Human Medical Solutions

Pre-Clinical Studies

UBM as a Laryngeal Repair / Replacement Scaffold

Pilot studies were conducted utilizing UBM as a scaffold for the replacement of completely resected vocal folds in a dog model. Results of this pilot study showed that there was reconstitution of the vocal fold with complete epithelialization over the surface of the fold, in-growth of innervated skeletal muscle into the fold and at least partially organized connective tissues constituting the submucosal portion of the fold. The submucosal portion of the fold is important for vocalization.

A second study utilizing the use of UBM as a laryngeal replacement device was conducted under SBIR grant funding. Dr. Peter Hilsamer performed complete hemilaryngectomies on ten animals with appropriate controls. A multilaminate sheet of UBM material was used to replace the laryngeal wall and a single layer of UBM was used to reconstruct the vocal fold. The study concluded that UBM remodeled into organized cartilage and skeletal muscle over a 2-3 month period and vocalization returned within four to six months. The results of this study are pending publication.

UBM for Esophageal Reconstruction

An in vivo study was conducted to determine if UBM could achieve constructive remodeling of esophageal tissue without stricture. UBM was configured into a tube shape for use as a bioscaffold for esophageal reconstruction in a dog model. Twenty-two dogs were repaired with either UBM, muscle tissue alone, UBM plus either a partial (30%) covering with muscle tissue or a complete (100%) covering with muscle tissue. It was concluded that UBM plus autologous muscle tissue can facilitate the in situ reconstitution of structurally and functionally acceptable esophageal tissue.[1]

In a second study, UBM was evaluated for the gastric pull-up procedure, a standard intervention after radical esophagectomy which is associated with high morbidity and mortality due to leaks and stricture. The aim of the present study was to determine if healing of end-to-end anastomoses of the esophagus could be improved by reinforcement with UBM. Twelve dogs underwent a complete transection of either the cervical esophagus (n = 6) or the gastroesophageal junction (n = 6). A portion of the endomucosa at the anastomotic site was resected and replaced with UBM in contact with the subjacent muscle and the muscle was anastomosed. The results concluded that no anastomotic leaks or systemic complications were observed in the UBM-treated animals. The remodeled esophageal tissue showed angiogenesis and complete epithelialization. Intact, organized layers of muscle tissue were present between the native muscularis externa and the submucosal layer and effectively bridged the transected ends. The study concluded that UBM altered the default mechanism of esophageal repair. Scar tissue formation with associated stricture was virtually eliminated, and the esophageal healing response was characterized by the replacement with structurally normal tissue layers. These findings suggest that the high morbidity rate associated with esophagectomy procedures may be reduced by this UBM augmentation procedure at the anastomotic site.[2]

[1]Badylak SF, Vorp DA, Spievack AR, et al. Esophageal reconstruction with ECM and muscle tissue in a dog model. J Surg Res. 2005 Sep;128(1):87-97.

[2]Nieponice A, Gilbert TW, Badylak SF. Reinforcement of esophageal anastomoses with an extracellular matrix scaffold in a canine model. Ann Thorac Surg. 2006 Dec;82(6):2050-8.

UBM for Congenital Defects

An SBIR grant evaluated the potential for UBM to repair congenitally absent musculoskeletal tissue in a diaphragmatic hernia model. Using an eight-week old dog model, 35% of the diaphragm was removed and repaired with a multi-laminate piece of UBM. The animals necropsied at skeletal maturity and the results indicated that UBM had been completely resorbed and replaced by a mixture of site-appropriate skeletal muscle and collagenous connective tissues.. These results have encouraged veterinarians to utilize UBM for the successful repair cleft palette deformities in dogs and cats.

UBM for Dura Mater Repair

Dr. Mark Cobb, while in the laboratory of Dr. Stephen Badylak, evaluated the use of UBM for dura mater repair. The hypothesis for this study included speculation that the epithelial basement membrane surface of UBM would function as a superior interface with the underlying CNS tissue compared a currently marketed material. The results of this study concluded that UBM completely remodeled and was replaced by dense organized connective tissue consistent with that of native dura mater. It was also concluded that adhesions to the underlying central nervous system were virtually non-existent (likely as a result of the smooth surface of the epithelial basement membrane present on UBM). Handling characteristics of the UBM material (single-layer) were excellent and showed good suture retention strength, water retention, and a consistency that neurosurgeons found comparable to the adjacent dura mater. These results are unpublished.

