# The Future for End-Stage Kidney Disease Treatment: Implantable Bioartificial Kidney Challenge
## 2 Future Perspective beyond Current Technical Limitations  
It is evident that the current technology was developed to overcome individual technical problems [41] but did not lead to real integrations in the artificial kidney development, as modern devices cannot mimic all kidney functions. The experimental results obtained so far have opened up the future for the design of prototypes to be used in clinical trials. Individually, these experimental achievements are not enough to obtain an efficient artificial bioreactor to reach physiological blood purification. To reach this objective, a new type of implantable iBAK is necessary. The iBAK may be inserted into a more complex system able to provide a ultrafiltrate from the blood to be processed by cells and eliminated as \"artificial urine\" through a stoma or bladder. At the same time, the contact between blood and the bioreactor should be able to provide nutritional substrates to renal cells and guarantee their  
Figure 1: iBAK and nephron, integration of nephron activities into a modular and complex device. In red, blood entering the device; in blue, blood leaving the device. In yellow, the dialysate and ultrafiltrate processed by the filter and bioreactor. The functions of filtration, reabsorption from the ultrafiltrate, secretion into the ultrafiltrate, regeneration of the dialysate, production of hormones, and modulation of water reabsorption/excretion are handled by different devices combined with the bioreactor in a more complex device. endocrine activity (Figure 1). While the use of silicon nanopore membranes looks very promising for the realization of a future iBAK [27], some technical aspects appear to limit its use. The number of renal cells in the bioreactor (1.2 \(\times\) 10\({}^{7}\) cells vs. 5 \(\times\) 10\({}^{9}\) proximal tubular cells in a human kidney) [42], compared to a physiological nephron mass, is too low to guarantee physiological solute secretion, reabsorption, and hormone production. Immunological isolation may no longer be effective as the number of cells increases, exposing them to damage and death. Cell viability could be limited in time, clearly opening the problem of a faster frequency of cell replacement in the bioreactor, which is not ideal for an implantable device whose functioning should last for several months. Another key point is the control of the blood flow and the regulation of ultrafiltration for fluid removal. Indeed, the blood flow in the iBAK should be based on the arteriovenous gradient with safe flow-pressure feedback to ensure continuous bioreactor perfusion, maintaining stable fluid ultrafiltration for continuous artificial urine production. Such a control mechanism also requires an engineering challenge in terms of fluid removal, which should rely on patient hematocrit and blood protein levels to maintain the patient euvoicmic state. In the event of patient hypovolemia, fluid reabsorption from the artificial urine is a major engineering challenge. This is due to its physical and biochemical complexity in terms of simultaneous reabsorption of sodium and water in relation to plasma osmolality [43]. This issue requires the use of advanced technology that allows the regulation of plasma osmolarity with complex feedback, including algorithms for the management of ultrafiltration [44], blood flow, and fluid reabsorption or elimination. The synergy of these ultrafiltration mechanisms becomes essential in anuric patients in whom a correct fluid balance is essential to avoid hypervolemia and its complications, such as acute pulmonary edema. On the other hand, the ability to concentrate on the device becomes essential in patients with preserved duires in order to avoid states of dehydration. The lack of bioreactor ability to regenerate bicarbonate and eliminate hydrogen ions could have repercussions on the maintenance of the acid-base balance.