evaluation of porcine small intestinal submucosa in achilles tendon repair

The Journal of Applied Research • Vol. 5, No. 1, 2005 115

Evaluation of Porcine SmallIntestinal Submucosa in AchillesTendon RepairFernando H. Greca, MD, PhDEduardo J. B. Ramos, MD, PhDVanessa C. Dallolmo, MDAntonio P. G. Silva, MDWilson H. Mima, MDLuciano Okawa, MDTiago G. Alencar, MD

Surgical Laboratory, Catholic University of Parana and Department of Surgery, FederalUniversity of Parana, Curitiba, Brazil

and histological analysis, includinginflammatory and foreign body reac-tions, fibroblastic proliferation and col-lagen densitometry were performed.Data were analyzed using t test.

Results: In SIS versus control, presenceof infection, dehiscence, incorporationand adhesions were not different (P <0.05). The mean rupture strength in SISversus control was not different (68.5 Nvs 61.3 N). In SIS there was a predomi-nantly chronic inflammatory reactionwith presence of fibroblasts and foreignbody reaction was evident in 41%. InSIS versus control, densitometryshowed a similar amount of mature(88.9 vs 93.3%) and immature (11.1 vs6.7%) collagen.

Conclusion: These data indicate thatSIS when assessed using clinical, histo-logical and tensiometric indices, can beused to repair Achilles tendon defect.

INTRODUCTIONThe Achilles tendon is essential for nor-mal ankle joint movement and particu-larly critical for activities like running

KEY WO R D S : Achilles tendon, s m a l lintestinal submucosa, t e n s i o m e t r y,collagen densitometry

ABSTRACT Background: Tendon defects remain amajor concern in orthopedic surgerybecause of the limited availability oftendon autografts. Since the extracellu-lar collagen-based matrix derived fromporcine small intestinal submucosa (SIS)has been successfully used in repair ofmany tissues, such as abdominal wall,vessels and bladder, we hypothesizedthat SIS can be used to repair an experi-mentally induced Achilles tendon defect.

Material and Methods: Seventeen NewZealand rabbits were submitted toAchilles tendon resection (1.5 cmlength) in the right posterior limb andthis defect was repaired with SIS. Theleft Achilles tendon (sham operated)was used as a control. Daily examinationwas performed for 30 days. On the dayof sacrifice, Achilles tendon from bothlimbs was excised and signs of infection,dehiscence, incorporation and degree ofadhesion were evaluated. Tensiometry,

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or stair climbing. The best method oftreatment for acute closed ruptures ofthe Achilles tendon is controversial, withadvocates of operative treatment recom-mending early surgical repair and advo-cates of non-operative treatmentpreferring cast immobilization.Currently, ruptured Achilles tendons aremost often operatively treated.Operative treatment is associated withshorter period of disability and low fre-quency of re-ruptures, although it isassociated with potential wound compli-cations, which occur in approximately7.5% of cases.1,2 Because of differencesin rehabilitation protocols, it is stillunclear whether differences betweensurgical and non-surgical treatment havea better outcome. Modern concepts ofnon-operative treatment have beenshown to produce good results withacceptable complication rates.3,4 Therupture rate of non-surgical treatmentvaries from 0% to 17%,4,5 with averageof 12.1%, whereas the re-rupture ratefrom surgical repair is only 2.2%.6

However, loss of Achilles tendonposes a difficult reconstructive problem.A successful reconstruction must havethe appropriate strength, durability, andtension to meet the dynamic workload.The lack of suitable local tissue at thissite makes the task even more difficult.Various innovative procedures havebeen used, including fascia lata auto-grafts,7 antero-lateral thigh free flap,8latissimus dorsi muscle,9 fasciocutaneousinfragluteal flap,10 and marlex mesh.11

Although various local flaps and freeflaps have been described for recon-struction of Achilles tendon, it is not aprocedure free of complication. There isa need for a biomaterial capable ofAchilles tendon reconstruction and pos-sibly, allowing complete tendon regeneration.

