biology and biomechanics - university of...

Biology and biomechanicsVolker Musahl, MD, Alexander Lehner, MD, Yasuhiko Watanabe, MD, andFreddie H. Fu, MD, DSc. (Hon), DPs (Hon)

Increased participation by the general population in athleticactivities leads to increased trauma to bones, joint surfaces,and soft tissues. Management and treatment of these injurieshas significantly improved over the past few decades. Theapplication of knowledge gained from basic science researchin biology and biomechanics has continuously contributed tothat. Biological advances have been made in the field of genetherapy, cell therapy, and tissue engineering. Certainly, thegreatest focus is bone and cartilage research that will lead toimproved fracture repair in the traumatic injured population, aswell as prevention of early osteoarthritic changes in the injuredathletic population. In biomechanical research, contributionshave been made to further understand kinematic behavior ofjoints that will lead to improved ligament reconstructiontechniques and rehabilitation regimens. Various fixationtechniques and several different ligament reconstructiontechniques have been studied and validated. In the future,improved understanding of ligament healing, graftincorporation, and revascularization will lead to improvedoutcome of surgical reconstruction techniques in orthopaedicsports medicine. Exciting research has been performed overthe past years and will be reviewed in this article. Curr Opin

Rheumatol 2002, 14:127–133 © 2002 Lippincott Williams & Wilkins, Inc.

With the general population’s increasing participation inathletic activities, the incidence of trauma to bones, jointsurfaces, and soft tissues is also increasing. Epidemio-logic studies from the early 1990s investigated the inci-dence of knee ligament injuries in the United States.The average rate of knee ligament injuries was approxi-mately 100/100,000 of the population annually [1] andcan be expected to increase. Management of these inju-ries involves conservative treatment in combination withthe sophistication of rehabilitation regimens and opera-tive treatment, extending from diagnostic procedures tocombined ligament and transplantation surgeries [2–5].Treatment of these injuries has significantly improvedover the past few decades, with the application of knowl-edge gained from both basic science and clinical research[6–15]. This article will review biologic and biomechan-ical aspects in sports traumatology and will summarizethe latest basic science knowledge in biology and bio-mechanics in this field.

BiologyIn ligament reconstruction surgeries, commonly usedtendon grafts undergo biologic modifications before theyform the final strong fibrous tissue. In the beginning, thegraft undergoes inflammation and (partial) necrosis. Thegraft then undergoes revascularization and repopulationwith fibroblasts. The last stage is marked by a gradualremodeling of the graft and continuous modification ofits collagenous structure [16,17]. There is evidence thatautograft as well as allograft transplants are repopulatedwith extrinsic fibroblasts within 4 weeks [18]. After 4 to6 weeks, the graft is completely repopulated. Donor fi-broblasts undergo cell death and are not detectablethereafter. The tendon structure, however, serves as atemplate for soft tissue remodeling [19,20].

Taking the anterior cruciate ligament (ACL) as an ex-ample, normal insertion site anatomy has a specific ar-rangement of collagen fibers, fibroblasts, fibrochondro-blasts, and osteoblasts forming a direct ligamentinsertion, which consists of four layers. The first layercomprises the ligament, the second layer is characterizedas a nonmineralized cartilage zone containing fibrocarti-laginous cells, the third layer is the mineralized cartilagezone, where the mineralized cartilage inserts into thesubchondral bone plate, the fourth layer, to which theligament is attached (Fig. 1). The design of this complexinsertion site allows for distribution of longitudinal andshear forces from the ligament into the subchondral bone

Department of Orthopedic Surgery, University of Pittsburgh School of Medicine,Pittsburgh Pennsylvania, USA.

Correspondence to Freddie H. Fu, MD, Chairman and David Silver Professor,Department of Orthopedic Surgery, University of Pittsburgh School of Medicine,Kaufmann Bldg., Suite 1010, 3471 Fifth Avenue, Pittsburgh, PA 15213, USA;e-mail: [email protected]

Current Opinion in Rheumatology 2002, 14:127–133

Abbreviations

ACL anterior cruciate ligamentBMP-2 bone morphogenic protein-2BMP-7 osteogenic protein-1IGF-I insulinlike growth factor-ILMP-1 LIM mineralization protein-1MCL medial collateral ligamentPCL posterior cruciate ligamentSIS small intestinal submucosaTGF-� transforming growth factor beta

ISSN 1040–8711 © 2002 Lippincott Williams & Wilkins, Inc.

