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Cell sheet technology relies on poly(N-isopropylacrylamide) (PIPAAm)-grafted temperature-responsive culture dishes (TRCDs) that facilitate cell adhesion and growth on these surfaces in culture at 37 degrees C. Below the PIPAAm lower critical solution temperature, 32 degrees C, cells spontaneously detach as confluent sheets without the damaging enzymes necessary for standard cell harvest. These cell sheets maintain the natural extracellular matrix (ECM), cell-cell junctions, and surface proteins that are broken or damaged during traditional enzymatic detachment methods. Retention of the ECM allows the cell sheets to be manipulated and spontaneously adhere when transplanted, ensuring localization and retention of cells at the transplantation site and negating the need for scaffold support materials. This cell sheet technology is applicable to a wide range of disease treatments and has shown clinical success in regenerating a variety of tissues in vivo.
CELL SHEET TISSUE ENGINEERING
Articular Cartilage Defects
Injuries to articular cartilage do not regenerate and increase the risk of developing degenerative cartilage disease (such as osteoarthritis) in the future. Cell therapy approaches for cartilage injury have had only measured successes due to limitations inherent in their preparation, delivery, and autologous sourcing. Our lab is developing allogeneic cell sheet approaches using a variety of mesenchymal stem cell and chondrocyte sources to develop clinically-translatable cell therapies that avoid the drawbacks of the current options.
Physician collaborators:
Dr. Travis Maak, MD
Dr. Angela Wang, MD
Dr. Douglas Hutchison, MD
Kidney Fibrosis
Kidney disease affects over 15% of the population in the United States, and currently, there are no effective treatments to prevent progression to end-stage kidney failure. Our lab has partnered with SCM Lifsciences to investigate the use of allogeneic bone marrow mesenchymal stem cell sheets as a treatment for kidney disease.
Liver Disease
Liver disease is the 12th most frequent cause of death in the US, owing in part to limited effective clinical interventions. Our group has fabricated cell sheets using allogeneic stem cells, and found that stem cell sheets exhibited higher expression levels of hepato-protective and liver regenerative cytokine (HGF, VEGF, IL-10) related genes compared to stem cell suspensions while preserving extra- and inter-cellular protein structural morphologies typical of native tissue, with inter-connected cells and cell adhesion and cell junction proteins. This project explores the effect of stem cell sheet transplantation to the liver, with direct cell-to-cell cross talk with native tissue, without and with the presence of liver disease, to determine if the proposed cell sheet therapy protects and/or regenerates damaged liver parenchyma to ameliorate the progression of liver fibrosis in a pre-clinical disease model. Furthermore, we are developing highly functional stem cell sheets by modifying conditions of cell density, cell-cell interfacing, and 3D tissue-like structural organization to improve therapeutic outcomes for liver disease. This technology will not only provide new cell-based treatments for liver disease, but also mechanistic understanding underlying the benefits of stem cell therapy.
Hyposalivation is a significant clinical concern leading to dental caries, oral mucositis, microbial infections, and difficulties with basic oral functions (e.g. speaking, mastication, swallowing), all of which significantly reduce the quality of life for afflicted patients. Current treatments for hyposalivation are limited to medications (e.g., pilocarpine) that induce saliva secretion from residual acinar cells or saliva substitutes. However, given that these therapies target relatively surface-level symptoms, development of alternative treatments to restore salivary gland (SG) function is essential. Based on advantageous characteristics of cell sheets (retention of cellular communication and intrinsic extracellular matrices (ECMs)), they can be applied to promote functionality of SGs. Our group is now fabricating mouse and human SG cell sheets and performing pre-clinical studies to determine therapeutic effects in SG regeneration as an alternative treatment.
Physician collaborators:
Dr. Olga Baker, DDS, PhD
Dr. Kihoon Nam, PhD
Hyposalivation
Uterine Fibrosis
Improper healing after a cesarean section can lead to fibrotic scar formation and puts women at risk for uterine wall rupture in subsequent pregnancies. Our lab has partnered with SCM Lifesciences to develop cell sheets to reduce the risk of fibrotic scar formation using bone marrow mesenchymal stem cells and umbilical cord mesenchymal stem cells.
Physician collaborators:
Dr. Bob Silver, MD
Research: Research
CURRENT APPLICATIONS
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