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Method of preparation of bioabsorbable porous reinforced tissue implants and implants thereof

The present invention relates to bioabsorbable, porous, reinforced implantable devices for use in the repair of soft tissue injuries, and methods of using and manufacturing such devices.

Injuries to soft tissue, including, for example, musculoskeletal tissue, may require repair by surgical intervention, depending upon factors such as the severity and type of injury. Such surgical repairs can be effected by using a number of conventional surgical procedures, for example, by suturing the damaged tissue, and/or by mounting an implant to the damaged tissue. It is known that an implant may provide structural support to the damaged tissue, and it may also serve as a substrate upon which cells can grow, thus facilitating more rapid healing.

One example of a fairly common tissue injury is damage to or prolapse of the pelvic floor. This is a potentially serious medical condition that may occur during childbirth or from subsequent complications, which can lead to an injury of the vesicovaginal fascia. This type of injury may result in a cystocele, which is a herniation of the bladder. Similar medical conditions include rectoceles (a herniation of the rectum), enteroceles (a protrusion of the intestine through the rectovaginal or vesicovaginal pouch), and enterocystoceles (a double hernia in which both the bladder and intestine protrude).

Another example of a fairly common soft tissue injury is damage to the rotator cuff or rotator cuff tendons. The rotator cuff facilitates circular motion of the humerus relative to the scapula. Damage to the rotator cuff is a potentially serious medical condition that may occur during hyperextension, from an acute traumatic tear or from overuse of the joint. The most common injury associated with the rotator cuff region is a strain or tear involving the supraspinatus tendon. A tear at the insertion site of the tendon with the humerus, may result in the detachment of the tendon from the bone. This detachment may be partial or full, depending upon the severity of the injury. Additionally, the strain or tear can occur within the tendon itself. Treatment for a strained tendon usually involves physical cessation from use of the tendon, i.e., rest. However, depending upon the severity of the injury, a tom tendon might require surgical intervention as in the case of a full tear or detachment of the supraspinatus tendon from the humerus. Damage to the rotator cuff may also include degeneration. This is a common situation that arises in elderly patients. In degenerative cases there is loss of the superior portion of the rotator cuff with complete loss of the supraspinatus tendon. Similar soft tissue pathologies include tears in the Achilles' tendon, the anterior cruciate ligament and other tendons or ligaments of the knee, wrist, hand, and hip, spine, etc.

An example of a common ligament injury is a torn anterior cruciate ligament (ACL), which is one of four major ligaments of the knee. The primary function of the ACL is to constrain anterior translation, rotary laxity and hyperextension. The lack of an ACL causes instability of the knee joint and leads to degenerative changes in the knee such as osteoarthritis. The most common repair technique is to remove and discard the ruptured ACL and reconstruct a new ACL using autologous bone-patellar, tendon-bone or hamstring tendons. Although this technique has shown long-term clinical efficacy, there is morbidity associated with the harvest site of the tissue graft. Synthetic prosthetic devices are known and have been clinically evaluated in the past with little long-term success. The advantages of a synthetic implant are that the patient does not suffer from the donor site morbidity that is associated with autograft procedures, and that patients having a synthetic implant are able to undergo faster rehabilitation of the knee. These synthetic prosthetic devices were composed of non-resorbable materials and were designed to be permanent prosthetic implants. A number of disadvantages may be associated with synthetic prosthetic implants, such as for example, synovitis, bone tunnel enlargement, wear debris, and elongation and rupture of the devices. Overall, autograft reconstuction is still the widely accepted solution for repairing a ruptured ACL.

Herniation and tears of soft tissue are typically treated by conventional surgical procedures in which the protruding organs or tissue tears are repositioned or reconsolidated. The prevailing standard of care for some procedures, for example, is to use a conventional mesh-like patch to repair the damaged site.

There is a constant need in this art for new surgical procedures for the treatment and repair of damaged soft tissue that facilitate more rapid healing and improved patient outcomes. In response to this need, a variety of implants, in addition to meshes, have been developed and used in surgical procedures to help achieve these benefits. One type of conventional implant is made from biologically derived tissue (e.g. allografts and autografts). Biologically derived materials, although generally safe and effective, may have several disadvantages associated with their use. For example, if not properly aseptically processed in accordance with prevailing and accepted standards and regulations, they may contribute to disease transmission. In addition, biologically derived products may be somewhat difficult to harvest and acquire, and, may be burdensome to process such that their properties are within required specifications and standards.

