Cell Cures' technology utilizes easily isolated and well characterized adult human skeletal muscle stem cells (satellite cells or myoblasts). These striated muscle progenitor cells provide an expandable source of proliferating cells which have already been utilized in numerous clinical trials. While the injection of the proliferating myoblasts has proven clinically safe in hundreds of adult patients, their survival and contractile function following transplantation into skeletal or cardiac muscle tissue has been severely limited due to poor cell survival and limited differentiation. The overall goal of this SBIR Phase 1 project is to develop a more effective method for the implantation of striated muscle cells for muscle repair applications. Human progenitor myoblasts can be partially differentiated in vitro into organized muscle tissue containing immature multinucleated post mitotic neonatal-like muscle fibers called 'myotubes'. The bioengineered construct, called a human 'bioartificial muscle' (HBAM), contains myotubes of small diameter (5-10 ?m) which are poorly striated, and when electrically stimulated, generate active forces which are only 2-3% of a normal adult muscle. Further differentiation of these immature HBAM myotubes into more differentiated and contractile muscle tissue would allow their use in regeneration/repair clinical applications. HBAM myotube to myofiber differentiation will be studied following implantation into the skeletal muscle bed of the immunodeficient NOD-SCID mouse by analyzing myofiber size, striations, sarcomeric protein content, myosin heavy chain isotypes, viscoelastic properties and active force generation. In vivo muscle differentiation will be compared to injected proliferating myoblasts and to HBAMs maintained in vitro in perfusion bioreactors. Possible innervation of the in vivo human myofibers will be determined by neuromuscular and axonal histological analyses. Vascularization of the implanted tissue will be analyzed histologically. Finally, HBAMs will be implanted into a severely damaged NOD-SCID mouse muscle bed and repair of the host muscle followed over a 30 day period. In these studies, a subgroup of HBAMs genetically engineered to locally secrete the anabolic muscle growth factor insulin-like growth factor 1 (IGF1) will be implanted. It is hypothesized that the local in vivo muscle bed will provide the nutrient, growth factors and mechanical environment for the further differentiation of skeletal muscle into a functional tissue capable of repairing damaged muscle tissue. The results of these studies will establish an improved protocol for implanting striated muscle precursor cells for the functional repair of damaged or diseased contractile tissues, and provide the basis for a large animal SBIR Phase 2 preclinical study. Musculoskeletal disorders affect greater than 60 million individuals in the U.S. today and the annual health care costs resulting from skeletal muscle weakness resulting from disease or aging is hundreds of billions of dollars. Few drugs are currently available to treat these disorders and CellCure, Inc. is developing a cell-based implantation technology using bioengineered muscle tissue for both muscle damage repair and to attenuate skeletal muscle weakness which occurs from the muscle loss associated with aging. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
6R43AG029705-02
Application #
7530519
Study Section
Special Emphasis Panel (ZRG1-MOSS-H (10))
Program Officer
Williams, John
Project Start
2007-08-01
Project End
2009-07-31
Budget Start
2007-11-01
Budget End
2008-07-31
Support Year
2
Fiscal Year
2007
Total Cost
$240,453
Indirect Cost
Name
Myomics, Inc.
Department
Type
DUNS #
139717537
City
Providence
State
RI
Country
United States
Zip Code
02906
Wang, Lin; Cao, Lan; Shansky, Janet et al. (2014) Minimally invasive approach to the repair of injured skeletal muscle with a shape-memory scaffold. Mol Ther 22:1441-1449
Shvartsman, Dmitry; Storrie-White, Hannah; Lee, Kangwon et al. (2014) Sustained delivery of VEGF maintains innervation and promotes reperfusion in ischemic skeletal muscles via NGF/GDNF signaling. Mol Ther 22:1243-1253
Wang, Lin; Shansky, Janet; Vandenburgh, Herman (2013) Induced formation and maturation of acetylcholine receptor clusters in a defined 3D bio-artificial muscle. Mol Neurobiol 48:397-403
Wang, Lin; Shansky, Janet; Borselli, Cristina et al. (2012) Design and fabrication of a biodegradable, covalently crosslinked shape-memory alginate scaffold for cell and growth factor delivery. Tissue Eng Part A 18:2000-7
Borselli, Cristina; Cezar, Christine A; Shvartsman, Dymitri et al. (2011) The role of multifunctional delivery scaffold in the ability of cultured myoblasts to promote muscle regeneration. Biomaterials 32:8905-14
Vandenburgh, Herman (2010) High-content drug screening with engineered musculoskeletal tissues. Tissue Eng Part B Rev 16:55-64
Borselli, Cristina; Storrie, Hannah; Benesch-Lee, Frank et al. (2010) Functional muscle regeneration with combined delivery of angiogenesis and myogenesis factors. Proc Natl Acad Sci U S A 107:3287-92
Vandenburgh, Herman; Shansky, Janet; Benesch-Lee, Frank et al. (2009) Automated drug screening with contractile muscle tissue engineered from dystrophic myoblasts. FASEB J 23:3325-34
Mooney, David J; Vandenburgh, Herman (2008) Cell delivery mechanisms for tissue repair. Cell Stem Cell 2:205-13