Article

Safe Delivery of Anti-Fibrotic Reagents into the Intra-Articular Rabbit Knee Using Biodegradable Oligo [Poly(ethylene glycol) Fumarate] (OPF) Implants

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Abstract

Implantable biomaterials supporting extended release of pharmacologic agents may permit localized intra-articular delivery of drugs that modulate the fibrotic response to injuries and surgery. Oligo[Poly (ethylene glycol)] Fumarate (OPF) is an attractive organic carrier, but its safety profile within synovial joints remains unclear. Here, we assessed the safety of OPF sponges using a validated in vivo model of knee arthrofibrosis. A cohort of 102 rabbits was divided into 5 groups: arthrotomy only (24), arthrotomy with OPF scaffold placement (24), surgically induced contracture (24), surgically induced contracture with OPF scaffold placement (24), and control without any surgical intervention (6). Six rabbits per surgical group were sacrificed at 72 hours, 2 weeks, 8 weeks, and 24 weeks. Outcomes included biomechanical testing of range of motion, histologic analysis of synovial and cartilage tissues, and scaffold degradation. Cartilage histology and biomechanical measurements were comparable between groups with and without OPF. Synovial inflammation scores were similar among most groups with a minimally elevated score in the rabbits with arthrotomy and OPF versus those with arthrotomy alone. Scores for synovial tissues in rabbits with contracture and OPF were clinically equivalent to those with contractures alone. Most animals (92%) retained scaffold fragments at 24 weeks. Thus, OPF scaffolds implanted into native or arthrofibrotic rabbit knees neither induce nor aggravate cartilage damage, synovial inflammation or contractures. The apparent safety of OPF scaffolds suggests it is a suitable carrier for the controlled delivery of reagents into the intra-articular joint space to treat arthrofibrosis.

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... We have previously published the ability of this technique to induce a severe joint contracture for 24 weeks. 1,[4][5][6][7][8][9][10][11][12][13] The remobilization procedure was performed eight weeks after the index procedure. In this procedure, the K-wire was removed. ...
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Contracture of the collateral ligaments is considered to be an important factor in post-traumatic stiffness of the elbow. We reviewed the results of isolated release of the medial collateral ligament in a series of 14 patients with post-traumatic loss of elbow flexion treated between 1998 and 2002. There were nine women and five men with a mean age of 45 years (17 to 76). They were reviewed at a mean follow-up of 25 months (9 to 48). The operation was performed through a longitudinal posteromedial incision centred over the ulnar nerve. After decompression of the ulnar nerve, release of the medial collateral ligament was done sequentially starting with the posterior bundle and the transverse component of the ligament, with measurement of the arc of movement after each step. If full flexion was not achieved the posterior half of the anterior bundle of the medial collateral ligament was released. At the latest follow-up, the mean flexion of the elbow improved significantly from 96° (85° to 115°) pre-operatively to 130° (110° to 150°) at final follow-up (p = 0.001). The mean extension improved significantly from 43° (5° to 90°) pre-operatively to 22° (5° to 40°) at final follow-up (p = 0.003). There was a significant improvement in the functional outcome. The mean Broberg and Morrey score increased from a mean of 54 points (29.5 to 85) pre-operatively to 87 points (57 to 99) at final follow-up (p < 0.001). All the patients had normal elbow stability. Our results indicate that partial surgical release of the medial collateral ligament is associated with improved range of movement of the elbow in patients with post-traumatic stiffness, but was less effective in controlling pain.
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The elbow is as prone to stiffness as it is essential for upper-extremity function. The elbow is a highly constrained synovial hinge joint that frequently becomes stiff after injury. Elbow contracture is challenging to treat, and therefore prevention is of paramount importance. When this approach fails, nonoperative followed by operative treatment modalities can be pursued. In the future, efforts to prevent and treat elbow stiffness may target the basic science mechanisms involved. (J Hand Surg 2009;34A:769-778. (C) 2009 Published by Elsevier Inc. on. behalf of the American Society for Surgery of the Hand.)
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Treatment of the stiff elbow by arthroscopic capsular release is a relatively new and effective procedure. The surgery is technically demanding and is not indicated in all cases of stiff elbow. Although neurologic complications are unusual, they can be severe and permanent. Neurologic structures at particular risk are the posterior interosseous and ulnar nerves. Rehabilitation is as important as the surgical procedure itself. Arthroscopic capsular release is particularly effective in elbows with minor flexion contractures (less than 30 degrees) and might have some advantages over an open procedure for these minor contractures.
