#3 - Combination of Tissue Reconstruction and Recurrence Prevention
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Title: Anti-Cancer Properties for Reconstructed Breast Tissue
AF Reference No.: 02-2009-078, 02-2011-085
Executive Summary:
General Description
Though surgical remedies are considerably effective in removing non-metastatic malignancies, the possibility of tumor recurrence following breast reconstruction does remain. What is proposed here is a therapeutic material comprising engineered collagen-based inclusions, to support cell attachment and tissue development, integrated with a tannic acid therapeutic agent. The combination system aims to simultaneously prevent tumor recurrence and support healthy breast tissue development
Type I collagen has been studied extensively as a primary substrate for tissue engineering carriers because it is intrinsically bioactive, mildly antigenic, biodegradable, and available in large quantities. Collagen is a naturally derived material and, uncrosslinked, is more unpredictable in absorption, which occurs by enzymatic means during normal remodeling in the body. Uncrosslinked collagen is also unstable over a period of time. As such, multiple plastic and reconstructive surgeries are required to gradually build tissue in a defect site. The introduction of crosslinking agents into collagen carriers leads to altered mechanics as well as decreased thermal and enzymatic degradability, and crosslinking agents give tissue engineers the ability to tailor rates of biodegradation. Tannic acid is specific to the class of hydrolysable tannins, and is comprised of a pentagalloyglucose core esterified at all hydroxyl functional groups with gallic acid molecules. Tannic acid functions as a collagen crosslinking agent through both hydrogen bonding mechanisms and hydrophobic effects; thus, as tannic acid crosslinked collagen is remodeled, tannic acid is released. Tannic acid has been studied extensively as possible candidate for anti-tumor therapies, as increased apoptotic activity as been observed in tumorigenic cells, possibly as a result of peroxisome proliferator activated receptors pathway interference. Because of the widespread use of collagen as a scaffold for cells in current tissue engineering applications and current advances in purification of tannic acid, the combination of collagen and tannic acid could prove to be an effective agent to induce apoptotic pathways in cancer cells or any transplanted adult stem cells that are inclined to spontaneously transform
Scientific Progress
Researchers in the Institute for Biological Interfaces of Engineering at Clemson University created a combination of breast tissue reconstruction and tumor prevention using their bioengineering expertise. 3D culture matrices comprising collagen, agarose and tannic acid (TA) beads have been successfully cast. A 3D matrix comprised of 1:1 1% agarose:bovine collagen type I with TA present in microbeads has been developed. Preliminary studies incorporating normal and breast cancer cells into the 3D matrices have been performed. Roller bottles are being used instead of stir flasks as they allow greater attachment of cells to beads and are more conducive to retaining bead integrity. Metabolic activity of breast cancer cells and stromal fibroblasts indicate that both cell types experience reduced metabolic activity, approximately 40%, after exposure to TA for 4 days. This matches their previous data indicating that TA induces apoptosis. So far the researchers discovered the following exciting findings: TA induces apoptosis not necrosis. TA-induced apoptosis is dose dependent. TA reduces metabolic activity of cells. TA does not interfere with 3D matrix creation. TA can be crosslinked into collagen/alginate beads and collagen microbeads. TA has minimal effects on normal breast epithelial and breast stromal fibroblasts when applied in the effective range of collagen crosslinking
The most significant finding is that tannic acid preferentially targets ER-positive breast cancer cells when compared to normal human breast epithelial cells or triple negative breast cancer cells. The tannic acid induced apoptosis to a greater extent within the ER-positive cancer cells and significantly reduced cell numbers
Future Direction
Strengths
Weaknesses
Patent Status
Tissue Engineering Composite US Patent Granted US6991652 B2 Google Patent
Three-Dimensional Ex Vivo System US Patent Granted US 8293531 Google Patent
Relevant Publications
