Biologic therapies in stress fractures: Current concepts.

Stress fractures, a common overuse injury in physically active individuals, present a significant challenge for athletes and military personnel. Patients who sustain stress fractures have demanding training regimes where periods of rest and immobilisation have unacceptable negative consequences on sports goals and finances. Aside from being an overuse injury, there are various contributing risk factors that put certain individuals at risk of a stress fracture. The main two being nutritional deficiencies and hormonal variations, which have significant effects on bone metabolism and turnover. Historically, treatment of stress fractures focused on conservative strategies such as rest and immobilisation. Calcium and vitamin D deficiencies have been closely linked to stress fractures and so over time supplementation has also played a role in treatment. With the introduction of biologics into orthopaedics, newer treatment strategies have been applied to accelerate fracture healing and perhaps improve fracture callus quality. If such therapies can reduce time spent away from sport and activity, it would be ideal for treating stress fractures. This article aims to offer insights into the evolving landscape of stress fracture management. It investigates the pre-clinical evidence and available published clinical applications. Though fracture healing is well understood, the role of biologics for fracture healing is still indeterminate. Available literature for the use of biologic therapies in stress fractures are restricted and most reports have used biologics as a supplement to surgical fixation in subjects in studies that lack control groups. Randomised control trials have been proposed and registered by a few groups, with results awaited. Assessing individuals for risk factors, addressing hormonal imbalances and nutritional deficiencies seems like an effective approach to addressing the burden of stress fractures. We await better designed trials and studies to accurately determine the clinical benefit of adding biologics to the management of these injuries.

Meniscal Circumferential Fiber Augmentation: A Biomechanical Arthroscopic Meniscal Repair Technique.

Radial tears of the human knee meniscus result in the loss of circumferential hoop stress and are highly correlated with knee degeneration. Although a variety of surgical techniques are available to repair radial meniscal tears, including inside-out, outside-in, and all-inside techniques, conventional repair techniques focus only on stabilizing the damaged portion. This Technical Note describes a biomechanical meniscus repair technique of meniscal circumferential fiber augmentation, concomitant with conventional repair, to promote meniscal healing from a biomechanical perspective.

Repair of osteochondral defects: efficacy of a tissue-engineered hybrid implant containing both human MSC and human iPSC-cartilaginous particles.

Both mesenchymal stromal cells (MSC) and induced pluripotent stem cells (iPSC) offer the potential for repair of damaged connective tissues. The use of hybrid implants containing both human MSC and iPSC was investigated to assess their combined potential to yield enhanced repair of osteochondral defects. Human iPSC-CP wrapped with tissue engineered constructs (TEC) containing human MSC attained secure defect filling with good integration to adjacent tissue in a rat osteochondral injury model. The presence of living MSC in the hybrid implants was required for effective biphasic osteochondral repair. Thus, the TEC component of such hybrid implants serves several critical functions including, adhesion to the defect site via the matrix and facilitation of the repair via live MSC, as well as enhanced angiogenesis and neovascularization. Based on these encouraging studies, such hybrid implants may offer an effective future intervention for repair of complex osteochondral defects.

Improved responsiveness for JKOOS+ compared to KOOS in Japanese patients undergoing total knee arthroplasty.

BACKGROUND: Existing knee related patient reported outcome measurements (PROMs) have overwhelmingly been developed and validated in western chair-based societies, suggesting a potential for a western bias in PROMs evaluation of patients with knee conditions. We, therefore, endeavor to evaluate the responsiveness of the previously developed culturally relevant Japanese version of the knee injury and osteoarthritis outcome score (JKOOS+). METHODS: We enrolled 114 patients scheduled for total knee arthroplasty (TKA) across 8 knee clinics in Japan. Patients completed the Oxford Knee Score (OKS) and JKOOS + both at the time of enrollment and again 1-year post-TKA. Responsiveness was evaluated using effect size and standardized response mean (SRM). An effect size or SRM >0.8 is considered adequately responsive. We further tested the difference in responsiveness between the original Japanese language KOOS activities of daily living (ADL) domain and the novel Japanese ADL (JADL) domain using the modified Jacknife test. RESULTS: All domains were adequately responsive with the exception of the KOOS sports and recreation domain, which has previously been ignored by TKA researchers due to its lack of applicability to elderly patients undergoing TKA. The JADL domain outperformed the ADL domain in both effect size (1.51 v. 1.45) and SRM (1.67 v. 1.57) (p < 0.001). The novel Knee Flexion (KF) domain was adequately responsive, though less responsive than other domains except sports and recreation (p < 0.01 v. all other PROMs domains). CONCLUSIONS: The JKOOS+ JADL domain is significantly more responsive than the Europe-developed ADL domain to TKA in Japanese knee patients suffering from knee osteoarthritis (OA). The KF domain, unique to the JKOOS+ and intended to assess difficulty with knee flexion, is adequately responsive to TKA in Japanese patients suffering from OA.