Article
Reported models of joint contracture fail to result in severe motion loss. Our purpose was to develop a rabbit model of knee contracture and compare it to another well-accepted model to determine if more severe stiffness can be achieved. Sixteen skeletally mature New Zealand White female rabbits had their right knee operated to create 3-mm defects on the noncartilaginous portions of the femoral condyles, hyperextend the joint to disrupt the posterior capsule, and immobilize the joint in maximum flexion with a Kirschner-wire for 8 weeks (group I). Sixteen additional rabbits were operated on using an identical protocol except for the absence of capsular injury (group II). In each group, mechanical testing was performed at the time of Kirschner-wire release in eight animals, and 16 weeks after remobilization in eight animals. At immobilization release, the average contracture was 76 +/- 24 degrees in group I versus 20 +/- 10 degrees in group II (p < 0.001). Sixteen weeks after remobilization, the mean contracture was 49 +/- 15 degrees group I versus 11 +/- 10 degrees in group II (p < 0.001). When associated with bone perforations and immobilization in forced flexion, injury to the posterior capsule results in a severe contracture in the rabbit knee.
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The right lower extremities of 64 young rabbits were immobilized by a plaster spica. The animals developed a gait pattern, which included internal tibial rotation and adduction of the left (unimmobilized) tibia. Twenty-one of the animals developed medial patellar dislocation in the unimmobilized lower extremity. The mechanism of the patellar dislocation in this experimental model was possibly overstretching of the lateral colateral ligament and the lateral side of the joint capsule, associated with medial rotation of the tibia and the tibial tubercle. The direction of patellar pull when gliding inferiorly during knee flexion was shifted medially, resulting in patellar dislocation and secondarily, in formation of an exostosis under the displaced patella. Hip arthrodesis in humans, as a course of rotational instability of the contralateral knee, resembles some aspects of this experimental condition.
Article
The problem of the contracted elbow is well-recognized for the circumstances under which it develops and the difficulty of operative and non-operative treatment. Earlier studies report this problem in an unfavorable manner; however, current studies suggest that posttraumatic stiffness of the elbow, particularly when the articular surface is left intact, may be treated reliably. The authors present a specific surgical approach to the elbow that has posttraumatic motion limitation described as extrinsic, that is, primarily attributable to contracture of the capsule and periarticular soft tissues. The limited surgical exposure termed the column procedure allows anterior capsular exposure through an interval in the brachioradialis and extensor carpi radialis longus. Using this procedure the authors report the treatment of 38 elbows (38 patients) with sufficient followup to accurately describe the postoperative course. At a mean of 3.5 years after surgery the total postoperative arc of motion improved from approximately 50 degrees to approximately 90 degrees. There were minimal complications. A static adjustable splint rather than physical therapy is used postoperatively. It is concluded that newer surgical techniques with carefully described programs can be successful in the majority of patients undergoing surgical release for extrinsic contracture of the elbow.
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The treatment of large cranial defects may be greatly improved by the development of precisely formed bone tissue engineering scaffolds. Such scaffolds could be constructed by using UV laser stereolithography to photocrosslink a linear, biodegradable polymer into a three-dimensional implant. We have previously presented a method to photocrosslink the biodegradable polyester, poly(propylene fumarate) (PPF). To ensure the safety and effectiveness of this technique, the soft and hard tissue response to photocrosslinked PPF scaffolds of different pore morphologies was investigated. Four classes of photocrosslinked PPF scaffolds, constructed with differing porosities (57-75%) and pore sizes (300-500 or 600-800 microm), were implanted both subcutaneously and in 6.3-mm-diameter cranial defects in a rabbit model. The rabbits were sacrificed at 2 and 8 weeks, and the implants were analyzed by light microscopy, histological scoring analysis, and histomorphometric analysis. Results showed the PPF scaffolds elicit a mild tissue response in both soft and hard tissues. Inflammatory cells, vascularization, and connective tissue were observed at 2 weeks; a decrease in inflammatory cell density and a more organized connective tissue were observed at 8 weeks. Scaffold porosity and scaffold pore size were not found to significantly affect the observed tissue response. Evidence of scaffold surface degradation was noted both by histology and histomorphometric analysis. Bone ingrowth in PPF scaffolds implanted into cranial defects was <3% of the defect area. The results indicate that photocrosslinked PPF scaffolds are biocompatible in both soft and hard tissues and thus may be an attractive platform for bone tissue engineering.
