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Regeneration of Meniscal Cartilage with Use of a Collagen Scaffold. Analysis of Preliminary Data*

KEVIN R. STONE, M.D., SAN FRANCISCO, CALIFORNIA, J. RICHARD STEADMAN, M.D., WILLIAM G. RODKEY, D.V.M., VAIL, COLORADO and SHU-TUNG LI, PH.D., FRANKLIN LAKES, NEW JERSEY

Investigation performed at The Stone Clinic, San Francisco

	Abstract

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A collagen scaffold was designed for use as a template for the regeneration of meniscal cartilage and was tested in ten patients in an initial, Food and Drug Administration-approved, clinical feasibility trial. The goal of the study was to evaluate the implantability and safety of the scaffold as well as its ability to support tissue ingrowth. The study was based on the findings of in vitro and in vivo investigations in dogs that had demonstrated cellular ingrowth and tissue regeneration through the scaffold. Nine patients remained in the study for at least thirty-six months, and one patient voluntarily withdrew after three months for personal reasons. The collagen scaffold was found to be implantable and to be safe over the three-year period. Histologically, it supported regeneration of tissue in meniscal defects of various sizes. No adverse immunological reactions were noted on sequential serological testing. On second-look arthroscopy, performed either three or six months after implantation, gross and histological evaluation revealed newly formed tissue replacing the implant as it was resorbed. At thirty-six months, the nine patients reported a decrease in the symptoms. According to a scale that assigned 1 point for strenuous activity and 5 points for an inability to perform sports activity, the average score was 1.5 points before the injury, 3.0 points after the injury and before the operation, and 2.4 points at six months postoperatively, 2.2 points at twelve months, 2.0 points at twenty-four months, and 1.9 points at thirty-six months. According to a scale that assigned 0 points for no pain and 3 points for severe pain, the average pain score was 2.2 points preoperatively and 0.6 point thirty-six months postoperatively. One patient, who had had a repair of a bucket-handle tear of the medial meniscus and augmentation with the collagen scaffold, had retearing of the cartilage nineteen months after implantation. Another patient had débridement because of an irregular area of regeneration at the scaffold-meniscus interface twenty-one months after implantation. Magnetic resonance imaging scans demonstrated progressive maturation of the signal within the regenerated meniscus at three, six, twelve, and thirty-six months. These findings suggest that regeneration of meniscal cartilage through a collagen scaffold is possible. Additional studies are needed to determine long-term efficacy.

	Introduction

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Loss of the meniscal cartilage can lead to degenerative osteoarthrosis in the knee joint^7,8. Currently, the treatment of a torn meniscal cartilage usually involves removal of the damaged tissue, although occasionally the tear is repaired with sutures. Replacement of damaged or removed cartilage with artificial materials, autogenous tissue, and allograft tissue has been reported, but the results generally have been poor^{11,15,18,19,22,24,28-32,34}. However, spontaneous partial regeneration of cartilage after a meniscectomy has been noted since 1929¹⁷. In 1990 and 1992, we reported the successful use of collagen scaffolds as templates for regeneration in dogs^25,26. The present paper reports the findings of the first clinical trial of a collagen implant designed to support the regeneration of meniscal cartilage in humans.

	Materials and Methods

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Preparation of the Collagen Scaffold
The materials used for the collagen implant had to conform to six criteria. They had to be biocompatible; they had to have a physical shape similar to that of the normal meniscus or to be able to be shaped at the time of implantation; they had to have a pore structure that would facilitate cellular ingrowth; they had to have an initial mechanical strength suitable for operative implantation; they had to be permeable to macromolecules for nutrient supply; and they had to have an initial in vivo stability in order to function as a template.

Collagen Material
The type-I collagen fibers were purified from bovine Achilles tendon with chemical treatments, including water, salt, base, and organic solvent extractions, to remove the non-collagenous materials. The resulting collagen fibers then were analyzed for purity. The amino acid composition and the hexosamine, neutral sugar, and hydroxyproline contents were determined for the purified collagen material.

