Zwitterionized hemodialysis membrane’s hemocompatibility assessment.
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Shaheer Akhtar completed his Ph.D. in Chemical Engineering, 2008, from Jeonbuk National University, Republic of Korea. Presently, he is working as Associate Professor at Jeonbuk National University, the Republic of Korea. 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Blood purification of metabolic toxins will result in an adjustment of pH and maintains the normal condition of the body. Renal systems could experience several types of complications and illnesses such as glomerular diseases or polycystic and other cyst diseases. These could result in lack of functionality to various extents. The worst extent of failure in the introduced systems is “end-stage renal diseases” (ESRD) through which patients are experiencing chronic illnesses (chronic kidney diseases (CKD)). Kidney transplant is the first option which only a small percentage of patients could get. Hemodialysis would be one of the options beside transplant. While hemodialysis therapies are proven to be life-sustaining to an extent, morbidity side effects and mortality rates for acute renal failure patients are still a huge concern despite several advances of the technology through past decades [1]. Enhancements have been attributed to many subsections of hemodialysis technology such as membrane materials, membrane configurations, pore size distributions, and cutoff and membrane modalities.
Rotational celluphone tubes in still dialysate bath (rotating drum dialyzer) were the initial configuration of dialyzers [2]. Unsubstituted and substituted cellulose materials were also chosen for the membrane fabrication. With further advances in the field, initial materials were identified as the source of hemoincompatibility, and more effort was put in developing materials with higher level of blood compatibility [3]. Synthetic polymers such as poly aryl sulfones and polyamides were the next used choice for blood purification applications [4]. These membranes also failed to perform ideally and modification resulted in next generations of hemodialysis membranes. The historical pathway of advances though which the current hollow fiber contactor modules were chosen as the best option could be found elsewhere [4]. The question of “why life-sustaining hemodialysis therapy still is not working to the best extent?” is not answered. The authors of this chapter believe the answer would be material incompatibility, and the next sections will try to cover this topic in addition to other aspects of hemodialysis.
The dialysis process is a chemical potential gradient-based separation process [5]. The process’s idea was first mentioned by Graham using a semipermeable barrier for selective transport of elements in a solution [6, 7, 8, 9, 10]. The dialysis process contains two main streams on different sides of the membrane which is called a dialyzer, one containing higher amount of targeted chemicals (blood from chronic kidney diseases (CKD) or ESRD patient) and one with zero or lower concentrations (dialyzing fluid or dialysate), as shown in Figure 1. The Uremic and metabolic-resulted substances (which were commonly removed from blood by the kidney), are passed through the membrane, from the bloodstream side to the dialyzer side due to the difference in chemical potential.
Schematic diagram of a membrane in hemodialysis process: The left side describes the blood side of the membrane and the right side shows the dialysate side of the process. P1 and P2 describe pressure within the blood and dialysate side, respectively. Due to the difference in chemical potential, solutes in blood move through the membrane to the dialysate side.
Hemodialysis aims to remove toxins and extra water from human bodies with renal failure diseases. Based on the controlling mechanism of solute removal from the main bloodstream, diffusion, convection, or adsorption, the renal replacement modality could be categorized into three main subsections [11]: in case diffusion is controlling the process, the method is called “hemodialysis”; if convection is predominant, the method would be known as “hemofiltration”; and finally when diffusion happens simultaneously with significant convection, the method is named as “hemodiafiltration.” It is worth mentioning that adsorption occurs all the time, however there are specific devices that use this as the main separation method in an adsorptive column [12, 13].
There are different classes based on which dialysis processes are classified. An old classification divides membranes into cellulosic and synthetic-based hemodialyzers. Based on the ability to remove small molecules (urea is chosen as the reference with the molecular weight of 60 kDa), dialyzer membranes are categorized to high-performance and low-performance membranes [14]. Another classification is based on the ability of the membranes to remove middle size molecules (
Since the emergence of the technology, several aspects of hemodialysis have been enhanced. Yet based on the reports, mortality rate in patients are still high. More importantly patients are suffering from inter- and post-dialysis health complications such as cardiovascular disease, cerebrovascular disease, peripheral vascular disease, and chronic obstructive pulmonary disease. A significant share of the current hemodialysis membranes are made out of poly aryl sulfone (with distribution of 22% PES and 77% PSF) [16]. A research observing more than 139,000 patients revealed that most mortality rate is attributed to PSF membranes (comparison was made between cellulose triacetate (CTA), polyester polymer alloy, poly(methyl methacrylate) (PMMA), PSF, PES, ethylene vinyl alcohol (EVAL), and PAN [17]). The research announced PMMA membranes to have the lowest hazard ratio (HR) (the factor that they defined for comparing membranes).
The current hemodialysis membranes create inflammation responses due to their bioincompatibility during the blood interaction with synthesized polymeric structures. This was reported for membranes with natural-based or synthetic-based polymers [3, 4]. Each specific interaction (contact of blood proteins with membrane surface which initiates different cascade reactions and results in immune system response), is considered as an issue for dialysis membranes. Furthermore, beside four main interactions (surface activation (coagulation), platelet, complement, and leukocyte activation), infections, allergic reactions, complete disinfection of dialysate, and finally backflow of contaminated compounds could be all mentioned as other hemodialysis barriers [18]. It should be noted that these are all general aspects of the hemodialysis therapies and each modality might have its own specific problems in addition to previously mentioned ones. Another barrier to consider is the deficient removal for middle size molecular products and uremic toxins.
Fouling and protein adsorption, the examples of the blood-polymer interaction related reactions, are barriers for dialysis process. This might not be considered as important as in other UF processes; however the reduction of performance, especially for common dialysis session with duration no longer as 5 hours, could affect patients’ wellness and results in mortality. Moreover, higher extent of fouling means more intense immune response of the body. Accordingly antifouling behavior (lower protein adsorption) of the polymeric dialysis membranes owns a great deal of importance to eliminate initial protein-polymer surface interaction and consequently patients’ physiological response.
Hemocompatibility levels are slightly modified as not as much complement activation is reported for current membrane, as compared with regenerated cellulose membranes used back in the 1960s [19]. Clearance factors were also improved since the 1970s with the introduction of hollow fiber configurations for dialysis and using countercurrent hollow fiber membrane modules [20, 21]. Currently, instrumental progresses with higher control over dialysate temperature, plasma osmolality and sodium profiling, ultrafiltration rates, and blood volume balance have led to a more enhanced level hemodialysis [22, 23]. This is while there are still intensive ongoing researches over reducing mortality rate and morbidity due to incompatibility issues.