UBM for Myocardial Repair

UBM was evaluated for repairing the left ventricle of Pigs (n=42) who underwent left ventricular (LV) infarction. UBM or expanded polytetrafluoroethlyene (ePTFE) was implanted as full-thickness LV wall patch replacement and were evaluated at 1-week, 1-month, or 3-month intervals. More alpha-smooth muscle actin-positive cells were present in UBM than in ePTFE (22.2+/-3.3% versus 8.4+/-2.7%; P=0.04). At 3 months, UBM was remodeled and a collagen-rich vascularized tissue with numerous myofibroblasts was present. Isolated regions of alpha-sarcomeric actin-positive, intensely alpha-smooth muscle actin-immunopositive and striated cells were observed. ePTFE at 3 months had foreign-body response with necrosis and calcification. Flow cytometry showed similarities of cells from UBM to normal myocardium, whereas ePTFE had limited cardiomyocyte markers. The study concluded that UBM appears superior to synthetic material for cardiac patching and trends toward myocardial replacement at 3 months.[1]

In a second study using a canine model, a full thickness defect in the right ventricle was repaired with either UBM or Dacron. A third group had no surgery and determined baseline RV function. Regional systolic function was greater in the UBM group compared with the Dacron group (SAC: 4.1+/-0.9% versus -1.8+/-1.1, P<0.05). Regional diastolic function was also greater in the UBM group (recoil rate (degrees sec (-1)): -44+/-7 versus -17+/-2, UBM versus Dacron; P<0.05). Immunohistochemical analysis revealed cardiomyocytes in the UBM implant region, a finding not seen with Dacron. At 8 weeks, UBM provided regional mechanical function, likely related to cardiomyocyte population of the UBM graft. These results are in sharp contrast to Dacron, a commonly used myocardial patch. [2]

[1]Robinson KA, Li J, Mathison M, Redkar A, et al. Extracellular matrix scaffold for cardiac repair. Circulation. 2005 Aug 30;112(9 Suppl):I135-43.

[2] Kochupura PV, Azeloglu EU, Kelly DJ, et al. Tissue-engineered myocardial patch derived from extracellular matrix provides regional mechanical function. Circulation. 2005 Aug 30;112(9 Suppl):I144-9.

UBM with the Treatment of Full-Thickness Skin Wounds

UBM was evaluated for repair of a 5 x 5 cm full-thickness lateral thoracic wall defect in a canine model (n = 6) including 5-cm segments of the 6th and 7th rib. The resected portion of the 7th rib was replaced as an interpositional graft along with the UBM scaffold. As a control, a Gore-Tex patch was used to repair the same defect (n = 2). The control animals healed by encapsulation of the Gore-Tex patch by dense collagenous tissue. The remodeled UBM grafts showed the presence of site-specific tissue, including organized fibrous connective tissue, muscle tissue, adipose tissue, and bone. Upon fluoroscopic examination, it was shown that both bony defects were replaced with new calcified bone. In the 6th rib space, new bone bridged the entire span. In the 7th rib space, there was evidence of bone formation between the interpositional graft and the existing bone, as well as de novo formation of organized bone in the shape of the missing rib segment parallel to the interpositional graft. This study concluded that UBM promotes site-specific constructive remodeling in a large thoracic wall defect. [1]

Studies evaluating the utility of UBM for the treatment of full-thickness and partial-thickness wounds have been conducted to address such issues as the source of cells that reconstitute the scaffold, the effect of cell-seeded grafts versus unseeded grafts, and the effect of multiple treatments versus single treatments upon wound outcome. The results of these studies will be submitted upon completion.

[1] Gilbert TW, Nieponice A, Spievak AR, Repair of the Thoracic Wall With an Extracellular Matrix Scaffold in a Canine Model. J Surg Res. 2007 Oct 18.

UBM for Urinary Incontinence and Lower Urinary Tract Reconstruction

UBM has been used to reconstruct the urinary bladder, urethra and vaginal wall in dog and rabbit models. The material becomes colonized by host cells that adhere, proliferate and differentiate. Most recently, ACell has completed a study of the use of a particulate-injectable form of UBM for the treatment of medically intractable urinary incontinence in dogs; a condition that closely mimics stress incontinence in post menopausal women. A single injection of UBM particulate into three sites of the internal sphincter provided a remodeling response that resulted in complete continence in these dogs immediately and lasting for at least 6 months. The study was designed as a crossover study and those dogs that failed in the control group were then treated with 100% efficacy with the UBM particulate. The use of the approach in a minimally invasive manner, on an outpatient basis, makes this potentially very useful. The results of this study were published in the Journal of the American Veterinary Medical Association.⁵

A particulate form of UBM was evaluated for treatment of acquired urinary incontinence in dogs resistant to medical treatment. Nine female dogs were injected into each of 3 equally spaced sites around the circumference of the internal urethral sphincter via an endoscopic technique with either 1.0 ml of UBM or a control. For dogs treated with UBM, median duration of urinary continence following treatment was 168 days (range, 84 to 616 days), whereas for the control dogs, median duration of urinary continence following the procedure was 14 days (range, 7 to 31 days). Two of the 3 control dogs were treated with the ECM at the end of the study and were continent for 119 and 252 days. Results suggest that endoscopically guided injection of UBM into the internal urethral sphincter may be useful for the treatment of acquired urinary incontinence in female dogs. [1]

[1] Jeffrey D. Wood , Abby Simmons-Byrd , Alan R. Spievack , Use of a particulate extracellular matrix bioscaffold for treatment of acquired urinary incontinence in dogs. Journal of the American Veterinary Medical Association Apr 2005, Vol. 226, No. 7: 1095-1097.