Use and Efficacy of Porcine Urinary Bladder Matrix for Tissue Regeneration: A Review

Complex soft tissue wounds have historically been treated with different variations of soft tissue skin grafting or flap procedures.¹ However, among the disadvantages of these treatments are the necessity for viable and available donor tissue, potential risks for procedural or donor site complications, and/or immunogenic failure and rejection.¹ Further, skin grafting cannot be used in wounds without a well-vascularized wound bed, while free tissue transfer procedures require microvascular experience, expertise, and resources that are not readily available at all institutions.^1,2 Flap failure due to vascular compromise also remains a significant risk, leading to further surgical morbidity and resource consumption.¹ Owing to these challenges, technologies that may harness the body’s intrinsic tissue regeneration and tissue remodeling mechanisms and processes have been developed to avoid risks associated with these higher levels of reconstruction. 

Wound healing is largely facilitated by processes driven by cells and biologically active molecules such as proteoglycans, HA, collagen, and elastin present in the ECM.³ The specific composition and mechanical properties of the ECM are crucial for proper tissue regeneration and remodeling, especially in the case of traumatic or chronic wounds, which can damage or deplete the local ECM, resulting in decreased healing potential and prolonged wound states. 

Porcine UBM, also referred to as porcine bladder acellular matrix, is a specific type of acellular ECM that is meant to act as a skin substitute and extracellular scaffolding to support cellular infiltration, revascularization, and soft tissue regeneration and repair, while mimicking the function and properties of the human ECM.^4,5 Porcine UBM is a naturally recurring biomaterial scaffold conducive for host integration and sutureless wound closure owing to pro-regenerative and immunomodulatory properties that enhance tissue repair while closely resembling native tissue.^4,5 UBM supports constructive remodeling following tissue injury by inducing local processes such as cell differentiation and proliferation, as well as angiogenesis and neovascularization via regulation of bioactive/immune cells and molecules.^3,6 Following integration, UBM is remodeled through the body’s regulatory immune processes.

Various types of UBM materials have been produced. UBM can be applied in the form of single-layer or multi-layer sheets, which may also be referred to as patches or grafts. Cytal Burn Matrix, Cytal Wound Matrix, and Gentrix Surgical Matrix are commercially available UBM sheets. These products are manufactured by Integra LifeSciences, who acquired ACell, Inc. UBM is also produced as a particulate, which can be used in its powder form or be prepared into a paste, hydrogel, suspension, or solution. MicroMatrix (Integra LifeSciences) is an example of a particulate UBM. With the early success of UBM, its application has advanced to include a variety of procedures across several surgical subspecialties.

This review summarizes the current literature evaluating the clinical and preclinical use of UBM across an expansive range of applications.

The databases PubMed, MEDLINE, Embase, Scopus, Cochrane, and Web of Science were searched, using keywords “extracellular matrix,” “acellular dermal matrix,” “urinary bladder matrix,” “porcine acellular matrix,” and “porcine-derived matrix.” The articles were then screened for inclusion by title and abstract, then by full text. The search was limited to English-language articles (or those with available English translations) published from January 1999 through December 2021. This review is focused on recent clinical and preclinical data along with the basic science of UBM. The study was conducted wholly in accordance with the ethical standards of the Declaration of Helsinki.

A summary of the findings from included clinical and preclinical studies is presented in tables, divided by clinical context. Within each table, articles are grouped by human vs. animal studies and level of evidence (eg, case report or case series, retrospective study, prospective study, meta-analysis).

UBM has become a preferred xenograft matrix for a variety of clinical applications. A total of 1482 records were identified; these underwent screening after removal of duplicates. After screening, 94 articles were included in this synthesis of the literature review. Five articles were included in abdominal wall hernia surgery, 10 in cardiothoracic and pulmonary surgery, 10 in gastrointestinal surgery, 4 in neurosurgery, 11 in oral and maxillofacial, otolaryngology, and head and neck surgery, 5 in ophthalmology, 3 in orthopedic surgery, 25 in plastic surgery (10 in burn and wound care, 7 in diabetic wound care, 8 in orthoplastic reconstruction), and 21 in urology and gynecology (13 in bladder, ureter, and urethra reconstruction, 8 in genito-pelvic reconstruction). These studies were collected, analyzed, and categorized by clinical and preclinical use of UBM across the aforementioned specialty categories.

Abdominal wall hernia surgery

Ventral hernias are common and difficult to treat owing to frequent reoccurrence. UBM, used in lieu of synthetic materials or standard surgical materials such as PP mesh, has been used in the repair of abdominal wall defects. UBM-aided repair of hernias and other fascial defects have been reported to minimize postoperative complications and reduce the inflammatory response.^7-11

High success rates in primary myofascial closure have been observed when using UBM in humans with catastrophic open abdomen due to etiologies such as bowel surgery complications, perforation, and abdominal compartment syndrome, while also maintaining 0% surgical site infection rates and 0% hernia recurrence in the 11 patients.¹²

Abdominal repair with UBM has also shown success in various animal models, promoting closure and largely preventing hernia recurrence.^9,10 One study compared the performance of single vs. multilayer UBM matrices in abdominal wall repair in rabbits.¹⁰ The single-layer UBM demonstrated superior stability, but more recurrent hernias were noted in this group. While the multilayer UBM group had less recurrence, this group demonstrated notable graft shrinkage after 3 months¹⁰ (Table 1).

