Lecture 5: Metallic and Ceramic Biomaterials

Metallic Implants

1. Corrosion Resistance and Biocompatibility:

○ Corrosion is the degradation of metal due to reactions with its environment,
which can release toxic ions into the body. Corrosion resistance is crucial for
metallic implants, particularly those meant for long-term use, such as in
orthopedic and cardiovascular applications.
○ Biocompatibility: Metallic implants must be compatible with body tissues to
prevent adverse reactions. For instance, NiTi alloys develop a passive titanium
oxide layer that protects against corrosion and acts as a barrier to prevent the
release of potentially harmful nickel ions.
2. Surface Modification for Enhanced Properties:
○ Cold-Working: This process involves deforming the metal at low temperatures,
increasing hardness and mechanical strength by modifying its internal structure.
○ Annealing: Annealing involves heating and then slowly cooling the metal to
control its hardness and microstructure, optimizing it for specific applications.
○ Grain Size: Smaller grain sizes generally result in harder metals. Fabrication
methods that influence grain size can thus alter the mechanical properties of the
implant.
3. Types of Metallic Alloys:
○ Titanium Alloys: Known for high strength, corrosion resistance, and
biocompatibility, titanium alloys have a high stress-shielding effect. This means
they carry more load, which can inadvertently reduce bone density over time
(bone loss due to stress reduction).
○ Stainless Steel: Common in cardiovascular stents and orthopedic screws due to
its durability and corrosion resistance. The 316L grade is particularly popular;
when cold-worked, it exhibits increased strength, suitable for applications
requiring both flexibility and robustness.
4. Bioinert vs. Bioactive Metallic Implants:
○ Bioinert Implants: These materials, like titanium and stainless steel, do not
actively interact with surrounding tissues, making them ideal when minimal
biological response is desired.
○ Bioactive and Porous Coatings: Porous metallic coatings encourage
biological fixation (bone growth into the implant) and enhance the stability of
implants by allowing bone ingrowth. This is especially useful in orthopedic
implants【69†source】.

Ceramic Implants and Bioceramics

 1. Types of Ceramics in Biomedical Applications:
○ Hydroxyapatite (HA): A calcium phosphate ceramic similar to bone mineral, HA
is osteoconductive (encourages bone growth) and bioresorbable, meaning it
gradually dissolves in the body over time.
○ Tricalcium Phosphate (TCP): Another calcium-based ceramic, TCP is
resorbable and supports bone growth, often used in bone grafts.
○ Bioactive Glasses: These materials bond with bone and soft tissues, promoting
tissue regeneration. Bioactive glasses are versatile and can be used in both
dental and orthopedic applications.
2. Bioceramic Properties:
○ Bioinert: Examples include alumina ceramics, which do not interact with tissue
and are stable in the body.
○ Bioresorbable: Materials like tricalcium phosphate dissolve in the body and are
replaced by new bone tissue over time.
○ Bioactive: Bioactive ceramics, such as hydroxyapatite, chemically bond to bone,
enhancing bone-implant integration and supporting long-term stability.
3. Porosity and Mechanical Strength:
○ Porous structures are ideal for biological integration as they allow cells to
attach and bone to grow within the implant. However, this also makes them
mechanically weaker compared to non-porous ceramics.
○ Bioceramic Porosity: Ideal pore sizes for bone attachment range from 50-100
microns, allowing for nutrient flow and bone tissue growth. Porosity levels must
be carefully controlled to maintain strength while supporting biological function.
4. Bioactive Glasses and Applications:
○ Bioactive Glass: Composed of silicon, calcium, and phosphorus oxides,
bioactive glass is used in bone grafts and dental applications. Its bioactivity
stimulates cellular responses, encouraging tissue attachment and growth.
○ Metal Doping for Enhanced Functionality: Doping bioactive glasses with
elements like aluminum, manganese, or chromium can reduce inflammation and
increase antibacterial properties due to the scavenging of reactive oxidative
species.

Lecture 6: Drug Delivery

Controlled Drug Delivery Systems

1. Challenges in Drug Delivery and Solutions:

○ Poor Solubility: Many drugs are hydrophobic, making them difficult to
administer. Drug delivery systems, such as lipid-based nanoparticles, help
increase solubility.
○ In Vivo Stability: Certain drugs degrade rapidly in the body, so protective
encapsulation can help preserve the active compound until it reaches the target
site.
 ○ Poor Biodistribution: Drug delivery systems help target specific tissues or
organs, minimizing side effects and toxicity. For example, passive targeting
leverages the enhanced permeability and retention effect (EPR) in tumor tissues.
2. Therapeutic Window and Drug Release:
○ Therapeutic Window: Effective drug delivery aims to maintain the drug
concentration between Cmin (minimum effective concentration) and Cmax
(maximum safe concentration). Falling outside this range can either render the
drug ineffective or toxic.
○ Controlled Release: Ensures a gradual release of the drug, prolonging its
therapeutic effect and reducing dosing frequency.
3. Mechanisms of Drug Release:
○ Diffusion-Controlled: The drug diffuses out of the delivery matrix slowly over
time, often used in tablets and capsules.
○ Degradation-Controlled: The polymer matrix gradually breaks down, releasing
the drug as it degrades. Common in biodegradable implants, this avoids the need
for surgical removal after the drug is exhausted.
○ Swelling-Controlled: The polymer swells upon contact with body fluids,
releasing the drug as it expands.
○ Pendant Cleavage: The drug is released as the chemical bonds attaching it to
the polymer backbone are broken, often triggered by enzymatic activity.
4. Biodegradable Polymers in Drug Delivery:
○ PLGA (Poly(lactic-co-glycolic acid)): Widely used for controlled drug release
due to its biodegradable nature and FDA approval. PLGA degrades through bulk
erosion, where water penetrates throughout the material.
○ Polyanhydrides: Polymers like polyanhydrides degrade on the surface (surface
erosion), offering a controlled release. They are particularly useful in localized
drug delivery, such as in Gliadel wafers for brain tumor treatment.
○ Gliadel wafers are a form of localized chemotherapy designed specifically for
treating brain tumors, particularly high-grade gliomas and glioblastomas.
These are aggressive brain cancers that often recur even after surgical removal.
○ The wafers deliver carmustine (BCNU), a potent chemotherapy agent, directly to
the tumor site after surgical resection. This localized delivery maximizes the
drug’s concentration at the target site, helping to kill residual cancer cells that
surgery may have missed.
● Gliadel wafers are small, biodegradable implants made of polyanhydride polymers.
This polymer matrix gradually degrades upon contact with water, releasing BCNU over
several days or weeks.
● The polyanhydride used in the wafers is designed for surface erosion, meaning the
drug is released from the surface layer-by-layer as the matrix erodes, rather than
degrading uniformly throughout. This controlled, sustained release helps maintain a high
local concentration of the chemotherapy drug while minimizing systemic exposure and
side effects.
○
Advanced Drug Delivery Devices

