Tissue interaction
Systemic and tissue-level responses to biomaterials and medical devices are largely driven by biomaterial– tissue interactions in the local environment where they are implanted.
- Particularly for devices that are not retrieved and are meant to be “permanently” implanted, their ability to function and alleviate the condition for which they were implanted is DEPENDENT ON MINIMIZING OR QUICKLY RESOLVING UNDESIRABLE INTERACTIONS WITH THE HOST TISSUE.
- The properties of the biomaterials influence the host response, and hence the biocompatibility of materials.
- Material properties include biomaterial size, shape, roughness, topography, surface chemistry, and stiffness.
- Biomaterial properties may be responsible for variations in intensity and duration of the inflammatory and wound-healing process phases.
Inflammation (foreign body response)
One of the most critical responses, which is required for healing but needs to be balanced and resolved over time to avoid chronic issues.
- The inflammatory response is fundamentally a protective response, the ultimate goal being to rid the organisms of both the initial cause of cell injury (e.g., microbes, toxins) and the consequences of such inflammation.
(1) Acute inflammatory response: This phase can last minutes to several days, as determined by the extent and persistence of an acute inflammatory stimulus such as bacteria or microparticles. - Infiltration of inflammatory cells, such as leukocytes, which will clear the site of any cellular debris, bacteria, or foreign material by receptor-mediated phagocytosis and release toxic products (e.g., reactive oxygen species, lysosomal enzymes) to kill or destroy the foreign matter.
- Neutrophils also release growth factor mediators of tissue regeneration and recruitment of the second wave of inflammatory cells, the monocytes that differentiate in the tissue to macrophages.
- Neutrophils and macrophages interact with foreign surfaces through receptor-mediated binding to implant surface-adsorbed proteins to result in cell attachment and activation, which includes secretion of cytokines, release of reactive oxygen intermediates, and proteolytic enzymes, the latter two aiming to degrade the foreign material upon phagocytosis of the implant.
(2) Chronic inflammation: persistence of an inflammatory stimulus leads to chronic inflammation. (as do repeated bouts of acute inflammation, persistence of intracellular microorganisms, prolonged exposure to nondegradable substances, immune reactions, and micromotion of implants). - Should resolve within a week or so, but with persistence of a stimulus it can last weeks to years.
- The cellular profile is characterized by the presence of monocytes/macrophages and particularly lymphocytes and plasma cells.
- During this stage, there is proliferation of blood vessels and fibroblasts, the latter to increase the presence of connective tissue.
- However, the chronic destructive nature of this stage of the inflammatory response will lead to tissue destruction that can then only be repaired by scarring.
(3) Granulation tissue: The healing phase of inflammation and is initiated by the action of macrophages and their release of molecular factors. - This phase is characterized by the proliferation of fibroblasts, synthesis of collagen and proteoglycans, and angiogenesis.
- Depending on the extent of injury, it can be seen as early as 3–5 days after injury.
(4) the foreign body reaction: Comprised of foreign body giant cells (FBGCs)/ macrophages apposed to the biomaterial surface surrounded by granulation tissue and/or fibrosis. - Blood vessels are seen within the granulation tissue, but typically not in the fibrous capsule.
- Foreign body giant cells are formed by the fusion of multiple macrophages as they try to engulf a surface that is too large for them to phagocytose, so they undergo “frustrated phagocytosis”. Foreign body cells are very large cells with abundant cytoplasm and as many as 10 nuclei of the macrophages are fused to form this cell.
- The presence of FBGCs at the surface of biomaterials, as with polyurethane pacemaker leads, is associated with stress cracking just beneath them on the biomaterial surface with subsequent device failure. This suggests that these FBGCs have presumably formed to intensify their local inflammatory activity at the biomaterial site.
- Fibrosis is characterized by a dense, aligned collagen produced by the interspersed fibroblasts.
- The response is characterized by mature fibroblasts and associated collagen that surround the material and wall it off from the rest of the native tissue.
- Fibroblasts can take on a myofibroblast phenotype to participate in the contraction of the fibrous capsule associated with the implant.
- Other deleterious consequences of a foreign body reaction/fibrosis are its mass transfer barrier and consumption of nutrients for tissue-engineered cell/biomaterial constructs, encapsulated cells, or biosensors for an analyte in the blood.
- The foreign body reaction lasts for the lifetime of the device recipient, as long as the implant remains in the body
Blood-material Interactions
Most if not all materials that are implanted surgically will come into contact with blood during implantation, so these issues are broadly important.
Host Respsonse
The host response to the biomaterial will determine the success or failure of a biomedical device.
