Graft Treatment for Rotator Cuff Tendon–Bone Interface Augmentation: Status and Prospects–A Narrative Review

Abstract

Sutures and suture anchors are commonly used in rotator cuff repairs as they offer cost-effective and mechanically robust solutions for tendon–bone interface (TBI) healing. However, in large to massive rotator cuff tears, where substantial tendon loss and limited intrinsic healing potential are present, conventional repair techniques alone often fail to restore the native biomechanics and structural integrity. Consequently, retear rates in these cases remain unacceptably high. This review summarizes recent advances in graft-based augmentation strategies aimed at improving outcomes in these challenging clinical scenarios. Furthermore, we propose a novel biomaterial that can be easily shaped, promotes endogenous cell activity throughout tendon regeneration, and offers sufficient mechanical support to the TBI.

Rotator cuff (RC) rupturing is a representative musculoskeletal disease commonly occurring at the interface between a tendon and bone (TBI), causing pain and dysfunction in the shoulder joint and significantly reducing the patient’s quality of life.¹,²⁾ RC tears impose a significant socioeconomic burden on 54% of asymptomatic people over 60 years of age, 62% of asymptomatic people over 80 years, and 20% of the general population.³⁾ It is estimated that more than 300,000 RC reconstruction surgeries are performed yearly in the United States, and the number continues to grow.⁴⁾ However, due to the limited regenerative capacity of the TBI, the rate of retear after repair is unacceptably high, ranging from 20% to 94%.⁵⁾

While small to medium-sized partial-thickness RC tears are typically managed through conservative measures such as physical rehabilitation or arthroscopic repair alone, graft augmentation is primarily indicated for large to massive tears. These more extensive injuries are associated with compromised tendon integrity, limited natural healing capacity, and substantially higher retear rates, necessitating the use of biological or synthetic scaffolds to provide mechanical reinforcement and support tissue regeneration. Sutures and reinforcing grafts at the initial stage of tear are highly effective treatments that can reduce the mechanical burden of the initial repair, increasing the load to fracture and the structural stability of the tendon repair.⁶⁾ Currently, the orthopedic graft types being studied include autografts, allografts, xenografts, and synthetic implants.⁷⁾ Additionally, the development of modern materials that can increase extracellular matrix (ECM) structure and arrangement, such as superconducting biomaterials, is attracting attention.⁸⁾ However, a potential fibrotic response to the graft and suboptimal integration with host tissue may lead to long-term graft failure, underscoring the need for more comprehensive medical data in preclinical and clinical settings for graft therapy.⁹,¹⁰,¹¹⁾

The discovery and translation of innovative treatments, including developing new drugs, biological products, and biomaterials for RC TBI augmentation, are accelerating to overcome these limitations. For example, advances in innovative bio-induced and responsive biomaterials have led to a new generation of synthetic grafts that have shown promising results in animal models.¹²,¹³,¹⁴⁾ Improved methods for differentiating human-induced pluripotent stem cells into various lineages and expanding progenitor cells have opened the door to advanced new cell therapies,¹⁵⁾ while the application of superconducting scaffolds utilizing biomimetic tissue engineering has led to the development of patient-derived tissue constructs. Thus, the biological graft limitations are being overcome.¹⁶,¹⁷⁾ Nevertheless, widespread clinical use of these new technologies requires more clinical data to be accumulated and academically reviewed.

In this review, we first discuss the physiological characteristics of TBI regeneration. Next, we summarize recent graft therapy research trends from the perspective of RC TBI healing. Then, we review the latest synthetic grafts for the treatment of RC TBI that have recently been approved for clinical use or are in preclinical development. Finally, we review the prospects of utilizing collagen-based next-generation bio-inductive grafts and electrically conductive scaffolds to improve ECM composition and structure.

