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16 pages, 3467 KiB

Open AccessArticle

RNU (Foxn1^RNU-Nude) Rats Demonstrate an Improved Ability to Regenerate Muscle in a Volumetric Muscle Injury Compared to Sprague Dawley Rats

by Michael J. McClure, Lucas C. Olson, David J. Cohen, Yen Chen Huang, Shirley Zhang, Tri Nguyen, Barbara D. Boyan and Zvi Schwartz

Bioengineering 2021, 8(1), 12; https://doi.org/10.3390/bioengineering8010012 - 15 Jan 2021

Cited by 8 | Viewed by 2972

Abstract

Products developed for skeletal muscle regeneration frequently incorporate allogeneic and xenogeneic materials to elicit a regenerative response to heal skeletal muscle wounds. To avoid graft rejection in preclinical studies, immunodeficient rodents are used. Whether the immunodeficiency alters the host response to the material [...] Read more.

Products developed for skeletal muscle regeneration frequently incorporate allogeneic and xenogeneic materials to elicit a regenerative response to heal skeletal muscle wounds. To avoid graft rejection in preclinical studies, immunodeficient rodents are used. Whether the immunodeficiency alters the host response to the material in skeletal muscle has not been studied. In this study, we hypothesized that an allogeneic acellular skeletal muscle grafts implanted in an immunodeficient rat (RNU, Foxn1-deficient) would exhibit better new muscle fiber formation compared to grafts implanted in immunocompetent Sprague Dawley (SD) rats. Decellularized SD skeletal muscle matrix (DMM) was implanted in the gastrocnemius (N = 8 rats/group). 56 days after surgery, animal gait was examined and animals were euthanized. Muscle force was assessed and fiber number as well as immune cell infiltrate was measured by histomorphometry and immunohistochemistry. Animal gait and percent recovery of muscle force were unchanged in both groups, but newly regenerated muscle fibers increased in RNU rats. Macrophage staining for CD68 was higher in RNU rats than in SD rats. These data show differences in muscle regeneration between animal models using the same biomaterial treatment, but these differences could not be ascribed to the immune response. Overall, our data provide awareness that more studies are needed to understand how host responses to biomaterials differ based on the animal model used. Full article

(This article belongs to the Special Issue Advances in Skeletal Muscle Tissue Engineering)

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16 pages, 4571 KiB

Open AccessEditor’s ChoiceArticle

Characterization of Gelatin Hydrogels Cross-Linked with Microbial Transglutaminase as Engineered Skeletal Muscle Substrates

by Divya Gupta, Jeffrey W. Santoso and Megan L. McCain

Bioengineering 2021, 8(1), 6; https://doi.org/10.3390/bioengineering8010006 - 06 Jan 2021

Cited by 28 | Viewed by 6369

Abstract

Engineered in vitro models of skeletal muscle are essential for efficiently screening drug safety and efficacy. However, conventional culture substrates poorly replicate physical features of native muscle and do not support long-term culture, which limits tissue maturity. Micromolded gelatin hydrogels cross-linked with microbial [...] Read more.

Engineered in vitro models of skeletal muscle are essential for efficiently screening drug safety and efficacy. However, conventional culture substrates poorly replicate physical features of native muscle and do not support long-term culture, which limits tissue maturity. Micromolded gelatin hydrogels cross-linked with microbial transglutaminase (gelatin-MTG hydrogels) have previously been shown to induce C21C2 myotube alignment and improve culture longevity. However, several properties of gelatin-MTG hydrogels have not been systematically characterized, such as changes in elastic modulus during incubation in culture-like conditions and their ability to support sarcomere maturation. In this study, various gelatin-MTG hydrogels were fabricated and incubated in ambient or culture-like conditions. Elastic modulus, mass, and transmittance were measured over a one- or two-week period. Compared to hydrogels in phosphate buffered saline (PBS) or ambient air, hydrogels in Dulbecco’s Modified Eagle Medium (DMEM) and 5% CO₂ demonstrated the most stable elastic modulus. A subset of gelatin-MTG hydrogels was micromolded and seeded with C2C12 or primary chick myoblasts, which aligned and fused into multinucleated myotubes with relatively mature sarcomeres. These data are important for fabricating gelatin-MTG hydrogels with predictable and stable mechanical properties and highlight their advantages as culture substrates for engineering relatively mature and stable muscle tissues. Full article

(This article belongs to the Special Issue Advances in Skeletal Muscle Tissue Engineering)

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15 pages, 5792 KiB

Open AccessArticle

Poly(ε-Caprolactone) Resorbable Auxetic Designed Knitted Scaffolds for Craniofacial Skeletal Muscle Regeneration

by Monica V. Deshpande, Andre J. West, Susan H. Bernacki, Kun Luan and Martin W. King

Bioengineering 2020, 7(4), 134; https://doi.org/10.3390/bioengineering7040134 - 24 Oct 2020

Cited by 11 | Viewed by 3020

Abstract

Craniofacial microsomia is a congenital deformity caused by asymmetric development of the skull (cranium) and face before birth. Current treatments include corrective surgery and replacement of the deformed structure using autograft tissue, which results in donor site morbidity. An alternative therapy can be [...] Read more.

