The principles of Bioethics
• Respect for patient autonomy (the patient is a participant in the medical process)
•Justice (there is a fair distribution of scarce healthcare resources) •
Beneficence (do good)
•Non-maleficence (do no harm)
The premise of tissue engineering
• Tissue engineering is trying to rebuild broken body parts by seeding a porous biomaterial scaffold with living biological cells, where necessary utilizing additional growth factors or other agents to try and encourage cell growth and development. • The cell source is a key consideration: the cells can be • autologous (from the person themselves) • allogenic (from a donor) • Cells can be from mature differentiated sources, from adult stem cells or from embryonic stem cells. •Scaffolds can be made from materials that are synthetic, hybrid or natural.
Explain the difference between bulk and surface erosion. What determines which form of hydrolysis will occur?
• Bulk erosion is when water enters a polymer uniformly and erosion occurs throughout the sample. The properties of the sample degrade uniformly with time. • Surface erosion is when water can only gain access to a limited depth of the implant, and the erosion only takes place along this limited (fixed width) front. If the water can diffuse into the polymer faster than the hydrolysis can occur, the bulk erosion mechanism occurs. If the hydrolysis reaction is much faster than the diffusion of water into the polymer, then surface erosion will occur. • NB for most polymers the diffusivity of water in the polymer is about the same, and the tunable parameter for device design is via choice of polymer with different hydrolysis reaction rate constants.
What are the key factors in the utilisation of erodible polymers in drug delivery devices? How are surface and bulk eroding materials used for drug delivery?
• For use of erodible polymers in drug delivery, we have the two tunable parameters as in the comparison between bulk and surface erosion above, the diffusion time constant for water in the polymer and the hydrolysis reaction time. • But now we have a third additional critical parameter, the diffusivity of the drug in the polymer. • For a bulk eroding polymer, the drug is released via the increase in porosity in the material as it degrades. • For a surface eroding polymer, the drug is released from the surface of the implant as the material is removed.
What roles do international standards play in medical device manufacturing? In particular, describe the role of ISO 13485.
• Standards are documented agreements containing technical specifications or other precise criteria to be used consistently as rules, guidelines or definitions of characteristics, to ensure that materials, products, process and services are fit for their purpose. • Standards approved by recognised bodies (e.g. ANSI, CEN, ISO, BSI) • ISO 13485: Requirements for the design and manufacture of medical devices • QMS: formalized system that documents processes, procedures, and responsibilities for achieving quality policies and objectives. • Regulations for quality systems covers: packaging, labelling, storage, installation etc. Examples of benefits to manufacturer •Importantly harmonisation will allow a route to market for medical devices in either region, irrespective of the location of the manufacturer. This will reduce the cost and time to bring a new device to a wider market. •Reduce complexity of sourcing items from global third parties.
Explain the rationale for selecting a multi-filament suture instead of a monofilament suture with the same diameter; use illustrations and calculations as appropriate. Note any disadvantages associated with multifilament sutures.
Factors to be considered include mechanical properties (bending stiffness, tensile strength).
- Multi-filament sutures maintain much (typically 70%) of the longitudinal tensile strength of monofilaments while exhibiting a significantly diminished (about 10%) bending stiffness due to the decreased moment of area for the smaller fibrils
- Multifilaments exhibit higher friction: they tend to cause more damage when being pulled through tissue, but on the other hand the knots tend to be more stable.
- Monofilaments are less prone to bacterial contamination
- Multifilaments erode faster than monofilaments made from the same material. However, there is a wide range of suture types available, with different degradation times, so this parameter can be determined independently
Describe the basic premise of tissue engineering, and the specific example of skin graft tissue engineering.
List the guiding principles of bioethics, and explain how these can be applied to skin graft tissue engineering.
- Tissue engineering (TE) is of great interest in regrowing malfunctioning body parts and thus has the potential to do good.
- There is some concern that if the implant does not perform, it could do harm; further there are concerns regarding harm done to the cell donor.
- Because TE is still emerging, there is the opportunity for these therapies to be significantly more expensive than traditional therapeutics, and thus there is a concern regarding justice and the fair distribution of scarce healthcare resources.