Review of Caplan (1991) on cell-based therapeutic technology using Mesenchymal Stem Cells.

This classic discusses the original 1991 publication 'Mesenchymal Stem Cells (MSCs)' by Dr. Caplan on the emergence of a new therapeutic technology of self-cell repair using MSCs. After the original classic publication, a large number of methods to regenerate injured tissue have been reported. Currently, MSCs are used clinically to repair articular cartilage defects, liver cirrhosis, cerebral infarction, spinal cord injury, graft-versus-host disease and others. As a result, MSCs are considered one of the most important cell sources for regenerative medicine. An MSC has been demonstrated to be a multipotent stem cell in cell culture and was thought to contribute to the regeneration of injured tissue at transplant sites, but recently, the concept of MSCs has changed such that they are now referred to as "medicinal signaling cells," owing to their often indirect effects on tissue repair and regeneration. Regardless of the name, either mesenchymal stem cells or medicinal signaling cells, MSCs will be used to regenerate injured tissue more widely in the near future.

Five-Year Outcomes After Implantation of a Scaffold-Free Tissue-Engineered Construct Generated From Autologous Synovial Mesenchymal Stromal Cells for Repair of Knee Chondral Lesions.

Background: In an earlier study, a scaffold-free tissue-engineered construct (TEC) derived from autologous synovial membrane mesenchymal stromal cells (MSCs) was developed and demonstrated to be safe and effective for cartilage repair at 2 years postoperatively. Purpose: To investigate clinical outcomes and magnetic resonance imaging (MRI) findings at 5 years after implantation. Study Design: Case series; Level of evidence, 4. Methods: This was an observational first-in-human study limited to 5 patients (age, 28-46 years) with symptomatic knee chondral lesions (size, 1.5-3.0 cm2) on the medial femoral condyle, lateral femoral condyle, or femoral groove. Synovial MSCs were isolated from arthroscopic biopsy specimens and cultured to develop a TEC that matched the lesion size. The TECs were then implanted into chondral defects without fixation and assessed at up to 5 years postoperatively. The patients were clinically evaluated using the visual analog scale for pain, Lysholm score, Tegner score, and Knee injury and Osteoarthritis Outcome Score. An MRI scan evaluation was also performed for morphologic and compositional quality of the repair tissue at both 2 and 5 years of follow-up. Results: All clinical scores were significantly improved from the preoperative evaluation to the 2- and 5-year follow-ups and the results were stable over time. The MRI scan evaluation showed cartilage defects filled with newly generated tissues with good tissue integration to adjacent host cartilage over time. The cartilage thickness and surface smoothness of the repair cartilage were maintained up to 5 years postoperatively. The MOCART (magnetic resonance observation of cartilage repair tissue) 2.0 Knee Scores remained high at 5 years, although the total points decreased slightly. Conclusion: The results highlight the efficacy and feasibility of autologous scaffold-free TEC derived from synovial MSCs for regenerative cartilage repair via a sutureless and simple implantation procedure, showing good clinical outcomes and MRI findings with stable results at midterm follow-up. Further follow-up will be needed to assess the long-term quality of the repair tissue.

Small extracellular vesicles derived from human adipose-derived mesenchymal stromal cells cultured in a new chemically-defined contaminate-free media exhibit enhanced biological and therapeutic effects on human chondrocytes in vitro and in a mouse osteoarthritis model.

