Porcine Small Intestine Submucosa for Repair of Goat Meniscal Defects

This study evaluated the effectiveness of small intestine submucosa used as a graft to fill surgically created meniscal defects in a large animal model. Four goats underwent unilateral interior subtotal meniscectomies (~70%) within the avascular portion of the medial meniscus. The contralateral meniscus acted as a control. Grafts of porcine small intestine submucosa were trimmed to fill the resected defects and sutured into place. After surgery the operated knees were casted in partial flexion to limit weight bearing on the affected limb. All of the animals were sacrificed at 12 weeks at which point meniscal regeneration and articular cartilage degradation were evaluated by gross and histologic examination. Grossly, the defects in the small intestine submucosa-grafted goats were partially filled with meniscal-appearing connective tissue. Histologically, the replacement tissue was typified by the presence of dense, cellular, irregularly organized connective tissue. Evaluation of the articular cartilage displayed increased degeneration in the grafted compartment of the operative knees. Each of the operative menisci partially regenerated. The grafts were conducive to repopulation with host meniscal elements. Despite partial meniscal regeneration, comparatively more articular cartilage degeneration in the treated knees was observed than in the untreated contralateral controls.

The long-term function of the knee joint is enhanced by an intact meniscus. The meniscus is an important stabilizer of the knee: its role in distributing contact forces and function as a shock absorber during gait are well documented. The meniscus has a limited ability for intrinsic healing. Consequently, preservation and restoration are the primary goals in treating damaged menisci. The current surgical options for a meniscal tear are debridement, repair, or transplantation, all of which have met with varying degrees of success.

Technologies are being developed that allow for potential restoration of the natural meniscus. The search for the optimal meniscal repair/replacement tissue led to the fabrication of natural or synthetic replacement menisci.

Previous investigators in our laboratory studied the regenerative capability of porcine small intestine submucosa in rabbit meniscal defects. The early rabbit studies showed encouraging results, but due to the size and nature of the model it was difficult to make firm conclusions. This study follows the preliminary study in rabbits designed to test the applicability of the small intestine submucosa graft as a scaffold for meniscal tissue regeneration. Functional considerations of the regenerated tissue were addressed in this study using larger animal subjects with a more clinically relevant meniscal injury model.

Materials and Methods

Unilateral subtotal medial meniscectomies were made in the left knees of four male goats aged 1 to 3 years. The right knee of each study animal served as a control. All surgery was approved by the University Animal Care and Use Committee, and was undertaken in a designated animal operatorium.

Each goat was premedicated with medetomide (0.25 mg/kg), induced with pentothal (450 mg), intubated, and then anesthetized with isoflurane. Antibiotic prophylaxis was 1.0 gm cefotaxime sodium. Following anesthetization, the left hind limb was shaved and the animal was placed on its back on the operating table, with its pelvis at the edge and its hind limbs extended off the end of the table to facilitate stifle flexion and abduction of the shank. The lower extremity then was prepped with povidone-iodine and draped in the standard sterile fashion.

The knee was approached via a medial parapatellar incision. A 6-cm skin incision was made over the medial aspect of the left knee. The incision was continued down through the fascial layers to expose the medial collateral ligament. An osteotome was then used to release the ligament at its femoral insertion site. The bone block removed with the femoral insertion was approximately 5 mm wide by 7 mm long. Prior to bone block removal a hole was pre-drilled to facilitate later fixation.

With the medial collateral ligament reflected, the knee joint capsule was opened parallel to the joint line. The knee was flexed to 90° and abducted to expose the medial meniscus. Two 1-0 vicryl sutures were passed through the outer margin of the meniscus so it could be controlled, and the meniscus was pulled medially for exposure. A scalpel then was used to cut the meniscus circumferentially, freeing the crescent-shaped inner margin of the meniscus.

Small intestine submucosa was supplied a flat disk, 7 cm in diameter (Restore Orthobiologic; DePuy Orthopaedics Inc, Warsaw, Ind). The material was hydrated for a few minutes in sterile saline. Using the excised meniscus as a template, the small intestine submucosa was cut into a crescent shape using scissors. Once the small intestine submucosa was shaped, it was secured to the remainder of the native meniscus using three 2-0 proline sutures in an inside-out fashion.