Cardiothoracic and pulmonary surgery

UBM has demonstrated promise in various visceral cardiothoracic injuries and pathologies by promoting repair in various tissue types^13-22 (Table 2). A total of 8 patients who were successfully treated by Abu Saleh and colleagues^20-22 presented with various cardiac tumors necessitating resection and reconstruction. In the 2 patients followed for a maximum of 6 months, the cardiac walls secured with UBM patches supported new cardiac tissue growth and did not lose integrity, deteriorate, enlarge, or shrink when evaluated via computed tomography.^20,22 Additionally, all patches were found to be hemostatic/stable, and there was no evidence of tumor recurrence.^20-22

UBM can effectively facilitate constructive remodeling of full-thickness myocardial tissue, as seen in various animal models.^15-19 In the setting of myocardial defects, UBM treatment led to decreased defect size, increased graft site thickness, and enhanced remodeling of myocardial/cardiomyocyte tissue, which exhibited spontaneous contractility.^17,18 In a canine model, the peak contractile force of the UBM-repaired area was found to be equivalent to approximately 70% of the adjacent native myocardium contractile force.¹⁷ In another canine model, UBM repairs demonstrated significantly greater regional systolic contraction when compared with cardiac defects repaired with PET (Dacron) (P < .05).¹⁸ Additionally, UBM treatment led to the regeneration of pericardial tissue in porcine subjects without causing complication, excessive inflammation, or adhesion formation.¹³ 

UBM also demonstrated a protective effect limiting the fibrosis of pulmonary tissue following bleomycin-induced lung injury in mice.¹⁴

Gastrointestinal surgery

UBM has been successfully used to repair and reinforce tissue along the gastrointestinal tract after iatrogenic and fistula defects (Table 3). Esophageal reinforcement with circumferentially applied UBM matrix following total gastrectomy in 37 human patients aided in decreasing esophagojejunal leakage and/or stricture and led to no intraoperative or in-hospital mortality.²³ One case of a persistent, nonhealing tracheoesophageal fistula that was unsuccessfully treated with stents for over 8 weeks was eventually deemed a candidate for UBM.²⁴ A 4-layer UBM sheet was placed over the defect bronchoscopically and secured by a Y-stent, leading to complete resolution of the defect within 10 days. Stents were removed, and at 10-month follow-up, the patient had not experienced any fistula recurrence.²⁴

Another retrospective patient series found that 79% of anal fistulas (various etiology) treated with UBM healed successfully, healing 75% of primary and 86% of recurrent fistulas.²⁵ The authors of this study stated that this was a higher success rate than that reported for other biologic grafts (fibrin glue, polyglycolic acid/trimethylene carbonate, and procine small bowel mucosa) in the literature (24%–58% efficacy).²⁵ The mean healing time in this study was 17 days.²⁵

A few studies evaluated the use of UBM for hiatal hernia repairs.^26-28 A retrospective review and a case series reported hernia recurrence rates of 22%²⁸ and 0%,²⁷ respectively. Both study groups overall demonstrated symptomatic improvements of dysphagia and gastroesophageal reflux disease reports.^27,28 Another retrospective series compared the outcomes of patients who received or did not receive UBM as an adjunct to cruroplasty for paraesophageal hiatal hernia repair.²⁶ UBM treatment was associated with longer mean surgical time, but there were no significant differences in postoperative complications, median length of stay, readmission, reoperation, or overall long-term outcomes between the 2 groups. 

UBM demonstrated beneficial utility for reconstructing partial esophageal defects in 2 canine and 2 porcine studies.^29-32 In these studies, UBM showed constructive remodeling with histology and organization resembling native tissue, which may decrease the risk of early complications and repair failure.^29,30,32 In a comparative study with canine subjects, UBM treated esophageal dysfunction in all cases, whereas all of the subjects treated with small intestinal submucosa scaffolds displayed signs of stricture formation within 45 days.³⁰ However, in a canine model of tabularized UBM used to manage complete circumferential esophageal defect, UBM alone was not effective and was associated with stricture formation.³¹

Neurosurgery

UBM has been proven to augment sensory nerve growth and facilitate epineural repairs in animal models.^33,34 Completely transected rat peripheral nerves, directly repaired with fetal UBM, demonstrated significantly improved epineural and endoneural organization with increased neovascularization and growth associated protein 43 expression at repair sites.³⁴ When compared with the criterion-standard nerve autograft for segmental loss peripheral nerve repairs in rats, UBM nerve conduits exhibited significantly improved foot fault asymmetry scores at 2 and 4 weeks (P < .05) and significantly increased sensory axon counts within and distal to the conduit (P < .01 for both).³³ Animal studies suggest that UBM may also exert protective effects on brain tissue from injury^35,36 (Table 4). To repair focal brain photochemical lesions in the motor cortex of rats, ECM hydrogel derived from human umbilical cord or porcine UBM, brain, and spinal cord were utilized.³⁵ UBM was found to have the highest elastic modulus while performing similarly regarding the concentration of collagen, migration and proliferation of hMSC, differentiation of neural stem cells, and axonal outgrowth in vitro. In a different study, following traumatic brain injury in rats, injection of hydrogel UBM reduced lesion volume, attenuated trauma-induced myelin disruption, and resulted in pronounced recovery of neurobehavioral function measured by vestibulomotor function compared to injection with phosphate-buffered saline, although no differences in recovery of cognitive function were observed.³⁶