Article
This study was designed to assess in vivo bone and soft tissue behavior of novel oligo(poly(ethylene glycol) fumarate) (OPF) hydrogels using a rabbit model. In vitro degradation of the OPF hydrogels was also investigated in order to compare with in vivo characteristics. Four groups of OPF hydrogel implants were synthesized by alternation of crosslinking density, poly(ethylene glycol) (PEG) block length of OPF, and cell-binding peptide content. The in vitro degradation rate of OPF hydrogels increased with decreasing crosslinking density of hydrogels, which was characterized by measuring weight loss and swelling ratio of hydrogels and medium pH change. Examination of histological sections of the subcutaneous and cranial implants showed that an uniform thin circumferential fibrous capsule was formed around the OPF hydrogel implants. Quantitative evaluation of the tissue response revealed that no statistical difference existed in capsule quality or thickness between implant groups, implantation sites or implantation times. At 4 weeks, there was a very limited number of inflammatory and multinuclear cells at the implant-fibrous capsule interface for all implants. However, at 12 weeks, OPF hydrogels with PEG block length of number average molecular weight 6090+/-90 showed extensive surface erosion and superficial fragmentation that was surrounded by a number of inflammatory cells, while OPF hydrogels with PEG block length of number average molecular weight 930+/-10 elicited minimal degradation. Constant fibrous capsule layers and number of inflammatory cells were observed regardless of the incorporation of cell-binding peptide and crosslinking density of OPF hydrogels with PEG block length of number average molecular weight 930+/-90. These results confirm that the degradation of implants can be controlled by tailoring the macromolecular structure of OPF hydrogels. Additionally, histological evaluation of implants proved that the OPF hydrogel is a promising material for biodegradable scaffolds in tissue engineering.
Article
To characterize the rabbit anterior cruciate ligament transection (ACLT) model of osteoarthritis (OA) at various stages of disease using high-resolution 3-D medical imaging systems, which, in turn, will facilitate future longitudinal studies evaluating disease progression and response to therapy in live animals. Degenerative changes in femorotibial cartilage, volumetric bone mineral density (vBMD), bone volume fraction (BV/TV), and osteophyte volume were characterized ex vivo using 4-T magnetic resonance imaging (MRI) and micro-computed tomography (micro-CT) at 4, 8, and 12 weeks post-ACLT. These changes were subsequently correlated to macroscopic joint evaluation. Macroscopic assessment demonstrated progressive cartilage degeneration post-surgery, which was significantly correlated to MRI evaluation (r=0.82, P<0.0001). Linear regression analysis indicated that vBMD and BV/TV are linearly related such that as vBMD increases, BV/TV increases (P<0.0001). Micro-CT revealed bone loss at 4 and 8 weeks post-ACLT, but recovery to control values at 12 weeks post-ACLT. Volumetric BMD was not strongly correlated with macroscopic assessment of articular cartilage degeneration (r=-0.35, P<0.0001). Quantitative measurement of osteophyte volume demonstrated a statistically significant difference (with respect to control groups) at both 8 and 12 weeks post-ACLT, but not at 4 weeks post-ACLT. The rabbit ACLT model of OA demonstrates progressive cartilage degeneration and intermediate bone changes at 4, 8, and 12 weeks post-surgery. Cartilage and bone lesions were characterized ex vivo using 4-T MRI and micro-CT, and MRI assessment of cartilage degeneration was correlated to macroscopic grading.
