The urinary bladder is an elastic reservoir that is responsible for the low pressure storage of urine. A continent, pain free and healthy bladder is crucial for the preservation of a good quality of life. Numerous conditions disturb the anatomy and physiology of the urinary bladder, leading to insufficient and restricted evacuation of urine (1).

Bladder cancer (BC) is the sixth most common cause of cancer-associated morbidity in the western world: In the UK in 2010, there were 10,300 new cases, and 4,900 cases of BC-associated mortality (2). It represents the most common malignancy of the urinary tract, with a median survival rate following metastasis that rarely surpasses 15 months (3). The vast majority (90%) of bladder tumours are histologically classified as urothelial cell carcinoma, these tumours are often further classified as being non-muscle invasive BC (NMIBC) or muscle invasive BC (MIBC) (4). On initial presentation, 30% of patients are diagnosed with an MIBC tumour. From the remainder of patients that had been diagnosed with an NMIBC tumour at presentation, 30% go on to develop an MIBC during follow-up (5). With the highest susceptibility of recurrence and progression of any malignancy, patients with BC require consistent surveillance and close follow-up during and, more importantly, following therapy. With such high odds of recurrence, BC has produced the most expensive management protocol of any malignancy, costing the National Health Service ~£55.39 million in the UK per annum (6). The gold standard treatment for organ-confined MIBC is radical cystectomy, with dissection of the pelvic lymph nodes. Regardless, malignancy is not the sole bladder-associated pathology in which cystectomy is indicated (7).

Bladder damage occurs in several additional disorders within the genitourinary (GU) system, including inflammatory conditions (interstitial cystitis/bladder pain syndrome), urinary tract infections, nerve damage (neuropathic bladder) and congenital disorders (spina bifida). In these cases, the essential task is to re-establish the function of the urinary bladder. Medical treatments are limited, and thus, surgical intervention, particularly cystectomy, is often required (8–11).

Since the first BC-associated cystectomy in 1887, the pursuit to identify the most appropriate replacement voiding system has been largely problematic (12). At present, the most common method of bladder replacement or repair involves the use of autologous segments of gastrointestinal tissue, in order to restore bladder storage and voiding capacity (13). This is often achieved through ileal conduit urinary diversion, orthotopic bladder substitution or continent cutaneous diversion (Table I) (14,15).

Since the original application of a free tissue graft in 1917, in which canine bladders were augmented with fascia, various additional materials have been utilized as free grafts (16). The ileum, however, is the most frequently utilized segment in bladder augmentation, due to its notably simple mobilization, extensive mesentery and copiousness; features that are particularly appropriate for urinary tract substitution (17). Although the use of gastrointestinal segments in bladder reconstruction was first proposed almost 150 years ago, it remains the gold standard due to the absence of a superior alternative. This was demonstrated by Stein et al (18), who observed excellent long-term survival rates in patients undergoing radical cystectomy. Whilst radical extirpation of the bladder is frequently successful, from an oncological perspective, substantial morbidity is associated with enteric interposition within the GU tract (Table II) (19–22). Surgical intervention itself requires procedures on the urinary and gastrointestinal tracts which are associated with complication rates of ≤66%. Considering that the vast majority of patients that require cystectomy and consequent bladder substitution are elderly and suffer from other co-morbidities, in particular renal impairment, urologists find themselves fighting an uphill battle in surgical management post-cystectomy (16).

Certain bladder pathologies, in particular metastatic BC, are managed medically prior to considering radical cystectomy. This method of organ preservation involves aggressive treatment through surgery and radiotherapy, often with neo-adjuvant chemotherapy as the treatment of choice (23). Currently, only multidrug platinum-based chemotherapeutic regimens have been successful (24,25), whereas monotherapy treatments have failed (26,27). The methotrexate, vinblastine, adriamycin and cisplatin (MVAC) and gemcitabine and cisplatin (gem-cis) regimens have been the most commonly used chemotherapeutic treatment regimens. However, the clinical efficacy of cisplatin-based therapy in BC is currently restricted by the rapid development of drug resistance in the majority of patients, frequently leading to therapeutic failure (28). This was demonstrated in a previous study in which response rates from BC patients receiving chemotherapeutic drug intervention in phase II trials varied between 20 and 60%, with the majority of survival rate advantage in the randomised control trial setting (29,30). This has resulted in the ever apparent requirement for bladder reconstruction.

The absence of autologous tissue with parallel properties to the native bladder has directed numerous studies to develop alternative methods of bladder substitution, avoiding the use of bowel tissue altogether. The theory of substituting the native bladder with a synthetic prosthesis has always been an attractive prospect in the development of cutting edge technology. Thus, tissue engineering, cell and stem cell biology, material science and regenerative medicine are at the forefront of medical research (31).

The fields of tissue engineering and regenerative medicine have witnessed substantial progression over the previous two decades. Various studies have investigated the possibility of regenerating multilayer urothelium, which led to the first clinical trial in 2006, in which Atala et al (32) investigated tissue engineered bladders created from cell seeded grafts. The potential of such novel findings has underlined the requirement for further advances in tissue engineering and material science in order to define the properties required for the ultimate reconstructive material and method of implantation.

