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Extracellular Matrix Bioscaffolds for Orthopaedic ApplicationsA Comparative Histologic Study
Jolene E. Valentin, BS1; John S. Badylak, MD2; George P. McCabe, PhD3; Stephen F. Badylak, DVM, PhD, MD1
1 McGowan Institute for Regenerative Medicine, University of Pittsburgh, 100 Technology Drive, Suite 200, Pittsburgh, PA 15219. E-mail address for S.F. Badylak: badylaks@upmc.edu
2 Department of Orthopedic Surgery, University of Wisconsin-Madison, 600 Highland Avenue, Madison,WI 53792-3236
3 Department of Statistics, Purdue University, 1399 Mathematical Science Building, West Lafayette, IN 47907-1399
View Disclosures and Other Information
In support of their research for or preparation of this manuscript, one or more of the authors received grants or outside funding from DePuy, Inc. and the National Institutes of Health (Grant #EB000261). None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.
Investigation performed at McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania

The Journal of Bone and Joint Surgery, Incorporated
J Bone Joint Surg Am, 2006 Dec 01;88(12):2673-2686. doi: 10.2106/JBJS.E.01008
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Background: Biologic scaffold materials prepared from extracellular matrix are currently available for the surgical repair of damaged or missing musculotendinous tissue. These scaffolds differ in their species and tissue of origin, methods of processing, and methods of terminal sterilization. The purpose of the present study was to evaluate the host-tissue morphologic response to five commercially available extracellular matrix-derived biologic scaffolds used for orthopaedic soft-tissue repair in a rodent model.

Methods: One hundred twenty-six Sprague-Dawley rats were divided into six groups of twenty-one animals each. A defect was created in the musculotendinous tissue of the abdominal wall of each animal and then was repaired with one of five different scaffold materials (GraftJacket, Restore, CuffPatch, TissueMend, Permacol) or with the excised autologous tissue. Three animals from each group were killed at one of seven time-points after surgery (two, four, seven, fourteen, twenty-eight, fifty-six, and 112 days), and the specimens were examined with histologic and morphologic methods. The degree of cellular infiltration, multinucleated giant cell presence, vascularity, and organization of the replacement connective tissue were evaluated with semiquantitative methods.

Results: Each device elicited a distinct morphologic response that differed with respect to cellularity (p < 0.001), vascularity (p < 0.01), the presence of multinucleated giant cells (p < 0.01), and organization of the remodeled tissue (p < 0.01) at or after the Day 7 time-point. More rapidly degraded devices such as Restore and autologous tissue showed the greatest amount of cellular infiltration, especially at the early time-points. Devices that degraded slowly, such as CuffPatch, TissueMend, and Permacol, were associated with the presence of foreign-body giant cells, chronic inflammation, and/or the accumulation of dense, poorly organized fibrous tissue.

Conclusions: Biologic scaffold materials composed of extracellular matrix elicit distinct host-tissue histologic and morphologic responses, depending on species of origin, tissue of origin, processing methods, and/or method of terminal sterilization.

Clinical Relevance: The temporal sequence of remodeling events of extracellular matrix devices, including the rapidity of scaffold degradation and the extent of new-tissue deposition by the host, may be predictive of the clinical course and may determine the optimal rehabilitation protocol and functional outcome of the procedure.

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    Accreditation Statement
    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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    Stephen F. Badylak, DVM, PhD, MD
    Posted on November 11, 2009
    Dr. Badylak and Ms. Valentin respond to Dr. James and colleagues
    University of Pittsburgh, McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania

    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 manuscript (1) 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 1) that processing methods are “proprietary”. The manuscript 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 multinucleate 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 are also possible including thermal, photo-oxidative, and irradiation methods. 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 orthopedic applications, but other applications as well, will depend upon 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 materials (2-4), the source and rate of cell recruitment (5, 6), the factors that affect cellular differentiation and organization (7, 8), and the factors that affect downstream remodeling and patient outcome (9). 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.


    1. Valentin JE, Badylak JS, McCabe GP, Badylak SF. Extracellular matrix bioscaffolds for orthopaedic applications. A comparative histologic study. J Bone Joint Surg Am. 2006;88:2673-86.

    2. Daly K, Stewart-Akers A, Hara H, Ezzelarab M, Long C, Cordero K, Johnson S, Ayares D, Cooper D, 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 Jun 29 [Epub ahead of print].

    3. Valentin JE, Stewart-Akers AM, Gilbert TW, Badylak SF. Macrophage participation in the degradation and remodeling of extracellular matrix scaffolds. Tissue Eng Part A. 2009;15:1687-94.

    4. Badylak SF, Gilbert TW. Immune response to biologic scaffold materials. Semin Immunol. 2008;20:109-16.

    5. Reing JE, Zhang L, Myers-Irvin J, Cordero KE, Freytes DO, Heber-Katz E, Bedelbaeva K, McIntosh D, Dewilde A, Braunhut SJ, Badylak SF. Degradation products of extracellular matrix affect cell migration and proliferation. Tissue Eng Part A. 2009;15:605-14.

    6. Beattie AJ, Gilbert TW, Guyot JP, Yates AJ, Badylak SF. Chemoattraction of progenitor cells by remodeling extracellular matrix scaffolds. Tissue Eng Part A. 2009;15:1119-25.