Fabrication of the Collagen Meniscal Implant
The purified collagen fibers were swollen in the presence of equal quantities of hyaluronic acid (LifeCore Biomedical, Chaska, Minnesota) and chondroitin sulfate (Seikagaku, Tokyo, Japan) (2.5 per cent glycosaminoglycans of the dry weight of the finished meniscal implant)¹ at a pH of 2.5 to 3.0 and were homogenized. The swollen collagen-glycosaminoglycan fibers then were treated with 0.6 per cent NH₄OH, as described by Stone²¹. The fibers were dehydrated, molded, lyophilized, chemically cross-linked with aldehyde vapor, and gamma-sterilized (Fig. 1).

View larger version (65K): [in this window] [in a new window]   Fig. 1 Photograph of the collagen meniscal implant.

Characterization of the Collagen Meniscal Implant
The density of the finished, dry collagen meniscal implant was determined with gravimetric and volumetric measurements. The pore structure was determined with scanning electron micrographs of the cross sections of the implant (Fig. 2). The maximum length from each pore and the range of pore sizes were measured. Mechanical strength was assessed with use of a force-gauge apparatus (Chatillon, Greensboro, North Carolina). A 2-0 suture was passed through the matrix three millimeters from the edge of the implant. A knot was made to produce a loop for attachment to the hook of the force-gauge. The implant was pulled at a rate of 2.5 centimeters per minute. The ultimate strength at the time of pullout of the suture was recorded. The permeability of the interstitial space of the implant to macromolecules the size of bovine serum albumin (molecular weight, 67,000 daltons) and the shrinkage temperature were determined with use of a modification of the method of Katz and Li¹².

View larger version (156K): [in this window] [in a new window]   Fig. 2 Scanning electron micrograph of a cross section of the collagen meniscal implant.

Safety Evaluation
The collagen meniscal implant was tested for cytotoxicity, sterility, hemolysis, pyrogenicity, mutagenicity, and immunogenicity at independent laboratories. Cytotoxicity, sterility, hemolysis, and pyrogenicity were tested according to United States Pharmacopeia (USP) XXII methods. Mutagenicity was tested according to a modification of the method of Ames et al.². The potential immunogenicity to bovine type-I collagen was tested in two animal models: a rabbit model, used to detect the humoral immune response with use of an enzyme-linked immunosorbent assay, and a mouse model, used to detect the cell-mediated immune response against the implant with use of a lymphoproliferation assay.

The amino acid composition of the purified tendon collagen was typical of that reported for both bovine and human type-I collagen¹⁴, as evidenced by a hexosamine content of 0.03 per cent, a hydroxyproline content of 13 per cent, and a neutral sugar content of 0.01 per cent. These results show minimum contamination of glycoproteins and glycosaminoglycans in the preparation and are consistent with a highly purified preparation of type-I collagen. The low content of neutral sugars indicates that most of the sugars that are O-glycosidically linked to hydroxylysine residues are likely to be lost during the base extraction procedure in the purification process.

The characteristics of the implant are the optimized values based on the design requirements for in vivo function. The density of the implant averaged 0.20 ± 0.02 gram per cubic centimeter, the pore size ranged from seventy-five to 400 micrometers, and the suture pullout strength averaged 2.5 ± 0.5 kilograms. The average accessibility of the interstitial space to the bovine serum albumin was 98 ± 5 per cent, and the average shrinkage temperature was 67 ± 3 degrees Celsius. The length of the implant (the distance from the anterior horn to the posterior horn) was approximately five centimeters, the width (the distance from the peripheral rim to the inner rim) was approximately 1.5 centimeters, and the thickness was 0.75 centimeter at the peripheral rim and 0.55 centimeter at the inner rim. The implant may be trimmed with respect to size and fit with use of surgical instruments. The matrix is elastic and conforms to the joint space after implantation. In vitro and in vivo studies have demonstrated ingrowth into the final design of the scaffold^25,26,33.

Clinical Trial in Humans
Ten patients were enrolled in the current Institutional Review Board and Food and Drug Administration-approved phase-one clinical feasibility trial for evaluation of the safety and implantability of the collagen implant and its ability to support tissue ingrowth. Written informed consent was obtained from all patients. The study was restricted to patients who had an irreparable tear of the meniscal cartilage or major loss of meniscal cartilage in a stable or stabilized knee. As this was a study of feasibility and not of efficacy, patients who had diverse clinical conditions were included.