The body’s immune systems are activated along with blood protein adsorption to the surface (which is a complicated phenomena). Protein attachment to the surface is commonly studied under the title of displacement processes (Vroman effect) which might initiate the coagulation cascade [24, 25]. Any adhered cell (or triggered cells by the surface) could be activated, which consequently results in cascade activation (autocatalytic enzymatic processes) of other cells through production of mediators (with various purposes ranging from hindering interfacial cell adherence to defensive system activation) [26]. Defensive system activation in hemodialysis reflects hemoincompatibility of the used polymeric membrane. Despite the fact that membranes are only one element of the whole extracorporeal circuit and there are other surfaces which blood contacts to reach to the membrane module and to return to the body, as the filters have the highest surface area and the highest share of contact with blood, they are considered as the primary culprit for hemoincompatibilty of blood purification systems.
The reactions resulting in incompatibility are complex, and there are many unknown regions still to be covered; however, platelets, leukocytes, the complement, and the coagulation system are proven to be role players of this concept [26].
Platelet activation which is commonly known as one of its resultants, blood clotting, could be initiated from either extrinsic or intrinsic pathway (with or without injury respectfully). Due to the lack of endothelium functionality of the membranes, polymeric surfaces are identified as a foreign threat to the body, and a series of reactions involving numerous enzymes and proteins occurs to protect the body. Activation of fibrinogen leads to their transformation to fibrin. Fibrins are turned into fibrin clots with a crosslinked and steady structure as a result of factor XIII (fibrin stabilizing factor) secretion which is activated by thrombin. Transformation of inactive zymogenes into its activated form also assists the process. Platelets will be activated and aggregated, boosting a continuous interaction which leads to blood clotting. Furthermore, other blood cells are attracted to the clot and contribute in more fibrin formation through enzymatic reactions. The formed biological layer or “protein cake” contains plasma proteins like factor XII, fibrinogen, vitronectin, kininogens, etc., which could result in further thrombogenesis [4, 27, 28].
Complement activation is a human immune system’s inflammatory response as a result of foreign threats. It starts by local inflammatory mediator production (C5a, C4a, and C3a). The elements of the complement cascade are mainly enzymes or binding proteins. Along with the first 15 minutes of hemodialysis, C3 is produced and cleaved into C3a, C3b, etc. The cascade continues into production of C5a and C5b-9 during the next stages of dialysis. As reported by Poppelaars et al. [26] during a single session of hemodialysis, the level designated to C5b-9 and C3d/C3 ratios in plasma (measures of complement system activation) reaches up to 70%. However this has been interpreted as an underestimation of the measures values as they are only calculated for fluid phase, while solid phase (deposited complement system’s element on the surface) is not considered. Considering all the efforts to clarify the pathway of complement activation, it could be summarized that the base mechanism is known to be the attachment of binding proteins (mannose-binding lectin (MBL) and ficolin-2) to the membrane surface which leads to lectin pathway (LP) activation. The same procedure also encounters for properdin and C3b which results in alternative pathway (AP) activation.
One result of complement activation in hemodialysis patients is the induced expression of adhesion molecules on leukocytes (white blood cell) [29]. Activation of neutrophils and other leukocytes results in activation of inflammatory mediators. This could consequently improve the adhesion to endothelial cells, chemoattraction for leukocytes, an additional activation of leukocytes or platelets on one hand, and oxidization of monocytes and neutrophils to release oxidants on the other hand [4, 29, 30].
Blood-membrane interactions could directly activate blood cells such as leukocytes, platelets, and red blood cells or indirectly activate them through the pathway that activates the complement system or coagulation factors.
Contact activation of proteins could be initiated by factor XII conversion into active enzyme state (factor XIIa) which leads to activation of prekallikrein (PK)). Activated factor XIIa also turns high molecular weight kallikrein (HMWK) continuously into bradykinin. Contact activation to this extent also results in inflammation promotion as interleukins and tumor necrosis factors (TNFs) would be produced along with stimulation of nitric oxide release [31, 32, 33]. A series of various factors’ activation continues till factor Xa is generated from which thrombin and fibrin production is stimulated. This is where clot formation happens. Factor Xa is the common step that all intrinsic and extrinsic cascades reach, before clot formation [34]. Figure 2 shows activation cascades process after blood-membrane contact.
Blood biological reactions including complement system activation, intrinsic and extrinsic coagulation activation, fibrin network formation, platelet attachment to the surface, and leukocyte activation [
Despite all the advances in compatibility of blood purification membranes, mortality rates are still reported to be high. Hemodialysis-related complications such as headache, fatigue, lack of functionality and concentration, anemia, mineral and bone metabolism disorder, and inadequate nutrition result in patients’ lower quality of life. This reflects the fact that even conventional hemodialysis has contributed in longer life span of patients, it fails to maintain full quality of life [35].
Humoral mediators including cytokines of inflammatory system and other high molecular weight molecular structures of protein bonded toxins were identified as probable responsible structures for deficient dialysis [36]. Systematic inflammatory response syndrome (SIRS or sepsis) is the side effect of inflammatory activation products. This includes several cytokines which are protein or pleiotropic polypeptides structures (hormone-like substances) secreted by the human body’s immune system. There exist several types of cytokines, namely, chemokine, interferon (IFN), interleukin (IL), lymphokines, colony-stimulating factors (CSF), and tumor necrosis factor (TNF) with different molecular weights. SIRS will result in coagulation, fibrinolytic, and complement activations which are all parts of plasma protein cascade system. In a normal condition, there are other cytokines and proteins secreted to mediate the condition, but in a SIRS, regulatory system’s element fails to control the condition [37].
