The musculoskeletal system (MSKS) is composed of specialized connective tissues including bone, muscle, cartilage, tendon, ligament, and their subtypes. The primary function of the MSKS is to provide protection, structure, mobility, and mechanical properties to the body. In the process of fulfilling these functions, the MSKS is subject to wear and tear during aging and after injury and requires subsequent repair. MSKS diseases are a growing burden due to the increasing population age.
1.1. MSKS Tissue Matrix Forms Barriers of Drug Delivery
The MSKS is an integrated system of various specialized connective tissues that achieve specific structural functions. For example, the knee joint consists of (1) articular cartilage that covers the joint bone structure; (2) the meniscus, which serves as a cushion for the opposing articular surfaces; (3) subchondral bone beneath the articular cartilage; (4) the ligament that connects bone to bone and the tendon that connects bone to muscle; and (5) skeletal muscle that surrounds the bone. Each of these MSKS tissues have different, independent structures and functions, which coordinate to create the structural integrity and mobility of the knee joint. The extracellular matrix (ECM) is highly enriched in MSKS tissues due to their mechanical functions. The ECM also serves as a barrier for the diffusion of molecules such as drugs to reach cells. Just like each tissue’s structure and function, the ECM organizational characteristics such as pore size and surface charge vary among the MSKS. Thus, the therapeutic delivery strategy needs to vary accordingly.
In addition to ECM, there are differences in vascularity among MSKS tissues. Due to the high demand of structural adaptation and regeneration, there is high vascularity in bone and muscle. On the other hand, cartilage, tendon, and ligament have low vascularity due to their structural properties that prioritize low tissue turnover and structural stability. Another consideration is that bone and muscle diseases such as osteoporosis and sarcopenia are usually systematic and affect the whole body. In these cases, systemic drug delivery is preferred because it reaches different sites of the body rather than just a single bone or muscle. High vascularity in bone and muscle also provides advantages for drugs to reach these tissues through blood vessel transport. On the other hand, degeneration of cartilage, tendon, and ligament is often local, affecting one or more joints. The lack of vascularity in these tissues also renders systemic drug delivery ineffective. Intra-articular injection is usually employed for local delivery of therapeutics for the treatment of these tissues. The considerations for systemic vs. local administration are described as follows.
2. Route of Administration
This section describe the advantages of local versus systemic deliveries (Figure 1
). The disease pathophysiology, target tissue or cell type, and therapeutic composition influence the chosen route of delivery. Based on these features, the MSKS actively compartmentalizes particles into different tissues through its tissue barrier function. Certain aspects of the MSKS tissue barrier act like physiologic barriers in the brain, gut, and lungs 
Figure 1. Administration routes targeting avascular and vascular tissues in the MSKS. Local delivery such as intra-articular injection is often used to target avascular tissues including tendon and ligament (A) and cartilage (B). Systemic delivery such as intravenous (IV) injection is often used for drug delivery to vascular tissues such as bone (C) and muscle (D).
2.1. Systemic Delivery
Systemic delivery introduces the drug into the bloodstream, resulting in widespread distribution of the compound primarily in vascularized tissues. There is a major advantage to using targeted systemic delivery when local injection is invasive or when the afflicted tissue is hard to reach. When diseases are not isolated to a particular area of the body, systemic delivery also holds major advantages because of the larger distribution coverage. The disadvantages of this method are that it requires relatively larger amounts of the drug or the composite vehicle/drug due to wide exposure in the plasma, blood vessels, and the vascular tissues. In addition, the sequestration in the liver and/or clearance in the kidneys may pose significant challenges for systemic drug delivery. If the drug particles are nanoscale, studies have found that less than 1% of the drug particles will reach the target tissue 
. Thus, both drug particle sizes and blood circulation characteristics are major considerations for systemic delivery to the MSKS.
Intrinsic molecular barriers of MSK tissues for systemic delivery were studied by Ngo et al. 
