Essay: ACL injury treatments

Soft fibrous tissues, named ligaments, connect bones within joints and act as load bearing. [1] The most ruptured ligament is the anterior cruciate ligament (ACL), with over 200000 reconstructive surgeries only in the US in 2002, covered by expenses of over 5 billion dollars, and it is also the most studied ligament. [2-4] In 1999, the incidence of ACL injuries was high (about 1 per 3000 Americans) and has increased a lot over years due a greater sport participation. [5, 6]. An important issue regarding the ACL is the fact that it does not heal by its own being poorly vascularized compared to other human ligaments. [7, 8] Injuries of the ACL cause joint dysfunctions, leading to the injury of other tissues and causing a poor life quality for the patient.
Over the past decades polymers gained more and more attention for various applications, from regular plastics, food packaging[9] to electronics[10], solar cells[11], biomedical applications [12] and tissue engineering [13]. Polymer biomedical applications include drug delivery systems[14], stimuli responsive systems[15], antimicrobial systems[16], tissue-engineering systems, implants[17] and biosensors[18]. To successful design, polymer biomaterials must have similar mechanical properties for their intended use, not to induce an inflammatory response, to release nontoxic degradation products and to have a degradation time similar to their function.[19]
The objective of this review is to show the evolution of polymer materials and the emerging approaches of the existing polymer systems for ligament reconstruction.
Natural grafts originating from living organisms
There are three ways for repairing or replacing the ruptured ligaments using grafts from living organisms: autografts[20], allografts[21] and xenografts[22]. In current clinical practice, autografts (bone-patellar bone grafts, hamstring tendon or quadriceps tendon) are the most popular surgical of the ACL[23]. Autografts present several drawbacks like donor-site morbidity (leading to pain, tendonitis and occasionally to patella fracture), longer recovery times and the requirement of harvesting operation[24]. Moreover, recurrent injury or failure of the reconstruction do not benefit of the same availability of autologous tissue for surgeries. [25] Allografts on the other hand reduce the surgery and recovery time, avoids the donor site morbidity and decreases the postoperative pain. However, in the case of allografts there is a limited tissue supply, a slow biological incorporation and a risk for diseases.[26] There are also some reviews regarding autografts and allografts.[27-30] Kaeding et al. affirmed that there were no significant differences regarding the graft failure rate, postoperative laxity of patient reported outcome scores when comparing ACL reconstruction with autografts or nonirradiated allografts.[31] Hu et al. published another review comparing allografts and autografts, this time for bone patellar tendon-bone, and they could not conclude which was better for ACL reconstruction.[32] Mulford et al. published a systematic review only about quadriceps autograft. [33] Dhawan et al. reported a review regarding hamstring autografts diameter dimension and their influence on the failure rates.[34]
Regarding xenografts there are only a few studies published in the last years. [35-37] Stone et al. used transplanted porcine patellar tendon treated with ??-galactosidase to eliminate ??-gal epitopes and with glutaraldehyde for moderate cross-linking of collagen fibers to replace ruptured ACL in patients. After two years, five of six implants were still in place. They concluded that this kind of porcine implant might be an option.[37]
Artificial devices
Another step further in developing ACL injury treatments was taken in the early 1970’s, with the FDA approval of the first ACL prosthesis introduced to the market, Proplast from Vitek Inc, [38] Next years other synthetic grafts were developed: Dacron, GORE-TEX, Leeds-Keio ligaments, Kennedy Ligament Augmentation Device (LAD), ABC Surgicraft, Ligament Advanced Reinforcement System (LARS).[39]
Dacron ligament approved in 1989 by the FDA was initially used for acromio-clavicular joint injuries and in tendon reconstructions. This ligament is made from a multilayer of polyethylene terephthalate and polyester with a woven structure from ten yarns and one multifilament transversal yarn, at which were added an external envelope for better tissue incorporation and a central filament for mechanical support. The reported results of this synthetic ligament were not satisfactory and in 1994 Striker withdrawn the product from the market.[39-43]
ABC Surgicraft ligament became available in 1985 and it is made from mixture of multiply braided carbon and PET fibers.[39, 40] Although its utilization had promising results, afterwards there were several reports about a progressive decrease of stability, implant degradation due to abrasion and the appearance of inflammatory reactions.[44-46]
The FDA approved Gore-Tex ligament in 1986 and it is made of continuous multifilament yarns of tightly braided microporous polytetrafluoroethylene.[39, 40] These kind of grafts have an ultimate strength that is twice the human ACL and a high density, reasons that led to the belief that Gore-Tex might be a very good alternative for ACL reconstruction.[47] Due to ruptures of the prosthesis, infections and associated inflammatory responses, this graft was withdrawn from the market in 1993. [48-51]
In 1982 the collaboration between University of Leeds and Keio University led to the development of the Leeds-Keio ligament that is made of woven PET fibers.[39, 40, 52] It was first proposed as a scaffold supporting collagen production, but it was proven that it is only a prosthetic. On long term Leeds-Keio ligaments do not provide suitable guarantees in ACL reconstruction.[53-57]
The Kennedy LAD was introduced in 1975 and is composed of braided polyethylene. It is designed to be implanted in conjunction with biological grafts.[39, 58] Because this device is associated with inflammatory responses, it is no longer recommended for utilization.[59-61]
The LARS ligaments (Ligament Advanced Reinforcement System) are made of PET fibers with a structure that allow tissue ingrowth, reducing shearing forces and increasing the resistance to wear and tear.[39, 40, 62] The short-term results of this ligament appear good but there is no confirmation of the success of the graft on long-term studies. [63-66]
The major disadvantage of the synthetic grafts is their failure over time due to the impossibility of reproducing the mechanical behavior of the native ligaments. These grafts suffer from deformation at the point of stress due to repetitive elongations, weakening due the friction with the bone tunnel, axial splitting, low tissue infiltration and debris creation, which may lead to synovitis. Eventually these implants fail, and certainly, there is a need for ACL reconstruction alternatives.[21, 23]
Non-degradable polymer scaffolds
After the synthetic grafts, researchers started paying a lot of attention towards the development of scaffolds for ACL reconstruction. Ideally, the scaffold used for the ACL replacement should be biodegradable, but there are certain studies presenting non-degradable ones.
