Biomimetic Stratified Scaffold Design for Ligament-to-Bone Interface Tissue Engineering

http://www.ncbi.nlm.nih.gov/sites/entrez

• ABSTRACT- "Biological fixation will require re-establishment of the structure-function relationship inherent at the native
  soft tissue-to-bone interface on these tissue engineered grafts. To this end, strategic biomimicry must be incorporated into
  advanced scaffold design."
• ADVANCES- "Significant advances have thus been
  made in the development of ligament- [1-7], tendon- [8-13],
  cartilage-[14-24] and bone-like [25-34] tissues by combining
  cells and biomaterials along with biochemical and/or biophysical
  stimulation"
• TISSUE TO TISSUE INTERFACE- "Therefore,
  the development of integrated musculoskeletal tissue
  systems will require not only the re-establishment of the inherent
  structure-function relationship of each type of tissue,
  but also the concurrent regeneration of the complex tissueto-
  tissue interface."
• MULTI-PHASE SCAFFOLD-" It is anticipated that the formation of integrated tissue
  systems similar to those observed at the junctions between
  orthopaedic soft and hard tissues will require a multi-phased
  scaffold which supports the growth and differentiation of
  multiple cell types."
• PROBLEM WITH TENDON ACL RECONST.- "While
  tendon-based ACL reconstruction grafts may restore the
  physiological range of motion through mechanical fixation,
  biological fixation is not achieved. In the absence of an anatomical
  interface, the graft-bone junction exhibits poor mechanical
  stability [56-58] and this remains the primary cause
  of graft failure"
• UNDERSTAND MATERIAL PROPERTIES- "In the paradigm for functional tissue engineering outlined
  by Butler et al., [37] significant emphasis is placed on understanding
  the material properties of the tissue to be replaced,
  as well as quantifying the in vivo strains and stresses experienced
  by the native tissue under physiological loading."
• 3 REGIONS OF TISSUES IN ACL- "three distinct tissue regions are found at the ACL-bone insertion site: ligament, fibrocartilage, and bone. The fibrocartilage
  region is further divided into non-mineralized fibrocartilage
  and mineralized fibrocartilage regions"
• DESIGN MORE THAN 1 TYPE OF TISSUE NEEDS TO BE ABLE TO REGENERATE- "Thus interface scaffold design
  must consider the need to regenerate more than one type of
  tissue"
• STRUCTURE-FUNCTION PERSPECTIVE
• REGIONAL TENSION- "when the joint is loaded in tension, the deformation
  across the insertion site is region-dependent, with the
  highest displacement found at the ACL, then decreasing in
  magnitude from the fibrocartilage interface to bone"
• COW STATS ACL REGION- "bovine ACL-bone interface,
  the compressive modulus of the non-mineralized fibrocartilage
  region was 0.32 ± 0.14 MPa [71], which is more
  than 50% lower than that of the mineralized fibrocartilage
  region which averaged 0.68 ± 0.39 MPa [71]. Both of these
  values are lower than that of trabecular bone which is reported to be 173 ± 97 MPa in the neonatal bovine model"
• FIGURE 1 Biomimetic Stratified Scaffold Design for Ligament-to-Bone Interface Tissue Engineering
• STRATEGY TO ENGINEER MECH. INHOMOGENITY IN SCAFFOLD- "one strategy to engineer controlled mechanical
  inhomogeneity on the interface scaffold is by regulating the
  distribution and concentration of calcium phosphate on the
  scaffold phases."
• LAYERED SCAFFOLD- "a stratified scaffold is required
  to recapitulate the multi-tissue organization observed at the
  native ligament-to-bone interface"
• CHALLENGE B/C DIFFERENT TISSUE TYPES IN ACL- "The multi-tissue transition from ligament to fibrocartilage
  and to bone at the ACL-bone interface represents a significant
  challenge for functional interface tissue engineering
  as several distinct types of tissue are observed at this insertion
  site."
• DIFF. TISSUE TYPES-"supporting the
  growth and differentiation of relevant cell populations, must
  direct heterotypic and homotypic cellular interactions while
  promoting the formation and maintenance of controlled matrix
  heterogeneity"
• DIFF. TISSUE TYPES- "The interface scaffold must also exhibit mechanical properties
  comparable to those of the ligament-to-bone interface. In
  addition, the scaffold phases should be biodegradable so that
  it can be gradually replaced by living tissue, and the degradation
  process must be balanced with respect to the scaffold
  mechanical properties in order to permit physiological loading
  and neo-interface function."
• STRENGTH- "strength of the ligamentous
  tissue is crucial to the success of the ACL graft"
• FROM OTHER ARTICLE COOPER ET. AL.- "Recently, Cooper et
  al. [6] reported on a multi-phased design of a synthetic ACL
  graft with a ligament proper as well as two bony regions.
  This novel ACL scaffold was fabricated from 3-D braiding
  of polylactide-co-glycolide fibers, and scaffold porosity differed
  between the bone and ligament regions, with the extended
  goal of promoting ACL graft integration within the
  bone tunnels. In vitro [7] and in vivo [91] evaluation of this
  ACL fibroblast seeded scaffold demonstrated biocompatibility,
  healing and mechanical strength in a rabbit model. This
  new design represents a significant improvement over single-
  phased ACL grafts, and the next step is to address the
  challenge of graft integration with bone, by including the
  fibrocartilage interface in the ligament scaffold design."
• 3 PHASE SCAFFOLD
• tri-phasic scaffold
• "With this scaffold design, a biomimetic
  phase-specific cell distribution was established, with osteoblasts
  and fibroblasts localized in their respective regions,
  while their interaction was restricted to Phase B, the interface
  region."
• 3 PHASE- "While both anatomic ligament- and bone-like matrices
  were formed on the tri-phasic scaffold in vitro and in vivo,
  no fibrocartilage-like tissue was observed in the interface
  phase through osteoblast-fibroblast co-culture."
• OPTIMAL CLINICAL OUTCOME- "The optimal clinical outcome is to have a completely mineralized tissue within the bone tunnel, accompanied by the formation
  of an anatomic fibrocartilage insertion on the soft tissue
  graft."