Two patients had reconstruction of the anterior cruciate ligament at the time of the index procedure. Two patients had tightening of the anterior cruciate ligament with use of a so-called healing-response method, which involves the creation of a microfracture of the posterior intercondylar notch without the placement of sutures in the ligament. One patient had had reconstruction of the anterior cruciate ligament within the previous year. Patients were excluded if they had had a previous treatment with collagen or if they had an allergy to collagen, a concomitant injury of the contralateral knee, inflammatory arthritis, or severe degenerative osteoarthrosis. There were no concomitant controls for this feasibility study.

All patients filled out detailed clinical questionnaires and had physical examination, radiographic studies, bone scans, serum analysis, and magnetic resonance images of both knees preoperatively and at three, six, nine, twelve, twenty-four, and thirty-six months postoperatively. The one-leg-hop test⁹ was added to the clinical examination at six and twelve months. One patient withdrew from the study after three months because of personal reasons and the pain caused by the operation. Second-look arthroscopy and a biopsy were performed in three of the remaining nine patients at three months after the implantation and in the other six patients at six months. Two patients subsequently had an additional operation: one, at twenty-one months, because of degeneration of the lateral joint space and pain, and the other, at nineteen months, because of a traumatic tear of the involved medial meniscus that the patient had sustained in a fall while skiing.

The average age of the ten patients was 39.3 years (range, twenty-four to fifty years). There were eight men and two women (Table I).

View larger version (180K): [in this window] [in a new window]   Fig. 3 Drawings showing insertion and suturing of the collagen meniscal implant.

View larger version (174K): [in this window] [in a new window]   Fig. 4 Drawings showing insertion and suturing of the collagen meniscal implant.

View larger version (82K): [in this window] [in a new window]   Fig. 5 The sizes and shapes of the meniscal lesions as well as the menisci after placement of the collagen meniscal implant.

Magnetic resonance images included T1-weighted axial and coronal images and T2-weighted gradient-echo contrast axial, sagittal, and coronal images. T2-weighted axial and coronal images subsequently were made with use of fast spin-echo and fat-suppression techniques²⁷. Inversion recovery coronal images also were made. During the latter part of the study, intravenous gadolinium-enhancement techniques were used.

	Results

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Human Clinical Trial
Nine patients remained in the study for thirty-six months, and one patient dropped out after three months. Mild, transient effusions, which resolved spontaneously in three to fourteen days, were noted in seven patients.

Clinically, the patients' activity scores were similar to those that we have observed during the same time-period after meniscectomy. According to a scale that assigned 1 point for strenuous activity, 2 points for moderate activity, 3 points for light activity, 4 points for a sedentary lifestyle, and 5 points for an inability to perform sports activity, the activity score averaged 1.5 points before the injury, 3.0 points before implantation, 2.4 points at six months, 2.2 points at twelve months, 2.0 points at twenty-four months, and 1.9 points at thirty-six months. According to a scale that assigned 0 points for no pain, 1 point for mild pain, 2 points for moderate pain, and 3 points for severe pain, the score for pain averaged 2.2 points preoperatively and 0.6 point at thirty-six months postoperatively. The overall knee rating improved from 3.0 points at twelve months to 2.0 points at twenty-four months and 1.4 points at thirty-six months, according to a scale that assigned 1 point for a normal knee, 2 points for a nearly normal knee, and 3 points for an abnormal knee. The score for performance, as assessed with the one-leg-hop test, continued to improve with time, increasing from an average of 90 per cent of that of the uninvolved limb at six months to an average of 94 per cent at twelve months. All nine patients who completed the study stated that they had had improvement and that they would have the procedure again if the circumstances were similar.

Radiographs, made with the patient standing, demonstrated no major change in the height of the joint space thirty-six months postoperatively compared with the height preoperatively.

The magnetic resonance images were evaluated by two independent radiologists. The sequential magnetic resonance images revealed progressive changes over time, indicating ongoing ingrowth and regeneration of tissue (Figs. 6-A and 6-B). There was increased signal intensity of this newly regenerated tissue, which is suggestive of maturation of tissue over time. A small amount of joint fluid was noted in all patients, but this fluid was interpreted to be within physiological limits. Furthermore, the interface between the remaining host meniscal rim and the implant-regenerated tissue complex became less distinct at each interval. This finding is another indication of the ingrowth and regeneration of new tissue with properties on imaging similar to those of a normal meniscus.

View larger version (120K): [in this window] [in a new window]   Fig. 6-A Magnetic resonance image of a meniscal lesion (arrow) six months after placement of the collagen meniscal implant.