- Finally, patients may be unfamiliar with these new technologies, and doctors have a responsibility to offer patients an unbiased set of information about the implants (including the cell source) with the provision of pros and cons allowing for the informed consent of the patient (respect for autonomy).
Write brief notes to describe any two concepts introduced with the implementation of the European Medical Device Directive (93/42/EEC).
- Defined the risk assessment requirements for medical devices (estimating the potential of a device becoming a hazard.
- Introduced 'classification': a ‘risk based’ system based on the vulnerability of the human body taking account of the potential risks associated with the devices.
- Introduced a means of dealing with drug-device combinations. Paper 3P10 Crib Final version
- Used performance as a criteria of acceptability (as opposed to effectiveness). (The action of a device with reference to its intended use when correctly applied).
- Defined the requirements for clinical data during the approval process for a medical device.
- Introduced the requirement for adverse event reporting and device monitoring in use
Describe briefly two challenges to harmonisation between the USA and EU of the procedures used to assess whether a medical device conforms to regulations.
What would be the benefits to medical device manufacturers if such harmonisation were achieved?
- U.S. require the manufacturer to show effectiveness: The extent to which a specific procedure does what it is intended to do for a defined population. (i.e. a benefit to the user).
- E.U. require the manufacturer to show performance: The action of a device with reference to its intended use when correctly applied. Performance does not refer to the outcome. Outcome may be influenced by other factors. (i.e. works as intended but not necessarily showing benefit to user)
- E.U. have four categories, U.S. have three.
- E.U. has a set of defined rules for classification, U.S. use a system of precedent.
Centralised vs. distributed approach to systems
- E.U. have Notified Bodies approve medical devices. A Notified Body can be authorised by the Competent Authority for this role (each Member State has one Competent Authority). The Notified Body is a private enterprise
- U.S. have a centralised system run by the FDA.
The U.S. and E. U. do not share an international standard defining the manufacturing of medical devices.
The U.S. have a system whereby demonstration of substantial equivalence of to an approved device allows a fast route to approval
Clinical data requirements
Definitions of both when clinical trials are required and the level of benefit they need to show differ between U.S. and E.U.
Examples of benefits to manufacturer (a wide selection expected)
mportantly harmonisation will allow a route to market for medical devices in either region, irrespective of the location of the manufacturer. This will reduce the cost and time to bring a new device to a wider market. Reduce complexity of sourcing items from global third parties.
Polymers and ceramics are two common biomaterials. For each material, describe two benefits and two challenges associated with including them in implanted medical devices
Polymer - Benefits
- A very wide range of mechanical, chemical and physical properties are accessible with polymers. An answer could include details about the key controls of such properties (functional groups, molecular weight, level of cross-linking, level of crystallinity, etc.)
- Polymers can achieve excellent transparency, which is not feasible with most other materials (other than some ceramics). This is due to the amorphous nature of many glassy polymers and is useful for permanent optical implants.
- Polymer implants can be designed to have a controlled rate of degradation. This can be used both as a means of removing a tissue engineering scaffold, for avoiding additional surgery through slow degradation of internal sutures or in a separate application for controlled release of pharmaceuticals.
Polymer - Challenges
- Degradation can also be a challenge, due to a change in mechanical properties that is not always beneficial.
- Polymers used in implanted devices can wear quite rapidly and release particulates around the body.
- Some polymers can be very challenging to fabricate into the required shapes, e.g. UHMWPE.
Ceramics - Benefits
- Ceramics can include oxides, nitrides, carbides as the non-metallic component. There are also carbon or silicate ceramics and a grouping known as bioceramics, Answers can refer to any type linked to implantation.
- For example, ceramics can be used in the femoral head of total hip replacements. They can withstand very significant compressive forces.
- Ceramics also have excellent wear properties and lubricity.
- These materials are highly resistant to corrosion but bioceramics can be designed to be bioresorbable and so is less permanent for tissue engineering applications.
Ceramics - Challenges
- A few of the challenges include, for example, the fact that ceramics are not ductile and so can be sensitive to catastrophic failure.
- Metals and polymers, however, can accommodate through deformation. Ceramics have a very low tolerance for stress concentrations. And have particularly poor tensile strength (compared with their compressive stress.
- Biocompatibility of some carbon ceramics is now also uncertain.
- Ceramics are especially difficult to machine into shape and into the right surface finish.