RC TBI AND ECM REGENERATION

Tendons are attached to bones through fibrous cartilaginous tissue, which helps reduce mechanical stress and prevent tissue damage.¹⁸,¹⁹⁾ However, these TBIs are still prone to tears due to sudden overload or the natural aging process. A common example of such an injury is an RC tear, which may occur partially or massively at the insertion site where the tendon connects to the bone. Standard treatment typically involves surgical reattachment of the tendon; however, this often leads to the regeneration of fibrous scar tissue rather than native fibrocartilage at the TBI.²⁰,²¹⁾ Although fibrotic healing lacks the zonal organization and biomechanical complexity of native enthesis, its clinical implications remain a subject of ongoing debate.²²⁾ Some studies have reported that fibrotic repair can result in functional outcomes comparable to those achieved through more physiologic enthesis healing, particularly in certain patient populations.²³⁾ Nevertheless, from a biomechanical standpoint, the resulting tissue mismatch at the junction between tendon and bone may increase localized stress and contribute to a higher risk of retear under physiological loading conditions. This discrepancy is thought to arise from the inherent wound healing pathways encoded in the human genome, which favor fibrotic repair rather than full tissue regeneration. Consequently, allogeneic and xenogeneic grafts often fail to completely restore the transitional architecture of the native TBI due to this biologically limited response. Therefore, novel therapeutic strategies are urgently needed to restore physiological ECM composition, modulate fibrotic gene expression, and ultimately restore the structural and functional integrity of the enthesis following RC surgery.²⁰,²¹,²²⁾ Physiologically, the native TBI features a structured transition through 4 distinct zones: tendon, noncalcified fibrocartilage, calcified fibrocartilage, and bone.²⁴⁾ This specialized interface, with its gradual change in mineralization, ensures effective stress distribution from the tendon to the bone and conversely. The most challenging aspect of tendon or ligament repair is achieving seamless integration between the tendon and bone. This is mainly due to the unique zone of transitional fibrocartilage where the tendon-to-bone insertion occurs and where a mix of calcified and noncalcified collagen fibers enables efficient force transmission without creating stress concentrations.²⁵⁾ However, the healing process at this interface is inherently complex and slow, as it involves integrating 2 different tissue types. This complexity presents a significant challenge in both research and clinical applications, making the repair and regeneration of the transitional zone particularly arduous. Despite decades of advances, new treatments have been developed to enhance TBI healing, including drugs, biological agents, therapeutic biomaterials, bone substitutes, periosteal autografts, growth factor and gene therapies, physical stimulation, and stem cell transplantation.²⁶,²⁷⁾ Yet, these approaches have not been fully successful in restoring the damaged area to its original state.

Biological graft treatments that improve ECM composition and structure are being increasingly used in various surgical and tissue engineering applications, particularly due to their ability to promote structural changes within the TBI microenvironment.²⁸⁾ These changes include new angiogenesis, stem cell migration and proliferation, anti-inflammation, macrophage polarization, and collagen matrix production.²⁹⁾ ECM autografts such as tensor fasciae latae (TFL), acellular human dermal allograft (ADHA), and xenograft (ADHX) are commonly used to reduce secondary complications after large to massive RC repair.³⁰⁾ This graft treatment minimizes the risk of complications and provides a scaffold for the ECM that aids tissue regeneration and enhances the mechanical integrity of the repaired area.³¹⁾ Using these methods could potentially improve functional outcomes and extend the durability of the repair.³¹⁾ Additionally, it is important to note that the therapeutic effect of grafts may vary depending on their anatomical placement. While some grafts, such as acellular dermal allografts and bio-inductive patches, are typically applied on top of the repaired tendon (epitenon), others, including certain autografts or interposition grafts, may be placed at the TBI.³²,³³⁾ This distinction is clinically significant, as grafts applied directly to the TBI may contribute more directly to mechanical reinforcement and enthesis-like tissue regeneration, whereas epitenon applications may primarily aid in biological modulation and tendon remodeling. Furthermore, although epitenon-applied grafts such as ADHA and ADHX do not contact the bone directly, they may still influence TBI healing indirectly through mechanical load redistribution and paracrine signaling mechanisms that enhance cellular recruitment, angiogenesis, and ECM remodeling at the interface.

However, despite these advantages, biological grafts are associated with several important limitations that must be carefully considered.³⁴⁾ ADHXs may elicit immune-mediated reactions due to the presence of residual cellular debris or xeno-antigens such as α-Gal, which can impair host integration and incite chronic inflammation. Autografts, while immunologically favorable, necessitate tissue harvesting that can result in donor site morbidity, including postoperative pain and functional compromise. Even decellularized allografts, although processed to minimize immunogenicity, carry a residual risk of pathogen transmission and batch-to-batch variability in biomechanical properties.¹²⁾ Furthermore, long-term clinical outcomes remain inconsistent, with some reports indicating progressive graft degradation, suboptimal remodeling, or structural insufficiency over time. These limitations underscore the need for individualized graft selection, rigorous quality control in processing techniques, and continued investigation through well-powered longitudinal studies to validate the safety, efficacy, and durability of biological scaffolds in RC TBI augmentation.³⁵,³⁶⁾