Porcine small intestinal submucosa(SIS) is an acellular resorbable biomate-rial that can serve as scaffolding for new

tissue growth. It has been used experi-mentally in animals as vascular grafts,12

abdominal wall repairs,13,14 and for blad-der15 and esophagus reconstruction.16 Inorthopedic surgery, SIS has been suc-cessfully used to regenerate fascialdefects,17 ligaments,18 and tendons.19

The aim of this study was to deter-mine the efficacy of SIS in Achilles ten-don repair. We hypothesis that porcineSIS can be used in repair experimentallyinduced Achilles tendon defect. SISinduces a gross and histological appear-ance and mechanical strength similar tothat of the contralateral sham-operatedtendon over a period of 30 days.

MATERIAL AND METHODSThe study was approved by theCommittee for the Humane Use ofAnimals at Catholic University ofParana and was in accordance withguidelines established by the ethicalprinciples in use of experimental animals.20

Preoperative Procedures Seventeen New Zealand male rabbits(Tecpar, Curitiba, Brazil) with meanweight of 3296 ± 246 g, were kept instandard rabbit cages (85 x 64 x 68 cm)and acclimated for one week to the con-stant study environmental conditions: 12to 12 hour light-dark cycle (lights on at06:00), 25 ± 4°C room temperature, and45% humidity. The rabbits were allowedad libitum diets and municipal tapwater. Prior to operation, rabbits werefood deprived for 12 hours.

Anesthesia Rabbits were anesthetized with keta-mine and acepromazine mixture (150:5mg/mL) via intramuscular injection (0.8mL/kg) to obtain effective anesthesia.Inhalation anesthesia with Isoflurane(Baxter Caribe Inc, Guayama, PuertoRico) in oxygen, was used to maintainanesthesia during the surgical proce-

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dures. Buprenorphine hydrochloride(Medley Pharmaceutics, Campinas,Brazil) 0.05 mg/kg was given twice a dayto all postoperative rabbits for threedays as analgesic therapy.

Preparation of Small IntestinalSubmucosa (SIS) A segment of proximal jejunum wasobtained following a midline incision ina porcine cadaver, within 2 hours ofdonor pig euthanasia, as previouslydescribed.21 The proximal jejunum waswrapped in surgical sponges that weresoaked in physiologic saline solution. Allmesenteric tissues were removed andthe segment of jejunum was everted.The tunica mucosa was removed using alongitudinal wiping motion with ascalpel handle and moistened gauze. Thesegment was returned to original orien-tation and the tunica serosa and tunicamuscularis were removed from theintestine by similar method. The remain-ing thin, whitish, translucent tube con-sisted of the tunica submucosa withattached stratum compactum and mus-cularis mucosa of the tunica mucosa.22

The SIS was rinsed in sterile normalsaline and refrigerated and stored for 1to 10 days in neomycin sulfate 10%(Medley Pharmaceutics, Campinas,Brazil). Single ply SIS is an anisotropicmaterial exhibiting grater hoop strengththan longitudinal strength. Therefore, toproduce and isotropic configuration ofsufficient mechanical strength, each SISimplant consisted of 4 individual sheetsof SIS.

Surgical ProcedureBoth back limbs were prepared foraseptic surgery. Their limbs were shavedand prepared with Betadine solution(Rimed, Sao Paulo, Brazil), a 5 cm inci-sion was performed in both limbs andthe Achilles tendon complex was dis-sected free from the surrounding tissues.The peri-tendon was split longitudinally

and the Achilles tendon was exposed,and a segment of 1.5 cm was excisedbetween its musculotendinous junctionand the bone insertion. A 1.5 cm SISimplant was used to replace the resectedtendon. Nonabsorbable sutures of 5-0polypropylene (Ethicon, Cincinnati,Ohio) were passed through both SISimplant and remaining tendon. The peri-tendon was closed with 6-0 polypropy-lene running sutures and the skin wasclosed with 3-0 nylon (Ethicon,Cincinnati, Ohio). For the sham opera-tion, the contralateral back limb wasincised, the Achilles tendon was exposedand manipulated for the same durationrequired in the repair procedure.Thereafter the surgery site was closed inlayers.