Craniofacial microsomia is a congenital deformity caused by asymmetric development of the skull (cranium) and face before birth. Current treatments include corrective surgery and replacement of the deformed structure using autograft tissue, which results in donor site morbidity. An alternative therapy can be achieved by developing a resorbable scaffold for skeletal muscle regeneration which will help restore the symmetry and function of the facial muscles and reduce donor site morbidity. Two resorbable weft knitted scaffolds were fabricated using poly(ε-caprolactone) multifilament yarns with unique auxetic design structures possessing negative Poisson’s ratio (NPR). These scaffolds exhibit their NPR elasticity through an increase in total volume as well as no lateral narrowing when stretched longitudinally, which can provide orientated mechanical supports to the cell growth of skeletal muscle regeneration. These scaffolds were evaluated for the required physical properties, mechanical performance and biocompatibility by culturing them with neonatal human dermal fibroblasts so as to determine their cell metabolic activity, cell attachment and proliferation. This study can facilitate the understanding and engineering of textile-based scaffolds for tissues/organs. The work also paves a pathway to emerge the NPR textiles into tissue engineering, which has an extensive potential for biomedical end-uses. Full article

(This article belongs to the Special Issue Advances in Skeletal Muscle Tissue Engineering)

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15 pages, 3704 KiB

Open AccessArticle

Characterization of Functional Human Skeletal Myotubes and Neuromuscular Junction Derived—From the Same Induced Pluripotent Stem Cell Source

by Xiufang Guo, Agnes Badu-Mensah, Michael C. Thomas, Christopher W. McAleer and James J. Hickman

Bioengineering 2020, 7(4), 133; https://doi.org/10.3390/bioengineering7040133 - 22 Oct 2020

Cited by 16 | Viewed by 4505

Abstract

In vitro generation of functional neuromuscular junctions (NMJs) utilizing the same induced pluripotent stem cell (iPSC) source for muscle and motoneurons would be of great value for disease modeling and tissue engineering. Although, differentiation and characterization of iPSC-derived motoneurons are well established, and [...] Read more.

In vitro generation of functional neuromuscular junctions (NMJs) utilizing the same induced pluripotent stem cell (iPSC) source for muscle and motoneurons would be of great value for disease modeling and tissue engineering. Although, differentiation and characterization of iPSC-derived motoneurons are well established, and iPSC-derived skeletal muscle (iPSC-SKM) has been reported, there is a general lack of systemic and functional characterization of the iPSC-SKM. This study performed a systematic characterization of iPSC-SKM differentiated using a serum-free, small molecule-directed protocol. Morphologically, the iPSC-SKM demonstrated the expression and appropriate distribution of acetylcholine, ryanodine and dihydropyridine receptors. Fiber type analysis revealed a mixture of human fast (Type IIX, IIA) and slow (Type I) muscle types and the absence of animal Type IIB fibers. Functionally, the iPSC-SKMs contracted synchronously upon electrical stimulation, with the contraction force comparable to myofibers derived from primary myoblasts. Most importantly, when co-cultured with human iPSC-derived motoneurons from the same iPSC source, the myofibers contracted in response to motoneuron stimulation indicating the formation of functional NMJs. By demonstrating comparable structural and functional capacity to primary myoblast-derived myofibers, this defined, iPSC-SKM system, as well as the personal NMJ system, has applications for patient-specific drug testing and investigation of muscle physiology and disease. Full article

(This article belongs to the Special Issue Advances in Skeletal Muscle Tissue Engineering)

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Review

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30 pages, 2159 KiB

Open AccessReview

Next Stage Approach to Tissue Engineering Skeletal Muscle

by Gregory Reid, Fabio Magarotto, Anna Marsano and Michela Pozzobon

Bioengineering 2020, 7(4), 118; https://doi.org/10.3390/bioengineering7040118 - 30 Sep 2020

Cited by 9 | Viewed by 4396

Abstract

Large-scale muscle injury in humans initiates a complex regeneration process, as not only the muscular, but also the vascular and neuro-muscular compartments have to be repaired. Conventional therapeutic strategies often fall short of reaching the desired functional outcome, due to the inherent complexity [...] Read more.