Oral maxillofacial, otolaryngology, and head and neck surgery

Oral maxillofacial defects due to various causes have been treated using UBM (Table 5). In a retrospective study involving 39 encounters in 35 patients, 64% of all encounters had successful healing of mucosal defects, with only 12 cases experiencing some scarring or functional defects.³⁷ In 14 cases including 10 patients, healing failure was attributed to osteoradionecrosis (n = 7), malignancy recurrence (n = 4), or osteomyelitis, premature graft removal, or hemorrhage (n = 1 each). In a different study, all 5 patients treated with UBM following dog bite avulsion injuries experienced no wound dehiscence, graft loss, or infection.³⁸ While none sought surgical scar revision, 4 of the patients received pulsed dye laser treatment to improve cosmesis. 

In another 2 studies, UBM was used to salvage failed local, regional, and free flaps.^39,40 UBM facilitated soft tissue growth in lieu of attempting a secondary flap attempt or so that an additional flap or implant could be applied.^39,40 In the post-oncological defects, half of the patients remained disease-free after the initial UBM treatment, while the other 2 patients received either secondary UBM or interferon therapy to minimize tumor recurrence.³⁹ Additionally, 1 patient being treated with UBM for a post-oncological gingival squamous cell carcinoma defect achieved complete muscularization for rehabilitation without complication, recurrence, or speech impediment.⁴¹

UBM has proven valuable in supporting the formation of functional native TMJ disk fibrocartilage and TMJ meniscus tissue in dogs while preventing gross degenerative changes in 16 of the 17 dogs between 2 studies.^42,43 The newly formed tissue exhibited biomechanical characteristics approaching that of the native disk at 6 months and performed better than controls, which had articular irregularities and disorganized or no indication of connective tissue growth.^42,43

In addition, 2 studies by Camacho-Alonso and colleagues^44,45 demonstrated that UBM is effective for oral mucosa and lingual musculature regeneration in the setting of rat tongue VML injuries. These studies each demonstrated that UBM used in conjunction with either Orabase (Convatec Inc.)⁴⁵ or myoblasts⁴⁴ performed best for tissue regeneration by mass compared with controls or any product used alone. Both UBM plus Orabase and UBM plus myoblast groups had a statistically significant lower percentage of tongue occupied by wound.^44,45

For chronic TM perforation repair in chinchillas, UBM patching allowed for the regeneration of all 3 layers of the TM, including the dense connective tissue stroma and resembling native tissue.⁴⁶ In contrast, control TMs appeared disorganized, and areas of thickened white patches were observed, indicative of myringosclerosis. 

Five beagles with hemilarynx injuries received UBM scaffold treatment, which resulted in epithelial, muscle, and cartilage regeneration, allowing for possible restoration of vocal fold function with minimal local inflammation.⁴⁷

Ophthalmology

UBM has been used for ophthalmic and periocular soft tissue repairs either as stand-alone procedures or with other reconstructive interventions, especially in nonsurgical candidates^48,49 (Table 6). In a retrospective study, healing was achieved in all 25 wounds in 17 patients.⁴⁸ In a different study, 1 wound created by tumor resection was healed with no sign of tumor recurrence after 15 months.⁴⁹

UBM appears to be effective in the surgical management of deep corneal ulcers, corneal sequestra, and keratomalacia in canine, equine, and feline subjects.^50-52 While the integration of biomaterial was successful and visual function was returned in most cases, a few subjects experienced postoperative ulceration, cataract formation, superficial corneal pigmentation, or epithelial inclusion cysts.^50,51 Additionally, 14 of the 17 equid developed keratouveitis, which responded positively to nonsteroidal anti-inflammatory drug therapy before healing.⁵²

Orthopedic surgery

UBM has been used in animal models to reduce cartilage degeneration in immune-mediated arthritis and osteoarthritis models^53,54 (Table 7). Despite detectable serum levels of anti-type II collagen immunoglobulin G in the UBM group, no mice developed signs of clinical arthritis, while those that received bovine collagen type II injections did.⁵³ Additionally, UBM improved cartilage integrity and reduced pain in mice in the osteoarthritis model compared with saline-injected controls.⁵⁴

Conversely, UBM scaffolds did not yield substantial muscle tissue regeneration in rat models with gastrocnemius MTJ or tibialis anterior VML injury.⁵⁵ Complete scaffold resorption and no tissue remodeling were present in the MTJ models. In the tibialis anterior VML model, UBM did facilitate fibrotic tissue growth, which supported vascularization and limited de novo muscle regeneration near remaining muscle tissue. Additionally, UBM-treated VML injuries slightly improved contractility and recovered approximately one-third of the functional defect; they also demonstrated 17% (P < .05) improvement of maximal isometric torque compared with the no-repair group.⁵⁵