Another common soft tissue injury involves damage to cartilage, which is a non-vascular, resilient, flexible connective tissue. Cartilage typically acts as a shock-absorber and/or sliding contact surface at articulating joints, but some types of cartilage provide support to tubular structures, such as for example, the larynx, air passages, and the ears. In general, cartilage tissue is comprised of cartilage cells, known as chondrocytes, located in an extracellular matrix composed of collagen, a structural scaffold, and aggrecan, a space-filling proteoglycan. Several types of cartilage can be found in the body, including hyaline cartilage, fibrocartilage and elastic cartilage. Hyaline cartilage is generally found in the body as articular cartilage, costal cartilage, and temporary cartilage (i.e., cartilage that is ultimately converted to bone through the process of ossification). Fibrocartilage is a transitional tissue that is typically located between tendon and bone, bone and bone, and hyaline cartilage and hyaline cartilage. Elastic cartilage, which contains elastic fibers distributed throughout the extracellular matrix, is typically found in the epliglottis, the ears and the nose.

One common example of hyaline cartilage injury is a traumatic focal articular cartilage defect to the knee. A strong impact to the joint can result in the complete or partial removal of a cartilage fragment of various size and shape. Damaged articular cartilage can severely restrict joint function, cause debilitating pain and may result in long term chronic diseases such as osteoarthritis, which gradually destroys the cartilage and underlying bone of the joint. Injuries to the articular cartilage tissue will typically not heal spontaneously and require surgical intervention if symptomatic. The current modality of treatment consists of lavage, removal of partially or completely unattached tissue fragments. In addition, the surgeon will often use a variety of methods such as abrasion, drilling or microfractures, to induce bleeding into the cartilage defect and formation of a dot. It is believed that the cells coming from the marrow will form a scar-like tissue called fibrocartilage that can provide temporary relief to some symptoms. Unfortunately, the fibrocartilage tissue does not have the same mechanical properties as hyaline cartilage and degrades faster over time as a consequence of wear. Patients typically have to undergo repeated surgical procedures which can lead to the complete deterioration of the cartilage surface. More recently, experimental approaches involving the implantation of autologous chondrocytes have been used with increasing frequency. The process involves the harvest of a small biopsy of articular cartilage in a first surgical procedure, which is then transported to a laboratory specialized in cell culture for amplification. The tissue biopsy is treated with enzymes that will release the chondrocyte cells from the matrix, and the isolated cells will be grown for a period of 3 to 4 weeks using standard tissue culture techniques. Once the cell population has reached a target number, the cells are sent back to the surgeon for implantation during a second surgical procedure. This manual labor-intense process is extremely costly and time consuming. Although, the clinical data suggest long term benefit for the patient, the prohibitive cost of the procedure combined with the traumatic impact of two surgical procedures to the knee, has hampered adoption of this technique.

Another example of cartilage injury is damage to the menisci of a knee joint. The meniscus is a C-shaped concave fibrocartilage tissue that is found between two bone ends of the leg, the femur and tibia. There are two menisci of the knee joint, a medial and a lateral meniscus. In addition to the menisci of the knee joint, fibrocartilage tissue can also be found in the acromioclavicular joint, i.e., the joint between the clavicle and the acromion of the scapula, in the sternoclavicular joint, i.e., the joint between the clavicle and the sternum, in the temporomandibular joint, i.e., the joint of the lower jaw, and in the intervertebral discs which lie between the vertebral bodies in the spine. The primary functions of meniscal cartilage are to bear loads, to absorb shock and to stabilize a joint. Meniscus tears of the knee often result from sudden traumatic injury, especially in association with ligament injuries, or due to the degeneration of the tissue. Meniscus tears often cause joint pain and catching or locking of the joint. If not treated properly, an injury to the meniscus, such as a “bucket-handle tear” in the knee joint, may lead to the development of osteoarthritis. Current conventional treatments for damaged meniscal cartilage include the removal and/or surgical repair of the damaged cartilage. Other less established or unproven techniques include allografts and collagen-based implants.

Synthetically based, non-absorbable materials have been developed as an alternative to biologically derived products. Although patches or implants made from such synthetically based non-absorbable materials are useful to repair some herniations, they are found to be inadequate in repairs made in regions such as the pelvic floor due to the fact that the patches or implants are made from non-bioabsorbable materials and may lead to undesirable tissue erosion and abrasion. Tissue erosion and abrasion may be counteracted by the use of patches, substrates, and implants manufactured from bioaborbable materials.

There continues to be a need for bioabsorbable tissue repair implant devices having sufficient structural integrity and sufficiently long residence time to effectively withstand the stresses associated with implantation into an affected area. There is also a continuing need for bioabsorbable tissue repair implant devices that minimize or eliminate long-term erosion and abrasion (or other pathology) to the tissues in the surrounding area.