Tannic acid cross-linked collagen scaffolds and their anti-cancer potential in a tissue engineered breast implant.J Biomater Sci Polym Ed. 2012;23(1-4):281-98. doi: 10.1163/092050610X550331. Epub 2011 Jan 18. PMID:21244722
Inventor Bio
Karen Burg, who holds the Hunter Endowed Chair in Bioengineering, is Director of the Institute for Biological Interfaces of Engineering at Clemson University. With a focus on reconstruction of breast tissue following cancer surgery, Burg's research into tissue engineering, biofabrication and absorbable polymers has led to 11 issued or pending U.S. patents. Her work is funded by the National Science Foundation and the Department of Defense, among others. Burg is a Fellow of the American Institute of Medical and Biological Engineering and the American Council on Education. She was named to MIT’s TR100 list and received the South Carolina Governor's Young Scientist Award for Excellence in Scientific Research. After earning her bachelor's degree in chemical engineering from North Carolina State University, Burg completed her master's and Ph.D. work in bioengineering at Clemson University. She joined the faculty in 1999 following a tissue engineering post-doctoral fellowship at Carolinas Medical Center in Charlotte, North Carolina
Title: Anti-Cancer Properties for Reconstructed Breast Tissue
AF Reference No.: 02-2009-078, 02-2011-085
Executive Summary:
- Category: Device/Therapeutic
- Disease Focus: ER positive breast cancer
- Basis of Invention: Combination device, platform
- How it works: A platform for new bioactive breast tissue lumpectomy and mastectomy reconstructive options targeting cancer recurrence prevention
- Patent status: Patent granted (#6,991,652) for a biocompatible composite for use in a living subject, comprising a material selected from the group consisting of alginate, collagen, polylactide, polyethylene glycol, polycaprolactone, polydioxanone, and derivatives, and copolymers thereof and having a diameter of about 1.5 mm or less distributed within a carrier. No patent for Tannic acid (TA)-collagen per se, however issued patent anticipates the incorporation of active agents i.e. Tannic Acid. Patent also granted (# 8,293,531) for a benchtop diagnostic system for testing therapies, devices, vaccines.
- Lead Inventor: Karen Burg
- Development Stage: Pre-clinical. Crosslinked collagen beads using varying concentrations of TA. Demonstrated that TA induces apoptosis in breast cancer cells grown in 2D culture.
- Novelty: Uses of a tannic acid-collagen composite tissue replacement material as a reconstruction platform with anti-tumor capabilities.
- Clinical Application: Could be used as a novel method of recurrence prevention for ER-positive breast cancer after mastectomy. Could be used in a benchtop diagnostic to personalize treatment by identifying cancer cell types within a tumor.
General Description
Though surgical remedies are considerably effective in removing non-metastatic malignancies, the possibility of tumor recurrence following breast reconstruction does remain. What is proposed here is a therapeutic material comprising engineered collagen-based inclusions, to support cell attachment and tissue development, integrated with a tannic acid therapeutic agent. The combination system aims to simultaneously prevent tumor recurrence and support healthy breast tissue development
Type I collagen has been studied extensively as a primary substrate for tissue engineering carriers because it is intrinsically bioactive, mildly antigenic, biodegradable, and available in large quantities. Collagen is a naturally derived material and, uncrosslinked, is more unpredictable in absorption, which occurs by enzymatic means during normal remodeling in the body. Uncrosslinked collagen is also unstable over a period of time. As such, multiple plastic and reconstructive surgeries are required to gradually build tissue in a defect site. The introduction of crosslinking agents into collagen carriers leads to altered mechanics as well as decreased thermal and enzymatic degradability, and crosslinking agents give tissue engineers the ability to tailor rates of biodegradation. Tannic acid is specific to the class of hydrolysable tannins, and is comprised of a pentagalloyglucose core esterified at all hydroxyl functional groups with gallic acid molecules. Tannic acid functions as a collagen crosslinking agent through both hydrogen bonding mechanisms and hydrophobic effects; thus, as tannic acid crosslinked collagen is remodeled, tannic acid is released. Tannic acid has been studied extensively as possible candidate for anti-tumor therapies, as increased apoptotic activity as been observed in tumorigenic cells, possibly as a result of peroxisome proliferator activated receptors pathway interference. Because of the widespread use of collagen as a scaffold for cells in current tissue engineering applications and current advances in purification of tannic acid, the combination of collagen and tannic acid could prove to be an effective agent to induce apoptotic pathways in cancer cells or any transplanted adult stem cells that are inclined to spontaneously transform
