LIMB - Research


Research


Promoting multidisciplinary fields such as tissue engineering, regenerative medicine, and drug delivery requires global efforts and collaborations between scientists with from different disciplines. Our research at LIMB involves developing technologies and fundamental tools including advanced manufacturing tools, flexible electronics, and miniaturized disease models that can be used to address key medical challenges including treatment of chronic wounds, engineering musculoskeletal tissues, and developing drug carriers passing barriers in human bodies.
The technologies that will be developed and the biomedical problems that will be addressed.

Fiber-based technologies (advanced manufacturing)

Rationale: Musculoskeletal diseases including tendon/ligament injuries and volumetric muscle loss are responsible for substantial morbidity, pain and disability, affecting athletes, active working people and elder population. This implies major social and economic hurdles, as musculoskeletal injuries represent a cost of $30 billion in U.S. each year. Current medical procedures fail to restore the function of the damaged tissue and thus a new paradigm is needed for engineering biological substitutes. A key challenge in engineering such organized fibrillar tissues is mimicking their architecture and mechanical properties. Fiber-based technologies including textile processes and 3D direct-write printing are powerful tools for producing finely tuned 2D and 3D constructs from natural or synthetic fibers. The engineered fibrous constructs can provide physical cues to guide cellular orientation; thus enabling to control the directionality of the cells in 3D. Of particular importance to musculoskeletal tissues, the alignment and mechanical properties of fibers can be adjusted during the fabrication process to mimic the directionality of native tissues. However, a key limitation of textile scaffolds in TE has been the inability of cells to grow into the dense scaffolds. In fact, the properties of the niche suitable for cellular growth and function can be different from the tissue-level mechanical properties and the engineered constructs fail to create an environment that supports 3D cellular growth. The extensive efforts for engineering cell-laden hydrogel fibers and then assembling them using textile processes has also failed to address these key challenges as hydrogels are not mechanically strong to withstand the applied stresses during the fabrication process. We proposed an innovative approach that benefits from the advantages of textile platforms, while collectively addressing all the above-mentioned challenges. We have recently developed composite fibers (CFs) comprised of a load bearing polymeric core covered by a layer of cell-laden hydrogel. These fibers possess two separate compartments that can be independently tailored. Upon the assembly of the engineered CFs, the network of polymeric cores forms a highly resilient construct with biomimetic mechanical properties. The hydrogel layer composition can govern the cell level properties independently and creates a niche for cells to grow into the construct and to form a highly organized tendon or ligament tissue. Thus, the proposed technology will be a paradigm shift in the field of tissue engineering and will generate a strong tool for engineering musculoskeletal tissues. Our goal is to develop technologies that can facilitate engineering of functional musculoskeletal tissues. 

Fiber based tissue engineering. (a) Coating of a cell-laden gel on a mechanically strong polymeric core thread to make composite living fibers; (b-d) fabrication of cell-laden myoblast-laden fibers; (e-f) Assembly of fibers into constructs using textile processes. Cellualr organization and alignment could be controlled in 3D (f).

Smart implantable and wearable devices

Non-healing wounds caused by diabetes mellitus account for one of the most common complications of this disease leading to increased healthcare cost, decreased quality of life, infections, amputations, and death. The wide prevalence of this disease and its projected increase in the near future have further necessitated therapeutics aimed at enhancing the healing of diabetic wounds1. In addition, a large number of surgeries fail and require post-op interventions due to infection or non-healing surgical cuts. Current strategies such as the use of tissue engineered skin substitutes or the application of growth factors and antibacterial compounds to the wound site are costly, non-combinatorial, labor intensive, time consuming, and require centralized laboratory. Thus there is an unmet need for engineering smart systems that can monitor the wound environment, deliver growth factors and chemokines, and administer antibiotics topically based on the sensing parameters.

Emergence of flexible and elastic electronics has advanced the wearable smart biomedical devices for disease diagnostics and treatment. This technology enables integration of different sensors and actuators with conformal contact to skin. We have been engineering two platforms for engineering implantable and wearable devices. We introduced polymeric nanofibrous substrates as a platform for fabrication of such elastic and bioresorbable systems. As the proof-of-principle, we fabricated temperature and strain sensors on the developed substrate and tested them in vitro. We have recently mixed thermoresponsive drug nanocarriers within these nanofibrous substrates to create a platform for on demand drug delivery. We have mirofabricated patterns from biodegradable metals to create fully resorbable systems. The second platform engineered by our team, can measure pH, temperature, and oxygen of the wound and based on the sensing parameters can administer therapeutics. This is the first integrated wearable bandage for treatment of chronic wounds. Our goal is to develop wound dressings and implantable devices that can minimize the complications and facilitate the healing process.

 

Engineered smart platforms for biomedical applications. (a) Nanofibrous polymeric sheets with embedded stimuli-responsive drug carriers for on demand release of drugs. (b) Smart capable of measuring properties of wound environment and deliver therapeutics if needed.