R.P.H. Veth

Tissue ingrowth and degradation of two biodegradable porous polymers with different porosities and pore sizes.

Commonly, spontaneous repair of lesions in the avascular zone of the knee meniscus does not occur. By implanting a porous polymer scaffold in a knee meniscus defect, the lesion is connected with the abundantly vascularized knee capsule and healing can be realized. Ingrowth of fibrovascular tissue and thus healing capacity depended on porosity, pore sizes and compression modulus of the implant. To study the lesion healing potential, two series of porous polyurethanes based on 50/50 epsilon-caprolactone/L-lactide with different porosities and pore sizes were implanted subcutaneously in rats. Also, in vitro degradation of the polymer was evaluated. The porous polymers with the higher porosity, more interconnected macropores, and interconnecting micropores of at least 30 microm showed complete ingrowth of tissue before degradation had started. In implants with the lower macro-porosity and micropores of 10-15 microm degradation of the polymer occurred before ingrowth was completed. Directly after implantation and later during degradation of the polymer, PMN cells infiltrated the implant. In between these phases the foreign body reaction remained restricted to macrophages and giant cells. We can conclude that both foams seemed not suited for implantation in meniscal reconstruction while either full ingrowth of tissue was not realized before polymer degradation started or the compression modulus was too low. Therefore, foams must be developed with a higher compression modulus and more connections with sufficient diameter between the macropores.

Tissue engineering of the meniscus

Meniscus lesions are among the most frequent injuries in orthopaedic practice and they will inevitably lead to degeneration of the knee articular cartilage. The fibro-cartilage-like tissue of the meniscus is notorious for its limited regenerative capacity. Tissue engineering could offer new treatment modalities for repair of meniscus tears and eventually will enable the replacement of a whole meniscus by a tissue-engineered construct. Many questions remain to be answered before the final goal, a tissue-engineered meniscus is available for clinical implementation. These questions are related to the selection of an optimal cell type, the source of the cells, the need to use growth factor(s) and the type of scaffold that can be used for stimulation of differentiation of cells into tissues with optimal phenotypes. Particularly in a loaded, highly complex environment of the knee, optimal mechanical properties of such a scaffold seem to be of utmost importance. With respect to cells, autologous meniscus cells seems the optimal cell source for tissue engineering of meniscus tissue, but their availability is limited. Therefore research should be stimulated to investigate the suitability of other cell sources for the creation of meniscus tissue. Bone marrow stroma cells could be useful since it is well known that they can differentiate into bone and cartilage cells. With respect to growth factors, TGF-beta could be a suitable growth factor to stimulate cells into a fibroblastic phenotype but the problems of TGF-beta introduced into a joint environment should then be solved. Polyurethane scaffolds with optimal mechanical properties and with optimal interconnective macro-porosity have been shown to facilitate ingrowth and differentiation of tissue into fibro-cartilage. However, even these materials cannot prevent cartilage degeneration in animal models. Surface modification and/or seeding of cells into the scaffolds before implantation may offer a solution for this problem in the future.This review focuses on a number of specific questions; what is the status of the development of procedures for lesion healing and how far are we from replacing the entire meniscus by a (tissue-engineered) prosthesis. Subquestions related to the type of scaffold used are: is the degree of tissue ingrowth and differentiation related to the initial mechanical properties and if so, what is the influence of those properties on the subsequent remodelling of the tissue into fibro-cartilage; what is the ideal pore geometry and what is the optimal degradation period to allow biological remodelling of the tissue in the scaffold. Finally, we will finish with our latest results of the effect of tear reconstruction and the insertion of prostheses on articular cartilage degradation.

Use of porous polyurethanes for meniscal reconstruction and meniscal prostheses

In the past, porous materials made of an aromatic polyurethane (PU) were successfully used to meniscal reconstruction in dogs. Since aromatic PUs yield very toxic fragments upon degradation, a linear PU was synthesized by curing a poly(epsilon-caprolactone) and 1,4-trans-cyclohexane diisocyanate based prepolymer with cyclohexanedimethanol. Porous materials of this polymer were also implanted for meniscal reconstruction. The results were comparable with the most successful implant series so far. Additionally, a porous meniscal prosthesis was developed to replace a total meniscus. Due to the very high shear stresses to which the prosthesis would be exposed, the stress hysteresis phenomenon linear PUs are known to exhibit could be of great consequence. Therefore an aliphatic PU network, synthesized by cross-linking poly(epsilon-caprolactone) and 1,4-trans-cyclohexane diisocyanate with glycerol, was used. Dislocation caused by tearing out of the sutures was found to be a problem because the tear resistance of the material was relatively low. In this study the tearing problem has been partly circumvented by using a complex suturing technique. Meniscal prostheses turned out to induce fibrocartilage upon implantation, and degeneration of articular cartilage was less severe than after meniscectomy.

Porous polymer implant for repair of meniscal lesions: a preliminary study in dogs

Artificial meniscal lesions extending into the avascular part of the meniscus, which do not heal by any other means, were repaired by suturing either a porous polymer implant or a synovial flap into the defect. The implant guided the ingrowth of vascular repair tissue into the defect. This fibrous tissue later on transformed into fibrocartilage. Reconstruction with a synovial flap was not successful. It appeared that healing can be achieved by implantation of a porous polymer implant in a large number of cases. Future research will be aiming at improvement of the results of meniscal repair and application of this type of polymer for repair of cartilage defects.

