WO2002000272A2 - Composition and method for the repair and regeneration of cartilage and other tissues - Google Patents
Composition and method for the repair and regeneration of cartilage and other tissues Download PDFInfo
- Publication number
- WO2002000272A2 WO2002000272A2 PCT/CA2001/000959 CA0100959W WO0200272A2 WO 2002000272 A2 WO2002000272 A2 WO 2002000272A2 CA 0100959 W CA0100959 W CA 0100959W WO 0200272 A2 WO0200272 A2 WO 0200272A2
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- Prior art keywords
- blood
- polymer composition
- chitosan
- tissue
- blood component
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Definitions
- the low friction properties are the result of a special molecular composition of the articular surface and of the synovial fluid as well as exudation of interstitial fluid during loading onto the articular surface (Ateshian, 1997; Higaki et al . , 1997; Schwartz and Hills, 1998) .
- the deeper portions of the granulation tissue reconstitute the subchondral bone plate while the upper portion transforms into a fibrocartilagenous repair tissue.
- This tissue can temporarily possess the histological appearance of hyaline cartilage although not its mechanical properties (Wei et al., 1997) and is therefore unable to withstand the local mechanical environment leading to the appearance of degeneration before the end of the first year post-injury.
- the natural response to repair in adult articular cartilage is that partial thickness lesions have no repair response (other than cartilage flow and localized chondrocyte cloning) while full- thickness lesions with bone penetration display a limited and failed response.
- Yet another related technique for treating focal lesions of articular cartilage is mosaicplasty or osteochondral autograft transplantation (OATS) where cartilage/bone cylinders are transferred from a peripheral "unused" region of a joint to the highly loaded region containing the cartilage lesion (Hangody et al., 1997).
- OATS osteochondral autograft transplantation
- Some of the problems associated with forming a good quality blood clot with these procedures are 1) the uncontrolled nature of the bleeding coming from the bone, which never fills up the cartilage lesion entirely 2) platelet mediated clot contraction occurring within minutes of clot formation reduces clot size and could detach it from surrounding cartilage (Cohen et al . , 1975) 3) dilution of the bone blood with synovial fluid or circulating arthroscopy fluid and 4) the fibrinolytic or clot dissolving activity of synovial fluid (Mankin, 1974) .
- periosteum When the implant is not amenable to press fitting, such as with contracting collagen gels or fibrin clots, or when cells alone without a support matrix are implanted, often a sutured patch of periosteum or another similar tissue is used to retain the implant material within the defect site (Grande et al . , 1989; Brittberg et al., 1994; Grande et al., 1989; Brittberg et al . , 1996; Breinan et al., 1997). Such a technique may benefit from an ability of the periosteum to stimulate cartilage formation (O'Driscoll et al .
- chitosan One technical difficulty that chitosan often presents is a low solubility at physiological pH and ionic strength, thereby limiting its use in a solution state.
- dissolution of chitosan is achieved via the protonation of amine groups in acidic aqueous solutions having a pH ranging from 3.0 to 5.6.
- Such chitosan solutions remain soluble up to a pH near
- Fig. 4 illustrates a RNase protection analysis of cartilage-specific mRNAs expressed by primary chondrocytes cultured in chitosan gel for 0, 14 and 20 days
- Fig. 5 illustrates a western blot analysis of cartilage-specific proteins expressed by primary chondrocytes cultured in chitosan gel for 0, 14 and 20 days
- Fig. 6 illustrates a mechanical behavior of gel discs cultured with and without chondrocytes
- Figs. 22A to 22C illustrate the preparation, mixing and injection of polymer/blood mixture to improve healing of articular cartilage defects
- the chitosan gel matrix was also found to bind Toluidine blue (Fig. 3C) . This property enabled to observe the lattice structure of the gel, after employing an aldehyde fixation. Interestingly, the pericellular ring of GAG observed around the chondrocytes contained little chitosan matrix, the latter appearing to have been degraded by chondrocyte-produced factors (Fig. 3D) .
- Primary calf chondrocytes were encapsulated in chitosan gel at 2xl0 7 primary chondrocytes per ml and cultured as 6 mm discs for up to 20 days.