Plastic surgery

Wound care. UBM is useful for various persistent wounds, even after failed primary reconstruction attempts. The benefits of UBM treatment include reduced wound manipulation, pain, invasiveness, and cost of treatment, as well as improved cosmesis and patient satisfaction when compared with traditional wound care, such as wet-to-dry dressings (Table 8).^56-60

In the studies reviewed, pilonidal wounds managed with UBM demonstrated average healing times at around 51 days⁵⁸ to 2.5 months⁵⁶, with low or no reoccurrence and minimal or no complications. One patient with a large pyoderma gangrenosum ulcer was also successfully treated using UBM to promote wound healing and coverage to prepare the wound for eventual skin grafting and experienced a drastic decrease in pain with no recurrence nor further need for surgery.⁵⁷ A patient who developed a year-long Pseudomonas infection following a radiation mastectomy experienced a rapid decrease in pain and wound size once UBM care was initiated.⁶¹

In 2 studies, 4 patients with nonhealing radiation wounds were treated with UBM, which resulted in closure within 3 weeks (3 patients)⁶² or 7 weeks (1 patient)⁵⁹ and no instances of complications or adverse effects. All 4 patients achieved healing without the need for grafting of skin or vascularized tissue. In a different case report, UBM also promoted complete wound closure within 16 weeks and prevented abscess recurrence or sinus formation for 1 patient with a large burn contracture defect.⁶⁰

A handful of other studies have exhibited successful healing of diabetes-related wounds.^63-69 Additionally, in a type II diabetic mouse model, UBM scaffolds facilitated superior wound repair and dermis reconstruction of full-thickness skin wounds compared with a dermal porcine acellular matrix.⁷⁰ By day 28, the wounds managed with UBM were completely epithelialized with normal dermal tissue structure, while some regions of epidermis were not formed in the acellular dermal matrix group. 

UBM has also been used for full-thickness wound management in 2 rabbit models. The 12 of 36 dorsum skin wounds treated with UBM resulted in faster healing than those receiving no graft, although all graft-assisted wounds were 100% reepithelialized by 30 days.⁷¹ In the second study, all UBM scaffolds facilitated complete healing within 3 weeks.⁷² It was observed that when UBM was cultured with keratinocytes, healing was augmented, resulting in early wound contraction and an increase in angiogenesis compared with UBM alone.⁷²

Orthoplastic reconstruction. UBM has proven useful for cases of complex injury involving soft tissue, bone, and articular structures. One case series documented UBM use for 51 patients who experienced trauma or combat wounds.⁷³ In 86% of these cases, UBM stimulated granulation formation, reepithelialization, and dermal regeneration to support skin grafts or flaps for definitive coverage. UBM failures (14%) were due to material losses from friction, shearing, debridement, superficial infection, or inadequate neovascularization. 

A case series documenting 4 patients with 5 complex wounds (including open fractures and large tissue defects) showed complete healing within 72 days to 6 months of UBM application for all patients and wounds.⁷⁴ In a retrospective study of 9 patients with 11 open wounds and concomitant fractures, complete healing occurred at an average of 26.5 weeks.⁷⁵ Six of these patients had exposed hardware prior to receiving UBM, but all achieved normal leg contours and appearance after treatment.⁷⁵ Similarly, in a case report by Bui et al,⁷⁶ a patient with complex wound dehiscence and subsequent hardware exposure and infection of the right big toe was treated with UBM, showing successful closure within 3 months. Of 13 patients with open distal lower extremity wounds involving an exposed Achilles tendon (n = 6), tibialis anterior (n = 6), or peroneal tendon (n = 1), wound closure occurred from 6 to 78 weeks.⁷⁷ Wound dehiscence (4 patients with Achilles wound) and bilateral venous stasis and ulcer flare (1 patient with Achilles wound) were reported, but these complications did not compromise healing or lead to product loss. 

UBM is also beneficial in preserving limb length following amputation.^78,79 Following a traumatic fingertip amputation, a patient was treated with UBM, debridement, and fat grafting, leading to increased salvage length of the digit, improved cosmesis, and returned sensation and fine-motor function.⁷⁸ In a case series of 5 patients with lower extremity amputation, 1 patient was treated with UBM, which regenerated the wound bed so that a split-thickness skin graft could be performed for stump coverage.⁷⁹ This preserved bone and limb length and allowed the patient to ambulate with a below-the-knee prothesis.⁷⁹

Lastly, a patient with nonhealing seromas resulting from repeat knee arthroplasty received traditional wound care for 5.5 months with no resolution.⁸⁰ UBM application and negative pressure wound therapy were then initiated, and resolution was achieved within 7 months. At 1-year follow-up, the wound remained healed, and the seroma did not recur. 

Urology and gynecology 

Bladder, ureter, and urethra reconstruction. UBM shows some promise in urologic cases when autografts or vaginal flap urethroplasty are not viable options (Table 9).⁸¹ In 2 female patients, UBM, along with fat-pad transposition and a biologic pubovaginal sling, was successfully used in urethral reconstruction.⁸¹ Both grafts resembled the native posterior wall, and when visualized via cystoscopy, bilateral ureteral efflux was observed with no injury to bladder tissue. One patient reported significant improvement in continence with no further voiding dysfunction; however, the other had recurrence of urinary stress leakage 7 months postoperatively. 