Bioabsorbable, porous foams may be used as implants to facilitate tissue growth. Bioabsorbable, foamed tissue engineered implant devices that have been reinforced to increase mechanical properties are disclosed in U.S. patent application Ser. No. 09/747,489 entitled “Reinforced Tissue Implants and Methods of Manufacture and Use” filed Dec. 21, 2000, and also disclosed in U.S. patent application Ser. No. 09/747,488 entitled “Reinforced Foam Implants with Enhanced Integrity for Soft Tissue Repair and Regeneration” filed Dec. 21, 2000, the disclosures of both of which are incorporated by reference. Methods for manufacturing the foam component of the tissue implant include a variety of methods known and used in this art. For example, they include lyophilization, supercritical solvent foaming, extrusion or mold foaming (e.g. external gas injection or in situ gas generation), casting with an extractable material (e.g., salts, sugar or similar suitable materials) and the like.

Of particular utility is foam formation by freeze drying or lyophilization. The advantages of lyophilization include the avoidance of elevated temperatures, thus minimizing the potential for temperature-associated degradation and enabling the inclusion of temperature sensitive bioactive agents. Additional advantages include the ability to control the pore size and porosity of the foamed material. Non-aqueous lyophilization also eliminates the need for exposure of the processed material to water as is required in salt leaching processes that may cause premature hydrolysis. Lyophylization is a cost effective, simple, one-step process that facilitates manufacturing, and is widely known and used in the food and pharmaceutical industries.

Lyophilization is a process for removing a (frozen or crystallized) solvent, frequently water, from various materials. Lyophilization of enzymes, antibodies, and sensitive biological materials is quite often the method of choice for extending the shelf life of these products and preserving their biological activity. As practiced as a means of foam formation, the lyophilization process usually requires that a polymeric material be rendered soluble in a crystallizable solvent capable of being sublimed, usually at reduced pressure. Although the solvent may be water, 1,4-dioxane is commonly used. This solvent has found great utility in foam formation because many medically important polymers are soluble in it. It is crystallizable (melting point approximately 12° C.), and it can generate a significant vapor pressure at temperatures in which it is still a solid, i.e. it can be sublimed at reduced pressure.

It will be generally recognized by one with ordinary skill, however, that lyophilization has certain limitations when applied to the manufacture of reinforced tissue engineered implant devices. For example, reinforcing elements must have limited solubility in the solvent employed. The integrity of reinforcing elements must withstand exposure to a solvent for the duration of the lyophilization process, otherwise the reinforcing elements (e.g, fibers, mesh, etc.) quickly lose their strength, and thus the advantages that the reinforcement is meant to provide. Selection of appropriate reinforcing materials may overcome at least one aspect of this problem. For example, absorbable polyglycolide (also known as polyglycolic acid) fibers, do not readily dissolve in many solvents and, in particular, do not dissolve in 1,4-dioxane. This property of polyglycolide fiber allows it to function as a suitable reinforcing element in many applications. Typically the fibers will be used in conjunction with a matrix polymer that is necessarily soluble in the same lyophilization solvent in which the fibers are not soluble. The matrix polymer, for example polylactide, is then capable of being foamed about these non-dissolving fibers during a lyophilization process.

However, bioabsorbable polyglycolide reinforcing elements are not acceptable for all surgical repairs. In some surgical applications, for example, they lose their mechanical strength too quickly after implantation. There is a need for bioabsorbable surgical devices in the form of a mechanically reinforced foam that retain their mechanical strength for extended periods of time after implantation to facilitate slow-to-heal tissue repairs. Surgical procedures requiring extended healing time include various soft tissue injury repairs, for example, damage to the pelvic floor, ligament or tendon tears, cartilage tears, and rotator cuff tears. Polylactide or certain lactide-rich lactide/glycolide copolymers such as 95/5 poly(lactide-co-glycolide), can be made into reinforcing elements that retain their strength for prolonged time periods. These polymers, however, readily dissolve in the commonly-used lyophilization solvent, 1,4-dioxane. Methods for making such mechanically reinforced foamed devices have not been discovered.

There continues to be a need in this art for bioabsorbable foam tissue repair implants having sufficient structural integrity that is sufficient to effectively withstand the stresses associated with implantation into an affected body area, and that can retain their mechanical strength for a sufficient time for use in slow-to-heal tissue repairs, and that can be made, at least in part, by lyophilization.

A bioabsorbable, reinforced tissue implant is disclosed. The tissue implant has a biocompatible polymeric foam and a biocompatible polymeric reinforcement member. The foam and the reinforcement member are soluble in a common solvent.

Yet another aspect of the present invention is a method for manufacturing a bioabsorbable, reinforced tissue implant. A solution of a foam-forming, biocompatible polymer in a solvent is provided. The solvent has a freezing point. A biocompatible polymeric reinforcement member is additionally provided. The polymeric reinforcement member is placed in a cavity of a suitable mold. The solution is added to the cavity of the mold such that at least a part of the cavity is filled with the solution and at least part of the reinforcing member is in contact with the solution. The reinforcement member and solution are quenched to below the freezing point of the solvent, and then are lyophilized.