With the graft securely sutured in place, the knee was flushed with saline and the capsule was closed with 0 vicryl. The bone block on the medial collateral ligament was secured using a 4.0×26-mm cancellous screw and washer (DePuy Inc). The fascia and soft tissues were closed in layers using 2-0 vicryl, and a running 3-0 vicryl was used on the skin. Once the incision was closed, hexabond was applied to the incision and 12 cc of sensorcaine was injected for postoperative analgesia.

At the completion of surgery a fiberglass short-leg cast was applied to the operated hind limb. The stifle and hock joints of the animals were casted with the stifle joints slightly flexed to prevent weight bearing and limit stifle motion. The casts were applied to prevent weight bearing and limit motion of the operated limb. The animals were kept casted for three weeks, after which the casts were removed and the animals were allowed to bear weight freely. The animals were housed in 10×20-foot pens throughout the study. All of the animals received buprenorphine hydrochloride and ketorolac for postoperative analgesia for 5 days.

All animals were euthanized 12 weeks postoperatively with an intravenous injection of barbiturate. After euthanasia, both hind limbs were amputated at the mid-femur, and anteroposterior and lateral radiographs were taken of the knee joint. The bones were cleaned of all muscle and other soft tissues, and the femurs were disarticulated from the tibias via careful sectioning of the collateral and cruciate ligaments and joint capsule. Photographs were taken of the dissected knee joints (Figure 1).

The medial and lateral menisci then were carefully removed from the tibia via sharp dissection of the anterior and posterior tethers. As the menisci were removed, care was taken to preserve a margin of soft tissue along the peripheral surfaces. All specimens (both menisci, distal femur, and proximal tibia) were placed in sealed plastic containers containing 10% formalin and refrigerated. During the dissection, photographs were taken of the distal femur, proximal tibia with the menisci in situ, proximal tibia with the menisci removed, and the explanted menisci.

Morphological and Histological Evaluation

As the hind limbs were dissected, the size and shape of the treated medial menisci were visually compared to the size and shape of the control medial menisci.

After the medial menisci were adequately fixed in formalin they were processed for histological evaluation. Three thin (~3 mm) radial tissue wafers were cut from anterior, middle, and posterior portions of the meniscus. The wafers were embedded in paraffin, and serial 6-µm radial sections were cut from each block. Alternating sections were stained with hematoxylin-eosin or safranin O/Fast Green. The slides were examined using an Olympus BH-2 photomicroscope (Olympus America Inc, Melville, NY). An attempt was made to quantify meniscal regeneration by cross sectional comparison, an area of the section from the treated menisci with the cross sectional area of the contralateral control menisci.

Cartilage degeneration was evaluated with India ink staining of the femoral and tibial articular surfaces (Table 1). The bones were removed from the formalin and blotted dry with a gauze sponge. India ink was applied directly to the cartilage surfaces of the femoral condyles and the tibial plateau, and then the excess ink was wiped off with a formalin dampened gauze sponge. The ink was retained in areas where the cartilage was cracked or destroyed; wiping removed it in areas where the cartilage was intact. The articular surfaces were photographed before and after the application of India ink.

Results

The animals tolerated surgery and casting well. They were able to stand and ambulate unsupported within hours after surgery. The short leg casts prohibited weight bearing, limited stifle motion, and lasted for the planned three weeks.

Morphology

Grossly, evaluation of the dissected joints revealed normal-appearing synovium and fat pads in all the stifles (operated and control), except in the operated stifle in one animal, where the synovium was edematous and the fat was slightly darker than in the other subjects.

Newly formed replacement tissue was present in the defects in all four of the grafted menisci, though the amount varied from animal to animal. In two of the animals the replacement tissue was nearly indistinguishable from the adjacent native meniscus, and in the remaining two the replacement tissue was almost translucent. None of the knees contained free bodies or identifiable remnants of the small intestine submucosa grafts.