Middle and large molecular structures (with average molecular weights higher than 500 Dalton) and excess water accumulation are mentioned to impose concentration-dependent toxicity and, accordingly, higher mortality [35, 36]. These molecular structures range from smaller ones such as phosphorus and uremia with molecular weight less than 0.6 kDa to cytokines such as interleukin with molecular weight equal to 26 kDa. Molecular structures such as urea, creatinine, and similar structures with a molecular weight less than 500 Da are efficiently being removed by HD. Higher molecular weight cutoff membranes are created for removal of larger molecular weight toxins and toxin-bonded proteins. Modalities involving higher fluxes use convection transport phenomena which are entitled as hemofiltration membranes (HF). These methods are capable of eliminating molecular substances with molecular weight equal to or higher than 40,000 Da. The region between diffusive and convective membranes covers hemodiafiltration membranes (HDF) [38, 39].
Convective dialysis is parallel to albumin and nutrient loss of the bloodstream. Currently, hemodiafiltration blood purification membranes are recommended to be more efficient in comparison with high-flux dialysis due to less intradialytic hypotension and less nutrient loss [40]. Cutoff adjustment of new MCO membranes is due to advances in membrane manufacturing technologies (high-tech fabrication equipment, improved packing densities, enhanced spinning techniques, fiber undulation, decreased internal filtration as a result of fiber diameter control) [41]. MCOs have permeability values between protein-leaking dialyzers and high cutoff membranes with ß2-microglobulin and albumin sieving coefficients equal to 1.0 and 0.2, respectively [41]. Accordingly, efficient middle toxin removal would also not solve the hemodialysis-related complications, and the solution to this problem should be found in compatibility of the membrane materials.
Since the two concepts of “biocompatibility” and “hemocompatibility” are frequently being used instead of each other, there has to be a clear definition of these two terms. While biocompatibility, as a more general concept, targets higher liquid and solid parts of living tissues’ endurance to foreign items, hemocompatibility focuses on eliminating blood’s interactions with non-blood surfaces and materials [42]. There is also a defined framework for hemocompatibility assessment of a material. The International Organization for Standardization (ISO) has issued guideline over hemocompatibility measures in medical device evaluations (ISO 10993-4) [34, 43]. Accordingly, modified bio-hemocompatible hemodialysis membrane should pass thrombosis, coagulation, platelet adhesion resistance, immunology (complement systems and leukocytes), and hematology tests [34].
Different modification approaches were presented throughout the past few decades which targeted hemocompatibility enhancement of blood-contacting membranes. These efforts resulted in various generations of hemodialysis membranes. First-generation hemodialysis membranes were commonly made out of hydroxyl methacrylate or cellulose polymers without any specific surface treatment or modification. Poor hemocompatibility of the materials used led to poly(ethylene glycol) (PEG) surface immobilization (second generation). PEG brushes enhanced membranes to an extent, but instability and cleavage along with low hemocompatibility was still an issue. Beside PEG, several hydrophilic structures, such as poly(vinyl pyrrolidone) (PVP) [34] and poly(vinyl alcohol) (PVA) [44], sulfonated structures [45], and nanomaterials [46, 47] were used for modification of dialysis membranes. Currently, researchers are targeting third generation, including zwitterionic polymeric surfaces which are believed to be better than second generation due to better performance of the PEG immobilizations due to higher hemocompatibility and stability [48, 49, 50, 51].
Zwitterionic structures (ZW) are in fact the amino acid-mimicking structures initially synthesized based on inner structures of specific human cells [52, 53]. Zwitterions have several applications in live cell imaging [54, 55], antibacterial surfaces [56] and wound dressings [57], dental applications [58], separative membrane coatings [59], and most importantly blood purification [51]. Academic efforts over immobilization of ZWs on hemodialysis membranes have been reported over different membrane materials (cellulose acetate (CA) [60], poly(ether sulfone) (PES) [61, 62, 63], poly(sulfone) (PSF) [64], poly(dimethyl siloxane) (PDMS) [65], poly(vinylidene fluoride) (PVDF) [66], etc.) using various chemical immobilization approaches.
Three main types of ZW structures are sulfobetaine, phosphobetaine, and carboxybetaine. Application of ZWs was initially introduced by phosphobetaine derivatives as mimicking the structure of human blood cells; however the two other types were more frequently used due to their less production cost and ease of processing. As explained by Chapman et al., ZWs must have dual positive-negative charged functional groups and own at least the following properties: electric charge neutrality, lack of H-bond donation sites, and possess of H-bond acceptors [67]. Pseudo-zwitterionic materials (or mixed charged polymers), as newer classes of biomedical surface modifiers, are enhanced semi-ZW structures with positively dual charged structures that are not affected by other chemical functional groups due to higher stability. Accordingly, they have been introduced as better candidates for improving hemodialysis membranes by surface immobilization or forming hydrogels [68, 69, 70].
Table 1 offers some of the most recent efforts focused on zwitterionization of membrane surfaces. Researches presented in the table offer various polymeric membranes zwitterionized with sulfobetaine (SBMA) and sodium polystyrene sulfonate (SSNa). Common indexes of hemocompatibility measurements, including clotting times, complement activation factors, and coagulation and hemolysis percentage, are reflected for each research in case of availability in the related literature.