- RNA A mixture of antisense 32 P-labeled RNA probes complementary to bovine type II collagen, aggrecan, and GAPDH was hybridized with tRNA (lane 1), or total RNA, from bovine kidney (lane 2), from primary chondrocytes (10 7 /ml) cultured in chitosan gel for 0 days (lane 3) 14 days (lane 4) or 20 days (lane 5), or adult bovine articular cartilage (lane 6) . Samples were treated with RNase A and Tl, then submitted to electrophoresis and autoradiography . Protected bands showing the presence of individual transcripts are as indicated. The maintenance of the chondrocyte phenotype in the chitosan/glycerol- phosphate gel is shown by the continued expression of aggrecan and type II collagen.
- thermogelling chitosan solution with primary chondrocytes and subcutaneous injection for in vivo growth of cartilage
- mice were similarly injected with chitosan gel alone. A palpable gel was formed within 10 minutes of injection. Implants were recovered at 21, 48, and 63 days post-injection. Toluidine blue staining revealed the gross production of GAG-rich extracellular matrix by the implants containing cells (Fig. 8A) . No GAG accumulation was seen in implants of chitosan gel alone
- FIG. 8B Primary calf chondrocytes at 2 x 10 7 cells/ml liquid chitosan gel were injected in liquid form as 100 ⁇ l subcutaneous dorsal implants in anesthetized nude mice. Control mice received 100 ⁇ l subcutaneous dorsal implants of liquid chitosan gel alone. 48 days after injection, implants were harvested and processed for paraffin histology and toluidine blue staining. Metachromatic violet staining reveals the accumulation of GAG in the implant with chondrocytes (Fig. 8A) . No GAG accumulation is detected in the implant with chitosan gel only (Fig. 8B) .
- Cartilage-specific proteins were detected in in vivo implants with primary chondrocytes from days 48 and 63 post-injection (Fig. 10). No cartilage-specific proteins were detected in implants with chitosan gel only
- Samples analysed include chitosan gel with no cells (lane 1) , bovine kidney (lane 2), two distinct in vivo nude mouse implants of chitosan gel only at day 63 (lanes 3 and 4), of in vivo implants of chitosan gel with 2 x IO 7 calf chondrocytes per ml gel at days 48 (lane 5) or day 63 (lane 6) , 2-week calf cartilage (lane 7), or adult bovine cartilage (lane 8).
- chondrocytes can be delivered in si tu, via injection, with the chitosan thermogelling solution as a carrier.
- the injected chondrocytes remain viable, and synthesize and assemble significant levels of a proteoglycan-rich extracellular matrix that stiffens over time to form a functional cartilaginous tissue.
- Fig. 11 chondrocytes can be delivered in si tu, via injection, with the chitosan thermogelling solution as a carrier.
- the injected chondrocytes remain viable, and synthesize and assemble significant levels of a proteoglycan-rich extracellular matrix that stiffens over time to form a functional cartilaginous tissue.
- Fig. 12B The articulating cartilage surface was opposed and simulated joint motions were performed after which the gel was observed to remain in the cartilage defect (Fig. 12B) .
- the ' gel not only remained in the defect but also adhered to the surrounding bone and cartilage surfaces and did not contract.
- liquid chitosan gel was deposited in 6 mm diameter full-thickness cartilage defects (Fig. 12A) and allowed to solidify at 37°C for 30 minutes in a humidified incubator. The joint was then closed, and joint motion simulated for several minutes. The chitosan gel adhered to and was retained in all of the defects after simulated joint motion (Fig. 12B) .
- a live New Zealand White rabbit was anesthetized, and a 3 x 4 mm chondral-only defect created in the trochlea of the femoral patellar groove.
- Several microfracture holes were introduced with a 16 gauge needle.
- Liquid thermogelling chitosan was loaded into the defect and allowed to gel for 5 minutes in si tu (Fig. 13A) .
- the joint was closed, and the rabbit allowed to recover with unrestricted motion for 24 hours before sacrifice and joint dissection (Fig. 13B) .
- thermogelling chitosan gel revealed the retention of this thermogelling chitosan gel in the very thin cartilage layer of the rabbit (only about 0.8mm thick) .
- the gel adhered firmly to surrounding bone and cartilage tissue, demonstrating good retention, thereby enabling its use as an injectable thermogelling polymer delivery vehicle for the repair of cartilage and other tissues.
- the joint and defect shown in Fig. 13B (filled with thermogelling chitosan, and residing 24 hours in vivo) was fixed, embedded in LR White plastic resin, sectioned, and stained with Toluidine Blue. A cross- section of the defect reveals retention of the chitosan gel in si tu, as well as adherence to cartilage and bone surfaces in the defect.
- Fig. 15A Several distinct mixing methods were employed to admix blood with an aqueous polymer solution (Fig. 15A) . Blood and polymer are admixed in a recipient, resulting in a homogenous liquid blend of blood and polymer.