Polyvinyl alcohol is a non-degradable polymer that presents a good compatibility.[67, 68] Bach et al. developed an implant model for the reconstruction of the anterior cruciate ligament, based on a PVA hydrogel. PVA hydrogel fibers that contain 50% w/w have similar tensile properties to the native ligament. Moreover, these properties can be improved by adding ultra-high molecular weight polyethylene (UHMWPE). The authors developed another implant model, which consist of PVA hydrogel core surrounded by a braided layer of UHMWPE fibers, design to have certain pores. This model can be adapted to the physiological needs through adjusting the core size, braiding angle and the hollows of the braiding.[69]
Polyurethane is a resistant non-degradable polymer characterized through a very weak interaction with the living cells. Lee et al. proposed to improve this aspect through a structural modification aided by the electrospinning technique. Therefore, human fibroblasts from ligaments, which adopted a specific fusiform morphology, were deposited on the polyurethane nanofibers, being oriented in fiber direction. The increased quantity of extracellular matrix and collagen deposited on the aligned polyurethane fibers, recommend them in disfavor of random oriented polyurethane fibers, although the cell proliferation difference was not significant. Moreover the ultimate strength of aligned fibers is approximately three times larger than the random oriented fibers.[70]
Degradable polymer scaffolds
Optimal structural scaffolds for ACL reconstruction should be biocompatible, biodegradable as to allow tissue ingrowth and regeneration of the new ligament, and maintain comparable mechanical strengths to the native ACL. Among the synthetic polymers mentioned in the literature as potential scaffolds for ligament reconstruction there is: poly-L-lactic acid (PLLA), poly-(L-lactide-co-D,L-lactide) (PLDLA), Polyglycolic acid (PGA), poly (D,L-lactide-co-glycolide) (PLGA), polycaprolactone (PCL), poly(desaminotyrosyl-tyrosine dodecyl dodecanedioate) p(DTD DD), poly(desaminotyrosyl-tyrosine dodecyl ethyl ester carbonate) p(DTE carbonate).[71]
Poly L-Lactic Acid
Poly L-Lactic Acid is an intensive studied, semi-crystalline, biodegradable polymer that has numerous medical applications. It has a higher degree of hydrophobicity and it is more amorphous than Polyglycolic acid.[72] PLLA degrades in vivo through de-esterification to lactic acid during a time interval between 10 months and 4 years (depending on the molecular weight, crystallinity degree, shape an place of implantation).[73, 74] Other studies show that PLLA is a suitable polymer for ligament reconstruction scaffolds because of its support for cell adherence, extracellular matrix production and maintaining structural integrity (after three days in the culture medium there was 12% mass weight loss) and good mechanical properties over time. Further, functionalizing PLLA scaffold surface with fibronectin, a protein with an increasing expression during ligament regeneration, improves the attachment of the cell and the extracellular matrix production. Several studies also showed some disadvantages of this polymer like, local modifications of the pH value, which lead to bone resorption, in case of the contact with bony tissue (the case for ligament reconstruction). This disadvantage is attributed to the lactic acid, the main degradation product of PLLA.[7]
Poly-(L-lactide-co-D,L-lactide)
Poly-(L-lactide-co-D,L-lactide) (PLDLA) is another biodegradable synthetic polymer and a potential candidate for ligament reconstruction scaffolds. PLDLA fibers obtained through the electrospining technique and treated with a warm phosphate buffer saline solution acquire a sinuous aspect, with an amplitude and wavelength similar to the collagen fibers from the ACL. This native similar morphology allows the adherence and proliferation of bovine fibroblasts and it favors the extracellular matrix deposition. In vitro degradation testing of 250 kDa PLDLA, on short (4 weeks) and long times (six months) showed no significant mass losses and no modification of the Young modulus between 2 and 6 months. The observed slow rate of degradation of the PLDLA is correlated with the slow hydrolysis and polymer crystallinity.[75]
Polyglycolic acid
Polyglycolic acid (PGA) is the polymer of glycolic acid. In vitro studies of 3D braided PGA fiber scaffolds showed a very high initial tensile strength, but there is a fast degradation of the matrix after a week. In addition, compared to other poly ??-hydroxyesters (PLLA, PLGA), PGA scaffolds do not sustain a satisfactory cell adherence and growth.[7]