Preclinical studies have most extensively studied UBM application for bladder reconstruction following cystectomy. In a rabbit model, UBM grafts cultured with skeletal muscle stem cells showed transitional cell and muscle cell growth after 6 weeks, and the reconstructed bladder resumed the construction and function of a normal bladder.⁸² Similarly, 2 studies using UBM grafts to repair cystectomy defects in porcine models both reported complete and functional regeneration of the bladders 4 weeks after implantation, with no stones in the lumen.^83,84 The use of UBM for a bladder wall substitute in a porcine model has shown positive short-term results (12 weeks).⁸⁵ However, the results proved less propitious at an extended time frame (22-week explant) as the average UBM graft had 48% shrinkage, indicating contracture. 

Two studies have demonstrated that UBM is an effective treatment for urethral conditions. In rabbits with long segment urethral stricture, UBM combined with autologous urethral tissue graft regenerated a near normal urethra while the UBM graft alone was less effective.⁸⁶ Dogs with acquired urinary incontinence were treated with UBM by injecting the particulate form into the internal urethral sphincter.⁸⁷ The group treated with UBM had a markedly longer median duration of urinary continence following treatment compared with the control group (168 days and 14 days, respectively). 

Incorporating HA, VEGF, PDGF-BB, ureters, or SF porous network with UBM may enhance its propitious effects in bladder reconstruction. Loai et al⁸⁸ assessed bladder tissue regeneration in a porcine model with various treatment combinations and found that HA-VEGF-UBM grafts proved most effective in stimulating strong graft recellularization and urothelial bladder development. In a rabbit study by Zhou et al,⁸⁹ UBM incorporated with PDGF-BB and VEGF resulted in improved bladder capacity and compliance recovery, bladder tissue strip contractility, smooth muscle regeneration, and vascularization compared with UBM alone controls. In a porcine model, Mitsui et al⁹⁰ reported that simultaneous implantation of bilateral ureters into a UBM graft following 50% partial cystectomy demonstrated enhanced epithelialization of the graft compared with UBM alone. A bilayer scaffold made up of an SF porous network with underlying UBM graft promoted smooth muscle, blood vessel, and nerve regeneration in a rat bladder augmentation model.⁹¹ At 12 weeks after implantation, the group treated with the UBM-SF scaffold displayed superior structural and functional properties compared with the group receiving cystotomy alone.

In 2 studies, urological tissue engineering in mice was assessed in vitro and in vivo. Liu et al⁹² seeded UBM with urothelial cells and SMCs harvested from human bladder tissue and demonstrated that cells seeded on decellularized UBM, grown in dynamic culture, promoted statistically significant cell–matrix penetration in vitro and cell growth and tissue regeneration in vivo. Kim et al⁹³ seeded UBM grafts with human bladder SMC, which was demonstrated to be useful for functional reconstruction of the bladder, ureter, and urethra. The seeded SMCs formed smooth muscle-like tissues both in vitro and in vivo. In vivo, this muscle contracted in response to both electrical and biochemical stimulation. 

Genital and pelvic reconstruction. Two female patients with complex rectovaginal fistulas underwent transvaginal repairs using UBM grafts.⁹⁴ Complete fistula resolution was noted in each patient at 6 and 8 months, and no vaginal bulges were observed after healing. However, 1 patient had persistent dyspareunia due to decreased vaginal length after reconstruction. 

UBM has also been shown to be a promising material for pelvic reconstruction in animal models. When compared with UBM, PP mesh, composite cross-linked UBM, and composite UBM, cross-linked UBM was deemed the best material for pelvic reconstructive surgery in rabbit abdominal walls.⁹⁵ In a second study comparing PP mesh and cross-linked UBM in a rabbit vaginal and abdominal model, UBM showed good biocompatibility and no sign of erosion in either location.⁹⁶ In contrast, vaginal PP was associated with 67% erosion reaction. In line with these results, a study in rats showed that when UBM is added to PP, the host immune rejection reaction to PP is suppressed by UBM-mediated transplant acceptance, allowing the PP to fuse with new tissue with less host rejection.⁹⁷

For pelvic reconstruction in mice, Li et al⁹⁸ used UBM scaffolds and UBM cross-linked with anti-sca-1 and bFGF. The anti-sca-1/bFGF-UBM scaffold demonstrated a stronger ability to enrich autologous stem cells, change the content of elastic fiber, and improve pelvic organ prolapse. 

UBM may also be beneficial for endometrial regeneration. When transplanted into the uterine horns of intrauterine adhesions in Sprague-Dawley rats, the UBM group demonstrated more obvious tissue cellularization and regeneration than the injury group.⁹⁹ UBM also improved endometrial receptivity and fertility as the number of fetuses was increased. 

Penile plaques, seen in Peyronie disease and tumor resection, may necessitate reconstruction of the penile tunica albuginea. Few functional data are available in the study of biomatrices for reconstruction, although UBM was used for penile tunica albuginea repair in 2 rabbit studies. In a study by Joo et al,¹⁰⁰ excised penile tunica albuginea was covered with UBM. Two months after implantation, the graft sites were healing well without contracture, and at 6 months there were no significant histological differences from normal controls.¹⁰⁰ Similarly, Eberli et al¹⁰¹ found that all replaced tunica albuginea implants resulted in normal erectile function with the maintenance of corporal tissue integrity indistinguishable from normal controls. 