Histology

The radial cross sections of the small intestine submucosa-grafted menisci approximated the shape of the untreated contralateral controls (Figures 2 and 3). In most of the sections, low power (10×) examination revealed a triangular-shaped structure that was thick peripherally and tapered to a point centrally. In a few samples, the cross sections were more rectangular with a small triangular nub of tissue on the central aspect. Qualitatively, the cross sectional sections of the treated menisci were 25% to 30% smaller than those of the corresponding untreated contralateral controls (accurate cross sectional area was impossible to obtain due to difficulty in determining the peripheral margins of the meniscal tissue).

Ultrastructurally, normal meniscus is a fibrocartilaginous tissue sparsely populated with fibroblasts superficially and fibrochondrocytes throughout the remainder of the tissue. In the substance of the normal meniscus the majority of collagen fibers run circumferentially, though radially oriented fibers also are present (Figure 4). In contrast, the replacement tissue in the grafted menisci was typified by the presence of dense, highly cellular, irregularly organized fibrous connective tissue (Figure 5). The replacement tissue was well vascularized, with blood vessels visible as far centrally as the central tip of the structure. In some areas, often near the central tip or along the upper and lower margins, the replacement tissue was hyaline cartilage-like in appearance. There was no well-defined hierarchical organization to the tissue.

Positive identification of residual small intestine submucosa was difficult. In most of the sections, remnants of amorphous, acellular, pink staining material that appeared to be small intestine submucosa were observed. The material typically was bordered on all sides by fibrovascular repair tissue, and it was traversed by bands of fibrous tissue. No encapsulation indicating a foreign body reaction was evident. The material did not appear to illicit much chronic inflammatory response, as there were few mononuclear cells. The residual small intestine submucosa often appeared to have been sparsely populated by native fibrocytes.

Articular Cartilage Degradation

Five anatomic regions were compared in each of the four animals (patellar groove, medial femoral condyle, lateral femoral condyle, medial tibial plateau, and lateral tibial plateau). Overall, the osteoarthritic changes in the weight-bearing areas of the small intestine submucosa-treated femurs and tibias only were slightly worse than the changes in the contralateral control stifles. Of the eight regions in the treated knees that had more cartilage degradation than the control stifles, six were one grade worse than their untreated counterparts; the remaining two were two grades worse (Table 2 and Figure 6).

The articular cartilage on the medial side of the stifle, where the grafts were placed, was most affected. Degradation of cartilage on the medial femoral condyles was slightly worse in three of the treated stifles compared to their untreated contralateral controls. Similarly, degradation of cartilage on the medial tibial plateau was slightly worse in three of the four treated stifles. Cartilage degradation increased in the lateral side of the stifle, both the lateral femoral condyle and lateral tibial plateau, in only one animal. The cartilage in the patellar groove was unaffected in all stifles in all four subjects.

Discussion

Meniscal injury is common and often leads to pain and loss of joint function. The long-term function of the knee joint is enhanced by intact menisci. The natural biomechanics of the knee are preserved by a functioning meniscus, and its role in stability, force transmission, and shock absorption is well documented.^1-5 Additionally, loss of a functional meniscus increases the likelihood and severity of osteoarthritis.⁶

Consequently, preservation and restoration are the primary goals in treating damaged menisci. The meniscus has a limited ability for intrinsic healing. The current surgical options for a meniscal tear are debridement, repair, or transplantation. The objective of repair and preservation of the meniscus is to restore normal knee biomechanics and minimize pathologic wear of the articular surface. Partial meniscectomy is superior to total meniscectomy, but preservation of the entire injured meniscus is most favorable, as it conserves normal knee biomechanics and prevents further articular cartilage damage.^7,8

The potential for meniscal healing is associated with the tissue vascularity. Tears in the avascular central third of the meniscus do not heal well.^9-11 Conversely, healing is good in the peripheral third, which is well vascularized via branches from geniculate arteries.¹² In the middle third, where the vascularized and the nonvascularized sections converge, healing is inconsistent. Correspondingly, the success of meniscal repairs depends on the site of the tear. Repairs of peripheral tears tend to heal well, while repairs of central tears are least successful.

Healing in the avascular zone of the meniscus is unpredictable. Novel methods for inducing or augmenting the normal restorative process are an area of exploration. As the potential for meniscal healing is linked with its vascularity, early research focused on techniques for stimulating or extending vascular ingrowth. Investigators achieved success by abrading the synovium and transplanting vascularized synovial flaps.¹³ The resultant proliferative vascular response creates full-thickness vascular access channels through the peripheral tissue.