Scientific Progress
Researchers in the Institute for Biological Interfaces of Engineering at Clemson University created a combination of breast tissue reconstruction and tumor prevention using their bioengineering expertise. 3D culture matrices comprising collagen, agarose and tannic acid (TA) beads have been successfully cast. A 3D matrix comprised of 1:1 1% agarose:bovine collagen type I with TA present in microbeads has been developed. Preliminary studies incorporating normal and breast cancer cells into the 3D matrices have been performed. Roller bottles are being used instead of stir flasks as they allow greater attachment of cells to beads and are more conducive to retaining bead integrity. Metabolic activity of breast cancer cells and stromal fibroblasts indicate that both cell types experience reduced metabolic activity, approximately 40%, after exposure to TA for 4 days. This matches their previous data indicating that TA induces apoptosis. So far the researchers discovered the following exciting findings: TA induces apoptosis not necrosis. TA-induced apoptosis is dose dependent. TA reduces metabolic activity of cells. TA does not interfere with 3D matrix creation. TA can be crosslinked into collagen/alginate beads and collagen microbeads. TA has minimal effects on normal breast epithelial and breast stromal fibroblasts when applied in the effective range of collagen crosslinking
The most significant finding is that tannic acid preferentially targets ER-positive breast cancer cells when compared to normal human breast epithelial cells or triple negative breast cancer cells. The tannic acid induced apoptosis to a greater extent within the ER-positive cancer cells and significantly reduced cell numbers
Future Direction
- Elucidate the mechanism(s) through which TA induces apoptosis
- Determine why/how certain subtypes of breast cancer are more susceptible to the effects of TA
- Evaluate the effects of TA in a 3D benchtop culture system that mimics the in vivo condition more accurately
- Develop accurate and effective delivery system of TA beads
Strengths
- The inventor is an expert on biomaterials engineering with a focus on reconstruction of breast tissue post surgery and 3D diagnostic benchtop systems
- TA, the crosslinking agent, also contains anti-tumor capabilities, and slowly releases to prevent recurrence.
- The final result is natural healthy breast tissue with no synthetic materials remaining or in need of removal due to the natural remodeling process
Weaknesses
- Multiple factors influence the gelling and degradation of the agarose-collagen beads. An accurate and effective delivery system of TA beads must be created before translation to the clinic
Patent Status
Tissue Engineering Composite US Patent Granted US6991652 B2 Google Patent
Three-Dimensional Ex Vivo System US Patent Granted US 8293531 Google Patent
Relevant Publications
Tannic acid cross-linked collagen scaffolds and their anti-cancer potential in a tissue engineered breast implant.J Biomater Sci Polym Ed. 2012;23(1-4):281-98. doi: 10.1163/092050610X550331. Epub 2011 Jan 18. PMID:21244722
Inventor Bio
Karen Burg, who holds the Hunter Endowed Chair in Bioengineering, is Director of the Institute for Biological Interfaces of Engineering at Clemson University. With a focus on reconstruction of breast tissue following cancer surgery, Burg's research into tissue engineering, biofabrication and absorbable polymers has led to 11 issued or pending U.S. patents. Her work is funded by the National Science Foundation and the Department of Defense, among others. Burg is a Fellow of the American Institute of Medical and Biological Engineering and the American Council on Education. She was named to MIT’s TR100 list and received the South Carolina Governor's Young Scientist Award for Excellence in Scientific Research. After earning her bachelor's degree in chemical engineering from North Carolina State University, Burg completed her master's and Ph.D. work in bioengineering at Clemson University. She joined the faculty in 1999 following a tissue engineering post-doctoral fellowship at Carolinas Medical Center in Charlotte, North Carolina