Membrane-ZW | Immobilization method | ZW Density (mg/cm2) | Clotting time (sec) | Hemolysis (%)*5 | Protein adhesion | Platelet adhesion | WCA (degree) | Ref. | ||
---|---|---|---|---|---|---|---|---|---|---|
APTT*2 | TT*3 | PT*4 | ||||||||
PDMS-GMA-SBMA | N/A | N/A | N/A | N/A | N/A | 90% fibrinogen adhesion reduction | 60% reduction | 79 | [65] | |
PVDF-SBMA | Interfacial atmospheric plasma-induced surface copolymerization | 0.7 | N/A | N/A | N/A | 0.3 | 88% fibrinogen adhesion reduction | Zero adhesion | 18 | [71] |
PVDF-SBMA | In situ immobilization | 5 | Plasma clotting time was reported to be 15 min | 2 | 90% fibrinogen adhesion reduction | 500 cells per mm2 | 10 | [66] | ||
PSF-SBMA-r-SSNa | Surface-initiated atom transfer radical polymerization | 0.95 | 78 | 18 | N/A | N/A | 4 μgBSA/ cm2 and 2 μgBFG/cm2 | Zero adhesion | 12.3 | [72] |
PSF-SBMA-b-SSNa | Surface-initiated atom transfer radical polymerization | 0.88 | 85 | 23 | N/A | N/A | 16 μgBSA/ cm2 and 13 μgBFG/cm2 | 87 × 105 cells/cm2 | 17.2 | [72] |
PSF-SBMA | Surface-initiated atom transfer radical polymerization | N/A | 58 | 19 | N/A | 0.9 | 2.5 μgBSA or BFG/cm2 | Zero adhesion | 30 | [64] |
PSF-DEPAS | Surface-initiated atom transfer radical polymerization | N/A | N/A | N/A | N/A | N/A | 32.5 μgBSA/cm2 | Qualitative reduction | 38 | [73] |
PSF-SBMA | Surface-initiated atom transfer radical polymerization | 0.171 | 52.5 | 22 | 11 | N/A | 2.70 μgBSA/cm2 and 2.51 μgBFG/cm2 | 0.34 × 105 cells/cm2 | 31.35 | [74] |
PSF-SSNa | Surface-initiated atom transfer radical polymerization | 0.110 | 73.1 | 22 | 11 | N/A | 13.02 μgBSA/cm2 and 10.07 μgBFG/cm2 | 6.94 × 105 cells/cm2 | 20.80 | [74] |
PES-SBMA | In situ polymerization | N/A | 75 | 19 | N/A | N/A | 8 μgBSA/cm2 and 10 μgBFG/cm2 | 10 × 105 cells/cm2 | 11.1 | [61] |
PES-SSNa | In situ polymerization | N/A | 115 | 18 | N/A | N/A | 12.5 μgBSA/cm2 and 12 μgBFG/cm2 | 40 × 105 cells/cm2 | 57 | [62] |
PES-SBMA-SSNa | In situ polymerization | N/A | 85 | 18 | N/A | N/A | 8 μgBSA/cm2 and 7 μgBFG/cm2 | 60 × 105 cells/cm2 | 45 | [62] |
PES-SSNa-SBMA | Radical graft polymerization | 0.2 | 55 | 30 | 10 | N/A | 6.5 μgBSA/cm2 and 4.2 μgBFG/cm2 | 3 × 105 cells/cm2 | 55 | [63] |
PES-SBMA | Radical graft polymerization | 0.22 | 51 | 30 | 10 | N/A | 5 μgBSA/cm2 and 4 μgBFG/cm2 | 3 × 105 cells/cm2 | 54 | [63] |
PES-SSNa | Radical graft polymerization | 0.14 | 90.10 | 30 | 10 | N/A | 10 μgBSA/cm2 and 7 μgBFG/cm2 | 37 × 105 cells/cm2 | 53 | [63] |
PSF-carboxyl-terminated SBMA | Carbodiimide-free radical polymerization | N/A | N/A | N/A | N/A | N/A | Zero fibrinogen adsorption | Zero adhesion | 32.8 | [75] |
PDMS-carboxyl-terminated SBMA | Carbodiimide-free radical polymerization | N/A | N/A | N/A | N/A | N/A | Zero fibrinogen adsorption | Zero adhesion | 10 | [76] |
PDMS-SBMA-co-AA | Carbodiimide-free radical polymerization | N/A | N/A | N/A | N/A | N/A | N/A | 0.1 × 105 cells/cm290% adhesion reduction | N/A | [77] |
PU-SBMA-co-AA | Carbodiimide-free radical polymerization | N/A | N/A | N/A | N/A | N/A | N/A | 0.2 × 105 cells/cm280% adhesion reduction | N/A | [77] |
PLA-SBMA*6 | Atom transfer radical polymerization | 1.3 | N/A | N/A | N/A | N/A | N/A | 3.2 × 105 cells/cm2 | 9 | [78] |
Zwitterionized hemodialysis membrane’s hemocompatibility assessment.
None of the papers reported values for C3a, C5a, TAT, or PF4.
Activated partial thromboplastin time.
Thrombin time.
Prothrombin time.
Hemolysis ranges: 0–2% of hemolysis, non-hemolytic; 2–5% of hemolysis, slightly hemolytic; more than 5% of hemolysis, hemolytic.
Toxin clearance was reported as 66% urea and 60% creatinine.
In case there are flux recovery ratio measurements more than one cycle, the first cycle is reported.
Different surface immobilization techniques were used to enhance membranes’ surface with various types of zwitterionic materials. An important factor to consider is the efficiency of grafting techniques which could be expressed by surface grafting density of zwitterionics on the membranes. Moreover, hydrophilicity and surface roughness are the other factors affecting the adsorption of proteins and consequently initiation of cascade reactions. PVDF-SBMA membranes with in situ polymerization technique resulted in highest grafting density and one of the highest hydrophilicity degrees. Yet the modified structure did not resist to platelet and protein adhesion significantly. This could probably be due to the deficient surface roughness of the enhanced hemodialysis membrane. PSF, PVDF, and PDMS membranes with SBMA modification have more frequently resulted in zero platelet adhesion [64, 71, 72, 76]. Among the three aforesaid membranes, PSF- and PDMS-carboxy-terminated SBMA membranes showed zero protein adsorption [76]. Hemolysis percentage, which shows the extent of blood cell damage when it touches the membrane surface, was reported to be the lowest for PVDF-SMBA membranes with plasma-induced surface copolymerization as modification technique [71]. Different clotting time parameters were also observed, and despite other parameters which were better for SBMA-modified surfaces, SSNa-zwitterionized membranes showed higher clotting time in general [53, 63]. The higher anticoagulant characteristics of SSNa-modified membranes could be interpreted into higher extent of coagulation cascade-resulted enzyme blockages (factor XII, factor XIIa, etc.).
Rather than ZW structures, other biomimetic surface modification approaches have been assessed by researchers for hemodialysis hemocompatibility improvements [5, 6, 7]. These bioinspired structures are mainly patterned from anticoagulants which are commonly used during a dialysis session. One of the most frequent reported structures from this class is heparin. Heparin and heparin-mimicking structures have been reported to be efficient in controlling the blood clotting process on the membrane and accordingly increasing its hemocompatibility. Due to high content of carboxyl and sulfate functional groups, heparin and heparin-mimicking structures are known as good candidate for both anticoagulation facilitator and membrane hydrophilicity’s enhancer [79]. Just like ZW, heparin is also reported to be effective as attached to different membrane materials such as poly(acrylonitrile) (PAN) [80], poly(lactic acid) (PLA) [81], PSF [82], etc.