RESEARCH TRENDS IN TRANSPLANT THERAPY FOR THE TREATMENT OF RC TBIs

Allogeneic Dermis and Xenografts

Advances in graft therapy for improving clinical outcomes and mechanical strength in advanced RC healing are relatively recent, and there is a preference for using the patient’s own tissue (Table 1). Superior capsular reconstruction (SCR) using TFL was first described by Mihata et al.³⁷⁾ in 2013 and showed significant short-term improvements. A follow-up study using skin allografts in SCR for large, irreversible tears showed fewer complications, improved shoulder function, and better scapular function compared to reverse shoulder arthroplasty.³⁸⁾ The TFL technique was modified due to donor site morbidity after tissue harvesting, and AHDA was introduced as an alternative.³⁹,⁴⁰⁾ Burkhart et al.³¹⁾ described a modified TFL technique that used a skin allograft instead. Results showed significant improvements in active anterior elevation, pain, and shoulder function at the 1-year follow-up, with 90% of patients regaining active overhead arm use. While these studies highlight the promising short-term outcomes of SCR using dermal allografts, such as improved range of motion, reduced pain, and enhanced patient satisfaction, several long-term studies have noted important limitations. Reports have documented instances of graft thinning, loss of mechanical integrity, and persistent joint instability over time, particularly in high-demand or biologically compromised patients. Furthermore, questions remain regarding the durability of these grafts under chronic biomechanical stress and their capacity for long-term integration into host tissues. These concerns underscore the need for cautious interpretation of early clinical success and highlight the importance of ongoing long-term evaluation. Similarly, although acellular dermal matrices such as GraftJacket and ArthroFlex have demonstrated favorable early results, challenges including immune reactions, residual DNA content, and inconsistent remodeling continue to be reported in the literature.

Table 1. Research Trends in Allogeneic Dermis and Xenografts.

Study	Level of evidence	Surgical method	Graft	Primary results
Johnson et al. (2020)42)	Level IV	Rotator cuff repair and GraftJacket allograft	Allograft; human	Mean constant score was 82.9 (range, 70–100) compared to 87.2 (range, 66–100) (p = 0.03) on the control (nonoperated) side.*
Mihata et al. (2013)37)	Level IV, therapeutic case series	Arthroscopic superior capsule reconstruction	Allograft; human	Acromiohumeral distance increased from 4.6 ± 2.2 mm preoperatively to 8.7 ± 2.6 mm postoperatively (p < 0.0001).†
Badhe et al. (2008)49)	Cohort study, pig	Open shoulder decompression	Xenograft; pig	Mean constant score improved significantly from 42 preoperatively to 63 at 1 year (p = 0.0003).‡
Bond et al. (2008)41)	Level IV, therapeutic case series	Arthroscopic graftJacket allograft	Allograft; human	Mean University of California, Los Angeles score increased from 18.4 preoperatively to 30.4 postoperatively (p = 0.0001). The constant score increased from 53.8 to 84.0 (p = 0.0001).§
Mihata et al. (2019)38)	Therapeutic level IV	Rotator cuff tear repair	Allograft; human	Compared with preoperative values, ASES and JOA scores, active elevation, and acromiohumeral distance increased postoperatively at both 1 year (p < 0.001) and 5 years (p < 0.001).∥
Schlegel et al. (2006)50)	Controlled laboratory study	Rotator cuff surgery	Xenograft; pig	The augmented group had significantly better stiffness than the nonaugmented group (215 ± 44 N/mm vs. 154 ± 63 N/mm, respectively; p = 0.03).

ASES: American Shoulder and Elbow Surgeons, JOA: Japanese Orthopaedic Association, ASCR: Arthroscopic Superior Capsular Reconstruction.