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plate, thus minimizing stress on single collagen bundles[21]. This complex anatomy, however, is not restored byconventional ACL-transplantations within the first 6month after graft implantation.

Various growth factors have been identified to affect thehealing process in tissues of the musculoskeletal system[22]. Growth factors are small peptides that can be syn-thesized both by the resident cells at the injury site (eg,fibroblasts, endothelial cells, mesenchymal stem cells)and by the infiltrating reparatory or inflammatory cells(eg, platelets, macrophages, monocytes). They are ca-pable of stimulating cell proliferation, migration, and dif-ferentiation as well as the matrix synthesis [23,24].Meanwhile, the stimulating effect of various growth fac-tors in different tissues has been demonstrated [25–27].The gene encoding for most of the known growth factorshas been determined, and using the recombinants DNAtechnology, we are now able to produce large quantitiesof these recombinant proteins for treatment.

Recent literature in growth factor research has focusedon enhancing bone healing and improving cartilage re-generation. Boden et al., who are focusing on lumbarspine arthrodesis, have developed an animal model tostudy nonunion rates in spine fusion. With the discoveryof an osteoinductive protein, LIM mineralization pro-tein-1 (LMP-1), adenoviral delivery of LMP-1 compli-mentary DNA (cDNA) to the spine in immune-competent rabbits could be achieved [28–30••]. Severalstudies on long bone healing have been performed.Bouxsein et al. developed an ulnar osteotomy model inthe rabbit and indicated that recombinant human bonemorphogenic protein-2 (BMP-2) is capable of enhancinghealing [31]. In a prospective randomized clinical trial, itwas shown that recombinant osteogenic protein-1 (BMP-7) that was implanted with a type I collagen layer was a

safe and effective treatment for tibial nonunions [32]. Incartilage research, the effect of growth factor applicationto chondrocytes has been shown to be feasible by severalgroups. Bonassar et al. recently studied the effect of dy-namic compression on the response of cartilage to insu-lin-like growth factor-I (IGF-I) and found that when ap-plied together, the two stimuli enhanced protein andproteoglycan synthesis by 180% and 290% [33]. Trans-forming growth factor beta (TGF-�) was found to stim-ulate the production of elastic cartilage in a porcinemodel [34].

Despite the fact that these approaches have been ca-pable of improving the local persistence of the growthfactor proteins, the results of these delivery techniquesremain limited. Gene therapy is a technique that relieson the delivery of therapeutic genes into cells and tis-sues. Originally, gene therapy was conceived for the ma-nipulation of germ-line cells for the treatment of inher-itable genetic disorders, however this method is limitedby inefficient technology and considerable ethical con-cerns. Gene therapy can be applied to orthopaedic sur-gery by transferring defined genes encoded for growthfactors or antibiotics into a target tissue (eg, ligament,cartilage, or bone). Thus, local cells at the injury site canpersistently produce therapeutic substances. For geneexpression, the transferred DNA material has to enterthe nucleus, where it either integrates into the chromo-somes of the host cells or remains episomal. After tran-scription, the generated messenger ribonucleic acid(mRNA) is then transported outside the nucleus, servingas a matrix for the production of proteins (eg, growthfactors) in the ribosomes (Fig. 2). Consequently, thetransduced cells become a reservoir of secreting growthfactors and cytokines capable of improving the healingprocess. Viral (eg, adenovirus, retrovirus) and nonviral (eg,

Figure 1. Direct anterior cruciate ligament insertion

The histology of a direct anterior cruciate ligament insertion is shown (left). The schematic is also detailed (right). Adapted with permission [9].

128 Sports-related injuries

liposomes, gene gun) vectors can be used for delivery ofgeneric material into cells [35,36].

The structural and functional relation in healing liga-ments is complex; the collagen fiber diameter and ori-entation is altered, in addition to collagen type ratios andcross-links [15,37–42]. The water content in healing liga-ments is higher with increased vascularity. Altering thewater content, however, was shown to affect prestressand creep behavior of ligaments [43]. In a study by Na-kamura et al., the functional healing of a ligament in arabbit model could be improved by decorin antisensegene therapy [44•]. It was furthermore shown that theengineering of healing ligaments seems to be possible bysupplying mechanical stimuli in vitro, such as cyclicstretching of fibroblasts on grooved surfaces [45], hydro-static compression, or cyclic tension [46].