- Examples of beneficial aspects of the tissue reaction to a biomaterial include a vascularized tissue reaction, a thin fibrous capsule, and integration of the material with the surrounding tissue to result in a seamless continuity within the tissue.
- Examples of deleterious consequences of an adverse tissue reaction include thick fibrous and avascular capsule, scar formation, and chronic inflammatory response.
Sequence of Host Response
The implantation of a biomedical device, if it involves surgical incision, initiates a host response analogous to a wound healing response.
- Haemostasis, inflammation, proliferation, and remodelling.
Processes used to evaluate blood-material interactions: In Vitro
- In vitro BMI tests involve placing blood or plasma in a container composed of a test material, or recirculating blood through a flow system in which test materials contact blood under well- defined flow regimes that simulate physiologic flow conditions.
- However, these tests are usually of short duration, and are strongly influenced by the blood source, handling methods, and use of anticoagulants.
- Thus, in vitro test results generally cannot be used to predict longer-term BMI and in vivo outcomes, and can provide only the most general guidelines for the selection of materials for particular devices.
- However, in vitro tests may be useful for screening materials that are highly reactive toward blood.
Processes used to evaluate blood-material interactions: In Vivo
- Many studies have been performed in which test materials, in the form of rings, tubes, and patches, are inserted for short or long time periods into the arteries or veins of experimental animals.
- The timing and type of measurements may be such that important blood responses are unrecognized. In particular, the measurement of gross thrombus formation at a single point in time may lead to incorrect conclusions about local thrombus formation, and does not provide assessment of systemic effects of thrombosis such as embolization and blood element consumption.
- With more commonly used animal species (e.g., sheep, dogs), blood responses may differ from humans both quantitatively and qualitatively.
- The blood flow conditions of the model may not be controlled or measured, and in fact may not even be relevant for actual implant device geometries.
- There may be variable blood vessel trauma and tissue injury that can cause local thrombus formation through the extrinsic pathway of blood coagulation.
Evaluations of BMI may be performed in animals having arteriovenous (A-V) or arterioarterial shunts.
- Test materials or devices are simply inserted as extension segments or between inlet and outlet portions of the chronic shunt.
- These systems have many advantages:
(1) blood flow is easily controlled and measured;
(2) native or anticoagulated blood can be employed;
(3) the animal’s physiology removes damaged blood elements and makes new blood with each circulation through the body; and
(4) both short-term and long-term BMI, including both local and systemic effects, can be evaluated. - The downsides of these tests are demanding surgery, high expense, and ethical issues associated with chronic shunting of larger animals.
Overall BMI evaluations
BMI are the interactions (reversible and irreversible) between surfaces and blood solutes, proteins, and cells (e.g., adsorption, absorption, adhesion, denaturation, activation, spreading) that occur under defined conditions of exposure time, blood composition, and blood flow. Since each of these variables influence BMI, we generally cannot:
(1) extrapolate results obtained under one set of test conditions to another set of conditions;
(2) use short-term testing to predict long-term results; and (3) predict in vivo device performance based on BMI testing of materials per se in idealized flow geometries.
- Since the blood response to devices is complex and not well predicted by testing of materials in idealized configurations or animal testing, ultimately clinical testing of functioning devices is required to establish safety and efficacy.
Blood compatibility
“Blood compatibility” can be defined as the property of a material or device that permits it to function in contact with blood without inducing adverse reactions.
- Very general
- It does not automatically follow that if the materials comprising a device are blood compatible, then a device fabricated from those materials will also be blood compatible.
- This is because there are many mechanisms for the body to respond to material intrusions into the blood. A material that will not trigger one response mechanism may be highly active in triggering an alternative pathway.
- Blood compatibility is impacted by the biochemistry of coagulation, the mechanisms of blood–materials interactions (BMI), and the design and function of a device in the bloodstream.
What is thrombogenicity?
- “Thrombogenicity” may be broadly defined as the extent to which a device, when employed in its intended use configuration, induces the adverse responses outlined below:
- A thrombogenic device may cause a localized accumulation of protein and cellular blood elements.
- Cardiovascular devices may also induce regions of disturbed flow or stasis that lead to the formation of blood clots.
- Thrombi may detach from a surface (embolize) and be carried downstream, eventually occluding a blood vessel of comparable size and impairing blood flow distal to the site of occlusion.
- While all artificial surfaces will interact with blood, an acceptably nonthrombogenic device can be defined as one that would produce neither local nor systemic effects with significant health consequence to the host organism.
Why is it difficult to understand the blood-compatibility of specific materials used in devices?
Understanding the blood compatibility of specific mate- rials used in blood-contacting devices is complex because:
(1) The types of blood-contacting devices used are numerous, and the device design will impact the apparent thrombogenicity of materials used in those devices.