Solvent-free fabrication of micro-porous polyurethane amide and polyurethane-urea scaffolds for repair and replacement of the knee-joint meniscus

New porous polyurethane urea and polyurethane amide scaffolds for meniscal reconstruction have been developed in a solvent-free process. As soft segments, copolymers of 50/50 L-lactide/epsilon-caprolactone have been used. After terminating the soft segment with diisocyanates, chain extension was performed with adipic acid and water. Reaction between the isocyanate groups and adipic acid or water provides carbon dioxide and results in a porous polymer. Extra hydroxyl-terminated prepolymer was added in order to regulate the amount of carbon dioxide formed in the foaming reaction. Furthermore, salt crystals ranging in size from 150 to 355 microm were added in order to induce macroporosity. The pore size was regulated by addition of surfactant and by the use of ultrasonic waves. The resulting porous polymer scaffolds exhibit good mechanical properties like a high-compression modulus of 150 kPa. Chain extension with adipic acid results in better mechanical properties due to better defined hard segments. This results from the lower nucleophilicity of carboxylic acids compared to water and alcohols. By adjusting the reaction conditions, materials in which macropores are interconnected by micropores can be obtained. On degradation only non-toxic products will be released; importantly, the materials were obtained by a simple, reproducible and solvent-free procedure.

Meniscal replacement using a porous polymer prosthesis : A preliminary study in the dog

A porous polyurethane prosthesis was used to replace the lateral meniscus in the dog. After an initial ingrowth of fibrous tissue, the prostheses became filled with tissue strongly resembling normal meniscal fibrocartilage. Although less severe than seen after total meniscectomy, cartilage degeneration was frequent, possibly because tissue ingrowth in the prostheses occurred too slowly. Porous polymers can be useful for replacement of the meniscus, provided that chemical and physical properties are optimized.

Use of porous biodegradable polymer implants in meniscus reconstruction. 1) Preparation of porous biodegradable polyurethanes for the reconstruction of meniscus lesions

Porous biodegradable poly(urethanes) for reconstructing menisci have been prepared using two different combinations of techniques: freeze-drying/salt-leaching and in-situ polymerization/salt-leaching. Using these methods, homogenous porous materials with a controllable and reproducible morphology can be prepared. The materials were made of three different poly(urethanes): a methylenediphenyldiisocyanate-based polyurethane, a lysine diisocyanate-based poly(urethane), and a poly(ɛ-caprolactone)-based poly(urethane). The compressive stress-strain behavior of the Estane foams was determined. Foams made by the freeze-drying/salt-leaching technique implanted in dogs showed healing and good ingrowth of fibrocartilaginous tissue.

A porous polymer scaffold for meniscal lesion repair--a study in dogs.

Meniscal lesions often occur in the avascular area of the meniscus with little chance of spontaneous repair. An access channel in the meniscal tissue can function as an entrance for ingrowing repair tissue from the vascular periphery of the meniscus to the lesion in the avascular zone which again induced healing of the lesion. Implantation of a porous polymer in a full-thickness access channel induced healing. However, a better integration between meniscal tissue and the implant might be achieved with the combination of the newly developed porous polymers and a modified surgical technique. This might improve meniscal lesion healing and the repair of the access channel with neo-meniscal tissue. Longitudinal lesions were created in the avascular part of 24 canine lateral menisci and a partial-thickness access channel was formed to connect the lesion with the meniscal periphery. In 12 menisci, the access channel was left empty (control group), while in the remaining 12 menisci the polymer implant was sutured into the access channel. Repair of the longitudinal lesions was achieved with and without polymer implantation in the partial-thickness access channel. Polymer implants induced fibrous ingrowth with cartilaginous areas, which resembled neo-meniscal tissue. Implantation did not prevent articular cartilage degeneration.

EXPERIMENTAL MENISCAL LESIONS RECONSTRUCTED WITH A CARBON FIBER-POLYURETHANE-POLY(L-LACTIDE) GRAFT

Reconstructive procedures were investigated in meniscal lesions in 14 dogs. Large wedge-shaped lesions were repaired with a graft containing carbon fibers and an organic polymer, prepared from physical mixtures of poly(L-lactide) and a segmented polyurethane. Four and eight weeks postoperation, arthroscopy was performed and the implants were excised. In ten dogs, the reconstructed area appeared to be invaded almost completely by fibrous tissue and, occasionally, by repair-simulating hyaline cartilage. There were no signs of infection.

REPAIR OF THE MENISCUS - AN EXPERIMENTAL INVESTIGATION IN RABBITS

The healing process of wedge-shaped and longitudinal lesions in the meniscus of the knee was investigated in 74 menisci in 24 Chinchilla rabbits. In four cases the whole meniscus was removed and reimplanted. healing was most evident in the wedge-shaped lesions, which were repaired by fibrocartilage. In longitudinal lesions the repair was markedly avascular and consisted of fibrous tissue only. Suturing did not facilitate the healing process.