Large-scale muscle injury in humans initiates a complex regeneration process, as not only the muscular, but also the vascular and neuro-muscular compartments have to be repaired. Conventional therapeutic strategies often fall short of reaching the desired functional outcome, due to the inherent complexity of natural skeletal muscle. Tissue engineering offers a promising alternative treatment strategy, aiming to achieve an engineered tissue close to natural tissue composition and function, able to induce long-term, functional regeneration after in vivo implantation. This review aims to summarize the latest approaches of tissue engineering skeletal muscle, with specific attention toward fabrication, neuro-angiogenesis, multicellularity and the biochemical cues that adjuvate the regeneration process. Full article

(This article belongs to the Special Issue Advances in Skeletal Muscle Tissue Engineering)

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16 pages, 3064 KiB

Open AccessReview

Sonodelivery in Skeletal Muscle: Current Approaches and Future Potential

by Richard E. Decker, Zachary E. Lamantia, Todd S. Emrick and Marxa L. Figueiredo

Bioengineering 2020, 7(3), 107; https://doi.org/10.3390/bioengineering7030107 - 09 Sep 2020

Cited by 5 | Viewed by 3663

Abstract

There are currently multiple approaches to facilitate gene therapy via intramuscular gene delivery, such as electroporation, viral delivery, or direct DNA injection with or without polymeric carriers. Each of these methods has benefits, but each method also has shortcomings preventing it from being [...] Read more.

There are currently multiple approaches to facilitate gene therapy via intramuscular gene delivery, such as electroporation, viral delivery, or direct DNA injection with or without polymeric carriers. Each of these methods has benefits, but each method also has shortcomings preventing it from being established as the ideal technique. A promising method, ultrasound-mediated gene delivery (or sonodelivery) is inexpensive, widely available, reusable, minimally invasive, and safe. Hurdles to utilizing sonodelivery include choosing from a large variety of conditions, which are often dependent on the equipment and/or research group, and moderate transfection efficiencies when compared to some other gene delivery methods. In this review, we provide a comprehensive look at the breadth of sonodelivery techniques for intramuscular gene delivery and suggest future directions for this continuously evolving field. Full article

(This article belongs to the Special Issue Advances in Skeletal Muscle Tissue Engineering)

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14 pages, 1432 KiB

Open AccessReview

Advanced Techniques for Skeletal Muscle Tissue Engineering and Regeneration

by Moon Sung Kang, Seok Hyun Lee, Won Jung Park, Ji Eun Lee, Bongju Kim and Dong-Wook Han

Bioengineering 2020, 7(3), 99; https://doi.org/10.3390/bioengineering7030099 - 26 Aug 2020

Cited by 30 | Viewed by 6771

Abstract

Tissue engineering has recently emerged as a novel strategy for the regeneration of damaged skeletal muscle tissues due to its ability to regenerate tissue. However, tissue engineering is challenging due to the need for state-of-the-art interdisciplinary studies involving material science, biochemistry, and mechanical [...] Read more.

Tissue engineering has recently emerged as a novel strategy for the regeneration of damaged skeletal muscle tissues due to its ability to regenerate tissue. However, tissue engineering is challenging due to the need for state-of-the-art interdisciplinary studies involving material science, biochemistry, and mechanical engineering. For this reason, electrospinning and three-dimensional (3D) printing methods have been widely studied because they can insert embedded muscle cells into an extracellular-matrix-mimicking microenvironment, which helps the growth of seeded or laden cells and cell signals by modulating cell–cell interaction and cell–matrix interaction. In this mini review, the recent research trends in scaffold fabrication for skeletal muscle tissue regeneration using advanced techniques, such as electrospinning and 3D bioprinting, are summarized. In conclusion, the further development of skeletal muscle tissue engineering techniques may provide innovative results with clinical potential for skeletal muscle regeneration. Full article

(This article belongs to the Special Issue Advances in Skeletal Muscle Tissue Engineering)

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14 pages, 611 KiB

Open AccessReview

Pre-Clinical Cell Therapeutic Approaches for Repair of Volumetric Muscle Loss

by Mahdis Shayan and Ngan F. Huang

Bioengineering 2020, 7(3), 97; https://doi.org/10.3390/bioengineering7030097 - 20 Aug 2020

Cited by 19 | Viewed by 5299

Abstract

Extensive damage to skeletal muscle tissue due to volumetric muscle loss (VML) is beyond the inherent regenerative capacity of the body, and results in permanent functional debilitation. Current clinical treatments fail to fully restore native muscle function. Recently, cell-based therapies have emerged as [...] Read more.