Human small extracellular vesicles (sEVs) derived from adipose-derived mesenchymal stromal cells (ASC) have been reported to suppress the progression of osteoarthritis (OA) in animal studies and subsequently, translation of this potential to assess their clinical efficacy is anticipated. However, fabrication protocols for sEVs to eliminate potential contamination by culture medium-derived components need to be established prior to their clinical use. The purpose of the present studies was to elucidate the influence of medium-derived contaminants on the biological effects of sEVs, and to establish isolation methods for sEVs using a new clinical grade chemically-defined media (CDM). The quantity and purity of ASC-derived sEVs cultured in four different CDMs (CDM1, 2, 3 and 4) were evaluated. The concentrates of the four media incubated without cells were used as the background (BG) control for each set of sEVs. The biological effect of sEVs fabricated in the four different CDMs on normal human articular chondrocytes (hACs) were evaluated in vitro using a variety of methodological assessments. Finally, the sEVs with the highest purity were tested for their ability to suppress the progression of knee OA mouse model. Analysis of the BG controls revealed that CDM1-3 contained detectable particles, while there was no visible contamination of culture media-derived components detected with CDM4. Accordingly, the sEVs fabricated with CDM4 (CDM4-sEVs) exhibited the highest purity and yield. Notably, the CDM4-sEVs were the most efficient in promoting the cellular proliferation, migration, chondrogenic differentiation, and anti-apoptotic activity of hACs. Furthermore, CDM4-sEVs significantly suppressed the osteochondral degeneration in vivo model. Small EVs derived from ASCs cultured in a CDM without detectable contaminants demonstrated enhanced biological effects on hACs and the progression of OA. Thus, sEVs isolated with CDM4 most optimally meet the requirements of efficacy and safety for assessment in their future clinical applications.

Freeze-dried noncoagulating platelet-derived factor concentrate is a safe and effective treatment for early knee osteoarthritis.

PURPOSE: While a wide variety of platelet-rich plasma (PRP) solutions has been developed, innovation continues. In this case, the freeze-dried platelet factor concentrate (PFC-FD) represents another step in PRP refinement. The preparation of PFC-FD at a central laboratory with freeze drying for shelf stabilization should provide additional quality improvements if clinical effectiveness can be demonstrated. Therefore, this study was undertaken to assess the safety and effectiveness of PFC-FD in a prospective open-label trial of patients suffering from knee osteoarthritis (OA). METHODS: 312 consecutive knee OA patients (67% female, mean age 63 ± 10 years), were prospectively recruited in an outpatient knee clinic in Japan. Of these, 10 (3.2%) were lost to follow-up at < 12 months and 17 (5.5%) sought additional knee therapy during the follow-up period. The primary outcome of interest was achievement of the OMERACT-OARSI responder criteria with secondary outcomes of adverse events and PROMs scores 1, 3, 6, 12 months following a single PFC-FD injection. RESULTS: 285 patients (91%) completed 12 month PROMs. The 17 who sought additional therapy were considered failures leaving an effective sample size of 302 for our primary outcome in which 62% of patients achieved OMERACT-OARSI responder status by 12 months. This varied by OA class with Kellgren-Lawrence grade 4 patients 3.6 times less likely to be responders than grade 1-2 patients. 6% of patients experienced a non-serious adverse event, primarily pain or swelling at the injection site. CONCLUSIONS: PFC-FD provides an observable clinical improvement in 62% of knee OA patients at 12 months post-injection with very little risk of any clinically relevant adverse event. Of course, nearly 40% of patients did not experience an observable clinical improvement, primarily among those with worse KL grades. LEVEL OF EVIDENCE: Therapeutic, Level II.

Open wedge high tibial osteotomy does not decrease patellar height relative to femur: A three-dimensional computer model analysis.

BACKGROUND: Patellar height, which decreases after open wedge high tibial osteotomy (OWHTO), has conventionally been assessed by tibial references using lateral radiographs of the knee; however, changes in the proximal tibia shape after OWHTO may affect this method. We aimed to evaluate the changes in patellar height position relative to the transepicondylar axis of the femur after OWHTO using in vivo three-dimensional (3D) computer models. METHODS: Fourteen patients who underwent 3D magnetic resonance imaging (MRI) at 30° and 50° knee flexion before OWHTO and after hardware removal were included. 3D computer models of the knee were created from the MRI scans and superimposed over the images taken in each position using voxel-based registration. For patellar height evaluation, a patellar reference point was established at each flexion angle and the femoral condylar planes (FCP) were set, including the transepicondylar axis. The patellar center angle was defined as the angle between an FCP that included the top of the intercondylar notch and an FCP that included the patellar reference point. The patellar center angle was evaluated at 30° and 50° knee flexion before and after OWHTO. RESULTS: The patellar center angle at 30° and 50° knee flexion did not significantly decrease after OWHTO, whereas the Caton-Deschamps index and Blackburne-Peel index based on tibia-referenced measurements significantly decreased postoperatively. CONCLUSION: Patellar height position relative to the femur in the 3D computer model did not decrease after OWHTO, whereas tibia-referenced conventional radiographic measurements significantly decreased. When evaluating patellar height, characteristics of each parameter should be considered.