Types of UBM

UBM can be manufactured in various ways to yield acellular ECM mimicking scaffolds in the form of injectable gels, powders, and sheets, which each may have different strengths and specific use cases.^5,102 While a less common method, UBM has also been produced within regeneration sleeves, 3-dimensional rotational cell-seeding rigs, or by laser-activation and electrospinning methods.^4,103-106 Irrespective of modality, surgeons have repeatedly stated that UBM is user friendly and that there were minimal or no difficulties when implanting and suturing UBM products to native tissue.^20-22

Injectable ECM hydrogels are a commonly used form of UBM, preferred owing to their structural adaptability to fill wound beds. Hydrogel scaffolds are proficient in performing chemotaxis, proper cellular adhesion, infiltration, stem cell differentiation, and proliferation.^5,102 The concentration and density of an ECM hydrogel are of important consideration because it affects the gelation, elasticity, stiffness, contraction, permeability, viscosity, degradation, and infiltration after injection.^5,102 UBM powders can be produced by snap freezing and pulverization and deliver some of the same structural adaptability as hydrogels.¹⁰⁷ The addition of sodium chloride to the UBM solution can improve porosity and allow for more uniform distribution.¹⁰⁷ Alginate microparticles can also be added to powdered UBM as an immunoprotective barrier.¹⁰⁸ While laminated UBM sheets are indicated for many scenarios, they do not provide the same adaptability to various wound sites as hydrogels or powders. However, they are preferred to synthetic materials owing to their wettability, adherence, and proliferation potential.¹⁰⁹

Production of UBM

First, bladder tissue is harvested from a porcine donor. Second, the tissue is decellularized, sterilized, and sometimes homogenized. Although the processes or protocols can vary widely, the schematic in Figure 1 can be used to gain a general understanding of UBM production.

UBM is decellularized to disrupt the cellular architecture and remove biological materials from the xenograft to improve cytocompatibility and reduce immunogenicity.¹¹⁰ A vast array of preparations have been documented in the literature, including the use of hypertonic or hypotonic buffers; enzymes (eg, nuclease, pepsin, papain, trypsin); chemical detergents (eg, CHAPS, sodium deoxycholate, SDS, Triton X-100); and mechanical agitation (eg, dissection, distention, high hydrostatic pressure).^111-116 Detergent application aims to remove nuclei and DNA content, without significantly affecting the ECM mechanical properties.^115,117 Experiments have demonstrated that detergents can disrupt collagen fibrils, and SDS and Triton X-100 specifically can denature the triple helix structure of collagen molecules.¹¹² However, the use of collagen hybridizing peptide can maintain ECM structure during decellularization, minimizing collagen denaturation.¹¹² 

Additional steps may be required to sterilize and preserve UBM. Ethylene oxide sterilization is preferred over gamma irradiation and electron-beam irradiation because it has the least detrimental effects on mechanical factors.^116,118 Careful control over pH and temperature, supplementation of proteinase inhibitors, lyophilization, and limitation of wash time can also enhance UBM preservation.¹¹⁶ ECM may be stored in a rehydrated form, potentially offering better results for storage and off-the-shelf use than lyophilized UBM, although storage can affect mechanical properties.^119,120

Mechanics of UBM

UBM permits tissue regeneration, repair, and remodeling via the manner in which it mimics the native ECM, because it acts as a strong structural support and allows for possible seeding of endogenous, native tissue.^20,21 The ECM, as well as its topology and molecular composition, is an important factor in wound repair and tissue remodeling owing to its ability to provide mechanical support, allow cellular invasion and adhesion, support gelatinase activity, and release bioactive molecules that modulate cellular recruitment, regulation, and differentiation.^105,121-125 ECM is also characterized by its polarity and porosity to allow for directional diffusion of oxygen and nutrients between cells and tissues.

The methods and chemicals used in the harvesting, decellularization, production, and storage of UBM can affect the mechanical characteristics of the scaffold when compared with ECM. While decellularization does not appear to affect tensile strength or loading strength from compression significantly, it can decrease extensibility by increasing collagen and elastin slopes.^111,126 Additionally, storage time and temperature can modulate the maximum elongation, maximum load, and maximum tangential stiffness of lyophilized UBM.¹¹⁹ Rehydrated UBM has shown increased ultimate tensile strength and stiffness compared with lyophilized UBM.¹²⁰

It is hypothesized that the porosity of UBM influences contracture, fibrosis, and the uptake and retention of bioactive molecules.¹²⁷ In both thin and thick UBM constructs, the abluminal surface demonstrated greater absorbance, oxygen diffusivity, and porosity than the luminal surface.^125,128 The thickness of UBM was positively correlated with porosity on both the abluminal and luminal surfaces.¹²⁸ The thickness and tensile strength of UBM can be increased by the addition of films or multilaminate, or by electrospinning UBM with biodegradable polyester urethane urea.^{4,109,129,130}