The main hemocompatibility mechanisms of previous and current generations of hemodialysis membranes are described to be related to hydrophilicity improvements (thicker hydration layer and less resistance to blood particle movements (higher degree of hemolysis)). Another class of modification which results in similar characteristics of surfaces is hydrogel. Several advantages of hydrogels in biomedical fields have been noted such as their living tissue resemblance or their 3D porous structures [75, 83]. Since hydrogels are polymeric networks, almost all possible polymeric modifications could be considered. This means adsorptive nanoparticles, ZWs, and biomimetic structures could all be used within this technique to have advantages of hybrid approaches [84]. A sample of such an approach is using graphene oxide-based heparin-mimicking hydrogel structures [85]. Interestingly, in comparison with common hemocompatibility approaches, hydrogel-based techniques could be significantly efficient. A support for such a hypothesis is a research reported by [86] who immobilized a heparin-mimicking thin film hydrogel on PES hemodialysis membrane which resulted in three times higher clotting time than best modified blood purification membranes (activated partial thromboplastin time value of 600 sec).
Several hemodialysis membranes’ enhancements for higher hemocompatibility characteristics have been achieved experimentally as reported by various studies. Nevertheless, there are many questions which are not answered nor assessed. As an instance, several immobilization techniques have been introduced, but there is no clear comparison that could recommend a final better method for surface modification. More importantly, not all the membrane hemocompatibility studies consider all standard aspects of hemocompatibility assessment. In other words, available papers are reporting few factors of hemocompatibility assessment. Accordingly, no accurate comparison between different immobilization techniques and enhancer materials such as zwitterions or anticoagulants could truly be made based on the literatures.
Several aspects of hemodialysis have been improved since the emergence of technology. Material improvement along with pore size adjustment and different modalities of blood purification systems have resulted in higher hemocompatibility of the membranes and wider range of products for hospital and home dialysis sessions. Despite the improvements in different aspects of hemodialysis, the patient’s quality of life is still not acceptable. Accordingly, there have to be more efforts put on incompatibility issues of the membranes.
The authors would like to acknowledge and express their gratitude to Saskatchewan Health Research Foundation (SHRF) for funding the project, and the Chemical and Biological Engineering Department at University of Saskatchewan for the support provided.
HD | hemodialysis |
ESRD | end-stage renal disease |
HFD | high-flux dialysis |
HF | hemofiltrations |
CKD | chronic kidney disease |
LP | lectin pathway |
AP | alternative pathway |
MBL | mannose-binding lectin |
HDF | hemodiafiltration |
kDa | kilodalton |
ISO | International Standardization Organization |
PEG | poly(ethylene glycol) |
PVP | poly(vinyl pyrrolidone) |
PVA | poly(vinyl alcohol) |
ZW | zwitterionic structures |
CA | cellulose acetate |
PES | poly(ether sulfone) |
PSF | poly(sulfone) |
PDMS | poly(dimethyl siloxane) |
PVDF | poly(vinylidene fluoride) |
PAN | poly(acrylonitrile) |
PLA | poly(lactic acid) |
Integrating arts-based practice within psychological interventions has been widely used to increase accessibility and cultural sensitivity and to enable emotional communication and expression. However, using arts within psychoeducation for people with a diagnosis of borderline personality disorder where traumatic events have led to interpersonal difficulties has been less well-documented. This chapter intends to illustrate the experience of patients and facilitators engaging in a mentalization-based psychoeducational programme being delivered in adult mental health services. We will look at the relevance of how images are used to embody relational struggles and how they are used to work through themes of anticipated interpersonal trauma. We then describe narratives of a 12-week arts-based psychoeducational programme from both the patient and professional perspectives.
We present an overview of the rationale of introducing arts-based psychoeducation into a mental health programme for people with a diagnosis of borderline personality disorder (BPD) followed by a description of the structure and a brief vignette of the programme. Finally, we will explore patient perceptions of the programme. All patients are anonymised and have given consent for this material to be published, including any images produced during the sessions. The authors are experienced clinician-researchers and have substantial experience of working within mental health services and related contexts.
We now know that understanding the relationship between attachment, trauma and affect regulation is central to treating patients with a diagnosis of BPD. Evidence suggests that symptoms of BPD have a multifactorial psychobiological aetiology and include attachment trauma reactions to a range of harmful events, including childhood physical and sexual abuse [1, 2, 3, 4, 5], early neglect [6, 7] and invalidation [8]. Attachment traumas in this context refer to an intergenerational disorganised condition of relationship that results in disassociation, high affect arousal ‘stemming from fright without solution’ [9]. In conditions of affect dysregulation due to experiencing attachment traumas, it is hard for the person to make sense of causal factors, including traumatic events and triggers that may produce reactive high arousal states. Stawarczyk et al. [10] proposed that thought suppression is a key survival mechanism developed to mitigate the effects of predictive processing, particularly in relation to interpersonal events. Given the propensity to evade direct linking between affect arousal and events preceding the arousal, acting out emotional experience within an interpersonal context where attachment traumas are perceived to occur is a core part of the work in the restoration of a capacity to mentalize. Here we are referring to mentalizing as having the capacity to imagine intentional states of mind that influence behaviours, for example, desires, beliefs, feelings and thoughts. This is highly relevant to working with patients with a diagnosis of BPD where there is marked reduction in mentalizing [11] due to high affect arousal [12] and attachment trauma triggers within interpersonal contexts [13]. A mentalization-based verbal group model has been developed with this theoretical premise in mind [14]. Mentalizing begins in early infancy through the mirroring actions of parental care that offers a capacity to sensitise to emotional experiences and develop symbolic representations of self-and other as well as narrativisation and restoration of affective homeostasis [12]. The actions of mentalizing another, that is the attuned awareness of internal states influencing behaviours, enable a secure attachment [15]. Where unsuccessful parental mentalizing happens, for example, misattunements, insensitivity, neglect or abuse, the psychobiological vulnerability of the infant is likewise managed with non-mentalizing behaviours. As the pre-requisite for secure attachment is a capacity to mentalize this can cause transgenerational patterns of insecure attachment and attachment traumas, potentially advancing to conditions of severe avoidance of abandonment, identity disturbance, impulsivity and self-harm. These are symptomatic of severe conditions of non- mentalizing and together are considered to be primary symptoms of borderline personality disorder [16]. Most treatments for borderline personality disorder focus on the restoration of mentalizing and enabling a second-order representational system to become established [11, 17, 18]. Second to this, the development of ‘positive thinking’ to replace anticipated catastrophe is also considered to be helpful, particularly for impulsive behaviours [19]. Most treatments are medium to long-term and psychoeducation, as a brief intervention is still in the early stages of development for this clinical group. Given that mentalizing involves imagining mental states and developing representations of self and others, the use of image-making as a reflexive tool is proposed as being a helpful addition to the models of BPD treatment. That said, in order to mobilise the process, framing the problem, understanding the aetiology and reflecting on relational patterns of behaviour are a fundamental first step towards engaging with treatment. Whilst the authors are not intending to describe the effectiveness of the process of using art in psychoeducation for this population, the development of a trauma focused model or the long term benefits, the authors are intending to understand what happens when art is used as a focal point within a psychoeducation programme and how it effects people’s experiences, self-understanding and the participant’s preparedness for psychological treatment.