Extensive damage to skeletal muscle tissue due to volumetric muscle loss (VML) is beyond the inherent regenerative capacity of the body, and results in permanent functional debilitation. Current clinical treatments fail to fully restore native muscle function. Recently, cell-based therapies have emerged as a promising approach to promote skeletal muscle regeneration following injury and/or disease. Stem cell populations, such as muscle stem cells, mesenchymal stem cells and induced pluripotent stem cells (iPSCs), have shown a promising capacity for muscle differentiation. Support cells, such as endothelial cells, nerve cells or immune cells, play a pivotal role in providing paracrine signaling cues for myogenesis, along with modulating the processes of inflammation, angiogenesis and innervation. The efficacy of cell therapies relies on the provision of instructive microenvironmental cues and appropriate intercellular interactions. This review describes the recent developments of cell-based therapies for the treatment of VML, with a focus on preclinical testing and future trends in the field. Full article

(This article belongs to the Special Issue Advances in Skeletal Muscle Tissue Engineering)

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39 pages, 2180 KiB

Open AccessReview

Skeletal Muscle Tissue Engineering: Biomaterials-Based Strategies for the Treatment of Volumetric Muscle Loss

by Meagan E. Carnes and George D. Pins

Bioengineering 2020, 7(3), 85; https://doi.org/10.3390/bioengineering7030085 - 31 Jul 2020

Cited by 47 | Viewed by 18543

Abstract

Millions of Americans suffer from skeletal muscle injuries annually that can result in volumetric muscle loss (VML), where extensive musculoskeletal damage and tissue loss result in permanent functional deficits. In the case of small-scale injury skeletal muscle is capable of endogenous regeneration through [...] Read more.

Millions of Americans suffer from skeletal muscle injuries annually that can result in volumetric muscle loss (VML), where extensive musculoskeletal damage and tissue loss result in permanent functional deficits. In the case of small-scale injury skeletal muscle is capable of endogenous regeneration through activation of resident satellite cells (SCs). However, this is greatly reduced in VML injuries, which remove native biophysical and biochemical signaling cues and hinder the damaged tissue’s ability to direct regeneration. The current clinical treatment for VML is autologous tissue transfer, but graft failure and scar tissue formation leave patients with limited functional recovery. Tissue engineering of instructive biomaterial scaffolds offers a promising approach for treating VML injuries. Herein, we review the strategic engineering of biophysical and biochemical cues in current scaffold designs that aid in restoring function to these preclinical VML injuries. We also discuss the successes and limitations of the three main biomaterial-based strategies to treat VML injuries: acellular scaffolds, cell-delivery scaffolds, and in vitro tissue engineered constructs. Finally, we examine several innovative approaches to enhancing the design of the next generation of engineered scaffolds to improve the functional regeneration of skeletal muscle following VML injuries. Full article

(This article belongs to the Special Issue Advances in Skeletal Muscle Tissue Engineering)

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11 pages, 572 KiB

Open AccessReview

Recent Trends in Injury Models to Study Skeletal Muscle Regeneration and Repair

by Sydnee T. Sicherer, Rashmi S. Venkatarama and Jonathan M. Grasman

Bioengineering 2020, 7(3), 76; https://doi.org/10.3390/bioengineering7030076 - 20 Jul 2020

Cited by 29 | Viewed by 7005

Abstract

Skeletal muscle injuries that occur from traumatic incidents, such as those caused by car accidents or surgical resections, or from injuries sustained on the battlefield, result in the loss of functionality of the injured muscle. To understand skeletal muscle regeneration and to better [...] Read more.

Skeletal muscle injuries that occur from traumatic incidents, such as those caused by car accidents or surgical resections, or from injuries sustained on the battlefield, result in the loss of functionality of the injured muscle. To understand skeletal muscle regeneration and to better treat these large scale injuries, termed volumetric muscle loss (VML), in vivo injury models exploring the innate mechanisms of muscle injury and repair are essential for the creation of clinically applicable treatments. While the end result of a muscle injury is often the destruction of muscle tissue, the manner in which these injuries are induced as well as the response from the innate repair mechanisms found in muscle in each animal models can vary. This targeted review describes injury models that assess both skeletal muscle regeneration (i.e., the response of muscle to myotoxin or ischemic injury) and skeletal muscle repair (i.e., VML injury). We aimed to summarize the injury models used in the field of skeletal muscle tissue engineering, paying particular attention to strategies to induce muscle damage and how to standardize injury conditions for future experiments. Full article

(This article belongs to the Special Issue Advances in Skeletal Muscle Tissue Engineering)

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