Other studies experimented with fibrin clot, hoping to capitalize on its ability to recruit and support the cells needed for tissue regeneration. The results indicate that healing in the marginal portions of the meniscus can be induced, even without maneuvers designed to extend the vascular supply.¹⁴ Subsequently other investigators began to explore the use of meniscal allografts and engineered collagen scaffolds. The use of these materials has met with varying degrees of success.

While appealing in theory, meniscal transplantation has inherent drawbacks that limit its applicability.^15-18 The preservation process can produce significant graft shrinkage.¹⁹ The transplant tissue must be sized and stored preoperatively. To insure an appropriate graft, a large number of samples must be available.²⁰ Procurement of adequate samples is limited by the donor pool of relatively young, disease-free patients with no prior meniscal pathology. Additionally, disease transmission is a potential drawback with human allogenic tissue transplantation.

The next logical progression in the search for an appropriate vehicle is the construction of a meniscal replacement. Inserting a synthetic meniscal polyurethane-coated Dacron prosthesis (DuPont, Wilmington, Del) provided protection to the articular surface, but did not reproduce the biomechanical functions of the normal meniscus.²¹ While the results of the polyurethane graft did not fulfill their promise, a prosthetic graft constructed of collagen has shown potential.²² A copolymeric collagen scaffold derived from bovine Achilles tendon was washed, purified, and cross-linked with glycosaminoglycans. In a dog model, the collagen scaffold was trimmed to size and implanted in place of the medial meniscus that had undergone an 80% subtotal resection. Meniscal fibrochondrocytes grew into the collagen scaffold and regeneration of meniscal tissue occurred.

Previous work done in our laboratory demonstrated that multilaminated collagenous graft is conducive for cellular repopulation with host meniscal elements, and at 24 weeks was capable of supporting complete healing of a large meniscal defect in rabbits.

This suggests that technologies exist that may allow for potential restoration of the natural meniscus.

The small intestine submucosa biomaterial was selected based on its performance as a ligament graft²³ and in vascular surgery studies.^24-26 Small intestine submucosa also has been used to repair bladder and abdominal wall defects.^27,28 Biomechanical properties for this purpose have been tested and reported. Dora et al²⁹ reported that porcine small intestinal submucosa demonstrated less tensile strength and stiffness, although most notably, the material decreased in surface area and contracted. Additionally, small intestine submucosa currently is available as a supplement to rotator cuff repairs based on research performed in a canine model.³⁰ When used for vascular graft, the small intestine submucosa was completely incorporated and the distinct layers of the arterial wall were reconstituted.³¹ Not only did the graft survive, the cells that repopulated the graft differentiated in accordance with their physical environment.

Any biomaterial used in meniscal tissue regeneration must grow in reflection to its physical environment. Fabricating a semilunar-shaped pad of fibrocartilage is not sufficient. The restoration of appropriate collagen fiber patterns by living fibrochondrocytes is necessary for a functional meniscal regeneration.^32-35

Made from the submucosa of porcine small intestine, small intestine submucosa is a naturally occurring extracellular matrix material that has been used successfully as a scaffold for repair in a number of soft-tissue applications. Small intestine submucosa consists primarily of type I collagen, but it also contains at least five different glycosaminoglycans and numerous growth factors, including basic fibroblast growth factor (basic-FGF), transforming growth factor B (TGFB), vascular endothelial growth factor (VEGF), and platelet derived growth factor (PDGF). With small intestine submucosa implantation, the repair tissue often is indistinguishable from normal host tissue, rather than a scar.

Small intestine submucosa was studied previously in the treatment of subtotal meniscal defects in dogs. The results suggest that the small intestine submucosa may be useful as a graft material for meniscal regeneration. In the grafted dogs, the new tissue was morphologically indistinguishable from the normal meniscus. Histological analysis revealed loose, well-vascularized connective tissue with no evidence of chondroid differentiation, similar to native meniscus.^36,37

Previous investigators in our laboratory studied the regenerative capability of small intestine submucosa in rabbit and goat meniscal defects. The early rabbit studies showed encouraging results, but due to the size and nature of the model it was difficult to make firm conclusions.