(2) Blood-contacting devices are commercially manufactured, and manufacturers are, for competitive reasons, reluctant to discuss specific chemical compositions or changes made to raw materials in the device design.
(3) The possible blood responses are numerous, complex, dynamic, and often not fully understood.
(4) It is difficult and expensive to measure device thrombogenicity (clinically significant local thrombosis or systemic effects) in a systematic way, in either experimental animals or humans.
(5) Alternate interpretations can be applied to data from “blood-compatibility” tests (see diagram in folder).
- Most tests purported to measure blood compatibility in fact evaluate BMI, which are the events that occur when blood contacts a material. For example, is a material that adheres platelets not blood compatible?
Key considerations for BMI assessment: Virchow’s Triad
- In 1856, Rudolph Virchow implied that three factors con- tribute to the coagulation of blood: blood chemistry, blood-contacting surface, and flow regime.
- Also, the interaction time of blood with materials (ranging from seconds to years) has an impact on BMI.
Key considerations for BMI assessment: Virchow’s Triad
BLOOD CHEMISTRY
- The source of the blood and methods for its handling can strongly influence BMI.
- Human blood and blood from various animal species have been employed in BMI assessment in vitro and in vivo, both in the presence and absence of anticoagulants.
- —> Blood may vary with respect to blood proteins (concentrations and functionality), and cells that participate in coagulation, thrombosis, and fibrinolysis.
- —> The size of blood-formed elements may also differ.
- Blood reactivity is also influenced by manipulations in vitro, the surface-to-volume ratio of blood in extracorporeal circuits, and the use of pumps for blood recirculation.
- Often impossible to use human blood –> also health concerns with human blood experimentation.
- Differences between human and animal blood responses can be large, and such differences should lead to caution in directly interpreting experimental results.
- Despite these limitations, animal testing has been helpful in defining mechanisms of BMI and thrombus formation, and the interdependence of blood biochemical pathways, the nature of the surface, and the blood flow regime.
- In addition, while results of animal testing may not quantitatively predict results in humans, in many cases results can be qualitatively similar and allow for relative comparisons between materials and devices.
Key considerations for BMI assessment: Virchow’s Triad
FLOW
Flow —-> Blood Interactions Dictated by Shear and Mass Transport.
- Blood flow controls the rate of transport (by diffusion and convection) of proteins, cells, and thrombi in the vicinity of artificial surfaces and thus plays a critical role in the multistep process of thrombus growth.
- Absence of flow, low shear flow, and high shear flow can each give dramatically different blood-material interaction results.
- —> thereby, it is important to accurately mimic the flow conditions of the material application.
Key considerations for BMI assessment: Virchow’s Triad
SURFACE
- Actively studied, but least well defined, of the BMI Variables.
- It is well documented that surface physicochemical properties of materials can influence early events, for example, on protein adsorption and platelet adhesion—yet how these effects relate to subsequent thrombus formation remains uncertain.
- When placed in contact with blood, most, if not all, artificial surfaces first acquire a layer of adsorbed blood proteins whose composition and mass may vary with time in a complex manner depending on substrate surface type.
- This layer mediates the subsequent attachment of platelets and other blood cells that can lead to the development of thrombi.
- The relationship between material properties, the protein layer, and the propensity of a material or device to accumulate thrombus is not well understood because: (1) protein–surface reactions involve complex, dynamic processes of competitive adsorption, denaturation, and activation;
(2) cell–surface interactions may modify the protein layer, i.e., cells may deposit lipid and protein “footprints” derived from the cell membrane;
(3) the importance of specific adsorbed proteins for sub- sequent cell interactions, especially in vivo, is not well defined; and
(4) there have been few relevant tests in which both protein adsorption and later thrombus formation have been assessed. - In most cases, material properties are constrained by the specific mechanical and morphological needs of the intended blood-contacting device application.
- For example, vascular grafts and the sewing ring of prosthetic heart valves are composed of fabric or porous materials to permit healing and tissue anchoring. Other materials must be permeable to blood solutes and gases (dialysis and oxygenator membranes) or distensible (pump ventricles, balloon catheters).
Platelets
- Platelets (“little plates”) are nonnucleated, disk-shaped cells having a diameter of 2–3μm, and an average volume of 10 × 10−9 mm3 (Haley et al., 2011).
- Platelets are produced in the bone marrow, circulate at an average concentration of about 250,000 cells per microliter of whole blood, and occupy approximately 0.3% of the total blood volume.
- Platelet functions are designed to:
(1) initially arrest bleeding through the formation of platelet plugs;
and (2) stabilize the initial platelet plugs by catalyzing coagulation reactions leading to the formation of fibrin.
