User:Yuri Hanada

Contact Info

• Yuri Hanada and Sohyun Park
• Massachusetts Institute of Technology
• Email us through OpenWetWare

20.109 Module 3

Brief Project Overview

Topic

Cell-biomaterial engineering: Improving current scaffold technology by reducing the in vivo inflammatory and immune response surrounding the implanted scaffold for use in pediatric patients.

Project Idea

Problem: Congenital cardiovascular defects are the most common congenital malformations in newborns and are the number one cause of death from birth defects during the first year of life. While tissue engineering (TE) has advanced the repair of these defects, current pediatric TE problems stem from 1. static scaffolds that do not "grow with" the child, requiring several replacements as the patient grows and 2. heightened immunologic sensitivity to foreign bodies in pediatric patients. A recent study investigated the use of an elastic polyesterurethane urea (PEUU) scaffold, which shows promise as a scaffold that minimizes the need for reoperation since it facilitates cellular ingrowth as the child develops. As with any newly developed technology, this PEUU scaffold can be optimized for pediatric patients by minimizing the inflammatory response.

Cell type: Umbilical cord cells

Scaffold type: Highly porous, elastic, biodegradable polyesterurethane urea (PEUU) scaffold

Scaffold modification: Incorporation of demineralized bone particles (DBPs) during polymer synthesis

Project References

<biblio>

1. Paper1 pmid=18352826

// In this study, researchers incorporated demineralized bone particles (DBPs) into poly-lactide-co-glycolic acid (PLGA) scaffolds to study the anti-inflammatory effects of DBPs. While PLGA scaffolds are biocompatible and approved by the U.S. FDA, their acidic degradation products can decrease the pH of the surrounding tissue, which results in local inflammation and subsequent poor tissue development. In previous studies, DBPs have been shown to induce osteogenesis without fibrotic capsule formation and enhance PLGA hydrophilicity, preventing adverse cellular response. Scaffolds were fabricated and impregnated with DBPs via a solvent casting-salt leaching method, and then NIH/3T3 fibroblasts were seeded onto the scaffolds. A DBP-impregnanted PLGA film was also constructed to evaluate the inflammatory response of HL-60 cells in vitro via RT-PCR analysis of TNF-α and IL-1β mRNA expression. PLGA films with varying percentages of DBPs were additionally implanted into rats. In vitro, both TNF-α and IL-1β mRNA were found to be more highly expressed on PLGA film versus DBP-PLGA films. In vivo, histology indicated that the inflammatory reaction surrounding the PLGA film was progressively diminished as the DBP content increased

1. Paper2 pmid=18427294

// Characteristics of an ideal scaffold

• Mechanical properties should be studied
  • Surrounding environment of scaffold in vivo
    • Ex: mandible is one of strongest bones; orbital bone really thin
  • Correct degradation rate (as scaffold degrades, replaced by natural tissue)
    • Depending on type of tissue to repair, control physical/chemical scaffold properties
    • Degradation rate influences creation of by-products
      • May interfere w/ repair process, obstruct tissue growth, inflammation
  • Porosity
    • Promote cell proliferation, differentiation
    • Exchange of nutrients, metabolites
  • Surface properties
  • Ability to mold scaffold into a specific construct
• Biological testing
  • Immune response to foreign bodies
  • Different types of cells or growth factors to possibly enhance scaffold properties

Pediatric TE:

• Biocompatible
• Biodegradable
• Nonimmunogenic
• Nontoxic
• Successfully promote cell growth

Types of scaffolds

• Natural scaffolds:
  • Made of protein/carbohydrates w/ particular biochemical/mechanical/structural properties
  • Can be derived from plant/animal sources
  • Mostly biocompatible and biodegradable
  • Advantages due to presence of multifunctional groups on scaffold surfaces (can be tailored depending on application)
  • Limitations include inability to control/modify chemical/biologic properties for specific applications
• Synthetic scaffolds:
  • Being favored as scaffolds
    • Physical & biologic properties can be modified
    • Can be reproduced in similar & large quantities
  • Major classes include
    • Glycolic acid derivatives
    • Lactic acid derivatives
    • Other polyester derivatives
  • Study on potential scaffold showed that condui diameter increased, while current prosthetic implants need to be replaced as pediatric patients grow
    • Promising in cardiovascular surgery
• Hydrogels
  • Made up of polymer chains
  • Swell in aqueous solution
  • Can be natural or synthetic
  • Designed to be biodegradable, typically biocompatible
  • Do not provoke an immune response and cause inflammation
  • Tissue-like properties; can successfully encapsulate cells, create cell-scaffold environment
  • Can be used in injectable form to repair irregular shaped defects/cosmetic surgery
  • Common application: contact lenses
  • Recent: cleft palate repair in children
    • Surgically easier using hydrogel implantation
    • Facial growth distortions may be reduced

Applications

• Drug delivery
  • Majority of drugs available cannot be used in children; usually dosage modified for pediatric use
  • Most common method of delivery in children is needle-vaccination
  • Recent study on oral delivery
    • Shown to reduce/inhibit growth of tumor cells
    • Treatment w/ powdered drug delivery increased survival rate in mice
• Bone tissue engineering
  • Pediatric patients' bones still in development stages
    • Osteointegration of scaffold should be considered
    • Ex: pediatric skull repair: osteogenesis induced by transplanting autologous bone marrow cells
      • Results indicated rapid osteogenesis, reduction in skull defect size
  • Thinner compared to adult bone
  • Long-term survival of child should be considered in surgery
• Cardiovascular tissue engineering
  • Recent study on elastic porous scaffold to facilitate cellular in-grwoth during healing
    • Current scaffolds do not grow in children
    • Exhibited increased cell confluency on surface of scaffold
    • Biomechanical properties similar to native heart valve
• Skin tissue engineering
  • 2nd degree burns are second most common cause of death in children
  • Usually apply autograft, which does not always result in ideal repair
  • Recent commercial treatment options
    • Biobrane
    • Integra artificial dermis
    • Mepitel
    • TransCyte
  • Study comparing commercial products
    • Fairly effective for intermediate burns
    • Cost is a problem
    • For deeper burns, other TE alternatives being researched
      • Fetal skin scaffolds from donated fetal skin grafts
        • Seeded into collagen sheets, directly applied for treatment of burns

1. Paper3 pmid=15626443

1. Paper4 pmid=15037283

1. Paper5 pmid=12400830