1. Transdermal Patches:
○ A transdermal patch releases medication through the skin by passive diffusion.
Ideal for lipophilic, low molecular weight drugs, transdermal systems provide a
controlled release alternative to oral or injectable routes, with applications in pain
relief, hormone therapy, and nicotine replacement.
2. Microneedle Patches:
○ Microneedles are small, dissolvable needles that deliver drugs by penetrating the
outer skin layer. Useful for vaccinations and other sensitive treatments, these
patches dissolve under the skin, providing a pain-free, sustained release
alternative to injections.
3. Implantable Osmotic Pumps:
○ Osmotic pumps contain a semi-permeable membrane that allows water to
enter, creating osmotic pressure that pushes the drug out at a controlled rate.
This method is often used in pain management and hormone therapies.

Gene Therapy and Nanoparticle Delivery

1. Nucleic Acid Delivery:

○ Delivery of nucleic acids, like DNA and RNA, presents challenges due to their
size, charge, and vulnerability to degradation. Common delivery systems include:
■ Viral Vectors: Modified viruses deliver nucleic acids directly into cells but
may trigger immune responses.
■ Non-Viral Vectors: Polymeric nanoparticles and liposomes encapsulate
nucleic acids, shielding them from degradation and helping with cellular
uptake.
○ Non-Viral Delivery Methods: Non-invasive and often repeated, these methods
are advantageous in chronic conditions like hemophilia, where gene therapy can
reduce the frequency of protein injections required for clotting factor
supplementation.
2. Targeted Drug Delivery in Cancer Treatment:
○ Enhanced Permeability and Retention (EPR) Effect: Tumors have leaky
vasculature and impaired lymphatic drainage, allowing drug-loaded nanoparticles
to accumulate more effectively. This is useful in targeting chemotherapeutics
directly to tumor sites, minimizing systemic side effects.
○ Theranostics: These multifunctional nanoparticles serve dual purposes,
combining therapeutic functions (drug delivery) with diagnostic functions
(imaging) to monitor and treat diseases in real-time.
3. Delivery to the Brain and Eyes:
 ○ Blood-Brain Barrier (BBB): The BBB restricts many drugs from reaching the
brain. Innovative drug carriers, such as lipid nanoparticles, are being developed
to transport drugs across this barrier for neurodegenerative diseases.
○ Ocular Delivery: Delivering drugs to the eye is challenging due to blinking and
limited corneal permeability. Techniques like contact lenses with drug
reservoirs or microneedles for injection offer more effective options for
conditions requiring targeted eye treatments.

Oral Delivery of DNA Nanoparticles

● Using Human Factor IX DNA-nanoparticles

● Non viral gene delivery is transient = no integration of foreign gene into the host
○ Needs to be given in a repeated manner ● Using Chitosan DNA

​
○ Measures proteins in the blood

○ Using functional FVII protein in systematic circulation of Hemophilic A mice

Oral Delivery of Insulin Gene

● Nanoparticles go to the liver, GI track

● 1 oral dosage = produce insulin protein

● Provide baso-level of the insulin

○ Can’t treat patients with diabetes because insulin needs to be produced on-demand

● Extended release formulation lasts for 1 day

Nanoparticle Technology to Enhance Efficacy of Drug Therapy

● Attractive field because of cancer therapy.

● Drug delivery isn’t used to treat condition but to lessen the toxicity of chemotherapeutic drugs

● EPR effect = enhanced permeation and retention

○ Based on the finding that in a tumor, the vasculature is abnormal. Density goes up. Blood flow
to the human tissue is chaotic. Drainage of the lymphatic system in the tumor is defected.

● Stay in the tumor and serve as a depot

Multifunctional Targeting Nanoparticle (Theranostic):

● Both diagnostics and therapeutics

Polymeric Drug Conjugate:

● Using polymer, water-soluble

● Same polymer for contact lenses (hard and soft)
● Side chain is used to chemically link the drug.
○ Becomes a macromolecule drug that has an improved pharmacokinetics
● Needs to be smaller than 25,000 daltons MW so it can be cleared by the renal system

Liposomes for Drug and Gene Delivery

● amphiphilic
● Lipophilic = can permeate to the core
● mRNA = charged and hydrophilic

○ To encapsulate a mRNA, we’d need a charged lipid so they complex together.