Psychoeducation is widely used in mental health contexts to help patients to understand living with a diagnosis of borderline BPD [20, 21], how and when presenting issues arise and to consider attachment trauma in the context of interpersonal relationships [22], identity and affect arousal [21]. Further to this, psychoeducation has been used to help impulsivity and suicidality often occurring in relation to attachment traumas [23]. In psychoeducation, participants usually engage between one and 2 hours on a weekly basis for 6–20 weeks. There is some evidence to suggest psychoeducation improves relationships, reducing attachment traumas [22] however the evidence of its effectiveness is limited to feasibility and pilot studies [20, 21, 22, 23, 24]. However, the true extent of the use of psychoeducation is not accounted for given that psychoeducation is often part of a psychotherapeutic intervention for borderline personality disorder [25]. Within the context of art psychotherapy this was also clear in a survey conducted by the British Association of Art Therapists [26]; it was evident that 50% of the art therapists that responded used psychoeducation as either a stand-alone intervention or as being integrated within their treatment. Springham and Whittaker [26] reflect on the survey outcomes and conclude that psychoeducation could be a ‘crucial unique feature of the practice of art therapy with BPD’. This is also clear in the emerging literature in this field where art psychotherapy methods of practice within a psychoeducational framework are often used alongside conventional methods of treatment [27, 28, 29, 30, 31]. For example, Sweig [30] uses a model of arts in psychoeducation and ‘the role of art therapy in clarifying issues and mobilizing creative energies in service of personal growth.’ Likewise Thorne [32] has published a specific model of using art within a psychoeducational framework for patients diagnosed with BPD similar to the one that we employed, that offers a structured and theme-based approach to engaging in understanding and reflecting upon self- and other-experience. Thorne [23] asserts that the image-making process adds to a psychoeducation model for BPD through enabling emotions and experiences to be more richly expressed and contained.
The theoretical assumption guiding the evaluation was that the use of arts in psychoeducation encourages the patient to view the perceived attachment trauma trigger from a ‘distance’. An intolerable, affectively charged trauma can be made more tolerable through seeing it as a human pattern of relating that all people may experience, and hence offering some normalisation according to human functioning [33, 34]. The nature of requesting the participant to see their experience through the lens of human patterns of relating and attachment trauma reactions helps the patient to consider potential aetiological factors. This requires the patient to relate to the subject but also to see the problem as an observer of themselves [35]. Psychoeducation uses a teaching-based model that encourages distance from the trauma and desensitisation to the predicated interpersonal response. We hypothesised that in the proposed model of psychoeducation there is a core mechanism that increases the capacity to reflect on the expected attachment trauma. The second key feature of taking a more distanced view of the attachment trauma, relates to the generalisability of the presenting difficulty. Arts psychotherapies engage the person in thinking about what they are expressing, how it is expressed and how the expression might be received. We propose that introducing arts to a psychoeducation model supports the process of imaginative reflexivity in psychoeducation as a method that enhances the person’s capacity to regulate affect and improve relating to the other [36, 37, 38, 39]. These features of developing imaginative flexibility are also described as a core mechanism in the capacity to mentalize attachment traumas [34] and therefore we deemed this as a helpful addition to the verbal methods of intervention.
Mentalization-based art psychotherapy is becoming an established method of treatment due to the accessibility, cultural sensitivity and scope for emotional communication and reflection [40, 41]. Mentalization based treatment draws on relational theory from attachment theory [42] and restoring mentalizing in the context of attachment trauma as a key part of the work [43]. The concept of mentalization also has its roots in early dynamic theory and cognitive science [44] and refers to a person’s capacity to reflect on self and others’ intentional states of mind [45].
Arts-based mentalization focused psychoeducation is a 12-week programme developed within a secondary care mental health context as both a standalone intervention and as a preparation for an 18-month arts-based mentalization treatment programme. Patients were offered up to four sessions to assess for presenting issues relating to attachment trauma such as self-harm, identity disturbance and affect dysregulation as well as the patient’s motivation for receiving therapy. To understand other stressors, a holistic view to the person’s life including family, finance, social factors and a risk assessment were assessed in relation to their potential treatment and was shared with patients as an assessment formulation report co-written with the patient. The facilitators regularly reviewed the formulation with the members throughout the programme. Following this process, the facilitators offered a place on the arts-based psychoeducation programme. The sessions included arts and ran for 1 hour and 30 minutes over 12 weeks. The themes for each week were modelled on the programme designed by Karterud and Bateman [46] that described preparatory sessions for mentalization-based treatment (MBT) [47]:
Week 1: Mentalization and mentalizing stance
Week 2: What does it mean to have problems with mentalizing?
Week 3: Why do we have emotions and what are the core emotions?
Week 4: How do we register and regulate emotions?
Week 5: The significance of attachment relationships
Week 6: Attachment and mentalization
Week 7: What is borderline personality disorder?