Additionally, the specific species and organs used to harvest and produce xenogeneic matrices can determine structural and morphological properties of the scaffold, as well as degradation resistance to collagenases and elastases.^122,131 Chemical cross-linking of ECM may be useful in increasing scaffold strength, but this can slow degradation, thus inhibiting tissue remodeling.¹³² Scaffold degradation is seen as a strength of UBM, because this allows for tissue replacement and minimizes the risk of immunogenic response owing to the absence of foreign material after a given period.¹³²

Composition of UBM

UBM can contain and deliver a wide array of peptides and bioactive factors. Structural proteins such as collagen and sGAG, as well as some insoluble residual intracellular proteins, survive the decellularization process.^111,116 The surviving remodeling products of ECM grafts can influence cellular migration, differentiation, and proliferation of multipotent progenitor cells, SMCs, and endothelial cells.^112,114,116

After decellularization, different matrix scaffolds retain collagen (type I, II, III, and IV); mildly reduced levels of elastin, laminin, and fibronectin; and residual cellular components such as actin, myosin, and vimentin.^117,133-135 UBM scaffolds also contain glycoproteins, proteoglycans, and ECM-associated factors.¹³⁵ Collagen, hyaluronan, and proteoglycans assist in establishing and maintaining cell-matrix and cell-cell interactions.¹²⁴ Collagen is necessary for ECM deposition, tissue repair, and remodeling because it allows cells to attach to the UBM-ECM directly.^124,136 Hyaluronan plays a role in cell migration and proliferation, elastin provides elasticity and tissue integrity, and laminins activate signaling cascades.¹²⁴ Proteoglycans have a multitude of functions, including water and carbohydrate retention, protection against compression cell signaling, and modulation of immune cell, chemokine, and growth factor functions.¹²⁴ Small leucine-rich proteoglycans are biologically active motifs that promote wound healing.¹²⁴

Many growth factors are maintained in the ECM after decellularization, including bFGF, bone morphogenetic proteins, epithelial growth factor, FGF, hepatocyte growth factor, keratinocyte growth factor, PDGF-BB, TGF-β, and VEGF.^133,137 One specific UBM product (MatriStem) was observed to contain insulinlike growth factor-1, tumor necrosis factor-α, TGF-β, VEGF, and the highest levels of bFGF when compared with other xenograft materials.^133,138,139 Other studies found 129 proteins with antiangiogenic, neurotrophic, tissue remodeling, tumor-suppressive, and wound repair properties¹⁴⁰ as well as 31 identifiable phosphoproteins¹⁴¹ in UBM products. PDGF-BB and VEGF were correlated with sGAG content, which may play a role in bioactive factor preservation.¹¹⁶ These factors facilitate wound repair and tissue regeneration by inducing angiogenesis, neovascularization, and cellularization.^142,143 Additionally, ECM contains matrix-bound nanovesicles, which may regulate cellular processes by carrying protein and RNA cargos; however, their biological function is not fully understood.^144,145

Biological and immune response to UBM

UBM, likely owing to its lack of cellular components, can modulate the innate immune response toward an anti-inflammatory or regulatory phenotype, which is associated with transplant acceptance and tissue remodeling.^{97,123,132,135,146-148} This response biases the immune system activation toward the Th2 lymphocytic pathway, which produces regulatory interleukins (IL-4, IL-5, IL-6, IL-10) and non-complement-fixing antibody isotypes, and does not activate inflammatory macrophages.^132,135,146 Repeatedly, UBM has been observed to demonstrate low inflammatory responses after implantation when compared with other grafts such as PP mesh, porcine small intestine submucosa matrices, porcine renal capsule matrices, and ePTFE.^8,19,97 UBM is harvested from a mammalian donor, and it can contain α-Gal epitopes, which can lead to a hyperacute or delayed rejection response upon implantation.^132,149 Fortunately, α-Gal epitope knockout pigs are available, and α-Gal removal does not significantly affect bioactive molecule, mechanical, or viscoelastic properties.^132,149

In addition, UBM scaffold components and peptides bias macrophages toward a regulatory M2 phenotype, which may present CD68+, CD80−, and CD163+ markers and enhanced nuclear labeling of glucocorticoid receptor and peroxisome proliferator-activated receptor gamma.^{132,135,150,151} A predominant M2 phenotype results in constructive remodeling, whereas M1 results in the deposition of dense connective tissue and/or scarring.¹¹ It has been concluded that the presence of cellular material within a scaffold modulates the phenotype of macrophages participating in the host response, which is also related to tissue remodeling.¹¹ Therefore, decellularization allows for this shift in lymphocyte differentiation toward M2 and fibroblast cell lines.^10,11

Along with M2 cell polarization that was CD31+ and α smooth muscle actin–positive, the levels of mRNA expression of FGF-2, VEGF, PDGF, and TGF-β1 in the wounds of the UBM group were also statistically significantly increased.^19,70 Regulatory F4/80+ macrophages, CD11c+ dendritic cells, CD3+ T cells, and CD19+ B cells have also been found in the UBM scaffold microenvironment.¹³⁵ Thus, the improved reconstruction by UBM was likely accomplished via myofibroblast and macrophage recruitment, neovascularization promotion, and increased expression of regulatory mitogenic/growth factors.⁷⁰ In addition to reducing the M1/M2 macrophage phenotype ratio, UBM was observed to upregulate VEGF, MRC1, and TIMP-3 in a study of patients with diabetes and without diabetes.⁶⁸ It has been proposed that UBM treatment may restore the inflammatory status of patients with diabetes to that of patients without diabetes, thus increasing the wound healing rate and potential of patients with diabetes.⁶⁸

