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Host Response to Biomaterials

Biological scaffold materials composed of extracellular matrix (ECM) have been used clinically in regenerative medicine for many years. These biomaterials are made from many different animal, tissue and cell sources, raising concerns about the effect of the immune response to materials from such varied origins (Table 1). Commonly used commercial products come from both allogeneic and xenogeneic sources, yet the well characterized immune responses to whole organ allo or xenotransplantation are not seen in response to these biologic scaffold materials. This is does not mean the biological scaffold materials are immunologically inert. Macrophage and neutrophil infiltration of the ECM is noted immediately post engraftment, and is thought to be correlated with the success of remodeling the implanted material.  Allogeneic and xenogeneic epitopes, DNA and damage-associated molecular patterns (PAMPs) present within the biomaterial are also thought to contribute to the host response. The immune response to biologic scaffolds rather than being a deleterious outcome, appears to be a necessary part of the remodeling process.

Extracellular matrix (ECM) device in a rat soft tissue repair model. The surrounding host tissue (cell nuclei stained blue) interacts directly with the ECM material (autofluorescence in red) through the recruitment of anti-inflammatory (M2) macrophages (orange) and the formation of a site-specific remodeling response. Neuromuscular junction (green) staining with alpha-bungarotoxin within an area of regenerating muscle 6 months following SIS-ECM implantation. Muscle fibers are stained red, nuceli are blue.

Table 1: Commercially available extracellular matrix (ECM) scaffolds

Product

Source

Tissue

Company

AlloDerm

human

skin

Lifecell

AlloPatch

human

dermis

Musculoskeletal Transplant Foundation

Avaulta®, CollaMend®

porcine

dermis

BARD

Axis™ dermis

human

dermis

Mentor

CuffPatch™

porcine

SIS

Athrotek

Graft Jacket®

human

skin

Wright Medical Tech

Oasis®

porcine

SIS

Healthpoint

OrthADAPT™, DurADAPT™

equine

pericardium

Pegasus Biologicals

Permacol™

porcine

skin

Tissue Science Laboratories

Restore™

porcine

SIS

DePuy

Surgisis®, Durasis®, Stratasis®

porcine

SIS

Cook SIS

Suspend™

human

Fascia lata

Mentor

TissueMend®, Durepair®, Xenform™, SurgiMend™, PriMatrix™

Fetal bovine

skin

TEI Biosciences

Veritas®, Dura-Guard®, Vascu-Guard®, Peri-Guard®

bovine

dermis

Synovis Surgical

Xelma™

porcine

Teeth enamel

Molnlycke

The focus of the Badylak laboratory is to develop an in-depth understanding of the host immune response to ECM biological scaffolds, and in particular the role of xenogeneic antigens, macrophages and DAMPs in directing this response. The Gal (Galα1,3-Galβ1-4GlcNAc-R) epitope is a xenogeneic antigen present on cell surfaces in all species apart from humans and old world monkeys (1-3). The gal epitope plays a major role in facilitating hyperacute rejection of xenotransplants (2), but despite its presence in ECM (4), its role in the host response to biological scaffolds is controversial. Determining the effect of this epitope in host response to biological scaffolds is one of the current focuses of the laboratory.
The presence of macrophages in response to engraftment of ECM has been previously noted, but it is only recently that a correlation between macrophage polarization and successful remodeling of ECM has been determined. A beneficial host response, i.e. remodeling of the implanted ECM and migration of native cells into the area, has been associated with a T helper cell type 2 (Th2) response (5, 6) and with alternatively activated or M2 macrophages (7, 8). Conversely, adverse host response, i.e. a persistent proinflammatory response and development of a foreign body reaction, is correlated with classically activated or M1 macrophages (7, 8). The role of xenoantigens within the ECM scaffold that direct this macrophage polarization and the effect that processing of ECM has on this, is a major area of interest for the Badylak laboratory.
DAMPs or damage-associated molecular patterns, are molecules released by cell death. The DAMP classification encompasses many different types of molecules, which normally have several intracellular and external roles. DAMPs may be pro or anti-inflammatory, and their action may be influenced by redox status of the microenvironment. Several well characterized DAMPs are already known to be part of the ECM, and it is proposed that others may also be present within biologic scaffolds. The characterization of DAMPs within biological scaffolds and their effect on the direction of the immune response is another area of focus for the Badylak laboratory.

References

  1. Spiro, R. G., and V. D. Bhoyroo. 1984. Occurrence of alpha-D-galactosyl residues in the thyroglobulins from several species. Localization in the saccharide chains of the complex carbohydrate units. J Biol Chem 259:9858-9866. PMID: 6086655
  2. Cooper, D. K., A. H. Good, E. Koren, R. Oriol, A. J. Malcolm, R. M. Ippolito, F. A. Neethling, Y. Ye, E. Romano, and N. Zuhdi. 1993. Identification of alpha-galactosyl and other carbohydrate epitopes that are bound by human anti-pig antibodies: relevance to discordant xenografting in man. Transpl Immunol 1:198-205. PMID: 7521740
  3. Galili, U., M. R. Clark, S. B. Shohet, J. Buehler, and B. A. Macher. 1987. Evolutionary relationship between the natural anti-Gal antibody and the Gal alpha 1----3Gal epitope in primates. Proc Natl Acad Sci U S A 84:1369-1373. PMID: 2434954
  4. McPherson, T. B., H. Liang, R. D. Record, and S. F. Badylak. 2000. Galalpha(1,3)Gal epitope in porcine small intestinal submucosa. Tissue Eng 6:233-239. PMID: 10941218
  5. Allman, A. J., T. B. McPherson, S. F. Badylak, L. C. Merrill, B. Kallakury, C. Sheehan, R. H. Raeder, and D. W. Metzger. 2001. Xenogeneic extracellular matrix grafts elicit a TH2-restricted immune response. Transplantation 71:1631-1640. PMID: 11435976
  6. Allman, A. J., T. B. McPherson, L. C. Merrill, S. F. Badylak, and D. W. Metzger. 2002. The Th2-restricted immune response to xenogeneic small intestinal submucosa does not influence systemic protective immunity to viral and bacterial pathogens. Tissue Eng 8:53-62. PMID: 11886654
  7. Badylak, S. F., and T. W. Gilbert. 2008. Immune response to biologic scaffold materials. Semin Immunol 20:109-116. PMID: 18083531
  8. Badylak, S. F., J. E. Valentin, A. K. Ravindra, G. P. McCabe, and A. M. Stewart-Akers. 2008. Macrophage phenotype as a determinant of biologic scaffold remodeling. Tissue Eng Part A 14:1835-1842. PMID: 18950271
  9. Daly KA, Stewart-Akers AM, Hara H, Ezzelarab M, Long C, Cordero K, Johnson SA, Ayares D, Cooper DK, Badylak SF. Effect of the alphaGal epitope on the response to small intestinal submucosa extracellular matrix in a nonhuman primate model. Tissue Eng Part A. 2009 Dec;15(12):3877-88. PMID: 19563260 

 

Updated 16-May-2011