S.F. Badylak and J.E. Valentin reply:
With regard to the letter by Dr. Kenneth James, Vice President of TEI Biosciences, we appreciate the opportunity to respond to the issues that were raised.
First, our article clearly states that TissueMend is not chemically crosslinked (see Discussion, page 2685: "… TissueMend does not include chemical crosslinking as a processing step."). The article also states (Table I) that processing methods are "proprietary." The article further describes the morphologic response to the implanted material as being a "typical response to a nonresorbable foreign material," but, again, no mention is made of any chemical crosslinking. The host response to a nonresorbable material does not necessarily include the presence of multinucleated giant cells. One of the major points of the Valentin article is that each biologic scaffold material elicits a distinct morphologic response, which is dictated by several factors including methods of processing.
Second, all biologic scaffolds contain natural crosslinks, which are susceptible to endogenous mechanisms of degradation. Chemical crosslinking agents such as carbodiimide and glutaraldehyde have typically been used to add strength to biologic scaffolds and/or modify surface antigens in the belief that this is necessary to prevent an adverse immune response. Non-chemical means of inducing crosslinks, including thermal, photo-oxidative, and irradiation methods, are also possible. Any method of crosslinking has the potential to slow the rate of in vivo degradation and thus elicit a host response characterized by fibrosis and low-grade chronic inflammation. Since the methods of processing for TissueMend are proprietary, it is not possible to know the cause of the decreased degradation rate.
The optimal use of biologic scaffold materials for not only orthopaedic applications but other applications as well will depend on an in-depth understanding of the mechanisms by which such materials support, maintain, and restore healthy tissue. New data are being published on an almost weekly basis regarding the host immune response to these scaffold materials1-3, the source and rate of cell recruitment4,5, the factors that affect cellular differentiation and organization6,7, and the factors that affect downstream remodeling and patient outcome8. We agree completely with Dr. James that the microenvironment into which these scaffolds are placed is a critical determinant of remodeling (adoption versus adaptation) events. We also believe that an open dialogue regarding such factors is healthy and will lead to a more comprehensive understanding of the potential use of biologic scaffolds by the entire scientific and surgical community.