UBM also upregulates macrophage prostaglandin E2 secretion, suppressing pro-inflammatory factor secretion, which may be enhanced by hyaluronan.¹⁵¹ Proteoglycan, which is also found in UBM, downregulates chemokines that affect cell proliferation and inhibits macrophage adhesion.¹²⁴ UBM also allowed for more 3T3 fibroblast invasion and presence, which are associated with growth and maintenance of regular morphology.^4,152 Further, UBM was found to have the highest level of dermal fibroblast proliferation and microvessel formation when compared with scaffold from other sources, as well as increased angiogenesis, more mature collagen deposition, and improved wound gap and scar indices.¹³⁸ In addition, increased levels of genes encoding structural cartilage proteins and anti-inflammatory cytokines were expressed in the UBM group, reducing cartilage degeneration, likely owing to decreased inflammation and high expression of proteoglycans.⁵⁴

Notably, UBM can induce chemogenic and mitogenic effects without negatively affecting cell viability or phenotype.¹⁵³ UBM can promote differentiation and proliferation of various cell progenitor lines, including adipose-derived, mesenchymal, and neural stem cells.^{131,148,154,155}

An additional benefit of UBM scaffolds is their bacteriostatic properties, which have been demonstrated against many gram-positive and gram-negative species.^147,156,157 This effect is due to various ECM peptides and degradation products (collagen, fibronectin, laminin, vitronectin, PDGFs, heparin binding–epithelial growth factors, FGF, PRELP, thrombospondin, and amphiregulin) that may inhibit biofilm formation in both abiotic and biotic conditions.^147,156,157 In concert, macrophages treated with UBM have increased iNOS expression and phagocytic activity.¹⁴⁷ Studies have shown that UBM may maintain bacteriostatic inhibition against Escherichia coli and Staphylococcus aureus for at least 13 hours.^147,156-158 

For additional visual aid, we provided examples of the healing course of two patients treated with UBM for complex wounds, which can be seen in Figure 2 and Figure 3.

Additives to UBM

The effectiveness of different UBM properties can be augmented through the addition of chemicals, enzymes, or proteins. Positive results have been reported with the addition of supplemental structural proteins to the UBM product studied, such as hyaluronan, SP4.2 peptides, and DPTH, and growth factors such as bFGF, CBD-HGF, VEGF, and PDGF-BB.^{15,88,89,98,159,160} Altogether, these combined UBM products can modulate cell migration, proliferation, organization, scar formation, structural integrity, and wound contracture.^88,159,160 

The addition of autologous tissue, keratinocytes, and spheroids from hMSC, human SMCs, and human urothelial cells demonstrated positive effects in cardiac, skin, and urologic repairs and reconstruction.^{15,72,86,92,93,97} These combined or cultured UBM products were associated with increased angiogenesis, capillary density, contractility, cell-matrix penetration, proliferation, early wound contraction, and tissue regeneration.^{15,72,86,92,93,97} 

Various other augmentations can be made to UBM during the production process. Fibrin glue can improve adhesion, continuous cell growth, and cellular organization.^4,161 Orabase addition to UBM led to increased weight gain, histological wound repair, and CD31 positivity scores.⁴⁵ Three percent polycaprolactone/Pluronic F127 was found to improve cell adhesion, viability, and proliferation; tensile strength and modulus; and porosity, degradability, hydrophilicity, surface properties, and functional group presence.¹⁶² Electrospun SF porous network, PLGA nanoparticles, and polyethylene glycol may also improve porosity as well as stem cell adherence, differentiation, and proliferation.^{88,129,163,164} PLGA also increased VEGF release while inhibiting collagen deposition and resulting contracture.¹⁶⁵ 

This review has several limitations. UBM is a relatively new product used for tissue reconstruction, and much of the current research is limited to case reports, small retrospective studies, and studies with animal subjects. Although there is a growing body of literature, further prospective studies with larger cohorts and longer-term follow-up periods are needed to enhance understanding of UBM’s clinical safety and efficacy. While efforts were made to include a comprehensive range of surgical specialties, wounds/pathologies, and tissue types, the scope of this review may not cover all potential applications of UBM. Future studies focusing on specific types of wound healing would provide a more detailed analysis. Finally, the lack of standardization among different UBM products used in the studies may hinder comparability and generalizability. These limitations should be considered when interpreting the results and conclusions of this review.

The use of UBM in clinical and surgical contexts continues to expand. The incorporation of UBM in reconstruction algorithms can facilitate improved wound healing and tissue regeneration, capitalizing on the properties of the ECM. There is clinical evidence to support the use of UBM in procedures spanning numerous specialties, including general surgery, cardiothoracic surgery, gastrointestinal surgery, neurosurgery, oral and maxillofacial surgery, head and neck surgery, otolaryngology, ophthalmology, orthopedic surgery, plastic surgery, burn and wound care, and urologic and gynecologic surgery. Further studies are needed to evaluate the use of UBM compared with other reconstructive techniques across the spectrum of specialties.