Regulatory and Ethical Aspects of Orthobiologic Therapies.

Orthobiologic therapies show significant promise to improve outcomes for patients with musculoskeletal pathology. There are considerable research efforts to develop strategies that seek to modulate the biological environment to promote tissue regeneration and healing and/or provide symptomatic relief. However, the regulatory pathways overseeing the clinical translation of these therapies are complex, with considerable worldwide variation. The introduction of novel biologic treatments into clinical practice raises several ethical dilemmas. In this review, we describe the process for seeking approval for biologic therapies in the United States, Europe, and Japan. We highlight a number of ethical issues raised by the clinical translation of these treatments, including the design of clinical trials, monitoring outcomes, biobanking, "off-label" use, engagement with the public, marketing of unproven therapies, and scientific integrity.

Creating an Optimal In Vivo Environment to Enhance Outcomes Using Cell Therapy to Repair/Regenerate Injured Tissues of the Musculoskeletal System.

Following most injuries to a musculoskeletal tissue which function in unique mechanical environments, an inflammatory response occurs to facilitate endogenous repair. This is a process that usually yields functionally inferior scar tissue. In the case of such injuries occurring in adults, the injury environment no longer expresses the anabolic processes that contributed to growth and maturation. An injury can also contribute to the development of a degenerative process, such as osteoarthritis. Over the past several years, researchers have attempted to use cellular therapies to enhance the repair and regeneration of injured tissues, including Platelet-rich Plasma and mesenchymal stem/medicinal signaling cells (MSC) from a variety of tissue sources, either as free MSC or incorporated into tissue engineered constructs, to facilitate regeneration of such damaged tissues. The use of free MSC can sometimes affect pain symptoms associated with conditions such as OA, but regeneration of damaged tissues has been challenging, particularly as some of these tissues have very complex structures. Therefore, implanting MSC or engineered constructs into an inflammatory environment in an adult may compromise the potential of the cells to facilitate regeneration, and neutralizing the inflammatory environment and enhancing the anabolic environment may be required for MSC-based interventions to fulfill their potential. Thus, success may depend on first eliminating negative influences (e.g., inflammation) in an environment, and secondly, implanting optimally cultured MSC or tissue engineered constructs into an anabolic environment to achieve the best outcomes. Furthermore, such interventions should be considered early rather than later on in a disease process, at a time when sufficient endogenous cells remain to serve as a template for repair and regeneration. This review discusses how the interface between inflammation and cell-based regeneration of damaged tissues may be at odds, and outlines approaches to improve outcomes. In addition, other variables that could contribute to the success of cell therapies are discussed. Thus, there may be a need to adopt a Precision Medicine approach to optimize tissue repair and regeneration following injury to these important tissues.

Clinical Safety and Effectiveness of Adipose-Derived Stromal Cell vs Stromal Vascular Fraction Injection for Treatment of Knee Osteoarthritis: 2-Year Results of Parallel Single-Arm Trials.