^*Patients included 6 men and 7 women, with a mean age at operation of 63 years (range, 31–77 years). All 13 patients attended follow-ups and a postoperative ultrasound with a mean follow-up of 41 months (range, 23–59 months). ^†From 2007 to 2009, 24 shoulders in 23 consecutive patients (mean, 65.1 years) with irreparable rotator cuff tears (11 large, 13 massive) underwent ASCR using fascia lata. ^‡The study group consisted of 10 patients (5 men and 5 women), with a mean age of 66 years (range, 46–80 years). ^§At a mean follow-up of 26.7 months (range, 12–38 months), 15 of 16 patients were satisfied with their procedure. ^∥The study enrolled 30 shoulders in 30 patients with a mean age of 68 years (range, 52–78 years): 29 primary cases and 1 revision case after a failed rotator cuff repair.

Subsequently, AHDA is a type of tissue graft derived from human skin that is engineered to remove cells while preserving the ECM. This process significantly reduces the risk of immune rejection and infection, as cellular components that normally trigger an immune response are removed and have advantages in forming a superior ECM composition and structure. Bond et al.⁴¹⁾ were the first to report the results of an arthroscopic technique using GraftJacket to bridge the gap in large, irreparable tears. GraftJacket NOW (Stryker/Wright Medical Group) is an acellular human dermal matrix designed for use in a variety of soft tissue repairs, made into patches containing collagen types I, III, IV, and VII, elastin, chondroitin sulfate, proteoglycan, and fibroblast growth factor.⁴¹,⁴²⁾ They found statistically significant improvements in pain, forward flexion, and external rotation strength following GraftJacket allograft placement in 16 patients. As a follow-up study, in a cadaveric study by Barber et al.,⁴³⁾ biomechanical testing showed a higher load to failure in the augmented group compared to the control group (p = 0.047). Additionally, in Burkhead’s case series, GraftJacket significantly improved clinical and functional outcome scores, with no other complications observed.⁴⁴⁾ A prospective follow-up study by Johnson et al.⁴²⁾ also used ultrasound imaging and observed intact RC repairs in 13 out of 14 patients over a mean follow-up period of 41 months. Although GraftJacket is still preferred in clinical practice, it possesses limitations due to the morbidity of existing tissue and the thickness of the harvested graft. In addition, although removed to some extent during the cell removal process, residual DNA and xenoantigen α-Gal, which still trigger immune responses, remain clear clinical challenges to be solved.⁴³,⁴⁵⁾

In addition, the acellular dermal ECM, commonly used for healing soft tissue damage, is LifeNet Health’s Arthrex product, which is manufactured using the MatrACELL decellularization process. ArthroFlex skin allografts are treated with Preservon, a patented preservation technology that prevents water-mediated dissolution of the native collagen and elastin scaffold while keeping the graft fully hydrated at room temperature.⁴⁶⁾ In particular, one of the decellularization technologies, MatrACELL (U.S. Patent 6,743,574; 2004) (LifeNet Health), has been applied to human lung patches and has received 510 k clearance from the Food and Drug Administration for clinical use. ArthroFlex (15.97 4.8 ng/mg) is considered an excellent product as it significantly lowers the residual DNA content, which was highlighted as a major limitation of ADHD mentioned in the previous paragraph, compared to GraftJacket (134.6 44.0 ng/mg).²³,⁴⁶⁾ In clinical trials, ArthroFlex has shown promising results. In the study by Gilot et al.,⁴⁷⁾ 35 of 36 patients were treated for nonhealing large RC tears, 20 received augmentation with allograft (treatment group), and 15 received only RC repair without augmentation (control group). Compared to the control group, patients in the treatment group showed statistically significant improvements in pain (p = 0.024), American Shoulder and Elbow Surgeons (ASES) score (p = 0.024), and subjective outcomes (p = 0.041) and a lower recurrence rate (p = 0.048). In another study examining the ArthroFlex implant, patients who underwent open RC surgery demonstrated a statistically significant improvement in functional ASES scores compared to preoperative measurements.⁴⁸⁾ Another scaffold-only strategy to restore the ECM to its pre-injury state involves the decellularization of xenogeneic tissues, mimicking the native structures provided by nature. Decellularization typically uses detergents to remove cellular debris, allowing host cells to infiltrate and remodel the scaffold.⁵¹⁾ As a result, the remaining ECM degrades, favoring an environment that favors remodeling rather than rejection. However, it is important to note that it is impossible to remove all cellular components completely. The importance of this limitation was highlighted when the failure of a decellularized porcine heart valve led to the death of a pediatric patient,⁵²⁾ which highlights the importance of a careful decellularization process in the manufacturing of existing and new products. Despite these limitations, decellularized biomaterials are increasingly being explored for various types of tissue regeneration, including intact implantable ECM and injectable ECM in the form of particles or hydrogels.⁵²,⁵³⁾