Postoperative Procedures After recovery, all animals were individ-ually housed and allowed free move-ment. No post-operative bandages wereused. During the post-operative time,clinical parameters including appetite,activity, infection, bleeding and wounddehiscence were devaluated daily. All ofthe animals were euthanized 30 daysafter the surgical procedures using anoverdose of pentobarbital (MedleyPharmaceutics, Campinas, Brazil). Onthe day of sacrifice, Achilles tendonfrom both limbs was excised and signs ofinfection, dehiscence, incorporation, anddegree of adhesion were evaluated.Tendons were harvested en bloc fromjust proximal to the adjacent musculo-tendinous junction to the bone insertion,and immediately submitted to tensio-metric evaluation.

Tensiometric Evaluation Mechanical evaluation was performedwith a tensiometric testing machine(EMIC, Sao Paulo, Brazil). The proximalend was scraped with a blunt scalpel toremove all muscle tissue. The tendonfibers were spread out in a fan-like



shape, sandwiched between two piecesof sandpaper (1.0 x 1.0 cm) and tightlyfixed in a metal clamp. The tendon waspulled with a constant speed of 1mm/sec until failure. Peak tendon loadat failure was automatically calculated.

Histologic Evaluation Tendons were fixed in 10% bufferedformaldehyde and prepared for histolog-ic evaluation. The specimens wereembedded in paraffin and 5-µm thicklongitudinal sections were taken every0.3 mm through the specimens andstained with hematoxylin and eosin andsirius-red techniques.

Collagen Densitometry Sirius red is a simple, sensitive, andquantitative procedure for the measure-ment of collagen and protein content intissue sections.23 Briefly, Sirius red stain-ing is based on the selective binding ofSirius red F3BA and Fast green FCF tocollagen components, when the sectionsare stained with both dyes dissolved inaqueous saturated picric acid. Thepicrosirius staining permits the quantifi-cation of mature and immaturecollagen.24,25 Mature collagen type Ifibers presents in yellow, orange, andred, while immature collagen type IIIappears in green26. The microscopicfields were taken from the midportionsof the tendon, using polarized light. Thesampling fields were digitized to a com-puter database via a polarization micro-scope (Leitz-Ortholux, Wetzlar,Germany), through a 200x objectivelens, coupled to a high-resolution colorcamera (Sony CCD, Tokyo, Japan).Images were captured using the digitalcamera that interfaced with an IBM-compatible Pentium computer (Everex,Freemont, Calif). The digitized samplefields were analyzed using Optimas 5.2image analysis software (Optimas Inc.,Edmonds, Wash), as previouslydescribed.27

RESULTSComplicationsOne rabbit showed a minor wound infec-tion that was locally treated and one rab-bit had dehiscence of the graft at day 4,which was evidenced by palpation of thesurgical site. This animal was not used intensiometric evaluation. Local abscesswas present in one rabbit. No complica-tions were noted in the sham-operatedl i m b. The remaining rabbits showed nor-mal activity and appetite, and there wasno evidence of clinical complicationssuch as local infection or wound dehis-c e n c e. In all rabbits, the skin was freelymovable across the implant site.

Pathologic EvaluationGross Evaluation: A thick scar of thegraft and a thin portion of the tendonproximally and distally to the graft waseasily palpable on clinical examination.By visual inspection, the graft was slight-ly thicker compared with the sham-oper-ated tendon (Figure 1); however, thelimits between the graft and the nativetendon were difficult to determine, withgood continuity and solid integration.