In unpublished data from our laboratory in an effort to evaluate healing in a larger model, a pilot goat study was undertaken. Initial evaluation of the data from the pilot study was less encouraging. The results demonstrated only limited meniscal repair at six months. However, the results of this study were complicated by the fact that the animals were allowed unrestricted weight bearing following surgery, which may have damaged the repair before substantial regeneration could occur. Other investigators have shown that placing an external fixator across the operative joint can protect meniscal repair.³⁸ In the present study the repair was protected via casting.

Previous work has reported chondral protection using small intestine submucosa grafts in dogs.³⁹ The results of our articular cartilage analysis are less encouraging in this large animal model. Our primary goal in this study was to establish meniscal tissue viability and healing. However, this articular wear may be secondary to surgical trauma and postoperative immobilization as our control was an unoperated contralateral leg. We chose this as our comparison to compare histologically our grafted meniscus with a normal unoperated meniscus.

Expanding on our preliminary study in rabbits, the small intestine submucosa implant successfully provided an acceptable scaffold for the regeneration of a large defect in the goat meniscus. Functional considerations of the regenerated tissue were addressed using larger animal subjects with a more clinically relevant meniscal injury model. On gross examination, some specimens had the appearance of a normal meniscus with respect to contour, color, and consistency. Histological examination showed early infiltration of the graft with host cellular elements without evidence of rejection or giant-cell reaction. At 12 weeks, cellular connective tissue was reliably joined to the margin of the native meniscal tissue. The replacement tissue was well vascularized, with blood vessels visible as far centrally as the central tip of the structure.

Conclusion

Small intestine submucosa-grafted menisci demonstrated partial filling in the surgically created meniscal defect. Small intestine submucosa is a promising biological graft that may provide a scaffold for meniscal healing. These findings support the following theories regarding the use of small intestine submucosa as a graft for meniscal defects:

• The results of our histological analysis suggest that the small intestine submucosa remained attached to the meniscus. No free small intestine submucosa was found in the knee at the time of sacrifice.
• The grafts were repopulated with connective tissue cellular elements.
• A limited amount of regeneration occurred in each of the four treated menisci at the 12-week sacrifice point. Qualitatively, the cross sectional areas of the regenerated menisci were 25%-30% smaller than the cross sectional areas of unoperated contralateral controls.
• Despite limited regeneration of the menisci, slightly increased cartilage degradation occurred in each of the four treated stifles. By 12 weeks, cartilage degradation in the operated compartment (medial femoral condyle and medial tibial plateau) was one grade worse than in the medial compartment of the unoperated side.

The current study addressed the shortcomings encountered in the pilot study. The larger animal model facilitated the technical aspects of the implantation procedure. The larger meniscus allowed for more secure suturing of the graft into a larger and more clinically relevant meniscal defect. The meniscus regenerated to a degree in all cases. With protected weight bearing, the small intestine submucosa graft may possess adequate structural support to withstand the biomechanical stresses applied to the meniscus during the regeneration phase, but future studies will need to determine this finding. Ultimately the regenerated tissue must not only be evident at a cellular level as the present study suggests, it also must restore mechanics on the level of joint function.

The present study built on our previous work focusing on histological analysis of the graft material and articular cartilage. The requirement of histological analysis in this small sample size did not allow for biomechanical testing and resulting tissue injury. To our knowledge, this histological analysis study represents the largest reported series of goat meniscal defects using small intestine submucosa material. The focus of future studies should be directed at biomechanical testing of this regenerated tissue and its long-term survivability.

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Authors

Drs Bradley, Fadale, Hulstyn, Muirhead, and Lifrak are from the Division of Sports Medicine, Department of Orthopedic Surgery, Brown Medical School, Providence, RI.

This study was funded by an educational grant from DePuy Orthopaedics Inc.

The authors thank Dan Labrador and Scott McAllister for providing technical assistance.

Correspondence should be addressed to: Michael P. Bradley, MD, MS, Dept of Orthopedic Surgery, Brown Medical School, Rhode Island Hospital, 2 Dudley St, COOP 1st Fl, Providence, RI 02905.

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