The porcine dermis, derived from the lower skin layer of pigs, is similar to human skin in terms of its structure and protein composition, meaning it can provide powerful repair capabilities to damaged tissues and act as a cross-linking scaffold through which healing can occur. The porcine skin collagen Zimmer patch, previously known as Permacol (Tissue Science Laboratories plc, Aldershot), is known to be effective in improving shoulder function and relieving pain without tissue rejection and complications of clinical concern.⁴⁹⁾ Although advances in decellularization processes continue to improve the safety and efficacy of porcine dermis, immunogenicity and disease transmission still need to be carefully considered. Several previous studies have shown the utility of porcine collagen patches for biologically enhancing the tendon healing process. Porcine small intestinal submucosa (SIS) grafts were shown by Dejardin et al.⁵⁴⁾ to stimulate the regeneration of completely resected infraspinatus tendons in a canine model study. Although the ultimate strength of the SIS regenerated tendon was significantly lower than that of normal controls, the gross and histological appearance of the tissue resulted in restoration very similar to that of the native infraspinatus tendon. Another study used the SIS patch on the infraspinatus tendon in sheep, which showed no difference in load failure after 12 weeks and a significant improvement in the stiffness of the construct.⁵⁰⁾ Although the results of this animal model study were encouraging, much caution is still needed when considering this technique clinically as an option for tissue replacement of irreparable RC tears.

Meanwhile, bioderived implants made from bovine collagen have been used for RC healing.⁵⁵⁾ These implants have been shown to promote healing of the RC tendon after surgery, and studies have shown significant improvements in healing partial RC tears.⁵⁶⁾ Subsequent studies continued to report significant increases in tendon thickness and clinical improvement.⁵⁷⁾ However, these implants have not been shown to add structural support. In summary, some studies have reported inflammatory responses and high failure rates for porcine SIS patches and bovine collagen implants, while others have concluded that they are effective in improving RC recovery outcomes. Therefore, clinical data demonstrating the insufficient immune tolerance of xenogeneic ECM patches remain a major issue that needs to be addressed.

Recently, the resorbable bioderived collagen implant Regenten has been applied epitenonally on top of the repaired tendon to enhance biological healing and tendon thickening. Although it does not directly interface with the bone, its placement supports cell-mediated regeneration via indirect biochemical modulation and regulation of the ECM.⁵⁸⁾ Previous studies using this implant have shown faster discontinuation of sling use, faster return to work, and better functional scores at the 6-month time-point compared with previously reported data for similar tears.¹⁴,¹⁷,⁵⁵⁾ Additionally, clinical trials have shown significant improvements in pain, function, and tendon healing, along with reduced tear progression in patients following the use of bioderived collagen implants for RC tears.¹⁴,⁵⁹,⁶⁰⁾ Therefore, rather than serving as a direct TBI augmentation material, bio-inductive collagen implants such as Regenten should be regarded as biological enhancers that promote tendon remodeling and ECM regeneration through indirect biochemical modulation, especially when applied epitenonally. The conclusion is that bio-derived collagen implants may provide a new, patient-friendly treatment option to reduce retear rates and complications through TBI augmentation and restoration of ECM composition and structure without immunogenic substances.

SYNTHETIC GRAFTS

Synthetic grafts may be relatively safe in clinical practice because they are unlikely to be contaminated with foreign DNA material that causes an inflammatory response.⁶¹⁾ In addition, it has superior immune tolerance and biomechanical durability compared to collagen grafting, improving suture fixation over a long period to help with healing.⁸,⁵³⁾ Above all, synthetic grafts have the advantage that they can be degradable or permanent and that the biomaterial can solve both tendon augmentation and regeneration.⁶²⁾ These synthetic grafts may help improve clinical practice outcomes after RC reconstruction. Composite materials used for RC repairs have been developed, including polyester, polycarbonate/polyurethane,⁶³⁾ polyglycolic acid, polytetrafluoroethylene, and polypropylene (Table 2). However, despite their biomechanical promise, clinical evidence supporting the use of synthetic grafts in RC repair remains limited. Most existing studies are either preclinical or based on small patient cohorts, and long-term outcomes, such as tissue integration, durability under repetitive motion, and functional restoration, are not yet fully understood. For example, while X-repair, a bioresorbable poly-L-lactic acid mesh, showed positive short-term outcomes in small trials, a high retear rate was still observed in certain patient groups.¹³,⁵⁷,⁶⁴⁾ Therefore, although synthetic grafts represent a promising direction in biomaterial development for RC augmentation, they should currently be regarded as investigational. Further high-quality, randomized controlled trials are essential to establish their safety, efficacy, and clinical indications.

