Pertinent Insights On Biologic Matrices For Soft Tissue Repair

Andrew Rice, DPM, FACFAS, and Erin Mathews, DPM

Given the emergence of biologic matrices, these authors examine the biologic and biomechanical potential of these modalities in the lower extremity. They also offer a review of the current research on these therapies and provide a pertinent case study.

Recently in the healthcare field, the use of tissue biologic matrices has become part of the surgical mainstream. Currently in foot and ankle reconstruction, the matrices provide essential aids in tendon strengthening and are becoming much needed necessities in tendon repair. Advancements in the technology and application of tissue grafts improve the successful outcomes of elective and non-elective tendon surgical procedures.

   Traditionally, tendon repair has been met with great frustration even in the hands of the most skilled surgeons. This is particularly the case when surgeons see injured tendons with large gaps between ends and/or diseased tendon substance. In these situations, surgeons often question how to restore the native tissue adequately.

   Biological matrices were introduced into the orthopedic arena with the intention of improving clinical outcomes of tendon repair and restoration. When it comes to tendon reinforcement with biological matrices, there are two primary goals that are biomechanical and biologic in nature. First, the matrix should reinforce the repair site and provide strength to the tendon. Second, the matrix should integrate itself into the tendon and serve as a new tendon substance.

A Closer Look At The Biomechanical Properties Of Biologic Matrices

Clinically important biomechanical properties of these matrices include the ability to: resist gap formation, load share across the repair and increase the ultimate load to failure. Furthermore, the material’s suture retention strength is critical for a successful repair construct.

   Mechanical testing of various biologic matrices has shown that different processing conditions result in a wide range of mechanical properties.1 More recent biomechanical testing of Achilles tendon repair applications has shown that the dermis-based regenerative matrices Conexa (Tornier) and GraftJacket® (KCI) significantly increase the ultimate load to failure versus unaugmented controls. This testing has also revealed that Conexa decreases gap formation under cyclic loading and exhibits load sharing.2,3

   In regard to suture retention strength of different tissue matrices, the thickest is GraftJacket MaxForce Extreme.2,3 This is followed by Conexa and then the standard GraftJacket MaxForce. Cross-linked materials are noted to have reduced suture retention strength. Neither Conexa nor GraftJacket are cross-linked products.

Understanding The Regenerative And Reparative Potential

In addition to providing adequate biomechanical support, biologic grafts should support the regeneration of native tissue over time and simultaneously prevent acute or chronic reactions.

   Critical factors such as processing, sterilization methods, surgical technique, repair application and rehabilitative programs contribute to the success or failure of these matrices. Failure of the biological matrix or tendon repair is usually multifactorial but the underlying reason often is associated with the host response.

   While some earlier biological matrices showed great promise in pre-clinical studies, the observed clinical success rate did not match these results. Some complications have included edema, cysts, immune reactions and expulsion of the matrix. More recent testing in primates, with immune systems similar to humans, has demonstrated distinct mechanisms of action of various grafts.4,5 While other grafts elicited a negative immune response, the primate data demonstrated that the Conexa porcine acelluar dermal matrix supported a regenerative response.

   How does this regenerative response occur? A matrix could have one of three types of mechanisms of action when one places it in a host.

   1. Regeneration is the desirable mechanism of action. This is a positive recognition as the host supports integration of the matrix.

   2. Resorption is a negative recognition, which leads to scar formation. This is less advantageous because scar formation results in inferior biomechanical characteristics in comparison to normal tissue.

   3. Encapsulation occurs when the host does not resorb the matrix. Pitfalls of this can include infection, chronic inflammation, complete mechanical failure and the need for surgical removal of the matrix.

   For further insights, see “A Guide To The Possible Mechanisms Of Action” (left), which provides an overview of the advantages and disadvantages of regeneration, resorption and encapsulation.

   One can further divide biological matrices into reparative matrices versus regenerative matrices based on the processing methods of the products. Regenerative products accomplish the following seven goals:
• reduce cellular and antigenic components;
• retain and not damage biochemical components;
• minimize the inflammatory response;
• support cellular repopulation and revascularization;
• provide mechanical properties that facilitate reinforcement of the repair;
• sterilize the matrix to medical standards; and
• stabilize the product so it can be stored at room temperature and used immediately without hydration.

What You Should Know About Host Acceptance And Rejection

The biological acceptance of matrices into host tissue is independent of the origin (porcine, human, primate, etc.) but directly related to the processing methods. The matrix must retain the architecture and biochemical integrity of the graft architecture in order to become biologically accepted by the host.

   Also, it is imperative that the cellular and α-Gal components are removed during the processing of the matrix.

   A host rejection response is attributed to the expression of galactose-α(1,3) galactose (α-Gal) terminal carbohydrate epitope, which is found in the tissue of most mammals. Humans lack this epitope and express high levels of α-Gal antibodies. Therefore, one usually encounters a hyperacute rejection response with xenogenic tissues unless this antigen is addressed in the processing of the matrix. The ability of the scaffold matrix to support regeneration of native tissue lies within producing a porcine-based graft material that retains structural integrity of the extracellular matrix and minimizes this antigenic response.

What The Research Reveals About The Efficacy Of The Available Matrices

Alloderm® (Lifecell) and GraftJacket are two acellular extracellular matrix scaffolds derived from human dermis. Surgeons have used these modalities for many years to treat significant soft tissue defects such as full-thickness burns, head/neck/post-mastectomy reconstructions and ventral hernias. Successful engraftment of allogenic tissues and formation of fully differentiated skin without contracture occurs through removal of viable cells from human dermis and preservation of the native dermal architecture and composition.

