market and proved to be better at preventing wound infections
and stimulating healing than traditional silver-based or plain
dressings.
• Similarly, nanophase silver incorporated onto the surface of titanium
orthopaedic implants in the form of titanium nanotubes, has
immediate powerful bactericidal and anti-adhesive effects, which last
up to 30 days.
• This could eventually prove to be of benefit in the prevention of the
acute post-operative infection of TJRs and trauma implants

46. Perihperal nerve injuries
• Peripheral nerve injuries may also benefit from nanotechnology.
• Ding et al41 have shown that nanophase silver impregnated type I
collagen scaffolds significantly increase the quantity of adsorbed
proteins critical to nerve healing and significantly reduce the time to
nerve regeneration.
• In a study that compared nanosilver-impregnated type I collagen
scaffolds to control type I collagen scaffolds in rabbits with an
experimentally induced 10 mm sciatic nerve defect, the nanosilver-
impregnated group showed thicker myelin sheaths, improved nerve
conduction and higher rates of laminin adsorption