Table 2. Research Trends in Synthetic Grafts.

Study	Level of evidence	Surgical method	Graft	Primary results
Mochizuki et al. (2015)65)	Cohort study; human	Partial bursectomy, acromioplasty, and adhesion release	Polyglycolic acid sheet patch	Mean JOA scores improved from 54.9 ± 1.1 points preoperatively to 90.7 ± 1.0 points at the 12-month follow-up (p < 0.01) in the PGA group and from 52.6 ± 1.5 points preoperatively to 91.7 ± 1.2 points at the 12-month follow-up (p < 0.01) in the PG group.*
Encalada-Diaz et al. (2011)63)	Level IV case series treatment study	Open rotator cuff repair	Polycarbonate polyurethane patch	Range of motion in forward flexion, abduction, internal rotation, and external rotation was significantly improved at both 6 and 12 months postoperatively (p < 0.05 and p < 0.01, respectively).†
Nada et al. (2010)66)	Cohort study; human	Open rotator cuff repair	A polyester ligament (Dacron)	Mean preoperative and postoperative constant scores were 46.7 (range, 39.0–61.0) and 85.4 (range, 52.0–96.0), respectively (p < 0.001).‡
Proctor (2014)13)	Level IV case series treatment study	Arthroscopic repair	X-repair; absorbable poly-L-lactic acid	ASES shoulder score increased from 25 to 71 on average, and the ultrasound showed an intact repair in 78% of cases.§
Hirooka et al. (2002)67)	Cohort study; human	Rotator cuff tear repair	Gore-Tex patch; expanded poly tetra fluoroethylene	Average total JOA score improved from 57.7 to 88.7 points, a statistically significant change.∥
Ozaki et al. (1986)68)	Cohort study; rat	Rotator cuff tear repair	Teflon felt; poly tetra fluoroethylene	The muscle strength tests on tendons repaired using Teflon felt (which was thicker than the other materials) were superior to the results of repairs using other materials.¶

JOA: Japanese Orthopaedic Association, PGA: polyglycolic acid, PG: patch graft, ASES: American Shoulder and Elbow Surgeons.

^*This study involved 62 patients selected from 336 patients evaluated by the shoulder surgery section of our department for shoulder pain during 2011–2013. Patients were assigned to surgical treatment of repair with a PGA sheet (Neoveil, Gunze), patch graft (PGA group: 30 patients), or a fascia lata patch graft (PG group: 32 patients). ^†The mean patient age was 56.2 years (range, 44–65 years), and the mean duration of symptoms before surgery was 16.2 months. ^‡The prospective study included 21 symptomatic patients (14 men and 7 women) with a mean age of 66.5 years (range, 55.0–85.0 years) who had magnetic resonance imaging evidence of massive rotator cuff tears. The mean symptom duration was 20.8 months (range, 6.0–48.0 months). ^§Consecutive arthroscopic repairs were performed on 18 patients with large to massive rotator cuff tears using a poly-l-lactic acid synthetic patch as a reinforcement device and fixation with 4 sutures. Patients were assessed preoperatively and at 6 months, 12 months, and a mean of 42 months after surgery by the ASES score to evaluate clinical performance and at 12 months by ultrasound to assess structural repair. ^∥A total of 28 shoulders from 27 patients underwent this procedure. The average age at surgery was 62 years, the average duration of symptoms before surgery was 16 months, and the average follow-up period was 44 months. ^¶Synthetic materials for repairing experimental massive rotator cuff tears were investigated in 60 rats. The same materials were investigated for massive rotator cuff ruptures in 25 patients.