Tissue engineering-based approaches aim at using cellsto deliver genes. These technologies might offer addi-tional opportunities to improve the healing process [47].Several different origin tissues have been investigated(eg, mesenchymal stem cells, muscle derived stem cell,dermal fibroblasts, or human adipose tissue) [48–50]. Se-lecting the appropriate gene delivery procedure dependsupon various factors such as the division rate of the targetcells, pathophysiology of the disorder, and the accessi-bility of the target tissues. Preparing muscle-derivedstem cells by transduction with an adenovirus containingBMP-2 cDNA, Lee et al. were able to heal a critical sizedbone defect in mice [51••]. Scaffolding materials wereused to study the in vitro behavior of cells and in vivothey were used to repair tissues. Canine chondrocyteswere shown to be viable when seeded on collagen ma-trices [52]. Murray et al. were able to show that humanACL fibroblasts migrated into a collagen-glycos-aminoglycan scaffold to bridge a gap between transected

ACL fascicles in vitro [53•]. Small intestinal submucosa(SIS) was used for repair of various musculoskeletal tis-sues [54,55]. Dejardin et al. replaced a resected infraspi-natus tendon with SIS in a dog model and found similarstructural properties in a sham operated control [56•].

BiomechanicsThe knee is a complex structure that involves the inter-action of stabilizing ligaments and muscle-force generat-ing tendons to provide locomotive, static, and dynamicfunctions. These motions are combinations of 3D trans-lations and rotations that are mediated by ligamentforces, joint contact forces, externally applied forces, andmusculoskeletal forces. Thereby, the tensile behavior ofligaments is suited to guide joint motion and providestability over a large range of motion. The disruption ofany of the major components of the knee causes abnor-mal kinematics and therefore osteoarthritis, over time.For disruption of the ACL, anterior tibial translation willbe increased [57], internal and valgus rotations will beincreased, especially when the medial collateral ligament(MCL) is disrupted [58,59]. Progressing osteoarthritis ofthe knee joint is a combination of biologic transforma-tions [60] and biomechanical dysfunction, evidenced bymeniscal damage, increased ligamentous laxity, and ar-ticular cartilage degeneration [61–65].

The kinetic response of a joint to internal and externalloads is governed by bone geometry and the anatomiclocation, morphology, and chemical composition of thetissues within and around the joint. The transfer of loadthrough a ligament must be considered to better under-stand its contribution to joint kinematics. Physiologi-cally, bone-ligament complexes have been designed totransfer load along the longitudinal direction of the liga-ment. The structural properties of a bone-ligament-bone

Figure 2. Gene transfer using a viral vector

DNA coding forgrowth factor

Growth factor releasedfrom cell

Ribosomes makinggrowth factors

NucleusCell

Viralvector carryinggrowth factorgene

The schematic of a gene transfer using a viral vector isshown. Adapted with permission [96].

Biology and biomechanics Musahl et al. 129

complex include stiffness, ultimate load, ultimate elon-gation, and energy absorbed at failure. Mechanical prop-erties of the ligament substance are obtained by normal-izing the force by the cross-sectional area of the ligament.The change in elongation by the initial length of a de-fined region of the ligament midsubstance is defined asstress and strain, respectively [66,67]. From the stress-strain curve, the elastic modulus, ultimate tensilestrength, ultimate strain, and strain energy density of theligament substance can be determined [15]. Individual

units of the ACL yielded an average modulus and ulti-mate tensile strength of 278 MPa and 35 MPa, respec-tively [68].

The in situ force of the knee is an experimentally mea-sured quantity that represents forces existing in the kneeat a given position. Various devices, such as buckle trans-ducers [69,70], implantable force and pressure transduc-ers, load cells [71,72], and universal force moment sen-sors in combination with a 6-degree of freedom robotic

Figure 3. Future direction of muscle cell-derived gene therapy

The future direction of muscle cell-derived gene therapy is shown. Adapted with permission [95].


manipulator [73–75] have been used to determine thein situ forces and in situ strains in ligaments. Forces anddistributions in both the anteromedial (AM) and the pos-terolateral (PL) bundle of the ACL have been quantifiedduring the anterior drawer test, Lachman test and simu-lated pivot shift test using human cadaveric knee speci-mens [76,77].