Tissue engineering is the mainstay of regenerative medicine. It employs the disciplines of cell biology, transplantation, material science and biomedical engineering, towards identifying alternatives that can re-establish and preserve the regular function of damaged tissues and organs (Fig. 1) (33). Although the human body is outstanding in its ability to repair damaged tissue, these reparative processes are frequently restricted to the development of scar tissue. This often proves detrimental in the function of the bladder (34). The ideal artificial bladder should possess properties similar to that of the native urinary bladder. It should possess the ability to store urine at low pressure in a watertight structure, similar to a mechanical reservoir, and permit voluntary voiding with minimal reflux. This structure should also be constructed from inert material and cause minimal complications in the patient so that long-term renal function is not compromised (35). Previously published animal studies have demonstrated promising results in the field of regenerative medicine, and it represents a possible solution for the treatment of a number of urological conditions in the future (31).

Tissue engineering strategies vary, and currently, studies are being orientated in two directions: Firstly, to identify the most appropriate type of stem cell for regeneration and to proficiently incorporate it into bladder cells; secondly, to determine the most appropriate material and technique of embedding these cells using tissue engineered grafts (Fig. 2) (36,37). The selected grafts must exhibit all the qualities of the native tissue, acting ultimately as microenvironments for the implanted cells to prosper (38).

Collagen is considered to be the most ubiquitous protein in the human body, and it is often used alongside alginate as a natural matrix. It is useful in tissue engineering, as it possesses the ability to be easily manipulated and does not provoke an immune response (47). Through the use of innovative inkjet technology, it has been possible to use bio-printing to create a naturally derived 3D construct, with a precise arrangement of growth factors and other cellular components, into a patient-specific scaffold (48).

Decellularised matrices are the most commonly used naturally derived urological matrices. They are usually harvested from autologous, allogenic or xenogenic tissue (49,50). Chemical or mechanical processing decellularises the matrix, removing all cellular components and leaving a natural platform for tissue development (51). The most common origin of decellularised matrices is tissue harvested from the bladder or small intestinal mucosa (52). Once implanted, the matrices eventually degrade and are ultimately replaced by an extracellular matrix. The matrices provide cells with a structural support that can dictate the tissue structure. Bladder acellular matrix may be the most extensively used scaffold in tissue engineering. It has been demonstrated that the cells have the ability to induce the ingrowth of urothelium, smooth muscle, endothelium and nerve cells (53). Perhaps the greatest advantage of the use of acellular matrices is the ability to provide a method of neovascularisation following graft insertion, promoting graft survival. Kikuno et al (54) demonstrated that nerve growth factor and vascular endothelial growth factor enhanced bladder acellular matrix grafting in neurogenic rat bladders through increased angiogenesis and neurogenesis (55).

However, in general, these materials possess various drawbacks depending on their graft origin. Autologous materials have proven difficult to reproduce as a result of increased patient morbidity associated with the graft harvest (56). The increased cost in allograft and xenograft material production, in addition to the risk of disease transmission and varied mechanical strength, is crucial in their limited clinical application (56,57). Furthermore, the use of natural decellularised matrices requires tissue that exhibits no principal pathological change, and is therefore unfeasible in certain patients (58,59). In addition, the aggressive decellularisation and sterilisation protocols used can denature proteins in the extracellular matrix, damaging the physiological environment (60).

The use of synthetic material in patients in which the native bladder has undergone pathological change, such as BC, is hypothesised to be the ideal solution. The most commonly used materials in experimental studies and clinical trials are Teflon, silicon and collagen matrices (61). However, cell and tissue incompatibilities appear to be the major restrictions of these materials, leading to the development of other synthetic polymers, such as PLGA (62–65). These materials were designed specifically to possess adequate structural and biological properties, which can be manipulated for optimal cell proliferation and differentiation (66). In addition, these scaffolds are safe, possess controlled properties of degradation rate and strength, are readily available and possess the ability to carry vital growth factors, such as vascular endothelial growth factor, for neovascularisation (67–69). Indeed, the most attractive property of PLGA compared with older polymers, such as Teflon, is its resorbable biodegradability. This eliminates the disadvantages of infection, calcification and unfavourable connective tissue responses observed in older polymers (70). When using polymers, tissue recognition is difficult, and often requires immunosuppressive therapy. However, it has now been demonstrated that novel biological factors, including adhesive proteins such as collagen and fibronectin and growth factors such as basic fibroblast growth factor, epidermal growth factor and insulin, are able to enhance cell recognition (71,72).

The failure of certain materials in clinical cases has been extensively reported, including plastic moulds (73,74), gelatin sponges (75,76), Japanese paper produced from the rice paper plant (Tetrapanax papyrifer) (77,78) and bovine pericardium (79,80).

Nanotechnology, which arose in the last decade of the 20th century, has been used in the formation of matrices that can be composed of natural and synthetic materials. The use of nanotechnology permits the development of a graft that can be manipulated to produce characteristics with definitive properties in order to promote optimal cell proliferation and tissue differentiation (53). A previous study investigated the effect of surface roughness on the interaction with matrix proteins (81). Vitronectin absorbance improved by 20% with the addition of nanotechnology-induced surface roughness in the synthetic materials compared with the nanosmooth surface. Similarly, enhanced adhesion and proliferation of urothelial cells has been demonstrated with increased synthetic surface roughness (82).