Histologic Evaluation: Histologically, theinflammatory response was semiquanti-tatively evaluated (Table). There was anacute inflammatory response in 5 of the12 grafts (29%). Foreign body reaction

Figure 1. Sham-operated tendon and SIS, 30days after surgical procedure.



represented by mononuclearmacrophages was present next to thesuture lines. The graft was essentiallycomposed of an abundant, laminated,and organized collagenous extracellularmatrix (Figure 2). Parallel collagenfibers were oriented along the longitudi-nal axes of the tendon. Fibroblasts weredistributed between the collagen fibers.The collagen fiber disposition was simi-lar to that of normal tendons. A moder-ately dense, regular collagenousconnective tissue was noted across theentire thickness of the graft. The SIS wasalso well integrated to the native tendonand no evidence of separation wasnoted. Histologic examination showedno signs of cartilage or bone formationwithin the tendon. Remnants of the orig-inal SIS was identified, but not quanti-fied. Collagen densitometry showed nostatistical significance between SIS andsham operated tendon, regarding theamount of mature type I (88.90% vs93.34%, respectively), and immature

type III collagen (11.10% vs 6.87%,respectively), as shown in Figure 3.

Tensiometric Evaluation The mean failure loads of SIS was 68.53N and in the sham operated tendons was61.34 N, which was not statistically dif-ferent. All of the sham operated Achillestendons ruptured in the proximal10 anddistal part of the tendon.6 Thirteen ofthe 16 SIS grafts failed in the proximalpart of the tendon and the remainingthree in the middle part. The tendon cal-lus was the weakest point in three SISgrafts.

DISCUSSIONLoss of Achilles tendon is a difficultreconstructive problem because of thelimited availability of tendon autografts.A successful reconstruction must havethe appropriate strength, durability andtension to meet the dynamic workload.Various procedures have been used;however, local flaps and free flaps are

Table. Semiquantitative Analyses of Inflammatory Response*

Rabbits Acute Inflammatory Response Chronic Inflammatory Response1 - +2 - +3 ++ +++4 - ++5 - ++6 - ++7 ++ +++8 - ++9 - ++10 +++ +++11 - +12 - +++13 - +14 - +15 - +16 ++ +++17 + +++

* - indicates absence; +, mild; ++, moderate; and +++, severe.



not procedures free of complication. Wetested the use of SIS in the repair ofexperimentally induced Achilles tendondefect. Results of this study suggest that,in a rabbit model, SIS can be used as atissue-engineered replacement of aresected Achilles tendon. The SIS graftmaintained sufficient strength, whileserving as a temporary scaffold for hosttissue ingrowth and remodeling.Furthermore, SIS graft was not associat-ed with significant presence of infection,wound and graft dehiscence and showeda good incorporation with the adjacent

tendon. Collagen densitometry showed asimilar amount of mature and immaturecollagen, when compared to sham oper-ated tendons.

Porcine small intestinal submucosa(SIS) is a 0.1-mm thick laminar materialcomposed of more than 90% protein(essentially collagen), less than 10%lipids and traces of carbohydrates.Components of the SIS are collagen (I,III, IV, V, and VI), fibronectin, laminin,glycoprotein and growth factors.28 Thiscollagenous resorbable material hasbeen successfully used as an autograft,

Figure 3. Collagen densitometry in sham operated tendon and SIS graft. Figure 3A shows aSham operated tendon. Figure 3B shows SIS. Mature collagen fibers type I presents in yellow,orange, and red, while immature collagen type III appears in green (200x).

Figure 2. Histologic evaluation. Figure 2A shows Sham operated tendon. Figure 2B shows SIS. InFigure 2A, the Achilles tendon is covered by a thin peri-tendon later in sham operated tendon(50x). In Figure 2B, a moderately dense, regular collagenous and connective tissue next to thenative tendon (arrow) was noted across the entire thickness of the graft (100x).

