top of page

PROMOTING HEALING

Multiple strategies have been employed to promote the healing of skeletal muscle following injury and onset of neuromuscular disease, including biomaterial application. In contrast to first generation (inert and non-reactive) and second generation (inert and reactive) biomaterials, third generation biomaterials (active and reactive) promote gene transcription within the local tissue environment through ion dissolution to promote regeneration and reduce disease pathology. Timed release ion matrix (TRIM) describes a novel family of bioactive ceramics (bioactive glasses) that replace the silicate of traditional bioactive ceramics, used for hard tissue (bone and tooth) regeneration, with biodegradable compounds for application to soft tissue regeneration. In addition, ions that have been shown to enhance the expression of regenerative genes as well as promote vascular growth have been incorporated for accelerated healing.

 

Children with Limb Girdle and Duchenne Muscle Dystrophy (MD) will learn to walk, run, and jump. Then, as early as 2 years of age, they will experience muscle fragility that progresses to immobility by ~12 years of age, some even earlier (5). While FDA-approved and pipeline treatments have therapeutic potential, they also are fraught with drawbacks that include dismal increases in dystrophin protein with exon skipping therapies (~5% for those FDA-approved), and minimal improvement in muscle function, while systemic medications such as corticosteroids have undesirable secondary consequences (4, 9). To date, there is no cure for patients with MD, a situation that is compounded by the lack of effective FDA-approved treatments. Our proposed Type II studies are crucial in aiding the refinement and scaling up of a novel therapy for therapeutic intervention against MD, dramatically improving the lives of children with MD.

            Our solution is an innovative timed-release ion matrix (Dystrophix) suitable for injection into myofascial compartments, positively affecting all muscles in each compartment. In an accepted mouse model of MD (D2.mdx) a single Dystrophix injection into the tibialis anterior muscle (TA) improved muscle force as early as 14 days post injection and as far out as 70 days post injection.

 

Regarding wound healing, we evaluated the effect of TRIM on GM capillary density during regeneration in C57Bl/6 mice, 250 µg of TRIM was suspended in 50 µL of sterile saline and injected beneath the GM at 3 dpi (when regeneration begins after the initial inflammatory response) as done for BaCl2 injection. Control mice were injected with saline (sham) at the same 3 dpi timepoint. Mice then recovered for an additional 5 dpi before muscles were harvested at 8 dpi. Following fixation, cross sections (10 µm thick) were taken from the center of the GM and labeled for laminin and eMyHC as a marker of regenerating myofibers and with DAPI to visualize myonuclei (Figure 2). At 8 dpi, ~60% of myofibers had completed regeneration following TRIM treatment compared to ~20% of myofibers completing regneration in saline (sham) treated muscles. These preliminary data indicate that TRIM enhances the rate of myofiber regeneration.

bottom of page