- peripheral blood from either rabbit artery, or human or equine vein was drawn into a sterile 10ml syringe.
- a 20-gauge needle was attached to the syringe, and inserted through the rubber stopper of the vial. 6ml of peripheral blood was admitted to the vial.
- the vial was vortex mixed for 10 seconds at full speed. Following any of these mixing techniques, the resulting mixture was deposited into a 4 ml borosilicate glass vial at room temperature, a plastic vial at 37°C, or an agarose well (Figs. 15B and 15C) , or an articular cartilage defect ex vivo .
- the same treatment was performed with peripheral whole blood only.
- a vacutainer vial of EDTA- treated blood was drawn to measure CBC and platelet number. All blood samples tested displayed normal CBC and platelet counts for the respective species . Regardless of the species, the prepared blood/polymer, solidified and adhered strongly to the walls of the glass vial within 2.5 to 18 minutes after mixing (Fig. 16). Mixed whole peripheral blood solidified in general more slowly compared to blood/chitosan gel (Fig. 16) . Separate samples of blood, with or without liquid chitosan gel, were mixed and solidification time was measured by the number of minutes elapsed between mixing, and achieving, a solid adherent mass in the original mixing vial, or secondary recipient.
- FIG. 17A Another sample consisted of 3 volumes whole peripheral blood mixed with 1 volume chitosan-glycerol phosphate solution. At intervals up to 18 hours after solidification, the excluded serum for each condition was measured in triplicate, as an indication of degree of contraction.
- Peripheral blood admixed with the polysaccharides alginate, hydroxyethyl cellulose, or hyaluronic acid contracted to 40%-50% of the original mass (Fig. 17A) .
- the blood/chitosan gel samples showed negligible contraction, with contraction to 90% of the original mass (Fig. 17A) .
- chitosan in glycerol-phosphate solution 1.5% chitosan in glycerol-phosphate solution, or three distinct 1.5% polysaccharide solutions, were admixed at a ratio of 1 volume polysaccharide solution, to 3 parts whole peripheral blood. 500 ⁇ l of each sample was deposited in a glass borosilicate tube and allowed to solidify for 60 minutes at 37 °C. Different polysaccharides include hyaluronic acid-PBS (1), hydroxyethyl cellulose-PBS (2), alginate-PBS (3), and chitosan-glycerol phosphate (4). As a control, heparin blood only was analyzed (5) . After 60 minutes, the tubes were laid horizontally and photodocumented. Only the mixture of chitosan-glycerol phosphate and heparinised blood became solid.
- FIGs. 19A to 19C Histological sections of solid blood/polymer samples showed that mixtures were homogenous, that red blood cells did not hemolyse after mixing or solidification, and that platelets became activated and were functional (as evidenced by the generation of a dense fibrin network)
- FIGs. 19A to 19C A solidified mixture of blood/chitosan was fixed, embedded in LR White plastic, sectioned, and stained with Toluidine Blue.
- Fig. 19A at 20x magnification, global homogeneous mixing is apparent.
- Fig. 19B at lOOx magnification, intermixed pools of red blood cells and chitosan hydropolymer is apparent.
- 2000x magnification by environmental electron scanning microscopy
- the presence of fibrin fiber network throughout the blood/chitosan composite is evident.
- Serum proteins were released more slowly more sustained from the blood/chitosan samples compared with blood samples (Fig. 21) . These data suggest that blood and platelet-derived proteins involved in wound healing are released in a more sustained and prolonged manner from blood/chitosan-filled defects, compared with blood clot-filled defects.
- Solid discs of blood/chitosan gel, or blood only were generated from 150 ⁇ l initial liquid volume. Resulting discs were washed in 1 ml PBS for 3 hours, then transferred successively at 4, 5, 7, and 19 hours for a total of four additional 1 ml PBS washes. After 3 or 19 hours of washing, representative discs were extracted with GuCl to solubilise total retained proteins.
- FIG. 22D A similar treatment in human patients is schematized in Fig. 22D, where prepared cartilage defects receive an arthroscopic injection of liquid blood/polymer that solidifies in si tu .
- an arthroscopic injection of liquid polymer is mixed with bone-derived blood at the defect site (Fig. 22E) .
- the patient blood is mixed with the polymer ex vivo, and delivered to a prepared defect by arthroscopic injection, or (Fig. 22E) the polymer is delivered arthroscopically or during open knee surgery and mixed at the defect site with patient blood issuing from the defect.