BACKGROUND: There are currently no disease-modifying treatments available for knee osteoarthritis (OA), although cultured adipose-derived stromal cells (ASCs) have shown promise in experimental models. However, given the regulatory limits on the use of cultured cells in humans, previous trials have focused primarily on the stromal vascular fraction (SVF) intra-articular injection. Therefore, the therapeutic value of ASCs for knee OA remains unknown. PURPOSE: To study ASC versus SVF intra-articular injection in patients with Kellgren-Lawrence (KL) knee OA grades 2 to 4 in parallel single-arm trials. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A total of 80 patients were enrolled, with 42 (72 knees) receiving ASC intra-articular injection and 38 (69 knees) receiving SVF. Patient-reported outcome measures were assessed at 1, 3, 6, 12, and 24 months using the Knee injury and Osteoarthritis Outcome Score 5 (KOOS5) and pain visual analog scale (VAS). The percentages of patients achieving the minimal clinically important difference (MCID) and Patient Acceptable Symptom State (PASS) were also calculated. Per protocol, a subset of the ASC group received an ASC booster injection after 6 months. A repeated-measures analysis of variance compared results between treatment arms and by KL grade over time. RESULTS: Patient-reported outcome measures improved substantially after both treatments (P < .05 at all time points), with the ASC group more likely to achieve the MCID (50% vs 24%; P = .01) and PASS (45% vs 24%; P = .04) for the pain VAS and the MCID (43% vs 16%; P = .02) for the KOOS5 at 12 months, although not at 24 months. Knees treated with ASC for KL grade 2/3 OA had significantly superior outcomes compared with those with KL grade 4 OA for the KOOS5 (P = .01) and pain VAS (P = .03), but no such difference was observed in knees treated with SVF. Three patients receiving ASCs (7%; all KL grade 3) sought additional nonoperative treatment by 24 months versus 9 patients receiving SVF (24%; all KL grade 3) (P = .06). ASC booster injections conferred no additional benefit. Notably, patients in the ASC cohort reported more injection-site pain and swelling after the booster injection than after the initial injection (P < .01). CONCLUSION: This represents the first head-to-head comparison of ASCs and SVF for the treatment of knee OA in humans. ASC and SVF injections both substantially improved knee pain and function at all follow-up time points, although ASC injections demonstrated significantly better improvements with regard to the MCID and PASS for the pain VAS and the MCID for the KOOS5 at 12 months. There appears to be no benefit to a booster ASC injection after initial treatment. Given less donor-site morbidity and equivalent superior outcomes at 2 years, the use of ASCs over SVF in the treatment of knee OA may be warranted.

Basic points to consider regarding the preparation of extracellular vesicles and their clinical applications in Japan.

In recent years, extracellular vesicles (EVs) have attracted attention as a new therapeutic tool. In Europe, the United States, and Asia, there is an accelerating trend of moving beyond basic research on clinical trials. However, treatment using EVs is still in the research and development stage, and the general public has insufficient awareness and understanding of the risks involved in ensuring safety and efficacy, the status of laws and regulations, and global research and development trends regarding their use. The Japanese Society for Regenerative Medicine, which has promoted the research and development of regenerative medicine, an innovative medical technology based on the principle of delivering it safely, effectively, and promptly, including the establishment of laws and regulations, would like to express two positions in light of the rapid development of therapies using EVs: 1) concern about treatments that are based solely on the discretion of medical practitioners, and 2) active promotion of treatments based on sound scientific evidence. Because EVs are released from cells, there are many similarities between EVs and processed cells in terms of manufacturing processes and safety hazards. As for efficacy, the mechanism of action of EVs is still unclear, as is the case with specified processed cellsb; in such cases, it is difficult to measure potency, identify efficacy-related quality attributes, and evaluate the comparability of quality before and after a change in the manufacturing process. In other words, the number of quality attributes that can be obtained for EVs is limited because of their complex characteristics, and it is difficult to grasp their quality through specifications and characterization. Therefore, while designing a quality control strategy for EVs, it is important to ensure the quality of the final product (EVs) by controlling the raw materials and manufacturing process. On the contrary, since EVs do not contain living cell components and are not classified into specified processed cells, non-commercial clinical research on treatments using EVs and individual medical treatments with EVs at the discretion of medical practitioners are out of the scope of the Act on the Safety of Regenerative Medicine of Japan. At present, there are no relevant laws or regulations for the use of EVs other than the Medical Practitioners' Act and the Medical Care Act in Japan. Therefore, there is a concern that treatment will be performed without sufficient objective evaluation of the scientific basis for safety and efficacy. Despite these concerns, the development of therapies using EVs is underway worldwide. This could potentially lead to a wide variety of new therapeutic areas if the methods needed to stably secure and mass cultivate cells as raw materials and the technologies needed for the mass production of EVs can be developed, in addition to understanding the risks involved and developing relevant laws and regulations. As part of the Japanese Society for Regenerative Medicine, we will continue to work on the development of these methods and technologies and hope that such a promising field will be promoted with a high level of safety before reaching the public.