Week 8: Mentalization-based arts therapies - Part 1
Week 9: Mentalization-based arts therapies - Part 2
Week 10: Anxiety, attachment and mentalizing
Week 11: Depression, attachment and mentalizing
Week 12: Summary and conclusion, feedback
The facilitators informed participants that the focus of the group would be on how we see ourselves and the way we relate to others and how these perceptions link to early attachment patterns and traumas to those attachments. Group rules, boundaries, confidentiality, respect for others and punctuality were discussed and agreed. Using alcohol, drugs and violence was prohibited in addition to contact between the members of the group, outside of the group. The format of the group included attendance and a refresher of the previous session, presentation and development of the theme of the current session and discussion, image making, feedback and preparation for the next session.
Each session had the purpose of clarifying the concept of mentalization and the point where it can fail, particularly in relation to anticipating attachment traumas and regulating the associated intense affect. The intention of the group was to work with recent attachment traumas, which group members had identified as being emotionally difficult. At the end of the psychoeducation group, there was a collaborative decision made whether further treatment was required.
The arts were introduced by the fourth author of this chapter and a co-facilitator (both art psychotherapists) to be used in an improvised and explorative way. Materials such as chalks, pens and paints were available to help the patient explore their experience of being in the group in relation to the weekly themes. The narrative uses pseudonyms for the patient names. All members of the group had a primary diagnosis of BPD which had been confirmed through the assessment process. George was a 61 year old, white British man, Henry was a 65 year old white British man, and Dalmar was a 27 year old British Somalian lady.
The artworks were treated as an important part of their personal and group experience and were kept until the end of the 12th session. Over the weeks, the patients’ engagement with the arts appeared to develop in emotional complexity, competency and confidence which was reflected in the way they used the arts media. With the presence of anticipated attachment traumas, the arts were also offered as a way of regulating feelings through making doodles or experimental marks when it felt too difficult to reflect on or explore themes. As sessions passed an increasing engagement with the arts was encouraged and there was clear intent to produce figurative drawings with a narrative that related to attachment trauma and how mentalizing could be restored in relation to the themes discussed.
A way of developing initial cohesion in the group was clear in Week 3, in response to the theme of ‘Why do we have emotions and what are the core emotions?’, George described how his image making on the first week was driven by the curiosity of using the pencil colours that were available, as it gave him an opportunity to ‘get a feel for being in a group’. In Week 3, his initial anxieties were reformulated to form rhythmically drawn patterns in distinct shades on the right top corner of the paper (Figure 1). The early stage of the work in the group and how the forms co-existed became a strong motif for his experience, where the spaces between people, the nuances of emotions and feelings remained compact and connected in a controlled space. We felt that the patient was using the arts materials to regulate his emotional response to feeling cornered, hemmed into a group where he was uncertain about how people could interact and function without disagreement and the resulting personal trauma and potential disassociation. His marks represented a tapestry like presence where form and colour could coexist in a similar way as his emergent feelings in the group’s context.
‘Myself in the group’.
Similarly, in the same session, Dalmar described her artwork (Figure 2) she said that her relationships were like these stone structures that had ‘collapsed’, ‘heavy and helpless’, ‘immovable’ and ‘stuck’. These terms are typical of the disorganised attachment state where there is no solution or relational flexibility and ultimately there is a sense of unresponsive or misattuned neglect. These early images showed a capacity to use image making as a tool for embodying complex emotional narratives that anticipated attachment traumas in ways that could be communicated within a group context.
‘Relationships as collapsing stones’.
By Week 3 some group members mentioned how the use of the arts seemed to enable a capacity to be more aware and talk about their mental and emotional processes within an interpersonal context. In Figures 1 and 2, the artwork allowed the opportunity to expressively articulate thoughts and emotions that had remained unspoken. In Week 4, ‘How do we register and regulate emotions?’ One group member (Henry) described his image as the traffic light in the middle of his drawing (Figure 3). He used the image to help the group reflect on his anxieties of being out of control, again in a disorganised state where he felt helpless and unwanted. He described the predominant affect as fear, represented by the sunset as a loss of light and something blinding. He described his wish to be like the lamp on the left of the page which he commented on as having a more ‘pleasant and balanced quality’. Again, key themes about the rupture to attachments as losing the sun and associated high ‘fight or flight’ arousal of feeling afraid were at the core of the work.
‘Loss of control’.
Using themes to structure sessions helped to enable experiences to be shared. For example, another group member (George) (Figure 4) described being ‘like the hectic river which was crossing and dividing the urban and green space’. In these early sessions, we focused the content on identifying emotional states and understanding how interpersonal contexts stimulate attachment anxieties about anticipated attachment traumas. In Figure 4, George described the urban environment as populated with fragile homes with empty windows, and a mass of green fluidity is sharply divided by an insertion of blue. The powerful disruption also described an intense experience of disconnection that he felt was difficult to bridge due to the uncertainties contained in the green grass of the hill and the disappearing, empty-looking town again drawing on the felt experience of the unavailable and unresponsive others.
‘I live in the space In-between’.
The cause of these intolerable conditions of loss of control and disorganised attachment was shared in the group. Dalmar stated that if her family understood her, they would not behave the way they do. Firmly stating, ‘It’s them that’s the problem.’ (Figure 5).
‘It’s them that’s the problem’.
The same member, later in the work during the session titled, ‘Anxiety Attachment and Mentalizing’, responded by describing how she manages those states of helplessness and abandonment rather than describing what causes them. She managed painful feelings by harming herself or attempting to overdose on her medication, depicting a blue and white pill in a smudged, surrounded by fingerprint smudges (Figure 6). The theme resonated with the group experience. Several people in the group said that this was the first time that they felt that they were being heard. The sense of having a shared experience within the group session contributed positively to the sense of being held in mind by another and developing a capacity to mentalize the other in the context of anticipated social rupture.
‘When I feel abandoned I can only think about dying’.
By the end of the 12 weeks, participants were asked to conclude the sessions through sharing thoughts about how they engaged with the use of the arts as a medium to foster reflective thinking about thoughts, emotions, beliefs, and their personal stories.
Following the psychoeducation, all members were invited to give feedback about their experience for the purposes of evaluating the group and for the results to be published. Three members came forward and gave consent for their interview to be published (George, Henry and Dalmar). The interviews were conducted by honorary researchers (authors 2 and 3) who were independent from the programme and who were supervised as part of an early career research initiative [48, 49] founded with the NHS by the first author. Each interview lasted about 1 hour and was semi-structures. Key extracts that appeared to be prevalent or represent the larger themes were extracted and are contextualised within the narrative below.
