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Timed Delivery of Therapy Enhances Functional Muscle Regeneration.

ABSTRACT: Cell transplantation is a promising therapeutic strategy for the treatment of traumatic muscle injury in humans. Previous investigations have typically focused on the identification of potent cell and growth factor treatments and optimization of spatial control over delivery. However, the optimal time point for cell transplantation remains unclear. Here, this study reports how myoblast and morphogen delivery timed to coincide with specific phases of the inflammatory response affects donor cell engraftment and the functional repair of severely injured muscle. Delivery of a biomaterial-based therapy timed with the peak of injury-induced inflammation leads to potent early and long-term regenerative benefits. Diminished inflammation and fibrosis, enhanced angiogenesis, and increased cell engraftment are seen during the acute stage following optimally timed treatment. Over the long term, treatment during peak inflammation leads to enhanced functional regeneration, as indicated by reduced chronic inflammation and fibrosis along with increased tissue perfusion and muscle contractile force. Treatments initiated immediately after injury or after inflammation had largely resolved provided more limited benefits. These results demonstrate the importance of appropriately timing the delivery of biologic therapy in the context of muscle regeneration. Biomaterial-based timed delivery can likely be applied to other tissues and is of potential wide utility in regenerative medicine.

SUBMITTER: Cezar CA

PROVIDER: S-EPMC5641972 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Timed Delivery of Therapy Enhances Functional Muscle Regeneration.

Cezar Christine A CA Arany Praveen P Vermillion Sarah A SA Seo Bo Ri BR Vandenburgh Herman H HH Mooney David J DJ

Advanced healthcare materials 20170713 19

Cell transplantation is a promising therapeutic strategy for the treatment of traumatic muscle injury in humans. Previous investigations have typically focused on the identification of potent cell and growth factor treatments and optimization of spatial control over delivery. However, the optimal time point for cell transplantation remains unclear. Here, this study reports how myoblast and morphogen delivery timed to coincide with specific phases of the inflammatory response affects donor cell e ...[more]

PMID: 28703489

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Project description:Skeletal muscle possesses efficient ability to regenerate upon minor injuries, but its capacity to regenerate is severely compromised with traumatic injuries and muscle-associated diseases. Recent evidence suggests that skeletal muscle regeneration can be enhanced by transplantation of muscle satellite cells (MuSCs) or treatment with pro-myogenic factors, such as Wingless-type MMTV Integrated 7a (Wnt7a) protein. Although direct intramuscular injection is the simplest method to deliver MuSCs and Wnt7a for regenerative therapy, direct injections are not viable in many clinical cases where structural integrity is severely compromised. To address this challenge, we evaluated the feasibility of co-delivering pro-myogenic factors, such as Wnt7a, and MuSCs using a synthetic poly(ethylene glycol) (PEG)-based hydrogel to the affected skeletal muscles. The Wnt7a release rate can be controlled by modulating the polymer density of the hydrogel, and this release rate can be further accelerated through the proteolytic degradation of the hydrogel. Treating cryo-injured tibialis anterior (TA) muscles with Wnt7a-loaded hydrogels resulted in an improved regenerative response by day 14, measured by increased muscle fiber cross-sectional area, bulk TA mass, and the number of Pax7+ MuSCs at the injury site, compared to the TA muscles treated with Wnt7a-free hydrogels. Co-delivery of Wnt7a and primary MuSCs using the synthetic hydrogel to the cryo-injured TA muscles significantly increased cellular migration during the engraftment process. This work provides a synthetic biomaterial platform for advancing treatment strategies of skeletal muscle conditions where direct intramuscular injection may be challenging. Finally, the current outcomes establish an important foundation for future applications in treating severe muscle trauma and diseases, where the endogenous repair capacity is critically impaired. STATEMENT OF SIGNIFICANCE: Skeletal muscle injuries and diseases cause debilitating health consequences, including disability and diminished quality of life. Treatment using protein and stem cell-based therapeutics may help regenerate the affected muscles, but direct intramuscular injection may not be feasible in severe muscle injuries due to the gravely damaged tissue structure. In chronic muscle diseases, such as Duchenne muscular dystrophy, local treatment of the diaphragm, a muscle critical for respiration, may be necessary but direct injection is difficult due to its thin dimensions. To address this challenge, this work presents a synthetic and bioactive muscle "patch" that enables concurrent administration of proteins and muscle stem cells for accelerated muscle healing.

Project description:Diseases that jeopardize the musculoskeletal system and cause chronic impairment are prevalent throughout the Western world. In Germany alone, ~1.8 million patients suffer from these diseases annually, and medical expenses have been reported to reach 34.2bn Euros. Although musculoskeletal disorders are seldom fatal, they compromise quality of life and diminish functional capacity. For example, musculoskeletal disorders incur an annual loss of over 0.8 million workforce years to the German economy. Among these diseases, traumatic skeletal muscle injuries are especially problematic because they can occur owing to a variety of causes and are very challenging to treat. In contrast to chronic muscle diseases such as dystrophy, sarcopenia, or cachexia, traumatic muscle injuries inflict damage to localized muscle groups. Although minor muscle trauma heals without severe consequences, no reliable clinical strategy exists to prevent excessive fibrosis or fatty degeneration, both of which occur after severe traumatic injury and contribute to muscle degeneration and dysfunction. Of the many proposed strategies, cell-based approaches have shown the most promising results in numerous pre-clinical studies and have demonstrated success in the handful of clinical trials performed so far. A number of myogenic and non-myogenic cell types benefit muscle healing, either by directly participating in new tissue formation or by stimulating the endogenous processes of muscle repair. These cell types operate via distinct modes of action, and they demonstrate varying levels of feasibility for muscle regeneration depending, to an extent, on the muscle injury model used. While in some models the injury naturally resolves over time, other models have been developed to recapitulate the peculiarities of real-life injuries and therefore mimic the structural and functional impairment observed in humans. Existing limitations of cell therapy approaches include issues related to autologous harvesting, expansion and sorting protocols, optimal dosage, and viability after transplantation. Several clinical trials have been performed to treat skeletal muscle injuries using myogenic progenitor cells or multipotent stromal cells, with promising outcomes. Recent improvements in our understanding of cell behaviour and the mechanistic basis for their modes of action have led to a new paradigm in cell therapies where physical, chemical, and signalling cues presented through biomaterials can instruct cells and enhance their regenerative capacity. Altogether, these studies and experiences provide a positive outlook on future opportunities towards innovative cell-based solutions for treating traumatic muscle injuries-a so far unmet clinical need.

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Timed Delivery of Therapy Enhances Functional Muscle Regeneration.

Publications

Timed Delivery of Therapy Enhances Functional Muscle Regeneration.

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