Poly (D,L-lactide-co-glycolide)
Poly (D,L-lactide-co-glycolide) (PLGA) is the synthetic copolymer of D,L ‘ Lactide and Glycolide and was used for the achievment of knitted fibers scaffolds having good mechanical properties.[76] PLGA was also the main material used in realizing triphasic scaffolds that facilitates the functional integration between the bone and the synthetic graft. These were made out of a PLGA fibrous mesh representing the ligament, PLGA microspheres representing the bone-ligament interface and PLGA-bioglass sintered composite microspheres representing the bony phase.[77, 78] Sahoo et al. developed a biodegradable nano-microfibrous polymer scaffold through the deposition of PLGA nanofibers by electrospining, on a knitted PLGA microfibers three-dimensional matrix. They observed that the nanofibers mimic the nanoarchitecture of the extracellular matrix of the ligament, facilitating the cell adherence and the formation of new tissue.[79] Matrices of knitted PLGA fibers were used for mesenchymal stem cells differentiation studies for ligament specific cells through mechanical stimulation.[80] Fabrication of a synthetic ligament used knitted PLGA/PLLA fibers and was tested in vivo for 20 weeks in an animal model (a rabbit) and it presented a Young modulus of 283 MPa, but a very small ultimate tensile load.[73]
Polycaprolactone
Polycaprolactone (PCL) is a degradable, semi-crystalline polymer obtained as derivative of the oil industry.[81] PCL is a proposed material for a lot of biomedical application because of its slow rate of degradation and its capability of forming mixtures.[73] PCL is often combined with PLLA to obtain less fragile materials, due to its low rigidity. It has a high degree of hydrophobicity leading to a less swelling material, which may affect the cell adherence that is very important for the ligament reconstruction.[82] Deepthi et al. synthesized a ligament reconstruction scaffold by depositing through electrospining a hydrogel layer of chitosan and hyaluronic acid for favoring the cell adherence and viability (due to the electrostatic charge which supports protein adsorption). The natural polymer hydrogel film deposition on PCL fibers reduce insignificant the mechanical properties. The aligned hydrogel covered PCL fibers supported the highest cell viability, while the random oriented PCL exhibited the highest cell infiltration degree due to its high porosity. The proposed scaffold has a high efficacy by utilizing the aligned covered PCL fibers, which also give a high mechanical strength, but it needs an improvement of the porosity to allow cell infiltration.[83]
Poly(desaminotyrosyl-tyrosine dodecyl dodecanedioate)
Poly(desaminotyrosyl-tyrosine dodecyl dodecanedioate) p(DTD DD) is a promising polymeric material, a polyarilate compound derived from tyrosine characterized through a low crystallinity and non-toxic degradation products. Kohn’s group from New Jersey developed p(DTD DD) and they proved the support for adherence and growing of fibroblasts. Moreover, these polymer fibers present a higher initial strength and lower modulus than PLLA fibers, which correspond to mechanical requirements of typical human ACL.[84] The polymer feasibility for ACL reconstruction was confirmed through in vivo studies that used a hybrid scaffold made from 75% braided p(DTD DD) fibers and 25% of I type bovine collagen, on an animal model (sheep). After 12 weeks, the implants were intact and they presented numerous cell and blood vessel infiltration without any inflammation sign. Nevertheless, the authors observed the presence of a high number of lymphocytes. [85]
Poly(desaminotyrosyl-tyrosine dodecyl ethyl ester carbonate)
Polycarbonates are the polyesters of carbonic acid and they degrade through hydrolysis. Particularly, tyrosine derived polycarbonates are synthetic polymeric materials with a slow degrading rate, easy processable and with a high mechanical strength. Poly(desaminotyrosyl-tyrosine dodecyl ethyl ester carbonate) or p(DTE carbonate) proved to be biocompatible, presenting a comparable cell attachment and proliferation rate to collagen and poly L-Lactic acid.[86] Furthermore, depending on the processing factors, aligned poly(DTE carbonate) fibers can achieve similar mechanical properties as the rabbit ACL. These properties recommend p(DTE carbonate) as a resorbable polymeric material for ligament reconstruction, but with the need of optimizing the fiber geometry to allow the development of the new tissue.[87]