NOVEL BIOMATERIALS OF RC TBI TREATMENT

Electroconductive Scaffolds (ES)

Complete removal of residual DNA and xenoantigenα-Gal, which are associated with the biocompatibility of bioderived homologous and xenogeneic scaffolds, is currently impossible and represents a significant clinical challenge to the development of user-friendly scaffolds.⁴⁵⁾ Additionally, creating an optimized shape for the repair area and reconstructing high-quality ECM for tendon cell proliferation and division and vascular regeneration remain expensive, cause patient pain, and often require repeated treatment procedures. Therefore, active research into biomaterials that have strong immune tolerance, high biocompatibility, and the ability to improve cell proliferation and ECM composition and structure on their own is essential. Recently, with the explosive development of engineering materials for tissue regeneration, research into ES related to tissue regeneration is actively underway (Table 3). ES support a 3-dimensional structure custom-designed for the repair site and can promote cell proliferation and division by inducing polarization of the tissue surface.⁶⁹⁾ Additionally, electrical stimulation of ES can promote the release of growth factors from cells in vivo; thus, they are expected to be used as a user-friendly material for tissue regeneration.⁷⁰⁾

Table 3. Research Trends in Bio-Inductive Patches and Electroconductive Scaffolds.

Study	Level of evidence	Surgical method	Condition	Primary results
Yoon et al. (2022)16)	Cohort study; rat	Rotator cuff repair	Electroconductive scaffolds	At 8 weeks after rotator cuff repair, the GO/alginate scaffold improved tendon-to-bone healing without causing any signs of toxicity in a rat model.
Tang et al. (2021)74)	Cohort study; rat	Open rotator cuff repair	Electroconductive scaffolds	The TT/2w and TT/6w groups showed significant differences compared with the sham, acute, and subacute repair groups 2 and 6 weeks after repair (p ≤ 0.01 and p ≤ 0.05).
McIntyre et al. (2019)14)	Retrospective case series, level IV evidence; human	Rotator cuff repair	Bio-inductive patches	A total of 84% and 83% patients in the partial thickness group and 72% and 77% of patients in the full thickness group met or exceeded the MCID for VAS pain and ASES scores, respectively.*
Thon et al. (2019)45)	Case series; level IV evidence; human	Rotator cuff repair	Bio-inductive patches	Overall, a 96% (22 of 23) healing rate was confirmed on US and MRI.†
Schlegel et al. (2018)55)	Level IV case series treatment study; sheep	Arthroscopic surgery	Bio-inductive patches	Although there were no differences in the load-to-failure data between the 2 groups, the statistically significant improvement in stiffness for the augmented group was clinically relevant.
Washburn et al. (2017)17)	Cohort study; human	Arthroscopic rotator cuff augmentation	Bio-inductive patches	Bovine collagen bio-guided patches were shown to induce tissue formation and provide load sharing, reducing peak strain in adjacent tissues and creating an environment more conducive to healing.
Zhang et al. (2016)71)	In vitro study	-	Electroconductive scaffolds	The interconnected structure in the PPY/PCL scaffold contributed to high porosity (87% ± 6%), which was beneficial for bone regeneration.

GO: graphene oxide, MCID: minimal clinically important difference, VAS: visual analog scale, ASES: American Shoulder and Elbow Surgeons, US: ultrasound, MRI: magnetic resonance imaging, PPY: polypyrrole, PCL: polycaprolactone.

^*One-year follow-up was completed for 173 out of 203 eligible patients; 85% follow-up completion rate. The average age was 54.2 years (range, 24–74 years) in 98 male and 75 female patients. ^†The 23 patients who completed the study protocol had a mean age of 57.9 years (range, 32–71 years); 15 were men and 8 were women.

The cellular mechanisms of ES are complex and still need to be fully established. Currently, galvanotaxis, in which cells move in a specific direction in response to electrical polarization on the scaffold surface, has been proposed as the underlying mechanism.⁷¹⁾ This causes cells to move toward the anode or cathode depending on the direction of the electric field, which is also related to changes in ion concentration inside and outside the cell. In human cells, the opening of ion channels and the resulting formation of cell membrane potentials regulate cell growth, migration, proliferation, and differentiation, improving the composition and arrangement of the ECM matrix at sites of tissue regeneration.⁷²⁾ ES can be an effective therapeutic strategy for mechanical and biological stimulation for cell growth and tissue regenerative functions. Recently, conductive polymers (polypyrrole, polythiophene, polyaniline), carbon-based materials (carbon nanotubes, graphene), metal nanomaterials (gold nanoparticles, silver nanoparticles), and electroactive biomaterials are attracting attention (Table 2).⁷³⁾