Factors Associated with Postoperative Knee Joint Line Obliquity After Medial Open Wedge High Tibial Osteotomy.

BACKGROUND: There are still few reports on factors associated with postoperative knee joint line obliquity (KJLO). PURPOSE: The purpose was to determine preoperative radiographic factors that are associated with KJLO postoperatively after open wedge high tibial osteotomy (OWHTO) using multivariable linear regression analysis and multivariable logistic regression analysis. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A total of 60 patients with 65 varus knees who underwent OWHTO between December 2012 and June 2018 at a single institution were retrospectively enrolled in this study. The authors evaluated radiologic parameters including the weightbearing line ratio, femorotibial angle, medial proximal tibial angle, mechanical lateral distal femoral angle (LDFA), lateral distal tibial angle, joint line convergence angle (JLCA), KJLO, and ankle joint obliquity. They also categorized these radiographic parameters as preoperative and postoperative and calculated the difference (Δ) between preoperative and postoperative values. To determine which of the radiographic parameters were most associated with postoperative KJLO, multivariable linear regression analysis was performed using the stepwise method. Multivariable logistic regression analysis was used to examine the relative contribution of the preoperative radiographic parameters to an abnormal postoperative KJLO (>4°). RESULTS: In the multivariable linear regression analysis, the preoperative LDFA and JLCA showed a statistically significant correlation. Multivariable logistic regression analysis revealed that the mean preoperative LDFA was significantly larger in the group with abnormal KJLO than in the group with the control group (odds ratio, 1.84; 95% CI, 1.12-3.02; P = .02), while preoperative JLCA tended to be larger in the abnormal KJLO group than the control group but not statistically significantly different. CONCLUSION: KJLO after OWHTO was associated with preoperative LDFA and JLCA in multivariable linear regression analysis, and preoperative LDFA was the most important factor associated with abnormal KJLO after OWHTO in multivariable logistic regression analysis.

Knee registries: state of the art.

Sports injuries, trauma and the globally ageing and obese population require increasing levels of knee surgery. Shared decision making has replaced the paternalistic approach to patient management. Evidence-based medicine underpins surgical treatment strategies, from consenting an individual patient to national healthcare system design. The evolution of successful knee-related registries starting from specific arthroplasty registries has given rise to ligament reconstruction, osteotomy and cartilage surgery registries developing as platforms for surgical outcome data collection. Stakeholders include surgeons and their patients, researchers, healthcare systems, as well as the funding insurers and governments. Lately, implant manufacturers have also been mandated to perform postmarket surveillance with some hoping to base that on registry data. Aiming to assess the current status of knee-related registries, we performed a comprehensive literature and web search, which yielded 23 arthroplasty, 8 ligament, 4 osteotomy and 3 articular cartilage registries. Registries were evaluated for their scope, measured variables, impact and limitations. Registries have many advantages as they aim to increase awareness of outcomes; identify trends in practice over time, early failing implants, outlier surgeon or institution performance; and assist postmarketing surveillance. International collaborations have highlighted variations in practice. The limitations of registries are discussed in detail. Inconsistencies are found in collected data and measured variables. Potential measurement and selection biases are outlined. Without mandated data collection and with apparent issues such as unverified patient reporting of complications, registries are not designed to replace adverse event recording in place of a proper safety and efficacy study, as demanded by regulators. Registry 'big data' can provide evidence of associations of problems. However, registries cannot provide evidence of causation. Hence, without careful consideration of the data and its limitations, registry data are at risk of incorrectly drawn conclusions and the potential of misuse of the results. That must be guarded against. Looking at the future, registry operators benefit from a collective experience of running registries as they mature, allowing for improvements across specialties. Large-scale registries are not only of merit, improving with stakeholder acceptance, but also are critical in furthering our understanding of our patients' outcomes. In doing so, they are a critical element for our future scientific discourse.

Perspective: Challenges Presented for Regeneration of Heterogeneous Musculoskeletal Tissues that Normally Develop in Unique Biomechanical Environments.