A B



allograft, and xenograft in many organsand tissues in animal models. Studieshave demonstrated that after implanta-tion, this biomaterial induces a site-spe-cific remodeling of various connectivetissues, supporting host tissue ingrowth,and appears to promote cellular differ-entiation. The regenerative process leadsto a tissue structurally and functionallysimilar to the original tissue and the col-lagenous connective tissue is analogousto scar tissue that occurs in most parts ofthe body.17,18,19 Other significant featuresof SIS have been identified: capillarygrowth into the tissue maintaining graftviability and permitting the diffusion ofoxygen and other nutrients to the vascu-lar tissue, conferring resistance to infec-tion,21 and no signs of rejection havebeen described.22,29

Two other authors have describedthe use of porcine SIS as a graft materialin Achilles tendon repair. Badylak et al19

created a 1.5 cm segmental defect of theAchilles tendon in twenty dogs, andreplaced it with SIS. The neotendonswere evaluated at 1, 2, 4, 8, 12, 16 and 48weeks and four dogs were euthanized ineach time point. Four additional dogswere submitted to 1.5 cm segmentalAchilles tendon defect and were surgi-cally repaired with the same tendon thatwas resected. They showed that the SISremodeled neotendons were strongerthan the sham operated tendons and thehistological evaluation consisted oforganized collagen similar to the normaltendons. This is in accordance to ourfindings. Of the four dogs in which theSIS was not implanted, inferior strengthwas observed compared to SIS implants.Gu et al30 removed part of the Achillestendon in 20 rabbits and substitutedporcine SIS, using the contralateral limbas control. As in Badylak et al, four rab-bits were evaluated at each euthanasiapoint, 1, 4, 8, 12 and 16 weeks after sur-gery. The differences of maximum loadat 4 weeks after surgery was inferior in

SIS regenerated tendons compared tosham operated limbs, and after 8 weeksno differences were observed. Changesin physical characteristics of the SISover time is an important consideration,however the number of animals tested30 days after the implants in both stud-ies was small, motivating us to use alarge number of animals. In our studywe evaluated the specimens 30 daysafter surgery and this period was suffi-cient to maintain strength compared tosham operated Achilles tendon.

Histologically, there was an acuteinflammatory response in 5 of the 12grafts because the analyses were per-formed a short period of time after thesurgical procedure. However, signs ofchronic inflammation were observed inall of the SIS implants and abundant,laminated and organized collagenousextracellular matrix was noted. The par-allel collagen fibers were oriented alongthe longitudinal axes of the tendon andthis is in accordance with previous studies.

SIS and collagen biomaterials canpromote calcification.31,32 Histologicalexamination showed no signs of carti-lage or bone formation within the ten-don in all of the specimens evaluated.This can be explained because the histo-logical analyses was performed 30 daysafter the surgery and the rabbits wereallowed free movement after the surgi-cal procedures. Tendon mobilization hasbeen shown to accelerate the healingprocess whereas immobilization wasshown to impair healing. The earlymechanical stimulation of the tendoncallus would probably minimize the riskof bone formation.33,34

Biomechanical and histologic com-parisons between ruptured and intacttendons in rabbits have shown a colla-gen content in transected tendonsamounting to 80% of the controls andcollagen cross-linking (measured by thehydroxy-pyridinium content) amounting



to 60% of the intact tendon controls.35

In the present study, collagen densitom-etry showed no statistical significancebetween SIS and sham operated tendon,regarding the amount of mature andimmature collagen. It was impressivehow fast the healing tendon regainedstrength and stiffness.

CONCLUSION Small intestinal submucosa may serve asa structural framework for the applica-tion of tissue engineering technologiesin the development of the ideal Achillestendon reconstruction material. Thepresent study should be considered apromising preliminary finding in thesearch for alternatives to Achilles ten-don repair.

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evaluation of porcine small intestinal submucosa in achilles tendon repair

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