Article
The development of joint contracture is a well-recognized complication of elbow injury. Precise causes of the propensity of this joint for ankylosis are understood poorly. Yet, treatment is emerging and therefore the indications and willingness on the part of the surgeon to address this problem is improving. Limited open procedures have emerged during the past several years that are safe and effective by improving arcs of motion of 50-70 degrees in approximately 80-90% of patients. For severe injuries that involve the articular surface, interposition arthroplasty is less documented but has been shown to be effective but constitutes one of the most challenging technical procedures. Joint replacement arthroplasty generally should not be considered as a treatment for posttraumatic stiffness unless the patient is older than 65 years. The experience with this procedure indicates that with linked semiconstrained implants, approximately 80% of patients will achieve a near functional arc of motion. Arthroscopic intervention shows the greatest activity of investigation and clinical expansion. The learning curve is defined by a concern of complications to the neural structures and the fear of this complication has limited the application but the emerging documentation of the safeness of this option also has been associated with improved effectiveness. Therefore, arthroscopic intervention for the stiff elbow, particularly those with soft tissue extrinsic involvement, is emerging as the treatment of choice in many instances. The investigation regarding the medical treatment of altering the tendency of the soft tissue to go through such intense contracture is in its infancy but suggests that this could be a long-term solution at least for many patients.
Article
The elbow joint is vulnerable to stiffness, especially after trauma. The aim of this study was to evaluate the results of open arthrolysis for posttraumatic elbow stiffness. Cohort retrospective study. Eighteen consecutive patients were evaluated by an independent observer at an average of 16 months (6 to 43) after open elbow arthrolysis was performed for posttraumatic stiffness. Initial traumas were: isolated fractures (11) or dislocation (1) and complex fracture-dislocations (6). Initial treatments were: nonoperative (3), radial head resection (1), and ORIF (14). Patients presented predominantly with mixed contractures (combined extrinsic and intrinsic contractures). Open elbow arthrolysis. Elbow function and patient satisfaction were the principal outcome measures. At follow-up European Society for Shoulder and Elbow Surgery (SECEC) elbow scores were calculated. Three patients had minor postoperative complications: 1 partial wound dehiscence, 1 subcutaneous infection, and one seroma. None of these complications influenced the final result clinically. The mean total increase in range of motion was 40 degrees (13 to 112 degrees), with a mean gain in flexion of 14 degrees (0 to 45 degrees) and 26 degrees in extension (5 to 67 degrees). No patient showed signs of elbow instability. There was no radiographic evidence of osteoarthritis progression at follow-up. We did not find any correlations between the type of stiffness, the approaches used, and the results. However, patients with the greatest preoperative stiffness had significantly better improvement of mobility (P<0.001). The best results were obtained in patients who had arthrolysis done within 1 year after the initial trauma (P=0.008). The mean SECEC scores were 88 (52 to 100) for the injured elbows, and 96 (88 to 100) for the contralateral elbows. Open elbow arthrolysis for patients with posttraumatic stiffness improves joint function and provides patient satisfaction. The best results, in terms of gain of motion and patient satisfaction, were obtained in patients with severe stiffness who had operations within the first year after initial trauma.
Article
Post-traumatic elbow stiffness can be caused by a tether and/or a block, and these structures can exist both anteriorly and posteriorly about the joint to prevent motion. The purpose of this article is to report the outcome of elbow release performed for post-traumatic stiffness by a single surgeon. A retrospective review of charts and radiographs was performed on 52 case of patients who underwent open surgical treatment for post-traumatic elbow contracture by the senior author (RHN). The mean age of the group was 35.1 years. There were 32 men and 20 women. Contracture release surgery was performed at an average of 14 months from the time of injury. Indication for operative release was functional loss of elbow arc of motion that failed nonoperative therapy and splinting program. Follow-up was 18.7 months. Comparison of ranges of motion was performed with Student's paired t tests. The average extension-flexion arc of motion improved from 57 to 116 degrees and forearm rotation improved from 119 to 145 degrees postoperatively. Fourteen patients (27%) required closed manipulation under anesthesia, in the early postoperative period. Five patients required a second contracture release at an average of 12 months after the index release. Four patients failed because of painful motion (n = 2) and elbow instability (n = 2). Other complications included wound infection (n = 3), cubital tunnel syndrome (n = 3) and reflex sympathetic dystrophy (n = 1). Open elbow release with excision of tethers and blocks is a valuable procedure for post-traumatic stiffness. Recurrence in postoperative period is common but is responsive to manipulation under anesthesia and repeat releases.