Perspective: Musculoskeletal (MSK) tissues such as articular cartilage, menisci, tendons, and ligaments are often injured throughout life as a consequence of accidents. Joints can also become compromised due to the presence of inflammatory diseases such as rheumatoid arthritis. Thus, there is a need to develop regenerative approaches to address such injuries to heterogeneous tissues and ones that occur in heterogeneous environments. Such injuries can compromise both the biomechanical integrity and functional capability of these tissues. Thus, there are several challenges to overcome in order to enhance success of efforts to repair and regenerate damaged MSK tissues. Challenges: 1. MSK tissues arise during development in very different biological and biomechanical environments. These early tissues serve as a template to address the biomechanical requirements evolving during growth and maturation towards skeletal maturity. Many of these tissues are heterogeneous and have transition points in their matrix. The heterogeneity of environments thus presents a challenge to replicate with regard to both the cells and the ECM. 2. Growth and maturation of musculoskeletal tissues occurs in the presence of anabolic mediators such as growth hormone and the IGF-1 family of proteins which decline with age and are low when there is a greater need for the repair and regeneration of injured or damaged tissues with advancing age. Thus, there is the challenge of re-creating an anabolic environment to enhance incorporation of implanted constructs. 3. The environments associated with injury or chronic degeneration of tissues are often catabolic or inflammatory. Thus, there is the challenge of creating a more favorable in vivo environment to facilitate the successful implantation of in vitro engineered constructs to regenerate damaged tissues. Conclusions: The goal of regenerating MSK tissues has to be to meet not only the biological requirements (components and structure) but also the heterogeneity of function (biomechanics) in vivo. Furthermore, for many of these tissues, the regenerative approach has to overcome the site of injury being influenced by catabolism/inflammation. Attempts to date using both endogenous cells, exogenous cells and scaffolds of various types have been limited in achieving long term outcomes, but progress is being made.

Return to the original sport at only 3 months after an Achilles tendon rupture by a combination of intra-tissue injection of freeze-dried platelet-derived factor concentrate and excessively early rehabilitation after operative treatment in a male basketball player: A case report.

BACKGROUND: Achilles tendon rupture is one of the most common serious injuries in athletes. Various studies to accelerate the healing process of the Achilles tendon have been performed as it takes a longer time to repair the tissue compared to other tendons. Here, we report a case of an acute Achilles tendon rupture in a male basketball player treated by a combination of an intra-tissue injection of freeze-dried platelet-derived factor concentrate, which included a platelet-derived growth factor with an early rehabilitation protocol after the operative treatment to facilitate the biological healing of the injured tendon tissue. To the best of our knowledge, this case is the first instance that enabled the athlete to return to original sport activity at only 3-months after the injury. CASE REPORT: A 23-year-old male basketball player who belonged to a university basketball team sustained an Achilles tendon rupture during running in a training match. The remaining time period until the final tournament of the university league as a senior player was only 3 months. The patient received a combination of an intra-tissue injection of freeze-dried platelet-derived factor concentrate and early rehabilitation protocol after operative treatment. Surgery was performed 4 days after the injury and the early rehabilitation protocols were applied postoperatively. A freeze-dried platelet-derived factor concentrate was injected into the ruptured site of the Achilles tendon under ultrasound guide at 4 weeks postoperatively. The patient could return to play at the pre-injury level without any symptoms and disfunctions at 3 months after surgery. At two years postoperatively, the patient could play basketball without symptoms or rerupture. CONCLUSIONS: We reported a case of an Achilles tendon rupture which was treated by a combination of intra-tissue injection of freeze-dried platelet-derived factor concentrate and an early rehabilitation protocol after the operative treatment. The patient could return to play basketball at the pre-injury activity level at only 3-months after the injury, suggesting that the role of applying excessively early rehabilitation of mechanical loading could facilitate tendon tissue healing when combined with an intra-tissue injection of freeze-dried platelet-derived factor concentrate.

Biologic Association Annual Summit: 2020 Report.

Interest and research in biologic approaches for tissue healing are exponentially growing for a variety of musculoskeletal conditions. The recent hype concerning musculoskeletal biological therapies (including viscosupplementation, platelet-rich plasma, and cellular therapies, or "stem cells") is driven by several factors, including demand by patients promising regenerative evidence supported by substantial basic and translational work, as well as commercial endeavors that complicate the scientific and lay understanding of biological therapy outcomes. While significant improvements have been made in the field, further basic and preclinical research and well-designed randomized clinical trials are needed to better elucidate the optimal indications, processing techniques, delivery, and outcome assessment. Furthermore, biologic treatments may have potential devastating complications when proper methods or techniques are ignored. For these reasons, an association comprising several scientific societies, named the Biologic Association (BA), was created to foster coordinated efforts and speak with a unified voice, advocating for the responsible use of biologics in the musculoskeletal environment in clinical practice, spearheading the development of standards for treatment and outcomes assessment, and reporting on the safety and efficacy of biologic interventions. This article will introduce the BA and its purpose, provide a summary of the 2020 first annual Biologic Association Summit, and outline the future strategic plan for the BA.

