Stem cells are defined by their potential for self-renewal and the ability to differentiate into numerous cell types, including cartilage and bone cells. Although basic laboratory studies demonstrate that cell therapies have strong potential for improvement in tissue healing and regeneration, there is little evidence in the scientific literature for many of the available cell formulations that are currently offered to patients. Numerous commercial entities and ‘regenerative medicine centres’ have aggressively marketed unproven cell therapies for a wide range of medical conditions, leading to sometimes indiscriminate use of these treatments, which has added to the confusion and unpredictable outcomes. The significant variability and heterogeneity in cell formulations between different individuals makes it difficult to draw conclusions about efficacy. The ‘minimally manipulated’ preparations derived from bone marrow and adipose tissue that are currently used differ substantially from cells that are processed and prepared under defined laboratory protocols. The term ‘stem cells’ should be reserved for laboratory-purified, culture-expanded cells. The number of cells in uncultured preparations that meet these defined criteria is estimated to be approximately one in 10 000 to 20 000 (0.005% to 0.01%) in native bone marrow and 1 in 2000 in adipose tissue. It is clear that more refined definitions of stem cells are required, as the lumping together of widely diverse progenitor cell types under the umbrella term ‘mesenchymal stem cells’ has created confusion among scientists, clinicians, regulators, and our patients. Validated methods need to be developed to measure and characterize the ‘critical quality attributes’ and biological activity of a specific cell formulation. It is certain that ‘one size does not fit all’ – different cell formulations, dosing schedules, and culturing parameters will likely be required based on the tissue being treated and the desired biological target. As an alternative to the use of exogenous cells, in the future we may be able to stimulate the intrinsic vascular stem cell niche that is known to exist in many tissues. The tremendous potential of cell therapy will only be realized with further basic, translational, and clinical research. Cite this article: Bone Joint J 2019;101-B:361–364

The ability of mesenchymal stem cells (MSCs) to differentiate in vitro into chondrocytes, osteocytes and myocytes holds great promise for tissue engineering. Skeletal defects are emerging as key targets for treatment using MSCs due to the high responsiveness of bone to interventions in animal models. Interest in MSCs has further expanded in recognition of their ability to release growth factors and to adjust immune responses.

Despite their increasing application in clinical trials, the origin and role of MSCs in the development, repair and regeneration of organs have remained unclear. Until recently, MSCs could only be isolated in a process that requires culture in a laboratory; these cells were being used for tissue engineering without understanding their native location and function. MSCs isolated in this indirect way have been used in clinical trials and remain the reference standard cellular substrate for musculoskeletal engineering. The therapeutic use of autologous MSCs is currently limited by the need for ex vivo expansion and by heterogeneity within MSC preparations. The recent discovery that the walls of blood vessels harbour native precursors of MSCs has led to their prospective identification and isolation. MSCs may therefore now be purified from dispensable tissues such as lipo-aspirate and returned for clinical use in sufficient quantity, negating the requirement for ex vivo expansion and a second surgical procedure.

In this annotation we provide an update on the recent developments in the understanding of the identity of MSCs within tissues and outline how this may affect their use in orthopaedic surgery in the future.

Cite this article: Bone Joint J 2014;96-B:291–8.

Cell therapies hold significant promise for the treatment of injured or diseased musculoskeletal tissues. However, despite advances in research, there is growing concern about the increasing number of clinical centres around the world that are making unwarranted claims or are performing risky biological procedures. Such providers have been known to recommend, prescribe, or deliver so called ‘stem cell’ preparations without sufficient data to support their true content and efficacy. In this annotation, we outline the current environment of stem cell-based treatments and the strategies of marketing directly to consumers. We also outline the difficulties in the regulation of these clinics and make recommendations for best practice and the identification and reporting of illegitimate providers. Cite this article: Bone Joint J 2020;102-B(2):148–154

Aims

Implantation of ultra-purified alginate (UPAL) gel is safe and effective in animal osteochondral defect models. This study aimed to examine the applicability of UPAL gel implantation to acellular therapy in humans with cartilage injury.

