Surgical Membranes as Directional Delivery Devices to Generate Tissue: Testing in an Ovine Critical Sized Defect Model

Abstract

PurposePluripotent cells residing in the periosteum, a bi-layered membrane enveloping all bones, exhibit a remarkable regenerative capacity to fill in critical sized defects of the ovine femur within two weeks of treatment. Harnessing the regenerative power of the periosteum appears to be limited only by the amount of healthy periosteum available. Here we use a substitute periosteum, a delivery device cum implant, to test the hypothesis that directional delivery of endogenous periosteal factors enhances bone defect healing.MethodsNewly adapted surgical protocols were used to create critical sized, middiaphyseal femur defects in four groups of five skeletally mature Swiss alpine sheep. Each group was treated using a periosteum substitute for the controlled addition of periosteal factors including the presence of collagen in the periosteum (Group 1), periosteum derived cells (Group 2), and autogenic periosteal strips (Group 3). Control group animals were treated with an isotropic elastomer membrane alone. We hypothesized that periosteal substitute membranes incorporating the most periosteal factors would show superior defect infilling compared to substitute membranes integrating fewer factors (i.e. Group 3>Group 2>Group 1>Control).ResultsBased on micro-computed tomography data, bone defects enveloped by substitute periosteum enabling directional delivery of periosteal factors exhibit superior bony bridging compared to those sheathed with isotropic membrane controls (Group 3>Group 2>Group 1, Control). Quantitative histological analysis shows significantly increased de novo tissue generation with delivery of periosteal factors, compared to the substitute periosteum containing a collagen membrane alone (Group 1) as well as compared to the isotropic control membrane. Greatest tissue generation and maximal defect bridging was observed when autologous periosteal transplant strips were included in the periosteum substitute.ConclusionPeriosteum-derived cells as well as other factors intrinsic to periosteum play a key role for infilling of critical sized defects.

Current insights on the regenerative potential of the periosteum: Molecular, cellular, and endogenous engineering approaches

“…Two recent bottom up approaches to engineering substitute periosteum comprise replicating the periosteum and its anisotropic mechanical and transport properties as well as biochemical synthetic and cell biological approaches to engineer architectures emulating periosteum's cellular and molecular organization [96–98]. In the first, an implant cum delivery device was created and tested successfully in an ovine critical sized defect model, enabling controlled and directional delivery of periosteal factors to the defect zone [97]. Furthermore, implementation of directional delivery implants designed as periosteum substitutes show that periosteum-derived cells as well as other biologic factors intrinsic to periosteum play a key role for infilling of critical sized defects.…”

Periosteal thickness and cellularity in mid‐diaphyseal cross‐sections from human femora and tibiae of aged donors

“…Finally, during surgical treatment of critical‐sized bone defects or non‐unions, adjacent, healthy diaphyseal periosteum might be accessible (Knothe & Springfield, ; Sauser, ), but further study is warranted for effective harnessing of its regenerative potential and smart material properties. As a first step, measurements of thickness of the respective fibrous and cambium layers as well as cellularity of the cambium layer are crucial for the translation and development of regenerative medicine therapies (Knothe Tate et al., ; Chang et al., ).…”

Mechanistic, Mathematical Model to Predict the Dynamics of Tissue Genesis in Bone Defects via Mechanical Feedback and Mediation of Biochemical Factors

“…Tissue genesis is rapid when periosteum derived cells (PDCs) seeded on collagen sheets or strips of periosteum with cells in situ are tucked into the pockets. These experiments demonstrate the power of PDCs to generate new bone de novo [4]–[10]. In addition, biochemical or molecular factors intrinsic to the periosteum enhance tissue genesis by PDCs even without a patent blood supply.…”

“…More complex models may assess the material properties of the periosteum substrate in context of transmitting mechanical cues to underlying progenitor cells, or from a poroelastic and permeability perspective to guide nutrients into the defect space [4], [68], [69].…”