Globally, around 6.9 million inflammatory bowel disease (IBD) cases have been reported and the numbers are continuously increasing. IBD is a multifactorial, complex disease that includes ulcerative colitis (UC) and Crohn’s disease (CD). Perianal fistulas (PAFs) are a severe complication of CD, which is resistant to the majority of available treatments.
Utilization of the injectable nanofiber-hydrogel composite loaded with stem cells to treat perianal fistulas. Image Credit: Florin Selaru
A recent Science Advances study has reported the development of a biodegradable, injectable, and mechanically fragmented nanofiber-hydrogel composite (mfNHC), which can be loaded with adipose-derived stem cells (ADSCs). The current study also evaluated its effectiveness for fistula treatment in a rat model of PAF in CD (CD-PAF).
Prevalence of and Treatment Strategies for Crohn’s disease (CD) - Perianal fistulas (PAFs)
In the United States, around 780,000 patients suffer from CD, and PAFs occur in around 30% to 40% of these patients. According to a recent estimation, around 15,000 new patients are affected by CD-PAF yearly. Patients with CD-PAF suffer from perianal pain, superimposed infections, frank fecal incontinence, and purulent or feculent drainage. These complications are linked to low quality of life and morbidity.
The current treatment strategies for CD-PAF are predominantly focused on long-term fistula healing and diverting stomas. These strategies have been effective in less than 50% of the patients. CD-PAF patients are also treated with infliximab (a tumor necrosis factor–α (TNF-α) antibody), antibiotics, or immunomodulators. Notably, around 70% of fistulas relapse on treatment discontinuation. Although surgical procedures are used to remove fistulas, it is associated with frequent fistula recurrence and local complications (e.g., impairment of the anal sphincter).
Recently, allogeneic adipose-derived stem cells (ADSCs) have been injected into and in the surrounding region of the fistula tract. A phase 3 clinical trial reported that the introduction of 120 million ADSCs into the fistula tract, post-surgery, caused clinical PAF remission at the 52nd week in around 59% of patients. Although the European Medicines Agency has approved this treatment for CD-PAF, the US regulatory body has not approved it yet. Nevertheless, new strategies must be developed to improve the efficacy of ADSCs, particularly concerning the persistence of ADSCs within the fistula tract for a prolonged period.
Another treatment strategy for PAF in CD is the application of bioprosthetic materials that could serve as fillers for fistula tracts. However, several complications have been associated with this treatment strategy, including surgical site infection and high healing time.
Development of Nanofiber-Hydrogel Composite for CD-PAF Treatment
Recently, scientists formulated a systemic treatment procedure that targets luminal inflammation coupled with local treatment of CD-PAF, for the highest impact in the fistula tract. Scientists hypothesized that the best treatment should be the one that can be directly applied to the fistula tract to alleviate local inflammation. It should also repair physical defects that cause drainage of stool, blood, and pus.
A novel nanofiber-hydrogel composite (NHC) was developed using hyaluronic acid (HA) hydrogel, which was covalently bound to electrospun poly(ε-caprolactone) (PCL) nanofiber fragments. Subsequently, NHC was mechanically fragmented (mfNHC) to lengths of 40 to 80 μm, and loaded with ADSCs. The efficacy of this newly developed strategy was tested using a rat model of CD-PAF. The NHC composite was directly administered to the fistula tract.
Optimization of the composite’s pore size was important because it directly affects the ability of the host’s regenerative cells to migrate into the nanocomposite. To determine optimal material stiffness, mfNHC was subjected to several stiffness levels at HA concentrations of 5, 10, and 15 mg/ml. When the pore size of NHC decreased, the material stiffness increased. The microstructure of mfNHC was assessed using scanning electron microscopy (SEM), which revealed that NHC-250 and NHC-400 were associated with uniform size distribution.
Rat ADSCs were isolated and these cells were found to be positive for mesenchymal stem cell (MSC) markers CD29 and CD90, but negative for the endothelial cell marker (CD31) and hematopoietic lineage marker (CD45). This finding confirmed the ADSC lineage of the isolated cells.
In the current study, around 0.2 million ADSCs were mixed with mfNHC (200 μl) and incubated for three days. The resultant mfNHC-ADSC mixture was studied using confocal microscopy, which confirmed that ADSCs proliferated and spread into mfNHC.
It was hypothesized that ADSCs injected alone would migrate from the injected site, while the mfNHC-ADSC mixture would be retained at the site of infection for a prolonged period. The retention rates of both mfNHC-400 and mfNHC-250 were similar.
Angiogenesis is a physiological process that indicates tissue repair and regeneration. The current study considered angiogenesis as a function of ADSC content and mfNHC stiffness, which was analyzed based on explanted mfNHC at days 3, 7, and 28. On day 28, mfNHC-100 and mfNHC-250 revealed significantly high blood vessel density compared to mfNHC-400. Based on all experimental findings, NHC-250 was considered to be the optimal mfNHC.
Based on the rat model of CD-PAF, the optimized ADSC-mfNHC-250 treatment revealed a six-fold reduction in the overall fistula volume. In addition, molecular analysis revealed that this treatment reduced local inflammation and enhanced tissue regeneration. ADSC-mfNHC-250 is highly advantageous because it is biodegradable and injectable in nature. In the future, more research is required to advance mfNHC toward clinical trials.
Reference
Li, L. et al. (2023) A nanofiber-hydrogel composite improves tissue repair in a rat model of Crohn’s disease perianal fistulas. Science Advances, 9(1). DOI: 10.1126/sciadv.ade106
Source: Johns Hopkins Medicine
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