Aims. The success of anterior cruciate ligament reconstruction (ACLR) depends on osseointegration at the graft-tunnel interface and intra-articular ligamentization. Our aim was to conduct a systematic review of clinical and preclinical studies that evaluated biological augmentation of graft healing in ACLR. . Materials and Methods. In all, 1879 studies were identified across three databases. Following assessment against strict criteria, 112 studies were included (20 clinical studies; 92 animal studies). . Results. Seven categories of biological interventions were identified: growth factors, biomaterials, stem cells, gene therapy, autologous tissue, biophysical/environmental, and pharmaceuticals. The methodological quality of animal studies was moderate in 97%, but only 10% used clinically relevant outcome measures. The most interventions in clinical trials target the graft-tunnel interface and are applied intraoperatively. Platelet-rich plasma is the most studied intervention, but the clinical outcomes are mixed, and the methodological quality of studies was suboptimal. Other biological therapies investigated in clinical trials include: remnant-augmented ACLR; bone substitutes; calcium phosphate-hybridized grafts; extracorporeal shockwave therapy; and adult autologus non-cultivated stem cells. Conclusion. There is extensive preclinical research supporting the use of biological therapies to augment ACLR. Further clinical studies that meet the minimum standards of reporting are required to determine whether emerging biological strategies will provide tangible benefits in patients undergoing ACLR. Cite this article: Bone Joint J 2018;100-B:271–84

Aims

The aim of this study was to prepare a scoping review to investigate the use of biologic therapies in the treatment of musculoskeletal injuries in professional and Olympic athletes.

Non-traumatic osteonecrosis of the femoral head is a potentially devastating condition, the prevalence of which is increasing. Many joint-preserving forms of treatment, both medical and surgical, have been developed in an attempt to slow or reverse its progression, as it usually affects young patients.

However, it is important to evaluate the best evidence that is available for the many forms of treatment considering the variation in the demographics of the patients, the methodology and the outcomes in the studies that have been published, so that it can be used effectively.

The purpose of this review, therefore, was to provide an up-to-date, evidence-based guide to the management, both non-operative and operative, of non-traumatic osteonecrosis of the femoral head.

Cite this article: Bone Joint J 2017;99-B:1267–79.

This article reviews the current knowledge of the intervertebral disc (IVD) and its association with low back pain (LBP). The normal IVD is a largely avascular and aneural structure with a high water content, its nutrients mainly diffusing through the end plates. IVD degeneration occurs when its cells die or become dysfunctional, notably in an acidic environment. In the process of degeneration, the IVD becomes dehydrated and vascularised, and there is an ingrowth of nerves. Although not universally the case, the altered physiology of the IVD is believed to precede or be associated with many clinical symptoms or conditions including low back and/or lower limb pain, paraesthesia, spinal stenosis and disc herniation.

New treatment options have been developed in recent years. These include biological therapies and novel surgical techniques (such as total disc replacement), although many of these are still in their experimental phase. Central to developing further methods of treatment is the need for effective ways in which to assess patients and measure their outcomes. However, significant difficulties remain and it is therefore an appropriate time to be further investigating the scientific basis of and treatment of LBP.

The aim of our study was to investigate the effect of platelet-rich plasma on the proliferation and differentiation of rat bone-marrow cells and to determine an optimal platelet concentration in plasma for osseous tissue engineering. Rat bone-marrow cells embedded in different concentrations of platelet-rich plasma gel were cultured for six days. Their potential for proliferation and osteogenic differentiation was analysed. Using a rat limb-lengthening model, the cultured rat bone-marrow cells with platelet-rich plasma of variable concentrations were transplanted into the distraction gap and the quality of the regenerate bone was evaluated radiologically.

Cellular proliferation was enhanced in all the platelet-rich plasma groups in a dose-dependent manner. Although no significant differences in the production and mRNA expression of alkaline phosphatase were detected among these groups, mature bone regenerates were more prevalent in the group with the highest concentration of platelets.

Our results indicate that a high platelet concentration in the platelet-rich plasma in combination with osteoblastic cells could accelerate the formation of new bone during limb-lengthening procedures.

In 1999, we developed a technique for biological reconstruction after excision of a bone tumour, which involved using autografts of the bone containing the tumour treated with liquid nitrogen. We have previously reported the use of this technique in 28 patients at a mean follow up of 27 months (10 to 54).

In this study, we included 72 patients who underwent reconstruction using this technique. A total of 33 patients died and three were lost to follow-up, at a mean of 23 months (2 to 56) post-operatively, leaving 36 patients available for a assessment at a mean of 101 months 16 to 163) post-operatively. The methods of reconstruction included an osteo-articular graft in 16, an intercalary in 13 and, a composite graft with prosthesis in seven.