Conjugated polypyrrole is known to be the most studied ES material due to its high electrical conductivity, excellent chemical stability, and biocompatibility. However, little is known regarding the clinical practice of ES, with most studies conducted in preclinical-stage animal models. Conjugated polypyrrole enhanced the migration and proliferation of mesenchymal stem cells and the activity of alkaline phosphatase protein in animal models.⁷¹⁾ Accordingly, the expression of osteogenic transcription factors significantly increased, and calcium deposition occurred. This demonstrates the high potential of ES applicability for cell stimulatory activity. Similar to bone regeneration, it has been reported that ES can have a cytostimulatory effect on the musculoskeletal system. ES combining poly-(1-lactide-co-epsilon-caprolactone) with polyaniline has significantly improved the number of sarcomatoid myosin-positive cells and myogenin expression in vitro.⁷⁵⁾ Meanwhile, the effectiveness of polycaprolactone nanofibers coated with poly(3,4-ethylenedioxythiophene): poly(styrenesulfonate), a conductive polymer known for its excellent electrical conductivity and biocompatibility, was confirmed in a rat model, where it alleviated muscle atrophy and promoted muscle tissue improvement within 6 weeks after RC injury.⁷⁴⁾ In summary, although the signaling pathways involved in cell division and proliferation metabolism were not identified, we showed that biocompatible electrically conductive biomaterials can induce the regeneration of RC muscle tissue by promoting cell division and proliferation.⁷⁴,⁷⁶,⁷⁷⁾

The excellent conductivity and biocompatibility of graphene, which is called a dream new material, have been shown to offer potential benefits in RC TBI healing.⁷⁶,⁷⁷⁾ Yoon et al.¹⁶⁾ first reported the effect of graphene oxidealginate scaffolds on RC tendon healing in a rat model. They found that the scaffolds improve mechanical properties such as tensile strength and ultimate load and do not exhibit cytotoxicity. Histological analysis showed better tendon–bone healing in the scaffold group compared to the control group, with more organized collagen fibers and improved fibrocartilage formation. This result expanded the application field of biocompatible natural polymer scaffolds and demonstrated the promising histological and biomechanical improvement effects of ES in TBI healing. Yoon et al.¹⁶⁾ explained in their discussion that graphene’s secondary structure and material properties conferred mechanical strength for higher tensile loads than previous alginate scaffolds; however, histological improvements were not mentioned. The histological improvement in RC healing was probably due to the electrical conductivity of graphene, which promotes the division and proliferation of RC tendon fibroblasts and enhances healthy ECM through the 3-dimensional structure of the scaffold.⁷⁸,⁷⁹⁾

In tissue regeneration, cell stimulation by ES is thought to be a highly effective therapeutic approach to promote cell activity.⁸⁰,⁸¹,⁸²⁾ In an animal model study by Saveh-Shemshaki et al.,⁷²⁾ ES enhanced the cellular activity of various cell types, such as mesenchymal stem cells, fibroblasts, and myoblasts in tissue regeneration. In summary, RC implantation of ES without natural healing ability can improve TBI healing by contacting bone, tendon, and muscle as a signal transduction promoter, improving muscle contractility, reducing fat accumulation and fibrosis, and improving regeneration of the affected area.⁷⁶,⁷⁷,⁷⁸,⁷⁹,⁸⁰,⁸¹,⁸²,⁸³⁾ They may also provide mechanical strength to withstand the tensile forces applied to RC TBI, allowing mechanical tendon augmentation and cell therapy. Although the use of ES in RC treatment is strongly advocated, issues that still need to be addressed include providing an optimized electric field and stability for implantation in vivo.

CONCLUSIONS

This review outlines current graft-based approaches for RC TBI repair and introduces emerging biomaterials with regenerative capabilities. While biological grafts such as autografts, allografts, and xenografts have improved outcomes, challenges including fibrotic healing and high ren tear rates persist. ES have gained attention for their dual capacity to provide mechanical support and modulate cell behavior through electrical cues. Preclinical studies suggest that ES may enhance matrix remodeling and reduce fibrosis; however, their clinical translation remains in the early stages. Further research focusing on scaffold standardization, long-term biocompatibility, and functional validation will be essential for fully realizing the therapeutic potential of ES in RC TBI augmentation.