- chondral defect with microdrill holes was created in both femoral patellar grooves of an adult New Zealand White rabbit, one of which was filled with blood/chitosan gel, and another left untreated.
- the joints were fixed, processed in LR-White, and Toluidine blue stained.
- Fig. 23A a large number of cells migrating towards the defect filled with blood/chitosan were evident
- Fig. 23B fewer migrating cells were seen at the same region of the untreated defect
- chondral defect with microdrill holes was created in both femoral patellar grooves of an adult New Zealand White rabbit, one of which was filled with blood/chitosan gel, and another left untreated. At 51 or 56 days after healing, the joints were fixed, processed in LR-White, and Toluidine blue stained.
- repair tissue from the blood/chitosan-treated defect had the appearance of metachromatically staining hyaline cartilage, which adhered to the defect surfaces, and filled the defect.
- repair tissue from the untreated defect had the appearance of fibro-cartilage, with practically no metachromatic staining for GAG, and only partial defect filling.
- Examples include: 1) altered chitosan concentration and mixing ratio with blood 2) altered choice of aqueous solution by changing buffer type and species concentration 3) an aqueous suspension of chitosan aggregates 4) a particulate chitosan powder combined with a proper mixing technique to distribute these particle throughout the blood and partly dissolve them.
- Other polymers may be used such as 1) another polysaccharide like hyaluronan if its anti-coagulant effect is overcome by formulating it in a procoagulating state (such as by using a low concentration or combining it with thrombin) and 2) a protein polymer such as polylysine or collagen could be used to achieve similar effects.
- these and other formulations are considered part of the present invention since they possess the characteristics of the polymer preparation of the present invention being that 1) it is mixable with blood or selected components of blood, 2) that the resulting mixture is injectable or can be placed at or in a body site that requires tissue repair, regeneration, reconstruction or bulking and 3) that the mixture has a beneficial effect on the repair, regeneration, reconstruction or bulking of tissue at the site of placement .
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MXPA03000203A MXPA03000203A (en) | 2000-06-29 | 2001-06-29 | Composition and method for the repair and regeneration of cartilage and other tissues. |
EP01947086A EP1294414B1 (en) | 2000-06-29 | 2001-06-29 | Composition and method for the repair and regeneration of cartilage and other tissues |
JP2002505053A JP5089006B2 (en) | 2000-06-29 | 2001-06-29 | Compositions and methods for repair and regeneration of cartilage and other tissues |
CN01814068.8A CN1471412B8 (en) | 2000-06-29 | 2001-06-29 | For repairing and regeneration of cartilage and the composition of other tissue and the purposes of said composition |
IL15349001A IL153490A0 (en) | 2000-06-29 | 2001-06-29 | Composition and method for the repair and regeneration of cartilage and other tissues |
AU2001268882A AU2001268882B2 (en) | 2000-06-29 | 2001-06-29 | Composition and method for the repair and regeneration of cartilage and other tissues |
AU6888201A AU6888201A (en) | 2000-06-29 | 2001-06-29 | Composition and method for the repair and regeneration of cartilage and other tissues |
CA002412505A CA2412505C (en) | 2000-06-29 | 2001-06-29 | Composition and method for the repair and regeneration of cartilage and other tissues |
NZ523763A NZ523763A (en) | 2000-06-29 | 2001-06-29 | Compostion and method for the repair and regeneration of cartilage and other tissues |
KR1020027017970A KR100880622B1 (en) | 2000-06-29 | 2001-06-29 | Composition and method for the repair and regeneration of cartilage and other tissues |
DE60117984T DE60117984T8 (en) | 2000-06-29 | 2001-06-29 | COMPOSITION AND METHOD FOR REPAIRING AND REGENERATING CARTIL AND OTHER WOVEN FABRICS |
BRPI0112109-0A BR0112109A (en) | 2000-06-29 | 2001-06-29 | composition and method for the correction and regeneration of cartilage and other tissues |
IL153490A IL153490A (en) | 2000-06-29 | 2002-12-16 | Composition and method for the repair and regeneration of cartilage and other tissues |
HK03106897A HK1055563A1 (en) | 2000-06-29 | 2003-09-25 | Composition and method for the repair and regeneration of cartilage and other tissues |
CY20061100743T CY1106313T1 (en) | 2000-06-29 | 2006-06-07 | COMPOSITION AND METHOD FOR THE RESTORATION AND REGENERATION OF CARTILAGE AND OTHER TISSUES |
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