Post-operative function was excellent in 26 patients (72.2%), good in seven (19.4%), and fair in three (8.3%) according to the functional evaluation system of Enneking. No recurrent tumour occurred within the grafts. The autografts survived in 29 patients (80.6%), and the rates of survival at five and ten years were 86.1% and 80.6 %, respectively. Seven of 16 osteo-articular grafts (44%) failed because of fracture or infection, but all the composite and intercalary grafts survived.

The long-term outcomes of frozen autografting, particularly using composite and intercalary grafts, are satisfactory and thus represent a good method of treatment for patients with a sarcoma of bone or soft tissue.

Cite this article: Bone Joint J 2014;96-B:555–61.

Articular cartilage repair remains a challenge to surgeons and basic scientists. The field of tissue engineering allows the simultaneous use of material scaffolds, cells and signalling molecules to attempt to modulate the regenerative tissue. This review summarises the research that has been undertaken to date using this approach, with a particular emphasis on those techniques that have been introduced into clinical practice, via in vitro and preclinical studies.

We used interconnected porous calcium hydroxyapatite ceramic to bridge a rabbit ulnar defect. Two weeks after inducing the defect we percutaneously injected rabbit bone marrow-derived mesenchymal stromal cells labelled with ferumoxide. The contribution of an external magnetic targeting system to attract these cells into the ceramic and their effect on subsequent bone formation were evaluated.

This technique significantly facilitated the infiltration of ferumoxide-labelled cells into ceramic and significantly contributed to the enhancement of bone formation even in the chronic phase. As such, it is potentially of clinical use to treat fractures, bone defects, delayed union and nonunion.

Successful healing of a nine-year tibial nonunion resistant to six previous surgical procedures was achieved by tissue engineering. We used autologous bone marrow stromal cells (BMSCs) expanded to 5 × 10⁶ cells after three weeks’ tissue culture. Calcium sulphate (CaSO₄) in pellet form was combined with these cells at operation. The nonunion was clinically and radiologically healed two months after implantation.

This is the description of on healing of a long-standing tibial nonunion by tissue engineering. The successful combination of BMSCs and CaSO₄ has not to our knowledge been reported in a clinical setting.

Orthopaedic surgery is in an exciting transitional period as modern surgical interventions, implants and scientific developments are providing new therapeutic options. As advances in basic science and technology improve our understanding of the pathology and repair of musculoskeletal tissue, traditional operations may be replaced by newer, less invasive procedures which are more appropriately targeted at the underlying pathophysiology. However, evidence-based practice will remain a basic requirement of care. Orthopaedic surgeons can and should remain at the forefront of the development of novel therapeutic interventions and their application. Progression of the potential of bench research into an improved array of orthopaedic treatments in an effective yet safe manner will require the development of a subgroup of specialists with extended training in research to play an important role in bridging the gap between laboratory science and clinical practice. International regulations regarding the introduction of new biological treatments will place an additional burden on the mechanisms of this translational process, and orthopaedic surgeons who are trained in science, surgery and the regulatory environment will be essential. Training and supporting individuals with these skills requires special consideration and discussion by the orthopaedic community.

In this paper we review some traditional approaches to the integration of orthopaedic science and surgery, the therapeutic potential of current regenerative biomedical science for cartilage repair and ways in which we may develop surgeons with the skills required to translate scientific discovery into effective and properly assessed orthopaedic treatments.

Post-traumatic arthritis is a frequent consequence of articular fracture. The mechanisms leading to its development after such injuries have not been clearly delineated. A potential contributing factor is decreased viability of the articular chondrocytes. The object of this study was to characterise the regional variation in the viability of chondrocytes following joint trauma. A total of 29 osteochondral fragments from traumatic injuries to joints that could not be used in articular reconstruction were analysed for cell viability using the fluorescence live/dead assay and for apoptosis employing the TUNEL assay, and compared with cadaver control fragments.

Chondrocyte death and apoptosis were significantly greater along the edge of the fracture and in the superficial zone of the osteochondral fragments. The middle and deep zones demonstrated significantly higher viability of the chondrocytes. These findings indicate the presence of both necrotic and apoptotic chondrocytes after joint injury and may provide further insight into the role of chondrocyte death in post-traumatic arthritis.