    7. Brown BN, Valentin JE, Stewart-Akers AM, McCabe GP, Badylak SF. Macrophage phenotype and remodeling outcomes in response to biologic scaffolds with and without a cellular component. Biomaterials. 2009;30:1482-91.

    8. Gilbert TW, Stewart-Akers AM, Sydeski J, Nguyen TD, Badylak SF, Woo SL. Gene expression by fibroblasts seeded on small intestinal submucosa and subjected to cyclic stretching. Tissue Eng. 2007;13:1313-23.

    9. Derwin, KA et al. Extracellular matrix scaffold devices for rotator cuff repair. J Shoulder Elbow Surg. In press.

    Kenneth S. James, PhD
    Posted on October 26, 2009
    TissueMend is not chemically crosslinked nor does it elicit a classic foreign body response
    TEI Biosciences

    To the Editor:

    We would like to address statements related to the product TissueMend made in the paper by Valentin et al (1). Subsequent articles referencing this paper have not accurately reported the data presented (2,3), errata to which are now appearing (4). Please note that:

    • TissueMend is not artificially chemically crosslinked. While explicitly stated as such in the paper, the authors' grouping of TissueMend with the chemically crosslinked products tested in the paper’s abstract and discussion has led some to conclude otherwise. Chemical crosslinking is specifically avoided to preserve the native biopolymer chemistry to permit host adoption and adaptation of the implanted collagen structure and to avoid eliciting a chronic foreign body reaction and encapsulation response associated with chemically crosslinked implants.

    • TissueMend does not elicit a classic foreign body response. The data presented does not support the statements that the response to TissueMend is, “consistent with the typical response to a nonresorbable foreign material”, or, “associated with the presence of foreign-body giant cells, chronic inflammation, and/or the accumulation of dense, poorly organized fibrous tissue.” To the contrary, Table III explicitly indicates a statistically significant difference in foreign body giant cells to TissueMend (absent) to the chemically crosslinked products Permacol and CuffPatch (present). The absence of an acute or chronic inflammatory/foreign body reaction directed towards the TissueMend implant is similarly evident in Figures 5-A and 5-B.

    • The authors are correct when stating that, “…the proprietary methodology of making the final product [TissueMend] may be related to its relatively slow rate of degradation”. However, the authors incorrectly suggest that non-crosslinked collagen implants must necessarily be “degraded”. The histological results illustrate that the TissueMend collagen implant has been adopted and adapted by the host, filling with fibroblasts and supporting vasculature, to generate a new, long-lived tissue that effectively heals the small, surgically created partial- thickness muscle defect. This result and the absence of an inflammatory response directed towards the implant and generated tissue is consistent with reports on this same material in other soft tissue repair sites (5,6). However, it should be noted that subsequent adaptation of this implant is dependent on the site of implantation. For example, when specifically evaluated in a tendon repair model, TissueMend is similarly adopted but followed by the progressive adaptation of the implanted dermal collagen fibers into an aligned, oriented collagen fiber architecture comparable to tendon (7).

    We refer readers to an article by Cornwell et al. for a comprehensive review of the TissueMend technology (7).

    TissueMend Advanced Soft Tissue Repair Matrix is marketed by Stryker Orthopaedics (Mahwah, NJ) and was developed and is manufactured by TEI Biosciences (Boston, MA).

    In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from TEI Biosciences. In addition, one or more of the authors or a member of his or her immediate family received, in any one year, payments or other benefits in excess of $10,000 or a commitment or agreement to provide such benefits from a commercial entity (TEI Biosciences).


    1. Valentin JE, Badylak JS, McCabe GP, Badylak SF. Extracellular matrix bioscaffolds for orthopaedic applications. A comparative histologic study. J Bone Joint Surg Am. 2006;88:2673-86.

    2. Chen J, Xu J, Wang A, Zheng M. Scaffolds for tendon and ligament repair: review of the efficacy of commercial products. Expert Rev Med Devices. 2009;6:61-73.

    3. Aurora A, McCarron J, Iannotti JP and Derwin K. Commercially available extracellular matrix materials for rotator cuff repairs: State of the art and future trends. J Shoulder Elbow Surg 2007;16:171S-178S.

    4. Aurora A, McCarron J, Iannotti JP, Derwin K. Commercially available extracellular matrix materials for rotator cuff repairs: state of the art and future trends. J Shoulder Elbow Surg. 2007;16(5 Suppl):S171-8. Erratum in: J Shoulder Elbow Surg. 2009 [In press, available online 2009 Aug 27].

    5. Zerris VA, James KS, Roberts JB, Bell E, Heilman CB. Repair of the dura mater with processed collagen devices. J Biomed Mater Res Part B Appl Biomater. 2007;83:580-8.

    6. Cook JL, Fox DB, Kuroki K, Jayo M, DeDeyne PG. In vitro and in vivo comparison of five biomaterials used for orthopedic soft tissue augmentation. Am J Vet Res. 2008;69:148-56.

    7. Cornwell KG, Landsman A, James KS. Extracellular matrix biomaterials for soft tissue repair. Clin Podiatr Med Surg. 2009;26:507-23.

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