View larger version (135K): [in this window] [in a new window]   Fig. 6-B Magnetic resonance image of a meniscal lesion (arrow) twelve months after placement of the collagen meniscal implant.

View larger version (74K): [in this window] [in a new window]   Fig. 7-A Intraoperative photograph of a meniscal lesion before and after placement of the collagen meniscal implant.

View larger version (101K): [in this window] [in a new window]   Fig. 7-B Photograph of a meniscal lesion, made at second-look arthroscopy, six months after placement of the collagen meniscal implant.

View larger version (90K): [in this window] [in a new window]   Fig. 8 Histological appearance of regenerated tissue (arrow) six months after placement of the collagen meniscal implant.

	Discussion

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We used a collagen scaffold to support the regeneration of meniscal tissue. In vitro studies have confirmed that porous collagen matrices can support cellular ingrowth and new matrix synthesis^6,10,16. On the basis of previous studies of animals, we concluded that a slowly resorbable regeneration template will support substantial meniscal regeneration in the canine stifle^25,26. This finding was consistent with those in previous reports of collagen matrices acting as templates for the growth of fibrous tissue^{6,10,16,35,36}. In those studies, the regenerated fibrocartilage that formed had a gross, histological, and biochemical appearance that was similar to that of normal canine meniscal cartilage. Therefore, a human clinical feasibility trial was designed.

In this initial clinical trial, the regenerated fibrocartilaginous tissue seemed to be similar, in gross and histological appearance, to meniscal cartilage. This observation is consistent with the meniscal regeneration that has been documented after meniscectomy^3,7,13,20. Additionally, the ability of fibrochondrocytes to grow into the preformed collagen structure is consistent with observations made by Arnoczky et al.^4,5. The collagen meniscal implant appears to support regeneration even in the inner portions of the meniscus. It does not appear to be rejected, and it is resorbed over time. The patients had subjective and objective improvement similar to that following meniscectomy. A prospective, controlled study is currently underway to provide accurate comparisons. However, certain limitations and questions remain. In the current investigation, we studied partial lesions rather than complete meniscectomies. The inner borders of the lesions were avascular and thinner than the periphery. Bonding of the implant to these edges with use of sutures alone is more difficult than bonding to the thicker vascular periphery and may leave the implant unstable in the early postoperative period. Although a six-week program of partial weight-bearing was used in this study, a longer period of postoperative protection may be needed for less stable implants. It is unknown whether the use of a growth-stimulating factor or other biochemical modulators to speed growth of tissue into the implant would be helpful.

Transient initial effusions that resolved spontaneously were noted in seven patients. Whether these effusions were due to normal postoperative activity or were the result of brief showers of particles from the collagen implant are unknown. There did not appear to be any consequences from the effusions during the course of the study. No evidence of the etiology was detected serologically or at the time of the second-look arthroscopy.

Although this investigation was not designed as an efficacy study, the patients have agreed to be followed over the years with various examinations to determine if the regenerated meniscus is able to survive, to endure progressive loading, and ultimately to protect the joint surfaces. Since the goal of the study was to assess the implantability, safety, and tissue ingrowth of the implant, no effort was made to compare this technique with meniscectomy, repair, use of allograft, or no treatment. Such evaluations are currently underway in controlled studies.

This study confirms that human meniscal cartilage-like tissue will grow into a resorbable collagen template if given an appropriate environment in which to do so. The collagen scaffold appears to be safe for three years, implantable, and able to support tissue ingrowth.

NOTE: The authors acknowledge the contributions of Ann W. Walgenbach, R.N.N.P., Joel Richnak, and Steven Irving to the clinical study.

	Footnotes

 
*One or more of the authors has received or will receive benefits for personal or professional use from a commercial party related directly or indirectly to the subject of this article. Funds were received in total or partial support of the research or clinical study presented in this article. The funding source was ReGen Biologics, Redwood City, California.

The Stone Clinic, 3727 Buchanan Street, San Francisco, California 94123. Please address requests for reprints to Dr. Stone. E-mail address: kstonemd@stoneclinic.com.

The Steadman-Hawkins Sports Medicine Foundation, 181 West Meadow Drive, Vail, Colorado 81657.

ReGen Biologics, 545 Penobscott Drive, Redwood City, California 94063.

	References

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