Woo et al. studied two popular grafts for ACL reconstruc-tion, quadruple semitendinosus/gracilis and B-PT-B[78]. Both were found to have little improvement overthe ACL deficient knee when rotational loads were ap-plied. An anatomic reconstruction replacing the AM andPL bundles resulted in knee kinematics significantlycloser to those in the intact ACL compared with conven-tional reconstruction procedures [79]. Additionally, thein situ forces in the anatomic reconstruction were sub-stantially closer to those of the intact ACL comparedwhen the knee was subjected to both the Lachman andsimulated pivot shift tests [80•] . The forces in the me-dial meniscus were shown to increase twofold in re-sponse to ACL transection in a human cadaveric kneemodel [81]. Likewise, Hollis et al. studied the meniscalstrain in ACL transected human cadaveric knees andreported significant increases. After ACL reconstructionthey observed meniscal strain similar to that detected inACL intact knees [82]. In a long-term follow-up study,Beynnon et al. reported that the elongation of an ACLgraft during surgery significantly increases the anteriortibial translation when graft elongation values producedby knee flexion were outside the limits of the nativeACL [83•].

For the posterior cruciate ligament (PCL), double-bundle reconstructions were studied and found to befavorable to single bundle reconstructions [84,85]. Berg-feld et al. studied two different PCL reconstruction tech-niques and found that a posterior inlay techniqueshowed significantly less mechanical degradation than anarthroscopic-assisted tunnel technique [86]. Fixation ofthe PCL graft at full extension was found to over-constrain the knee and elevate the in situ graft forces,whereas fixation with the knee in flexion and under ananterior tibial load was found to restore the intact kneemore closely [87]. The forces in the PCL were found toincrease and the forces in the ACL were found to de-crease in response to hamstring muscle loads [88,89].

Technical considerations for ACL reconstruction wererecently studied in biomechanical investigations. Con-troversies still exist whether to use grafts with one or twobone plugs (patellar, quadriceps, Achilles tendon) or softtissue grafts (hamstring tendons). The length and size of(bio)interference screws [90,91] and the insertiontorque[92] were found to be indicators of graft fixationstrength. Fleming et al. developed a goat model to studythe relation between pretension of an ACL graft andanterior tibial translation. A tension of 60 N, applied at a

knee flexion angle of 30° was thereby the best combi-nation for restoring anterior tibial translation [93]. In an-other study on pretensioning grafts, a dog model wasdeveloped to study the effect of placing a pretensionedgraft across open growth plates. Significant deformity ofboth the femur and tibia was observed in the treatedlimbs [94].

Future directionsIn the future, gene therapy, cell therapy, and tissue en-gineering will be the available biologic tools. Therapeu-tic genes, encoding growth factors such as BMP-2 andTGF-� can be delivered into cells and tissues. Further-more, improvement of biologic incorporation of replace-ment grafts will lead to better insertion site healing aswell as faster ingrowth of graft materials. Gene-based celltherapy, relying on the ability of mesenchymal stem cells(eg, from blood, fat, bone marrow, muscle) to divide intoa variety of cell types, may enable simple biopsies toprovide the cell that can restore any kind of defect bygrowing the local cell line (Fig. 3). However, extensiveanimal research before application on humans is neededto grant the necessary safety.

Biomechanical research will provide ligament forces thatare based on in vivo studies, so that surgical reconstruc-tion procedures can restore the anatomy as closely aspossible to normal. Specific knowledge on in vivo forcesof ligaments will further enhance rehabilitation to regi-mens that exercise the knee at forces that do not exceedthe normal. Biomechanical research in computer-assistedorthopedic surgery and computed imaging will enhanceboth surgical precision and preoperative evaluation. Ul-timately, biologic and biomechanical research will allowinjured athletes to obtain a stable and well-functioningknee that allocates them to go back to original sports atthe same level as before injury.

References and recommended readingPapers of particular interest, published within the annual period of review,have been highlighted as:• Of special interest•• Of outstanding interest

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