   Conexa and GraftJacket both support regeneration.4-6 GraftJacket is human allograft tissue. It is noteworthy that one does not have to sterilize this biologic matrix. GraftJacket is processed under aseptic conditions. Allograft rejection is reportedly not a problem with this matrix because the tissue processing limits damage associated with removal of the donor cellular components. Also, there is no need to address the aforementioned immune response to α-Gal antigen as this matrix is derived from human dermis.

   Researchers have reported good clinical results with GraftJacket.7 However, many limitations do exist and include certain handling characteristics such as lengthy hydration time and particular orientation requirements. Furthermore, the lack of sterility also may be subject to institutional concerns associated with traditional allograft tissues. These can include variations in properties of the matrix material based on inconsistencies of donor tissue (e.g. age, history).

   Conexa was developed through extensive pre-clinical primate animal tests with the goal of achieving the key regenerative characteristics of GraftJacket with a focus to improving the product handling, storage, consistency and sterility. Those who developed Conexa came up with a process that successfully reduced the antigenic material while preserving the remainder of the matrix even after terminal sterilization. The processing of Conexa removes the cells and significantly reduces the residual α-Gal remaining in the porcine extracellular matrix. The matrix is not denatured or damaged during this treatment, which allows for regeneration.

   Histological evidence in a primate model has shown that Conexa supports tissue regeneration.4 This study demonstrates that cellular repopulation occurs in just two weeks in the abdominal interpositional model without an inflammatory response. Within six months, Conexa was well integrated into the primate abdominal fascia.

   In addition to testing in primates, in vitro studies of the response of human tenocytes to several commercially available matrices have shown significant differences between the various products in cell adhesion, cell proliferation and cellular production of collagen and other molecules related to tendon regeneration.6 These tests demonstrated that Conexa and GraftJacket garnered the most favorable responses from the human tenocytes.

   Early clinical experiences in several thousand orthopedic patients who have received the Conexa graft since 2008 are consistent with the positive findings in the primate animal and in vitro studies.6 Researchers have reported a case of successful use of Conexa for Achilles tendon repair with full return to activity and no inflammatory response at long-term follow-up.8 Further study is ongoing with a multicenter postmarketing trial examining the use of Conexa for large and massive reparable rotator cuff tears.9

Case Study: When A Patient Presents With Degenerative Tenosynovitis And A Peroneus Longus Tear

A 53-year-old patient presented with a chronic severe degenerative tenosynovitis and a partial tear of the peroneus longus tendon distal to the lateral malleolus.

   The patient has a past medical history of diabetes mellitus (preoperative hemoglobin A1c of 6.4), hypertension, hyperlipidemia and gastroesophageal reflux disease. Patient medications at the time of surgery were telmisartan (Micardis, Boehringer Ingelheim), hydrochlorothiazide, insulin, zolpidem tartrate (Ambien, Sanofi Aventis), metformin, atorvastatin calcium (Lipitor, Pfizer), carvedilol (Coreg, GlaxoSmithKline) and dexlansoprazole (Dexilant, Takeda).

   The patient initially had a conservative course of treatment including physical therapy, platelet-rich plasma injection, immobilization, physical medicine and rehabilitation. All of these modalities failed to relieve pain and the patient’s symptoms. The primary care physician cleared the patient for surgery.

   After the patient received a spinal anesthetic, the surgeon marked the left limb and made the incision from the lateral malleolus to the peroneal sulcus of the cuboid. The surgeon carefully distracted the sural nerve in a plantar direction. After identifying the diseased portion of the left peroneus longus tendon, the surgeon performed an elliptical resection of this portion.

   Then the surgeon measured and trimmed a 4 x 4 cm surgical mesh (Conexa), and wrapped it around the circumference of the resected portion of the tendon. The surgeon sutured the Conexa in position, surrounding the peroneus longus tendon in the area of the greatest deficit to reinforce the tendon repair.

   We subsequently employed a short leg cast and had the patient non-weightbearing for three weeks. Cast removal at three weeks facilitated mobilization of the ankle. She remained non-weightbearing for six weeks. Due to intolerance to weightbearing, she wore a controlled ankle motion (CAM) walker for an additional two weeks. The patient was fully weightbearing at eight weeks postoperatively in an athletic shoe. Her course was uneventful with no evidence of infection.

   Pathology results revealed a dense fibrous tissue with tendonosis and focal degenerative changes. No complications of surgery occurred. The patient returned to full activity at 12 weeks postoperatively.

In Summary

Biologic matrices can provide potential benefits in foot and ankle tendon surgery by providing both mechanical and biologic support. However, the mechanism of action of the biologic response of the matrix is of critical importance for optimal clinical outcomes and this depends heavily upon the manufacturing process of the matrix material.

   Conexa tissue matrix may offer several advantages as a graft choice for foot and ankle applications. It provides for mechanical support of the repair and offers an intact, non-cross-linked matrix, which allows rapid cell population and vascular ingrowth to support a regenerative mechanism of action.

   Conexa further provides a sterility assurance level (SAL) of 10-6, which is the FDA standard for medical device sterility. It is a product the surgeon can easily use for tendon supplementation because it can be stored at room temperature and used immediately after a two-minute rinse. It is also available in a variety of sizes and thicknesses tailored for orthopedic soft tissue use.

   Dr. Rice is a Clinical Assistant Professor in the Department of Orthopaedics and Rehabilitation at the Yale University School of Medicine. He is the Chief of Podiatry at Norwalk Hospital and is in private practice at Fairfield County Foot Surgeons in Norwalk, Conn. Dr. Rice is a Fellow of the American College of Foot and Ankle Surgeons.

   Dr. Mathews recently completed her residency at the Yale University School of Medicine Podiatric Residency Program.


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9. Available at

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