Abrasion arthroplasty promotes improvement of degenerated femoral trochlear cartilage after medial open wedge high tibial osteotomy.

OBJECTIVES: Several studies have reported negative effects of open wedge high tibial osteotomy (OWHTO) on patellofemoral joints with cartilage degeneration and recommended performing other procedures. However, if chondral resurfacing surgery could promote improvement of cartilage degeneration in the patellofemoral joint, OWHTO would be an acceptable option. The purposes of this study were to arthroscopically evaluate the femoral trochlear articular cartilage after abrasion arthroplasty combined with OWHTO and to investigate the factors promoting improvement of that cartilage. METHODS: The present study cohort comprised 18 knees of 18 patients with varus osteoarthritis of the knee who had (1) International Cartilage Repair Society (ICRS) grade 4 femoral trochlear chondral lesions at the time of OWHTO; (2) undergone abrasion arthroplasty of the femoral trochlear cartilage in combination with OWHTO; (3) undergone second-look arthroscopy; and (4) been followed up for more than 2 years. Cartilage status was arthroscopically graded at the time of OWHTO and second-look arthroscopy. Patients were allocated to two groups according to the status of the femoral trochlear cartilage at the time of second-look arthroscopy: the improved group comprised patients with an ICRS grade of less than 3, and the not improved group comprised those with an ICRS grade of 4. Clinical outcomes, expressed as Knee Injury and Osteoarthritis Outcome Score (symptoms, pain, activities of daily living, function in sports/recreation and quality of life) and selected radiographic variables were compared between the two groups. RESULTS: There were 11 (61%) knees in the improved group and 7 (39%) in the not improved group. A comparison of radiographic variables between the two groups revealed that neither limb alignment nor patellar height affected cartilage changes. The two groups had similar results on the symptoms, pain, sports/recreation and activities of daily living subscales of the Knee Injury and Osteoarthritis Outcome Score. However, the quality of life subscale significantly differed between the two groups (p=0.025). CONCLUSION: Degenerated femoral trochlear cartilage can improve after combined abrasion arthroplasty and OWHTO. A comparison of clinical outcomes between the improved and not improved groups revealed that neither radiographic variables nor clinical symptoms, including pain, affected cartilage changes at short-term follow-up. LEVEL OF EVIDENCE: Case series, level V.

Histological Analysis of Cartilage Defects Repaired with an Autologous Human Stem Cell Construct 48 Weeks Postimplantation Reveals Structural Details Not Detected by T2-Mapping MRI.

OBJECTIVE: The aim of this study was to elucidate the efficacy of T2-mapping MRI and correlation with histology for the evaluation of tissue repair quality following the first-in-human implantation of an autologous tissue engineered construct. DESIGN: We directly compared the results of T2-mapping MRI of cartilage repair tissue with the histology of a biopsy specimen from the corresponding area at 48 weeks postoperatively in 5 patients who underwent the implantation of a scaffold-free tissue-engineered construct generated from autologous synovial mesenchymal stem cells to repair an isolated cartilage lesion. T2 values and histological scores were compared at each of 2 layers of equally divided halves of the repair tissue (upper and lower zones). RESULTS: Histology showed that the repair tissue in the upper zone was dominated by fibrous tissue and the ratio of hyaline-like matrix increased with the depth of the repair tissue. There were significant differences between upper and lower zones in histological scores. Conversely, there were no detectable statistically significant differences in T2 value detected among zones of the repair tissue, but zonal differences were detected in corresponding healthy cartilage. Accordingly, there were no correlations detected between histological scores and T2 values for each repair cartilage zone. CONCLUSION: Discrepancies in the findings between T2 mapping and histology suggest that T2 mapping was limited in ability to detect details in the architecture and composition of the repair cartilage.