. After a bolus injection of different sized dyes into the hearts of guinea pigs, the distribution of the dye in joint tissues was analyzed. The injection consisted of high (70 kDa) and low (10 kDa) molecular weight, neutrally charged dyes, which were allowed to circulate before the knee joints were harvested and assessed for distribution. A distinct size separation was found in the tissues. Small tracers were distributed in the avascular meniscus, ligaments, and tendons but had low presence in the articular cartilage. Larger tracers were found primarily in the vascular regions such as the muscle fascia, marrow, and surrounding blood vessels. These data suggest that larger-sized particles can be delivered to vascular MSKS tissues via systemic delivery. However, systemic delivery to avascular MSKS tissues requires the infiltration of smaller-sized particles by diffusion through smaller pores in the ECM. The data also indicate that articular cartilage may be the most difficult MSKS tissue to deliver due to its avascular nature, a pore size as small as 20 nm, and the negatively charged matrix due to the high abundance of proteoglycans 
The direction of the blood supply may also significantly contribute to how therapeutics are delivered to target tissues in the MSKS. In a study performed by Evans et al., a directionally dependent and mechanically responsive flow from the bone to the muscle is described 
. The periosteum subjected to a high flow rate is significantly more permeable from the bone to muscle direction rather than the muscle to bone direction. This high flow rate is mimetic of increased flow during a traumatic injury, which increases the periosteum permeability by orders of magnitude 
. While this implication suggests that there is significant molecular and nutrient supply to support muscle health from the bone, it also may be an indication that systemically injected therapeutics will be, at least in some part, dependent on the anisotropic permeability of the periosteum. This was also validated in the previously described study by Ngo et al., where joint tissues had much higher tracer concentrations in the actual tissues and bones than the surrounding muscles 
. The distribution of the tracers indicates the direction of the blood supply from the bone to the surrounding muscle.
In addition to blood flow and drug size, disease states may also affect systemic drug delivery. In the young, healthy guinea pigs, small channels through the articular cartilage fluoresced with the small tracer with higher overall fluorescent concentration compared with the older, arthritic animals 
. These findings suggest not only that the size of the delivered particle alters tissue distribution but also that the disease status may affect the permeability and physiology of the affected tissue. Specifically, degenerative cartilage pathophysiology during osteoarthritis (OA) affects the small channels running through the articular cartilage into the subchondral bone, impacting OA treatment via systemic delivery 
. Much like OA alters the delivery capacity, an injury, trauma, and disease state may increase the flow rate of the surrounding fluids, increasing the permeability of the bone 
. Diseases such as osteoporosis and aging reduce the periosteum and bone thickness, causing the increase in permeability to nutrients and potential therapeutics 
. With these findings, the simplest method for delivering therapeutics for treating OA would be local delivery. In OA of the knee, intra-articular injection would be the most viable method to maximize delivery to the articular cartilage. The strategies for local delivery are described as follows.
2.2. Local Delivery
Local drug delivery has attracted great attention for the treatment of MSKS disorders, mainly because it could deliver therapeutic agents directly to the desired site of action, provide an optimal drug level for controlled periods of time, and reduce undesirable side effects or toxicity 
. Local delivery is often associated with increased retention of the drug depending on the target site. For example, drug particles delivered to the joint capsule can diffuse into the cartilage, meniscus, and tendons and ligaments. They will then be cleared by diffusion into the vascular synovium or through lymphatic drainage. The balance between delivery and clearance of the drug is key to maintaining half-life and efficacy.
In particular, intra-articular (IA) injection is a commonly used form of local injection to target MSKS tissues in the joint. The most common use for IA injection is for the treatment or pain management of OA. While IA injection is a promising way to reach avascular tissue of joints such as articular cartilage, disease modifying treatments are yet to be successful 
. The rapid clearance of therapeutics injected into the joint space is a significant problem. The ideal therapeutic must have a long retention time, high local concentration, a controlled and sustainable release, and a disease-modifying or regenerative effect to compete with invasive, disease-ending procedures such as knee arthroplasty 
Larger particles injected into the joint are known to be phagocytized by macrophages, while smaller particles can penetrate the cartilage and the surrounding tissue; however, these smaller particles are rapidly cleared into the bloodstream. To address the need for increased retention time in the joint, a biodistribution study of nanoscale and microscale particles after intra-articular injection was conducted 
. This study determined the fate of large- (~10 µm and ~3 µm) and small- (300 nm) sized Poly(D,L-Lactide) (PLA) particles containing a fluorescent dye. In healthy mice, both micron-sized particles had significantly higher retention time than the small, nano-sized particles. The clearance pathway for the nano-sized particles was as expected: through the blood and ultimately arriving at the liver. Once an arthritic condition was induced, the retention of ~10 μm stayed constant, while ~3 μm particles escaped from the inflamed joints, most likely due to the increased capillary permeability caused by synovial inflammation 
. Thus, a large size is critical for drug retention within the joint space when considering an inflammatory disease state. Therein lies a dilemma where the drug particles need to be small enough to infiltrate ECM and yet large enough to retain in the joint space. Thus, considering size alone is not sufficient to create effective delivery and efficacy of a drug. Other strategies in addition to size must be considered based on specific properties of the targeted MSKS tissues.