Article
To standardize the histopathological assessment of synovial membrane specimens in order to contribute to the diagnostics of rheumatic and non-rheumatic joint diseases. Three features of chronic synovitis (enlargement of lining cell layer, cellular density of synovial stroma, leukocytic infiltrate) were semiquantitatively evaluated (from 0, absent to 3, strong) and each feature was graded separately. The sum provided the synovitis score, which was interpreted as follows: 0-1, no synovitis; 2-4, low-grade synovitis; 5-9, high-grade synovitis. Five hundred and fifty-nine synovectomy specimens were graded by two independent observers. Clinical diagnoses were osteoarthrosis (n=212), post-traumatic arthritis (n=21), rheumatoid arthritis (n=246), psoriatic arthritis (n=22), reactive arthritis (n=9), as well as controls (n=49) from autopsies of patients without joint damage. Median synovitis scores when correlated with clinical diagnoses were: controls 1.0, osteoarthritis 2.0, post-traumatic arthritis 2.0, psoriatic arthritis 3.5, reactive arthritis 5.0 and rheumatoid arthritis 5.0. The scores differed significantly between most disease groups, especially between degenerative and rheumatic diseases. A high-grade synovitis was strongly associated with rheumatic joint diseases (P<0.001, sensitivity 61.7%, specificity 96.1%). The correlation between the two observers was high (r=0.941). The proposed synovitis score is based on well-defined, reproducible histopathological criteria and may contribute to diagnosis in rheumatic and non-rheumatic joint diseases.
Article
Etiologies of elbow contractures can be classified into intrinsic versus extrinsic causes. Posttraumatic elbow stiffness is the most common intrinsic cause and HO formation is the most common extrinsic cause of elbow contractures. Patients who sustain significant elbow trauma and have one or more risk factors for HO formation should be given prophylaxis against HO formation in the form of either indomethacin or radiation therapy. Early excision of HO has been shown to be safe and effective. Nonoperative measures are most effective if used within 6 months of contracture onset. These measures include physical therapy and an aggressive splinting program. If nonoperative measures are unsuccessful and the patient has functionally limiting elbow ROM, then surgical intervention should be considered. Careful preoperative assessment of the ulnar nerve is mandatory, as it may need to be transposed. Satisfactory results have been reported with arthroscopic elbow contracture releases. However, this procedure is technically challenging, with the potential for serious neurovascular complications. Satisfactory results have been published for open procedures as well. The direction of the greatest limitation of motion, the presence of ulnar nerve dysfunction, and the location of osteophytes all help to dictate which surgical approach should be selected.
Article
This study describes investigation of porous photocrosslinked oligo[(polyethylene glycol) fumarate] (OPF) hydrogels as potential matrix for osteoblastic differentiation of marrow stromal cells (MSCs). The porosity and interconnectivity of porous hydrogels were assessed using magnetic resonance microscopy (MRM) as a noninvasive investigative tool that could image the water construct inside the hydrogels at a high-spatial resolution. MSCs were cultured onto the porous hydrogels and cell number was assessed using PicoGreen DNA assay. Our results showed 10% of cells initially attached to the surface of scaffolds. However, cells did not show significant proliferation over a time period of 14 days. MSCs cultured on porous hydrogels had increased alkaline phosphatase activity as well as deposition of calcium, suggesting successful differentiation and maturation to the osteoblastic phenotype. Moreover, continued expression of type I collagen and osteonectin over 14 days confirmed osteoblastic differentiation of MSCs. MRM was also applied to monitor osteogenesis of MSCs on porous hydrogels. MRM images showed porous scaffolds became consolidated with osteogenic progression of cell differentiation. These findings indicate that porous OPF scaffolds enhanced MSC differentiation leading to development of bone-like mineralized tissue.
Article
The joint cavity constitutes a discrete anatomical compartment that allows for local drug action after intra-articular injection. Drug delivery systems providing local prolonged drug action are warranted in the management of postoperative pain and not least arthritic disorders such as osteoarthritis. The present review surveys various themes related to the accomplishment of the correct timing of the events leading to optimal drug action in the joint space over a desired time period. This includes a brief account on (patho)physiological conditions and novel potential drug targets (and their location within the synovial space). Particular emphasis is paid to (i) the potential feasibility of various depot formulation principles for the intra-articular route of administration including their manufacture, drug release characteristics and in vivo fate, and (ii) how release, mass transfer and equilibrium processes may affect the intra-articular residence time and concentration of the active species at the ultimate receptor site.