The first sessions appeared to have a heightened sense of vulnerability and members were tentatively engaging. For example, one member (George.) described drawing an image of a baby without a mother in response to the theme of what it means to have problems with secure attachment, describing the image as having a re-traumatising quality. The image making was originally seen as tentative, bearing no genuine relationship to the psychoeducation, and sometimes felt uncomfortable. Members also expressed cautious engagement through feeling self-conscious and unskilled when using the art media, which they felt expressed a sense of vulnerability and the feeling that using the art media was exposing a sense of vulnerability, feeling like they would fail or not be good enough. For example, one member stuttered and looked embarrassed when she was asked about the use of the art materials.
The unexpected effect of the image was often experienced as both offering helpful insight and emotional disturbance. George described how a sense of profound attachment re-traumatisation was immediately evoked,
Henry also expressed an experience of re-traumatisation from being in the presence of others during the group experience whilst attempting to avoid group conflicts. He described an avoidance of unmanageable disorganised attachment arousal in the group that could be provoked by group conflicts to try to keep his stability.
However, in this early stage, there was a sense that the structure could contain and guide, often helped to reduce anxieties through a sense of being in a group with a direction which felt supportive; being held by the frame of the task. Henry stated,
However, through having a practical task, the sense of accomplishment of improvising was felt to be useful and could express a state of attachment trauma rather than acting out interpersonally. George said that he used the image as a retreat when one he ‘could not get a word in’. As the work progressed, members said the image making became more comfortable and automatic, perhaps less pre-meditated, but often members said that the relational tension meant that it was hard to be playful or to improvise. As the work progressed, members began to monitor themselves, restore a capacity to mentalize, using the psychoeducation to make sense of their experience. For example, using images helped Dalmar to reflect on the experience of attachment trauma, exploring what felt like part of an illness and what was felt like a ‘normal’ response to relationships,
As the group progressed, what seems to accompany the image making and inform the process were several key areas directly related to the aims of the group. Members said that image-making was used to reflect on feeling states relating to attachment traumas that had otherwise been considered as overwhelming and this marked the beginning of feeling more trusting of others.
Members also described an experience of image-making as a way of processing over-thinking and an opportunity to make sense of the salient teaching points provided by the facilitator.
During the latter sessions they described a growing sense of stability and confidence in themselves and their own agency, which enabled a capacity to be more reflective about other people’s states of mind. However, this appeared to be less so with the experience of what motivated other people’s actions, which often produced feelings of anxiety or distrust. Two of the participants described having a more structured interpersonal experience where they were trying to unravel their problems and consider ways of reflecting on their experience. For example, one participant stated,
Towards the end, members suggested an experience of hope that was linked with an educational ‘structure’ that enabled people to be together and learn about how they might experience one another and what might cause a perceived attachment trauma. There was also an experience of being together and appreciating each other’s struggles, in effect beginning to mentalize the others’ experience.
The ending marked a hard transition and whilst the psychoeducation was successful in helping members of the group to reflect on their experience and form tentative relationships, there was also a sense that they were left with uncertainties given the brief period of the group. Members described the first steps towards alternative ways of relating, but they seemed to be left with a fragile footing.
This brief narrative echoes some similar anxieties as the therapist’s account of the session, and overall, the quality and stories of the members felt like a brief but important encounter that opened up the emotionality and contextual issues in relation to their presenting issues. Following the psychoeducation, most members agreed to continue the work of understanding mentalizing in a non-directive mentalization art psychotherapy group.
The arts-based psychoeducation offered a structured experiential approach to understanding attachment traumas and mentalizing relationships. The image making seemed to offer powerful access to feelings and experiences that sometimes, and especially at the beginning of the psychoeducation, could be uncomfortable and even ‘re-traumatising’. The art psychotherapists’ perspective of the work provides a comprehensive narrative, highlighting the small but significant positive changes. In the follow-up evaluation we see the patient’s autonomy emerging, also describing a tentative grasp of the concepts and emergent alternative forms of relating. We believe that the image-making process facilitated an affective experience of relationships, often revealing vulnerability in safe ways that could be reflected on.
The images offered a powerful account of this process, and particularly the anxieties and uncertainties about developing a secure attachment. The images also revealed anticipated attachment traumas and an invalidating environment, for example in the stuck, rigid invalidating stones; being surrounded by a family that ‘should be in therapy’; the constant traffic light ‘fight or flight’ dance or being stuck in a turbulent place between haunting empty houses and the green grass. Whilst we believe that the use of arts is a valuable tool for communicating, engaging with and reflecting on feeling states; careful, structured and sensitive facilitation is required to maintain safe and effective practice especially where the focus is on how therapists facilitate brief educational work focusing on attachment trauma.
This study revealed that the psychoeducation can expose deep relational vulnerabilities, where the principal focus for members had often been to manage pain in isolation. Perhaps most importantly, the emergent capacity for group members to recover from attachment trauma and to restore mentalizing indicated that there was the conceptual and reflective infrastructure that formed the foundations for further work and would enable members to engage with explorative forms of psychotherapy.
The authors would like to thank the following people for their dedication to the development of the programme as honorary researchers: Charlotte Barker, Kirstin Leyton-Boyce, Dr. Jennifer Townell and the participants for their commitment to the project.
The authors declare no conflict of interest.
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",metaTitle:"What Does It Cost?",metaDescription:"Open Access publishing helps remove barriers and allows everyone to access valuable information, but article and book processing charges also exclude talented authors and editors who can’t afford to pay. The goal of our Women in Science program is to charge zero APCs, so none of our authors or editors have to pay for publication.",metaKeywords:null,canonicalURL:null,contentRaw:'[{"type":"htmlEditorComponent","content":"We are currently in the process of collecting sponsorship. If you have any ideas or would like to help sponsor this ambitious program, we’d love to hear from you. Contact us at info@intechopen.com.
\\n\\nAll of our IntechOpen sponsors are in good company! The research in past IntechOpen books and chapters have been funded by:
\\n\\nWe are currently in the process of collecting sponsorship. If you have any ideas or would like to help sponsor this ambitious program, we’d love to hear from you. Contact us at info@intechopen.com.
\n\nAll of our IntechOpen sponsors are in good company! The research in past IntechOpen books and chapters have been funded by:
\n\n