Hyperkalemia (serum potassium level >5 mmol/L) is the most common condition of electrolyte imbalance, especially in patients who have chronic renal failure and receive long-term heparin anticoagulation.[1] For these patients, periodic removal of excess serum potassium is routine management until receiving kidney transplantation. Sodium polystyrene sulfonate resins, the mainstay oral medication for hyperkalemia, achieve potassium binding in the gastrointestinal tract but have modest potassium selectivity.[2] Hemodialysis is another strategy for hyperkalemia that directly removes serum potassium in extracorporeal circuits primarily by nonspecific transmembrane diffusion, but it requires bulky dialysis machines and large dialysate consumption.[3] The limitations of these strategies encourage the provision of new treatment options, especially for patients without access to hospitalization during the COVID-19 pandemic. The developing wearable artificial kidney technology promises tantalizing convenience, and the adsorbent-based miniaturized blood purification devices enable toxin removal without presenting dialysate problems.[4] Substantial efforts have been devoted to specialized adsorbents for uremic toxins (e.g., bilirubin, endotoxin, and creatinine) and revealed extensive prospects in treating many diseases (e.g., hyperbilirubinemia, sepsis, and renal failure). However, there remains a lack of absorbents to redress electrolyte imbalance in the exclusively adsorbent-based system.

Combining potassium selectivity with blood compatibility in the design of absorbents for hyperkalemia is a challenge. Recent advances in ion-selective materials aim at specific binding/transport/recognition of target ions. These materials (e.g., crown ether [5,6], tannic acid [7,8], graphene [9,10], polymer [11,12], and metal-organic framework [13,14]) possess unique characteristics in pore size, surface hydrophobicity, or electrostatic interactions. However, insufficient biomedical optimization of these materials may result in unpredictable efficacy and potential risks in biofluids. Recent designs of blood-contacting materials follow the characteristics of heparin [15], cytomembrane [16], or endothelium [17] to improve blood compatibility. Flexible chemical synthesis methods allow these artificial materials to exhibit desired biological responses while offering the removal capability of K+ under the complex competition effects from ions, proteins, and cells in biofluids.[18]

Our inspiration stems from cells. In the human body, they serve as the biological K+ storage units that accumulate K+ through multiple mechanisms, including passive transport facilitated by potassium channels, active transport by the Na⁺/K⁺-ATPase, and mitigated intracellular potassium efflux by negative-charged matter. Across cell membranes, the free diffusion of cells, proteins, and ions is hindered by lipid bilayers. Instead, ions are distinguished by corresponding ion channels that facilitate transmembrane transport. In particular, the selectivity filter of potassium channels matches dehydrated K+ in dimension and contributes to the energetically-favorable transport of K+ over other cations.[19] Inside the cell, negatively-charged groups (e.g., phospholipids and proteins) act as affinity sites for K+ and reduce potassium outflux along the leak channel. Recent studies on constructing Angstrom-scale rigid channels in flat membranes for ion sieving have left unsolved problems in simultaneously achieving high selectivity and flux.[20] Alternatively, we envisage the typical core-shell microsphere as a promising structure for selective potassium removal. Such structure allows tolerance of reduced selectivity in the shell in exchange for enhanced permeability and relies on the binding effect of chemical groups for the enrichment of K+ in the core.

Implementing this material design relies on selecting compatible chemical structures. First, we focus on crown ethers (CEs) among macrocyclic ligands to seek K+ specificity. The CEs bind ions and form complexes based on the dimension matching of the target ions with their ring structure.[21] The CEs with the ring structure of 18-crown-6 or 15-crown-5 have high K+ affinity, mimicking the selectivity filter in potassium channels, whose four carbonyl oxygen atoms on the protein subunits form a loop structure to match K+ in dimension. Such affinity is influenced by the chemical structures of CEs (e.g., ring size and adjacent subunit) and the external conditions (e.g., ionic strength and pH value).[22,23] Next, heparin mimetic polymer (HMP) may complement our strategy by introducing CE-grafting sites and heparin-like groups (e.g., SO3H). Such heparin-like groups are hydrophilic and negatively charged; as reported recently, these groups aim to improve blood compatibility and anticoagulant properties in blood-contacting applications [24], and they can also serve as affinity sites for cations in ion sieving.[25]

The application of electro-spraying and phase-inversion technologies in our strategy permits an efficient process to mass-produce core-shell microspheres. During this process, tiny droplets of polymer solution form in an electrostatic field and fall into a non-solvent coagulation bath to form microspheres.[24,26,27] Our strategy is based on microspheres for selective potassium removal. The HMP is synthesized via in situ crosslinking polymerizations and fabricated into heparin mimetic polymeric microspheres (HMPMs). Via the acid-promoted epoxide ring-opening reactions, CEs are grafted on the HMPMs to obtain the crown ether grafted heparin mimetic polymeric microspheres ([email protected]).[28] The physicochemical properties, K+ removal capability, and blood compatibility of these microspheres are investigated.